Nevin Manimala

SAR QSAR Environ Res. 2023 Feb 6:1-26. doi: 10.1080/1062936X.2023.2167860. Online ahead of print.

ABSTRACT

PLK1 is the key target for dealing with different cancer because it plays an important role in cell proliferation. According to the regulation of OECD, a QSAR model was developed from a dataset of 68 tetrahydropteridin derivatives. Three descriptors (maxHaaCH, ATSC7i, AATS7m) were considered for the development of the QSAR model. The reliability and predictability of the developed QSAR model were evaluated by various statistical parameters (r² = 0.8213, r²_ext = 0.8771 and CCC_ext = 0.9364). The maxHaaCH descriptor is positively correlated to pIC₅₀ whereas, the ATSC7i and AATS7m are negatively correlated with pIC₅₀. The QSAR model explains all the structural features and shows a good correlation with the activity. Based on molecular modelling techniques, five compounds (D1-D5) were designed. Molecular docking and dynamics studies of the most active compound were performed with PDB ID: 2RKU. The results of the present investigation may be employed to identify and develop effective inhibitors for the treatment of PLK1-related pathophysiological disorders.

PMID:36744430 | DOI:10.1080/1062936X.2023.2167860

Int Angiol. 2023 Feb 6. doi: 10.23736/S0392-9590.22.04974-4. Online ahead of print.

ABSTRACT

BACKGROUND: We aimed to study the discriminative power of 3 comorbidity scores for predicting 5-year survival after the elective repair of aorto-iliac aneurysms (AAA).

METHODS: 444 patients with AAA undergoing elective repair (33% open and 67% endovascular) between 2000 and 2020 were reviewed. The Charlson Comorbidity Index (CCI) and subsequent adjustments by Schneeweiss, Quan and Armitage, the Modified Frailty Index (MFI) and the American Society of Anesthesiologists Score (ASA) were calculated from preoperative data. Their association with 5-year survival was analyzed using Cox regression models and their discriminative power and its changes with C statistics and Net Reclassification Index (NRI).

RESULTS: All comorbidity scores were associated with survival after adjusting by age, sex and type of surgical repair: original CCI HR=1.24, P<0.001; Schneeweiss CCI HR=1.23, P<0.001; Quan CCI HR=1.27, P<0.001, Armitage CCI HR=1.46, P<0.001, MFI HR=1.39, P<0.001 and ASA HR=1.68 (P=0.04) and 2.86 (P=0.01) for classes III and IV, respectively. Associated C statistics were of 0.64, 0.65, 0.65, 0.64, 0.61 and 0.59, respectively. Compared with the original CCI, models based on Schneeweiss CCI and Armitage CCI provided minor improvements in NRI (0.32 and 0.23), and the model based on ASA showed lower C statistics (P=0.014) and NRI (-0.30).

CONCLUSIONS: Established comorbidity scores, such as CCI, MFI or ASA, are all associated with 5-year survival after the elective repair of AAAs, being ASA the worst of them. However, their predictive power is in no case sufficient to identify, by themselves, those patients who may not be eligible for intervention on the basis of life expectancy.

PMID:36744425 | DOI:10.23736/S0392-9590.22.04974-4

Phys Sportsmed. 2023 Feb 6. doi: 10.1080/00913847.2023.2177080. Online ahead of print.

ABSTRACT

OBJECTIVE: Evaluate the on-ice performance and return to play (RTP) rate following COVID-19 for National Hockey League (NHL) players during the 2020-21 season.

METHODS: Players with COVID-19 during the abbreviated 2020-21 season were identified using publicly accessible online sources. Demographics and on-ice metrics were accessed using the NHL’s online statistics website. The length of time, rate of RTP, and games missed due to COVID-19 were analyzed. Primary outcomes included average time on ice (TOI) per game (TOI/G), average TOI per shift (TOI/S), and points per game (PPG) compared at different timepoints including pre- and post-COVID-19.

