High Proliferative Activity Research Articles

T Lymphocyte Exhaustion During Human and Experimental Visceral Leishmaniasis.

A key point of immunity against protozoan Leishmania parasites is the development of an optimal T cell response, which includes a low apoptotic rate, high proliferative activity and polyfunctionality. During acute infection, antigen-specific T cells recognize the pathogen resulting in pathogen control but not elimination, promoting the development and the maintenance of a population of circulating effector cells that mount rapid response quickly after re-exposure to the parasite. However, in the case of visceral disease, the functionality of specific T cells is lost during chronic infection, resulting in inferior effector functions, poor response to specific restimulation, and suboptimal homeostatic proliferation, a term referred to as T cell exhaustion. Multiple factors, including parasite load, infection duration and host immunity, affect T lymphocyte exhaustion. These factors contribute to antigen persistence by promoting inhibitory receptor expression and sustained production of soluble mediators, influencing suppressive cell function and the release of endogenous molecules into chronically inflamed tissue. Together, these signals encourage several changes, reprogramming cells into a quiescent state, which reflects disease progression to more severe forms, and development of acquired resistance to conventional drugs to treat the disease. These points are discussed in this review.

A mediator complex subunit 12 gain-of-function mutation induces partial leiomyoma cell properties in human uterine smooth muscle cells

To clarify whether a mediator complex subunit 12 (MED12) gain-of-function mutation induces leiomyoma cell properties in human uterine smooth muscle cells (USMCs). Experimental study. Academic research laboratory. Women undergoing hysterectomy for leiomyoma. CRISPR/Cas9-mediated genome editing to introduce an MED12 gain-of-function mutation (G44D) into human USMCs. Cell proliferation, collagen production, and invivo tumorigenicity of USMCs with vs. without the MED12 mutation. Uterine smooth muscle cells isolated from the uterine myometrium of a 44-year-old patient were subjected to lentiviral vector-mediated gene transduction of the fluorescent protein Venus, followed by long-term passage. Uterine smooth muscle cells with a normal female karyotype, high cell proliferative activity, and Venus expression, but without stem/progenitor cell populations, were obtained and designated as USMC44. Using CRISPR/Cas9-mediated genome editing, mtUSMC44 (MED12, 131G>A, p.G44D) and mock USMC44 without MED12 mutation (wtUSMC44) were established from USMC44. wtUSMC44 and mtUSMC44 showed similar cell proliferation activity, even in the presence of estradiol and progesterone (EP) together with transforming growth factor-beta 3 (TGFB3). In addition, wtUSMC44 and mtUSMC44 generated similar tiny smooth muscle-like tissue constructs when xenotransplanted beneath the kidney capsule in immunodeficient mice treated with EP alone or TGFB3. In contrast, mtUSMC44 produced more collagen type I than wtUSMC invitro, and this production was likely enhanced by EP and TGFB3. The results suggest that the MED12 gain-of-function mutation is involved in collagen production. Although approximately 70% of leiomyomas have MED12 mutations, additional factors and/or events other than MED12 and/or myometrialstem/progenitor cells may be required for fully inducing leiomyoma cell properties, including transformation, in USMCs.

Morphological features of complicated gastroduodenal ulcers

The objective of the study was to evaluate structural changes in the margin of gastroduodenal ulcers complicated by perforation, bleeding or penetration in terms of the features of ulcer healing.Methods and materials. Histological and IHC studies were performed on 25 patients of the main group with perforated gastroduodenal ulcers and 23 patients of the control group with chronic recurrent ulcers complicated by bleeding and penetration. Histological sections were stained with hematoxylin and eosin, and Van Gieson's picrofuchsin. Immunohistochemical reactions were performed with antibodies to Ki-67, CD68, CD138, and CD34.Results. On macroscopic evaluation, a clear even margin of the perforation was noted. Histological examination with the background of acute dyscirculatory changes clearly shows a zone of necrosis and a weakly expressed layer of granulation tissue, which in majority of the cases was practically absent. The margin of a perforated ulcer consists of a minimally presented, clearly delimited zone of tissue detritus and a practically unchanged muscle layer. Plasma cells dominated in the cell infiltrate, and the index of proliferative activity in the epithelium of the ulcer margins was about 45 %, distributed fairly evenly.Conclusions. Perforated ulcers can be considered as a special group of ulcers with the most pronounced changes of infiltration by plasmatic cells and eosinophils, edema and acute dyscirculatory changes, uniform and fairly high proliferative activity of the epithelium. Changes in the margins of the perforated ulcer allow for complete regeneration without excessive scarring with precise suturing of the perforation.

