Synthesis and cytotoxicity evaluation of N-(2-oxo-2-((5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)amino)ethyl)-2-phenylacetamide derivatives as apoptosis inducers with potential anticancer effects

Introduction: The statistics show that the numbers of cancer reports is increasing and need for development of new anticancer drugs is a principal aim in current medicinal chemistry. Due to very limitations of current antineoplastic therapeutics such as high incidence of adverse effects and intuitive resistance of tumor, discovery of new anticancer agents feel to be crucial. Methods and Results: Synthesis and cytotoxicity assessment of 1,3,4-thiadiazole derivatives led to the discovery of new compounds with potential anticancer activity. MTT assay was done against three cancerous cell lines containing PC3 (prostate carcinoma), HT-29 (human colon adenocarcinoma) and SKNMC(neuroblastoma) in comparison with doxorubicin as reference drug. All synthesized compounds were identified using spectroscopic techniques like 1HNMR, IR and MS. The synthesized derivatives were afforded with high yields. All target compounds were tested against MCF-7 (breast cancer), H1299 (non-small cell lung carcinoma), A2780 (ovarian carcinoma). Tested derivatives exhibited favorable anticancer activity in vitro compared to doxorubicin in MTT assay. Various derivatives such as Cl, Br, CH3 and F substituents were the best moieties for para positions of the phenyl ring (less than 1 µM). Some of tested compounds with these moieties showed superior activity than doxorubicin. Caspases activation was also explored for tested derivatives. Conclusions: The 1,3,4-thiadiazole derivatives that prepared in the current project displayed significant anticancer activity and apoptosis induction. These agents could be proposed as novel anticancer lead compounds

Persia, the Land of Shiite Faith: The Migration of Imam Ahl al-Bayt and the Encounter between Two Belief Systems in Persia

This article attempts to trace the fundamental role of early Persian beliefs, Zoroastrians, to the decision of Ahl al-Bayt’s choice to migrate to Persia (Iran). This research is based on the fact that there are many places for pilgrimage to imams in Iran.  Specifically, this research investigates the similarity of several concepts in both religions, Zoroaster and Islam, regarding the teaching in the principle of God (Ilahiyyah), the principle of life after death (eschatology), and the principle of justice and morals of the religion embraced before Islam in Persia. Several studies have also reported on the distortions, opposition, and the consequences of encountering the two beliefs for the first time between Persian beliefs and Islamic teachings. This study employs a qualitative method with historical analysis and literature study along with relevant information of the study.  This article also uses the theory of migration and identity to see the interconnectedness of religion in the migration context. The results of this study show the factors that the Persians are interested in accepting and understanding the teachings of Islam. Those are: first, the emotional closeness of beliefs and moral values between Muslims and Zoroastrians (Magi); Second, the inclusive nature of Islam; third, the absence of racial, gender, and status discrimination in Islamic teachings. The descendants of imams Ahl al-Bayt of the Prophet Muhammad SAW continued the prophet's preaching and the Imams in expanding the spread of Islamic teachings to various regions. During this expansion process, they found Iran as the most secure, and suitable region to accept the presence and teaching of Islam especially the Shiite sect. Therefore, they decided to migrate to Iran, and until now Iran is known as a Shiite country

Synthesis, Cytotoxicity Assessment, and Molecular Docking of 4-Substituted-2-p-tolylthiazole Derivatives as Probable c-Src and erb Tyrosine Kinase Inhibitors

In the current project we focused on the synthesis of 4-Substituted-2-p-tolylthiazole derivatives. Cytotoxicity of synthesized compounds were evaluated against T47D breast cancer cell line and also all of the final compounds 3−7 were docked into the active site of c-Src and erb tyrosine kinases. Compound 4 was the most potent derivative in cytotoxicity assay (IC50 = 2.5 µg/mL) and it was also the most potent inhibitor of erb tyrosine kinase (Binding free energy: −10.18 kcal/mol).(doi: 10.5562/cca1939

Preclinical studies conducted on nanozyme antioxidants: Shortcomings and challenges based on US FDA regulations

