Antiproliferative effect of indeno[1,2-d]thiazolo[3,2-a]pyrimidine analogues on IL-6 mediated STAT3 and role of the apoptotic pathway in albino Wistar rats of ethyl carbamate-induced lung carcinoma: In-silico, In-vitro, and In-vivo study.

Lung cancer (LC) ranks second most prevalent cancer in females after breast cancer and second in males after prostate cancer. Based on the GLOBOCAN 2020 report, India represented 5.9% of LC cases and 8.1% of deaths caused by the disease. Several clinical studies have shown that LC occurs because of biological and morphological abnormalities and the involvement of altered level of antioxidants, cytokines, and apoptotic markers. In the present study, we explored the antiproliferative activity of indeno[1,2-d]thiazolo[3,2-a]pyrimidine analogues against LC using in-vitro, in-silico, and in-vivo models. In-vitro screening against A549 cells revealed compounds 9B (8-methoxy-5-(3,4,5-trimethoxyphenyl)-5,6-dihydroindeno[1,2-d]thiazolo[3,2-a]pyrimidine) and 12B (5-(4-chlorophenyl)-5,6-dihydroindeno[1,2-d]thiazolo[3,2-a]pyrimidine) as potential pyrimidine analogues against LC. Compounds 9B and 12B were docked with different molecular targets IL-6, Cyt-C, Caspase9, and Caspase3 using AutoDock Vina 4.1 to evaluate the binding affinity. Subsequently, in-vivo studies were conducted in albino Wistar rats through ethyl-carbamate (EC)- induced LC. 9B and 12B imparted significant effects on physiological (weight variation), and biochemical (anti-oxidant [TBAR's, SOD, ProC, and GSH), lipid (TC, TG, LDL, VLDL, and HDL)], and cytokine (IL-2, IL-6, IL-10, and IL-1ß) markers in EC-induced LC in albino Wistar rats. Morphological examination (SEM and H&E) and western blotting (IL-6, STAT3, Cyt-C, BAX, Bcl-2, Caspase3, and caspase9) showed that compounds 9B and 12B had antiproliferative effects. Accordingly, from the in-vitro, in-silico, and in-vivo experimental findings, we concluded that 9B and 12B have significant antiproliferative potential and are potential candidates for further evaluation to meet the requirements of investigation of new drug application.

Interaction of the III-As monolayer with SARS-CoV-2 biomarkers: implications for biosensor development.

The emergence of SARS-CoV-2 in 2019 led to the global COVID-19 pandemic, highlighting the urgency for developing cost-effective and non-invasive methods to detect diseases at an early stage. Human breath, rich in volatile organic compounds (VOCs), is promising for cost-effective and rapid disease detection, with specific VOCs like methanol, ethanal, butanone, acetone, and ethyl butyrate linked to COVID-19. Recent advances in biomarker detection and gas sensing with 2D materials, particularly III-As monolayers like BAs, GaAs, and AlAs, offer high sensitivity at low concentrations, providing a novel avenue for exploring their potential in detecting COVID-19 biomarkers. This article aims to examine the effects of adsorption on different properties of III-Arsenide (BAs, GaAs and AlAs) monolayers, particularly in connection with SARS-CoV-2 biomarkers. In order to examine the interaction between the monolayers and biomarkers, first-principles computations within the framework of density functional theory (DFT) are utilized. The present study involves an investigation of the modifications in the band structure, density of states (DOS), work function, electron density difference, and optical properties (reflectance and absorbance) of III-As monolayers, with the aim of assessing their viability for the detection of SARS-CoV-2 biomarkers along with interfering gases such as CO2 and H2O. It is observed that VOCs induce a notable change in the work function of GaAs which serves as an indicator of the presence of these biomarkers. However, the changes in work function are not as substantial as those for AlAs and BAs. Additionally, the chemiresistive sensitivity, optical sensitivity and recovery time of III-As are investigated. The findings suggest that the pristine GaAs monolayer displays a significant level of sensitivity and selectivity towards the SARS-CoV-2 biomarkers, rendering it a material with potential for utilization in sensing applications. Furthermore, it has been observed that the recovery time of the GaAs monolayer subsequent to its exposure to the VOC biomarkers lies within an acceptable threshold. Upon exposure to UV light, the recovery time is further reduced. The outcomes of our study indicate that GaAs monolayers exhibit considerable potential as chemiresistive, work function-based and optical sensors for the precise and discerning identification of VOCs linked to the SARS-CoV-2 virus compared to the other two III-As monolayers.

