Oncolytic viruses (OV) are promising treatments for cancer, with several currently undergoing testing in randomised clinical trials. Measles virus (MV) has not yet been tested in models of human ...melanoma. This study demonstrates the efficacy of MV against human melanoma. It is increasingly recognised that an essential component of therapy with OV is the recruitment of host antitumour immune responses, both innate and adaptive. MV-mediated melanoma cell death is an inflammatory process, causing the release of inflammatory cytokines including type-1 interferons and the potent danger signal HMGB1. Here, using human in vitro models, we demonstrate that MV enhances innate antitumour activity, and that MV-mediated melanoma cell death is capable of stimulating a melanoma-specific adaptive immune response.
Purpose Since its introduction in 1996 Mulcahy salvage has significantly improved outcomes for the removal and replacement of infected inflatable penile prostheses. Long-term followup data of Mulcahy ...salvage show an infection-free rate of 82%. A multicenter retrospective analysis of the malleable implant salvage technique was conducted to assess infection outcomes and the feasibility of conversion from malleable device back to inflatable penile prosthesis. Materials and Methods This is a retrospective, institutional review board exempt, multi-institution study of 58 patients who underwent Mulcahy salvage with inflatable penile prosthesis removal and replacement with malleable prosthesis. Patient operative notes and charts were extensively reviewed to compile study data. Results Between 2002 and 2014 a total of 58 patients underwent infected inflatable penile prosthesis removal and replacement with a malleable prosthesis via Mulcahy salvage. Of these patients 54 (93%) have remained infection-free postoperatively. Average patient age was 56.4 years and average operative time was 148 minutes. Postoperative followup (as of May 2015) ranged from 1 month to 84 months. Of the 54 patients 37 retained the malleable prosthesis and 17 (31%) subsequently underwent replacement with an inflatable penile prosthesis. This occurred on average 6.7 months after Mulcahy salvage. Four patients had persistent infection after Mulcahy salvage with the malleable prosthesis and underwent explantation. Conclusions This retrospective analysis of Mulcahy salvage procedure and replacement of inflatable penile prosthesis with malleable prosthesis shows a high infection-free rate. Additionally, 17 of the 54 patients who remained infection-free were able to successfully undergo subsequent removal of the malleable prosthesis and replacement with an inflatable penile prosthesis. Further prospective studies are needed to compare salvage with malleable vs inflatable penile prosthesis.
Invasive species pose serious threats to ecosystems. To reduce ecological and economic consequences of invasions, efforts are made to control invaders and evaluating the effects of such efforts is ...paramount. Lionfishes (Pterois volitans and Pterois miles) are native to the Indo‐Pacific Ocean and pose a major threat to local ecosystems in the invaded Atlantic and Mediterranean. Culling via spearfishing is a widespread measure to limit lionfish population size in invaded ranges. However, like most hunted fishes, lionfish alter their behavior after repeated culling, potentially decreasing the effectiveness of future culls. Previous studies on lionfish in the Caribbean have shown that lionfish are less bold after repeated culling. However, the impact of culling on lionfish in their newest invasive range, the Mediterranean, remains enigmatic. To determine the behavioral changes in response to culling in this second area of invasion, we tested for effects of culling on the behavior of lionfish in Cyprus, a region heavily impacted by the lionfish invasion in the Mediterranean. We compared the response of lionfish to an approaching free diver holding a metal pole (imitating a spear fisher) between protected areas where spearfishing is restricted and areas where culls are frequently conducted. We also assessed whether activity, hiding pattern, and site fidelity differed between these culled and unculled sites. Overall, we found limited effects of culling on the traits measured, indicating surprising resistance to culling‐induced behavioral changes in Mediterranean lionfish. Future studies should monitor invasive lionfish population densities and the effects of culling in more detail to tailor management plans and reduce the negative effects of these fish in specific invaded ranges.
