Suppression of HIV-TAT and cocaine-induced neurotoxicity and inflammation by cell penetrable itaconate esters.

HIV-associated neurological disorder (HAND) is a serious complication of HIV infection marked by neurotoxicity induced by viral proteins like Tat. Substance abuse exacerbates neurocognitive impairment in people living with HIV. There is an urgent need for therapeutic strategies to combat HAND comorbid with Cocaine Use Disorder (CUD). Our analysis of HIV and cocaine-induced transcriptomes in primary cortical cultures revealed significant overexpression of the macrophage-specific gene aconitate decarboxylase 1 (Acod1). The ACOD1 protein converts the tricarboxylic acid intermediate cis-aconitate into itaconate during the activation of inflammation. Itaconate then facilitates cytokine production and activates anti-inflammatory transcription factors, shielding macrophages from infection-induced cell death. However, the immunometabolic function of itaconate was unexplored in HIV and cocaine-exposed microglia. We assessed the potential of 4-octyl-itaconate (4OI), a cell-penetrable ester form of itaconate known for its anti-inflammatory properties. When primary cortical cultures exposed to Tat and cocaine were treated with 4OI, microglial cell number increased and the morphological altercations induced by Tat and cocaine were reversed. Microglial cells also appeared more ramified, resembling the quiescent microglia. 4OI treatment inhibited secretion of the proinflammatory cytokines IL-1α, IL-1ß, IL-6, and MIP1-α induced by Tat and cocaine. Transcriptome profiling determined that Nrf2 target genes were significantly activated in Tat and 4OI treated cultures relative to Tat alone. Further, genes associated with cytoskeleton dynamics in inflammatory microglia were downregulated by 4OI treatment. Together, the results strongly suggest 4-octyl-itaconate holds promise as a potential candidate for therapeutic development to treat HAND coupled with CUD comorbidities.

The use of antibiotic-loaded bone cement and systemic antibiotic prophylactic use in 2,971,357 primary total knee arthroplasties from 2010 to 2020: an international register-based observational study among countries in Africa, Europe, North America, and Oceania.

BACKGROUND AND PURPOSE: Antibiotic-loaded bone cement (ALBC) and systemic antibiotic prophylaxis (SAP) have been used to reduce periprosthetic joint infection (PJI) rates. We investigated the use of ALBC and SAP in primary total knee arthroplasty (TKA). PATIENTS AND METHODS: This observational study is based on 2,971,357 primary TKAs reported in 2010-2020 to national/regional joint arthroplasty registries in Australia, Denmark, Finland, Germany, Italy, the Netherlands, New Zealand, Norway, Romania, South Africa, Sweden, Switzerland, the UK, and the USA. Aggregate-level data on trends and types of bone cement, antibiotic agents, and doses and duration of SAP used was extracted from participating registries. RESULTS: ALBC was used in 77% of the TKAs with variation ranging from 100% in Norway to 31% in the USA. Palacos R+G was the most common (62%) ALBC type used. The primary antibiotic used in ALBC was gentamicin (94%). Use of ALBC in combination with SAP was common practice (77%). Cefazolin was the most common (32%) SAP agent. The doses and duration of SAP used varied from one single preoperative dosage as standard practice in Bolzano, Italy (98%) to 1-day 4 doses in Norway (83% of the 40,709 TKAs reported to the Norwegian arthroplasty register). CONCLUSION: The proportion of ALBC usage in primary TKA varies internationally, with gentamicin being the most common antibiotic. ALBC in combination with SAP was common practice, with cefazolin the most common SAP agent. The type of ALBC and type, dose, and duration of SAP varied among participating countries.

Benchmarking total hip replacement constructs using noninferiority analysis: the New Zealand joint registry study.

