Drug Repurposing Using FDA Adverse Event Reporting System (FAERS) Database.

Drug repurposing is an emerging approach to reassigning existing pre-approved therapies for new indications. The FDA Adverse Event Reporting System (FAERS) is a large database of over 28 million adverse event reports submitted by medical providers, patients, and drug manufacturers and provides extensive drug safety signal data. In this review, four common drug repurposing strategies using FAERS are described, including inverse signal detection for a single disease, drug-drug interactions that mitigate a target ADE, identifying drug-ADE pairs with opposing gene perturbation signatures and identifying drug-drug pairs with congruent gene perturbation signatures. The purpose of this review is to provide an overview of these different approaches to FAERS-based drug repurposing using existing successful applications in the literature. With the fast expansion of adverse drug event reports, FAERS-based drug repurposing represents a versatile and promising strategy for discovering new uses for existing therapies.

A lower bound for set-coloring Ramsey numbers.

The set-coloring Ramsey number Rr,s(k) is defined to be the minimum n such that if each edge of the complete graph Kn is assigned a set of s colors from {1,…,r}, then one of the colors contains a monochromatic clique of size k. The case s=1 is the usual r-color Ramsey number, and the case s=r-1 was studied by Erdos, Hajnal and Rado in 1965, and by Erdos and Szemerédi in 1972. The first significant results for general s were obtained only recently, by Conlon, Fox, He, Mubayi, Suk and Verstraëte, who showed that Rr,s(k)=2Θ(kr) if s/r is bounded away from 0 and 1. In the range s=r-o(r), however, their upper and lower bounds diverge significantly. In this note we introduce a new (random) coloring, and use it to determine Rr,s(k) up to polylogarithmic factors in the exponent for essentially all r, s, and k.

APOE2 gene therapy reduces amyloid deposition and improves markers of neuroinflammation and neurodegeneration in a mouse model of Alzheimer disease.

Epidemiological studies show that individuals who carry the relatively uncommon APOE ε2 allele rarely develop Alzheimer disease, and if they do, they have a later age of onset, milder clinical course, and less severe neuropathological findings than people without this allele. The contrast is especially stark when compared with the major genetic risk factor for Alzheimer disease, APOE ε4, which has an age of onset several decades earlier, a more aggressive clinical course and more severe neuropathological findings, especially in terms of the amount of amyloid deposition. Here, we demonstrate that brain exposure to APOE ε2 via a gene therapy approach, which bathes the entire cortical mantle in the gene product after transduction of the ependyma, reduces Aß plaque deposition, neurodegenerative synaptic loss, and, remarkably, reduces microglial activation in an APP/PS1 mouse model despite continued expression of human APOE ε4. This result suggests a promising protective effect of exogenous APOE ε2 and reveals a cell nonautonomous effect of the protein on microglial activation, which we show is similar to plaque-associated microglia in the brain of Alzheimer disease patients who inherit APOE ε2. These data increase the potential that an APOE ε2 therapeutic could be effective in Alzheimer disease, even in individuals born with the risky ε4 allele.

Comparing the risk of deep vein thrombosis of two combined oral contraceptives: Norethindrone/ethinyl estradiol and drospirenone/ethinyl estradiol.

Background: Deep vein thrombosis (DVT) has been reported as an adverse event for patients receiving combined oral contraceptives. Norethindrone/ethinyl estradiol (NET/EE) and drospirenone/ethinyl estradiol (DRSP/EE) are two commonly prescribed combined hormonal oral contraceptive agents used in the United States, differing in their progestin component. Objective: The purpose of this study was to determine the association between the progestin component of a combined oral contraceptive and the risk of DVT in patients taking oral contraceptives for birth control using data derived from the FDA Adverse Event Reporting System (FAERS). Methods: The risk of DVT was compared between patients that had taken NET/EE with those that had taken the DRSP/EE COC formulation for birth control. In addition, age was assessed as a possible confounder and the outcome severity for those diagnosed with DVT were compared between the two groups. Finally, association rule mining was utilized to identify possible drug-drug interactions that result in elevated DVT risk. Results: DVT was the fourth most commonly adverse event reported for patients taking DRSP/EE accounting for 8558 cases and the seventeenth most commonly reported adverse event for NET/EE accounting for 298 cases. Age was found to be a significant confounder for users of DRSP/EE with regards to DVT risk across all age groups assessed: 2040 (ROR = 3.69, 95% CI 3.37-4.04) However, there was only a statistically significant elevated risk in patients over 40 years of age taking NET/EE (ROR = 1.98, 95% CI 1.36-2.88). Patients that had taken DRSP/EE and the corticosteroid prednisone simultaneously had an approximately 3-fold increase in DVT risk (ROR = 2.77, 95% CI 2.43-3.15) relative to individuals that had only taken DRSP/EE. Conclusion: Based on this analysis, there is a higher risk of developing DVT when taking DRSP/EE than when taking NET/EE as hormonal contraception. In addition, a possibly significant drug-drug interaction between different COC formulations and prednisone were identified. This interaction may result in elevated DVT risk due to a synergistic impairment of fibrinolysis and a decrease in plasmin production.

