Risk Factors, Incidence, and Outcomes Associated With Clinically Significant Airway Ischemia.

Airway complications following lung transplantation remain an important cause of morbidity and mortality. We aimed to identify the incidence, risk factors and outcomes associated with clinically significant airway ischemia (CSAI) in our center. We reviewed 217 lung transplants (386 airway anastomoses) performed at our institution between February 2016 and December 2020. Airway images were graded using the 2018 ISHLT grading guidelines modified slightly for retrospective analysis. Airways were considered to have CSAI if they developed ischemia severity >B2, stenosis >50%, and/or any degree of dehiscence within 6-months of transplant. Regression analyses were used to evaluate outcomes and risk factors for CSAI. Eighty-two patients (37.8%) met criteria for CSAI. Of these, twenty-six (32%) developed stenosis and/or dehiscence, and 17 (21%) required interventions. Patients with CSAI had lower one-year (80.5% vs. 91.9%, p = 0.05) and three-year (67.1% vs. 77.8%, p = 0.08) survival than patients without CSAI. Factors associated with CSAI included younger recipient age, recipient diabetes, single running suture technique, performance of the left anastomosis first, lower venous oxygen saturation within 48-h, and takeback for major bleeding. Our single-center analysis suggests that airway ischemia remains a major obstacle in contemporary lung transplantation. Improving the local healing milieu of the airway anastomosis could potentially mitigate this risk.

A randomised-controlled trial (TARGET-C) of high vs. low target mean arterial pressure in patients with cirrhosis and septic shock.

BACKGROUND & AIMS: A high mean arterial pressure (MAP) target has been associated with improved renal outcomes in patients with cirrhosis, though it has not been studied in critically ill patients with cirrhosis and septic shock (CICs). We compared the efficacy of a high (80-85 mmHg; H-MAP) vs. low (60-65; L-MAP) target MAP strategy in improving 28-day mortality in CICs. METHODS: We performed open-label 1:1 randomisation of 150 CICs (H-MAP 75; L-MAP 75). The primary endpoint was 28-day mortality and secondary endpoints included reversal of shock, acute kidney injury (AKI) at day 5, the incidence of intradialytic hypotension (IDH), and adverse events. Endothelial markers were analysed in a subset of patients. RESULTS: The baseline characteristics were comparable. On intention-to-treat analysis, 28-day mortality (65% vs. 56%; p = 0.54), reversal of shock (47% vs. 53%; p = 0.41) and AKI development (45% vs. 31%;p = 0.06) were not different between the H-MAP and L-MAP groups, respectively. A lower incidence of IDH (12% vs. 48%; p <0.001) and higher adverse events necessitating protocol discontinuation (24% vs. 11%; p = 0.031) were noted in the H-MAP group. On per-protocol analysis (L-MAP 67; H-MAP 57), a significantly higher reversal of AKI (53% vs. 31%; p = 0.02) and a lower incidence of IDH (4% vs. 53%; p <0.001) were observed in the H-MAP group. Endothelial repair markers such as ADAMTS (2.11 ± 1.13 vs. 1.15 ± 0.48; p = 0.002) and angiopoietin-2 (74.08 ± 53.00 vs. 41.80 ± 15.95; p = 0.016) were higher in the H-MAP group. CONCLUSIONS: A higher MAP strategy does not confer a survival benefit in CICs, but improves tolerance to dialysis, lactate clearance and renal recovery. Higher adverse events indicate the need for better tools to evaluate target microcirculation pressures in CICs. IMPACT AND IMPLICATIONS: Maintaining an appropriate organ perfusion pressure during sepsis is the ultimate goal of haemodynamic management. A higher mean arterial pressure (MAP) improves renal outcomes in patients with hepatorenal syndrome. Patients with cirrhosis and septic shock have severe circulatory disturbances, low MAP, and poor tissue perfusion. In these patients, targeting higher MAP vs. lower MAP does not confer any survival benefit but is associated with more adverse events. A higher target strategy was associated with better tolerance and lesser episodes of hypotension on dialysis. Patients who could achieve the higher target MAP, without the development of adverse events, had improved renal outcomes and better lactate clearance. Higher MAP was also associated with improvements in markers of endothelial function. A higher target MAP strategy, with close monitoring of adverse events, may be recommended for patients with cirrhosis and septic shock. CLINICAL TRIAL NUMBER: NCT03145168.

