[The role of the main risk factors and endocrine cells of the antrum of the stomach producing motilin in the occurrence of cholelithiasis].

AIM: To establish the role of the main risk factors and endocrine cells of the antrum of the stomach producing motilin (M-cells) in the occurrence of cholelithiasis. MATERIALS AND METHODS: The first group included 122 patients with cholelithiasis. The second group consisted of 30 healthy individuals who underwent medical examination. The groups were matched for gender and age. The work analyzed anamnestic, biochemical and anthropometric data. All patients underwent esophagogastroduodenoscopy with targeted biopsy of the mucous membrane from the antrum. Biopsies were subjected to cytological and immunohistochemical studies in order to verify Helicobacter pylori and estimate the number of M-cells. RESULTS: Patients with cholelithiasis more often belonged to the group of people of mental labor, had low physical activity, were committed to inappropriate nutrition and more often indicated the presence of aggravated heredity for cholelithiasis. Patients with gallstone disease had higher body mass index, waist volume, total cholesterol, low-density lipoprotein cholesterol, triglycerides, glucose, lower high-density lipoprotein cholesterol, H. pylori infection was more often verified and M-cell hypoplasia in the mucous membrane was established. stomach in comparison with the representatives of the second group. CONCLUSION: Our results suggest that certain external factors, nutritional characteristics of the metabolic syndrome components, hypoplasia of M-cells in the gastric mucosa are important factors in the formation of calculi in the gallbladder.

Endocrine cell micronests in an ovarian mucinous borderline tumor: a potential diagnostic pitfall for microinvasion.

The occurrence of endocrine cell micronests in ovarian tumors is rarely reported. To our knowledge, there are only three prior cases reported to date: one occurring in an ovarian mucinous cystadenoma, one in an ovarian mucinous cystadenofibroma, and another in an ovarian mucinous carcinoma with a predominant borderline component. This is a 27-year-old woman that presented with a one-month history of abdominal pain and fullness. Imaging studies revealed a large multiloculated cystic and solid mass measuring 23 cm occupying the majority of the pelvis and abdomen concerning for a primary ovarian malignancy. The patient underwent a right salpingo-oophorectomy with appendectomy. Histologic sections from the ovary showed a multiloculated, cystic and focally solid mass lined by gastrointestinal-type mucinous epithelium with variable degrees of proliferation accounting for greater than 10% of the tumor. In addition to the mucinous epithelial component, there were several foci of bland, monotonous epithelioid cells arranged in solid nests with focal tubular/acinar formation within the fibrous septa and mucinous epithelium. Immunohistochemical studies showed that these cells were positive for cytokeratin, EMA, and synaptophysin, while negative for inhibin. The Ki-67 proliferation index was low (<1%). The presence of endocrine cell nests associated with an ovarian mucinous neoplasm is a rare phenomenon. Whether this represents preservation of endocrine cells in the context of epithelial degeneration or an independent neoplastic component is unclear. Progression related to this endocrine cell proliferation is unlikely and the recognition of this phenomenon holds more diagnostic value than prognostic significance, as it could be confused with microinvasion or sex cord stromal elements.

Renin Cell Baroreceptor, a Nuclear Mechanotransducer Central for Homeostasis.

[Figure: see text].

Stromal Endocrine Cell Micronests Associated With an Ovarian Mucinous Cystadenoma: Endocrine Cell Preservation (Pseudohyperplasia) Potentially Mimicking Stromal Sex Cord Proliferation or Tumor Microinvasion.

Endocrine cell micronests (ECMs) have been described only twice previously in the ovary, both in association with mucinous neoplasms exhibiting intraepithelial endocrine cell hyperplasia. We report a 31-yr-old patient with a mucinous cystadenoma in which ECMs were distributed in the stroma surrounding degenerate glandular elements. Immunohistochemistry demonstrated only sparse endocrine cells within the neoplastic glands. We postulate that the ECMs in this case reflected relative preservation of endocrine elements in the context of epithelial atrophy, a process more commonly encountered in gastrointestinal pathology. Ovarian ECMs should also be distinguished from stromal sex cord proliferations and tumor microinvasion.

Fructose-induced metabolic disturbances in rats and its impact on stomach endocrine cell number and smooth muscle contractility.

