benzofurans and Colorectal-Neoplasms

The management of patients with metastatic colorectal cancer (mCRC) has the continuum of care as the treatment paradigm. To date, trifluridine/tipiracil, a biochemically modulated fluoropyrimidine, and regorafenib, a multi-kinase inhibitor, remain the main options for the majority of patients who progressed to standard doublet- or triplet-based chemotherapies, although a tailored approach could be indicated in certain circumstances. Being highly selective for vascular endothelial growth factor receptor (VEGFR)-1, -2 and -3, fruquintinib demonstrated a strong anti-tumor activity in preclinical models and received approval from China's National Medical Products Administration (NMPA) in 2018 for the treatment of patients with chemo-refractory mCRC. The approval was based on the results of the phase III FRESCO trial. Then, in order to overcome geographic differences in clinical practice, the FRESCO-2 trial was conducted in the US, Europe, Japan, and Australia. In a heavily pretreated patient population, the study met its primary endpoint, demonstrating an advantage of fruquintinib over a placebo in overall survival (OS). Here, we review the clinical development of fruquintinib and its perspectives in gastrointestinal cancers. Then, we discuss the introduction of fruquintinib in the continuum of care of CRC paying special attention to unmet needs, including the identification of cross-resistant and potentially susceptible populations, evaluation of radiological response, and identification of novel biomarkers of clinical benefit.

Topics: Benzofurans; Colonic Neoplasms; Colorectal Neoplasms; Continuity of Patient Care; Humans; Rectal Neoplasms; Vascular Endothelial Growth Factor A

Unprecedented community containment measures were taken following the recent outbreak of COVID-19 in Italy. The aim of the study was to explore the self-reported future compliance of citizens with such measures and its relationship with potentially impactful psychological variables.. An online survey was completed by 931 people (18-76 years) distributed across the Italian territory. In addition to demographics, five dimensions were measured: self-reported compliance with containment measures over time (today, at 7, 14, 30, 60, 90, and 180 days from now) at three hypothetical risk levels (10, 50, 90% of likelihood of contracting the COVID-19), perceived risk, generalized anxiety, intolerance of uncertainty, and relevance of several psychological needs whose satisfaction is currently precluded.. The duration of containment measures plays a crucial role in tackling the spread of the disease as people will be less compliant over time. Psychological needs of citizens impacting on the compliance should be taken into account when planning an easing of the lockdown, along with interventions for protecting vulnerable groups from mental distress.. La apendicitis aguda (AA) es la urgencia quirúrgica abdominal más frecuente. No encontramos estudios específicos que evalúen el impacto de la pandemia causada por el coronavirus 2 (SARS-Cov-2) sobre la AA y su tratamiento quirúrgico. Analizamos la influencia de esta nueva patología sobre la AA.. Estudio observacional retrospectivo en pacientes intervenidos por AA desde enero hasta abril de 2020. Fueron clasificados según el momento de la apendicectomía, antes de la declaración del estado de alarma (Pre-COVID19) y después de la declaración del estado de alarma (Post-COVID19) en España. Se evaluaron variables demográficas, duración de la sintomatología, tipo de apendicitis, tiempo quirúrgico, estancia hospitalaria y complicaciones postoperatorias.. La pandemia por SARS-Cov-2 influye en el momento de diagnóstico de la apendicitis, así como en su grado de evolución y estancia hospitalaria. La peritonitis fue lo más frecuentemente observado. Una sospecha y orientación clínica más temprana, es necesaria para evitar un manejo inadecuado de este trastorno quirúrgico común.. The primary outcome is improvement in PaO. Findings will provide timely information on the safety, efficacy, and optimal dosing of t-PA to treat moderate/severe COVID-19-induced ARDS, which can be rapidly adapted to a phase III trial (NCT04357730; FDA IND 149634).. None.. The gut barrier is crucial in cirrhosis in preventing infection-causing bacteria that normally live in the gut from accessing the liver and other organs via the bloodstream. Herein, we characterised gut inflammation by measuring different markers in stool samples from patients at different stages of cirrhosis and comparing this to healthy people. These markers, when compared with equivalent markers usually measured in blood, were found to be very different in pattern and absolute levels, suggesting that there is significant gut inflammation in cirrhosis related to different immune system pathways to that seen outside of the gut. This provides new insights into gut-specific immune disturbances that predispose to complications of cirrhosis, and emphasises that a better understanding of the gut-liver axis is necessary to develop better targeted therapies.. La surveillance de l’intervalle QT a suscité beaucoup d’intérêt durant la pandémie de la COVID-19 en raison de l’utilisation de médicaments prolongeant l’intervalle QT et les préoccupations quant à la transmission virale par les électrocardiogrammes (ECG) en série. Nous avons posé l’hypothèse que la surveillance en continu de l’intervalle QT par télémétrie était associée à une meilleure détection des épisodes de prolongation de l’intervalle QT.. Nous avons introduit la télémétrie cardiaque en continu (TCC) à l’aide d’un algorithme de surveillance automatisée de l’intervalle QT dans nos unités de COVID-19. Les mesures automatisées quotidiennes de l’intervalle QT corrigé (auto-QTc) en fonction de la fréquence cardiaque maximale ont été enregistrées. Nous avons comparé la proportion des épisodes de prolongation marquée de l’intervalle QTc (QTc long), définie par un intervalle QTc ≥ 500 ms, chez les patients montrant une suspicion de COVID-19 ou ayant la COVID-19 qui avaient été admis avant et après la mise en place de la TCC (groupe témoin. La surveillance en continu de l’intervalle QT est supérieure à la norme de soins dans la détection des épisodes de QTc long et exige peu d’ECG. La réponse clinique aux épisodes de QTc long est sous-optimale.. Exposure to a model wildfire air pollution source modifies cardiovascular responses to HC challenge, suggesting air pollution sensitizes the body to systemic triggers.. Though the majority of HIV-infected adults who were on HAART had shown viral suppression, the rate of suppression was sub-optimal according to the UNAIDS 90-90-90 target to help end the AIDS pandemic by 2020. Nonetheless, the rate of immunological recovery in the study cohort was low. Hence, early initiation of HAART should be strengthened to achieve good virological suppression and immunological recovery.. Dust in Egyptian laying hen houses contains high concentrations of microorganisms and endotoxins, which might impair the health of birds and farmers when inhaled. Furthermore, laying hens in Egypt seem to be a reservoir for ESBL-producing Enterobacteriaceae. Thus, farmers are at risk of exposure to ESBL-producing bacteria, and colonized hens might transmit these bacteria into the food chain.. The lack of significant differences in the absolute changes and relative ratios of injury and repair biomarkers by contrast-associated AKI status suggests that the majority of mild contrast-associated AKI cases may be driven by hemodynamic changes at the kidney.. Most comparisons for different outcomes are based on very few studies, mostly low-powered, with an overall low CoE. Thus, the available evidence is considered insufficient to either support or refute CH effectiveness or to recommend one ICM over another. Therefore, further well-designed, larger RCTs are required.. PROSPERO database Identifier: CRD42016041953.. Untouched root canal at cross-section perimeter, the Hero 642 system showed 41.44% ± 5.62% and Reciproc R40 58.67% ± 12.39% without contact with instruments. Regarding the untouched area, Hero 642 system showed 22.78% ± 6.42% and Reciproc R40 34.35% ± 8.52%. Neither instrument achieved complete cross-sectional root canal debridement. Hero 642 system rotary taper 0.02 instruments achieved significant greater wall contact perimeter and area compared to reciprocate the Reciproc R40 taper 0.06 instrument.. Hero 642 achieved higher wall contact perimeter and area but, regardless of instrument size and taper, vital pulp during. The functional properties of the main mechanisms involved in the control of muscle Ca. This study showed that the anti-inflammatory effect of the iron-responsive product DHA in arthritis can be monitored by an iron-like radioactive tracer (. Attenuated vascular reactivity during pregnancy suggests that the systemic vasodilatory state partially depletes nitric oxide bioavailability. Preliminary data support the potential for MRI to identify vascular dysfunction in vivo that underlies PE. Level of Evidence 2 Technical Efficacy Stage 1 J. MAGN. RESON. IMAGING 2021;53:447-455.. La evaluación de riesgo es importante para predecir los resultados postoperatorios en pacientes con cáncer gastroesofágico. Este estudio de cohortes tuvo como objetivo evaluar los cambios en la composición corporal durante la quimioterapia neoadyuvante e investigar su asociación con complicaciones postoperatorias. MÉTODOS: Los pacientes consecutivos con cáncer gastroesofágico sometidos a quimioterapia neoadyuvante y cirugía con intención curativa entre 2016 y 2019, identificados a partir de una base de datos específica, se incluyeron en el estudio. Se utilizaron las imágenes de tomografía computarizada, antes y después de la quimioterapia neoadyuvante, para evaluar el índice de masa muscular esquelética, la sarcopenia y el índice de grasa visceral y subcutánea.. In this in vitro premature infant lung model, HF oscillation of BCPAP was associated with improved CO. Our results showed that HPC significantly promotes neurogenesis after MCAO and ameliorates neuronal injury.. Inflammatory markers are highly related to signs of systemic hypoperfusion in CS. Moreover, high PCT and IL-6 levels are associated with poor prognosis.. These findings indicate that Tetrapleura tetraptera fruit has a protective potential against stroke through modulation of redox and electrolyte imbalances, and attenuation of neurotransmitter dysregulation and other neurochemical dysfunctions. Tetrapleura tetraptera fruit could be a promising source for the discovery of bioactives for stroke therapy.

