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Objective. To analyze early results of surgical treatment in patients with lumbar spinal stenosis using minimally invasive techniques for recon- struction of the spinal canal and fixation of the spine. Material and Methods. A total of 168 patients were treated with minimally invasive unilateral microsurgical decompression for spinal stenosis at the lumbar level. Results. The average length of post-operative inpatient care was 5.8 ± 2.8 days. When assessing the pain intensity in the legs and lumbar spine, as well as in daily activity, positive dynamics was noted after 1 and 6 months. Of the installed 732 screws, 18 (2.4 %) screws were displaced into the spinal canal by less than 2 mm and 4 (0.5 %) – by less than 4 mm. Signs of persistent subcompensated spinal stenosis at the operated level were detected in 5 (2.9 %) patients. The average intraoperative blood loss was 121.1 ± 22.0 ml. All patients were activated at the first day after surgery. Conclusion. Minimally invasive unilateral decompression, if necessary in combination with correction and fixation with percutaneous pedicle screw system and TLIF, eliminates factors causing compression of neural structures, reduces intraoperative blood loss, allows early activation of patients and shortens the length of hospital stay.

Cardiac fibrosis can be mitigated by limiting fibroblast-to-myofibroblast differentiation and proliferation. Human antigen R (HuR) modulates messenger RNA stability and expression of multiple genes. However, the direct role of cardiac myofibroblast HuR is unknown. Myofibroblast-specific deletion of HuR limited cardiac fibrosis and preserved cardiac functions in pressure overload injury. Knockdown of HuR in transforming growth factor-β1-treated cardiac fibroblasts suppressed myofibroblast differentiation and proliferation. HuR deletion abrogated the expression and messenger RNA stability of cyclins D1 and A2, suggesting a potential mechanism by which HuR promotes myofibroblast proliferation. Overall, these data suggest that inhibition of HuR could be a potential therapeutic approach to limit cardiac fibrosis., Competing Interests: This work was supported by National Institutes of Health grants HL116729 (Dr Krishnamurthy) and HL138023 (Drs Krishnamurthy and Zhang), an American Heart Association Transformational Project Award (19TPA34850100, Dr Krishnamurthy), and an American Heart Association postdoctoral fellowship (916497, Dr Singh). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Myocardial infarction (MI) is the leading cause of death worldwide. Glycogen synthase kinase-3 (GSK-3) has been considered to be a promising therapeutic target for cardiovascular diseases. GSK-3 is a family of ubiquitously expressed serine/threonine kinases. GSK-3 isoforms appear to play overlapping, unique, and even opposing functions in the heart. Previously, our group identified that cardiac fibroblast (FB) GSK-3β acts as a negative regulator of fibrotic remodeling in the ischemic heart. However, the role of FB-GSK-3α in MI pathology is not defined. To determine the role of FB-GSK-3α in MI-induced adverse cardiac remodeling, GSK-3α was deleted specifically in the residential fibroblast or myofibroblast (MyoFB) using tamoxifen (TAM) inducible Tcf21 or Periostin (Postn) promoter-driven Cre recombinase, respectively. Echocardiographic analysis revealed that FB- or MyoFB-specific GSK-3α deletion prevented the development of dilative remodeling and cardiac dysfunction. Morphometrics and histology studies confirmed improvement in capillary density and a remarkable reduction in hypertrophy and fibrosis in the KO group. We harvested the hearts at 4 weeks post-MI and analyzed signature genes of adverse remodeling. Specifically, qPCR analysis was performed to examine the gene panels of inflammation (TNFα, IL-6, IL-1β), fibrosis (COL1A1, COL3A1, COMP, Fibronectin-1, Latent TGF-β binding protein 2), and hypertrophy (ANP, BNP, MYH7). These molecular markers were essentially normalized due to FB-specific GSK-3α deletion. Further molecular studies confirmed that FB-GSK-3α could regulate NF-kB activation and expression of angiogenesis-related proteins. Our findings suggest that FB-GSK-3α plays a critical role in the pathological cardiac remodeling of ischemic hearts, therefore, it could be therapeutically targeted., (© 2023. Springer-Verlag GmbH Germany, part of Springer Nature.)

Glycogen synthase kinase-3 (GSK-3) is a family of serine/threonine kinases. The GSK-3 family has 2 isoforms, GSK-3α and GSK-3β. The GSK-3 isoforms have been shown to play overlapping as well as isoform-specific-unique roles in both, organ homeostasis and the pathogenesis of multiple diseases. In the present review, we will particularly focus on expanding the isoform-specific role of GSK-3 in the pathophysiology of cardiometabolic disorders. We will highlight recent data from our lab that demonstrated the critical role of cardiac fibroblast (CF) GSK-3α in promoting injury-induced myofibroblast transformation, adverse fibrotic remodeling, and deterioration of cardiac function. We will also discuss studies that found the exact opposite role of CF-GSK-3β in cardiac fibrosis. We will review emerging studies with inducible cardiomyocyte (CM)-specific as well as global isoform-specific GSK-3 KOs that demonstrated inhibition of both GSK-3 isoforms provides benefits against obesity-associated cardiometabolic pathologies. The underlying molecular interactions and crosstalk among GSK-3 and other signaling pathways will be discussed. We will briefly review the specificity and limitations of the available small molecule inhibitors targeting GSK-3 and their potential applications to treat metabolic disorders. Finally, we will summarize these findings and offer our perspective on envisioning GSK-3 as a therapeutic target for the management of cardiometabolic diseases., Competing Interests: Declaration of competing interest All authors have read the journal's authorship statement and have reviewed and approved the manuscript. The authors have no conflicting interests to disclose in relation to this work., (Published by Elsevier B.V.)

