Synaptic enrichment and dynamic regulation of the two opposing dopamine receptors within the same neurons.

Dopamine can play opposing physiological roles depending on the receptor subtype. In the fruit fly , and encode the D- and D-like receptors, respectively, and are reported to oppositely regulate intracellular cAMP levels. Here, we profiled the expression and subcellular localization of endogenous Dop1R1 and Dop2R in specific cell types in the mushroom body circuit.

Nelonemdaz and Patients With Acute Ischemic Stroke and Mechanical Reperfusion: The RODIN Randomized Clinical Trial.

Importance: Nelonemdaz selectively antagonizes the 2B subunit of the N-methyl-d-aspartate glutamate receptor and scavenges free radical species.

Objective: To evaluate whether nelonemdaz enhances the clinical outcomes of patients with acute ischemic stroke undergoing emergent reperfusion therapy.

Design, Setting, And Participants: This multicenter double-blind placebo-controlled randomized phase 3 trial (December 25, 2021, to June 30, 2023, in South Korea) recruited patients with acute ischemic stroke who met the following criteria: National Institutes of Health Stroke Scale score greater than or equal to 8, Alberta Stroke Program Early Computed Tomography score greater than or equal to 4, and endovascular thrombectomy within 12 hours after stroke onset.

Encorafenib, cetuximab and chemotherapy in BRAF-mutant colorectal cancer: a randomized phase 3 trial.

Encorafenib + cetuximab (EC) is approved for previously treated BRAF V600E-mutant metastatic colorectal cancer (mCRC) based on the BEACON phase 3 study. Historically, first-line treatment of BRAF V600E-mutant mCRC with chemotherapy regimens has had limited efficacy. The phase 3 BREAKWATER study investigated EC+mFOLFOX6 versus standard of care (SOC) in patients with previously untreated BRAF V600E mCRC.

Investigating the functional and structural effect of non-synonymous single nucleotide polymorphisms in the cytotoxic T-lymphocyte antigen-4 gene: An in-silico study.

The cytotoxic T-lymphocyte antigen-4 (CTLA4) is essential in controlling T cell activity within the immune system. Thus, uncovering the molecular dynamics of single nucleotide polymorphisms (SNPs) within the CTLA4 gene is critical. We identified the non-synonymous SNPs (nsSNPs), examined their impact on protein stability, and identified the protein sequences associated with them in the human CTLA4 gene.

SARS-CoV-2 transmission dynamics in Mozambique and Zimbabwe during the first 3 years of the pandemic.

The 2019 emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its rapid spread created a public health emergency of international concern. However, the impact of the pandemic in Sub-Saharan Africa, as documented in cases, hospitalizations and deaths, appears far lower than in the Americas, Europe and Asia. Characterization of the transmission dynamics is critical for understanding how SARS-CoV-2 spreads and the true scale of the pandemic.

Genomics yields biological and phenotypic insights into bipolar disorder.

Bipolar disorder is a leading contributor to the global burden of disease. Despite high heritability (60-80%), the majority of the underlying genetic determinants remain unknown. We analysed data from participants of European, East Asian, African American and Latino ancestries (n = 158,036 cases with bipolar disorder, 2.

A multicenter Phase II randomized, placebo-controlled single-blind trial with the SV2A ligand seletracetam in photosensitive epilepsy patients.

The objective of this study was to evaluate the effect of seletracetam (SEL), a potent modulator of synaptic vesicle glycoprotein 2A (SV2A), in patients with photoparoxysmal EEG response (PPR) to intermittent photic stimulation (IPS) as proof-of-principle of efficacy in patients with epilepsy. In this multicenter, single-blind Phase II study, adults with photosensitive epilepsy, with/without concomitant antiseizure medication therapy, underwent IPS under 3 eye conditions (at eye closure, eyes closed and eyes open) after a single oral dose of placebo (day - 1) or SEL (day 1; 0.5, 1, 2, 4, 10, or 20 mg).

Neutralizing antibody immune correlates in COVAIL trial recipients of an mRNA second COVID-19 vaccine boost.

Neutralizing antibody titer has been a surrogate endpoint for guiding COVID-19 vaccine approval and use, although the pandemic's evolution and the introduction of variant-adapted vaccine boosters raise questions as to this surrogate's contemporary performance. For 985 recipients of an mRNA second bivalent or monovalent booster containing various Spike inserts [Prototype (Ancestral), Beta, Delta, and/or Omicron BA.1 or BA.