BACKGROUND: The aim of this study was to compare the relative performance of total hip replacement constructs and discern if there is substantial variability in performance in currently commonly used prostheses in the New Zealand Joint Registry (NZJR) using a noninferiority analysis. METHODS: All patients who underwent a primary total hip replacement (THR) registered in the NZJR between 1st January 1999 to June 2020 were identified. Using a noninferiority analysis, the performance of hip prostheses were compared with the best performing contemporary construct. Construct failure was estimated using the 1-Kaplan Meier survival function method to estimate net failure. The difference in failure between the contemporary benchmark and other constructs was examined. RESULTS: In total 135,432 THR were recorded comprising 1035 different THR constructs. Notably 328 constructs were used just once. Forty-eight constructs (62,251 THR) had > 500 procedures at risk at 3 years post-primary of which 28 were inferior by at least 20% relative risk of which, 10 were inferior by at least 100% relative risk. Sixteen constructs were identified with > 500 procedures at risk at 10 years with 9 inferior by at least 20%, of which one was inferior by > 100% relative risk. There were fewer constructs noninferior to the best practice benchmark when we performed analysis by gender. In females at 10 years, from 5 constructs with > 500 constructs at risk, 2 were inferior at the 20% margin. In males at 10 years, there were only 2 eligible constructs of which one was inferior at the 20% margin. CONCLUSIONS: We discerned that there is substantial variability in construct performance and at most time points, just over half of constructs are inferior to the best performing construct by at least 20%. These results can facilitate informed decision-making when considering THR surgery.

Improving oncology biosimilar launches in the EU, the USA, and Japan: an updated Policy Review from the Southern Network on Adverse Reactions.

The EU, the USA, and Japan account for the majority of biological pharmacotherapy use worldwide. Biosimilar regulatory approval pathways were authorised in the EU (2006), in Japan (2009), and in the USA (2015), to facilitate approval of biological drugs that are highly similar to reference products and to encourage market competition. Between 2007 and 2020, 33 biosimilars for oncology were approved by the European Medicines Agency (EMA), 16 by the US Food and Drug Administration (FDA), and ten by the Japan Pharmaceuticals and Medical Devices Agency (PMDA). Some of these approved applications were initially rejected because of manufacturing concerns (four of 36 [11%] with the EMA, seven of 16 [44%] with the FDA, none of ten for the PMDA). Median times from initial regulatory submission before approval of oncology biosimilars were 1·5 years (EMA), 1·3 years (FDA), and 0·9 years (PMDA). Pharmacists can substitute biosimilars for reference biologics in some EU countries, but not in the USA or Japan. US regulation prohibits substitution, unless the biosimilar has been approved as interchangeable, a designation not yet achieved for any biosimilar in the USA. Japan does not permit biosimilar substitution, as prescribers must include the product name on each prescription and that specific product must be given to the patient. Policy Reviews published in 2014 and 2016 in The Lancet Oncology focused on premarket and postmarket policies for oncology biosimilars before most of these drugs received regulatory approval. In this Policy Review from the Southern Network on Adverse Reactions, we identify factors preventing the effective launch of oncology biosimilars. Introduction to the market has been more challenging with therapeutic than for supportive care oncology biosimilars. Addressing region-specific competition barriers and educational needs would improve the regulatory approval process and market launches for these biologics, therefore expanding patient access to these products in the EU, the USA, and Japan.

Are Lipped Polyethylene Liners Associated with Increased Revision Rates in Patients with Uncemented Acetabular Components? An Observational Cohort Study.

