Metabolism in acute myeloid leukemia: mechanistic insights and therapeutic targets.

Metabolic rewiring and cellular reprogramming are trademarks of neoplastic initiation and progression in acute myeloid leukemia (AML). Metabolic alteration in leukemic cells is often genotype specific, with associated changes in epigenetic and functional factors resulting in the downstream upregulation or facilitation of oncogenic pathways. Targeting abnormal or disease-sustaining metabolic activities in AML provides a wide range of therapeutic opportunities, ideally with enhanced therapeutic windows and robust clinical efficacy. This review highlights the dysregulation of amino acid, nucleotide, lipid, and carbohydrate metabolism in AML; explores the role of key vitamins and enzymes that regulate these processes; and provides an overview of metabolism-directed therapies currently in use or development.

The direct and indirect effect of neuroticism on work engagement of nurses during COVID-19: A temporal analysis.

Healthcare professionals such as nurses faced a tough time during the pandemic. Despite the personal and professional challenges, they contributed immensely during the pandemic. However, there were variations in nurses' work engagement during the pandemic. One reason could be their personality, especially neuroticism. Neuroticism represents individuals' proneness to distress in stressful situations, such as COVID-19. Hence, understanding how and in which conditions neuroticism influences work engagement is crucial. We used the Job Demand-Resource (JD-R) model to test the association between neuroticism and work engagement. As neuroticism represents the stress-proneness of an individual, we further investigated if stress mediates the neuroticism-work engagement link. For the nurses, patient interaction is an integral part of their job. Based on the data collected from the nurses, we tested if contact with patients (i.e., beneficiary contact) alleviates the adverse effect of neuroticism on work engagement. During COVID-19, there was an intense need for nursing support. Hence, avoiding duty when society is looking for support might induce a fear of stigmatization among the nurses. We examined if the perceived stigma of duty avoidance would affect the neuroticism-engagement relationship. Our results indicated that higher patient contact alleviated the adverse effect of neuroticism on work engagement. On the other hand, higher fear of stigma exacerbated the adverse effect of neuroticism on work engagement. We further checked the combined effect of beneficiary contact and fear of stigma on neuroticism-work engagement relationships. The findings highlighted the importance of societal factors and policymakers in enhancing nurses' work engagement.

Reflection of Types of Prosocial Behavior During COVID-19 in Collectivistic Asian Countries-India and Indonesia.

COVID-19 is an infectious disease that has widened the gap between victims and non-victims in society. Understanding how individuals support and assist COVID-19 sufferers in a pandemic crisis is critical. Thus, this study aims to qualitatively evaluate the prosocial intention and types of prosocial behavior toward COVID-19 victims by low socioeconomic individuals from India and Indonesia's collectivistic societies. We conducted semi-structured and in-depth interviews during the lockdown from March to May 2020, via phone and in-person, using a purposive selection of respondents (total n = 50). The data were analyzed using the qualitative synthesis method. Five themes were discovered: 1) too scared to help, 2) love to help but scared: moral dilemma, 3) informing authority who knows how to handle, 4) caring, sharing, and supporting, but with a distance, and 5) helping at one's personal health risk. This study highlights that prosocial intentions range from minor acts of kindness to self-harm and out-of-bounds acts of kindness for COVID-19 victims.

Financial fragility and financial optimism linkage during COVID-19: Does financial literacy matter?

COVID-19 and its consequences induced many challenges for individuals, and many of them experienced financial fragility. Financial optimism is crucial in this situation as it helps individuals and organizations recover from such situations. We argue that financial fragility has a long-term consequence on individuals and examined the adverse effect of financial fragility on financial optimism. Using a nationally representative dataset from the USA, we tested if financial literacy could minimize financial fragility's adverse impact on financial optimism. We found a negative linkage between financial fragility and financial optimism; the linkage was stronger for women. To address potential endogeneity, we conducted robustness analyses using instrumental variable regression and propensity score matching. The findings of the study provide implications to increase financial optimism during the pandemic.

Optimistic bias, risky behavior, and social norms among Indian college students during COVID-19.

