Preclinical assessment of ulixertinib, a novel ERK1/2 inhibitor

Ulixertinib (BVD-523) is a novel and selective reversible inhibitor of ERK1/ERK2. In xenograft studies it inhibited tumor growth in BRAF-mutant melanoma and colorectal xenografts as well as KRAS-mutant colorectal and pancreatic models. Ulixertinib is currently in Phase I clinical development for the treatment of advance solid tumors. The objective of the study is to assess the metabolic stability (in various pre-clinical and human liver microsomes/hepatocytes), permeability, protein binding, CYP inhibition, CYP induction and CYP phenotyping of ulixertinib. We have also studied the oral and intravenous pharmacokinetics of ulixertinib in mice, rats and dogs. Ulixertinib was found to be moderately to highly stable in various liver microsomes/hepatocytes tested. It is a medium permeable (2.67 x 10-6 cm /sec) drug and a substrate for efflux (efflux ratio: 3.02) in Caco-2 model. Ulixertinib was highly bound to plasma proteins. CYPs involved in its limited metabolism and it is CYP inhibition IC50 ranged between 10-20 μM. Post oral administration ulixertinib exhibited early Tmax (0.50-0.75 h) in mice and rats indicating absorption was rapid, however in dogs Tmax attained at 2 h. The half-life (t½) of ulixertinib by intravenous and oral routes ranged between 1.0-2.5 h across the species. Clearance and volume of distribution by intravenous route for ulixertinib were found to be 6.24 mL/min/kg and 0.56 L/kg; 1.67 mL/min/kg and 0.36 L/kg and 15.5 mL/min/kg and 1.61 L/kg in mice, rats and dogs, respectively. Absolute oral bioavailability in mice and rats was > 92 %, however in dogs it was 34 %

Preclinical assessment of ulixertinib, a novel ERK1/2 inhibitor

Ulixertinib (BVD-523) is a novel and selective reversible inhibitor of ERK1/ERK2. In xenograft studies it inhibited tumor growth in BRAF-mutant melanoma and colorectal xenografts as well as KRAS-mutant colorectal and pancreatic models. Ulixertinib is currently in Phase I clinical development for the treatment of advance solid tumors. The objective of the study is to assess the metabolic stability (in various pre-clinical and human liver microsomes/hepatocytes), permeability, protein binding, CYP inhibition, CYP induction and CYP phenotyping of ulixertinib. We have also studied the oral and intravenous pharmacokinetics of ulixertinib in mice, rats and dogs. Ulixertinib was found to be moderately to highly stable in various liver microsomes/hepatocytes tested. It is a medium permeable (2.67 x 10-6 cm /sec) drug and a substrate for efflux (efflux ratio: 3.02) in Caco-2 model. Ulixertinib was highly bound to plasma proteins. CYPs involved in its limited metabolism and it is CYP inhibition IC50 ranged between 10-20 µM. Post oral administration ulixertinib exhibited early Tmax (0.50-0.75 h) in mice and rats indicating absorption was rapid, however in dogs Tmax attained at 2 h. The half-life (t½) of ulixertinib by intravenous and oral routes ranged between 1.0-2.5 h across the species. Clearance and volume of distribution by intravenous route for ulixertinib were found to be 6.24 mL/min/kg and 0.56 L/kg; 1.67 mL/min/kg and 0.36 L/kg and 15.5 mL/min/kg and 1.61 L/kg in mice, rats and dogs, respectively. Absolute oral bioavailability in mice and rats was > 92 %, however in dogs it was 34 %

Delta radiomic patterns on serial bi-parametric MRI are associated with pathologic upgrading in prostate cancer patients on active surveillance: preliminary findings

