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mRNA incorporated in lipid nanoparticles (LNPs) became a new class of vaccine modality for induction of immunity against COVID-19 and ushered in a new era in vaccine development. Here, we report a novel, easy-to-execute, and cost effective engineered extracellular vesicles (EVs)-based combined mRNA and protein vaccine platform (EVX-M+P vaccine) and explore its utility in proof-of-concept immunity studies in the settings of cancer and infectious disease. As a first example, we engineered EVs to contain ovalbumin mRNA and protein (EVOvaM+P) to serve as cancer vaccine against ovalbumin-expressing melanoma tumors. EVOvaM+P administration to mice with established melanoma tumors resulted in tumor regression associated with effective humoral and adaptive immune responses. As a second example, we generated engineered EVs, natural nanoparticle carriers shed by all cells, that contain mRNA and protein Spike (S) protein to serve as a combined mRNA and protein vaccine (EVSpikeM+P vaccine) against SARS-CoV-2 infection. EVSpikeM+P vaccine administration in mice and baboons elicited robust production of neutralizing IgG antibodies against RBD (receptor binding domain) of S protein and S protein specific T cell responses. Our proof-of-concept study describes a new platform with an ability for rapid development of combination mRNA and protein vaccines employing EVs for deployment against cancer and other diseases.
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Inflammation and tissue damage associated with pancreatitis can precede or occur concurrently with pancreatic ductal adenocarcinoma (PDAC). We demonstrate that in PDAC coupled with pancreatitis (ptPDAC), antigen-presenting type I conventional dendritic cells (cDC1s) are specifically activated. Immune checkpoint blockade therapy (iCBT) leads to cytotoxic CD8+ T cell activation and elimination of ptPDAC with restoration of life span even upon PDAC rechallenge. Using PDAC antigen-loaded cDC1s as a vaccine, immunotherapy-resistant PDAC was rendered sensitive to iCBT with elimination of tumors. cDC1 vaccination coupled with iCBT identified specific CDR3 sequences in the tumor-infiltrating CD8+ T cells with potential therapeutic importance. This study identifies a fundamental difference in the immune microenvironment in PDAC concurrent with, or without, pancreatitis and provides a rationale for combining cDC1 vaccination with iCBT as a potential treatment option.
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Carcinoma Ductal Pancreático , Células Dendríticas , Imunoterapia , Neoplasias Pancreáticas , Microambiente Tumoral , Animais , Camundongos , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Carcinoma Ductal Pancreático/terapia , Carcinoma Ductal Pancreático/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/métodos , Camundongos Endogâmicos C57BL , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/imunologia , Pancreatite/imunologia , Pancreatite/terapia , Microambiente Tumoral/imunologiaRESUMO
BACKGROUND: For assessment of COVID-19 vaccine efficacy, neutralization activity of anti-SARS-CoV-2 antibody is measured. This study was undertaken to determine optimum levels of binding antibody units (BAU/ml) in new quantitative chemiluminescent assay (CLIA) that corresponded to neutralizing potential (30% inhibition) of sVNT assay. METHODS: Ninety-one blood samples were analyzed by CLIA and sVNT assays. Test samples (n = 75) were collected from blood donors post-2nd vaccination dose, while control samples (n = 16) were archived pre-COVID donor samples. Correlation between CLIA and sVNT was calculated and receiver operating characteristic (ROC) curve was drawn and analyzed. RESULTS: Results indicated excellent correlation between 57.5 BAU/ml on CLIA and 30%inhibition on sVNT assay. ROC curve analysis revealed that the area under the curve (AUC) was 0.971. DISCUSSION: The present study determined that 57.5 BAU/ml on CLIA corresponded to 30% inhibition on sVNT assay. Periodic quantitative analysis.