Background: The tyrosine kinase inhibitor ponatinib is the only treatment option for chronic myelogenous leukemia patients with T315I (gatekeeper) mutation. Pharmacovigilance analysis of Food and Drug Administration and World Health Organization datasets has revealed that ponatinib is the most cardiotoxic agent among all Food and Drug Administration-approved tyrosine kinase inhibitors in a real-world scenario. However, the mechanism of ponatinib-induced cardiotoxicity is unknown., Methods: The lack of well-optimized mouse models has hampered the in vivo cardio-oncology studies. Here, we show that cardiovascular comorbidity mouse models evidence a robust cardiac pathological phenotype upon ponatinib treatment. A combination of multiple in vitro and in vivo models was employed to delineate the underlying molecular mechanisms., Results: An unbiased RNA sequencing analysis identified the enrichment of dysregulated inflammatory genes, including a multifold upregulation of alarmins S100A8/A9, as a top hit in ponatinib-treated hearts. Mechanistically, we demonstrate that ponatinib activates the S100A8/A9-TLR4 (Toll-like receptor 4)-NLRP3 (NLR family pyrin domain-containing 3)-IL (interleukin)-1β signaling pathway in cardiac and systemic myeloid cells, in vitro and in vivo, thereby leading to excessive myocardial and systemic inflammation. Excessive inflammation was central to the cardiac pathology because interventions with broad-spectrum immunosuppressive glucocorticoid dexamethasone or specific inhibitors of NLRP3 (CY-09) or S100A9 (paquinimod) nearly abolished the ponatinib-induced cardiac dysfunction., Conclusions: Taken together, these findings uncover a novel mechanism of ponatinib-induced cardiac inflammation leading to cardiac dysfunction. From a translational perspective, our results provide critical preclinical data and rationale for a clinical investigation into immunosuppressive interventions for managing ponatinib-induced cardiotoxicity.

Background: Heart failure is the leading cause of mortality, morbidity, and health care expenditures worldwide. Numerous studies have implicated GSK-3 (glycogen synthase kinase-3) as a promising therapeutic target for cardiovascular diseases. GSK-3 isoforms seem to play overlapping, unique and even opposing functions in the heart. Previously, we have shown that of the 2 isoforms of GSK-3, cardiac fibroblast GSK-3β acts as a negative regulator of myocardial fibrosis in the ischemic heart. However, the role of cardiac fibroblast-GSK-3α in the pathogenesis of cardiac diseases is completely unknown., Methods: To define the role of cardiac fibroblast-GSK-3α in myocardial fibrosis and heart failure, GSK-3α was deleted from fibroblasts or myofibroblasts with tamoxifen-inducible Tcf21- or Postn-promoter-driven Cre recombinase. Control and GSK-3α KO mice were subjected to cardiac injury and heart parameters were evaluated. The fibroblast kinome mapping was carried out to delineate molecular mechanism followed by in vivo and in vitro analysis., Results: Fibroblast-specific GSK-3α deletion restricted fibrotic remodeling and preserved function of the injured heart. We observed reductions in cell migration, collagen gel contraction, α-SMA protein levels, and expression of ECM genes in TGFβ1-treated KO fibroblasts, indicating that GSK-3α is required for myofibroblast transformation. Surprisingly, GSK-3α deletion did not affect SMAD3 activation, suggesting the profibrotic role of GSK-3α is SMAD3 independent. The molecular studies confirmed decreased ERK signaling in GSK-3α-KO CFs. Conversely, adenovirus-mediated expression of a constitutively active form of GSK-3α (Ad-GSK-3α S21A ) in fibroblasts increased ERK activation and expression of fibrogenic proteins. Importantly, this effect was abolished by ERK inhibition., Conclusions: GSK-3α-mediated MEK-ERK activation is a critical profibrotic signaling circuit in the injured heart, which operates independently of the canonical TGF-β1-SMAD3 pathway. Therefore, strategies to inhibit the GSK-3α-MEK-ERK signaling circuit could prevent adverse fibrosis in diseased hearts.

Background: Takotsubo cardiomyopathy (TC) or stress-induced cardiomyopathy is a transient heart condition that clinically resembles an acute coronary syndrome. This study aims to assess the incidence of life-threatening arrhythmias in patients with Takotsubo cardiomyopathy and evaluate the outcomes of patients with life-threatening arrhythmias (LTAs) in Takotsubo cardiomyopathy compared with those without LTA., Methods: We comprehensively searched the PubMed, Google Scholar, and Embase databases from inception to February 2021. The primary aim of the study was to determine the incidence of LTAs in TC patients. Other outcomes of interest were the odds of in-hospital, long-term mortality, and cardiogenic shock (CS) in TC patients with LTAs versus those without LTAs. For all statistical analyses, ReviewManager and MedCalc were used., Results: Eighteen studies were included in this study involving 55,557 participants (2,185 with LTAs and 53,372 without LTAs). The pooled incidence of LTAs in the patients of TC was found to be 6.29% (CI: 4.70-8.08%; I2 = 94.67%). There was a statistically significant increased risk of in-hospital mortality (OR = 4.74; CI: 2.24-10.04; I2 = 77%, p < 0.0001) and cardiogenic shock (OR = 5.60; CI: 3.51-8.95; I2 = 0%, p < 0.00001) in the LTA group versus the non-LTA group. LTA was not associated with long-term mortality (OR = 2.23; CI: 0.94-5.28; I2 = 53%, p = 0.07)., Conclusion: The pooled incidence of life-threatening arrhythmias in the patients of TC was found to be 6.29%. In the group of TC patients with LTAs, the odds of in-hospital mortality and CS, was higher than in the TC patients without LTAs., Competing Interests: Declaration of competing interest The authors declare they have no conflict of interest., (Copyright © 2022 Cardiological Society of India. Published by Elsevier, a division of RELX India, Pvt. Ltd. All rights reserved.)

Obesity-associated metabolic disorders are rising to pandemic proportions; hence, there is an urgent need to identify underlying molecular mechanisms. Glycogen synthase kinase-3 (GSK-3) signaling is highly implicated in metabolic diseases. Furthermore, GSK-3 expression and activity are increased in Type 2 diabetes patients. However, the isoform-specific role of GSK-3 in obesity and glucose intolerance is unclear. Pharmacological GSK-3 inhibitors are not isoform-specific, and tissue-specific genetic models are of limited value to predict the clinical outcome of systemic inhibiion. To overcome these limitations, we created novel mouse models of ROSA26CreERT2-driven, tamoxifen-inducible conditional deletion of GSK-3 that allowed us to delete the gene globally in an isoform-specific and temporal manner. Isoform-specific GSK-3 KOs and littermate controls were subjected to a 16-week high-fat diet (HFD) protocol. On an HFD, GSK-3α KO mice had a significantly lower body weight and modest improvement in glucose tolerance compared to their littermate controls. In contrast, GSK-3β-deletion-mediated improved glucose tolerance was evident much earlier in the timeline and extended up to 12 weeks post-HFD. However, this protective effect weakened after chronic HFD (16 weeks) when GSK-3β KO mice had a significantly higher body weight compared to controls. Importantly, GSK-3β KO mice on a control diet maintained significant improvement in glucose tolerance even after 16 weeks. In summary, our novel mouse models allowed us to delineate the isoform-specific role of GSK-3 in obesity and glucose tolerance. From a translational perspective, our findings underscore the importance of maintaining a healthy weight in patients receiving lithium therapy, which is thought to work by GSK-3 inhibition mechanisms.

