CARs derived from broadly neutralizing, human monoclonal antibodies identified by single B cell sorting target hepatitis B virus-positive cells.

To design new CARs targeting hepatitis B virus (HBV), we isolated human monoclonal antibodies recognizing the HBV envelope proteins from single B cells of a patient with a resolved infection. HBV-specific memory B cells were isolated by incubating peripheral blood mononuclear cells with biotinylated hepatitis B surface antigen (HBsAg), followed by single-cell flow cytometry-based sorting of live, CD19+ IgG+ HBsAg+ cells. Amplification and sequencing of immunoglobulin genes from single memory B cells identified variable heavy and light chain sequences. Corresponding immunoglobulin chains were cloned into IgG1 expression vectors and expressed in mammalian cells. Two antibodies named 4D06 and 4D08 were found to be highly specific for HBsAg, recognized a conformational and a linear epitope, respectively, and showed broad reactivity and neutralization capacity against all major HBV genotypes. 4D06 and 4D08 variable chain fragments were cloned into a 2nd generation CAR format with CD28 and CD3zeta intracellular signaling domains. The new CAR constructs displayed a high functional avidity when expressed on primary human T cells. CAR-grafted T cells proved to be polyfunctional regarding cytokine secretion and killed HBV-positive target cells. Interestingly, background activation of the 4D08-CAR recognizing a linear instead of a conformational epitope was consistently low. In a preclinical model of chronic HBV infection, murine T cells grafted with the 4D06 and the 4D08 CAR showed on target activity indicated by a transient increase in serum transaminases, and a lower number of HBV-positive hepatocytes in the mice treated. This study demonstrates an efficient and fast approach to identifying pathogen-specific monoclonal human antibodies from small donor cell numbers for the subsequent generation of new CARs.

MIL-101(Cr)/aminoclay nanocomposites for conversion of CO2 into cyclic carbonates.

We present the use of an amine functionalized two-dimensional clay i.e., aminoclay (AC), in the chemistry of a three-dimensional metal-organic framework (MOF) i.e., MIL-101(Cr), to prepare MIL-101(Cr)/AC composites, which are exploited as catalysts for efficient conversion of CO2 gas into cyclic carbonates under ambient reaction conditions. Three different MOF nanocomposites, denoted as MIL-101(Cr)/AC-1, MIL-101(Cr)/AC-2, and MIL-101(Cr)/AC-3, were synthesized by an in situ process by adding different amounts of AC to the precursor solutions of the MIL-101(Cr). The composites were characterized by various techniques such as FT-IR, PXRD, FESEM, EDX, TGA, N2 adsorption, as well as CO2 and NH3-TPD measurements. The composites were exploited as heterogeneous catalysts for CO2 cycloaddition reactions with different epoxides and the catalytic activity was investigated at atmospheric pressure under solvent-free conditions. Among all the materials, MIL-101(Cr)/AC-2 shows the best catalytic efficiency under the optimized conditions and exhibits enhanced efficacy compared to various MIL-101(Cr)-based MOF catalysts, which typically need either high temperature and pressure or a longer reaction time or a combination of all the parameters. The present protocol using MIL-101(Cr)/AC-2 as the heterogeneous catalyst gives 99.9% conversion for all the substrates into the products at atmospheric pressure.

Quest for a Desolvated Structure Unveils Breathing Phenomena in a MOF Leading to Greener Catalysis in a Solventless Setup: Insights from Combined Experimental and Computational Studies.

The crystal structure of the metal-organic framework (MOF), {Mn2(1,4-bdc)2(DMF)2}n (1) (1,4-bdcH2, 1,4-benzenedicarboxylic acid; DMF, N,N-dimethylformamide), is known for a long time; however, its desolvated structure, {Mn2(1,4-bdc)2}n (1'), is not yet known. The first-principles-based computational simulation was used to unveil the structure of 1' that shows the expansion in the framework, leading to pore opening after the removal of coordinated DMF molecules. We have used 1' that contains open metal sites (OMSs) in the structure in cyanosilylation and CO2 cycloaddition reactions and recorded complete conversions in a solventless setup. The pore opening in 1' allows the facile diffusion of small aldehyde molecules into the channels, leading to complete conversion. The reactions with larger aldehydes, 2-naphthaldehyde and 9-anthracenecarboxaldehyde, also show 99.9% conversions, which are the highest reported until date in solventless conditions. The in silico simulations illustrate that larger aldehydes interact with Mn(II) OMSs on the surfaces, enabling a closer interaction and facilitating complete conversions. The catalyst shows high recyclability, exhibiting 99.9% conversions in the successive reaction cycles with negligible change in the structure. Our investigations illustrate that the catalyst 1' is economical, efficient, and robust and allows reactions in a solventless greener setup, and therefore the catalysis with 1' can be regarded as "green catalysis".

