Diffuse Neuroendocrine System Research Articles

Celebrating 50+ years of research on the reproductive biology and endocrinology of the green frog: An overview

This issue is dedicated to the late Professor Giovanni Chieffi, and this article is an overview of the research on Comparative Endocrinology of reproduction using Rana esculenta (alias Pelophylax esculentus) as a model system. Starting from the early 1970s till today, a large quantity of work have been conducted both in the fields of experimental endocrinology and in the definition of the diffuse neuroendocrine system, with a major focus on the increasing role of regulatory peptides. The various aspects investigated concerned the histological descriptions of principal endocrine glands of the hypothalamic–pituitary–gonadal (HPG) axis, the localization and distribution in the HPG of several different substances (i.e. neurosteroids, hypothalamic peptide hormones, pituitary gonadotropins, gonadal sex steroids, and other molecules), the determination of sex hormone concentrations in both serum and tissues, the hormone manipulations, as well as the gene and protein expression of steroidogenic enzymes and their respective receptors. All together these researches, often conducted considering different periods of the annual reproductive cycle of the green frog, allowed to understand the mechanism of cascade control/regulation of the HPG axis of R. esculenta, characterizing the role of different hormones in the two sexes, and testing the hypotheses about the function of single hormones in different target organs. It becomes evident from the review that, in their simplest form, several features of this species are specular as compared to those of other vertebrate species and that reproduction in this frog species is either under endogenous multi-hormonal control or by a wide array of different factors. Our excursus of this research, spanning almost five decades, shows that R. esculenta has been intensively and successfully used as an animal model in reproductive endocrinology as well as several field studies such as those involving environmental concerns that focus on the effects of endocrine disruptors and other environmental contaminants.

Neuroendocrine neoplasm update: toward universal nomenclature.

Neuroendocrine neoplasia is described in almost every tissue, either in the pure endocrine organs, the nerve structures or in the so-called diffuse neuroendocrine system. The current nomenclature contains time-honored, widely accepted definitions; however, it is different according to anatomical sites. Diverse definitions may generate confusion and non-standard patient management. The International Agency for Research on Cancer - World Health Organization (IARC-WHO) proposed a framework for universal classification of neuroendocrine neoplasia. Evidence indicates that neuroendocrine cancer is composed by cells with a distinctive phenotype characterized by the expression of general and specific neuroendocrine markers. The neuroendocrine phenotype is indicated as descriptor of a unique cancer category, now recommended for all organs as neuroendocrine neoplasm. Evidence indicates that neuroendocrine neoplasia may be well or poorly differentiated, with diverse incidence and prevalence in different organs. It is proposed that the well-differentiated neoplasm is universally defined as neuroendocrine tumor (NET) and the poorly differentiated as neoplasm neuroendocrine carcinoma (NEC). Evidence indicates that a cancer grading tool based on a proliferation measure by mitotic count, Ki67 % and/or necrosis assessment is useful to predict NET patient behavior. It is proposed to utilize this tool for grading NET universally, with site-specific cut-offs to be defined. It is also acknowledged that significant biological site-specific differences exist. It is recommended that current pathology reports contain this classification together with the current traditional classifiers. This IARC-WHO common classification framework for neuroendocrine neoplasm aims at uniformizing nomenclature toward different organs and at fostering the definition of a similar site-specific gene signature.

Bronchial carcinoid, unusual manifestation: a case report

Carcinoid tumors are neuroendocrine tumors that originate from the cells of the diffuse neuroendocrine system. Typical bronchial carcinoids tend to grow slowly, near the center of the lungs, and may remain asymptomatic for a long time. Bronchial carcinoids can rarely release serotonin or its metabolite urinary 5-hydroxyindoleacetic acid directly into the system circulation and may be reason of absence of lung perfusion even when atelectasis absents. Carcinoid crisis is life threatening form of carcinoid syndrome, which can happen spontaneously, more often it is caused by some stressful situations. Carcinoid crisis associated with bronchial carcinoids is often atypical, dominant symptoms are dyspnea, hypotension and acute right heart failure. In case of absence of lung perfusion it may imitate acute pulmonary embolism. In this case presentation authors are presenting 55-year-old Caucasian male with unknown bronchial carcinoid, manifested as carcinoid crisis, that imitated acute pulmonary embolism.

