Citations

Prostate cancer (PCa) progression is driven by intricate molecular mechanisms involving dysregulated signaling networks and posttranslational modifications of key regulatory proteins. In this study, we identify a novel oncogenic pathway wherein cyclin-dependent kinase 12 (CDK12) physically interacts with and phosphorylates forkhead box A1 (FOXA1) at serine 234 (S234). Phosphorylation at this residue markedly enhances FOXA1 transcriptional activity, leading to up-regulation of downstream targets including murine double minute 2 (MDM2), a critical negative regulator of the p53 tumor suppressor. Mechanistically, this CDK12–FOXA1–MDM2 axis destabilizes p53, attenuates apoptotic signaling, and promotes PCa cell survival and proliferation. Therapeutic targeting of CDK12 using the small-molecule inhibitor THZ531 or RNA interference effectively abrogates FOXA1 phosphorylation, restores p53 stability, reactivates apoptotic pathways, and suppresses tumor growth. Notably, the identification of S234 as a functional phosphorylation site in FOXA1 reveals a previously uncharacterized posttranslational regulatory mechanism in PCa biology. These findings establish the CDK12–FOXA1–MDM2 axis as a pivotal driver of PCa progression and underscore the therapeutic potential of targeting FOXA1 phosphorylation to restore tumor suppressor function and induce apoptosis in PCa. Our work provides a mechanistic framework for developing precision therapies aimed at disrupting this oncogenic cascade in PCa.

ABSTRACT Background Ureteral stents are commonly placed during kidney transplantation (KT) to mitigate urologic complications. The objective of this study was to compare clinical outcomes in KT recipients with either early stent removal when attached to the Foley catheter or late removal via cystoscopy when unattached. Methods We conducted a multi‐center retrospective analysis of consecutive living donor KT patients (8/18/21‐4/21/23) stratified into Foley‐attached and unattached stent groups. Outcomes assessed were ureteral stricture, urine leaks, UTIs at 90 days and allograft failure and BKV DNAemia (BK virus DNAemia) at 1 year. Data are reported as mean and standard deviation. Results Among 247 patients with attached and 260 with unattached stents, baseline demographics (age, sex, diabetes) were similar between groups. There was a difference in race (87.9% vs. 77.8% Caucasian; p = 0.004). Foley catheters remained longer in the attached group (3.7 ± 1.8 vs. 3.0 ± 2.0 days; p < 0.001), but stents were removed earlier (3.7 ± 1.8 vs. 21.9 ± 4.7 days; p < 0.001). Comparing attached versus unattached, there were no differences in ureteral stricture (0.4% vs. 1.5%; p = 0.197), urine leak (0.8% vs. 0.4%; p = 0.533), BKV DNAemia (17.7% vs. 16.9%; p = 0.616), or allograft failure (0% vs. 0.8%; p = 0.167). However, UTI incidence by 90 days was lower in the attached group (5.7% vs. 11.9% p = 0.013). Induction therapy differed significantly between groups, with Alemtuzumab more common in the unattached group (58.1% vs. 19.4%, p < 0.001), Basiliximab more common in the attached group (43.3% vs. 35.0%, p < 0.001), and Thymoglobulin more common in the attached group (36.0% vs. 6.9%, p < 0.001). Baseline steroid use was higher in the unattached group (81.9% vs. 57.9%, p < 0.001). Conclusion Early stent removal via connection to the Foley catheter had similarly low rates of ureteral complications while reducing urinary tract infections and avoiding cystoscopic removal.

ABSTRACT Objective The optimal treatment for neurosarcoidosis myelitis is uncertain. We characterize incident neurosarcoidosis myelitis and assess treatment response by MRI and clinical scales. Methods Incident probable or definite neurosarcoidosis myelitis in adults was retrospectively identified from 13 academic medical centers. Cases were analyzed by initial treatment. The primary outcome was T1 post‐contrast gadolinium enhancement resolution at 6 months post‐treatment. Secondary outcomes were changes in modified Rankin scale (mRS) and Expanded Disability Status Scale (EDSS) from nadir to final follow‐up. Results Two hundred two patients were identified (median diagnosis age: 47 years (IQR 39–55); male: female 1.3:1). Median nadir mRS and EDSS were 2 (IQR 2–3) and 4 (IQR 2.5–6). At initial treatment, 129 (63.9%) received prolonged corticosteroids ≥ 4 weeks (group A 1 ), 36 (17.8%) received corticosteroids < 4 weeks (B 1 ), 21 (10.4%) received corticosteroids plus sarcoidosis‐directed immunosuppressant (E), and 16 (7.9%) received corticosteroids plus non‐sarcoidosis‐directed agents (F). In 167 cases with sufficient imaging, there were no significant differences in contrast enhancement resolution at 6 months (A 1 27/106 (25.5%), B 1 9/28 (32.1%), E 5/19 (26.3%), F 5/14 (35.7%); Fisher's exact p = 0.76). There were no significant differences in changes in mRS or EDSS among treatment groups (Kruskal–Wallis p = 0.69 and 0.63, respectively) after median follow‐up of 46.5 months (IQR 18–91.3). Interpretation Different initial immunosuppression strategies did not correlate with MRI contrast enhancement resolution at 6 months or clinical scales (mRS, EDSS). However, conclusions are limited by retrospective design, imbalanced cohorts, and insensitivity of binary MRI outcomes and available clinical scales for treatment response in neurosarcoidosis.