Targeting Angiogenic Factors for the Treatment of Medulloblastoma.

Medulloblastoma (MB) is the most frequent pediatric brain tumor. Despite conventional therapy, MB patients have high mortality and morbidity rates mainly due to the incomplete understanding of the molecular and cellular processes involved in development of this cancer. Similar to other solid tumors, MB demonstrated high endothelial cell proliferation and angiogenic activity, wherein new blood vessels arise from the pre-existing vasculature, a process named angiogenesis. MB angiogenesis is considered a hallmark for MB development, progression, and metastasis emphasizing its potential target for antitumor therapy. However, angiogenesis is tightly regulated by a set of angiogenic factors making it a complex process to be targeted. Although agents targeting these factors and their receptors are early in development, the potential for their targeting may translate into improvement in the clinical care for MB patients. In this review, we focus on the most potent angiogenic factors and their corresponding receptors, highlighting their basic properties and expression in MB. We describe their contribution to MB tumorigenesis and angiogenesis and the potential therapeutic targeting of these factors.

Telomere length was associated with grade and pathological features of meningioma

Telomeres are tandem repeats of the TTAGGG sequence at chromosomal ends and afford protection against chromosomal instability. To investigate the contribution of telomere dysfunction in meningiomas, here we estimate the associations between telomere length, tumor grade, and proliferation index in a series of 14 archived samples, using quantitative-fluorescence in situ hybridization, Ki67 immunostaining, and pathological analysis. The number of mitoses per 10 high-power fields (HPF) and Ki67 index was higher in grade III cases than in grade I or grade II cases. Telomere length was negatively associated with both the number of mitoses/10HPF and Ki67 index. Meningioma cases with atypical mitosis, a morphological marker of chromosomal instability, exhibited shortened telomeres. Among telomere-shortened meningioma cases, 40% were grade I, 20% were grade II, and 100% were grade III. In grade I or II meningiomas, shortened telomeres lacked high proliferation activity and atypical mitosis. In conclusion, telomere shortening might be pivotal in the development of high-grade meningioma. Analysis of telomere length might be a selective marker for meningiomas with high-grade malignant potential.

Effects and molecular mechanism of histone methyltransferase enhancer of zeste homolog 2 on regulating sepsis-induced T cell dysfunction

To investigate the effect and mechanism of histone methyltransferase enhancer of zeste homolog 2 (EZH2) on sepsis-induced T cell dysfunction. Twenty-four male C57BL/6 mice were divided into three groups randomly: sham operated group, sepsis model group [cecum ligation and puncture (CLP)+dimethyl sulfoxide (DMSO) group] and EZH2 selective inhibitor treated group (CLP+GSK126 group), with 8 mice in each group. Sepsis murine model was reproduced by CLP. CLP+DMSO group and CLP+GSK126 group were treated with DMSO or GSK126 (10 mg/kg) respectively right after surgery through intraperitoneal injection. The mice were sacrificed 24 hours after operation, and the mesenteric lymph nodes were collected. The expression of EZH2, apoptosis rates, cell proliferation marker ki-67 antigen positive T lymphocytes (ki-67+ cell), interferon-γ positive T lymphocytes (IFN-γ + cell), programmed death receptor-1 positive T lymphocytes (PD-1+ cell) and programmed death-ligand 1 positive T lymphocytes (PD-L1+ cell) were determined by flow cytometry. Compared with sham operated group, the expression of EZH2 in T lymphocytes was up-regulated on mesenteric lymph nodes of CLP+DMSO group. Compared with CLP+DMSO group, the ratio of CD3+ T lymphocytes in CLP+GSK126 group was up-regulated (0.70±0.02 vs. 0.50±0.07, P < 0.01), indicating that the EZH2 inhibitor could increase the number of T lymphocytes in lymph nodes of septic mice; the ratio of ki-67+ cells in CD4+ and CD8+ T lymphocytes in CLP+GSK126 group was increased (CD4+: 0.74±0.05 vs. 0.63±0.04, CD8+: 0.82±0.06 vs. 0.70±0.04, both P < 0.05), indicating that the EZH2 inhibitor could increase the ratio of T lymphocytes with high proliferative activity in lymph nodes of septic mice. However, no significant difference was found on both CD4+ and CD8+ T lymphocytes apoptosis rates in the mesenteric lymph nodes of mice between CLP+GSK126 group and CLP+DMSO group [CD4+: (21.53±2.87)% vs. (20.48±3.21)%, CD8+: (8.34±1.02)% vs. (7.71±1.38)%, both P > 0.05], indicating that no extra T lymphocytes apoptosis was induced by EZH2 inhibitor. Compared with CLP+DMSO group, the ratios of IFN-γ + CD4+ and IFN-γ + CD8+ T lymphocytes were increased in CLP+GSK126 group (IFN-γ +CD4+: 0.31±0.11 vs. 0.14±0.06, IFN-γ +CD8+: 0.30±0.10 vs. 0.13±0.06, both P < 0.05), suggesting that secretion of IFN-γ in lymph nodes by sepsis T lymphocytes was augmented after EZH2 inhibitor administration. Furthermore, compared with CLP+DMSO group, the ratio of PD-1+ cell in CD8+ T lymphocyte was down-regulated in CLP+GSK126 group (0.092±0.006 vs. 0.135±0.004, P < 0.01), suggesting that EZH2 inhibitor restrained the PD-1 expression on sepsis lymphoid node CD8+ T lymphocytes, however, it had no significant effect on PD-L1+ cells. EZH2, regulates sepsis-induced T lymphocyte dysfunction, possibly through modulating the expression of PD-1.