Enterectomia en el tratamiento del carcinoide neuroendocrino obstructivo en un perro: relato de caso

Carcinoids in dogs are rare neoplasms of the diffuse neuroendocrine cell system. The term neuroendocrine tumor has been proposed and the clinical manifestation is related to the location. Despite the low rate of growth and metastasis, such neoplasms are often malignant and must undergo surgical resection. When this is done properly, the outcome is usually satisfactory. The objective of this study was to describe a case of carcinoid in a 10-year-old female with tenesmus and presence of fecaloma. The patient was received at a private veterinary clinic and, after clinical consultation and imaging examinations, she was submitted to the enterotomy and removal of fecaloma in the descending colon. The obstruction of the intestinal flow was resulting from a neoplastic mass in a pre-pubic region, also resected and forwarded for analysis. The histopathological revealed neuroendocrine carcinoid and the dog was followed for 60 days after the procedure, without signs of recurred or metastasis. Therefore, it is understood that neuroendocrine carcinoids should be considered as a cause of tenesmus and constipation in dogs, especially in the elderly, and the prognosis is favorable when patients undergo the surgical procedure with adequate resection of the tumor.

Specific and Non-Specific Biomarkers in Neuroendocrine Gastroenteropancreatic Tumors.

The diagnosis of neuroendocrine tumors (NETs) is a challenging task: Symptoms are rarely specific, and clinical manifestations are often evident only when metastases are already present. However, several bioactive substances secreted by NETs can be included for diagnostic, prognostic, and predictive purposes. Expression of these substances differs between different NETs according to the tumor hormone production. Gastroenteropancreatic (GEP) NETs originate from the diffuse neuroendocrine system of the gastrointestinal tract and pancreatic islets cells: These tumors may produce many non-specific and specific substances, such as chromogranin A, insulin, gastrin, glucagon, and serotonin, which shape the clinical manifestations of the NETs. To provide an up-to-date reference concerning the different biomarkers, as well as their main limitations, we reviewed and summarized existing literature.

Chromogranin A regulates neuroblastoma proliferation and phenotype.

ABSTRACTNeuroblastoma is a commonly encountered solid tumor in early childhood with high neuroplasticity, and differentiation therapy is hypothesized to lead to tumor mass shrinkage and/or symptom relief. CgA is a tissue specific protein restricted to the diffuse neuroendocrine system, and widely expressed in neuroblastomas. Using knockdown and knockout approaches to deplete CgA levels, we demonstrated that CgA loss inhibits SH-SY5Y cell proliferation and leads to a morphological shift with increased expression of Schwann and extracellular matrix specific molecules, and suppression of chromaffin features. We further confirmed the effects of CgA in a series of neuroblastoma cells with [BE(2)-M17 and IMR-32] and without (SK-N-SH) N-Myc amplification. We demonstrated that CgA depletion reduced IGF-II and IGFBP-2 expression, increased IGFBP-3 levels, and suppresses IGF downstream signaling as evidenced by reduced AKT/ERK pathway activation. This was further supported by an increased anti-proliferative effect of the ERK inhibitor in the CgA depleted cells. In an in vivo xenograft neuroblastoma model, CgA knockdown led to increased S-phenotypic marker expression at both protein and mRNA levels. Together these results suggest that CgA maintains IGF secretion and intracellular signaling to regulate proliferation and differentiation in neuroblastomas.

Merkel cells immunohistochemical study in striped dolphin (Stenella coeruleoalba) skin.

Cetacean mechanical senses, such as hearing, echolocation, active touch and the perception of water movements, are essential for their survival. Dolphins skin possesses dense packing of dermal papillae associated with the cutaneous ridges that suggests a sensory function, furthermore they are well innervated and very sensitive to touch. This is mediated by mechanoreceptors, abundant in the region of the head and in the dorsal part of the body. Most odontocetes possess vibrissae (i.e., sensory hair) that have been well described in literature and present a microanatomy similar to that of terrestrial mammals. The aim of this study was to characterize Merkel cell through use of specific antibodies: Substance P, Anti-calbindin DK28, Anti-5HT, Leu- enkephalin, Protein Gene Product 9.5 (PGP9.5) and Anti-Human Neuronal Protein, for the first time. Merkel cells (MCs) in the dolphin skin are specialized skin receptors, characterized by their particular location and close association with nerve terminals. The presence of neuroendocrine markers and different neuropeptides confirms that MCs play also neuroendocrine function and are considered as part of the diffuse neuroendocrine system. Furthermore, the presence of Leu-enkephalin in Merkel cells could involve these cells in inflammatory responses in the skin.