Key Points BeWell360-PKD shows that integrating certified health and wellness coaches and augmenting patients' personal capacity as part of autosomal dominant polycystic kidney disease care is feasible and acceptable. Embedding BeWell360 coaches reduced care burden, improved caregiver self-efficacy, and enhanced care engagement by patients with autosomal dominant polycystic kidney disease and by their informal caregivers. This aligns with evolving care standards and guidelines promoting sustainable healthy lifestyle changes through tailored, integrative behavior-change centered interventions. Background Autosomal dominant polycystic kidney disease (ADPKD) imposes substantial care burden on patients and their informal caregivers (CGs), often contributing to nonadherence and impaired quality of life. Existing care models insufficiently address the behavioral and psychosocial dimensions of this burden. To evaluate the feasibility and effect of BeWell360-PKD , a person-centered intervention integrating Health and Wellness Coaching and capacity-workload support into ADPKD care, on care burden, adherence, self-efficacy, activation, and resilience. Methods In this 6-month, single-arm, mixed-methods pilot study, seven patient-CG dyads were enrolled from tertiary care polycystic kidney disease clinic. Board-certified Health and Wellness Coachings delivered individualized coaching within routine nephrology care, emphasizing capacity-building, goal setting, and care enactment support. Primary outcomes included changes in treatment burden (treatment burden questionnaire, ADPKD impact scale) and CG burden (burden scale for family CGs short version). Secondary outcomes included patient activation and resilience and CG self-efficacy. Semistructured interviews explored participant experiences. Results Patients experienced reduced treatment burden (treatment burden questionnaire mean change −9.3) and modest, domain-specific improvements in physical and fatigue-related ADPKD symptom burden. CG self-efficacy improved (+2.4), while CG burden increased (+14.8), and patient activation declined (−6.6). Qualitative themes reflected disease burden, emotional adaptation, and the perceived value of coaching in promoting behavior change and relational support. Conclusions BeWell360-PKD was feasible to implement and demonstrated early signals of benefit in reducing patient burden and improving CG self-efficacy. Increased CG burden and declining activation highlight the complexity of dyadic adaptation in ADPKD and the need for larger, controlled studies to refine and tailor coaching interventions.

Pancreas transplant is the standard treatment for restoring endocrine function and limiting complications from diabetes, and radiologists should understand the surgical techniques, normal imaging spectrum, and various complications associated with this surgical procedure.

Abstract The effectiveness of T cell–based immunotherapy depends on durable T-cell responses that can efficiently eliminate tumor cells. NKG7 was discovered three decades ago as a protein associated with lytic granules. However, only studies published over the past 5 years have contributed substantially to our understanding of NKG7 in T-cell biology. NKG7 has been recognized as an important T-cell functional marker in responses to immune checkpoint inhibitor therapy and in the prognosis of certain cancers. Besides its role in the generation, trafficking, and release of lytic granules, which is critical for efficient T-cell cytotoxicity against tumor cells, NKG7 has been identified as a key negative regulator of mTORC1 activity. By restraining mTORC1 activity, NKG7 promotes T-cell longevity and memory generation after infection. Importantly, NKG7 upregulation has demonstrated therapeutic potential in preclinical T-cell therapy for cancer. Collectively, NKG7 is emerging as a promising biomarker and therapeutic addition to T cell–based immunotherapies.

