Heteroaryl Glutarimides and Dihydrouracils as Cereblon Ligand Scaffolds for Molecular Glue Degrader Discovery.

Stabilization of cereblon (CRBN)/neosubstrate complexes with molecular glues followed by degradation of those neosubstrates is an emerging strategy in drug discovery with compelling potential to target certain proteins that were previously considered to be undruggable. In this context, the discovery of novel CRBN ligands is an important area of ongoing research that holds promise to expand the scope of proteins that can be targeted through this mode of action. Herein, we describe the synthesis and evaluation of CRBN ligands featuring heteroaryl glutarimide and dihydrouracil scaffolds.

The Impact of Spliceosome Inhibition in SF3B1-Mutated Uveal Melanoma.

Purpose: Unfortunately, treatment of patients with uveal melanoma (UM) with metastatic disease is limited. Twenty percent of patients with UM harbor a mutation in the splicing factor gene SF3B1, suggesting that aberrant spliceosome function plays a vital role in tumorigenesis. Splicing inhibitors exploit the preferential sensitivity of spliceosome-compromised leukemic cells to these compounds.

Deconwolf enables high-performance deconvolution of widefield fluorescence microscopy images.

Microscopy-based spatially resolved omic methods are transforming the life sciences. However, these methods rely on high numerical aperture objectives and cannot resolve crowded molecular targets, limiting the amount of extractable biological information. To overcome these limitations, here we develop Deconwolf, an open-source, user-friendly software for high-performance deconvolution of widefield fluorescence microscopy images, which efficiently runs on laptop computers.

Ipsilateral and contralateral coadministration of influenza and COVID-19 vaccines produce similar antibody responses.

Background: World Health Organisation (WHO) and USA Centers for Disease Control and Prevention (U.S. CDC) recommendations now allow simultaneous administration of COVID-19 and other vaccines.

Demonstration Project of Long-Acting Antiretroviral Therapy in a Diverse Population of People With HIV.

Background: Intramuscular cabotegravir (CAB) and rilpivirine (RPV) is the only long-acting antiretroviral therapy (LA-ART) regimen approved for people with HIV (PWH). Long-acting ART holds promise for improving outcomes among populations with barriers to adherence but is only approved for PWH who have virologic suppression with use of oral ART before initiating injectables.

Objective: To examine LA-ART in a population of PWH that includes those with viremia.

Assessing Geographic Overlap between Zero-Dose Diphtheria-Tetanus-Pertussis Vaccination Prevalence and Other Health Indicators.

The integration of immunization with other essential health services is among the strategic priorities of the Immunization Agenda 2030 and has the potential to improve the effectiveness, efficiency, and equity of health service delivery. This study aims to evaluate the degree of spatial overlap between the prevalence of children who have never received a dose of the diphtheria-tetanus-pertussis-containing vaccine (no-DTP) and other health-related indicators, to provide insight into the potential for joint geographic targeting of integrated service delivery efforts. Using geospatially modeled estimates of vaccine coverage and comparator indicators, we develop a framework to delineate and compare areas of high overlap across indicators, both within and between countries, and based upon both counts and prevalence.

Maternal Consumption of Dairy Products during Pregnancy Is Associated with Decreased Risk of Emotional Problems in 5-Year-Olds: The Kyushu Okinawa Maternal and Child Health Study.

Milk is a good source of fats, minerals, and vitamins. The present prebirth cohort study examined the association between maternal dairy product intake during pregnancy and the risk of childhood behavioral problems in 5-year-old Japanese children. Study subjects were 1199 mother-child pairs.

Use of Retrospective Continuous Glucose Monitoring Data Is Underrated and Underused.

Access to real-time glucose data in real time allows users to make informed decisions about their insulin dosages, appropriate carbohydrate intake, exercise, and other health behaviors. Programmable alarms and alerts warn users about current and/or impending acute glycemic events. However, the value and utility of retrospective data analysis for clinical decision-making have gone mostly unrecognized.

Selective Inhibition of Aurora Kinase A by AK-01/LY3295668 Attenuates MCC Tumor Growth by Inducing MCC Cell Cycle Arrest and Apoptosis.

Merkel cell carcinoma (MCC) is an often-lethal skin cancer with increasing incidence and limited treatment options. Although immune checkpoint inhibitors (ICI) have become the standard of care in advanced MCC, 50% of all MCC patients are ineligible for ICIs, and amongst those treated, many patients develop resistance. There is no therapeutic alternative for these patients, highlighting the urgent clinical need for alternative therapeutic strategies.

Global Impact of COVID-19 on Stroke Care and IV Thrombolysis.

Objective: To measure the global impact of COVID-19 pandemic on volumes of IV thrombolysis (IVT), IVT transfers, and stroke hospitalizations over 4 months at the height of the pandemic (March 1 to June 30, 2020) compared with 2 control 4-month periods.

Methods: We conducted a cross-sectional, observational, retrospective study across 6 continents, 70 countries, and 457 stroke centers. Diagnoses were identified by their ICD-10 codes or classifications in stroke databases.

Fecal Lactoferrin and Other Stool Markers during Normal Pregnancy and in Inflammatory Bowel Diseases: A Prospective Study and Review of the Literature.

Introduction: Management of inflammatory bowel diseases (IBDs) - both Crohn's disease (CD) and ulcerative colitis (UC) - during pregnancy can be challenging since most monitoring tools available in nonpregnant patients are contraindicated.

