Thrombopoietin mimetic stimulates bone marrow vascular and stromal niches to mitigate acute radiation syndrome.

BACKGROUND: Acute radiation syndrome (ARS) manifests after exposure to high doses of radiation in the instances of radiologic accidents or incidents. Facilitating regeneration of the bone marrow (BM), namely the hematopoietic stem and progenitor cells (HSPCs), is key in mitigating ARS and multi-organ failure. JNJ-26366821, a PEGylated thrombopoietin mimetic (TPOm) peptide, has been shown as an effective medical countermeasure (MCM) to treat hematopoietic-ARS (H-ARS) in mice. However, the activity of TPOm on regulating BM vascular and stromal niches to support HSPC regeneration has yet to be elucidated. METHODS: C57BL/6J mice (9-14 weeks old) received sublethal or lethal total body irradiation (TBI), a model for H-ARS, by 137Cs or X-rays. At 24 h post-irradiation, mice were subcutaneously injected with a single dose of TPOm (0.3 mg/kg or 1.0 mg/kg) or PBS (vehicle). At homeostasis and on days 4, 7, 10, 14, 18, and 21 post-TBI with and without TPOm treatment, BM was harvested for histology, BM flow cytometry of HSPCs, endothelial (EC) and mesenchymal stromal cells (MSC), and whole-mount confocal microscopy. For survival, irradiated mice were monitored and weighed for 30 days. Lastly, BM triple negative cells (TNC; CD45-, TER-119-, CD31-) were sorted for single-cell RNA-sequencing to examine transcriptomics after TBI with or without TPOm treatment. RESULTS: At homeostasis, TPOm expanded the number of circulating platelets and HSPCs, ECs, and MSCs in the BM. Following sublethal TBI, TPOm improved BM architecture and promoted recovery of HSPCs, ECs, and MSCs. Furthermore, TPOm elevated VEGF-C levels in normal and irradiated mice. Following lethal irradiation, mice improved body weight recovery and 30-day survival when treated with TPOm after 137Cs and X-ray exposure. Additionally, TPOm reduced vascular dilation and permeability. Finally, single-cell RNA-seq analysis indicated that TPOm increased the expression of collagens in MSCs to enhance their interaction with other progenitors in BM and upregulated the regeneration pathway in MSCs. CONCLUSIONS: TPOm interacts with BM vascular and stromal niches to locally support hematopoietic reconstitution and systemically improve survival in mice after TBI. Therefore, this work warrants the development of TPOm as a potent radiation MCM for the treatment of ARS.

Thrombopoietin mimetic stimulates bone marrow vascular and stromal niches to mitigate acute radiation syndrome.

Background: Acute radiation syndrome (ARS) manifests after exposure to high doses of radiation in the instances of radiologic accidents or incidents. Facilitating the regeneration of the bone marrow (BM), namely the hematopoietic stem and progenitor cells (HSPCs), is a key in mitigating ARS and multi-organ failure. JNJ-26366821, a PEGylated thrombopoietin mimetic (TPOm) peptide, has been shown as an effective medical countermeasure (MCM) to treat hematopoietic-ARS (H-ARS) in mice. However, the activity of TPOm on regulating BM vascular and stromal niches to support HSPC regeneration has not yet been elucidated. Methods: C57BL/6J mice (9-14 weeks old) received sublethal or lethal total body irradiation (TBI), a model for H-ARS, by 137Cs or X-rays. At 24 hours post-irradiation, mice were subcutaneously injected with a single dose of TPOm (0.3 mg/kg or 1.0 mg/kg) or PBS (vehicle). At homeostasis and on days 4, 7, 10, 14, 18, and 21 post-TBI with and without TPOm treatment, BM was harvested for histology, BM flow cytometry of HSPCs, endothelial (EC) and mesenchymal stromal cells (MSC), and whole-mount confocal microscopy. For survival, irradiated mice were monitored and weighed for 30 days. Lastly, BM triple negative cells (TNC; CD45-, TER-119-, CD31-) were sorted for single-cell RNA-sequencing to examine transcriptomics after TBI with or without TPOm treatment. Results: At homeostasis, TPOm expanded the number of circulating platelets and HSPCs, ECs, and MSCs in the BM. Following sublethal TBI, TPOm improved BM architecture and promoted recovery of HSPCs, ECs, and MSCs. Furthermore, TPOm elevated VEGF-C levels in normal and irradiated mice. Following lethal irradiation, mice improved body weight recovery and 30-day survival when treated with TPOm after 137Cs and X-ray exposure. Additionally, TPOm reduced vascular dilation and permeability. Finally, single-cell RNA-seq analysis indicated that TPOm increased the expression of collagens in MSCs to enhance their interaction with other progenitors in BM and upregulated the regeneration pathway in MSCs. Conclusions: TPOm interacts with BM vascular and stromal niches to locally support hematopoietic reconstitution and systemically improve survival in mice after TBI. Therefore, this work warrants the development of TPOm as a potent radiation MCM for the treatment of ARS.