BACKGROUND: Recurrent dislocation after THA remains a serious complication that carries with it a high risk of revision surgery. Previous studies have shown reduced dislocation rates with the use of lipped polyethylene (PE) liners in modular uncemented acetabular components, but there may be increased wear because of impingement, which may lead to aseptic loosening in the longer term; whether the aggregate benefit of lipped PE liners outweighs the risks associated with their use remains controversial. QUESTIONS/PURPOSES: We used data from the New Zealand Joint Registry to (1) compare Kaplan-Meier survival rates, (2) rates of revisions for dislocation between neutral and lipped PE liners, and (3) revision rates for aseptic loosening for the four most commonly used modular uncemented cups. METHODS: We used data from the New Zealand Joint Registry (NZJR) to identify 31,247 primary THAs using the four most commonly used uncemented modular acetabular implants from January 1, 1999 to December 31, 2018. The lipped liner group comprised 49% males (9924 of 20,240) compared with 42% (4669 of 11,007) in the neutral group (p < 0.001); 96% (19,382 of 20,240) of patients in the liner group had OA versus 95% (10,450 of 11,007) in the neutral group (p < 0.001). There was no difference in other patient characteristics such as age (mean 66.9 years), BMI (mean 29 ± 6 kg/m) and American Society of Anesthesiologists grade. The mean follow-up was 5.1 years (SD 3.9) and longest follow-up 19.3 years. The NZJR has more than 96% capture rate and data entry is a mandatory requirement of members of the New Zealand Orthopaedic Association. Kaplan-Meier survival rates were compared between 20,240 lipped and 11,007 neutral PE liners. Highly cross-linked polyethylene was used in 99% of lipped liner cups and 85% of neutral liner cups. Associated hazard ratios were calculated using a Cox regression analysis with a Kaplan-Meier revision-free estimates plot. RESULTS: The Kaplan-Meier survival at 10 years for lipped PE liners was 96% (95% confidence interval 95.4 to 96.2) and for neutral liners 95% (95% CI 94.7 to 95.9). After controlling for age, gender approach, femoral head size, and the use of image guidance, the all-cause revision risk was greater for neutral PE liners than that for lipped PE liners (HR 1.17 [95% CI 1.06 to 1.36]; p = 0.032). There was a higher risk of revision for dislocation in those with neutral PE liners than in those with lipped liners (HR 1.84 [95% CI 1.41 to 2.41]; p < 0.001) but no difference in the revision rate for aseptic acetabular component loosening (HR 0.85 [95% CI 0.52 to 1.38]; p = 0.511). CONCLUSIONS: The use of a lipped PE liner is not associated with a higher rate of aseptic loosening in patients who undergo primary THA compared with a neutral PE liner. Lipped PE liners are associated with lower rates of dislocation and lower all-cause revision rates without any increased association with revision rates for wear and aseptic loosening. LEVEL OF EVIDENCE: Level III, therapeutic study.

Despite Improved Survivorship of Uncemented Fixation in Total Knee Arthroplasty for Osteoarthritis, Cemented Fixation Remains the Gold Standard: An Analysis of a National Joint Registry.

BACKGROUND: Total knee arthroplasty (TKA) numbers are increasing worldwide. While cement fixation for both femoral and tibial components is commonly used, alternatives include hybrid and uncemented TKAs. This study aimed to evaluate survivorship, revision rates, and patient-reported outcomes for cemented, hybrid, and uncemented TKAs using New Zealand Joint Registry (NZJR) data. METHODS: NZJR data relating to all TKAs performed during the 19 years up to the end of December 2017 were analyzed. Outcomes were assessed using prosthesis survivorship data (including reasons for revision) and Oxford scores at 6 months, 5 years, and 10 years postoperatively. RESULTS: A total 96,519 primary TKAs were performed during the period examined. Most (91.5%) were fully cemented with 4.8% hybrid and 3.7% uncemented. Mean Oxford scores at 6 months were highest in cemented and lowest in uncemented TKAs (P < .001). However, this was not clinically significant. There was no difference at 5 or 10 years. Ten-year survival rates were 97%, 94.5%, and 95.8% for cemented, uncemented, and hybrid TKAs, respectively. Revision rates were 0.47, 0.74, and 0.52 per 100 component years for cemented, uncemented, and hybrid prostheses, respectively. The revision rate for uncemented prostheses compared with cemented was higher (P < .001). When stratified by age group, there were differences in survival rates between cemented and uncemented groups (P = .001) and hybrid and uncemented groups (P = .038) in patients aged <55 years; between cemented and uncemented groups in those aged 55-64 years (P = .031); and between cemented and hybrid groups in those aged >75 years (P = .004). CONCLUSION: Uncemented TKAs had similar patient-reported outcomes but higher revision rates and worse survivorship compared with hybrid or fully cemented TKAs.

The Femoro-Epiphyseal Acetabular Roof (FEAR) Index: A New Measurement Associated With Instability in Borderline Hip Dysplasia?

