Highly multiplexed imaging reveals prognostic immune and stromal spatial biomarkers in breast cancer.

Spatial profiling of tissues promises to elucidate tumor-microenvironment interactions and generate prognostic and predictive biomarkers. We analyzed single-cell, spatial data from three multiplex imaging technologies: cyclic immunofluorescence (CycIF) data we generated from 102 breast cancer patients with clinical follow-up, and publicly available imaging mass cytometry and multiplex ion-beam imaging datasets. Similar single-cell phenotyping results across imaging platforms enabled combined analysis of epithelial phenotypes to delineate prognostic subtypes among estrogen-receptor positive (ER+) patients.

FDA Approval Summary: Tovorafenib for Relapsed or Refractory BRAF-altered Pediatric Low-Grade Glioma.

On April 23, 2024, FDA granted accelerated approval to tovorafenib, a type II RAF kinase inhibitor, for the treatment of patients 6 months of age and older with relapsed or refractory pediatric low-grade glioma (pLGG) harboring a BRAF fusion or rearrangement, or BRAF V600 mutation. Efficacy was evaluated in FIREFLY-1 (NCT04775485), a single-arm, open-label, multicenter trial that enrolled patients 6 months to 25 years of age with relapsed or refractory pLGG with an activating BRAF alteration who had received prior systemic therapy. The major efficacy outcome measure was radiologic overall response rate (ORR), defined as the proportion of patients with complete response, partial response, or minor response as determined by blinded independent central review using Response Assessment in Pediatric Neuro-Oncology (RAPNO) criteria.

TRAIL agonists rescue mice from radiation-induced lung, skin or esophageal injury.

Radiotherapy can be limited by pneumonitis which is impacted by innate immunity, including pathways regulated by TRAIL death receptor DR5. We investigated whether DR5 agonists could rescue mice from toxic effects of radiation and found two different agonists, parenteral PEGylated trimeric-TRAIL (TLY012) and oral TRAIL-Inducing Compound (TIC10/ONC201) could reduce pneumonitis, alveolar-wall thickness, and oxygen desaturation. Lung protection extended to late effects of radiation including less fibrosis at 22-weeks in TLY012-rescued survivors versus un-rescued surviving irradiated-mice.

PDGFRα inhibition reduces myofibroblast expansion in the fibrotic rim and enhances recovery after ischemic stroke.

Ischemic stroke is a major cause of adult disability. Early treatment with thrombolytics and/or thrombectomy can significantly improve outcomes; however, following these acute interventions, treatment is limited to rehabilitation therapies. Thus, the identification of therapeutic strategies that can help restore brain function in the post-acute phase remains a major challenge.

An Activin Receptor-Like Kinase 1-governed monocytic lineage shapes an immunosuppressive landscape in breast cancer metastases.

The biology centered around the TGF-beta type I receptor Activin Receptor-Like Kinase (ALK)1 (encoded by ACVRL1) has been almost exclusively based on its reported endothelial expression pattern since its first functional characterization more than two decades ago. Here, in efforts to better define the therapeutic context in which to use ALK1 inhibitors, we uncover a population of tumor-associated macrophages (TAMs) that, by virtue of their unanticipated Acvrl1 expression, are effector targets for adjuvant anti-angiogenic immunotherapy in mouse models of metastatic breast cancer. The combinatorial benefit depended on ALK1-mediated modulation of the differentiation potential of bone marrow-derived granulocyte-macrophage progenitors, the release of CD14+ monocytes into circulation, and their eventual extravasation.

LIN28B-mediated PI3K/AKT pathway activation promotes metastasis in colorectal cancer models.

Colorectal cancer (CRC) remains a leading cause of cancer death due to metastatic spread. LIN28B is overexpressed in 30% of CRCs and promotes metastasis, yet its mechanisms remain unclear. In this study, we genetically modified CRC cell lines to overexpress LIN28B, resulting in enhanced PI3K/AKT pathway activation and liver metastasis in mice.

Impaired hydrogen sulfide biosynthesis underlies eccentric contraction-induced force loss in dystrophin-deficient skeletal muscle.

Eccentric contraction- (ECC) induced force loss is a hallmark of murine dystrophin-deficient (mdx) skeletal muscle that is used to assess efficacy of potential therapies for Duchenne muscular dystrophy. While virtually all key proteins involved in muscle contraction have been implicated in ECC force loss, a unifying mechanism that orchestrates force loss across such diverse molecular targets has not been identified. We showed that correcting defective hydrogen sulfide (H2S) signaling in mdx muscle prevented ECC force loss.

A Proposed mHealth Intervention to Address Patient Barriers to Colposcopy Attendance: Qualitative Interview Study of Clinic Staff and Patient Perspectives.

Background: Cervical cancer disparities persist among minoritized women due to infrequent screening and poor follow-up. Structural and psychosocial barriers to following up with colposcopy are problematic for minoritized women. Evidence-based interventions using patient navigation and tailored telephone counseling, including the Tailored Communication for Cervical Cancer Risk (TC3), have modestly improved colposcopy attendance.

