CD81 Controls Beige Fat Progenitor Cell Growth and Energy Balance via FAK Signaling.

Adipose tissues dynamically remodel their cellular composition in response to external cues by stimulating beige adipocyte biogenesis; however, the developmental origin and pathways regulating this process remain insufficiently understood owing to adipose tissue heterogeneity. Here, we employed single-cell RNA-seq and identified a unique subset of adipocyte progenitor cells (APCs) that possessed the cell-intrinsic plasticity to give rise to beige fat. This beige APC population is proliferative and marked by cell-surface proteins, including PDGFRα, Sca1, and CD81. Notably, CD81 is not only a beige APC marker but also required for de novo beige fat biogenesis following cold exposure. CD81 forms a complex with αV/ß1 and αV/ß5 integrins and mediates the activation of integrin-FAK signaling in response to irisin. Importantly, CD81 loss causes diet-induced obesity, insulin resistance, and adipose tissue inflammation. These results suggest that CD81 functions as a key sensor of external inputs and controls beige APC proliferation and whole-body energy homeostasis.

Thermal stress induces glycolytic beige fat formation via a myogenic state.

Environmental cues profoundly affect cellular plasticity in multicellular organisms. For instance, exercise promotes a glycolytic-to-oxidative fibre-type switch in skeletal muscle, and cold acclimation induces beige adipocyte biogenesis in adipose tissue. However, the molecular mechanisms by which physiological or pathological cues evoke developmental plasticity remain incompletely understood. Here we report a type of beige adipocyte that has a critical role in chronic cold adaptation in the absence of ß-adrenergic receptor signalling. This beige fat is distinct from conventional beige fat with respect to developmental origin and regulation, and displays enhanced glucose oxidation. We therefore refer to it as glycolytic beige fat. Mechanistically, we identify GA-binding protein α as a regulator of glycolytic beige adipocyte differentiation through a myogenic intermediate. Our study reveals a non-canonical adaptive mechanism by which thermal stress induces progenitor cell plasticity and recruits a distinct form of thermogenic cell that is required for energy homeostasis and survival.

BCAA catabolism in brown fat controls energy homeostasis through SLC25A44.

Branched-chain amino acid (BCAA; valine, leucine and isoleucine) supplementation is often beneficial to energy expenditure; however, increased circulating levels of BCAA are linked to obesity and diabetes. The mechanisms of this paradox remain unclear. Here we report that, on cold exposure, brown adipose tissue (BAT) actively utilizes BCAA in the mitochondria for thermogenesis and promotes systemic BCAA clearance in mice and humans. In turn, a BAT-specific defect in BCAA catabolism attenuates systemic BCAA clearance, BAT fuel oxidation and thermogenesis, leading to diet-induced obesity and glucose intolerance. Mechanistically, active BCAA catabolism in BAT is mediated by SLC25A44, which transports BCAAs into mitochondria. Our results suggest that BAT serves as a key metabolic filter that controls BCAA clearance via SLC25A44, thereby contributing to the improvement of metabolic health.

Top Hepatobiliary Articles from 2022 to Inform Your Cancer Practice.

Until recently, there have been only modest therapeutic advances in the treatment of hepatobiliary malignancies. However, the introduction of immune checkpoint inhibitors in combination with targeted therapy or chemotherapy has changed the therapeutic landscape of hepatocellular carcinoma and biliary tract cancers. As such, revisions have been made to guidelines reflecting therapeutic advances for patients who can be considered for surgical options including resection and liver transplantation. This article highlights recently published studies that have impacted both the oncological and surgical approach to the treatment of patients with hepatobiliary malignancies.

Brown fat thermogenesis and branched-chain amino acids in metabolic disease.

