muramidase and Carcinoma--Squamous-Cell

Dental care costs in the United States exceed $100 billion annually. Personalized medicine efforts in dentistry are driven by potentially compelling clinical utility and cost-effectiveness prospects in the major diseases of periodontitis, caries, and oral cancers. This review discusses progress and challenges identifying genetic markers and showing clinical utility in dentistry. Genome-wide association studies (GWAS) of chronic periodontitis (CP) identified no significant variants, but CDKN2BAS variants on chromosome 9 were significantly associated with aggressive periodontitis. Stratifying patients by interleukin (IL)-1 gene variants, smoking and diabetes differentiated CP prevention outcomes. Dental caries' GWAS identified significant signals in LYZL2, AJAp1, and KPNA4; and efforts are ongoing to identify genetic factors for multiple caries phenotypes. Trials of molecularly targeted therapies are in progress for oral, head, and neck squamous cell carcinomas (OHNSCC) and results have been promising but limited in their effectiveness. Current opportunities and challenges for molecular targeting for OHNSCC are discussed.

Topics: alpha Karyopherins; Carcinoma, Squamous Cell; Cell Adhesion Molecules; Dental Caries; Genetic Markers; Genetic Variation; Genome-Wide Association Study; Head and Neck Neoplasms; Humans; Interleukin-1; Mouth Neoplasms; Muramidase; Periodontitis; Precision Medicine; RNA, Long Noncoding

10 pleomorphic adenomas of the human parotid gland were transplanted on several groups of nude mice. For comparative reasons, 10 other pleomorphic adenomas, a neurinoma and a chordoma and transplants of squamous cell carcinomas and of normal salivary gland tissue were also analysed. In the primary tumours and in the transplants, the presence of keratin, carcinoembryonic antigen, tissue polypeptide antigen, lactoferrin, lysozyme, immunoglobulins, secretory component, amylase, fibronectin and of several lectin-receptors (PNA, WGA, HPA, Ulex europaeus) was sought. The immunohistological observations show that many of the features of a pleomorphic adenoma are constant under the conditions of transplantation. In the transplanted tumour, the same heterogeneity as in the primary tumours can be observed. Autoradiographic studies show little labelling with 3-H thymidine, which is in good accordance with the biological behaviour of the tumour. The distribution of fibronectin shows an interesting association with myoepithelial-like cells. Our results support the hypothesis that the histogenetic origin of the pleomorphic adenoma is a cell pool of the terminal ductal segment. A differentiation towards ductal cells (with production of secretory substances) and towards myoepithelial cells (associated with large amounts of basal membrane like substances) is observed.

Topics: Adenoma, Pleomorphic; Animals; Autoradiography; Carcinoembryonic Antigen; Carcinoma, Squamous Cell; Cell Division; Fibronectins; Histocytochemistry; Humans; Immunochemistry; Immunoglobulin A; Immunoglobulin A, Secretory; Immunoglobulin G; Immunoglobulin M; Keratins; Lactoferrin; Lectins; Mice; Mice, Nude; Muramidase; Neoplasm Transplantation; Salivary Gland Neoplasms; Tetradecanoylphorbol Acetate; Transplantation, Heterologous

CD68 and lysozyme expression in cannibalistic tumor cells of oral squamous cell carcinoma (OSCC) is well established. Transformation of cancer cells into cannibalistic cells is a process involving sequential events. Initial event could be genetic expression of proteins that is required for execution of cannibalism. Hence, it is quite possible that some non-cannibalistic tumor cells can also show expression of cannibalistic markers (CD68 and lysozyme).. Formalin-fixed tissues of 30 OSCC cases with cellular cannibalism (CC) (positive control), 30 OSCC cases without CC, and 17 normal oral epithelium specimens (negative control) were subjected to immunohistochemical analysis for CD68 and lysozyme expression.. OSCC with CC showed CD68 and lysozyme expression in 30 (100%) cases each {CD68: [weak: 21 (70%), strong: 9 (30%)]; lysozyme: [weak: 24 (80%), strong: 6 (20%)]}. In OSCCs without CC, CD68-positive tumor cells were present in 13 (43.33%) cases [weak: 10 (33.33%); strong: 3 (10%)] and lysozyme expression was present in 13 (43.33%) cases [weak: 12 (40%); strong: 1 (3.33%)]. Control group showed negative expression for CD68 and lysozyme in the oral epithelium. The CD68 and lysozyme expression in OSCCs without CC, OSCCs with CC, and control group showed statistically significant differences (P < 0.001). Significant correlation was also observed between CD68 and lysozyme expression and different grades of OSCC.. CD68 and lysozyme expression in non-cannibalistic tumor cells of OSCC can be related to CC.

