Since the first case reports in Wuhan, China, the SARS-CoV-2 has caused a pandemic and took lives of > 8,35,000 people globally. This single-stranded RNA virus uses Angiotensin-converting enzyme 2 (ACE2) as a receptor for entry into the host cell. Overexpression of ACE2 is mainly observed in hypertensive, diabetic and heart patients that make them prone to SARS-CoV-2 infection. Mitigations strategies were opted globally by the governments to minimize transmission of SARS-CoV-2 via the implementation of social distancing norms, wearing the facemasks, and spreading awareness using digital platforms. The lack of an approved drug treatment regimen, and non-availability of a vaccine, collectively posed a challenge for mankind to fight against the SARS-CoV-2 pandemic. In this scenario, repurposing of existing drugs and old treatment options like convalescent plasma therapy can be one of the potential alternatives to treat the disease. The drug repurposing provides a selection of drugs based on the scientific rationale and with a shorter cycle of clinical trials, while plasma isolated from COVID-19 recovered patients can be a good source of neutralizing antibody to provide passive immunity. In this review, we provide in-depth analysis on these two approaches currently opted all around the world to treat COVID-19 patients. For this, we used "Boolean Operators" such as AND, OR & NOT to search relevant research articles/reviews from the PUBMED for the repurposed drugs and the convalescent plasma in the COVID-19 treatment. The repurposed drugs like Chloroquine and Hydroxychloroquine, Tenofovir, Remdesivir, Ribavirin, Darunavir, Oseltamivir, Arbidol (Umifenovir), Favipiravir, Anakinra, and Baricitinib are already being used in clinical trials to treat the COVID-19 patients. These drugs have been approved for a different indication and belong to a diverse category such as anti-malarial/anti-parasitic, anti-retroviral/ anti-viral, anti-cancer, or against rheumatoid arthritis. Although, the vaccine would be an ideal option for providing active immunity against the SARS-CoV-2, but considering the current situation, drug repurposing and convalescent plasma therapy and repurposed drugs are the most viable option against SARS-CoV-2. Keywords Cytokine storm syndrome • ARDS • Rheumatoid arthritis • Herd immunity • Vertical transmission • Vaccine nationalism COVID-19 and SARS-CoV-2 virus An infectious disease COVID-19 caused by a virus belongs to the Coronaviridae family was first reported in December 2019 in the Wuhan city of China. Several other lethal viruses such as Severe Acute Respiratory Syndrome-related Coronavirus (SARS-CoV) and Middle Eastern Respiratory Syndrome coronavirus (MERS-CoV) also belong to this family. The SARS-CoV is a single-stranded, enveloped positive-sense strand RNA virus with a genome size between 27 and 34 kilobases that is comparatively larger than other RNA viruses. SARS-CoV-2 driven endemic unfurled into
Glioblastomas (GBMs) are heterogeneous, treatment-resistant tumors driven by populations of cancer stem cells (CSCs). However, few molecular mechanisms critical for CSC population maintenance have been exploited for therapeutic development. We developed a spatially resolved loss-of-function screen in GBM patient-derived organoids to identify essential epigenetic regulators in the SOX2-enriched, therapy-resistant niche and identified WDR5 as indispensable for this population. WDR5 is a component of the WRAD complex, which promotes SET1 family-mediated Lys4 methylation of histone H3 (H3K4me), associated with positive regulation of transcription. In GBM CSCs, WDR5 inhibitors blocked WRAD complex assembly and reduced H3K4 trimethylation and expression of genes involved in CSC-relevant oncogenic pathways. H3K4me3 peaks lost with WDR5 inhibitor treatment occurred disproportionally on POU transcription factor motifs, including the POU5F1(OCT4)::SOX2 motif. Use of a SOX2/OCT4 reporter demonstrated that WDR5 inhibitor treatment diminished cells with high reporter activity. Furthermore, WDR5 inhibitor treatment and WDR5 knockdown altered the stem cell state, disrupting CSC in vitro growth and self-renewal, as well as in vivo tumor growth. These findings highlight the role of WDR5 and the WRAD complex in maintaining the CSC state and provide a rationale for therapeutic development of WDR5 inhibitors for GBM and other advanced cancers.
Reversion of tumor to a normal differentiated cell once considered a dream is now at the brink of becoming a reality. Different layers of molecules/events such as microRNAs, transcription factors, alternative RNA splicing, post-transcriptional, post-translational modifications, availability of proteomics, genomics editing tools, and chemical biology approaches gave hope to manipulation of cancer cells reversion to a normal cell phenotype as evidences are subtle but definitive. Regardless of the advancement, there is a long way to go, as customized techniques are required to be fine-tuned with precision to attain more insights into tumor reversion. Tumor regression models using available genome-editing methods, followed by in vitro and in vivo proteomics profiling techniques show early evidence. This review summarizes tumor reversion developments, present issues, and unaddressed challenges that remained in the uncharted territory to modulate cellular machinery for tumor reversion towards therapeutic purposes successfully. Ongoing research reaffirms the potential promises of understanding the mechanism of tumor reversion and required refinement that is warranted in vitro and in vivo models of tumor reversion, and the potential translation of these into cancer therapy. Furthermore, therapeutic compounds were reported to induce phenotypic changes in cancer cells into normal cells, which will contribute in understanding the mechanism of tumor reversion. Altogether, the efforts collectively suggest that tumor reversion will likely reveal a new wave of therapeutic discoveries that will significantly impact clinical practice in cancer therapy.