Since the 1960s, researchers have recognized an association between elevated plasma branched chain amino acids (BCAA) and metabolic disease, including type 2 diabetes mellitus and obesity, but the cause for it remained poorly understood. Recent advances in metabolomics, advanced imaging techniques, and genetic analyses over the past decade have enabled newfound insights into the mechanism of BCAA metabolic dysregulation across a variety of peripheral tissues and its impact on metabolic disease, suggesting a key role for brown adipose tissue (BAT) in determining BCAA metabolic homeostasis. Previous investigations into BAT have emphasized fatty acids and glucose as substrates for BAT thermogenesis. Here, we address the importance of BAT in systemic BCAA metabolism, driven via the newly identified mitochondrial BCAA carrier (MBC), as well as the impact of BAT-driven BCAA clearance on glucose homeostasis and metabolic disease. The newly identified MBC offers new therapeutic avenues by which BAT activity may be enhanced to improve metabolic and cardiovascular health, as well as other diseases in which increases of circulating BCAA may play a role in pathogenicity.

Comparison of tumor response and outcomes of patients with hepatocellular carcinoma after multimodal treatment including immune checkpoint inhibitors - a systematic review and meta-analysis.

BACKGROUND: The efficacy of immune checkpoint inhibitors (ICIs) combined with tyrosine kinase inhibitors (TKIs), trans-arterial chemoembolization (TACE), and radiotherapy to treat hepatocellular carcinoma (HCC) has not been well-defined. We performed a meta-analysis to characterize tumor response and survival associated with multimodal treatment of HCC. METHODS: PubMed, Embase, Medline, Scopus, and CINAHL databases were searched (1990-2022). Random-effect meta-analysis was conducted to compare efficacy of treatment modalities. Odds ratios (OR) and standardized mean difference (SMD) were reported. RESULTS: Thirty studies (4170 patients) met inclusion criteria. Triple therapy regimen (ICI + TKI + TACE) had the highest overall disease control rate (DCR) (87%, 95% CI 83-91), while ICI + radiotherapy had the highest objective response rate (ORR) (72%, 95% CI 54%-89%). Triple therapy had a higher DCR than ICI + TACE (OR 4.49, 95% CI 2.09-9.63), ICI + TKI (OR 3.08, 95% CI 1.63-5.82), and TKI + TACE (OR 2.90, 95% CI 1.61-5.20). Triple therapy demonstrated improved overall survival versus ICI + TKI (SMD 0.72, 95% CI 0.37-1.07) and TKI + TACE (SMD 1.13, 95% CI 0.70-1.48) (both p < 0.05). Triple therapy had a greater incidence of adverse events (AEs) compared with ICI + TKI (OR 0.59, 95% CI 0.29-0.91; p = 0.02), but no difference in AEs versus ICI + TACE or TKI + TACE (both p > 0.05). CONCLUSION: The combination of ICIs, TKIs and TACE demonstrated superior tumor response and survival and should be considered for select patients with advanced HCC.

Comparison of Standard Versus Intermediate Prophylaxis Dose for Venous Thromboembolism Prophylaxis in Patients Hospitalized With COVID-19 Infection.

