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Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) have been highly successful in the treatment of cancer. While PD-1 expression has been widely investigated, its role in CD4+ effector T cells in the setting of health and cancer remains unclear, particularly in the setting of glioblastoma multiforme (GBM), the most aggressive and common form of brain cancer. We examined the functional and molecular features of PD-1+CD4+CD25-CD127+Foxp3-effector cells in healthy subjects and in patients with GBM. In healthy subjects, we found that PD-1+CD4+ effector cells are dysfunctional: they do not proliferate but can secrete large quantities of IFNγ. Strikingly, blocking antibodies against PD-1 did not rescue proliferation. RNA-sequencing revealed features of exhaustion in PD-1+ CD4 effectors. In the context of GBM, tumors were enriched in PD-1+ CD4+ effectors that were similarly dysfunctional and unable to proliferate. Furthermore, we found enrichment of PD-1+TIM-3+ CD4+ effectors in tumors, suggesting that co-blockade of PD-1 and TIM-3 in GBM may be therapeutically beneficial. RNA-sequencing of blood and tumors from GBM patients revealed distinct differences between CD4+ effectors from both compartments with enrichment in multiple gene sets from tumor infiltrating PD-1-CD4+ effectors cells. Enrichment of these gene sets in tumor suggests a more metabolically active cell state with signaling through other co-receptors. PD-1 expression on CD4 cells identifies a dysfunctional subset refractory to rescue with PD-1 blocking antibodies, suggesting that the influence of immune checkpoint inhibitors may involve recovery of function in the PD-1-CD4+ T cell compartment. Additionally, co-blockade of PD-1 and TIM-3 in GBM may be therapeutically beneficial.

BackgroundHereditary diffuse gastric cancer (HDGC) is an autosomal-dominant syndrome most often caused by pathogenic variants in CDH1. The International Gastric Cancer Linkage Consortium (IGCLC) recently updated its criteria for genetic testing. The purpose of this study was to estimate the sensitivity of IGCLC’s 2020 criteria for identifying carriers of CDH1 pathogenic variants and to formulate a new set of criteria that is simpler and more sensitive.MethodsMedical histories of 112 CDH1 mutation carriers, identified predominantly by multigene panel testing, and their 649 family members were reviewed. The percentage of subjects fulfilling the IGCLC 2015 and 2020 criteria was calculated, once without making any assumptions about unavailable pathology, and once assuming gastric cancer to be diffuse when pathology was unavailable. For comparison, we calculated the percentage of subjects who fulfilled our proposed criteria.ResultsWhen making no assumptions about missing pathology, a small (19%) and equal percentage of CDH1 mutation carriers fulfilled the IGCLC 2015 and 2020 criteria. When assuming unspecified gastric cancer to be diffuse, 45 out of 112 (40%) subjects met the 2015 criteria and 53 out of 112 (47%) met the 2020 criteria. Eighty-seven per cent (97/112) fulfilled our proposed criteria.ConclusionIn consecutive cases, mostly unselected for clinical criteria of HDGC, the IGCLC 2020 criteria are, at best, marginally more sensitive than previous iterations, but they are also more cumbersome. Unavailable cancer pathology reports are a real-world obstacle to their proper application. Our proposed Yale criteria both address this issue and offer significantly greater sensitivity than the IGCLC 2020 criteria.

While the gluten-free diet (GFD) is the only known effective therapy for celiac disease, in recent years it has become increasingly popular in the USA and worldwide, with many believing it to be more “healthful” and others claiming that it has beneficial effects for health conditions, many extraintestinal, other than celiac disease. This review examines the evidence for use of the GFD in patients without celiac disease who self-report intestinal and/or extraintestinal symptoms (non-celiac gluten sensitivity), as well as for enhancement of athletic performance and treatment of autism, rheumatoid arthritis, and psychiatric disorders. Overall, the evidence for use of GFDs in conditions other than celiac disease is poor. Though non-celiac gluten sensitivity may ultimately emerge as a biomarker-defined condition, a large proportion of patients with apparent non-celiac gluten sensitivity have, after careful investigation, an alternative diagnosis. In light of this, and coupled with the potential physical and psychological harms associated with the avoidance of gluten, initiating a GFD should not be encouraged for people who have these other conditions or are seeking physical/athletic enhancement.