Pan-PPAR agonist lanifibranor improves insulin resistance and hepatic steatosis in patients with T2D and MASLD.

Background & Aims: Lanifibranor is a pan-PPAR agonist that improves glucose/lipid metabolism and reverses steatohepatitis and fibrosis in adults with MASH. We tested its effect on insulin resistance at the level of different target tissues in relationship to change in intrahepatic triglyceride (IHTG) content.

Methods: This phase 2, single center, study randomized (1:1) 38 patients with T2D and MASLD to receive lanifibranor 800 mg or placebo for 24 weeks.

Feasibility and acceptability of a mindfulness app-based intervention among patients with metastatic renal cell carcinoma: a multinational study.

Background: Patients with metastatic renal cell carcinoma (mRCC) experience emotional distress and limited supportive care access. This study assesses a mindfulness app's feasibility, acceptability, and preliminary efficacy in improving emotional symptoms, trait mindfulness, and overall quality of life for patients with mRCC on immunotherapy.

Methods: This multinational study recruited patients with mRCC undergoing immunotherapy from Brazil and the United States.

Health Disparities in Rheumatology in the United States.

Objective: Underserved populations are often at risk of experiencing systematic healthcare disparities. Existing disparities in care access, quality of care received, and treatment outcomes among patients with rheumatic disease are not well understood.

Methods: We conducted a targeted literature review to understand disparities in health outcomes, treatment patterns, and healthcare management faced by rheumatology patients in the United States, with a focus on rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS).

Construction and characterization of chimeric FcγR T cells for universal T cell therapy.

Background: Several approaches are being explored for engineering off-the-shelf chimeric antigen receptor (CAR) T cells. In this study, we engineered chimeric Fcγ receptor (FcγR) T cells and tested their potential as a versatile platform for universal T cell therapy.

Methods: Chimeric FcγR (CFR) constructs were generated using three distinct forms of FcγR, namely CD16A, CD32A, and CD64.

Multi-Cancer Early Detection Tests: State of the Art and Implications for Radiologists.

Multi-cancer early detection (MCED) tests are already being marketed as noninvasive, convenient opportunities to test for multiple cancer types with a single blood sample. The technology varies-involving detection of circulating tumor DNA, fragments of DNA, RNA, or proteins unique to each targeted cancer. The priorities and tradeoffs of reaching diagnostic resolution in the setting of possible false positives and negatives remain under active study.

Determinants of Racial and Ethnic Differences in Maternal Cardiovascular Health in Early Pregnancy.

Background: Suboptimal cardiovascular health (CVH) in pregnancy is associated with adverse maternal and offspring outcomes. To guide public health efforts to reduce disparities in maternal CVH, we determined the contribution of individual- and neighborhood-level factors to racial and ethnic differences in early pregnancy CVH.

Methods: We included nulliparous individuals with singleton pregnancies who self-identified as Hispanic, non-Hispanic Black (NHB), or non-Hispanic White (NHW) and participated in the nuMoM2b cohort study (Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be).

Harnessing the tumor microenvironment: targeted cancer therapies through modulation of epithelial-mesenchymal transition.

The tumor microenvironment (TME) is integral to cancer progression, impacting metastasis and treatment response. It consists of diverse cell types, extracellular matrix components, and signaling molecules that interact to promote tumor growth and therapeutic resistance. Elucidating the intricate interactions between cancer cells and the TME is crucial in understanding cancer progression and therapeutic challenges.

Prevalence and Temporal Trends of Attention Deficit Hyperactivity Disorder Medication Fills During Pregnancy and Breastfeeding in Denmark.

Background And Objectives: Females of reproductive age are increasingly using attention deficit hyperactivity disorder (ADHD) medication, but its use during pregnancy and breastfeeding is largely unknown. The aim of this study is to examine the prevalence of ADHD medication fills during pregnancy and breastfeeding, including characteristics of these females and cohort differences over time.

Methods: We conducted a descriptive study using Danish nationwide registers.

Lifetime risk and projected burden of dementia.

Understanding the lifetime risk of dementia can inform public health planning and improve patient engagement in prevention. Using data from a community-based, prospective cohort study (n = 15,043; 26.9% Black race, 55.

Updates in the Management of Richter Transformation.