Background: COVID-19 infection is associated with a high risk of venous thromboembolism (VTE) events. VTE prophylaxis reduces the risk of these events. The optimal dose of VTE prophylaxis however remains uncertain. Objectives: To compare the incidence of VTE in patients treated with either standard dose VTE versus intermediate dose VTE prophylaxis. Methods: In this retrospective cohort study, we analyzed data from 1786 adult patients admitted into the hospital with polymerase chain reaction confirmed COVID-19 infection between April 2020 to September 2021. For analysis, patients were divided into 2 cohorts: either standard dose prophylaxis treatment group (patients who received either unfractionated heparin 5000units 3 times a day or enoxaparin 30-40 mg daily subcutaneously) or intermediate dose VTE prophylaxis group (patients received either unfractionated heparin 7500 units 3 times daily or enoxaparin 30-40 mg twice a day subcutaneously). The primary outcome was incidence of VTE events described as either deep vein thrombosis (DVT) or pulmonary embolism (PE). Secondary outcome was bleeding events. Results: During the study period, 398 (22%) patients were primarily treated with standard dose VTE prophylaxis, whereas 1388 (78%) patients were treated with intermediate dose VTE prophylaxis. There was a significantly higher incidence of venous thromboembolism events noted in the standard dose prophylaxis treatment group when compared with the intermediate dose prophylaxis group (25/398 (6.3%) vs 35/1388 (2.5%) P < .001, [Odds Ratio 2.6197, 95% confidence interval = 1.5482-4.4327]). Multivariable-adjusted logistic regression, adjusting for age, obesity, and smoking, with the intermediate dose prophylaxis treatment group as the referent category revealed higher odds for incident venous thromboembolism events in the standard dose prophylaxis group. There was no statistically significant difference in bleeding events between the 2 treatment groups (9 (2.3%) for standard dose prophylaxis group vs 46 (3.3%) for intermediate dose prophylaxis group P = .26). Conclusions: Among patients hospitalized with COVID-19 infection, patients receiving intermediate dose VTE prophylaxis experienced lower incident rates of venous thromboembolism events compared to those receiving standard dose VTE prophylaxis without a statistically significant increase in the risk of bleeding events.

Chemoproteomics Yields a Selective Molecular Host for Acetyl-CoA.

Chemoproteomic profiling is a powerful approach to define the selectivity of small molecules and endogenous metabolites with the human proteome. In addition to mechanistic studies, proteome specificity profiling also has the potential to identify new scaffolds for biomolecular sensing. Here, we report a chemoproteomics-inspired strategy for selective sensing of acetyl-CoA. First, we use chemoproteomic capture experiments to validate the N-terminal acetyltransferase NAA50 as a protein capable of differentiating acetyl-CoA and CoA. A Nanoluc-NAA50 fusion protein retains this specificity and can be used to generate a bioluminescence resonance energy transfer (BRET) signal in the presence of a CoA-linked fluorophore. This enables the development of a ligand displacement assay in which CoA metabolites are detected via their ability to bind the Nanoluc-NAA50 protein "host" and compete binding of the CoA-linked fluorophore "guest". We demonstrate that the specificity of ligand displacement reflects the molecular recognition of the NAA50 host, while the window of dynamic sensing can be controlled by tuning the binding affinity of the CoA-linked fluorophore guest. Finally, we show that the method's specificity for acetyl-CoA can be harnessed for gain-of-signal optical detection of enzyme activity and quantification of acetyl-CoA from cellular samples. Overall, our studies demonstrate the potential of harnessing insights from chemoproteomics for molecular sensing and provide a foundation for future applications in target engagement and selective metabolite detection.

Disparities in Care Access to Liver-Directed Therapy Among Medicare Beneficiaries with Colorectal Cancer Liver Metastasis.

BACKGROUND: Liver-directed therapies (LDT) are important components of the multidisciplinary care of patients with colorectal cancer liver metastases (CRCLM) that contribute to improved long-term outcomes. Factors associated with receipt of LDT are poorly understood. PATIENTS AND METHODS: Patients > 65 years old diagnosed with CRCLM were identified within the Medicare Standard Analytic File (2013-2017). Patients with extrahepatic metastatic disease were excluded. Mixed-effects analyses were used to assess patient factors associated with the primary outcome of LDT, defined as hepatectomy, ablation, and/or hepatic artery infusion chemotherapy (HAIC), as well as the secondary outcome of hepatectomy. RESULTS: Among 23,484 patients with isolated CRCLM, only 2004 (8.5%) received LDT, although resectability status could not be determined for the entire cohort. Among patients who received LDT, 61.7% underwent hepatectomy alone, 28.1% received ablation alone, 8.5% underwent hepatectomy and ablation, and 1.8% received HAIC either alone (0.8%) or in combination with hepatectomy and/or ablation (0.9%). Patient factors independently associated with lower odds of LDT included older age, female sex, Black race, greater comorbidity burden, higher social vulnerability index, primary rectal cancer, synchronous liver metastasis, and further distance from a high-volume liver surgery center (p < 0.05). Results were similar for receipt of hepatectomy. CONCLUSIONS: Despite the well-accepted role of LDT for CRCLM, only a small proportion of Medicare beneficiaries with CRCLM receive LDT. Increasing access to specialized centers with expertise in LDT, particularly for Black patients, female patients, and those with higher levels of social vulnerability or long travel distances, may improve outcomes for patients with CRCLM.