Cascade testing of children and adolescents for elevated Lp(a) in pedigrees with familial hypercholesterolaemia.

Elevated plasma lipoprotein(a) [Lp(a)] is a common, inherited condition independently causing cardiovascular disease. Recent expert recommendations suggest opportunistically testing for elevated Lp(a) during cascade testing for familial hypercholesterolaemia (FH). We investigated the effectiveness of detecting elevated Lp(a) in 103 children and adolescents who were first-degree relatives of 66 adult index FH cases as part of an established FH cascade screening program. The yield of detection of elevated Lp(a) using a threshold of ≥30 mg/dL in children and adolescents was assessed. Cascade testing from FH index cases with elevated Lp(a) ≥50 mg/dL identified 1 case of Lp(a) ≥30 mg/dL for every 2 children or adolescents tested. In contrast, opportunistic screening from index cases with FH but normal Lp(a) levels demonstrated 1 case of Lp(a) ≥30 mg/dL for every 7.5 children or adolescents tested (p < 0.001). In conclusion, cascade testing for elevated Lp(a) from index cases with FH and elevated Lp(a) is effective in identifying new cases of elevated Lp(a).

Biocompatible Drug Delivery System Based on a MOF Platform for a Sustained and Controlled Release of the Poorly Soluble Drug Norfloxacin.

Norfloxacin (NFX), an important antibacterial fluoroquinolone, is a class IV drug according to the biopharmaceutics classification system (BCS) and has low solubility and permeability issues. Such poor physicochemical properties of drug molecules lead to poor delivery and are of serious concern to the pharmaceutical industry for clinical development. We present here a conceptually new approach to deliver NFX, by loading the drug molecule on the porous platform of a biocompatible metal-organic framework (MOF), MIL-100(Fe). The loading of the drug on the MOF leading to NFX@MIL-100(Fe) was characterized by Fourier transform infrared (FTIR), UV-visible spectroscopy, thermogravimetric analyses (TGA), and nitrogen adsorption studies. Controlled experiments resulted in the high loading of the drug molecule (∼20 wt %) along with the desired sustained release. We could further control the release of norfloxacin by coating drug-loaded MIL-100(Fe) with PEG, PEG{NFX@MIL-100(Fe)}. Both drug delivery systems (DDSs), NFX@MIL-100(Fe) and PEG{NFX@MIL-100(Fe)}, were tested for their biocompatibility through toxicity studies. The DDSs are biocompatible and show insignificant cytotoxicity, as revealed by cell viability studies through the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay.

Metal-organic framework based drug delivery systems as smart carriers for release of poorly soluble drugs hydrochlorothiazide and dapsone.

Drug delivery systems (DDSs) that are derived from biocompatible carriers are attractive platforms for sustained release of drugs. In particular, sustained and controlled release of poorly soluble BCS (Biopharmaceutics Classification System) class IV drugs is important and this requires the development of new DDSs. In this work, we exploit two porous metal-organic frameworks (MOFs) MIL-100(Fe) and MIL-53(Fe) as carriers/DDSs for the release of two BCS class IV drugs hydrochlorothiazide (HCT) and dapsone (DAP). The chosen MOFs are known to possess good physicochemical stability and we realized high drug loading capacity that is attributed to the high porosity of the MOFs. The drug-encapsulated MOFs were characterized thoroughly and our results show ∼23.1% loading of HCT in MIL-100(Fe) and ∼27.6% loading of DAP in MIL-Fe(53), respectively. The release study of these drugs was carried out under simulated physiological conditions that shows sustained release of the drug molecules from the MOFs up to 72 h. Cell viability studies through MTT assays show insignificant cytotoxicity signalling biocompatibility of the proposed DDSs. Our investigations suggest MIL-100(Fe) and MIL-53(Fe) are potential DDSs for enhancing the performance of poorly soluble drugs HCT and DAP.

