tofacitinib and Breast-Neoplasms

The constitutional isomers and tautomers of oxadiazolones, as well as their mono- and disulfur analogues, were calculated at the B3LYP/aug-cc-pVDZ level. Four groups of 30 molecules each were considered: oxadiazolone, oxadiazolthione, thiadiazolone, and thiadiazolthione isomers. The compounds were categorized into six groups according to permutations of three heteroatoms in the five-membered ring. Additionally, each of the constitutional isomer was considered to have five tautomers conserving stable five-membered ring: two NH tautomers, two rotameric OH (or SH) forms and one CH. La trombocitosis es un hallazgo casual frecuente en pediatría. En niños, predominan las formas secundarias, siendo las infecciones su causa más prevalente. Se distinguen 4 grados de trombocitosis en función del número de plaquetas; en la forma extrema, se supera el 1.000.000/mm. Endoscopic thrombin injection was similar to glue injection in achieving successful hemostasis of AGVH. However, a higher incidence of complications may be associated with glue injection.

Topics: Acetaminophen; Administration, Oral; Adolescent; Adsorption; Adult; Allyl Compounds; Amylopectin; Amylose; Anaerobiosis; Animals; Anti-Bacterial Agents; Anura; Arginase; Arthritis, Rheumatoid; Asthma; Atmosphere; B-Lymphocytes; Basic Helix-Loop-Helix Transcription Factors; Bioelectric Energy Sources; Biofilms; Biofuels; Biomarkers; Biopolymers; Bioreactors; Brain; Brain Injuries, Traumatic; Breast Neoplasms; Calibration; Carbon Tetrachloride; Caspase 3; Catalysis; Catechin; Cations; Cattle; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Body; Cell Line, Tumor; Cell Plasticity; Chemical and Drug Induced Liver Injury; Chemistry Techniques, Synthetic; China; Chitosan; Chloride Channels; Chromatography, High Pressure Liquid; Chromosome Mapping; Cognition; Cognitive Dysfunction; Cohort Studies; Colitis, Ulcerative; Colloids; Coloring Agents; Congresses as Topic; Correlation of Data; Crystallization; Cyanoacrylates; Cyclohexane Monoterpenes; Cyprinidae; Cytochrome P-450 CYP1A1; Death, Sudden; Dent Disease; Dietary Supplements; Diffusion Magnetic Resonance Imaging; Disease Models, Animal; Disease Progression; Disease Resistance; Disulfides; Drug Monitoring; Drug Stability; Ecotoxicology; Electricity; Electrodes; Endocytosis; Environmental Exposure; Environmental Monitoring; Enzyme Inhibitors; Epithelial-Mesenchymal Transition; Esophageal and Gastric Varices; Esters; Fagopyrum; Female; Ferrosoferric Oxide; Flame Retardants; Flavobacteriaceae; Flow Cytometry; Follow-Up Studies; Formoterol Fumarate; Fusarium; Garlic; Gastrointestinal Hemorrhage; Gene Expression; Genes, Plant; Genetic Markers; Glial Fibrillary Acidic Protein; Gliosis; Global Health; Glutathione Transferase; Glycine max; Gum Arabic; Hemostasis, Endoscopic; Hepatocytes; Hippocampus; Humans; Hydrogen-Ion Concentration; Illinois; Immunoglobulin G; Indoleamine-Pyrrole 2,3,-Dioxygenase; Infant, Newborn; Infant, Small for Gestational Age; Injections, Intraperitoneal; Interleukin-4; Iowa; Iron; Ki-67 Antigen; Kidney; Kinetics; Kynurenine; Lakes; Levofloxacin; Lipid Peroxidation; Lipids; Liver; Liver Cirrhosis, Experimental; Magnetic Fields; Magnetic Iron Oxide Nanoparticles; Male; Manure; Maze Learning; Memory, Short-Term; Metal Nanoparticles; Metals, Heavy; Methane; Mice; Mice, Inbred C57BL; Mice, Knockout; Michigan; Microalgae; Microbial Consortia; Mitochondria; Models, Animal; Models, Chemical; Models, Neurological; Molecular Structure; Molecular Weight; Mutation; Myeloid-Derived Suppressor Cells; NADPH Oxidase 2; Neoplasm Recurrence, Local; Neurites; Neurons; Neuroprotective Agents; NF-kappa B; NIH 3T3 Cells; Nitric Oxide Synthase Type II; Nitrogen; Ohio; Ointments; Ontario; Organelle Biogenesis; Organophosphates; Organophosphorus Compounds; Oxidative Stress; Palladium; Particle Size; Pectins; Phenotype; Phytotherapy; Piperidines; Placenta; Plant Diseases; Plant Extracts; Polymers; Polymorphism, Genetic; Polyphenols; Powders; Pregnancy; Pregnancy Trimester, First; Prospective Studies; Protein Kinase Inhibitors; Protein Structure, Secondary; Proteins; Pyridines; Pyrimidines; Rats, Wistar; Real-Time Polymerase Chain Reaction; Receptors, Aryl Hydrocarbon; Receptors, Chemokine; Receptors, Formyl Peptide; Receptors, Lipoxin; Recovery of Function; Recurrence; Reference Standards; Reference Values; Reproducibility of Results; Respiratory Function Tests; Retrospective Studies; Risk; Sensitivity and Specificity; Sewage; Signal Transduction; Sodium Glutamate; Soil; Solanum tuberosum; Solubility; Solutions; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis; Spermatozoa; STAT3 Transcription Factor; Sulfamethoxazole; Tea; Temperature; Thermodynamics; Thrombin; Treatment Outcome; Triazoles; United States; Viscosity; Waste Disposal, Fluid; Wastewater; Water; Water Pollutants, Chemical; Water Purification; White Matter; Wisconsin; X-Ray Diffraction; Zea mays