Application of Hazard Function to Investigate Recurrence of Intrahepatic Cholangiocarcinoma After Curative-Intent Liver Resection: A Novel Approach to Characterize Recurrence.

PURPOSE: To investigate recurrence patterns after surgery for intrahepatic cholangiocarcinoma (ICC) relative to lymph node status, tumor extension, tumor burden score (TBS), and adjuvant chemotherapy. METHODS: Patients who underwent curative-intent resection for ICC from 1990 to 2020 were enrolled from a multi-institutional database. The hazard function was applied to plot the hazard rates over time, with further stratification by T and N AJCC 8th edition categories, TBS, and adjuvant chemotherapy. RESULTS: A total of 1192 patients underwent curative-intent resection for ICC and 59.9% experienced recurrence. Overall, the peak of recurrence occurred at 6.6 months. Among patients with negative lymph nodes, the T4-category had a higher peak rate of recurrence (0.1199 at 10.2 months) compared with other T-categories, while high TBS had an earlier peak of recurrence (4.2 months) compared with lower TBS. Among patients with N1 disease, T2-T4 categories had multipeak patterns of recurrence with higher hazard rates during the first 3 years after surgery in comparison with T1-category, while patients with high TBS had an earlier (4.0 months) and higher hazard peak rate compared with lower TBS groups. The administration of adjuvant chemotherapy was associated with delayed hazard rates of recurrence for N1 (4 months) and NX (6 months) categories. DISCUSSION: The novel application of the hazard function to assess hazard rates and timing patterns of recurrence following resection for ICC demonstrated that recurrence varied based on T- and N-categories, as well as TBS. Hazard function-based recurrence data may be helpful to tailor counseling, surveillance, and adjuvant therapy recommendations.

Military and Civilian Trauma System Integration: A Global Case Series.

INTRODUCTION: Traumatic injury is a leading cause of morbidity globally, particularly in low-income and middle-income countries (LMICs). In high-income countries (HICs), it is well documented that military and civilian integration can positively impact trauma care in both healthcare systems, but it is unknown if this synergy could benefit LMICs. This case series examines the variety of integration between the civilian and military systems of various countries and international partnerships to elucidate if there are commonalities in facilitators and barriers. METHODS: A convenience sampling method was utilized to identify subject matter experts on civilian and military trauma system integration. Data were collected and coded through an iterative process, focusing on the historical impetuses and subsequent outcomes of civilian and military trauma care collaboration. RESULTS: Eight total case studies were completed, five addressing specific countries and three addressing international partnerships. Themes which emerged as drivers for integration included history of conflict, geography, and skill maintenance for military physicians. High-level government support was a central theme for successful integration, and financial issues were often seen as the greatest barrier. CONCLUSIONS: Various approaches in civilian-military integration exist throughout the world, and the studied nations and international partnerships demonstrated similar motivators and barriers to integration. This study highlights the need for further investigation, particularly in LMICs, where less is known about integration strategies.

ISWI chromatin remodellers sense nucleosome modifications to determine substrate preference.

