Targeted Polymersome Delivery of a Stapled Peptide for Drugging the Tumor Protein p53:BCL-2-Family Axis in Diffuse Large B-Cell Lymphoma.

Diffuse large B-cell lymphoma (DLBCL) remains a formidable diagnosis in need of new treatment paradigms. In this work, we elucidated an opportunity for therapeutic synergy in DLBCL by reactivating tumor protein p53 with a stapled peptide, ATSP-7041, thereby priming cells for apoptosis and enhancing their sensitivity to BCL-2 family modulation with a BH3-mimetic, ABT-263 (navitoclax). While this combination was highly effective at activating apoptosis in DLBCL , it was highly toxic , resulting in a prohibitively narrow therapeutic window.

CRISPR-Cas9 Editing of the and Promoters to Treat Sickle Cell Disease.

Background: Sickle cell disease is caused by a defect in the β-globin subunit of adult hemoglobin. Sickle hemoglobin polymerizes under hypoxic conditions, producing deformed red cells that hemolyze and cause vaso-occlusion that results in progressive organ damage and early death. Elevated fetal hemoglobin levels in red cells protect against complications of sickle cell disease.

Effects of levothyroxine substitution therapy on hunger and food intake in individuals with hypothyroidism.

Context: In individuals with hypothyroidism and overweight, levothyroxine substitution therapy is often expected to cause weight loss due to its effect on resting energy expenditure. However, despite levothyroxine-induced enhancement of resting energy expenditure, fat mass loss is rarely seen after levothyroxine substitution therapy. The mechanism behind this conundrum is unknown.

Skin Cancer and Hydrochlorothiazide: Novel Population-Based Analyses Considering Personal Risk Factors Including Race/Ethnicity.

Background: Hydrochlorothiazide, a common antihypertensive, has photosensitive properties, potentially increasing skin cancer risk. We evaluated melanoma and nonmelanoma skin cancer among hydrochlorothiazide users with 3 different cohorts as each allows assessment of different potential cofounders/effect modifiers, including race/ethnicity.

Methods: We built 3 cohorts using IBM MarketScan Research Databases: Commercial and Encounters (>3.

Combination fedratinib and venetoclax has activity against human B-ALL with high FLT3 expression.

Treatment of relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) remains a challenge, particularly in patients who do not respond to traditional chemotherapy or immunotherapy. The objective of this study was to assess the efficacy of fedratinib, a semi selective JAK2 inhibitor and venetoclax, a selective BCL-2 inhibitor, on human B-ALL using both single-agent and combinatorial treatments. The combination treatment of fedratinib and venetoclax improved killing of the human B-ALL cell lines RS4;11 and SUPB-15 in vitro over single-agent treatments.

Medium-Term Outcomes of Conservative and Surgical Treatments for Stress Urinary Incontinence: A Medicare Claims Analysis: Developed by the AUGS Payment Reform Committee.

Objective: This study aimed to evaluate the 3- to 5-year retreatment outcomes for conservatively and surgically treated urinary incontinence (UI) in a population of women 66 years and older.

Methods: This retrospective cohort study used 5% Medicare data to evaluate UI retreatment outcomes of women undergoing physical therapy (PT), pessary treatment, or sling surgery. The data set used inpatient, outpatient, and carrier claims from 2008 to 2016 in women 66 years and older with fee-for-service coverage.

Multimodality Cardiac Imaging in COVID.

Infection with SARS-CoV-2, the virus that causes COVID, is associated with numerous potential secondary complications. Global efforts have been dedicated to understanding the myriad potential cardiovascular sequelae which may occur during acute infection, convalescence, or recovery. Because patients often present with nonspecific symptoms and laboratory findings, cardiac imaging has emerged as an important tool for the discrimination of pulmonary and cardiovascular complications of this disease.

Healthcare resource use and associated costs in a cohort of hospitalized COVID-19 patients in Spain: A retrospective analysis from the first to the third pandemic wave. EPICOV study.

