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OLIG2 mediates a rare targetable stem cell fate transition in sonic hedgehog medulloblastoma.
No full textFunctional cellular heterogeneity in tumours often underlies incomplete response to therapy and relapse. Previously, we demonstrated that the growth of the paediatric brain malignancy, sonic hedgehog subgroup medulloblastoma, is rooted in a dysregulated developmental hierarchy, the apex of which is defined by characteristically quiescent SOX2+ stem-like cells. Integrating gene expression and chromatin accessibility patterns in distinct cellular compartments, we identify the transcription factor Olig2 as regulating the stem cell fate transition from quiescence to activation, driving the generation of downstream neoplastic progenitors. Inactivation of Olig2 blocks stem cell activation and tumour output. Targeting this rare OLIG2-driven proliferative programme with a small molecule inhibitor, CT-179, dramatically attenuates early tumour formation and tumour regrowth post-therapy, and significantly increases median survival in vivo. We demonstrate that targeting transition from quiescence to proliferation at the level of the tumorigenic cell could be a pivotal medulloblastoma treatment strategy
Safety and Feasibility of 3D Intracardiac Echocardiography in Guiding Left Atrial Appendage Occlusion With WATCHMAN FLX.
No full textBACKGROUND: Intracardiac echocardiography (ICE) is an alternative to transesophageal echocardiography to guide left atrial appendage occlusion (LAAO). However, 2-dimensional ICE has important limitations that hinder its adoption in routine practice.
OBJECTIVES: This prospective multicenter study (NCT04569734) investigated the feasibility and safety of ICE-guided LAAO with Watchman FLX using a novel 3-dimensional ICE catheter (VeriSight Pro, Philips).
METHODS: A total of 100 patients undergoing LAAO with the Watchman FLX device were recruited. All cases were performed under moderate sedation. A simplified 2 orthogonal view ICE imaging protocol was adopted to assess PASS (position, anchoring, sizing, and sealing) criteria. The feasibility endpoint was successful implantation of the FLX device and adequate seal (peri-device leak \u3c5 \u3emm) at 45 days. The safety endpoint was the incidence of major complications at 7 and 45 days. Physician experience and imaging quality scores were collected (1 = lowest, 5 = highest).
RESULTS: The mean age was 77.0 ± 8.1 years, and 39 (39%) were women. CHA
CONCLUSIONS: The novel 3-dimensional ICE VeriSight Pro Probe can safely and effectively guide LAAO with Watchman FLX using a simplified imaging protocol
American Society for Gastrointestinal Endoscopy guideline on the diagnosis and management of GERD: methodology and review of evidence.
No full textThis clinical practice guideline from the American Society for Gastrointestinal Endoscopy (ASGE) provides an evidence-based approach for strategies to diagnose and manage GERD. This document was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework and serves as an update to the prior ASGE guideline on the role of endoscopy in the management of GERD (2014). The updated guideline addresses the indications for endoscopy in patients with GERD, including patients who have undergone sleeve gastrectomy (SG) and peroral endoscopic myotomy (POEM). It also discusses endoscopic evaluation of gastroesophageal junctional integrity comprehensively and uniformly. Important, this guideline discusses management strategies for GERD including lifestyle interventions, proton pump inhibitors (PPIs), and endoscopic antireflux therapy including transoral incisionless fundoplication (TIF), radiofrequency energy, and TIF combined with hiatal hernia repair (cTIF). The ASGE recommends upper endoscopy for the evaluation of GERD in patients with alarm symptoms. The ASGE suggests upper endoscopy for symptomatic patients with a history of SG and POEM. The ASGE recommends careful endoscopic evaluation, reporting, and photo-documentation of objective GERD findings and gastroesophageal junction landmarks and integrity to improve patient care and outcomes. In patients with GERD symptoms, the ASGE recommends lifestyle modifications. In patients with symptomatic and confirmed GERD with predominant heartburn symptoms, the ASGE recommends medical management including PPIs at the lowest dose for the shortest duration while initiating discussion about long-term management options. In patients with confirmed GERD with small hiatal hernia (≤2 cm) and Hill grade I or II flap valve who meet specific criteria, the ASGE suggests evaluation for TIF as an alternative to long-term medical management. In patients with confirmed GERD with a large hiatal hernia (\u3e2 cm) and Hill grade 3 or 4 flap valve, the ASGE suggests evaluation for combined endoscopic-surgical TIF (cTIF) in a multidisciplinary review. This document clearly outlines the methodology, analysis, and decision used to reach the final recommendations and represents the official ASGE recommendations on the above topics
Evaluation of a Program Designed to Support Implementation of Prescribing Medication for Treatment of Opioid Use Disorder in Primary Care Practices.