Topics: 3T3-L1 Cells; A Kinase Anchor Proteins; Acetates; Achilles Tendon; Acute Kidney Injury; Acute Pain; Acyclic Monoterpenes; Adenine Nucleotides; Adhesins, Escherichia coli; Adipocytes; Adipocytes, Brown; Adipogenesis; Administration, Inhalation; Administration, Oral; Adrenal Cortex Hormones; Adsorption; Adult; Aeromonas hydrophila; Africa; Aged; Aged, 80 and over; Agrobacterium tumefaciens; Air; Air Pollutants; Air Pollution; Air Pollution, Indoor; Algorithms; Alkaloids; Alkynes; Allosteric Regulation; Amines; Amino Acid Sequence; Amino Acids; Amino Acids, Branched-Chain; Aminoisobutyric Acids; Aminopyridines; Amyotrophic Lateral Sclerosis; Anaerobic Threshold; Angiography; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animal Distribution; Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Ankle Joint; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Inflammatory Agents; Antibodies, Bacterial; Antifungal Agents; Antimalarials; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antioxidants; Antiretroviral Therapy, Highly Active; Antiviral Agents; Aotidae; Apelin; Apoptosis; Arabidopsis Proteins; Argentina; Arginine; Artemisinins; Arthritis, Experimental; Arthritis, Rheumatoid; Arthroscopy; Aspergillus; Aspergillus niger; Asteraceae; Asthma; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; Auditory Cortex; Autoantibodies; Autophagy; Bacteria; Bacterial Infections; Bacterial Proteins; Bacterial Typing Techniques; Base Composition; Base Sequence; Basketball; Beclin-1; Benzhydryl Compounds; Benzimidazoles; Benzo(a)pyrene; Benzofurans; Benzoxazines; Bereavement; beta Catenin; beta-Lactamase Inhibitors; beta-Lactamases; beta-Lactams; Betacoronavirus; Betaine; Binding Sites; Biofilms; Biological Assay; Biological Availability; Biological Evolution; Biomarkers; Biomechanical Phenomena; Biopolymers; Biopsy; Bismuth; Blood Glucose; Blood Platelets; Blood Pressure; Body Composition; Body Weight; Bone Marrow; Bone Marrow Cells; Bone Regeneration; Boron; Botrytis; Brain Ischemia; Brain Neoplasms; Brain-Derived Neurotrophic Factor; Brazil; Breast Neoplasms; Breath Tests; Bronchoalveolar Lavage Fluid; Burkholderia; C-Reactive Protein; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Calcification, Physiologic; Calcium; Calcium Signaling; Calorimetry, Differential Scanning; Cameroon; Camptothecin; Candida; Candida albicans; Capillaries; Carbapenem-Resistant Enterobacteriaceae; Carbapenems; Carbohydrate Conformation; Carbon; Carbon Dioxide; Carbon Isotopes; Carcinoma, Ovarian Epithelial; Cardiac Output; Cardiomyopathy, Hypertrophic; Cardiotonic Agents; Cardiovascular Diseases; Caregivers; Carps; Case-Control Studies; Catalase; Catalysis; Cats; CD4 Lymphocyte Count; Cell Culture Techniques; Cell Differentiation; Cell Line, Tumor; Cell Membrane; Cell Movement; Cell Proliferation; Cell Survival; Cells, Cultured; Cellulose; Centrosome; Ceratopogonidae; Chickens; Child; China; Cholera Toxin; Choline; Cholinesterases; Chromatography, High Pressure Liquid; Chromatography, Liquid; Chromatography, Micellar Electrokinetic Capillary; Chromatography, Reverse-Phase; Chronic Disease; Cinnamates; Cities; Citrates; Climate Change; Clinical Trials, Phase III as Topic; Coal; Coal Mining; Cohort Studies; Coinfection; Colchicine; Colony Count, Microbial; Colorectal Neoplasms; Coloring Agents; Common Cold; Complement Factor H; Computational Biology; Computer Simulation; Continuous Positive Airway Pressure; Contrast Media; Coordination Complexes; Coronary Artery Bypass; Coronavirus 3C Proteases; Coronavirus Infections; Coronavirus Protease Inhibitors; Corynebacterium glutamicum; Cosmetics; COVID-19; Creatinine; Cross-Sectional Studies; Crotonates; Crystallography, X-Ray; Cues; Culicidae; Culture Media; Curcuma; Cyclopentanes; Cyclopropanes; Cymbopogon; Cystine; Cytochrome P-450 CYP2B6; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP2C19 Inhibitors; Cytokines; Databases, Genetic; Death; Dendritic Cells; Density Functional Theory; Depsides; Diabetes Mellitus, Type 2; Diamond; Diarylheptanoids; Dibenzofurans; Dibenzofurans, Polychlorinated; Diclofenac; Diet; Dietary Carbohydrates; Dietary Supplements; Diffusion Magnetic Resonance Imaging; Dioxins; Diphenylamine; Disease Outbreaks; Disease Susceptibility; Disulfides; Dithiothreitol; Dizocilpine Maleate; DNA Methylation; DNA-Binding Proteins; DNA, Bacterial; Dogs; Dose-Response Relationship, Drug; Double-Blind Method; Doublecortin Protein; Drosophila melanogaster; Droughts; Drug Carriers; Drug Combinations; Drug Delivery Systems; Drug Liberation; Drug Resistance; Drug Resistance, Bacterial; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Dust; Dynactin Complex; Dysferlin; Echo-Planar Imaging; Echocardiography; Edaravone; Egypt; Elasticity; Electrodes; Electrolytes; Emodin; Emtricitabine; Endometriosis; Endothelium, Vascular; Endotoxins; Energy Metabolism; Energy Transfer; Enterobacteriaceae; Enterococcus faecalis; Enterotoxigenic Escherichia coli; Environmental Monitoring; Enzyme Inhibitors; Epidemiologic Factors; Epigenesis, Genetic; Erythrocytes; Escherichia coli; Escherichia coli Infections; Escherichia coli Vaccines; Esophageal Neoplasms; Esophagectomy; Esophagogastric Junction; Esterases; Esterification; Ethanol; Ethiopia; Ethnicity; Eucalyptus; Evidence-Based Practice; Exercise; Exercise Tolerance; Extracorporeal Membrane Oxygenation; Family; Fatty Acids; Feedback; Female; Ferric Compounds; Fibrin Fibrinogen Degradation Products; Filtration; Fish Diseases; Flavonoids; Flavonols; Fluorodeoxyglucose F18; Follow-Up Studies; Food Microbiology; Food Preservation; Forests; Fossils; Free Radical Scavengers; Freund's Adjuvant; Fruit; Fungi; Gallium; Gender Identity; Gene Expression Regulation; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Plant; Gene Knockdown Techniques; Genes, Bacterial; Genes, Plant; Genetic Predisposition to Disease; Genitalia; Genotype; Glomerulonephritis, IGA; Glottis; Glucocorticoids; Glucose; Glucuronides; Glutathione Transferase; Glycogen Synthase Kinase 3 beta; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Grassland; Guinea Pigs; Half-Life; Head Kidney; Heart Atria; Heart Rate; Heart Septum; HEK293 Cells; Hematopoietic Stem Cells; Hemodynamics; Hep G2 Cells; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Hepatocytes; Hesperidin; High-Frequency Ventilation; High-Temperature Requirement A Serine Peptidase 1; Hippocampus; Hirudins; History, 20th Century; History, 21st Century; HIV Infections; Homeostasis; Hominidae; Housing, Animal; Humans; Hydrocarbons, Brominated; Hydrogen Bonding; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydroxybutyrates; Hydroxyl Radical; Hypertension; Hypothyroidism; Image Interpretation, Computer-Assisted; Immunoconjugates; Immunogenic Cell Death; Indoles; Infant, Newborn; Infant, Premature; Infarction, Middle Cerebral Artery; Inflammation; Inflammation Mediators; Infrared Rays; Inhibitory Concentration 50; Injections, Intravenous; Interferon-gamma; Interleukin-23; Interleukin-4; Interleukin-6; Intermediate Filaments; Intermittent Claudication; Intestine, Small; Iridoid Glucosides; Iridoids; Iron; Isomerism; Isotope Labeling; Isoxazoles; Itraconazole; Kelch-Like ECH-Associated Protein 1; Ketoprofen; Kidney Failure, Chronic; Kinetics; Klebsiella pneumoniae; Lactams, Macrocyclic; Lactobacillus; Lactulose; Lakes; Lamivudine; Laparoscopy; Laparotomy; Laryngoscopy; Leucine; Limit of Detection; Linear Models; Lipid A; Lipopolysaccharides; Listeria monocytogenes; Liver; Liver Cirrhosis; Logistic Models; Longitudinal Studies; Losartan; Low Back Pain; Lung; Lupinus; Lupus Erythematosus, Systemic; Machine Learning; Macular Degeneration; Madin Darby Canine Kidney Cells; Magnetic Phenomena; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Magnetics; Malaria, Falciparum; Male; Mannans; MAP Kinase Signaling System; Mass Spectrometry; Melatonin; Membrane Glycoproteins; Membrane Proteins; Meniscectomy; Menisci, Tibial; Mephenytoin; Mesenchymal Stem Cells; Metal Nanoparticles; Metal-Organic Frameworks; Methionine; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Nude; Mice, Obese; Mice, Transgenic; Microbial Sensitivity Tests; Microcirculation; MicroRNAs; Microscopy, Video; Microtubules; Microvascular Density; Microwaves; Middle Aged; Minimally Invasive Surgical Procedures; Models, Animal; Models, Biological; Models, Molecular; Models, Theoretical; Molecular Docking Simulation; Molecular Structure; Molecular Weight; Morus; Mouth Floor; Multicenter Studies as Topic; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Muscle, Skeletal; Myocardial Ischemia; Myocardium; NAD; NADP; Nanocomposites; Nanoparticles; Naphthols; Nasal Lavage Fluid; Nasal Mucosa; Neisseria meningitidis; Neoadjuvant Therapy; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Neoplasms, Experimental; Neural Stem Cells; Neuroblastoma; Neurofilament Proteins; Neurogenesis; Neurons; New York; NF-E2-Related Factor 2; NF-kappa B; Nicotine; Nitriles; Nitrogen; Nitrogen Fixation; North America; Observer Variation; Occupational Exposure; Ochrobactrum; Oils, Volatile; Olea; Oligosaccharides; Omeprazole; Open Field Test; Optimism; Oregon; Oryzias; Osmolar Concentration; Osteoarthritis; Osteoblasts; Osteogenesis; Ovarian Neoplasms; Ovariectomy; Oxadiazoles; Oxidation-Reduction; Oxidative Stress; Oxygen; Ozone; p38 Mitogen-Activated Protein Kinases; Pakistan; Pandemics; Particle Size; Particulate Matter; Patient-Centered Care; Pelargonium; Peptides; Perception; Peripheral Arterial Disease; Peroxides; Pets; Pharmaceutical Preparations; Pharmacogenetics; Phenobarbital; Phenols; Phenotype; Phosphates; Phosphatidylethanolamines; Phosphines; Phospholipids; Phosphorus; Phosphorylation; Photoacoustic Techniques; Photochemotherapy; Photosensitizing Agents; Phylogeny; Phytoestrogens; Pilot Projects; Plant Components, Aerial; Plant Extracts; Plant Immunity; Plant Leaves; Plant Oils; Plants, Medicinal; Plasmodium berghei; Plasmodium falciparum; Platelet Activation; Platelet Function Tests; Pneumonia, Viral; Poaceae; Pogostemon; Poloxamer; Poly I; Poly(ADP-ribose) Polymerase Inhibitors; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Polycyclic Compounds; Polyethylene Glycols; Polylysine; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Population Dynamics; Portasystemic Shunt, Transjugular Intrahepatic; Positron Emission Tomography Computed Tomography; Postoperative Complications; Postprandial Period; Potassium Cyanide; Predictive Value of Tests; Prefrontal Cortex; Pregnancy; Prepulse Inhibition; Prevalence; Procalcitonin; Prodrugs; Prognosis; Progression-Free Survival; Proline; Proof of Concept Study; Prospective Studies; Protein Binding; Protein Conformation; Protein Domains; Protein Folding; Protein Multimerization; Protein Sorting Signals; Protein Structure, Secondary; Proton Pump Inhibitors; Protozoan Proteins; Psychometrics; Pulse Wave Analysis; Pyridines; Pyrrolidines; Quality of Life; Quantum Dots; Quinoxalines; Quorum Sensing; Radiopharmaceuticals; Rain; Random Allocation; Randomized Controlled Trials as Topic; Rats; Rats, Sprague-Dawley; Rats, Wistar; RAW 264.7 Cells; Reactive Oxygen Species; Receptor, Angiotensin, Type 1; Receptor, PAR-1; Receptors, CXCR4; Receptors, Estrogen; Receptors, Glucocorticoid; Receptors, Interleukin-1; Receptors, Interleukin-17; Receptors, Notch; Recombinant Fusion Proteins; Recombinant Proteins; Reducing Agents; Reflex, Startle; Regional Blood Flow; Regression Analysis; Reperfusion Injury; Reproducibility of Results; Republic of Korea; Respiratory Tract Diseases; Retrospective Studies; Reverse Transcriptase Inhibitors; Rhinitis, Allergic; Risk Assessment; Risk Factors; Rituximab; RNA, Messenger; RNA, Ribosomal, 16S; ROC Curve; Rosmarinic Acid; Running; Ruthenium; Rutin; Sarcolemma; Sarcoma; Sarcopenia; Sarcoplasmic Reticulum; SARS-CoV-2; Scavenger Receptors, Class A; Schools; Seasons; Seeds; Sequence Analysis, DNA; Severity of Illness Index; Sex Factors; Shock, Cardiogenic; Short Chain Dehydrogenase-Reductases; Signal Transduction; Silver; Singlet Oxygen; Sinusitis; Skin; Skin Absorption; Small Molecule Libraries; Smoke; Socioeconomic Factors; Soil; Soil Microbiology; Solid Phase Extraction; Solubility; Solvents; Spain; Spectrometry, Mass, Electrospray Ionization; Spectroscopy, Fourier Transform Infrared; Speech; Speech Perception; Spindle Poles; Spleen; Sporothrix; Staphylococcal Infections; Staphylococcus aureus; Stereoisomerism; Stomach Neoplasms; Stress, Physiological; Stroke Volume; Structure-Activity Relationship; Substrate Specificity; Sulfonamides; Surface Properties; Surface-Active Agents; Surveys and Questionnaires; Survival Rate; T-Lymphocytes, Cytotoxic; Tandem Mass Spectrometry; Temperature; Tenofovir; Terpenes; Tetracycline; Tetrapleura; Textiles; Thermodynamics; Thiobarbituric Acid Reactive Substances; Thrombin; Thyroid Hormones; Thyroid Neoplasms; Tibial Meniscus Injuries; Time Factors; Tissue Distribution; Titanium; Toluidines; Tomography, X-Ray Computed; Tooth; Tramadol; Transcription Factor AP-1; Transcription, Genetic; Transfection; Transgender Persons; Translations; Treatment Outcome; Triglycerides; Ubiquinone; Ubiquitin-Specific Proteases; United Kingdom; United States; Up-Regulation; Vascular Stiffness; Veins; Ventricular Remodeling; Viral Load; Virulence Factors; Virus Replication; Vitis; Voice; Voice Quality; Wastewater; Water; Water Pollutants, Chemical; Water-Electrolyte Balance; Weather; Wildfires; Wnt Signaling Pathway; Wound Healing; X-Ray Diffraction; Xenograft Model Antitumor Assays; Young Adult; Zoogloea

Direct randomized comparisons of regorafenib, TAS-102, and fruquintinib for treating metastatic colorectal cancer (mCRC) are lacking. Here, we evaluated the efficacy and safety of three agents by a systematic review and a network meta-analysis.. We included phase III randomized controlled trials in the PubMed, Embase, and Scopus Cochrane databases and ClinicalTrials.gov registry from initiation until January 2019. Data from randomized controlled trials including overall survival (OS), progression-free survival (PFS), and adverse events (AEs) were extracted. Direct meta-analysis and indirect meta-analysis using network meta-analysis were assessed.. Five trials comprising a total of 2586 patients were included. For efficacy analysis of OS, no statistically significant differences were observed between regorafenib and TAS-102 (HR 0.945, 95% CI [0.677, 1.320], P = 0.753), regorafenib and fruquintinib (HR 1.056, 95% CI [0.690, 1.621], P = 0.814), or TAS-102 and fruquintinib (HR 1.117, 95% CI [0.740, 1.685], P = 0.610). However, fruquintinib was superior in PFS compared with TAS-102 (HR 1.756, 95% CI [1.079, 2.857], P = 0.023). Regorafenib and TAS-102 appeared to have a similar effect on PFS (HR 0.907, 95% CI [0.611, 1.346], P = 0.641), as did regorafenib and fruquintinib (HR 1.592, 95% CI [0.968, 2.618], P = 0.067). None of the three agents were better in terms of all grade AEs or any grade of 3-5 AEs. However, subgroup analysis of AEs exhibited different toxicity profiles between the three drugs.. Indirect comparison suggested that the three agents had similar OS but that fruquintinib was superior in terms of PFS compared with that of TAS-102. These three agents had different toxicity profiles.

