Polyamines Drive Myeloid Cell Survival by Buffering Intracellular pH to Promote Immunosuppression in Glioblastoma

Glioblastoma is characterized by the robust infiltration of immunosuppressive tumor-associated myeloid cells (TAMCs). It is not fully understood how TAMCs survive in the acidic tumor microenvironment to cause immunosuppression in glioblastoma. Metabolic and RNA-seq analysis of TAMCs revealed that the arginine-ornithine-polyamine axis is up-regulated in glioblastoma TAMCs but not in tumor-infiltrating CD8+ T cells. Active de novo synthesis of highly basic polyamines within TAMCs efficiently buffered low intracellular pH to support the survival of these immunosuppressive cells in the harsh acidic environment of solid tumors. Administration of difluoromethylornithine (DFMO), a clinically approved inhibitor of polyamine generation, enhanced animal survival in immunocompetent mice by causing a tumor-specific reduction of polyamines and decreased intracellular pH in TAMCs. DFMO combination with immunotherapy or radiotherapy further enhanced animal survival. These findings indicate that polyamines are used by glioblastoma TAMCs to maintain normal intracellular pH and cell survival and thus promote immunosuppression during tumor evolution

Mitochondrial electron transport chain is necessary for NLRP3 inflammasome activation

The NLRP3 inflammasome is linked to sterile and pathogen-dependent inflammation, and its dysregulation underlies many chronic diseases. Mitochondria have been implicated as regulators of the NLRP3 inflammasome through several mechanisms including generation of mitochondrial reactive oxygen species (ROS). Here, we report that mitochondrial electron transport chain (ETC) complex I, II, III and V inhibitors all prevent NLRP3 inflammasome activation. Ectopic expression of Saccharomyces cerevisiae NADH dehydrogenase (NDI1) or Ciona intestinalis alternative oxidase, which can complement the functional loss of mitochondrial complex I or III, respectively, without generation of ROS, rescued NLRP3 inflammasome activation in the absence of endogenous mitochondrial complex I or complex III function. Metabolomics revealed phosphocreatine (PCr), which can sustain ATP levels, as a common metabolite that is diminished by mitochondrial ETC inhibitors. PCr depletion decreased ATP levels and NLRP3 inflammasome activation. Thus, the mitochondrial ETC sustains NLRP3 inflammasome activation through PCr-dependent generation of ATP, but via a ROS-independent mechanism.publishedVersionPeer reviewe

Global variations in diabetes mellitus based on fasting glucose and haemogloblin A1c

Fasting plasma glucose (FPG) and haemoglobin A1c (HbA1c) are both used to diagnose diabetes, but may identify different people as having diabetes. We used data from 117 population-based studies and quantified, in different world regions, the prevalence of diagnosed diabetes, and whether those who were previously undiagnosed and detected as having diabetes in survey screening had elevated FPG, HbA1c, or both. We developed prediction equations for estimating the probability that a person without previously diagnosed diabetes, and at a specific level of FPG, had elevated HbA1c, and vice versa. The age-standardised proportion of diabetes that was previously undiagnosed, and detected in survey screening, ranged from 30% in the high-income western region to 66% in south Asia. Among those with screen-detected diabetes with either test, the agestandardised proportion who had elevated levels of both FPG and HbA1c was 29-39% across regions; the remainder had discordant elevation of FPG or HbA1c. In most low- and middle-income regions, isolated elevated HbA1c more common than isolated elevated FPG. In these regions, the use of FPG alone may delay diabetes diagnosis and underestimate diabetes prevalence. Our prediction equations help allocate finite resources for measuring HbA1c to reduce the global gap in diabetes diagnosis and surveillance.peer-reviewe

Using modified early warning score to predict need of lifesaving intervention in adult non-trauma patients in a tertiary state hospital

Background: Modified early warning score has been validated in many uses in the emergency department. We propose that the modified early warning score performs well in predicting the need of lifesaving interventions in the emergency department, as a predictor of patients who are critically ill. Objective: The study aims to evaluate the use of modified early warning score in sorting out critically ill patients in the emergency department. Methods: The patients’ demographic data and first vital signs (blood pressure, heart rate, temperature, respiratory rate, and level of consciousness) were collected prospectively. Individual modified early warning score was calculated. The outcome was a patient received one or more lifesaving interventions toward the end of stay in emergency department. Multivariate logistic regression analysis was utilized to assess the association between modified early warning score and other potential predictors with outcome. Results: There are a total of 259 patients enrolled into the study. The optimal modified early warning score in predicting lifesaving intervention was ≥4 with a sensitivity of 95% and specificity of 81%. Modified early warning score ≥4 (odds ratio = 96.97, 95% confidence interval = 11.82-795.23, p < 0.001) was found to significantly increase the risk of receiving lifesaving intervention in the emergency department. Conclusion: Modified early warning score is found to be a good predictor for patients in need of lifesaving intervention in the emergency department

Bioethical issues of tissue engineering and regenerative medicine from Islamic perspective

Modern advances in biochemistry, cell and molecular biology, genetics, biomedical engineering and material sciences, have contributed to the development of tissue engineering and regenerative medicine (TERM). Although TERM is still in its initial phases, significant breakthrough in this crossdisciplinary area has clearly marked the way for the establishment of a promising new biomedicine technology which actively seeks to reconstruct tissues/organs or spare parts for the human body to repair, restore or replace damaged tissues. However, these breakthroughs have raised number of moral and legal questions, including among others, is it moral to genetically modify the human genes? What are the moral and legal implications of regenerative medicine? Does organ reconstruction or tissue replacement activity violate basic religious beliefs or legal status of the person? What is the scope and limitation of these practices? Through textual and analytical methods, this paper aims to answer these questions and other relevant concerns from Islamic perspective. Besides the texts of the Qur‟an and the Prophetic narrations (hadith), both Muslim jurists (fuqaha) and ethicists‟ opinion on these matters would be unveiled