ATP-dependent chromatin remodellers regulate access to genetic information by controlling nucleosome positions in vivo. However, the mechanism by which remodellers discriminate between different nucleosome substrates is poorly understood. Many chromatin remodelling proteins possess conserved protein domains that interact with nucleosomal features. Here we used a quantitative high-throughput approach, based on the use of a DNA-barcoded mononucleosome library, to profile the biochemical activity of human ISWI family remodellers in response to a diverse set of nucleosome modifications. We show that accessory (non-ATPase) subunits of ISWI remodellers can distinguish between differentially modified nucleosomes, directing remodelling activity towards specific nucleosome substrates according to their modification state. Unexpectedly, we show that the nucleosome acidic patch is necessary for maximum activity of all ISWI remodellers evaluated. This dependence also extends to CHD and SWI/SNF family remodellers, suggesting that the acidic patch may be generally required for chromatin remodelling. Critically, remodelling activity can be regulated by modifications neighbouring the acidic patch, signifying that it may act as a tunable interaction hotspot for ATP-dependent chromatin remodellers and, by extension, many other chromatin effectors that engage this region of the nucleosome surface.

Crop rotation mitigates impacts of corn rootworm resistance to transgenic Bt corn.

Transgenic crops that produce insecticidal proteins from Bacillus thuringiensis (Bt) can suppress pests and reduce insecticide sprays, but their efficacy is reduced when pests evolve resistance. Although farmers plant refuges of non-Bt host plants to delay pest resistance, this tactic has not been sufficient against the western corn rootworm, Diabrotica virgifera virgifera In the United States, some populations of this devastating pest have rapidly evolved practical resistance to Cry3 toxins and Cry34/35Ab, the only Bt toxins in commercially available corn that kill rootworms. Here, we analyzed data from 2011 to 2016 on Bt corn fields producing Cry3Bb alone that were severely damaged by this pest in 25 crop-reporting districts of Illinois, Iowa, and Minnesota. The annual mean frequency of these problem fields was 29 fields (range 7 to 70) per million acres of Cry3Bb corn in 2011 to 2013, with a cost of $163 to $227 per damaged acre. The frequency of problem fields declined by 92% in 2014 to 2016 relative to 2011 to 2013 and was negatively associated with rotation of corn with soybean. The effectiveness of corn rotation for mitigating Bt resistance problems did not differ significantly between crop-reporting districts with versus without prevalent rotation-resistant rootworm populations. In some analyses, the frequency of problem fields was positively associated with planting of Cry3 corn and negatively associated with planting of Bt corn producing both a Cry3 toxin and Cry34/35Ab. The results highlight the central role of crop rotation for mitigating impacts of D. v. virgifera resistance to Bt corn.

Management of adult renal trauma: a practice management guideline from the eastern association for the surgery of trauma.

BACKGROUND: The kidney is the most frequently injured component of the genitourinary system, accounting for 5% of all trauma cases. Several guidelines by different societies address the management of urological trauma. However, unanswered questions remain regarding optimal use of angioembolization in hemodynamically stable patients, indications for operative exploration of stable retroperitoneal hematomas and renal salvage techniques in the setting of hemodynamic instability, and imaging practices for patients undergoing non-operative management. We performed a systematic review, meta-analysis, and developed evidence-based recommendations to answer these questions in both blunt and penetrating renal trauma. METHODS: The working group formulated four population, intervention, comparator, outcome (PICO) questions regarding the following topics: (1) angioembolization (AE) usage in hemodynamically stable patients with evidence of ongoing bleeding; (2) surgical approach to stable zone II hematomas (exploration vs. no exploration) in hemodynamically unstable patients and (3) surgical technique (nephrectomy vs. kidney preservation) for expanding zone II hematomas in hemodynamically unstable patients; (4) frequency of repeat imaging (routine or symptom based) in high-grade traumatic renal injuries. A systematic review and meta-analysis of currently available evidence was performed. RevMan 5 (Cochran Collaboration) and GRADEpro (Grade Working Group) software were used. Recommendations were voted on by working group members and concurrence was obtained for each final recommendation. RESULTS: A total of 20 articles were identified and analyzed. Two prospective studies were encountered; the majority were retrospective, single-institution studies. Not all outcomes projected by PICO questions were reported in all studies. Meta-analysis was performed for all PICO questions except PICO 3 secondary to the discrepant patient populations included in those studies. PICO 1 had the greatest number of articles included in the meta-analysis with nine studies; yet, due to differences in study design, no critical outcomes emerged; similar differences among a smaller set of articles prevented observation of critical outcomes for PICO 4. Analyses of PICOs 2 and 3 favored a non-invasive or minimally invasive approach in-line with current international practice trends. CONCLUSION: In hemodynamically stable adult patients with clinical or radiographic evidence of ongoing bleeding, no recommendation could be made regarding the role of AE vs. observation. In hemodynamically unstable adult patients, we conditionally recommend no renal exploration vs. renal exploration in stable zone II hematomas. In hemodynamically unstable adult patients, we conditionally recommend kidney preserving techniques vs. nephrectomy in expanding zone II hematomas. No recommendation could be made for the optimal timing of repeat imaging in high grade renal injury. LEVEL OF EVIDENCE: Guideline; systematic review, level III.

