Citations

Deregulated inflammatory signaling via STAT family transcription factors, particularly STAT1, underlies a variety of immune-related diseases, including inflammatory bowel disease. Whereas activation of STATs by JAKs via canonical receptor-driven JAK–STAT signaling is well understood, little is known about JAK-independent mechanisms of STAT activation. Here, we identify the understudied nonreceptor tyrosine kinase TNK1 as a therapeutically targetable, JAK-independent activator of STAT signaling. Using a multiomics approach, we mapped a network of TNK1 substrates associated with protein condensates and proinflammatory signaling, including STAT1. We found that TNK1, but not its sister kinase ACK1, directly phosphorylates STATs at well described STAT-activating JAK sites. In cells, TNK1-mediated STAT1 phosphorylation and activation occurs independently of JAKs. Imaging and interactomics data suggest that TNK1 interacts with STAT1 in cytosolic condensates, which likely compartmentalize TNK1-substrate interactions. We show that an intrinsically disordered proline-rich region in TNK1, which includes a 14-3-3 docking phosphorylation site, is required for the formation of kinase-active TNK1 condensates and STAT1 phosphorylation. Mutations within the proline-rich region that eliminate 14-3-3 binding increase formation of TNK1 condensates, suggesting a model in which 14-3-3 acts as a clamp that constrains the flexible PRR to inhibit condensate formation and STAT1 activation. Finally, we show that TNK1 is a targetable driver of STAT1-mediated inflammation in the gut as inhibition of TNK1 reduces active STAT1 in the colon and ameliorates colitis symptoms in mice.

Background: Pregnancies complicated by fetal growth restriction are at increased risk of fetal demise and adverse neonatal outcomes. Distinguishing growth-restricted fetuses from constitutionally small ones remains challenging. Given the variability in current diagnostic criteria and the importance of identifying at-risk fetuses, fetal growth velocity has emerged as a predictor of adverse neonatal outcomes. Objective: To evaluate whether percentile-based fetal growth velocity, defined as change in estimated fetal weight percentile per week, predicts adverse neonatal outcomes in pregnancies affected by fetal growth restriction or small-for-gestational-age neonates. The primary aim was to determine the relationship between growth velocity and a composite of adverse neonatal outcomes. Study Design: This was a retrospective cohort study of pregnant patients 18 - 45 years old who delivered between August 2017 to December 2022 in a single healthcare system. Patients were excluded who had fewer than 2 ultrasounds after 16 weeks gestation, genetic or anatomic abnormalities, or a multiple gestation. Results: 300 patients met all inclusion criteria, and most patients (n=199) delivered at the tertiary care center. Three had an intrauterine fetal demise at a mean gestational age of 35w3d. 74 neonates were admitted to the NICU with a mean length of stay of 8.5 days; 29 required respiratory support. No neonatal deaths occurred. In fetuses with initial estimated fetal weight <3rd percentile (n=33), the probability of composite outcome was increased (50%, 95% CI 44.8-55.2) compared to those >50th percentile (5%, 95% CI 3.7-6.6). In the 3-10th and 10 - 50th percentile subgroups with decelerated growth, composite outcome rates were also increased (56.2% and 44.1%) compared to those with neutral or increased growth velocity. Conclusion: Percentile-based fetal growth velocity is a simple calculation that correlates with adverse neonatal outcomes regardless of initial estimated fetal weight. As fetal growth velocity decreased, our cohort saw increased rates of adverse outcomes. Change in EFW percentile normalizes for gestational age and allows ease of clinical interpretation. Decelerated growth identified fetuses at highest risk, suggesting growth velocity as a useful metric in routine surveillance.

Medial ulnar collateral ligament (MUCL) injuries of the elbow have increased over the past 2 decades, particularly among adolescent and young adult overhead throwing athletes. Over time, operative techniques for MUCL injuries have evolved, with the goals of improving time to return and rates of return to sport and meeting athlete-specific demands. The purpose of this review is to evaluate the state of surgical management of MUCL injuries, assessing indications, techniques, and outcomes. Surgical techniques reviewed included MUCL-augmented repair with internal bracing, traditional reconstruction, reconstruction augmented with internal bracing, and revision MUCL reconstruction. While MUCL reconstruction has been the gold standard of treatment, augmented reconstruction and repair techniques have shown promising outcomes; these strategies emphasize anatomic restoration, preservation of native tissue, and individualized patient selection.

