Citations

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive and chemo-resistant sarcomas with poor survival rates. Loss of CDKN2A or P53 following NF1 disruption is a key event in MPNST development. Here, we used CRISPR-Cas9 somatic tumorigenesis in mice to identify transcriptomic and metabolomic features distinguishing CDKN2A - versus P53 -deleted MPNSTs. Convergent, multiomic analyses revealed that CDKN2A -deleted MPNSTs are especially dependent on the pentose phosphate pathway (PPP) and NADPH metabolism for growth and viability. Disruption of glucose-6-phosphate dehydrogenase (G6PD), the PPP rate-limiting enzyme, slowed CDKN2A -deleted MPNST growth and sensitized MPNSTs to standard-of-care chemotherapy. Knockdown of the redox-regulated transcription factor NRF2 slowed MPNST growth and decreased G6PD transcription. Analysis of patient MPNSTs identified a NRF2 gene signature correlating with tumor transformation. Furthermore, G6PD and NRF2 expression in PanCancer TCGA samples correlates with patient survival. This work identifies NRF2-PPP dependency as a targetable vulnerability in these difficult-to-treat MPNSTs, particularly in the NF1/CDKN2A -deleted majority.

ABSTRACT Background The association between transjugular intrahepatic portosystemic shunt TIPS and waitlist outcomes in simultaneous liver‐kidney (SLK) transplant recipients remains unclear. Methods Between 2003 and 2023, we examined the scientific registry of transplant recipients. All adult candidates with overlapping waiting lists for liver and kidney transplants ( N = 15 087) were analyzed (entire cohort). Candidates without TIPS ( n = 13 980) and with ( n = 1107) were followed through November 30, 2023, and the following outcomes were analyzed: death, SLK transplant, liver‐ or kidney‐alone transplant, or removal from the list. The Aalen–Johansen method was used to calculate the cumulative incidence rates of the outcomes, where the outcomes were considered competing risks. Mixed effects Cox proportional hazard models were used to compare the outcomes by TIPS status. We separately analyzed dialysis‐dependent candidates ( n = 10 370). Results In the entire cohort, the 1‐year cumulative incidence of death in those without TIPS was higher than in those with (12.5% vs. 9%). In the dialysis‐dependent cohort, the 1‐year death incidence was 13.3% versus 8.8% in those without TIPS and those with, respectively. In the multivariable Cox proportional hazard models, TIPS was associated with a 29% lower mortality risk in the entire cohort (HR = 0.71, 95% CI: 0.60–0.84, p < 0.001) and a 33% lower risk of mortality in the dialysis‐dependent cohort. The likelihood of receiving SLK was lower for recipients with TIPS in the univariable analysis. However, this association was attenuated after adjustment. The causes of removal were similar irrespective of TIPS status in both cohorts. Conclusion In this large cohort of SLK candidates, those with TIPS had a better waitlist survival, irrespective of their dialysis requirements before transplantation. Prospective studies are needed to validate these findings.

Objectives Guidelines advise repeat screening within four months if Papanicolaou (Pap) results are unsatisfactory for evaluation. This utilizes healthcare system resources and may decrease patient satisfaction due to needing a second clinic appointment. We assessed unsatisfactory Pap test (UPT) rates and associations with clinician and patient characteristics to inform future interventions to decrease UPTs. Setting Multisite midwestern United States primary care practice. Methods Retrospective analysis of women aged 21–65 with a Pap between 7/1/2021 and 6/30/2023. Bivariate and multivariable logistic regression analyses were conducted to assess for associations between UPTs and clinician gender, degree, residency status, and experience. Results Of 51,195 Paps completed, 2.3% were unsatisfactory. Female clinicians performed the most Pap tests (83.2%) with slightly less likelihood of UPTs compared with male clinicians ( p = 0.015). There was no significant difference comparing physicians to advanced practice providers in UPTs ( p = 0.18). Residency training level did not affect UPT rates ( p = 0.95). Clinician experience was associated with higher UPT rates in first and fourth quartiles (least and most Paps performed) compared to middle two quartiles ( p = 0.004). UPTs were more likely among women aged > 50 years old ( p < 0.001), married ( p < 0.001), and Asian ( p < 0.001). Conclusions Clinician characteristics played a small role in predicting UPTs but patient age may be the factor most amenable to intervention to lower UPTs. Transitioning to primary human papillomavirus (HPV) screening in peri/post-menopausal women could decrease UPTs given Paps are performed on the clinician-collected cervical specimen only if HPV testing is positive.