An Ex Vivo Model of Ovarian Cancer Peritoneal Metastasis Using Human Omentum.

Ovarian cancer is the deadliest gynecologic malignancy. The omentum plays a key role in providing a supportive microenvironment to metastatic ovarian cancer cells as well as immune modulatory signals that allow tumor tolerance. However, we have limited models that closely mimic the interaction between ovarian cancer cells and adipose-rich tissues. To further understand the cellular and molecular mechanisms by which the omentum provides a pro-tumoral microenvironment, we developed a unique 3D ex vivo model of cancer cell-omentum interaction. Using human omentum, we are able to grow ovarian cancer cells within this adipose-rich microenvironment and monitor the factors responsible for tumor growth and immune regulation. In addition to providing a platform for the study of this adipose-rich tumor microenvironment, the model provides an excellent platform for the development and evaluation of novel therapeutic approaches to target metastatic cancer cells in this niche. The proposed model is easy to generate, inexpensive, and applicable to translational investigations.

Reactivity umpolung (reversal) of ligands in transition metal complexes.

The success and power of homogeneous catalysis derives in large part from the wide choice of transition metal ions and their ligands. This tutorial review introduces examples where the reactivity of a ligand is completely reversed (umpolung) from Lewis basic/nucleophilic to acidic/electrophilic or vice versa on changing the metal and co-ligands. Understanding this phenomenon will assist in the rational design of catalysts and the understanding of metalloenzyme mechanisms. Labelling a metal and ligand with Seebach donor and acceptor labels helps to identify whether a reaction involving the intermolecular attack on the ligand is displaying native reactivity or reactivity umpolung. This has been done for complexes of nitriles, carbonyls, isonitriles, dinitrogen, Fischer carbenes, alkenes, alkynes, hydrides, methyls, methylidenes and alkylidenes, silylenes, oxides, imides/nitrenes, alkylidynes, methylidynes, and nitrides. The electronic influence of the metal and co-ligands is discussed in terms of the energy of (HOMO) d electrons. The energy can be related to the pKLACa (LAC is ligand acidity constant) of the theoretical hydride complexes [H-[M]-L]+ formed by the protonation of pair of valence d electrons on the metal in the [M-L] complex. Preliminary findings indicate that a negative pKLACa indicates that nucleophilic attack by a carbanion or amine on the ligand will likely occur while a positive pKLACa indicates that electrophilic attack by strong acids on the ligand will usually occur when the ligand is nitrile, carbonyl, isonitrile, alkene and η6-arene.

Tumour-infiltrated cortex participates in large-scale cognitive circuits.

The extent to which tumour-infiltrated brain tissue contributes to cognitive function remains unclear. We tested the hypothesis that cortical tissue infiltrated by diffuse gliomas participates in large-scale cognitive circuits using a unique combination of intracranial electrocorticography (ECoG) and resting-state functional magnetic resonance (fMRI) imaging in four patients. We also assessed the relationship between functional connectivity with tumour-infiltrated tissue and long-term cognitive outcomes in a larger, overlapping cohort of 17 patients. We observed significant task-related high gamma (70-250 Hz) power modulations in tumour-infiltrated cortex in response to increased cognitive effort (i.e., switch counting compared to simple counting), implying preserved functionality of neoplastic tissue for complex tasks probing executive function. We found that tumour locations corresponding to task-responsive electrodes exhibited functional connectivity patterns that significantly co-localised with canonical brain networks implicated in executive function. Specifically, we discovered that tumour-infiltrated cortex with larger task-related high gamma power modulations tended to be more functionally connected to the dorsal attention network (DAN). Finally, we demonstrated that tumour-DAN connectivity is evident across a larger cohort of patients with gliomas and that it relates to long-term postsurgical outcomes in goal-directed attention. Overall, this study contributes convergent fMRI-ECoG evidence that tumour-infiltrated cortex participates in large-scale neurocognitive circuits that support executive function in health. These findings underscore the potential clinical utility of mapping large-scale connectivity of tumour-infiltrated tissue in the care of patients with diffuse gliomas.

