A Disintegrin and metalloprotease (ADAM) family encompasses a diverse array of widely expressed proteases functioning in pathological processes. ADAM15 stands out as a pivotal mediator in multiple tumor types, responding to immune checkpoint inhibitors (ICI) significantly. By promoting pro-angiogenic genes, potentiating integrin binding as well as modulating the inflammatory response, ADAM15 orchestrates cellular adhesion and migration, thereby fostering tumor progression. Despite these compelling insights, the intricate roles of ADAM15 in prediction, immune modulation, and therapeutic targeting among malignant disorders remain largely unexplored. To decipher the pan-cancer landscape of ADAM15, we integrated data from multiple databases. Immunohistochemical profiles of ADAM15 were retrieved from the human protein atlas (HPA) database. Furthermore, the tumor immune estimation resource (TIMER) and the ESTIMATE (Estimation of Stromal and Immune cells in Malignant Tumor tissues using Expression data) algorithm were harnessed to dissect the immune infiltration patterns and immune checkpoint genes associated with ADAM15. The tumor immune single-sample gene set enrichment analysis (TISMO) was employed to explore the impact of ADAM15 on the tumor immune microenvironment. Additionally, drug sensitivity analysis and subsequent molecular docking studies were conducted to identify potential therapeutic compounds targeting ADAM15. These findings were rigorously validated through reverse transcription-polymerase chain reaction (RT-PCR), western blotting (WB), and immunohistochemistry (IHC) by cell lines and clinical samples from hepatocellular carcinoma (HCC) as well as colon adenocarcinoma (COAD). Our comprehensive analysis revealed that ADAM15 is markedly upregulated in diverse cancer types. IHC, WB, and RT-PCR assays of HCC and COAD confirmed these findings. Notably, elevated ADAM15 correlates with adverse prognosis in pan-cancer, positioning it as a promising novel biomarker. Drug sensitivity profiling unveiled a positive and statistically significant association between ADAM15 and AZD-8055 and Nitazoxanide, whereas a negative correlation was observed with Oxaliplatin and Ponatinib. These findings were further corroborated by molecular docking simulations, highlighting the potential of these compounds as therapeutic targets for ADAM15-driven cancers. Our study underscores the multifaceted role of ADAM15 in cancer progression, immune evasion, and response to therapy. By elucidating the intricate interplay between ADAM15 and the tumor microenvironment (TME), we have identified novel diagnostic biomarkers and potential therapeutic avenues.
Publications by Year: 2026
2026
The present three-wave longitudinal study tested two transdiagnostic mediators - anger and racism-related vigilance - of the link between racism and internalizing and externalizing problems. At Wave 1, the sample included 344 Mexican-origin adolescents (Mage = 13.5 years; 51.7% male, 45.9% female; 2.3% non-binary) residing in the Midwestern United States. Data across the three waves were collected from April 2021 through October 2024. The study examined how both direct and vicarious racism were related to internalizing and externalizing problems over time. Results from latent growth curve mediation analyses indicated that outward anger expression was a significant mediator; both direct and vicarious racism at Wave 1 were significantly associated with higher levels of anger at Wave 2, which in turn, were associated with higher levels of internalizing and externalizing problems at Wave 3. Racism-related vigilance was a significant mediator of the association between vicarious racism and internalizing problems only, according to results from post hoc sensitivity analyses. Implications for future theory, research, and clinical practice are discussed to help mitigate the effects of racism in new migration contexts for this vulnerable population.