BACKGROUND: The definition of osseous instability in radiographic borderline dysplastic hips is difficult. A reliable radiographic tool that aids decision-making-specifically, a tool that might be associated with instability-therefore would be very helpful for this group of patients. QUESTIONS/PURPOSES: (1) To compare a new radiographic measurement, which we call the Femoro-Epiphyseal Acetabular Roof (FEAR) index, with the lateral center-edge angle (LCEA) and acetabular index (AI), with respect to intra- and interobserver reliability; (2) to correlate AI, neck-shaft angle, LCEA, iliocapsularis volume, femoral antetorsion, and FEAR index with the surgical treatment received in stable and unstable borderline dysplastic hips; and (3) to assess whether the FEAR index is associated clinical instability in borderline dysplastic hips. METHODS: We defined and validated the FEAR index in 10 standardized radiographs of asymptomatic controls using two blinded independent observers. Interrater and intrarater coefficients were calculated, supplemented by Bland-Altman plots. We compared its reliability with LCEA and AI. We performed a case-control study using standardized radiographs of 39 surgically treated symptomatic borderline radiographically dysplastic hips and 20 age-matched controls with asymptomatic hips (a 2:1 ratio), the latter were patients attending our institution for trauma unrelated to their hips but who had standardized pelvic radiographs between January 1, 2016 and March 1, 2016. Patient demographics were assessed using univariate Wilcoxon two-sample tests. There was no difference in mean age (overall: 31.5 ± 11.8 years [95% CI, 27.7-35.4 years]; stable borderline group: mean, 32.1± 13.3 years [95% CI, 25.5-38.7 years]; unstable borderline group: mean, 31.1 ± 10.7 years [95% CI, 26.2-35.9 years]; p = 0.96) among study groups. Treatment received was either a periacetabular osteotomy (if the hip was unstable) or, for patients with femoroacetabular impingement, either an open or arthroscopic femoroacetabular impingement procedure. The association of received treatment categories with the variables AI, neck-shaft angle, LCEA, iliocapsularis volume, femoral antetorsion, and FEAR index were evaluated first using Wilcoxon two-sample tests (two-sided) followed by stepwise multiple logistic regression analysis to identify the potential associated variables in a combined setting. Sensitivity, specificity, and receiver operator curves were calculated. The primary endpoint was the association between the FEAR index and instability, which we defined as migration of the femoral head either already visible on conventional radiographs or recentering of the head on AP abduction views, a break of Shenton's line, or the appearance of a crescent-shaped accumulation of gadolinium in the posteroinferior joint space at MR arthrography. RESULTS: The FEAR index showed excellent intra- and interobserver reliability, superior to the AI and LCEA. The FEAR index was lower in the stable borderline group (mean, -2.1 ± 8.4; 95% CI, -6.3 to 2.0) compared with the unstable borderline group (mean, 13.3 ± 15.2; 95% CI, 6.2-20.4) (p < 0.001) and had the highest association with treatment received. A FEAR index less than 5° had a 79% probability of correctly assigning hips as stable and unstable, respectively (sensitivity 78%; specificity 80%). CONCLUSIONS: A painful hip with a LCEA of 25° or less and FEAR index less than 5° is likely to be stable, and in such a situation, the diagnostic focus might more productively be directed toward femoroacetabular impingement as a potential cause of a patient's pain, rather than instability. LEVEL OF EVIDENCE: Level III, diagnostic study.

Human Papillomavirus Type 16 L2 DNA Methylation in Exfoliated Cervical Cells From College-Age Women.

OBJECTIVES: The Carolina Women's Care Study (CWCS) at the University of South Carolina followed 467 young women with the goal of identifying biomarkers of human papillomavirus (HPV) persistence. In this study, we analyzed the methylation of HPV16 DNA. METHODS: The aims of this study were to determine the methylation status of the HPV16 L2 gene in DNA isolated from exfoliated cervical cells collected longitudinally as part of the CWCS and to determine the prevalence of polymorphisms (single nucleotide polymorphisms [SNPs]) in folate metabolizing enzymes and DNA repair enzymes known to affect DNA methylation in blood-derived genomic DNA from CWCS participants. For methylation studies, DNA samples were bisulfite converted and amplified with the EpiTect Whole Bisulfitome kit. Polymerase chain reaction was performed for amplicons containing 5 CpG sites in L2. Pyrosequencing was carried out using EpigenDx and analyzed with PyroMark Software. Taqman genotyping assays were performed to determine selected SNP alleles in the CWCS cohort. RESULTS AND CONCLUSIONS: Methylation data were obtained for 82 samples from 27 participants. Of these, 22 participants were positive for HPV16 for 3 or more visits (≥12 months). Methylation in L2 was detectable, but methylation levels varied and were not associated with HPV16 persistence. No linearity of methylation levels over time was observed in participants for whom longitudinal data could be analyzed. Analysis of 9 selected SNPs did not reveal an association with persistence. We conclude that at early stages of infection methylation of HPV16 L2 DNA in Pap test samples is not a predictive biomarker of HPV persistence.