Using survey data of college students in India, we investigate whether COVID-19 optimistic bias among individuals increases risky behavior. We also explore whether participants' optimistic bias differs depending on their degree of closeness with others. We found that the presence of friends instead of neighbors/strangers make participants with high COVID-19 optimistic bias inclined to take more risks. Besides, it has been found that preventive behavioral norms followed by peers minimize risky behavior among participants with high optimistic bias. Our findings offer important implications for policymakers to minimize the transmission of the disease among college students.

A Distinctive MRI-Based Absolute Bias Correction Protocol for the Potential Labelling and In Vivo Tracking of Stem Cells in a TBI Mice Model.

Traumatic brain injury (TBI) is a leading cause of death and disability. The condition is difficult to treat owing to its heterogeneous nature and complex biological pathways. Stem cell transplantation is an emerging self-deliverable therapeutic modality which could immensely improve the invigorating management of the problem. The synergistic interaction of the stem cells with the paracrine niche molecules at the site of injury is an end point that decides the cells' effective tissue-forming regenerative response. Thus, noninvasive monitoring and tracking of the infused stem cells is quite decisive after transplantation. Here, we have designed and validated a distinctive in vivo magnetic resonance imaging protocol to monitor the transplanted mesenchymal stem cells (MSCs) longitudinally in TBI-induced mice. We have further described the synthesis of improved transverse relaxivity contrast agent, a protocol for the efficient labelling of MSCs, preparation of a TBI model system in mice, and the imaging and tracking of the implanted stem cells at the injury site through 7T MRI. MGE-T2∗ imaging in association with relaxometry-based quantitative assessment using absolute bias correction provided a suitable mechanism to monitor and track the infused labelled stem cells at the TBI site. High transverse relaxivity negative contrast agent synthesis, MSC labelling procedure, and quantitative T2∗ time measurement normalized with absolute bias correction are the key features of this protocol. This procedure has immense application potential and could therefore be extrapolated to stem cell tracking during the treatment of various diseases.

Homing and Tracking of Iron Oxide Labelled Mesenchymal Stem Cells After Infusion in Traumatic Brain Injury Mice: a Longitudinal In Vivo MRI Study.

Stem cells transplantation has emerged as a promising alternative therapeutic due to its potency at injury site. The need to monitor and non-invasively track the infused stem cells is a significant challenge in the development of regenerative medicine. Thus, in vivo tracking to monitor infused stem cells is especially vital. In this manuscript, we have described an effective in vitro labelling method of MSCs, a serial in vivo tracking of implanted stem cells at traumatic brain injury (TBI) site through 7 T magnetic resonance imaging (MRI). Proper homing of infused MSCs was carried out at different time points using histological analysis and Prussian blue staining. Longitudinal in vivo tracking of infused MSCs were performed up to 21 days in different groups through MRI using relaxometry technique. Results demonstrated that MSCs incubated with iron oxide-poly-L-lysine complex (IO-PLL) at a ratio of 50:1.5 µg/ml and a time period of 6 h was optimised to increase labelling efficiency. T2*-weighted images and relaxation study demonstrated a significant signal loss and effective decrease in transverse relaxation time on day-3 at injury site after systemic transplantation, revealed maximum number of stem cells homing to the lesion area. MRI results further correlate with histological and Prussian blue staining in different time periods. Decrease in negative signal and increase in relaxation times were observed after day-14, may indicate damage tissue replacement with healthy tissue. MSCs tracking with synthesized negative contrast agent represent a great advantage during both in vitro and in vivo analysis. The proposed absolute bias correction based relaxometry analysis could be extrapolated for stem cell tracking and therapies in various neurodegenerative diseases.

Effects of iron oxide contrast agent in combination with various transfection agents during mesenchymal stem cells labelling: An in vitro toxicological evaluation.

The use of iron oxide nanoparticles for different biomedical applications, hold immense promise to develop negative tissue contrast in magnetic resonance imaging (MRI). Previously, we have optimized the labelling of mesenchymal stem cells (MSCs) with iron oxide nanoparticles complexed to different transfection agents like poly-l-lysine (IO-PLL) and protamine sulfate (Fe-Pro) on the basis of relaxation behaviour and its biological expressions. However, there is a distinct need to investigate the biocompatibility and biosafety concerns coupled with its cytotoxicity and genotoxicity. This study was prepared to evaluate the viability of cells, generation of ROS, changes in actin cytoskeleton, investigation of cell death, level of GSH and TAC, activities of SOD and GPx, and stability of DNA in MSCs after labelling. Results demonstrated a marginal alteration in toxicological parameters like ROS generation, cell length, actin cytoskeleton, total apoptosis and DNA damage was detected after stem cell labelling. Insignificant depletion of GSH and SOD level, and increase in GPx and TAC level in MSCs were measured after labelling with IO-PLL and Fe-Pro complexes, which later on recovered and normalized to its baseline. This MSCs labelling could provide a reference guideline for toxicological analysis and relaxometry based in vivo MRI detection.