The Australian SKA Pathfinder (ASKAP) telescope has started to localize fast radio bursts (FRBs) to arcsecond accuracy from the detection of a single pulse, allowing their host galaxies to be ...reliably identified. We discuss the global properties of the host galaxies of the first four FRBs localized by ASKAP, which lie in the redshift range 0.11 < z < 0.48. All four are massive galaxies (log(M*/M ) ∼ 9.4-10.4) with modest star formation rates of up to 2 M yr−1-very different to the host galaxy of the first repeating FRB 121102, which is a dwarf galaxy with a high specific star formation rate. The FRBs localized by ASKAP typically lie in the outskirts of their host galaxies, which appears to rule out FRB progenitor models that invoke active galactic nuclei or free-floating cosmic strings. The stellar population seen in these host galaxies also disfavors models in which all FRBs arise from young magnetars produced by superluminous supernovae, as proposed for the progenitor of FRB 121102. A range of other progenitor models (including compact-object mergers and magnetars arising from normal core-collapse supernovae) remain plausible.
Traditional kidney biomarkers are insensitive indicators of acute kidney injury, with meaningful changes occurring late in the course of injury. The aim of this work was to demonstrate the diagnostic ...potential of urinary osteopontin (OPN) and neutrophil gelatinase-associated lipocalin (NGAL) for drug-induced kidney injury (DIKI) in rats using data from a recent regulatory qualification submission of translational DIKI biomarkers and to compare performance of NGAL and OPN to five previously qualified DIKI urinary biomarkers. Data were compiled from 15 studies of 11 different pharmaceuticals contributed by Critical Path Institute's Predictive Safety Testing Consortium (PSTC) Nephrotoxicity Working Group (NWG). Rats were given doses known to cause DIKI or other target organ toxicity, and urinary levels of the candidate biomarkers were assessed relative to kidney histopathology and serum creatinine (sCr) and blood urea nitrogen (BUN).OPN and NGAL outperformed sCr and BUN in identifying DIKI manifested as renal tubular epithelial degeneration or necrosis. In addition, urinary OPN and NGAL, when used with sCr and BUN, increased the ability to detect renal tubular epithelial degeneration or necrosis. NGAL and OPN had comparable or improved performance relative to Kim-1, clusterin, albumin, total protein, and beta-2 microglobulin. Given these data, both urinary OPN and NGAL are appropriate for use with current methods for assessing nephrotoxicity to identify and monitor DIKI in regulatory toxicology studies in rats. These data also support exploratory use of urinary OPN and NGAL in safety monitoring strategies of early clinical trials to aid in the assurance of patient safety.
In humans, muscle-invasive bladder cancer (MIBC) is highly aggressive and associated with a poor prognosis. With a high mutation load and large number of altered genes, strategies to delineate key ...driver events are necessary. Dogs and cats develop urothelial carcinoma (UC) with histological and clinical similarities to human MIBC. Cattle that graze on bracken fern also develop UC, associated with exposure to the carcinogen ptaquiloside. These species may represent relevant animal models of spontaneous and carcinogen-induced UC that can provide insight into human MIBC.
Whole-exome sequencing of domestic canine (n = 87) and feline (n = 23) UC, and comparative analysis with human MIBC reveals a lower mutation rate in animal cases and the absence of APOBEC mutational signatures. A convergence of driver genes (ARID1A, KDM6A, TP53, FAT1, and NRAS) is discovered, along with common focally amplified and deleted genes involved in regulation of the cell cycle and chromatin remodelling. We identify mismatch repair deficiency in a subset of canine and feline UCs with biallelic inactivation of MSH2. Bovine UC (n = 8) is distinctly different; we identify novel mutational signatures which are recapitulated in vitro in human urinary bladder UC cells treated with bracken fern extracts or purified ptaquiloside.
Canine and feline urinary bladder UC represent relevant models of MIBC in humans, and cross-species analysis can identify evolutionarily conserved driver genes. We characterize mutational signatures in bovine UC associated with bracken fern and ptaquiloside exposure, a human-linked cancer exposure. Our work demonstrates the relevance of cross-species comparative analysis in understanding both human and animal UC.