Bioethical issues of tissue engineering and regenerative medicine: a preliminary review from Islamic perspective

Modern advances in biochemistry, cell and molecular biology, genetics, biomedical engineering and material sciences, have contributed to the development of tissue engineering and regenerative medicine (TERM). Although TERM is still in its initial phases, significant breakthrough in this cross- disciplinary area has clearly marked the way for the establishment of a promising new biomedicine technology which actively seeks to reconstruct tissues/organs or spare parts for the human body to repair, restore or replace damaged tissues. However, these breakthroughs have raised number of moral and legal questions, including among others, is it moral to genetically modify the human genes? What are the moral and legal implications of regenerative medicine? Does organ reconstruction or tissue replacement activity violate basic religious beliefs or legal status of the person? Through textual and analytical methods, this paper aims to explore relevant concerns from t he Islamic perspective. Besides the texts of the Qur’an and the Prophetic narrations (hadith), both Muslim jurists (fuqaha) and ethicists’ opinion on these matters would be unveiled

Mothers’ perceptions and experiences on tongue-tie and frenotomy: a qualitative study

Introduction: Tongue-tie is a congenital condition of a thickened, tightened or shortened frenulum. This condition may cause breastfeeding difficulties to both mother and infant, such as ineffective suckling and painful nipple. In older children, it can cause speech difficulties. Although many studies have investigated the problems associated with tongue-tie and its treatments, there are limited studies on the mother’s experiences of tongue-tie and post frenotomy. This study aimed to explore the mother’s experiences of tongue-tie associated problems, frenotomy and the outcome. Methods: In-depth interviews were conducted in a one-on-one setting with fifteen mothers whose infant and children underwent frenotomy. Data were collected, transcripted, translated and analysed according to themes. Results: The analysis revealed a common story of stressful challenges and difficulties of breastfeeding. The mothers described that tongue-tie caused poor latching, nipple pain and bleeding, prolong feeding and lack of sleep. Their infant had poor weight gain, sleeping problems, insufficient milk transfer, fatigue and constant crying. For the older children, mothers complained of restricted tongue movement, difficulty in licking ice cream and speech problems. All of them agreed that the frenotomy procedure was easy, simple and less invasive and the outcome was positive. Furthermore, mothers continued breastfeeding without any difficulties and complications. Conclusion: Mothers in this study had difficulties with breastfeeding. However, all of the reported symptoms improved after frenotomy. They considered frenotomy was a simple and safe procedure that was highly recommended for symptomatic tongue-tie

Anti-GITR therapy promotes immunity against malignant glioma in a murine model

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Mechanical Properties of Recycled Aggregate Concretes Containing Silica Fume and Steel Fibres

In this study, the impact of steel fibres and Silica Fume (SF) on the mechanical properties of recycled aggregate concretes made of two different types of Recycled Coarse Aggregates (RCA) sourced from both low- and high-strength concretes were evaluated through conducting 60 compressive strength tests. The RCAs were used as replacement levels of 50% and 100% of Natural Coarse Aggregates (NCA). Hook-end steel fibres and SF were also used in the mixtures at the optimised replacement levels of 1% and 8%, respectively. The results showed that the addition of both types of RCA adversely affected the compressive strength of concrete. However, the incorporation of SF led to compressive strength development in both types of concretes. The most significant improvement in terms of comparable concrete strength and peak strain with ordinary concrete at 28 days was observed in the case of using a combination of steel fibres and SF in both recycled aggregate concretes, especially with RCA sourced from high strength concrete. Although using SF slightly increased the elastic modulus of both recycled aggregate concretes, a substantial improvement in strength was observed due to the reinforcement with steel fibre and the coexistence of steel fibre and SF. Moreover, existing models to predict the elastic modulus of both non-fibrous and fibrous concretes are found to underestimate the elastic modulus values. The incorporation of SF changed the compressive stress-strain curves for both types of RCA. The addition of steel fibre and SF remarkably improved the post-peak ductility of recycled aggregates concretes of both types, with the most significant improvement observed in the case of RCA sourced from a low-strength parent concrete. The existing model to estimate the compressive stress-strain curve for steel fibre-reinforced concrete with natural aggregates was found to reasonably predict the compressive stress-strain behaviour for steel fibres-reinforced concrete with recycled aggregate

[In Press] Geotechnical properties of lime-geogrid improved clayey subgrade under various moisture conditions

This research evaluated the effect of different moisture conditions on the ductility, geotechnical and microstructural characteristics of the improved clayey subgrade with various lime contents and geogrid layers. The results of more than 120 tests showed that the combined application of lime and geogrid to the clayey subgrade significantly enhanced the ductility and geotechnical characteristics by increasing the moisture content up to an optimal value. It was observed that higher water pressure led to the separation of the geogrid layers from the improved subgrade; thus, the uniformity, consistency, and geotechnical properties were significantly reduced. Microstructural analysis showed that increasing the amounts of moisture more than the optimal values caused more voids which led to a substantial decrease in the geotechnical properties as well as the physical bonding between geogrid layers and lime-stabilised soil. Finally, a simple prediction model was developed to estimate the geotechnical characteristics of the improved clayey subgrade