Topics: Antigens, CD; Antigens, Differentiation, Myelomonocytic; Biomarkers, Tumor; Carcinoma, Squamous Cell; Cytophagocytosis; Female; Humans; Male; Middle Aged; Mouth Neoplasms; Muramidase; Phagocytosis

Cannibalism was recognized as a phenomenon seen mainly with the tumor cells ingesting other tumor cells. Recent reports have shown tumor cell engulfing other cells (xeno-cannibalism) as well, such as neutrophils, lymphocytes and erythrocytes. But no such finding has been reported in oral squamous cell carcinoma (OSCC) in the literature till date.. Retrospective histopathological analysis of OSCC for identification of neutrophil-tumor cell cannibalism (NTCC) and its correlation with clinico-pathological parameters.. The hematoxylin and eosin stained tissue sections of 500 OSCC cases were thoroughly screened at high power magnification (400X) for NTCC. Cases showing only frank NTCC were selected. Cases were subjected to immunohistochemical analysis using CD68 and lysozyme.. Seven (1.4%) cases of OSCC which showed classical features of extreme NTCC on histopathological examination. Seventeen Cases (3.4%) showing occasional isolated NTCC were excluded. All the cases were poorly differentiated and showed cervical lymph node metastasis. Immunohistochemical analysis showed mild (+) to moderate (++) positivity in tumor cells for CD68 and lysozyme markers.. NTCC in OSCC can predict the biological behavior and could serve as a useful prognostic marker in future. Tumor cell displaying macrophage phenotype and cell digestion could be mediated through lysosomal enzyme activity.

Topics: Adult; Aged; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Biomarkers, Tumor; Carcinoma, Squamous Cell; Cytophagocytosis; Female; Humans; Immunohistochemistry; Lymphatic Metastasis; Macrophages; Male; Middle Aged; Mouth Neoplasms; Muramidase; Neoplasm Recurrence, Local; Neutrophils; Retrospective Studies; Survival Rate

In connection with quantitative sialochemical investigations in mixed saliva from patients with oral squamous cell carcinoma (OPC), the enzymes phosphohexoseisomerase (PHI) and lysozyme (Ly) were investigated. The glycolytic enzyme PHI recently became interesting as a tumor marker. Lysozyme represents the main enzyme of the nonspecific salivary immune defense.. The enzyme concentrations were specified in 25 men with OPC and in a control group of 20 healthy men of comparable age.. In the mixed saliva of the OPC patients, the PHI concentration was significantly diminished according to the Mann-Whitney-Wilcoxon test compared to the control group (p = 0.022). The lysozyme concentration, however, significantly increased (p = 0.011). These results prove serious sialochemical alterations in mixed saliva of OPC patients. They extend our former studies on kallikrein in glandular mixed saliva, but at present only have a descriptive character. Further pathobiochemical investigations on this subject should be carried out.

Topics: Adult; Aged; Biomarkers, Tumor; Carcinoma, Squamous Cell; Glucose-6-Phosphate Isomerase; Humans; Lymphatic Metastasis; Male; Middle Aged; Mouth Neoplasms; Muramidase; Predictive Value of Tests; Reference Values; Saliva