Lifestyle Optimization Leads to Superior Liver Regeneration in Live Liver Donors and Decreases Early Allograft Dysfunction in Recipients: A Randomized Control Trial.

INTRODUCTION: The aim of the current randomized control trial was to assess the efficacy of donor lifestyle optimization on liver regeneration and outcome following live donor liver transplantation. METHODS: Live liver donors (LLDs) who were fit with no or minimal steatosis were randomized to receive either a customized low-calorie diet with calorie intake equalling their basal requirement along with exercise for 2 weeks before surgery versus to continue their normal routine lifestyle. Primary objectives were the difference in the day of normalization of serum bilirubin and PT-International normalized ratio and the percentage growth of the liver at postoperative day 7 and 14. Secondary objectives were differences in intraoperative liver biopsy, liver-regeneration markers, blood loss, hospital stay, the complication rate in LLDs, and rates of early graft dysfunction (EGD) in recipients. RESULTS: Sixty-two consecutive LLDs were randomized (28 in intervention vs. 34 in control). Baseline parameters and graft parameters were similar in both groups. LLDs in the intervention arm had significantly decreased calorie intake ( P <0.005), abdominal girth ( P <0.005), BMI ( P =0.05), and weight ( P <0.0005). The mean blood loss ( P =0.038), day of normalization of bilirubin ( P =0.005) and International normalized ratio ( P =0.061), postoperative peak aspartate transaminase ( P =0.003), Alanine transaminase ( P =0.025), and steatosis ( P <0.005) were significantly less in the intervention group. There was significantly higher volume regeneration ( P =0.03) in donors in the intervention arm. The levels of TNF-α, IL-6, and IL-10 levels were significantly higher, while the TGF-ß level was lower in donors in the intervention group. The rate of EGD was significantly higher in recipients in the control group ( P =0.043). CONCLUSION: Lifestyle optimization of LLD is simple to comply with, improves liver regeneration in LLDs, and decreases EGD in recipients, thus can enhance donor safety and outcomes in live donor liver transplantation.

Safety and utility of indwelling pleural catheters in lung transplant recipients.

INTRODUCTION: The safety and efficacy of indwelling pleural catheters (IPCs) in lung allograft recipients is under-reported. METHODS: We performed a multicenter, retrospective analysis between 1/1/2010 and 6/1/2022 of consecutive IPCs placed in lung transplant recipients. Outcomes included incidence of infectious and non-infectious complications and rate of auto-pleurodesis. RESULTS: Seventy-one IPCs placed in 61 lung transplant patients at eight centers were included. The most common indication for IPC placement was recurrent post-operative effusion. IPCs were placed at a median of 59 days (IQR 40-203) post-transplant and remained for 43 days (IQR 25-88). There was a total of eight (11%) complications. Infection occurred in five patients (7%); four had empyema and one had a catheter tract infection. IPCs did not cause death or critical illness in our cohort. Auto-pleurodesis leading to the removal of the IPC occurred in 63 (89%) instances. None of the patients in this cohort required subsequent surgical decortication. CONCLUSIONS: The use of IPCs in lung transplant patients was associated with an infectious complication rate comparable to other populations previously studied. A high rate of auto-pleurodesis was observed. This work suggests that IPCs may be considered for the management of recurrent pleural effusions in lung allograft recipients.

Pyrethroids toxicity in vertebrates and invertebrates and amelioration by bioactive compounds: A review.

