Phase I study of CD19 CAR T-cell therapy harboring a fully human scFv in CAR-naïve adult B-ALL patients.

CD19-directed chimeric antigen receptor-engineered (CD19 CAR) T-cell therapy elicits high response rates but fails to induce durable responses in most adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). In a previous clinical trial (NCT01865617), we observed anti-CAR immune responses associated with impaired in vivo CAR T-cell expansion after second infusions. Because these CD8+ T-cell responses were predominantly directed at peptides derived from the murine single chain variable fragment (scFv) in the CAR, we conducted a clinical trial investigating the safety and efficacy of CD19 CAR T-cells engineered with a CAR incorporating a fully human scFv (JCAR021) in adults with R/R B-ALL (NCT03103971).

Trial of Labor After Cesarean Delivery in Individuals With Twin Pregnancies and Two Prior Cesarean Deliveries.

Objective: To investigate short-term maternal and neonatal outcomes in individuals with twin pregnancies and two prior cesarean deliveries who underwent trial of labor after cesarean (TOLAC).

Methods: A cross-sectional study of live-birth data was conducted between 2014 and 2021 in the United States. Individuals with more than two prior cesarean deliveries and multiple gestations higher than twins were excluded.

The FBXO45-GEF-H1 axis controls germinal center formation and B-cell lymphomagenesis.

The role of ubiquitin-mediated degradation mechanisms in the pathogenesis of diffuse large B cell (DLBCL) and follicular lymphoma (FL) is not completely understood. We show that conditional deletion of the E3 ubiquitin ligase Fbxo45 in germinal center B-cells results in B-cell lymphomagenesis in homozygous (100%) and heterozygous (48%) mice. Mechanistically, FBXO45 targets the RHO guanine exchange factor ARHGEF2/GEF-H1 for ubiquitin-mediated degradation.

Cigarette smoke components modulate the MR1-MAIT axis.

Tobacco smoking is prevalent across the world and causes numerous diseases. Cigarette smoke (CS) compromises immunity, yet little is known of the components of CS that impact T cell function. MR1 is a ubiquitous molecule that presents bacterial metabolites to MAIT cells, which are highly abundant in the lungs.

Challenges in Geographic Access to Specialized Pediatric Burn Care in the United States.

Background: Geographical access to pediatric burn centers in the US is not well described. Patients may receive care at American Burn Association (ABA)-verified burn centers, unverified burn centers, or non-burn centers. A recent study indicated that most US counties do not have an ABA-verified pediatric burn center within 100 miles.

Integrating single-cell multimodal epigenomic data using 1D-convolutional neural networks.

Motivation: Recent experimental developments enable single-cell multimodal epigenomic profiling, which measures multiple histone modifications and chromatin accessibility within the same cell. Such parallel measurements provide exciting new opportunities to investigate how epigenomic modalities vary together across cell types and states. A pivotal step in using this type of data is integrating the epigenomic modalities to learn a unified representation of each cell, but existing approaches are not designed to model the unique nature of this data type.

Phase I study of adavosertib with radiation therapy and temozolomide in newly diagnosed glioblastoma and intratumoral drug levels in recurrent glioblastoma.

Purpose: Adavosertib is an oral small molecular inhibitor of Wee1. The Adult Brain Tumor Consortium performed a phase I study of adavosertib, radiation (RT) and temozolomide (TMZ) in newly diagnosed glioblastoma (GBM) as well as a surgical window of opportunity study in recurrent GBM.

Patients And Methods: The maximum tolerated dose (MTD) of adavosertib was determined in adult patients with newly diagnosed GBM using a standard 3+3 design in 2 separate cohorts: with concurrent RT/TMZ or with adjuvant TMZ.

Influence of Lens Power on IOL/Posterior Lens Capsule Interactions and IOL's PCO Potential.

Purpose: Severely myopic eyes have been associated with high posterior capsule opacification (PCO) incidence. Although it has been reported that myopic eyes have weaker or more delayed capsule adhesion than emmetropic eyes, it is unclear whether/how dioptric power and posterior curvature of IOLs affect IOLs' affinity for the posterior lens capsule (PLC) and their PCO potential.

Methods: To investigate this, acrylic foldable IOLs with increasing dioptric power of 6.

