Endothelin receptor B antagonists decrease glioma cell viability independently of their cognate receptor

Background: Endothelin receptor antagonists inhibit the progression of many cancers, but research into their influence on glioma has been limited. Methods: We treated glioma cell lines, LN-229 and SW1088, and melanoma cell lines, A375 and WM35, with two endothelin receptor type B (ETRB)-specific antagonists, A-192621 and BQ788, and quantified viable cells by the capacity of their intracellular esterases to convert non-fluorescent calcein AM into green-fluorescent calcein. We assessed cell proliferation by labeling cells with carboxyfluorescein diacetate succinimidyl ester and quantifying the fluorescence by FACS analysis. We also examined the cell cycle status using BrdU/propidium iodide double staining and FACS analysis. We evaluated changes in gene expression by microarray analysis following treatment with A-192621 in glioma cells. We examined the role of ETRB by reducing its expression level using small interfering RNA (siRNA). Results: We report that two ETRB-specific antagonists, A-192621 and BQ788, reduce the number of viable cells in two glioma cell lines in a dose- and time-dependent manner. We describe similar results for two melanoma cell lines. The more potent of the two antagonists, A-192621, decreases the mean number of cell divisions at least in part by inducing a G2/M arrest and apoptosis. Microarray analysis of the effects of A-192621 treatment reveals up-regulation of several DNA damage-inducible genes. These results were confirmed by real-time RT-PCR. Importantly, reducing expression of ETRB with siRNAs does not abrogate the effects of either A-192621 or BQ788 in glioma or melanoma cells. Furthermore, BQ123, an endothelin receptor type A (ETRA)-specific antagonist, has no effect on cell viability in any of these cell lines, indicating that the ETRB-independent effects on cell viability exhibited by A-192621 and BQ788 are not a result of ETRA inhibition. Conclusion: While ETRB antagonists reduce the viability of glioma cells in vitro, it appears unlikely that this effect is mediated by ETRB inhibition or cross-reaction with ETRA. Instead, we present evidence that A-192621 affects glioma and melanoma viability by activating stress/DNA damage response pathways, which leads to cell cycle arrest and apoptosis. This is the first evidence linking ETRB antagonist treatment to enhanced expression of DNA damage-inducible genes

Estimation of Serum Urea, Creatinine, And Electrolytes in Corona Virus Disease 2019 Covid-19 Positive Patients

Introduction: China saw the outbreak of Coronavirus Disease 2019 (COVID-19), an emerging infectious disease with an unknown etiology, during the winter of 2019. This unidentified virus was later identified and given the name severe acute respiratory syndrome.  second coronavirus (SARS-CoV-2). More data point to the association between renal dysfunction and coronavirus disease 2019 (COVID-19). Uncertainty surrounds the relationship between renal dysfunction brought on by the SARS-CoV-2 virus and prognosis. Objectives: The objectives center around recognizing the impact of COVID-19 on renal function, advocating for continuous monitoring, and proposing specific blood markers as indicators for predicting patient outcomes. Methods: 160 hospitalised COVID-19-positive patients were enrolled in the current study, of which 80 were assigned to Group I — COVID-19 patients who were critically sick (severe cases), and 80 to Group II — COVID-19 patients who were not critically ill (mild and moderate cases). Using the Architect system (201837-110) to measure serum urea and creatinine levels, data were reported as mg/dL Results: In the current investigation, group I samples demonstrated a highly significant increase in serum urea, creatinine, and Sodium compared to group II samples When comparing critically sick COVID-19 patients (severe cases) to non-critically ill COVID-19 patients (mild and moderate cases), there was no discernible difference in the mean difference of serum potassium. Conclusions: Impaired kidney function, hyponatremia, and developing kidney damage should notify clinicians during COVID-19 patient care. In clinical practice, serum electrolytes, as well as serum urea and creatinine, can be utilized to predict Covid-19 patient survival

