Design, Synthesis, and Biological Evaluation of Thieno[3,2-]pyrimidine Derivatives as the First Bifunctional PI3Kδ Isoform Selective/Bromodomain and Extra-Terminal Inhibitors.

The concomitant inhibition of PI3Kδ and bromodomain and extra-terminal (BET) that exerts a synergistic effect on the B-cell receptor signaling pathway provides a new strategy for the treatment of aggressive diffuse large B-cell lymphoma (DLBCL). Herein, a merged pharmacophore strategy was utilized to discover a series of thieno[3,2-]pyrimidine derivatives as the first-in-class bifunctional PI3Kδ-BET inhibitors. Through optimization, a highly potent compound () was identified to possess excellent and balanced activities against PI3Kδ [inhibitory concentration (IC) = 112 ± 8 nM] and BRD4-BD1 (IC = 19 ± 1 nM) and exhibited strong antiproliferative activities in DLBCL cells.

Clinical use of measurable residual disease in adult ALL: recommendations from a panel of U.S. experts.

Measurable residual disease (MRD) is a powerful predictor of clinical outcomes in acute lymphoblastic leukemia (ALL). In addition to its clear prognostic importance, MRD information is increasingly used in clinical decision algorithms to guide therapeutic interventions. While it is well-established that achievement of MRD-negative remission is an important endpoint of ALL therapy, the prognostic and therapeutic implications of MRD in an individual patient are influenced by both disease-related factors (e.

Radical -Adenosylmethionine Sulfurtransferase MybB Catalyzed Formation of the 4-Thiazolidinone Core in Mycobacidin Represents an Intersection between Primary and Secondary Metabolism.

Mycobacidin is an antitubercular antibiotic structurally composed of a sulfur-containing 4-thiazolidinone ring, yet its biosynthesis including the mechanism of sulfur incorporation has remained an open question since its discovery in 1952. In this study, the mycobacidin biosynthetic gene cluster is identified from soil-dwelling , and the corresponding biosynthetic pathway starting with 7-oxoheptanoate is characterized. The radical SAM enzyme MybB catalyzes two sulfur insertion reactions, thereby bridging C and C to complete the 4-thiazolidinone heterocycle as the final step in mycobacidin maturation.

TP53 Mutant Variant Allele Frequency and Cytogenetics Determine Prognostic Groups in MDS/AML for Transplantation.

Results following hematopoietic stem cell transplantation (HSCT) for TP53-mutated myeloid malignancies are disappointing. Several HSCT centers decline to perform HSCT for patients with TP53 mutation because of poor outcomes. In this study, we analyzed 240 patients with TP53-mutated myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) that underwent HSCT.

Accumulation of CD38 in Hybrid Epithelial/Mesenchymal Cells Promotes Immune Remodeling and Metastasis in Breast Cancer.

Triple-negative breast cancer (TNBC) is a highly metastatic subtype of breast cancer. The epithelial-to-mesenchymal transition is a nonbinary process in the metastatic cascade that generates tumor cells with both epithelial and mesenchymal traits known as hybrid EM cells. Recent studies have elucidated the enhanced metastatic potential of cancers featuring the hybrid EM phenotype, highlighting the need to uncover molecular drivers and targetable vulnerabilities of the hybrid EM state.

The role of Iowa gambling task performance in response to citalopram treatment for cocaine use disorder.

Cocaine use disorder (CUD) is associated with executive functioning impairments linked to serotonergic function. Previous studies reported efficacy with the selective serotonin reuptake inhibitor citalopram in reducing cocaine use. The current study explored moderation and mediation of citalopram effects on cocaine use by performance across executive function domains.

Development and Pilot Implementation of a Theory-Based Cognitive Rehabilitation Protocol for Adults With Chronic Cognitive Complaints After Mild Traumatic Brain Injury.

Purpose: The aim of this study was to describe the development of and pilot feasibility outcomes for a strategy-based, brief, intensive cognitive rehabilitation intervention delivered to U.S. service members and veterans with mild traumatic brain injury in a recently completed 3-year pragmatic clinical trial: Symptom-Targeted Approach to Rehabilitation for Concussion (STAR-C).