NAC and Zuotin/Hsp70 chaperone systems coexist at the ribosome tunnel exit in vivo.

The area surrounding the tunnel exit of the 60S ribosomal subunit is a hub for proteins involved in maturation and folding of emerging nascent polypeptide chains. How different factors vie for positioning at the tunnel exit in the complex cellular environment is not well understood. We used in vivo site-specific cross-linking to approach this question, focusing on two abundant factors-the nascent chain-associated complex (NAC) and the Hsp70 chaperone system that includes the J-domain protein co-chaperone Zuotin. We found that NAC and Zuotin can cross-link to each other at the ribosome, even when translation initiation is inhibited. Positions yielding NAC-Zuotin cross-links indicate that when both are present the central globular domain of NAC is modestly shifted from the mutually exclusive position observed in cryogenic electron microscopy analysis. Cross-linking results also suggest that, even in NAC's presence, Hsp70 can situate in a manner conducive for productive nascent chain interaction-with the peptide binding site at the tunnel exit and the J-domain of Zuotin appropriately positioned to drive stabilization of nascent chain binding. Overall, our results are consistent with the idea that, in vivo, the NAC and Hsp70 systems can productively position on the ribosome simultaneously.

Radiological Patterns of Lung Injury on HRCT in COVID-19 Patients: An Experience From Tertiary Care Centre in India.

INTRODUCTION: During the outbreak of the COVID-19 pandemic, radiological examinations became crucial in assessing the severity and progression of lung injuries in COVID-19 patients. AIM: This study was done to identify radiological patterns of lung injuries in COVID-19 patients, assess lobar involvement, and perform CT severity scoring on symptomatic patients on a baseline scan. METHODS AND MATERIAL: All the RT-PCR-positive patients were retrospectively enrolled in the study from August 16, 2020 to October 12, 2020. The final heart-resolution computed tomographic (HRCT) thorax data of a total of 119 COVID-19 patients was analyzed using simple statistical methods. A p-value of less than 0.05 (p < 0.05) was considered statistically significant. RESULTS: A total of 119 HRCT thorax scans of symptomatic indoor RT-PCR-positive patients were reviewed. Over 50% of the patients were under 50 (n = 66; 25 = 5; 25-50 = 61). Males > females: 3.25:1 (M = 91; F = 28). Peripheral involvement dominated (n = 90). Both lungs were affected equally, but the right lower lobe was more involved (n = 103) than the left (n = 98). Inpatient care was needed for 64.70% of CT severity score (CTSS) 10 COVID-19 patients (n = 77). Most positive CT scans (n = 115) revealed ground glass opacities (n = 112; 97.39%). Vascular dilatation or vasculitis (n = 65; 56.62%) and organizing pneumonia-like changes (n = 61; 53.04%) were also common. Vascular enlargement (56.53 percent, n = 65) and reverse halo (52.17%, n = 60) were the most common CT signs. CONCLUSION:  The most common chest CT finding in COVID-19 was ground-glass opacity in peripheral distribution with extensive lung involvement. These ground glass opacities may coalesce into consolidations. Vascular dilatation, organizing pneumonia, interlobular septal thickening, and crazy paving were other important imaging characteristics.

