NLRP3 inflammasome-induced pyroptosis in digestive system tumors.

Programmed cell death (PCD) refers to cell death in a manner that depends on specific genes encoding signals or activities. PCD includes apoptosis, pyroptosis, autophagy and necrosis (programmed necrosis). Among these mechanisms, pyroptosis is mediated by the gasdermin family and is accompanied by inflammatory and immune responses. When pathogens or other danger signals are detected, cytokine action and inflammasomes (cytoplasmic multiprotein complexes) lead to pyroptosis. The relationship between pyroptosis and cancer is complex and the effect of pyroptosis on cancer varies in different tissue and genetic backgrounds. On the one hand, pyroptosis can inhibit tumorigenesis and progression; on the other hand, pyroptosis, as a pro-inflammatory death, can promote tumor growth by creating a microenvironment suitable for tumor cell growth. Indeed, the NLRP3 inflammasome is known to mediate pyroptosis in digestive system tumors, such as gastric cancer, pancreatic ductal adenocarcinoma, gallbladder cancer, oral squamous cell carcinoma, esophageal squamous cell carcinoma, in which a pyroptosis-induced cellular inflammatory response inhibits tumor development. The same process occurs in hepatocellular carcinoma and some colorectal cancers. The current review summarizes mechanisms and pathways of pyroptosis, outlining the involvement of NLRP3 inflammasome-mediated pyroptosis in digestive system tumors.

Effectiveness of Etoposide and Cisplatin vs Irinotecan and Cisplatin Therapy for Patients With Advanced Neuroendocrine Carcinoma of the Digestive System: The TOPIC-NEC Phase 3 Randomized Clinical Trial.

Importance: Etoposide plus cisplatin (EP) and irinotecan plus cisplatin (IP) are commonly used as community standard regimens for advanced neuroendocrine carcinoma (NEC). Objective: To identify whether EP or IP is a more effective regimen in terms of overall survival (OS) in patients with advanced NEC of the digestive system. Design, Setting, and Participants: This open-label phase 3 randomized clinical trial enrolled chemotherapy-naive patients aged 20 to 75 years who had recurrent or unresectable NEC (according to the 2010 World Health Organization classification system) arising from the gastrointestinal tract, hepatobiliary system, or pancreas. Participants were enrolled across 50 institutions in Japan between August 8, 2014, and March 6, 2020. Interventions: In the EP arm, etoposide (100 mg/m2/d on days 1, 2, and 3) and cisplatin (80 mg/m2/d on day 1) were administered every 3 weeks. In the IP arm, irinotecan (60 mg/m2/d on days 1, 8, and 15) and cisplatin (60 mg/m2/d on day 1) were administered every 4 weeks. Main Outcomes and Measures: The primary end point was OS. In total, data from 170 patients were analyzed to detect a hazard ratio (HR) of 0.67 (median OS of 8 and 12 months in inferior and superior arms, respectively) with a 2-sided α of 10% and power of 80%. The pathologic findings were centrally reviewed following treatment initiation. Results: Among the 170 patients included (median [range] age, 64 [29-75] years; 117 [68.8%] male), median OS was 12.5 months in the EP arm and 10.9 months in the IP arm (HR, 1.04; 90% CI, 0.79-1.37; P = .80). The median progression-free survival was 5.6 (95% CI, 4.1-6.9) months in the EP arm and 5.1 (95% CI, 3.3-5.7) months in the IP arm (HR, 1.06; 95% CI, 0.78-1.45). A subgroup analysis of OS demonstrated that EP produced more favorable OS in patients with poorly differentiated NEC of pancreatic origin (HR, 4.10; 95% CI, 1.26-13.31). The common grade 3 and 4 adverse events in the EP vs IP arms were neutropenia (75 of 82 [91.5%] patients vs 44 of 82 [53.7%] patients), leukocytopenia (50 of 82 [61.0%] patients vs 25 of 82 [30.5%] patients), and febrile neutropenia (FN) (22 of 82 [26.8%] patients vs 10 of 82 [12.2%] patients). While incidence of FN was initially high in the EP arm, primary prophylactic use of granulocyte colony-stimulating factor effectively reduced the incidence of FN. Conclusions and Relevance: Results of this randomized clinical trial demonstrate that both EP and IP remain the standard first-line chemotherapy options. Although AEs were generally manageable, grade 3 and 4 AEs were more common in the EP arm. Trial Registration: Japan Registry of Clinical Trials: jRCTs031180005; UMIN Clinical Trials Registry: UMIN000014795.

