Faculty Bibliography

BLU-451 is a potent and selective tyrosine kinase inhibitor designed to target uncommon epidermal growth factor receptor (EGFR) mutations, spare wild-type EGFR, and be active in the central nervous system (CNS). In vitro EGFR enzyme assays and engineered cell line models revealed selectivity and anti-proliferative potency of BLU-451 against a wide range of EGFR mutations in non-small cell lung cancer, including common mutations, atypical mutations, and exon 20 insertions. Particularly, BLU-451 demonstrated robust antitumor activity in EGFR exon 20 insertion cell-derived and patient-derived xenograft models and was well tolerated in animal studies. Pharmacokinetic and pharmacodynamics analyses showed that BLU-451 suppressed exon 20 insertion phosphorylated EGFR expression levels within tumor tissues but not in skin and intestinal tissues, potentially indicative of lower toxicity associated with wild-type EGFR. In intracranial tumor models with imaging-based analyses, BLU-451 showed CNS antitumor efficacy. Early clinical data from patients enrolled in the phase 1 portion of the phase 1/2 CONCERTO trial (NCT05241873) demonstrated the overall clinical potential of BLU-451, including its CNS antitumor activity in patients with EGFR exon 20 insertions and atypical mutations. Initial data suggest that BLU-451 is an active molecule. Further evaluation of the safety profile and pharmacokinetic properties of BLU-451 is needed.

Microplastics (MPs), conventionally defined as plastic particles 1 μm-5 mm in size, are ubiquitous contaminants, infiltrating both our environment and our bodies. These particles, either manufactured at this scale or formed from the breakdown of larger plastics, possess diverse characteristics that allow them to absorb and release toxic substances, form biofilms, and abrade and inflame tissues. In humans, MPs have been detected in testes, semen, ovarian follicular fluid, placental tissue, and other locations in the reproductive system. Recent studies suggest that MPs may disrupt male and female reproduction through mechanisms involving oxidative stress, inflammation, DNA damage, and endocrine disruption. Over the past 5 years, there has been increasing excitement about MPs research and a burgeoning literature in this area. Despite this growing body of evidence, the full spectrum of MP-associated reproductive toxicity in humans remains poorly understood, with limited research on effects at environmentally relevant exposure levels and in the general population, and a poor understanding of the specific toxicity of different polymer types, sizes, and shapes. As the literature rapidly expands, it is important to take note of current constraints and how research in this field may be optimized for quality. This review summarizes current knowledge about MPs and their reproductive toxicity, highlights emerging research areas, and identifies key challenges and needs for future research on this class of contaminant.

The gold standard for patella fracture fixation is tension band wiring; however, achieving stable anatomic fixation can be challenging in comminuted patterns. The "star" variable-angle locking patella plate is an alternative fixation construct that is meant to address these limitations by providing multiple fixation points and dorsal cortical stability. The purpose of this study was to analyze the outcomes of patients treated with the variable-angle locking "star" patella plate. A total of 358 patients who underwent repair of a displaced patella fracture over a 10-year period were reviewed. Patients who sustained an isolated orthopaedic trauma association (OTA) 34-C3 patella fracture and underwent open reduction internal fixation (ORIF) with the variable-angle locking star-shaped patella plating system with at least 6 months of follow-up were analyzed. Demographic and treatment characteristics, fracture union, complications, and functional outcome measures as measured by knee range of motion (ROM) were collected retrospectively at standard follow-up intervals. Thirty-seven patients (mean age 60.17 ± 16.72 [standard deviation, SD] years; mean body mass index [BMI] 25.12 ± 5.04 [SD] kg/m²) treated at one multisite, urban, academic institution were identified. All fractures were classified as OTA 34-C3. The mean operating room time (wheels-in wheels-out) was 149.43 ± 50.82 (SD) minutes. One patient (2.7%) developed a fracture-related infection (FRI), two patients (5.4%) had wound complications, and one patient (2.7%) developed a deep vein thrombosis (DVT) following surgery. All fractures healed by 6 months, and no patient underwent removal of symptomatic hardware. Three patients underwent secondary operation; one patient had repeated irrigation and debridement of a confirmed FRI, one manipulation under anesthesia for knee contracture, and one revision ORIF after loss of distal fixation. Patients displayed a mean knee ROM of 106.53 ± 21.64 degrees (SD) and 118.51 ± 16.87 degrees (SD) at the 3- and 6-month points, respectively. The novel locking "star" patella plate appears to be a reliable and safe method of treatment for the most complex patella fractures.

AIMS/HYPOTHESIS/OBJECTIVE:levels. METHODS:levels. We additionally assessed these staging schemas requiring an initial clinical score cutoff of ≥10% probability of developing diabetes in 10 years before proceeding to laboratory testing. We calculated baseline insulin responsiveness (insulin secretion-sensitivity index-2, ISSI-2) and the frequency of an estimated high risk of complications (Whitehall subphenotype clusters) across stages. We estimated relative risks of developing diabetes ascertained by self-report and glucose measurements after a 5.31 (0.44) year follow-up using robust Poisson regression with an offset for person-years. We calculated the prognostic properties of staging schemas in the prediction of diabetes. RESULTS:staging schemas were superior to the binary categorisation of prediabetes (intermediate hyperglycaemia). CONCLUSIONS/INTERPRETATION/CONCLUSIONS:schemas. Applying a predictive clinical score in staging reduced laboratory testing and false positives.