Collective cell migration (CCM), where cell-cell integrity remained preserved during the movement, plays an important role in the progression of cancer. However, studies describing CCM in cancer progression are majorly focused on the effect of extracellular tissue components on moving cell plasticity. The molecular and cellular mechanisms of CCM during cancer progression remained poorly explored. Here we report that proteolipid protein 2 (PLP2), a colonic epithelium enriched transmembrane protein, plays a vital role in the CCM of invasive colorectal cancer (CRC) epithelium by modulating leading-edge cell dynamics in 2D (two-dimension). The extracellular pool of PLP2, secreted via exosomes was also found to contribute to the event. During CCM, the protein was found to exist in association with ZO-1 and involved in the positioning of the latter at the migrating edge. PLP2 mediated positioning of ZO-1 at the leading-edge further alters actin cytoskeletal organization that involves Rac1 activation. Together our findings demonstrate that PLP2, via its association with ZO-1, drives the collective cell migration in CRC epithelium by modulating leading-edge actin cytoskeleton and thereby opened up new avenues of cancer research.
Abstract:In this paper we have presented the design of the voice based navigation system for blind using voice recognition module and GPS module implemented on arduino board. This system helps the blind person to navigate. The blind person will give the destination's name as the input to voice recognition module. GPS module continously receives the latitude and longitude of the current location . GPS compares it with the destination's latitude and longitude. The blind person receives the pronounced directions which he needs to follow to reach his destination.
Caloric restriction and vegan diets have demonstrated protective effects for diabetes, however their role in improving clinically relevant outcomes has not been summarized. Our aim was to evaluate the evidence for low-calorie diets (VLCD) and vegan diets on weight and glycemic control in the management of patients with Type 2 Diabetes. Database searches were conducted using Cochrane Library, MEDLINE (Ovid) and Embase. Systematic Review Registration: CRD42022310299. Methodological quality of studies was assessed using Cochrane RoB Tool for RCTs, Cochrane ROBINS-I RoB Tool for non-RCTs and NIH Quality Assessment tool for other studies. Sixteen studies with a total of 834 individuals were included and assessed to have a moderate to high risk of bias. Statistically significant changes in weight, BMI, and HbA1c were not observed in vegan diet cohorts. However, LDL cholesterol was significantly decreased by vegan diet. VLCDs significantly improved glycaemic control, with reductions in fasting glucose, pooled mean difference (MD) −1.51 mmol/L (95% CI −2.89, −0.13; p = 0.03; 2 studies) and HbA1c, pooled MD −0.66% (95% CI −1.28, −0.03; p = 0.04; 3 studies) compared to non-dietary therapy. Both diets suggested a trend towards improved weight loss and anthropometric markers vs. control. VLCD diet intervention is associated with improvement in glycaemia control in patients with Type 2 Diabetes.
Glioblastoma (GBM) progression and resistance to conventional therapies is driven in part by cells within the tumor with stem cell properties including quiescence, self-renewal and drug efflux potential. It is thought that eliminating these cancer stem cells (CSCs) is a key component to successful clinical management of GBM. However, currently, few known molecular mechanisms driving CSCs can be exploited for therapeutic development. Core transcription factors such as SOX2, OLIG2, OCT4 and NANOG maintain the CSC state in GBM. Our laboratory recently uncovered a self-renewal signaling axis involving RBBP5 that is necessary and sufficient for CSC maintenance through driving expression of these core stem cell maintenance transcription factors. RBBP5 is a component of the WRAD complex, which promotes Lys4 methylation of histone H3 to positively regulate transcription. We hypothesized that targeting RBBP5 could be a means to disrupt epigenetic programs that maintain CSCs in stemness transcriptional states. We found that genetic and pharmacologic inhibition of the WRAD complex reduced CSC growth, self-renewal and tumor initiation potential. WRAD inhibitors partially dissembled the WRAD complex and reduced H3K4 trimethylation both globally and at the promoters of key stem cell maintenance transcription factors. Using a CSC reporter system, we demonstrated that WRAD complex inhibition decreased growth of SOX2/OCT4 expressing CSCs in a concentration-dependent manner as quantified by live imaging. Overall, our studies assess the function of the WRAD complex and the effect of WRAD complex inhibitors in preclinical models and specifically on the stem cell state for the first time in GBM. Studying the functions of the WRAD complex in CSCs may improve understanding of GBM pathogenesis and elucidate how CSCs survive despite aggressive chemotherapy and radiation. Our ongoing studies aim to develop brain penetrant inhibitors targeting the WRAD complex as an anti-CSC strategy that could potentially synergize with standard of care treatments.
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