Mixed neuroendocrine-non-neuroendocrine neoplasms of the digestive system: A mini-review.

Mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) are rare mixed tumors containing both neuroendocrine (NE) and non-NE components. Each component must occupy at least 30% of the tumor volume by definition. Recent molecular evidence suggests MiNENs are clonal neoplasms and potentially harbor targetable mutations similar to conventional carcinomas. There have been multiple changes in the nomenclature and classification of MiNENs which has created some confusion among pathologists on how to integrate the contributions of each component in a MiNEN, an issue which in turn has resulted in confusion in communication with front-line treating oncologists. This mini review summarizes our current understanding of MiNENs and outline diagnosis, prognosis, and management of these neoplasms. The authors emphasize the importance of treating the most aggressive component of the tumor regardless of its percentage volume.

[Focused dilemmas in the diagnosis and treatment of digestive system neuroendocrine neoplasms].

Neuroendocrine neoplasms (NENs) originate from neuroendocrine cells diffusely distributed throughout the body. NENs are liable to be misdiagnosed and missed clinically, which brings great difficulties to clinical diagnosis and treatment, and seriously affects their prognosis. This article will introduce the difficulties and hot spots in the diagnosis and treatment of NENs from the aspects of laboratory and pathological examinations, anatomical and functional imaging examinations, including endoscopy, peptide receptor radionuclide therapy, somatostatin analogue and immune checkpoint inhibitor therapy. It aims to provide more ideas for the early diagnosis and early treatment of NENs, standardized diagnosis and treatment of high-grade NENs in the middle and late stages, and to provide more strategies for clinical multidisciplinary experts towards the management of focused dilemmas in NENs.

Histopathology of Gastrointestinal Immune-related Adverse Events: A Practical Review for the Practicing Pathologist.

Immune checkpoint inhibitors target checkpoint proteins with the goal of reinvigorating the host immune system and thus restoring antitumor response. With the dramatic increase in the use of checkpoint inhibitors for cancer treatment, surgical pathologists have assumed a major role in predicting the therapeutic efficacy (score based on programmed cell death ligand 1 immunohistochemistry and mismatch repair protein loss) as well as diagnosing the complications associated with these medications. Immune-related adverse events (irAEs) manifest as histologic changes seen in both the upper and lower gastrointestinal tract, and when viewed in isolation, may be morphologically indistinguishable from a wide range of diseases including infections, celiac disease, and inflammatory bowel disease, among others. Evaluation of biopsies from both the upper and lower gastrointestinal tract can aid in the distinction of gastrointestinal irAEs from their mimics. In the liver, the histologic changes of hepatic irAEs overlap with de novo diseases associated with hepatitic and cholangitic patterns of injury. The diagnosis of irAEs requires communication and collaboration from the pathologist, oncologist, and gastroenterologist. This review provides a background framework and illustrates the histologic features and differential diagnosis of gastrointestinal and hepatic irAEs.

Conditional CRISPR-Cas Genome Editing in Drosophila to Generate Intestinal Tumors.

CRISPR-Cas has revolutionized genetics and extensive efforts have been made to enhance its editing efficiency by developing increasingly more elaborate tools. Here, we evaluate the CRISPR-Cas9 system in Drosophila melanogaster to assess its ability to induce stem cell-derived tumors in the intestine. We generated conditional tissue-specific CRISPR knockouts using different Cas9 expression vectors with guide RNAs targeting the BMP, Notch, and JNK pathways in intestinal progenitors such as stem cells (ISCs) and enteroblasts (EBs). Perturbing Notch and BMP signaling increased the proliferation of ISCs/EBs and resulted in the formation of intestinal tumors, albeit with different efficiencies. By assessing both the anterior and posterior regions of the midgut, we observed regional differences in ISC/EB proliferation and tumor formation upon mutagenesis. Surprisingly, high continuous expression of Cas9 in ISCs/EBs blocked age-dependent increase in ISCs/EBs proliferation and when combined with gRNAs targeting tumor suppressors, it prevented tumorigenesis. However, no such effects were seen when temporal parameters of Cas9 were adjusted to regulate its expression levels or with a genetically modified version, which expresses Cas9 at lower levels, suggesting that fine-tuning Cas9 expression is essential to avoid deleterious effects. Our findings suggest that modifications to Cas9 expression results in differences in editing efficiency and careful considerations are required when choosing reagents for CRISPR-Cas9 mutagenesis studies. In summary, Drosophila can serve as a powerful model for context-dependent CRISPR-Cas based perturbations and to test genome-editing systems in vivo.

