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Background and Aims: Helicobacter pylori (H. pylori)‐induced gastric pathology involves remodeling of extracellular matrix mediated by aberrant activity of matrix metalloproteinases (MMPs). We have previously shown that in vitro H. pylori infection leads to MMP‐3 and MMP‐9 overexpression, associated with phosphorylation of bacterial oncoprotein CagA. We extended these findings in an in vivo model of H. pylori infection and further assessed the involvement of MAPK pathways in MMP expression. Materials and Methods: C57BL/6 mice were infected with H. pylori strains HPARE, HPARE ΔCagA, and SS1, for 6 and 9 months. Transcriptional expression of Mmp‐3 and Mmp‐9 was evaluated via qPCR while respective protein levels in the gastric mucosa were determined immunohistochemically. Epithelial cell lines AGS and GES‐1 were infected with H. pylori strain P12 in the presence of chemical inhibitors of JNK, ERK1/2, and p38 pathways, for 24 h. mRNA and protein expression of MMP‐3 and MMP‐9 were determined via qPCR and Western blot, respectively. Results: We observed transcriptional activation of Mmp‐3 and Mmp‐9 as well as aberrant MMP‐3 and MMP‐9 protein expression in murine gastric tissue following H. pylori infection. CagA expression was associated with MMP upregulation, particularly during the early time points of infection. We found that inhibition of ERK1/2 resulted in reduced mRNA and protein expression of MMP‐3 and MMP‐9 during H. pylori infection, in both cell lines. Expressed protein levels of both MMPs were also found reduced in the presence of JNK pathway inhibitors in both cell lines. However, p38 inhibition resulted in a more complex effect, probably attributed to the accumulation of phospho‐p38 and increased phospho‐ERK1/2 activity due to crosstalk between MAPK pathways. Conclusions: H. pylori colonization leads to the upregulation of MMP‐3 and MMP‐9 in vivo, which primarily involves ERK1/2 and JNK pathways. Therefore, their inhibition may potentially offer a protective effect against gastric carcinogenesis and metastasis. [ABSTRACT FROM AUTHOR]

A unique case of multiple metastatic melanoma skin nodules regression in a heavily pretreated, 72-year-old Caucasian female, after administering the second dose of the SARS-CoV-2 mRNA Pfizer-BioNTech vaccine, is presented. Two days after vaccination, all her melanoma skin nodules became painful and were significantly reduced in size. Physical examination and ultrasound imaging confirmed the patient's observation. The effect was sustained, and further reduction of the nodules occurred after the third vaccine dose. One of the reduced nodules was removed, histologically examined, and its histopathology was compared to that of another such nodule removed and examined earlier. Distinct differences were observed between the two histopathologies, with the most notable the unexpected finding of the absence of infiltrating lymphocytes in the reducer nodule's melanoma tissue. Based on this observation, the possible immunological mechanism(s) leading to the vaccine's effect are speculated. More possible is the vaccine's antitumor and apoptotic activity via stimulation of the Tol Like Receptors 3, 7, and 8, and (downstream) the nuclear factor kappa-light-chain-enhancer of the activated B cells pathway of the non-lymphocytic immune effector cells. [ABSTRACT FROM AUTHOR]

Among the products of enteroendocrine cells are the incretins glucagon-like peptide-1 (GLP-1, secreted by L cells) and glucose-dependent insulinotropic peptide (GIP, secreted by K cells). These are key modulators of insulin secretion, glucose homeostasis, and gastric emptying. Because of the rapid early rise of GLP-1 in plasma after oral glucose, we wished to definitively establish the absence or presence of L cells, as well as the relative distribution of the incretin cell types in human duodenum. We confirmed the presence of proglucagon and pro-GIP genes, their products, and glucosensory molecules by tissue immunohistochemistry and RT-PCR of laser-captured, single duodenal cells. We also assayed plasma glucose, incretin, and insulin levels in subjects with normal glucose tolerance and type 2 diabetes for 120 min after they ingested 75 g of glucose. Subjects with normal glucose tolerance (n = 14) had as many L cells (15 [+ or -] 1), expressed per 1,000 gut epithelial cells, as K cells (13 [+ or -] 1), with some containing both hormones (L/K cells, 5 [+ or -] 1). In type 2 diabetes, the number of L and L/K cells was increased (26 [+ or -] 2; P < 0.001 and 9 [+ or -] 1; P < 0.001, respectively). Both L and K cells contained glucokinase and glucose transporter-1, -2, and -3. Newly diagnosed type 2 diabetic subjects had increased plasma GLP-1 levels between 20 and 80 min, concurrently with rising plasma insulin levels. Significant coexpression of the main incretin peptides occurs in human duodenum. L and K cells are present in equal numbers. New onset type 2 diabetes is associated with a shift to the L phenotype. duodenum; euglycemia; type 2 diabetes; glucagon-like peptide-1; gastric inhibitory polypeptide

