Viewpoints Research Institute

Abstract Constitutive activation of the Wnt/beta catenin pathway drives malignancy in a wide range of cancers. The oncogenic transcription factor beta catenin has been notoriously difficult to target due to its disordered nature and lack of defined drug-binding pockets. Using Dewpoint’s proprietary AI/ML-powered discovery platform, we have identified and optimized small molecule condensate modulators (c-mods) that act via a novel mechanism of action, sequestering beta catenin into inactive condensate depots. Sequestering beta catenin into nuclear condensates selectively inhibits beta catenin-driven transcription and induces robust cancer cell death. The development candidate DPTX3186 is an orally bioavailable small molecule that demonstrates strong anti-tumor activity across multiple tumor types driven by various defects along the Wnt/beta catenin pathway and modulates Wnt pathway activity in vivo. Profound pharmacological efficacy, including regressions and complete responses, has been observed in murine models of gastric cancer. Collectively, these findings highlight the potential of condensate biology to target previously undruggable, high-value oncology targets, paving the way for novel treatments for patients with significant unmet medical needs. Citation Format: Isaac Klein, Kip West, Doug Baumann, Adam Talbot, Thomas Durand-Reville, Karl Hsu, Ann Boija. Beta catenin c-mods are orally bioavailable small-molecules targeting Wnt-driven tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1751.

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2024 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal

Microfinance initiatives have emerged as crucial tools in poverty alleviation, particularly in developing countries. These initiatives extend small loans to underserved populations and marginalized communities, as a means to improve their financial standing. This research leverages machine learning models to analyze a large microfinance initiative and find the key variables that drive micro-loan allocation. By conducting an in-depth feature analysis of a comprehensive microloan dataset, we aimed to pinpoint key variables that impact the allocation and size of microloans. Our study finds that the repayment period, lender networks, and the geographic location of borrowers significantly influence the loan allocation and size. The insights from our study can provide strategic guidance to microfinance programs in their loan allocation decisions. More specifically, lending decisions can be targeted more effectively to maximize impact of microfinance programs. In addition, this research also demonstrates the application of machine learning models in the realm of microfinance.

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Neurology HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Neurology journal

Status epilepticus (SE) is associated with poor clinical outcomes and high cost. Increased levels of refractory SE require treatment with additional medications and carry increased morbidity and mortality, but the associations between SE refractoriness, clinical outcomes, and cost remain poorly characterized. To examine differences in clinical outcomes and costs associated with hospitalization for SE of varying refractoriness. A cross-sectional study of 43 988 US hospitalizations from January 1, 2016 to December 31, 2018, was conducted, including patients with primary or secondary International Statistical Classification of Diseases, Tenth Revision, diagnosis specifying "with status epilepticus." Patients were categorized by administration of antiseizure drugs given during hospitalization. Low refractoriness denoted treatment with none or 1 intravenous antiseizure drug. Moderate refractoriness denoted treatment with more than 1 intravenous antiseizure drug. High refractoriness denoted treatment with 1 or more intravenous antiseizure drug, more than 1 intravenous anesthetic, and intensive care unit admission. Outcomes included discharge disposition, hospital length of stay, intensive care unit length of stay, hospital-acquired conditions, and cost (total and per diem). Among 43 988 hospitalizations for SE, 22 851 patients (51.9%) were male; mean age was 49.9 years (95% CI, 49.7-50.1 years). There were 14 694 admissions (33.4%) for low refractory, 10 140 (23.1%) for moderate refractory, and 19 154 (43.5%) for highly refractory SE. In-hospital mortality was 11.2% overall, with the highest rates among patients with highly (18.9%) compared with moderate (6.3%) and low (4.6%) refractory SE (P < .001 for all comparisons). Median hospital length of stay was 5 days (interquartile range [IQR], 2-10 days) with greater length of stay in highly (8 days; IQR, 4-15 days) compared with moderate (4 days; IQR, 2-8 days) and low (3 days; IQR, 2-5 days) refractory SE (P < .001 for all comparisons). Patients with highly refractory SE also had greater hospital costs, with median costs of $25 105 (mean [SD], $41 858 [$59 063]) in the high, $10 592 (mean [SD], $18 328 [$30 776]) in the moderate, and $6812 (mean [SD], $11 532 [$17 228]) in the low refractory cohorts (P < .001 for all comparisons). Status epilepticus apparently continues to be associated with a large burden on patients and the US health system, with high mortality and costs that increase with disease refractoriness. Interventions that prevent SE from progressing to a more refractory state may have the potential to improve outcomes and lower costs associated with this neurologic condition.