The constitutional isomers and tautomers of oxadiazolones, as well as their mono- and disulfur analogues, were calculated at the B3LYP/aug-cc-pVDZ level. Four groups of 30 molecules each were considered: oxadiazolone, oxadiazolthione, thiadiazolone, and thiadiazolthione isomers. The compounds were categorized into six groups according to permutations of three heteroatoms in the five-membered ring. Additionally, each of the constitutional isomer was considered to have five tautomers conserving stable five-membered ring: two NH tautomers, two rotameric OH (or SH) forms and one CH. La trombocitosis es un hallazgo casual frecuente en pediatría. En niños, predominan las formas secundarias, siendo las infecciones su causa más prevalente. Se distinguen 4 grados de trombocitosis en función del número de plaquetas; en la forma extrema, se supera el 1.000.000/mm. Endoscopic thrombin injection was similar to glue injection in achieving successful hemostasis of AGVH. However, a higher incidence of complications may be associated with glue injection.

Topics: Acetaminophen; Administration, Oral; Adolescent; Adsorption; Adult; Allyl Compounds; Amylopectin; Amylose; Anaerobiosis; Animals; Anti-Bacterial Agents; Anura; Arginase; Arthritis, Rheumatoid; Asthma; Atmosphere; B-Lymphocytes; Basic Helix-Loop-Helix Transcription Factors; Bioelectric Energy Sources; Biofilms; Biofuels; Biomarkers; Biopolymers; Bioreactors; Brain; Brain Injuries, Traumatic; Breast Neoplasms; Calibration; Carbon Tetrachloride; Caspase 3; Catalysis; Catechin; Cations; Cattle; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Body; Cell Line, Tumor; Cell Plasticity; Chemical and Drug Induced Liver Injury; Chemistry Techniques, Synthetic; China; Chitosan; Chloride Channels; Chromatography, High Pressure Liquid; Chromosome Mapping; Cognition; Cognitive Dysfunction; Cohort Studies; Colitis, Ulcerative; Colloids; Coloring Agents; Congresses as Topic; Correlation of Data; Crystallization; Cyanoacrylates; Cyclohexane Monoterpenes; Cyprinidae; Cytochrome P-450 CYP1A1; Death, Sudden; Dent Disease; Dietary Supplements; Diffusion Magnetic Resonance Imaging; Disease Models, Animal; Disease Progression; Disease Resistance; Disulfides; Drug Monitoring; Drug Stability; Ecotoxicology; Electricity; Electrodes; Endocytosis; Environmental Exposure; Environmental Monitoring; Enzyme Inhibitors; Epithelial-Mesenchymal Transition; Esophageal and Gastric Varices; Esters; Fagopyrum; Female; Ferrosoferric Oxide; Flame Retardants; Flavobacteriaceae; Flow Cytometry; Follow-Up Studies; Formoterol Fumarate; Fusarium; Garlic; Gastrointestinal Hemorrhage; Gene Expression; Genes, Plant; Genetic Markers; Glial Fibrillary Acidic Protein; Gliosis; Global Health; Glutathione Transferase; Glycine max; Gum Arabic; Hemostasis, Endoscopic; Hepatocytes; Hippocampus; Humans; Hydrogen-Ion Concentration; Illinois; Immunoglobulin G; Indoleamine-Pyrrole 2,3,-Dioxygenase; Infant, Newborn; Infant, Small for Gestational Age; Injections, Intraperitoneal; Interleukin-4; Iowa; Iron; Ki-67 Antigen; Kidney; Kinetics; Kynurenine; Lakes; Levofloxacin; Lipid Peroxidation; Lipids; Liver; Liver Cirrhosis, Experimental; Magnetic Fields; Magnetic Iron Oxide Nanoparticles; Male; Manure; Maze Learning; Memory, Short-Term; Metal Nanoparticles; Metals, Heavy; Methane; Mice; Mice, Inbred C57BL; Mice, Knockout; Michigan; Microalgae; Microbial Consortia; Mitochondria; Models, Animal; Models, Chemical; Models, Neurological; Molecular Structure; Molecular Weight; Mutation; Myeloid-Derived Suppressor Cells; NADPH Oxidase 2; Neoplasm Recurrence, Local; Neurites; Neurons; Neuroprotective Agents; NF-kappa B; NIH 3T3 Cells; Nitric Oxide Synthase Type II; Nitrogen; Ohio; Ointments; Ontario; Organelle Biogenesis; Organophosphates; Organophosphorus Compounds; Oxidative Stress; Palladium; Particle Size; Pectins; Phenotype; Phytotherapy; Piperidines; Placenta; Plant Diseases; Plant Extracts; Polymers; Polymorphism, Genetic; Polyphenols; Powders; Pregnancy; Pregnancy Trimester, First; Prospective Studies; Protein Kinase Inhibitors; Protein Structure, Secondary; Proteins; Pyridines; Pyrimidines; Rats, Wistar; Real-Time Polymerase Chain Reaction; Receptors, Aryl Hydrocarbon; Receptors, Chemokine; Receptors, Formyl Peptide; Receptors, Lipoxin; Recovery of Function; Recurrence; Reference Standards; Reference Values; Reproducibility of Results; Respiratory Function Tests; Retrospective Studies; Risk; Sensitivity and Specificity; Sewage; Signal Transduction; Sodium Glutamate; Soil; Solanum tuberosum; Solubility; Solutions; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis; Spermatozoa; STAT3 Transcription Factor; Sulfamethoxazole; Tea; Temperature; Thermodynamics; Thrombin; Treatment Outcome; Triazoles; United States; Viscosity; Waste Disposal, Fluid; Wastewater; Water; Water Pollutants, Chemical; Water Purification; White Matter; Wisconsin; X-Ray Diffraction; Zea mays