C-Met specific CAR-T cells as a targeted therapy for non-small cell lung cancer cell A549

ABSTRACT Non-small cell lung cancer (NSCLC) is considered to be one of the most prevalent and fatal malignancies, with a poor survival rate. Chimeric antigen receptor T cell (CAR-T) cell therapy is one of the most exciting directions in the field of Cellular immunotherapy. Therefore, CAR-T cells that target c-Met have been developed for use in NSCLC therapy and might be a potential therapeutic strategy. The anti c-Met ScFv structure was fused with the transmembrane and intracellular domains. Using a lentiviral vector to load the c-Met CAR gene, then transfected the c-Met CAR lentiviral into human T cells to obtain the second generation c-Met CAR-T expressing CARs stably. In vitro co-culture, experiments revealed that CAR-T cells have high proliferative activity and the potential to secrete cytokines (IL-2, TNF-α, and IFN-γ). c-Met CAR-T cells showed special cellular cytotoxicity in LDH release assay. A subcutaneous tumor model in nude mice was used to test the anticancer effectiveness of c-Met CAR-T cells in vivo. For c-Met positive NSCLC tissue, according to tumor volume, weight, fluorescence intensity, and immunohistochemical detection, c-Met CAR-T cells had stronger tumor growth suppression compared to untransduced T cells. HE staining revealed that c-Met CAR-T cells did not produced side effects in nude mice. Taken together, we provided useful method to generate c-Met CAR- T cells, which exhibit enhanced cytotoxicity against NSCLC cells in vitro and in vivo. Thus, providing a new therapeutic avenue for treating NSCLC clinically. Highlights (1) c-Met CAR-T capable of stably expressing c-Met CARs were constructed. (2) c-Met CAR-T have strong anti-tumor ability and proliferation ability in vitro. (3) c-Met CAR-T can effectively inhibit the growth of A549 cells subcutaneous xenografts.

Silk fibroin/gelatin/calcium alginate composite materials: Preparation, pore characteristics, comprehensive hemostasis in vitro

Hemostasis is achieved through the comprehensive effect of multiple pathways. A composite porous material was designed consisting of silk fibroin (SF), gelatin (GA) and calcium alginate (CA), integrating the good biocompatibility of SF, swelling property of GA and hemostatic factor Ca2+ of CA. Water absorption, platelet adhesion, fibrinogen adsorption, blood coagulation activity, and cytotoxicity were investigated. Pore size in SF/GA porous materials increased with increasing content of GA in SF but decreased significantly in SF/CA porous materials after incorporating CA in SF. Based on the water binding capacity of materials and capillary effect of pores, the binary composites SF/GA1:1 and SF/CA3:1 displayed the best water absorption. Although GA and CA were more favorable for fibrinogen adsorption, SF/GA1:1 and SF/CA1:1 exhibited greater numbers of adhered platelets, shorter clotting times, and greater whole blood coagulation ability. Human skin fibroblasts spread well on the pure SF and GA and all the composites of SF/GA and SF/CA, and they showed high proliferative activity. Pure CA inhibited cell proliferation. For ternary composite materials, the comprehensive hemostatic ability of SF/GA/CA1:1:1 was greater than that of SF/GA/CA1:1:3.