The purpose of this study was to discuss the anti-tumor function of lysozyme (LZM) to laryngocarcinoma. The LZM distribution of regional lymph nodes incised from laryngocarcinoma patients in paraffin sections was observed by immunohistochemical technique. By the cell culture technique, autologus laryngocarcinoma cells were used as target cells to evaluate the tumoridical activity of MØ which were isolated from the regional lymph nodes of laryngocarcinoma patients. At the same time, ConA was added as control group. The supernatant of cell culture was collected after 24 hours to detect LZM content. The results indicated that the number of LPM in non-metastatic lymph nodes was significantly more than in metastatic lymph nodes (P < 0.01). The MØ isolated from patients' regional lymph nodes released LZM content and it's tumoridical activity to autologus tumor cells were significantly increased after adding ConA (P < 0.01). The LZM releasing content and tumoridical activity of MØ in non-metastatic lymph nodes were much more than metastatic lymph nodes (P < 0.05). The LZM content and tumoridical activity of MØ were analyzed with linearity relapsing statistics, it was positive linearity relation (r = 0.94, P < 0.01). All above suggests that the LZM of laryngocarcinoma patients is closely related to the anti-tumor function, it improves the tumoridical activity of MØ to autologus laryngocarcinoma cells and accelerates the death of laryngocarcinoma cells.

Topics: Adult; Aged; Carcinoma, Squamous Cell; Female; Humans; Laryngeal Neoplasms; Lymph Nodes; Macrophages; Male; Middle Aged; Muramidase; Neck; Tumor Cells, Cultured

This is a report on the clinical, anatomical and immunohistochemical study of thirty patients presenting dermatofibrosarcoma protuberans. Its incidence (4.8 percent), covering a 15-year period in a specialized oncological unit, wider age range and high rate of relapses (66.6 percent) are established as the result of clinical and anatomical revision. The latter findings necessitate radical removal of the neoplasm as early at its primary resection. The practical implications of the so-called "spoke-like" structures, pathognomonic for histological identification of the tumor, are discussed. The immunohistochemical study for S100 [correction of C100] protein and lysozyme is negative, while alpha 1-antitrypsin reaction is positive in single rounded histiocyte-like cells which is by no means a conclusive evidence of the phenotype characteristics of the cell population in dermatofibrosarcoma protuberans.

Topics: Adolescent; Adult; Aged; alpha 1-Antitrypsin; Carcinoma, Squamous Cell; Dermatofibrosarcoma; Histiocytoma, Benign Fibrous; Humans; Immunohistochemistry; Middle Aged; Muramidase; Neoplasm Recurrence, Local; S100 Proteins; Skin Neoplasms; Soft Tissue Neoplasms

We investigated immunohistochemically the localization of lysozyme and Leu M1 in normal skin, 76 cases of benign sweat gland tumors, 28 cases of malignant sweat gland tumors, 23 cases of extramammary Paget's disease, 7 cases of sebaceous carcinoma, 6 cases of malignant trichilemmoma, 10 cases of squamous cell carcinoma, and 10 cases of basal cell carcinoma and compared the results with those for gross cystic disease fluid protein (GCDFP)-15 to assess the sensitivity and specificity of our assay conditions for apocrine differentiation. Normal apocrine glands were stained with all three antibodies, while eccrine glands were positive only for GCDFP-15, and other portions of normal skin were not stained with any of the antibodies used. In neoplastic tissue thought to be from apocrine tumors, antibodies raised against lysozyme and GCDFP-15 had a greater specificity (100%) for apocrine differentiation, while Leu M1 had a greater sensitivity (88%). Tissues that were stained with two or three of these antibodies appeared to exhibit apocrine differentiation. In the tumors examined, the specificity for apocrine differentiation was 100% and the sensitivity for such differentiation was 92% by these criteria. According to these criteria, some cases of syringocystadenoma papilliferum, primary mucinous carcinoma of the skin, and extramammary Paget's disease with underlying adenocarcinoma showed apocrine differentiation.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Adenocarcinoma, Sebaceous; Adenoma, Sweat Gland; Adolescent; Adult; Aged; Apocrine Glands; Apolipoproteins; Apolipoproteins D; Biomarkers, Tumor; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Carrier Proteins; Cell Differentiation; Eccrine Glands; Female; Glycoproteins; Humans; Immunohistochemistry; Lewis X Antigen; Male; Membrane Transport Proteins; Muramidase; Neoplasm Proteins; Neoplasms, Basal Cell; Paget Disease, Extramammary; Sensitivity and Specificity; Skin; Skin Neoplasms; Sweat Gland Neoplasms

