The University of Tennessee system (UT system) is a system of public universities in the U.S. state of Tennessee. It is one of two public university systems, the other being the Tennessee Board of Regents (TBR). It consists of four primary campuses in Knoxville, Chattanooga, Pulaski and Martin; a health sciences campus in Memphis; a research institute in Tullahoma; and various extensions throughout the state.The UT system has a combined student enrollment of more than 49,000 students, over 320,000 living alumni, and a total endowment that tops $1 billion.S.S.
Dysregulated ribosome biogenesis and p53 mutations are known to play oncogenic roles in various cancers, including pancreatic cancer. In this study, we demonstrated the therapeutic potential of BMH-21, a pharmacologic inhibitor of RNA polymerase I, against pancreatic cancer by uncovering a novel molecular mechanism involving RPA194-mediated ubiquitination of mutant p53 without affecting the ubiquitination of wild-type p53. Our key findings are that (i) BMH-21 selectively induces apoptosis and cell growth inhibition of pancreatic cancer cells with no effect on normal human pancreatic ductal epithelial cells; (ii) BMH-21 degrades RPA194; (iii) BMH-21 inhibits recruitment of both RPA194 and RPA135 on rDNA to suppress pre-rRNA synthesis; (iv) RPA194 physically interacts with p53 and BMH-21-induced degradation of RPA194 selectively exposes truncated and mutated p53 for ubiquitination with no effect on ubiquitination of wild-type p53 in pancreatic cancer cells; and (v) BMH-21 treatment significantly reduces the growth of orthotopic xenograft pancreatic tumors in athymic nude mice with no observed toxicity. Altogether, these findings suggest that BMH-21 is a promising, nontoxic therapeutic agent for patients with pancreatic cancer with aberrant ribosome biogenesis and mutant p53, offering a potential new avenue for targeted treatment.
PURPOSE:To replace an existing clinical practice guideline for the diagnosis and management of phenylalanine hydroxylase (PAH) deficiency. METHODS:The PAH Deficiency Guideline Workgroup used the Grading of Recommendations Assessment, Development, and Evaluation evidence-to-decision framework to develop evidence summaries and practice recommendations based on the recent American College of Medical Genetics and Genomics systematic review. RESULTS:Many recommendations from the 2014 PAH practice guideline are recognized as standard of care in this evidence-based guideline. Key recommendations from the previous guideline that were not supported by strong evidence are now strongly supported; (1) treatment for PAH deficiency should be lifelong for individuals with untreated phenylalanine (Phe) levels >360 μmol/L, (2) individuals with lifelong Phe levels ≤360 μmol/L have better intellectual outcomes than those who do not, (3) achieving Phe levels ≤360 μmol/L before conception is strongly recommended to prevent pregnancy complications and negative outcomes for the offspring, and (4) genetic testing for PAH variants is recommended at birth to confirm diagnosis and guide therapy. CONCLUSION:We strongly recommend lifelong maintenance of Phe ≤360 μmol/L (using plasma or whole blood) for optimal intellectual outcomes and for reduced teratogenicity, utilizing all available and necessary dietary, pharmaceutical, and patient-educational modalities.
BACKGROUND:Recent studies support the effectiveness of mechanical thrombectomy (MT) for distal medium vessel occlusions (DMVOs). The RED 43 catheter has been introduced as a primary catheter for distal aspiration in acute ischemic stroke. In this multicenter study, we share our experience of using the RED 43 catheter for MT in DMVOs. METHODS:We identified consecutive patients with DMVOs who underwent primary aspiration thrombectomy using the RED 43 catheter at four high-volume stroke centers. We collected baseline clinical data, angiographic and clinical outcomes, and procedural complications. We divided the patients into two groups: those with primary DMVOs included patients who presented with more distal occlusions requiring mechanical thrombectomy; and those with secondary DMVOs being patients presenting with large vessel occlusion that later developed a DMVO. Primary outcomes included the rate of first pass effect, (modified treatment in cerebral infarction (mTICI) 2c or 3 on the first pass) and successful recanalization (mTICI≥2b at end of procedure). Secondary outcomes included good functional outcomes (modified Rankin Scale (mRS) 0-2 at 3 months), symptomatic intracerebral hemorrhage (sICH), asymptomatic intracerebral hemorrhage (aICH), subarachnoid hemorrhage (SAH), and in-hospital mortality. RESULTS:We identified 102 consecutive DMVO cases undergoing thrombectomy with the RED 43 catheter. The mean age was 70 years, and the median National Institutes of Health Stroke Scale (NIHSS) score was 9. The first pass effect (FPE) rate was 57% (primary) and 61% (secondary). Successful recanalization occurred in 83% (primary) and 87% (secondary). Good functional outcome was observed in 57% of patients. sICH occurred in one patient, and two patients died during hospitalization. We observed aICH in five (4.9%) patients and SAH in seven (6.9%) patients. CONCLUSION:The RED 43 catheter is safe and effective for aspiration thrombectomy in primary and secondary DMVOs, with high recanalization rates and a favorable safety profile.
Recent technologic advances in neonatal dialysis have changed current dialysis practices. The goal of this study was to define demographics, diagnoses, initial dialysis modality, modality changes, and outcomes of neonates receiving dialysis. Retrospective, multicenter cohort of neonates (≤ 30 days of age) from 26 U.S. centers, who received dialysis between 6/2017 and 5/2022. Measures of central tendency were calculated to describe the cohort stratified by the primary dialysis-related diagnosis including acute kidney injury requiring dialysis (AKI-D), stage 5 chronic kidney disease (CKD 5), hyperammonemia, and other causes. The primary outcome was death during the initial hospitalization. For the 405 neonates in this cohort, AKI-D (57
Our study investigates the association between income inequality and carbon dioxide (CO2) emissions in Canada, using data from 1981 to 2021. We employ the autoregressive distributed lag bounds testing approach to cointegration. The central finding is a positive long-run cointegrating relationship between changes in the share of income of the top 1% and changes in CO2 emissions. Specifically, a 1% increase in the share of income of the top 1% is associated with a 0.07% increase in CO2 emissions. This finding, which aligns with the political economy argument and the Veblen effect, has significant policy implications. One is that it underscores the importance of considering income redistribution in the context of addressing environmental degradation in Canada.