Significance of Ki67 expression in endometriosis for infertility

ObjectiveThe aim of the study was to show the significance of Ki67 expression in endometriosis for infertility. Study designIt was a retrospective analysis. 670 cases were analyzed. In 484 cases, immunohistochemical proliferation analysis was performed to determine the expression of Ki67.The indicated percentages of Ki67 expression were divided into three groups. An expression below 10% is considered low, 10–30% intermediate, and over 30% is considered high. ResultsThere was a significant correlation between Ki67 expression and postoperative pregnancy onset: 66,7% of patients with high proliferation activity became pregnant within one year postoperatively, whereas the 38,7% of patients with moderate and only 17,3% of patients with low Ki67 expression became pregnant. ConclusionIn this work, high Ki67 expression was more frequent than low Ki67 expression in women with infertility than in patients without infertility. These results contribute to the importance of endometrial resection in the context of infertility treatment.

Single-cell transcriptomics analysis reveals intratumoral heterogeneity and identifies a gene signature associated with prognosis of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) tumors exhibit high heterogeneity. However, current understanding of tumor cell heterogeneity of HCC and the association with prognosis remains very limited. In the present study, we collected and examined tumor tissue from one HCC patient by single-cell RNA sequencing (scRNA-seq). We identified 5753 cells and 16 clusters including hepatocytes/cancer cells, T cells, macrophages, endothelial cells, fibroblasts, NK cells, neutrophils, and B cells. In six tumor cell subclusters, we identified a cluster of proliferative tumor cells associated with poor prognosis. We downloaded scRNA-seq data of GSE125449 from the NCBI-GEO as validation dataset, and found that a cluster of hepatocytes exhibited high proliferation activity in HCC. Furthermore, we identified a gene signature related to the proliferation of HCC cells. This gene signature is efficient to classify HCC patients into two groups with distinct prognosis in both TCGA and ICGC database cohorts. Our results reveal the intratumoral heterogeneity of HCC at single cell level and identify a gene signature associated with HCC prognosis.

Establishment and characterisation of cell lines and xenograft mouse models of canine systemic histiocytosis and disseminated histiocytic sarcoma.

Canine histiocytic proliferative disorders include reactive diseases (histiocytosis) and neoplastic diseases (histiocytic sarcoma [HS]), however discrimination is challenging due to their overlapping pathological features. In the present study, novel cell lines and xenograft mouse models of systemic histiocytosis (SyH) and disseminated HS were established, and examined together with cell lines previously established from localized HS and Langerhans cell histiocytosis (LCH). The chromosomal numbers of the SyH and HS cell lines were abnormal, and their population doubling time and morphological features were comparable. Immunophenotypically, SyH and HS cells were CD204+/E-cadherin+ in vitro and in vivo, like their original tissues. Western blot analysis for E-cadherin revealed an immunopositive band of full-length E-cadherin (120 kDa) in cultured cells of localized HS and LCH but not in disseminated HS and SyH; expression level was weaker in localized HS than in LCH. An immunopositive band of fragmented E-cadherin (45 kDa) was detected in cell lines of disseminated HS and SyH. These results suggest that cultured SyH cells have features that are similar to disseminated HS, including chromosomal aberration, high proliferation activity, weak cell adhesion, and expression of fragmented E-cadherin. Fragmentation of the E-cadherin cell adhesion molecule may be associated with the loss of cell adhesion and increased abilities of invasion and migration of neoplastic cells. The established cell lines and xenograft mouse models will aid in understanding the pathogenesis and developing novel treatments of canine histiocytic proliferative disorders.

Diagnostic Interval in Extranodal Non-Hodgkin Head and Neck Lymphomas.

