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Nonalcoholic liver disease is a component of metabolic syndrome associated with obesity, insulin resistance, and hyperlipidemia. Excessive alcohol consumption may accelerate the progression of steatosis, steatohepatitis, and fibrosis. While simple steatosis is considered a benign condition, nonalcoholic steatohepatitis with inflammation and fibrosis may progress to cirrhosis, liver failure, and hepatocellular cancer. Studies in rodent experimental models and primary cell cultures have demonstrated several common cellular and molecular mechanisms in the pathogenesis and regression of liver fibrosis. Chronic injury and death of hepatocytes cause the recruitment of myeloid cells, secretion of inflammatory and fibrogenic cytokines, and activation of myofibroblasts, resulting in liver fibrosis. In this review, we discuss the role of metabolically injured hepatocytes in the pathogenesis of nonalcoholic steatohepatitis and alcohol-associated liver disease. Specifically, the role of chemokine production and de novo lipogenesis in the development of steatotic hepatocytes and the pathways of steatosis regulation are discussed.

While the efficacy of internet-based acceptance and commitment therapy (ACT) has been examined for different mental health concerns in high-income countries, evidence for the potential efficacy of culturally-adapted ACT in non-Western, low- and middle-income countries is scarce. The present study is a randomized, waitlist-controlled trial of culturally-adapted, online, manualized group ACT for anxiety in Iranian adolescent females. To participate, adolescents had to identify as female, report interfering anxiety symptoms, be currently attending high school, and be within the age range of 15–18 years old. Individuals in the active condition (n = 24) participated in eight group sessions delivered over the Shad platform, the largest technological application in the Iranian school system. All individuals in the active condition participated in the same ACT group sessions in a class-like format. Multilevel models were used to test between-group differences for primary and secondary outcomes over time. Participants in the ACT group reported a significant reduction in anxiety and depression, along with improvements in worry, emotion regulation, and intolerance of uncertainty. Treatment gains were maintained over a one-month follow-up period. The effect sizes for the main outcome measures were small to large (d = .39–1.56) and comparable to other online ACT interventions for youth with anxiety disorders in Western countries. In sum, this pilot study provides preliminary evidence that culturally-adapted, online ACT is effective for the treatment of anxiety symptoms in Iranian female youth.

Supplementary Figure from An Ex Vivo Organotypic Culture Platform for Functional Interrogation of Human Appendiceal Cancer Reveals a Prominent and Heterogenous Immunological Landscape

Purpose:Epithelial neoplasms of the appendix are difficult to study preclinically given their low incidence, frequent mucinous histology, and absence of a comparable organ in mice for disease modeling. Although surgery is an effective treatment for localized disease, metastatic disease has a poor prognosis as existing therapeutics borrowed from colorectal cancer have limited efficacy. Recent studies reveal that appendiceal cancer has a genomic landscape distinct from colorectal cancer and thus preclinical models to study this disease are a significant unmet need.Experimental Design:We adopted an ex vivo slice model that permits the study of cellular interactions within the tumor microenvironment. Mucinous carcinomatosis peritonei specimens obtained at surgical resection were cutoff using a vibratome to make 150-μm slices cultured in media.Results:Slice cultures were viable and maintained their cellular composition regarding the proportion of epithelial, immune cells, and fibroblasts over 7 days. Within donor specimens, we identified a prominent and diverse immune landscape and calcium imaging confirmed that immune cells were functional for 7 days. Given the diverse immune landscape, we treated slices with TAK981, an inhibitor of SUMOylation with known immunomodulatory functions, in early-phase clinical trials. In 5 of 6 donor samples, TAK981-treated slices cultures had reduced viability, and regulatory T cells (Treg). These data were consistent with TAK981 activity in purified Tregs using an in vitro murine model.Conclusions:This study demonstrates an approach to study appendiceal cancer therapeutics and pathobiology in a preclinical setting. These methods may be broadly applicable to the study of other malignancies.

Supplementary Table from An Ex Vivo Organotypic Culture Platform for Functional Interrogation of Human Appendiceal Cancer Reveals a Prominent and Heterogenous Immunological Landscape

Supplementary Data from An Ex Vivo Organotypic Culture Platform for Functional Interrogation of Human Appendiceal Cancer Reveals a Prominent and Heterogenous Immunological Landscape

Risk stratification of gastrointestinal stromal tumors (GISTs) is based on experience with tumors of the stomach, small bowel, and rectum, which are far more common than GISTs of other sites. In this study from 47 institutions, we analyzed GISTs of the esophagus (n = 102), colon (n = 136), and appendix (n = 27) for their size, mitotic rate, morphology, and outcome to determine which criteria predict their behavior. Esophageal GISTs were small (median: 2.5 cm) with spindle cell morphology and a low mitotic rate (mean: 3.6/5 mm2). Twelve (12%) tumors progressed, including 11 with a mitotic rate >5/5 mm2 and one large (6.8 cm) GIST with a mitotic rate of 2/5 mm2. Colonic GISTs were smaller (median: 1.4 cm) and presented with abdominal pain or bleeding in 29% of cases. Most (92%) were composed of spindle cells with a mean mitotic rate of 4.6/5 mm2. Sixteen (12%) tumors progressed: 14 had mitotic rates >5/5 mm2, and two were >5.0 cm with a mitotic rate 5/5 mm2) and size >5.0 cm. These findings support the use of size and mitotic rate for prognostication of GISTs in these locations, similar to tumors of the stomach, small bowel, and rectum.

