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Present bladder cancer therapies have relatively limited therapeutic impact and account for one of the highest lifetime treatment costs per patient. Therefore, there is an urgent need to explore novel and optimized treatment strategies. The present study investigated the effects of inhibiting endogenous hydrogen sulfide (H2S) production on bladder cell viability and in vivo tumor progression. We targeted the H2S-producing enzyme, cystathionine γ-lyase, in 5637 cells using propargylglycine (H2S inhibitor) and performed cytofluorimetric analysis to evaluate cell viability. We then tested the efficacy of propargylglycine alone or in combination with gemcitabine (conventional chemotherapy) in an intravesical murine model of bladder cancer. Magnetic resonance imaging and immunohistochemical staining for cell proliferation, apoptosis, immune-cell infiltration, and neovascularization were performed to evaluate tumor response. Compared to control conditions or cohorts, propargylglycine administration significantly attenuated bladder cancer cell viability in vitro (p < 0.0001) and tumor growth (p < 0.002) and invasion in vivo. Furthermore, propargylglycine enhanced the anti-cancer effects of gemcitabine, resulting in tumor regression (p < 0.0001). Moreover, propargylglycine induced cleaved PARP-1-activated apoptosis (p < 0.05), as well as intratumoral CD8+ T cell (p < 0.05) and F4/80+ macrophage (p < 0.002) infiltration. Propargylglycine also reduced intratumoral neovascularization (p < 0.0001) and cell proliferation (p < 0.0002). Importantly, the pro-apoptotic and anti-neovascularization effects of gemcitabine were enhanced by propargylglycine co-administration. Our findings suggest that inhibition of endogenous H2S production can be protective against bladder cancer by enhancing the chemotherapeutic action of gemcitabine and may be a novel pharmacological target and approach for improved bladder cancer diagnosis and treatments in the future.

We recently reported in a rat model of kidney transplantation that the addition of sodium thiosulfate (STS) to organ preservation solution improved renal graft quality and prolonged recipient survival. The present study investigates whether STS pre-treatment would produce a similar effect. In vitro, rat kidney epithelial cells were treated with 150 μM STS before and/or during exposure to hypoxia followed by reoxygenation. In vivo, donor rats were treated with PBS or 2.4 mg/kg STS 30 min before donor kidneys were procured and stored in UW or UW+150 μM STS solution at 4 °C for 24 h. Renal grafts were then transplanted into bilaterally nephrectomised recipient rats which were then sacrificed on post-operative day 3. STS pre-treatment significantly reduced cell death compared to untreated and other treated cells in vitro (p < 0.05), which corresponded with our in vivo result (p < 0.05). However, no significant differences were observed in other parameters of tissue injury. Our results suggest that STS pre-treatment may improve renal graft function after transplantation.

Kidney transplantation is preferred for end-stage renal disease. The current gold standard for kidney preservation is static cold storage (SCS) at 4 °C. However, SCS contributes to renal graft damage through ischemia–reperfusion injury (IRI). We previously reported renal graft protection after SCS with a hydrogen sulfide donor, sodium thiosulfate (STS), at 4 °C. Therefore, this study aims to investigate whether SCS at 10 °C with STS and Hemopure (blood substitute), will provide similar protection. Using in vitro model of IRI, we subjected rat renal proximal tubular epithelial cells to hypoxia–reoxygenation for 24 h at 10 °C with or without STS and measured cell viability. In vivo, we preserved 36 donor kidneys of Lewis rats for 24 h in a preservation solution at 10 °C supplemented with STS, Hemopure, or both followed by transplantation. Tissue damage and recipient graft function parameters, including serum creatinine, blood urea nitrogen, urine osmolality, and glomerular filtration rate (GFR), were evaluated. STS-treated proximal tubular epithelial cells exhibited enhanced viability at 10 °C compared with untreated control cells (p < 0.05). Also, STS and Hemopure improved renal graft function compared with control grafts (p < 0.05) in the early time period after the transplant, but long-term function did not reach significance. Overall, renal graft preservation at 10 °C with STS and Hemopure supplementation has the potential to enhance graft function and reduce kidney damage, suggesting a novel approach to reducing IRI and post-transplant complications.

