Epigenetic dissection of human blood group genes reveals regulatory elements and detailed characteristics of KEL and four other loci.

BACKGROUND: Blood typing is essential for safe transfusions and is performed serologically or genetically. Genotyping predominantly focuses on coding regions, but non-coding variants may affect gene regulation, as demonstrated in the ABO, FY and XG systems. To uncover regulatory loci, we expanded a recently developed bioinformatics pipeline for discovery of non-coding variants by including additional epigenetic datasets. METHODS: Multiple datasets including ChIP-seq with erythroid transcription factors (TFs), histone modifications (H3K27ac, H3K4me1), and chromatin accessibility (ATAC-seq) were analyzed. Candidate regulatory regions were investigated for activity (luciferase assays) and TF binding (electrophoretic mobility shift assay, EMSA, and mass spectrometry, MS). RESULTS: In total, 814 potential regulatory sites in 47 blood-group-related genes were identified where one or more erythroid TFs bound. Enhancer candidates in CR1, EMP3, ABCB6, and ABCC4 indicated by ATAC-seq, histone markers, and co-occupancy of 4 TFs (GATA1/KLF1/RUNX1/NFE2) were investigated but only CR1 and ABCC4 showed increased transcription. Co-occupancy of GATA1 and KLF1 was observed in the KEL promoter, previously reported to contain GATA1 and Sp1 sites. TF binding energy scores decreased when three naturally occurring variants were introduced into GATA1 and KLF1 motifs. Two of three GATA1 sites and the KLF1 site were confirmed functionally. EMSA and MS demonstrated increased GATA1 and KLF1 binding to the wild-type compared to variant motifs. DISCUSSION: This combined bioinformatics and experimental approach revealed multiple candidate regulatory regions and predicted TF co-occupancy sites. The KEL promoter was characterized in detail, indicating that two adjacent GATA1 and KLF1 motifs are most crucial for transcription.

Ancestral TALE homeobox protein transcription factor regulates actin dynamics and cellular activities of protozoan parasite Entamoeba invadens.

Entamoeba histolytica causes invasive amoebiasis, an important neglected tropical disease with a significant global health impact. The pathogenicity and survival of E. histolytica and its reptilian equivalent, Entamoeba invadens, relies on its ability to exhibit efficient motility, evade host immune responses, and exploit host resources, all of which are governed by the actin cytoskeleton remodeling. Our study demonstrates the early origin and the regulatory role of TALE homeobox protein EiHbox1 in actin-related cellular processes. Several genes involved in different biological pathways, including actin dynamics are differentially expressed in EiHbox1 silenced cells. EiHbox1 silenced parasites showed disrupted F-actin organization and loss of cellular polarity. EiHbox1's presence in the anterior region of migrating cells further suggests its involvement in maintaining cellular polarity. Loss of polarized morphology of EiHbox1 silenced parasites leads to altered motility from fast, directionally persistent, and highly chemotactic to slow, random, and less chemotactic, which subsequently leads to defective aggregation during encystation. EiHbox1 knockdown also resulted in a significant reduction in phagocytic capacity and poor capping response. These findings highlight the importance of EiHbox1 of E. invadens in governing cellular processes crucial for their survival, pathogenicity, and evasion of the host immune system.

Combining extracellular matrix proteome and phosphoproteome of chickpea and meta-analysis reveal novel proteoforms and evolutionary significance of clade-specific wall-associated events in plant.

Extracellular matrix (ECM) plays central roles in cell architecture, innate defense and cell wall integrity (CWI) signaling. During transition to multicellularity, modular domain structures of ECM proteins and proteoforms have evolved due to continuous adaptation across taxonomic clades under different ecological niche. Although this incredible diversity has to some extent been investigated at protein level, extracellular phosphorylation events and molecular evolution of ECM proteoform families remains unexplored. We developed matrisome proteoform atlas in a grain legume, chickpea and performed meta-analyses of 74 plant matrisomes. MS/MS analysis identified 1,424 proteins and 315 phosphoproteins involved in diverse functions. Cross-species ECM protein network identified proteoforms associated with CWI maintenance system. Phylogenetic characterization of eighteen matrix protein families highlighted the role of taxon-specific paralogs and orthologs. Novel information was acquired on gene expansion and loss, co-divergence, sub functionalization and neofunctionalization during evolution. Modular networks of matrix protein families and hub proteins showed higher diversity across taxonomic clades than among organs. Furthermore, protein families differ in nonsynonymous to synonymous substitution rates. Our study pointed towards the matrix proteoform functionality, sequence divergence variation, interactions between wall remodelers and molecular evolution using a phylogenetic framework. This is the first report on comprehensive matrisome proteoform network illustrating presence of CWI signaling proteins in land plants.