Generations of different synthetic pesticides have been launched over time to maintain balance between production and consumption of the agricultural yield, control various disease programmes, store grains, etc. Pyrethroids, which are supposed to be non-toxic, have been excessively implemented and have contaminated soil and water bodies. Thus, pyrethroids cause severe and dreadful pernicious effects on various life forms residing in soil, air, and water. Various obnoxious effects of pyrethroids have been analyzed in the vertebrate and invertebrate systems of the animal kingdom. Pyrethroids, namely, Cypermethrin, Deltamethrin, Beta-cyfluthrin, Esfenvalerate, Fenvalerate, and Bifenthrin, have set out various types of degenerative and toxic impacts that include oxidative stress, hepatotoxicity, immunotoxicity involving thymic and splenic toxicity, neurotoxicity, nephrotoxicity, foetal toxicity, alterations in serum calcium and phosphate levels, cerebral and bone marrow degeneration, degeneration of the reproductive system, histological alteration, and DNA damage. Bioactive compounds like Diosmin, Curcumin, Rutin, Spirulina platensis, sesame oil, Naringin, Allicin, Piperine, alpha-lipoic acid, alpha-tocopherol, Cyperus rotundus L. tuber extract, herbal syrup from chicory and artichoke leaves, green tea extract, Quercetin, Trans-ferulic acid, Ascorbic acid, Propolis, ethanolic extract of grape pomace, and Melatonin have been reported to sublime the toxic effects of these pesticides. The expanding harmfulness of pesticides is a real and demanding issue that needs to be overcome, and bioactive compounds have been shown to reduce the toxicity in vivo as well as in vitro.

Unknown presentation of a rare genetic disorder: Monogenic diabetes in young type 4 presenting with hepatic cysts and procoagulant state.

Maturity onset diabetes in young (MODY) is the most common form of monogenic diabetes, which characteristically presents in adolescents and young adults. Till date, pathogenic variations involving 14 different genes have been causally implicated with the development of MODY. Maturity onset diabetes in young type 4 (MODY-4) is a very rare form of MODY. We present here case of 28-year-old nonobese male patient with distinct family history of diabetes spanning two generations, incidentally, detected to have a rare form of diabetes on genetic analysis when he presented with recurrent thromboembolic manifestations: deep vein thrombosis and pulmonary thromboembolism. Our case highlights a previously unknown disease association of a rare genetic disorder. Increasing awareness about this genetic disorder and early identification of such cases will enhance our understanding of hitherto unknown disease associations and the pathophysiological role of genetic mutations. This may contribute to the improved treatment and prevention of debilitating diseases such as diabetes.

Standard-Volume Plasma Exchange Improves Outcomes in Patients With Acute Liver Failure: A Randomized Controlled Trial.

BACKGROUND: High volume plasma-exchange (HVPE) improves survival in patients with acute liver failure (ALF), but apprehension regarding volume overload and worsening of cerebral edema remain. METHODS: In an open-label randomized controlled trial, 40 consecutive patients of ALF were randomized 1:1 to either standard medical treatment (SMT) or SMT with standard-volume plasma-exchange (SVPE). SVPE was performed using centrifugal apheresis [target volume of 1.5 to 2.0 plasma volumes per session] until desired response was achieved. Cerebral edema was assessed by brain imaging. Results were analyzed in an intention-to-treat analysis. Primary outcome was 21-day transplant-free survival. The levels of cytokines, damage-associated molecular patterns (DAMPs) and endotoxins were analyzed at baseline and day 5. RESULTS: ALF patients [aged 31.5 ± 12.2 years, 60% male, 78% viral, 83% hyperacute, 70% with SIRS were included. At day 5, SVPE [mean sessions 2.15 ± 1.42, median plasma volume replaced 5.049 L] compared to SMT alone, resulted in higher lactate clearance (p = .02), amelioration of SIRS (84% vs. 26%; P = .02), reduction in ammonia levels [(221.5 ± 96.9) vs.(439 ± 385.6) µg/dl, P = .02) and SOFA scores [9.9(±3.3) vs. 14.6(±4.8); P = .001]. There were no treatment related deaths. SVPE was associated with a higher 21-day transplant free-survival [75% vs. 45%; P = .04, HR 0.30, 95%CI 0.01-0.88]. A significant decrease in levels of pro-inflammatory cytokines and an increase in anti-inflammatory cytokines along with a decrease in endotoxin and DAMPs was seen with SVPE. CONCLUSION: In ALF patients with cerebral edema, SVPE is safe and effective and improves survival possibly by a reduction in cytokine storm and ammonia. CLINICALTRIAL: gov (identifier: NCT02718079).