Physician antimicrobial prescribing and patient outcomes on general medical wards: a multicentre retrospective cohort study.

BACKGROUND: Variability in antimicrobial prescribing may indicate an opportunity for improvement in antimicrobial use. We sought to measure physician-level antimicrobial prescribing in adult general medical wards, assess the contribution of patient-level factors to antimicrobial prescribing and evaluate the association between antimicrobial prescribing and clinical outcomes. METHODS: Using the General Medicine Inpatient Initiative (GEMINI) database, we conducted a retrospective cohort study of physician-level volume and spectrum of antimicrobial prescribing in adult general medical wards in 4 academic teaching hospitals in Toronto, Ontario, between April 2010 and December 2019. We stratified physicians into quartiles by hospital site based on volume of antimicrobial prescribing (days of therapy per 100 patient-days and antimicrobial-free days) and antibacterial spectrum (modified spectrum score). The modified spectrum score assigns a value to each antibacterial agent based on the breadth of coverage. We assessed patient-level differences among physician quartiles using age, sex, Laboratory-based Acute Physiology Score, discharge diagnosis and Charlson Comorbidity Index. We evaluated the association of clinical outcomes (in-hospital 30-day mortality, length of stay, intensive care unit [ICU] transfer and hospital readmission) with antimicrobial volume and spectrum using multilevel modelling. RESULTS: The cohort consisted of 124 physicians responsible for 124 158 hospital admissions. The median physician-level volume of antimicrobial prescribing was 56.1 (interquartile range 51.7-67.5) days of therapy per 100 patient-days. We did not find any differences in baseline patient characteristics by physician prescribing quartile. The difference in mean prescribing between quartile 4 and quartile 1 was 15.8 days of therapy per 100 patient-days (95% confidence interval [CI] 9.6-22.0), representing 30% higher antimicrobial prescribing in the fourth quartile than the first quartile. Patient in-hospital deaths, length of stay, ICU transfer and hospital readmission did not differ by physician quartile. In-hospital mortality was higher among patients cared for by prescribers with higher modified spectrum scores (odds ratio 1.13, 95% CI 1.04-1.24). INTERPRETATION: We found that physician-level variability in antimicrobial prescribing was not associated with differences in patient characteristics or outcomes in academic general medicine wards. These findings provide support for considering the lowest quartile of physician antimicrobial prescribing within each hospital as a target for antimicrobial stewardship.

Recent developments in the creation of a single molecular sensing tool for ternary iron (III), chromium (III), aluminium (III) ionic species: A review.

Rational design of a molecular sensing tool is an important topic in molecular recognition, signalling, and optoelectronics that has piqued the interest of chemists, biologists, and environmental scientists. Approximately 150 years have passed since the beginning of the fluorescent chemosensor sector. Due to the paramagnetic properties of Cr3+ and Al3+ , it is tough to prepare a photoluminescence plug-in detector. Most dye-based Al3+ sensors must be utilized in organic or mixed solvents for robust hydration of Al3+ in water. The sophisticated molecular design of sensors, conversely, allows for the detection of these metal ions in aqueous medium. The design of chemosensors using various fluorophores and their mechanisms of action have been thoroughly discussed. A literature survey covering the design of chemosensors and their mechanisms of action have been thoroughly discussed covering the period 2010-2022 and that was carried out including innovative and exemplary activities from numerous groups throughout the world that have significantly contributed to this sector. The most important advantages of these probes are their aqueous solubility and quick response with outstanding selectivity and sensitivity for temporal distribution with high fidelity of metals in living cells.

Strong Coupling of Chiral Frenkel Exciton for Intense, Bisignate Circularly Polarized Luminescence.

We show that chiral Frenkel excitons yield intense circularly polarized luminescence with an intrinsic dissymmetry factor in emission glum as high as 0.08. This outstanding value is measured through thin films of cyanine J-aggregates that form twisted bundles. Our measurements, obtained by a Mueller polarization analysis, are artifact-free and reveal a quasi-perfect correlation between the dissymmetry factors in absorption, gabs , and in emission glum . We interpret the bisignate dissymmetry factors as the signature of a strong coupling between chiral Frenkel excitons longitudinally excited along the bundles. We further resolve by polarimetry analysis the split in energy between the excited states with a Davydov splitting as small as 28 meV. We finally show the anti-Kasha nature of the chiral emission bands with opposite optical chirality. These mirror-imaged emissive chiroptical features emerge from the structural rigidity of the bundles that preserves the ground- and excited-state chirality.