Diagnosis and management of choledochal cysts.

BACKGROUND: Choledochal cysts (CCs) are rare cystic dilatations of the intrahepatic and/or extrahepatic bile ducts. We review the pathophysiology, diagnosis, and management of CCs. METHODS: MEDLINE/PubMed and Web of Science databases were queried for "choledochal cyst", "bile duct cyst", "choledochocele", and "Caroli disease". Data were synthesized and systematically reviewed. RESULTS: Classified according to the Todani Classification, CCs are generally believed to arise secondary to reflux of pancreatic enzymes into the biliary tree due to anomalous pancreaticobiliary duct union. Complications of CCs include abdominal pain, jaundice, cystolithiasis, cholecystitis, pancreatitis, liver abscess, liver cirrhosis and malignant transformation (3-7.5%). Radiological and endoscopic imaging is the cornerstone of CC diagnosis and full delineation of cyst anatomy is imperative for proper management. Management is generally guided by cyst classification with complete cyst excision necessary for CCs with high potential of malignant transformation such as types I and IV. 5-year overall survival after choledochal cyst excision is 95.5%. CONCLUSION: Most CCs should undergo surgical intervention to mitigate the risk of cyst related complications such as cholangitis and malignant transformation.

Application of hazard functions to investigate recurrence after curative-intent resection for hepatocellular carcinoma.

BACKGROUND: Defining patterns and risk of recurrence can help inform surveillance strategies and patient counselling. We sought to characterize peak hazard rates (pHR) and peak time of recurrence among patients who underwent resection of hepatocellular carcinoma (HCC). METHODS: 1434 patients who underwent curative-intent resection of HCC were identified from a multi-institutional database. Hazard, patterns, and peak rates of recurrence were characterized. RESULTS: The overall hazard of recurrence peaked at 2.4 months (pHR: 0.0384), yet varied markedly. The incidence of recurrence increased with Barcelona Clinic Liver Cancer (BCLC) stage 0 (29%), A (54%), and B (64%). While the hazard function curve for BCLC 0 patients was relatively flat (pHR: <0.0177), BCLC A patients recurred with a peak at 2.4 months (pHR: 0.0365). Patients with BCLC B had a bimodal recurrence with a peak rate at 4.2 months (pHR: 0.0565) and another at 22.8 months. The incidence of recurrence also varied according to AFP level (≤400 ng/mL: 52.6% vs. >400 ng/mL: 36.3%) and Tumor Burden Score (low: 73.7% vs. medium: 50.6% vs. high: 24.2%) (both p < 0.001). CONCLUSION: Recurrence hazard rates for HCC varied substantially relative to both time and intensity/peak rates. TBS and AFP markedly impacted patterns of hazard risk of recurrence.

Preoperative risk score (PreopScore) to predict overall survival after resection for hepatocellular carcinoma.

