Preclinical studies of RA475, a guanidine-substituted spirocyclic candidate RPN13/ADRM1 inhibitor for treatment of ovarian cancer.

There is an urgent unmet need for more targeted and effective treatments for advanced epithelial ovarian cancer (EOC). The emergence of drug resistance is a particular challenge, but small molecule covalent inhibitors have promise for difficult targets and appear less prone to resistance. Michael acceptors are covalent inhibitors that form bonds with cysteines or other nucleophilic residues in the target protein. However, many are categorized as pan-assay interference compounds (PAINS) and considered unsuitable as drugs due to their tendency to react non-specifically. Targeting RPN13/ADRM1-mediated substrate recognition and deubiquitination by the proteasome 19S Regulatory Particle (RP) is a promising treatment strategy. Early candidate RPN13 inhibitors (iRPN13) produced a toxic accumulation of very high molecular weight polyubiquitinated substrates, resulting in therapeutic activity in mice bearing liquid or solid tumor models, including ovarian cancer; however, they were not drug-like (PAINS) because of their central piperidone core. Up284 instead has a central spiro-carbon ring. We hypothesized that adding a guanidine moiety to the central ring nitrogen of Up284 would produce a compound, RA475, with improved drug-like properties and therapeutic activity in murine models of ovarian cancer. RA475 produced a rapid accumulation of high molecular polyubiquitinated proteins in cancer cell lines associated with apoptosis, similar to Up284 although it was 3-fold less cytotoxic. RA475 competed binding of biotinylated Up284 to RPN13. RA475 shows improved solubility and distinct pharmacodynamic properties compared to Up284. Specifically, tetraubiquitin firefly luciferase expressed in leg muscle was stabilized in mice more effectively upon IP treatment with RA475 than with Up284. However, pharmacologic analysis showed that RA475 was more rapidly cleared from the circulation, and less orally available than Up284. RA475 shows reduced ability to cross the blood-brain barrier and in vitro inhibition of HERG. Treatment of mice with RA475 profoundly inhibited the intraperitoneal growth of the ID8-luciferase ovarian tumor model. Likewise, RA475 treatment of immunocompetent mice inhibited the growth of spontaneous genetically-engineered peritoneal tumor, as did weekly cisplatin dosing. The combination of RA475 and cisplatin significantly extended survival compared to individual treatments, consistent with synergistic cytotoxicity in vitro. In sum, RA475 is a promising candidate covalent RPN13i with potential utility for treatment of patients with advanced EOC in combination with cisplatin.

Safety of Early Discharge After Coronary Artery Bypass Grafting: A Nationwide Readmissions Analysis.

BACKGROUND: We determined the safety of early discharge after coronary artery bypass grafting (CABG) in patients with uncomplicated postoperative courses and compared outcomes to routine discharge in a national cohort. We identified preoperative factors associated with readmission following early discharge after CABG. METHODS: The Nationwide Readmissions Database was queried to identify patients undergoing CABG from 01/2016-12/2018. Patients were stratified based on length of stay (LOS) as early (≤4 days) versus routine (5-10 days) discharge. Patients were excluded with hospital courses indicative of complicated stays (emergent procedures, LOS>10 days, discharge to extended care facility or with home health, index-hospitalization mortality). Propensity-score matching was performed to compare outcomes between cohorts. Multivariable logistic regression models were used to identify factors associated with readmission following early discharge. RESULTS: A total of 91,861 patients underwent CABG with an uncomplicated postoperative course during the study period (≈20% of CABG population). Of these 31% (28,790/91,861) were discharged early and 69% (63,071/91,861) routine. After propensity-score matching, patients discharged early had lower readmission rates at 30-days, 90-days, and up to one year (P<.001, all). Index-hospitalization cost was lower with early discharge ($26,676 versus $32,859; P<.001). Early discharge was associated with a lower incidence of nosocomial infection at index-hospitalization (0.17% versus 0.81%, P<.001) and readmission from infection (14.5% versus 18%, P=.016). CONCLUSIONS: Early discharge after uncomplicated CABG can be considered in a highly selective patient population. Early discharge patients are readmitted less frequently than matched routine discharge patients, with a lower incidence of readmission from infection. Appropriate post-discharge processes to facilitate early discharge after CABG should be further pursued.