Dietary Fiber, Insulin and Breast Tissue Composition at Age 15-18: A Cross-Sectional Study.

BACKGROUND: Risk of breast cancer in adult life is influenced by body size and height in childhood, but the mechanisms responsible for these associations are currently unknown. We carried out research to determine if, at age 15-18, measures of dietary intake were associated with body size, hormones, and with variations in breast tissue composition that in adult life are associated with risk of breast cancer. METHODS: In a cross-sectional study of 766 healthy Caucasian women aged 15-18, we measured percent breast water (PBW), total breast water and fat by magnetic resonance (MR), and assessed dietary intake using a validated food frequency questionnaire. We also measured height, weight, skin-fold thicknesses and waist-to-hip ratio, and in fasting blood assayed glucose and insulin. RESULTS: After adjustment for age, measures of body size, and energy intake, dietary fiber (insoluble and total fiber) and insulin were associated positively and significantly with PBW. CONCLUSIONS: Dietary fiber and fasting insulin were associated with breast tissue measures. These data suggest a potential approach to breast cancer prevention.

Diversity among health care leaders in Canada: a cross-sectional study of perceived gender and race.

BACKGROUND: Diverse health care leadership teams may improve health care experiences and outcomes for patients. We sought to explore the race and gender of hospital and health ministry executives in Canada and compare their diversity with that of the populations they serve. METHODS: This cross-sectional study included leaders of Canada's largest hospitals and all provincial and territorial health ministries. We included individuals listed on institutional websites as part of the leadership team if a name and photo were available. Six reviewers coded and analyzed the perceived race and gender of leaders, in duplicate. We compared the proportion of racialized health care leaders with the race demographics of the general population from the 2016 Canadian Census. RESULTS: We included 3056 leaders from 135 institutions, with reviewer concordance on gender for 3022 leaders and on race for 2946 leaders. Reviewers perceived 37 (47.4%) of 78 health ministry leaders as women, and fewer than 5 (< 7%) of 80 as racialized. In Alberta, Saskatchewan, Prince Edward Island and Nova Scotia, provinces with a centralized hospital executive team, reviewers coded 36 (50.0%) of 72 leaders as women and 5 (7.1%) of 70 as racialized. In British Columbia, New Brunswick and Newfoundland and Labrador, provinces with hospital leadership by region, reviewers perceived 120 (56.1%) of 214 leaders as women and 24 (11.5%) of 209 as racialized. In Manitoba, Ontario and Quebec, where leadership teams exist at each hospital, reviewers perceived 1326 (49.9%) of 2658 leaders as women and 243 (9.2%) of 2633 as racialized. We calculated the representation gap between racialized executives and the racialized population as 14.5% for British Columbia, 27.5% for Manitoba, 20.7% for Ontario, 12.4% for Quebec, 7.6% for New Brunswick, 7.3% for Prince Edward Island and 11.6% for Newfoundland and Labrador. INTERPRETATION: In a study of more than 3000 health care leaders in Canada, gender parity was present, but racialized executives were substantially under-represented. This work should prompt health care institutions to increase racial diversity in leadership.

Outcomes in patients with and without disability admitted to hospital with COVID-19: a retrospective cohort study.

BACKGROUND: Disability-related considerations have largely been absent from the COVID-19 response, despite evidence that people with disabilities are at elevated risk for acquiring COVID-19. We evaluated clinical outcomes in patients who were admitted to hospital with COVID-19 with a disability compared with patients without a disability. METHODS: We conducted a retrospective cohort study that included adults with COVID-19 who were admitted to hospital and discharged between Jan. 1, 2020, and Nov. 30, 2020, at 7 hospitals in Ontario, Canada. We compared in-hospital death, admission to the intensive care unit (ICU), hospital length of stay and unplanned 30-day readmission among patients with and without a physical disability, hearing or vision impairment, traumatic brain injury, or intellectual or developmental disability, overall and stratified by age (≤ 64 and ≥ 65 yr) using multivariable regression, controlling for sex, residence in a long-term care facility and comorbidity. RESULTS: Among 1279 admissions to hospital for COVID-19, 22.3% had a disability. We found that patients with a disability were more likely to die than those without a disability (28.1% v. 17.6%), had longer hospital stays (median 13.9 v. 7.8 d) and more readmissions (17.6% v. 7.9%), but had lower ICU admission rates (22.5% v. 28.3%). After adjustment, there were no statistically significant differences between those with and without disabilities for in-hospital death or admission to ICU. After adjustment, patients with a disability had longer hospital stays (rate ratio 1.36, 95% confidence interval [CI] 1.19-1.56) and greater risk of readmission (relative risk 1.77, 95% CI 1.14-2.75). In age-stratified analyses, we observed longer hospital stays among patients with a disability than in those without, in both younger and older subgroups; readmission risk was driven by younger patients with a disability. INTERPRETATION: Patients with a disability who were admitted to hospital with COVID-19 had longer stays and elevated readmission risk than those without disabilities. Disability-related needs should be addressed to support these patients in hospital and after discharge.