No full textPURPOSE: Offering medication for opioid use disorder (MOUD) in primary care can increase access to effective opioid use disorder treatment and help address the US opioid crisis. We describe a primary care office-based opioid treatment program and addiction consultation service model designed to support small, rural clinics to increase their capacity for MOUD.
METHODS: This is an evaluation of an intervention to increase clinic capacity to offer MOUD. The intervention consists of a standardized curriculum, addiction medicine consultants, practice facilitation, and financial incentives. Fifteen Colorado primary care practices participated from January 2022 through January 2023. Primary outcomes included overall change in the number of active buprenorphine prescriptions and implementation of MOUD milestones before and after the intervention.
RESULTS: The mean number of active buprenorphine prescriptions in the 3 months preceding the intervention (baseline) increased from 2.1 (SD = 7.7) to 11.3 (SD = 11.2) at 13 months. Adjusted means from the Poisson model demonstrated significant improvement over time (
CONCLUSIONS: This model supported primary care practices that were initially doing little to no MOUD prescribing, to prescribe at significantly higher levels by the end of the program. This scalable model for addiction consultation in primary care settings illustrates how education and support to clinical teams can help practices makes changes, especially those with limited MOUD experience
Abemaciclib in combination with therapies for patients with metastatic breast cancer: a phase 1b study.
No full textBACKGROUND: The oral, selective, and potent small molecule cyclin-dependent kinases (CDK) 4/6 inhibitor (CDK4/6i) abemaciclib has demonstrated efficacy in advanced breast cancer and high-risk early breast cancer. This Phase 1b study evaluated the safety, tolerability, pharmacokinetics, and antitumor activity of abemaciclib in combination with endocrine therapies (Parts A-D), exemestane + everolimus (Part E), or fulvestrant + LY3023414 (a PI3K/mTOR inhibitor; Part G) in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC), or trastuzumab (Part F), or trastuzumab + pertuzumab (Part H) in patients with HER2-positive (HER2+) MBC.
PATIENTS AND METHODS: This study enrolled women aged ≥18 years old with either HR+, HER2- (Parts E and G), or HER2+ (Parts F and H) MBC. Additional requirements included measurable disease or non-measurable but evaluable bone disease (Parts E and F), or measurable disease (Parts G and H), an Eastern Cooperative Oncology Group performance status of 0-1, and no prior treatment with CDK4/6i (Parts E, F, and H). Adverse events were graded, and tumor response was assessed.
RESULTS: Nineteen patients in Part E received abemaciclib (150 mg, n=15; 200 mg, n=4) with exemestane + everolimus, 24 patients in Part F received abemaciclib (150 mg, n=18; 200 mg, n=6) with trastuzumab, 12 patients in Part G received 150 mg abemaciclib with fulvestrant + LY3023414 (100 mg, n=7; 150 mg, n=5), and four patients in Part H received abemaciclib (100 mg) with trastuzumab + pertuzumab (with prophylactic loperamide). The most common treatment-emergent adverse events (TEAEs) were diarrhea, fatigue, neutropenia, and nausea. Grade ≥3 TEAEs were reported in 16, 18, 10, and 4 patients in Parts E-H, respectively. Abemaciclib had no effect on the pharmacokinetics of the combination study drugs. The objective response rates for patients with measurable disease were 46.2%, 10.0%, 66.7%, and 25.0% in Parts E-H, respectively. A recommended Phase 2 dose was not established for Parts E, G, and H at the dose levels evaluated, and was determined to be 150 mg Q12H in Part F.
CONCLUSIONS: Overall, our results demonstrate safety profiles consistent with those previously established for abemaciclib and provide preliminary data for these combination therapies in the treatment of HR+, HER2- or HER2+ MBC
The Reasonable Ineffectiveness of Mathematics in the Biological Sciences.
No full textThe known laws of nature in the physical sciences are well expressed in the language of mathematics, a fact that caused Eugene Wigner to wonder at the unreasonable effectiveness of mathematical concepts to explain physical phenomena. The biological sciences, in contrast, have resisted the formulation of precise mathematical laws that model the complexity of the living world. The limits of mathematics in biology are discussed as stemming from the impossibility of constructing a deterministic Laplacian model and the failure of set theory to capture the creative nature of evolutionary processes in the biosphere. Indeed, biology transcends the limits of computation. This leads to a necessity of finding new formalisms to describe biological reality, with or without strictly mathematical approaches. In the former case, mathematical expressions that do not demand numerical equivalence (equations) provide useful information without exact predictions. Examples of approximations without equal signs are given. The ineffectiveness of mathematics in biology is an invitation to expand the limits of science and to see that the creativity of nature transcends mathematical formalism