Topics: Antineoplastic Agents; Benzofurans; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Disease Progression; Drug Combinations; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Network Meta-Analysis; Phenylurea Compounds; Progression-Free Survival; Pyridines; Pyrrolidines; Quinazolines; Randomized Controlled Trials as Topic; Thymine; Time Factors; Trifluridine; Uracil

BACKGROUND This study aimed to conduct a systematic review of the literature to identify key randomized controlled clinical trials (RCTs), followed by network meta-analysis, to compare the efficacy and safety profiles of regorafenib, fruquintinib, and TAS-102 in previously treated patients with metastatic colorectal carcinoma (mCRC). MATERIAL AND METHODS Systematic literature review was performed using the Medline, Embase, and Cochrane library online databases to identify published randomized controlled trials (RCTs). Hazard ratios (HRs) for progression-free survival (PFS), overall survival (OS), and the odds ratios (ORs) for the objective response rate (ORR), disease control rate (DCR), adverse events (AEs), serious adverse events (SAEs), and fatal adverse events (FAEs) were compared indirectly using network meta-analysis based on a random-effects model. RESULTS Five RCTs that included 2,604 patients fulfilled the eligibility criteria and were analyzed. Indirect comparisons showed that fruquintinib was associated with significant superiority for PFS (HR, 0.57; 95% CI, 0.34-0.95) and DCR (OR, 1.80; 95% CI, 1.08-3.01) when compared with TAS-102 in patients with mCRC. However, there was no significant difference between OS or ORR between regorafenib, fruquintinib, and TAS-102. Fruquintinib was associated with a significantly higher risk of SAEs when compared with TAS-102 or regorafenib. There was no significant difference in the risk of AEs or FAEs following indirect comparison between fruquintinib, regorafenib, and TAS-102. CONCLUSIONS The findings from network meta-analysis showed that fruquintinib was associated with significant superiority for PFS and DCR compared with TAS-102, but fruquintinib was associated with significantly increased risk for SAEs compared with regorafenib and TAS-102.

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzofurans; Colonic Neoplasms; Colorectal Neoplasms; Disease-Free Survival; Drug Combinations; Humans; Network Meta-Analysis; Phenylurea Compounds; Pyridines; Pyrrolidines; Quinazolines; Rectal Neoplasms; Thymine; Trifluridine; Uracil

Topics: Angiogenesis Inhibitors; Animals; Benzofurans; Colorectal Neoplasms; Drug Resistance, Neoplasm; Humans; Molecular Targeted Therapy; Quinazolines; Receptors, Vascular Endothelial Growth Factor

The optimal treatment in the third-line and later-line setting for metastatic colorectal cancer (mCRC) has not been established. As reported, regorafenib and fruquintinib have shown to be superior to placebo in mCRC. However, no direct clinical comparison of regorafenib and fruquintinib has been conducted; we performed a systematic review and network meta-analysis to compare the efficacy and safety of regorafenib and fruquintinib.. PubMed, Embase, and the Cochrane Library were systematically searched and randomized-controlled trials (RCTs) assessing the effect and safety of regorafenib or fruquintinib versus placebo for patients with mCRC were included. Two investigators independently searched articles, extracted data, and assessed the quality of included studies. After that, we performed pairwise direct meta-analyses (regorafenib vs. placebo and fruquintinib vs. placebo) and indirect comparison (regorafenib vs. fruquintinib) using network meta-analyses methods.. Three RCTs involving 1380 patients were included in the meta-analysis. In the direct meta-analysis, regorafenib and fruquintinib both showed survival benefits when compared with placebo. For the indirect comparison, fruquintinib shows no significant difference in OS compared to regorafenib (HR 0.97; 95% CI 0.64-1.46). Regarding PFS, there was a tendency that fruquintinib was superior to regorafenib (HR 0.65; 95% CI 0.39-1.08); however, there was no statistic difference. For the safety analysis, in indirect comparison, fruquintinib showed significant difference in all-grade toxicity compared to regorafenib (OR 0.73; 95% CI 0.65-0.82), especially in subgroup of proteinuria (OR 0.31; 95% CI 0.11-0.86). For the grade 3-5 toxicity, fruquintinib showed no significant difference when compared with regorafenib (OR 0.92; 95% CI 0.64-1.32).. Based on efficacy and safety, there was a tendency that fruquintinib was superior to regorafenib, as a whole, regorafenib and fruquintinib demonstrated similar clinical benefit for patients with refractory mCRC. It seems that fruquintinib has less toxic in all-grade toxicity when compared with regorafenib.

Topics: Benzofurans; Colorectal Neoplasms; Disease-Free Survival; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Network Meta-Analysis; Phenylurea Compounds; Pyridines; Quinazolines; Treatment Outcome

Fruquintinib (Elunate

Topics: Antineoplastic Agents; Benzofurans; Carcinoma, Non-Small-Cell Lung; Colorectal Neoplasms; Humans; Lung Neoplasms; Protein Kinase Inhibitors; Quinazolines; Vascular Endothelial Growth Factor Receptor-1

Colorectal cancer continues to be a major problem. There are a number of new agents with promising clinical activity, including the multitargeted antifolate LY 231514 and the thymidylate synthesis inhibitor capecitabine. In addition, other agents have shown promising preclinical activity against the disease: 6-hydroxymethylacylfulvene (HMAF; MGI 114), LY 295501, bizelesin (U-7779; NSC615291), and ONYX-015. Finally, several agents may prevent colorectal cancer through prevention of the formation of colorectal polyps (eg, cyclooxygenase inhibitors).

Topics: Adenoviridae; Antineoplastic Agents; Benzofurans; Colorectal Neoplasms; Drug Screening Assays, Antitumor; Duocarmycins; Enzyme Inhibitors; Humans; Indoles; Phenylurea Compounds; Sesquiterpenes; Thymidylate Synthase; Tumor Cells, Cultured; Urea

Unprecedented community containment measures were taken following the recent outbreak of COVID-19 in Italy. The aim of the study was to explore the self-reported future compliance of citizens with such measures and its relationship with potentially impactful psychological variables.. An online survey was completed by 931 people (18-76 years) distributed across the Italian territory. In addition to demographics, five dimensions were measured: self-reported compliance with containment measures over time (today, at 7, 14, 30, 60, 90, and 180 days from now) at three hypothetical risk levels (10, 50, 90% of likelihood of contracting the COVID-19), perceived risk, generalized anxiety, intolerance of uncertainty, and relevance of several psychological needs whose satisfaction is currently precluded.. The duration of containment measures plays a crucial role in tackling the spread of the disease as people will be less compliant over time. Psychological needs of citizens impacting on the compliance should be taken into account when planning an easing of the lockdown, along with interventions for protecting vulnerable groups from mental distress.. La apendicitis aguda (AA) es la urgencia quirúrgica abdominal más frecuente. No encontramos estudios específicos que evalúen el impacto de la pandemia causada por el coronavirus 2 (SARS-Cov-2) sobre la AA y su tratamiento quirúrgico. Analizamos la influencia de esta nueva patología sobre la AA.. Estudio observacional retrospectivo en pacientes intervenidos por AA desde enero hasta abril de 2020. Fueron clasificados según el momento de la apendicectomía, antes de la declaración del estado de alarma (Pre-COVID19) y después de la declaración del estado de alarma (Post-COVID19) en España. Se evaluaron variables demográficas, duración de la sintomatología, tipo de apendicitis, tiempo quirúrgico, estancia hospitalaria y complicaciones postoperatorias.. La pandemia por SARS-Cov-2 influye en el momento de diagnóstico de la apendicitis, así como en su grado de evolución y estancia hospitalaria. La peritonitis fue lo más frecuentemente observado. Una sospecha y orientación clínica más temprana, es necesaria para evitar un manejo inadecuado de este trastorno quirúrgico común.. The primary outcome is improvement in PaO. Findings will provide timely information on the safety, efficacy, and optimal dosing of t-PA to treat moderate/severe COVID-19-induced ARDS, which can be rapidly adapted to a phase III trial (NCT04357730; FDA IND 149634).. None.. The gut barrier is crucial in cirrhosis in preventing infection-causing bacteria that normally live in the gut from accessing the liver and other organs via the bloodstream. Herein, we characterised gut inflammation by measuring different markers in stool samples from patients at different stages of cirrhosis and comparing this to healthy people. These markers, when compared with equivalent markers usually measured in blood, were found to be very different in pattern and absolute levels, suggesting that there is significant gut inflammation in cirrhosis related to different immune system pathways to that seen outside of the gut. This provides new insights into gut-specific immune disturbances that predispose to complications of cirrhosis, and emphasises that a better understanding of the gut-liver axis is necessary to develop better targeted therapies.. La surveillance de l’intervalle QT a suscité beaucoup d’intérêt durant la pandémie de la COVID-19 en raison de l’utilisation de médicaments prolongeant l’intervalle QT et les préoccupations quant à la transmission virale par les électrocardiogrammes (ECG) en série. Nous avons posé l’hypothèse que la surveillance en continu de l’intervalle QT par télémétrie était associée à une meilleure détection des épisodes de prolongation de l’intervalle QT.. Nous avons introduit la télémétrie cardiaque en continu (TCC) à l’aide d’un algorithme de surveillance automatisée de l’intervalle QT dans nos unités de COVID-19. Les mesures automatisées quotidiennes de l’intervalle QT corrigé (auto-QTc) en fonction de la fréquence cardiaque maximale ont été enregistrées. Nous avons comparé la proportion des épisodes de prolongation marquée de l’intervalle QTc (QTc long), définie par un intervalle QTc ≥ 500 ms, chez les patients montrant une suspicion de COVID-19 ou ayant la COVID-19 qui avaient été admis avant et après la mise en place de la TCC (groupe témoin. La surveillance en continu de l’intervalle QT est supérieure à la norme de soins dans la détection des épisodes de QTc long et exige peu d’ECG. La réponse clinique aux épisodes de QTc long est sous-optimale.. Exposure to a model wildfire air pollution source modifies cardiovascular responses to HC challenge, suggesting air pollution sensitizes the body to systemic triggers.. Though the majority of HIV-infected adults who were on HAART had shown viral suppression, the rate of suppression was sub-optimal according to the UNAIDS 90-90-90 target to help end the AIDS pandemic by 2020. Nonetheless, the rate of immunological recovery in the study cohort was low. Hence, early initiation of HAART should be strengthened to achieve good virological suppression and immunological recovery.. Dust in Egyptian laying hen houses contains high concentrations of microorganisms and endotoxins, which might impair the health of birds and farmers when inhaled. Furthermore, laying hens in Egypt seem to be a reservoir for ESBL-producing Enterobacteriaceae. Thus, farmers are at risk of exposure to ESBL-producing bacteria, and colonized hens might transmit these bacteria into the food chain.. The lack of significant differences in the absolute changes and relative ratios of injury and repair biomarkers by contrast-associated AKI status suggests that the majority of mild contrast-associated AKI cases may be driven by hemodynamic changes at the kidney.. Most comparisons for different outcomes are based on very few studies, mostly low-powered, with an overall low CoE. Thus, the available evidence is considered insufficient to either support or refute CH effectiveness or to recommend one ICM over another. Therefore, further well-designed, larger RCTs are required.. PROSPERO database Identifier: CRD42016041953.. Untouched root canal at cross-section perimeter, the Hero 642 system showed 41.44% ± 5.62% and Reciproc R40 58.67% ± 12.39% without contact with instruments. Regarding the untouched area, Hero 642 system showed 22.78% ± 6.42% and Reciproc R40 34.35% ± 8.52%. Neither instrument achieved complete cross-sectional root canal debridement. Hero 642 system rotary taper 0.02 instruments achieved significant greater wall contact perimeter and area compared to reciprocate the Reciproc R40 taper 0.06 instrument.. Hero 642 achieved higher wall contact perimeter and area but, regardless of instrument size and taper, vital pulp during. The functional properties of the main mechanisms involved in the control of muscle Ca. This study showed that the anti-inflammatory effect of the iron-responsive product DHA in arthritis can be monitored by an iron-like radioactive tracer (. Attenuated vascular reactivity during pregnancy suggests that the systemic vasodilatory state partially depletes nitric oxide bioavailability. Preliminary data support the potential for MRI to identify vascular dysfunction in vivo that underlies PE. Level of Evidence 2 Technical Efficacy Stage 1 J. MAGN. RESON. IMAGING 2021;53:447-455.. La evaluación de riesgo es importante para predecir los resultados postoperatorios en pacientes con cáncer gastroesofágico. Este estudio de cohortes tuvo como objetivo evaluar los cambios en la composición corporal durante la quimioterapia neoadyuvante e investigar su asociación con complicaciones postoperatorias. MÉTODOS: Los pacientes consecutivos con cáncer gastroesofágico sometidos a quimioterapia neoadyuvante y cirugía con intención curativa entre 2016 y 2019, identificados a partir de una base de datos específica, se incluyeron en el estudio. Se utilizaron las imágenes de tomografía computarizada, antes y después de la quimioterapia neoadyuvante, para evaluar el índice de masa muscular esquelética, la sarcopenia y el índice de grasa visceral y subcutánea.. In this in vitro premature infant lung model, HF oscillation of BCPAP was associated with improved CO. Our results showed that HPC significantly promotes neurogenesis after MCAO and ameliorates neuronal injury.. Inflammatory markers are highly related to signs of systemic hypoperfusion in CS. Moreover, high PCT and IL-6 levels are associated with poor prognosis.. These findings indicate that Tetrapleura tetraptera fruit has a protective potential against stroke through modulation of redox and electrolyte imbalances, and attenuation of neurotransmitter dysregulation and other neurochemical dysfunctions. Tetrapleura tetraptera fruit could be a promising source for the discovery of bioactives for stroke therapy.