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Anticorpos Antivirais , Doadores de Sangue , Vacinas contra COVID-19 , COVID-19 , Medições Luminescentes , SARS-CoV-2 , Humanos , COVID-19/prevenção & controle , COVID-19/sangue , COVID-19/imunologia , SARS-CoV-2/imunologia , Vacinas contra COVID-19/imunologia , Medições Luminescentes/métodos , Anticorpos Antivirais/sangue , Masculino , Feminino , Vacinação/métodos , Anticorpos Neutralizantes/sangueRESUMO
With the advent of the modern era, there is a huge demand for memristor-based neuromorphic computing hardware to overcome the von Neumann bottleneck in traditional computers. Here, we have prepared two-dimensional titanium carbide (Ti3C2Tx) MXene following the conventional HF etching technique in solution. After confirmation of Ti3C2Tx properties by Raman scattering and crystallinity measurements, high-quality thin-film deposition is realized using an immiscible liquid-liquid interfacial growth technique. Following this, the memristor is fabricated by sandwiching a Ti3C2Tx layer with a thickness of 70 nm between two electrodes. Subsequently, current-voltage (I-V) characteristics are measured, revealing a nonvolatile resistive switching property characterized by a swift switching speed of 30 ns and an impressive current On/Off ratio of approximately 103. Furthermore, it exhibits endurance through 500 cycles and retains the states for at least 1 × 104 s without observable degradation. Additionally, it maintains a current On/Off ratio of about 102 while consuming only femtojoules (fJ) of electrical energy per reading. Systematic I-V results and conductive AFM-based current mapping image analysis are converged to support the electroforming mediated filamentary conduction mechanism. Furthermore, our Ti3C2Tx memristor was found to be truly versatile as an all-in-one device for demonstrating edge computation, logic gate operation, and classical conditioning of learning by the brain in Psychology.
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Background: COVID-19 belongs to the beta-corona cluster that spreads enormously via aerosols. Physiotherapists must be knowledgeable about the symptoms, mode of transmission, risk mitigation strategies, and practice guidelines for COVID-19. Objective: This study aimed to assess physiotherapists' knowledge of COVID-19 guidelines, their attitude toward this new evolving field, and their practice routines in India's COVID-19 ICUs. Methods: It was a cross-sectional study. A total of 600 questionnaires were distributed through e-mail and WhatsApp to physiotherapists using Google Forms between February 2022 and January 2023. The questionnaires consisted of demographics and 23 questions in three sections about the knowledge, attitude, and practice of physiotherapists working in the COVID-19 ICU. Data analysis was carried out using Jamovi. Results: A total of 136 responses were obtained from 18 states of India. Of 136 participants, 89 were female (65.4%) and 47 were male (34.6%). The highest level of qualification was BPT (n = 69 (50.7%)), followed by MPT (n = 62 (45.6%)) and Ph.D. (3 (3.7%)). The knowledge about COVID-19 guidelines is fair. Only 21.3% of the physiotherapists received training before being deployed in COVID-19 ICUs, and the CARP protocol was well known by only as few as 10.3%. The criteria advised for close monitoring of patients during treatment was aware by 29.4%. Most physiotherapists have a good attitude toward treating COVID-19 patients; 70.63% strongly agree that physiotherapy is vital in these patients despite the risk of self-exposure, and 64.7% agree that physiotherapy should be initiated during all phases of COVID-19. Physiotherapists follow good practices for COVID-19 patients in the ICU, which is as per the guideline recommendation. Conclusion: Physiotherapists working in COVID-19 ICUs have a fair knowledge of the existing physiotherapy guidelines for COVID-19, and they exhibit good attitudes and practice patterns.
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COVID-19 , Fisioterapeutas , Humanos , Feminino , Masculino , Estudos Transversais , Conhecimentos, Atitudes e Prática em Saúde , COVID-19/epidemiologia , Unidades de Terapia IntensivaRESUMO
The tumor microenvironment (TME) is a complex ecosystem of both cellular and noncellular components that functions to impact the evolution of cancer. Various aspects of the TME have been targeted for the control of cancer; however, TME composition is dynamic, with the overall abundance of immune cells, endothelial cells (ECs), fibroblasts, and extracellular matrix (ECM) as well as subsets of TME components changing at different stages of progression and in response to therapy. To effectively treat cancer, an understanding of the functional role of the TME is needed. Genetically engineered mouse models have enabled comprehensive insight into the complex interactions within the TME ecosystem that regulate disease progression. Here, we review recent advances in mouse models that have been employed to understand how the TME regulates cancer initiation, progression, metastasis, and response to therapy.