ObjectiveThe aim of this study was to quantify radiomic changes in prostate cancer (PCa) progression on serial MRI among patients on active surveillance (AS) and evaluate their association with pathologic progression on biopsy.MethodsThis retrospective study comprised N = 121 biopsy-proven PCa patients on AS at a single institution, of whom N = 50 at baseline conformed to the inclusion criteria. ISUP Gleason Grade Groups (GGG) were obtained from 12-core TRUS-guided systematic biopsies at baseline and follow-up. A biopsy upgrade (AS+) was defined as an increase in GGG (or in number of positive cores) and no upgrade (AS−) was defined when GGG remained the same during a median period of 18 months. Of N = 50 patients at baseline, N = 30 had MRI scans available at follow-up (median interval = 18 months) and were included for delta radiomic analysis. A total of 252 radiomic features were extracted from the PCa region of interest identified by board-certified radiologists on 3T bi-parametric MRI [T2-weighted (T2W) and apparent diffusion coefficient (ADC)]. Delta radiomic features were computed as the difference of radiomic feature between baseline and follow-up scans. The association of AS+ with age, prostate-specific antigen (PSA), Prostate Imaging Reporting and Data System (PIRADS v2.1) score, and tumor size was evaluated at baseline and follow-up. Various prediction models were built using random forest (RF) classifier within a threefold cross-validation framework leveraging baseline radiomics (Cbr), baseline radiomics + baseline clinical (Cbrbcl), delta radiomics (CΔr), delta radiomics + baseline clinical (CΔrbcl), and delta radiomics + delta clinical (CΔrΔcl).ResultsAn AUC of 0.64 ± 0.09 was obtained for Cbr, which increased to 0.70 ± 0.18 with the integration of clinical variables (Cbrbcl). CΔr yielded an AUC of 0.74 ± 0.15. Integrating delta radiomics with baseline clinical variables yielded an AUC of 0.77 ± 0.23. CΔrΔclresulted in the best AUC of 0.84 ± 0.20 (p < 0.05) among all combinations.ConclusionOur preliminary findings suggest that delta radiomics were more strongly associated with upgrade events compared to PIRADS and other clinical variables. Delta radiomics on serial MRI in combination with changes in clinical variables (PSA and tumor volume) between baseline and follow-up showed the strongest association with biopsy upgrade in PCa patients on AS. Further independent multi-site validation of these preliminary findings is warranted

Zika Virus: An Emerging Public Health Challenge

Emerging infectious diseases comprise a substantial proportion of global morbidity and mortality. The world has been hit by Zika virus (ZIKV) after it was able to surmount an effective public health response for its control. ZIKV disease is an emerging mosquitoborne disease which occurred as large outbreaks in Yap since 2007, Polynesia in 2013 and Brazil in 2015. ZIKV infection in pregnant women has been observed to be associated with congenital microcephaly with neurological and autoimmune sequelae in general population of Brazil. The incubation period of ZIKV varies from few days to weeks. Only 20% of infected cases have symptoms like any other arboviral illness. ZIKV is diagnosed using RT-PCR (reverse transcriptase-polymerase chain reaction) and virus isolation from blood samples. The treatment comprises of relief of symptoms by conservative management with no specific vaccine being available. The prevention and control of ZIKV is based on reduction of vector density by Integrated Vector Management and personal protection measures. As per Indian scenario, Ministry of Health had issued guidelines based on effective surveillance, risk communication, laboratory and travel regulations. Approaches to such a potential global health security threat should be consistent, proactive, and should involve coordinated, multi-pronged, multilateral collaborative efforts since the concern is at the highest and immediate because of Global epidemic, Rio de Janeiro Olympic Games starting from Aug 5-21, 2016 and strong association with microcephaly. Most importantly the need of the hour is the development of vaccine for protection especially the young women who are in the reproductive age groups. The research for which is ongoing as far as the current situation of global epidemic response is concerned

Interfacial Stresses in Shape Memory Alloy Reinforced Composites

Debonding of Shape Memory Alloy (SMA) wires in SMA reinforced polymer matrix composites is a complex phenomenon compared to other fabric fiber debonding in similar matrix composites. This paper focuses on experimental study and analytical correlation of stress required for debonding of thermal SMA actuator wire reinforced composites. Fiber pull-out tests are carried out on thermal SMA actuator at parent state to understand the effect of stress induced detwinned martensites. An ASTM standard is followed as benchmark method for fiber pull-out test. Debonding stress is derived with the help of non-local shear-lag theory applied to elasto-plastic interface. Furthermore, experimental investigations are carried out to study the effect of Laser shot peening on SMA surface to improve the interfacial strength. Variation in debonding stress due to length of SMA wire reinforced in epoxy are investigated for non-peened and peened SMA wires. Experimental results of interfacial strength variation due to various L/d ratio for non-peened and peened SMA actuator wires in epoxy matrix are discussed