BACKGROUND: This study aimed to develop a holistic risk score incorporating preoperative tumor, liver, nutritional, and inflammatory markers to predict overall survival (OS) after hepatectomy for hepatocellular carcinoma (HCC). METHODS: Patients who underwent curative-intent surgery for HCC between 2000 and 2020 were identified using an international multi-institutional database. Preoperative predictors associated with OS were selected and a prognostic risk score model (PreopScore) was developed and validated using cross-validation. RESULTS: A total of 1676 patients were included. On multivariable analysis, preoperative parameters associated with OS included α-feto protein (hazard ratio [HR]1.17, 95%CI 1.03-1.34), neutrophil-to-lymphocyte ratio (HR2.62, 95%CI 1.30-5.30), albumin (HR0.49, 95%CI 0.34-0.70), gamma-glutamyl transpeptidase (HR1.00, 95%CI 1.00-1.00), as well as vascular involvement (HR3.52, 95%CI 2.10-5.89) and tumor burden score (medium, HR3.49, 95%CI 1.62-7.58; high, HR3.21, 95%CI 1.40-7.35) on preoperative imaging. A weighted PreopScore was devised and made available online (https://yutaka-endo.shinyapps.io/PrepoScore_Shiny/). Patients with a PreopScore 0-2, 2-3.5, and >3.5 had incrementally worse 5-year OS of 85.8%, 70.7%, and 52.4%, respectively (p < 0.001). The c-index of the test and validation cohort were 0.75 and 0.71, respectively. The PreopScore outperformed individual parameters and previous HCC staging systems. DISCUSSION: The PreopScore can be used as a better guide to preoperatively identify patients and individualize pre-/post-operative strategies.

Steatohepatitis Impairs T-cell-Directed Immunotherapies Against Liver Tumors in Mice.

BACKGROUND & AIMS: Nonalcoholic steatohepatitis causes loss of hepatic CD4+ T cells and promotes tumor growth. The liver is the most common site of distant metastases from a variety of malignancies, many of which respond to immunotherapy. We investigated the effects of steatohepatitis on the efficacy of immunotherapeutic agents against liver tumors in mice. METHODS: Steatohepatitis was induced by feeding C57BL/6NCrl or BALB/c AnNCr mice a methionine and choline-deficient diet or a choline-deficient l-amino acid-defined diet. Mice were given intrahepatic or subcutaneous injections of B16 melanoma and CT26 colon cancer cells, followed by intravenous injections of M30-RNA vaccine (M30) or intraperitoneal injections of an antibody against OX40 (aOX40) on days 3, 7, and 10 after injection of the tumor cells. We measured tumor growth and analyzed immune cells in tumor tissues by flow cytometry. Mice were given N-acetylcysteine to prevent loss of CD4+ T cells from liver. RESULTS: Administration of M30 and aOX40 inhibited growth of tumors from intrahepatic injections of B16 or CT26 cells in mice on regular diet. However, M30 and/or aOX40 did not slow growth of liver tumors from B16 or CT26 cells in mice with diet-induced steatohepatitis (methionine and choline-deficient diet or choline-deficient l-amino acid-defined diet). Steatohepatitis did not affect the ability of M30 to slow growth of subcutaneous B16 tumors. In mice with steatohepatitis given N-acetylcysteine, which prevents loss of CD4+ T cells, M30 and aOX40 were able slow growth of hepatic tumors. Flow cytometry analysis of liver tumors revealed reduced CD4+ T cells and effector memory cells in mice with vs without steatohepatitis. CONCLUSIONS: Steatohepatitis reduces the abilities of immunotherapeutic agents, such as M30 and aOX40, to inhibit tumor liver growth by reducing tumor infiltration by CD4+ T cells and effector memory cells. N-acetylcysteine restores T-cell numbers in tumors and increases the ability of M30 and aOX40 to slow tumor growth in mice.

The Relationship Between Atrial Fibrillation, Mitral Regurgitation, and Heart Failure Subtype: The ARIC Study.

