Rpd3l contributes to the DNA damage sensitivity of saccharomyces cerevisiae checkpoint mutants

DNA replication forks that are stalled by DNA damage activate an S-phase checkpoint that prevents irreversible fork arrest and cell death. The increased cell death caused by DNA damage in budding yeast cells lacking the Rad53 checkpoint protein kinase is partially suppressed by deletion of the EXO1 gene. Using a whole-genome sequencing approach, we identified two additional genes, RXT2 and RPH1, whose mutation can also partially suppress this DNA damage sensitivity. We provide evidence that RXT2 and RPH1 act in a common pathway, which is distinct from the EXO1 pathway. Analysis of additional mutants indicates that suppression works through the loss of the Rpd3L histone deacetylase complex. Our results suggest that the loss or absence of histone acetylation, perhaps at stalled forks, may contribute to cell death in the absence of a functional checkpoint.Cancer Research UK FC001066UK Medical Research Council FC001066Wellcome Trust FC001066European Molecular Biology Organization ALTF 263–2011European Research Council Advanced 669424-CHROMORE

A Review: Radioactive Microspheres as a Theranostics

Microspheres as a drug delivery system hold great promise in reaching the goal of controlled drug delivery as well as site specific delivery. In the last few decades, scientific and technological advancements have been made in the research and development of radio labeled microspheres. These are used successfully for the treatment of various cancers and tumors. Since response to chemotherapy and external radiotherapy is not so effective and hazardous too, so an alternative to this is internal radiation therapy. These radio labeled microspheres are very stable and have a proven efficacy in the field of primary as well as metastatic cancers. Radioactive microspheres can be selectively targeted to various tumors without undue radiation to the nontumorous tissues. The radioactive microspheres are injected to halt tumor growth via the blood supply, thereby enabling surgical removal once the tumor size decreases. This review provides an outlook to various aspects of radioactive microspheres and their role in treatment of various tumors and cancers

Nanosuspension: a novel approach to enhance solubility of poorly water soluble drugs- A review

Solubility is the crucial factor for drug effectiveness, independence of the route of administration. Large proportion of newly discovered drugs are water insoluble and therefore poorly bioavailable contributing to desert development effort. Nanosuspensions have emerged as a promising strategy for the efficicent delivery of hydrophilic drugs because of their versatile features and unique advantages. The reduction of drug particles into submicron range leads to a significant increase in dissolution rate and therefore enhances bioavailability. Nanosuspension contain submicron colloidal dispersion of the pharmaceutical active ingredient particles in a liquid phase stabilised by surfactant. Nanosuspensions can be delivered by oral and non-oral route of administration. Study is focused on various methods of preparation with advantages and disadvantages, characterization properties, applications

Formulation And Development Of Nanosuspension As An Alternative Approach For Solubility And Dissolution Enhancement Of Aceclofenac

Main objectives to develop Aceclofenac Nanosuspension are to enhance solubility and dissolution rate of poorly soluble Drug (aceclofenac), substantially leading to its bioavailability enhancement and Improvement of aqueous and saturation solubility in turn rapid release of Drug which leads to enhancing therapeutic efficacy. Aceclofenac Nanosuspension was prepared by quasi solvent evaporation method with help of different polymer and concentration. There was changes polymer ratio, volume of organic solvent and stirring speed. Aceclofenac nanosuspension gives immediate release. Aceclofenac nanosuspension were showing highest dissolution rate within 10 minutes comparison with marketed formulations. Aceclofenac Nanosuspension compacts may enhance aqueous solubility and dissolution rate in compare to other solubility enhancement technique hence, this research work may be useful to formulate Aceclofenac Nanosuspension which may give rapid onset of action by rapid absorption, maximize efficacy, dose frequency and hence increase patient Compliance

A review- Recent research on microsponge a novel new drug delivery system

Microsponge is recent novel technique for control release and target specific drug delivery system. Therefore many scientist or researcher attracted towards the microsponge drug delivery system. Also Microsponge technology has been introduced in topical drug products to facilitate the controlled release of active drug into the skin in order to reduce systemic exposure and minimize local cutaneous reactions to active drugs. More and more developments in delivery systems are being integrated to optimize the efficacy and cost-effectiveness of the therapy. Microsponge technology offers entrapment of ingredients and is believed to contribute towards reduced side effects, improved stability, increased elegance, and enhanced formulation flexibility. In addition, numerous studies have confirmed that microsponge systems are non-irritating, non-mutagenic, non-allergenic, and non-toxic. Microsponge drug delivery system technology is being used currently in cosmetics, over-the-counter (OTC) skin care, sunscreens and prescription products

Role of CBP and SATB-1 in Aging, Dietary Restriction, and Insulin-Like Signaling

Increased transcriptional complex activity, or pharmacological mimics of increased complex activity, predict lifespan in mice and mediate the protective effects of dietary restriction during aging

Functional antibody and T-cell immunity following SARS-CoV-2 infection, including by variants of concern, in patients with cancer: the CAPTURE study

Patients with cancer have higher COVID-19 morbidity and mortality. Here we present the prospective CAPTURE study (NCT03226886) integrating longitudinal immune profiling with clinical annotation. Of 357 patients with cancer, 118 were SARS-CoV-2-positive, 94 were symptomatic and 2 patients died of COVID-19. In this cohort, 83% patients had S1-reactive antibodies, 82% had neutralizing antibodies against WT, whereas neutralizing antibody titers (NAbT) against the Alpha, Beta, and Delta variants were substantially reduced. Whereas S1-reactive antibody levels decreased in 13% of patients, NAbT remained stable up to 329 days. Patients also had detectable SARS-CoV-2-specific T cells and CD4+ responses correlating with S1-reactive antibody levels, although patients with hematological malignancies had impaired immune responses that were disease and treatment-specific, but presented compensatory cellular responses, further supported by clinical. Overall, these findings advance the understanding of the nature and duration of immune response to SARS-CoV-2 in patients with cancer

The evolution of lung cancer and impact of subclonal selection in TRACERx

Lung cancer is the leading cause of cancer-associated mortality worldwide. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource

Genomic–transcriptomic evolution in lung cancer and metastasis

Intratumour heterogeneity (ITH) fuels lung cancer evolution, which leads to immune evasion and resistance to therapy. Here, using paired whole-exome and RNA sequencing data, we investigate intratumour transcriptomic diversity in 354 non-small cell lung cancer tumours from 347 out of the first 421 patients prospectively recruited into the TRACERx study. Analyses of 947 tumour regions, representing both primary and metastatic disease, alongside 96 tumour-adjacent normal tissue samples implicate the transcriptome as a major source of phenotypic variation. Gene expression levels and ITH relate to patterns of positive and negative selection during tumour evolution. We observe frequent copy number-independent allele-specific expression that is linked to epigenomic dysfunction. Allele-specific expression can also result in genomic–transcriptomic parallel evolution, which converges on cancer gene disruption. We extract signatures of RNA single-base substitutions and link their aetiology to the activity of the RNA-editing enzymes ADAR and APOBEC3A, thereby revealing otherwise undetected ongoing APOBEC activity in tumours. Characterizing the transcriptomes of primary–metastatic tumour pairs, we combine multiple machine-learning approaches that leverage genomic and transcriptomic variables to link metastasis-seeding potential to the evolutionary context of mutations and increased proliferation within primary tumour regions. These results highlight the interplay between the genome and transcriptome in influencing ITH, lung cancer evolution and metastasis