Mouse models in endocrine tumors.

Endocrine and neuroendocrine tumors comprise a highly heterogeneous group of neoplasms that can arise from (neuro)endocrine cells, either from endocrine glands or from the widespread diffuse neuroendocrine system, and, consequently, are widely distributed throughout the body. Due to their diversity, heterogeneity and limited incidence, studying in detail the molecular and genetic alterations that underlie their development and progression is still a highly elusive task. This, in turn, hinders the discovery of novel therapeutic options for these tumors. To circumvent these limitations, numerous mouse models of endocrine and neuroendocrine tumors have been developed, characterized and used in pre-clinical, co-clinical (implemented in mouse models and patients simultaneously) and post-clinical studies, for they represent powerful and necessary tools in basic and translational tumor biology research. Indeed, different in vivo mouse models, including cell line-based xenografts (CDXs), patient-derived xenografts (PDXs) and genetically engineered mouse models (GEMs), have been used to delineate the development, progression and behavior of human tumors. Results gained with these in vivo models have facilitated the clinical application in patients of diverse breakthrough discoveries made in this field. Herein, we review the generation, characterization and translatability of the most prominent mouse models of endocrine and neuroendocrine tumors reported to date, as well as the most relevant clinical implications obtained for each endocrine and neuroendocrine tumor type.

Gastroenteropancreatic Neuroendocrine Tumors.

Neuroendocrine tumors (NETs) are heterogeneous malignancies arising from the diffuse neuroendocrine system. They frequently originate in the gastroenteropancreatic (GEP) tract and the bronchopulmonary tree, and their incidence has steadily increased in the last 3 decades. Fundamental biologic and genomic differences underlie the clinical heterogeneity of NETs, and distinct molecular features characterize NETs of different grades and different primary sites. Although surgery remains the cornerstone of treatment for localized tumors, systemic treatment options for patients with metastatic NETs have expanded considerably. Somatostatin analogs have demonstrated both antisecretory and antitumor efficacy. Peptide receptor radionuclide therapy with lutetium-177 dotatate (177 Lu-DOTATATE) has been approved for advanced GEP-NETs. The antitumor activity of everolimus has been demonstrated across a wide spectrum of NETs, and the antiangiogenic agent sunitinib has been approved for pancreatic NETs (pNETs). Chemotherapy with temozolomide and capecitabine has recently demonstrated an unprecedented prolongation of progression-free survival in a randomized trial of pNETs. Multiple retrospective series have reported the efficacy of liver-directed therapies both for palliating symptoms of hormone excess and for controlling tumor growth. Telotristat, an oral inhibitor of tryptophan hydroxylase, has been shown to reduce diarrhea in patients with carcinoid syndrome. Defining the therapeutic algorithm and identifying biomarkers predictive of response to treatments are among the main priorities for the next decade of research in the NET field.

Clinical profile and treatment outcomes of metastatic neuroendocrine carcinoma: A single institution experience.

Background:Neuroendocrine carcinoma (NEC) is a rare tumor arising from the diffuse neuroendocrine system. Most of these present in the advanced stage and palliative chemotherapy remains the only option. The prognosis remains poor with the standard chemotherapy regimen of platinum and etoposide (EP) providing modest survival benefit.Methods:The study was done for 3 years at a tertiary cancer center in South India. Patients with a diagnosis of metastatic NEC were analyzed for clinical and pathological characteristics. The treatment outcomes and prognostic factors were evaluated using appropriate statistical test.Results:A total of 114 patients of metastatic NEC satisfied the inclusion criteria and were analyzed. Gastrointestinal including hepatobiliary tract (33%) was the most common site of primary disease followed by lung (26%), genitourinary (15%), head and neck (14%), and unknown primary (9%). On analysis of pattern of metastasis, liver (65%) was the most common site followed by bone (54%) and lung (42%). The median overall survival was 11 months with a statistically significant difference between pulmonary and extrapulmonary disease (8 vs. 13 months; P = 0.003). Ki67% value was strongly associated with prognosis (hazard ratio 0.517, 95% confidence interval; 0.318–0.840, P = 0.008) whereas age, sex, and lactate dehydrogenase level did not show any relation with survival.Conclusion:The outcome of advanced NEC with standard chemotherapy remains poor. Larger studies with other therapeutic and novel agents are warranted to improve the treatment outcomes.