A complex interplay of intra- and extracellular factors regulates the outcome of fetal- and adult-derived MLL-rearranged leukemia.

Infant and adult MLL1/KMT2A-rearranged (MLLr) leukemia represents a disease with a dismal prognosis. Here, we present a functional and proteomic characterization of in utero-initiated and adult-onset MLLr leukemia. We reveal that fetal MLL::ENL-expressing lymphomyeloid multipotent progenitors (LMPPs) are intrinsically programmed towards a lymphoid fate but give rise to myeloid leukemia in vivo, highlighting a complex interplay of intra- and extracellular factors in determining disease subtype. We characterize early proteomic events of MLL::ENL-mediated transformation in fetal and adult blood progenitors and reveal that whereas adult pre-leukemic cells are mainly characterized by retained myeloid features and downregulation of ribosomal and metabolic proteins, expression of MLL::ENL in fetal LMPPs leads to enrichment of translation-associated and histone deacetylases signaling proteins, and decreased expression of inflammation and myeloid differentiation proteins. Integrating the proteome of pre-leukemic cells with their secretome and the proteomic composition of the extracellular environment of normal progenitors highlights differential regulation of Igf2 bioavailability, as well as of VLA-4 dimer and its ligandome, upon initiation of fetal- and adult-origin leukemia, with implications for human MLLr leukemia cells' ability to communicate with their environment through granule proteins. Our study has uncovered opportunities for targeting ontogeny-specific proteomic vulnerabilities in in utero-initiated and adult-onset MLLr leukemia.

Dibutyl phthalate degradation by Paenarthrobacter ureafaciens PB10 through downstream product myristic acid and its bioremediation potential in contaminated soil.

Dibutyl phthalate (DBP) is a widely used plasticizer to make plastic flexible and long-lasting. It is easily accessible in a broad spectrum of environments as a result of the rising level of plastic pollution. This compound is considered a top-priority toxicant and persistent organic pollutant by international environmental agencies for its endocrine disruptive and carcinogenic propensities. To mitigate the DBP in the soil, one DBP-degrading bacterial strain was isolated from a plastic-polluted landfill and identified as Paenarthrobacter ureafaciens PB10 by 16S rRNA gene sequence-based homology. The strain was found to develop a distinct transparent halo zone around grown colonies on an agar plate supplemented with DBP. The addition of yeast extract (100 mg/L) as a nutrient source accelerated cell biomass production and DBP degradation rate; however, the presence of glucose suppressed DBP degradation by the PB10 strain without affecting its ability to proliferate. The strain PB10 was efficient in eliminating DBP under various pH conditions (5.0-8.0). Maximum cell growth and degradation of 99.49% at 300 mg/L DBP were achieved in 72 h at the optimized mineral salt medium (MS) conditions of pH 7.0 and 32 °C. Despite that, when the concentration of DBP rose to 3000 mg/L, the DBP depletion rate was measured at 79.34% in 72 h. Some novel intermediate metabolites, like myristic acid, hexadecanoic acid, stearic acid, and the methyl derivative of 4-hydroxyphenyl acetate, along with monobutyl phthalate and phthalic acid, were detected in the downstream degradation process of DBP through GC-MS profiling. Furthermore, in synchronization with native soil microbes, this PB10 strain successfully removed a notable amount of DBP (up to 54.11%) from contaminated soil under microcosm study after 10 d. Thus, PB10 has effective DBP removal ability and is considered a potential candidate for bioremediation in DBP-contaminated sites.

A Digital Respiratory Ward in Leicester, Leicestershire, and Rutland, England, for Patients With COVID-19: Economic Evaluation of the Impact on Acute Capacity and Wider National Health Service Resource Use.