Depression is disabling and highly prevalent. Intravenous (IV) ketamine displays rapid-onset antidepressant properties, but little is known regarding which patients are most likely to benefit, ...limiting personalized prescriptions. We identified randomized controlled trials of IV ketamine that recruited individuals with a relevant psychiatric diagnosis (e.g., unipolar or bipolar depression; post-traumatic stress disorder), included one or more control arms, did not provide any other study-administered treatment in conjunction with ketamine (although clinically prescribed concurrent treatments were allowable), and assessed outcome using either the Montgomery-Åsberg Depression Rating Scale or the Hamilton Rating Scale for Depression (HRSD-17). Individual patient-level data for at least one outcome was obtained from 17 of 25 eligible trials pooled n = 809. Rates of participant-level data availability across 33 moderators that were solicited from these 17 studies ranged from 10.8% to 100% (median = 55.6%). After data harmonization, moderators available in at least 40% of the dataset were tested sequentially, as well as with a data-driven, combined moderator approach. Robust main effects of ketamine on acute ~24-hours; β*(95% CI) = 0.58 (0.44, 0.72); p < 0.0001 and post-acute ~7 days; β*(95% CI) = 0.38 (0.23, 0.54); p < 0.0001 depression severity were observed. Two study-level moderators emerged as significant: ketamine effects (relative to placebo) were larger in studies that required a higher degree of previous treatment resistance to federal regulatory agency-approved antidepressant medications (≥2 failed trials) for study entry; and in studies that used a crossover design. A comprehensive data-driven search for combined moderators identified statistically significant, but modest and clinically uninformative, effects (effect size r ≤ 0.29, a small-medium effect). Ketamine robustly reduces depressive symptoms in a heterogeneous range of patients, with benefit relative to placebo even greater in patients more resistant to prior medications. In this largest effort to date to apply precision medicine approaches to ketamine treatment, no clinical or demographic patient-level features were detected that could be used to guide ketamine treatment decisions.Review Registration: PROSPERO Identifier: CRD42021235630.
Myeloid cell leukemia 1 (MCL-1) is a BCL-2 family protein that has been implicated in the progression and survival of multiple tumor types. Herein we report a series of MCL-1 inhibitors that emanated ...from a high throughput screening (HTS) hit and progressed via iterative cycles of structure-guided design. Advanced compounds from this series exhibited subnanomolar affinity for MCL-1 and excellent selectivity over other BCL-2 family proteins as well as multiple kinases and GPCRs. In a MCL-1 dependent human tumor cell line, administration of compound 30b rapidly induced caspase activation with associated loss in cell viability. The small molecules described herein thus comprise effective tools for studying MCL-1 biology.
COVID-19 disrupted access to bereavement support. The objective of this study was to identify the bereavement supports used by Australians during the COVID-19 pandemic, perceived helpfulness of ...supports used, prevalence and areas of unmet support need, and characteristics of those with unmet support needs. A convenience sample of bereaved adults completed an online questionnaire (April 2021-April 2022) about their bereavement experiences including support use and perceived helpfulness, unmet support needs and mental health. Multiple logistic regression was conducted to determine sociodemographic correlates of unmet needs. Open-ended responses were examined using content analysis to determine key themes. 1,878 bereaved Australians completed the questionnaire. Participants were mostly women (94.9%) living in major cities (68%) and reported the death of a parent (45%), with an average age of 55.1 years (SD = 12.2). The five most used supports were family and friends, self-help resources, general practitioners, psychologists, and internet/online community groups. Notably, each was nominated as most helpful and most unhelpful by participants. Two-thirds (66%) reported specific unmet support needs. Those with unmet needs scored lower on mental health measures. Correlates of unmet needs included being of younger age, being a spouse or parent to the deceased; reporting more impacts from public health measures, and not reporting family and friends as supports. The most frequent unmet need was for social support after the death and during lockdown. This study demonstrates the complexity of bereavement support needs during a pandemic. Specialised grief therapy needs to be more readily available to the minority of grievers who would benefit from it. A clear recommendation for a bereavement support action plan is to bolster the ability of social networks to provide support in times of loss. The fostering of social support in the wake of bereavement is a major gap that needs to be addressed in practice, policy, and research.
PDF