The antitumor effect of bleomycin (BLM) ointment in combination with lysozyme (LY) ointment was investigated. Nine-week-old male and female WHT/Ht mice were implanted with a graft of WHT squamous cell carcinoma into the subcutis of back, and the skin covering the developed solid tumor was resected 7 days after implantation. Thereafter, the mice were administered twice daily for 7 days with each of the following: 220 mg of 0.25% BLM ointment, 2.5% LY ointment, and a 1:1 mixture of 0.5% BLM ointment plus 5% LY ointment. BLM ointment and the combination of BLM ointment and LY ointment were effective with an inhibition rate of 79.3 and 89.7%, respectively. The inhibition rates of these groups showed a statistically significant increase over that of control group. Further, the rate of the combination group displayed a statistically significant increase over that of the BLM ointment group. Formation of crusta on the solid tumor was markedly inhibited in the groups applied LY ointment and the combination of LY ointment and BLM ointment. LY was ineffective against cultured cells of WHT squamous cell carcinoma and did not potentiate the antitumor activity of BLM in combination. These results suggest that potentiation of the antitumor effect of BLM ointment in combination with LY ointment is due to inhibition of crusta formation by LY resulting in an increased permeation of BLM into tumor tissue.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Carcinoma, Squamous Cell; Female; Male; Mice; Muramidase; Neoplasm Transplantation; Ointments

The present study evaluated the degree of renal impairment caused by intra-arterial hypertensive chemotherapy (CDDP, PEP). In 11 cases of advanced cancer of the uterine cervix, serum and urinary levels of alpha 1-microglobulin (alpha 1-m) and beta 2-microglobulin (beta 2-m), and urinary albumin (Alb) and lysozyme (LZM) were determined before the chemotherapy and 1,2 and 3 weeks after the therapy. Results are summarized as follows: 1. After intra-arterial chemotherapy, the histological classification was Grade I in 1 case (9.1%), Grade IIa in 2 cases (18.2%), and Grade IIb in 8 cases (72.7%). 2. Serum alpha 1-m and beta 2-m levels remained within the normal range after chemotherapy. 3. Urinary alpha 1-m, beta 2-m and LZM levels exceeded the normal limit between 1 and 2 weeks after the therapy, but thereafter they returned to normal. 4. Urinary Alb was significantly increased (p less than 0.05) between 1 and 2 weeks after therapy, but thereafter it returned to normal. These results suggested that intra-arterial chemotherapy (CDDP 100mg and PEP 40 mg in a dose) was effective for advanced cancer of the cervix and that renal disorders including tubular and glomerular impairment, which are the adverse effects of the therapy, were mild and reversible.

Topics: Adult; Aged; Albuminuria; Alpha-Globulins; Angiotensin II; Antineoplastic Combined Chemotherapy Protocols; beta 2-Microglobulin; Bleomycin; Blood Pressure; Carcinoma, Squamous Cell; Cisplatin; Female; Humans; Infusions, Intra-Arterial; Kidney; Middle Aged; Muramidase; Peplomycin; Uterine Cervical Neoplasms

The formation of syncytia in cell monolayers infected with a macroplaque strain (MP) of herpes simplex virus was found to be inhibited by hen egg-white lysozyme. Inhibition was roughly proportional to the enzyme concentration. The virus titres in supernatant fluids of lysozyme-treated cultures were also reduced compared with untreated cultures. Control experiments excluded the possibility that lysozyme altered the virus viability and infectivity or impaired cell growth. Since lysozyme is a cationic protein, further experiments were performed in order to discover whether its antisyncytiogenic effect depended on its enzymatic activity or on its positive charge. Inhibition of the MP-induced polycaryocytosis was found to be caused by heat-inactivated lysozyme and three chemically-modified lysozymes with a higher positive charge (one retaining and two lacking enzymatic activity).