日本の産学連携を活用した科学技術・イノベーション政策

Scientific research is a process that generates new knowledge, which can be deployed in the industry to create innovation and become an engine of economic growth. In Japan, the Basic Law on Science and Technology was enacted in 1995, and the system was transformed to create an innovation policy with a view to everything from university research to industrialization.This paper outlines the policies for innovation creation from the 1995 Basic Law on Science and Technology to the 5th Science and Technology Basic Plan, and analyzes the environment surrounding innovation in Japan from data from the NISTEP Science and Technology Indicators 2019 (NISTEP, 2019) and the White Paper on Science and Technology (MEXT, 2019). While there is an upward trend in the joint research budgets of universities and companies and also the number of university-launched ventures, the global share of the number of highly cited papers is on the decline. Improving the research environment and resources in universities was identified as a challenge.If industry-academia collaboration encourages only research that is useful for solving immediate problems with an awareness of practical application and commercialization, a variety of knowledge will not be accumulated in the long term, and this may be a factor that hinders the creation of innovation. The presentation of the Society 5.0 concept in the 5th Science and Technology Basic Plan can be seen as an effort to change the policy stance on innovation by presenting a vision of the future and the direction of research and development rather than the immediate issues.科学研究は新たな知識を生み出すプロセスであり、産業に展開してイノベーションを創出することで経済成長のエンジンとなる。日本では1995年に科学技術基本法が成立し、大学での研究から産業化までを視野に入れたイノベーション政策を打ち出す体制へと変わった。本稿では、1995年の科学技術基本法から、第5期科学技術基本計画までのイノベーション創出に向けた政策を概観し、NISTEP科学技術指標2019(NISTEP,2019)や科学技術白書(MEXT,2019)のデータから日本のイノベーションを取り巻く環境の分析を行った。大学と企業の共同研究予算や大学発ベンチャーの創業数には増加傾向が見られる一方で、高被引用論文数の世界シェアは低下傾向にある。大学における研究環境・資源の改善が課題であることが明らかとなった。実用化・商品化を意識して直近の課題解決に役立つ研究だけを推奨する産学連携では、長期的に多様な知識が蓄積されなくなり、イノベーション創出を妨げる要因にもなりうる。第5期科学技術基本計画においてSociety 5.0の概念が示されたことは、直近の課題ではなく未来のビジョンと研究開発の方向性を示すことで、イノベーションに対する政策のスタンスを変える取組みと考えられる。This research was supported by the JST-RISTEX Science of Science, Technology and Innovation Policy "Star Scientists and Innovation in Japan". and KAKENHI (18H00840)

“Metabolic Alterations in Chronic Kidney Disease Patients: A Comprehensive Biochemical Analysis.”

Introduction Chronic Kidney Disease (CKD) is a global health concern affecting millions of individuals, with a disproportionate impact on developing nations. Renal replacement therapies, such as kidney transplants, hemodialysis, and peritoneal dialysis, play a crucial role in saving lives but contribute significantly to healthcare spending. This research paper presents a comprehensive study conducted at the Department of Biochemistry, Bharati Vidyapeeth (Deemed To Be University) Medical College and Hospital Sangli, focusing on the evolution of metabolic alterations in bones causing abnormal bone homeostasis in CKD patients..Objectives: The primary objective of this study is to conduct a stage-wise biochemical analysis of CKD patients, examining key parameters related to metabolic alterations in bones, including blood urea, serum creatinine, calcium, phosphorous, iPTH, vit.D3, alkaline phosphatase, and osteocalcin. The study aims to provide valuable insights into the interconnectedness of abnormal mineral metabolism, bone health, and extraskeletal problems, with a focus on age, gender, dialysis specifics, medication use, surgical interventions, co-morbidities, and dietary changes. Methods: The study enrolled a cohort of CKD patients, and their biochemical parameters were analyzed at different stages of the disease progression. The parameters were measured using standardized laboratory techniques. Statistical analyses were performed to identify correlations and significant associations.  Results: The study observed a highly significant elevation and positive correlation (p<0.001) of blood urea and serum creatinine in CKD patients, emphasizing their utility as markers for disease progression. Significant lowering of serum calcium levels (p<0.004) was noted, primarily attributed to hypovitaminosis D and reduced kidney capacity to release active vitamin D3. Furthermore, a significant elevation of serum phosphorous levels (p<0.009) was identified, indicating progressive hyperphosphatemia associated with CKD. Conclusions: This research sheds light on the complex interplay of factors in CKD-MBD, emphasizing the implications for bone health and cardiovascular disease. The stage-wise biochemical analysis provides valuable insights for clinicians in managing CKD patients at different disease stages, guiding personalized and effective care strategies

EGFRvIV: a previously uncharacterized oncogenic mutant reveals a kinase autoinhibitory mechanism

Tumor cells often subvert normal regulatory mechanisms of signal transduction. This study shows this principle by studying yet uncharacterized mutants of the epidermal growth factor receptor (EGFR) previously identified in glioblastoma multiforme, which is the most aggressive brain tumor in adults. Unlike the well-characterized EGFRvIII mutant form, which lacks a portion of the ligand-binding cleft within the extracellular domain, EGFRvIVa and EGFRvIVb lack internal segments distal to the intracellular tyrosine kinase domain. By constructing the mutants and by ectopic expression in naive cells, we show that both mutants confer an oncogenic potential in vitro, as well as tumorigenic growth in animals. The underlying mechanisms entail constitutive receptor dimerization and basal activation of the kinase domain, likely through a mechanism that relieves a restraining molecular fold, along with stabilization due to association with HSP90. Phosphoproteomic analyses delineated the signaling pathways preferentially engaged by EGFRvIVb-identified unique substrates. This information, along with remarkable sensitivities to tyrosine kinase blockers and to a chaperone inhibitor, proposes strategies for pharmacological interception in brain tumors harboring EGFRvIV mutations.Goldhirsh FoundationNational Cancer Institute (U.S.) (CA118705)National Cancer Institute (U.S.) (CA141556)National Cancer Institute (U.S.) (U54-CA112967