Objectives: Describe healthcare resource use and costs per hospitalized coronavirus disease-2019 (COVID-19) patient during the three main outbreak waves.

Methods: A retrospective observational study. COVID-19 patient data were collected from a dataset from 17 hospitals in the HM Hospitals Group.

Compact Cas9d and HEARO enzymes for genome editing discovered from uncultivated microbes.

Programmable, RNA-guided nucleases are diverse enzymes that have been repurposed for biotechnological applications. However, to further expand the therapeutic application of these tools there is a need for targetable systems that are small enough to be delivered efficiently. Here, we mined an extensive genome-resolved metagenomics database and identified families of uncharacterized RNA-guided, compact nucleases (between 450 and 1,050 aa).

Targeting RARA overexpression with tamibarotene, a potent and selective RARα agonist, is a novel approach in AML.

A superenhancer at the retinoic acid receptor alpha (RARA) gene is associated with RARA mRNA overexpression in ∼30% of non-acute promyelocytic leukemia acute myeloid leukemia (AML) and in ∼50% of myelodysplastic syndromes (MDS). RARA overexpression is an actionable target for treatment with tamibarotene, an oral potent and selective RARα agonist. Sensitivity to the RARα agonist tamibarotene was demonstrated in RARA-high but not RARA-low preclinical AML models.

Dasatinib/prednisone induction followed by blinatumomab/dasatinib in Ph+ acute lymphoblastic leukemia.

Novel treatment strategies are needed for the treatment of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) in older patients. This trial evaluated the feasibility and outcomes with the anti-CD19 bispecific T-cell-engaging antibody, blinatumomab, in combination with dasatinib and steroids. Patients 65 years of age or older with Ph+ or Ph-like ALL (with dasatinib-sensitive fusions/mutations) were eligible and could be newly diagnosed or relapsed/refractory.

VISTA Targeting of T-cell Quiescence and Myeloid Suppression Overcomes Adaptive Resistance.

V domain immunoglobulin suppressor of T-cell activation (VISTA) is a premier target for cancer treatment due to its broad expression in many cancer types and enhanced expression upon development of adaptive immune checkpoint resistance. In the CT26 colorectal cancer model, monotherapy of small tumors with anti-VISTA resulted in slowed tumor growth. In a combination therapy setting, large CT26 tumors showed complete adaptive resistance to anti-PD-1/CTLA-4, but inclusion of anti-VISTA led to rejection of half the tumors.

Learners' Responses to a Virtual Cadaver Dissection Nerve Course in the COVID Era: A Survey Study.

 Virtual education is an evolving method for teaching medical learners. During the coronavirus disease 2019 pandemic, remote learning has provided a replacement for conferences, lectures, and meetings, but has not been described as a method for conducting a cadaver dissection. We aim to demonstrate how learners perceive a virtual cadaver dissection as an alternative to live dissection.

Maternal, Infant, and Child Health Outcomes Associated With the Special Supplemental Nutrition Program for Women, Infants, and Children : A Systematic Review.

Background: The Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) is intended to improve maternal and child health outcomes. In 2009, the WIC food package changed to better align with national nutrition recommendations.

Purpose: To determine whether WIC participation was associated with improved maternal, neonatal-birth, and infant-child health outcomes or differences in outcomes by subgroups and WIC enrollment duration.

A Pragmatic, Data-Driven Method to Determine Cutoffs for CSF Biomarkers of Alzheimer Disease Based on Validation Against PET Imaging.

Background And Objectives: To elaborate a new algorithm to establish a standardized method to define cutoffs for CSF biomarkers of Alzheimer disease (AD) by validating the algorithm against CSF classification derived from PET imaging.

Methods: Low and high levels of CSF phosphorylated tau were first identified to establish optimal cutoffs for CSF β-amyloid (Aβ) peptide biomarkers. These Aβ cutoffs were then used to determine cutoffs for CSF tau and phosphorylated tau markers.

