CHD1L Inhibitor OTI-611 Synergizes with Chemotherapy to Enhance Antitumor Efficacy and Prolong Survival in Colorectal Cancer Mouse Models.

Colorectal cancer (CRC) is one of the most prevalent and deadly forms of cancer. It is universally treated with a combination of the DNA damaging chemotherapy drugs irinotecan, 5-Fluorouracil (5-FU), and oxaliplatin. is a novel oncogene that plays critical roles in chromatin remodeling and DNA damage repair, as well as the regulation of malignant gene expression.

Cannabidiol promotes apoptosis and downregulation of oncogenic factors.

Patients with high-grade serous carcinoma of tubo-ovarian origin (HGSC) often experience significant side effects related to their disease and treatments, such as pain, discomfort, nausea, and vomiting. Over the last two decades, the use of cannabinoids (CBD) to manage pain and anxiety has become more mainstream. However, there is limited data on how CBD interacts with HGSC tumor cells or whether CBD impacts the effect of chemotherapy.

The Epigenetic Landscape of Breast Cancer, Metabolism, and Obesity.

Obesity is a risk factor for developing breast cancer, and significantly increases mortality rates in patients diagnosed with this disease. Drivers of this unfortunate relationships are multifactorial, with obesity-induced changes in the epigenetic state of breast cancer cells being identified as a critical mechanism that impact survival, metastasis, and therapeutic responses. Recent studies have investigated the epigenetic landscape of breast cancer to elucidate the molecular interplay between the breast tissue epigenome and its cellular microenvironment.

Development and Psychometric Evaluation of the Lifestyle Medicine Health Behavior Scale.

The purpose of this study was to develop and validate a scale to measure health behavior across the six pillars of lifestyle medicine: sleep, social connectedness, physical activity, nutrition, substance use, and stress management. A pilot study (n = 94) investigated the construct, convergent, and content validity and reliability of the Lifestyle Medicine Health Behavior (LMHB) scale. Based on the pilot study results and literature, the scale was revised for further psychometric evaluation.

Neighborhood Environment and Longitudinal Follow-Up of Glycosylated Hemoglobin for Youth with Overweight or Obesity.

Neighborhood environment, which includes multiple social drivers of health, has been associated with a higher incidence of chronic conditions in adult cohorts. We examine if neighborhood environment is associated with glycosylated hemoglobin (HbA1c) and body mass index (BMI) as a percentage of the 95th percentile (BMIp95) for youth with overweight and obesity. Cohort study using electronic health record data from a large Midwestern Children's Hospital.

Claudin-4 remodeling of nucleus-cell cycle crosstalk maintains ovarian tumor genome stability and drives resistance to genomic instability-inducing agents.

During cancer development, the interplay between the nucleus and the cell cycle leads to a state of genomic instability, often accompanied by observable morphological aberrations. These aberrations can be controlled by tumor cells to evade cell death, either by preventing or eliminating genomic instability. In epithelial ovarian cancer (EOC), overexpression of the multifunctional protein claudin-4 is a key contributor to therapy resistance through mechanisms associated with genomic instability.

Global inequities in adverse pregnancy outcomes: what can we do?

The Health Equity Leadership & Exchange Network states that "health equity exists when all people, regardless of race, sex, sexual orientation, disability, socioeconomic status, geographic location, or other societal constructs, have fair and just access, opportunity, and resources to achieve their highest potential for health." It is clear from the wide discrepancies in maternal and infant mortalities, by race, ethnicity, location, and social and economic status, that health equity has not been achieved in pregnancy care. Although the most obvious evidence of inequities is in low-resource settings, inequities also exist in high-resource settings.

CHD1L Regulates Cell Survival in Breast Cancer and Its Inhibition by OTI-611 Impedes the DNA Damage Response and Induces PARthanatos.

The Chromodomain helicase DNA-binding protein 1-like (CHD1L) is a nucleosome remodeling enzyme, which plays a key role in chromatin relaxation during the DNA damage response. Genome editing has shown that deletion of CHD1L sensitizes cells to PARPi, but the effect of its pharmacological inhibition has not been defined. Triple-negative breast cancer SUM149PT, HCC1937, and MDA-MB-231 cells were used to assess the mechanism of action of the CHD1Li OTI-611.