Pediatric lung transplantation for COVID-19: Unique clinical and psychosocial barriers.

BACKGROUND: SARS-CoV-2 infection in the age group of 0-17 years contributes to approximately 22% of all laboratory-confirmed SARS-CoV-2 infections. Fortunately, this age group has a lower death rate (0.5 per 100 000) that accounts for only 4% of the total deaths due to COVID-19. Despite the low mortality rate in the pediatric population, children of minority groups represented 78% of the deaths highlighting the existing disparities in access to health care. METHODS: With the emergence of the more contagious COVID-19 variants and the relatively slow pace of vaccination among the pediatric population, it is possible to see more cases of significant lung injury and potential for transplantation for the younger age group. RESULTS: To our knowledge, our patient is the youngest to have undergone lung transplantation for SARS-CoV-2. CONCLUSION: The case presented unique challenges, particularly in relation to timing for listing and psychosocial support for parents who were his decision makers.

Insights into the Role of Granulocyte Colony-Stimulating Factor in Severe Alcoholic Hepatitis.

Alcohol use disorder is the predominant cause of chronic liver disease globally. The standard of care for the treatment of alcoholic hepatitis, corticosteroids, has been shown to provide a therapeutic response in ∼60% of carefully selected patients with a short-term survival benefit. The patients who do not respond to steroids, or are ineligible due to infections or very severe disease, have little options other than liver transplantation. There is, thus, a large unmet need for new therapeutic strategies for this large and sick group of patients. Granulocyte colony stimulating factor (G-CSF) has been shown to favorably modulate the intrahepatic immune milieu and stimulate the regenerative potential of the liver. Initial studies have shown encouraging results with G-CSF in patients with severe alcoholic hepatitis. It has also been found to help steroid nonresponsive patients. There is, however, a need for careful selection of patients, regular dose monitoring and close observation for adverse events of G-CSF. In this review, we analyze the basis of the potential benefits, clinical studies, cautions and challenges in the use of G-CSF in alcoholic hepatitis.

Therapeutic plasma-exchange improves systemic inflammation and survival in acute-on-chronic liver failure: A propensity-score matched study from AARC.

BACKGROUND AND AIM: Plasma-exchange (PE) has improved survival in acute liver failure by ameliorating systemic inflammatory response syndrome (SIRS). We evaluated PE and compared it to Fractional Plasma Separation and Adsorption (FPSA) and standard medical treatment (SMT) in a large multinational cohort of ACLF patients. METHODS: Data were prospectively collected from the AARC database and analysed. Matching by propensity risk score (PRS) was performed. Competing risk survival analysis was done to identify deaths because of multiorgan failure (MOF). In a subset of 10 patients, we also evaluated the mechanistic basis of response to PE. RESULTS: ACLF patients (n = 1866, mean age 44.3 ± 12.3 yrs, 93% males, 65% alcoholics) received either artificial liver support (ALS) (n = 162); [PE (n = 131), FPSA (n = 31)] or were continued on standard medical therapy (SMT) (n = 1704). In the PRS-matched cohort (n = 208, [ALS-119; PE-94, FPSA-25)], SMT-89). ALS therapies were associated with a significantly higher resolution of SIRS (Odd's ratio 9.23,3.42-24.8), lower and delayed development of MOF (Hazard ratio 7.1, 4.5-11.1), and lower liver-failure-related deaths as compared to FPSA and SMT (P < .05). PE cleared inflammatory cytokines, damage-associated molecular patterns, and endotoxin in all patients. Responders improved monocyte phagocytic function and mitochondrial respiration and increased the anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1RA) compared to non-responders. PE was associated with lesser adverse effects as compared to FPSA. CONCLUSIONS: PE improves systemic inflammation and lowers the development of MOF in patients with ACLF. Plasma-exchange provides significant survival benefit over FPSA and could be a preferred modality of liver support for ACLF patients.