Introduction Vitamin D deficiency is a rising health issue in patients with chronic kidney disease (CKD). It can lead to serious issues such as rickets, periodontitis, osteoporosis, weakness, muscle ache, and depression. This study was conducted to determine the vitamin D status of patients with CKD in Pakistan and evaluate the correlation between serum vitamin D and renal function progression. Methodology A retrospective study enrolled patients who visited Liaquat National Hospital, Karachi, Pakistan, from January 2015 to January 2021 with a primary diagnosis of CKD. Anthropometric, laboratory, and demographic data were collected from the hospital management information system (HMIS). Results A total of 513 patients with CKD were included in the study. More than 50% of the patients were from stage 3 to stage 5 of CKD while the rest were from stage 1 and stage 2. Significant differences are in relation to calcium, phosphate, and albumin across categories of severity of CKD. Calcium is lowest in stage 5 while phosphate is highest in stage 5. Vitamin D deficiency was found in all participants, but serum vitamin D concentration was lowest in stage 5, i.e., 8.14+6.00. The changing of vitamin D level was associated with the severity of CKD staging (p-value=0.003). Conclusion The current study has shown that vitamin D deficiency, calcium deficiency, and hyperphosphatemia are more common in patients with CKD, but their severity is more common in advanced stages of CKD., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Kantas et al.)

Observational studies indicate that pleural effusion has an association with risk and the clinical prognosis of COVID-19 disease; however, the available literature on this area is inconsistent. The objective of this systematic review and meta-analysis is to evaluate the correlation between COVID-19 disease and pleural effusion. A rigorous literature search was conducted using multiple databases. All eligible observational studies were included from around the globe. The pooled prevalence and associated 95% confidence interval (CI) were calculated using the random effect model. Mantel-Haenszel odds ratios were produced to report overall effect size using random effect models for severity and mortality outcomes. Funnel plots, Egger regression tests, and Begg-Mazumdar's rank correlation test were used to appraise publication bias. Data from 23 studies including 6234 COVID-19 patients was obtained. The overall prevalence of pleural effusion in COVID-19 patients was 9.55% (95% CI, I 2  = 92%). Our findings also indicated that the presence of pleural effusions associated with increased risk of severity of disease(OR = 5.08, 95% CI 3.14-8.22, I 2  = 77.4%) and mortality due to illness(OR = 4.53, 95% CI 2.16-9.49, I 2  = 66%) compared with patients without pleural effusion. Sensitivity analyses illustrated a similar effect size while decreasing the heterogeneity. No significant publication bias was evident in the meta-analysis. The presence of pleural effusion can assist as a prognostic factor to evaluate the risk of worse outcomes in COVID-19 patients hence, it is recommended that hospitalized COVID-19 patients with pleural effusion should be managed on an early basis., (© 2021 Wiley Periodicals LLC.)

Introduction Coronavirus disease 2019 (COVID-19) is a major social and economic challenge, devastating the health care system in several countries around the world. Mortality scores are important as they can help health care professionals to plan treatment as per the patients' condition for proper resource allocation. When it comes to patients, it provides invaluable information for implementing advance directives. The aim of the study is to validate mortality scores for predicting in-hospital mortality in patients with COVID-19. Methodology This was a retrospective cohort study that included data from three tertiary care hospitals in Karachi, Pakistan. Data of patients diagnosed with confirmed COVID-19 infection and hospitalized in Ziauddin Hospital, Aga Khan Hospital, and Liaquat National Hospital were enrolled in the study from November 1, 2020, to April 30, 2021. Data was extracted from the hospital management information system (HMIS) using a structured questionnaire. Results Overall, 835 patients were included in the final analysis. The mean age of patients was 53.29 (SD ± 15.17) years, and 675 patients (80.72%) were males. The sensitivity of the CALL score is highest among all four scores, i.e., 77.25%, and the quick Sequential Organ Failure Assessment (qSOFA) score has the lowest sensitivity (59.79%). However, CALL has the lowest specificity (58.04%), while qSOFA has the highest specificity (73.91%). However, MulBSTA and CRB-65 have a sensitivity of 70.11% and 64.96%, respectively. Conclusion The current study showed that the CALL score had better sensitivity as compared to other mortality scores., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Jilanee et al.)

Introduction: Statin use in secondary prevention after acute coronary syndrome (ACS) can play an important role in enhancing clinical outcomes, this has been proven in several randomized trials. This study was conducted to compare the efficacy of moderate-intensity and high-intensity statins in controlling low-density lipoprotein (LDL) after ACS., Methodology: A randomized control trial was conducted at the Cardiology Department of Liaquat National Hospital, Karachi, Pakistan, from July 2020 to September 2021. During admission, patients were either started on a high-intensity statin dose (rosuvastatin 20 mg) or moderate-intensity statin (rosuvastatin 10 mg) by a computer-generated allocation sequence. Patients were followed-up in the outpatient department (OPD) after 3 months, and a lipid profile at follow-up was obtained. The percentage of LDL change was determined on 3 months of follow-up., Results: A total of 590 patients were enrolled in the study. Out of all participants enrolled, 334 (80.48%) completed the 3-month follow-up. The mean age of participants was 58.08 (+12.06) years. High-intensity statin therapy is positively associated with positive LDL change (adjusted odds ratio [AOR]=4.45, P-value=0.001)., Conclusion: Our data implies that high-intensity statin medication may be an initial therapeutic option to decrease LDL. However, future randomized clinical trials should corroborate these findings., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Rupasinghe et al.)

Introduction: Charlson Comorbidity Index (CCI) is a simple, validated, and readily acceptable method of determining the risk of mortality from comorbid disease. It has been used as a predictor of long-term survival and prognosis. The aim of this study is to determine the impact of CCI score on mortality in COVID-19 hospitalized patients and test the efficacy of the CoLACD score (COVID-19 lymphocyte ratio, age, CCI score, dyspnoea) in predicting mortality among hospitalized COVID-19 patients., Methodology: It was a retrospective cohort, and the data of this study were gathered from two tertiary hospitals of Karachi, including Liaquat National Hospital and Ziauddin Hospital. Data of patients hospitalized in any of these tertiary care hospitals and diagnosed with confirmed COVID-19 infection were used in the study from January 15, 2021, to April 30, 2021., Results: The mean age of participants was 53.22 (±14.21) years. The majority of participants were males (74.91%). Predictors of mortality include CCI score, age of participants, D-dimer, smoking status, and shortness of breath. The sensitivity of this CoLACD score was 80.23%, and specificity was 50.23% (diagnostic accuracy is 60.45%). The negative predictive value (NPV) of this test was 39.44%, and the positive predictive value (PPV) was 83.01%., Conclusion: Our study showed that CCI can be used in a clinical setting to achieve a prediction of mortality in COVID-19 patients., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Ahmed et al.)