EHMT1/2 Inhibition Promotes Regression of Therapy-Resistant Ovarian Cancer Tumors in a CD8 T-cell-Dependent Manner.

Poly ADP-ribose polymerase inhibitors (PARPi) are first-line maintenance therapy for ovarian cancer and an alternative therapy for several other cancer types. However, PARPi-resistance is rising, and there is currently an unmet need to combat PARPi-resistant tumors. Here, we created an immunocompetent, PARPi-resistant mouse model to test the efficacy of combinatory PARPi and euchromatic histone methyltransferase 1/2 inhibitor (EHMTi) in the treatment of PARPi-resistant ovarian cancer.

The Role of B Lymphocytes in Type 1 Diabetes.

While autoreactive T cells are known to induce β-cell death in type 1 diabetes (T1D), self-reactive B cells also play an important role in the pathogenesis of T1D. Studies have shown that individuals living with T1D have an increased frequency of self-reactive B cells that escape from the bone marrow and populate peripheral organs, become activated, and participate in disease. These failed tolerance mechanisms may be attributed to genetic risk alleles that are associated with the development of T1D.

Harm Reduction and Treatment Among People at High Risk of Overdose.

Importance: Rates of overdose deaths involving synthetic opioids remain high, increasingly involve stimulants combined with opioids, and are increasing rapidly in racially and ethnically minoritized communities, yet little is known about access to harm reduction and treatment services in these groups.

Objective: To characterize access and barriers to harm reduction and treatment in a racially and ethnically diverse population of people who use drugs.

Design, Setting, And Participants: A cross-sectional telephone survey of people recruited from 39 treatment, harm reduction, and social service organizations in Milwaukee County, Wisconsin; Flint and Detroit, Michigan; and statewide in New Jersey was conducted from January 30 to July 28, 2023.

The Spatial Structure of the Tumor Immune Microenvironment Can Explain and Predict Patient Response in High-Grade Serous Carcinoma.

Ovarian cancer is the deadliest gynecologic malignancy, and therapeutic options and mortality rates over the last three decades have largely not changed. Recent studies indicate that the composition of the tumor immune microenvironment (TIME) influences patient outcomes. To improve spatial understanding of the TIME, we performed multiplexed ion beam imaging on 83 human high-grade serous carcinoma tumor samples, identifying approximately 160,000 cells across 23 cell types.

Clinician Insights into Effective Components, Delivery Characteristics and Implementation Strategies of Ambulatory Palliative Care for People with Heart Failure: A Qualitative Analysis.

Objectives: To elicit perspectives from specialist palliative care (SPC) and cardiology clinicians concerning the necessary components, delivery characteristics and implementation strategies of successful ambulatory SPC for people with heart failure (HF).

Background: Palliative care is a recommended component of guideline-directed care for people with HF. However, optimal strategies to implement SPC within ambulatory settings are unknown.

What Should Clinicians in Organizations Without Established MLP Programs Do When Their Patients Need Lawyers to Meet Their Health Needs?

Undocumented people in the United States face innumerable legal and structural barriers to health and health care services, including for kidney failure. Their experiences vary across states and regions due to wide variation in insurance coverage and unreliable access to health-promoting resources, including medical-legal partnerships. This commentary on a case canvasses key policy about structural and legal determinants of health for undocumented persons.

Meeting the Health Needs of Society Through Curricular Innovation in Physical Therapist Education: Examples From 3 Entry-Level Programs.

Background And Purpose: Entry-level physical therapist (PT) education programs play a critical role in inspiring future leaders to become moral change agents, capable of understanding and addressing evolving societal health needs. Social reconstructionism represents an educational philosophy focused on alleviating pervasive inequities and improving the health of society; however, its application in PT education is not well understood. The purpose of this article is to describe the approach 3 entry-level PT programs used to manifest social reconstructionism within their curricula to foster social consciousness and strengthen moral agency.

Combining EHMT and PARP Inhibition: A Strategy to Diminish Therapy-Resistant Ovarian Cancer Tumor Growth while Stimulating Immune Activation.

