Synthesis and Quantitative Structure–Activity Relationship of Imidazotetrazine Prodrugs with Activity Independent of O6-Methylguanine-DNA-methyltransferase, DNA Mismatch Repair and p53.

The antitumor prodrug Temozolomide is compromised by its dependence for activity on DNA mismatch repair (MMR) and the repair of the chemosensitive DNA lesion, O6-methylguanine (O6-MeG), by O6-methylguanine-DNA-methyltransferase (EC 2.1.1.63, MGMT). Tumor response is also dependent on wild-type p53. Novel 3-(2-anilinoethyl)-substituted imidazotetrazines are reported that have activity independent of MGMT, MMR and p53. This is achieved through a switch of mechanism so that bioactivity derives from imidazotetrazine-generated arylaziridinium ions that principally modify guanine-N7 sites on DNA. Mono- and bi-functional analogs are reported and a quantitative structure-activity relationship (QSAR) study identified the p-tolyl-substituted bi-functional congener as optimized for potency, MGMT-independence and MMR-independence. NCI60 data show the tumor cell response is distinct from other imidazotetrazines and DNA-guanine-N7 active agents such as nitrogen mustards and cisplatin. The new imidazotetrazine compounds are promising agents for further development and their improved in vitro activity validates the principles on which they were designed

Quantifying donor-to-donor variation in macrophage responses to the human fungal pathogen Cryptococcus neoformans

Cryptococcosis remains the leading cause of fungal meningitis worldwide, caused primarily by the pathogen Cryptococcus neoformans. Symptomatic cryptococcal infections typically affect immunocompromised patients. However, environmental exposure to cryptococcal spores is ubiquitous and most healthy individuals are thought to harbor infections from early childhood onwards that are either resolved, or become latent. Since macrophages are a key host cell for cryptococcal infection, we sought to quantify the extent of individual variation in this early phagocyte response within a small cohort of healthy volunteers with no reported immunocompromising conditions. We show that rates of both intracellular fungal proliferation and non-lytic expulsion (vomocytosis) are remarkably variable between individuals. However, we demonstrate that neither gender, in vitro host inflammatory cytokine profiles, nor polymorphisms in several key immune genes are responsible for this variation. Thus the data we present serve to quantify the natural variation in macrophage responses to this important human pathogen and will hopefully provide a useful "benchmark" for the research community

APOE4 allele-specific associations between diet, multimodal biomarkers, and cognition among Puerto Rican adults in Massachusetts

BackgroundApolipoprotein E (APOE) is the strongest genetic risk factor for sporadic Alzheimer’s Disease (AD), and the ε4 allele (APOE4) may interact with lifestyle factors that relate to brain structural changes, underlying the increased risk of AD. However, the exact role of APOE4 in mediating interactions between the peripheral circulatory system and the central nervous system, and how it may link to brain and cognitive aging requires further elucidation. In this analysis, we investigated the association between APOE4 carrier status and multimodal biomarkers (diet, blood markers, clinical diagnosis, brain structure, and cognition) in the context of gene–environment interactions.MethodsParticipants were older adults from a longitudinal observational study, the Boston Puerto Rican Health Study (BPRHS), who self-identified as of Puerto Rican descent. Demographics, APOE genotype, diet, blood, and clinical data were collected at baseline and at approximately 12th year, with the addition of multimodal brain magnetic resonance imaging (MRI) (T1-weighted and diffusion) and cognitive testing acquired at 12-year. Measures were compared between APOE4 carriers and non-carriers, and associations between multimodal variables were examined using correlation and multivariate network analyses within each group.ResultsA total of 156 BPRHS participants (mean age at imaging = 68 years, 77% female, mean follow-up 12.7 years) with complete multimodal data were included in the current analysis. APOE4 carriers (n = 43) showed reduced medial temporal lobe (MTL) white matter (WM) microstructural integrity and lower mini-mental state examination (MMSE) score than non-carriers (n = 113). This pattern was consistent with an independent sample from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) of n = 283 non-Hispanic White adults without dementia (mean age = 75, 40% female). Within BPRHS, carriers showed distinct connectivity patterns between multimodal biomarkers, characterized by stronger direct network connections between baseline diet/blood markers with 12-year blood/clinical measures, and between blood markers (especially lipids and cytokines) and WM. Cardiovascular burden (i.e., hypertension and diabetes status) was associated with WM integrity for both carriers and non-carriers.ConclusionAPOE4 carrier status affects interactions between dietary factors, multimodal blood biomarkers, and MTL WM integrity across ~12 years of follow-up, which may reflect increased peripheral-central systems crosstalk following blood–brain barrier breakdown in carriers

Characterizing the Mechanisms of Nonopsonic Uptake of Cryptococci by Macrophages

The pathogenic fungus Cryptococcus enters the human host via inhalation into the lung and is able to reside in a niche environment that is serum- (opsonin) limiting. Little is known about the mechanism by which nonopsonic phagocytosis occurs via phagocytes in such situations. Using a combination of soluble inhibitors of phagocytic receptors and macrophages derived from knockout mice and human volunteers, we show that uptake of nonopsonized Cryptococcus neoformans and C. gattii via the mannose receptor is dependent on macrophage activation by cytokines. However, although uptake of C. neoformans is via both dectin-1 and dectin-2, C. gattii uptake occurs largely via dectin-1. Interestingly, dectin inhibitors also blocked phagocytosis of unopsonized Cryptococci in wax moth (Galleria mellonella) larvae and partially protected the larvae from infection by both fungi, supporting a key role for host phagocytes in augmenting early disease establishment. Finally, we demonstrated that internalization of nonopsonized Cryptococci is not accompanied by the nuclear translocation of NF-κB or its concomitant production of proinflammatory cytokines such as TNF-α. Thus, nonopsonized Cryptococci are recognized by mammalian phagocytes in a manner that minimizes proinflammatory cytokine production and potentially facilitates fungal pathogenesis

