Repurposing Linezolid in Conjunction with Histone Deacetylase Inhibitor Access in the Realm of Glioblastoma Therapies.

Since decades after temozolomide was approved, no effective drugs have been developed. Undoubtedly, blood-brain barrier (BBB) penetration is a severe issue that should be overcome in glioblastoma multiforme (GBM) drug development. In this research, we were inspired by linezolid through structural modification with several bioactive moieties to achieve the desired brain delivery.

The Splice Index as a prognostic biomarker of strength and function in myotonic dystrophy type 1.

Background: Myotonic dystrophy type 1 (DM1) is a multisystemic, CTG repeat expansion disorder characterized by a slow, progressive decline in skeletal muscle function. A biomarker correlating RNA mis-splicing, the core pathogenic disease mechanism, and muscle performance is crucial for assessing response to disease-modifying interventions. We evaluated the Myotonic Dystrophy Splice Index (SI), a composite RNA splicing biomarker incorporating 22 disease-specific events, as a potential biomarker of DM1 muscle weakness.

The Role of Race/Ethnicity on the Association between Neighborhood Deprivation and Breast Cancer Outcomes among Kentucky Breast Cancer Patients years 2010-2022.

Background: Kentucky is within the top five leading states for breast mortality nationwide. This study investigates the association between neighborhood socioeconomic disadvantage and breast cancer outcomes, including surgical treatment, radiation therapy, chemotherapy, and survival, and how associations vary by race and ethnicity in Kentucky.

Methods: We conducted a retrospective cohort analysis using data from the Kentucky Cancer Registry (KCR) for breast cancer patients diagnosed between 2010 and 2017, with follow-up through December 31, 2022.

Identifying and targeting key driver genes for collagen production within the 11q13/14 breast cancer amplicon.

Breast cancers of the IntClust-2 type, characterized by amplification of a small portion of chromosome 11, have a median survival of only five years. Several cancer-relevant genes occupy this portion of chromosome 11, and it is thought that overexpression of a combination of driver genes in this region is responsible for the poor outcome of women in this group. In this study we used a gene editing method to knock out, one by one, each of 198 genes that are located within the amplified region of chromosome 11 and determined how much each of these genes contributed to the survival of breast cancer cells.

Population Pharmacokinetics of Orvacabtagene Autoleucel, an Autologous BCMA-Directed Chimeric Antigen Receptor T-Cell Product, in Patients with Relapsed/Refractory Multiple Myeloma.

Purpose: Orvacabtagene autoleucel (orva-cel; JCARH125), a CAR T-cell therapy targeting B-cell maturation antigen (BCMA), was evaluated in relapsed/refractory multiple myeloma (RRMM) patients in the EVOLVE phase 1/2 study (NCT03430011). We applied a modified piecewise model to characterize orva-cel transgene kinetics and assessed the impact of various covariates on its pharmacokinetics (PK).

Experimental Design: The population PK analysis included 159 patients from the EVOLVE study.

Factors Associated With Semaglutide Initiation Among Adults With Obesity.

Importance: Semaglutide, a novel glucagon-like peptide-1 (GLP-1) receptor agonist medication, was approved for weight management in individuals with obesity in June 2021. There is limited evidence on factors associated with uptake among individuals in this subgroup without diabetes.

Objective: To explore factors associated with semaglutide initiation among a population of commercially insured individuals with obesity but no diagnosed diabetes.

Travel Time as an Indicator of Poor Access to Care in Surgical Emergencies.

Importance: Timely access to care is a key metric for health care systems and is particularly important in conditions that acutely worsen with delays in care, including surgical emergencies. However, the association between travel time to emergency care and risk for complex presentation is poorly understood.

Objective: To evaluate the impact of travel time on disease complexity at presentation among people with emergency general surgery conditions and to evaluate whether travel time was associated with clinical outcomes and measures of increased health resource utilization.

Probing Surface Reactions on Multicomponent Glass Using Reflection-Absorption Infrared Spectroscopy.

The chemical reactivity of glass surfaces is often studied with elemental analysis techniques, and although such characterization methods provide insights on compositional changes from exposure to specific chemical conditions, molecule-specific chemical reactions are not determined unambiguously. This study demonstrates the use of reflection-absorption infrared spectroscopy (RAIRS) to detect molecular species on alkali-free boroaluminosilicate and alkali aluminosilicate glasses, using acetic acid vapor as a model reactant to probe reaction sites at the surface with or without pretreatment by aqueous solutions of varied pH. With the assistance of the theoretical calculation of spectral changes based on refractive indices of bulk materials, it was possible to identify the molecular species being removed and produced at the glass surface.