Effect of in-office bleaching agent on the surface roughness and microhardness of nanofilled and nanohybrid composite resins.

Background: To compare the surface roughness and microhardness of Ceram.x® SphereTEC™ one and Filtek Z350 XT after in-office bleaching with Pola office. Methods: Twenty samples each of (10 mm diameter and 2 mm height) Ceram.x® SphereTEC™ one and Filtek Z350 XT were prepared. The samples were subjected to three bleaching sessions with 35% hydrogen peroxide (Pola office) with a seven-day interval between each session. Surface roughness and microhardness of the prepared samples prior to and after the bleaching regimen were measured using a profilometer and Vickers hardness tester, respectively. Results: A significant reduction (p <0.001) in the surface hardness of Filtek Z350 XT from 27.67 ± 2.10 to 17.83 ± 1.36 Vickers hardness number (VHN) was observed after the bleaching whereas no significant reduction in surface hardness was observed with Ceram.x® SphereTEC™ one. The adjusted mean (estimated marginal mean) microhardness after bleaching for Ceram.x ® SphereTEC™ one (35.79 ± 1.45) was significantly higher than Filtek Z350 XT (19.54 ± 1.45) (p < 0.001). However, in-office bleaching of these materials did not significantly alter their surface roughness. Conclusions: In office-bleaching with 35% hydrogen peroxide can reduce the microhardness of nanofilled composite. However, the surface roughness was not influenced by the bleaching procedure in both nanohybrid and nanofilled composite resin materials.

Exploring the role of CD151 in the tumor immune microenvironment: Therapeutic and clinical perspectives.

CD151 is a transmembrane protein implicated in tumor progression and has been shown to regulate various cellular and molecular mechanisms contributing to malignancy. More recently, the role of CD151 in the tumor immune microenvironment (TIME) has gained attention as a potential target for cancer therapy. This review aims to explore the role of CD151 in the TIME, focusing on the therapeutic and clinical perspectives. The role of CD151 in regulating the interactions between tumor cells and the immune system will be discussed, along with the current understanding of the molecular mechanisms underlying these interactions. The current state of the development of CD151-targeted therapies and the potential clinical applications of these therapies will also be reviewed. This review provides an overview of the current knowledge on the role of CD151 in the TIME and highlights the potential of CD151 as a therapeutic target for cancer treatment.

Proteomic profiling and ROC analysis identify CD151 and ELAVL1 as potential therapy response markers for the antiviral drug in resistant TNBC.

Triple-negative breast cancer is high heterogeneous, aggressive, and metastatic with poor prognosis. Despite of advances in targeted therapies, TNBC has been reported to cause high morbidity and mortality. A rare subpopulation within the tumor microenvironment organized into a hierarchy of cancer stem cells is responsible for therapy resistance and tumor recurrence. Repurposing of antiviral drugs for cancer treatment is gaining momentum due to reduced cost, labour, and research time, but limited due to lack of prognostic, and predictive markers. The present study investigates proteomic profiling and ROC analysis to identify CD151 and ELAVL1 as potential therapy response markers for the antiviral drug 2-thio-6-azauridine (TAU) in resistant TNBC. The stemness of MDA-MB 231 and MDA-MD 468 adherent cells was enriched by culturing them under non-adherent and non-differentiation conditions. Then, CD151+ subpopulation was isolated and characterized for the enrichment of stemness. This study found that CD151 has overexpressed in stemness enriched subpopulations, and also showed CD44 high and CD24 low expression along with stem cell-related transcription factors octamer-binding transcription factor 4 (OCT4) and Sex determining Y-box 2 (SOX2). This study also found that TAU induced significant cytotoxicity and genotoxicity in the CD151+TNBC subpopulation and inhibited their proliferation by inducing DNA damage, cell cycle arrest at the G2M phase, and apoptosis. Further, a proteomic profiling study showed that the expression of CD151 along with ELAVL1, an RNA-binding protein, was significantly reduced with TAU treatment. KM plotter showed correlation of CD151 and ELAVL1 gene expression with a poor prognosis of TNBC. ROC analysis predicted and validated CD151 and ELAVL1 as best therapy response marker for TAU in TNBC. These findings provide new insight into repurposing antiviral drug TAU for treatment of metastatic and drug resistant TNBC.