Cortical interneuron (cIN) dysfunction is associated with various neurodevelopmental and neurological disorders, including developmental epilepsies, autism spectrum disorders, and intellectual disabilities. Mutations in ARX (aristaless-related homeobox) are linked to these conditions, with or without accompanying structural brain anomalies. We have previously demonstrated that the loss of Arx in the mouse ganglionic eminence, the birthplace of cINs, is associated with seizures in mice, whereas the loss in cortical excitatory neuron progenitor cells results in structural anomalies but no seizures. To elucidate the pathophysiological role of ARX in cINs and their relationship to the seizure phenotype, Arx conditional mutant mouse lines were interrogated using Gad2- and Nkx2.1-Cre drivers to target distinct populations in the cIN lineage. Our data demonstrate that the abrogation of ARX results in cIN density and distribution defects as well as perinatal lethality. In these mice, we observed defects in cell cycle exit, a biased loss of the marginal zone migration stream of cINs, shifts in cell fate from caudal ganglionic eminence (CGE) to medial ganglionic eminence (MGE) identity, and a reduced number of parvalbumin⁺ and somatostatin⁺ cINs, with parvalbumin⁺ cINs being more severely affected. Single-cell RNA sequencing combined with chromatin immunoprecipitation (ChIP)-seq revealed ARX regulates key processes involved in cell cycle progression, cIN subtype differentiation, guidance cues and receptors, as well as other transcription factors. Interrogation of one downregulated target gene, Lmo1, uncovered a potential mechanism by which ARX regulates cIN number and distribution in the cortex. Cortical slice cultures demonstrate that LMO1 inhibits cIN migration by repressing Cxcr4 expression, which encodes a key receptor involved in cortical guidance. These data indicate ARX positively regulates cIN migration by derepressing LMO1's repressive role. Consistent with our mouse model, we observed a significant loss of parvalbumin+ and somatostatin+ cINs in the brain of a patient carrying a pathogenic variant of ARX and diagnosed with developmental epileptic encephalopathy. Together our data provide novel insights into how ARX and its target genes regulate cIN development and migration and the pathogenic mechanisms of a spectrum of neurodevelopmental disorders linked to loss of ARX.
UNLABELLED: Policy Points Ultraprocessed foods (UPFs) are engineered to heighten reward and accelerate delivery of reinforcing ingredients, driving compulsive consumption and disrupting appetite regulation. This is a growing challenge for health policy. UPFs share key engineering strategies adopted from the tobacco industry, such as dose optimization and hedonic manipulation. These parallels should inform how we classify and regulate UPFs. Policy tools that helped reduce tobacco-related harm, including restrictions on child-targeted marketing, taxes, improved labeling, limits on availability in schools and hospitals, and litigation, should be adapted to address the public-health threat posed by UPFs.
CONTEXT: Ultraprocessed foods (UPFs) now dominate the global food supply and are strongly associated with risks for heart disease, cancers, metabolic disease, diabetes, and obesity. UPFs are likely associated with rates of neurologic issues such as dementia and Parkinson's disease and predict premature death. Drawing on the history of tobacco regulation, we examine how the design, marketing, and distribution of UPFs mirror those of industrial tobacco products. Such information speaks to the sophistication and aims of food product manipulation and its consequences.
METHODS: This review synthesizes findings from addiction science, nutrition, and public health history to identify structural and sensory features that increase the reinforcing potential of both cigarettes and UPFs. We focus on five key areas: dose optimization, delivery speed, hedonic engineering, environmental ubiquity, and deceptive reformulation.
FINDINGS: Cigarettes and UPFs are not simply natural products but highly engineered delivery systems designed specifically to maximize biological and psychological reinforcement and habitual overuse. Both industries have used similar strategies to increase product appeal, evade regulation, and shape public perception, including adding sensory additives, accelerating reward delivery, expanding contextual access, and deploying health-washing claims. These design features collectively hijack human biology, undermine individual agency, and contribute heavily to disease and health care costs.
CONCLUSIONS: UPFs should be evaluated not only through a nutritional lens but also as addictive, industrially engineered substances. Lessons from tobacco regulation, including litigation, marketing restrictions, and structural interventions, offer a roadmap for reducing UPF-related harm. Public health efforts must shift from individual responsibility to food industry accountability, recognizing UPFs as potent drivers of preventable disease.
BACKGROUND: Mechanisms driving aggressive meningiomas remain poorly understood. Given the pivotal role of the immune microenvironment in tumor progression, we developed a comprehensive atlas of the meningioma microenvironment, with a view towards identifying modifiable opportunities.