Glioblastoma extracellular vesicles modulate immune PD-L1 expression in accessory macrophages upon radiotherapy.

Glioblastoma (GBM) is the most aggressive brain tumor, presenting major challenges due to limited treatment options. Standard care includes radiation therapy (RT) to curb tumor growth and alleviate symptoms, but its impact on GBM is limited. In this study, we investigated the effect of RT on immune suppression and whether extracellular vesicles (EVs) originating from GBM and taken up by the tumor microenvironment (TME) contribute to the induced therapeutic resistance. We observed that (1) ionizing radiation increases immune-suppressive markers on GBM cells, (2) macrophages exacerbate immune suppression in the TME by increasing PD-L1 in response to EVs derived from GBM cells which is further modulated by RT, and (3) RT increases CD206-positive macrophages which have the most potential in inducing a pro-oncogenic environment due to their increased uptake of tumor-derived EVs. In conclusion, RT affects GBM resistance by immuno-modulating EVs taken up by myeloid cells in the TME.

How denialist amplification spread COVID misinformation and undermined the credibility of public health science.

Denialist scientists played an outsized role in shaping public opinion and determining public health policy during the recent COVID pandemic. From early on, amplification of researchers who denied the threat of COVID shaped public opinion and undermined public health policy. The forces that amplify denialists include (1) Motivated amplifiers seeking to protect their own interests by supporting denialist scientists, (2) Conventional media outlets giving disproportionate time to denialist opinions, (3) Promoters of controversy seeking to gain traction in an 'attention economy,' and (4) Social media creating information silos in which denialists can become the dominant voice. Denialist amplification poses an existential threat to science relevant to public policy. It is incumbent on the scientific community to create a forum to accurately capture the collective perspective of the scientific community related to public health policy that is open to dissenting voices but prevents artificial amplification of denialists.

The complete genome sequences of Thioglobus autotrophicus strains EF2 and EF3, isolated from an oxycline in Effingham Inlet, British Columbia.

Here we provide the complete genome sequences of two chemoautotrophic isolates from the Thioglobaceae family of marine gamma-proteobacteria. The genomes were obtained from pure cultures that were initially isolated from Effingham Inlet in 2013 and revived from freezer stocks for whole genome sequencing in 2023.

Horse to human: Streptococcus equi septicemia presenting as endogenous endophthalmitis.

Purpose: To present a rarely reported systemic infection with streptococcus equi subspecies zooepidemicus (streptococcus equi), transmitted from a horse, and to describe successful treatment when complicated by endogenous endophthalmitis. Observations: We diagnosed suspected streptococcus equi septicemia presenting as loss of vision in the right eye of an otherwise healthy polo player/horse trainer. He received immediate intravenous antibiotics and three vitrectomies with two intravitreal antibiotic injections during the first week, to cure infection and subsequent retinal detachment. Blood and initial vitreous cultures rapidly grew streptococcus equi. The septicemia was quickly controlled by systemic antibiotics without developing commonly seen and often fatal meningitis. The right eye recovered 20/30 visual acuity three months post infection. Conclusions: Presentation of this rare septicemia as endogenous endophthalmitis illustrates the potentially lifesaving role of early diagnosis by the ophthalmologist. Immediate and recurrent vitrectomy in conjunction with intravitreal and systemic antibiotic therapy resulted in recovery of near normal vision, whereas less timely and interventional treatments have failed heretofore.

Genetic retargeting of E3 ligases to enhance CAR T cell therapy.