Regulatory and clinical considerations for biosimilar oncology drugs.

Biological oncology products are integral to cancer treatment, but their high costs pose challenges to patients, families, providers, and insurers. The introduction of biosimilar agents-molecules that are similar in structure, function, activity, immunogenicity, and safety to the original biological drugs-provide opportunities both to improve health-care access and outcomes, and to reduce costs. Several international regulatory pathways have been developed to expedite entry of biosimilars into global marketplaces. The first wave of oncology biosimilar use was in Europe and India in 2007. Oncology biosimilars are now widely marketed in several countries in Europe, and in Australia, Japan, China, Russia, India, and South Korea. Their use is emerging worldwide, with the notable exception of the USA, where several regulatory and cost barriers to biosimilar approval exist. In this Review, we discuss oncology biosimilars and summarise their regulatory frameworks, clinical experiences, and safety concerns.

The contribution of heavy metals in cigarette smoke condensate to malignant transformation of breast epithelial cells and in vivo initiation of neoplasia through induction of a PI3K-AKT-NFκB cascade.

Cigarette smoking is a crucial factor in the development and progression of multiple cancers including breast. Here, we report that repeated exposure to a fixed, low dose of cigarette smoke condensate (CSC) prepared from Indian cigarettes is capable of transforming normal breast epithelial cells, MCF-10A, and delineate the biochemical basis for cellular transformation. CSC transformed cells (MCF-10A-Tr) were capable of anchorage-independent growth, and their anchorage dependent growth and colony forming ability were higher compared to the non-transformed MCF-10A cells. Increased expression of biomarkers representative of oncogenic transformation (NRP-1, Nectin-4), and anti-apoptotic markers (PI3K, AKT, NFκB) were also noted in the MCF-10A-Tr cells. Short tandem repeat (STR) profiling of MCF-10A and MCF-10A-Tr cells revealed that transformed cells acquired allelic variation during transformation, and had become genetically distinct. MCF-10A-Tr cells formed solid tumors when implanted into the mammary fat pads of Balb/c mice. Data revealed that CSC contained approximately 1.011µg Cd per cigarette equivalent, and Cd (0.0003µg Cd/1×10(7) cells) was also detected in the lysates from MCF-10A cells treated with 25µg/mL CSC. In similar manner to CSC, CdCl2 treatment in MCF-10A cells caused anchorage independent colony growth, higher expression of oncogenic proteins and increased PI3K-AKT-NFκB protein expression. An increase in the expression of PI3K-AKT-NFκB was also noted in the mice xenografts. Interestingly, it was noted that CSC and CdCl2 treatment in MCF-10A cells increased ROS. Collectively, results suggest that heavy metals present in cigarettes of Indian origin may substantially contribute to tumorigenesis by inducing intercellular ROS accumulation and increased expression of PI3K, AKT and NFκB proteins.

Endovascular management of a penetrating abdominal aortic injury.

Penetrating aortic trauma is associated with high mortality rates. We report the case of a 24-year-old man who presented with a self-inflicted abdominal aortic penetration injury, resulting in a pseudoaneurysm. Rather uniquely, he was managed through prophylactic stenting to his abdominal aorta; this case was also rare in that there were remarkably no associated visceral injuries. Stenting was preferred because of risks of an aortic graft in a young man. A 14-mm Atrium Advanta™ stent was deployed, and angiography confirmed adequate exclusion of the pseudoaneurysm. He had no complications at follow-up.

Synthesis and Monoamine Oxidase Inhibitory Activity of Halogenated Flavones.

Small molecule neurotransmitters containing amines are metabolized by monoamine oxidase (MAO) in the nervous system. Monoamine oxidase inhibitors are a valuable class of drugs prescribed for the management of neurological disorders, including depression. A series of halogenated flavonoids similar to the dietary flavonoid acacetin were designed as selective MAO-B inhibitors. MAO-A and -B inhibition of 36 halogenated flavones were tested. The halogens (fluorine and chlorine) were placed at positions 5 and 7 on ring A of the flavone scaffold. All compounds were selective MAO-B inhibitors with micro- and nanomolar IC50 values. Compounds 9f, 10a-c, 11a-c, 11g,h, and 11l displayed inhibitory activity toward MAO-B with IC50 values between 16 to 74 nM. We conclude that halogenated flavonoids are promising molecules in pursuit of developing new agents for neurological disorders.