Global Longitudinal Strain Is Associated with Mortality in Patients with Multiple Myeloma.

Patients with multiple myeloma (MM) are at a high risk for developing cardiovascular complications. Global longitudinal strain (GLS) can detect early functional impairment before structural abnormalities develop. It remains unknown if reduced GLS is associated with reduced survival in patients with MM. We conducted a retrospective cohort analysis of patients diagnosed with MM between 1 January 2000 and 31 December 2017 at our institution. Patients with a 2D transthoracic echocardiogram completed within 1 year of MM diagnosis, left ventricular ejection fraction (LVEF) greater than 40%, and no history of myocardial infarction prior to MM diagnosis were included. GLS was measured using an artificial-intelligence-powered software (EchoGo Core), with reduced GLS defined as an absolute value of <18%. The primary outcome of interest was overall survival since myeloma diagnosis. Our cohort included 242 patients with a median follow up of 4.28 years. Fifty-two (21.5%) patients had reduced average GLS. Patients with reduced GLS were more likely to have an IVSd ≥ 1.2cm, E/E' > 9.6, LVEF/GLS > 4.1, higher LV mass index, and low-voltage ECG. A Total of 126 (52.1%) deaths occurred during follow-up. Overall survival was lower among patients with reduced GLS (adjusted HR: 1.81, CI: 1.07-3.05).

Transcription elongation defects link oncogenic splicing factor mutations to targetable alterations in chromatin landscape.

Transcription and splicing of pre-messenger RNA are closely coordinated, but how this functional coupling is disrupted in human disease remains unexplored. Here, we investigated the impact of non-synonymous mutations in SF3B1 and U2AF1, two commonly mutated splicing factors in cancer, on transcription. We find that the mutations impair RNA Polymerase II (RNAPII) transcription elongation along gene bodies leading to transcription-replication conflicts, replication stress and altered chromatin organization. This elongation defect is linked to disrupted pre-spliceosome assembly due to impaired association of HTATSF1 with mutant SF3B1. Through an unbiased screen, we identified epigenetic factors in the Sin3/HDAC complex, which, when modulated, normalize transcription defects and their downstream effects. Our findings shed light on the mechanisms by which oncogenic mutant spliceosomes impact chromatin organization through their effects on RNAPII transcription elongation and present a rationale for targeting the Sin3/HDAC complex as a potential therapeutic strategy. HIGHLIGHTS: Oncogenic mutations of SF3B1 and U2AF1 cause a gene-body RNAPII elongation defectRNAPII transcription elongation defect leads to transcription replication conflicts, DNA damage response, and changes to chromatin organization and H3K4me3 marksThe transcription elongation defect is linked to disruption of the early spliceosome formation through impaired interaction of HTATSF1 with mutant SF3B1.Changes to chromatin organization reveal potential therapeutic strategies by targeting the Sin3/HDAC pathway.

The human proton pump inhibitors inhibit Mycobacterium tuberculosis rifampicin efflux and macrophage-induced rifampicin tolerance.

Tuberculosis treatment requires months-long combination chemotherapy with multiple drugs, with shorter treatments leading to relapses. A major impediment to shortening treatment is that Mycobacterium tuberculosis becomes tolerant to the administered drugs, starting early after infection and within days of infecting macrophages. Multiple lines of evidence suggest that macrophage-induced drug tolerance is mediated by mycobacterial drug efflux pumps. Here, using assays to directly measure drug efflux, we find that M. tuberculosis transports the first-line antitubercular drug rifampicin through a proton gradient-dependent mechanism. We show that verapamil, a known efflux pump inhibitor, which inhibits macrophage-induced rifampicin tolerance, also inhibits M.tuberculosis rifampicin efflux. As with macrophage-induced tolerance, the calcium channel-inhibiting property of verapamil is not required for its inhibition of rifampicin efflux. By testing verapamil analogs, we show that verapamil directly inhibits M. tuberculosis drug efflux pumps through its human P-glycoprotein (PGP)-like inhibitory activity. Screening commonly used drugs with incidental PGP inhibitory activity, we find many inhibit rifampicin efflux, including the proton pump inhibitors (PPIs) such as omeprazole. Like verapamil, the PPIs inhibit macrophage-induced rifampicin tolerance as well as intramacrophage growth, which has also been linked to mycobacterial efflux pump activity. Our assays provide a facile screening platform for M. tuberculosis efflux pump inhibitors that inhibit in vivo drug tolerance and growth.