Visible light-promoted photocatalyst-free activation of persulfates: a promising strategy for C-H functionalization reactions.

The employment of renewable energy resources is highly desirable according to the twelve principles of green chemistry. In this context, visible light promoted organic transformations have gained much attention from synthetic chemists due to the employment of renewable energy. However, the inability of the majority of organic molecules to absorb visible light encouraged the use of photocatalysts in visible light-mediated organic transformations. As a result, different types of photocatalysts like transition-metal containing photoredox catalysts, organophotoredox catalysts, heterogeneous photocatalysts, etc. have emerged over the years. On the other hand, persulphates (K2S2O8, Na2S2O8, and (NH4)2S2O8) have been widely used as oxidants in various oxidative organic transformations under thermal and photochemical conditions. The initial formation of an active persulfate radical anion from a persulfate anion is the crucial step for these oxidative transformations and the conversions under visible light are generally carried out employing different photocatalysts. Although numerous methodologies have been successfully developed employing these photocatalysts, the development of new processes under photocatalyst-free conditions are more preferable from the viewpoint of sustainable development. Persulphates could be very useful for various organic transformations through C-H functionalizations under photocatalyst-free visible light irradiation. In this review, we will exemplify the efficiency of persulphates in various oxidative organic transformations under visible light irradiation without the employment of any photocatalysts. The utilities and mechanistic pathways of the methodologies will also be highlighted.

Outcomes for upper gastrointestinal bleeding during the first wave of the COVID-19 pandemic in the Toronto area.

BACKGROUND AND AIM: Changes to endoscopy service availability during the COVID-19 pandemic may have affected management of upper gastrointestinal bleeding (UGIB). The aim of this study was to describe the impact of the pandemic on UGIB outcomes in the Toronto area in Canada. METHODS: We described all adults admitted to general medicine wards or intensive care units at six hospitals in Toronto and Mississauga, Canada, with UGIB during the first wave of the COVID-19 pandemic (March 1 to June 30, 2020) and compared them with a historical cohort (March 1 to June 30, 2018 and 2019). We compared clinical outcomes (in-hospital mortality, length of stay, 30-day readmission, intensive care utilization, receipt of endoscopy, persistent bleeding, receipt of second endoscopy, and need for angiographic or surgical intervention) using multivariable regression models, controlling for demographics, comorbidities, and severity of clinical presentation. RESULTS: There were 82.5 and 215.5 admissions per month for UGIB during the COVID-19 and control periods, respectively. There were no baseline differences between groups for demographic characteristics, comorbidities, or severity of bleeding. Patients in the COVID-19 group did not have significantly different unadjusted (3.9% vs 4.2%, P = 0.983) or adjusted mortality (adjusted odds ratio [OR] = 0.64, 95% confidence interval [CI] = 0.25-1.48, P = 0.322). Patients in COVID-19 group were less likely to receive endoscopy for UGIB in the unadjusted (61.8% vs 71.0%, P = 0.003) and adjusted (adjusted OR = 0.64, 95% CI = 0.49-0.84, P < 0.01) models. There were no differences between groups for other secondary outcomes. CONCLUSIONS: While patients admitted for UGIB during the first wave of the pandemic were less likely to receive endoscopy, this had no impact on mortality or any secondary outcomes.

