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The article examines the effect of proteasome inhibitors with different chemical structures on the ubiquitin-proteasome system in vitro. The authors state that results indicate that each of the investigated proteasome inhibitors induced identical proteasome-inhibitor-specific ubiquitin-positive immunostaining and nuclear displacement in PC12 cells. They mention that other agents like paclitaxel and cisplatin did not cause ubiquitinated protein aggregate (UPA) or nuclear displacement.

Aim: To explore the effect of canagliflozin on kidney and cardiovascular events and safety outcomes in individuals with type 2 diabetes and chronic kidney disease across geographic regions and racial groups., Materials and Methods: A stratified Cox proportional hazards model was used to assess efficacy and safety outcomes by geographic region and racial group. The primary composite outcome was a composite of end-stage kidney disease (ESKD), doubling of the serum creatinine (SCr) level, or death from kidney or cardiovascular causes. Secondary outcomes included: (i) cardiovascular death or heart failure (HF) hospitalization; (ii) cardiovascular death, myocardial infarction (MI) or stroke; (iii) HF hospitalization; (iv) doubling of the SCr level, ESKD or kidney death; (v) cardiovascular death; (vi) all-cause death; and (vii) cardiovascular death, MI, stroke, or hospitalization for HF or for unstable angina., Results: The 4401 patients were divided into six geographic region subgroups: North America (n = 1182, 27%), Central and South America (n = 941, 21%), Eastern Europe (n = 947, 21%), Western Europe (n = 421, 10%), Asia (n = 749, 17%) and Other (n = 161, 4%). The analyses included four racial groups: White (n = 2931, 67%), Black or African American (n = 224, 5%), Asian (n = 877, 20%) and Other (n = 369, 8%). Canagliflozin reduced the relative risk of the primary composite outcome in the overall trial by 30% (hazard ratio 0.70, 95% confidence interval 0.59-0.82; P = 0.00001). Across geographic regions and racial groups, canagliflozin consistently reduced the primary composite endpoint without evidence of heterogeneity (interaction P values of 0.39 and 0.91, respectively) or significant safety outcome differences., Conclusions: Canagliflozin reduces the risk of kidney and cardiovascular events similarly across geographic regions and racial groups., (© 2024 John Wiley & Sons Ltd.)

Mushroom (amatoxin) poisoning from ingestion is a rare but life-threatening medical emergency characterized by gastrointestinal symptoms before progression to multisystem organ failure in severe cases. Many therapies of amatoxin intoxication have been described, including supportive care, medical therapies, detoxification strategies, and liver transplant. The evidence supporting these therapies remains limited due to the rarity of amatoxin poisoning and challenge of a timely diagnosis. We report a case of amatoxin poisoning in Los Angeles causing severe liver injury without acute liver failure treated successfully using medical therapies, gallbladder drainage, and plasma exchange., (© 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Formative assessments are primarily used as a tool to gauge learning throughout an anatomy course. They have also been demonstrated to improve student mastery and exam performance, although the precise nature of this relationship is poorly understood. In this study, it is hypothesized that formative assessment questions targeting higher cognitive levels, integrating topics from multiple lessons, and including visuospatial elements will increase student exam performance. Formative and summative questions provided to students during the Clinical Anatomy block at the University of Arizona College of Medicine-Phoenix between 2015 and 2018 were assessed for cognitive level, integration of targeted learning objectives, and presence or absence of visuospatial elements. These variables were entered into a hierarchical linear model along with demographic variables for each cohort to assess the relationships between these variables and cohort performance on exam questions. The best predictor of exam performance was the inclusion of constituent learning objectives within the formative assessment. Additionally, students performed better on exam questions with visuospatial elements when the targeted learning objectives were also associated with visuospatial elements on the formative assessment. Surprisingly, the cognitive level of formative questions and the integration of learning objectives within them were not correlated with student exam performance. This study demonstrates the importance of including a broad range of topics in formative assessments and highlights a potential benefit of adopting consistent question formats for formative assessments and exams., (© 2023 The Authors. Anatomical Sciences Education published by Wiley Periodicals LLC on behalf of American Association for Anatomy.)