Unlocking the potential of approved drugs for the allosteric inhibition of tropomyosin-receptor kinase A using molecular docking and molecular dynamics studies

Tropomyosin-receptor kinase A (TrkA) is the primary isoform among the tropomyosin-receptor kinases that have been associated with human cancer development, contributing to approximately 7.4% of all cancer cases. TrkA represents an attractive target for cancer treatment; however, currently available TrkA inhibitors face limitations in terms of resistance development and potential toxicity. Hence, the objective of this study was to identify new allosteric-approved inhibitors of TrkA that can overcome these challenges and be employed in cancer therapy. To achieve this goal, a screening of 9,923 drugs from the ChEMBL database was conducted to assess their repurposing potential using molecular docking. The top 49 drug candidates, exhibiting the highest docking scores (−11.569 to −7.962 kcal/mol), underwent MM-GBSA calculations to evaluate their binding energies. Delanzomib and tibalosin, the top two drugs with docking scores of −10.643 and −10.184 kcal/mol, respectively, along with MM-GBSA dG bind values of −67.96 and −50.54 kcal/mol, were subjected to 200 ns molecular dynamic simulations, confirming their stable interactions with TrkA. Based on these findings, we recommend further experimental evaluation of delanzomib and tibalosin to determine their potential as allosteric inhibitors of TrkA. These drugs have the potential to provide more effective and less toxic therapeutic alternatives. The approach employed in this study, which involves repurposing drugs through molecular docking and molecular dynamics, serves as a valuable tool for identifying novel drug candidates with distinct therapeutic uses. This methodology can contribute to reducing the attrition rate and expediting the process of drug discovery

Abstract MP05: Sex Differences In Mortality And 30-day All Cause Readmission Following Carotid Endarterectomy Following Acute Ischemic Stroke: A Nsqip Study (2014 - 2017)

Abstract only Background: Studies report that acute ischemic stroke (AIS) affects males and females differently. For example, the treatment outcomes of intra-arterial thrombolysis differ between males and females. In this study, we examined mortality and 30-day readmission differences by sex among AIS patients who had carotid endarterectomy (CEA). Methods: We used data from National Surgical Quality Improvement Program (NSQIP) registry (2014-2017). Patients ≥18 years of age, with CEA for AIS were included. AIS and CEA were identified using ICD-9 and ICD-10 diagnosis, and CPT codes, respectively. Using machine learning methods such as Hierarchical clustering, we grouped patients (low, medium, and high-risk clusters) based on their demographics, past medical history, and preoperative variables. Differences in means, and differences in proportions were calculated. Logistic regression was conducted for 30-day readmission and survival analysis for mortality, accounting for cluster groups and sex. Results: There were a total of 22,373 AIS patients who received CEA treatment. Mean (SD) age of the sample was 70.7 (9.4) years, and 61% were males while 39% were females. Mortality rates were 0.8% and 0.7% for men and women (p=0.113), respectively. Thirty-day readmission rates were 6.3% and 7.6% for men and women (p<0.0001), respectively. There were 56.3%, 34.4%, and 9.3% patients in Low, Medium, and High-Risk clusters, respectively. Females were 1.2 times (OR 95% CI: 1.1 - 1.3) as likely to be readmitted compared to males. Survival analysis showed that there was no significant difference in mortality between males and females (HR: 0.8; 95% CI: 0.6 - 1.2; p = 0.28). Conclusion: Our study found sex related disparities in short-term readmissions as it was higher among females. This could be because of underlaying sex specific pathophysiology of AIS. Healthcare providers should consider sex-specific management to improve post-stroke recovery for women and reduce their excess burden

New Sudanese Reference Chart of Fetal Biometry and Weight Using Ultrasonography

Abstract Background: Many centers in Sudan use the reference data for fetal biometry. The recently published population-based reference either overestimated or underestimated the weight of the fetuses. Objective: To establish a national reference for fetal biometry, and weight by gestational age for singleton fetuses in Sudan. Methods: Data were collected on all singleton live births documented in the data collection sheet done at Saudi Hospital from 2015 to 2016 (n = 225). Gestational age estimation was based on the last menstrual period and fetal ultrasound thereafter. Fetal biometry and weight and other 6 fetal weight formulae were assessed. Reference data for fetal growth by gestational age were created. Results: New charts and reference equations are reported in Sudanese population for fetal biparietal diameter, head circumference, abdominal circumference and femur length and fetal weight. Conclusion: We advocate that these reference charts and equations for fetal biometry and weight might be valuable in the clinical use for appropriate ethnic Sudanese

Variation in host responses to <i>C</i>. <i>neoformans</i> infections.

<p>(A) A measured intracellular proliferation rate (IPR) for each donor showing median of at least 2 biological repeats each (median = 0.53, mean = 0.6307, SD = 0.5275 and Coefficient of variation = 83.64%). (B) Variable rates of vomocytosis observed between and within donors showing median of at least 2 biological repeats each (median = 41.11%, mean = 41.55%, SD = 15.53 and Coefficient of variation = 37.37%). (C) Correlation between intracellular parasitism and non-lytic expulsion events (R square = 0.2501, P-value = 0.0005). Each point on the graph represents data from a single blood donation. Since not all participants were available to provide four repeat donations across the study period, the number of repeated samples varies from donor to donor.</p