Identification of subfunctionalized aggregate-remodeling J-domain proteins in Arabidopsis thaliana.

J-domain proteins (JDPs) are critical components of the cellular protein quality control machinery, playing crucial roles in preventing the formation and, solubilization of cytotoxic protein aggregates. Bacteria, yeast, and plants additionally have large, multimeric heat shock protein 100 (Hsp100)-class disaggregases that resolubilize protein aggregates. JDPs interact with aggregated proteins and specify the aggregate-remodeling activities of Hsp70s and Hsp100s. However, the aggregate-remodeling properties of plant JDPs are not well understood. Here we identify eight orthologs of Sis1 (an evolutionarily conserved Class II JDP of budding yeast) in Arabidopsis thaliana with distinct aggregate-remodeling functionalities. Six of these JDPs associate with heat-induced protein aggregates in vivo and co-localize with Hsp101 at heat-induced protein aggregate centers. Consistent with a role in solubilizing cytotoxic protein aggregates, an atDjB3 mutant had defects in both solubilizing heat-induced aggregates and acquired thermotolerance as compared with wild-type seedlings. Next, we used yeast prions as protein aggregate models to show that the six JDPs have distinct aggregate-remodeling properties. Results presented in this study, as well as findings from phylogenetic analysis, demonstrate that plants harbor multiple, evolutionarily conserved JDPs with capacity to process a variety of protein aggregate conformers induced by heat and other stressors.

Cell-free SLC30A10 messenger ribonucleic acid (mRNA) expression and their association with vitamin-D level among non-small cell lung cancer (NSCLC) patients.

BACKGROUND: Lung cancer has been major cause of cancer related death and day by day Non-small cell lung cancer (NSCLC) cases are increasing globally. Present study explored the link between SLC30A10 mRNA expression with vitamin-D level among the NSCLC patients. METHODS: Present study included newly diagnosed 100 NSCLC patients and 100 healthy controls. Quantitative real time PCR was performed to check the SLC30A10 mRNA expression after cDNA synthesis from extracted total RNA from serum sample. Vitamin-D level was also analyzed in all the NSCLC patients by electrochemiluminscence based immunoassay method. RESULTS: Present research work observed decreased SLC30A10 mRNA expression (0.16 fold) among the NSCLC patients, decreased SLC30A10 mRNA expression was linked with advanced stage (0.15 fold, P < 00001) of disease and distant organ metastases (0.11 fold, P < 00001) compared to its contrast. Decreased level of vitamin-D was also observed with advanced stage (17.98 ng/ml, P < 00001) of disease and distant organ metastases (16.23 ng/ml, P < 00001) compared to its contrast. Positive correlation was observed between SLC30A10 mRNA expression with vitamin-D level among the NSCLC patients suggesting decrease or increase in SLC30A10 mRNA expression mau decreases or increase the vitamin-D level. NSCLC patients with vitamin-D deficiency had 0.14 reduced SCL30A10 mRNA expression while insufficient (P = 0 .06) and sufficient (P = 0.03) showed comparatively high SCL30A10 mRNA expression. CONCLUSION: Study concluded that down regulation of SLC30A10 mRNA and vitamin-D deficiency may involve in advancement of disease and distant organ metastases. It was also suggested that the decrease of increase in SLC30A10 expression may cause the decrease of increase in vitamin-D level among the NSCLC patients may be involved in disease severity and worseness of NSCLC disease.