METHODS: The immune microenvironment of 2,727 meningiomas was profiled using orthogonal methodologies, including 24 with mass cytometry, 24 single-cell RNAseq, 1,437 bulk RNAseq, 1,125 DNA methylation, 117 multiplex immunofluorescence, as well as that of 5 paired peripheral blood samples and 10 human meninges. Patient-derived organotypic tumor spheroids (PDOTS) were established to assess the effect of STING stimulation combined with anti-PD-1 treatment.
RESULTS: We revealed a rich immune infiltration in meningioma, among the highest across 34 human cancer types (n = 12,188). Macrophages predominated in meningioma microenvironment, in contrast to the lymphoid dominance of peripheral blood, with meninges exhibiting an intermediate immune profile between meningiomas and peripheral blood. Cellular states and phenotypes of both immune and tumor cells shifted during tumor progression, with aggressive meningiomas possessing earlier-stage, immunosuppressive immune cells and proliferative tumor cells. Using ex vivo meningioma PDOTS, we demonstrated inducible responses to STING activation, marked by elevated cytokine release, which were synergistic when combined with PD-1 blockade.
CONCLUSIONS: These findings offer an extensive resource on the cellular heterogeneity of the meningioma microenvironment and provide a framework for rational therapeutic modeling and strategy development.
PURPOSE: Biomarkers, or specific somatic alterations, are increasingly required for clinical trial eligibility. Finding and enrolling patients with these biomarkers is essential not only for continuous progress in the treatment of disease but also for democratizing clinical trial participation. Here, we use data from the National Cancer Institute Clinical Trials Reporting Program (NCI CTRP), combined with large language model applications, to survey the current landscape of cancer clinical trials.
METHODS: We extracted 20,894 trials from Cancer.gov from the application programming interface (API) of the NCI CTRP. We quantified biomarker rates in cancer subtypes, described the geographic distribution of trial sites, and identified failure causes for these trials. Finally, we built an application from this API to match patients with clinical trials.
RESULTS: We showed that 5,044 of the 20,894 interventional clinical trials contained biomarker eligibility data and trials tended to cluster around large academic centers and cities. We identified 630 biomarkers in 36 cancer subtypes and show that most biomarkers are used as eligibility criteria for multiple cancer subtypes. We highlight that the difficulties with accrual and sponsorship were the most common reason for discontinuing clinical trials. Finally, we demonstrate a novel method to automatically match natural language queries with eligible clinical trials, NCI Clinical Trials Navigator.
CONCLUSION: A survey of our clinical genomics showed that many individuals likely have mutations that would make them eligible for biomarker-driven trials. We used the NCI Clinical Trials database to show that the distribution of biomarker trials across the United States limits access for many patients and likely leads to the frequent trial termination because of inadequate accrual. Finally, we built an automated publicly available tool that can improve patient-to-trial biomarker-based matching.
CONTEXT: Gestational diabetes (GDM) is associated with long-term risk for type 2 diabetes (T2D).
OBJECTIVE: We evaluated metabolic characteristics and β-cell function during pregnancy and at 12 months postpartum among individuals with varying levels of gestational glucose intolerance.
DESIGN: This was a planned 12-month postpartum follow-up to the Gestational Diabetes Diagnostic Methods (GDM2) trial, which randomized pregnant individuals to GDM testing using either the IADPSG or Carpenter-Coustan (CC) criteria.
PARTICIPANTS: All GDM2 participants with treated GDM (diagnosed by either CC or IADPSG), those with untreated glucose intolerance in the CC arm, and half of the participants with normal glucose tolerance were invited for 12-month follow-up.
MAIN OUTCOME MEASURES: Glucose values, Stumvoll and Matsuda Indices to evaluate insulin sensitivity and resistance, the Disposition Index (DI), lipids, leptin, and adiponectin were assessed at 12-months postpartum. .