Background: Healthcare personnel (HCP) working in non–acute-care facilities are at high risk of COVID-19. We sought to determine SARS-CoV-2 seroprevalence, and analyzed behaviors and activities related to COVID-19 acquisition in this cohort. Methods: Between May and June 2021, HCP were enrolled at a skilled nursing facility and a memory care facility in St. Louis, Missouri. Data regarding demographics, prior SARS-CoV-2 testing, symptoms consistent with COVID-19 in the previous 6 months, COVID-19 vaccination, personal protective equipment (PPE) use, and COVID-19 exposures were collected via survey. Blood specimens were obtained to determine SARS-CoV-2 nucleocapsid IgG antibody seroprevalence (Abbott Laboratories). Study protocol was approved by the Washington University Institutional Review Board. Results: The survey was completed by 74 HCP. 82% of participants were female, and 31% reported >10 years of healthcare experience. The overall SARS-CoV-2 seropositivity rate was 8.9% (5 HCP). Of the surveyed HCP, 50% reported symptoms concerning for COVID-19 in the prior 6 months. Headache (38%), fatigue (35%) and fever (27%) were the most common self-reported symptoms. Among symptomatic HCP, only 35% sought medical care for these symptoms. All HCP reported having taken at least 1 COVID-19 test prior to study enrollment. Of note, 18.9% (14 HCP) had a self-reported prior positive SARS-CoV-2 PCR test, of whom 9 HCP were seronegative. All seronegative HCP with a self-reported history of COVID-19 reported infection >3 months before study participation. Completion of a primary COVID-19 vaccination series was reported by 86% of HCP. Known exposure to COVID-19 at work was reported by 28% of HCP. When asked about PPE at the time of workplace exposure, N95 mask use was reported by 81%, gloves by 57%, gowns by 33%, face shields by 29% and surgical masks by 14%. Known specific exposure to COVID-19 outside work was reported by 31% of HCP. Conclusions: One year after the initial COVID-19 pandemic impacted the St. Louis region, HCP at non–acute-care facilities had a SARS-CoV-2 seroprevalence of 8.9%. Similar frequency of exposures were reported from both the workplace and community, with high rates of PPE use at the workplace. HCP in such settings remain at high risk of COVID-19 exposure from workplace and community exposures. Ongoing efforts are needed to maintain PPE use to prevent SARS-CoV-2 transmission within non–acute-care facilities, and continue access to timely COVID-19 screening for HCP.

Background: Ascending aortic aneurysms constitute an important hazard for individuals with a bicuspid aortic valve (BAV). However, the processes that degrade the aortic wall in BAV disease remain poorly understood. Methods: We undertook in situ analysis of ascending aortas from 68 patients, seeking potentially damaging cellular senescence cascades. Aortas were assessed for senescence-associated-ß-galactosidase activity, p16Ink4a and p21 expression, and double-strand DNA breaks. The senescence-associated secretory phenotype (SASP) of cultured-aged BAV aortic smooth muscle cells (SMCs) was evaluated by transcript profiling and consequences probed by combined immunofluorescence and circular polarization microscopy. The contribution of p38 MAPK signaling was assessed by immunostaining and blocking strategies. Findings: We uncovered SMCs at varying depths of cellular senescence within BAV- and tricuspid aortic valve (TAV)-associated aortic aneurysms. Senescent SMCs were also abundant in non-aneurysmal BAV aortas but not in non-aneurysmal TAV aortas. Multivariable analysis revealed that BAV disease independently associated with SMC senescence. Furthermre, SMC senescence was heightened at the convexity of aortas associated with right-left coronary cusp fusion. Aged BAV SMCs had a pronounced collagenolytic SASP. Moreover, senescent SMCs in the aortic wall were enriched with surface-localized MMP1 and surrounded by weakly birefringent collagen fibrils. The senescent-collagenolytic SMC phenotype depended on p38 MAPK signaling, which was chronically activated in BAV aortas. Interpretation: We have identified a cellular senescence-collagen destruction axis in at-risk ascending aortas. This novel “seno-destructive” SMC phenotype could open new opportunities for managing BAV aortopathy. Fund: Canadian Institutes of Health Research, Lawson Health Research Institute, Heart and Stroke Foundation of Ontario/Barnett-Ivey Chair. Keywords: Bicuspid aortic valve, Aortic aneurysm, Smooth muscle cells, Cellular senescence, Collagenase

Summary: Critical limb ischemia (CLI) is a hazardous manifestation of atherosclerosis and treatment failure is common. Abnormalities in the arterioles might underlie this failure but the cellular pathobiology of microvessels in CLI is poorly understood. We analyzed 349 intramuscular arterioles in lower limb specimens from individuals with and without CLI. Arteriolar densities were 1.8-fold higher in CLI muscles. However, 33% of small (

A major transformation programme is underway across seven technological higher education institutions in Ireland. Investment of €40m #NextGenerationEU funding enables a programme to empower learners, to enhance staff capabilities, to improve the digital infrastructure, and to ensure long-lasting sustainable impact. Designed and implemented by significant collaboration of partner institutions, the programme explicitly adopts a holistic approach with inter-related work streams and work packages. The programme is underpinned by the six core themes of academic integrity, digital transformation, education for sustainability, employability, equality diversity & inclusion, universal design for learning. This comprehensive structure enables focus on key issues, emerging topics, and ensuring sustainable enhancement of learning, teaching and assessment across the technological sector. Multiple elements of the programme provided opportunities to reflect on the role of artificial intelligence, ranging from the perspective of challenges associated with academic integrity to the wider potential to be exploited to support and enhance learning and teaching. Students play an active role in considering these issues through focussed projects in partnership with staff and by acting as student champions to ensure that students‟ perspectives inform related discussions. Staff development opportunities have focussed on artificial intelligence and specific training is in place for senior institutional leaders. Active cooperation with the National Academic Integrity Network, which is facilitated by the national external quality agency, has led to complementary focussed activities. A national practitioners‟ network is being established to examine the impact of generative AI on higher education. Many of these structures could be replicated in other institutions or groups of institutions. While there are many examples of programme activities addressing important or topical issues, this paper particularly focuses on themes relating to the 2024 EDEN conference.