Valgus-impacted subcapital neck of femur fractures: a systematic review, meta-analysis with cost analysis of fixation in-situ versus nonoperative management.

BACKGROUND: The management of the valgus-impacted neck of femur fracture (AO/OTA 31-B1) remains contentious. The objective of this study was to determine whether operative intervention is cost-effective. METHODS: We conducted a systematic review using electronic databases (Medline, Embase, Cochrane, Ebsco, Scholar) identifying studies published in the English language concerning valgus-impacted neck of femur fractures until June 2022. Additional studies were identified through hand searches of major orthopaedic journals, and bibliographies of major orthopaedic textbooks. MeSH terms (hip fracture and femoral neck fracture) and keywords (undisplaced, valgus-impacted, valgus, subcapital, Garden) connected by the Boolean operators "AND" and "OR" were used to identify studies. 2 reviewers independently extracted the data using standardised forms and recording spreadsheet. Methodological validity prior to inclusion in the review using standardized critical appraisal instruments from the Joanna Briggs Institute Meta-analysis of Statistics Assessment and Review Instrument. Meta-analysis was undertaken. Outcome measures were rate of displacement, avascular necrosis, non-union, mortality and requirement of further operative intervention. A cost utility analysis was then conducted to compare the 2 groups on the basis of the cost of initial treatment and the potential requirement of secondary intervention to hemiarthroplasty. RESULTS: 47 studies met the inclusion criteria. Meta-analysis data demonstrated a significant difference in the displacement rate of 22.8% and 2.8% between the nonoperative and internal fixation groups respectively (p = 0.05). The overall incidence of further operative intervention for each group was 23% and 10% respectively. There was no significant difference with respect to avascular necrosis, mortality or union rates. The cost utility analysis revealed nonoperative management to be approximately 60% more costly than initial internal fixation when the costs of subsequent surgery were included. CONCLUSIONS: This meta-analysis of the existing literature concludes that whilst nonoperative management is possible for valgus impacted neck of femur fractures, it is associated with higher complication rates and greater expense than management by internal fixation.

AI-based mining of biomedical literature: Applications for drug repurposing for the treatment of dementia.

Neurodegenerative pathologies such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, Multiple sclerosis, HIV-associated neurocognitive disorder, and others significantly affect individuals, their families, caregivers, and healthcare systems. While there are no cures yet, researchers worldwide are actively working on the development of novel treatments that have the potential to slow disease progression, alleviate symptoms, and ultimately improve the overall health of patients. Huge volumes of new scientific information necessitate new analytical approaches for meaningful hypothesis generation. To enable the automatic analysis of biomedical data we introduced AGATHA, an effective AI-based literature mining tool that can navigate massive scientific literature databases, such as PubMed. The overarching goal of this effort is to adapt AGATHA for drug repurposing by revealing hidden connections between FDA-approved medications and a health condition of interest. Our tool converts the abstracts of peer-reviewed papers from PubMed into multidimensional space where each gene and health condition are represented by specific metrics. We implemented advanced statistical analysis to reveal distinct clusters of scientific terms within the virtual space created using AGATHA-calculated parameters for selected health conditions and genes. Partial Least Squares Discriminant Analysis was employed for categorizing and predicting samples (122 diseases and 20889 genes) fitted to specific classes. Advanced statistics were employed to build a discrimination model and extract lists of genes specific to each disease class. Here we focus on drugs that can be repurposed for dementia treatment as an outcome of neurodegenerative diseases. Therefore, we determined dementia-associated genes statistically highly ranked in other disease classes. Additionally, we report a mechanism for detecting genes common to multiple health conditions. These sets of genes were classified based on their presence in biological pathways, aiding in selecting candidates and biological processes that are exploitable with drug repurposing. Author Summary: This manuscript outlines our project involving the application of AGATHA, an AI-based literature mining tool, to discover drugs with the potential for repurposing in the context of neurocognitive disorders. The primary objective is to identify connections between approved medications and specific health conditions through advanced statistical analysis, including techniques like Partial Least Squares Discriminant Analysis (PLSDA) and unsupervised clustering. The methodology involves grouping scientific terms related to different health conditions and genes, followed by building discrimination models to extract lists of disease-specific genes. These genes are then analyzed through pathway analysis to select candidates for drug repurposing.