Genitofemoral Nerve Variation: An Attempt to Explain the Embryological Basis via a Case Report.

The genitofemoral nerve (GFN) presents with a variable course in nearly half of the population. This variation can be seen in its availability, course, and branching. Here, a notable case during a cadaveric dissection revealed an unusually high bifurcation of the GFN on the left side, contrasting with the typical bifurcation observed on the right. This divergence was highlighted using colored markers to aid educational visualization, facilitating a comprehensive learning experience about the nerve's variability and its functional implications, such as the cremasteric reflex. Embryologically, these variations stem from the migratory paths of myotomes during development, influenced by extrinsic signals and growth factors. Despite the high incidence of anatomical variability, the muscular structure remains consistent, suggesting that the nerve's formation is more susceptible to developmental shifts than the muscles it innervates. Clinically, understanding GFN variations is crucial due to the nerve's involvement in conditions like genitofemoral neuropathy, which can arise from surgical procedures. Accurate knowledge of these variations aids in precise diagnostic and therapeutic interventions, reducing complications, and enhancing patient outcomes in lower abdominal and groin surgeries. However, further research is needed to elucidate the exact embryological and genetic underpinnings of these variations.

Large-Scale Direct Growth of Monolayer MoS2 on Patterned Graphene for van der Waals Ultrafast Photoactive Circuits.

Two-dimensional (2D) van der Waals heterostructures combine the distinct properties of individual 2D materials, resulting in metamaterials, ideal for emergent electronic, optoelectronic, and spintronic phenomena. A significant challenge in harnessing these properties for future hybrid circuits is their large-scale realization and integration into graphene interconnects. In this work, we demonstrate the direct growth of molybdenum disulfide (MoS2) crystals on patterned graphene channels. By enhancing control over vapor transport through a confined space chemical vapor deposition growth technique, we achieve the preferential deposition of monolayer MoS2 crystals on monolayer graphene. Atomic resolution scanning transmission electron microscopy reveals the high structural integrity of the heterostructures. Through in-depth spectroscopic characterization, we unveil charge transfer in Graphene/MoS2, with MoS2 introducing p-type doping to graphene, as confirmed by our electrical measurements. Photoconductivity characterization shows that photoactive regions can be locally created in graphene channels covered by MoS2 layers. Time-resolved ultrafast transient absorption (TA) spectroscopy reveals accelerated charge decay kinetics in Graphene/MoS2 heterostructures compared to standalone MoS2 and upconversion for below band gap excitation conditions. Our proof-of-concept results pave the way for the direct growth of van der Waals heterostructure circuits with significant implications for ultrafast photoactive nanoelectronics and optospintronic applications.

An ISHLT consensus statement on strategies to prevent and manage hemocompatibility related adverse events in patients with a durable, continuous-flow ventricular assist device.

Life expectancy of patients with a durable, continuous-flow left ventricular assist device (CF-LVAD) continues to increase. Despite significant improvements in the delivery of care for patients with these devices, hemocompatability-related adverse events (HRAEs) are still a concern and contribute to significant morbility and mortality when they occur. As such, dissemination of current best evidence and practices is of critical importance. This ISHLT Consensus Statement is a summative assessment of the current literature on prevention and management of HRAEs through optimal management of oral anticoagulant and antiplatelet medications, parenteral anticoagulant medications, management of patients at high risk for HRAEs and those experiencing thrombotic or bleeding events, and device management outside of antithrombotic medications. This document is intended to assist clinicians caring for patients with a CF-LVAD provide the best care possible with respect to prevention and management of these events.

Biotechnological Breakthroughs in Resveratrol Synthesis and Health Advancements.