"Advancements in Biomarkers for Early Diagnosis and Management of Neonatal Sepsis: Insights into Oxidative Stress, Inflammatory Markers, and Novel Biomarkers"

Introduction:  Neonatal sepsis presents a critical challenge in clinical practice, requiring swift identification and intervention to mitigate its potentially devastating effects. Recent advancements in understanding its pathophysiology have led to the development of biomarkers as crucial tools for aiding clinical decision-making. This review focuses on recent progress in biomarkers for diagnosing and managing neonatal sepsis, particularly emphasizing the roles of Procalcitonin (PCT), Neutrophil Gelatinase Associated Lipocalin (NGAL), and C-reactive protein (CRP) in conjunction with oxidative stress and inflammatory markers. Objectives: Assess the diagnostic efficacy of Procalcitonin (PCT), Neutrophil Gelatinase Associated Lipocalin (NGAL), and C-reactive protein (CRP) in distinguishing between bacterial and non-bacterial causes of neonatal sepsis.Methods: This case-control study was conducted at the Department of Biochemistry, in collaboration with the Department of Pediatrics, Bharati Vidyapeeth (Deemed to be University) Medical College & Hospital, Sangli, from February 2015 to August 2017. A total of 140 neonates were included, comprising 70 clinically suspected sepsis cases and 70 healthy controls. Blood samples were collected from each subject, and various markers including CRP, PCT, Neutrophil Gelatinase Associated Lipocalin (NGAL).Results: The review found that Procalcitonin (PCT), Neutrophil Gelatinase Associated Lipocalin (NGAL), and C-reactive protein (CRP) exhibit promising diagnostic utility in distinguishing between bacterial and non-bacterial etiologies of neonatal sepsis. Elevated concentrations of these biomarkers were consistently observed in septic neonates compared to non-septic controls. Conclusions: Through a comprehensive discussion, the review elucidated the distinct roles of PCT, CRP, and NGAL in the pathophysiology of neonatal sepsis. These biomarkers were found to be associated with inflammation, tissue injury, and modulation of microbial growth, underscoring their multifaceted contributions to the disease process. Overall, the results of this study suggest that PCT, CRP, and NGAL hold promise as valuable biomarkers for improving outcomes in neonatal sepsis. Their integration into clinical practice has the potential to enhance early diagnosis, facilitate prompt intervention, and ultimately mitigate the devastating consequences of this challenging condition

Investigating the Impact of Plateletpheresis on Biochemical Bone Markers: A Focus on Osteocalcin, C-Telopeptide Type I Collagen, and Serum Calcium in Donors

Introduction: : In plateletpheresis Citrate is used as an anticoagulant. The property of citrate is to chelate the calcium and prevent the coagulation cascade may causes hypocalcaemia in the plateletpheresis donor. Objectives: Aim and objects of this study is to investigate effect of citrate on bone markers in pre and post plateletpheresis donors. Methods: Comparative analytical Study was conducted among 90 healthy donors at Biochemistry Dept. and Blood Bank, Bharati Vidyapeeth (Deemed To Be ) University Medical College and Hospital .Sangli  Maharashtra .from November 2018 to December 2020.  Blood sample was taken from donors before and after 30 min. and measure the levels of serum calcium, osteocalcin, CTX and i-PTH  in pre and post donations. Results: The statistical significance (p < 0.000) of the observed changes in serum calcium, osteocalcin, CTX, and i-PTH levels after plateletpheresis emphasizes the robustness of these alterations across all donors. Further research is essential to elucidate the underlying mechanisms and potential implications of these changes on bone health and overall physiological homeostasis. Conclusions: The changes in serum calcium, osteocalcin, CTX, and i-PTH levels post-plateletpheresis suggest a dynamic interplay between the procedure and the body\u27s regulatory mechanisms. Further research is needed to elucidate the specific mechanisms underlying these alterations and their potential implications for bone health and overall physiology

A niche-mimicking polymer hydrogel-based approach to identify molecular targets for tackling human pancreatic cancer stem cells.