Using a Theoretical Model to Assess the Impact of Vascular Risk Factors on Autoregulation in the Retina.

Purpose: Vascular impairments, including reduced capillary density (CD), impaired autoregulation capacity (Reg), and elevated intraocular pressure (IOP), have been identified as significant contributors to glaucomatous disease. This study implemented a theoretical model to quantify the impact of these impairments on retinal blood flow and oxygenation as intraluminal pressure (Pa) is varied.

Methods: A theoretical model of the retinal vasculature was used to simulate reductions in CD by 10% (early glaucoma) and 30% to 50% (advanced glaucoma), a range in autoregulation capacity from 0% (totally impaired) to 100% (totally functional), and normal (15 mm Hg) and elevated (25 mm Hg) levels of IOP.

Tubulin Acetylation Enhances Microtubule Stability in Trabecular Meshwork Cells Under Mechanical Stress.

Purpose: To study the roles of tubulin acetylation and cyclic mechanical stretch (CMS) in trabecular meshwork (TM) cells and their impact on outflow pathway physiology and pathology.

Methods: Primary TM cell cultures were subjected to CMS (8% elongation, 24 hours), and acetylated α-tubulin at lysine 40 (Ac-TUBA4) was assessed by western blotting and immunofluorescence. Enzymes regulating tubulin acetylation were identified via siRNA-mediated knockdowns of ATAT1, HDAC6, and SIRT2.

Community engagement to inform multi-level analyses of the role of neighborhood factors in cancer control behaviors in African Americans.

Background: While community engagement has had a substantial presence in public health research, community input to inform geospatial and health analyses remains underutilized and novel. This manuscript reports on community engagement activities to solicit stakeholder perspectives on the role of neighborhood conditions in health and cancer. We discuss how this community input refined a priori conceptual model to be tested in the larger Families, Friends, and Neighborhoods (FFAN) Study.

Genomic Profiling of Cardiac Angiosarcoma Reveals Novel Targetable KDR Variants, Recurrent MED12 Mutations and a High Burden of Germline POT1Alterations.

Purpose: Cardiac angiosarcoma (CAS) is a rare, aggressive malignancy with limited treatment options. Both sporadic and familial cases occur, with recent links to germline POT1 mutations. The genomic landscape of this disease is poorly understood.

Artificial intelligence in cryo-EM protein particle picking: recent advances and remaining challenges.

Cryo-electron microscopy (cryo-EM) has revolutionized structural biology by enabling the determination of high-resolution 3-Dimensional (3D) structures of large biological macromolecules. Protein particle picking, the process of identifying individual protein particles in cryo-EM micrographs for building protein structures, has progressed from manual and template-based methods to sophisticated artificial intelligence (AI)-driven approaches in recent years. This review critically examines the evolution and current state of cryo-EM particle picking methods, with an emphasis on the impact of AI.

Incomplete remyelination via therapeutically enhanced oligodendrogenesis is sufficient to recover visual cortical function.

Myelin loss induces neural dysfunction and contributes to the pathophysiology of neurodegenerative diseases, injury conditions, and aging. Because remyelination is often incomplete, better understanding endogenous remyelination and developing remyelination therapies that restore neural function are clinical imperatives. Here, we use in vivo two-photon microscopy and electrophysiology to study the dynamics of endogenous and therapeutic-induced cortical remyelination and functional recovery after cuprizone-mediated demyelination in mice.

Improving reading competence in aphasia with combined aerobic exercise and phono-motor treatment: Protocol for a randomized controlled trial.

Aphasia, a communication disorder caused primarily by left-hemisphere stroke, affects millions of individuals worldwide, with up to 70% experiencing significant reading impairments. These deficits negatively impact independence and quality of life, highlighting the need for effective treatments that target the cognitive and neural processes essential to reading recovery. This Randomized Clinical Trial (RCT) aims to test the efficacy of a combined intervention incorporating aerobic exercise training (AET) and phono-motor treatment (PMT) to enhance reading recovery in individuals with post-stroke aphasia.

Outcomes of pediatric liver retransplantation candidates in the modern era: Strategies are needed to avoid waitlist mortality in the United States.