Regulatory B cells (Breg) are IL-10 producing subsets of B cells that contribute to immunosuppression in the tumor microenvironment (TME). Breg are elevated in patients with lung cancer; however, the mechanisms underlying Breg development and their function in lung cancer have not been adequately elucidated. Herein, we report a novel role for Indoleamine 2, 3- dioxygenase (IDO), a metabolic enzyme that degrades tryptophan (Trp) and the Trp metabolite L-kynurenine (L-Kyn) in the regulation of Breg differentiation in the lung TME. Using a syngeneic mouse model of lung cancer, we report that Breg frequencies significantly increased during tumor progression in the lung TME and secondary lymphoid organs, while Breg were reduced in tumor-bearing IDO deficient mice (IDO -/- ). Trp metabolite L-Kyn promoted Breg differentiation in-vitro in an aryl hydrocarbon receptor (AhR), toll-like receptor-4-myeloid differentiation primary response 88, (TLR4-MyD88) dependent manner. Importantly, using mouse models with conditional deletion of IDO in myeloid-lineage cells, we identified a significant role for immunosuppressive myeloid-derived suppressor cell (MDSC)-associated IDO in modulating in-vivo and ex-vivo differentiation of Breg. Our studies thus identify Trp metabolism as a therapeutic target to modulate regulatory B cell function during lung cancer progression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tousif, Wang, Jackson, Hough, Strenkowski, Athar, Thannickal, McCusker, Ponnazhagan and Deshane.)

[Figure: see text].

Introduction Double J stents (DJS) are commonly used in urological practice, but they do have a risk of complications, such as infection and hematuria. This study explored the association between ureteral double J stent colonization and lower urinary tract symptom (LUTS) severity. Methodology This cross-sectional study was conducted from January 2021 to June 2021 in patients admitted to a tertiary care hospital in Karachi, Pakistan, who required double J stent (DJS) insertion. Patients who came to the site for stent removal were invited to participate in the study and enrolled using a consecutive sampling technique between January 15, 2021, and March 15, 2021. Results The study enrolled 176 patients, of whom 73.33% had colonization and the remaining had no colonization. The factors significantly associated with symptom severity included colonization of the DJS (P-value = 0.001) and the patients' ages (P-value = 0.046). The two groups have significantly different symptoms, which included incontinence (P-value = 0.001), polyuria (P-value = 0.001), and nocturia (P-value = 0.001). Conclusion Our study found more severe symptoms in DJS patients with colonization than in those without colonization. Irritative voiding symptoms, including nocturia and dysuria, are more common in DJS patients with colonization., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Hussain et al.)

Background: Covid-19 is an extremely contagious illness caused by the severe acute respiratory syndrome (SARS-CoV-2) virus. The cardiac involvement in such a public health emergency disease has not been well studied and a conflicting evidence exists on this issue., Objective: This systematic review article aimed to compile and illustrate clinical characteristics, diagnostic findings, management, and outcomes manifesting in myocarditis linked with Covid-19., Methods: A literature search was accomplished for published eligible articles with MEDLINE/PubMed and Embase databases. All eligible case reports and case series were included from around the world without any language restrictions. For this review, inclusion criteria were laboratory-confirmed SARS-CoV-2 infection cases reporting a diagnosis of acute myocarditis., Results: Data from 41 studies describing myocarditis in 42 Covid-19 patients was obtained. The median age of these patients was 43.4 years, with 71.4% of them being men. Fever was the most prevalent presenting symptoms seen in 57% of patients. Hypertension was the most pervasive comorbidity accompanying these patients. Cardiac biomarkers troponin and brain natriuretic peptide (BNP) were raised in almost 90% and 87% of patients, respectively. Electrocardiogram findings were nonspecific and included ST-segment and T-wave changes. Echocardiogram commonly showed left ventricular systolic dysfunction with increased heart size. Cardiac magnetic resonance imaging (CMRI) exhibited myocardial edema and injury. The most prevalent histopathological feature appreciated was diffuse lymphocytic inflammatory infiltrates. Antivirals and corticosteroids were the most frequently used medications. About 38% of patients also needed vasopressor assistance. Out of 42 patients, 67% recovered, and eight died., Conclusion: Because of the risk of a sudden worsening of patients conditions and myocarditis association with considerable mortality and morbidity, a knowledge of this cardiac complication of Covid-19 disease is crucial for healthcare professionals., (© 2021 John Wiley & Sons Ltd.)

Introduction Spontaneous pregnancy loss is unquestionably common worldwide, with roughly 5% of pregnancies ending in this way. Miscarriage can lead to serious psychological issues for women as well as their mothers. Although, it is irreversible but can be prevented through proper risk assessment of women. The goal of this study is to find clinical predictors of miscarriages in Karachi, Pakistani women. Methodology The study is a retrospective chart review that used data of women having livebirth and miscarriages at the Liaquat National Hospital Karachi Pakistan. Data of a total of 517 women were included in the study, out of which 453 have had a live birth, and 64 had miscarriages. To determine the factors associated with miscarriages, multivariable logistic regression was used.  Results The mean age of women was 31.08 (±5.10) years. Age of mother over 40 years (adjusted odds ratio [AOR]=10.28; p-value=0.001), overweight and obesity (AOR=3.01; p-value=0.001) and history of miscarriage (AOR=2.91; p-value=0.003) are variables significantly associated with miscarriages. Conclusion Findings of the current study shown that risk factors of miscarriages included age of mother, increased BMI and previous history of miscarriages. All these factors need to be considered while providing antenatal care to mothers to mitigate the risk of miscarriages., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Iqbal et al.)