Topics: 3T3-L1 Cells; A Kinase Anchor Proteins; Acetates; Achilles Tendon; Acute Kidney Injury; Acute Pain; Acyclic Monoterpenes; Adenine Nucleotides; Adhesins, Escherichia coli; Adipocytes; Adipocytes, Brown; Adipogenesis; Administration, Inhalation; Administration, Oral; Adrenal Cortex Hormones; Adsorption; Adult; Aeromonas hydrophila; Africa; Aged; Aged, 80 and over; Agrobacterium tumefaciens; Air; Air Pollutants; Air Pollution; Air Pollution, Indoor; Algorithms; Alkaloids; Alkynes; Allosteric Regulation; Amines; Amino Acid Sequence; Amino Acids; Amino Acids, Branched-Chain; Aminoisobutyric Acids; Aminopyridines; Amyotrophic Lateral Sclerosis; Anaerobic Threshold; Angiography; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animal Distribution; Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Ankle Joint; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Inflammatory Agents; Antibodies, Bacterial; Antifungal Agents; Antimalarials; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antioxidants; Antiretroviral Therapy, Highly Active; Antiviral Agents; Aotidae; Apelin; Apoptosis; Arabidopsis Proteins; Argentina; Arginine; Artemisinins; Arthritis, Experimental; Arthritis, Rheumatoid; Arthroscopy; Aspergillus; Aspergillus niger; Asteraceae; Asthma; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; Auditory Cortex; Autoantibodies; Autophagy; Bacteria; Bacterial Infections; Bacterial Proteins; Bacterial Typing Techniques; Base Composition; Base Sequence; Basketball; Beclin-1; Benzhydryl Compounds; Benzimidazoles; Benzo(a)pyrene; Benzofurans; Benzoxazines; Bereavement; beta Catenin; beta-Lactamase Inhibitors; beta-Lactamases; beta-Lactams; Betacoronavirus; Betaine; Binding Sites; Biofilms; Biological Assay; Biological Availability; Biological Evolution; Biomarkers; Biomechanical Phenomena; Biopolymers; Biopsy; Bismuth; Blood Glucose; Blood Platelets; Blood Pressure; Body Composition; Body Weight; Bone Marrow; Bone Marrow Cells; Bone Regeneration; Boron; Botrytis; Brain Ischemia; Brain Neoplasms; Brain-Derived Neurotrophic Factor; Brazil; Breast Neoplasms; Breath Tests; Bronchoalveolar Lavage Fluid; Burkholderia; C-Reactive Protein; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Calcification, Physiologic; Calcium; Calcium Signaling; Calorimetry, Differential Scanning; Cameroon; Camptothecin; Candida; Candida albicans; Capillaries; Carbapenem-Resistant Enterobacteriaceae; Carbapenems; Carbohydrate Conformation; Carbon; Carbon Dioxide; Carbon Isotopes; Carcinoma, Ovarian Epithelial; Cardiac Output; Cardiomyopathy, Hypertrophic; Cardiotonic Agents; Cardiovascular Diseases; Caregivers; Carps; Case-Control Studies; Catalase; Catalysis; Cats; CD4 Lymphocyte Count; Cell Culture Techniques; Cell Differentiation; Cell Line, Tumor; Cell Membrane; Cell Movement; Cell Proliferation; Cell Survival; Cells, Cultured; Cellulose; Centrosome; Ceratopogonidae; Chickens; Child; China; Cholera Toxin; Choline; Cholinesterases; Chromatography, High Pressure Liquid; Chromatography, Liquid; Chromatography, Micellar Electrokinetic Capillary; Chromatography, Reverse-Phase; Chronic Disease; Cinnamates; Cities; Citrates; Climate Change; Clinical Trials, Phase III as Topic; Coal; Coal Mining; Cohort Studies; Coinfection; Colchicine; Colony Count, Microbial; Colorectal Neoplasms; Coloring Agents; Common Cold; Complement Factor H; Computational Biology; Computer Simulation; Continuous Positive Airway Pressure; Contrast Media; Coordination Complexes; Coronary Artery Bypass; Coronavirus 3C Proteases; Coronavirus Infections; Coronavirus Protease Inhibitors; Corynebacterium glutamicum; Cosmetics; COVID-19; Creatinine; Cross-Sectional Studies; Crotonates; Crystallography, X-Ray; Cues; Culicidae; Culture Media; Curcuma; Cyclopentanes; Cyclopropanes; Cymbopogon; Cystine; Cytochrome P-450 CYP2B6; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP2C19 Inhibitors; Cytokines; Databases, Genetic; Death; Dendritic Cells; Density Functional Theory; Depsides; Diabetes Mellitus, Type 2; Diamond; Diarylheptanoids; Dibenzofurans; Dibenzofurans, Polychlorinated; Diclofenac; Diet; Dietary Carbohydrates; Dietary Supplements; Diffusion Magnetic Resonance Imaging; Dioxins; Diphenylamine; Disease Outbreaks; Disease Susceptibility; Disulfides; Dithiothreitol; Dizocilpine Maleate; DNA Methylation; DNA-Binding Proteins; DNA, Bacterial; Dogs; Dose-Response Relationship, Drug; Double-Blind Method; Doublecortin Protein; Drosophila melanogaster; Droughts; Drug Carriers; Drug Combinations; Drug Delivery Systems; Drug Liberation; Drug Resistance; Drug Resistance, Bacterial; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Dust; Dynactin Complex; Dysferlin; Echo-Planar Imaging; Echocardiography; Edaravone; Egypt; Elasticity; Electrodes; Electrolytes; Emodin; Emtricitabine; Endometriosis; Endothelium, Vascular; Endotoxins; Energy Metabolism; Energy Transfer; Enterobacteriaceae; Enterococcus faecalis; Enterotoxigenic Escherichia coli; Environmental Monitoring; Enzyme Inhibitors; Epidemiologic Factors; Epigenesis, Genetic; Erythrocytes; Escherichia coli; Escherichia coli Infections; Escherichia coli Vaccines; Esophageal Neoplasms; Esophagectomy; Esophagogastric Junction; Esterases; Esterification; Ethanol; Ethiopia; Ethnicity; Eucalyptus; Evidence-Based Practice; Exercise; Exercise Tolerance; Extracorporeal Membrane Oxygenation; Family; Fatty Acids; Feedback; Female; Ferric Compounds; Fibrin Fibrinogen Degradation Products; Filtration; Fish Diseases; Flavonoids; Flavonols; Fluorodeoxyglucose F18; Follow-Up Studies; Food Microbiology; Food Preservation; Forests; Fossils; Free Radical Scavengers; Freund's Adjuvant; Fruit; Fungi; Gallium; Gender Identity; Gene Expression Regulation; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Plant; Gene Knockdown Techniques; Genes, Bacterial; Genes, Plant; Genetic Predisposition to Disease; Genitalia; Genotype; Glomerulonephritis, IGA; Glottis; Glucocorticoids; Glucose; Glucuronides; Glutathione Transferase; Glycogen Synthase Kinase 3 beta; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Grassland; Guinea Pigs; Half-Life; Head Kidney; Heart Atria; Heart Rate; Heart Septum; HEK293 Cells; Hematopoietic Stem Cells; Hemodynamics; Hep G2 Cells; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Hepatocytes; Hesperidin; High-Frequency Ventilation; High-Temperature Requirement A Serine Peptidase 1; Hippocampus; Hirudins; History, 20th Century; History, 21st Century; HIV Infections; Homeostasis; Hominidae; Housing, Animal; Humans; Hydrocarbons, Brominated; Hydrogen Bonding; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydroxybutyrates; Hydroxyl Radical; Hypertension; Hypothyroidism; Image Interpretation, Computer-Assisted; Immunoconjugates; Immunogenic Cell Death; Indoles; Infant, Newborn; Infant, Premature; Infarction, Middle Cerebral Artery; Inflammation; Inflammation Mediators; Infrared Rays; Inhibitory Concentration 50; Injections, Intravenous; Interferon-gamma; Interleukin-23; Interleukin-4; Interleukin-6; Intermediate Filaments; Intermittent Claudication; Intestine, Small; Iridoid Glucosides; Iridoids; Iron; Isomerism; Isotope Labeling; Isoxazoles; Itraconazole; Kelch-Like ECH-Associated Protein 1; Ketoprofen; Kidney Failure, Chronic; Kinetics; Klebsiella pneumoniae; Lactams, Macrocyclic; Lactobacillus; Lactulose; Lakes; Lamivudine; Laparoscopy; Laparotomy; Laryngoscopy; Leucine; Limit of Detection; Linear Models; Lipid A; Lipopolysaccharides; Listeria monocytogenes; Liver; Liver Cirrhosis; Logistic Models; Longitudinal Studies; Losartan; Low Back Pain; Lung; Lupinus; Lupus Erythematosus, Systemic; Machine Learning; Macular Degeneration; Madin Darby Canine Kidney Cells; Magnetic Phenomena; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Magnetics; Malaria, Falciparum; Male; Mannans; MAP Kinase Signaling System; Mass Spectrometry; Melatonin; Membrane Glycoproteins; Membrane Proteins; Meniscectomy; Menisci, Tibial; Mephenytoin; Mesenchymal Stem Cells; Metal Nanoparticles; Metal-Organic Frameworks; Methionine; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Nude; Mice, Obese; Mice, Transgenic; Microbial Sensitivity Tests; Microcirculation; MicroRNAs; Microscopy, Video; Microtubules; Microvascular Density; Microwaves; Middle Aged; Minimally Invasive Surgical Procedures; Models, Animal; Models, Biological; Models, Molecular; Models, Theoretical; Molecular Docking Simulation; Molecular Structure; Molecular Weight; Morus; Mouth Floor; Multicenter Studies as Topic; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Muscle, Skeletal; Myocardial Ischemia; Myocardium; NAD; NADP; Nanocomposites; Nanoparticles; Naphthols; Nasal Lavage Fluid; Nasal Mucosa; Neisseria meningitidis; Neoadjuvant Therapy; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Neoplasms, Experimental; Neural Stem Cells; Neuroblastoma; Neurofilament Proteins; Neurogenesis; Neurons; New York; NF-E2-Related Factor 2; NF-kappa B; Nicotine; Nitriles; Nitrogen; Nitrogen Fixation; North America; Observer Variation; Occupational Exposure; Ochrobactrum; Oils, Volatile; Olea; Oligosaccharides; Omeprazole; Open Field Test; Optimism; Oregon; Oryzias; Osmolar Concentration; Osteoarthritis; Osteoblasts; Osteogenesis; Ovarian Neoplasms; Ovariectomy; Oxadiazoles; Oxidation-Reduction; Oxidative Stress; Oxygen; Ozone; p38 Mitogen-Activated Protein Kinases; Pakistan; Pandemics; Particle Size; Particulate Matter; Patient-Centered Care; Pelargonium; Peptides; Perception; Peripheral Arterial Disease; Peroxides; Pets; Pharmaceutical Preparations; Pharmacogenetics; Phenobarbital; Phenols; Phenotype; Phosphates; Phosphatidylethanolamines; Phosphines; Phospholipids; Phosphorus; Phosphorylation; Photoacoustic Techniques; Photochemotherapy; Photosensitizing Agents; Phylogeny; Phytoestrogens; Pilot Projects; Plant Components, Aerial; Plant Extracts; Plant Immunity; Plant Leaves; Plant Oils; Plants, Medicinal; Plasmodium berghei; Plasmodium falciparum; Platelet Activation; Platelet Function Tests; Pneumonia, Viral; Poaceae; Pogostemon; Poloxamer; Poly I; Poly(ADP-ribose) Polymerase Inhibitors; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Polycyclic Compounds; Polyethylene Glycols; Polylysine; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Population Dynamics; Portasystemic Shunt, Transjugular Intrahepatic; Positron Emission Tomography Computed Tomography; Postoperative Complications; Postprandial Period; Potassium Cyanide; Predictive Value of Tests; Prefrontal Cortex; Pregnancy; Prepulse Inhibition; Prevalence; Procalcitonin; Prodrugs; Prognosis; Progression-Free Survival; Proline; Proof of Concept Study; Prospective Studies; Protein Binding; Protein Conformation; Protein Domains; Protein Folding; Protein Multimerization; Protein Sorting Signals; Protein Structure, Secondary; Proton Pump Inhibitors; Protozoan Proteins; Psychometrics; Pulse Wave Analysis; Pyridines; Pyrrolidines; Quality of Life; Quantum Dots; Quinoxalines; Quorum Sensing; Radiopharmaceuticals; Rain; Random Allocation; Randomized Controlled Trials as Topic; Rats; Rats, Sprague-Dawley; Rats, Wistar; RAW 264.7 Cells; Reactive Oxygen Species; Receptor, Angiotensin, Type 1; Receptor, PAR-1; Receptors, CXCR4; Receptors, Estrogen; Receptors, Glucocorticoid; Receptors, Interleukin-1; Receptors, Interleukin-17; Receptors, Notch; Recombinant Fusion Proteins; Recombinant Proteins; Reducing Agents; Reflex, Startle; Regional Blood Flow; Regression Analysis; Reperfusion Injury; Reproducibility of Results; Republic of Korea; Respiratory Tract Diseases; Retrospective Studies; Reverse Transcriptase Inhibitors; Rhinitis, Allergic; Risk Assessment; Risk Factors; Rituximab; RNA, Messenger; RNA, Ribosomal, 16S; ROC Curve; Rosmarinic Acid; Running; Ruthenium; Rutin; Sarcolemma; Sarcoma; Sarcopenia; Sarcoplasmic Reticulum; SARS-CoV-2; Scavenger Receptors, Class A; Schools; Seasons; Seeds; Sequence Analysis, DNA; Severity of Illness Index; Sex Factors; Shock, Cardiogenic; Short Chain Dehydrogenase-Reductases; Signal Transduction; Silver; Singlet Oxygen; Sinusitis; Skin; Skin Absorption; Small Molecule Libraries; Smoke; Socioeconomic Factors; Soil; Soil Microbiology; Solid Phase Extraction; Solubility; Solvents; Spain; Spectrometry, Mass, Electrospray Ionization; Spectroscopy, Fourier Transform Infrared; Speech; Speech Perception; Spindle Poles; Spleen; Sporothrix; Staphylococcal Infections; Staphylococcus aureus; Stereoisomerism; Stomach Neoplasms; Stress, Physiological; Stroke Volume; Structure-Activity Relationship; Substrate Specificity; Sulfonamides; Surface Properties; Surface-Active Agents; Surveys and Questionnaires; Survival Rate; T-Lymphocytes, Cytotoxic; Tandem Mass Spectrometry; Temperature; Tenofovir; Terpenes; Tetracycline; Tetrapleura; Textiles; Thermodynamics; Thiobarbituric Acid Reactive Substances; Thrombin; Thyroid Hormones; Thyroid Neoplasms; Tibial Meniscus Injuries; Time Factors; Tissue Distribution; Titanium; Toluidines; Tomography, X-Ray Computed; Tooth; Tramadol; Transcription Factor AP-1; Transcription, Genetic; Transfection; Transgender Persons; Translations; Treatment Outcome; Triglycerides; Ubiquinone; Ubiquitin-Specific Proteases; United Kingdom; United States; Up-Regulation; Vascular Stiffness; Veins; Ventricular Remodeling; Viral Load; Virulence Factors; Virus Replication; Vitis; Voice; Voice Quality; Wastewater; Water; Water Pollutants, Chemical; Water-Electrolyte Balance; Weather; Wildfires; Wnt Signaling Pathway; Wound Healing; X-Ray Diffraction; Xenograft Model Antitumor Assays; Young Adult; Zoogloea