This academic review examines the latest biotechnology methods for resveratrol synthesis. We aim to study the health advantages of resveratrol consumption beyond synthesis and demonstrate its potential as a therapeutic agent. An extensive examination of the current state of literature was performed, employing a diverse range of scholarly databases with the purpose of collating pertinent information and conducting in-depth research on the subject matter. The main goal was to find and assess research on resveratrol's health effects and the latest biotechnology methods for synthesizing it. This review paper discusses resveratrol synthesis methods, including their efficacy and current advances. The findings highlight the significant potential of biotechnological methods in improving both the synthesis of resveratrol and its beneficial effects on health. Our comprehensive analysis substantiates the importance of biotechnological methodologies in synthesizing resveratrol. The literature review highlights resveratrol's therapeutic properties, which have been scientifically approved for the prevention and treatment of various ailments, such as cardiovascular disease, metabolic illnesses, cancer, aging, and immunomodulation.

Anatomical correlates for the newly discovered meningeal layer in the existing literature: A systematic review.

The existence of a previously unrecognized subarachnoid lymphatic-like membrane (SLYM) was reported in a recent study. SLYM is described as an intermediate leptomeningeal layer between the arachnoid and pia mater in mouse and human brains, which divides the subarachnoid space (SAS) into two functional compartments. Being a macroscopic structure, having missed detection in previous studies is surprising. We systematically reviewed the published reports in animals and humans to explore whether prior descriptions of this meningeal layer were reported in some way. A comprehensive search was conducted in PubMed/Medline, EMBASE, Google Scholar, Science Direct, and Web of Science databases using combinations of MeSH terms and keywords with Boolean operators from inception until 31 December 2023. We found at least eight studies that provided structural evidence of an intermediate leptomeningeal layer in the brain or spinal cord. However, unequivocal descriptions for this layer all along the central nervous system were scarce. Obscure names like the epipial, intermediate meningeal, outer pial layers, or intermediate lamella were used to describe it. Its microscopic/ultrastructural details closely resemble the recently reported SLYM. We further examined the counterarguments in current literature that are skeptical of the existence of this layer. The potential physiological and clinical implications of this new meningeal layer are significant, underscoring the urgent need for further exploration of its structural and functional details.

Social Determinants of Health and Other Predictors in Initiation of Treatment with CDK4/6 Inhibitors for HR+/HER2- Metastatic Breast Cancer.

In hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (MBC), cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) have replaced endocrine therapy alone as the standard of care; however, several barriers to treatment initiation still exist. We assessed social determinants of health (SDOH) and other factors associated with the initiation of CDK4/6i for HR+/HER2- MBC in the Medicare population. Using a retrospective cohort design, patients aged ≥65 years and diagnosed during 2015-2017 were selected from the SEER-Medicare database. Time from MBC diagnosis to first CDK4/6i initiation was the study outcome. The effect of SDOH measures and other predictors on the outcome was assessed using the multivariable Fine and Gray hazard modeling. Of 752 eligible women, 352 (46.8%) initiated CDK4/6i after MBC diagnosis (median time to initiation: 27.9 months). In adjusted analysis, SDOH factors significantly associated with CDK4/6i initiation included high versus low median household income (HHI) (hazard ratio [HR] = 1.70; 95% CI = 1.03-2.81) and the percentage of population with high versus low Medicare-only coverage (HR = 1.54; 95% CI = 1.04-2.27). In summary, older Medicare patients with HR+/HER2- MBC residing in areas with high median HHI and a high proportion of Medicare-only coverage had higher rates of initiating CDK4/6i, suggesting inequitable access to these novel, effective treatments and a need for policy intervention.

To Revise or Not Revise? Isolated Margin Positivity in Localized Pancreatic Ductal Adenocarcinoma.