Introduction Multimorbidity is defined as the coexistence of more than one chronic condition in one individual. It is related to enhanced rates of disability and mortality, enhanced disease burden, decreased function levels, and it can affect the wellbeing and daily activities of people, including loss of autonomy and independence. The aim of the current study is to determine the predictors of quality of life among patients with multimorbidity in Karachi, Pakistan. Methodology It was a cross-sectional study conducted in 12 health care facilities of six districts in Karachi, Pakistan. Two health care facilities were selected from each district using a convenient sampling technique. The total sample size of this study was 690, equally distributed among 12 health care facilities. Results The majority of participants (33.47%) belonged to the age group of 40 to 49 years, while 29.85% of participants had an age between 30 to 39 years. More than half of the participants were females (50.87%). Overall, the multivariate analysis showed being male, married, younger, high educational status and employed were positively associated with quality of life. While having lower family income is negatively associated with quality of life. Conclusion The findings of this study had important implications for identifying distinct multimorbidity individuals who were at risk of a lower quality of life, and they emphasized the need for disease detection and treatment at an early stage. The study can also give important evidence for decision-makers when it comes to allocating health resources more efficiently, and health administrative departments can improve chronic disease management., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Hussain et al.)

Background:  The aim of this study is to assess the correlation and agreement between venous blood gas (VBG) values and arterial blood gas (ABG) values in patients presented in the emergency department of the Indus Hospital, Karachi. This study also included the evaluation of specificity and sensitivity of VBGs values for the identification of abnormal ABG values., Method: It was a retrospective, observational study conducted at the Indus Hospital and Health Network, Karachi, Pakistan. All VBG and ABG values in the same patient which were collected at the same time from April 2020 to May 2021 were included in the study.  Results: The study involved 377 patients; 52.8% of patients were female, while 47.2% were male. The mean age of patients was 53.4 years (±17.2). There is an acceptable agreement between the arterial and venous values of pH, bicarbonate (mEq/l), and lactate (mEq/l), respectively, and poor agreement in PCO 2 (mmHg) and PO 2 ., Conclusion: The study found that analysis of VBG has the potential to be used in the emergency setting in general. Blood gas values of Lactate, HCO 3 , and pH have shown acceptable association and significant correlation, and they can be considered clinically interchangeable with ABGs values. However, venous PCO 2 and PO 2 were found to be different between the two., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Tousif et al.)

Heart failure (HF) is a leading cause of morbidity and mortality across the world. Cardiac fibrosis is associated with HF progression. Fibrosis is characterized by the excessive accumulation of extracellular matrix components. This is a physiological response to tissue injury. However, uncontrolled fibrosis leads to adverse cardiac remodeling and contributes significantly to cardiac dysfunction. Fibroblasts (FBs) are the primary drivers of myocardial fibrosis. However, until recently, FBs were thought to play a secondary role in cardiac pathophysiology. This review article will present the evolving story of fibroblast biology and fibrosis in cardiac diseases, emphasizing their recent shift from a supporting to a leading role in our understanding of the pathogenesis of cardiac diseases. Indeed, this story only became possible because of the emergence of FB-specific mouse models. This study includes an update on the advancements in the generation of FB-specific mouse models. Regarding the underlying mechanisms of myocardial fibrosis, we will focus on the pathways that have been validated using FB-specific, in vivo mouse models. These pathways include the TGF-β/SMAD3, p38 MAPK, Wnt/β-Catenin, G-protein-coupled receptor kinase (GRK), and Hippo signaling. A better understanding of the mechanisms underlying fibroblast activation and fibrosis may provide a novel therapeutic target for the management of adverse fibrotic remodeling in the diseased heart.

Introduction Rheumatoid arthritis (RA) is a chronic, progressive inflammatory illness that primarily affects peripheral joints and belongs to systemic connective tissue diseases. Rheumatoid arthritis can cause varied and significant impacts on patients' health, including mental and physical wellbeing. The aim of this study is to analyze the factors affecting the quality of life of rheumatoid arthritis patients. Methodology A cross-sectional study was conducted in the outpatient orthopedics department of Indus Hospital and Health Network. The survey questionnaire was used to collect data from participants. The study's 36-item short-form survey (SF-36) questionnaire was used to assess the quality of life (QoL) among RA patients. Linear regression was used to assess the factors associated with the mental and physical components of QoL. Results A total of 154 patients were interviewed in this study. The mean age of participants was 48.96 (±51.35). Factors that contributed to the physical component of QoL included severity of disease, income, age, comorbidity, and anxiety while factors affecting the mental component of QoL included quality of sleep, anxiety, education, comorbidity, and disease severity. Conclusion Healthcare professionals need to work closely with patients to increase their capabilities of being more independent and controlling all the factors that can affect their QoL., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Irfan et al.)

Tuberculosis (TB) remains a major health problem throughout the world with one third of the population latently infected and ~1.74 million deaths annually. Current therapy consists of multiple antibiotics and a lengthy treatment regimen, which is associated with risk for the generation of drug-resistant Mycobacterium tuberculosis variants. Therefore, alternate host directed strategies that can shorten treatment length and enhance anti-TB immunity during the treatment phase are urgently needed. Here, we show that Luteolin, a plant-derived hepatoprotective immunomodulator, when administered along with isoniazid as potential host directed therapy promotes anti-TB immunity, reduces the length of TB treatment and prevents disease relapse. Luteolin also enhances long-term anti-TB immunity by promoting central memory T cell responses. Furthermore, we found that Luteolin enhances the activities of natural killer and natural killer T cells, both of which exhibit antitubercular attributes. Therefore, the addition of Luteolin to conventional antibiotic therapy may provide a means to avoid the development of drug-resistance and to improve disease outcome., Competing Interests: The authors have declared that no competing interests exist.