Lay abstract In this analysis of the FRESCO trial, we evaluated the efficacy and safety of fruquintinib in two different groups of patients (subgroups) with metastatic colorectal cancer - patients who received prior targeted therapy (PTT) and patients who did not (non-PTT). Of the 278 patients treated with fruquintinib, 111 patients received PTT. Patients treated with fruquintinib had longer overall survival and it took longer for their disease to worsen in both PTT and non-PTT subgroups compared with placebo. Patients in both subgroups treated with fruquintinib showed measurable reduction in their tumor size and disease control with similar side effects in patients of both the subgroups. These results suggest that fruquintinib is safe and effective in patients with metastatic colorectal cancer in both subgroups.

Topics: Aged; Benzofurans; Colorectal Neoplasms; Double-Blind Method; ErbB Receptors; Female; Humans; Male; Middle Aged; Progression-Free Survival; Quinazolines; Receptors, Vascular Endothelial Growth Factor; Survival Rate; Treatment Outcome; Vascular Endothelial Growth Factor A

Fruquintinib, a novel, highly selective, small-molecule tyrosine kinase inhibitor of VEGF receptors (VEGFRs)-1, -2 and -3, is approved in China for the treatment of metastatic colorectal cancer. FRESCO-2, a global, randomized, double-blind, placebo-controlled, Phase III study, is investigating the efficacy and safety of fruquintinib in patients with refractory metastatic colorectal cancer. Key inclusion criteria include: progression on or intolerance to TAS-102 and/or regorafenib; and prior treatment with approved chemotherapy, anti-VEGF therapy, and, if. Lay abstract Fruquintinib is a drug that slows down, reduces or prevents the growth of vessels that supply blood to certain tumors. Fruquintinib is approved in China for the treatment of cancer of the colon and rectum that has spread to these parts of the body from the primary site of cancer: metastatic colorectal cancer. The FRESCO-2 study is being conducted globally to determine how safe and effective fruquintinib is at treating patients with metastatic colorectal cancer that has grown or spread following other forms of treatment, such as chemotherapy. About 687 patients will be enrolled globally to receive either fruquintinib or a matching placebo in a 2:1 ratio, respectively. The FRESCO-2 study is enrolling patients in the USA, Europe, Australia and Japan.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Benzofurans; Colorectal Neoplasms; Double-Blind Method; Humans; Protein Kinase Inhibitors; Quinazolines

Napabucasin is an oral NAD(P)H:quinone oxidoreductase 1 bioactivatable agent that generates reactive oxygen species, is hypothesised to affect multiple oncogenic cellular pathways, including STAT-3, and is expected to result in cancer cell death. This phase I study investigated the safety, tolerability, and pharmacokinetics of napabucasin co-administered with fluorouracil, l-leucovorin, and irinotecan (FOLFIRI) chemotherapy plus bevacizumab in Japanese patients with metastatic colorectal cancer (CRC).. Patients with histologically confirmed unresectable stage IV CRC received oral napabucasin 240 mg twice daily (BID). Intravenous FOLFIRI and bevacizumab therapy was initiated on day 3 at approved doses. Unacceptable toxicity was evaluated over the first 30 days of treatment, after which treatment continued in 14-day cycles until toxicity or disease progression. Endpoints included safety, pharmacokinetics, and tumour response based on RECIST v1.1.. Four patients received treatment; three were evaluable during the unacceptable toxicity period. All four patients experienced diarrhoea and decreased appetite (considered napabucasin-related in four and two patients, respectively), and three patients experienced neutrophil count decreased. No unacceptable toxicity was reported during the 30-day evaluation period. No grade 4 events, deaths, or serious adverse events were reported. The addition of FOLFIRI and bevacizumab to napabucasin did not significantly change the pharmacokinetic profile of napabucasin; however, results were variable among patients. The best overall response was stable disease in two patients (50.0%).. Napabucasin 240 mg BID in combination with FOLFIRI and bevacizumab was tolerated, with a manageable safety profile in Japanese patients with metastatic CRC.

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzofurans; Bevacizumab; Camptothecin; Colorectal Neoplasms; Humans; Japan; Leucovorin; Naphthoquinones

Napabucasin is a cancer stemness inhibitor that targets a number of oncogenic pathways, including signal transducer and activator of transcription 3 (STAT3). Phase 1/2 studies suggest tolerability and anti-tumor activity in various types of cancer; a Phase 3 study of napabucasin plus standard therapy in colorectal cancer is ongoing. This is a Phase 1 dose-escalation study in patients with advanced solid tumors, and the first study of napabucasin in Japanese patients.. Patients received napabucasin 480, 960, or 1440 mg daily in 28-day cycles until disease progression or intolerable toxicity. Primary objectives were to determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and the pharmacokinetic (PK) profile of napabucasin. Blood samples were taken for PK analysis on Days 1, 2, 8, and 15 of Cycle 1, and Days 29 and 30 of Cycle 2. Secondary objectives were to assess napabucasin antitumor activity, and the relationship between biomarkers and antitumor activity. JapicCTI-No: JapicCTI-132152.. Enrolled were 14 patients (480 mg [n = 3], 960 mg [n = 4], 1440 mg [n = 7]). One patient experienced a DLT (Grade 3, anorexia). MTD was 1440 mg/day. Most common drug-related adverse events were diarrhea (n = 9), nausea (n = 4), vomiting (n = 3), and anorexia (n = 3). Napabucasin showed a similar PK profile to previous studies and no abnormal accumulation was observed. Following treatment, two patients had stable disease; the remaining 12 had progressive disease.. Napabucasin was well-tolerated at doses up to 1440 mg/day in Japanese patients with advanced solid tumors; the PK profile was comparable to that reported previously.

Topics: Adrenal Gland Neoplasms; Antineoplastic Agents; Benzofurans; Biological Availability; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Monitoring; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Naphthoquinones; Progression-Free Survival; STAT3 Transcription Factor; Treatment Outcome

This is a phase I/II trial to assess the efficacy and safety of napabucasin plus pembrolizumab for metastatic colorectal cancer (mCRC).. Phase I was conducted to determine the recommended phase 2 dose (RP2D) in a dose escalation design of napabucasin (240 to 480 mg twice daily) with 200 mg pembrolizumab every 3 weeks. Phase II included cohort A (. A total of 55 patients were enrolled in this study. In phase I, no patients experienced dose-limiting toxicities, and napabucasin 480 mg was determined as RP2D. The irORR was 50.0% in cohort A and 10.0% in cohort B. In cohort B, the irORR was 0%, 5.3%, and 42.9% in CPS < 1, 1≤ CPS <10, and CPS ≥ 10, respectively. Patients with objective response tended to have higher tumor mutation burden than those without. Of evaluable 18 patients for CMS classification in cohort B, the irORR was 33.3%, 0%, 33.3%, and 33.3% in CMS1, CMS2, CMS3, and CMS4, respectively. The common grade 3 or higher treatment-related adverse events included fever (10.0%) in cohort A and decreased appetite (7.5%) and diarrhea (5.0%) in cohort B.. Napabucasin with pembrolizumab showed antitumor activity with acceptable toxicities for patients with MSS mCRC as well as MSI-H mCRC, although it did not meet the primary end point. The impact of related biomarkers on the efficacy warrants further investigations in the additional cohort.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; Benzofurans; Colorectal Neoplasms; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Microsatellite Instability; Middle Aged; Naphthoquinones; Neoplasm Metastasis

In FRESCO (Fruquintinib Efficacy and Safety in 3+ Line Colorectal Cancer Patients) trial, fruquintinib demonstrated a statistically significant and clinically meaningful overall survival benefit in Chinese patients with metastatic colorectal cancer (mCRC). However, its safety profile, including adverse events of special interest (AESIs) and treatment-emergent adverse events (TEAEs) by age, sex, and body mass index (BMI), is not well known. The present analysis evaluated the safety profile and AESIs for fruquintinib in the FRESCO trial.. In FRESCO, eligible Chinese patients were randomized (2:1) to receive fruquintinib (5 mg once daily for 3 weeks, followed by 1 week off in 28-day cycles) or placebo plus best supportive care. Treatment-related AESIs and time to first occurrence of AESIs were summarized. Treatment-related TEAEs by age, sex, and BMI were also summarized.. A total of 266 patients (95.7%) in the fruquintinib group and 97 (70.8%) in the placebo group had at least one treatment-related TEAE; the mean relative dose intensity was 92% and 98%, respectively. In the fruquintinib group, the most common (in > 40% of patients) treatment-related AESIs were hypertension (55.4%), palmar-plantar erythrodysesthesia syndrome [known as hand-foot skin reaction (HFSR)] (49.3%), and proteinuria (42.1%). The most common treatment-related grade ≥ 3 AESIs (≥ 3% of patients) were hypertension (21.2%), HFSR (10.8%), and proteinuria (3.2%); the median time to onset of these events was 10, 21, and 20 days, respectively. Subgroup analysis by age, sex, and BMI revealed that the frequencies of treatment-related TEAEs were similar across all subgroups, and were consistent with the overall safety profile of fruquintinib.. The most common treatment-related grade ≥ 3 AEs were hypertension, HFSR, and proteinuria. The treatment-related TEAE profile of fruquintinib in Chinese patents with mCRC was comparable among different subgroups and consistent with that reported in the overall population.. Clinical Trials identifier NCT02314819.

Topics: Benzofurans; China; Colorectal Neoplasms; Humans; Quinazolines

Napabucasin is a first-in-class cancer stemness inhibitor that targets STAT3, which is a poor prognostic factor in colorectal cancer. This study aimed to test napabucasin in advanced colorectal cancer.. This study was a double-blind randomised phase 3 trial done at 68 centres in Canada, Australia, New Zealand, and Japan. Patients with advanced colorectal cancer with a good Eastern Cooperative Oncology Group (ECOG) performance status (0-1) for whom all available standard therapies had failed were eligible for the study. Patients were randomly assigned (1:1) to receive placebo or napabucasin through a web-based system with a permuted block method, after stratification by ECOG performance status, KRAS status, previous VEGF inhibitor treatment, and time from diagnosis of metastatic disease. Napabucasin 480 mg or matching placebo was taken orally every 12 h. All patients received best supportive care. The primary endpoint was overall survival assessed in an intention-to-treat analysis. This is the final analysis of this trial, which is registered at ClinicalTrials.gov, number NCT01830621.. Accrual began on April 15, 2013, and was stopped for futility on May 23, 2014, at which point 282 patients had undergone randomisation (138 assigned to the napabucasin group and 144 to the placebo group). Overall survival did not differ significantly between groups: median overall survival was 4·4 months (95% CI 3·7-4·9) in the napabucasin group and 4·8 months (4·0-5·3) in the placebo group (adjusted hazard ratio [HR] 1·13, 95% CI 0·88-1·46, p=0·34). The safety population included 136 patients in the napabucasin group and 144 patients in the placebo group. More patients who received napabucasin had any grade of treatment-related diarrhoea (108 [79%] of 136 patients), nausea (69 [51%]), and anorexia (52 [38%]) than did patients who received placebo (28 [19%] of 144 patients, 35 [24%], and 23 [16%], respectively). The most common severe (grade 3 or worse) treatment-related adverse events were abdominal pain (five [4%] patients receiving napabucasin vs five [3%] receiving placebo), diarrhoea (21 [15%] vs one [1%]), fatigue (14 [10%] vs eight [6%]), and dehydration (six [4%] vs one [1%]). 251 (89%) patients had data on pSTAT3 expression, of whom 55 (22%) had pSTAT3-positive tumours (29 in the napabucasin group, 26 in the placebo group). In a prespecified biomarker analysis of pSTAT3-positive patients, overall survival was longer in the napabucasin group than in the placebo group (median 5·1 months [95% CI 4·0-7·5] vs 3·0 months [1·7-4·1]; HR 0·41, 0·23-0·73, p=0·0025).. Although there was no difference in overall survival between groups in the overall unselected population, STAT3 might be an important target for the treatment of colorectal cancer with elevated pSTAT3 expression. Nevertheless, these results require validation.. Canadian Cancer Society Research Institute and Boston Biomedical.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Benzofurans; Biomarkers, Tumor; Colorectal Neoplasms; Double-Blind Method; Female; Humans; Intention to Treat Analysis; Male; Middle Aged; Naphthoquinones; Neoplasm Metastasis; Prospective Studies; STAT3 Transcription Factor; Survival Analysis; Time-to-Treatment