Complexity and diversity of FOXP3 isoforms: Novel insights into the regulation of the immune response in metastatic breast cancer.

FOXP3 is a key transcription factor in the regulation of immune responses, and recent studies have uncovered the complexity and diversity of FOXP3 isoforms in various cancers, including metastatic breast cancers (mBCs). It has dual role in the tumor microenvironment of mBCs. This review aims to provide novel insights into the complexity and diversity of FOXP3 isoforms in the regulation of the immune response in breast cancer. We discuss the molecular mechanisms underlying the function of FOXP3 isoforms, including their interaction with other proteins, regulation of gene expression, and impact on the immune system. We also highlight the importance of understanding the role of FOXP3 isoforms in breast cancer and the potential for using them as therapeutic targets. This review highlights the crucial role of FOXP3 isoforms in the regulation of the immune response in breast cancer and underscores the need for further research to fully comprehend their complex and diverse functions.

Investigating the synergistic role of heavy metals in Arsenic-induced skin lesions in West Bengal, India.

BACKGROUND: Arsenic toxicity is one of the major health issues throughout the world. Approximately 108 countries that account for more than 230 million people worldwide are at high risk of arsenic poisoning mainly through drinking water and diet. Chronic exposure to arsenic causes several pathophysiological end-points including skin lesions, peripheral neuropathy, cancer, etc. In India, the population living in the lower Gangetic basin possesses a great risk of arsenicosis and other diseases. Scientists are trying to understand the gene-environmental interactions behind arsenic toxicity revealing the potential role of genetic variants of individuals. Few pieces of the literature showed that the population is not exposed to a mixture of metals. Hence, in this study, an attempt has been made to explore whether some other metals play a synergistic role in As-induced toxicity. METHODS: For this, an assessment of the level of heavy metals using ED-XRF in soil, vegetables from As-exposed areas along with quantification of the heavy metal concentration in human blood and hair of the As-exposed population were conducted. RESULTS: Results show the concentration of urinary arsenic is very high signifying the magnitude of the exposure. In addition to this, the levels of iron (Fe), copper (Cu), chromium (Cr) were found to be very high in soil and Fe, manganese (Mn), lead (Pb) in vegetables were exceeding the WHO/FAO recommended permissible limit. However, Fe and zinc (Zn) were predominantly high in whole blood and hair of the arsenic-exposed population when compared with the control population. CONCLUSION: It can be confirmed that the population from Murshidabad is exposed to As and other heavy metals through drinking water as well as food. Particularly for this population, Fe, Zn and rubidium (Rb) may play a synergistic role in arsenic-induced toxicity. However, further studies on the large population-based investigation are required to establish the chemistry of the metal toxicity.

Open metal site (OMS)-inspired investigation of adsorption and catalytic functions in a porous metal-organic framework (MOF).

In this article, we report the adsorption and catalytic study of the three-dimensional (3D) metal-organic framework (MOF) {Mn2(1,4-bdc)2(DMF)2} (1) (1,4-bdcH2, 1,4-benzene dicarboxylic acid; DMF, N,N-dimethylformamide) together with the synthesis and structure of two new Mn(II)-MOFs {Mn3(Br-bdc)3(DMF)4} (2) and {Mn3(NO2-bdc)3(DMF)4} (3) (Br-bdcH2, 2-bromo-1,4-benzene dicarboxylic acid; NO2-bdcH2, 2-nitro-1,4-benzene dicarboxylic acid) under solvothermal conditions. Compounds 2 and 3 have two-dimensional (2D) extended structures and feature trimeric {Mn3(CO2)6} units that serve as secondary building units for the frameworks. The desolvated compound of 1, denoted as 1', having potential Mn(II) open metal sites (OMSs) lined in a one-dimensional (1D) Mn-chain interconnected by carboxylate groups, exhibits guest-selective adsorption of solvent vapours wherein the compound shows a stepwise profile with H2O vapour, while a gated isotherm was recorded with MeOH. After realizing the favourable interaction of 1' with polar solvent molecules, we have used Mn(II) OMSs in 1' for efficient cyanosilylation reactions of aromatic aldehydes. We have recorded 100% conversion for eight aromatic aldehydes, while several other aldehydes showed appreciable conversion. Notably, the recorded conversions in the case of many substrates are higher than those for many other reported MOF catalysts.