Head and neck imaging manifestations in COVID-19: collective experience of 17 months during 2nd wave of the pandemic

Abstract Background COVID-19 is well known to result in pulmonary and multiple extra-pulmonary manifestations. Among them, head and neck manifestations were commonly recognized in the 2nd wave of the pandemic. With the growing global COVID-19 burden, imaging is of utmost importance in diagnosing the disease and its related complications. The study aims to enumerate the various head and neck manifestations and their complications in COVID-19. Additionally, in sinusitis patients, the invasion was correlated with the neutrophil–lymphocyte ratio (NLR). Results A cross-sectional observational study in which total of 78 COVID-19 cases that underwent head and neck imaging were retrospectively evaluated. The cohort included 52 males (66.7%) and 26 females (33.3%) with a mean age of 46.19 years (median = 49.0, SD = 16.47). The various head and neck manifestations included non invasive rhinosinusitis (n = 48), invasive sinusitis and its complications (n = 25), nasal septal abscess (n = 1), dacryoadenitis (n = 1), pre-septal and post-septal orbital cellulitis and its complications (n = 13), otitis media, mastoiditis and its complications (n = 6), parotitis (n = 2), neck vessel thrombosis (n = 2) and cervical lymphadenopathy (n = 3). An increase in the invasive nature of sinusitis was demonstrated among patients with comorbidities and elevated NLR. Conclusions Early diagnosis and management of head and neck manifestations of COVID-19 are aided by prompt imaging. It is imperative that we are armed with the knowledge of various head and neck manifestations and how they may bear semblance to other pathologies for us to ensure COVID as a differential, especially in the background of known infection

Vancomycin population pharmacokinetics in critically ill adults during sustained low-efficiency dialysis

Background: Sustained low-efficiency dialysis (SLED) is a hybrid form of dialysis that is increasingly used in critically ill patients with kidney injury and hemodynamic instability. Antimicrobial dosing for patients receiving SLED is informed by pharmacokinetic studies that describe the drug clearance. Studies available to assist in the dosing of vancomycin in the context of SLED are lacking. Objective: The objective of this prospective observational study was to describe the population pharmacokinetics of vancomycin in critically ill patients receiving SLED, and use simulation studies to propose dosing strategies. Methods: Serial serum samples were obtained from 31 critically ill patients prescribed vancomycin while receiving SLED. Vancomycin concentrations were quantified in plasma using a validated liquid chromatography mass spectrometry/mass spectrometry method. A population pharmacokinetic model was developed, and Monte Carlo simulation was used to determine the probability of target attainment at different doses. Results: From a total of 335 serum samples from 31 patients receiving 52 sessions of SLED therapy, a two-compartment linear model with zero-order input was developed. The mean (standard deviation) clearance of vancomycin on and off SLED was 5.97 (4.04) and 2.40 (1.46)\ua0L/h, respectively. Using pharmacodynamic targets for efficacy (area under the concentration–time curve from time zero to 24\ua0h [AUC]/minimum inhibitory concentration [MIC] ≥ 400) and safety (AUC ≥ 700), a loading dose of 2400\ua0mg followed by daily doses of 1600\ua0mg is recommended. Subsequent dosing should be informed by therapeutic drug monitoring of vancomycin levels. Conclusions: In critically ill patients receiving SLED, vancomycin clearance is highly variable with a narrow therapeutic window. Empiric dosing is proposed but subsequent dosing should be guided by drug levels

An integrated radiology-pathology machine learning classifier for outcome prediction following radical prostatectomy: Preliminary findingsKey points