Despite improvements in kidney transplantation rates, the shortage of donor kidneys remains a critical issue, exacerbated by non-utilization of recovered kidneys due to quality concerns, necessitating advancements in perfusion methods to enhance graft outcomes and usage. Although static cold storage remains the default standard for kidney preservation, newer methods like hypothermic machine perfusion have shown improved outcomes, including reduced delayed graft function and better survival rates. Hypothermic oxygenated machine perfusion and normothermic machine perfusion offer some potential clinical benefits but studies to date have demonstrated mixed results. In the United States, LifePort and the XVIVO’s Kidney Assist Transport are the most popular hypothermic perfusion devices, with NMP devices mostly in trials. Combining perfusion with biomarkers such as mitochondrial flavin mononucleotide, neutrophil gelatinase-associated lipocalin, and osteopontin shows promise in assessing kidney viability and predicting post-transplant outcomes, though further research is also needed. Emphasis on repair biomarkers, such as uromodulin and osteopontin, aims to better predict graft outcomes and develop new therapies. While notable advancements have been made in the use of machine perfusion and viability testing for liver transplantation, additional research with larger sample sizes is essential to substantiate these results and enhance kidney transplantation outcomes.

Abstract Background Methylation class pleomorphic xanthoastrocytoma (mcPXA) comprises tumors with the DNA methylation signature of classical PXA but with a wider histologic spectrum, including overlap with glioblastoma (GBM). Methods To clarify the histologic and molecular scope of mcPXA and characterize its clinical behavior, a cohort of 469 tumor samples from 458 patients matching to mcPXA by the DKFZ classifier (v12.6 score ≥0.85) was interrogated. Results Patient median age was 23 years (range 1-73 years) with a female predominance (259 female/199 male). CDKN2A/B homozygous deletion was observed in 406 of 469 (87%) samples. In samples tested for BRAF p.V600E mutations (n = 279), 240 (86%) harbored the mutation. A chr7+/chr10− pattern was observed in 103 of 469 (22%) samples. Among samples tested for TERT promoter mutations (n = 143), 32 (22%) harbored the mutation. Progression-free and overall survival of patients with mcPXA were comparable to patients with methylation class IDH-mutant astrocytoma, low grade, but a GBM-like subset (ie, cases with a pre-methylation working diagnosis of GBM) showed shorter survival. Histologic features of high grade, including palisading necrosis and microvascular proliferation, were prognostic in mcPXA. Compared to patients with BRAF p.V600E-altered GBM, patients with mcPXA were younger and had a lower frequency of TERT promoter mutations. Conclusion Tumors in mcPXA share molecular characteristics with histologically defined PXA, and high-grade histologic features can help predict their clinical behavior. The use of an epigenetic classification of PXA reveals that this group of tumors is more common than previously appreciated and warrants in-depth study to identify efficacious therapeutic options.

Key Points This study demonstrates that peritoneal dialysis is a safe and feasible option for patients with autosomal dominant polycystic kidney disease, even with high cystic organ volumes. Larger organ volumes, including height-adjusted cumulative kidney and liver volume, were not associated with increased peritoneal dialysis–related complications. Background Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent genetic kidney disorder and the fourth leading cause of kidney failure. Peritoneal dialysis (PD), preferred for its home-based convenience and cost-effectiveness, is often underutilized in ADPKD because of concerns over enlarged kidneys and heightened risk of complications. Methods This retrospective cohort study used data from the Mayo Clinic Polycystic Kidney Disease Database to evaluate individuals with ADPKD undergoing PD. We analyzed demographics, clinical parameters, and PD-related parameters. Complications were correlated with kidney and liver volumes derived from pre-kidney failure imaging. Results A total of 155 individuals with ADPKD on PD were included, of whom 45.1% were male. The mean age at PD initiation was 54.3±12.8 years, and the mean body mass index was 28.0±7.0 kg/m 2 . The median duration of PD was 24.3 months (interquartile range [IQR], 10.7–43.1), with 21.9% transitioning to hemodialysis. The most common complications were abdominal hernias (30.3%) and peritonitis (23.9%), with a peritonitis rate of 0.11 episodes per patient-year. Imaging analyses performed on a subset of 50 patients showed a median height-adjusted total kidney liver volume of 2731.9 ml/m (IQR, 2102.5–3131.1) and a median height-adjusted total kidney volume of 1303.5 ml/m (IQR, 733.1–1829.4). Kaplan–Meier analysis demonstrated no differences in complications rates on the basis of height-adjusted total kidney liver volume or height-adjusted total kidney volume (above versus below median values) or body mass index categories. Multivariate Cox regression analysis revealed that higher height-adjusted cumulative organ volume was associated with a lower risk of PD-related complications (hazard ratio=0.56, P = 0.026). Conclusions PD is a safe and feasible treatment option for patients with ADPKD, with no increased risk of PD-related complications associated with larger height-adjusted cumulative organ volumes. Infectious complication rates in this cohort were within International Society of Peritoneal Dialysis guideline thresholds, further supporting the safety of PD in this population.