Peptide Receptor Radionuclide Therapy for Advanced Gastroenteropancreatic Neuroendocrine Tumors - from oncology perspective.

Peptide Receptor Radionuclide Therapy (PRRT) is a form of molecular targeted therapy which is performed by using a small peptide (somatostatin analogue - SSA) that is coupled with a radionuclide beta emitting radiation. PRRT is a nuclear medicine for the systemic treatment of non-resectable, metastasized well/moderately differentiated, neuroendocrine tumours (NET) with overexpression of somatostatin receptor. These types of tumours include gastroenteropancreatic neoplasm (GEP-NENs), e.g. arising from the small bowel (often called carcinoid tumours), the pancreas, duodenum or stomach, but also from the large bowel or the lung and many other tissues (so called diffuse neuroendocrine system). The goal of PRRT is irradiation of tumour cells, via direct binding into specific receptor, somatostatin receptors (SSTR) family, overexpressed on the cell membrane of the primary tumours as well as on the metastasis. Over many years of clinical use of PRRT with ⁹⁰Y and current with ¹⁷⁷Lu DOTA conjugated somatostatin analogues proved to be efficient therapy option for NETs, with tumour responses, base on radiological evaluation. Also, a clinical response with symptoms relief and improvement in quality of life based on standard EORTC questioners is seen. Additional, common NET biomarker reduction and, ultimately, an impact on overall survival (OS) of patients with advanced non-resectable often progressive NEN can be expected. PRRT with ⁹⁰Y or ¹⁷⁷Lu-labelled peptides is generally well tolerated by most of the patients. The acute side effects (Adverse Events - AEs) are usually mild; most of them are related to the co-administration of amino acids (AA), such as nausea and vomiting. Others are related to the radioisotopes, such as fatigue or the exacerbation of endocrine syndromes, which are very rarely and they occurs, only in patients with functional tumours and large tumours burden. Chronic and permanent damage has an effect on target organs, particularly the kidneys and the bone marrow, which are generally mild. Currently, when ¹⁷⁷Lu DOTATATE is used, the potential risk to kidney damage is significantly reduced, compared to the previous usage of ⁹⁰Y labelled analogues. Up to now, kidney and bone marrow toxicity limits the dose of radioactivity of PRRT.

The Role of Chromogranin A in Adrenal Tumors

Chromogranin A (CgA) is part of the family of granins, which are acidic glycoproteins that represent an important part of secretory dense core granules. They are specific to various neuroendocrine and endocrine tissues, as components of diffuse neuroendocrine system and endocrine glands. CgA is co-secreted and co-released in the circulation along with hormones, bioamines and peptides secreted from the neuroendocrine cells . In the last decade, studies have emphasized the major importance of serum CgA in the diagnosis and follow-up of neuroendocrine tumors such as gastroenteropancreatic tumors, pheochromocytoma, medullary thyroid carcinoma. But its diagnostic value for adrenocortical adenomas or for adrenal malignancy, is still controversial. The current study aims to provide a comprehensive review , for synthesizing current knowledge regarding corelations between plasma CgA concentration and various adrenal tumors. Furthermore, there will be also analyzed and synthesized the clinical applicability and the diagnostic usefulness of dosing CgA in adrenal pathology, both medullary and cortical benign and malignant lesions.

Radionuclide imaging and therapy in patients with neuroendocrine tumors

Neuroendocrine tumors (NETs) are heterogeneous group of the tumors that arise from the enterochromaffin cells of the diffuse neuroendocrine system and occurr in 0.5% of all neoplasms. Recently there has been a significant increase in the incidence of neuroendocrine tumors, which is undoubtedly associated with the improvement of diagnostic methods. However, despite significant success in studying the biological and molecular mechanisms of its behavior, a single algorithm for the diagnosis and treatment of neuroendocrine tumors remains unclear today. Treatment of neuroendocrine tumors largely depends on their functional status and the stage of the disease. While the treatment of localized NETs is surgical resection, varieties of therapeutic options are available for patients with advanced NETs. These include medical control of excess hormone levels and associated symptoms, cytoreductive surgery for patients with advanced disease, systemic chemotherapy, somatostatin analogues, and peptide receptor-targeted radionuclide therapy. However, the right choice of the therapeutic approach in current clinical practice in heterogeneous group of patients with neuroendocrine tumors requires further discussion.