BACKGROUND: The study determined the proportion of patients with pancreatic adenocarcinoma (PDAC) who had margin-positive disease and no other adverse pathologic findings (APF) using institutional and administrative datasets. METHODS: Patients with clinical stage I or II PDAC in the National Cancer Database (NCDB 2010-2020) and those who underwent pancreatectomy at the authors' institution (2010-2021) were identified. Isolated margin positivity (IMP) was defined as a positive surgical margin with no APF (negative nodes, no lymphovascular/perineural invasion). RESULTS: The study included 225 patients from the authors' institution and 23,598 patients from the NCDB. The margin-positive rates were 21.8% and 20.3%, and the IMP rates were 0.4% and 0.5%, respectively. In the institutional cohort, 68.4% of the patients had recurrence, and most of the patients (65.6%) had distant recurrences. The median recurrence-free survival (RFS) was 63.3 months for no APF, not reached for IMP, 14.8 months for negative margins & 1 APF, 20.3 months for positive margins & 2 APFs, and 12.9 months with all APF positive. The patients in the NCDB with IMP had a lower median OS than the patients with no APF (20.5 vs 390 months), but a higher median OS than those with margin positivity plus 1 APF (20.5 vs 18.0 months) or all those with APF positivity (20.5 vs 15.4 months). Based on institutional rates of IMP, any margin positivity, neck margin positivity (NMP), and no APF, the fraction of patients who might benefit from neck margin revision was 1 in 100,000, and those likely to benefit from any margin revision was 1 in 18,500. In the NCDB, those estimated to derive potential benefit from margin revision was 1 in 25,000. CONCLUSIONS: Isolated margin positivity in resected PDAC is rare, and most patients experience distant recurrence. Revision of IMP appears unlikely to confer benefit to most patients.

Accelerating Genome- and Phenome-Wide Association Studies using GPUs - A case study using data from the Million Veteran Program.

The expansion of biobanks has significantly propelled genomic discoveries yet the sheer scale of data within these repositories poses formidable computational hurdles, particularly in handling extensive matrix operations required by prevailing statistical frameworks. In this work, we introduce computational optimizations to the SAIGE (Scalable and Accurate Implementation of Generalized Mixed Model) algorithm, notably employing a GPU-based distributed computing approach to tackle these challenges. We applied these optimizations to conduct a large-scale genome-wide association study (GWAS) across 2,068 phenotypes derived from electronic health records of 635,969 diverse participants from the Veterans Affairs (VA) Million Veteran Program (MVP). Our strategies enabled scaling up the analysis to over 6,000 nodes on the Department of Energy (DOE) Oak Ridge Leadership Computing Facility (OLCF) Summit High-Performance Computer (HPC), resulting in a 20-fold acceleration compared to the baseline model. We also provide a Docker container with our optimizations that was successfully used on multiple cloud infrastructures on UK Biobank and All of Us datasets where we showed significant time and cost benefits over the baseline SAIGE model.

Optimized Properties and Synthesis of Photoactivatable Diazoketorhodamines Facilitate and Enhance High-Throughput Single-Molecule Tracking.

Photoactivatable (PA) rhodamine dyes are widely used in single-molecule tracking (SMT) and a variety of other fluorescence-based imaging modalities. One of the most commonly employed scaffolds uses a diazoketone to lock the rhodamine in the nonfluorescent closed form, which can be activated with 405 nm light. However, poor properties of previously reported dyes require significant washing, which can be resource- and cost-intensive, especially when performing microscopy in a large scale and high-throughput fashion. Here, we report improved diazoketorhodamines that perform exceptionally well in single-molecule tracking microscopy. We also report on the optimization of an improved synthetic method for further iteration and tailoring of diazoketorhodamines to the requirements of a specific user.

AI and machine learning in medical imaging: key points from development to translation.

Innovation in medical imaging artificial intelligence (AI)/machine learning (ML) demands extensive data collection, algorithmic advancements, and rigorous performance assessments encompassing aspects such as generalizability, uncertainty, bias, fairness, trustworthiness, and interpretability. Achieving widespread integration of AI/ML algorithms into diverse clinical tasks will demand a steadfast commitment to overcoming issues in model design, development, and performance assessment. The complexities of AI/ML clinical translation present substantial challenges, requiring engagement with relevant stakeholders, assessment of cost-effectiveness for user and patient benefit, timely dissemination of information relevant to robust functioning throughout the AI/ML lifecycle, consideration of regulatory compliance, and feedback loops for real-world performance evidence. This commentary addresses several hurdles for the development and adoption of AI/ML technologies in medical imaging. Comprehensive attention to these underlying and often subtle factors is critical not only for tackling the challenges but also for exploring novel opportunities for the advancement of AI in radiology.