In situ RAS:RAF binding correlates with response to KRASG12C inhibitors in KRASG12C--mutant non-small cell lung cancer.

Purpose: Therapeutic efficacy of KRASG12C(OFF) inhibitors (KRASG12Ci) in KRASG12C-mutant non-small cell lung cancer (NSCLC) varies widely. The activation status of RAS signaling in tumors with KRASG12C mutation remains unclear, as its ability to cycle between the active GTP-bound and inactive GDP-bound states may influence downstream pathway activation and therapeutic responses. We hypothesized that the interaction between RAS and its downstream effector RAF in tumors may serve as indicators of RAS activity, rendering NSCLC tumors with a high degree of RAS engagement and downstream effects more responsive to KRASG12Ci compared to tumors with lower RAS---RAF interaction.

Randomized phase II study of bevacizumab with weekly anetumab ravtansine or weekly paclitaxel in platinum-resistant/refractory high grade ovarian cancer (NCI trial).

Purpose: Mesothelin (MSLN) is highly expressed in high grade serous/ endometrioid ovarian cancers (HGOC). Anetumab ravtansine (AR) is an antibody drug conjugate directed at MSLN antigen with a tubulin polymerization inhibitor. We assessed safety, activity and pharmacokinetics of the combination AR/bevacizumab (Bev) (ARB) versus weekly paclitaxel (wP)/Bev (PB) in patients with platinum resistant/refractory HGOC (prrHGOC).

CA-125 as a Biomarker in Renal Medullary Carcinoma: Integrated Molecular Profiling, Functional Characterization, and Prospective Clinical Validation.

Purpose: Renal medullary carcinoma (RMC) is a highly aggressive malignancy defined by the loss of the SMARCB1 tumor suppressor. It mainly affects young individuals of African descent with sickle cell trait, and it is resistant to conventional therapies used for other renal cell carcinomas. This study aimed to identify potential biomarkers for early detection and disease monitoring of RMC.

Pyrimidinergic P2Y1-Like Nucleotide Receptors Are Functional in Rat Conjunctival Goblet Cells.

Purpose: To investigate the presence of uridine-5'-triphosphate (UTP)-activated P2Y1-like nucleotide receptors (P2Y2R, P2Y4R, and P2Y6R) in conjunctival goblet cells (CGCs) and determine if they increase intracellular Ca2+ concentration ([Ca2+]i) and induce mucin secretion.

Methods: Adult, male rat conjunctiva was used for culture of CGCs. To investigate the expression of P2YRs, mRNA was extracted from CGCs and used for reverse transcription PCR (RT-PCR) with commercially obtained primers specific to P2Y2R, P2Y4R, and P2Y6R.

The Landscape of Vascular Endothelial Growth Factor Inhibition in Retinal Diseases.

Ever since the US Food and Drug Administration (FDA) approved the first vascular endothelial growth factor (VEGF) antagonist 2 decades ago, inhibitors of VEGF have revolutionized the treatment of a variety of ocular disorders involving pathologic neovascularization and retinal exudation. In this perspective, we evaluate the current status of anti-VEGF therapies and the real-world challenges encountered with maintaining therapeutic outcomes. Finally, we describe novel VEGF-based and combinatorial approaches that are in clinical development.

Safety of Human USH1C Transgene Expression Following Subretinal Injection in Wild-Type Pigs.

Purpose: This study aimed to evaluate early-phase safety of subretinal application of AAVanc80.CAG.USH1Ca1 (OT_USH_101) in wild-type (WT) pigs, examining the effects of a vehicle control, low dose, and high dose.

Fundus Autofluorescence Variation in Geographic Atrophy of Age-Related Macular Degeneration: A Clinicopathologic Correlation.

Purpose: The purpose of this study was to develop ground-truth histology about contributors to variable fundus autofluorescence (FAF) signal and thus inform patient selection for treating geographic atrophy (GA) in age-related macular degeneration (AMD).

Methods: One woman with bilateral multifocal GA, foveal sparing, and thick choroids underwent 535 to 580 nm excitation FAF in 6 clinic visits (11 to 6 years before death). The left eye was preserved 5 hours after death.