Background Missed polyps during colonoscopy are considered an important factor for interval cancer appearance, especially in the ascending colon (AC). We evaluated the contribution of retroflexion to polyp and adenoma detection in the AC. Methods This prospective observational study included consecutive patients who underwent a complete colonoscopy between 06/2017 and 06/2018. The AC was examined in 2 phases: the first included 2 forward views from the hepatic flexure to the cecum; the second involved a retroflexion in the cecum, inspection up to the hepatic flexure and reinsertion to the cecum. Results The study included 655 patients, 628 (95.88%) with successful retroflexion (mean age: 62.5±10.8 years, 332 male). Indications for colonoscopy were screening in 33.28%, follow up in 36.03%, and diagnostic assessment in 30.69%. In total, 286 polyps and 220 adenomas were detected in the AC. Phase 1 identified 119 adenomas, yielding an adenoma detection rate (ADR) in the AC of 14.2% (95% confidence interval [CI] 11.52-16.84%) while phase 2 identified 86 additional adenomas, improving the ADR in the AC to 22.75% (95%CI 19.54-25.96%; P<0.01). Adenoma miss rate was 39.1% (86/225) and per-patient adenoma miss rate was 11.15% (73/655). Retroflexion proved beneficial mainly in the upper third of the AC (odds ratio [OR] 4.29, 95%CI 1.84-11.56; P<0.01) and for small (<5 mm) adenomas (OR 1.61, 95%CI 1.02-2.56; P=0.04). Multivariate analysis showed that age >60 years, detection of adenomas in forward views and the indication “follow up” influenced ADR during retroflexion. Conclusion Retroflexion is a simple and safe maneuver that increases the ADR in the AC and should complete a second forward view. [ABSTRACT FROM AUTHOR]

In the current study, we performed a complete analysis, with four different methods, of all four HER family receptors, in a series of patients with metastatic breast cancer treated with trastuzumab-based regimens and evaluated their prognostic value. Formalin-fixed paraffin-embedded tumor tissue samples were collected from 227 patients, considered to be HER2-positive when assessed at the local laboratories. We evaluated gene amplification, copy number variations (CNVs), mRNA and protein expression of all four HER family members. In addition, our analysis included the evaluation of several other factors by immunohistochemistry (IHC), such as pHER2Tyr1221/1222, pHER2Tyr877 and PTEN. Central review of HER2 status by IHC and fluorescence in situ hybridization revealed that of the 227 patients, only 139 (61.2%) were truly HER2-positive. Regarding the 191 patients treated with trastuzumab as first-line therapy, median time to progression (TTP) was 15.3 and 10.4 months for HER2-positive and HER2-negative participants, respectively, whereas median survival was 50.4 and 38.1 months, respectively. In HER2-positive patients, high HER3 mRNA expression was of favorable prognostic significance for TTP and survival (HR = 0.43, 95% CI 0.21–0.88, Wald’s p = 0.022 and HR = 0.43, 95% CI 0.21–0.88, p = 0.021, respectively), while EGFR copy gain and EGFR protein expression were associated with higher risk for disease progression in HER2-negative patients (HR = 3.53, 95% CI 1.19–10.50, p = 0.023 and HR = 3.37, 95% CI 1.12–10.17, p = 0.031, respectively). Positive HER3 protein expression was a favorable factor for TTP in HER2-negative patients (HR = 0.43, 95% CI 0.22–0.84, p = 0.014). In the multivariate analysis, only EGFR copy gain retained its prognostic significance for TTP in the HER2-negative population (HR = 3.96, 95% CI 1.29–12.16, p = 0.016), while high HER3 mRNA expression retained its favorable prognostic significance for TTP in the HER2-positive subgroup (HR = 0.47, 95% CI 0.23–0.99, p = 0.048). The present study suggests that EGFR copy gain represents a negative prognostic factor for TTP in HER2-negative patients with metastatic breast cancer treated with trastuzumab. In addition, high HER3 mRNA expression appears to be of favorable prognostic significance for TTP in HER2-positive patients. Given the small number of patients included in the current analysis and the retrospective nature of the study, our findings should be validated in larger cohorts. [ABSTRACT FROM AUTHOR]