Therapeutic Prospective of Infused Allogenic Cultured Mesenchymal Stem Cells in Traumatic Brain Injury Mice: A Longitudinal Proton Magnetic Resonance Spectroscopy Assessment.

Improved therapeutic assessment of experimental traumatic brain injury (TBI), using mesenchymal stem cells (MSCs), would immensely benefit its therapeutic management. Neurometabolite patterns at injury site, measured with proton magnetic resonance spectroscopy (1H-MRS) after MSCs transplantation, may serve as a bio-indicator of the recovery mechanism. This study used in vivo magnetic resonance imaging and 1H-MRS to evaluate the therapeutic prospects of implanted MSCs at injury site in experimental mice longitudinally up to 21 days. Negative tissue contrast and cytotoxic edema formation were observed in susceptibility-based contrast (T2*) and an apparent diffusion coefficient map, respectively. Lesion site showed decreased N-acetylaspartate, total choline, myo-inositol, total creatine, glutamate-glutamine complex, and taurine neurometabolic concentrations by 1H-MRS investigation. There was a considerable decrease in locomotor activity, depression index, and cognitive index after TBI. It may, therefore, be inferred that MSC transplantation prompted recovery by decreasing negative signals and edema, restoring metabolites to baseline concentrations, and enhancing behavioral activity. Overall findings support the potential of MSC transplantation for the enhancement of endogenous neuroprotective responses, which may provide future clinical applications for translating laboratory research into therapeutic clinical advances. Stem Cells Translational Medicine 2017;6:316-329.

Biological effects of iron oxide-protamine sulfate complex on mesenchymal stem cells and its relaxometry based labeling optimization for cellular MRI.

Mesenchymal stem cells (MSCs) are frequently used as a therapeutic, but reliable imaging technique to longitudinally evaluate the engraftment of transplanted cells is inadequate. For magnetic resonance imaging (MRI), it is essential to understand the technical competence of in vitro stem cells labeling with iron oxide with regard to its relaxation behavior and significance of its biological expressions. The purpose of the study was to optimize the effective labeling of MSCs with high transverse relaxivity iron oxide contrast agent with protamine sulfate and also evaluate the biological effects (phenotype and function) of labeled MSCs. Our results demonstrated that 50:3µg/ml of Fe-Pro complex containing 10% serum at an incubation time of 6h were ideal for effective in vitro labeling. Relaxometry study demonstrated that almost an 8-fold increase in relaxation rate (R2) was observed in labeled MSCs by comparing with unlabeled. Marginal alteration in Oct4 and CD146 genes, and phenotypic CD45 expressions were detected after labeling. T2-weighted images and histological analysis confirmed the homing of transplanted cells to the site of injury. The relaxometry based optimized labeling method of MSCs could be extrapolated for cellular MRI and may be useful in stem cell tracking in various pre-clinical and clinical studies.

Development and Implementation of Module for Medical Graduates to Improve Socio-cultural Sensitivity towards People Living with HIV.

BACKGROUND: Health professionals are documented as an important cause for stigmatizing people living with HIV (PLHIV). Since traditional teaching on HIV in India does not address cultural competencies, medical graduates lack sociocultural sensitiveness while addressing the health needs of PLHIV. AIM: The aim of this study is to develop and to implement a module for medical graduates to improve their sociocultural sensitivity toward PLHIV. METHODOLOGY: A module was designed and introduced to address the core sensitive issues in HIV among medical graduates with the help of trained faculty. It included community education sessions including interaction with PLHIV to address cross-cultural issues and understand their health needs. Feedback for the perception of faculty and students was obtained. Knowledge and skills improvement was assessed through pre- and post test and direct observation of procedural skills (DOPS). RESULTS: Mean feedback score was high for all the components covered by the module. It was found to be more for "usefulness of module" (4.91 ± 0.27836 on a scale of 5) than other components of the module. Feedback by faculty showed almost perfect agreement on "improvement of student's clinical skills" and "bringing perfection in their future practice" across multiple raters. Multiple response open-ended feedback showed, 78 (19%) responses affirmed improvement in communication skills with training in this module. Pre- and post test mean score for knowledge showed an increase (22.1 to 26.49). Mean skills improvement as per expectations were 86.81 and beyond expectations were 5.34. CONCLUSIONS: Training the medical graduates in structured HIV specific module improves their socio-cultural sensitivity toward PLHIV and is perceived useful.