Patients with metastatic colorectal cancer (CRC) have limited effective and tolerable treatment options.. To evaluate the efficacy and safety of oral fruquintinib, a vascular endothelial growth factor receptor (VEGFR) inhibitor, as third-line or later therapy in patients with metastatic CRC.. FRESCO (Fruquintinib Efficacy and Safety in 3+ Line Colorectal Cancer Patients) was a randomized, double-blind, placebo-controlled, multicenter (28 hospitals in China), phase 3 clinical trial. From December 2014 to May 2016, screening took place among 519 patients aged 18 to 75 years who had metastatic CRC that progressed after at least 2 lines of chemotherapy but had not received VEGFR inhibitor therapy; 416 met the eligibility criteria and were stratified by prior anti-VEGF therapy and K-ras status. The final date of follow-up was January 17, 2017.. Patients were randomized in a 2:1 ratio to receive either fruquintinib, 5 mg (n = 278) or placebo (n = 138) orally, once daily for 21 days, followed by 7 days off in 28-day cycles, until disease progression, intolerable toxicity, or study withdrawal.. The primary end point was overall survival. Key secondary efficacy endpoints were progression-free survival (time from randomization to disease progression or death), objective response rate (confirmed complete or partial response), and disease control rate (complete or partial response, or stable disease recorded ≥8 weeks postrandomization). Duration of response was also assessed. Safety outcomes included treatment-emergent adverse events.. Of the 416 randomized patients (mean age, 54.6 years; 161 [38.7%] women), 404 (97.1%) completed the trial. Median overall survival was significantly prolonged with fruquintinib compared with placebo (9.3 months [95% CI, 8.2-10.5] vs 6.6 months [95% CI, 5.9-8.1]); hazard ratio (HR) for death, 0.65 (95% CI, 0.51-0.83; P < .001). Median progression-free survival was also significantly increased with fruquintinib (3.7 months [95% CI, 3.7-4.6] vs 1.8 months [95% CI, 1.8-1.8] months); HR for progression or death, 0.26 (95% CI, 0.21 to 0.34; P < .001). Grades 3 and 4 treatment-emergent adverse events occurred in 61.2% (170) of patients who received fruquintinib and 19.7% (27) who received placebo. Serious adverse events were reported by 15.5% (43) of patients in the fruquintinib group and 5.8% (8) in the placebo group, with 14.4% (40) of fruquintinib-treated and 5.1% (7) of placebo-treated patients requiring hospitalization.. Among Chinese patients with metastatic CRC who had tumor progression following at least 2 prior chemotherapy regimens, oral fruquintinib compared with placebo resulted in a statistically significant increase in overall survival. Further research is needed to assess efficacy outside of China.. ClinicalTrials.gov Identifier: NCT02314819.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzofurans; China; Colorectal Neoplasms; Combined Modality Therapy; Double-Blind Method; Female; Humans; Intention to Treat Analysis; Male; Middle Aged; Quinazolines; Survival Analysis; Vascular Endothelial Growth Factor A; Young Adult

To assess the efficacy and safety of fruquintinib, a vascular endothelial growth factor receptor (VEGFR) inhibitor, in metastatic colorectal cancer (mCRC) patients.. A phase Ib open-label study and phase II randomized, placebo-controlled trial compared the efficacy of fruquintinib plus best supportive care (BSC) with placebo plus BSC in mCRC patients with ≥2 lines of prior therapies. The primary endpoint was progression-free survival (PFS).. In the phase Ib study, 42 patients took fruquintinib 5 mg for 3 weeks on/1 week off. The median PFS was 5.80 months, and the median overall survival (OS) was 8.88 months. In the phase II study, 71 patients were randomized (47 to fruquintinib, 24 to placebo). PFS was significantly improved with fruquintinib plus BSC (4.73 months; 95% confidence interval [CI] 2.86-5.59) versus placebo plus BSC (0.99 months; 95% CI 0.95-1.58); (hazard ratio [HR] 0.30; 95% CI 0.15-0.59; P < 0.001). The median OS was 7.72 versus 5.52 months (HR 0.71; 95% CI 0.38-1.34). The most common grade 3-4 adverse events were hypertension and hand-foot skin reaction.. Fruquintinib showed a significant PFS benefit of 3.7 months in patients with treatment-refractory mCRC. The safety profile was consistent with that of VEGFR tyrosine kinase inhibitors. A randomized phase III confirmatory study in mCRC is underway.. NCT01975077 and NCT02196688.

Topics: Adenocarcinoma; Aged; Angiogenesis Inhibitors; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Benzofurans; Colorectal Neoplasms; Disease-Free Survival; Double-Blind Method; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Proteins; Protein Kinase Inhibitors; Quinazolines; Receptors, Vascular Endothelial Growth Factor

In a phase II trial, the activity of carzelesin, a cyclopropylpyrroloindole prodrug analog, was assessed.. Carzelesin was used as second- or third-line chemotherapy in patients with breast, ovarian, head and neck cancer and non-Hodgkin's lymphoma, and as first-line chemotherapy in patients with colorectal and gastric cancer and melanoma. The drug was given as a bolus infusion at a 4-weekly dose of 150 microg/m2. A total of 140 patients were entered and a total of 285 courses were administered.. In general, the compound was well tolerated. Myelotoxicity was the most common toxicity. Grade 3 and 4 leukopenia was observed in 18.6% of the courses, neutropenia in 20.3%, thrombocytopenia in 16.2% and anemia in 8.7%. Double nadirs were seen in a total of 41 courses for neutrophils, in 40 for leukocytes and in 3 for platelets. Non-hematological toxicity was very mild. Only one partial response in a patient with melanoma was seen.. At this dose and schedule carzelesin did not yield activity in the types of tumors studied.

Topics: Adult; Aged; Antineoplastic Agents; Benzofurans; Breast Neoplasms; Colorectal Neoplasms; Duocarmycins; Female; Head and Neck Neoplasms; Humans; Indoles; Infusions, Intravenous; Lymphoma, Non-Hodgkin; Male; Melanoma; Middle Aged; Neoplasm Staging; Neoplasms; Ovarian Neoplasms; Prodrugs; Stomach Neoplasms

Lappaol F (LAF), a natural lignan from. This study determined the molecular mechanism by which LAF regulates cell cycle progression.. Various colon cancer cell lines (SW480, HCT15, and HCT116) were treated with LAF (25, 50, and 75 μmol/L) for 48 h. The effects of LAF on cell proliferation and cell cycle were determined using sulforhodamine B and flow cytometry assays. Differentially expressed proteins (DEPs) were identified using quantitative proteomics. Bioinformatic analysis of DEPs was conducted

Topics: Benzofurans; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Cyclin-Dependent Kinase Inhibitor p57; Humans

Fruquintinib, also called HMPL-013, was first discovered by Hutchison Whampoa Pharmaceuticals Co. Ltd., Shanghai, China, and it is an oral vascular endothelial growth factor receptor (VEGFR) inhibitor. In clinical trials, fruquintinib has demonstrated a survival benefit in metastatic colorectal cancer (mCRC) patients. The purpose of this study was to retrospectively evaluate the efficacy and toxicity of fruquintinib in real-world patients. We collected data from patients with mCRC treated with oral fruquintinib from 2018 to 2020 in six different institutions. Patients with mCRC initially received 5 mg of oral fruquintinib daily for 3 weeks. Progression-free survival (PFS) was evaluated using the KaplanMeier method. The efficacy and safety of fruquintinib were also assessed. Seventy-five patients were involved in our study, and 29.3% of patients achieved stable disease (SD). Median PFS was 5.4 months (95% CI: 4.8415.959). The treatment-emergent adverse events (TEAEs) with fruquintinib were acceptable with grade 3 TEAEs of 6%. The grade 3 TEAEs were handfoot skin reaction (HFSR), fatigue, and stomatitis. The ECOG performance status was associated with PFS. In this real-world study, the clinical activity of fruquintinib was consistent with what has been reported in previous clinical trials. The level of safety was acceptable, and the side effects were manageable.

Topics: Benzofurans; China; Colonic Neoplasms; Colorectal Neoplasms; Humans; Quinazolines; Retrospective Studies; Vascular Endothelial Growth Factor A

Regorafenib and fruquintinib are tyrosine kinase inhibitors that are recommended for refractory colorectal cancer (CRC) in China. However, to date, no head-to-head trials have been conducted to guide clinical practice.. An ambispective observational cohort study was conducted in Beijing Cancer Hospital. Patients with metastatic CRC who received regorafenib or fruquintinib were retrospectively collected between January 2018 and April 2020, and prospectively enrolled between May 2020 and February 2021. The primary outcome was time-to-treatment failure (TTF), and secondary outcomes were overall survival (OS) and adverse events. An additional goal of the study was to explore the appropriate sequence of regorafenib and fruquintinib treatment.. A total of 366 patients with metastatic CRC were enrolled to receive regorafenib (n = 260) or fruquintinib (n = 106) between January 2018 and February 2021. No difference was observed for median TTF (regorafenib 2.7 months vs. fruquintinib 3.1 months, P = .200) or median OS (regorafenib 13.8 months vs. fruquintinib 11.3 months, P = .527). The propensity score analysis showed similar results for median TTF and median OS between the 2 groups, as did the results of subgroup analysis for prospective set (n = 146). For sequence analysis, patients with regorafenib followed by fruquintinib (n = 84) showed longer OS than that with the reverse (n = 29) (28.1 months vs. 18.4 months, P = .024). Most patients tolerated regorafenib at a reduced dose (93.1%), and most patients tolerated fruquintinib at a standard dose (68.9%). The incidences of most adverse events were similar between the two groups, while any grade of hand-foot skin reaction and hyperbilirubinemia were more frequently observed in the regorafenib group and ≥grade 3 hypertension was more common in the fruquintinib group.. Regorafenib and fruquintinib had similar efficacy and toxicity profiles with various frequency. Regorafenib followed by fruquintinib showed longer OS than the reverse, but the sequence needs to be further confirmed.

Topics: Benzofurans; Colonic Neoplasms; Colorectal Neoplasms; Humans; Phenylurea Compounds; Prospective Studies; Pyridines; Quinazolines; Rectal Neoplasms; Retrospective Studies

Topics: Antineoplastic Agents; Apoptosis; Benzofurans; beta Catenin; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Glycogen Synthase Kinase 3 beta; Humans; Wnt Signaling Pathway

Usnic Acid (UA), also known as lichenol, has been reported to have inhibitory effects on a variety of cancer cells, but its specific mechanism remained to be elucidated. Tumor chemotherapy drugs, especially DNA damage chemotherapeutic drugs, target Chromosomal DNA, but their spontaneous and acquired drug resistance are also an urgent problem to be solved. Therefore, drug combination research has become the focus of researchers.. Here, we evaluated the tumor-suppressing molecular mechanism of UA in colorectal cancer cells RKO from the perspective of the ATM-mediated DNA damage signaling pathway through H2O2 simulating DNA damage chemotherapeutic drugs. CCK8 cell proliferation assay was used to determine the inhibition of RKO cells by hydrogen peroxide and UA alone or in combination, and wound healing assay was applied to determine the effect of the drug on cell migration.. Transfected cells with miRNA18a-5p mimics and inhibitors, MDC and DCFH-DA staining for the measurement of autophagy and ROS, cell cycle and apoptosis were detected by flow cytometry, expressions of microRNA and mRNA were determined by fluorescence quantitative PCR, and protein by Western blot.. We found that UA can upregulate ATM via miR-18a to activate the DNA damage signaling pathway and inhibit the proliferation and migration of RKO cells in a concentration-dependent manner.. At the same time, DNA damage responses, including cell cycle, autophagy, apoptosis and ROS levels, are also regulated by UA. Therefore, UA combined with DNA damage chemotherapeutic drugs may be an effective treatment for cancer.

Topics: Apoptosis; Ataxia Telangiectasia Mutated Proteins; Autophagy; Benzofurans; Cell Cycle; Cell Line, Tumor; Cell Movement; Cell Proliferation; Colorectal Neoplasms; DNA Damage; Drug Therapy, Combination; Humans; Hydrogen Peroxide; MicroRNAs; Signal Transduction; Up-Regulation; Wound Healing

Lay abstract The objective of the study was to assess the benefit of fruqintinib, a chemotherapy drug for patients with metastatic colorectal cancer (mCRC) who do not respond well to previous chemotherapy. The study considered both the time of survival and the quality of life after patients received fruqintinib. In measuring patients’ quality of life, the study assessed the time that was free from cancer symptoms and any severe side effects from treatment. The study used data obtained from a Phase III clinical trial, FRESCO, which included 416 mCRC patients receiving fruqintinib or placebo. The results showed that fruqintinib significantly extended patients’ symptom-free and side effects-free survival time by approximately 2 months and 5 days. Fruqintinib was 16.7–39.9% more effective than placebo in extending mCRC patients’ high-quality life, regardless of prior targeted therapy.