Utilization of Colonoscopy Following Treatment Initiation in U.S. Commercially Insured Patients With Inflammatory Bowel Disease, 2013-2019.

Background: Evaluation of mucosal healing with colonoscopy is recommended for inflammatory bowel disease (IBD) management; however, little is known about real-world use of treat-to-target monitoring following IBD treatment initiation. We aimed to estimate the proportion of U.S.

Determinants in the Underdiagnosis of COPD in Spain-CONOCEPOC Study.

Factors such as seeking medical attention for respiratory symptoms and health professionals ordering spirometry come into play in the underdiagnosis of chronic obstructive pulmonary disease (COPD). The objective of this study was to analyze seeking medical attention and the use of spirometry in individuals with chronic respiratory symptoms and to compare these results with those obtained in the 2005 and 2011 surveys. Material and Methods: A cross-sectional, observational, epidemiological study was conducted via phone interview in December 2020 in Spain, with a representative sample from 17 autonomous communities.

Predictive biomarkers for survival benefit with ramucirumab in urothelial cancer in the RANGE trial.

The RANGE study (NCT02426125) evaluated ramucirumab (an anti-VEGFR2 monoclonal antibody) in patients with platinum-refractory advanced urothelial carcinoma (UC). Here, we use programmed cell death-ligand 1 (PD-L1) immunohistochemistry (IHC) and transcriptome analysis to evaluate the association of immune and angiogenesis pathways, and molecular subtypes, with overall survival (OS) in UC. Higher PD-L1 IHC and immune pathway scores, but not angiogenesis scores, are associated with greater ramucirumab OS benefit.

Three-year quantitative magnetic resonance imaging and phosphorus magnetic resonance spectroscopy study in lower limb muscle in dysferlinopathy.

Background: Natural history studies in neuromuscular disorders are vital to understand the disease evolution and to find sensitive outcome measures. We performed a longitudinal assessment of quantitative magnetic resonance imaging (MRI) and phosphorus magnetic resonance spectroscopy ( P MRS) outcome measures and evaluated their relationship with function in lower limb skeletal muscle of dysferlinopathy patients.

Methods: Quantitative MRI/ P MRS data were obtained at 3 T in two different sites in 54 patients and 12 controls, at baseline, and three annual follow-up visits.

Adjusted D-dimer cutoff levels to rule out pulmonary embolism in patients hospitalized for COPD exacerbation: results from the SLICE trial.

Background: For patients with suspected pulmonary embolism (PE), age- or clinically-adjusted D-dimer threshold level can be used to define a negative test that safely excludes PE and reduces the use of imaging. However, the utility of this approach in patients hospitalized for chronic obstructive pulmonary disease (COPD) exacerbation is undefined.

Methods: We ran an analysis of the patients hospitalized for COPD exacerbation and randomized to the intervention in the SLICE trial.

How Should Clinical Wound Care and Management Translate to Effective Engineering Standard Testing Requirements from Foam Dressings? Mapping the Existing Gaps and Needs.

Wounds of all types remain one of the most important, expensive, and common medical problems, for example, up to approximately two-thirds of the work time of community nurses is spent on wound management. Many wounds are treated by means of dressings. The materials used in a dressing, their microarchitecture, and how they are composed and constructed form the basis for the laboratory and clinical performances of any advanced dressing.

Using a 31-Gene Expression Profile Test to Stratify Patients with Stage I-II Cutaneous Melanoma According to Recurrence Risk: Update to a Prospective, Multicenter Study.

Background: Fifteen to forty percent of patients with localized cutaneous melanoma (CM) (stages I-II) will experience disease relapse. The 31-gene expression profile (31-GEP) uses gene expression data from the primary tumor in conjunction with clinicopathologic features to refine patient prognosis. The study's objective was to evaluate 31-GEP risk stratification for disease-free survival (DFS) in a previously published cohort with longer follow-up.