RESULTS: A total of 73 players (47 forwards, 18 defencemen, 8 goalies) had a documented COVID-19 diagnosis during the abbreviated 2020-21 season. Players missed an average of 5.6 games (14.7 days) due to COVID-19. The post-COVID-19 RTP rate was 97.3%, including playoffs. No differences were found in TOI/G between the pre- (15.7 ± 3.9 min) and post-COVID-19 (15.8 ± 3.4 min, p = 0.874) or in the first (15.8 ± 4.0 min) and second week (15.9 ± 3.8 min, p = 0.925) returned. TOI/shift did not change from pre- (45.6 ± 5.3 sec) to post-COVID-19 (46.7 ± 4.6 sec, p = 0.035) or in first (46.2 ± 5.4 sec) and second week post-COVID-19 (46.2 ± 4.8 sec, p = .854). No differences were identified for PPG between career, pre-COVID-19, and post-COVID-19 (0.44 vs 0.38 vs 0.41; p = 0.274).

CONCLUSION: RTP post-COVID was markedly high for NHL players. While the effects of COVID-19 on specific physiological measures remains to be elucidated, this study found NHL players do not have reduced performance following COVID-19.

PMID:36744406 | DOI:10.1080/00913847.2023.2177080

Expert Rev Mol Diagn. 2023 Feb 6. doi: 10.1080/14737159.2023.2176223. Online ahead of print.

ABSTRACT

BACKGROUND: : Colorectal cancer (CRC) is the most common cancer and the second leading cause of cancer deaths in Hong Kong. We tested the hypothesis that circulating tumor cell (CTC) analysis by ARB101 antibody could be used as a tool for CRC detection, progression, and therapy response.

RESEARCH DESIGN AND METHODS: : ARB101 antibody was used for investigation of CDH17 expression in formalin-fixed, paraffin-embedded (FFPE) tissue sections and circulating tumor cells (CTCs) of CRC patients.

RESULTS: Using ARB101, highest sensitivity was observed in 98/100 (98%) colorectal cancer tissue compared to 72/100 gastric cancer (72%) and 27/32 pancreatic cancer (84%). Immunoreactivity of CDH17 was significantly higher in distant metastatic (tumor-node-metastasis [TNM] stage IV) than non-distant metastatic (TNM stage I to III) colorectal cancer. ARB101 antibody also manifested the higher sensitivity than c-erbB2 (8%) and epidermal growth factor receptor (EGFR)-targeting antibodies (37%) with the significance (p < 0.0001). ARB101 positive CTCs were detected in 64/83 (77%) TNM stage I to IV colorectal cancer patients. Detailed analysis showed that ARB101 positive CTCs (threshold ⩾1) were identified in 17/25 stage I (68%), 14/21 stage II (67%), 18/21 stage III (86%) and 15/16 stage IV (94%) colorectal cancer patients. Furthermore, ARB101 positive CTCs were detected in TNM stage I to III colorectal cancer patients before and after surgical operation. The difference of ARB101 positive CTCs between those 2 groups of matched patient samples are statistically significant (p < 0.0001).

CONCLUSIONS: CTC detection by ARB101 antibody could serve as a potential non-invasive approach for CRC detection, progression, and monitoring treatment response of colorectal cancers.

PMID:36744385 | DOI:10.1080/14737159.2023.2176223

Work. 2023 Feb 2. doi: 10.3233/WOR-220189. Online ahead of print.

ABSTRACT

BACKGROUND: Vehicular emissions on long-term exposure predispose metropolitan bus drivers to cardiorespiratory ailments.

OBJECTIVE: To evaluate the cardiorespiratory risk of urban metropolitan bus drivers related to vehicular emission exposure.

METHODS: Bus drivers (with service >5 years, n = 254) and their administrative controls (primarily engaged in indoor white collared jobs, n = 73) were recruited. Demographic, occupational and clinical details were collected through pre-validated standardized format. Pulmonary Function Test (PFT) and lipid profile were carried out with standard protocol. Risk for cardiovascular events for preceding 10-years was estimated with WHO/ISH risk prediction chart and QRISK3 score. Exposure assessments for particulate matter (PM) were performed for both groups while duty hours.

RESULTS: Exposure of drivers to PM2.5 six times and PM10 five times higher in comparison to administration staff (PM2.5- 970.9 v/s 145.0μg/m3 TWA and PM10- 1111.7 v/s 233.8μg/m3 TWA). Bus drivers exhibited significantly higher prevalence of respiratory symptoms (dyspnea-25% v/s 6.8% and cough-20.1% v/s 9.8%) and compromised PFT (obstructive-21% v/s 5.7% and restrictive-4.2% v/s 2.9%) in comparison to controls. Multivariate regression statistics reveal a significant decline for FEV1/FVC and FEV25-75 % among bus drivers compared to controls, controlling the influence of physiological and environmental factors. The difference between predicted cardiac age and their respective chronological age was twice higher (8.3 v/s 4.3 years) among drivers compared to their administration staff.