Oxygen-Passivated Sulfur Vacancies in Monolayer MoS for Enhanced Piezoelectricity.

Modern-day applications demand onboard electricity generation that can be achieved using piezoelectric phenomena. Reducing the dimensionality of materials is a pathway to enhancing the piezoelectric properties. Transition-metal dichalcogenides have been shown to exhibit high piezoelectricity.

Analogue-Sensitive Inhibition of Histone Demethylases Uncovers Member-Specific Function in Ribosomal Protein Synthesis.

Lysine demethylases (KDMs) catalyze the oxidative removal of the methyl group from histones using earth-abundant iron and the metabolite 2-oxoglutarate (2OG). KDMs have emerged as master regulators of eukaryotic gene expression and are novel drug targets; small-molecule inhibitors of KDMs are in the clinical pipeline for the treatment of human cancer. Yet, mechanistic insights into the functional heterogeneity of human KDMs are limited, necessitating the development of chemical probes for precision targeting.

The Combined Effect of Multisensory Stimulation and Therapist Support on Physical and Mental Health of Older Adults Living in Nursing Homes: Pilot Randomized Controlled Trial.

Background: Increasing life expectancy has led to a rise in nursing home admissions, a context in which older adults often experience chronic physical and mental health conditions, chronic pain, and reduced well-being. Nonpharmacological approaches are especially important for managing older adults' chronic pain, mental health conditions (such as anxiety and depression), and overall well-being, including sensory stimulation (SS) and therapist support (TS). However, the combined effects of SS and TS have not been investigated.

Unusual Iron-Independent Ferroptosis-like Cell Death Induced by Photoactivation of a Typical Iridium Complex for Hypoxia Photodynamic Therapy.

Ferroptosis is a unique cell death mode that relies on iron and lipid peroxidation (LPO) and is extensively utilized to treat drug-resistant tumor. However, like the other antitumor model, requirement of oxygen limited its application in treating the malignant tumors in anaerobic environments, just as photodynamic therapy, a very promising anticancer therapy. Here, we show that an iridium(III) complex (Ir-dF), which was often used in proton-coupled electron transport (PCET) process, can induce efficient cell death upon photo irradiation, which can be effectively protected by the typical ferroptosis inhibitor Fer-1 but not by the classic iron chelating agents and ROS scavengers.

PKCδ germline variants and genetic deletion in mice augment antitumor immunity through regulation of myeloid cells.

Based on the notion that hypomorphic germline genetic variants are linked to autoimmune diseases, we reasoned that novel targets for cancer immunotherapy might be identified through germline variants associated with greater T-cell infiltration into tumors. Here, we report that while investigating germline polymorphisms associated with a tumor immune gene signature, we identified PKCδ as a candidate. Genetic deletion of PKCδ in mice resulted in improved endogenous antitumor immunity and increased efficacy of anti-PD-L1.

Preferred and Actual Location of Death in Adolescents and Young Adults With Cancer.

Importance: Adolescent and young adult (AYA) patients with advanced cancer often die in hospital settings. Data characterizing the degree to which this pattern of care is concordant with patient goals are sparse.

Objective: To evaluate the extent of concordance between the preferred and actual location of death among AYA patients with cancer.

Knowledge and Use of Menthol-Mimicking Cigarettes Among Adults in the US.

Importance: Cigarette companies have been introducing synthetic cooling agent menthol-mimicking cigarettes into the US marketplace as menthol cigarette bans are implemented. These cigarettes may reduce the public health benefits of menthol cigarette bans.

Objective: To examine the epidemiology of the use of synthetic cooling agent menthol-mimicking cigarettes among adults in the US.

Use and Costs of Supplemental Benefits in Medicare Advantage, 2017-2021.

Importance: Nearly all Medicare Advantage (MA) plans offer dental, vision, and hearing benefits not covered by traditional Medicare (TM). However, little is known about MA enrollees' use of those benefits or how much they cost MA insurers or enrollees.

Objective: To estimate use, out-of-pocket (OOP) spending, and insurer payments for dental, hearing, and vision services among Medicare beneficiaries.

Identification of Butyrylcholinesterase-Derived Small Molecule Peptides Indicative of Novichok Nerve Agent Exposures.

Novichok nerve agents, such as A-230, A-232, and A-234, were classified as Schedule 1 chemicals under the Chemical Weapons Convention (CWC) by the Organisation for the Prohibition of Chemical Weapons (OPCW) following poisoning incidents in 2018. As a result, the production, storage, and use of these chemicals are strictly prohibited by CWC signatory nations. The identification of biomarkers indicating Novichok exposure in humans is crucial for prompt detection and response to potential incidents involving these banned chemical weapons.

Adapting Methods for Isolation and Enumeration of Microplastics to Quantify Tire Road Wear Particles with Confirmation by Pyrolysis GC-MS.