Somatic Embryogenesis of Anthurium andraeanum Linden., -A Tropical Florists' Plant.

The global floriculture market is expected to reach US$41.1 billion by 2027 at a CAGR of 5% over the analysis period 2020-2027; on the year 2020, the recorded market value in this trade was US$29.2 billion. The florists mainly use Anthurium andraeanum flowers in fashionable bouquets and floral arrangements because of their beautiful, attractive bright colored eye-catching spathe, candle-like spadix, prolonged vase life, etc. The cut flower industry always seeks elite cultivars and new hybrids of A. andraeanum, that in turn depend on the availability of large numbers of clonal planting propagules. In vitro somatic embryogenesis is an important technique for large-scale clonal propagation, development of transgenic plants, creation of new variety by somaclonal variation, mutagenesis on in vitro plants, and germplasm preservation for future use. Here, we describe the protocol of somatic embryogenesis of Anthurium andraeanum cv. Cancan, an important commercial cultivated variety. The protocol has been optimized by using 4 different types of culture media which are used during embryogenic callus induction, multiplication of callus, induction of somatic embryogenesis, and maturation plus conversion of embryos into plantlets. The protocol outlines the detailed methods from mother plant procurement to hardening of micro plants that is ready to transfer in the field and it can be used for large-scale commercial propagation.

Proteomic profiling of Deinococcus radiodurans with response to thioredoxin reductase inhibitor and ionizing radiation treatment.

This study explains the importance of cellular redox system in preserving the proteome of the radioresistant Deinococcus radiodurans. The thioredoxin reductase (TrxR) redox system was inhibited by ebselen (10 µM), and then the bacterium was exposed to 4 kGy of ionizing radiation. The differentially expressed proteins were analyzed using label-free quantitative (LFQ) proteomics. The 4 kGy radiation treatment increases the expression of stress response proteins like osmotically inducible protein OsmC, catalase, and metallophosphoesterase compared to control. Ebselen plus radiation treatment augments oxidoreductases proteins in D. radiodurans. Further, the proteins involved in glycolysis, tricarboxylic acetic acid (TCA) and proteins like proteases, peptidase, and peptide transporters were significantly decreased in the ebselen plus radiation group compared to radiation treated group. Further, ebselen plus radiation treatment increases the ATP-binding cassette (ABC) transporters involved in the efflux of toxic chemicals and nutrient uptake and the stress response related membrane protein like S-layer homology domain-containing protein in D. radiodurans. Thus, the results show that the altered redox status via inhibition of TrxR redox system significantly affects the expression of essential cellular proteins for the survival. The cellular content of D. radiodurans may be used to handle redox imbalances in the normal cells during cancer radiotherapy. SIGNIFICANCE: Deinococcus radiodurans is a popular radioresistance organism with efficient antioxidant systems and DNA repair mechanisms. There are many antioxidant systems and small molecules that responsible for its resistance. The importance of thiol based antioxidant systems in its resistance property has not fully studied yet. Thioredoxin reductase is an important disulfide containing protein that involved in maintaining redox homeostasis. The TrxR inhibition affects the cell survival and synthesis of molecules against ionizing radiation. In this study we are reporting the effects of TrxR inhibitor on proteome of D. radiodurans upon ionizing radiation. This study reveals the significance of TrxR antioxidant system on the proteome of D. radiodurans. The inhibition of TrxR antioxidant system and the subsequent disturbances in the proteome content makes the organism vulnerable to oxidative stress.

The interaction of oxidative stress with MAPK, PI3/AKT, NF-κB, and DNA damage kinases influences the fate of γ-radiation-induced bystander cells.