MEOX2 serves as a novel biomarker associated with macrophage infiltration in oesophageal squamous cell carcinoma and other digestive system carcinomas.

BACKGROUND: Oesophageal squamous cell carcinoma (ESCC) is a malignant tumour of the digestive system that is associated with high morbidity and mortality rates worldwide. With the increased use of immunotherapy in cancer treatment, there is an urgent need to elucidate the immune-related mechanisms in ESCC and other digestive system carcinomas. METHODS: In our study, single-sample gene set enrichment analysis (ssGSEA) was first performed to analyse the expression profile downloaded from the NCBI Gene Expression Omnibus (GEO) database. Then, via a series of bioinformatic analyses, including the Mann-Whitney test, weighted gene co-expression network analysis (WGCNA), functional enrichment analysis and differentially expressed genes (DEGs) analysis, we identified target immunocytes and related genes. Finally, we validated the results with the TIMER database. RESULTS: Our analyses showed that the numbers of infiltrating macrophages were obviously higher in advanced stages in ESCC compared with other types of immunocytes. MEOX2 was identified as a biomarker correlated with macrophage infiltration in ESCC and other types of digestive system carcinomas. And MEOX2 expression was strongly associated with the mRNA expression of colony-stimulating factor 1 (CSF-1) and CSF-1 receptor (CSF-1R) in these kinds of carcinomas. CONCLUSION: We speculated that MEOX2 could facilitate macrophage infiltration via CSF-1/CSF-1R signalling in ESCC and other kinds of digestive system carcinomas, and MEOX2 might serve as a novel target in prospective tumour immunotherapies.

Introduction to neuroendocrine neoplasms of the digestive system: definition and classification.

Neoplasms characterized by the expression of markers of neuroendocrine differentiation in neoplastic cells are defined neuroendocrine. This broad definition comprises tumors found at different sites of the body with similar morphology but different behavior and genetic background. From a clinical standpoint neuroendocrine neoplasms may be functioning, when they give rise to unregulated secretion of hormones. Functioning tumors account for about one-third of neuroendocrine neoplasms. From a pathological standpoint neuroendocrine neoplasm are classified by cancer category, cancer families/classes, cancer types, cancer grade and cancer stage. The category identifies the cancer major trait and thus defined as neuroendocrine neoplasia (NEN) to comprise all families/classes of neuroendocrine cancer. The cancer family/types are neuroendocrine tumors (NET) as well differentiated, and neuroendocrine carcinoma (NEC) as poorly differentiated forms. Cancer grade, based on proliferation measure by mitotic count and Ki-67%, and cancer stage, based on tumor size and invasion (T), node deposits (N) and distant metastases (M), complete the pathological classification. Site-specific differences are the rule. Still missing is a genetic classification tool to complement current pathological descriptors.

Cinnamaldehyde Could Reduce the Accumulation of Diarrhetic Shellfish Toxins in the Digestive Gland of the Mussel Perna viridis under Laboratory Conditions.

Diarrhetic shellfish toxins (DSTs), some of the most important phycotoxins, are distributed almost all over the world, posing a great threat to human health through the food chain. Therefore, it is of great significance to find effective methods to reduce toxin accumulation in shellfish. In this paper, we observed the effects of four phytochemicals including cinnamaldehyde (CA), quercetin, oridonin and allicin on the accumulation of DSTs in the digestive gland of Perna viridis after exposure to the DSTs-producing Prorocentrum lima. We found that, among the four phytochemicals, CA could effectively decrease the accumulation of DSTs (okadaic acid-eq) in the digestive gland of P. viridis. Further evidence demonstrated that CA could reduce the histological alterations of the digestive gland of a mussel caused by DSTs. RT-qPCR showed that CA could suppress the CYP3A4 induction by DSTs, suggesting that the DSTs' decrease induced by CA might be related to the inhibition of CYP3A4 transcription induction. However, further studies on the underlying mechanism, optimal treatment time, ecological safety and cost should be addressed before cinnamaldehyde is used to decrease the accumulation of DSTs in field.

Toxicity of gamma aluminium oxide nanoparticles in the Mediterranean mussel (Mytilus galloprovincialis): histopathological alterations and antioxidant responses in the gill and digestive gland.