Diabetic foot ulcers (DFUs) are common complications of suboptimally controlled diabetes, characterised by non-healing, high morbidity, infection, recurrence (40–50%) and mortality. Ultrasonic debridement technology has been used for >30 years to treat cataracts safely and effectively, and animal studies have suggested that ultrasound debridement stimulates collagen turnover. This technology was applied in developing a system for soft tissue removal in tendons and elsewhere, with intended use in the elbow, knee, ankle, foot and shoulder. It was then modified for the treatment of DFUs. In this study, the rationale behind using this technology is discussed, the procedural technique is described, and photographic examples of treatment outcomes presented.

ABSTRACT Post‐translational modifications, such as glycosylation and phosphorylation, play a critical role in protein trafficking, interactions, and stability. Disruptions in these pathways can lead to glycosylphosphatidylinositol (GPI) deficiencies, which present with a spectrum of clinical features, including congenital anomalies, dysmorphic features, developmental delay, hypotonia, and epilepsy. Biallelic variants in PIGV , a key mannosyltransferase in GPI biosynthesis, cause Hyperphosphatasia with Impaired Intellectual Development Syndrome 1 (HPMRS1), a rare disorder characterized by hyperphosphatasia, seizures, developmental delay, hypotonia, abnormal MRI findings, and distinct facial dysmorphisms. Fewer than 30 cases have been reported to date. We conducted a case study and literature review; with clinical data obtained from medical records. A 2‐year‐old female presented with developmental delay, myoclonic epilepsy, hypotonia, and mild facial dysmorphism. Laboratory results showed elevated alkaline phosphatase (899 U/L) and low pyridoxal 5′‐phosphate levels in cerebrospinal fluid (CSF). Brain MRI revealed diffuse cerebral volume loss and ventriculomegaly. Trio genome sequencing identified two PIGV variants: c.1415T>C‐p.(Leu472Pro) and c.524T>C‐p.(Leu175Pro). Functional studies using PIGV ‐knockout HEK293 cells transfected with wild‐type or mutant PIGV constructs demonstrated reduced GPI‐anchored protein (GPI‐AP) expression under weaker promoters, indicating impaired enzymatic activity. We report two novel PIGV variants associated with HPMRS1, emphasizing the value of functional assays in variant interpretation. Our findings also highlight the diagnostic relevance of alkaline phosphatase measurement in patients with refractory seizures.

Introduction: Mitral valve transcatheter edge-to-edge repair (M-TEER) has emerged as a minimally invasive option for high-risk surgical candidates with severe and symptomatic mitral regurgitation (MR), but post-procedure residual mitral valve (MV) dysfunction remains a significant concern. This study evaluates the clinical utility of combining artificial intelligence applied to electrocardiograms (ECG-AI) for diastolic dysfunction (DD) grading and the echocardiography-derived velocity time integral of the MV and left ventricular outflow tract ratio (VTIMV/LVOT) in predicting prognosis in patients post-M-TEER. Methods: A retrospective analysis of patients who underwent M-TEER between 2014 and 2021 was conducted. Patients were categorized based on VTIMV/LVOT and ECG-AI scores into three groups: both normal parameters, either abnormal parameter, or both abnormal parameters to compare outcomes (mortality, major adverse cardiovascular events [MACE], and the need for subsequent MV reintervention) using Kaplan–Meier analysis, multivariable Cox regression models, and net reclassification improvement. Results: Overall, 250 patients were included; the median age was 79.5 (IQR: 73.1, 84.6) and 66.4% were male. The combined abnormal VTIMV/LVOT (≥2.5) and ECG-AI score for DD (>1) was associated with higher risk of one-year mortality (adjusted HR: 4.56 [1.04–19.89], p = 0.044) and MACE (adjusted HR: 3.72 [1.09–12.72], p = 0.037) compared to patients with both normal parameters. Conclusions: This study highlights the potential additive value of integrating VTIMV/LVOT and ECG-AI scores as a prognostic tool for a personalized approach to the post-operative evaluation and risk stratification in M-TEER patients.