Context: Gastric ghrelin-positive endocrine cells (GHR + EC) were most dense in the oxyntic mucosa.Objective: We evaluated ECs and contractile activity in rat stomach with metabolic disorders.Materials and methods: Male Wistar rats were divided into two groups: Control (n = 9) received tap water and Fructose (n = 9) drank 15% fructose solution for 12 weeks. Streptozotocin was applied in a dose of 20 mg/kg b.w. two weeks after the beginning of the experiment on Fructose group. Smooth-muscle strips from the stomach were influenced by Angiotensin II for analysis of parameters of contractions. Stomach samples were elaborated with immunohistochemistry for ghrelin, somatostatin, gastrin antibodies and with double immunofluorescence.Results: In treated animals, GHR + EC were significantly increased in the corpus where somatostatin-positive cells were decreased. Contractile activity was decreased.Conclusions: The increase number of GHR + EC was discussed in the context of Somatostatin and Gastrin-positive ECs variations and correlated with the decrease of smooth muscle contraction.

Single Rectal Neuroendocrine Tumor Associated with Multiple Endocrine Cell Micronests.

Although a few reports of neuroendocrine tumor (NET) in the stomach or appendix with surrounding micronests have been published, cases of rectal NET are rare. We herein report a unique case of a patient with single rectal NET treated endoscopically. A pathological examination revealed multiple endocrine cell micronests (ECMs) in the submucosal layer around the main NET lesion. Neither lymph node metastasis nor distant metastasis in computed tomography was observed six years after the treatment. Because case reports of multiple ECM are very rare, the significance of malignancy is unclear. It therefore appears to be necessary to accumulate similar cases.

Human Pluripotent Stem Cells: A Unique Tool for Toxicity Testing in Pancreatic Progenitor and Endocrine Cells.

Diabetes prevalence is increasing worldwide, and epidemiological studies report an association between diabetes incidence and environmental pollutant exposure. There are >84,000 chemicals in commerce, many of which are released into the environment without a clear understanding of potential adverse health consequences. While in vivo rodent studies remain an important tool for testing chemical toxicity systemically, we urgently need high-throughput screening platforms in biologically relevant models to efficiently prioritize chemicals for in depth toxicity analysis. Given the increasing global burden of obesity and diabetes, identifying chemicals that disrupt metabolism should be a high priority. Pancreatic endocrine cells are key regulators of systemic metabolism, yet often overlooked as a target tissue in toxicology studies. Immortalized ß-cell lines and primary human, porcine, and rodent islets are widely used for studying the endocrine pancreas in vitro, but each have important limitations in terms of scalability, lifespan, and/or biological relevance. Human pluripotent stem cell (hPSC) culture is a powerful tool for in vitro toxicity testing that addresses many of the limitations with other ß-cell models. Current in vitro differentiation protocols can efficiently generate glucose-responsive insulin-secreting ß-like cells that are not fully mature, but still valuable for high-throughput toxicity screening in vitro. Furthermore, hPSCs can be applied as a model of developing pancreatic endocrine cells to screen for chemicals that influence endocrine cell formation during critical windows of differentiation. Given their versatility, we recommend using hPSCs to identify potential ß-cell toxins, which can then be prioritized as chemicals of concern for metabolic disruption.

Clinical Evaluation of Dynamic Monitoring of Neutrophil-to-lymphocyte and Platelet-to-lymphocyte Ratios in Primary Endocrine Therapy for Advanced Breast Cancer.

BACKGROUND/AIM: The utility of peripheral blood neutrophil-to-lymphocyte ratios (NLRs) and platelet-to-lymphocyte ratios (PLRs) as prognostic predictors of surgery and chemotherapy in breast cancer has been reported. In this study, NLRs and PLRs were calculated before treatment and during cancer progression in primary hormone receptor-positive breast cancer (HRBC) patients who chose endocrine therapy (ET) as the primary treatment, and prognostic prediction and factor analysis were performed. PATIENTS AND METHODS: A total of 55 patients diagnosed with stage IIIB, IIIC, or IV HRBC who received ET as the primary treatment were included. RESULTS: Increased NLRs were found to significantly contribute to a shorter overall survival from cancer progression (OS-CP) (p=0.040, log-rank). Increased PLRs were similarly associated with a shorter OS-CP (p=0.036, log-rank). In multivariate analysis, an increased NLR was an independent prognostic factor (p=0.035, hazard ratio(HR)=5.221). CONCLUSION: Changes in NLRs and PLRs become prognostic indicators when the therapeutic effect of ET is limited.