ULTRASTRUCTURAL FEATURES OF THE DIFFUSE NEUROENDOCRINE SYSTEM OF THE DUODENUM IN ACUTE INTESTINAL OBSTRUCTION

Study of changes in the structure of the duodenal endocrinocytes with intestinal obstruction is a step towards finding out the pathogenesis of the disease. The aim is to establish the ultrastructural features of the diffuse neuroendocrine system of the duodenum in the modeling of high acute obstructive intestinal obstruction. Material and methods. Experimental studies were performed on 20 white mature male rats weighing 300350 g. Animals were divided into 2 groups: control (5) and experimental (15). Animals of the experimental group were created a model of high acute obstructive intestinal obstruction. Euthanasia was performed by overdose of thiopental sodium at 24, 48 and 72 hours.. Pieces of the duodenum was used for microscopic examination, they were fixed in 10% neutral formalin solution. The preparations were stained by van Gison method, hematoxylin-eosin, for studying endocrinocytes, stained using the Grimmel and Mason-Hamperl method. For electron microscopic examination, the pieces of the duodenum were fixed in a 2.5% solution of glutaraldehyde in 0.1 g phosphate buffer. Results and discussion. Endocrinocytes of the mucous membranes of the small intestine under conditions of high intestinal obstruction above the blockade site differ sharply from similar cells in the villi and crypts of the gut of the animals of the control group. Characteristics of endocrine cells in the content of secretory granules sharply changes. In this group, we observed endocrinocytes whose cytoplasm was slightly saturated with granules up to complete degranulation. The integrity of the membranes of individual granules has been broken, which led to the possibility of secretion in the cytoplasm. Conclusions. In the dynamics of the development of high obstructive acute narrow-hearth obstruction in the cells of the diffuse neuroendocrine system, destructive changes have been identified, which are manifested by a decrease in the total number of endocrine cells and, at the same time, an increase in the number of destroyed endocrinocytes. Ultrastructural changes are characterized by a violation of the integrity of the membranes of the individual secretory granules with the possibility of secretion in the cytoplasm, violation of the structure of mitochondria, illumination of their matrix, and cristae disintegration.

P182 Intestinal diffuse neuroendocrine system and proliferation indicators in prediction of non-specific ulcerative colitis occurrence and course

P182 Intestinal diffuse neuroendocrine system and proliferation indicators in prediction of non-specific ulcerative colitis occurrence and course

Mass Spectrometry Profiling of Pituitary Glands.

Many chronic diseases are associated with hypothalamic-pituitary-adrenal axis dysfunction. Therefore, proteomic profiling of the pituitary gland has potential to uncover new information on the underlying pathways affected in these conditions. This could lead to identification of new biomarkers or drug targets for development of novel therapeutics. Here we present a protocol for preparation of pituitary protein extracts and analysis of the major hormones and accessory proteins using liquid chromatography tandem mass spectrometry (LC-MS/MS). The same methods can be applied in the study of other tissues of the diffuse neuroendocrine system.

Activity of Entrectinib in a Patient With the First Reported NTRK Fusion in Neuroendocrine Cancer.

Despite advances in genomic analysis, the molecular origin of neuroendocrine tumors (NETs) is complex and poorly explained by described oncogenes. The neurotrophic TRK family, including NTRK1, 2, and 3, encode the proteins TRKA, TRKB, TRKC, respectively, involved in normal nerve development. Because NETs develop from the diffuse neuroendocrine system, we sought to determine whether NTRK alterations occur in NETs and whether TRK-targeted therapy would be effective. A patient with metastatic well-differentiated NET, likely of the small intestine, was enrolled on the STARTRK2 trial (ClinicalTrials.gov identifier: NCT02568267) and tissue samples were analyzed using an RNA-Seq next-generation sequencing platform. An ETV6:NTRK3 fusion was identified and therapy was initiated with the investigational agent entrectinib, a potent oral tyrosine kinase inhibitor of TRKA, TRKB, and TRKC. Upon treatment with entrectinib, the patient experienced rapid clinical improvement; his tumor response was characterized by initial tumor growth and necrosis. This is the first report of an NTRK fusion in NETs. Our patient's response to entrectinib suggests that NTRK fusions can be important in the pathogenesis of NETs. Recent DNA-based genomic analyses of NETs may have missed NTRK fusions due its large gene rearrangement size and multiple fusion partners. The tumor's initial pseudoprogression may represent a unique response pattern for TRK-targeted therapies. An effort to characterize the prevalence of NTRK fusions in NETs using optimal sequencing technology is important.