Circulating extracellular vesicles induce monocyte dysfunction and are associated with sepsis and high mortality in cirrhosis.

BACKGROUND: Sepsis is common in cirrhosis and is often a result of immune dysregulation. Specific stimuli and pathways of inter-cellular communications between immune cells in cirrhosis and sepsis are incompletely understood. Immune cell-derived extracellular vesicles (EV) were studied to understand mechanisms of sepsis in cirrhosis. METHODS: Immune cell-derived EV were measured in cirrhosis patients [Child-Turcotte-Pugh (Child) score A, n = 15; B n = 16; C n = 43 and Child-C with sepsis (n = 38)], and healthy controls (HC, n = 11). In vitro and in vivo functional relevance of EV in cirrhosis and associated sepsis was investigated. RESULTS: Monocyte, neutrophil and hematopoietic stem cells associated EV progressively increased with higher Child score (P < .001)and correlated with liver disease severity indices (r2  > 0.3, P < .001), which further increased in Child C sepsis than without sepsis(P < .001); monocyte EV showing the highest association with disease stage [P = .013; Odds ratio-4.14(1.34-12.42)]. A threshold level of monocyte EV of 53/µl predicted mortality in patients of Child C with sepsis [Odds ratio-6.2 (2.4-15.9), AUROC = 0.76, P < .01]. In vitro EV from cirrhotic with sepsis compared without sepsis, induced mobilization arrest in healthy monocytes within 4 hours (P = .004), reduced basal oxygen consumption rate (P < .001) and induced pro-inflammatory genes (P < .05). The septic-EV on adoptive transfer to C57/BL6J mice, induced sepsis-like condition within 24 h with leukocytopenia (P = .005), intrahepatic inflammation with increased CD11b + cells (P = .03) and bone marrow hyperplasia (P < .01). CONCLUSION: Extracellular vesicles induce functional impairment in circulating monocytes and contribute to the development and perpetuation of sepsis. High levels of monocyte EV correlate with mortality and can help early stratification of sicker patients.

Flexible nickel disulfide nanoparticles-anchored carbon nanofiber hybrid mat as a flexible binder-free cathode for solid-state asymmetric supercapacitors.

Nickel disulfide nanoparticles (NiS2NPs)-anchored carbon nanofibers (NiS2NPs@CNF) hybrid mats were fabricated via the sequential process of stabilization and carbonization of electrospun polyacrylonitrile-based fibers followed by hydrothermal growth of NiS2NPs on the porous surface of CNFs. The vertical growth of NiS2NPs on entire surfaces of porous CNFs appeared in the SEM images of hybrid mat. The hierarchical NiS2NPs@CNF core-shell hybrid nanofibers with 3D interconnected network architecture can endow continuous channels for easy and rapid ionic diffusion to access the electroactive NiS2NPs. The conductive and interconnected CNF core could facilitate electron transfer to the NiS2shell. Moreover, the porous CNF as a buffering matrix can resist volumetric deformation during the long-term charge-discharge process. The NiS2NPs@CNF electrode can yield high specific capacitance (916.3 F g-1at 0.5 A g-1) and reveal excellent cycling performances. The solid-state asymmetric supercapacitor (ASC) was fabricated with NiS2NPs@CNF mat as a binder-free positive electrode and activated carbon cloth as a negative electrode. As-assembled ASC not only produce high specific capacitance (364.8 F g-1at 0.5 A g-1) but also exhibit excellent cycling stability (∼92.8% after 5000 cycles). The ASC delivered a remarkably high energy density of 129.7 Wh kg-1at a power density of 610 W kg-1. These encouraging results could make this NiS2NPs@CNF hybrid mat a good choice of cathode material for the fabrication of flexible solid-state ASC for various flexible/wearable electronics.