Richter transformation (RT) is a rare albeit devastating complication of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL). RT is defined as an aggressive lymphoma, typically diffuse large B-cell lymphoma, in the setting of CLL. A clonal relationship to the preceding CLL clone is detected in the majority of RT cases and confers more aggressive clinicopathologic kinetics, resistance to standard chemoimmunotherapy regimens, and inferior survival.

Engineered GM-CSF polarizes protumorigenic tumor-associated macrophages to an antitumorigenic phenotype and potently synergizes with IL-12 immunotherapy.

Background: The use of immune checkpoint inhibitors (CPIs) has become a dominant regimen in modern cancer therapy, however immune resistance induced by tumor-associated macrophages (TAMs) with immune suppressive and evasion properties limits responses. Therefore, the rational design of immune modulators that can control the immune suppressive properties of TAMs and polarize them, as well as dendritic cells (DCs), toward a more proinflammatory phenotype is a principal objective in cancer immunotherapy.

Methods: Here, using a protein engineering approach to enhance cytokine residence in the tumor microenvironment, we examined combined stimulation of the myeloid compartment via tumor stroma-binding granulocyte-macrophage colony-stimulating factor (GM-CSF) to enhance responses in both DCs and T cells via stroma-binding interleukin-12 (IL-12).

Integrating artificial intelligence with mechanistic epidemiological modeling: a scoping review of opportunities and challenges.

Integrating prior epidemiological knowledge embedded within mechanistic models with the data-mining capabilities of artificial intelligence (AI) offers transformative potential for epidemiological modeling. While the fusion of AI and traditional mechanistic approaches is rapidly advancing, efforts remain fragmented. This scoping review provides a comprehensive overview of emerging integrated models applied across the spectrum of infectious diseases.

Binding mode-guided development of high-performance antibodies targeting site-specific posttranslational modifications.

Posttranslational modifications (PTMs) of proteins play critical roles in regulating many cellular events. Antibodies targeting site-specific PTMs are essential tools for detecting and enriching PTMs at sites of interest. However, fundamental difficulties in molecular recognition of both PTM and surrounding peptide sequence have hindered the efficient generation of highly sequence-specific anti-PTM antibodies.

Pediatric Snowboarding-Related Concussions and Musculoskeletal Injuries Decreased From 2012 to 2022.

Purpose: To analyze mechanisms, diagnoses, and incidence of youth snowboarding-related injuries presenting to US emergency departments.

Methods: Data from the National Electronic Injury Surveillance System were analyzed for pediatric snowboarding injuries (≤18 years old) from 2012 to 2022. Data were collected for mechanism of injury, diagnosis, location of injury, and disposition.

Prediction of checkpoint inhibitor immunotherapy efficacy for cancer using routine blood tests and clinical data.

Predicting whether a patient with cancer will benefit from immune checkpoint inhibitors (ICIs) without resorting to advanced genomic or immunologic assays is an important clinical need. To address this, we developed and evaluated SCORPIO, a machine learning system that utilizes routine blood tests (complete blood count and comprehensive metabolic profile) alongside clinical characteristics from 9,745 ICI-treated patients across 21 cancer types. SCORPIO was trained on data from 1,628 patients across 17 cancer types from Memorial Sloan Kettering Cancer Center.

Autogene cevumeran with or without atezolizumab in advanced solid tumors: a phase 1 trial.

Effective targeting of somatic cancer mutations to enhance the efficacy of cancer immunotherapy requires an individualized approach. Autogene cevumeran is a uridine messenger RNA lipoplex-based individualized neoantigen-specific immunotherapy designed from tumor-specific somatic mutation data obtained from tumor tissue of each individual patient to stimulate T cell responses against up to 20 neoantigens. This ongoing phase 1 study evaluated autogene cevumeran as monotherapy (n = 30) and in combination with atezolizumab (n = 183) in pretreated patients with advanced solid tumors.

Overcoming CD226-related immune evasion in acute myeloid leukemia with CD38 CAR-engineered NK cells.

CD226 plays a vital role in natural killer (NK) cell cytotoxicity, interacting with its ligands CD112 and CD155 to initiate immune synapse formation, primarily through leukocyte function-associated-1 (LFA-1). Our study examined the role of CD226 in NK cell surveillance of acute myeloid leukemia (AML). NK cells in patients with AML had lower expression of CD226.