BACKGROUND: The COVID-19 pandemic stressed global health care systems' acute capacity and caused a diversion of resources from elective care to the treatment of acute respiratory disease. In preparing for a second wave of COVID-19 infections, England's National Health Service (NHS) in Leicester, Leicestershire, and Rutland sought to protect acute capacity in the winter of 2020-2021. Their plans included the introduction of a digital ward where patients were discharged home early and supported remotely by community-based respiratory specialists, who were informed about patient health status by a digital patient monitoring system. OBJECTIVE: The objective of the digital ward was to maintain acute capacity through safe, early discharge of patients with COVID-19 respiratory disease. The study objective was to establish what impact this digital ward had on overall NHS resource use. METHODS: There were no expected differences in patient outcomes. A cost minimization was performed to demonstrate the impact on the NHS resource use from discharging patients into a digital COVID-19 respiratory ward, compared to acute care length of stay (LOS). This evaluation included all 310 patients enrolled in the service from November 2020 (service commencement) to November 2021. Two primary methods, along with sensitivity analyses, were used to help overcome the uncertainty associated with the estimated comparators for the observational data on COVID-19 respiratory acute LOS, compared with the actual LOS of the 279 (90%) patients who were not discharged on oxygen nor were in critical care. Historic comparative LOS and an ordinary least squares model based on local monthly COVID-19 respiratory median LOS were used as comparators. Actual comparator data were sourced for the 31 (10%) patients who were discharged home and into the digital ward for oxygen weaning. Resource use associated with delivering care in the digital ward was sourced from the digital system and respiratory specialists. RESULTS: In the base case, the digital ward delivered estimated health care system savings of 846.5 bed-days and US $504,197 in net financial savings across the 2 key groups of patients-those on oxygen and those not on oxygen at acute discharge (both P<.001). The mean gross and net savings per patient were US $1850 and US $1626 in the base case, respectively, without including any savings associated with a potential reduction in readmissions. The 30-day readmission rate was 2.9%, which was below comparative data. The mean cost of the intervention was US $223.53 per patient, 12.1% of the estimated gross savings. It was not until the costs were increased and the effect reduced simultaneously by 78.4% in the sensitivity analysis that the intervention was no longer cost saving. CONCLUSIONS: The digital ward delivered increased capacity and substantial financial savings and did so with a high degree of confidence, at a very low absolute and relative cost.

Development and performance evaluation of self-assembled pH-responsive curcumin-bacterial exopolysaccharide micellar conjugates as bioactive delivery system.

The present study reports the synthesis of micellar conjugates, wherein curcumin (Cur), a bioactive compound with poor bioavailability, was covalently bonded to a bacterial exopolysaccharide (EPS). These conjugates were synthesized by utilizing succinic acid that linked Cur to the pyranosyl moiety of the EPS. The Cur-EPS conjugates appeared as spherical micelles in aqueous solution and were found to have an average hydrodynamic diameter of 254 ± 2.7 nm. The micellar conjugates showed superior stability than Cur as evident from their negative surface charge (-27 ± 1.8 mV) and low polydispersity index (PDI) (0.33 ± 0.04). The in vitro studies on release kinetics helped elucidate the pH-responsive characteristics of the Cur-EPS conjugate, as 87.50 ± 1.45 % of Cur was released at an acidic pH of 5.6, in contrast to 30.15 ± 2.61 % at systemic pH of 7.4 at 150 h. The conjugates were hemocompatible and exhibited cytotoxic effect against the osteosarcoma cell line (MG-63) after 48 h treatment. They also demonstrated superior antibacterial, antibiofilm, and antioxidant activities in comparison to free Cur. Therefore, the Cur-EPS conjugates have potential pharmaceutical applications as therapeutic biomaterial that can be applied as a drug delivery system.

Energetic, exergetic, economic and environmental performance of a rice husk gasification based carbon negative combined power and cooling plant.

This article presents the proposed configuration of a biomass gasification based carbon-negative combined power and cooling system. Parametric alteration of the response variables with respect to the individual input variables as well as the interaction of the input variables on response have been studied. Detailed analysis of variance has been carried out for the response variables (exergy utilization factor and modified unit electricity cost) and optimization of the whole plant has been performed employing response surface methodology. At the optimum operating condition, for both power and cooling, the plant utilizes 32.39 % of input exergy at an effective electricity cost of 0.1186 $/kWh (including the cost of CO2 capture), having a desirability of about 1. CO2 capture and the environmental benefit due to CO2 cutting at optimum operating condition found to be 1.517 M ton/yr and 0.2275 B$/yr respectively.