Rationale & Objective: It is unclear whether the effect of canagliflozin on adverse kidney and cardiovascular events in those with diabetic kidney disease varies by age and sex. We assessed the effects of canagliflozin among age group categories and between sexes in the Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study., Study Design: Secondary analysis of a randomized controlled trial., Setting & Participants: Participants in the CREDENCE trial., Intervention: Participants were randomly assigned to receive canagliflozin 100mg/d or placebo., Outcomes: Primary composite outcome of kidney failure, doubling of serum creatinine concentration, or death due to kidney or cardiovascular disease. Prespecified secondary and safety outcomes were also analyzed. Outcomes were evaluated by age at baseline (<60, 60-69, and≥70 years) and sex in the intention-to-treat population using Cox regression models., Results: The mean age of the cohort was 63.0±9.2 years, and 34% were female. Older age and female sex were independently associated with a lower risk of the composite of adverse kidney outcomes. There was no evidence that the effect of canagliflozin on the primary outcome (a composite of kidney failure, a doubling of serum creatinine concentration, or death from kidney or cardiovascular causes) differed between age groups (HRs, 0.67 [95% CI, 0.52-0.87], 0.63 [0.48-0.82], and 0.89 [0.61-1.29] for ages<60, 60-69, and≥70 years, respectively; P=0.3for interaction) or sexes (HRs, 0.71 [95% CI, 0.54-0.95] and 0.69 [0.56-0.84] in women and men, respectively; P=0.8for interaction). No differences in safety outcomes by age group or sex were observed., Limitations: This was a post hoc analysis with multiple comparisons., Conclusions: Canagliflozin consistently reduced the relative risk of kidney events in people with diabetic kidney disease in both sexes and across age subgroups. As a result of greater background risk, the absolute reduction in adverse kidney outcomes was greater in younger participants., Funding: This post hoc analysis of the CREDENCE trial was not funded. The CREDENCE study was sponsored by Janssen Research and Development and was conducted collaboratively by the sponsor, an academic-led steering committee, and an academic research organization, George Clinical., Trial Registration: The original CREDENCE trial was registered at ClinicalTrials.gov with study number NCT02065791., (Copyright © 2023 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Older adults ≥65 years of age represent the majority of new cancer diagnoses and are vulnerable to developing depression-like symptoms. Evaluation and management of depression in older cancer patients is underappreciated despite its high prevalence and impact on health-related quality of life. Although antidepressants are the primary pharmacologics used to treat depressive-like symptoms, the efficacy and overall benefit(s) are not well-characterized in older adult patients with cancer. The objective of this investigation was to review what is known about the efficacy of pharmacologic treatment for older adults with depression and cancer., Methods: PubMed (Medline) and EMBASE (Elsevier) databases were analyzed for relevant literature in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines., Results: 1,919 unique studies were identified for title and abstract screening. Forty-eight publications were retrieved for full review. None of the identified studies evaluated the potential for benefit after pharmacological treatment among older adults with cancer and depression. Twenty-seven publications met all study criteria except for an analysis focused on older patients., Conclusion: We discovered a universal absence of literature with a relevance to pharmacologic antidepressant treatment effects in older adult patients with cancer. This included a lack of evaluation in patients with brain tumors who have an unusually high predilection for developing depression. Our findings suggest that new research is critically needed for understanding optimal clinical management strategies in older adults with cancer and depression who are treated with antidepressants., Competing Interests: The authors declare no conflicts of interest., (© 2022 The Authors.)

Takotsubo cardiomyopathy (TC) is associated with significant short-term morbidity and mortality. Several risk factors for poor outcomes have been identified; however, the prognostic implications of pre-existing comorbidity in TC are poorly delineated. We sought to assess the association of aggregate pre-existing comorbidity with short-term outcomes in TC. We performed a retrospective observational study of adult subjects diagnosed with TC at two academic tertiary care hospitals between 2005 and 2018. Overall burden of medical comorbidity was estimated using the Charlson comorbidity index (CCI). Multivariable logistic regression was used to test for independent association of CCI with 30-day mortality and severe shock at index presentation. Multivariable poisson regression was performed to assess the association of CCI with duration of hospitalization. Five-hundred and thirty-eight subjects were diagnosed with TC during the study period. The median CCI score of all subjects was 2 (IQR 1-4). Among subjects with physical triggers of TC, the median CCI score was 2 (IQR 1-4) compared to a median CCI score of 1 (IQR 0-1) in subjects with non-physical triggers of TC (P < 0.001). Seventy-six (14%) subjects died within 30 days of index diagnosis and 185 (34%) subjects experienced severe shock. The median duration of hospitalization was 7 days (IQR 3-14 days). In multivariable logistic regression, CCI was not associated with 30-day mortality or severe shock. In multivariable Poisson regression, CCI (IRR 1.17, 95% CI 1.16-1.18, P < 0.001) was associated with duration of hospitalization. Increased burden of pre-existing medical comorbidity was not independently associated with 30-day mortality or severe shock at index presentation, but was associated with increased duration of hospitalization after diagnosis of TC.

Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the first and rate-limiting reaction of l-tryptophan (Trp) conversion into l-kynurenine (Kyn). The depletion of Trp, and the accumulation of Kyn have been proposed as mechanisms that contribute to the suppression of the immune response-primarily evidenced by in vitro study. IDO1 is therefore considered to be an immunosuppressive modulator and quantification of IDO1 metabolism may be critical to understanding its role in select immunopathologies, including autoimmune- and oncological-conditions, as well as for determining the potency of IDO1 enzyme inhibitors. Because tryptophan 2,3-dioxygenase (TDO), and to a significantly lesser extent, IDO2, also catabolize Trp into Kyn, it's important to differentiate the contribution of each enzyme to Trp catabolism and Kyn generation. Moreover, a great variety of detection methods have been developed for the quantification of Trp metabolites, but choosing the suitable protocol remains challenging. Here, we review the differential expression of IDO1/TDO/IDO2 in normal and malignant tissues, followed by a comprehensive analysis of methodologies for quantifying Trp and Kyn in vitro and in vivo, with an emphasis on the advantages/disadvantages for each application., (© 2019 Elsevier Inc. All rights reserved.)

The great emphasis on ethical and humane treatment of animals in biomedical research has culminated in the promulgation of the rule of 3Rs - Replacement, Reduction, and Refinement. We have proposed an addition to the 3Rs - a fourth R for Recycling the animal. In drug discovery single-dose pharmacokinetic studies in rats, each animal is generally used only once and then euthanized. A reduction in the number of rats used in this high-throughput era can be readily implemented by reusing animals, just as larger animals are reused in multiple pharmacokinetic studies, consequently reducing the overall number of animal lives sacrificed in research. We provide evidence here for the reproducibility of pharmaco-kinetic studies of tolbutamide and fluconazole, used as test compounds, in rats receiving once-weekly oral and intravenous doses for 4 weeks, proving that recycling rats for multiple single low-dose pharmacokinetic studies is a viable option.

Single-dose pharmacokinetics of 1-aminobenzotriazole (ABT), a potent nonspecific inhibitor of cytochromes P450 (P450s), were characterized after oral administration to mice and guinea pigs at doses of 50, 100, and 150 mg/kg using serial sampling in both species. Only 30-microl blood samples were drawn from jugular vein-cannulated mice using Microvette capillary tubes containing lithium heparin. A comparison of the pharmacokinetics of antipyrine (AP) administered i.v. at 20 mg/kg to mice followed by serial and terminal sampling techniques yielded similar results. The ABT concentrations in plasma were sustained at high levels (5-100 microM) for at least 12 h in both species. Pretreatment of animals with ABT 2 h prior to AP administration decreased the plasma AP clearance by about 95% in mice at all ABT doses studied and 84, 95, and 95% in guinea pigs at a dose of 50, 100, and 150 mg/kg ABT, respectively. In vitro, the dissociation constants (KI) for ABT as the P450 mechanism-based inactivator were determined to be 45.6 and 193 microM, and the maximal inactivation rate constants (kinact) were determined to be 0.089 and 0.075 min(-1) for the mouse and guinea pig liver microsomes, respectively. The projected P450 inactivations at the plasma Cmax of ABT agreed with the inhibitions of P450-mediated AP clearance observed in vivo. For mechanistic studies in vivo overall, a 2-h prior oral pretreatment with ABT at 50 mg/kg in mice and 100 mg/kg in guinea pigs would provide significant systemic concentrations of the inhibitor over 24 h and inhibition of P450-dependent clearance of test compounds.