Importance Elevated low-density lipoprotein cholesterol (LDL-C) is a modifiable risk factor for cardiovascular disease, the leading cause of premature death worldwide. Assessing the LDL-C–related burden is critical for guiding prevention and treatment strategies. Objectives To estimate the global, regional, and national burden of ischemic heart disease and ischemic stroke attributable to elevated LDL-C (relative to 35-54 mg/dL) from 1990 to 2023 and to quantify the contributions of population growth, aging, risk-deleted burden, and exposure changes to burden trends. Design, Setting, and Population This comparative risk assessment, part of the Global Burden of Disease Study 2023, estimated population-level LDL-C exposure and associated health loss in 204 countries and territories. Mean LDL-C levels were estimated using spatiotemporal gaussian process regression based on 806 studies across 161 countries. Relative risks were derived from meta-analyses of 38 randomized clinical trials. Population-attributable fractions for deaths and disability-adjusted life-years (DALYs) were estimated by age and sex for adults aged 25 years or older from 1990 to 2023, with 95% uncertainty intervals. Exposure Population-level LDL-C concentrations. Main Outcomes and Measures Population-attributable fractions, counts, and rates (all ages and age standardized per 100 000) of LDL-C–attributable deaths and DALYs from ischemic heart disease and ischemic stroke, with uncertainty intervals. Results In 2023, elevated LDL-C accounted for 3.6 million deaths (95% uncertainty interval, 2.2-5.4 million; 6.0% of global mortality) and 90.7 million DALYs (95% uncertainty interval, 58.9-123.3 million; 3.2% of DALYs). Although global all-ages rates remained stable, age-standardized death and DALY rates decreased by 45.6% and 39.5%, respectively, since 1990. In 2023, age-standardized LDL-C–attributable DALY rates were highest in Eastern Europe and lowest in high-income Asia-Pacific. One-third of the global LDL-C burden occurred in India and China. Population growth and aging drove the increasing burden, with notable regional disparities in LDL-C exposure and risk-deleted DALY rates shifting toward middle-sociodemographic settings. Conclusions and Relevance Despite declining age-standardized rates, the absolute LDL-C burden has increased since 1990 due to demographic changes and has shifted toward middle-sociodemographic countries. Measurement and surveillance gaps persist. Strengthened prevention, diagnosis, and treatment access strategies are essential to mitigate the health burden of LDL-C.

PURPOSE Bone metastases (BM) occur in approximately 30% of patients with metastatic renal cell carcinoma (mRCC) and are associated with poor survival and symptomatic skeletal events (SSEs). Radium-223, an alpha-emitting bone-seeking radioisotope, and cabozantinib, a tyrosine kinase inhibitor, have demonstrated activity in BM. RADICAL (Alliance A031801; ClinicalTrials.gov identifier: NCT04071223 ) evaluated cabozantinib ± radium-223 in mRCC with BM. METHODS This phase II trial enrolled patients with mRCC of any histology with ≥1 BM. Patients were randomly assigned 1:1 to cabozantinib ± radium-223, stratified by osteoclast-targeted therapy (OTT), prior therapy, opioid use, and International mRCC Database Consortium (IMDC) risk. The primary end point was SSE-free survival (SSE-FS). Secondary end points included safety, objective response rate (ORR), progression-free survival, and overall survival (OS). A target of 124 evaluable patients was planned, with a prespecified interim futility analysis at 50% of expected SSE-FS events; the trial would stop if the stratified hazard ratio (sHR) > 1.0. RESULTS The prespecified interim futility analysis was conducted after 90 patients were enrolled and crossed the futility boundary, leading to closure at 98 patients. The final analysis included all 98 patients. Median age was 63 years, 82.7% had clear cell histology, and 79.6% were using an OTT. IMDC risk was favorable (18.4%), intermediate (67.3%), and poor (14.3%). Median follow-up was 13.1 months. Median SSE-FS for cabozantinib with radium-223 versus cabozantinib was 16.7 versus 17.6 months (sHR, 1.46 [90% CI, 0.86 to 2.51]). Median OS was 28.3 versus 19.7 months (sHR, 1.40 [95% CI, 0.70 to 2.79]). ORR was 19.4% versus 25.0% ( P = .78). Grade ≥3 adverse events were similar across arms (69.6% v 75.5%). CONCLUSION Radium-223 did not improve SSE-FS when added to cabozantinib. The combination demonstrated a manageable safety profile.