CONCLUSION: Bus drivers were exposed to high levels of outdoor air pollutants. Further, the drivers exhibited higher risk for ischemic attack and obstructive airway diseases as compared to administration staff.

PMID:36744353 | DOI:10.3233/WOR-220189

J Alzheimers Dis. 2023 Jan 28. doi: 10.3233/JAD-220894. Online ahead of print.

ABSTRACT

BACKGROUND: Diabetes increases the risk for cognitive decline, but the mechanisms behind this association remain unknown. Impaired early insulin secretion in elderly men and insulin resistance, both of which are pathophysiological features of type 2 diabetes, have previously been linked to Alzheimer’s disease.

OBJECTIVE: To examine if the early insulin response to oral glucose load predicts cognitive performance after 10 years in men and women aged 45-74 years.

METHODS: This study was based on a subpopulation of the Health 2000 Survey, a Finnish nationwide, population-based health examination study, and its follow-up, the Health 2011 Study. In total, 961 45-74-year-old individuals (mean age at baseline 55.6 years, 55.8% women) were examined. An oral glucose tolerance test was performed in 2001-2002, and early insulin response was defined as the ratio of the 30-min increment in insulin concentration to that of glucose concentration. Cognitive function was evaluated at baseline and follow-up with categorical verbal fluency, word-list learning, and word-list delayed recall. Statistical analyses were performed using multivariable linear models adjusted for age, sex, education, APOE&z.epsi;4 genotype, vascular risk factors including diabetes, and depressive symptoms.

RESULTS: A lower early insulin response to glucose load predicted lower performance (β: 0.21, p = 0.03) and greater decline (β: 0.19, p = 0.03) in the word-list delayed recall test. Baseline early insulin response did not predict verbal fluency or word-list learning (all p-values≥0.13).

CONCLUSION: Our results suggest that decreased early insulin secretion predicts episodic memory decline in middle-aged to elderly men and women.

PMID:36744339 | DOI:10.3233/JAD-220894

J Alzheimers Dis. 2023 Feb 2. doi: 10.3233/JAD-220727. Online ahead of print.

ABSTRACT

BACKGROUND: The oxidative stress hypothesis is challenging the dominant position of amyloid-β (Aβ) in the field of understanding the mechanisms of Alzheimer’s disease (AD), a complicated and untreatable neurodegenerative disease.

OBJECTIVE: The goal of the present study was to uncover the oxidative stress mechanisms causing AD, as well as the potential therapeutic targets and neuroprotective drugs against oxidative stress mechanisms.

METHODS: In this study, a systematic workflow combining pharmacological experiments and computational prediction were proposed. 222 drugs and natural products were collected first and then tested on SH-SY5Y cells to obtain phenotypic screening data on neuroprotection. The preliminary screening data were integrated with drug-target interactions (DTIs) and multi-scale biomedical data, which were analyzed with statistical tests and gene set enrichment analysis. A polypharmacology network was further constructed for investigation.

RESULTS: 340 DTIs were matched in multiple databases, and 222 cell viability ratios were calculated for experimental compounds. We identified significant potential therapeutic targets based on oxidative stress mechanisms for AD, including NR3C1, SHBG, ESR1, PGR, and AVPR1A, which might be closely related to neuroprotective effects and pathogenesis. 50% of the top 14 enriched pathways were found to correlate with AD, such as arachidonic acid metabolism and neuroactive ligand-receptor interaction. Several approved drugs in this research were also found to exert neuroprotective effects against oxidative stress mechanisms, including beclometasone, methylprednisolone, and conivaptan.

CONCLUSION: Our results indicated that NR3C1, SHBG, ESR1, PGR, and AVPR1A were promising therapeutic targets and several drugs may be repurposed from the perspective of oxidative stress and AD.

PMID:36744334 | DOI:10.3233/JAD-220727

J Alzheimers Dis. 2023 Feb 2. doi: 10.3233/JAD-220599. Online ahead of print.

ABSTRACT

BACKGROUND: Our understanding of the pathophysiology underlying Alzheimer’s disease (AD) has benefited from genomic analyses, including those that leverage polygenic risk score (PRS) models of disease. The use of functional annotation has been able to improve the power of genomic models.