Genetic Polymorphism in Xenobiotic Metabolising Genes and Increased Oxidative Stress among Pesticides Exposed Agricultural Workers Diagnosed with Cancers.

BACKGROUND: Oxidative stress combined with nullity of xenobiotic metabolizing GSTT1/GSTM1/CYP2E1 genes may increase the susceptibility of agricultural workers to adverse health effects including cancer. The present study was conducted to determine; the prevalence of polymorphisms in GSTM1, GSTT1 and CYP2E1 genes, serum 8-hydroxy-2'-deoxygunosine levels, and the role of these markers in risk of cancer among agricultural workers occupationally exposed to pesticides. METHODS: A total of 360 participants, of which 180 belonging to farming group diagnosed with leukemia (n=60), lymphoma (n=60) and breast cancers (n=60), 90 in non-farming group diagnosed with similar cancers and the other 90 as healthy controls with neither history of occupational exposure nor diagnosed with any type of cancers were recruited. Following the questionnaire survey, serum 8-OHdG and genetic polymorphisms in the three genes were determined using ELISA and PCR methods respectively. RESULTS: The results of the study revealed that farm workers carrying GSTT1 null genotype had increased risk for lymphoma (OR = 5.34; 95% CI = 1.80-15.82) and breast cancer (OR=4.04; 95% CI = 1.24-13.07). For farm workers carrying GSTM1 null genotype, the risk was six-fold for breast cancer (OR = 6.88; 95% CI =1.88-25.99). Further, there found a significant difference between 8-OHdG and nullity of CYP2E1 among the farm workers diagnosed with leukemia. CONCLUSION: The findings of the present study suggest that the polymorphisms in detoxifying genes among farm workers occupationally exposed to pesticides and the oxidative stress may likely be responsible for triggering the mechanism of malignancy.

The PPE2 protein of Mycobacterium tuberculosis is secreted during infection and facilitates mycobacterial survival inside the host.

Mycobacterium tuberculosis secrets various effector proteins to evade host immune responses for facilitating its intracellular survival. The bacterial genome encodes several unique PE/PPE family proteins, which have been implicated to play important role in mycobacterial pathogenesis. A member of this family, PPE2 have been shown to contain a monopartite nuclear localization signal (NLS) and a DNA binding domain. In this study, we demonstrate that PPE2 protein is present in the sera of mice infected with either M. smegmatis expressing PPE2 or a clinical strain of M. tuberculosis (CDC1551). It was found that exogenously added PPE2 can permeate through the macrophage cell membrane and eventually translocate into the nucleus which requires the presence of NLS which showed considerable homology to HIV-tat like cell permeable peptides. Exogenously added PPE2 could inhibit NO production and decreased mycobacterial survival in macrophages. PPE2-null mutant of M. tuberculosis failed to inhibit NO production and had poor survival in macrophages which could be rescued by complementation with full-length PPE2. PPE2-null mutants also had poor survival in the lungs of infected mice indicating that PPE2 even when present in the bloodstream can confer a survival advantage to mycobacteria.

Curcumin attenuates replicative senescence in human dental follicle cells and restores their osteogenic differentiation.

OBJECTIVE: This study aimed to examine the therapeutic effects of curcumin against replicative senescence in dental follicle cells (DFCs). METHODS: Human DFCs were cultured in Dulbecco's Modified Eagle Medium with growth supplements. Replicative senescence in DFCs at different passages was assessed using ß-galactosidase activity assay. Cell proliferation and size of DFCs at different passages were determined by CCK-8 kit and microscopy method, respectively. In addition, curcumin's effect on replicative senescence, cell proliferation, and size of DFCs at different passages was analyzed. Using western-blot analysis and siRNA-mediated gene silencing, we determined the molecular mechanisms involved in curcumin's effect against replicative senescence and osteogenic differentiation in DFCs at different passages. RESULTS: We observed decreased proliferation and increased cell size and replicative senescence in cultured human DFCs at higher passages. Intriguingly, despite not showing any effect on cell size, curcumin (50 µM) significantly restored proliferation ability in DFCs and inhibited their replicative senescence. Concerning mechanisms, we found that curcumin inhibits replicative senescence in DFCs via down-regulation of senescence markers (P16 & P21) and restoration of proliferation markers (E2F1 & P53). Additionally, curcumin also rescued the osteogenic differentiation potential in higher-passage DFCs via restoration of osteogenic markers RUNX2 and OPN. CONCLUSION: Our findings reveal for the first time that curcumin could act as a potential anti-senescence therapeutic for DFCs via regulation of proliferation, senescence, and osteogenic differentiation markers.