Heart Failure (HF) is the leading cause of death worldwide. Myocardial fibrosis, one of the clinical manifestations implicated in almost every form of heart disease, contributes significantly to HF development. However, there is no approved drug specifically designed to target cardiac fibrosis. Nintedanib (NTB) is an FDA approved tyrosine kinase inhibitor for idiopathic pulmonary fibrosis (IPF) and chronic fibrosing interstitial lung diseases (ILD). The favorable clinical outcome of NTB in IPF patients is well established. Furthermore, NTB is well tolerated in IPF patients irrespective of cardiovascular comorbidities. However, there is a lack of direct evidence to support the therapeutic efficacy and safety of NTB in cardiac diseases. In this study we examined the effects of NTB treatment on cardiac fibrosis and dysfunction using a murine model of HF. Specifically, 10 weeks old C57BL/6J male mice were subjected to Transverse Aortic Constriction (TAC) surgery. NTB was administered once daily by oral gavage (50 mg/kg) till 16 weeks post-TAC. Cardiac function was monitored by serial echocardiography. Histological analysis and morphometric studies were performed at 16 weeks post-TAC. In the control group, systolic dysfunction started developing from 4 weeks post-surgery and progressed till 16 weeks. However, NTB treatment prevented TAC-induced cardiac functional decline. In another experiment, NTB treatment was stopped at 8 weeks, and animals were followed till 16 weeks post-TAC. Surprisingly, NTB's beneficial effect on cardiac function was maintained even after treatment interruption. NTB treatment remarkably reduced cardiac fibrosis as confirmed by Masson's trichrome staining and decreased expression of collagen genes (COL1A1, COL3A1). Compared to the TAC group, NTB treated mice showed a lower HW/TL ratio and cardiomyocyte cross-sectional area. NTB treatment reduced myocardial and systemic inflammation by inhibiting pro-inflammatory subsets and promoting regulatory T cells (Tregs). Our in vitro studies demonstrated that NTB prevents myofibroblast transformation, TGFβ1-induced SMAD3 phosphorylation, and the production of fibrogenic proteins (Fibronectin-1, α-SMA). However, NTB promoted immunosuppressive phenotype in Tregs, and altered vital signaling pathways in isolated cardiac fibroblast and cardiomyocytes, suggesting that its biological effect and underlying cardiac protection mechanisms are not limited to fibroblast and fibrosis alone. Our findings provide a proof of concept for repurposing NTB to combat adverse myocardial fibrosis and encourage the need for further validation in large animal models and subsequent clinical development for HF patients., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background and objective The coronavirus disease 2019 (COVID-19) pandemic has become a global healthcare emergency. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, has a wide range of clinical manifestations ranging from subclinical infection to multi-organ failure. In addition to the respiratory system, COVID-19 also adversely affects the kidneys. In this study, we aimed to measure the prevalence of acute kidney injury (AKI) in COVID-19 and its association with the disease severity and mortality in COVID-19 patients. Materials and methods We conducted our study by following the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) guidelines. A comprehensive literature search using four databases (PubMed, EMBASE, Google Scholar, and clinicaltrial.gov) was performed. Our initial search returned 2,771 articles. After excluding review articles, duplicates, and non-relevant studies, we included 20 articles that reported an association between COVID-19 and AKI. We subsequently performed a random effect analysis to find the pooled prevalence, pooled odds ratio (OR) estimates, and 95% confidence intervals for severe COVID-19 and mortality outcomes in AKI using Cochrane RevMan (version 5.4) and R programming language (version 4.16-2). Results A total of 14,415 patients from various countries were included. Among the 20 cohorts, the median age was 55.8 ±8.39 years (range: 43-72 years), and 43.78% of the subjects were female. Out of a total of 14,415 patients, 3,820 developed AKI with a pooled prevalence of 11% (95% CI: 0.07-0.15; p<0.01; I 2 =98%). AKI was found to have a significant association with severe COVID-19 disease, with a pooled OR of 8.45 (95% CI: 5.56-12.56; p<0.00001; I 2 =0%). AKI was associated with significantly higher mortality in patients with COVID-19 with an OR of 13.52 (95% CI: 5.43-33.67; p<0.00001; I 2 =88%). Conclusion AKI manifests as a common COVID-19 complication, and COVID-19 patients with AKI generally have poor outcomes in terms of disease severity and mortality., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Menon et al.)

In this systematic review, we anticipated in summarizing clinical features, histopathological hallmarks, and possible pathology behind the maculopapular skin eruptions occurring in Covid-19 patients. A literature search was executed using MEDLINE/PubMed and Embase databases for articles published till 20 November 2020. All eligible articles including observational studies, case reports, and case series reporting the maculopapular skin lesion in Covid-19 patients were included. Data were obtained for 354 Covid-19 patients presenting with maculopapular lesions from 40 studies. The mean age of these patients was 53 years, and with 42% of them being male. These maculopapular lesions differed considerably in terms of distribution and appearance, ranging from diffuse erythematous maculopapular lesions to scattered erythematous macules coalescing into papules to maculopapular lesions in plaques. The mean duration of the lesion was 8 days. These lesions were frequently localized on trunks and extremities. Superficial perivascular dermatitis with lymphocytic infiltrate was a histopathological hallmark of these lesions. As these skin lesions may have a possible association with diagnosis, management, prognosis, and severity of the disease, all health practitioners need to be well acquainted with these Covid-19 skin lesions. Also, in the middle of this worldwide pandemic, early identification of this eruption may help manage this infection's further spread., (© 2021 Wiley Periodicals LLC.)

Breast cancer (BCa) proliferates within a complex, three-dimensional microenvironment amid heterogeneous biochemical and biophysical cues. Understanding how mechanical forces within the tumor microenvironment (TME) regulate BCa phenotype is of great interest. We demonstrate that mechanical strain enhanced the proliferation and migration of both estrogen receptor + and triple-negative (TNBC) human and mouse BCa cells. Furthermore, a critical role for exosomes derived from cells subjected to mechanical strain in these pro-tumorigenic effects was identified. Exosome production by TNBC cells increased upon exposure to oscillatory strain (OS), which correlated with elevated cell proliferation. Using a syngeneic, orthotopic mouse model of TNBC, we identified that preconditioning BCa cells with OS significantly increased tumor growth and myeloid-derived suppressor cells (MDSCs) and M2 macrophages in the TME. This pro-tumorigenic myeloid cell enrichment also correlated with a decrease in CD8 + T cells. An increase in PD-L1 + exosome release from BCa cells following OS supported additive T cell inhibitory functions in the TME. The role of exosomes in MDSC and M2 macrophage was confirmed in vivo by cytotracking fluorescent exosomes, derived from labeled 4T1.2 cells, preconditioned with OS. In addition, in vivo internalization and intratumoral localization of tumor-cell derived exosomes was observed within MDSCs, M2 macrophages, and CD45-negative cell populations following direct injection of fluorescently-labeled exosomes. Our data demonstrate that exposure to mechanical strain promotes invasive and pro-tumorigenic phenotypes in BCa cells, indicating that mechanical strain can impact the growth and proliferation of cancer cell, alter exosome production by BCa, and induce immunosuppression in the TME by dampening anti-tumor immunity.