OBJECTIVE: We sought to leverage genomic functional annotations to build tissue-specific AD PRS models and study their relationship with AD and its biomarkers.

METHODS: We built 13 tissue-specific AD PRS and studied the scores’ relationships with AD diagnosis, cerebrospinal fluid (CSF) amyloid, CSF tau, and other CSF biomarkers in two longitudinal cohort studies of AD.

RESULTS: The AD PRS model that was most predictive of AD diagnosis (even without APOE) was the liver AD PRS: n = 1,115; odds ratio = 2.15 (1.67-2.78), p = 3.62×10-9. The liver AD PRS was also statistically significantly associated with cerebrospinal fluid biomarker evidence of amyloid-β (Aβ 42:Aβ 40 ratio, p = 3.53×10-6) and the phosphorylated tau:amyloid-β ratio (p = 1.45×10-5).

CONCLUSION: These findings provide further evidence of the role of the liver-functional genome in AD and the benefits of incorporating functional annotation into genomic research.

PMID:36744333 | DOI:10.3233/JAD-220599

Biomed Mater Eng. 2023 Jan 31. doi: 10.3233/BME-222513. Online ahead of print.

ABSTRACT

BACKGROUND: Acrylic resins used in dental and biomedical applications do not have antimicrobial properties, their surface is susceptible to colonization of microorganisms.

OBJECTIVE: The aim of this study was to evaluate the antibiofilm properties of silver nanoparticles (AgNPs) deposited in a polymethyl methacrylate (PMMA) surface against a Staphylococcus aureus biofilm.

METHODS: The PMMA was impregnated with AgNPs by using the in-situ polymerization method. To determine the solubility of the incorporated silver (Ag+) atomic absorption spectrophotometry was used (AAS) at 24 h, 48 h, 7 days, and 30 days. Thirty specimens of PMMA with AgNPs and without NP (control group) were assembled in the CDC Biofilm Bioreactor system with a cell suspension of S. aureus. The specimens were removed at 6, 12, 24, 48, and 72 h to determine the viability profile and quantify the Arbitrary Fluorescence Units (AFU).

RESULTS: The AgNPs showed an irregular and quasispherical shape with an average size of 25 nm. AAS analysis demonstrated a low solubility of Ag+. The formation of the S. aureus biofilm increased as the evaluation periods continued up to 72 h. The experimental group showed poor growth, and a decrease in the intensity of the fluorescence demonstrated a statistically significant inhibition of the formation of the biofilm (P < 0.05) in relation to the control group at 6, 12, 24, 48, and 72 h.

CONCLUSION: AgNPs incorporated into PMMA decreased the growth and maturation of S. aureus biofilm.

PMID:36744329 | DOI:10.3233/BME-222513

Cardiol Young. 2023 Feb 6:1-4. doi: 10.1017/S1047951123000136. Online ahead of print.

ABSTRACT

OBJECTIVES: When cardiac muscle damage occurs, cardiac troponins are released to blood and their detection is used as a marker in clinical setting. The prognostic value of the quantitative levels of blood troponin I in cases of myocarditis and myopericarditis is unclear. The aim of this study was to analyse whether troponin quantitative blood levels can be correlated with the course of hospitalisation and prognosis.

METHODS: Retrospective data was collected from all consecutive patients aged ≤30 hospitalised with a diagnosis of acute myocarditis or acute myopericarditis in our health Care Campus between the years 2010-2016.

RESULTS: Ninety-three patients with myocarditis and myopericarditis were identified. Higher peak troponin levels correlated with longer hospitalisation times in the cardiac or paediatric wards (p = 0.03, Pearson correlation: r -0.23), and median troponin level at admission correlated with longer overall hospitalisation (p = 0.026, Pearson correlation: r = 0.23). Patients admitted to ICU, received oral cardiac supportive therapy or that were discharged with cardiac drugs had higher median troponin compared to patients who were not but this was not statistically significant. A small group of patients that needed intravenous cardiac support had significantly lower median peak troponin levels (n = 4, 0.375ng/ml, p = 0.048). Only two patients needed extracorporeal membrane oxygenation support, and one died. The small number of patients precludes statistical analysis.

CONCLUSION: Higher troponin levels correlated significantly with longer hospitalisation, lower troponin values correlated with intravenous cardiac support, while other variables related to the severity of disease could not be significantly related to higher troponin levels.

PMID:36744328 | DOI:10.1017/S1047951123000136