PURPOSE: Accumulation of Gamma aluminium oxide nanoparticles γ-Al2O3 NPs significant impact on aquatic ecosystems. However, the toxicity of γ-Al2O3 NPs in aquatic organisms has been limited investigated. This study investigated histopathological changes and antioxidant responses induced by different concentrations of γ-Al2O3 NPs in Mytilus galloprovincialis. MATERIAL AND METHODS: In this study, mussels were exposed to different concentrations of 5 nm γ-Al2O3 NPs (0, 5, 20 and 40 mg/L) for 96 h under controlled laboratory conditions. Gill and digestive gland from mussels were assessed to histopathological (light microscopy, histopathological condition indices, digestive gland tubule types), SOD, CAT, GPx activities. RESULTS: Histopathological indices calculated higher, and significantly different in all exposure groups compared to the control group in gill and digestive gland (p < 0.05). Atrophic phase tubules proportion very high in 20 and 40 mg/L γ-Al2O3 NPs exposure groups. No significant changes in CAT activities in the gill and digestive gland (p > 0.05). Superoxide dismutase (SOD) activities significantly different (p ≤ 0.05) in the digestive gland from 20 mg/L γ-Al2O3 NPs exposures, and GPx activities significantly different (p < 0.05) in gill from 40 mg/L γ-Al2O3 NPs exposures. CONCLUSION: These results indicate that contamination of γ-Al2O3 NPs negatively affects the aquatic organism.

What is New in the 2019 World Health Organization (WHO) Classification of Tumors of the Digestive System: Review of Selected Updates on Neuroendocrine Neoplasms, Appendiceal Tumors, and Molecular Testing.

CONTEXT.­: The 5th edition of the World Health Organization classification of digestive system tumors discusses several advancements and developments in understanding the etiology, pathogenesis, and diagnosis of several digestive tract tumors. OBJECTIVE.­: To provide a summary of the updates with a focus on neuroendocrine neoplasms, appendiceal tumors, and the molecular advances in tumors of the digestive system. DATA SOURCES.­: English literature and personal experiences. CONCLUSIONS.­: Some of the particularly important updates in the 5th edition are the alterations made in the classification of neuroendocrine neoplasms, understanding of pathogenesis of appendiceal tumors and their precursor lesions, and the expanded role of molecular pathology in establishing an accurate diagnosis or predicting prognosis and response to treatment.

Fine Needle Aspiration Cytology of Malignant Digestive System Gastrointestinal Neuroectodermal Tumor in a Lymph Node Metastasis from a Previously Diagnosed Liver Primary: A Case Report and Review of Literature.

Malignant gastrointestinal neuroectodermal tumor (GNET) is an extremely rare neoplasm. Immunohistochemically, GNET typically demonstrates neural differentiation but lacks melanocytic differentiation, making it distinct from clear cell sarcoma of the soft tissues (CCS). Herein we report for the first time the cytomorphologic features of lymph node metastasis from presumably liver GNET. A 36-year-old female presented with fevers, night sweats, loss of appetite, and a 20-lbs weight loss. Radiographic imaging showed a 13 cm heterogeneously enhancing mass in the right lobe of the liver and a hypermetabolic 0.9 cm periportal lymph node on positron emission tomography-computed tomography (PET/CT). Initially, a CT-guided liver biopsy was performed followed by right hepatic lobectomy and portal lymphadenectomy. The liver biopsy and resection showed an S100-protein and SOX10 positive malignant neoplasm and genomic profiling of liver biopsy revealed EWSR1-CREB1gene rearrangement. These findings in conjunction with the morphologic and immunohistochemical profile were diagnostic of GNET. Two months later, she presented with recurrent lymphadenopathy in the upper abdomen. Fine needle aspiration of the periportal nodal mass revealed single and clusters of primitive, large to medium-sized neoplastic cells with round to oval nuclei, high nuclear-cytoplasmic ratio, vesicular chromatin, and prominent nucleoli. The tumor cells were S100 protein and SOX10 positive, consistent with metastasis of the patient's recently diagnosed malignant digestive system GNET. Palliative chemotherapy was administered but the patient died a few days later, 4 months from the initial diagnosis. Awareness of this entity and judicial use of ancillary studies including molecular testing are essential for achieving accurate diagnosis.

Pathologic Manifestations of Gastrointestinal and Hepatobiliary Injury in Immune Checkpoint Inhibitor Therapy.