Contribution of the unfolded protein response to breast and prostate tissue homeostasis and its significance to cancer endocrine response.

Resistant breast and prostate cancers remain a major clinical problem, new therapeutic approaches and better predictors of therapeutic response are clearly needed. Because of the involvement of the unfolded protein response (UPR) in cell proliferation and apoptosis evasion, an increasing number of publications support the hypothesis that impairments in this network trigger and/or exacerbate cancer. Moreover, UPR activation could contribute to the development of drug resistance phenotypes in both breast and prostate cancers. Therefore, targeting this pathway has recently emerged as a promising strategy in anticancer therapy. This review addresses the contribution of UPR to breast and prostate tissues homeostasis and its significance to cancer endocrine response with focus on the current progress on UPR research related to cancer biology, detection, prognosis and treatment.

Variability in endocrine cell identity in patients with chronic pancreatitis undergoing islet autotransplantation.

Beta-cell dedifferentiation as shown by cellular colocalization of insulin with glucagon and/or vimentin, and decreased expression of MAFA and/or urocortin3 has been suggested to contribute to metabolic decompensation in type 2 diabetes, and was recently described postimplantation in islet allotransplant patients. Dysglycaemia and diabetes mellitus are often encountered preoperatively in patients undergoing pancreatectomy and islet autotransplantation (PIAT). In this series of case reports, we document variation in islet phenotypic identity in three patients with chronic pancreatitis (CP) without diabetes or significant insulin resistance who subsequently underwent PIAT. Pancreas histology was examined using colocalization of endocrine hormones, mesenchymal and pan-endocrine markers in islets, and the relative expression of MAFA and urocortin3 in insulin-expressing cells as compared to that of nondiabetic and type 2 diabetic donors. We present results of pre- and posttransplant clinical metabolic testing. Varying degrees of islet-cell dedifferentiation are identified in nondiabetic patients with CP at the time of PIAT, and may need further investigation.

[A Case of Resected Esophageal Endocrine Cell Carcinoma That Responded to Combination Therapy Comprising Irinotecan and Cisplatin].

We report a case of resected esophagealcancer that responded wellto first-line combination therapy comprising irinotecan and cisplatin. The patient was a 71-year-old woman being treated for liver cirrhosis. She was admitted to our hospital in April 2015 because of dysphasia. Endoscopic examination revealed a tumor in the mid-thoracic esophagus, which was diagnosed as an endocrine cell carcinoma following pathological examination. Contrast-enhanced computed tomography and positron emission tomography did not show lymph node or distant metastases. She was treated with irinotecan and cisplatin combination therapy. After 6 courses of treatment, the tumor size had remarkably reduced. Subsequently, we performed subtotal esophagectomy and gastric tube reconstruction through the retroposterior mediastinalroute and the histologicaleffect was reported as a partial response. No viable tumor cells were observed in the extracted lymph nodes. However, bone metastasis and lymph node swelling occurred after 4 months. She received other therapeutic regimens, such as etoposide and carboplatin combination therapy. However, the tumor gradually progressed, and she died 18 months after the first treatment. Irinotecan and cisplatin combination therapy is a possible option for the management of esophageal endocrine cell carcinoma as a first-line treatment.

[A Case of Endocrine Cell Carcinoma of the Transverse Colon with Very Poor Prognosis, Onset with Bowel Obstruction].

We report a case of endocrine cell carcinoma of the colon with very poor prognosis, onset with bowel obstruction and multiple liver metastases. The patient was a 77-year-old man who underwent left hemicolectomy after a colon stent treatment for bowel obstruction due to cancer of the transverse colon with unresectable multiple liver metastases. Chemotherapy was not initiated because of his poor health. He died of primary cancer 52 days after the surgery. Endocrine cell carcinoma of the large intestine has a poor prognosis due to an early onset of liver and lymph node metastases, as well as peritoneal dissemination. A large-scale clinical study is needed to establish an effective adjuvant chemotherapy.

Abnormalities in endocrine and immune cells are correlated in dextran­sulfate­sodium­induced colitis in rats.