The routes by which antibody-based therapeutics reach malignant cells are poorly defined. Tofacitinib, an FDA-approved JAK inhibitor, reduced tumor-associated inflammatory cells and allowed increased delivery of antibody-based agents to malignant cells. Alone, tofacitinib exhibited no antitumor activity, but combinations with immunotoxins or an antibody-drug conjugate resulted in increased antitumor responses. Quantification using flow cytometry revealed that antibody-based agents accumulated in malignant cells at higher percentages following tofacitinib treatment. Profiling of tofacitinib-treated tumor-bearing mice indicated that cytokine transcripts and various proteins involved in chemotaxis were reduced compared with vehicle-treated mice. Histological analysis revealed significant changes to the composition of the tumor microenvironment, with reductions in monocytes, macrophages, and neutrophils. Tumor-associated inflammatory cells contributed to non-target uptake of antibody-based therapeutics, with mice treated with tofacitinib showing decreased accumulation of therapeutics in intratumoral inflammatory cells and increased delivery to malignant cells. The present findings serve as a rationale for conducting trials where short-term treatments with tofacitinib could be administered in combination with antibody-based therapies.

Topics: Animals; Antibodies; Arginase; Breast Neoplasms; Cell Line, Tumor; Cytokines; Disease Models, Animal; Female; Immunoconjugates; Immunotherapy; Immunotoxins; Macrophages; Mice; Mice, Nude; Monocytes; Neoplasms; Neutrophils; Piperidines; Pyrimidines; Pyrroles; RNA, Messenger; Tumor Microenvironment; Xenograft Model Antitumor Assays

The aberrant activation of STAT3 occurs in many human cancers and promotes tumor progression. Phosphorylation of a tyrosine at amino acid Y705 is essential for the function of STAT3. Synthesized carbazole derived with fluorophore compound 12 was discovered to target STAT3 phosphorylation. Compound 12 was found to inhibit STAT3-mediated transcription as well as to reduce IL-6 induced STAT3 phosphorylation in cancer cell lines expressing both elevated and low levels of phospho-STAT3 (Y705). Compound 12 potently induced apoptosis in a broad number of TNBC cancer cell lines in vitro and was effective at inhibiting the in vivo growth of human TNBC xenograft tumors (SUM149) without any observed toxicity. Compound 12 also effectively inhibited the growth of human lung tumor xenografts (A549) harboring aberrantly active STAT3. In vitro and in vivo studies showed that the inhibitory effects of 12 on phospho-STAT3 were through up-regulation of the protein-tyrosine phosphatase PTPN6. Our present studies strongly support the continued preclinical evaluation of compound 12 as a potential chemotherapeutic agent for TNBC and cancers with constitutive STAT3 signaling.

Topics: Animals; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Drug Screening Assays, Antitumor; Enzyme Induction; Female; Heterografts; Humans; Interleukin-6; Lung Neoplasms; Mice, Inbred BALB C; Mice, Nude; Naphthalenesulfonates; Neoplasm Transplantation; Phosphorylation; Protein Tyrosine Phosphatase, Non-Receptor Type 6; STAT3 Transcription Factor; Structure-Activity Relationship; Transcription, Genetic