CONTEXT.­: Immune checkpoint inhibitors (CPIs), including cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors and the programmed death receptor-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitors, are being increasingly used for treating many advanced malignancies. However, CPI therapy is also associated with gastrointestinal and hepatobiliary adverse effects. OBJECTIVES.­: To review the adverse effects of CPI therapy on the gastrointestinal tract and hepatobiliary system. To describe histopathologic patterns and discuss differential diagnostic considerations in the diagnosis of CPI injuries. DATA SOURCES.­: Published peer-reviewed literature in the English language and personal experience in the diagnosis of CPI injuries. CONCLUSIONS.­: The pathologic manifestations of CPI therapy-induced gastrointestinal and hepatobiliary injury are broad. The patterns of esophageal CPI injury include lymphocytic inflammation and ulcerative esophagitis, while those of gastric injury include chronic active gastritis, lymphocytic gastritis, focal enhancing gastritis, and periglandular inflammation. The duodenal injury may present as duodenitis with villous blunting and granulomas. We also noticed active colitis, microscopic colitis, chronic active colitis, increased apoptosis, ischemic colitis, and nonspecific inflammatory reactive changes in colonic injuries. The reported histologic features of hepatobiliary injuries are panlobular hepatitis, centrilobular necrosis, portal inflammation with bile duct injury, steatosis, nodular regenerative hyperplasia, and secondary sclerosing cholangitis. In summary, we discuss the pathologic features and differential diagnosis of CPI therapy-induced gastrointestinal and hepatobiliary injury. Recognition of CPI injury is important to determine the proper management that often includes cessation of CPI therapy, and administration of steroids or other immunosuppressive agents, based on severity of injury.

Digestive disorders associated with the consumption of palm fiber (Elaeis guineensis) in feedlot cattle / Distúrbios digestivos associados ao consumo de fibra de dendê (Elaeis guineensis) em bovinos criados em regime de confinamento

Digestive disorders in cattle are associated with the breeding system and feed provided to the animals. Abomasal compaction is primarily related to the ingestion of forage with elevated levels of lignin, low quality, and difficult digestibility. In addition, the excess of fibrous food in the diet can lead to phytobezoars that may be responsible for intestinal obstruction disorders. This study aimed to describe pathological and clinical aspects of an outbreak of digestive disorders associated with the consumption of palm fiber (Elaeis guineensis). The outbreak struck a herd of 499 animals raised in a feedlot system after a change in diet that included an increase in the amount of palm fiber. Forty (8.01%) animals showed clinical signs such as fattening and regurgitation during rumination, and 21 (4.2%) animals died later. The cattle affected presented with apathy, emaciation, dehydration, distended abdomen, incomplete or absent ruminal movements, and congestive mucosa. Three animals were submitted to necropsy, and distended rumen and reticulum has a large amount of brownish liquid, long and tangled vegetable fibers with sand and stones. In two animals, the omasum had many rounded structures measuring approximately 5cm in diameter, made of vegetable fiber (phytobezoars). Abomasum of animals had similar material to the rumen, and one animal had compressed content. In two animals, dilatation was observed in the small intestine, and in the opening, the total obstruction of the lumen by phytobezoar was observed. During the follow-up of the slaughter of 76 cattle, 15 (19.7%) had phytobezoars of different sizes in the omasum and abomasum. The increased amount of oil palm fiber in animal feeding favored the occurrence of compression abomasum and intestinal obstruction phytobezoa, causing significant economic losses.(AU)

Alguns distúrbios digestivos em bovinos podem estar associados ao sistema de criação e alimentação dos animais. Entre estes estão à compactação de abomaso e a obstrução intestinal por fitobezoários, ambas relacionadas principalmente com a ingestão de alimentos com altos níveis de lignina e, consequentemente, de difícil digestibilidade. Neste trabalho são descritos os aspectos clínicos e patológicos de um surto de distúrbios digestivos em bovinos associados ao consumo de fibra de dendê (Elaeis guineensis). O surto acometeu um rebanho de 499 bovinos, criados em sistema de confinamento, após uma mudança na dieta que incluiu o aumento na quantidade de fibra de dendê. Após a mudança 40 animais (8,01%) apresentaram diarreia, distensão abdominal e regurgitação durante a ruminação e 21 animais (4,2%) morreram. Os bovinos examinados clinicamente apresentavam sinais de apatia, emagrecimento, desidratação, abdômen distendido, movimentos ruminais incompletos e ausentes, além de mucosas congestas. Três animais foram submetidos à necropsia e observou-se rúmen e reticulo distendidos e com grande quantidade de líquido acastanhado, fibras vegetais longas e emaranhadas e presença de areia e pedras. Em dois animais o omaso continha grande número de estruturas arredondadas medindo aproximadamente 5cm de diâmetro, constituídas de fibras vegetais (fitobezoários). No abomaso dos animais havia material semelhante ao do rúmen, sendo que um animal apresentou conteúdo compactado e um deles também tinha fitobezoários. Em dois animais foram observadas dilatação e obstrução total do lúmen do intestino delgado por fitobezoários. Durante o acompanhamento do abate de 76 bovinos, 15 (19,7%) apresentavam fitobezoários de diferentes tamanhos no abomaso e omaso. O aumento da quantidade de fibra de dendê na alimentação dos animais favoreceu a ocorrência de casos de compactação de abomaso e obstrução intestinal por fitobezoários, ocasionando perdas econômicas significativas.(AU)