Development of a conditional plasmid for gene deletion in non-model strains.

is an opportunistic pathogen with four subspecies: (FNN), (FNV), (FNP), and (FNA), each with distinct disease potentials. Research on fusobacterial pathogenesis has mainly focused on the model strain ATCC 23726 from FNN. However, this narrow focus may overlook significant behaviors of other FNN strains and those from other subspecies, given the genetic and phenotypic diversity within .

Venoms and Extracellular Vesicles: A New Frontier in Venom Biology.

Extracellular vesicles (EVs) are nanoparticle-sized vesicles secreted by nearly all cell types under normal physiological conditions. In toxicological research, EVs have emerged as a crucial link between public health and multi-omics approaches, offering insights into cellular responses to disease-causing injury agents such as environmental and biological toxins, contaminants, and drugs. Notably, EVs present a unique opportunity to deepen our understanding of the pathophysiology of envenomation by natural toxins.

Comprehensive Structural, Chemical, and Optical Characterization of CuZnSnS Films on Kapton Using the Automated Successive Ionic Layer Adsorption and Reaction Method.

This study provides a comprehensive structural, chemical, and optical characterization of CZTS thin films deposited on flexible Kapton substrates via the Successive Ionic Layer Adsorption and Reaction (SILAR) method. The investigation explored the effects of varying deposition cycles (40, 60, 70, and 80) and annealing treatments on the films. An X-ray diffraction (XRD) analysis demonstrated enhanced crystallinity and phase purity, particularly in films deposited with 70 cycles.

Volatile Organic Metabolites as Potential Biomarkers for Genitourinary Cancers: Review of the Applications and Detection Methods.

Cancer is one of the leading causes of death globally, and is ranked second in the United States. Early detection is crucial for more effective treatment and a higher chance of survival rates, reducing burdens on individuals and societies. Genitourinary cancers, in particular, face significant challenges in early detection.

Concussion and the Autonomic, Immune, and Endocrine Systems: An Introduction to the Field and a Treatment Framework for Persisting Symptoms.

A significant proportion of patients who sustain a concussion/mild traumatic brain injury endorse persisting, lingering symptoms. The symptoms associated with concussion are nonspecific, and many other medical conditions present with similar symptoms. Medical conditions that overlap symptomatically with concussion include anxiety, depression, insomnia, chronic pain, chronic fatigue, fibromyalgia, and cervical strain injuries.

Bone Marrow Stromal Cells Generate a Pro-Healing Inflammasome When Cultured on Titanium-Aluminum-Vanadium Surfaces with Microscale/Nanoscale Structural Features.

The surface topography and chemistry of titanium-aluminum-vanadium (Ti6Al4V) implants play critical roles in the osteoblast differentiation of human bone marrow stromal cells (MSCs) and the creation of an osteogenic microenvironment. To assess the effects of a microscale/nanoscale (MN) topography, this study compared the effects of MN-modified, anodized, and smooth Ti6Al4V surfaces on MSC response, and for the first time, directly contrasted MN-induced osteoblast differentiation with culture on tissue culture polystyrene (TCPS) in osteogenic medium (OM). Surface characterization revealed distinct differences in microroughness, composition, and topography among the Ti6Al4V substrates.

Interaction Between Malat1 and miR-499-5p Regulates Meis1 Expression and Function with a Net Impact on Cell Proliferation.

Meis1 is a transcription factor involved in numerous functions including development and proliferation and has been previously shown to harness cell cycle progression. In this study, we used in silico analysis to predict that miR-499-5p targets Meis1 and that Malat1 sponges miR-499-5p. For the first time, we demonstrated that the overexpression of miR-499-5p led to the downregulation of Meis1 mRNA and protein in C166 cells by directly binding to its 3'UTR.

Targeting EP2 Receptor Improves Muscle and Bone Health in Dystrophin/Utrophin Double-Knockout Mice.

Duchenne muscular dystrophy (DMD) is a severe genetic muscle disease occurring due to mutations of the dystrophin gene. There is no cure for DMD. Using a dystrophinutrophin (DKO-Hom) mouse model, we investigated the PGE2/EP2 pathway in the pathogenesis of dystrophic muscle and its potential as a therapeutic target.

Optimizing Neurobehavioral Assessment for Patients with Disorders of Consciousness: Proposal of a Comprehensive Pre-Assessment Checklist for Clinicians.