Association of lncRNA LINC01173 Expression with Vitamin-D and Vitamin B12 Level Among Type 2 Diabetes Patients.

Background: Type 2 diabetes mellitus (T2DM) has risen to become the world's most serious public health problem in recent years, and the role of long noncoding RNAs (lncRNAs) in the onset and progression of T2DM, as well as special attention to vitamins, has gotten a lot of attention recently. Methods: The aim of the study was to analyze lncRNA LINC01173 expression along with assessment of vitamin-D and B12 among the T2DM cases. Quantitative RT-PCR was used to analyze the expression of lncRNA LINC01173. Vitamin-D and B12 were analyzed by chemiluminescence-based assay. Results: The present study observed that the T2DM cases had 6.67-fold increased lncRNA LINC01173 expression compared to healthy controls. Expression of lncRNA LINC01173 was found to be associated with hypertension (p=0.03), wound healing (p=0.04), and blurred vision (p<0.0001). It was observed that the T2DM cases with vitamin-D deficiency had a significant association with fasting glucose level (p=0.01) and HbA1C level (p=0.01) among the T2DM cases. The association of lncRNA LINC01173 with vitamin-D was analyzed and it was observed that the vitamin-D deficient cases had higher lncRNA LINC01173 expression compared to insufficient T2DM cases (p=0.01) and sufficient T2DM cases (p=0.0006). It was also observed that the T2DM cases with smoking had a 8.33-fold lncRNA LINC01173 expression while non-smokers had a 5.43-fold lncRNA LINC01173 expression (p<0.0001). Conclusion: The study concluded that the increased lncRNA LINC01173 expression was observed to be linked with alteration in vitamin-D level and smoking habit. Altered expression of lncRNA LINC01173 expression was linked with fasting glucose and HbA1C alteration. Collectively, lncRNA LINC01173 expression, vitamin-D alteration, as well as smoking habit may cause the disease severity and increase the pathogenesis of disease.

Role of metabolizing MTHFR gene polymorphism (rs1801133) and its mRNA expression among Type 2 Diabetes.

Objective: Type 2 Diabetes is a glucose metabolic disorder occurred by insulin insensitivity in which folate metabolism plays an important role. it is believed that polymorphism of Methylenetetrahydrofolate reductase (MTHFR) C677T linked with type 2 diabetes mellitus. However, results are conflicted. therefore, in this study we re-examine the relationship between MTHFR C677T in type 2 diabetes mellitus patients. Methods: Present research work included 100 newly diagnosed type 2 diabetic mellitus (T2DM) cases and 100 healthy individuals. After the blood sample collection all the biochemical parameters were evaluated among the T2DM cases and healthy individuals. DNA and RNA extraction from whole blood was done to study the MTHFR gene polymorphism by allele specific polymerase chain reaction method and its expression analysis was done by quantitative real time polymerase chain reaction method. Results: The significant difference was observed in genotype distribution among case and control group (p=0.0002). Compared with wildtype CC genotype, CT heterozygous (OR=2.95, 95% Cl=1.62-5.38) and TT homozygous (OR=3.20, CI=1.79-5.73) suggest to have effect of MTHFR polymorphism on type 2 mellitus risk. Moreover, relative MTHFR mRNA expression was found for wild type CC genotype 3.02-fold, CT heterozygous genotype 2.57 fold and mutant TT homozygous genotype 0.50-fold which is down regulated (p<0.0001). Conclusion: Our results indicates that the polymorphism in MTHFR C677T plays significant role in type II diabetes risk. MTHFR CT heterozygous and mutant TT genotype showed reduced mRNA expression among the T2DM patients. However, large scale case-control studies are needed to strengthen such conclusion in the future.

Clinical Importance of FNDC-5 and Selectin-E mRNA Expression Among Type 2 Diabetics with and without Obesity.