TGFß in pancreas and colorectal cancer: opportunities to overcome therapeutic resistance.

TGFß is a pleiotropic signaling pathway, which plays a pivotal role in regulating a multitude of cellular functions. TGFß has a dual role in cell regulation where it induces growth inhibition and cell death; however, it can switch to a growth-promoting state under cancerous conditions. TGFß is upregulated in CRC and pancreatic cancer, altering the tumor microenvironment, immune system, and promoting a mesenchymal state. The upregulation of TGFß in certain cancers leads to resistance to immunotherapy, and attempts to inhibit TGFß expression have led to reduced therapeutic resistance when combined with chemo- and immunotherapy. Here, we review the current TGFß inhibitor drugs in clinical trials for pancreatic and colorectal cancer, with the goal of uncovering advances in improving clinical efficacy for TGFß combinational treatments in patients. Furthermore, we discuss the relevance of alterations in TGFß signaling and germline variants in the context of personalizing treatment for patients who show lack of response to current therapeutics.

Offshore produced water treatment by a biofilm reactor on the seabed: The effect of temperature and matrix characteristics.

In many industrial processes a large amount of water with high salinity is co-produced whose treatment poses considerable challenges to the available technologies. The produced water (PW) from offshore operations is currently being discharged to sea without treatment for dissolved pollutants due to space limitations. A biofilter on the seabed adjacent to a production platform would negate all size restrictions, thus reducing the environmental impact of oil and gas production offshore. The moving bed biofilm reactor (MBBR) was investigated for PW treatment from different oilfields in the North Sea at 10 °C and 40 °C, corresponding to the sea and PW temperature, respectively. The six PW samples in study were characterized by high salinity and chemical oxygen demand with ecotoxic effects on marine algae S. pseudocostatum (0.4%

Distinct microbial communities enriched in water-saturated and unsaturated reactors influence performance of integrated hydroponics-microbial electrochemical technology.

This study aimed to understand the wastewater treatment and electricity generation performance besides the microbial communities of the integrated Hydroponics-Microbial Electrochemical Technology (iHydroMET) systems operated with water-saturated and water-unsaturated reactors. The organics removal was slightly higher in the water-unsaturated system (93 ± 4 %) than in the water-saturated system (87 ± 2 %). The total nitrogen removal and electric voltage were considerably higher in the water-saturated system (42 ± 5 %; 111 ± 8 V per reactor) than in the water-unsaturated system (18 ± 3 %; 95 ± 9 V per reactor). The enhanced organics and nitrogen removal and high voltage output in respective conditions were due to the dominance of polysaccharide-degrading aerobes (e.g., Pirellula), anammox bacteria (e.g., Anammoximicrobium), denitrifiers (e.g., Thauera and Rheinheimera), and electroactive microorganisms (e.g., Geobacter). The differential performance governed by distinct microbial communities under the tested conditions indicates that an appropriate balancing of water saturation and unsaturation in reactors is crucial to achieving optimum iHydroMET performance.

Biotechnological Advances in Enzymatic Hydrolysis and Fermentation for Edible Insects: Functionality, Acceptability, and Safety.

OBJECTIVE: This review paper examines biotechnological methods for enhancing edible insects using enzymatic hydrolysis and fermentation. Evaluations involve improving functionality, analyzing consumer acceptability elements, guaranteeing safety and quality, negotiating regulatory frameworks, and suggesting field breakthroughs and applications. METHODS: Our method comprises a thorough literature analysis and academic database searches for edible insect enzymatic hydrolysis and fermentation investigations. Based on gaps in the literature, we investigate edible insect safety, consumer acceptability, and legal and regulatory issues. RESULTS: The results show biotechnological advances in enzymatic hydrolysis and fermentation for edible insect functioning. Sensory and cultural aspects affect consumer acceptability. To ensure edible insect product safety, hazards and pollutants are addressed. The legal analysis highlights compliance issues and possibilities. CONCLUSION: This review shows how enzymatic hydrolysis and fermentation improve edible insect functioning, safety, and nutrition. The review includes consumer acceptability dynamics, legal issues, and safety analysis.