Fabrication of Imatinib Mesylate-Loaded Lactoferrin-Modified PEGylated Liquid Crystalline Nanoparticles for Mitochondrial-Dependent Apoptosis in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a major cause of concern as it has substantial morbidity associated with it. Previous reports have ascertained the antiproliferative activity of imatinib mesylate (IMS) against diverse types of carcinomas, but limited bioavailability has also been reported. The present study envisaged optimized IMS-loaded lactoferrin (LF)-modified PEGylated liquid crystalline nanoparticles (IMS-LF-LCNPs) for effective therapy of IMS to HCC via asialoglycoprotein receptor (ASGPR) targeting. Results displayed that IMS-LF-LCNPs presented an optimum particle size of 120.40 ± 2.75 nm, a zeta potential of +12.5 ± 0.23 mV, and 73.94 ± 2.69% release. High-resolution transmission electron microscopy and atomic force microscopy were used to confirm the surface architecture of IMS-LF-LCNPs. The results of cytotoxicity and 4,6-diamidino-2-phenylindole revealed that IMS-LF-LCNPs had the highest growth inhibition and significant apoptotic effects. Pharmacokinetics and biodistribution studies showed that IMS-LF-LCNPs have superior pharmacokinetic performance and targeted delivery compared to IMS-LCNPs and plain IMS, which was attributed to the targeting action of LF that targets the ASGPR in hepatic cells. Next, our in vivo experiment established that the HCC environment existed due to suppression of BAX, cyt c, BAD, e-NOS, and caspase (3 and 9) genes, which thus owed upstream expression of Bcl-xl, iNOS, and Bcl-2 genes. The excellent therapeutic potential of IMS-LF-LCNPs began the significant stimulation of caspase-mediated apoptotic signals accountable for its anti-HCC prospect. 1H nuclear magnetic resonance (serum) metabolomics revealed that IMS-LF-LCNPs are capable of regulating the disturbed levels of metabolites linked to HCC triggered through N-nitrosodiethylamine. Therefore, IMS-LF-LCNPs are a potentially effective formulation against HCC.

Changes in the dollar value of per capita alcohol, essential, and non-essential retail sales in Canada during COVID-19.

BACKGROUND: Multiple survey reports suggest that alcohol use has increased in Canada during the COVID-19 pandemic. However, less is known about how per capita alcohol sales, which predict population-level alcohol use, have changed and whether changes in alcohol sales differ from changes in sales of other products due to pandemic factors. METHODS: We obtained monthly retail sales data by industry from Statistics Canada, for the six largest provinces in Canada (containing 93% of the national population), between January 2010 and November 2020, representing time before and 9 months after the start of the pandemic in Canada. We used an interrupted time series analysis to estimate pandemic impacts on the dollar value of monthly per capita (per individuals 15+ years) alcohol, essential and non-essential retail sales. We adjusted our analyses for pre-pandemic sales trends, inflation, seasonality and changing population demographics over time. RESULTS: During the first 9 months of the pandemic, the values of per capita alcohol, essential and non-essential sales were, respectively, 13.2% higher, 3.6% higher and 13.1% lower than the average values during the same period in the prior 3 years. Interrupted time series models showed significant level change for the value of monthly per capita alcohol sales (+$4.86, 95% CIs: 2.88, 6.83), essential sales (-$59.80, 95% CIs: - 78.47, - 41.03) and non-essential sales (-$308.70, 95% CIs: - $326.60, - 290.79) during the pandemic. Alcohol sales were consistently elevated during the pandemic, and the pre- and post-pandemic slopes were comparable. In contrast, essential and non-essential retail sales declined in the early months of the pandemic before returning to regular spending levels. CONCLUSION: During the first 9 months of the pandemic, per capita alcohol sales were moderately elevated in Canada. In contrast, non-essential sales were lower than prior years, driven by large decreases during the initial months of the pandemic. These findings suggest that the pandemic was associated with increased population-level alcohol consumption, which may lead to increased alcohol-related harms. Ongoing research is needed to examine how factors, including pandemic-related stressors and specific alcohol sales-related policies, may have influenced changes in alcohol use and harms.

SARS-CoV-2: Pathogenic Mechanisms and Host Immune Response.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an enveloped, positive-sense RNA coronavirus responsible for the COVID-19 pandemic. Since December 2019, coronavirus disease 2019 (COVID-19) has affected more than 127 million people, 2.7 million deaths globally (as per WHO dashboard, dated 31 March, 2020), the virus is capable of transmitting from human to human via inhalation of infected respiratory droplets or aerosols or contact with infected fomites. Clinically, patients with COVID-19 present with severe respiratory distress syndrome, which is very similar to the presentation of other respiratory viral infections. A huge variation in the host response exists, with the resulting symptoms varying from mild to moderate. Comorbidities such as cardiovascular disease, hypertension, diabetes, coagulation dysfunction, stroke, malignant tumor and multiple organ dysfunction syndrome, as well as age and sex, are associated with severe COVID-19 cases. So far, no targeted therapies have been developed to treat this disease and existing drugs are being investigated for repurposing. This chapter discusses the epidemiology, clinical features of COVID-19, pathogenesis and the innate and adaptive immune response mounted by the host to the SARS-CoV-2 infection. A deeper understanding of the host-pathogen interaction is fundamental to the development of a vaccine.