Óbitos pós-cirúrgicos em neonatos com malformações congênitas do aparelho digestivo ou osteomuscular / Post-surgical deaths in neonates with congenital malformations in the digestive or musculoskeletal systems / Muertes post-quirúrgicas en neonatos con malformaciones congénitas digestivas o musculoesqueléticas

Objetivo: Analisar a ocorrência de óbitos pós-cirúrgicos em recém-nascidos com malformação do aparelho digestivo ou osteomuscular em uma maternidade de referência. Método: Estudo exploratório, retrospectivo, de abordagem quantitativa, realizado em uma maternidade de referência localizada em Teresina ­ PI. Os dados foram coletados do Tabwin e de fichas de investigação de óbito infantil de neonatos nascidos em 2016 e 2017 e analisados no software Statistical Package for the Social Sciences. Resultados: O tipo de malformação mais prevalente do aparelho digestivo e osteomuscular entre os neonatos que foram a óbito após cirurgia foi o ânus imperfurado (41%) e a gastrosquise (64,2%), respectivamente. O choque séptico, seguido da insuficiência renal aguda foram os fatores determinantes dos óbitos analisados. Conclusão: O diagnóstico precoce é o fator primordial para redução da morbimortalidade de neonatos acometidos por malformações congênitas, uma vez que contribui para o direcionamento e planejamento dos cuidados imprescindíveis a esses pacientes

Objective: To analyze the occurrence of post-surgical deaths in newborns with malformation in the digestive or musculoskeletal systems in a reference maternity hospital. Method: This is an exploratory and retrospective study, with a quantitative approach, conducted in a reference maternity located in Teresina ­ PI. Data were collected from Tabwin and infant death investigation forms of neonates born in 2016 and 2017 and analyzed through the Statistical Package for the Social Sciences software. Results: The most prevalent type of malformation of the digestive and musculoskeletal systems among neonates who died after surgery was the imperforate anus (41%) and gastroschisis (64.2%), respectively. Septic shock, followed by acute kidney failure, constituted the determining factors of the analyzed deaths. Conclusion: Early diagnosis is the key factor for reducing morbidity and mortality in neonates affected by congenital malformations, as it contributes to the targeting and planning of care actions essential for these patients

Objetivo: Analizar la ocurrencia de muertes post-quirúrgicas en recién nacidos con malformación digestiva o musculoesquelética en una maternidad de referencia. Método: Estudio exploratorio, retrospectivo, con enfoque cuantitativo, realizado en una maternidad de referencia ubicada en Teresina - PI. Los datos se recopilaron de Tabwin y de registros de investigación de muerte infantil de neonatos en 2016 y 2017 y se analizaron utilizando el programa Statistical Package for the Social Sciences. Resultados: El tipo de malformación digestiva y musculoesquelética más frecuente entre los neonatos que murieron después de la cirugía fue el ano imperforado (41%) y la gastrosquisis (64,2%), respectivamente. El shock séptico, seguido de insuficiencia renal aguda, constituyeron los factores determinantes de las muertes analizadas. Conclusión: El diagnóstico temprano es el factor principal para reducir la morbimortalidad en los neonatos afectados por malformaciones congénitas, ya que contribuye a la dirección y planificación de la atención esencial para estos pacientes

Roles of Adipokines in Digestive Diseases: Markers of Inflammation, Metabolic Alteration and Disease Progression.