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Modelos Animais de Doenças , Progressão da Doença , Neoplasias , Microambiente Tumoral , Animais , Camundongos , Neoplasias/patologia , Neoplasias/terapia , Neoplasias/imunologia , Humanos , Matriz ExtracelularRESUMO
BACKGROUND: Colorectal cancer (CRC) is considered the second deadliest cancer in the world. One of the reasons for the occurrence of this cancer is the deregulation of the Epidermal Growth Factor Receptor (EGFR), which plays a critical role in regulating cell division, persistence, differentiation, and migration. The overexpression of the EGFR protein leads to its dysregulation and causes CRC. OBJECTIVES: Hence, this work aims to identify and validate novel EGFR inhibitors for the treatment of colorectal cancer employing various computer aided techniques such as pharmacophore modeling, docking, molecular dynamic simulation and Quantitative Structure-Activity Relationship (QSAR) analysis. METHODS: In this work, a shared-featured ligand-based pharmacophore model was generated using the known inhibitors of EGFR. The best model was validated and screened against ZincPharmer and Maybridge databases, and 143 hits were obtained. Pharmacokinetic and toxicological properties of these hits were studied, and the acceptable ligands were docked against EGFR. The best five protein-ligand complexes with binding energy less than -5 kcal/mol were selected. The molecular dynamic simulation studies of these complexes were conducted for 100 nanoseconds (ns), and the results were analyzed. The biological activity of this ligand was calculated using QSAR analysis. RESULTS: The best complex with Root Mean Square Deviation (RMSD) 3.429 Å and Radius of Gyration (RoG) 20.181 Å was selected. The Root Mean Square Fluctuations (RMSF) results were also found to be satisfactory. The biological activity of this ligand was found to be 1.38 µM. CONCLUSION: This work hereby proposes the ligand 2-((1,6-dimethyl-4-oxo-1,4-dihydropyridin-3-yl)oxy)-N- (1H-indol-4-yl)acetamide as a potential EGFR inhibitor for the treatment of colorectal cancer. The wet lab analysis must be conducted, however, to confirm this hypothesis.
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Antineoplásicos , Neoplasias Colorretais , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB , Inibidores de Proteínas Quinases , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Relação Dose-Resposta a Droga , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Farmacóforo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/síntese química , Relação Quantitativa Estrutura-AtividadeRESUMO
The KRASG12D mutation is present in nearly half of pancreatic adenocarcinomas (PDAC). We investigated the effects of inhibiting the KRASG12D mutant protein with MRTX1133, a non-covalent small molecule inhibitor of KRASG12D, on early and advanced PDAC and its influence on the tumor microenvironment. Employing 16 different models of KRASG12D-driven PDAC, we demonstrate that MRTX1133 reverses early PDAC growth, increases intratumoral CD8+ effector T cells, decreases myeloid infiltration, and reprograms cancer-associated fibroblasts. MRTX1133 leads to regression of both established PanINs and advanced PDAC. Regression of advanced PDAC requires CD8+ T cells and immune checkpoint blockade (ICB) synergizes with MRTX1133 to eradicate PDAC and prolong overall survival. Mechanistically, inhibition of KRASG12D in advanced PDAC and human patient derived organoids induces FAS expression in cancer cells and facilitates CD8+ T cell-mediated death. Collectively, this study provides a rationale for a synergistic combination of MRTX1133 with ICB in clinical trials.