Background: Clinicians are challenged by the ambiguity and uncertainty in assessing level of consciousness in individuals with disorder of consciousness (DoC). There are numerous challenges to valid and reliable neurobehavioral assessment and classification of DoC due to multiple environmental and patient-related biases including behavioral fluctuation and confounding or co-occurring medical conditions. Addressing these biases could impact accuracy of assessment and is an important aspect of the DoC assessment process.

Meeting Challenges in the Diagnosis and Treatment of Glaucoma.

Glaucoma, a progressive and multifactorial optic neurodegenerative disease, still poses significant challenges in both diagnosis and management and remains a perpetual enigma [...

Taba Binary, Multinomial, and Ordinal Regression Models: New Machine Learning Methods for Classification.

The classification methods of machine learning have been widely used in almost every discipline. A new classification method, called Taba regression, was introduced for analyzing binary, multinomial, and ordinal outcomes. To evaluate the performance of Taba regression, liver cirrhosis data obtained from a Mayo Clinic study were analyzed.

Relations between Distress Tolerance and Psychosocial Variables in Adults Experiencing Homelessness.

Background: Distress Tolerance (DT) is a transdiagnostic factor that may help better understand vulnerability to mental health problems. This study explores DT among recently incarcerated adults experiencing homelessness (RIHAs).

Methods: Participants (298) were recruited from an ongoing clinical trial at a homeless shelter in Texas.

Long term outcomes associated with the use of perioperative systemic chemotherapy on low grade appendiceal mucinous neoplasms with pseudomyxoma peritonei treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

Introduction: Low grade appendiceal mucinous neoplasms (LAMN) are indolent tumors that lack invasive potential but may present as pseudomyxoma peritonei. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) significantly improves both overall and recurrence free survival. While systemic chemotherapy is generally considered ineffective for LAMN, little literature is available to support this notion.

Dominant Occipital Sinus: A Rare Anatomical Variant With Potentially Catastrophic Consequences if Unrecognized Preoperatively.

The occipital sinus is often thought of as a redundant vestigial structure in adults. However, in rare cases, it can form the dominant route of intracerebral venous drainage, with a risk of significant surgical morbidity if unrecognised. We present an illustrative case describing this anatomical variant and tailoring of a midline suboccipital craniotomy to allow resection of a fourth ventricular epidermoid tumour with preservation of a dominant occipital sinus, and a review of the published literature.

Childhood executive control and adolescent substance use: Mediation via parent-child relationship quality.

Objective: The goal of the current study was to test prospective direct and indirect associations between preschool executive control (EC), parental affective quality and harsh discipline, and adolescent substance use (e-cigarettes, cannabis, and alcohol) while accounting for participants' age, sex, family history of substance use, and family socioeconomic status.

Method: Participants were 313 youth (49% boys; 70.9% European American) and their parents who participated in a longitudinal cohort-sequential study on the development of EC in preschool and its associations with subsequent health outcomes.

Biocompatible EDOT-Pyrrole Conjugated Conductive Polymer Coating for Augmenting Cell Attachment, Activity, and Differentiation.

Developing scaffolds supporting functional cell attachment and tissue growth is critical in basic cell research, tissue engineering, and regenerative medicine approaches. Though poly(ethylene glycol) (PEG) and its derivatives are attractive for hydrogels and scaffold fabrication, they often require bioactive modifications due to their bioinert nature. In this work, biomimetic synthesized conductive polypyrrole-poly(3,4-ethylenedioxythiophene) copolymer doped with poly(styrenesulfonate) (PPy-PEDOT:PSS) was used as a biocompatible coating for poly(ethylene glycol) diacrylate (PEGDA) hydrogel to support neuronal and muscle cells' attachment, activity, and differentiation.

Addressing Health-Related Social Needs During COVID-19 Through a Hospital-Based, Community Health Worker Program: A Case Study.

. Despite accounting for 34% of the population in Austin, Texas, Latinx individuals made up 50% of those who tested positive for coronavirus, 54% of COVID-related hospitalizations, and 51% of COVID-related deaths between March and June 2020. Of hospitalized Latinx patients, 40% had never seen a primary care provider and many had undiagnosed health conditions.