Role of autophagy in stress and drug-responsive cell death in Entamoeba histolytica and its cross-talk with apoptosis-inducing factor.

Cell death in unicellular protozoan parasite Entamoeba histolytica is not yet reported though it displays several features of autophagic cell death. Autophagic cell death was reported to take place in ancient protozoans under several stresses. Here we report the occurrence of autophagic cell death in the Entamoeba histolytica trophozoites under oxidative stress as well as by the treatment with metronidazole, the most-widely-used drug for amoebiasis treatment and was shown to generate oxidative stress in the trophozoites. The autophagic flux increases during nutrient deprivation and metronidazole treatment and decreases upon oxidative stress. During oxidative stress the autophagy leads to nucleophagy that is ultimately destined to be digested within the lysosomal chamber. The formation of nucleophagosome depends on the apoptosis-inducing factor (AIF) that translocates to the nucleus from cytoplasm upon oxidative stress. It was experimentally proved that ATG8 (Autophagy-related protein 8) binds with the AIF in the nucleus of the trophozoites and helps in ATG8 recruitment and autophagy initiation overall suggesting that oxidative stress-driven AIF translocation to nucleus results in binding with ATG8 and initiates nucleophagy leading to cell death.

Phyto-assisted synthesis of CuO/industrial waste derived biochar composite for adsorptive removal of doxycycline hydrochloride and recycling of spent biochar as green energy storage device.

The highest exposure of Endocrine disrupting compounds (EDC) into the water bodies as a result of extensive production and application of Covid-19 related drugs is a growing concern now a days. Herein, a novel nanocomposite material was developed by impregnating green synthesized copper oxide nanoparticles on the porous surface of fabric waste derived biochar to eliminate the concerned EDCs along with a sustainable disposal strategy for the spent adsorbent. Morphological characterizations by Field emission scanning electron microscopy confirmed the formation of hierarchical porous structured material. X-ray analysis revealed presence of both amorphous nature of biochar matrix as well as the crystalline nature attributed from monodispersion of copper oxide nanoparticles onto biochar surface. Batch sorption study showed removal of doxycycline hydrochloride (DOX) of >97% after 2 h at pH 7, 30 mg L-1 initial concentration of DOX and 2 g L-1 of adsorbent dose at room temperature after a two-step optimization process. Spectroscopic study and Raman shift suggested that pore filling, strong complexation and electrostatic interactions maximise the adsorption of DOX in the CuO/biochar composite as compared to the pristine biochar. However disposal of spent adsorbent is a crucial aspect for the environment and therefore, a sustainable recycling strategy for DOX loaded adsorbent as electrode material has been proposed for the first time in this study. Maximum specific capacitance value was observed in the range of 221.9-297.3 F g-1 for the DOX loaded nanocomposite at 1 mV s-1 comparable with other reported heteroatom-doped carbonaceous material as electrode. Therefore the excellent adsorption capacity of green synthesized CuO/biochar composite and its recycling after DOX adsorption can be recommended as a sustainable solution for mitigation of pharmaceuticals from wastewater. A detail study on degradation of DOX into eco-friendly products and its cost-effectiveness would be beneficial to suggest appropriate mitigation strategy for such compounds.

Obesity, Metabolic Syndrome, and Osteoarthritis-An Updated Review.