Early detection of whole body radiation induced microstructural and neuroinflammatory changes in hippocampus: A diffusion tensor imaging and gene expression study.

Ionizing radiation is known to a cause systemic inflammatory response within hours of exposure that may affect the central nervous system (CNS). The present study was carried out to look upon the influence of radiation induced systemic inflammatory response in hippocampus within 24 hr of whole body radiation exposure. A Diffusion Tensor Imaging (DTI) study was conducted in mice exposed to a 5-Gy radiation dose through a 60 Co source operating at 2.496 Gy/min at 3 hr and 24 hr post irradiation and in sham-irradiated controls using 7 T animal MRI system. The results showed a significant decrease in Mean Diffusivity (MD), Radial Diffusivity (RD), and Axial Diffusivity (AD) in hippocampus at 24 hr compared with controls. Additionally, marked change in RD was observed at 3 hr. Increased serum C-Reactive Protein (CRP) level depicted an increased systemic/peripheral inflammation. The neuroinflammatory response in hippocampus was characterized by increased mRNA expression of IL-1ß, IL-6, and Cox-2 at the 24 hr time point. Additionally, in the irradiated group, reactive astrogliosis was illustrated, with noticeable changes in GFAP expression at 24 hr. Altered diffusivity and enhanced neuroinflammatory expression in the hippocampal region showed peripheral inflammation induced changes in brain. Moreover, a negative correlation between gene expression and DTI parameters depicted a neuroinflammation induced altered microenvironment that might affect water diffusivity. The study showed that there was an influence of whole body radiation exposure on hippocampus even during the early acute phase that could be reflected in terms of neuroinflammatory response as well as microstructural changes. © 2016 Wiley Periodicals, Inc.

Early monitoring and quantitative evaluation of macrophage infiltration after experimental traumatic brain injury: A magnetic resonance imaging and flow cytometric analysis.

The inflammatory response following traumatic brain injury (TBI) is regulated by phagocytic cells. These cells comprising resident microglia and infiltrating macrophages play a pivotal role in the interface between early detrimental and delayed beneficial effects of inflammation. The aim of the present study was to monitor the early effect of monocyte/phagocytic accumulation and further to explore its kinetics in TBI mice. Localized macrophage population was monitored using ultrasmall superparamagnetic iron oxide (USPIO) nanoparticle enhanced in vivo serial magnetic resonance imaging (MRI). Flow cytometry based gating study was performed to discriminate between resident microglia (Ly6G-CD11b+CD45low) and infiltrating macrophages (Ly6G-CD11b+CD45high) at the injury site. The T2* relaxation analysis revealed that maximum macrophage infiltration occurs between 66 and 72h post injury (42-48h post administration of USPIO) at the site of inflammation. This imaging data was well supported by iron oxide specific Prussian blue staining and macrophage specific F4/80 immunohistochemistry (IHC) analysis. Quantitative real-time PCR analysis found significant expression of monocyte chemoattractant protein-1 (MCP-1) at 72h post injury. Also, we found that flow cytometric analysis demonstrated a 7-fold increase in infiltrating macrophages around 72h post injuries as compared to control. The MR imaging in combination with flow cytometric analysis enabled the dynamic measurement of macrophage infiltration at the injury site. This study may help in setting an optimal time window to intervene and prevent damage due to inflammation and to increase the therapeutic efficacy.

Increased transverse relaxivity in ultrasmall superparamagnetic iron oxide nanoparticles used as MRI contrast agent for biomedical imaging.