Adipose tissue is a highly dynamic endocrine tissue and constitutes a central node in the interorgan crosstalk network through adipokines, which cause pleiotropic effects, including the modulation of angiogenesis, metabolism, and inflammation. Specifically, digestive cancers grow anatomically near adipose tissue. During their interaction with cancer cells, adipocytes are reprogrammed into cancer-associated adipocytes and secrete adipokines to affect tumor cells. Moreover, the liver is the central metabolic hub. Adipose tissue and the liver cooperatively regulate whole-body energy homeostasis via adipokines. Obesity, the excessive accumulation of adipose tissue due to hyperplasia and hypertrophy, is currently considered a global epidemic and is related to low-grade systemic inflammation characterized by altered adipokine regulation. Obesity-related digestive diseases, including gastroesophageal reflux disease, Barrett's esophagus, esophageal cancer, colon polyps and cancer, non-alcoholic fatty liver disease, viral hepatitis-related diseases, cholelithiasis, gallbladder cancer, cholangiocarcinoma, pancreatic cancer, and diabetes, might cause specific alterations in adipokine profiles. These patterns and associated bases potentially contribute to the identification of prognostic biomarkers and therapeutic approaches for the associated digestive diseases. This review highlights important findings about altered adipokine profiles relevant to digestive diseases, including hepatic, pancreatic, gastrointestinal, and biliary tract diseases, with a perspective on clinical implications and mechanistic explorations.

Fungicide pyraclostrobin affects midgut morphophysiology and reduces survival of Brazilian native stingless bee Melipona scutellaris.

Native stingless bees are key pollinators of native flora and important for many crops. However, the loss of natural fragments and exposure to pesticides can hinder the development of colonies and represent a high risk for them. Nevertheless, most studies are conducted with honeybees and there are not many studies on native species, especially in relation to the effects of fungicides on them. Therefore, the objective of this paper is to evaluate the effects of sublethal concentrations of pyraclostrobin, on Melipona scutellaris forager workers. These Brazilian native stingless bees were submitted to continuous oral exposure to three concentrations of pyraclostrobin in sirup: 0.125 ng a.i./µL (P1), 0.025 ng a.i./µL (P2), and 0.005 ng a.i./µL (P3). Histopathological and histochemical parameters of midgut, as well as survival rate were evaluated. All concentrations of fungicide showed an increase in the midgut lesion index and morphological signs of cell death, such as cytoplasmic vacuolizations, presence of atypical nuclei or pyknotic nuclei. Histochemical analyzes revealed a decreased marking of polysaccharides and neutral glycoconjugates both in the villi and in peritrophic membrane in all exposed-groups in relation to control-groups. P1 and P2 groups presented a reduction in total protein marking in digestive cells in relation to control groups. As a consequence of alteration in the midgut, all groups exposed to fungicide showed a reduced survival rate. These findings demonstrate that sublethal concentrations of pyraclostrobin can lead to significant adverse effects in stingless bees. These effects on social native bees indicate the need for reassessment of the safety of fungicides to bees.

Biovar-related differences apparent in the flea foregut colonization phenotype of distinct Yersinia pestis strains do not impact transmission efficiency.

BACKGROUND: Yersinia pestis is the flea-transmitted etiological agent of bubonic plague. Sylvatic plague consists of complex tripartite interactions between diverse flea and wild rodent species, and pathogen strains. Transmission by flea bite occurs primarily by the Y. pestis biofilm-mediated foregut blockage and regurgitation mechanism, which has been largely detailed by studies in the model interaction between Y. pestis KIM6+ and Xenopsylla cheopis. Here, we test if pathogen-specific traits influence this interaction by determining the dynamics of foregut blockage development in X. cheopis fleas among extant avirulent pCD1-Y. pestis strains, KIM6+ and CO92, belonging to distinct biovars, and a non-circulating mutant CO92 strain (CO92gly), restored for glycerol fermentation; a key biochemical difference between the two biovars. METHODS: Separate flea cohorts infected with distinct strains were evaluated for (i) blockage development, bacterial burdens and flea foregut blockage pathology, and (ii) for the number of bacteria transmitted by regurgitation during membrane feeding. Strain burdens per flea was determined for fleas co-infected with CO92 and KIM6+ strains at a ratio of 1:1. RESULTS: Strains KIM6+ and CO92 developed foregut blockage at similar rates and peak temporal incidences, but the CO92gly strain showed significantly greater blockage rates that peak earlier post-infection. The KIM6+ strain, however, exhibited a distinctive foregut pathology wherein bacterial colonization extended the length of the esophagus up to the feeding mouthparts in ~65% of blocked fleas; in contrast to 32% and 26%, respectively, in fleas blocked with CO92 and CO92gly. The proximity of KIM6+ to the flea mouthparts in blocked fleas did not result in higher regurgitative transmission efficiencies as all strains transmitted variable numbers of Y. pestis, albeit slightly lower for CO92gly. During competitive co-infection, strains KIM6+ and CO92 were equally fit maintaining equivalent infection proportions in fleas over time. CONCLUSIONS: We demonstrate that disparate foregut blockage pathologies exhibited by distinct extant Y. pestis strain genotypes do not influence transmission efficiency from X. cheopis fleas. In fact, distinct extant Y. pestis genotypes maintain equivalently effective blockage and transmission efficiencies which is likely advantageous to maintaining continued successful plague spread and establishment of new plague foci.