Topics: Aged; Benzofurans; Cancer Survivors; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Female; Humans; Male; Middle Aged; Placebos; Quality-Adjusted Life Years; Quinazolines; Randomized Controlled Trials as Topic; Survival Analysis

This study was to investigate the efficacy and safety of regorafenib or fruquintinib combined with camrelizumab in patients with microsatellite stable (MSS) and/or proficient mismatch repair (pMMR) metastatic colorectal cancer (mCRC). Medical records of MSS/pMMR mCRC patients who received regorafenib (80 mg) or fruquintinib (3 mg) once a day (21 days on/7 days off) plus camrelizumab (200 mg) every three weeks in Yuhuangding Hospital between January 2020 and June 2020 were retrospectively collected. Follow-up data up to November 1st, 2020 was gathered. The primary endpoint was the objective response rate (ORR) and disease control rate (DCR). The safety profile was the secondary endpoint. A total of 16 patients were enrolled. The ORR was 25.0% (4/16) and the DCR was 62.5% (10/16). The main adverse events (AEs) included reactive cutaneous capillary endothelial proliferation (RCCEP) (81.3%), fatigue (43.8%), hypertension (37.5%), hand-foot skin reaction (25.0%), and thyroid dysfunction (25.0%). Most AEs were grade 1 or 2, with only 1 patient of grade 3 liver dysfunction. All the AEs were ameliorated by effective symptomatic treatment. Regorafenib or fruquintinib plus camrelizumab exhibited promising efficacy in patients with MSS/pMMR mCRC. The toxicity was moderate and manageable.

Topics: Antibodies, Monoclonal, Humanized; Benzofurans; Colorectal Neoplasms; DNA Mismatch Repair; Humans; Microsatellite Repeats; Phenylurea Compounds; Pilot Projects; Pyridines; Quinazolines; Retrospective Studies

To evaluate the cost-effectiveness of addition of fruquintinib to best supportive care (BSC) in third-line treatment for patients with metastatic colorectal cancer (CRC).. To conduct the cost-effectiveness analysis, a Markov model was established to simulate the course of metastatic CRC. Three health states-progression-free survival (PFS), progressive disease (PD), and death-were included. Clinical data were derived from the FRESCO trial and health utility values were extracted from previous literature. The primary outcome of the study was incremental cost-effectiveness ratio (ICER) in US dollars per quality-adjusted life-years (QALYs) from a Chinese societal perspective. One-way sensitivity analyses and probabilistic sensitivity analyses were performed to test the robustness of the study.. Addition of fruquintinib to BSC gained 0.54 QALY at a cost of $15,404.57 while the BSC group gained 0.38 QALY at a cost of $9603.94. ICER of fruquintinib versus BSC was $36,253.94/QALY. In the 1-way sensitivity analyses, utility for PD in both groups, utility for PFS in both groups, and cost of fruquintinib significantly influenced the results of the analysis. At the willingness-to-pay threshold of $28,988.40/QALY, probabilities of addition of fruquintinib to BSC or BSC alone as the cost-effective option were 0% and 100%, indicating addition of fruquintinib is not a dominant option compared with BSC.. Addition of fruquintinib to BSC is not a cost-effective regimen in the third-line setting for patients with metastatic CRC from the Chinese societal perspective.

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzofurans; Colorectal Neoplasms; Cost-Benefit Analysis; Female; Humans; Male; Markov Chains; Neoplasm Metastasis; Progression-Free Survival; Quality-Adjusted Life Years; Quinazolines

Abnormal glycerophospholipid (GPL) metabolism represented by phosphatidylcholine (PC) and phosphatidylethanolamine (PE) has been as a universal metabolic hallmark of cancer, which is involved in tumor progression. Our previous finding showed that peroxidase from foxtail millet bran (FMBP) exhibited significant anticolorectal cancer (CRC) activity in vitro and in nude mice. Presently, the potential of FMBP in clinical application was further evaluated by an azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colitis-associated carcinogenesis (CAC) mice model, revealed the pivotal role of GPL metabolism in anti-CRC effects of FMBP. Excitedly, FMBP significantly reduced the number and volume of CAC polyps of mice and effectively improved physiological indexes of CAC mice. Meanwhile, the elevated expressions of CRC early markers (cyclooxygenase 2, tumor-proliferating nuclear antigen Ki-67, and EGF module-containing mucin-like receptor 1) in CAC mice were efficiently prevented by FMBP treatment. Metabolomics analysis showed that the elevated abundances of PC and PE involved in GPL metabolism in CAC mice were markedly decreased in FMBP-treated groups, which was also verified in human CRC cells. Further, FMBP reduced the expression levels of PE and PC key metabolic enzymes, resulting in the blockage of GPL metabolism and insufficient adenosine triphosphate to maintain CRC growth. Collectively, FMBP has the potential as a preventive and therapeutic candidate for CRC through the blockage of GPL metabolism.

Topics: Animals; Benzofurans; Carcinogenesis; Cell Line, Tumor; Colitis; Colorectal Neoplasms; Dextran Sulfate; Disease Models, Animal; Glycerophospholipids; Humans; Male; Mice; Mice, Nude; Peroxidase; Plant Proteins; Quinolines; Setaria Plant

The clinical efficiency and adverse reactions of anlotinib in metastatic colorectal cancer (mCRC) as a third-line treatment compared with chemotherapy and regorafenib or fruquintinib was explored in this study. Clinical data from 105 mCRC patients who failed at least two lines of chemotherapy were collected. The patients were divided into three groups based on their third-line therapeutic regimen: third-line chemotherapy only (group A); anlotinib (group B); and fruquintinib or regorafenib (group C). The result showed that the ORR and DCR of group B (14.29%, 85.71%) were higher than those of group A (0%, 40.00%). The ORRs of group B and group C were 14.29% and 20.00%, respectively. Group B and group C had the same DCR, 85.71%. The mean PFS values of group B (3.46 months) and group C (3.33 months) were longer than that of group A (2.25 months) (χ2=84.255, p<0.001) and the mean PFS values of group B and group C were similar (χ2=0.884, p=0.347). The mean OS of group B was 9.22 months, which was longer than that of group A (6.95 months) (χ2=38.837, p<0.001). The mean OS values of group B (9.22 months) and group C (9.38 months) were not significantly different (χ2=0.456, p=0.499). The incidences of proteinuria, hand-foot skin reaction, myelosuppression, and gastrointestinal reaction were similar between group B and group C (p=0.173, 0.188, 1.00, 0.154, respectively). Myelosuppression and gastrointestinal reaction were more common in group A than in group B and group C (p<0.001). For mCRC, anlotinib as a third-line treatment is better than chemotherapy and similar to regorafenib or fruquintinib. The associated adverse reactions are tolerable.

Topics: Benzofurans; Colorectal Neoplasms; Humans; Indoles; Phenylurea Compounds; Pyridines; Quinazolines; Quinolines

Topics: Animals; Axin Protein; Benzofurans; Cell Transformation, Neoplastic; Colorectal Neoplasms; Gene Expression Regulation, Neoplastic; Humans; Mice; Mice, Inbred C57BL; Mice, Transgenic; Organoids; Prohibitins; Repressor Proteins; Wnt Signaling Pathway

Many types of oncolytic viruses (OVs) were enrolled in clinical trials. Recently, an OV named Talimogene laherparepvec approved for the treatment of melanoma. This achievement highlighted the clinical application of OVs. Scientists focus on using these anticancer agents in combination with the current or/and new anticancer chemotherapeutics. They aim to increase the oncolytic effect of a new approach for the treatment of cancer cells.. The present study aimed to assess the anticancer impacts of ReoT3D, irinotecan (CPT-11), and napabucasin (BBI608) against murine colorectal cancer cells (CT26). They are assessed alone and in combination with each other.. Here, oncolytic reovirus was propagated and titrated. Then MTT assay was carried out to assess the toxicity of this OV and chemotherapeutics effect on CT26 cells. The anticancer effects of ReoT3D, CPT-11, and BBI608, alone and simultaneously, on CT26 cell line, were assessed by the induction of apoptosis, cell cycle arrest, colony-forming, migration, and real-time PCR experiments.. Alone treatment with ReoT3D, CPT-11, and BBI608 led to effectively inducing of apoptosis, cell cycle arrest, and apoptotic genes expression level and significantly reduce of colony-forming, migration, and anti-apoptotic genes expression rate. Importantly, the maximum anticancer effect against CT26 cell line was seen upon combination ReoT3D, CPT-11, and BBI608 treatment.. The present study highlights that combination of ReoT3D, CPT-11, and BBI560 showed synergistic anticancer activity against CT26 cell line. This modality might be considered as a new approach against colorectal cancer (CRC) in the in vivo and clinical trial investigations.

Topics: Animals; Apoptosis Regulatory Proteins; Benzofurans; Biological Products; Cell Cycle Proteins; Cell Line; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Colorectal Neoplasms; Combined Modality Therapy; Drug Synergism; Gene Expression Regulation, Neoplastic; Herpesvirus 1, Human; Irinotecan; Mice; Naphthoquinones; Oncolytic Viruses; Proto-Oncogene Proteins p21(ras); Reoviridae; STAT3 Transcription Factor

Most colorectal cancers are microsatellite-stable with no response to anti-PD-1 therapy, necessitating the development of new immunomodulatory treatment strategies. Coinhibition of anti-PD-1 and STAT3 can elicit an effective antitumor response in a small subset of patients with microsatellite-stable colorectal cancer, and biomarkers predictive of response are under investigation.

Topics: Antibodies, Monoclonal, Humanized; Benzofurans; Colorectal Neoplasms; Humans; Microsatellite Instability; Microsatellite Repeats; Naphthoquinones

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Benzofurans; CD8 Antigens; Cell Line, Tumor; Chemotherapy, Adjuvant; Colectomy; Colorectal Neoplasms; Disease Models, Animal; Drug Synergism; Humans; Immune Checkpoint Inhibitors; Male; Mice; Mice, Knockout; Microsatellite Instability; Programmed Cell Death 1 Receptor; Quinazolines; Receptors, Vascular Endothelial Growth Factor; T-Lymphocytes, Regulatory; Treatment Outcome; Tumor Microenvironment; Young Adult

In this study, we analyze the cost-effectiveness of fruquintinib as third-line treatment for patients with metastatic colorectal cancer in China, especially after a recent price drop suggested by the National Healthcare Security Administration.. A Markov model was developed to investigate the cost-effectiveness of fruquintinib compared to placebo among patients with metastatic colorectal cancer. Effectiveness was measured in quality-adjusted life years (QALY). The Chinese healthcare payer's perspective was considered with a lifetime horizon, including direct medical cost (2019 US dollars [USD]). A willing-to-pay threshold was set at USD 27,130/QALY, which is three times the gross domestic product (GDP) per capita. We examined the robustness of the model in one-way and probabilistic sensitivity analysis.. Fruquintinib was associated with better health outcomes than placebo (0.640 vs 0.478 QALYs) with a higher cost (USD 20750.9 vs USD 12042.2), resulting in an incremental cost-effectiveness ratio (ICER) of USD 53508.7 per QALY. This ICER is 25% lower than the one calculated before the price drop (USD 70952.6 per QALY).. After the price negotiation, the drug becomes cheaper and the ICER is lower, but the drug is still not cost effective under the standard of 3 times GDP willing-to-pay threshold. For patients with metastatic colorectal cancer in China, fruquintinib is not a cost-effective option under the current circumstances in China.

Topics: Benzofurans; China; Colorectal Neoplasms; Cost-Benefit Analysis; Humans; Neoplasm Metastasis; Quinazolines

Fruquintinib is a potent, highly selective and orally active inhibitor of VEGFR1, 2, 3 tyrosine kinases. It inhibits VEGF-induced VEGFR2 phosphorylation, endothelial cell proliferation and tubule formation. Currently, it has been approved for the treatment of metastatic colorectal cancer in patients who have failed at least two prior systemic antineoplastic therapies in China. However, it is not approved outside China, and there is another similar small molecular VEGFR multitarget drug approved in China, USA, Europe, etc. Here, we summarize the mechanism characteristics and clinical development of fruquintinib supporting its use in the treatment of metastastic colorectal cancer as well as explorations in other tumor types.