Abstract Objectives Understanding whether the novel long-T ITC complex might assist in interpreting clinical prognostic utility compared to established cardiac biomarkers is needed. We determined long term major adverse cardiac events (MACE) and all-cause mortality (ACM) predicated on novel long-T ITC complex and high sensitivity cardiac troponin I (hs-cTnI) and T (hs-cTnT) assays in the emergency department (ED). Methods cTn assays were measured on the Mindray CL-1200i platform at presentation in consecutive patients enrolled in ‘Mindray hs-cTnI Assay Analytical and Clinical Evaluation for the Diagnosis and RIsk Assessment of Myocardial InfarctIon’ (MERITnI) (NCT05853042) trial with suspected ischemia. Sex specific 99th percentiles upper reference limits (URLs) were: hs-cTnI female 14 ng/L, male 15 ng/L; hs-cTnT female 10 ng/L, male 19 ng/L; long-T ITC complex 0.9 ng/L, same for female and male. Results Of 1,070 patients, 59.4 % were male, 43.4 % White, 45.5 % Black, and 39.5 % ≥65 years. Independent of biomarkers, a continuum of risk over 1 year showed MACE increased to 16.1 % and ACM to 16.5 %. Long-T ITC complex did not show a continuum change, increasing only 0.1 % (HR: 1.001 (1.0–1.001) per ng/L. However, hs-cTnI increased 1.8 % (HR: 1.018 [1.009–1.027] for each ng/L (p<0.0001) and hs-cTnT increased 0.3 % per ng/L (HR: 1.003 [1.001–1.006]) (p=0.0028). Between subjects ≤URLs and >URLs, MACE and ACM all biomarkers showed significant (p<0.0001) differences over 1 year. For MACE in those >URL long-T ITC complex increased 11.2–25.2 %, hs-cTnI 18.0–35.0 % and hs-cTnT 8.9–24.2 %. For ACM in those >URL long-T ITC complex increased 4.5–23.3 %, hs-cTnI 5.0–26.2 %, and hs-cTnT 3.6–24.1 %. Conclusions Novel long-T ITC complex did not provide new prognostic value to either hs-cTnI or hs-cTnT. Patients with increased hs-cTnI and hs-cTnT concentrations had marked increases in MACE and ACM risk at 1-year.

Abstract Background We determined whether circulating cardiac troponin I–cardiac troponin T–troponin C (ITC) complex containing long-form cardiac troponin T (long-T ITC) complex and ratios of high-sensitivity cardiac troponin I (hs-cTnI) and high-sensitivity cardiac troponin T (hs-cTnT) could differentiate myocardial infarction (MI) from chronic and acute non-MI myocardial injuries in patients with suspected acute coronary syndrome. Methods We measured long-T ITC complex, hs-cTnI, and hs-cTnT (Mindray) at 0- and 2-h in consecutive patients enrolled in the Mindray hs-cTnI Assay Analytical and Clinical Evaluation for the Diagnosis and RIsk Assessment of Myocardial InfarctIon (MERITnI) trial. Results Among the 882 subjects studied (median 3.0 h presentation), 47 had acute MI (5.3%), 116 had acute non-MI myocardial injury, and 90 had chronic myocardial injury. At 0 and 2 h, areas under the curve (AUC) significantly differentiated acute MI from chronic myocardial injury for long-T ITC complex (0.72 and 0.81, respectively; P = 0.0082) but not acute non-MI myocardial injury (AUC, 0.65 and 0.69, respectively; P = 0.23). 0 and 2 h AUCs for long-T ITC complex/hs-cTnT and hs-cTnI/hs-cTnT ratios also significantly differentiated acute MI from chronic myocardial injury (AUC, 0.79 and 0.86, respectively) and acute non-MI myocardial injury (AUC, 0.68 and 0.71, respectively). There was no biomarker concentration or ratio value discrimination between type 1 and type 2 MIs. Conclusions Long-T ITC concentrations and long-T ITC complex/hs-cTnT and hs-cTnI/hs-cTnT ratios may clinically assist in differentiating acute MI from non-MI myocardial injuries when evaluating patients with suspected acute coronary syndrome. ClinicalTrials.gov Registration Number: NCT05853042.

Solitary plasmacytomas (SPs) are rare localized tumors of clonal plasma cells, either in the bone (solitary bone plasmacytoma) or in soft tissue/extraosseous (extramedullary) with either no or with minimal bone marrow (BM) infiltration (<10% clonal plasma cells by immunohistochemistry) and no evidence of systemic involvement or myeloma defining events. Approximately 50% of SPs will progress to symptomatic myeloma within 5 years after initial definitive local radiotherapy. Increased availability of improved diagnostic and monitoring tools has increased the sensitivity of detection of additional lesions and marrow involvement and has implications for the follow-up strategy after treatment. Thus, the definitions and requirements for the diagnosis and follow-up of SPs are evolving. The diagnosis of SP requires the careful exclusion of multiple myeloma (MM) that would require systemic therapy, by using all the available methods to detect systemic disease (advanced imaging, sensitive BM assessment methods, blood and urine tests). Local radiotherapy remains the mainstay of therapy, and despite the availability of innovative drugs for MM, the clinical benefit of systemic therapy currently remains poorly defined. The International Myeloma Working Group provides here updated recommendations for the diagnosis, evaluation, treatment, and response assessment of patients with SPs, incorporating recent data and advances in diagnostic tools.