Background: Type 2 diabetes mellitus (T2DM) is growing illnesses associated with metabolic dysregulation such as obesity affecting a large population become leading causes of death worldwide. Fibronectin type III domain-containing protein 5 (FNDC-5) and selectin-E were suggested to have effects on metabolism and diabetes, therefore present study aimed to evaluate the clinical importance of FNDC-5 and selectin-E among the T2DM patients with and without obesity. Methods: Study included cohort of 200 T2DM patients with and without obesity. We evaluated FNDC-5, selectin-E mRNA expression as well as vitamin-D, and vitamin-B12 levels in among the T2DM patients with and without obesity. Results: Study observed significant difference in biochemical parameters included in study. T2DM patients with obesity had significantly higher fasting blood glucose levels (p<0.0001) and HbA1c (glycated hemoglobin) (p<0.0001) compared to those T2DM patients without obesity. T2DM patients with obesity also had higher systolic blood pressure (p=0.001), LDL (low density lipoprotein) (p=0.02), TG (triglycerides) (p=0.02) and cholesterol (p=0.01) compared to T2DM patients without obesity. The mRNA expression of FNDC-5 (p<0.0001) was lower in T2DM patients with obesity compared to T2DM patients without obesity. It was observed that the T2DM patients with vitamin-D deficiency had significantly lower FNDC-5 mRNA expression (p=0.03) when compared with those with sufficient vitamin-D level. T2DM patients with clinically normal vitamin-B12 level expressed 0.60 fold FNDC-5 mRNA expression while B12 deficient T2DM patients had 0.28 fold FNDC-5 mRNA expression (p=0.005). No as such significant association was was observed with selectin-E. A negative correlation of FNDC-5 mRNA expression with Post prandial glucose (mg/dl) (p=0.04) and TG (mg/dl) (p=0.02) was observed. Conclusion: FNDC-5 down regulation was observed with T2DM with obesity, vitamin-D and vitamin-B12 deficiency suggesting obesity, vitamin-D and vitamin-B12 deficiency could be the factor for FNDC-5 down-regulation leading to worseness or progression of disease. We suggest that FNDC-5 down-regulation could be used as an indicator for T2DM worseness and development of other associated complications.

J-like protein family of Arabidopsis thaliana: the enigmatic cousins of J-domain proteins.

KEY MESSAGE: J-like proteins (JLPs) are emerging as ancillaries to the cellular chaperone network. They modulate functions of Hsp70:J-domain protein (JDP) systems in novel ways thereby having key roles in diverse plant processes. J-domain proteins (JDPs) form an obligate co-chaperone partnership with Hsp70s with their highly conserved J-domain to steer protein quality control processes in the cell. The HPD motif between helix II and helix III of the J-domain is crucial for JDP's interaction with Hsp70s. According to the most recent classification, J-like proteins (JLPs) form an extended class of the JDP family possessing a degenerate J-domain with the HPD motif non-conservatively replaced by other amino acid residues and hence are not able to interact with Hsp70s. Considering this most updated and acceptable JLP classification, we identified 21 JLPs in Arabidopsis thaliana that share a structurally conserved J-like domain (JLD), but lack the HPD motif. Analysis of publicly available gene expression data as well as real-time quantitative PCR performed for a few selected JLPs implicated some of these proteins in growth, development and stress response. Here, we summarize the current state of knowledge on plant JLPs and their involvement in vital plant cellular/metabolic processes, including chloroplast division, mitochondrial protein import and flowering. Finally, we propose possible modes of action for these highly elusive proteins and other DnaJ-related proteins (DNAJRs) in regulating the Hsp70 chaperone network.

Diffuse cystic lung diseases: Imaging spectrum and diagnostic approach using high-resolution computed tomography.