Pediatric liver retransplantation (rLT) has historically shown poorer outcomes compared to primary liver transplantation (pLT). Comprehensive studies assessing outcomes for pediatric rLT candidates under the modern allocation policy are lacking. OPTN data from January 1, 2010, to December 31, 2022 were obtained; exclusion criteria included candidates ≥18years of age and those listed or transplanted for multiple organs.

Empirically validating a computational model of automatic behavior shaping.

Background: Mobile sensing technology allows automated behavior shaping routines to be incorporated into health behavior interventions and other settings. In previous work, a computational model was built to investigate how to best arrange automatic behavior shaping procedures, but the degree to which this model reflects actual human behavior is not known.

Purpose: To translate a previously developed computational model of automatic behavior shaping into an experimental setting.

Kaposi's sarcoma-associated herpesvirus (KSHV) gB dictates a low-pH endocytotic entry pathway as revealed by a dual-fluorescent virus system and a rhesus monkey rhadinovirus expressing KSHV gB.

Interaction with host cell receptors initiates internalization of Kaposi's sarcoma-associated herpesvirus (KSHV) particles. Fusion of viral and host cell membranes, which is followed by release of the viral capsid into the cytoplasm, is executed by the core fusion machinery composed of glycoproteins H (gH), L (gL), and B (gB), that is common to all herpesviruses. KSHV infection has been shown to be sensitive to inhibitors of vacuolar acidification, suggestive of low pH as a fusion trigger.

Single-cell and bulk RNA sequencing analysis reveals CENPA as a potential biomarker and therapeutic target in cancers.

Background: Cancer remains one of the most significant public health challenges worldwide. A widely recognized hallmark of cancer is the ability to sustain proliferative signaling, which is closely tied to various cell cycle processes. Centromere Protein A (CENPA), a variant of the standard histone H3, is crucial for selective chromosome segregation during the cell cycle.

Impacts of host phylogeny, diet, and geography on the gut microbiome of rodents.

Mammalian gut microbial communities are thought to play a variety of important roles in health and fitness, including digestion, metabolism, nutrition, immune response, behavior, and pathogen protection. Gut microbiota diversity among hosts is strongly shaped by diet as well as phylogenetic relationships among hosts. Although various host factors may influence microbial community structure, the relative contribution may vary depending on several variables, such as taxonomic scales of the species studied, dietary patterns, geographic location, and gut physiology.

Universal parent-focused child sexual abuse prevention: A quasi-experimental protocol.

Background: Child sexual abuse (CSA) is a significant public health concern, and there is a lack of universal, evidence-based primary prevention interventions that extend beyond a focus solely on children. Parents remain a consistently underutilized target for primary prevention efforts aimed at mitigating CSA despite their unique relationship and close proximity to their children. CSA risk is not confined to any specific demographic, and its effects on affected children are well-documented, significantly impacting numerous dimensions of their wellbeing.

Investigative genetic genealogy practices warranting policy attention: Results of a modified policy Delphi.

A technique known as investigative genetic genealogy (IGG) was first introduced to criminal investigations in 2018, and it has since been used by U.S. law enforcement to help identify hundreds of criminal perpetrators and unidentified human remains.

Psychometric assessment of scales used to evaluate sexual assault prevention programming in the United States Air Force.

Background: Preventing sexual assault in the United States (U.S.) military is essential to safeguard the overall well-being of military personnel and support the military to function in alignment with its intended mission and objectives.

Association between age at first birth and risk of rheumatoid arthritis in women: Evidence from NHANES 2011-2020.

Objective: This study focused on investigating the relation of age at first birth (AFB) with rheumatoid arthritis (RA) risk in women based on the 2011-2020 NHANES (National Health and Nutrition Examination Survey) data.

Methods: Women were analyzed using National Health and Nutrition Examination Survey (NHANES) data from 2011 to 2020 in the US. Both AFB and RA diagnoses were obtained through self-reported questionnaires.

Terahertz conductivity of two-dimensional materials: a review.

Two-dimensional (2D) van der Waals materials are shaping the landscape of next-generation devices, offering significant technological value thanks to their unique, tunable, and layer-dependent electronic and optoelectronic properties. Time-domain spectroscopic techniques at terahertz (THz) frequencies offer noninvasive, contact-free methods for characterizing the dynamics of carriers in 2D materials. They also pave the path toward the applications of 2D materials in detection, imaging, manufacturing, and communication within the increasingly important THz frequency range.