Transcriptome-wide association analysis identifies candidate susceptibility genes for prostate-specific antigen levels in men without prostate cancer.

Deciphering the genetic basis of prostate-specific antigen (PSA) levels may improve their utility for prostate cancer (PCa) screening. Using genome-wide association study (GWAS) summary statistics from 95,768 PCa-free men, we conducted a transcriptome-wide association study (TWAS) to examine impacts of genetically predicted gene expression on PSA. Analyses identified 41 statistically significant (p < 0.05/12,192 = 4.10 × 10-6) associations in whole blood and 39 statistically significant (p < 0.05/13,844 = 3.61 × 10-6) associations in prostate tissue, with 18 genes associated in both tissues. Cross-tissue analyses identified 155 statistically significantly (p < 0.05/22,249 = 2.25 × 10-6) genes. Out of 173 unique PSA-associated genes across analyses, we replicated 151 (87.3%) in a TWAS of 209,318 PCa-free individuals from the Million Veteran Program. Based on conditional analyses, we found 20 genes (11 single tissue, nine cross-tissue) that were associated with PSA levels in the discovery TWAS that were not attributable to a lead variant from a GWAS. Ten of these 20 genes replicated, and two of the replicated genes had colocalization probability of >0.5: CCNA2 and HIST1H2BN. Six of the 20 identified genes are not known to impact PCa risk. Fine-mapping based on whole blood and prostate tissue revealed five protein-coding genes with evidence of causal relationships with PSA levels. Of these five genes, four exhibited evidence of colocalization and one was conditionally independent of previous GWAS findings. These results yield hypotheses that should be further explored to improve understanding of genetic factors underlying PSA levels.

Drug resistance through ribosome splitting and rRNA disordering in mycobacteria.

HflX is known to rescue stalled ribosomes and is implicated in antibiotic resistance in several bacteria. Here we present several high-resolution cryo-EM structures of mycobacterial HflX in complex with the ribosome and its 50S subunit, with and without antibiotics. These structures reveal a distinct mechanism for HflX-mediated ribosome splitting and antibiotic resistance in mycobacteria. In addition to dissociating ribosome into two subunits, mycobacterial HflX mediates persistent disordering of multiple 23S rRNA helices to generate an inactive pool of 50S subunits. Mycobacterial HflX also acts as an anti-association factor by binding to pre-dissociated 50S subunits. A mycobacteria-specific insertion in HflX reaches further into the peptidyl transferase center. The position of this insertion overlaps with ribosome-bound macrolides or lincosamide class of antibiotics. The extended conformation of insertion seen in the absence of these antibiotics retracts and adjusts around the bound antibiotics instead of physically displacing them. It therefore likely imparts antibiotic resistance by sequestration of the antibiotic-bound inactive 50S subunits.

Distinct pulmonary and systemic effects of dexamethasone in severe COVID-19.

Dexamethasone is the standard of care for critically ill patients with COVID-19, but the mechanisms by which it decreases mortality and its immunological effects in this setting are not understood. Here we perform bulk and single-cell RNA sequencing of samples from the lower respiratory tract and blood, and assess plasma cytokine profiling to study the effects of dexamethasone on both systemic and pulmonary immune cell compartments. In blood samples, dexamethasone is associated with decreased expression of genes associated with T cell activation, including TNFSFR4 and IL21R. We also identify decreased expression of several immune pathways, including major histocompatibility complex-II signaling, selectin P ligand signaling, and T cell recruitment by intercellular adhesion molecule and integrin activation, suggesting these are potential mechanisms of the therapeutic benefit of steroids in COVID-19. We identify additional compartment- and cell- specific differences in the effect of dexamethasone that are reproducible in publicly available datasets, including steroid-resistant interferon pathway expression in the respiratory tract, which may be additional therapeutic targets. In summary, we demonstrate compartment-specific effects of dexamethasone in critically ill COVID-19 patients, providing mechanistic insights with potential therapeutic relevance. Our results highlight the importance of studying compartmentalized inflammation in critically ill patients.