The wide prevalence of oxidative stress-induced diseases has led to a growing demand for antioxidant therapeutics worldwide. Nanozyme antioxidants are drawing enormous attention as practical alternatives for conventional antioxidants. The considerable body of research over the last decade and the promising results achieved signify the potential of nanozyme antioxidants to secure a place in the expanding market of antioxidant therapeutics. Nonetheless, there is no report on clinical trials for their further evaluation. Through analyzing in-depth selected papers which have conducted in vivo studies on nanozyme antioxidants, this review aims to pinpoint and discuss possible reasons impeding development of research toward clinical studies and to offer some practical solutions for future studies to bridge the gap between preclinical and clinical stages. "We did not experience these kinds of strange illnesses in the past." Everybody might have heard such a familiar sentence from their grandparents and asked themselves, why? The current paper aims to provide readers with one of the answers: "Oxidative stress", which happens when the body fails to neutralize damage caused by unstable molecules called free radicals. In this paper, the authors present the seriousness of oxidative stress-induced clinical conditions. They discuss one of the promising treatments, nanozyme antioxidants, these are mostly based on nano-sized materials with enzyme-like function, in other words, they can speed up chemical reactions. Despite significant results, nanozyme antioxidants have not been investigated in clinical studies. This paper intends to search for the main reasons for this and suggest possible solutions. © 2021 Future Medicine Ltd

A combinatorial cell-laden gel microarray for inducing osteogenic differentiation of human mesenchymal stem cells

Development of three dimensional (3D) microenvironments that direct stem cell differentiation into functional cell types remains a major challenge in the field of regenerative medicine. Here, we describe a new platform to address this challenge by utilizing a robotic microarray spotter for testing stem cell fates inside various miniaturized cell-laden gels in a systematic manner. To demonstrate the feasibility of our platform, we evaluated the osteogenic differentiation of human mesenchymal stem cells (hMSCs) within combinatorial 3D niches. We were able to identify specific combinations, that enhanced the expression of osteogenic markers. Notably, these ‘hit' combinations directed hMSCs to form mineralized tissue when conditions were translated to 3D macroscale hydrogels, indicating that the miniaturization of the experimental system did not alter stem cell fate. Overall, our findings confirmed that the 3D cell-laden gel microarray can be used for screening of different conditions in a rapid, cost-effective, and multiplexed manner for a broad range of tissue engineering applications

Three doses of a recombinant conjugated SARS-CoV-2 vaccine early after allogeneic hematopoietic stem cell transplantation: predicting indicators of a high serologic response—a prospective, single-arm study

BackgroundAllogeneic hematopoietic stem cell transplant (allo-HSCT) recipients must be vaccinated against SARS-CoV-2 as quickly as possible after transplantation. The difficulty in obtaining recommended SARS-CoV-2 vaccines for allo-HSCT recipients motivated us to utilize an accessible and affordable SARS-CoV-2 vaccine with a recombinant receptor-binding domain (RBD)–tetanus toxoid (TT)-conjugated platform shortly after allo-HSCT in the developing country of Iran.MethodsThis prospective, single-arm study aimed to investigate immunogenicity and its predictors following a three-dose SARS-CoV-2 RBD–TT-conjugated vaccine regimen administered at 4-week (± 1-week) intervals in patients within 3–12 months post allo-HSCT. An immune status ratio (ISR) was measured at baseline and 4 weeks (± 1 week) after each vaccine dose using a semiquantitative immunoassay. Using the median ISR as a cut-off point for immune response intensity, we performed a logistic regression analysis to determine the predictive impact of several baseline factors on the intensity of the serologic response following the third vaccination dose.ResultsThirty-six allo-HSCT recipients, with a mean age of 42.42 years and a median time of 133 days between hematopoietic stem cell transplant (allo-HSCT) and the start of vaccination, were analyzed. Our findings, using the generalized estimating equation (GEE) model, indicated that, compared with the baseline ISR of 1.55 [95% confidence interval (CI) 0.94 to 2.17], the ISR increased significantly during the three-dose SARS-CoV-2 vaccination regimen. The ISR reached 2.32 (95% CI 1.84 to 2.79; p = 0.010) after the second dose and 3.87 (95% CI 3.25 to 4.48; p = 0.001) after the third dose of vaccine, reflecting 69.44% and 91.66% seropositivity, respectively. In a multivariate logistic regression analysis, the female sex of the donor [odds ratio (OR) 8.67; p = 0.028] and a higher level donor ISR at allo-HSCT (OR 3.56; p = 0.050) were the two positive predictors of strong immune response following the third vaccine dose. No serious adverse events (i.e., grades 3 and 4) were observed following the vaccination regimen.ConclusionsWe concluded that early vaccination of allo-HSCT recipients with a three-dose RBD–TT-conjugated SARS-CoV-2 vaccine is safe and could improve the early post-allo-HSCT immune response. We further believe that the pre-allo-HSCT SARS-CoV-2 immunization of donors may enhance post-allo-HSCT seroconversion in allo-HSCT recipients who receive the entire course of the SARS-CoV-2 vaccine during the first year after allo-HSCT