BACKGROUND: Pancreatic adenocarcinoma (PAAD) is one of the most fatal human cancers, but effective therapies remain to be established. Cancer stem cells (CSCs) are highly resistant to anti-cancer drugs and a deeper understanding of their microenvironmental niche has been considered important to provide understanding and solutions to cancer eradication. However, as the CSC niche is composed of a wide variety of biological and physicochemical factors, the development of multidisciplinary tools that recapitulate their complex features is indispensable. Synthetic polymers have been studied as attractive biomaterials due to their tunable biofunctionalities, while hydrogelation technique further renders upon them a diversity of physical properties, making them an attractive tool for analysis of the CSC niche. METHODS: To develop innovative materials that recapitulate the CSC niche in pancreatic cancers, we performed polymer microarray analysis to identify niche-mimicking scaffolds that preferentially supported the growth of CSCs. The niche-mimicking activity of the identified polymers was further optimized by polyethylene glycol (PEG)-based hydrogelation. To reveal the biological mechanisms behind the activity of the optimized hydrogels towards CSCs, proteins binding onto the hydrogel were analyzed by liquid chromatography with tandem mass spectrometry (LC-MS/MS), and the potential therapeutic targets were validated by looking at gene expression and patients' outcome in the TCGA database. RESULTS: PA531, a heteropolymer composed of 2-methoxyethyl methacrylate (MEMA) and 2-(diethylamino)ethyl methacrylate (DEAEMA) (5.5:4.5) that specifically supports the growth and maintenance of CSCs was identified by polymer microarray screening using the human PAAD cell line KLM1. The polymer PA531 was converted into five hydrogels (PA531-HG1 to HG5) and developed to give an optimized scaffold with the highest CSC niche-mimicking activities. From this polymer that recapitulated CSC binding and control, the proteins fetuin-B and angiotensinogen were identified as candidate target molecules with clinical significance due to the correlation between gene expression levels and prognosis in PAAD patients and the proteins associated with the niche-mimicking polymer. CONCLUSION: This study screened for biofunctional polymers suitable for recapitulation of the pancreatic CSC niche and one hydrogel with high niche-mimicking abilities was successfully fabricated. Two soluble factors with clinical significance were identified as potential candidates for biomarkers and therapeutic targets in pancreatic cancers. Such a biomaterial-based approach could be a new platform in drug discovery and therapy development against CSCs, via targeting of their niche

The ErbB signalling pathway: protein expression and prognostic value in epithelial ovarian cancer

Ovarian cancer is the most frequent cause of death from gynaecological cancer in the Western world. Current prognostic factors do not allow reliable prediction of response to chemotherapy and survival for individual ovarian cancer patients. Epidermal growth factor receptor (EGFR) and HER-2/neu are frequently expressed in ovarian cancer but their prognostic value remains unclear. In this study, we investigated the expression and prognostic value of EGFR, EGFR variant III (EGFRvIII), HER-2/neu and important downstream signalling components in a large series of epithelial ovarian cancer patients. Immunohistochemical staining of EGFR, pEGFR, EGFRvIII, Her-2/neu, PTEN (phosphatase and tensin homologue deleted on chromosome 10), total and phosphorylated AKT (pAKT) and phosphorylated ERK (pERK) was performed in 232 primary tumours using the tissue microarray platform and related to clinicopathological characteristics and survival. In addition, EGFRvIII expression was determined in 45 tumours by RT–PCR. Our results show that negative PTEN immunostaining was associated with stage I/II disease (P=0.006), non-serous tumour type (P=0.042) and in multivariate analysis with a longer progression-free survival (P=0.015). Negative PTEN staining also predicted improved progression-free survival in patients with grade III or undifferentiated serous carcinomas (P=0.011). Positive pAKT staining was associated with advanced-stage disease (P=0.006). Other proteins were expressed only at low levels, and were not associated with any clinicopathological parameter or survival. None of the tumours were positive for EGFRvIII. In conclusion, our results indicate that tumours showing negative PTEN staining could represent a subgroup of ovarian carcinomas with a relatively favourable prognosis

Comprehensive defect suppression in perovskite nanocrystals for high-efficiency light-emitting diodes

Electroluminescence efficiencies of metal halide perovskite nanocrystals (PNCs) are limited by a lack of material strategies that can both suppress the formation of defects and enhance the charge carrier confinement. Here we report a one-dopant alloying strategy that generates smaller, monodisperse colloidal particles (confining electrons and holes, and boosting radiative recombination) with fewer surface defects (reducing non-radiative recombination). Doping of guanidinium into formamidinium lead bromide PNCs yields limited bulk solubility while creating an entropy-stabilized phase in the PNCs and leading to smaller PNCs with more carrier confinement. The extra guanidinium segregates to the surface and stabilizes the undercoordinated sites. Furthermore, a surface-stabilizing 1,3,5-tris(bromomethyl)-2,4,6-triethylbenzene was applied as a bromide vacancy healing agent. The result is highly efficient PNC-based light-emitting diodes that have current efficiency of 108 cd A−1 (external quantum efficiency of 23.4%), which rises to 205 cd A−1 (external quantum efficiency of 45.5%) with a hemispherical len