Medaka liver developed Human NAFLD-NASH transcriptional signatures in response to ancestral bisphenol A exposure.

The progression of fatty liver disease to non-alcoholic steatohepatitis (NASH) is a leading cause of death in humans. Lifestyles and environmental chemical exposures can increase the susceptibility of humans to NASH. In humans, the presence of bisphenol A (BPA) in urine is associated with fatty liver disease, but whether ancestral BPA exposure leads to the activation of human NAFLD-NASH-associated genes in the unexposed descendants is unclear. In this study, using medaka fish as an animal model for human NAFLD, we investigated the transcriptional signatures of human NAFLD-NASH and their associated roles in the pathogenesis of the liver of fish that were not directly exposed, but their ancestors were exposed to BPA during embryonic and perinatal development three generations prior. Comparison of bulk RNA-Seq data of the liver in BPA lineage male and female medaka with publicly available human NAFLD-NASH patient data revealed transgenerational alterations in the transcriptional signature of human NAFLD-NASH in medaka liver. Twenty percent of differentially expressed genes (DEGs) were upregulated in both human NAFLD patients and medaka. Specifically in females, among the total shared DEGs in the liver of BPA lineage fish and NAFLD patient groups, 27.69% were downregulated, and 20% were upregulated. Of all DEGs, 52.31% of DEGs were found in ancestral BPA-lineage females, suggesting that NAFLD in females shared the majority of human NAFLD gene networks. Pathway analysis revealed beta-oxidation, lipoprotein metabolism, and HDL/LDL-mediated transport processes linked to downregulated DEGs in BPA lineage males and females. In contrast, the expression of genes encoding lipogenesis-related proteins was significantly elevated in the liver of BPA lineage females only. BPA lineage females exhibiting activation of myc, atf4, xbp1, stat4, and cancerous pathways, as well as inactivation of igf1, suggest their possible association with an advanced NAFLD phenotype. The present results suggest that gene networks involved in the progression of human NAFLD and the transgenerational NAFLD in medaka are conserved and that medaka can be an excellent animal model to understand the development and progression of liver disease and environmental influences in the liver.

Sex-specific expression of the human NAFLD-NASH transcriptional signatures in the liver of medaka with a history of ancestral bisphenol A exposure.

The progression of fatty liver disease to non-alcoholic steatohepatitis (NASH) is a leading cause of death in humans. Lifestyles and environmental chemical exposures can increase the susceptibility of humans to NASH. In humans, the presence of bisphenol A (BPA) in urine is associated with fatty liver disease, but whether ancestral BPA exposure leads to the activation of human NAFLD-NASH-associated genes in the unexposed descendants is unclear. In this study, using medaka fish as an animal model for human NAFLD, we investigated the transcriptional signatures of human NAFLD-NASH and their associated roles in the pathogenesis of the liver of fish who were not directly exposed but their ancestors were exposed to BPA during embryonic and perinatal development three generations prior. Comparison of bulk RNA-Seq data of the liver in BPA lineage male and female medaka with publicly available human NAFLD-NASH patient data revealed transgenerational alterations in the transcriptional signature of human NAFLD-NASH in medaka liver. Twenty percent of differentially expressed genes (DEGs) were upregulated in both human NAFLD patients and medaka. Specifically in females, among the total shared DEGs in the liver of BPA lineage fish and NAFLD patient groups, 27.69% DEGs were downregulated and 20% DEGs were upregulated. Off all DEGs, 52.31% DEGs were found in ancestral BPA-lineage females, suggesting that NAFLD in females shared majority of human NAFLD gene networks. Pathway analysis revealed beta-oxidation, lipoprotein metabolism, and HDL/LDL-mediated transport processes linked to downregulated DEGs in BPA lineage males and females. In contrast, the expression of genes encoding lipogenesis-related proteins was significantly elevated in the liver of BPA lineage females only. BPA lineage females exhibiting activation of myc, atf4, xbp1, stat4, and cancerous pathways, as well as inactivation of igf1, suggest their possible association with an advanced NAFLD phenotype. The present results suggest that gene networks involved in the progression of human NAFLD and the transgenerational NAFLD in medaka are conserved and that medaka can be an excellent animal model to understand the development and progression of liver disease and environmental influences in the liver.