Despite the success of poly-ADP-ribose polymerase inhibitors (PARPi) in the clinic, high rates of resistance to PARPi presents a challenge in the treatment of ovarian cancer, thus it is imperative to find therapeutic strategies to combat PARPi resistance. Here, we demonstrate that inhibition of epigenetic modifiers euchromatic histone lysine methyltransferases 1/2 (EHMT1/2) reduces the growth of multiple PARPi-resistant ovarian cancer cell lines and tumor growth in a PARPi-resistant mouse model of ovarian cancer. We found that combinatory EHMT and PARP inhibition increases immunostimulatory double-stranded RNA formation and elicits several immune signaling pathways in vitro.

Harmonizing the Tripartite Mission in Academic Family Medicine: A Longitudinal Case Example.

Academic practices and departments are defined by a tripartite mission of care, education, and research, conceived as being mutually reinforcing. But in practice, academic faculty have often experienced these 3 missions as competing rather than complementary priorities. This siloed approach has interfered with innovation as a learning health system in which the tripartite missions reinforce each other in practical ways.

Mechanisms and Barriers in Nanomedicine: Progress in the Field and Future Directions.

In recent years, steady progress has been made in synthesizing and characterizing engineered nanoparticles, resulting in several approved drugs and multiple promising candidates in clinical trials. Regulatory agencies such as the Food and Drug Administration and the European Medicines Agency released important guidance documents facilitating nanoparticle-based drug product development, particularly in the context of liposomes and lipid-based carriers. Even with the progress achieved, it is clear that many barriers must still be overcome to accelerate translation into the clinic.

Agnostic identification of plasma biomarkers for postpartum hemorrhage risk.

Background: Postpartum hemorrhage is difficult to predict, is associated with significant maternal morbidity, and is the leading cause of maternal mortality worldwide. The identification of maternal biomarkers that can predict increased postpartum hemorrhage risk would enhance clinical care and may uncover mechanisms that lead to postpartum hemorrhage.

Objective: This retrospective case-control study employed agnostic proteomic profiling of maternal plasma samples to identify differentially abundant proteins in controls and postpartum hemorrhage cases.

Validation of dot blot immunoassay for measurement of complement opsonization of nanoparticles.

Complement plays a critical role in the immune response toward nanomaterials. The complement attack on a foreign surface results in the deposition of C3, assembly of C3 convertases, the release of anaphylatoxins C3a and C5a, and finally, the formation of membrane attack complex C5b-9. Various technologies can measure complement activation markers in the fluid phase, but measurements of surface C3 deposition are less common.

The spatial structure of the tumor immune microenvironment can explain and predict patient response in high-grade serous carcinoma.

Despite ovarian cancer being the deadliest gynecological malignancy, there has been little change to therapeutic options and mortality rates over the last three decades. Recent studies indicate that the composition of the tumor immune microenvironment (TIME) influences patient outcomes but are limited by a lack of spatial understanding. We performed multiplexed ion beam imaging (MIBI) on 83 human high-grade serous carcinoma tumors - one of the largest protein-based, spatially-intact, single-cell resolution tumor datasets assembled - and used statistical and machine learning approaches to connect features of the TIME spatial organization to patient outcomes.

Peer feedback: A tool to improve PA, NP, and physician collaboration and clinical practice.

The increasing use of physician associates/assistants (PAs) and NPs on clinical teams creates an opportunity for colleagues to provide feedback that can drive growth and improvement in PA and NP clinical skills. Through a needs assessment, month-long pilot, and buy-in from our academic hospital medicine group, we initiated a peer feedback platform that sought to highlight individual faculty strengths, facilitate thoughtful and constructive feedback, and create effective collaboration among colleagues. Three months after implementation, results indicated that the platform provided important information on clinical skills and identified areas for growth and opportunities for additional training.

Canine diabetes mellitus demonstrates multiple markers of chronic inflammation including Th40 cell increases and elevated systemic-immune inflammation index, consistent with autoimmune dysregulation.

Introduction: Canine diabetes mellitus (CDM) is a relatively common endocrine disease in dogs. Many CDM clinical features resemble human type 1 diabetes mellitus (T1DM), but lack of autoimmune biomarkers makes calling the disease autoimmune controversial. Autoimmune biomarkers linking CDM and T1DM would create an alternative model for drug development impacting both human and canine disease.