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Linfócitos T CD8-Positivos , Neoplasias Pancreáticas , Proteínas Proto-Oncogênicas p21(ras) , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Proteínas Proto-Oncogênicas p21(ras)/genética , Microambiente TumoralRESUMO
Oncogenic KRASG12D (KRAS∗) is critical for the initiation and maintenance of pancreatic ductal adenocarcinoma (PDAC) and is a known repressor of tumor immunity. Conditional elimination of KRAS∗ in genetic mouse models of PDAC leads to the reactivation of FAS, CD8+ T cell-mediated apoptosis, and complete eradication of tumors. KRAS∗ elimination recruits activated CD4+ and CD8+ T cells and promotes the activation of antigen-presenting cells. Mechanistically, KRAS∗-mediated immune evasion involves the epigenetic regulation of Fas death receptor in cancer cells, via methylation of its promoter region. Furthermore, analysis of human RNA sequencing identifies that high KRAS expression in PDAC tumors shows a lower proportion of CD8+ T cells and demonstrates shorter survival compared with tumors with low KRAS expression. This study highlights the role of CD8+ T cells in the eradication of PDAC following KRAS∗ elimination and provides a rationale for the combination of KRAS∗ targeting with immunotherapy to control PDAC.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Proteínas Proto-Oncogênicas p21(ras) , Animais , Humanos , Camundongos , Apoptose , Carcinoma Ductal Pancreático/genética , Linfócitos T CD8-Positivos , Epigênese Genética , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogênicas p21(ras)/genéticaRESUMO
An efficient 1,4-dihydropyridine synthesis under mild conditions has been developed. Numerous substrates were tested, with yields of 1,4-dihydropridines ranging from good to excellent and a wide range of functional group tolerance. A549, HT-29, and HepG2 cancer cells were used to investigate the anticancer efficacy of each of the produced compounds. Additionally, in-silico docking studies were conducted to understand the structure-based features of the anticancer mechanism with the cancer medication target of Adenosineâ A2A receptor as well as the molecular level interactions of the compounds.
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Antineoplásicos , Di-Hidropiridinas , Humanos , Células Hep G2 , Di-Hidropiridinas/farmacologia , Di-Hidropiridinas/química , Células HT29 , Simulação de Acoplamento Molecular , Antineoplásicos/química , Relação Estrutura-Atividade , Estrutura Molecular , Ensaios de Seleção de Medicamentos AntitumoraisRESUMO
Per- and polyfluorinated chemicals (PFASs) are very toxic industrial compounds, and fewer studies have been conducted on their presence in the sedimentary environment of the polar region. The present study is a preliminary assessment of the concentration and distribution of PFOA (Perfluorooctanoic acid) in selected fjord systems of the Svalbard archipelago, Norwegian Arctic. The ∑PFOA observed for Smeerenburgfjorden, Krossfjorden, Kongsfjorden Hotmiltonbuktafjorden, Raudfjorden and Magdalenefjorden were 1.28 ng/g, 0.14 ng/g, 0.68 ng/g, 6.54 ng/g, 0.41 ng/g and BDL respectively. Of the twenty-three fjord samples studied, the sediments from Hotmiltonbuktafjorden exhibited the presence of a higher concentration of PFOA in the sediment matrices. More studies are needed to understand their fate in the sedimentary environment with respect to the physio-chemical properties of the sediments.
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Estuários , Fluorocarbonos , Svalbard , Sedimentos Geológicos/químicaRESUMO
OBJECTIVES: Sarcopenia has emerged as a significant aging-related disease that affects many facets of societal-level and patient-level public health. This study analysed knowledge of sarcopenia and associated socio-demographic factors among the general public of Malaysia in order to effectively improve its prevention and countermeasures. METHODS: A cross-sectional online survey was conducted in Selangor, Malaysia, using Google Forms among 202 Malaysian adults from January 1, 2021 to March 31, 2021. Descriptive statistics were used to analyse the socio-demographic characteristics and knowledge scores. The continuous variables were evaluated using the independent t-test, Mann-Whitney test, and one-way analysis of variance test. The Spearman correlation coefficient was employed to determine the correlation between socio-demographic characteristics and knowledge score levels. RESULTS: The final analysis included 202 participants. The mean±standard deviation age was 49.03±12.65. Only 6.9% of participants had good knowledge of sarcopenia and were aware of sarcopenia's characteristics, consequences, and treatments. Post-hoc comparisons using the Dunnett T3 test showed statistical significance in mean knowledge score and age group (p=0.011) and education level (p≤0.001). The Mann-Whitney test revealed that gender (p=0.026) and current smoking status (p=0.023) significantly influenced knowledge scores. CONCLUSIONS: The general public's knowledge of sarcopenia was found to be poor to moderate and associated with age and education status. Therefore, education and interventions by policymakers and healthcare professionals to improve public knowledge of sarcopenia in Malaysia are needed.