Mitochondrial Dysfunction in Heart Failure With Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome with an increasingly recognized heterogeneity in pathophysiology. Exercise intolerance is the hallmark of HFpEF and appears to be caused by both cardiac and peripheral abnormalities in the arterial tree and skeletal muscle. Mitochondrial abnormalities can significantly contribute to impaired oxygen utilization and the resulting exercise intolerance in HFpEF. We review key aspects of the complex biology of this organelle, the clinical relevance of mitochondrial function, the methods that are currently available to assess mitochondrial function in humans, and the evidence supporting a role for mitochondrial dysfunction in the pathophysiology of HFpEF. We also discuss the role of mitochondrial function as a therapeutic target, some key considerations for the design of early-phase clinical trials using agents that specifically target mitochondrial function to improve symptoms in patients with HFpEF, and ongoing trials with mitochondrial agents in HFpEF.

Early cirrhosis and a preserved bone marrow niche favour regenerative response to growth factors in decompensated cirrhosis.

BACKGROUND: Exogenous growth factor-mobilized bone marrow (BM) stem cells have shown a differential response in the management of decompensated cirrhosis (DC). This study was designed to evaluate potential clinical benefit of adding Erythropoietin (EPO) in granulocyte-colony stimulating factor (G-CSF)-mobilized stem cell therapy, possible mechanisms of regeneration and predictive factors of regenerative response. METHODS: Sixty consecutive DC patients received either G-CSF with EPO (Group A; n = 30) or G-CSF and placebo (Group B; n = 30) for 2 months and were carefully followed up for 1 year. Baseline and post-treatment liver biopsy, BM biopsy and BM aspirate were analysed for fibro-inflammatory and regenerative response and BM hematopoietic reservoir. RESULTS: Addition of EPO to G-CSF showed a significant improvement in Child-Pugh score (P = 0.03) and MELD score (P = 0.003) as compared to G-CSF alone, with reduction in mortality (16.6% vs 36.7%, P = 0.09). The combination arm also demonstrated a decreased incidence of acute kidney injury (P < 0.001), encephalopathy (P = 0.005) and refilling of ascites (P = 0.03). Compared to monotherapy, it increased CD163+ macrophages (P = 0.013), Ki67+ index (P < 0.001) with decrease in α-SMA levels (P < 0.001) in liver tissue. The response was better with grade 1 and 2 than with grade 3 ascites; Child B cirrhosis and MELD < 16. Non-responders had lower hematopoietic stem cells (HSCs) at baseline. On multivariate analysis, the liver disease severity (MELD < 16) and a relatively preserved BM (BM-HSCs > 0.4) predicted therapeutic response (AUROC = 0.82). CONCLUSIONS: Early DC (MELD < 16) patients with mild-moderate ascites and those with a healthy cellular baseline BM respond better to growth factor therapy. Addition of EPO to G-CSF provides better regenerative response than G-CSF monotherapy.

Identification of miR-379/miR-656 (C14MC) cluster downregulation and associated epigenetic and transcription regulatory mechanism in oligodendrogliomas.