Oxidative stress is associated with the induction of a plethora of effects on cellular macromolecules and signaling cascades. The onset of oxidative imbalance characterizes irradiated cells. The present study investigates the effects of ionizing radiation on oxidative stress induction in bystander cells and their interactions with critical cell signaling mediators. The effect of irradiated cell-conditioned medium (ICCM) from γ-irradiated hepatocellular carcinoma (HepG2) cells were studied in bystander HepG2 and normal liver (BRL-3A) cells at early (1 h, 2 h) and later (24 h) time points post-irradiation. Although ROS generation and lipid peroxidation showed the highest effects in both bystander cell groups at the early time points, antioxidant enzymes superoxide dismutase and catalase showed the lowest activity. Oxidative stress was persistent up to 24 h, but the highest level was seen in 1 h ICCM treated 8By cells. Although the levels of all pro-survival signaling factors (p-PI3K, p-Akt, p-p38MAPK, p-JNK, and p-NFκB) increased in bystander HepG2 cells, they showed a significant decrease in bystander BRL-3A cells. JAK2-STAT3 activation, however, was reduced only in BRL-3A cells, with no effect in HepG2 cells. However, in both bystander cell groups, activation of DNA damage sensors ATM, ATR, and cell cycle inhibitor p21 increased. Elevated ROS levels down-regulated the activation of PI3K, Akt, JNK, and NF-κB in BRL-3A cells but enhanced the activation of ATM and p21. In contrast, in HepG2 cells, increased ROS level elevated the activation of PI3K, JNK, p38MAPK, NF-κB with no effect on p-ATM or p21. ROS differentially influenced the interactions between the signaling mediators in the bystander cells. p-ATR levels, although increased in both bystander cell groups, showed no association with other factors. ICCM from the same HepG2 cells differently affected signaling factors in two groups of cells, highlighting the critical significance of the study in the field of radiation biology.

Cascade testing for elevated lipoprotein(a) in relatives of probands with high lipoprotein(a).

Objective: Elevated lipoprotein(a) [Lp(a)] is a common inherited condition associated with cardiovascular disease. This study investigated whether cascade testing for Lp(a) was effective in detecting new cases of elevated Lp(a) in families. Methods: Relatives from adult probands with Lp(a) concentration ≥100 mg/dL were tested for elevated Lp(a) (≥50 mg/dL) via a cascade testing program in a tertiary hospital setting. The prevalence and yield of detecting new cases of elevated Lp(a) among the relatives were assessed. Results: Of the 83 probands, 43.4% had familial combined hyperlipidemia (FCHL) and 34.9% common hypercholesterolemia (CH). Among 182 relatives tested (151 adults and 31 children), elevated Lp(a) was found in 68.1%, with 32.9% having Lp(a) between 50 and 99 mg/dL and 35.2% having Lp(a) ≥100 mg/dL. One new case of elevated Lp(a) ≥50 mg/dL was identified for every 1.5 relatives tested and 1 new case of elevated Lp(a) ≥100 mg/dL for every 2.8 relatives tested. The proportion of relatives detected with elevated Lp(a) was significantly higher when tested from probands with Lp(a) >150 mg/dL compared with those with Lp(a) between 100 and 150 mg/dL (81.1% vs. 55.5%; P = 0.001). The concordance rates (kappa coefficient) for the detection of elevated Lp(a) with FCHL and CH were 34.8% (0.026) and 53.2% (0.099), respectively. Conclusion: Cascade testing for elevated Lp(a) from affected probands with phenotypic dyslipidemia is highly effective in identifying new cases of high Lp(a) in families. The yield of detecting elevated Lp(a) is greater when probands have higher levels of Lp(a) and exceeds the detection of relatives with FCHL and CH.

Diallyl disulfide and diallyl trisulfide in garlic as novel therapeutic agents to overcome drug resistance in breast cancer.

Breast cancer is one of the leading causes of cancer-related deaths in women worldwide. It is a cancer that originates from the mammary ducts and involves mutations in multiple genes. Recently, the treatment of breast cancer has become increasingly challenging owing to the increase in tumor heterogeneity and aggressiveness, which gives rise to therapeutic resistance. Epidemiological, population-based, and hospital-based case-control studies have demonstrated an association between high intake of certain Allium vegetables and a reduced risk in the development of breast cancer. Diallyl disulfide (DADS) and diallyl trisulfide (DATS) are the main allyl sulfur compounds present in garlic, and are known to exhibit anticancer activity as they interfere with breast cancer cell proliferation, tumor metastasis, and angiogenesis. The present review highlights multidrug resistance mechanisms and their signaling pathways in breast cancer. This review discusses the potential anticancer activities of DADS and DATS, with emphasis on drug resistance in triple-negative breast cancer (TNBC). Understanding the anticancer activities of DADS and DATS provides insights into their potential in targeting drug resistance mechanisms of TNBC, especially in clinical studies.