Topics: Animals; Carcinoma, Squamous Cell; Cell Fusion; HeLa Cells; Hexosaminidases; Humans; Lysostaphin; Muramidase; Polylysine; Ribonucleases; Simplexvirus; Tumor Cells, Cultured

The numbers of Langerhans cells and lysozyme-positive macrophages were assessed quantitatively in normal ectocervical epithelium, cervical intraepithelial neoplasia (CIN), microinvasive squamous cell carcinoma (MICA), clinical invasive squamous cell carcinoma (CICA), and koilocytotic atypia using the avidin-biotin-peroxidase complex (ABC) method. The distribution of Langerhans cells was different from that of lysozyme-positive macrophages in that the former were intermingled with the cervical lesion, while the latter were present mainly surrounding the cervical lesion and/or on the edge of the cervical lesion. The numbers of Langerhans cells and lysozyme-positive macrophages in CIN were significantly larger than those in normal ectocervical epithelium and significantly smaller than those in invasive squamous cell carcinoma (MICA + CICA). Langerhans cell number significantly increased as the grade of CIN advanced. In contrast, the number of lysozyme-positive macrophages did not differ significantly between progressive grades of CIN. As for koilocytotic atypia, the numbers of Langerhans cells and lysozyme-positive macrophages in koilocytotic atypia were significantly greater than those in normal ectocervical epithelium but did not differ significantly from those in CIN 1 and CIN 2. With respect to stromal lymphoid infiltration, invasive squamous cell carcinoma with moderate or dense stromal lymphoid infiltration showed significantly greater numbers of Langerhans cells and lysozyme-positive macrophages than that with no or scattered stromal lymphoid infiltration, but such a correlation was not found in CIN.

Topics: Carcinoma, Squamous Cell; Epithelium; Female; Histiocytes; Humans; Immunoenzyme Techniques; Langerhans Cells; Muramidase; S100 Proteins; Uterine Cervical Neoplasms

Sections of primary lung carcinomas, lung metastases, mesotheliomas, and lung metastases of some rare mesenchymal tumors were incubated with different cytokeratin (CK), vimentin, desmin, and tissue polypeptide antigen (TPA) antibodies and with antibodies reactive with different hormones (ACTH, PTH, alpha-HCG, Calcitonin CT), CEA, carcinoma-associated antigen (CA1), secretory component (SC), neuron-specific enolase (NSE), alpha-1-antitrypsin (alpha-1-AT), lysozyme (lyso), and S-100 protein (S 100). CK antibodies derived from a 49 kD (reactive with simple epithelia [SE]) and a 67 kD CK polypeptide fraction (reaction with complex epithelia [CE] were useful differentiation markers for the four major groups of lung carcinomas. In one half of small cell carcinomas a positive reaction with NSE antibodies was found. S 100 and SC were good markers for papillary and bronchioloalveolar adenocarcinomas, whereas CEA was less important because of its reactivity with different types of lung carcinomas. To discern clear cell carcinomas of lung and renal origin a positive reaction with vimentin antibodies (some renal but not lung types) and with CA1 (no renal but all lung types) seemed to be useful. All hormone antibodies were of no importance as markers for difficult differential diagnosis, because positive reactivities were found in cases from every major carcinoma group. In addition, a Ca2+-activated adenosine triphosphatase (ATPase) was found in mesotheliomas but not in papillary adenocarcinomas.

Topics: Adenocarcinoma; Carcinoembryonic Antigen; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Cell Differentiation; Desmin; Diagnosis, Differential; Histocytochemistry; Hormones; Humans; Immunologic Techniques; Keratins; Kidney Neoplasms; Lung Neoplasms; Mesothelioma; Muramidase; Neoplasm Metastasis; Peptides; Phosphopyruvate Hydratase; Pleural Neoplasms; S100 Proteins; Secretory Component; Tissue Polypeptide Antigen; Vimentin

In the literature you can find several therapeutic possibilities in the treatment of carcinoma by additive ozone therapy. We investigated the consequences of ozone therapy for the immunological status, lysozyme and vitamin A. 21 women with progressive cervical cancer (Stage III, IV) got besides the conventional irradiation therapy also an additive ozone therapy. After irradiation and ozone therapy a small decrease in IgG, IgA and IgM can be seen. A statistical significance could not be evaluated. There was no difference to the control group in lysozyme and vitamin A.