A Rare Case of Rectal Carcinoid in a Young Female With SLE

Carcinoids slow-growing tumors that originate in cells of the diffuse neuroendocrine system with majority from the midgut. Arising from the enterochromaffin cells and the characteristic feature of converting tryptophan to serotonin and exhibiting signs and symptoms of serotonin syndrome, this tumor is commonly seen in African Americans. Our case is is a young female diagnosed with rectal carcinoid tumor. 28 yo female with a hx of SLE for 3 years presents to the emergency department with complaints of intermittent left sided abdominal discomfort and pain for approximately 3 weeks duration. She characterized the pain dull nagging-like, associated with nausea, no vomiting, no association with sleeping or laying supine, that regressed in 30 minutes. She was discharged after conservative management with PPI and outpatient clinic follow up in 4 weeks. She presented 2 months later with continued abdominal pain now associated with 3 lbs unintentional weight loss, bloating, with diarrhea/ constipation. EGD perfromed revealed minor erythematous mucosa that was negative for h.pylori on biopsy. Colonoscopy revealed a 1 cm soft, submucosal lesion appearing with a yellowish hue just proximal to the dentate line. Biopsies showed a well differentiated neuroendocrine tumor tumor less than 1mm in diameter. IHC staining positive for synaptophysin and KI-67. Patient underwent a endoscopic sub mucosal resection showing a 0.7 cm well-differentiated, neuroendocrine tumor with uninvolved margins.Figure: Normal goblet cells with mucin production when compared with abnormal well differentiated nests of cells.Figure: Abnormal NES cells stained via Synaptophysin, marker for neuroendocrine tumors; Immunohistochemistry.GI Carcinoid tumors arise mainly in 6th decade of life. NANETS guidelines for screening recommends serum serotonin, chromogranin A and urine serotonin and 5- HIAA. No blood tests are of value in detecting NET tumors. Once diagnosed by endoscpy, endoscopic mucosal resection/radical surgery is recommended. Surveillance after intervention depends on staging. In our literature review, there has been only 3 other cases of patient with SLE diagnosed with rectal carcinoid at a young age. Prospective studies are linking auto-immune diseases to early onset of neuroendocrine tumors. Majority of these tumors do not present with symptoms and are found incidentally. It is imperative to diagnose these cases early as risk of metastasis to the liver may occur up to 3 years even after endoscopic removal. There are limited studies and case presentations available to medical population and therefore it is important to be familiar with the the NANETS guidelines for diagnostic and therapeutic intervention.

Consensus and controversy of endoscopic diagnosis and treatment of gastroenteropancreatic neuroendocrine tumors

Neuroendocrine neoplasms(NENs) are relatively rare tumors originating from the diffuse neuroendocrine system, and gastrointestinal tract is one of the most common location of the tumors. Currently, the European Neuroendocrine Neoplasm Society (ENETS) and the National Comprehensive Cancer Network (NCCN) have released the international guidelines for NENs management. And also, experts from Chinese Society of Clinical Oncology (CSCO) have proposed "The Consensus on Gastroenteropancreatic Neuroendocrine Neoplasm in China" in 2016, which is also one of the most important reference standard for the diagnosis and treatment of gastroenteropancreatic(GEP) NENs in China. Here we will interpret these three guidelines or consensus. There are few controversies about endoscopic management principle for GEP-NEN of different locations and sizes among these three guidelines or consensus, but for small NENs without involving intrinsic muscularis, endoscopic resection is recommended and considered. We hope that this interpretation may help clinicians for clinical decision making.

The role of diffuse neuroendocrine system of the digestive tract in the
 development of disorders of proliferation and apoptosis in the stomach of patients with Helicobacter pylori infection

In the implementation of oncogenesis and, in particular, the cascade of Correa, a significant role is played by the relationship of proliferation and apoptosis with the system functioning of the digestive tract of the diffuse neuroendocrine system and Helicobacter pylori