RESULTS: Of the 407 individuals seen at 12 months, 49 (12%) had untreated glucose intolerance and 53 (13%) had treated GDM (CC and IADPSG). Both during pregnancy and at 12-months postpartum, there were significant differences in insulin sensitivity, beta cell function, dyslipidemia, and alterations in leptin and adiponectin among individuals with both untreated glucose tolerance and treated GDM when compared to those with normal glucose testing.
CONCLUSIONS: Individuals with untreated glucose intolerance in pregnancy by the CC Criteria have impaired β-cell function and significant metabolic abnormalities at 12 months postpartum similar to individuals with treated GDM, highlighting the need for ongoing preventive attention in this population to prevent T2D later in life.
BACKGROUND: Researchers have examined associations between sport specialization and injury. However, no studies have investigated associations between sport specialization and health-related quality of life (HRQoL) after injury.
HYPOTHESIS: Among injured youth athletes, level of sport specialization is not associated with differences in HRQoL approximately 1 month after sport-related injury.
STUDY DESIGN: Cross-sectional study.
LEVEL OF EVIDENCE: Level 4.
METHODS: A multicenter, cross-sectional study was performed at 3 primary care sports medicine clinics. Eligible 8- to 18-year-old athletes who presented for musculoskeletal injury or concussion were enrolled. At the initial clinic visit, patients completed the Player Development Survey (PDS) to determine sport specialization level. Approximately 1 month after enrollment, patients completed the Patient-Reported Outcomes Measurement Information System (PROMIS) to determine HRQoL measures.
RESULTS: Of 720 athletes invited to participate, 336 (age, 14.2 ± 2.4 years) completed the PDS and PROMIS surveys; 22% were highly specialized, 39% were moderately specialized, and 39% were low specialized athletes. Overall, there were no differences in HRQoL scores across the 3 levels of sport specialization. In subgroup analysis based on sex, female HRQoL scores were worse than male HRQoL scores irrespective of sport specialization level in 3 categories: pain interference (mean difference between female and male scores [± SEM] = 2.3 ± 1.1; P = 0.04), depression/sadness (2.9 ± 1.1; P = 0.01), and anxiety/fear (2.8 ± 1.2; P = 0.02).
CONCLUSION: Higher level of sport specialization is not associated with worse HRQoL approximately 1 month after sport-related injury. Female athletes have worse short-term HRQoL after an injury irrespective of sport specialization level. While sex differences were statistically significant, the magnitude of differences was small.
CLINICAL RELEVANCE: Sport specialization is not associated with differences in HRQoL after injury. Injured female athletes may need closer monitoring due to possibly worse short-term HRQoL, but further investigation is needed.
Limited information on the business practices of liver transplant (LT) centers worldwide has been published. Characterizing this data could help identify best practices as well as opportunities for improvement. As such, the International Liver Transplant Society (ILTS) Business Practice Committee conducted a global online survey of LT centers, which was sent to the ILTS membership. Questions focused on 5 main domains: transplant practice and volumes, workforce, finances, quality assessment and performance improvement, and overall program function. Data was compared across program geographic regions and transplant volume. A total of 89 discrete centers were represented, of which 76.4% were academic/university-affiliated, and about one-third each were from Europe (36.0%) and North America (31.5%). The top 3 problems programs reported were finances/funding (60.7%), adequate program support/guidance (48.3%), and transplant volumes (43.8%). In all, 59.6% of respondents felt their salary was undercompensated, consistent across geographic regions. In addition, 69.7% felt their center was not adequately funded to meet program goals, with programs in Europe (N=28/32, 87.5%) and Oceania (N=2/3, 66.7%) most impacted. Transplant surgeon retainment was noted as more difficult for lower volume programs (<50 liver transplants/year, N=13/31). Nearly half (42.7%) of all programs felt under-resourced to provide high-quality care, and the majority (80.9%) felt there was room for growth and improvement under their current model. While international concerns varied widely among LT centers, inadequate salary and center funding, low transplant and referral volumes, and staff retainment were persistent themes. Focusing on adopting region-specific best practices and developing transplant systems of care that focus on these elements is critical to provide optimal care to LT patients worldwide.