Synthesis of a contrast agent for biomedical imaging is of great interest where magnetic nanoparticles are concerned, because of the strong influence of particle size on transverse relaxivity. In the present study, biocompatible magnetic iron oxide nanoparticles were synthesized by co-precipitation of Fe2+ and Fe3+ salts, followed by surface adsorption with reduced dextran. The synthesized nanoparticles were spherical in shape, and 12 ± 2 nm in size as measured using transmission electron microscopy; this was corroborated with results from X-ray diffraction and dynamic light scattering studies. The nanoparticles exhibited superparamagnetic behavior, superior T2 relaxation rate and high relaxivities (r1 = 18.4 ± 0.3, r2 = 90.5 ± 0.8 s-1 mM-1 , at 7 T). MR image analysis of animals before and after magnetic nanoparticle administration revealed that the signal intensity of tumor imaging, specific organ imaging and whole body imaging can be clearly distinguished, due to the strong relaxation properties of these nanoparticles. Very low concentrations (3.0 mg Fe/kg body weight) of iron oxides are sufficient for early detection of tumors, and also have a clear distinction in pre- and post-enhancement of contrast in organs and body imaging. Many investigators have demonstrated high relaxivities of magnetic nanoparticles at superparamagnetic iron oxide level above 50 nm, but this investigation presents a satisfactory, ultrasmall, superparamagnetic and high transverse relaxivity negative contrast agent for diagnosis in pre-clinical studies. Copyright © 2016 John Wiley & Sons, Ltd.

Potential stem cell labeling ability of poly-L-lysine complexed to ultrasmall iron oxide contrast agent: An optimization and relaxometry study.

For non-invasive stem cells tracking through MRI, it is important to understand the efficiency of in vitro labeling of stem cells with iron oxide with regard to its relaxation behavior. In this study, we have carried out a pilot study of labeling mice mesenchymal stem cells (mMSCs) with ultrasmall superparamagnetic iron oxide (USPIO) entrapped with poly-L-lysine (PLL) in different ratios and incubated with different times. Our results demonstrated that 50:1.5 µg/ml of iron oxide and PLL at an incubation time of 6h with 10% serum concentration are sufficient enough for effective labeling. Optimized labeling showed that >98% of viability and <3% toxicity were observed at a total iron content of 11.8 pg/cell. In vitro relaxometry study showed that almost a 6.6 fold reduction in transverse relaxation time (T2) was observed after labeling as compared to unlabeled. IO-PLL complex was more effective than iron oxide alone in labeling and a detectable lower limit found to be hundred with optimized concentration. Significant increase in Oct-4 expression on day-3 after labeling was observed, whereas CD146 expression remains unchanged in real time RT-PCR. This optimized labeling method of MSCs may be very useful for cellular MRI and stem cells tracking studies.

Neurodegenerative evidences during early onset of depression in CMS rats as detected by proton magnetic resonance spectroscopy at 7 T.

Depression is a complex psychiatric disorder characterized by anhedonia and feeling of sadness and chronic mild stress (CMS) seems to be a valuable animal model of depression. CMS animal model was induced and validated using behavioral studies. In the present study we investigated the neuro-metabolite changes occurring in prefrontal cortex and hippocampus during the onset of depression, in CMS rat model using in vivo proton magnetic resonance spectroscopy ((1)H MRS) at field strength of 7 T. Results showed that CMS caused depression-like behavior in rats, as indicated by the decrease in sucrose consumption and locomotor activity. (1)H MRS was performed in both control and CMS rats (n=10, in each group) and the quantitative assessment of the neurometabolites was done using LC model. Relative concentrations of all the metabolites along with the macromolecules were calculated for analysis. The results revealed a significant decrease of glutamate (Glu), glutamine (Gln), NAA+NAAG, Glx and GABA levels in both hippocampus and prefrontal cortex of CMS animals and an elevated level of myo-ionisitol (mI) and taurine (Tau) was observed only in hippocampus. These metabolite fluctuations revealed by proton MRS indicate that there might be change in the neuronal integrity of the glial cells and neurons within prefrontal cortex and hippocampus in CMS model of depression. The present study also suggests that there may be a degenerative process concerning the brain morphology in the CMS rats. The overall finding using (1)H MRS suggests that, there might be a major role of the glia and neuron in the onset of depression.