The interaction between the gut hormones and the immune system has been suggested to serve an important role in the pathophysiology of inflammatory bowel disease. The aims of the present study were to elucidate the possible abnormalities in the colonic endocrine cells in rats with dextran sodium sulfate (DSS)­induced colitis, and to determine whether they are correlated with alterations in the immune cells. A total of 24 male Wistar rats were divided into two groups: Control and DSS­induced colitis. Colonic tissues were harvested via postmortem laparotomy from all of the animals at the end of the experimental period, and fixed and sectioned for histology. The colonic endocrine and immune cells in those tissue samples were immunostained and their densities quantified by computerized image analysis. The densities of chromogranin A, serotonin, peptide YY and oxyntomodulin cells were significantly higher, and those of pancreatic peptide and somatostatin cells were lower in rats with DSS­induced colitis than in the controls. The densities of mucosal leukocytes, T and B lymphocytes, macrophages/monocytes, and mast cells were significantly higher than in the controls, and these changes were closely associated with the aforementioned changes in all endocrine cell types. These observations indicate an interaction between intestinal hormones and the immune system as represented by immune cells.

The role of microRNAs in the pathophysiology of adrenal tumors.

MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression in a sequence-specific manner. Due to its association with an assortment of diseases, miRNAs have been extensively studied in the last decade. In this review, the current understanding of the role of miRNAs in the pathophysiology of adrenal tumors is discussed. The recent contributions of high-throughput miRNA profiling studies have identified miRNAs that have functional and molecular roles in adrenal tumorigenesis. With respect to the biological heterogeneity of adrenal tumors and the limitations of the current treatments, an improved understanding of miRNAs may hold potential diagnostic and therapeutic value to facilitate better clinical management.

MicroRNAs in parathyroid physiopathology.

Parathyroid glands regulate calcium homeostasis through synthesis and secretion of parathormone (PTH). They sense the extracellular calcium concentration through the G-protein coupled calcium sensing receptor (CASR) and release PTH in order to preserve calcium concentration in the physiological range. Tumors of the parathyroid glands are common endocrine neoplasia associated with primary or secondary/tertiary hyperparathyroidisms. Small non-coding RNAs are regulators of gene expression able to modulate hormone synthesis, hormone release and endocrine cell proliferation. In this scenario, microRNA (miRNA) expression profiles have been investigated in parathyroid tumors, while miRNAs are involved in hypocalcemia and uremia-induced PTH release from normal parathyroid cells. Here we reviewed data about the role of miRNAs in the regulation of: 1) PTH synthesis and secretion; 2) CASR expression; 3) parathyroid cell tumorigenesis. Though studies about miRNAs in parathyroid gland pathophysiology are limited, they contribute in elucidating regulatory pathways involved in PTH release and parathyroid cell tumorigenesis.

Three-dimensional ultrastructural analyses of anterior pituitary gland expose spatial relationships between endocrine cell secretory granule localization and capillary distribution.

Endocrine and endothelial cells of the anterior pituitary gland frequently make close appositions or contacts, and the secretory granules of each endocrine cell tend to accumulate at the perivascular regions, which is generally considered to facilitate secretory functions of these cells. However, three-dimensional relationships between the localization pattern of secretory granules and blood vessels are not fully understood. To define and characterize these spatial relationships, we used scanning electron microscopy (SEM) three-dimensional reconstruction method based on focused ion-beam slicing and scanning electron microscopy (FIB/SEM). Full three-dimensional cellular architectures of the anterior pituitary tissue at ultrastructural resolution revealed that about 70% of endocrine cells were in apposition to the endothelial cells, while almost 30% of endocrine cells were entirely isolated from perivascular space in the tissue. Our three-dimensional analyses also visualized the distribution pattern of secretory granules in individual endocrine cells, showing an accumulation of secretory granules in regions in close apposition to the blood vessels in many cases. However, secretory granules in cells isolated from the perivascular region tended to distribute uniformly in the cytoplasm of these cells. These data suggest that the cellular interactions between the endocrine and endothelial cells promote an uneven cytoplasmic distribution of the secretory granules.

Increased Hormone-Negative Endocrine Cells in the Pancreas in Type 1 Diabetes.