Emerging Role of Plant-Based Bioactive Compounds as Therapeutics in Parkinson's Disease.

Neurological ailments, including stroke, Alzheimer's disease (AD), epilepsy, Parkinson's disease (PD), and other related diseases, have affected around 1 billion people globally to date. PD stands second among the common neurodegenerative diseases caused as a result of dopaminergic neuron loss in the midbrain's substantia nigra regions. It affects cognitive and motor activities, resulting in tremors during rest, slow movement, and muscle stiffness. There are various traditional approaches for the management of PD, but they provide only symptomatic relief. Thus, a survey for finding new biomolecules or substances exhibiting the therapeutic potential to patients with PD is the main focus of present-day research. Medicinal plants, herbal formulations, and natural bioactive molecules have been gaining much more attention in recent years as synthetic molecules orchestrate a number of undesired effects. Several in vitro, in vivo, and in silico studies in the recent past have demonstrated the therapeutic potential of medicinal plants, herbal formulations, and plant-based bioactives. Among the plant-based bioactives, polyphenols, terpenes, and alkaloids are of particular interest due to their potent anti-inflammatory, antioxidant, and brain-health-promoting properties. Further, there are no concise, elaborated articles comprising updated mechanism-of-action-based reviews of the published literature on potent, recently investigated (2019-2023) medicinal plants, herbal formulations, and plant based-bioactive molecules, including polyphenols, terpenes, and alkaloids, as a method for the management of PD. Therefore, we designed the current review to provide an illustration of the efficacious role of various medicinal plants, herbal formulations, and bioactives (polyphenols, terpenes, and alkaloids) that can become potential therapeutics against PD with greater specificity, target approachability, bioavailability, and safety to the host. This information can be further utilized in the future to develop several value-added formulations and nutraceutical products to achieve the desired safety and efficacy for the management of PD.

The PCOS-NAFLD Multidisease Phenotype Occurred in Medaka Fish Four Generations after the Removal of Bisphenol A Exposure.

As a heterogeneous reproductive disorder, polycystic ovary syndrome (PCOS) can be caused by genetic, diet, and environmental factors. Bisphenol A (BPA) can induce PCOS and nonalcoholic fatty liver disease (NAFLD) due to direct exposure; however, whether these phenotypes persist in future unexposed generations is not currently understood. In a previous study, we observed that transgenerational NAFLD persisted in female medaka for five generations (F4) after exposure to an environmentally relevant concentration (10 µg/L) of BPA. Here, we demonstrate PCOS in the same F4 generation female medaka that developed NAFLD. The ovaries contained immature follicles, restricted follicular progression, and degenerated follicles, which are characteristics of PCOS. Untargeted metabolomic analysis revealed 17 biomarkers in the ovary of BPA lineage fish, whereas transcriptomic analysis revealed 292 genes abnormally expressed, which were similar to human patients with PCOS. Metabolomic-transcriptomic joint pathway analysis revealed activation of the cancerous pathway, arginine-proline metabolism, insulin signaling, AMPK, and HOTAIR regulatory pathways, as well as upstream regulators esr1 and tgf signaling in the ovary. The present results suggest that ancestral BPA exposure can lead to PCOS phenotypes in the subsequent unexposed generations and warrant further investigations into potential health risks in future generations caused by initial exposure to EDCs.

NFκB1 inhibits memory formation and supports effector function of ILC2s in memory-driven asthma.

Background: ILC2s are capable of generating memory. The mechanism of memory induction and memory-driven effector function (trained immunity) in ILC2s is unknown. Objective: NFκB1 is preferentially expressed at a high level in ILC2s. We examined the role of NFkB1 in memory induction and memory-driven effector function in a mouse model of asthma. Methods: Intranasal administration of Alternaria, flexivent, ELISA, histology, real-time PCR, western blot, flow cytometry and immunofluorescence staining. Results: NFκB1 was essential for the effector phase of memory-driven asthma. NFκB1 was critical for IL33 production, ILC2 generation, and production of type-2 cytokines, which resulted in eosinophilic inflammation and other features of asthma. NFκB1 induction of type-2 cytokines in ILC2s was independent of GATA3. NFκB1 was important for allergen induction of ILC3s and FoxP3+ Tregs. NFκB1 did not affect Th2 cells or their cytokine production. In contrast to its protagonistic role in the effector phase, NFκB1 had an antagonistic role in the memory phase. NFκB1 inhibited allergen-induced upregulation of memory-associated repressor and preparedness genes in ILC2s. NFκB1 upregulated RUNX1. NFκB1 formed a heterodimer with RUNX1 in ILC2s. Conclusions: NFκB1 positively regulated the effector phase but inhibited the induction phase of memory. The foregoing pointed to an interdependent antagonism between the memory induction and the memory effector processes. The NFκB1-RUNX1 heterodimer represented a non-canonical transcriptional activator of type-2 cytokines in ILC2s.