Collateral damage of NUDT15 deficiency in cancer provides a cancer pharmacogenetic therapeutic window with thiopurines.

Genome instability is a hallmark of cancer and are driven by mutations in oncogenes and tumor suppressor genes. Despite successes seen with select targeted therapeutics, this type of personalized medicine is only beneficial for a small subpopulation of cancer patients who have one of a few actionable genetic changes. Most tumors also contain hundreds of passenger mutations that offered no fitness advantage or disadvantage during tumor evolution. Mutations in known pharmacogenetic (PGx) loci for which germline variants encode variability in drug response can cause somatically acquired drug sensitivity. The NUDT15 gene is a known PGx locus that participates in the rate-limiting metabolism of thiopurines. People with two defective germline alleles of NUDT15 are hypersensitive to the toxic effects of thiopurines. NUDT15 is located adjacent to the Retinoblastoma ( RB1 ) tumor suppressor gene, which often undergoes homozygous deletion in retinoblastomas and other epithelial cancers. We observed that RB1 undergoes homozygous deletions in 9.4% of prostate adenocarcinomas and 2.5% of ovarian cancers, and in nearly all of these cases NUDT15 is also lost. Moreover, 44% of prostate adenocarcinomas and over 60% of ovarian cancers have lost one allele of NUDT15, which predicts that a majority of all prostate and ovarian cancers have somatically acquired hypersensitivity to thiopurine treatment. We performed a retrospective analysis of >16,000 patients in the US Veterans Administration health care system and found concurrent xanthine oxidase inhibition (XOi) and thiopurine usage for non-cancer indications is significantly associated with reduced incidence of prostate cancer. The hazard ratio for the development of prostate cancer in patients treated with thiopurines and XOi was 0.562 (0.301-1.051) for the unmatched cohort and 0.389 (0.185-0.819) for the propensity score matched cohort. We experimentally depleted NUDT15 from ovarian and prostate cancer cell lines and observed a dramatic sensitization to thiopurine-induced and DNA damage-dependent toxicity. These results indicate that somatic loss of NUDT15 predicts therapeutic sensitivity to a low cost and well tolerated drug with a broad therapeutic window.

Exposure to angiotensin-converting enzyme inhibitors that cross the blood-brain barrier and the risk of dementia among patients with human immunodeficiency virus.

More than one million people in the United States and over 38 million people worldwide are living with human immunodeficiency virus (HIV) infection. Antiretroviral therapy (ART) greatly improves the health of people living with HIV (PLWH); however, the increased life longevity of PLWH has revealed consequences of HIV-associated comorbidities. HIV can enter the brain and cause inflammation even in individuals with well-controlled HIV infection. The quality of life for PLWH can be compromised by cognitive deficits and memory loss, termed HIV-associated neurological disorders (HAND). HIV-associated dementia is a related but distinct diagnosis. Common causes of dementia in PLWH are similar to the general population and can affect cognition. There is an urgent need to identify treatments for the aging PWLH population. We previously developed AI-based biomedical literature mining systems to uncover a potential novel connection between HAND the renin-angiotensin system (RAAS), which is a pharmacological target for hypertension. RAAS-targeting anti-hypertensives are gaining attention for their protective benefits in several neurocognitive disorders. To our knowledge, the effect of RAAS-targeting drugs on the cognition of PLWH development of dementia has not previously been analyzed. We hypothesized that exposure to angiotensin-converting enzyme inhibitors (ACEi) that cross the blood brain barrier (BBB) reduces the risk/occurrence of dementia in PLWH. We report a retrospective cohort study of electronic health records (EHRs) to examine the proposed hypothesis using data from the United States Department of Veterans Affairs, in which a primary outcome of dementia was measured in controlled cohorts of patients exposed to BBB-penetrant ACEi versus those unexposed to BBB-penetrant ACEi. The results reveal a statistically significant reduction in dementia diagnosis for PLWH exposed to BBB-penetrant ACEi. These results suggest there is a potential protective effect of BBB ACE inhibitor exposure against dementia in PLWH that warrants further investigation.