The aim of this study is to measure the diagnostic interval (DI) of primary extranodal non-Hodgkin lymphomas (PE-NHL) affecting the head and neck and to discover any associated factors. With this aim, we performed a retrospective observational study in northwestern Spain on patients diagnosed between 1 January 2005 and 1 January 2016. A search was made across the electronic health records of the public health system of this region (SERGAS). DI was used as the dependent variable, and different clinicopathological data of the corresponding patients and tumors were analyzed as exposure variables. PE-NHLs were mostly located in Waldeyer’s ring, and they presented a B phenotype and had a median DI of 65 days. Shorter diagnostic intervals were observed in (1) PE-NHL patients who had comorbidities (p = 0.02), (2) PE-NHL that caused symptoms of dysphagia (p = 0.04), (3) tumors with the highest proliferative activity (Ki67 > 80%) (p = 0.04), and (4) tumors diagnosed in the advanced stages of the disease (p = 0.004). Univariate analysis revealed a significant association between dysphagia and a shorter DI. We conclude that raising awareness about these neoplasms and warning about the presenting symptoms can contribute to earlier diagnoses of these tumors and to better outcomes.

Fatty acid synthetase expression in triple-negative breast cancer.

BackgroundTriple-negative breast cancer (TNBC) has a relatively poor prognosis. Research has identified potential metabolic targets, including fatty acid metabolism, in TNBC. The absence of effective target therapies for TNBC led to exploration of the role of fatty acid synthetase (FASN) as a potential target for TNBC therapy. Here, we analyzed the expression of FASN, a representative lipid metabolism–related protein, and investigated the association between FASN expression and Ki-67 and the programmed death ligand 1 (PD-L1) biomarkers in TNBC.MethodsImmunohistochemical expression of FASN was analyzed in 166 patients with TNBC. For analytical purposes, patients with 0–1+ FASN staining were grouped as low-grade FASN and patients with 2–3+ FASN staining as high-grade FASN.ResultsFASN expression was observed in 47.1% of TNBC patients. Low and high expression of FASN was identified in 75.9% and 24.1%, respectively, and no statistically significant difference was found in T category, N category, American Joint Committee on Cancer stage, or recurrence rate between the low and high-FASN expression groups. Ki-67 proliferation level was significantly different between the low and high-FASN expression groups. FASN expression was significantly related to Ki-67 as the level increased. There was no significant difference in PD-L1 positivity between the low- and high-FASN expression groups.ConclusionsWe identified FASN expression in 166 TNBC patients. The Ki-67 proliferation index was positively correlated with FASN level, indicating higher proliferation activity as FASN increases. However, there was no statistical association with PD-L1 SP142, the currently FDA-approved assay, or FASN expression level.

Successful treatment of synchronous hairy cell leukaemia and diffuse large B cell lymphoma in a patient with severe hypercalcemia and extensive osteolytic lesions

Introduction. Although secondary malignancies usually occur at different times after hairy cell leukemia (HCL) treatment, the occurrence of HCL and other malignancies at the same time is very rare. Synchronous HCL and diffuse large B-cell lymphoma (DLBCL) have not been described so far. Case report. The report presents a 62-year-old female patient with intense constitutional symptoms, hypercalcemia, pancytopenia, and osteolytic destruction of the left shoulder joint. Immunohistochemical analysis of the bone marrow revealed the presence of two cell populations: a population of HCL cells and a population of DLBCL cells with the expression of CMYC and BCL-2 proteins ("double expressor" DLBCL) and high proliferative activity (Ki-67+cells &gt; 90%). Fluorescence in situ hybridization (FISH) analysis showed amplification of the BCL-2 gene. In addition, BRAF gene V600E mutation was detected. After intensive treatment with immunochemotherapy, radiotherapy, and bisphosphonates, the patient achieved complete remission, lasting for more than two years. Conclusion. As the association of HCL and lymphoma is very rare, diagnosis of synchronous occurrence of two lymphoproliferative diseases is a diagnostic and therapeutic challenge. It remains unclear whether DLBC and HCL originated from two different malignant clones or DLBCL developed by the transformation of HCL as the result of clonal evolution of the B-cell clone.

Associations Between Dynamic Contrast Enhanced Magnetic Resonance Imaging and Clinically Relevant Histopathological Features in Breast Cancer: A Multicenter Analysis.