The emerging role of PI3K inhibitors for solid tumour treatment and beyond.

Phosphoinositide 3-kinases (PI3Ks) play a central role in tumourigenesis with recurrent activating mutations of its p110α subunit (PIK3CA) identified in several tumours. Although several PI3K inhibitors are approved for haematological malignancies, only alpelisib was approved in solid tumours and for the treatment of PIK3CA-related overgrowth spectrum (PROS) syndrome. Traditional PI3K inhibitors inhibit both wild-type and mutant PI3K with almost equal potency, thus limiting their efficacy due to on-target toxicity. Since the initiation of phase I clinical trials investigating next generation allosteric mutant and isoform selective PIK3CA inhibitors, there has been a surge in interest in PIK3CA targeting in solid tumours. Preclinical characterisation of these compounds showed that maximal mutant protein inhibition fails to elicit metabolic and glucose homoeostasis dysregulation, one of the dose limiting toxicities of both selective and pan PI3K inhibitors. While extreme selectivity can be hypothesised to grant activity and safety advantage to these novel agents, on the other hand reduced benefit can be speculated for patients harbouring multiple or rare PIK3CA mutations. This review summarises the current understanding of PI3K alterations and the state-of-the-art treatment strategies in PI3K driven solid tumours, while also exploring the potential intrinsic and acquired resistance mechanisms to these agents, and the emerging role of mutant selective PIK3CA inhibitors.

Polyphenols and Their Nanoformulations: Protective Effects against Human Diseases.

Polyphenols are the secondary metabolites synthesized by the plants as a part of defense machinery. Owing to their antioxidant, anti-inflammatory, anticancerous, antineoplastic, and immunomodulatory effects, natural polyphenols have been used for a long time to prevent and treat a variety of diseases. As a result, these phytochemicals may be able to act as therapeutic agents in treating cancer and cardiovascular and neurological disorders. The limited bioavailability of polyphenolic molecules is one issue with their utilization. For the purpose of increasing the bioavailability of these chemicals, many formulation forms have been developed, with nanonization standing out among them. The present review outlines the biological potential of nanoformulated plant polyphenolic compounds. It also summarizes the employability of various polyphenols as nanoformulations for cancer and neurological and cardiovascular disease treatment. Nanoencapsulated polyphenols, singular or in combinations, effective both in vitro and in vivo, need more investigation.

Necrotic debris and STING exert therapeutically relevant effects on tumor cholesterol homeostasis.

Malignant tumors commonly display necrosis, which invariably triggers an inflammatory response that supports tumor growth. However, the effect on tumor cells of necrotic debris, or damage-associated molecular patterns (DAMPs) released by dying cells is unknown. Here, we addressed the effect of DAMPs on primary Ewing sarcoma (EwS) cells and cell lines grown in 3D (spheroids) and 2D culture. We show that DAMPs promote the growth of EwS spheroids but not 2D cultures and that the underlying mechanism implicates an increase in cholesterol load in spheroids. In contrast, stimulation of the nucleic acid sensor signaling platform STING by its ligand cyclic GMP-AMP decreases the tumor cell cholesterol load and reduces their tumor initiating ability. Overexpression of STING or stimulation with cyclic GMP-AMP opposes the growth stimulatory effect of DAMPs and synergizes with the cholesterol synthesis inhibitor simvastatin to inhibit tumor growth. Our observations show that modulation of cholesterol homeostasis is a major effect of necrotic cell debris and STING and suggest that combining STING agonists with statins may help control tumor growth.

Correlation of serum cornitine levels with bone mineral density among Indian male tobacco users.