Objectives: To evaluate the added benefit of integrating features from pre-treatment MRI (radiomics) and digitized post-surgical pathology slides (pathomics) in prostate cancer (PCa) patients for prognosticating outcomes post radical-prostatectomy (RP) including a) rising prostate specific antigen (PSA), and b) extraprostatic-extension (EPE). Methods: Multi-institutional data (N = 58) of PCa patients who underwent pre-treatment 3-T MRI prior to RP were included in this retrospective study. Radiomic and pathomic features were extracted from PCa regions on MRI and RP specimens delineated by expert clinicians. On training set (D1, N = 44), Cox Proportional-Hazards models MR, MP and MRaP were trained using radiomics, pathomics, and their combination, respectively, to prognosticate rising PSA (PSA > 0.03 ng/mL). Top features from MRaP were used to train a model to predict EPE on D1 and test on external dataset (D2, N = 14). C-index, Kalplan-Meier curves were used for survival analysis, and area under ROC (AUC) was used for EPE. MRaP was compared with the existing post-treatment risk-calculator, CAPRA (MC). Results: Patients had median follow-up of 34 months. MRaP (c-index = 0.685 ± 0.05) significantly outperformed MR (c-index = 0.646 ± 0.05), MP (c-index = 0.631 ± 0.06) and MC (c-index = 0.601 ± 0.071) (p < 0.0001). Cross-validated Kaplan-Meier curves showed significant separation among risk groups for rising PSA for MRaP (p < 0.005, Hazard Ratio (HR) = 11.36) as compared to MR (p = 0.64, HR = 1.33), MP (p = 0.19, HR = 2.82) and MC (p = 0.10, HR = 3.05). Integrated radio-pathomic model MRaP (AUC = 0.80) outperformed MR (AUC = 0.57) and MP (AUC = 0.76) in predicting EPE on external-data (D2). Conclusions: Results from this preliminary study suggest that a combination of radiomic and pathomic features can better predict post-surgical outcomes (rising PSA and EPE) compared to either of them individually as well as extant prognostic nomogram (CAPRA)

Enhanced Wear Resistance in Carbon Nanotube-Filled Bio-Epoxy Composites: A Comprehensive Analysis via Scanning Electron Microscopy and Atomic Force Microscopy

This investigation focuses on the wear resistance and surface morphology of multi-walled carbon nanotube (MWCNT)-filled bio-based epoxy composites. This study examines the impact of different MWCNT concentrations (0 Wt.%, 0.25 Wt.%, 0.50 Wt.%, and 0.75 Wt.%) on the wear properties of these composites. Techniques such as scanning electron microscopy (SEM) and atomic force microscopy (AFM) were utilized for comprehensive surface characterization. The results demonstrated a direct correlation between the MWCNT content and the wear resistance of the composites, which were corroborated by robust statistical analysis. Furthermore, SEM and AFM observations disclosed incremental enhancements in both wear resistance and surface quality as the MWCNT concentration increased. This research not only augments the understanding of wear mechanisms in bio-based epoxy composites but also aligns with the burgeoning focus on sustainable materials

Piperacillin population pharmacokinetics in critically ill adults during sustained low-efficiency dialysis

Background: Sustained low-efficiency dialysis (SLED), is increasingly being used in intensive care units (ICUs) but studies informing drug dosing for such patients is lacking. Objective: To describe the population pharmacokinetics (PKs) of piperacillin/tazobactam in critically ill adults receiving SLED and to provide dosing recommendations. Methods: This prospective population PK study was conducted in adult ICU patients prescribed piperacillin/tazobactam while receiving SLED; 321 blood samples were obtained from 34 participants during and between approximately 50 SLED treatments for quantification of piperacillin and tazobactam concentrations in plasma. A population PK model was developed. Monte Carlo simulation was used to determine the probability of target attainment and pathogen-specific fractional target attainment at different doses. Results: From a 2-compartment linear model with zero-order input, the mean (SD) clearance of piperacillin on SLED and off SLED were 4.81 (8.48) and 1.42 (1.54) L/h, respectively. Tazobactam concentrations were not sufficient for analysis. For the target of 50% fT>MIC (unbound concentrations of drug are above the minimum inhibitory concentration for >50% of the dosing interval), 3-g of piperacillin infused over 0.5 hours every 8 hours was appropriate for susceptible organisms with MIC ≤16 mg/L. For life-threatening infections where the target of 100% fT>MIC is preferred, a 9-g dose administered as a continuous infusion every 24 hours was appropriate for susceptible organisms with MIC ≤32 mg/L. Conclusions and Relevance: In critically ill patients receiving SLED, piperacillin doses need to be guided by the frequency of SLED treatments and susceptibility of the known or suspected pathogen