INTRODUCTION: Although role of individual microRNAs (miRNAs) in the pathogenesis of gliomas has been well studied, their role as a clustered remains unexplored in gliomas. METHODS: In this study, we performed the expression analysis of miR-379/miR-656 miRNA-cluster (C14MC) in oligodendrogliomas (ODGs) and also investigated the mechanism underlying modulation of this cluster. RESULTS: We identified significant downregulation of majority of the miRNAs from this cluster in ODGs. Further data from The Cancer Genome Atlas (TCGA) also confirmed the global downregulation of C14MC. Furthermore, we observed that its regulation is maintained by transcription factor MEF2. In addition, epigenetic machinery involving DNA and histone-methylation are also involved in its regulation, which is acting independently or in synergy. The post- transcriptionally regulatory network of this cluster showed enrichment of key cancer-related biological processes such as cell adhesion and migration. Also, there was enrichment of several cancer related pathways viz PIK3 signaling pathway and glioma pathways. Survival analysis demonstrated association of C14MC (miR-487b and miR-409-3p) with poor progression free survival in ODGs. CONCLUSION: Our work demonstrates tumor-suppressive role of C14MC and its role in pathogenesis of ODGs and therefore could be relevant for the development of new therapeutic strategies.

Donor CD163 and nestin-positive cells predict graft function in living donor liver transplant.

AIMS: To evaluate the effect of donor liver resident mesenchymal cells, M2 macrophages on liver graft outcome after living donor liver transplantation. MATERIALS AND METHODS: Seventy donor biopsies were included in the study. Outcomes at day 3, 7, 30, and 180 postliver transplantation were assessed. Mesenchymal stem cells and M2 macrophages in donor liver biopsies were evaluated. RESULTS: Mean age of recipients was 40.9 ± 13.6 years. Sex mismatched transplants were 44 (M→F = 9; F→M = 35). On area under receiver operative curve analysis, donor biopsy (DB) nestin ≥3 and CD 163 ≥ 32/200x at day 3; CD163 ≥ 32 at day 7; CD 163 > 32, pRBC of <6.5 units at day 30, and DB nestin ≥3, CD 163 ≥ 32 and pRBC<6.5 units at day 180 predicted adequate graft functions. On multivariate analysis, higher DB nestin (P = .009) and lower cryoprecipitate (P = .009) usage at day 3, higher DB CD163 (P = .006) at day 7, higher DB CD163 (P = .018) and reduced transfusion of packed cell (pRBC) (P = .014) at day 30 and higher DB nestin (P = .011), higher CD163 (P = .009), and reduced pRBC (P = .045) at day 180 were the predictors of better outcome. CONCLUSIONS: Donor liver biopsy nestin+ and CD163+ can predict early graft outcome in living donor liver transplantation.

Clinicopathological and molecular characteristics of pediatric meningiomas.

Molecular and clinical characteristics of pediatric meningiomas are poorly defined. Therefore, we analyzed clinical, morphological and molecular profiles of pediatric meningiomas. Forty pediatric meningiomas from January 2002 to June 2015 were studied. 1p36, 14q32 and 22q-deletion were assessed by fluorescent in situ hybridization and mutations of most relevant exons of AKT, SMO, KLF4, TRAF and pTERT using sequencing. Expression of GAB1, stathmin, progesterone receptor (PR), p53 along with MIB-1 LI was examined using immunohistochemistry. There were 36 sporadic and four NF2 associated meningiomas. Among sporadic meningiomas, the majority (72.2%) of cases harbored 22q-deletion. Difference in frequency of combined 1p/14q deletion in Grade-I versus Grade-II/III tumors was not significant (13.7% vs 28.5%, P = 0.57). PR immunoreactivity was seen in 65.5% of Grade-I and 14.2% of Grade-II/III tumors (P = 0.03). The majority (97.2%) of meningiomas were immunonegative for p53. Stathmin and GAB co-expression was observed in 58.3% of cases. Notably, AKT, SMO, KLF4, TRAF7 (exon 17) and pTERT mutations were seen in none of the cases analyzed. 1p/14q codeletion was frequent in skull base as compared to non-skull base meningiomas (23% vs 11.1%, P = 0.37). All NF2 meningiomas harbored 22q-deletion and showed GAB and stathmin co-expression while none showed 1p/14q loss. Pediatric meningiomas share certain phenotypic and cytogenetic characteristics with adult counterparts, but GAB and stathmin co-expression in the majority of cases and non-significant difference in frequency of 1p/14q co-deletion between low- and high-grade meningiomas indicate an inherently aggressive nature. Characteristic AKT/SMO, KLF4/TRAF7 and pTERT genetic alterations seen in adults are distinctly absent in pediatric meningiomas.