It is of interest to assess levels of serum cornitine in male tobacco users and also find its correlation with bone mineral density. Assessment for serum cotinine levels was done using commercially available Enzyme Linked Immunosorbent Assay (ELISA Kit). While bone mineral density was measured using bone densitometry through ultrasound in the wrist region. Karl Pearson's coefficient was used to assess correlation between BMD values and serum cotinine (ng/ml) levels. Inter group BMD association was measured using Chi square test. The present study showed that the first 3 groups had a low BMD level compared to control group, indicative of osteopenia. BMD values were lesser for chewers from group II as compared to smokers from group I and individuals using both smoked and smokeless form of tobacco from Group III. In group III (both forms of tobacco), osteopenic individuals were more. Thus, data shows effect of tobacco usage on bone mineral density. Smokeless form of tobacco has relatively serious effects on bone density.

Genomic and functional evaluation of TNFSF14 in multiple sclerosis susceptibility.

Among multiple sclerosis (MS) susceptibility genes, the strongest non-human leukocyte antigen (HLA) signal in the Italian population maps to the TNFSF14 gene encoding LIGHT, a glycoprotein involved in dendritic cell (DC) maturation. Through fine-mapping in a large Italian dataset (4,198 patients with MS and 3,903 controls), we show that the TNFSF14 intronic SNP rs1077667 is the primarily MS-associated variant in the region. Expression quantitative trait locus (eQTL) analysis indicates that the MS risk allele is significantly associated with reduced TNFSF14 messenger RNA levels in blood cells, which is consistent with the allelic imbalance in RNA-Seq reads (P < 0.0001). The MS risk allele is associated with reduced levels of TNFSF14 gene expression (P < 0.01) in blood cells from 84 Italian patients with MS and 80 healthy controls (HCs). Interestingly, patients with MS are lower expressors of TNFSF14 compared to HC (P < 0.007). Individuals homozygous for the MS risk allele display an increased percentage of LIGHT-positive peripheral blood myeloid DCs (CD11c+, P = 0.035) in 37 HCs, as well as in in vitro monocyte-derived DCs from 22 HCs (P = 0.04). Our findings suggest that the intronic variant rs1077667 alters the expression of TNFSF14 in immune cells, which may play a role in MS pathogenesis.

Fabrication and in vitro Evaluation of 4-HIA Encapsulated PLGA Nanoparticles on PC12 Cells.

PURPOSE: 4-Hydroxyisophthalic acid (4-HIA) is a bioactive compound present in the roots of Decalepis hamiltonii, which has attracted considerable attention in attenuating oxidative stress-related neurodegenerative diseases. However, its efficacy is limited because of its low solubility and bioavailability. Therefore, the present study aimed to encapsulate 4-HIA using biocompatible copolymer polylactide-co-glycolide (PLGA) and evaluate its antioxidant and neuroprotective potential. METHODS: The nanoparticles (NPs) were fabricated by solid/oil/water (s/o/w) emulsion technique and characterized using XRD, SEM, HR-TEM, and FTIR spectroscopy. Antioxidant assays such as 1,1 diphenyl-2-picrylhydrazyl (DPPH), superoxide, and hydroxyl radical scavenging ability were performed to assess the antioxidant potential of the fabricated NPs. RESULTS: The bioactive component, 4-HIA, was efficiently encapsulated by the PLGA polymer and was found to be spherical and smooth with a size <10nm. 4-HIA showed better scavenging capability in DPPH and superoxide assays as compared to 4-HIA encapsulated PLGA and butylated hydroxytoluene (BHT). In contrast, 4-HIA encapsulated PLGA NPs exhibited a significant hydroxyl radical scavenging activity than 4-HIA and BHT alone. Further, the encapsulated NPs efficiently curtailed hydrogen peroxide (H2O2)-induced cytotoxicity in PC12 cells. CONCLUSION: Our findings indicate that 4-HIA encapsulated PLGA NPs might be a therapeutic intervention towards the effective management of oxidative stress as it has exhibited efficient neuroprotective potential against H2O2-induced oxidative stress in PC12 cells.

Biomarkers for Hepatocellular Carcinoma-An Updated Review.

