Forced Degradation Studies and Development and Validation of HPLC-UV Method for the Analysis of Velpatasvir Copovidone Solid Dispersion.

Analytical methods for the drug substance and degradation products (DPs) are validated by performing forced degradation studies. Forced degradation studies of Velpatasvir (VEL) drug substance and Velpatasvir copovidone solid dispersion (VEL-CSD) were performed under the stressed alkaline, acidic, oxidative and thermal conditions according to ICH guidelines ICH Q1A (R2). VEL is labile to degrade in stressed alkaline, acidic, and oxidative conditions. It is also photolabile and degraded during photostability studies as described by ICH Q1B, and showed no degradation on exposure to extreme temperature when protected from light. A sensitive stability indicating HPLC-UV method was developed and validated for the separation of VEL and eight DPs. The DPs of VEL are separated using gradient elution of mobile phase containing 0.05% Trifluoroacetic acid (TFA) and methanol over symmetry analytical column C18 (250 mm × 4.6 mm, 5 µm) with a flow rate of 0.8 mL min-1. Simultaneous detection of all DPs and VEL was performed on UV detector at 305 nm. The performance parameters like precision, specificity and linearity of the method were validated using reference standards as prescribed by ICHQ2 (R1). Limits of quantification and limits of detection were determined from calibration curve using the expression 10δ/slope and 3δ/slope respectively. The proposed method is stability-indicating and effectively applied to the analysis of process impurities and DPs in VEL drug substance and VEL-CSD.

COVID-19 vaccinations: The unknowns, challenges, and hopes.

The entire world has been suffering from the coronavirus disease 2019 (COVID-19) pandemic since March 11, 2020. More than a year later, the COVID-19 vaccination brought hope to control this viral pandemic. Here, we review the unknowns of the COVID-19 vaccination, such as its longevity, asymptomatic spread, long-term side effects, and its efficacy on immunocompromised patients. In addition, we discuss challenges associated with the COVID-19 vaccination, such as the global access and distribution of vaccine doses, adherence to hygiene guidelines after vaccination, the emergence of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, and vaccine resistance. Despite all these challenges and the fact that the end of the COVID-19 pandemic is still unclear, vaccines have brought great hope for the world, with several reports indicating a significant decline in the risk of COVID19-related infection and hospitalizations.

In silico functional and tumor suppressor role of hypothetical protein PCNXL2 with regulation of the Notch signaling pathway.

Since the last decade, various genome sequencing projects have led to the accumulation of an enormous set of genomic data; however, numerous protein-coding genes still need to be functionally characterized. These gene products are called "hypothetical proteins". The hypothetical protein pecanex-like protein 2 Homo sapiens (PCNXL2) is found to be mutated in colorectal carcinoma with microsatellite instability; therefore, annotation of the function of PCNXL2 in tumorigenesis is very important. In the present study, bioinformatics analysis of PCNXL2 was performed at the molecular level to assess its role in the progression of cancer for designing new anti-cancer drugs. The retrieved sequence of PCNXL2 was functionally and structurally characterized through the web tools Pfam, Batch CD (conserved domain) search, ExPASy, COACH and I-TASSER directed for pathway analysis and design to explore the intercellular interactions of PCNXL2 involved in cancer development. The present study has shown that PCNXL2 encodes multi-pass transmembrane proteins whose tumor suppressor function may involve regulating Notch signaling by transporting protons across the membrane to provide suitable membrane potential for γ secretase function, which may liberate the Notch intracellular domain NICD from the receptor to inside the cell. Furthermore, domain A of PCNXL2 may exhibit nuclear transport activity of NICD from the cytoplasm to the nucleus through interaction with a nuclear localization signal that may act as an activator for Notch signaling in the nucleus. Conclusively, the tumor suppressor role of PCNXL2 by regulation of the Notch signaling pathway and its functional and structural characteristics are important findings. However, further studies are required to validate the putative role of PCNXL2 as a cancer biomarker in cancer development.

Potential involvement of mi-RNA 574-3p in progression of prostate cancer: A bioinformatic study.

Aberrant gene expression is a hallmark of prostate cancer (PCa), the second deadliest disease affecting males worldwide. Dysregulation of miRNA has been associated with the progression of PCa and in recent studies, miRNA 574-3p was found to be upregulated in cancerous prostate tissue. In this study, we characterize the effects of upregulated miRNA 574-3p on gene expression in the tumor microenvironment through different bioinformatic tools such as Diana-Tools, the KEGG Pathway Database, and the Reactome Database. We have identified nine regulatory genes that are targeted by miRNA 574-3p and downregulated in prostate cells. Pathway analysis of these genes shows that they are involved in the regulation of the Notch signaling pathway, Wnt signaling pathway, apoptosis, DNA damage response, G1 to S cell-cycle control, inflammatory response pathway, angiogenesis, translation factors, and the expression of oncogenes. Our results show the oncogenic potential of miRNA 574-3p in PCa progression and metastasis. Moreover, this study highlights the complex molecular mechanisms and pathways affected by the upregulation of miRNA 574-3p in prostate cells. In future studies, the presented data may aid in designing new therapies for PCa with improved efficacy.

Effects of health on changing labor force participation in Pakistan.

ABSTRACT: The objective of the study investigates the effects of health on changing labor force participation during Pakistan's economic transition in the 1980s, a period of several economic liberalization and international integration on the health and financial sectors. The study employed the autoregressive distributed lag (ARDL) co-integration technique to estimate the short- and long-run elasticities, while the Wald coefficient restrictions tests was used to determine the dynamic short-run causality between the variables over a period of 1975-2011. The study was limited to a few variables, including age dependency, health expenditures, trade openness, population per bed, life expectancy, gross capital formation, mortality rate, secondary school enrolment and labor force participation rate, in order to manage robust data analysis. The results suggest that infant mortality rate (IMR), gross capital formation (GCF) and secondary school enrolment (SSE) decrease the labor force participation rate in the long-run, as if there is one percent increase IMR, GCF and SSE, labor force participation decreases by 0.653 percent, 0.137 percent and 0.220 percent respectively, however, these results invert the relationship in short-run. The study also finds that health expenditures has positive and significant impact on labor force participation rate in the short-run, but this result disappear in the long-run. Trade liberalization has a positive effect in the short run, while a negative effect is observed in the long run upon labor force participation rate of Pakistan. The study confirms that Pakistan did not enjoy substantial growth benefits related to health care because human capital (secondary school enrolment), trade openness, public investment and infant mortality rate have a negative impact on labor force participation rate. These findings have important policy implications. JEL CODES: H51, I21, J21.