MAPK pathway activating alteration and immunotherapy efficacy in squamous cell lung carcinoma: results from the randomized, prospective SQUINT trial.

Background: The role of activating alterations in the MAPK pathway in predicting immunotherapy efficacy in lung squamous cell carcinoma (LSCC) patients is largely unknown. The aims of the randomized, phase II SQUINT trial were to assess the efficacy of nivolumab plus ipilimumab (NI) versus platinum-based chemotherapy plus nivolumab (N-CT) and to identify clinically available biomarkers of response to immunotherapy in patients with advanced or metastatic LSCC.

Methods: SQUINT was an open-label, randomized, parallel, non-comparative, phase II trial of NI versus N-CT in chemo-naïve, metastatic or recurrent LSCC adult patients.

Location of Care Delivery for Pulmonary Arterial Hypertension in the United States.

Rationale: Guidelines recommend patients with pulmonary arterial hypertension (PAH) be referred to pulmonary hypertension (PH) centers, but little is known about where care is actually delivered in the United States (US).

Objectives: To use prescription patterns to estimate the proportion of PAH care delivered at US PH centers and explore factors associated with location of care.

Methods: This retrospective study analyzed claims from the Komodo database in adults who received ≥1 PAH prescription between March 2021 and February 2022.

Analytical Validation and Performance of a Blood-Based P-tau217 Diagnostic Test for Alzheimer Disease.

Background: Blood-based biomarkers, especially P-tau217, have been gaining interest as diagnostic tools to measure Alzheimer disease (AD) pathology.

Methods: We developed a plasma P-tau217 chemiluminescent immunoassay using 4G10E2 and IBA493 as antibodies, a synthetic tau peptide as calibrator, and the Quanterix SP-X imager. Analytical validation performed in a College of American Pathologists-accredited CLIA laboratory involved multiple kit lots, operators, timepoints, and imagers.

The pregnant moms' empowerment program - Mexico enhances mental health for women exposed to intimate partner violence: a pilot randomized controlled trial.

Purpose: Given the lack of available and effective interventions to address the detrimental consequences of perinatal exposure to intimate partner violence (IPV) on maternal mental health, and reported very low access to IPV-related mental health services in Mexico, we examined the feasibility and efficacy of a culturally adapted, virtual, brief group psychosocial intervention designed to improve maternal mental and physical health and reduce IPV revictimization for pregnant women exposed to IPV. In this pilot randomized controlled trial, we evaluated maternal outcomes after participation in the Pregnant Moms' Empowerment Program (PMEP) in Mexico.

Methods: Women were recruited from social service agencies and health centers in the community, as well as social media advertisements that targeted pregnant women living in Mexico.

"Update on pediatric primary liver tumors".

Liver masses are common in children, however primary malignant neoplasms are rare, representing only 1% of all pediatric cancers. Hepatocellular neoplasms are the most common primary liver malignancies and hepatoblastoma (HB) is the most frequently diagnosed. The incidence of HB, which is increasing, is approximately of 2 cases per million in the United States, followed by hepatocellular carcinoma (HCC).

Early vs. Delayed Switching from Controlled to Assisted Ventilation: A Target Trial Emulation.

Rationale: In critically ill patients receiving invasive mechanical ventilation, switching from controlled to assisted ventilation is a crucial milestone towards ventilator liberation. The optimal timing for switching to assisted ventilation has not been studied.

Objectives: Our objective was to determine whether a strategy of early as compared to delayed switching affects the duration of invasive mechanical ventilation, ICU length of stay, and mortality.

Which comes first, puberty or identity? The longitudinal interrelations between pubertal timing and sexual minority self-identification among early adolescents.

Sexual minority adolescents experience puberty earlier than their heterosexual peers. Early puberty is an indicator of premature aging and can be partly driven by chronic stress linked to discrimination. Nonetheless, the neural, cognitive, and social development linked to puberty enables adolescents to explore and understand their sexual identities.

Multidimensional profiles of adolescent social-ecological risk and protective factors and young adult sexual behavior.

Research has demonstrated that social-ecological risk and protective factors at multiple levels are associated with sexual behavior in adolescence. However, relatively little is known about how different patterns of these factors may work together in combination to influence sexual risk. In this study, we use nationally representative data from the U.