The advent of tyrosine kinase inhibitors (TKIs) targeted therapy revolutionized the treatment of chronic myeloid leukemia (CML) patients. However, cardiotoxicity associated with these targeted therapies puts the cancer survivors at higher risk. Ponatinib is a third-generation TKI for the treatment of CML patients having gatekeeper mutation T315I, which is resistant to the first and second generation of TKIs, namely, imatinib, nilotinib, dasatinib, and bosutinib. Multiple unbiased screening from our lab and others have identified ponatinib as most cardiotoxic FDA approved TKI among the entire FDA approved TKI family (total 50+). Indeed, ponatinib is the only treatment option for CML patients with T315I mutation. This review focusses on the cardiovascular risks and mechanism/s associated with CML TKIs with a particular focus on ponatinib cardiotoxicity. We have summarized our recent findings with transgenic zebrafish line harboring BNP luciferase activity to demonstrate the cardiotoxic potential of ponatinib. Additionally, we will review the recent discoveries reported by our and other laboratories that ponatinib primarily exerts its cardiotoxicity via an off-target effect on cardiomyocyte prosurvival signaling pathways, AKT and ERK. Finally, we will shed light on future directions for minimizing the adverse sequelae associated with CML-TKIs., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In light of the favorable outcomes of few small, non-randomized clinical studies, the Food and Drug Administration (FDA) has issued an Emergency Use Authorization (EUA) to Hydroxychloroquine (HCQ) for hospitalized coronavirus disease 2019 (COVID-19) patients. In fact, subsequent clinical studies with COVID-19 and HCQ have reported limited efficacy and poor clinical benefits. Unfortunately, a robust clinical trial for its effectiveness is not feasible at this emergency. Additionally, HCQ was suspected of causing cardiovascular adverse reactions (CV-AEs), but it has never been directly investigated. The objective of this pharmacovigilance analysis was to determine and characterize HCQ-associated cardiovascular adverse events (CV-AEs). We performed a disproportionality analysis of HCQ-associated CV-AEs using the FDA adverse event reporting system (FAERS) database. The FAERS database, comprising more than 11,901,836 datasets and 10,668,655 patient records with drug-adverse reactions, was analyzed. The disproportionality analysis was used to calculate the reporting odds ratios (ROR) with 95% confidence intervals (CI) to predict HCQ-associated CV-AEs. HCQ was associated with higher reporting of right ventricular hypertrophy (ROR: 6.68; 95% CI: 4.02 to 11.17), left ventricular hypertrophy (ROR: 3.81; 95% CI: 2.57 to 5.66), diastolic dysfunction (ROR: 3.54; 95% CI: 2.19 to 5.71), pericarditis (ROR: 3.09; 95% CI: 2.27 to 4.23), torsades de pointes (TdP) (ROR: 3.05; 95% CI: 2.30 to 4.10), congestive cardiomyopathy (ROR: 2.98; 95% CI: 2.01 to 4.42), ejection fraction decreased (ROR: 2.41; 95% CI: 1.80 to 3.22), right ventricular failure (ROR: 2.40; 95% CI: 1.64 to 3.50), atrioventricular block complete (ROR: 2.30; 95% CI: 1.55 to 3.41) and QT prolongation (ROR: 2.09; 95% CI: 1.74 to 2.52). QT prolongation and TdP are most relevant to the COVID-19 treatment regimen of high doses for a comparatively short period and represent the most common HCQ-associated AEs. The patients receiving HCQ are at higher risk of various cardiac AEs, including QT prolongation and TdP. These findings highlight the urgent need for prospective, randomized, controlled studies to assess the risk/benefit ratio of HCQ in the COVID-19 setting before its widespread adoption as therapy.

Cellular cross-talk within the tumor microenvironment (TME) by exosomes is known to promote tumor progression. Tumor promoting macrophages with an M2 phenotype are suppressors of anti-tumor immunity. However, the impact of tumor-derived exosomes in modulating macrophage polarization in the lung TME is largely unknown. Herein, we investigated if lung tumor-derived exosomes alter transcriptional and bioenergetic signatures of M0 macrophages and polarize them to an M2 phenotype. The concentration of exosomes produced by p53 null H358 lung tumor cells was significantly reduced compared to A549 (p53 wild-type) lung tumor cells, consistent with p53-mediated regulation of exosome production. In co-culture studies, M0 macrophages internalized tumor-derived exosomes, and differentiated into M2 phenotype. Importantly, we demonstrate that tumor-derived exosomes enhance the oxygen consumption rate of macrophages, altering their bioenergetic state consistent with that of M2 macrophages. In vitro co-cultures of M0 macrophages with H358 exosomes demonstrated that exosome-induced M2 polarization may be p53 independent. Murine bone marrow cells and bone marrow-derived myeloid-derived suppressor cells (MDSCs) co-cultured with lewis lung carcinoma (LLC)-derived exosomes differentiated to M2 macrophages. Collectively, these studies provide evidence for a novel role for lung tumor-exosomes in M2 macrophage polarization, which then offers new therapeutic targets for immunotherapy of lung cancer.

Tuberculosis (TB) is one of the deadliest diseases, claiming ~2 million deaths annually worldwide. The majority of people in TB endemic regions are vaccinated with Bacillus Calmette Guerin (BCG), which is the only usable vaccine available. BCG is efficacious against meningeal and disseminated TB in children, but protective responses are relatively short-lived and fail to protect against adult pulmonary TB. The longevity of vaccine efficacy critically depends on the magnitude of long-lasting central memory T (TCM) cells, a major source of which is stem cell-like memory T (TSM) cells. These TSM cells exhibit enhanced self-renewal capacity as well as to rapidly respond to antigen and generate protective poly-functional T cells producing IFN-γ, TNF-α, IL-2 and IL-17. It is now evident that T helper Th 1 and Th17 cells are essential for host protection against TB. Recent reports have indicated that Th17 cells preserve the molecular signature for TSM cells, which eventually differentiate into IFN-γ-producing effector cells. BCG is ineffective in inducing Th17 cell responses, which might explain its inadequate vaccine efficacy. Here, we show that revaccination with BCG along with clofazimine treatment promotes TSM differentiation, which continuously restores TCM and T effector memory (TEM) cells and drastically increases vaccine efficacy in BCG-primed animals. Analyses of these TSM cells revealed that they are predominantly precursors to host protective Th1 and Th17 cells. Taken together, these findings revealed that clofazimine treatment at the time of BCG revaccination provides superior host protection against TB by increasing long-lasting TSM cells., Competing Interests: The authors have declared that no competing interests exist.

Background: Recent studies suggest that alterations in lung microbiome are associated with occurrence of chronic lung diseases and transplant rejection. To investigate the host-microbiome interactions, we characterized the airway microbiome and metabolome of the allograft (transplanted lung) and native lung of single lung transplant recipients., Methods: BAL was collected from the allograft and native lungs of SLTs and healthy controls. 16S rRNA microbiome analysis was performed on BAL bacterial pellets and supernatant used for metabolome, cytokines and acetylated proline-glycine-proline (Ac-PGP) measurement by liquid chromatography-high-resolution mass spectrometry., Results: In our cohort, the allograft airway microbiome was distinct with a significantly higher bacterial burden and relative abundance of genera Acinetobacter & Pseudomonas. Likewise, the expression of the pro-inflammatory cytokine VEGF and the neutrophil chemoattractant matrikine Ac-PGP in the allograft was significantly higher. Airway metabolome distinguished the native lung from the allografts and an increased concentration of sphingosine-like metabolites that negatively correlated with abundance of bacteria from phyla Proteobacteria., Conclusions: Allograft lungs have a distinct microbiome signature, a higher bacterial biomass and an increased Ac-PGP compared to the native lungs in SLTs compared to the native lungs in SLTs. Airway metabolome distinguishes the allografts from native lungs and is associated with distinct microbial communities, suggesting a functional relationship between the local microbiome and metabolome.