Hepatocellular carcinoma (HCC) stands third among cancer-related deaths globally. Owing to its high incidence and linked mortality, early diagnosis is alarming for patient survival and the management of patients with developing HCC requires immediate attention. Advances in the knowledge of cancer biology and recognizing unique molecular candidates, including genomic and proteomic profiles, substantiate our understanding about several biological signatures connected with HCC. Precise identification and differential diagnosis of early HCC can remarkably improve patient survival. Currently, detection of HCC in clinical practice is performed by diagnostic imaging and noninvasive methods such as evaluation of serum biomarkers, growth factors, and the like. In this review, we discuss recent developments in targeting biomarkers for HCC.

Functional Pro-metastatic Heterogeneity Revealed by Spiked-scRNAseq Is Shaped by Cancer Cell Interactions and Restricted by VSIG1.

How cells with metastatic potential, or pro-metastatic states, arise within heterogeneous primary tumors remains unclear. Here, we have used one index primary colon cancer to develop spiked-scRNAseq to link omics-defined single-cell clusters with cell behavior. Using spiked-scRNAseq we uncover cell populations with differential metastatic potential in which pro-metastatic states are correlated with the expression of signaling and vesicle-trafficking genes. Analyzing such heterogeneity, we define an anti-metastatic, non-cell-autonomous interaction originating from non-/low-metastatic cells, and identify membrane VSIG1 as a critical mediator of this interaction. VSIG1 acts to restrict the development of pro-metastatic states autonomously and non-cell autonomously, in part by inhibiting YAP/TAZ-TEAD signaling. As VSIG1 re-expression is able to reduce metastatic behavior from multiple colon cancer cell types, the regulation of VSIG1 or its effectors opens new interventional opportunities. In general, we propose that crosstalk between cancer cells, including the action of VSIG1, dynamically defines the degree of pro-metastatic intra-tumoral heterogeneity.

Development and Validation of a Serum Metabolomic Signature for Endometrial Cancer Screening in Postmenopausal Women.

Importance: Endometrial carcinoma (EC) is the most commonly diagnosed gynecologic cancer. Its early detection is advisable because 20% of women have advanced disease at the time of diagnosis. Objective: To clinically validate a metabolomics-based classification algorithm as a screening test for EC. Design, Setting, and Participants: This diagnostic study enrolled 2 cohorts. A multicenter prospective cohort, with 50 cases (postmenopausal women with EC; International Federation of Gynecology and Obstetrics stage I-III and grade G1-G3) and 70 controls (no EC but matched on age, years from menopause, tobacco use, and comorbidities), was used to train multiple classification models. The accuracy of each trained model was then used as a statistical weight to produce an ensemble machine learning algorithm for testing, which was validated with a subsequent prospective cohort of 1430 postmenopausal women. The study was conducted at the San Giovanni di Dio e Ruggi d'Aragona University Hospital of Salerno (Italy) and Lega Italiana per la Lotta contro i Tumori clinic in Avellino (Italy). Data collection was conducted from January 2018 to February 2019, and analysis was conducted from January to March 2019. Main Outcomes and Measures: The presence or absence of EC based on evaluation of the blood metabolome. Metabolites were extracted from dried blood samples from all participants and analyzed by gas chromatography-mass spectrometry. A confusion matrix was used to summarize test results. Performance indices included sensitivity, specificity, positive and negative predictive values, positive and negative likelihood ratios, and accuracy. Confirmation or exclusion of EC in women with a positive test result was by means of hysteroscopy. Participants with negative results were followed up 1 year after enrollment to investigate the appearance of EC signs. Results: The study population consisted of 1550 postmenopausal women. The mean (SD) age was 68.2 (11.7) years for participants with no EC in the training cohort, 69.4 (13.8) years for women with EC in the training cohort, and 59.7 (7.7) years for women in the validation cohort. Application of the ensemble machine learning to the validation cohort resulted in 16 true-positives, 2 false-positives, and 0 false-negatives, and it correctly classified more than 99% of samples. Disease prevalence was 1.12% (16 of 1430). Conclusions and Relevance: In this study, dried blood metabolomic profile was used to assess the presence or absence of EC in postmenopausal women not receiving hormonal therapy with greater than 99% accuracy.

Progresses Toward Precision Medicine in RET-altered Solid Tumors.