To provide data regarding relationships between quantitative dynamic contrast enhanced magnetic resonance imaging (DCE MRI) and prognostic factors in breast cancer (BC). Data from 4 Centers (200 female patients, mean age, 51.2±11.5 years) were acquired. The following data were collected: histopathological diagnosis, tumor grade, stage, hormone receptor status, KI 67, and DCE MRI values including Ktrans (volume transfer constant), Ve (volume of the extravascular extracellular leakage space (EES) and Kep (diffusion of contrast medium from the EES back to the plasma). DCE MRI values between different groups were compared using the Mann-Whitney U-test and by the Kruskal-Wallis H test. The association between DCE MRI and Ki 67 values was calculated by the Spearman's rank correlation coefficient. DCE MRI values of different tumor subtypes overlapped significantly. There were no statistically significant differences of DCE MRI values between different tumor grades. All DCE MRI parameters correlated with KI-67: Ktrans, r=0.44, p=0.0001; Ve, r=0.34, p=0.0001; Kep, r=0.28, p=0.002. ROC analysis identified a Ktrans threshold of 0.3 min-1 for discrimination of tumors with low KI-67 expression (<25%) and high KI-67 expression (≥25%): sensitivity, 75.5%, specificity, 73.0%, accuracy, 74.0%, AUC, 0.78. DCE MRI values overlapped between tumors with different T and N stages. Ktrans, Kep, and Ve cannot be used as reliable a surrogate marker for hormone receptor status, tumor stage and grade in BC. Ktrans may discriminate lesions with high and lower proliferation activity.

Clinicopathological Analysis of Non-B Non-C Hepatocellular Carcinoma Focusing on Cellular Proliferation.

Non-B non-C hepatocellular carcinomas (NBNC-HCCs) are larger than hepatitis virus-related HCCs. We conducted a clinicopathological study of patients who underwent curative NBNC-HCC resection, including proliferative activity assessments, such as nuclear grade and Ki-67 labelling index (LI). Histopathological findings of 197 patients were examined, including 56 NBNC-HCCs, 45 hepatitis B virus (HBV)-related HCCs (HBV-HCC), and 96 hepatitis C virus (HCV)-related HCCs (HCV-HCC). NBNC-HCCs were significantly larger than HCV-HCCs, but not significantly different from HBV-HCCs. Mitotic counts, nuclear grade, and Ki-67 LI of NBNC-HCCs were not significantly different from those of HCV-HCCs, but were significantly lower than those of HBV-HCCs. Recurrence-free survival was significantly better in the NBNC-HCC group than in the HBV-HCC group in cases with mild liver fibrosis. NBNC-HCCs were significantly larger in diameter, but their nuclear grade or Ki-67 LI were not significantly different from those of other HCCs, suggesting that they do not have a higher proliferative activity.

A study of 399 cardiac tumors: Characteristics of echocardiography and pathological features.

This study aimed to summarize the transthoracic echocardiography (TTE) characteristics of cardiac tumors with different pathologies. The data of 399 patients with cardiac tumors confirmed by pathology, who had undergone surgical resection were consecutively collected in our hospital between January 1, 2011 and December 31, 2019. The TTE characteristics were summarized and compared with the pathology. Mean patient age was 49.8±15.7 years (22 children and 377 adults), and 62.2% were female. Of the tumors, 90.5% (361) were primary and 9.5% (38) were secondary. Further, 88.7% (354) were benign and 11.3% (45) were malignant. Of the primary tumors (96.1% benign and 3.9% malignant), 84.2% were myxomas, followed by 3.5% lipomas and 1.5% fibromas in adults, while in children, 31.8% were rhabdomyomas and 22.7% were fibromas. The most common type of secondary cardiac tumor was malignant liver carcinoma metastasis (39.5%) and benign intravenous leiomyomatosis with cardiac extension from the uterus (18.4%). TTE features of myxoma showed four variation types among 8.9% of myxomas: liquefaction (anechoic region mostly), calcification (hyperechoic range with a shadow), multiple nodules, and high proliferative activity (a large irregular mass with a wide base and a high Ki67 index). The TTE characteristics of some common benign non-myxoma tumors had specific findings. The TTE features of malignant tumors mostly showed hypoechogenicity, an unclear boundary, a wide basement, and multi-chambers or tissue invasion. Most cardiac tumors have typical ultrasonic manifestations. Preoperative echocardiography could roughly judge cardiac tumor type and may be helpful for guiding clinical treatment decisions.

