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Importance: Microsatellite (MS) instability (MSI-H) occurs frequently in Lynch syndrome (LS)-associated tumors and is associated with response to immune checkpoint blockade (ICB) therapy. MSI-H is conferred by germline or somatic variants in mismatch repair genes. The contribution of somatic oncogenesis to MSI-H in pancreatic cancer (PC) is unknown., Objective: To evaluate an LS-related PC cohort to define clinicogenomic features, describe somatic MSI-H cases (germline negative), characterize response to ICB, and guide preferred MS testing methods., Design, Setting, and Participants: This single-institution, retrospective analysis was conducted from March 2012 to July 2023 at Memorial Sloan Kettering Cancer Center and included 55 patients with PC and either an LS germline pathogenic variant (gPV) or somatic mismatch repair (MMR) variant., Main Outcomes and Measures: Composite MMR and MS status determined using orthogonal methods. An artificial intelligence classifier was used to account for low-cellularity specimens. Demographic and clinical data were abstracted from medical record. Zygosity status and somatic comutation landscape analyzed., Results: Fifty-five patients (23 women [42%]) had PC and an MMR variant: 32 (58%) had LS (LS cohort) and 23 (42%) had a somatic MMR variant (no germline pathogenic variant, somatic MMR cohort). In the LS cohort, 10 (31%) had gMSH2, 9 (28%) gMSH6, 8 (25%) gPMS2, 4 (13%) gMLH1, 1 (3%) gEPCAM. The median age at diagnosis was 68 years (range, 45-88 years). For composite MS status, 17 (59%) were MSI-H, 12 (41%) MS stable, and 3 MS unknown. Five cases were reclassified as MSI-H by the artificial intelligence classifier. In the somatic MMR cohort, 11 (48%) had MSH6, 7 (30%) MLH1, 3 (13%) MSH2, and 2 (9%) PMS2. The median age at diagnosis was 72 years (range, 66-85 years). For composite MS status, 10 (43%) were MSI-H, 11 (48%) MS stable, and 2 (9%) MS indeterminate. Six cases were reclassified as MSI-H by the artificial intelligence classifier. For the LS and somatic MMR cohorts, 20 received ICB (n = 17 MSI-H). The median ICB duration was 27.7 months (95% CI, 11.5 to not reached); the disease control rate was 80%., Conclusion: The results of this cross-sectional study suggest that MSI-H occurs due to LS or somatic oncogenesis in PC. Orthogonal MS testing is key in PC; the artificial intelligence classifier reclassified approximately 20% of cases, most of which were low cellularity. ICB for patients with LS or somatic MSI-H PC provided significant benefit.

Background: Systematic reviews of Randomized Controlled Trials (RCTs) are an important part of the evidence-based medicine paradigm. However, the creation of such systematic reviews by clinical experts is costly as well as time-consuming, and results can get quickly outdated after publication. Most RCTs are structured based on the Patient, Intervention, Comparison, Outcomes (PICO) framework and there exist many approaches which aim to extract PICO elements automatically. The automatic extraction of PICO information from RCTs has the potential to significantly speed up the creation process of systematic reviews and this way also benefit the field of evidence-based medicine., Results: Previous work has addressed the extraction of PICO elements as the task of identifying relevant text spans or sentences, but without populating a structured representation of a trial. In contrast, in this work, we treat PICO elements as structured templates with slots to do justice to the complex nature of the information they represent. We present two different approaches to extract this structured information from the abstracts of RCTs. The first approach is an extractive approach based on our previous work that is extended to capture full document representations as well as by a clustering step to infer the number of instances of each template type. The second approach is a generative approach based on a seq2seq model that encodes the abstract describing the RCT and uses a decoder to infer a structured representation of a trial including its arms, treatments, endpoints and outcomes. Both approaches are evaluated with different base models on a manually annotated dataset consisting of RCT abstracts on an existing dataset comprising 211 annotated clinical trial abstracts for Type 2 Diabetes and Glaucoma. For both diseases, the extractive approach (with flan-t5-base) reached the best F 1 score, i.e. 0.547 ( ± 0.006 ) for type 2 diabetes and 0.636 ( ± 0.006 ) for glaucoma. Generally, the F 1 scores were higher for glaucoma than for type 2 diabetes and the standard deviation was higher for the generative approach., Conclusion: In our experiments, both approaches show promising performance extracting structured PICO information from RCTs, especially considering that most related work focuses on the far easier task of predicting less structured objects. In our experimental results, the extractive approach performs best in both cases, although the lead is greater for glaucoma than for type 2 diabetes. For future work, it remains to be investigated how the base model size affects the performance of both approaches in comparison. Although the extractive approach currently leaves more room for direct improvements, the generative approach might benefit from larger models., (© 2024. The Author(s).)