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Sarcopenia , Adulto , Humanos , Estudos Transversais , Inquéritos e Questionários , Escolaridade , Povo Asiático , Conhecimentos, Atitudes e Prática em SaúdeRESUMO
Microbial L-asparaginase is well known for its application in food industries to reduce acrylamide content in fried starchy food. L-asparaginase produced by Arctic actinomycetes Streptomyces koyangensis SK4 was purified and studied for biochemical characterization. The L-asparaginase was purified with a yield of 15.49% and final specific activity of 179.77 IU/mg of protein. The enzyme exhibited a molecular weight of 43 kDa. The optimum pH and temperature for maximum activity of the purified enzyme were 8.5 °C and 40 °C, respectively. The enzyme expressed maximum activity at an incubation period of 30 min and a substrate concentration of 0.06 M. The enzyme has a low Km value of 0.041 M and excellent substrate specificity toward L-asparagine. The enzyme activity was inhibited by metal ions Ba2+ and Hg2+, while Mn2+ and Mg2+ enhanced the activity. The study evaluated the acrylamide reduction potential of L-asparaginase from Streptomyces koyangensis SK4 in potato chips. The blanching plus L-asparaginase treatment of potato slices resulted in a 50% reduction in acrylamide content. The study illustrated an effective acrylamide reduction strategy in potato chips using L-asparaginase from a psychrophilic actinomycete. Besides the acrylamide reduction potential, L-asparaginase from Streptomyces koyangensis SK4 also did not exhibit any glutaminase or urease activity which is an outstanding feature of L-asparaginase to be used as a chemotherapeutic agent.
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Asparaginase , Streptomyces , Asparaginase/genética , Asparaginase/metabolismo , Acrilamida/química , Acrilamida/metabolismo , Streptomyces/metabolismo , TemperaturaRESUMO
Inflammation and tissue damage associated with pancreatitis can precede or occur concurrently with pancreatic ductal adenocarcinoma (PDAC). We demonstrate that in PDAC coupled with pancreatitis (ptPDAC), antigen-presenting type-I conventional dendritic cells (cDC1s) are specifically activated. Immune checkpoint blockade therapy (iCBT) leads to cytotoxic CD8 + T cell activation and eradication of ptPDAC with restoration of lifespan even upon PDAC re-challenge. Such eradication of ptPDAC was reversed following specific depletion of dendritic cells. Employing PDAC antigen-loaded cDC1s as a vaccine, immunotherapy-resistant PDAC was rendered sensitive to iCBT with a curative outcome. Analysis of the T-cell receptor (TCR) sequences in the tumor infiltrating CD8 + T cells following cDC1 vaccination coupled with iCBT identified unique CDR3 sequences with potential therapeutic significance. Our findings identify a fundamental difference in the immune microenvironment and adaptive immune response in PDAC concurrent with, or without pancreatitis, and provides a rationale for combining cDC1 vaccination with iCBT as a potential treatment option.
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Rapid urbanization has recently caused serious problems for cities all around the world. Smart cities have drawn much interest from researchers in the present research paradigm to manage the expanding urban population. Frameworks for smart cities are planned and implemented using platforms based on blockchain and the Internet of Things (BIOT). Smart cities may use the BIoT platform to provide improved transportation, food traceability, and healthcare services. Food safety is one of the sectors where less research has been done than the others. The importance of food safety is now more widely recognized, making it essential to improve the traceability and transparency of the food supply chain. In this paper, a novel BIOT-based layered framework using EOSIO has been proposed for effective food traceability. The proposed system first identifies the suitable traceability units to provide better transparency and traceability and then defines and implements a layered architecture using Ethereum and EOSIO blockchain platforms. The performance of the proposed EOSIO-based model is evaluated using the practicality of the consensus algorithm, block production rate, throughput, and block confirmation time. The proposed traceability system attains a block production rate of 0.5 s and a block confirmation time of 1 s, which is much lower than the Ethereum-based traceability system. Hence, from the experimental evidence, the superiority of the proposed EOSIO-based food traceability can be observed.