Measuring universal health coverage based on an index of effective coverage of health services in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

© 2020 Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license Background: Achieving universal health coverage (UHC) involves all people receiving the health services they need, of high quality, without experiencing financial hardship. Making progress towards UHC is a policy priority for both countries and global institutions, as highlighted by the agenda of the UN Sustainable Development Goals (SDGs) and WHO's Thirteenth General Programme of Work (GPW13). Measuring effective coverage at the health-system level is important for understanding whether health services are aligned with countries' health profiles and are of sufficient quality to produce health gains for populations of all ages. Methods: Based on the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, we assessed UHC effective coverage for 204 countries and territories from 1990 to 2019. Drawing from a measurement framework developed through WHO's GPW13 consultation, we mapped 23 effective coverage indicators to a matrix representing health service types (eg, promotion, prevention, and treatment) and five population-age groups spanning from reproductive and newborn to older adults (≥65 years). Effective coverage indicators were based on intervention coverage or outcome-based measures such as mortality-to-incidence ratios to approximate access to quality care; outcome-based measures were transformed to values on a scale of 0–100 based on the 2·5th and 97·5th percentile of location-year values. We constructed the UHC effective coverage index by weighting each effective coverage indicator relative to its associated potential health gains, as measured by disability-adjusted life-years for each location-year and population-age group. For three tests of validity (content, known-groups, and convergent), UHC effective coverage index performance was generally better than that of other UHC service coverage indices from WHO (ie, the current metric for SDG indicator 3.8.1 on UHC service coverage), the World Bank, and GBD 2017. We quantified frontiers of UHC effective coverage performance on the basis of pooled health spending per capita, representing UHC effective coverage index levels achieved in 2019 relative to country-level government health spending, prepaid private expenditures, and development assistance for health. To assess current trajectories towards the GPW13 UHC billion target—1 billion more people benefiting from UHC by 2023—we estimated additional population equivalents with UHC effective coverage from 2018 to 2023. Findings: Globally, performance on the UHC effective coverage index improved from 45·8 (95% uncertainty interval 44·2–47·5) in 1990 to 60·3 (58·7–61·9) in 2019, yet country-level UHC effective coverage in 2019 still spanned from 95 or higher in Japan and Iceland to lower than 25 in Somalia and the Central African Republic. Since 2010, sub-Saharan Africa showed accelerated gains on the UHC effective coverage index (at an average increase of 2·6% [1·9–3·3] per year up to 2019); by contrast, most other GBD super-regions had slowed rates of progress in 2010–2019 relative to 1990–2010. Many countries showed lagging performance on effective coverage indicators for non-communicable diseases relative to those for communicable diseases and maternal and child health, despite non-communicable diseases accounting for a greater proportion of potential health gains in 2019, suggesting that many health systems are not keeping pace with the rising non-communicable disease burden and associated population health needs. In 2019, the UHC effective coverage index was associated with pooled health spending per capita (r=0·79), although countries across the development spectrum had much lower UHC effective coverage than is potentially achievable relative to their health spending. Under maximum efficiency of translating health spending into UHC effective coverage performance, countries would need to reach $1398 pooled health spending per capita (US$ adjusted for purchasing power parity) in order to achieve 80 on the UHC effective coverage index. From 2018 to 2023, an estimated 388·9 million (358·6–421·3) more population equivalents would have UHC effective coverage, falling well short of the GPW13 target of 1 billion more people benefiting from UHC during this time. Current projections point to an estimated 3·1 billion (3·0–3·2) population equivalents still lacking UHC effective coverage in 2023, with nearly a third (968·1 million [903·5–1040·3]) residing in south Asia. Interpretation: The present study demonstrates the utility of measuring effective coverage and its role in supporting improved health outcomes for all people—the ultimate goal of UHC and its achievement. Global ambitions to accelerate progress on UHC service coverage are increasingly unlikely unless concerted action on non-communicable diseases occurs and countries can better translate health spending into improved performance. Focusing on effective coverage and accounting for the world's evolving health needs lays the groundwork for better understanding how close—or how far—all populations are in benefiting from UHC. Funding: Bill & Melinda Gates Foundation