Carbon Monoxide Being Hydrogen Sulfide and Nitric Oxide Molecular Sibling, as Endogenous and Exogenous Modulator of Oxidative Stress and Antioxidative Mechanisms in the Digestive System.

Oxidative stress reflects an imbalance between oxidants and antioxidants in favor of the oxidants capable of evoking tissue damage. Like hydrogen sulfide (H2S) and nitric oxide (NO), carbon monoxide (CO) is an endogenous gaseous mediator recently implicated in the physiology of the gastrointestinal (GI) tract. CO is produced in mammalian tissues as a byproduct of heme degradation catalyzed by the heme oxygenase (HO) enzymes. Among the three enzymatic isoforms, heme oxygenase-1 (HO-1) is induced under conditions of oxidative stress or tissue injury and plays a beneficial role in the mechanism of protection against inflammation, ischemia/reperfusion (I/R), and many other injuries. According to recently published data, increased endogenous CO production by inducible HO-1, its delivery by novel pharmacological CO-releasing agents, or even the direct inhalation of CO has been considered a promising alternative in future experimental and clinical therapies against various GI disorders. However, the exact mechanisms underlying behind these CO-mediated beneficial actions are not fully explained and experimental as well as clinical studies on the mechanism of CO-induced protection are awaited. For instance, in a variety of experimental models related to gastric mucosal damage, HO-1/CO pathway and CO-releasing agents seem to prevent gastric damage mainly by reduction of lipid peroxidation and/or increased level of enzymatic antioxidants, such as superoxide dismutase (SOD) or glutathione peroxidase (GPx). Many studies have also revealed that HO-1/CO can serve as a potential defensive pathway against oxidative stress observed in the liver and pancreas. Moreover, increased CO levels after treatment with CO donors have been reported to protect the gut against formation of acute GI lesions mainly by the regulation of reactive oxygen species (ROS) production and the antioxidative activity. In this review, we focused on the role of H2S and NO molecular sibling, CO/HO pathway, and therapeutic potential of CO-releasing pharmacological tools in the regulation of oxidative stress-induced damage within the GI tract with a special emphasis on the esophagus, stomach, and intestines and also two solid and important metabolic abdominal organs, the liver and pancreas.

Loss of control of the culturable bacteria in the hindgut of Bombyx mori after Cry1Ab ingestion.

Bt protein, produced by Bacillus thuringiensis, can bind receptors to destroy the physiological functions of the insect midgut. It is unknown whether Bt can also target the hindgut and influence its defense against fecal bacteria. Here we show that Crystal protein 1Ab (Cry1Ab), a Bt protein, was detected in the larval hindgut contents of Bombyx mori after ingestion of this toxin protein. The number of fecal bacteria that can be inhibited by the hindgut prophenoloxidase-induced melanization was significantly enhanced after oral ingestion of Cry1Ab. Although the hindgut contents became brown, the activity of hindgut phenoloxidase was decreased. LC-MS/MS analysis of the hindgut lumen contents revealed that many new proteins including several proteases were newly secreted. The enhanced secretion of proteases cleaved prophenoloxidase to decrease its activity, including the corresponding activity to inhibit the fecal bacteria. In addition, after ingestion of Cry1Ab, the pylorus (between the midgut and hindgut) could not autonomously contract due to the physical detachment of the acellular cuticle-like membrane from the epidermal cells, which prevented the movement of food from the midgut to the hindgut. Some cells in the cryptonephry of the hindgut became swollen and degraded, possibly due to the presence of Cry1Ab in the hindgut. These findings demonstrate that the inhibition of feces bacteria by the hindgut prophenoloxidase-induced melanization is out of control after Cry1Ab ingestion.