Chimeric antigen receptor (CAR) T cell therapies are medical breakthroughs in cancer treatment. However, treatment failure is often caused by CAR T cell dysfunction. Additional approaches are needed to overcome inhibitory signals that limit anti-tumor potency. Here, we developed bifunctional fusion "degrader" proteins that bridge one or more target proteins and an E3 ligase complex to enforce target ubiquitination and degradation. Conditional degradation strategies were developed using inducible degrader transgene expression or small molecule-dependent E3 recruitment. We further engineered degraders to block SMAD-dependent TGFß signaling using a domain from the SARA protein to target both SMAD2 and SMAD3. SMAD degrader CAR T cells were less susceptible to suppression by TGFß and demonstrated enhanced anti-tumor potency in vivo. These results demonstrate a clinically suitable synthetic biology platform to reprogram E3 ligase target specificity for conditional, multi-specific endogenous protein degradation, with promising applications including enhancing the potency of CAR T cell therapy.

Current state of musculoskeletal fellowship program directors and future directions.

OBJECTIVE: To better understand the current state of musculoskeletal fellowship program directors and identify opportunities for formal training that could increase job satisfaction, provide a broader knowledge base for mentoring/advising trainees and increase diversity in musculoskeletal radiology. MATERIALS AND METHODS: Eighty-one fellowship program directors who signed the Fellowship Match Memorandum of Understanding with the Society of Skeletal Radiology were sent a survey with questions about demographics, career, background, and training both for musculoskeletal radiology and for the fellowship director role. RESULTS: A 57/81 (70%) of program directors responded, representing 27 different states with a range of 1-9 fellowship positions. Nearly half are in their forties (48%) with most identifying as White (67%) followed by Asian (30%). The majority are male (72%) with over half (60%) remaining at the institution where they completed prior training. Over half plan to change roles within 5 years and do not feel adequately compensated. Top qualities/skills identified as important for the role include effective communication, being approachable, and clinical excellence. Other than clinical excellence, most do not report formal training in skills identified as important for the role. CONCLUSIONS: Given the high amount of interaction with trainees, program directors play a key role in the future of our subspecialty. The low diversity among this group, the lack of formal training, and the fact that most do not feel adequately compensated could limit mentorship and recruitment. Program directors identified effective communication, organizational/planning skills, and conflict resolution as the top skills they would benefit from formal training.

Five Years of the Musculoskeletal Radiology Fellowship Match: Trends and Perspectives.

RATIONALE AND OBJECTIVES: The 2023 Match marks 5 years since the Musculoskeletal (MSK) Radiology Fellowship Match first took place in June 2019. The objective of this study is to analyze trends in the MSK Match over its 5-year course. MATERIALS AND METHODS: Data from the National Resident Matching Program were evaluated for the number of applicants, medical school type of matched applicants, number of programs, and number of positions. Programs were grouped according to geographic region, program size, and ACGME accreditation status. These data were plotted to look for trends over time and by program characteristics. RESULTS: There has been little variation in the number of eligible programs registering for the Match (range 80-83). The number of available positions has had a wider variation (range 204-218), and the number of applicants preferring MSK has varied from 156 to 178. The gap between positions and applicants has resulted in a percentage of positions filled that has ranged from 70.9% to 82.4%. Program size is positively correlated with Match rates, with 100% of programs with five or more positions filling ≥ 50% in 4 out of 5 years. CONCLUSION: The variable numbers of fellowship positions and applicants have resulted in variable success of the Match by all metrics. Maintaining or increasing the number of applicants is the most critical factor for ongoing Match success.

Monomeric myeloperoxidase is a specific biomarker for early-stage ovarian cancer.

Background: Ovarian cancer cells are known to express myeloperoxidase (MPO), an oxidant-producing enzyme with a 150 kDa homodimer, consisting of two identical monomers connected by a disulfide bond. Here, we aim to validate monomeric MPO (mMPO) as a biomarker for the early detection of ovarian cancer.Methods: Human ovarian cancer cells, sera from patients at various stages, sera from non-cancer inflammatory gynecological diseases, and healthy volunteers were used. Monomeric and dimeric MPO were measured by ELISA. Receiver operating curves were used to compare the predictive powers of serum dimeric and monomeric MPO to discriminate between samples.Results: The expression of MPO was unique to ovarian cancer cells. Specifically, mMPO was found to be the only form of MPO in all ovarian cancer cell lines. Intriguingly, mMPO was detected in the sera from all patients with ovarian cancer at various stages, but not from healthy individuals. Serum mMPO discriminated between early-stage ovarian cancer, healthy controls, and benign inflammatory gynecologic disorders. In addition, mMPO discriminated between the early and late stages of the disease.Conclusion: This work highlights mMPO as a potential biomarker for early detection of ovarian cancer, which is critically needed.