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Pancreatic ductal adenocarcinoma (PDAC) is associated with mutations in Kras, a known oncogenic driver of PDAC; and the KRAS G12D mutation is present in nearly half of PDAC patients. Recently, a non-covalent small molecule inhibitor (MRTX1133) was identified with specificity to the Kras G12D mutant protein. Here we explore the impact of Kras G12D inhibition by MRTX1133 on advanced PDAC and its influence on the tumor microenvironment. Employing different orthotopic xenograft and syngeneic tumor models, eight different PDXs, and two different autochthonous genetic models, we demonstrate that MRTX1133 reverses early PDAC growth, increases intratumoral CD8 + effector T cells, decreases myeloid infiltration, and reprograms cancer associated fibroblasts. Autochthonous genetic mouse models treated with MRTX1133 leads to regression of both established PanINs and advanced PDAC. Regression of advanced PDAC requires CD8 + T cells and immune checkpoint blockade therapy (iCBT) synergizes with MRTX1133 to eradicate PDAC and prolong overall survival. Mechanistically, inhibition of mutant Kras in advanced PDAC and human patient derived organoids (PDOs) induces Fas expression in cancer cells and facilitates CD8 + T cell mediated death. These results demonstrate the efficacy of MRTX1133 in different mouse models of PDAC associated with reprogramming of stromal fibroblasts and a dependency on CD8 + T cell mediated tumor clearance. Collectively, this study provides a rationale for a synergistic combination of MRTX1133 with iCBT in clinical trials.
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Actinomycetes isolated from the Arctic sediment were evaluated for the production of the enzyme l-asparaginase, an enzyme used to treat acute lymphoblastic leukemia. The most potent strain Streptomyces koyangensis SK4 was selected for l-asparaginase enzyme production by submerged fermentation. The effect of various fermentation parameters on enzyme production was analyzed statistically using the Plackett-Burman design and response surface method. Effects of eight parameters including temperature, pH, incubation time, inoculum size, agitation speed, the concentration of starch, l-asparagine, and yeast extract were studied on l-asparaginase production by the Arctic isolate S. koyangensis SK4. Factors such as temperature, pH, incubation time, agitation speed, and l-asparagine concentration were found to be important factors influencing l-asparaginase production. Maximum enzyme activity of 136 IU/ml was obtained at 20°C on the seventh day of incubation in the asparagine dextrose broth maintained at pH 7.5, agitation speed 125 rpm, and l-asparagine concentration of 7.5 g/L. The statistical optimization method described in this study proved effective for increasing the l-asparaginase production by Arctic actinomycetes.
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Actinobacteria , Streptomyces , Asparaginase/metabolismo , Asparagina/metabolismo , Streptomyces/metabolismo , Fermentação , Actinobacteria/metabolismoRESUMO
This is the first detailed study on 14C activity in the environment surrounding a nuclear facility in India. Samples of food matrices and wild plants from the off-site locations of the PHWR nuclear power plant (NPP) at Kaiga were analysed by liquid scintillation spectrometry, results were validated by accelerator mass spectrometry, and an extensive database (N = 142) was established. The stable isotope ratio of carbon (δ13C) in terrestrial plants varied from -33.5 to -23.3 . The maximum excess 14C activity recorded in terrestrial biota was 44 Bq kg-1C (19 pMC). About 75 % of the samples exhibited specific activity in the range 228-249 Bq kg-1C (101-110 pMC). Statistical tests on the 14C specific activity dataset for 2.3-5, 5-10, and 10-20 km radial zones confirmed that the impact of the operation of the NPP on the environment beyond 5 km is minimal. The study suggests that the 14C activity released through gaseous effluents from Kaiga NPP is transported to greater distances along the axis of the valley than that predicted by the Gaussian plume model and those reported for other NPP sites worldwide. This is due to the unique topography of the Kaiga valley in which wind flow channelling, strong winds in the valley mouth, and calm wind within the valley due to the blocking effect by hills for the south-westerly wind regime play dominant roles in the transport of gaseous effluents. The 14C specific activity values at upwind monitoring stations located at >5 km distance from the NPP during the south-westerly wind regime were higher than those observed during the north-easterly wind regime when the same monitoring stations were located on the downwind side. The ingestion dose to the population in the 2.3-5 km radius zone, attributable to the release of 14C from the NPP, was 0.75 µSv y-1. This is a negligibly small fraction of the ICRP recommended dose limit of 1000 µSv y-1 for the public from other than natural sources. The dose due to the natural 14C activity in the Kaiga region was 12 µSv y-1, corresponding to the ambient natural activity of 230 Bq kg-1 C.