The lung cyst is an air-containing lucent area surrounded by thin imperceptible walls. Other lucent lung lesions like centrilobular emphysema, cavity, cystic bronchiectasis, honeycomb cyst, and pneumatoceles are close mimics of a lung cyst on high-resolution computed tomography (HRCT). Various diseases with multiple lung cysts throughout both the lungs are classified as diffuse cystic lung diseases (DCLDs). HRCT is considered the imaging of choice for diagnosis of such diffuse cystic lung diseases. Common DCLDs like lymphangioleiomyomatosis, Birt-Hogg-Dubé syndrome (BHS), Langerhans cell histiocytosis (LCH), lymphocytic interstitial pneumonia (LIP), and desquamative interstitial pneumonia (DIP) can be confidently diagnosed on HRCT without further requirement of histopathological confirmation. The imaging also helps in differentiation of uncommon DCLDs and exclusion of the mimics. This review describes a simple algorithmic approach for DCLDs on HRCT based on scrutinizing the cyst's distribution, size, and shape, background parenchymal changes, and its correlation with clinical features and extrapulmonary imaging findings.

Regulation of miR-126 and miR-122 Expression and Response of Imatinib Treatment on Its Expression in Chronic Myeloid Leukemia Patients.

BACKGROUND: MicroRNAs (miRNAs) have been observed to exhibit altered expression patterns in chronic myeloid leukemia (CML). Therefore, this study was aimed to evaluate the clinical importance of miR-126 and miR-122 expression in concert to imatinib response in CML patients. METHODS: The present study included 100 CML and 100 healthy subjects. The expression of the 2 miRNAs was performed using TaqMan probe chemistry, and snU6 was used as internal control. RESULTS: The expression of miR-126 and miR-122 was downregulated in CML patients, with a mean fold change ± SD 0.20 ± 0.33 and 0.22 ± 0.37, respectively. While the expression of both miRNAs was analysed before and after imatinib treatment, it was observed that the expression levels of both were increased after imatinib treatment by 26.25-fold (5.33 against 0.20) and 13.95-fold (3.07 against 0.22) and the increase was statistically significant (p < 0.0001 and p < 0.0001, respectively). The expression of miR-126 was not conclusive when compared in different clinical stages of the CML disease as it showed a decreased expression in patients with accelerated phase compared to chronic phase (mean fold change = 0.03 and 0.27, respectively), but patients with chronic phase and blastic phase had comparable expression (mean fold change = 0.27 and 0.24, respectively). We also observed an increased expression of both miRNAs after imatinib therapy in each clinical phase. CONCLUSION: The study concludes that expression of miR-126 and miR-122 increases after imatinib treatment in CML patients and that miR-126 defines the good responders of imatinib therapy.

Clinical Trials Assessing Hypomethylating Agents Combined with Other Therapies: Causes for Failure and Potential Solutions.

PURPOSE: Azacitidine and decitabine are hypomethylating agents (HMA), that is, both inhibit and deplete DNA methyltransferase 1 (DNMT1). HMAs are standard single-agent therapies for myelodysplastic syndromes and acute myelogenous leukemias. Several attempts to improve outcomes by combining HMAs with investigational agents, excepting with the BCL2-inhibitor venetoclax, have failed in randomized clinical trial (RCT) evaluations. We extract lessons from decades of clinical trials to thereby inform future work. EXPERIMENTAL DESIGN: Serial single-agent clinical trials were analyzed for mechanism and pathway properties of HMAs underpinning their success, and for rules for dose and schedule selection. RCTs were studied for principles, dos and don'ts for productive combination therapy. RESULTS: Single-agent HMA trial results encourage dose and schedule selection to increase S-phase-dependent DNMT1 targeting, and discourage doses that cause indiscriminate antimetabolite effects/cytotoxicity, because these attrit myelopoiesis reserves needed for clinical response. Treatment-related myelosuppression should prompt dose/frequency reductions of less active investigational agents rather than more active HMA. Administering cytostatic agents concurrently with HMA can antagonize S-phase-dependent DNMT1 targeting. Supportive care that enables on-time administration of S-phase (exposure-time)-dependent HMA could be useful. Agents that manipulate pyrimidine metabolism to increase HMA pro-drug processing into DNMT1-depleting nucleotide, and/or inhibit other epigenetic enzymes implicated in oncogenic silencing of lineage differentiation, could be productive, but doses and schedules should adhere to therapeutic index/molecular-targeted principles already learned. CONCLUSIONS: More than 40 years of clinical trial history indicates mechanism, pathway, and therapeutic index properties of HMAs that underpin their almost exclusive success and teaches lessons for selection and design of combinations aiming to build on this treatment foundation.