RET (rearranged during transfection) gene encodes a receptor tyrosine kinase essential for many physiologic functions, but RET aberrations are involved in many pathologies. While RET loss-of-function mutations are associated with congenital disorders like Hirschsprung disease and CAKUT, RET gain-of-function mutations and rearrangements are critical drivers of tumor growth and proliferation in many different cancers. RET-altered (RET+ ) tumors have been hitherto targeted with multikinase inhibitors (MKI) having anti-RET activities, but they inhibit other kinase targets more potently and show limited clinical activities. The lack of target specificity and consequently increased side effects, responsible for dose reduction and drug discontinuation, are critical limitations of MKIs in the clinics. New selective RET inhibitors, selpercatinib and pralsetinib, are showing promising activities, improved response rates, and more favorable toxicity profiles in early clinical trials. This review critically discusses the oncogenic activation of RET and its role in different kinds of tumors, clinical features of RET+ tumors, clinically actionable genetic RET alterations and their diagnosis, and the available data and results of nonselective and selective targeting of RET.

The protein secretion modulator TMED9 drives CNIH4/TGFα/GLI signaling opposing TMED3-WNT-TCF to promote colon cancer metastases.

How cells in primary tumors initially become pro-metastatic is not understood. A previous genome-wide RNAi screen uncovered colon cancer metastatic suppressor and WNT promoting functions of TMED3, a member of the p24 ER-to-Golgi protein secretion family. Repression of canonical WNT signaling upon knockdown (kd) of TMED3 might thus be sufficient to drive metastases. However, searching for transcriptional influences on other family members here we find that TMED3 kd leads to enhanced TMED9, that TMED9 acts downstream of TMED3 and that TMED9 kd compromises metastasis. Importantly, TMED9 pro-metastatic function is linked to but distinct from the repression of TMED3-WNT-TCF signaling. Functional rescue of the migratory deficiency of TMED9 kd cells identifies TGFα as a mediator of TMED9 pro-metastatic activity. Moreover, TMED9 kd compromises the biogenesis, and thus function, of TGFα. Analyses in three colon cancer cell types highlight a TMED9-dependent gene set that includes CNIH4, a member of the CORNICHON family of TGFα exporters. Our data indicate that TGFA and CNIH4, which display predictive value for disease-free survival, promote colon cancer cell metastatic behavior, and suggest that TMED9 pro-metastatic function involves the modulation of the secretion of TGFα ligand. Finally, TMED9/TMED3 antagonism impacts WNT-TCF and GLI signaling, where TMED9 primacy over TMED3 leads to the establishment of a positive feedback loop together with CNIH4, TGFα, and GLI1 that enhances metastases. We propose that primary colon cancer cells can transition between two states characterized by secretion-transcription regulatory loops gated by TMED3 and TMED9 that modulate their metastatic proclivities.

Minimally Invasive Esophagectomy with Thoracic Duct Resection Post Neoadjuvant Chemoradiotherapy for Carcinoma Esophagus-Impact on Lymph Node Yield and Hemodynamic Parameters.

BACKGROUND: Neoadjuvant therapy followed by surgery is the current recommended treatment for locally advanced esophageal carcinoma. Thoracic duct (TD) resection was indicated for radical mediastinal lymphadenectomy. However, TD resection can cause hemodynamic disturbances. The presence of metastasis in TD has not been previously studied. METHODS: Twenty-two patients who underwent minimally invasive esophagectomy with D2 lymphadenectomy after neoadjuvant chemoradiotherapy for esophageal squamous cell carcinoma were analyzed. Ten patients had their TD resected from thoracic inlet till the esophageal hiatus. Multiple histopathological sections of the TD were examined for evidence of tumor spread. Intraoperative and immediate (48 h) postoperative hemodynamic parameters, lymph node yield, and postoperative morbidity were compared between TD-resected and TD-preserved groups. RESULTS: The median postoperative day 1 fluid requirement (3310 mL vs. 2875 mL, P = 0.059) and the median postoperative day 2 pulse rate were higher in the TD-resected group (111/min vs. 95/min, P = 0.043). There was no significant difference in the intraoperative fluid infusion, blood loss, urine output, mean blood pressure, pulse rate, postoperative urine output, and mean blood pressure between two groups. Median (range) mediastinal lymph node count was similar in TD-resected and TD-preserved groups [15(11-32) vs. 14(9-31), P = 0.283]. Pathological examination of TD did not reveal tumor cells in any of the patients. There was no significant difference in the postoperative morbidity between two groups except for cervical anastomotic dehiscence (P = 0.007). CONCLUSIONS: Minimally invasive esophagectomy with TD resection causes minor hemodynamic changes in the immediate postoperative period, without adversely affecting the postoperative outcome. In the setting of neoadjuvant chemoradiotherapy, TD resection does not increase lymph node yield.