Diverse refugee, immigrant, and migrant (RIM) populations in the United States face complex mental health needs that are shaped by migration experiences, cultural transitions, and structural barriers to accessing care. Although RIM populations have different legal statuses, cultural backgrounds, and lengths of U.S. residence, many encounter common stressors related to uncertain immigration policies, economic instability, and limited access to culturally responsive services. Recent federal actions-including suspension of the U.S. Refugee Admissions Program and revocation of "protected areas" policies-have intensified fears and mental health vulnerabilities among these populations. Using a multilevel, biopsychosocial approach, the authors aimed to provide clinical guidance on the biological, structural, sociocultural, and health care system factors that affect mental health care delivery for RIM populations. This article provides evidence-based clinical guidance and actionable recommendations that allow clinicians to selectively apply interventions (e.g., trauma-informed practices, low-barrier care models, medical-legal partnerships, and culturally responsive approaches that respect alternative healing frameworks) on the basis of individual patient circumstances. Key recommendations pertain to working with professional interpreters, navigating diagnostic ambiguity, and interfacing with immigration enforcement.

BACKGROUNDS/BACKGROUND:The mental health and wellbeing of university students have become increasingly pressing concerns, with rates of psychological distress rising in recent years. This study investigates the factors contributing to psychological distress among university students, focusing on resilience, coping self-efficacy, acculturation, and cultural backgrounds. METHODS:Utilizing a biopsychosocial model, the study examines how sociocultural stressors and individual coping mechanisms interact to influence mental health outcomes. Data were collected from 291 undergraduate domestic and international psychology students at a large urban university in the United States during the Spring 2023 semester. RESULTS:Results indicated that domestic students reported significantly higher levels of psychological distress and life stressors compared to international students. Factors such as stressful life events, resilience, and coping self-efficacy were significantly associated with psychological distress. Acculturation was not directly associated with distress but was linked to coping self-efficacy among international students. Regression analysis revealed that higher numbers of stressful life events, lower resilience, and domestic residence are associated with psychological distress. CONCLUSIONS:The study highlights the importance of protective factors like resilience and coping self-efficacy in managing life stress and adversity among university students. These insights can inform efforts to promote mental health and wellbeing through resilience-building, coping strategy workshops, and community engagement.

Early-career investigators face growing challenges: dwindling public funding, limited trial leadership opportunities, systemic mentorship barriers, and widening global disparities. At the 20th Breast International Group (BIG) – NCI National Clinical Trials Network (NCTN) annual meeting, four key themes emerged: funding, mentorship, clinical trials, and translational research. This report outlines recommendations for funding and mentorship. Investment in this area is strategic to ensure continued advances for patients globally.

Protease-activated receptor 2 (PAR₂) mediates oral cancer pain. Patients with metastatic (N + ) cancers report greater pain. PAR₂ is activated by N-terminal proteolytic cleavage. Here we show that proteases encoded by genes overexpressed in N+ cancers from patients with pain (matrix metallopeptidase 1, MMP1 and serine protease 23, PRSS23) elicit protease-specific receptor redistribution (trafficking) and signaling that differs from that promoted by proteases encoded by genes not differentially expressed (transmembrane serine protease matriptase, ST14 and cathepsin S, CTSS). Mixtures of the proteases prepared to model the oral cancer microenvironment revealed that ST14-mediated PAR₂ activation predominated at low protease concentrations. At high concentrations, MMP1 and PRSS23 prevailed over the greater potency of ST14. We propose that PAR₂ activation in oral N+ cancers from patients with pain is driven by high levels of MMP1 and PRSS23. Our study informs design of signaling and location-specific antagonists to provide more efficacious analgesia.

BACKGROUND:GBC is an aggressive biliary tract malignancy with limited survival. Although actionable genomic alterations (AGAs) are increasingly recognized in GBC, their prognostic association in real-world practice remains incompletely defined because genomic status is often confounded by stage at presentation and treatment selection. We evaluated the association between documented AGA status and overall survival (OS) using a tiered matching strategy to account for major clinical confounders. METHODS:, and a comparison cohort with no documented AGA (representing a real-world population of untested and wild-type patients). Two 1:1 propensity score-matched models were constructed: Model 1 matched for age, sex, and race/ethnicity; Model 2 additionally matched for metastatic disease, surgical resection, and chemotherapy history. Outcomes were evaluated using risk analysis and Kaplan-Meier survival methods. RESULTS:subgroup was limited by small sample size. CONCLUSIONS:In this real-world matched analysis, the presence of documented AGAs in GBC were associated with higher mortality even after matching for major demographic, stage-related, and treatment-related variables. These findings support the prognostic relevance of genomic status in GBC and underscore the need to address disparities in access to genomic documentation and testing.