Topics: Angiogenesis Inhibitors; Benzofurans; Cell Proliferation; China; Clinical Trials as Topic; Colorectal Neoplasms; Europe; Humans; Neoplasm Metastasis; Neovascularization, Pathologic; Phosphorylation; Quinazolines; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

Immunosuppressive myeloid-derived suppressor cells (MDSC) subvert antitumor immunity and limit the efficacy of chimeric antigen receptor T cells (CAR-T). Previously, we reported that the GM-CSF/JAK2/STAT3 axis drives liver-associated MDSC (L-MDSC) proliferation and blockade of this axis rescued antitumor immunity. We extended these findings in our murine liver metastasis (LM) model, by treating tumor-bearing mice with STAT3 inhibitors (STATTIC or BBI608) to further our understanding of how STAT3 drives L-MDSC suppressive function. STAT3 inhibition caused significant reduction of tumor burden as well as L-MDSC frequencies due to decrease in pSTAT3 levels. L-MDSC isolated from STATTIC or BBI608-treated mice had significantly reduced suppressive function. STAT3 inhibition of L-MDSC was associated with enhanced antitumor activity of CAR-T. Further investigation demonstrated activation of apoptotic signaling pathways in L-MDSC following STAT3 inhibition as evidenced by an upregulation of the pro-apoptotic proteins Bax, cleaved caspase-3, and downregulation of the anti-apoptotic protein Bcl-2. Accordingly, there was also a decrease of pro-survival markers, pErk and pAkt, and an increase in pro-death marker, Fas, with activation of downstream JNK and p38 MAPK. These findings represent a previously unrecognized link between STAT3 inhibition and Fas-induced apoptosis of MDSCs. Our findings suggest that inhibiting STAT3 has potential clinical application for enhancing the efficacy of CAR-T cells in LM through modulation of L-MDSC.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; bcl-2-Associated X Protein; Benzofurans; Cell Line, Tumor; Colorectal Neoplasms; Cyclic S-Oxides; Drug Screening Assays, Antitumor; fas Receptor; Gene Expression Regulation, Neoplastic; Immunotherapy; Liver Neoplasms, Experimental; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Targeted Therapy; Myeloid-Derived Suppressor Cells; Naphthoquinones; Neoplasm Proteins; Signal Transduction; Specific Pathogen-Free Organisms; STAT3 Transcription Factor; Tumor Burden; Tumor Escape

Topics: Antineoplastic Agents; Benzofurans; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Humans; Male; Quinazolines; Salvage Therapy

Usnic acid (UA), a lichen secondary substance, has considerable anticancer activity in vitro, whereas its effect in vivo is limited. Here, potassium usnate (KU) was prepared by the salinization of UA to enhance its water solubility. KU showed increased bioavailability compared with UA in the tumor, liver, and plasma of a CT26 syngeneic mouse tumor xenograft model after oral administration, as determined by LC-MS/MS analysis. KU exhibited potent anticancer effects on colorectal cancer cells and inhibited liver metastasis in an orthotopic murine colorectal cancer model. KU treatment downregulated the epithelial-mesenchymal markers Twist, Snail, and Slug and the metastasis-related genes CAPN1, CDC42, CFL1, IGF1, WASF1, and WASL in cells and tumor tissues. The present results suggest the potential application of the water-soluble form of UA, KU, in anticancer therapy.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Benzofurans; Biological Availability; Cell Line, Tumor; Cell Movement; Cell Proliferation; Colorectal Neoplasms; Disease Models, Animal; Drug Screening Assays, Antitumor; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Neoplasm Invasiveness; Potassium; Selenic Acid; Treatment Outcome

Trans-Scirpusin A (TSA) is a resveratrol oligomer found in Borassus flabellifer L. We found that TSA inhibited the growth of colorectal cancer Her2/CT26 cells in vivo in mice. Although some cytotoxic T lymphocytes (CTLs) were induced against the tumor-associated antigen Her2, TSA treatment did not significantly increase the level of Her2-specific CTL response compared to that with vehicle treatment. However, there was a significant increase in the level of TNF-α mRNA in tumor tissue and Her2-specific Ab (antibody) production. More importantly, we found that TSA overcomes the tumor-associated immunosuppressive microenvironment by reducing the number of CD25+FoxP3+ regulatory T cells and myeloid-derived suppressor cells (MDSCs). We detected the induction of autophagy in TSA-treated Her2/CT26 cells, based on the increased level of the mammalian autophagy protein LC3 puncta, and increased conversion of LC3-I to LC3-II. Further, TSA induced 5' AMP-activated protein kinase (p-AMPK) (T172) and inhibited mammalian target of rapamycin complex 1 (mTORC1) activity as estimated by phosphorylated ribosomal protein S6 kinase beta-1 (p-p70S6K) levels, thereby suggesting that TSA-mediated AMPK activation and inhibition of mTORC1 pathway might be associated with autophagy induction. TSA also induced apoptosis of Her2/CT26 cells, as inferred by the increased sub-G1 mitotic phases in these cells, Annexin V/PI-double positive results, and TUNEL-positive cells. Finally, we found that the combined treatment of mice with docetaxel and TSA successfully inhibited tumor growth to a greater extent than docetaxel alone. Therefore, we propose the use of TSA for supplementary anticancer therapy to support anti-neoplastic drugs, such as docetaxel, by inducing apoptosis in cancer cells and resulting in the induction of neighborhood anti-cancer immunity.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Autophagy; Benzofurans; Cell Line, Tumor; Cell Survival; Colorectal Neoplasms; Docetaxel; Drug Synergism; Gene Expression Regulation, Neoplastic; Humans; Mice, Inbred BALB C; Molecular Structure; Receptor, ErbB-2; Stilbenes; Taxoids; Tumor Burden

Salvianolic acid B (SalB) a water‑soluble phenolic compound, extracted from Salvia miltiorrhiza, has previously been demonstrated to reverse tumor multidrug resistance (MDR), including in colorectal cancer. Reactive oxygen species (ROS) are oxygen radicals generated during aerobic metabolism (superoxide and hydroxyl radicals) and superoxide easily generating free radicals (H2O2). The concept that increased ROS levels can lead to augmented tumor cell‑sensitivity to chemotherapy drugs has become notable. The aim of the present study was to elucidate the role of ROS in mediating the effect of SalB on drug resistance and the correlation with drug resistance‑associated protein, P‑glycoprotein (P‑gp), and apoptosis‑associated proteins, B‑cell lymphoma 2 (Bcl‑2) and Bcl‑2‑associated X (Bax). In the current study, through utilizing the multidrug resistant colorectal cancer cell line, HCT‑8/VCR, it was demonstrate that SalB reversed MDR in HCT‑8/VCR. In addition, SalB significantly increased ROS levels, which may have accelerated the apoptosis of HCT‑8/VCR cells by downregulating Bcl‑2 and increasing Bax protein expression. Furthermore the increased intracellular ROS levels may have inhibited P‑gp expression at the gene and protein levels. In conclusion, the data of the current study demonstrate that SalB reversed MDR in HCT‑8/VCR cells, and the effect is associated with increased ROS levels, which may downregulate P‑gp expression and promote tumor cell apoptosis, which in turn increases the sensitivity of drug‑resistant cells to chemotherapy drugs.

Topics: Acetylcysteine; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; bcl-2-Associated X Protein; Benzofurans; Cell Line, Tumor; Colorectal Neoplasms; Drug Resistance, Neoplasm; Drugs, Chinese Herbal; Humans; Hydrogen Peroxide; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species

Phlorofucofuroeckol A (PFF-A), one of the phlorotannins found in brown algae, has been reported to exert anti-cancer property. However, the molecular mechanism for the anti-cancer effect of PFF-A has not been known. Activating transcription factor 3 (ATF3) has been reported to be associated with apoptosis in colorectal cancer. The present study was performed to investigate the molecular mechanism by which PFF-A stimulates ATF3 expression and apoptosis in human colorectal cancer cells. PFF-A decreased cell viability through apoptosis of human colorectal cancer cells. PFF-A increased ATF3 expression through regulating transcriptional activity. The responsible cis-element for ATF3 transcriptional activation by PFF-A was cAMP response element binding protein (CREB), located between positions -147 and -85 of the ATF3 promoter. Inhibition of p38, c-Jun N-terminal kinases (JNK), glycogen synthase kinase (GSK) 3β, and IκB kinase (IKK)-α blocked PFF-A-mediated ATF3 expression. ATF3 knockdown by ATF3 siRNA attenuated the cleavage of poly (ADP-ribose) polymerase (PARP) by PFF-A, while ATF3 overexpression increased PFF-A-mediated cleaved PARP. These results suggest that PFF-A may exert anti-cancer property through inducing apoptosis via the ATF3-mediated pathway in human colorectal cancer cells.

Topics: Activating Transcription Factor 3; Antineoplastic Agents; Apoptosis; Benzofurans; Cell Line, Tumor; Cell Survival; Colorectal Neoplasms; CREB-Binding Protein; Dioxins; Glycogen Synthase Kinase 3 beta; HCT116 Cells; HT29 Cells; Humans; I-kappa B Kinase; JNK Mitogen-Activated Protein Kinases; Promoter Regions, Genetic; Signal Transduction; Transcription, Genetic; Transcriptional Activation; Up-Regulation

Salvianolic Acid B (Sal B), an active compound extracted from the Chinese herb Salvia miltiorrhiza, is attracting more and more attention due to its biological activities, including antioxidant, anticoagulant and antitumor effects. However, autophagy induction in cancer cells by Sal B has never been recognized. In this study, we demonstrated that Sal B induced cell death and triggered autophagy in HCT116 and HT29 cells in a dose-dependent manner. Specific inhibition of autophagy by 3-MA or shRNA targeting Atg5 rescued Sal B-induced cell death in vitro and in vivo, suggesting that Sal B-induced autophagy may play a pro-death role and contribute to the cell death of colorectal cancer cell lines. Furthermore, AKT/mTOR signaling pathway was demonstrated to be a critical mediator in regulating Sal B-induced cell death. Overexpression of AKT by the transfection with AKT plasmid or pretreatment with insulin decreased Sal B-induced autophagy and cell death. Inversely, inhibition of AKT by LY294002 treatment markedly enhanced Sal B-induced autophagy and cell death. Taken together, our results demonstrate, for the first time, that Sal B is a novel autophagy inducer and exerts its antitumor activity as a single agent in colorectal cancer cells through the suppression of AKT/mTOR pathway.

Topics: Adenine; Animals; Antineoplastic Agents; Autophagosomes; Autophagy; Autophagy-Related Protein 5; Benzofurans; Chromones; Colorectal Neoplasms; Drugs, Chinese Herbal; Female; HCT116 Cells; HT29 Cells; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Microscopy, Electron, Transmission; Microscopy, Fluorescence; Morpholines; Proto-Oncogene Proteins c-akt; RNA Interference; RNA, Small Interfering; Salvia miltiorrhiza; Signal Transduction; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays

Hypoxia-induced epithelial-mesenchymal transition (EMT) has been identified as essential for tumor progression and metastasis. The present study examined the effects of an antioxidant, dieckol, on hypoxia‑induced EMT in HT29 human colorectal cancer cells. HT29 cells were treated with a hypoxia‑inducing agent, CoCl2, and an increase in the levels of intracellular reactive oxygen species (ROS) and various morphological changes, such as loss of cell‑cell contact and aggressive cell migration were observed. CoCl2 also induced an increase in the expression of hypoxia‑inducible factor 1α (HIF1α) and various mesenchymal‑specific markers, including vimentin and snail family transcriptional repressor 1 (Snail1), and a decrease in the expression of E‑cadherin, thus suggesting that CoCl2 induced EMT in HT29 cells. Conversely, the CoCl2‑induced EMT of HT29 cells was suppressed following treatment with dieckol. In addition, ROS generation, EMT marker protein expression and intracellular localization, cell migration and cell invasion were attenuated following dieckol treatment. The findings of the present study suggested that dieckol may inhibit hypoxia‑induced EMT in HT29 cells by regulating the levels of cellular ROS and protein expression levels downstream of the HIF1α signaling pathway. Therefore, dieckol has the potential to become an attractive therapeutic agent for the treatment of colorectal cancer.

Topics: Benzofurans; Cell Line, Tumor; Cell Movement; Cell Survival; Colorectal Neoplasms; Epithelial-Mesenchymal Transition; HT29 Cells; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Phenotype; Reactive Oxygen Species; Signal Transduction

Angelica sinensis is a Chinese medicinal herb for treating gynecological and gastrointestinal disorders, and also in conjunction with cancer chemotherapy.. In the present study, the cytotoxic and anti-proliferative effects of three main Angelica sinensis phthalides, namely n-butylidenephthalide (BLP), senkyunolide A (SKA) and z-ligustilide (LGT), and their synergy on colon cancer HT-29 cells were investigated. Moreover, the results obtained in both human colon cancer HT-29 and normal colon CCD-18Co cells were compared for the investigation of selectivity.. MTT and [3H] thymidine incorporation assays were used for the evaluation of cytotoxic and anti-proliferative effects, respectively. Interactions among phthalides were determined by median-effect analysis.. All three phthalides dose-dependently decreased cell viability more potently in HT-29 than in CCD-18Co cells. The IC50 values for inhibition of cell proliferation for SKA, LGT and BLP were 54.17+/-5.10, 60.63+/-6.79 and 236.90+/-18.22microM, respectively, in HT-29 cells. Angelica sinensis extract demonstrated significant synergy in inhibiting cell proliferation.. The three phthalides might have anti-cancer potential, yet the phthalides, in combination with other ingredients in Angelica sinensis extract, display significant synergy leading to a stronger anti-tumor effect.

Topics: Adenocarcinoma; Angelica; Antineoplastic Agents, Phytogenic; Benzofurans; Cell Line; Cell Proliferation; Cell Survival; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Synergism; Drugs, Chinese Herbal; HT29 Cells; Humans; Inhibitory Concentration 50; Plant Extracts

Flavaglines are flavonol-cinnamate-derived cyclopenta[b]benzofurans, so far reported only for the genus Aglaia of the plant family Meliaceae. They represent a group of highly bioactive metabolites already known for their strong antileukemic activities. To assess their suitability as chemotherapeutic drugs in colorectal cancer, their cytostatic effects and the underlying mechanisms of action were analyzed in colorectal tumor cell lines. Aglaiastatin was the most active flavagline, inhibiting growth and inducing apoptosis at nanomolar concentrations in SW480 and HT29/HI1 carcinoma cells, while the premalignant adenoma cell lines VACO235 and LT97 as well as the normal intestinal epithelial cell line IEC18 were 1,000 times less sensitive (IC50>10 microM). In SW480 cells, aglaiastatin caused cell cycle block in early mitosis, demonstrated by a shift of cell cycle distribution 24 and 48 hr after addition of aglaiastatin and by an increased content of cyclin B after 6 hr together with a decreased level of cyclin A as early as 2 hr after exposure. In addition, induction of apoptosis could be shown by the characteristic morphology of apoptotic nuclei, loss of MMP and downmodulation of bcl(xl). Strong activation of p38 was observed after 2 hr of exposure, indicating that apoptosis may be induced via a p38-mediated stress pathway.

Topics: Adenoma; Animals; Apoptosis; bcl-X Protein; Benzofurans; Cell Cycle; Colorectal Neoplasms; Epithelial Cells; Growth Inhibitors; Humans; Intestinal Mucosa; Matrix Metalloproteinases; Meliaceae; Mitogen-Activated Protein Kinases; p38 Mitogen-Activated Protein Kinases; Proto-Oncogene Proteins c-bcl-2; Rats