Adherence to a gluten-free (GF) diet is the mainstay of therapy for celiac disease. Until now, those wishing to avoid gluten in restaurants had to rely on menu labels, word of mouth, intuition, and restaurant workers' advice, with a relative dearth of supporting data. We used crowd-sourced data from users of a portable gluten detection device to estimate rates of, and identify risk factors for, gluten contamination of supposed GF restaurant foods. We analyzed data from a portable gluten detection device (Nima), collected across the United States during an 18-month period by users who opted to share the results of their point-of-care tests. Data were sorted by region, time of day, median household income in the restaurant's vicinity, restaurant genre, and food items. We used the χ test for bivariate analysis and multiple logistic regression for multivariate analysis to identify predictors of gluten detection in restaurant food. There were 5,624 tests, performed by 804 users, in the examined period. Gluten was detected in 32% of GF labeled foods. Rates of gluten detection differed by meal, with 27.2% at breakfast and 34.0% at dinner (P = 0.0008). GF labeled pizza and pasta were most likely to test positive for gluten, with gluten detected in 53.2% of pizza and 50.8% of pasta samples. On multivariate analysis, GF labeled food was less likely to test positive for gluten in the West than in the Northeast United States (odds ratio 0.80; 95% confidence interval 0.67-0.95). This study of crowd-sourced data suggests that a substantial fraction of GF labeled restaurant foods contain detectable gluten. Although the highly sensitive Nima device may detect gluten at levels <20 parts per million (ppm), leading to gluten exposure of unknown clinical significance, our findings raise a potential concern. In addition, our findings of higher rates of gluten detection in pizza and pasta provide practical data when providing dining strategies for patients with celiac disease.

BackgroundDiffuse gastric and lobular breast cancer (LBC) syndrome is an autosomal-dominant syndrome characterised by early-onset diffuse gastric cancer and LBC most often caused by germline pathogenic variants (PVs) in CDH1. We previously showed the International Gastric Cancer Linkage Consortium (IGCLC) criteria for genetic testing to have poor sensitivity for CDH1 PV and proposed our own simpler and more sensitive Yale criteria. The European Reference Network on Genetic Tumour Risk Syndromes subsequently proposed expanding the IGCLC criteria and showed its LBC-expanded criteria to be more sensitive than the IGCLC criteria in a European cohort of CDH1 PV carriers.MethodsWe aggregated demographic and clinical data of all CDH1 PV carriers identified at three US commercial laboratories. These data were used to calculate the sensitivity of the IGCLC, LBC-expanded and National Comprehensive Cancer Network (NCCN)/Yale criteria.ResultsData on 708 probands and their 4318 family members were included in the analysis. In this cohort, the sensitivities for detecting CDH1 PVs were 23.6% for IGCLC criteria, 35.7% for LBC-expanded criteria and 82.2% for NCCN/Yale criteria.ConclusionIn a large cohort of CDH1 PV carriers to date, the IGCLC and LBC-expanded criteria called for genetic testing in a minority of CDH1 PV carriers while the Yale criteria detected the large majority. Along with their superior sensitivity, the NCCN/Yale criteria address critical practical challenges in cancer genetics by not depending heavily on pathology information from family members which is often lacking and by incorporating recommendations from other cancer genetics guidelines.

Objectives To assess public awareness and interest in retrograde cricopharyngeus dysfunction (R‐CPD) in the United States by analyzing trends in internet search behavior. Methods Using Google Trends, data from Google Search queries from the United States related to R‐CPD between January 2013 to May 2024 were obtained. The means of RSV from 2013 to 2018 were compared to RSV from 2019 (when R‐CPD was officially defined) to the present. Comparisons of the RSV means between these two periods were performed using paired t‐tests with p value < 0.05 considered statistically significant. Results Google Trends data from January 2013 through May 2024 were analyzed for 24 R‐CPD–related search terms. Mean RSV values from 2013 to 2018 were compared with those from 2019 to 2024, corresponding to the period following formal description of R‐CPD. The mean RSV for “R‐CPD” increased by 116% (11.5 ± 3.9 vs. 24.6 ± 15.4; p < 0.002). Significant increases were also observed for related symptom‐based queries, including “why can't I burp” (4.3 ± 4.8 vs. 17.6 ± 4.8; p < 0.002), “can't burp” (5.9 ± 1.2 vs. 9.3 ± 1.6; p < 0.002), “need to burp” (35.7 ± 10.0 vs. 61.7 ± 9.9; p < 0.002), and “no burp” (10.9 ± 4.0 vs. 18.4 ± 5.9; p < 0.002). Across all terms, metropolitan areas demonstrated consistently higher RSVs than broader regional areas. Conclusion Search interest related to R‐CPD has increased significantly since its formal description, suggesting rising public awareness and information‐seeking behavior. Higher search volumes in metropolitan areas may reflect increased recognition, access to specialty care, or disease awareness in urban settings.