A Novel Role of Connective Tissue Growth Factor in the Regulation of the Epithelial Phenotype.

BACKGROUND: Epithelial-mesenchymal transition (EMT) is a biological process where epithelial cells lose their adhesive properties and gain invasive, metastatic, and mesenchymal properties. Maintaining the balance between the epithelial and mesenchymal stage is essential for tissue homeostasis. Many of the genes promoting mesenchymal transformation have been identified; however, our understanding of the genes responsible for maintaining the epithelial phenotype is limited. Our objective was to identify the genes responsible for maintaining the epithelial phenotype and inhibiting EMT. METHODS: RNA seq was performed using an vitro model of EMT. CTGF expression was determined via qPCR and Western blot analysis. The knockout of CTGF was completed using the CTGF sgRNA CRISPR/CAS9. The tumorigenic potential was determined using NCG mice. RESULTS: The knockout of CTGF in epithelial ovarian cancer cells leads to the acquisition of functional characteristics associated with the mesenchymal phenotype such as anoikis resistance, cytoskeleton remodeling, increased cell stiffness, and the acquisition of invasion and tumorigenic capacity. CONCLUSIONS: We identified CTGF is an important regulator of the epithelial phenotype, and its loss is associated with the early cellular modifications required for EMT. We describe a novel role for CTGF, regulating cytoskeleton and the extracellular matrix interactions necessary for the conservation of epithelial structure and function. These findings provide a new window into understanding the early stages of mesenchymal transformation.

A phase III, multicenter, randomized study of olvimulogene nanivacirepvec followed by platinum-doublet chemotherapy and bevacizumab compared with platinum-doublet chemotherapy and bevacizumab in women with platinum-resistant/refractory ovarian cancer.

BACKGROUND: Treatment options for patients with platinum-resistant/refractory ovarian cancers are limited and only marginally effective. The development of novel, more effective therapies addresses a critical unmet medical need. Olvimulogene nanivacirepvec (Olvi-Vec), with its strong immune modulating effect on the tumor microenvironment, may provide re-sensitization to platinum and clinically reverse platinum resistance or refractoriness in platinum-resistant/refractory ovarian cancer. PRIMARY OBJECTIVE: The primary objective is to evaluate the efficacy of intra-peritoneal Olvi-Vec followed by platinum-based chemotherapy and bevacizumab in patients with platinum-resistant/refractory ovarian cancer. STUDY HYPOTHESIS: This phase III study investigates Olvi-Vec oncolytic immunotherapy followed by platinum-based chemotherapy and bevacizumab as an immunochemotherapy evaluating the hypothesis that such sequential combination therapy will prolong progression-free survival (PFS) and bring other clinical benefits compared with treatment with platinum-based chemotherapy and bevacizumab. TRIAL DESIGN: This is a multicenter, prospective, randomized, and active-controlled phase III trial. Patients will be randomized 2:1 into the experimental arm treated with Olvi-Vec followed by platinum-doublet chemotherapy and bevacizumab or the control arm treated with platinum-doublet chemotherapy and bevacizumab. MAJOR INCLUSION/EXCLUSION CRITERIA: Eligible patients must have recurrent, platinum-resistant/refractory, non-resectable high-grade serous, endometrioid, or clear-cell ovarian, fallopian tube, or primary peritoneal cancer. Patients must have had ≥3 lines of prior chemotherapy. PRIMARY ENDPOINT: The primary endpoint is PFS in the intention-to-treat population. SAMPLE SIZE: Approximately 186 patients (approximately 124 patients randomized to the experimental arm and 62 to the control arm) will be enrolled to capture 127 PFS events. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Expected complete accrual in 2024 with presentation of primary endpoint results in 2025. TRIAL REGISTRATION: NCT05281471.

Clinical science and practice in the age of large language models and generative artificial intelligence.

In this article, Schueller and Morris discuss the recent advances made from large language models (LLMs) and generative artificial intelligence (AI). These advances include supporting humans to provide better interventions, understanding processes in clinical interventions, and providing ethical considerations for the use of generative AI in clinical research and practice. (PsycInfo Database Record (c) 2023 APA, all rights reserved).