To fully appreciate genetics, one must understand the link between genotype (DNA sequence) and phenotype (observable characteristics). Advances in high-throughput genomic sequencing technologies and applications, so-called "-omics," have made genetic sequencing readily available across fields in biology from applications in non-traditional study organisms to precision medicine. Thus, understanding these tools is critical for any biologist, especially those early in their career. This comprehensive review discusses the chronological development of different sequencing methods, the bioinformatics steps to analyzing this data, and social and ethical issues raised by these techniques that must be discussed and evaluated, including anticipatory guides and discussion questions for active engagement in the classroom. Additionally, the Supporting Information includes a case study to apply technical and ethical concepts from the text., (© 2021 The Authors. Biochemistry and Molecular Biology Education published by Wiley Periodicals LLC on behalf of International Union of Biochemistry and Molecular Biology.)

Disrupting a gene to determine its effect on an organism's phenotype is an indispensable tool in molecular biology. Such techniques are critical for understanding how a gene product contributes to the development and cellular identity of organisms. The explosion of genomic sequencing technologies combined with recent advances in genome-editing techniques has elevated the possibilities of genetic manipulations in numerous organisms in which these experiments were previously not readily accessible or possible. Introducing the next generation of molecular biologists to these emerging techniques is key in the modern biology classroom. This comprehensive review introduces undergraduates to CRISPR/Cas9 editing and its uses in genetic studies. The goals of this review are to explain how CRISPR functions as a prokaryotic immune system, describe how researchers generate mutations with CRISPR/Cas9, highlight how Cas9 has been adapted for new functions, and discuss ethical considerations of genome editing. Additionally, anticipatory guides and questions for discussion are posed throughout the review to encourage active exploration of these topics in the classroom. Finally, the supplement includes a study guide and practical suggestions to incorporate CRISPR/Cas9 experiments into lab courses at the undergraduate level. © 2018 The Authors Biochemistry and Molecular Biology Education published by Wiley Periodicals, Inc. on behalf of International Union of Biochemistry and Molecular Biology, 46(2):195-205, 2018., (© 2018 The Authors Biochemistry and Molecular Biology Education published by Wiley Periodicals, Inc. on behalf of International Union of Biochemistry and Molecular Biology.)

Objectives: We aim to understand how the second epidemiologic transition unfolded on the island of Newfoundland during the early 20th century. The focus is on changes in predominant causes of mortality throughout this period, urban and rural differences, and comparisons with other Western nations. We explore factors driving these patterns including the economy, nutrition, sanitation, and access to healthcare and discuss their relevance to understanding epidemiologic transitions in other developing regions., Methods: We examined official provincial death records (n = 65,394) and census materials from 1900 to 1939 for three rural districts (Burgeo-La Poile, Bonavista, and Twillingate) and the large city of St. John's. Life expectancies, infant mortality rates, survival curves, and proportionate mortality from communicable and non-communicable diseases (NCDs) were calculated., Results: In all districts, old age mortality increased while infant and childhood mortality decreased, with corresponding increases in life expectancy. Proportionate mortality from communicable causes decreased while deaths from NCDs increased. These changes occurred earlier in urban St. John's than in outlying districts, suggesting rural-urban differences played a significant role in Newfoundland's second epidemiologic transition. However, the transition was significantly delayed relative to other Western nations., Conclusions: We suggest that observed mortality patterns were the result of complex interactions between the poor economy, malnutrition, high prevalence of tuberculosis, and limited health and social services. These factors contribute to the delayed onset of the second epidemiologic transition in Newfoundland relative to other Western nations and the earlier onset in St. John's than in rural areas., (© 2017 Wiley Periodicals, Inc.)