Teaching computation in science courses can enhance science education, but doing so requires that teachers expand the vision of their discipline beyond the traditional view of science presented in most curricula. This article describes a design-based research (DBR) program that included collaboration among high school teachers and professional development leaders in physics and computer science education. Through three years of professional development and teacher-led development, field testing, and refinement of integrated curricular resources, we have combined instructional modeling practices, physical lab materials, and computer programming activities. One of the outcomes is a co-created framework for the integration of computational modeling into physics that is sensitive to teachers’ interests and expressed needs in addition to learning goals. This framework merges two evidence-based approaches to teaching: Bootstrap:Algebra, a web-based computing curriculum that emphasizes using multiple representations of functions and scaffolds that make the programming process explicit, and Modeling Instruction in physics, an approach that emphasizes the use of conceptual models, modeling practices and representational tools. In doing so, we uncover the need to balance teachers’ visions for integration opportunities with practical instructional needs and emphasize that frameworks for integration need to reflect teachers’ values and goals.

Purpose of reviewGastric cancer is a leading cause of cancer death in the world. Between 1 and 3% of cases are associated with specific genetic cancer risk syndromes. The purpose of this article is to review the latest insights, as well as gaps in knowledge, regarding some of the most common hereditary gastric cancer syndromes: hereditary diffuse gastric cancer (HDGC), gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS), Lynch syndrome, the adenomatous polyposis syndromes, and the hamartomatous polyposis syndromes.Recent findingsPatients carrying pathogenic variants in CDH1, but not meeting clinical criteria for HDGC, are increasingly being identified thanks to multigene panel testing; their absence from previous analyses overestimated gastric cancer penetrance. GAPPS is a recently described hereditary gastric cancer syndrome associated with specific point mutations in the promoter 1B region of the APC gene.SummaryRisk of gastric cancer is highest among carriers of pathogenic variants in CDH1, with cumulative incidences approximately 40% and 30% for men and women, respectively. Mutations associated with Lynch syndrome and adenomatous polyposis syndromes confer greatest risk for gastric cancer in East Asian populations. Risk of gastric cancer in GAPPS and hamartomatous polyposis syndromes is difficult to estimate due to their rarity, but mutation status likely determines risk. Future research is needed to more precisely define risk of gastric cancer in these syndromes, so strategies for screening and prophylactic gastrectomy can be optimized.

We report and analyze eight cases in which patients were referred from gastroenterology (GI) to otolaryngology following esophagogastroduodenoscopy (EGD). We aim to provide specific examples of head and neck pathology encountered by gastroenterologists during upper endoscopy. A series of eight cases between 2016 and 2019 were analyzed by chart review. In each case, otolaryngology consultation was requested after an abnormality was noticed by a gastroenterologist during EGD. Subsequent laryngoscopy or bronchoscopy was performed in all cases allowing for image comparison. Select images comparing EGD to laryngoscopy findings are included as well as a literature review concerning the nature of communication between the two specialties. Eight adult patients were referred to otolaryngology for abnormalities noted by a gastroenterologist during EGD at the following anatomic sites: soft palate (n=1), base of tongue (n=2), glottis (n=3), and interarytenoid mucosa (n=1). Additionally, a potential airway foreign body was noted on EGD which was ultimately determined to represent normal subglottic anatomy by bronchoscopy. Some 5/8 (63%) cases were considered true pathology while 3/8 (37%) represented normal anatomy or anatomic variants upon subsequent otolaryngologic evaluation. There is minimal literature regarding the nature of referrals from GI to otolaryngology following EGD. Our findings suggest that EGD offers a unique opportunity for early detection of otolaryngologic pathology. However, certain inter-specialty anatomic knowledge gaps were noted which contributed to occasional unnecessary referrals, procedures, and associated patient anxiety. We hope that the results of this study can inform future research aimed at improving communication and collaboration between the two specialties.