Telomerase reverse transcriptase (TERT) - enhancer of zeste homolog 2 (EZH2) network regulates lipid metabolism and DNA damage responses in glioblastoma.

Elevated expression of enhancer of zeste homolog 2 (EZH2), a histone H3K27 methyltransferase, was observed in gliomas harboring telomerase reverse transcriptase (TERT) promoter mutations. Given the known involvement of TERT and EZH2 in glioma progression, the correlation between the two and subsequently its involvement in metabolic programming was investigated. Inhibition of human telomerase reverse transcriptase either pharmacologically or through genetic manipulation not only decreased EZH2 expression, but also (i) abrogated FASN levels, (ii) decreased de novo fatty acid accumulation, and (iii) increased ataxia-telangiectasia-mutated (ATM) phosphorylation levels. Conversely, diminished TERT and FASN levels upon siRNA-mediated EZH2 knockdown indicated a positive correlation between TERT and EZH2. Interestingly, ATM kinase inhibitor rescued TERT inhibition-mediated decrease in FASN and EZH2 levels. Importantly, TERT promoter mutant tumors exhibited greater microsatellite instability, heightened FASN levels and lipid accumulation. Coherent with in vitro findings, pharmacological inhibition of TERT by costunolide decreased lipid accumulation and elevated ATM expression in heterotypic xenograft glioma mouse model. By bringing TERT-EZH2 network at the forefront as driver of dysregulated metabolism, our findings highlight the non-canonical but distinct role of TERT in metabolic reprogramming and DNA damage responses in glioblastoma.

Bone marrow stem cells and their niche components are adversely affected in advanced cirrhosis of the liver.

UNLABELLED: Bone marrow (BM) is a reservoir for immune and hematopoietic cells and critical for tissue repair and regeneration. All of these functions are severely altered in cirrhosis. We investigated the cellular and functional state of BM in cirrhosis patients. We studied the histological, cellular, and molecular changes in BM of cirrhosis patients (n = 168) and controls (n = 44). Hematopoietic stem cells (HSCs) and associated niche cells, mesenchymal stem cells, Schwann cells, neural fibers, and endothelial cells were evaluated by immunohistochemistry. Cytokines and growth factors were analyzed in peripheral blood and BM plasma. Cirrhotic BM showed an inverse correlation between cluster of differentiation 34+HSCs and Model of End-Stage Liver Disease (ρ = -0.582, P < 0.001) and Child's scores (P < 0.038). BMs of cirrhosis patients with higher Model of End-Stage Liver Disease (>15) showed significantly decreased HSCs, mesenchymal stem cells, Schwann cells, and neural fibers; increased interleukin-1ß (P = 0.004), tumor necrosis factor-α (P = 0.040), and interferon-γ (P = 0.03); and decreased oncostatin M (P = 0.04), stem cell factor (P = 0.05), and stromal cell-derived factor 1 (P = 0.03) compared to those with lower Model of End-Stage Liver Disease scores (≤15). The cluster of differentiation 34+ cell population was a predictor for the development of sepsis (P < 0.001), and per unit loss increased the probability of sepsis by 16%. Cirrhosis patients with fewer HSCs had lower hemoglobin (P = 0.05) and platelet counts (P = 0.05) and showed early graft dysfunction. CONCLUSIONS: Increasing severity of cirrhosis causes derangement of the hematopoietic niche and loss of HSCs, contributing to the hematological and immunological dysfunctions and reduced potential for regeneration; restoring BM functions could provide new therapeutic options in cirrhosis. (Hepatology 2016;64:1273-1288).