BACKGROUND: Atrial fibrillation (AF) and mitral regurgitation (MR) are closely interrelated in the setting of heart failure (HF). Here we investigate the prevalence and prognostic significance of AF in patients with acute decompensated HF (ADHF) stratified by MR severity. METHODS AND RESULTS: The Atherosclerosis Risk in Communities Study investigated ADHF hospitalizations in residents greater than or equal to 55 years of age in 4 US communities. ADHF cases were stratified by MR severity (none/mild or moderate/severe) and HF subtype (HF with reduced [HFrEF] or preserved [HFpEF] ejection fraction). The odds of AF in patients with increasing MR severity was estimated using multivariable logistic regression, adjusting for age, race, sex, diabetes, hypertension, coronary artery disease, hemodialysis, stroke, and anemia. Cox regression models were used to assess the association of AF with 1-year mortality in patients with HFpEF and HFrEF, stratified by MR severity and adjusted as described, also adjusting for the year of hospitalization. From 2005 to 2014, there were 3,878 ADHF hospitalizations (17,931 weighted). AF was more likely in those with higher MR severity regardless of HF subtype; more so in HFpEF (odds ratio [OR] 1.38, 95% confidence interval [CI], 1.31-1.45) than in HFrEF (OR, 1.19, 95% CI, 1.13-1.25) (interaction P [by HF subtype] < .01). When stratified by HF type, association between AF and 1-year mortality was noted in patients with HFpEF (OR, 1.28, 95% CI 1.04-1.56) but not HFrEF (OR 0.96, 95% CI 0.79-1.16) (interaction by EF subtype, P = .02). CONCLUSIONS: In patients with ADHF, AF prevalence increased with MR severity and this effect was more pronounced in HFpEF compared with HFrEF. AF was associated with an increased 1-year mortality only in patients with HFpEF and concomitant moderate/severe MR. REGISTRATION: NCT00005131, https://clinicaltrials.gov/ct2/show/NCT00005131.

Surgical resection rates after neoadjuvant therapy for localized pancreatic ductal adenocarcinoma: meta-analysis.

BACKGROUND: Neoadjuvant therapy is increasingly being used before surgery for localized pancreatic cancer. Given the importance of completing multimodal therapy, the aim of this study was to characterize surgical resection rates after neoadjuvant therapy as well as the reasons for, and long-term prognostic impact of, not undergoing resection. METHODS: A systematic review and meta-analysis of prospective trials and high-quality retrospective studies since 2010 was performed to calculate pooled resection rates using a generalized random-effects model for potentially resectable, borderline resectable, and locally advanced pancreatic cancer. Median survival times were calculated using random-effects models for patients who did and did not undergo resection. RESULTS: In 125 studies that met the inclusion criteria, neoadjuvant therapy consisted of chemotherapy (36.8 per cent), chemoradiation (15.2 per cent), or chemotherapy and radiation (48.0 per cent). Among 11 713 patients, the pooled resection rates were 77.4 (95 per cent c.i. 71.3 to 82.5), 60.6 (54.8 to 66.1), and 22.2 (16.7 to 29.0) per cent for potentially resectable, borderline resectable, and locally advanced pancreatic cancer respectively. The most common reasons for not undergoing resection were distant progression for resectable and borderline resectable cancers, and local unresectability for locally advanced disease. Among 42 studies with survival data available, achieving surgical resection after neoadjuvant therapy was associated with improved survival for patients with potentially resectable (median 38.5 versus 13.3 months), borderline resectable (32.3 versus 13.9 months), and locally advanced (30.0 versus 14.6 months) pancreatic cancer (P < 0.001 for all). CONCLUSION: Although rates of surgical resection after neoadjuvant therapy vary based on anatomical stage, surgery is associated with improved survival for all patients with localized pancreatic cancer. These pooled resection and survival rates may inform patient-provider decision-making and serve as important benchmarks for future prospective trials.