Natural Products in Therapeutic Management of Multineurodegenerative Disorders by Targeting Autophagy.

Autophagy is an essential cellular process that involves the transport of cytoplasmic content in double-membraned vesicles to lysosomes for degradation. Neurons do not undergo cytokinesis, and thus, the cell division process cannot reduce levels of unnecessary proteins. The primary cause of neurodegenerative disorders (NDs) is the abnormal deposition of proteins inside neuronal cells, and this could be averted by autophagic degradation. Thus, autophagy is an important consideration when considering means of developing treatments for NDs. Various pharmacological studies have reported that the active components in herbal medicines exhibit therapeutic benefits in NDs, for example, by inhibiting cholinesterase activity and modulating amyloid beta levels, and α-synuclein metabolism. A variety of bioactive constituents from medicinal plants are viewed as promising autophagy controllers and are revealed to recover the NDs by targeting the autophagic pathway. In the present review, we discuss the role of autophagy in the therapeutic management of several NDs. The molecular process responsible for autophagy and its importance in various NDs and the beneficial effects of medicinal plants in NDs by targeting autophagy are also discussed.

Role of Cytokines and Chemokines in NSCLC Immune Navigation and Proliferation.

With over a million deaths every year around the world, lung cancer is found to be the most recurrent cancer among all types. Nonsmall cell lung carcinoma (NSCLC) amounts to about 85% of the entire cases. The other 15% owes it to small cell lung carcinoma (SCLC). Despite decades of research, the prognosis for NSCLC patients is poorly understood with treatment options limited. First, this article emphasises on the part that tumour microenvironment (TME) and its constituents play in lung cancer progression. This review also highlights the inflammatory (pro- or anti-) roles of different cytokines (ILs, TGF-ß, and TNF-α) and chemokine (CC, CXC, C, and CX3C) families in the lung TME, provoking tumour growth and subsequent metastasis. The write-up also pinpoints recent developments in the field of chemokine biology. Additionally, it covers the role of extracellular vesicles (EVs), as alternate carriers of cytokines and chemokines. This allows the cytokines/chemokines to modulate the EVs for their secretion, trafficking, and aid in cancer proliferation. In the end, this review also stresses on the role of these factors as prognostic biomarkers for lung immunotherapy, apart from focusing on inflammatory actions of these chemoattractants.

Assessment and Management of Diabetic Patients During the COVID-19 Pandemic.

COVID-19 has become a great challenge across the globe, particularly in developing and densely populated countries, such as India. COVID-19 is extremely infectious and is transmitted via respiratory droplets from infected persons. DM, hypertension, and cardiovascular disease are highly prevalent comorbidities associated with COVID-19. It has been observed that COVID-19 is associated with high blood-glucose levels, mainly in people with type 2 diabetes mellitus (T2DM). Several studies have shown DM to be a significant risk factor affecting the severity of various kinds of infection. Dysregulated immunoresponse found in diabetic patients plays an important role in exacerbating severity. DM is among the comorbidities linked with mortality and morbidity in COVID-19 patients. Chronic conditions like obesity, cardiovascular disorders, and hypertension, together with changed expression of ACE2, dysregulated immunoresponse, and endothelial dysfunction, may put diabetic patients at risk of greater COVID-19 severity. Therefore, it is important to study specific characteristics of COVID-19 in diabetic people and treat these comorbidities along with COVID-19 infection, mainly among old individuals who are already suffering from serious and critical infections. This review will be helpful in understanding the mechanisms involved in COVID-19 and DM, the role of ACE2 in COVID-19 pathogenesis, management of DM, and associated complications in COVID-19 patients.