Redox status and metabolomic profiling of thioredoxin reductase inhibitors and 4 kGy ionizing radiation-exposed Deinococcus radiodurans.

The gram-positive bacterium Deinococcus radiodurans can survive under extreme ionizing radiation environment. This study aims to rationalize the role of redox balance, antioxidant status, and metabolite content on the radiation survival of D. radiodurans. We found that the TrxR inhibitors, i.e., ebselen, auranofin, and epigallocatechin gallate (EGCG) (10 µM) treatment affects the radiation survival of D. radiodurans. The TrxR inhibitors treatment affects the redox status, activities of antioxidant enzymes, increases the intracellular ROS levels and protein carbonylation upon 4 kGy ionizing radiation treatments. Moreover, the alteration in cellular redox status affects the metabolites content of the organism. In addition, we noticed differential metabolomic profiles in sham control, radiation control (4 kGy), and TrxR inhibitors plus radiation-treated D. radiodurans. The TrxR inhibitors plus radiation treated groups exhibit more variation compare to sham control and 4 kGy radiation-exposed D. radiodurans. Further, some novel metabolites can possess the high antioxidant property and involved in vital cellular metabolism were found in sham control and radiation treated cells of D. radiodurans. Thus, the results illustrate the role of intracellular redox status in the survival and metabolomic profile of D. radiodurans.

PA1 cells containing a truncated DNA polymerase ß protein are more sensitive to gamma radiation.

PURPOSE: DNA polymerase ß (Polß) acts in the base excision repair (BER) pathway. Mutations in DNA polymerase ß (Polß) are associated with different cancers. A variant of Polß with a 97 amino acid deletion (PolßΔ), in heterozygous conditions with wild-type Polß, was identified in sporadic ovarian tumor samples. This study aims to evaluate the gamma radiation sensitivity of PolßΔ for possible target therapy in ovarian cancer treatment. MATERIALS AND METHODS: PolßΔ cDNA was cloned in a GFP vector and transfected in PA1 cells. Stable cells (PA1PolßΔ) were treated with 60Co sourced gamma-ray (0-15 Gy) to investigate their radiation sensitivity. The affinity of PolßΔ with DNA evaluated by DNA protein in silico docking experiments. RESULTS: The result showed a statistically significant (p < 0.05) higher sensitivity towards radiation at different doses (0-15 Gy) and time-point (48-72 hours) for PA1PolßΔ cells in comparison with normal PA1 cells. Ten Gy of gamma radiation was found to be the optimal dose. Significantly more PA1PolßΔ cells were killed at this dose than PA1 cells after 48 hours of treatment via an apoptotic pathway. The in silico docking experiments revealed that PolßΔ has more substantial binding potential towards the dsDNA than wild-type Polß, suggesting a possible failure of BER pathway that results in cell death. CONCLUSION: Our study showed that the PA1PolßΔ cells were more susceptible than PA1 cells to gamma radiation. In the future, the potentiality of ionizing radiation to treat this type of cancer will be checked in animal models.

Microbe-Mediated Thermotolerance in Plants and Pertinent Mechanisms- A Meta-Analysis and Review.

Microbial symbionts can mediate plant stress responses by enhancing thermal tolerance, but less attention has been paid to measuring these effects across plant-microbe studies. We performed a meta-analysis of published studies as well as discussed with relevant literature to determine how the symbionts influence plant responses under non-stressed versus thermal-stressed conditions. As compared to non-inoculated plants, inoculated plants had significantly higher biomass and photosynthesis under heat stress conditions. A significantly decreased accumulation of malondialdehyde (MDA) and hydrogen peroxide (H2O2) indicated a lower oxidation level in the colonized plants, which was also correlated with the higher activity of catalase, peroxidase, glutathione reductase enzymes due to microbial colonization under heat stress. However, the activity of superoxide dismutase, ascorbate oxidase, ascorbate peroxidase, and proline were variable. Our meta-analysis revealed that microbial colonization influenced plant growth and physiology, but their effects were more noticeable when their host plants were exposed to high-temperature stress than when they grew under ambient temperature conditions. We discussed the mechanisms of microbial conferred plant thermotolerance, including at the molecular level based on the available literature. Further, we highlighted and proposed future directions toward exploring the effects of symbionts on the heat tolerances of plants for their implications in sustainable agricultural production.