As the only catalytic member of the Sir-protein gene-silencing complex, Sir2's catalytic activity is necessary for silencing. The only known role for Sir2's catalytic activity in Saccharomyces cerevisiae silencing is to deacetylate N-terminal tails of histones H3 and H4, creating high-affinity binding sites for the Sir-protein complex, resulting in association of Sir proteins across the silenced domain. This histone deacetylation model makes the simple prediction that preemptively removing Sir2's H3 and H4 acetyl substrates, by mutating these lysines to unacetylatable arginines, or removing the acetyl transferase responsible for their acetylation, should restore silencing in the Sir2 catalytic mutant. However, this was not the case. We conducted a genetic screen to explore what aspect of Sir2's catalytic activity has not been accounted for in silencing. Mutation of a nonsirtuin histone deacetylase, Rpd3, restored Sir-protein-based silencing in the absence of Sir2's catalytic activity. Moreover, this antagonism could be mediated by either the large or the small Rpd3-containing complex. Interestingly, this restoration of silencing appeared independent of any known histone H3 or H4 substrates of Rpd3 Investigation of Sir-protein association in the Rpd3 mutant revealed that the restoration of silencing was correlated with an increased association of Sir proteins at the silencers, suggesting that Rpd3 was an antagonist of Sir2's function in nucleation of Sir proteins to the silencer. Additionally, restoration of silencing by Rpd3 was dependent on another sirtuin family member, Hst3, indicating multiple antagonistic roles for deacetylases in S. cerevisiae silencing., (Copyright © 2016 by the Genetics Society of America.)

Background: Increasing numbers of survivors of critical illness are at risk for physical, cognitive, and/or mental health impairments that may persist for months or years after hospital discharge. The post-intensive care syndrome framework encompassing these multidimensional morbidities was developed at the 2010 Society of Critical Care Medicine conference on improving long-term outcomes after critical illness for survivors and their families., Objectives: To report on engagement with non-critical care providers and survivors during the 2012 Society of Critical Care Medicine post-intensive care syndrome stakeholder conference. Task groups developed strategies and resources required for raising awareness and education, understanding and addressing barriers to clinical practice, and identifying research gaps and resources, aimed at improving patient and family outcomes., Participants: Representatives from 21 professional associations or health systems involved in the provision of both critical care and rehabilitation of ICU survivors in the United States and ICU survivors and family members., Design: Stakeholder consensus meeting. Researchers presented summaries on morbidities for survivors and their families, whereas survivors presented their own experiences., Meeting Outcomes: Future steps were planned regarding 1) recognizing, preventing, and treating post-intensive care syndrome, 2) building strategies for institutional capacity to support and partner with survivors and families, and 3) understanding and addressing barriers to practice. There was recognition of the need for systematic and frequent assessment for post-intensive care syndrome across the continuum of care, including explicit "functional reconciliation" (assessing gaps between a patient's pre-ICU and current functional ability at all intra- and interinstitutional transitions of care). Future post-intensive care syndrome research topic areas were identified across the continuum of recovery: characterization of at-risk patients (including recognizing risk factors, mechanisms of injury, and optimal screening instruments), prevention and treatment interventions, and outcomes research for patients and families., Conclusions: Raising awareness of post-intensive care syndrome for the public and both critical care and non-critical care clinicians will inform a more coordinated approach to treatment and support during recovery after critical illness. Continued conceptual development and engagement with additional stakeholders is required.