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Biota , Centrais Nucleares , Radioisótopos de Carbono , Índia , GasesRESUMO
Major impediments to conveyance of intravenously administered drugs to tumors are biofouling, opsonization, and rapid clearance from the circulation by macrophages and reticuloendothelial phagocytes. Cloaking nanoparticles with stealth epilayers partly overcomes these hurdles but it also foils interactions with tumor cells. Here, we describe the synthesis, characterization, and validation of smart gold nanorods (GNRs) that spontaneously transform from inert passengers in the blood stream to active cell-penetrating nanoparticles within tumors to potently sensitize tumors to radiation therapy. Intrinsically cationic and cell-penetrating GNRs were shielded from phagocytosis with a cloaking polyethylene glycol epilayer containing an intervening cleavable peptide. In the absence of an external trigger, this epilayer is clipped off by the tumor microenvironmental protease, cathepsin B, in colorectal cancers to uncloak and expose the free-circulating native unPEGylated GNR that is readily internalized by cancer cells and turn into immovable small clusters of GNRs. Selective uncloaking of GNRs in the tumor reduced off-target toxicity confirmed by hematologic, biochemical, and histopathological analysis of blood, serum, and normal organs, respectively. Subsequent irradiation led to significant tumor growth delay and improved survival of mice. By addressing multiple barriers to efficient transport and cellular internalization of nanoparticles, our results demonstrate that clinically meaningful radiosensitization can be achieved with rationally designed GNRs.
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Nanotubos , Neoplasias , Camundongos , Animais , Ouro/química , Catepsina B , Microambiente Tumoral , Nanotubos/química , Neoplasias/radioterapiaRESUMO
This is a detailed study on oxide (CO2) and reduced (hydrocarbons, CnHm) forms of 14C releases through gaseous effluents from the Kaiga nuclear power plant (NPP), on the West Coast of India, where 4 × 220 MW(e) pressurized heavy water reactors (PHWRs) are operating. The gaseous effluent from the common stack of reactor units 3 and 4 (each of 220 MW(e)) was sampled from 2017 to 2020 for 14C activity monitoring and analysed for 14C activity by liquid scintillation counting. The normalized release rate corresponding to the four-year monitoring period had a geometric mean value of 0.12 TBq GW(e)-1 a-1 (geometric standard deviation = 7.4), and the arithmetic mean with associated standard deviation was 0.75 ± 1.47 TBq GW(e)-1 a-1. The relative percentage contribution of reduced form (CH4) of 14C species was less than 1.27% of the total release. The normalized release rate from Kaiga NPP was similar to those reported for the other PHWR NPPs of the world. The 14C specific activity in the ambient air in the vicinity of the NPP was monitored at four locations. The maximum excess 14C activity values in the ambient air in the vicinity of the NPP, evaluated by comparing the specific activity recorded for the clean air region at â¼300 km from the NPP, were 65.1 Bq kg-1C (28.76 pMC) and 222.4 Bq kg-1C (98.23 pMC) for the years 2019 and 2020 respectively. In addition, the release rates were calculated from the Gaussian plume model using site-specific atmospheric dilution factors and the excess 14C specific activity measured at four off-site monitoring stations. The calculated values of release rates were in agreement (within a factor of â¼3) with the measured values.