PURPOSE OF REVIEW: Metabolic syndrome (MetS), also called the 'deadly quartet' comprising obesity, diabetes, dyslipidemia, and hypertension, has been ascertained to have a causal role in the pathogenesis of osteoarthritis (OA). This review is aimed at discussing the current knowledge on the contribution of metabolic syndrome and its various components to OA pathogenesis and progression. RECENT FINDINGS: Lately, an increased association identified between the various components of metabolic syndrome (obesity, diabetes, dyslipidemia, and hypertension) with OA has led to the identification of the 'metabolic phenotype' of OA. These metabolic perturbations alongside low-grade systemic inflammation have been identified to inflict detrimental effects upon multiple tissues of the joint including cartilage, bone, and synovium leading to complete joint failure in OA. Recent epidemiological and clinical findings affirm that adipokines significantly contribute to inflammation, tissue degradation, and OA pathogenesis mediated through multiple signaling pathways. OA is no longer perceived as just a 'wear and tear' disease and the involvement of the metabolic components in OA pathogenesis adds up to the complexity of the disease. Given the global surge in obesity and its allied metabolic perturbations, this review aims to throw light on the current knowledge on the pathophysiology of MetS-associated OA and the need to address MetS in the context of metabolic OA management. Better regulation of the constituent factors of MetS could be profitable in preventing MetS-associated OA. The identification of key roles for several metabolic regulators in OA pathogenesis has also opened up newer avenues in the recognition and development of novel therapeutic agents.

Cytological features of chordoid glioma: A case report with summary of prior published cases.

Chordoid glioma is an uncommon low-grade glioma and is a CNS WHO grade 2 tumour in the current WHO 2021 classification. Predominantly it is seen in the third ventricle and in young adults. Although the histological features of chordoid glioma are well documented, there is sparse literature describing its cytological features. Here we describe the squash cytological features of a case of chordoid glioma along with summary of prior published cases. The smears tend to be quite cellular, the cells show mild pleomorphism, anisonucleosis, and absent mitotic activity. The background shows a distinctive bluish myxoid stroma. It can be mistaken for high grade glioma on squash cytology.

Three-amino acid loop extension homeodomain proteins regulate stress responses and encystation in Entamoeba.

It is interesting to identify factors involved in the regulation of the encystation of Entamoeba histolytica that differentiate trophozoites into cysts. Evolutionarily conserved three amino acid loop extension (TALE) homeodomain proteins act as transcription factors and execute a variety of functions that are essential for life. A TALE homeodomain (EhHbox) protein-encoding gene has been identified in E. histolytica (Eh) that is highly upregulated during heat shock, glucose, and serum starvation. Its ortholog, EiHbox1, a putative homeobox protein in E. invadens (Ei), is also highly upregulated during the early hours of encystation, glucose starvation, and heat shock. They belong to the PBX family of TALE homeobox proteins and have conserved residues in the homeodomain that are essential for DNA binding. Both are localized in the nucleus during encystation and under different stress conditions. The electrophoretic mobility shift assay confirmed that the recombinant GST-EhHbox binds to the reported TGACAG and TGATTGAT motifs. Down-regulation of EiHbox1 by gene silencing reduced Chitin synthase, Jacob, and increased Jessie gene expression, resulting in defective cysts and decreased encystation efficiency and viability. Overall, our results suggest that the TALE homeobox family has been conserved during evolution and acts as a transcription factor to control the differentiation of Entamoeba by regulating the key encystation-induced genes.

The cause-effect relation of tuberculosis on incidence of diabetes mellitus.

Tuberculosis (TB) is one of the oldest human diseases and is one of the major causes of mortality and morbidity across the Globe. Mycobacterium tuberculosis (Mtb), the causal agent of TB is one of the most successful pathogens known to mankind. Malnutrition, smoking, co-infection with other pathogens like human immunodeficiency virus (HIV), or conditions like diabetes further aggravate the tuberculosis pathogenesis. The association between type 2 diabetes mellitus (DM) and tuberculosis is well known and the immune-metabolic changes during diabetes are known to cause increased susceptibility to tuberculosis. Many epidemiological studies suggest the occurrence of hyperglycemia during active TB leading to impaired glucose tolerance and insulin resistance. However, the mechanisms underlying these effects is not well understood. In this review, we have described possible causal factors like inflammation, host metabolic changes triggered by tuberculosis that could contribute to the development of insulin resistance and type 2 diabetes. We have also discussed therapeutic management of type 2 diabetes during TB, which may help in designing future strategies to cope with TB-DM cases.

Effect of ethyl gallate and propyl gallate on dextran sulfate sodium (DSS)-induced ulcerative colitis in C57BL/6 J mice: preventive and protective.