Obesity is an independent risk factor for cardiovascular diseases (CVD), including heart failure. Thus, there is an urgent need to understand the molecular mechanism of obesity-associated cardiac dysfunction. We recently reported the critical role of cardiomyocyte (CM) Glycogen Synthase Kinase-3 beta (GSK-3β) in cardiac dysfunction associated with a developing obesity model (deletion of CM-GSK-3β prior to obesity). In the present study, we investigated the role of CM-GSK-3β in a clinically more relevant model of established obesity (deletion of CM-GSK-3β after established obesity). CM-GSK-3β knockout (GSK-3β fl/flCre+/- ) and controls (GSK-3β fl/flCre-/- ) mice were subjected to a high-fat diet (HFD) in order to establish obesity. After 12 weeks of HFD treatment, all mice received tamoxifen injections for five consecutive days to delete GSK-3β specifically in CMs and continued on the HFD for a total period of 55 weeks. To our complete surprise, CM-GSK-3β knockout (KO) animals exhibited a globally improved glucose tolerance and maintained normal cardiac function. Mechanistically, in stark contrast to the developing obesity model, deleting CM-GSK-3β in obese animals did not adversely affect the GSK-3αS21 phosphorylation (activity) and maintained canonical β-catenin degradation pathway and cardiac function. As several GSK-3 inhibitors are in the trial to treat various chronic conditions, including metabolic diseases, these findings have important clinical implications. Specifically, our results provide critical pre-clinical data regarding the safety of GSK-3 inhibition in obese patients.

Chronic inflammation involving both innate and adaptive immune cells is implicated in the pathogenesis of asthma. Intercellular communication is essential for driving and resolving inflammatory responses in asthma. Emerging studies suggest that extracellular vesicles (EVs) including exosomes facilitate this process. In this report, we have used a range of approaches to show that EVs contain markers of mitochondria derived from donor cells which are capable of sustaining a membrane potential. Further, we propose that these participate in intercellular communication within the airways of human subjects with asthma. Bronchoalveolar lavage fluid of both healthy volunteers and asthmatics contain EVs with encapsulated mitochondria; however, the % HLA-DR + EVs containing mitochondria and the levels of mitochondrial DNA within EVs were significantly higher in asthmatics. Furthermore, mitochondria are present in exosomes derived from the pro-inflammatory HLA-DR + subsets of airway myeloid-derived regulatory cells (MDRCs), which are known regulators of T cell responses in asthma. Exosomes tagged with MitoTracker Green, or derived from MDRCs transduced with CellLight Mitochondrial GFP were found in recipient peripheral T cells using a co-culture system, supporting direct exosome-mediated cell-cell transfer. Importantly, exosomally transferred mitochondria co-localize with the mitochondrial network and generate reactive oxygen species within recipient T cells. These findings support a potential novel mechanism of cell-cell communication involving exosomal transfer of mitochondria and the bioenergetic and/or redox regulation of target cells., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Myeloid-derived suppressor cells (MDSCs) are known suppressors of antitumor immunity, affecting amino acid metabolism and T cell function in the tumor microenvironment. However, it is unknown whether MDSCs regulate B cell responses during tumor progression. Using a syngeneic mouse model of lung cancer, we show reduction in percentages and absolute numbers of B cell subsets including pro-, pre-, and mature B cells in the bone marrow (BM) of tumor-bearing mice. The kinetics of this impaired B cell response correlated with the progressive infiltration of MDSCs. We identified that IL-7 and downstream STAT5 signaling that play a critical role in B cell development and differentiation were also impaired during tumor progression. Global impairment of B cell function was indicated by reduced serum IgG levels. Importantly, we show that anti-Gr-1 Ab-mediated depletion of MDSCs not only rescued serum IgG and IL-7 levels but also reduced TGF-β1, a known regulator of stromal IL-7, suggesting MDSC-mediated regulation of B cell responses. Furthermore, blockade of IL-7 resulted in reduced phosphorylation of downstream STAT5 and B cell differentiation in tumor-bearing mice and administration of TGF-β-blocking Ab rescued these IL-7-dependent B cell responses. Adoptive transfer of BM-derived MDSCs from tumor-bearing mice into congenic recipients resulted in significant reductions of B cell subsets in the BM and in circulation. MDSCs also suppressed B cell proliferation in vitro in an arginase-dependent manner that required cell-to-cell contact. Our results indicate that tumor-infiltrating MDSCs may suppress humoral immune responses and promote tumor escape from immune surveillance., (Copyright © 2018 by The American Association of Immunologists, Inc.)

Curcumin, the bioactive component of turmeric also known as "Indian Yellow Gold," exhibits therapeutic efficacy against several chronic inflammatory and infectious diseases. Even though considered as a wonder drug pertaining to a myriad of reported benefits, the translational potential of curcumin is limited by its low systemic bioavailability due to its poor intestinal absorption, rapid metabolism, and rapid systemic elimination. Therefore, the translational potential of this compound is specifically challenged by bioavailability issues, and several laboratories are making efforts to improve its bioavailability. We developed a simple one-step process to generate curcumin nanoparticles of ~200 nm in size, which yielded a fivefold enhanced bioavailability in mice over regular curcumin. Curcumin nanoparticles drastically reduced hepatotoxicity induced by antitubercular antibiotics during treatment in mice. Most interestingly, co-treatment of nanoparticle-formulated curcumin along with antitubercular antibiotics dramatically reduced the risk for disease reactivation and reinfection, which is the major shortfall of current antibiotic treatment adopted by Directly Observed Treatment Short-course. Furthermore, nanoparticle-formulated curcumin significantly reduced the time needed for antibiotic therapy to obtain sterile immunity, thereby reducing the possibility of generating drug-resistant variants of the organisms. Therefore, adjunct therapy of nano-formulated curcumin with enhanced bioavailability may be beneficial to treatment of tuberculosis and possibly other diseases.