PurposeWe previously identified an oxysterol, VP1-001 (also known as compound 29), that partially restores the transparency of lenses with cataracts. To understand the mechanism of VP1-001, we tested the ability of its enantiomer, ent-VP1-001, to bind and stabilize αB-crystallin (cryAB) in vitro and to produce a similar therapeutic effect in cryAB(R120G) mutant and aged wild-type mice with cataracts. VP1-001 and ent-VP1-001 have identical physicochemical properties. These experiments are designed to critically evaluate whether stereoselective binding to cryAB is required for activity.MethodsWe compared the binding of VP1-001 and ent-VP1-001 to cryAB using in silico docking, differential scanning fluorimetry (DSF), and microscale thermophoresis (MST). Compounds were delivered by six topical administrations to mouse eyes over 2 weeks, and the effects on cataracts and lens refractive measures in vivo were examined. Additionally, lens epithelial and fiber cell morphologies were assessed via transmission electron microscopy.ResultsDocking studies suggested greater binding of VP1-001 into a deep groove in the cryAB dimer compared with ent-VP1-001. Consistent with this prediction, DSF and MST experiments showed that VP1-001 bound cryAB, whereas ent-VP1-001 did not. Accordingly, topical treatment of lenses with ent-VP1-001 had no effect, whereas VP1-001 produced a statistically significant improvement in lens clarity and favorable changes in lens morphology.ConclusionsThe ability of VP1-001 to bind native cryAB dimers is important for its ability to reverse lens opacity in mouse models of cataracts.

The aim of this study was to describe risk factors for heat-related illness (HRI) in U.S. workers. We reviewed a subset of HRI enforcement investigations conducted by the Occupational Safety and Health Administration (OSHA) from 2011 through 2016. We assessed characteristics of the workers, employers, and events. We stratified cases by severity to assess whether risk factors were more prevalent in fatal HRIs. We analyzed 38 investigations involving 66 HRIs. Many workers had predisposing medical conditions or used predisposing medications. Comorbidities were more prevalent in workers who died. Most (73%) fatal HRIs occurred during the first week on the job. Common clinical findings in heat stroke cases included multiorgan failure, muscle breakdown, and systemic inflammation. Severe HRI is more likely when personal susceptibilities coexist with work-related and environmental risk factors. Almost all HRIs occur when employers do not adhere to preventive guidelines.

Carvajal House is the crystallisation of a deep reflection on the role of courtyards in Modern Architecture. Modern architects had initially dismissed the use of courtyards on their designs, because they used to associate them to the traditional spatial conception, characterised by introversion and a clear conceptual distinction between inside and outside. After this initial rejection, the courtyard was gradually reintroduced, and paradoxically, we will show how it was in fact an element that led to the evolution and development of modern spatial concepts, such as openness, phenomenological transparency and phenomenisation of space, because it constituted a way to integrate concavity again. The aim of this paper is showing how these modern concepts appear clearly in the interiorised courtyards of the Carvajal House, revealing the decisive role that they had in the evolution of modernity. We analysed the formal order and the perceptions that a person can experiment throughout the spatial sequence, from the access to the surroundings of the courtyards. This makes clear how the courtyards are fundamental elements in the design strategy, both at a morpho-syntax level (as the seed of the formal logic) and at a perceptual-emotional level (qualifying space as the stage for life).