The complex, varied composition (i.e., rubbers/elastomers, carbon black, fillers, additives, and embedded road materials) and wide density range of tire road wear particles (TRWPs) present challenges for their isolation and identification from environmental matrices.

[C]MK-6884 PET imaging reveals lower M muscarinic acetylcholine receptor availability following cocaine self-administration in male rats.

Background: Cocaine Use Disorder (CUD) remains a significant problem in the United States, with high rates of relapse and no present FDA-approved treatment. The acetylcholine neurotransmitter system, specifically through modulation of muscarinic acetylcholine receptor (mAChR) function, has shown promise as a therapeutic target for multiple aspects of CUD. Enhancement of the M mAChR subtype via positive allosteric modulation has been shown to inhibit the behavioral and neurochemical effects of cocaine across several rodent models of CUD.

Dementia Diagnosis Unawareness and Caregiver Burden in a Multi-ethnic Cohort.

Background: Previous reports suggest patient and caregiver lack of awareness of dementia. Little is known about how this varies by ethnicity and how informal (family) caregiver burden is associated with knowing a dementia diagnosis.

Objective: To investigate whether participants with probable dementia were aware of a diagnosis provided by a physician and how this differed among Mexican American and non-Hispanic White participants; whether having a primary care physician was associated with dementia diagnosis unawareness; and the association of dementia diagnosis unawareness with caregiver burden.

Advanced Markers for Hemodynamic Monitoring in Cardiogenic Shock and End-Stage Heart Failure: A Mini Review.

Right heart catheterization (RHC) provides critical hemodynamic insights by measuring atrial, ventricular, and pulmonary artery pressures, as well as cardiac output (CO). Although the use of RHC has decreased, its application has been linked to improved outcomes. Advanced hemodynamic markers such as cardiac power output (CPO), aortic pulsatility index (API), pulmonary artery pulsatility index (PAPi), right atrial pressure to pulmonary capillary wedge pressure ratio (RAP/PCWP) and right ventricular stroke work index (RVSWI) have been introduced to enhance risk stratification in cardiogenic shock (CS) and end-stage heart failure (HF) patients.

Romosozumab adverse event profile: a pharmacovigilance analysis based on the FDA Adverse Event Reporting System (FAERS) from 2019 to 2023.

Objective: This study aims to analyze adverse drug events (ADE) related to romosozumab from the second quarter of 2019 to the third quarter of 2023 from FAERS database.

Methods: The ADE data related to romosozumab from 2019 Q2 to 2023 Q3 were collected. After data normalization, four signal strength quantification algorithms were used: ROR (Reporting Odds Ratios), PRR (Proportional Reporting Ratios), BCPNN (Bayesian Confidence Propagation Neural Network), and EBGM (Empirical Bayesian Geometric Mean).

The CD74 inhibitor DRhQ improves short-term memory and mitochondrial function in 5xFAD mouse model of Aβ accumulation.

Neuroinflammation and mitochondrial dysfunction are early events in Alzheimer's disease (AD) and contribute to neurodegeneration and cognitive impairment. Evidence suggests that the inflammatory axis mediated by macrophage migration inhibitory factor (MIF) binding to its receptor, CD74, plays an important role in many central nervous system (CNS) disorders such as AD. Our group has developed DRhQ, a novel CD74 binding construct which competitively inhibits MIF binding, blocks macrophage activation and migration into the CNS, enhances anti-inflammatory microglia cell numbers and reduces pro-inflammatory gene expression.

Outcomes for infants with BRUE diagnosed with oropharyngeal dysphagia or gastroesophageal reflux disease: a multicenter study from the Pediatric Health Information System Database.

We aimed to determine the prevalence of gastroesophageal reflux disease (GERD) and oropharyngeal dysphagia as explanatory diagnoses, risk factors for acid suppression treatment, and risk factors for repeat hospital visit in infants hospitalized after brief resolved unexplained event (BRUE) using a multicenter pediatric database. We performed a multicenter retrospective database study of infants admitted with BRUE in the Pediatric Health Information System between 2016 and 2021. Data included diagnostic testing, explanatory diagnoses, treatment with acid suppression, and related repeat hospital visits within 6 months.

Predictors of Bilateral Disease in Low-Risk Papillary Thyroid Cancer: Histopathologic Insights and Preoperative Ultrasonography.

Background: With the current shift toward de-escalation of surgical management in low-risk papillary thyroid cancer (PTC), understanding predictors and the clinical significance of additional tumors in the contralateral lobe is important. This study investigated the histopathologic predictors of bilateral disease in low-risk PTC patients and the utility of preoperative ultrasonography in guiding completion thyroidectomy decisions.

Methods: Patients treated with total thyroidectomy (TT) for low-risk PTCs (< 4 cm) at the Endocrine Surgical Unit of the Royal North Shore Hospital, University of Sydney from 2013 to 2020 were identified from a prospectively maintained database.