OBJECTIVE AND DESIGN: Inflammatory bowel disease (IBD) is an idiopathic inflammatory condition of the digestive system marked by oxidative stress, leukocyte infiltration, and elevation of inflammatory mediators. In this study, we demonstrate the protective effect of ethyl gallate (EG), a phytochemical, and propyl gallate (PG), an anti-oxidant, given through normal drinking water (DW) and copper water (CW) in various combinations, which had a positive effect on the amelioration of DSS-induced ulcerative colitis in C57BL/6 J mice. MATERIALS AND METHODS: We successfully determined the levels of proinflammatory cytokines and anti-oxidant enzymes by ELISA, tracked oxidative/nitrosative stress (RO/NS) by in vivo imaging (IVIS) using L-012 chemiluminescent probe, disease activity index (DAI), and histopathological and morphometric analysis of colon in DSS-induced colitis in a model. RESULTS: The results revealed that oral administration of ethyl gallate and propyl gallate at a dose of 50 mg/kg considerably reduced the severity of colitis and improved both macroscopic and microscopic clinical symptoms. The level of proinflammatory cytokines (TNF-α, IL-6, IL-1ß, and IFN-γ) in colonic tissue was considerably reduced in the DSS + EG-treated and DSS + PG-treated groups, compared to the DSS alone-treated group. IVIS imaging of animals from the DSS + EG and DSS + PG-treated groups showed a highly significant decrease in RO/NS species relative to the DSS control group, with the exception of the DSS + PG/CW and DSS + EG + PG/CW-treated groups. We also observed lower levels of myeloperoxidase (MPO), nitric oxide (NO), and lipid peroxidation (LPO), and restored levels of GST and superoxide dismutase (SOD) in DSS + EG-DW/CW, DSS + PG/DW, and DSS + EG + PG/DW groups compared to DSS alone-treated group. In addition, we showed that the EG, PG, and EG + PG treatment significantly reduced the DAI score, and counteracted the body weight loss and colon shortening in mice compared to DSS alone-treated group. In this 21-day study, mice were treated daily with test substances and were challenged to DSS from day-8 to 14. CONCLUSION: Our study highlights the protective effect of ethyl gallate and propyl gallate in various combinations which, in pre-clinical animals, serve as an anti-inflammatory drug against the severe form of colitis, indicating its potential for the treatment of IBD in humans. In addition, propyl gallate was investigated for the first time in this study for its anti-colitogenic effect with normal drinking water and reduced effect with copper water.

Stereotactic body radiation therapy and thermal ablation for treatment of NSCLC: A systematic literature review and meta-analysis.

RATIONALE: Stereotactic body radiation therapy (SBRT) is the standard of care for inoperable early stage non-small cell lung cancer (NSCLC). Use of image guided thermal ablation (IGTA; including microwave ablation [MWA] and radiofrequency ablation [RFA]) has increased in NSCLC, however there are no studies comparing all three. OBJECTIVE: To compare the efficacy of IGTA (including MWA and RFA) and SBRT for the treatment of NSCLC. METHODS: Published literature databases were systematically searched for studies assessing MWA, RFA, or SBRT. Local tumor progression (LTP), disease-free survival (DFS), and overall survival (OS) were assessed with single-arm pooled analyses and meta-regressions in NSCLC patients and a stage IA subgroup. Study quality was assessed with a modified methodological index for non-randomized studies (MINORS) tool. RESULTS: Forty IGTA study-arms (2,691 patients) and 215 SBRT study-arms (54,789 patients) were identified. LTP was lowest after SBRT at one and two years in single-arm pooled analyses (4% and 9% vs. 11% and 18%) and at one year in meta-regressions when compared to IGTA (OR = 0.2, 95%CI = 0.07-0.63). MWA patients had the highest DFS of all treatments in single-arm pooled analyses. In meta-regressions at two and three-years, DFS was significantly lower for RFA compared to MWA (OR = 0.26, 95%CI = 0.12-0.58; OR = 0.33, 95%CI = 0.16-0.66, respectively). OS was similar across modalities, timepoints, and analyses. Older age, male patients, larger tumors, retrospective studies, and non-Asian study region were also predictors of worse clinical outcomes. In high-quality studies (MINORS score ≥ 7), MWA patients had better clinical outcomes than the overall analysis. Stage IA MWA patients had lower LTP, higher OS, and generally lower DFS, compared to the main analysis of all NSCLC patients. CONCLUSIONS: NSCLC patients had comparable outcomes after SBRT and MWA, which were better than those with RFA.