Topics: Carcinoma, Squamous Cell; Cobalt Radioisotopes; Combined Modality Therapy; Female; Humans; Immunoglobulins; Muramidase; Ozone; Radioisotope Teletherapy; Uterine Cervical Neoplasms; Vitamin A

The heterogeneity of histiocytes in primary lung cancer was investigated by immunohistochemical methods using anti-S100 protein and anti-lysozyme antibodies on paraffin sections and OKT-6 monoclonal antibody on frozen sections. T-zone histiocytes (Langerhans cells and their precursors stained by anti-S100 protein and/or OKT-6 monoclonal antibodies) heavily infiltrated tumor tissues and regional lymph nodes in cases of moderately or well-differentiated adenocarcinoma, especially in areas of papillary growth or bronchiolo-alveolar pattern. These cells were interspersed amongst tumor cells showing dendritic figures and were occasionally present in squamous cell carcinoma. However, they were seldom found in other histological types, particularly in small cell carcinoma and carcinoid tumor. The distribution of these cells was different from that of lysozyme-positive macrophages. In this connection, T-zone histiocytes were thought to have a different immunological function from that of the monocyte-macrophage series against lung cancer. The closely similar reactivity of T-zone histiocytes with anti-S100 protein and OKT-6 monoclonal antibodies indicated that these two markers can be employed for paraffin and frozen sections, respectively.

Topics: Adenocarcinoma; Antibodies, Monoclonal; Carcinoma, Squamous Cell; Histiocytes; Histocytochemistry; Humans; Lung Neoplasms; Macrophages; Muramidase; S100 Proteins; Staining and Labeling

Twelve cases of malignant spindle-cell and sarcomatoid tumours of the skin of debatable nature were studied by immunocytochemical methods, using four antisera which might help contribute to resolution of the problems. The initial diagnosis made on structural grounds was confirmed by immunocytochemistry in six of eight cases in which a specific diagnosis had been made (one melanoma, three squamous carcinomas and two atypical fibroxanthomas). One case, initially regarded as AFX was reclassified as a squamous carcinoma, while a further case of possible AFX could not be confirmed by immunocytochemical study. Of the four cases in which structural examination was inconclusive, two were identified as squamous carcinomas and one as a melanoma by virtue of tumour markers. The fourth case was an intriguing actin-rich tumour of uncertain nature. Immunocytochemistry, despite certain limitations, has a valuable role to play in the analysis of the problematic spindle-cell malignant and pseudomalignant tumours of the skin.

Topics: Actins; Aged; Carcinoma, Squamous Cell; Female; Fibroma; Humans; Immunoenzyme Techniques; Keratins; Male; Melanoma; Middle Aged; Muramidase; S100 Proteins; Skin; Skin Neoplasms

Lactoferrin and lysozyme, parts of the non-specific defense system, were studied in normal and diseased parotid glands, using the immunohistochemical PAP-method. 31 normal and inflamed glands were investigated. The presence of lactoferrin and lysozyme was demonstrated in the acinar cells and some duct cells. The amount of these substances was increased in obstructive parotitis. The 52 carcinomas showed a distinct distribution pattern for lactoferrin (positive cases: adenocarcinomas 5 of 8; cystadenocarcinoma: 3 of 5; adenoid cystic carcinomas 2 of 4; salivary duct carcinomas 2 of 3). Some of the carcinomas in pleomorphic adenomas were positive for lactoferrin. Squamous cell carcinomas and anaplastic carcinomas were constantly negative. All carcinomas were negative for lysozyme. These observations are discussed with respect to their physiological and pathological significance.

Topics: Adenocarcinoma; Adenoma, Pleomorphic; Carcinoma; Carcinoma, Squamous Cell; Cystadenocarcinoma; Humans; Lactoferrin; Lactoglobulins; Muramidase; Parotid Neoplasms; Parotitis

74 patients with untreated cervical cancer (FIGO II and III) were skintested with a battery of recall antigens, and also sensitised and challenged with DNCB. A significant reduction of reaction to Tuberkulin, Varidase and also to DNCB was found in patients with stage III in comparison to healthy females of the same age group. Significant changes in immunoglobulin levels, increase of IgA and decrease of IgG were observed in the cancer patients. Serum lysozyme values were the same as in the control group.

Topics: Carcinoma, Squamous Cell; Dinitrochlorobenzene; Female; Humans; Hypersensitivity, Delayed; Immunity; Immunoglobulin A; Immunoglobulin G; Muramidase; Skin Tests; Uterine Cervical Neoplasms

Topics: Amnion; Animals; Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Line; HeLa Cells; Humans; Laryngeal Neoplasms; Mathematics; Mitosis; Muramidase; Ovalbumin; Placenta