Is histopathological examination of sleeve gastrectomy specimens necessary in areas endemic for gastric cancer?

Background: The value of histopathological examination of a laparoscopic sleeve gastrectomy (LSG) specimen in areas endemic for Helicobacter pylori (H. pylori) and gastric cancer is not known. We assessed the histopathological findings of LSG specimens to determine whether routine histopathological examination of these would be useful in patients with normal preoperative upper gastrointestinal endoscopy findings in an area endemic for gastric cancer. Methods: We did a retrospective analysis of the histopathological findings of LSG specimens in patients who underwent the procedure between March 2015 and March 2017. We ascertained the association of positive histopathological findings with the clinical profile of patients and preoperative upper gastrointestinal endoscopy findings. Results: Twenty-six patients (16 females) with a mean age of 37.5 years underwent LSG during the study period. On preoperative upper gastrointestinal endoscopy, 18 patients had unremarkable findings. Of the three patients with gastric or duodenal erosions on upper gastrointestinal endoscopy, two had H. pylori infection. On histopathological examination, 14 patients had unremarkable findings. Chronic gastritis with or without follicle formation was the most common finding (n=7). None of the patients with normal upper gastrointestinal endoscopy findings had significant histopathological findings or evidence of H. pylori infection. No significant association was found between age, gender, body mass index, smoking and alcohol intake with positive histopathological findings (p=0.64, 0.91, 0.90, 0.10 and 0.94, respectively). Conclusions: We did not find clinically important histopathological findings on routine examination of the LSG specimen in bariatric patients with normal preoperative upper gastrointestinal endoscopy findings.

Totally Robotic Roux-en-Y Gastric Bypass: Technique.

The da Vinci(TM) robotic system (Intuitive Surgical, Inc, Sunnyvale, CA) has been used frequently for urological procedures including radical prostatectomy and pyeloplasty. Its use in bariatric surgery is limited to few high volume centres in the western world. The advantages of robotic assistance are three-dimensional vision, ergonomic advantage and improved precision. We report our experience of using this advanced technology to perform a robotic Roux-en-Y gastric bypass in a 55-year-old obese diabetic patient. We were able to reproduce our standard laparoscopic technique and all the steps of the surgical procedure were done using robotic assistance.

Food protein-derived bioactive peptides in management of type 2 diabetes.

BACKGROUND: Type 2 diabetes (T2D), one of the major common human health problems, is growing at an alarming rate around the globe. Alpha-glucosidase and dipeptidyl peptidase IV (DPP-IV) enzymes play a significant role in development of T2D. Hence, reduction or inhibition of their activity can be one of the important strategies in management of T2D. Studies in the field of bioactive peptides have shown that dietary proteins could be natural source of alpha-glucosidase and DPP-IV inhibitory peptides. PURPOSE: The purpose of this review is to provide an overview of food protein-derived peptides as potential inhibitors of alpha-glucosidase and DPP-IV with major focus on milk proteins. METHODS: Efforts have been made to review the available information in literature on the relationship between food protein-derived peptides and T2D. This review summarizes the current data on alpha-glucosidase and dipeptidyl peptidase IV inhibitory bioactive peptides derived from proteins and examines the potential value of these peptides in the treatment and prevention of T2D. In addition, the proposed modes of inhibition of peptide inhibitors are also discussed. RESULTS: Studies revealed that milk and other food proteins-derived bioactive peptides play a vital role in controlling T2D through several mechanisms, such as the satiety response, regulation of incretin hormones, insulinemia levels, and reducing the activity of carbohydrate degrading digestive enzymes. CONCLUSIONS: The bioactive peptides could be used in prevention and management of T2D through functional foods or nutraceutical supplements. Further clinical trials are necessary to validate the findings of in vitro studies and to confirm the efficiency of these peptides for applications.