Mapping local patterns of childhood overweight and wasting in low- and middle-income countries between 2000 and 2017

A double burden of malnutrition occurs when individuals, household members or communities experience both undernutrition and overweight. Here, we show geospatial estimates of overweight and wasting prevalence among children under 5 years of age in 105 low- and middle-income countries (LMICs) from 2000 to 2017 and aggregate these to policy-relevant administrative units. Wasting decreased overall across LMICs between 2000 and 2017, from 8.4% (62.3 (55.1–70.8) million) to 6.4% (58.3 (47.6–70.7) million), but is predicted to remain above the World Health Organization’s Global Nutrition Target of <5% in over half of LMICs by 2025. Prevalence of overweight increased from 5.2% (30 (22.8–38.5) million) in 2000 to 6.0% (55.5 (44.8–67.9) million) children aged under 5 years in 2017. Areas most affected by double burden of malnutrition were located in Indonesia, Thailand, southeastern China, Botswana, Cameroon and central Nigeria. Our estimates provide a new perspective to researchers, policy makers and public health agencies in their efforts to address this global childhood syndemic

Mapping 123 million neonatal, infant and child deaths between 2000 and 2017

Since 2000, many countries have achieved considerable success in improving child survival, but localized progress remains unclear. To inform efforts towards United Nations Sustainable Development Goal 3.2—to end preventable child deaths by 2030—we need consistently estimated data at the subnational level regarding child mortality rates and trends. Here we quantified, for the period 2000–2017, the subnational variation in mortality rates and number of deaths of neonates, infants and children under 5 years of age within 99 low- and middle-income countries using a geostatistical survival model. We estimated that 32% of children under 5 in these countries lived in districts that had attained rates of 25 or fewer child deaths per 1,000 live births by 2017, and that 58% of child deaths between 2000 and 2017 in these countries could have been averted in the absence of geographical inequality. This study enables the identification of high-mortality clusters, patterns of progress and geographical inequalities to inform appropriate investments and implementations that will help to improve the health of all populations

Mapping child growth failure across low- and middle-income countries

Child growth failure (CGF), manifested as stunting, wasting, and underweight, is associated with high 5 mortality and increased risks of cognitive, physical, and metabolic impairments. Children in low- and middle-income countries (LMICs) face the highest levels of CGF globally. Here we illustrate national and subnational variation of under-5 CGF indicators across LMICs, providing 2000–2017 annual estimates mapped at a high spatial resolution and aggregated to policy-relevant administrative units and national levels. Despite remarkable declines over the study period, many LMICs remain far from the World Health 10 Organization’s ambitious Global Nutrition Targets to reduce stunting by 40% and wasting to less than 5% by 2025. Large disparities in prevalence and rates of progress exist across regions, countries, and within countries; our maps identify areas where high prevalence persists even within nations otherwise succeeding in reducing overall CGF prevalence. By highlighting where subnational disparities exist and the highest-need populations reside, these geospatial estimates can support policy-makers in planning locally 15 tailored interventions and efficient directing of resources to accelerate progress in reducing CGF and its health implications