Periprosthetic Joint Infection After Total Knee Arthroplasty With or Without Antibiotic Bone Cement.

Importance: Despite increased use of antibiotic-loaded bone cement (ALBC) in joint arthroplasty over recent decades, current evidence for prophylactic use of ALBC to reduce risk of periprosthetic joint infection (PJI) is insufficient. Objective: To compare the rate of revision attributed to PJI following primary total knee arthroplasty (TKA) using ALBC vs plain bone cement. Design, Setting, and Participants: This international cohort study used data from 14 national or regional joint arthroplasty registries in Australia, Denmark, Finland, Germany, Italy, New Zealand, Norway, Romania, Sweden, Switzerland, the Netherlands, the UK, and the US. The study included primary TKAs for osteoarthritis registered from January 1, 2010, to December 31, 2020, and followed-up until December 31, 2021. Data analysis was performed from April to September 2023. Exposure: Primary TKA with ALBC vs plain bone cement. Main Outcomes and Measures: The primary outcome was risk of 1-year revision for PJI. Using a distributed data network analysis method, data were harmonized, and a cumulative revision rate was calculated (1 - Kaplan-Meier), and Cox regression analyses were performed within the 10 registries using both cement types. A meta-analysis was then performed to combine all aggregated data and evaluate the risk of 1-year revision for PJI and all causes. Results: Among 2 168 924 TKAs included, 93% were performed with ALBC. Most TKAs were performed in female patients (59.5%) and patients aged 65 to 74 years (39.9%), fully cemented (92.2%), and in the 2015 to 2020 period (62.5%). All participating registries reported a cumulative 1-year revision rate for PJI of less than 1% following primary TKA with ALBC (range, 0.21%-0.80%) and with plain bone cement (range, 0.23%-0.70%). The meta-analyses based on adjusted Cox regression for 1 917 190 TKAs showed no statistically significant difference at 1 year in risk of revision for PJI (hazard rate ratio, 1.16; 95% CI, 0.89-1.52) or for all causes (hazard rate ratio, 1.12; 95% CI, 0.89-1.40) among TKAs performed with ALBC vs plain bone cement. Conclusions and Relevance: In this study, the risk of revision for PJI was similar between ALBC and plain bone cement following primary TKA. Any additional costs of ALBC and its relative value in reducing revision risk should be considered in the context of the overall health care delivery system.

Lycopene synergistically enhances quinacrine action to inhibit Wnt-TCF signaling in breast cancer cells through APC.

We previously reported that quinacrine (QC) has anticancer activity against breast cancer cells. Here, we examine the mechanism of action of QC and its ability to inhibit Wnt-TCF signaling in two independent breast cancer cell lines. QC altered Wnt-TCF signaling components by increasing the levels of adenomatous polyposis coli (APC), DAB2, GSK-3ß and axin and decreasing the levels of ß-catenin, p-GSK3ß (ser 9) and CK1. QC also reduced the activity of the Wnt transcription factor TCF/LEF and its downstream targets cyclin D1 and c-MYC. Using a luciferase-based Wnt-TCF transcription factor assay, it was shown that APC levels were inversely associated with TCF/LEF activity. Induction of apoptosis and DNA damage was observed after treatment with QC, which was associated with increased expression of APC. The effects induced by QC depend on APC because the inhibition of Wnt-TCF signaling by QC is lost in APC-knockdown cells, and consequently, the extent of apoptosis and DNA damage caused by QC is reduced compared with parental cells. Because we previously showed that QC inhibits topoisomerase, we examined the effect of another topoisomerase inhibitor, etoposide, on Wnt signaling. Interestingly, etoposide treatment also reduced TCF/LEF activity, ß-catenin and cyclin D1 levels commensurate with induction of DNA damage and apoptosis. Lycopene, a plant-derived antioxidant, synergistically increased QC activity and inhibited Wnt-TCF signaling in cancer cells without affecting the MCF-10A normal breast cell line. Collectively, the data suggest that QC-mediated Wnt-TCF signal inhibition depends on APC and that the addition of lycopene synergistically increases QC anticancer activity.