Objectives: The aim of the study was to test whether fecal inflammatory markers - specifically fecal lactoferrin - physiologically change during normal pregnancy as a prerequisite to use them to monitor IBD activity during pregnancy.

Methods: Fecal lactoferrin was tested in healthy pregnant and nonpregnant women from the same geographic area and age range (18-40 years) - all negative for clinical gastrointestinal tract inflammation.

Leveraging Quantitative Systems Pharmacology Approach into Development of Human Recombinant Follistatin Fusion Protein for Duchenne Muscular Dystrophy.

Quantitative understanding about the dynamics of drug-target interactions in biological systems is essential, especially in rare disease programs with small patient populations. Follistatin, by antagonism of myostatin and activin, which are negative regulators of skeletal muscle and inflammatory response, is a promising therapeutic target for Duchenne Muscular Dystrophy. In this study, we constructed a quantitative systems pharmacology model for FS-EEE-Fc, a follistatin recombinant protein to investigate its efficacy from dual target binding, and, subsequently, to project its human efficacious dose.

Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System: Celebrating the 20th Anniversary of the Discovery of ACE2.

ACE2 (angiotensin-converting enzyme 2) has a multiplicity of physiological roles that revolve around its trivalent function: a negative regulator of the renin-angiotensin system, facilitator of amino acid transport, and the severe acute respiratory syndrome-coronavirus (SARS-CoV) and SARS-CoV-2 receptor. is widely expressed, including, in the lungs, cardiovascular system, gut, kidneys, central nervous system, and adipose tissue. ACE2 has recently been identified as the SARS-CoV-2 receptor, the infective agent responsible for coronavirus disease 2019, providing a critical link between immunity, inflammation, ACE2, and cardiovascular disease.

Technical and imaging factors influencing performance of deep learning systems for diabetic retinopathy.

Deep learning (DL) has been shown to be effective in developing diabetic retinopathy (DR) algorithms, possibly tackling financial and manpower challenges hindering implementation of DR screening. However, our systematic review of the literature reveals few studies studied the impact of different factors on these DL algorithms, that are important for clinical deployment in real-world settings. Using 455,491 retinal images, we evaluated two technical and three image-related factors in detection of referable DR.

Renal Denervation in Asia: Consensus Statement of the Asia Renal Denervation Consortium.

The Asia Renal Denervation Consortium consensus conference of Asian physicians actively performing renal denervation (RDN) was recently convened to share up-to-date information and regional perspectives, with the goal of consensus on RDN in Asia. First- and second-generation trials of RDN have demonstrated the efficacy and safety of this treatment modality for lowering blood pressure in patients with resistant hypertension. Considering the ethnic differences of the hypertension profile and demographics of cardiovascular disease demonstrated in the SYMPLICITY HTN (Renal Denervation in Patients With Uncontrolled Hypertension)-Japan study and Global SYMPLICITY registry data from Korea and Taiwan, RDN might be an effective hypertension management strategy in Asia.

Sexual dimorphism in an animal model of Sjögren's syndrome: a potential role for Th17 cells.

Sjögren's syndrome is a complex autoimmune disease with an array of diverse immunological, genetic and environmental etiologies, making identification of the precise autoimmune mechanism difficult to define. One of the most distinctive aspects of Sjögren's syndrome is the high sexual dimorphism with women affected 10-20 times more than men. It is nearly impossible to study the sexual dimorphic development of Sjögren's syndrome in human patients; therefore it is pertinent to develop an appropriate animal model which resembles human disease.

Accelerated intestinal glucose absorption in morbidly obese humans: relationship to glucose transporters, incretin hormones, and glycemia.

Context: Intestinal glucose absorption is mediated by sodium-dependent glucose transporter 1 (SGLT-1) and glucose transporter 2 (GLUT2), which are linked to sweet taste receptor (STR) signaling and incretin responses.

Objective: This study aimed to examine intestinal glucose absorption in morbidly obese humans and its relationship to the expression of STR and glucose transporters, glycemia, and incretin responses.

Design/setting/participants: Seventeen nondiabetic, morbidly obese subjects (body mass index [BMI], 48 ± 4 kg/m(2)) and 11 lean controls (BMI, 25 ± 1 kg/m(2)) underwent endoscopic duodenal biopsies before and after a 30-minute intraduodenal glucose infusion (30 g glucose and 3 g 3-O-methylglucose [3-OMG]).

Vision outcomes and major complications after endovascular coil embolization of ophthalmic segment aneurysms.

Background And Purpose: As aneurysms arising from the ophthalmic segment of the internal carotid artery increase in size, they can compress the optic nerve, prompting patients to present with visual disturbances. The purpose of this article is to describe the clinical and angiographic results with an emphasis on visual outcomes following the endovascular treatment of ophthalmic segment ICA aneurysms.

Materials And Methods: The records of 1254 patients who presented for endovascular treatment of a cerebral aneurysm were retrospectively reviewed to identify 65 consecutive patients who underwent coil embolization of an ophthalmic segment ICA aneurysm.

Heterogeneity in lung (18)FDG uptake in pulmonary arterial hypertension: potential of dynamic (18)FDG positron emission tomography with kinetic analysis as a bridging biomarker for pulmonary vascular remodeling targeted treatments.

Background: Pulmonary arterial hypertension (PAH) is a disease of progressive vascular remodeling, characterized by dysregulated growth of pulmonary vascular cells and inflammation. A prevailing view is that abnormal cellular metabolism, notably aerobic glycolysis that increases glucose demand, underlies the pathogenesis of PAH. Increased lung glucose uptake has been reported in animal models.