CONTEXT AND OBJECTIVE: Type 1 diabetes (T1D) is characterized by a ß-cell deficit due to autoimmune inflammatory-mediated ß-cell destruction. It has been proposed the deficit in ß-cell mass in T1D may be in part due to ß-cell degranulation to chromogranin-positive, hormone-negative (CPHN) cells. DESIGN, SETTING, AND PARTICIPANTS: We investigated the frequency and distribution of CPHN cells in the pancreas of 15 individuals with T1D, 17 autoantibody-positive nondiabetic individuals, and 17 nondiabetic controls. RESULTS: CPHN cells were present at a low frequency in the pancreas from nondiabetic and autoantibody-positive, brain-dead organ donors but are more frequently found in the pancreas from donors with T1D (islets: 1.11% ± 0.20% vs 0.26% ± 0.06 vs 0.27% ± 0.10% of islet endocrine cells, T1D vs autoantibody positive [AA+] vs nondiabetic [ND]; T1D vs AA+, and ND, P < .001). CPHN cells are most commonly found in the single cells and small clusters of endocrine cells rather than within established islets (clusters: 18.99% ± 2.09% vs 9.67% ± 1.49% vs 7.42% ± 1.26% of clustered endocrine cells, T1D vs AA+ vs ND; T1D vs AA+ and ND, P < .0001), mimicking the distribution present in neonatal pancreas. CONCLUSIONS: From these observations, we conclude that CPHN cells are more frequent in T1D and, as in type 2 diabetes, are distributed in a pattern comparable with the neonatal pancreas, implying a possible attempted regeneration. In contrast to rodents, CPHN cells are insufficient to account for loss of ß-cell mass in T1D.

Quantitative evaluation of CART-containing cells in urinary bladder of rats with renovascular hypertension.

Recent biological advances make it possible to discover new peptides associated with hypertension. The cocaine- and amphetamine-regulated transcript (CART) is a known factor in appetite and feeding behaviour. Various lines of evidence suggest that this peptide participates not only in control of feeding behaviour but also in the regulation of the cardiovascular and sympathetic systems and blood pressure. The role of CART in blood pressure regulation led us to undertake a study aimed at analysing quantitative changes in CART-containing cells in urinary bladders (UB) of rats with renovascular hypertension. We used the Goldblatt model of arterial hypertension (two-kidney, one clip) to evaluate quantitative changes. This model provides researchers with a commonly used tool to analyse the renin-angiotensin system of blood pressure control and, eventually, to develop drugs for the treatment of chronic hypertension. The study was performed on sections of urinary bladders of rats after 3-, 14-, 28-, 42 and 91 days from hypertension induction. Immunohistochemical identification of CART cells was performed on paraffin for the UBs of all the study animals. CART was detected in the endocrine cells, especially numerous in the submucosa and muscularis layers, with a few found in the transitional epithelium and only occasionally in serosa. Hypertension significantly increased the number of CART-positive cells in the rat UBs. After 3 and 42 days following the procedure, statistically significantly higher numbers of CART-positive cells were identified in comparison with the control animals. The differences between the hypertensive rats and the control animals concerned not only the number density of CART-immunoreactive cells but also their localization. After a 6-week period, each of the rats subjected to the renal artery clipping procedure developed stable hypertension. CART appeared in numerous transitional epithelium cells. As this study provides novel findings, the question appears about the type of connection between hypertension and the functioning and activity of CART in the urinary tract (UT). The study gives rise to the assumption that high blood pressure can be a factor that intensifies CART secretion. In conclusion, the endocrine system of the urinary tract is modified by renovascular hypertension. This may affect the production of hormones and biologically active substances and contribute to the development of possible hypertension complications. In order to fully comprehend the role of the CART peptide in blood pressure regulation, further analyses are necessary.

Colocalization of insulin and glucagon in insulinoma cells and developing pancreatic endocrine cells.

A significant portion of human and rat insulinomas coexpress multiple hormones. This character termed as multihormonality is also observed in some early pancreatic endocrine cells which coexpress insulin and glucagon, suggesting an incomplete differentiation status of both cells. Here we demonstrate that insulinoma cells INS-1 and INS-1-derived single cell clone INS-1-15 coexpressed insulin and glucagon in a portion of cells. These two hormones highly colocalized in the intracellular vesicles within a cell. Due to the existence of both PC1/3 and PC2 in INS-1-derived cells, proglucagon could be processed into glucagon, GLP-1 and GLP-2. These glucagon-family peptides and insulin were secreted simultaneously corresponding to the elevating glucose concentrations. The coexpression and partial colocalization of insulin and glucagon was also observed in rat fetal pancreatic endocrine cells, but the colocalization rate was generally lower and more diverse, suggesting that in the developing pancreatic endocrine cells, insulin and glucagon may be stored in nonidentical pools of secreting vesicles and might be secreted discordantly upon stimulus.