Assessments of in vitro and in vivo antineoplastic potentials of ß-sitosterol-loaded PEGylated niosomes against hepatocellular carcinoma.

ß-sitosterol (BS), a phytosterol, exhibits ameliorative effects on hepatocellular carcinoma (HCC) due to its antioxidant activities. However, its poor aqueous solubility and negotiated bioavailability and short elimination half-life is a huge limitation for its therapeutic applications. To overcome these two shortcomings, BS-loaded niosomes were made to via, film hydration method and process parameters were optimized using a three-factor Box-Behnken design. The optimized formulation (BSF) was further surface-modified with polyethylene glycol (PEG). The resulting niosomes (BSMF) have spherical shapes, particle sizes, 219.6 ± 1.98 nm with polydispersity index (PDI) and zeta potential of 0.078 ± 0.04 and -19.54 ± 0.19 mV, respectively. The drug loading, entrapment efficiency, and drug release at 24 h of the BSMF were found to be 16.72 ± 0.09%, 78.04 ± 0.92%, and 75.10 ± 3.06%, respectively. Moreover, BSMF showed significantly greater cytotoxic potentials on Hep G2 cells with an enhanced cellular uptake relative to pure BS and BSF. The BSMF also displayed potentially improved curative property of HCC in albino wistar rat. Thus, the BSMF could be one of the promising therapeutic modalities for HCC treatment in terms of targeting potential resulting in enhanced therapeutic efficacy.

Human Cytomegalovirus miR-UL70-3p Downregulates the H2O2-Induced Apoptosis by Targeting the Modulator of Apoptosis-1 (MOAP1).

Human Cytomegalovirus (HCMV) is a prototypic beta herpesvirus, causing persistent infections in humans. There are medications that are used to treat the symptoms; however, there is no cure yet. Thus, understanding the molecular mechanisms of HCMV replication and its persistence may reveal new prevention strategies. HCMV evasive strategies on the antiviral responses of the human host largely rely on its significant portion of genome. Numerous studies have highlighted the importance of miRNA-mediated regulation of apoptosis, which is an innate immune mechanism that eradicates virus-infected cells. In this study, we explore the antiapoptotic role of hcmv-miR-UL70-3p in HEK293T cells. We establish that hcmv-miR-UL70-3p targets the proapoptotic gene Modulator of Apoptosis-1 (MOAP1) through interaction with its 3'UTR region of mRNA. The ectopic expression of hcmv-miR-UL70-3p mimic significantly downregulates the H2O2-induced apoptosis through the translational repression of MOAP1. Silencing of MOAP1 through siRNA also inhibits the H2O2-induced apoptosis, which further supports the hcmv-miR-UL70-3p mediated antiapoptotic effect by regulating MOAP1 expression. These results uncover a role for hcmv-miR-UL70-3p and its target MOAP1 in regulating apoptosis.

Instrumental variable estimation of early treatment effect in randomized screening trials.

The primary analysis of randomized screening trials for cancer typically adheres to the intention-to-screen principle, measuring cancer-specific mortality reductions between screening and control arms. These mortality reductions result from a combination of the screening regimen, screening technology and the effect of the early, screening-induced, treatment. This motivates addressing these different aspects separately. Here we are interested in the causal effect of early versus delayed treatments on cancer mortality among the screening-detectable subgroup, which under certain assumptions is estimable from conventional randomized screening trial using instrumental variable type methods. To define the causal effect of interest, we formulate a simplified structural multi-state model for screening trials, based on a hypothetical intervention trial where screening detected individuals would be randomized into early versus delayed treatments. The cancer-specific mortality reductions after screening detection are quantified by a cause-specific hazard ratio. For this, we propose two estimators, based on an estimating equation and a likelihood expression. The methods extend existing instrumental variable methods for time-to-event and competing risks outcomes to time-dependent intermediate variables. Using the multi-state model as the basis of a data generating mechanism, we investigate the performance of the new estimators through simulation studies. In addition, we illustrate the proposed method in the context of CT screening for lung cancer using the US National Lung Screening Trial data.