Placental markers of miscarriage

Successful implantation involves a high degree of development of spiral arteries, combined with high proliferative activity, which ensures the formation of a healthy placenta, full uterine-placental circulation, and the birth of a healthy child. The placenta is the unique organ of the biological monitoring, the mirror of pregnancy. Identification of placental markers of miscarriage is a promising direction for preventing reproductive losses. The aim of the work is to identify the markers of miscarriage and premature labor in the structures of the chorion and placenta. Materials and methods. The main group included tissue samples of the 22 chorions and 64 placentas after termination of current pregnancy from women with a history of reproductive losses. The control group included tissue samples of the 20 chorions after artificial abortion and 20 placentas after physiological pregnancy and birth. The placenta was examined according to the protocol (form No. 013-1/0). The expressions of VEGF, CD31/PECAM1, CD105/Endoglin/TGFβ 1/3 Receptor, Bcl-2α Ab-1, TNF-α, CD45/T200/LCA, CD56/NCAM1 were studied in the structures of chorion and placenta by immunohistochemistry. Results. Based on histological and immuno-histochemical study of chorion and placenta samples in women with reproductive history and termination of the current pregnancy, it was established that embryo-endometrial dysfunction is the cause of miscarriage in the first trimester, and inflammation is the precondition of preterm birth; markers of miscarriage and premature labor in the structures of the chorion and placenta have been identified. Conclusions. The markers of miscarriage are pathomorphological changes in endometrium and chorion combined with high expression of TNF-α and NK-CD56, low expression of CD31/PECAM1, negative expression of VEGF to indicate a violation of cytotrophoblast invasions. The markers of inflammation and premature labor are structural and functional changes of placenta in combination with moderate expression of TNF-α in syncytium, high expression of NK-CD56 in villous stroma, high expression of CD45/T200/LCA in the decidual membrane.

Extrapulmonary small cell carcinoma. Literature review

The review shows the features of rare tumors extrapulmonary small cell carcinomas (EPSCC). The possible approaches for the treatment of this unfavorable group of tumors are discussed. EPSCC can occur in every organ. The clinical course and morphology of EPSCC are similar to small lung cell carcinoma (SCLC). EPSCC belongs to the group of low-grade neuroendocrine tumors with high proliferative activity. There are a small number of publications in the literature concerning EPSCC. Basically, these publications concerning the various clinical cases with comments. Most often, EPSCC occurs in the female genital tract, gastrointestinal tract, genitourinary SCC and known cases of SCC of the head and neck. The cases concerning SCC in other organs are also described. For the treatment of EPSCC are usually applied guidelines developed for SCLC, and several publications on the use of immunotherapy in the treatment of EPSCC have already appeared. The analysis of the available literature let us suggest EPSCC is a big problem that requires a more in-depth study and consensus guidelines adoption for the management of these patients.

Immunophenotyping of intraepithelial lymphocytes in canine chronic enteropathy and intestinal T-cell lymphoma using endoscopic samples.

Human enteropathy-associated T-cell lymphoma (EATL) is considered to be derived from intraepithelial lymphocytes (IELs); however, the origin of canine intestinal T-cell lymphoma (ITCL) remains unclear. Histological, immunohistochemical, and clonality examinations were performed using endoscopically collected canine duodenum samples of mucosal lesions of chronic enteropathy (CE; 73 cases) and ITCL without transmural neoplastic mass lesions (64 cases). Histopathological examinations revealed the intraepithelial accumulation of lymphocytes (called "intraepithelial lymphocytosis") in 54/73 CE cases (74%) and the epitheliotropism of neoplastic lymphocytes in 63/64 ITCL cases (98%). Immunohistochemically, IELs in CE with intraepithelial lymphocytosis (IEL+CE) were diffusely immunopositive for CD3, with scattered immunopositivity for CD5, CD8, CD20, and granzyme B (GRB). The percentage of CD8+ in CD3+ IELs was significantly lower in IEL+CE than in CE without intraepithelial lymphocytosis (IEL-CE). Double-labeling immunohistochemistry revealed a high percentage of GRB expression in CD8- IEL among IEL+CE. Among 64 ITCL cases, CD3 was immunopositive in 64 (100%), CD5 in 22 (34%), CD8 in 8 (13%), CD20 in 12 (19%), CD30 in 13 (20%), and GRB in 49 (77%). In CD3+ cells, Ki67 immunopositivity was highest in ITCL, intermediate in IEL+CE, and lower in IEL-CE. A clonal TCR gene rearrangement was detected in 1/19 IEL-CE cases (5%), 15/54 IEL+CE (28%), and 38/58 ITCL (66%). These results indicate that the immunophenotype of canine ITCL (CD8-GRB+) is similar to that of the increased IELs in CE. The high proliferative activity and clonality of T cells in IEL+CE suggest that canine ITCL originates from these IELs, similar to human EATL.