Self validating Mueller matrix Micro-Mesoscope (SAMMM) for the characterization of biological media.

Reflectance Mueller matrix (MM) polarimetry is being used to characterize biological media in multiple clinical applications. The origin of the reflectance polarimetric data is often unclear due to the impact of multiple scattering and tissue heterogeneity. We have developed a new, to the best of our knowledge, multimodal imaging technique combining MM reflectance, MM digital confocal imaging, and co-registered nonlinear microscopy techniques. The instrument unveils the origin of reflectance polarimetric signature in terms of confocal reflectance data. The reconstructed reflected MM demonstrates the capability of our method to provide depth-resolved 3D polarization response from complex biological media in terms of depolarization, retardance, and orientation parameters.

Novel 1,3,4-thiadiazoles inhibit colorectal cancer via blockade of IL-6/COX-2 mediated JAK2/STAT3 signals as evidenced through data-based mathematical modeling.

We attempted a preclinical study using DMH-induced CRC rat model to evaluate the antitumor potential of our recently synthesized 1,3,4-thiadiazoles. The molecular insights were confirmed through ELISA, qRT-PCR and western blot analyses. The CRC condition was produced in response to COX-2 and IL-6 induced activation of JAK2/STAT3 which, in turn, was due to the enhanced phosphorylation of JAK2 and STAT3. The treatment with 1,3,4-thiadiazole derivatives (VR24 and VR27) caused the significant blockade of this signaling pathway. The behavior of STAT3 populations in response to IL-6 and COX-2 stimulations was further confirmed through data-based mathematical modeling using the quantitative western blot data. Finally, VR24 and VR27 restored the perturbed metabolites associated to DMH-induced CRC as evidenced through 1H NMR based serum metabolomics. The tumor protecting ability of VR24 and VR27 was found comparable or to some degree better than the marketed chemotherapeutics, 5-flurouracil.

"Dial-In" Emission from a Unique Flexible Material with Polarization Tuneable Spectral Intensity.

The development of organic photoluminescent materials, which show promising roles as catalysts, sensors, organic light-emitting diodes, logic gates, etc., is a major demand and challenge for the global scientific community. In this context, a photoclick polymerization method is adopted for the growth of a unique photoluminescent three-dimensional (3D) polymer film, E, as a model system that shows emission tunability over the range 350-650 nm against the excitation range 295-425 nm. The DFT analysis of energy calculations and π-stacking supports the spectroscopic observations for the material exhibiting a broad range of emission owing to newly formed chromophoric units within the film. Full polarization spectroscopic Mueller matrix studies were employed to extract and quantify the molecular orientational order of both the ground (excitation) and excited (emission) state anisotropies through a set of newly defined parameters, namely the fluorescence diattenuation and fluorescence polarizance. The information contained in the recorded fluorescence Mueller matrix of the organic polymer material provided a useful way to control the spectral intensity of emission by using pre- and post-selection of polarization states. The observation was based on the assumption that the longer lifetime of the excited dipolar orientation is attributed to the compactness of the film.

Antineoplastic properties of zafirlukast against hepatocellular carcinoma via activation of mitochondrial mediated apoptosis.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwideand haslimited treatment options. In view of this, zafirlukast (ZAF) was administered orally to DEN-induced HCC rats to evaluate its antineoplastic properties. ELISA, qRT-PCR and Western blot were used to determine the molecular mechanism associated with ZAF therapy for HCC. We found that HCC developed as a result of lower expression of caspases 3 and 9, but their levels returned to normal when the expression of eNOS, BAX, BAD, and Cyt C was decreased and when the expression of iNOS, Bcl-xl, and Bcl-2 was increased. Again, ZAF (80 mg/kg dose) treatment normalized the expression of caspase-mediated apoptotic factors, i.e. BAX and Bcl-2 proteins, as established through Western blot analysis. Later, 1H NMR-based serum metabolomics study revealed that levels of perturbed metabolites in DEN-induced rat serum returned to normal after ZAF administration. Altogether, the antineoplastic potential of ZAF was found to be comparable, and to some degree better, than the marketed chemotherapeutic 5-flurouracil, which may be beneficial for anti-HCC treatment from a future drug design perspective.