PURPOSE: We explore the use of intravenously delivered perfluorocarbon (PFC) nanoemulsion and (19)F MRI for detecting inflammation in a mouse model of non-alcoholic fatty liver disease (NAFLD). Correlative studies of (1)H-based liver proton density fat fraction (PDFF) and T(1) measurements and histology are also evaluated. PROCEDURES: C57BL/6 mice were fed standard or high-fat diet (HFD) for 6 weeks to induce NAFLD. (1)H MRI measurements of PDFF and T(1) relaxation time were performed at baseline to assess NAFLD onset prior to administration of a PFC nanoemulsion to enable (19)F MRI of liver PFC uptake. (1)H and (19)F MRI biomarkers were acquired at 2, 21, and 42 days post-PFC to assess changes. Histopathology of liver tissue was performed at experimental endpoint. RESULTS: Significant increases in liver volume, PDFF, and total PFC uptake were noted in HFD mice compared to Std diet mice. Liver fluorine density and T(1) relaxation time were significantly reduced in HFD mice. CONCLUSIONS: We demonstrated longitudinal quantification of multiple MRI biomarkers of disease in NAFLD mice. The changes in liver PFC uptake in HFD mice were compared with healthy mice that suggests that (19)F MRI may be a viable biomarker of liver pathology.

Immune checkpoint inhibitors (ICI) have been used to treat hepatocellular carcinoma (HCC) since 2017. The safety of ICIs in the setting of solid organ transplantation remains controversial. When used in the post-transplant setting, ICIs have been associated with high allograft rejection rates, but there are few published reports on the use of ICIs prior to transplant. We present the first reported case of rescue liver re-transplantation after loss of the first allograft due to severe acute rejection with extensive hepatic necrosis in the setting of pre-transplant ICI therapy with the PD-1 inhibitor nivolumab. It is likely that the durable immune response triggered by nivolumab contributes to graft rejection, therefore extreme caution should be taken when using ICIs before transplant until further investigation has been conducted on their safety in the pre-transplant setting.

Hepatocellular carcinoma (HCC) is a malignancy with variable biologic aggressiveness based on the tumor grade, presence or absence of vascular invasion, and pathologic and molecular classification. Knowledge and understanding of the prognostic implications of different pathologic and molecular phenotypes of HCC are emerging, with therapeutics that promise to provide improved outcomes in what otherwise remains a lethal cancer. Imaging has a central role in diagnosis of HCC. However, to date, the imaging algorithms do not incorporate prognostic features or subclassification of HCC according to its biologic aggressiveness. Emerging data suggest that some imaging features and further radiologic, pathologic, or radiologic-molecular phenotypes may allow prediction of the prognosis of patients with HCC.

Noncoding genetic variation is a major driver of phenotypic diversity but determining the underlying mechanisms and the cell types in which it acts remain challenging problems. Here, we investigate the impact of natural genetic variation provided by phenotypically diverse inbred strains of mice on gene expression and epigenetic landscapes of Kupffer cells. Analysis of gene expression in Kupffer cells and other liver cell types derived from C57BL/6J, BALB/cJ and A/J mice provided evidence for strain-specific differences in environmental factors influencing Kupffer cell phenotypes, including preferential Leptin signaling in BALB/cJ Kupffer cells. Systematic analysis of transcriptomic and epigenetic data from F1 hybrids of these mice, and transcriptomic data from strain-specific Kupffer cells engrafted into a common host enabled quantitative assessment of cis versus trans effects of genetic variation on gene expression and an estimate of cell autonomous versus non cell autonomous effects. Under homeostatic conditions, trans effects of genetic variation were dominant, with the majority of trans regulation being non cell autonomous. In contrast, strain specific responses to acutely administered LPS were primarily associated with genetic variation acting in cis to modify response elements for lineage determining and signal dependent transcription factors. Collectively, these findings reveal cell intrinsic and environmental effects of natural genetic variation on gene expression, demonstrate the use of enhancers as detectors of trans effects of genetic variation, and provide a new resource for understanding the impact of genetic variation on gene expression in Kupffer cells.

Accurately identifying metastatic disease is critical to directing the appropriate treatment in pancreatic cancer. Mucin 5AC is overexpressed in pancreatic cancer but absent in normal pancreas tissue. The present proof-of-concept study demonstrates the efficacy of an anti-mucin 5AC antibody conjugated to an IR800 dye (MUC5AC-IR800) to preferentially label a liver metastasis of pancreatic cancer (Panc Met) in a unique patient-derived orthotopic xenograft (PDOX) model. In orthotopic models, the mean tumor to background ratio was 1.787 (SD ± 0.336), and immunohistochemistry confirmed the expression of MUC5AC within tumor cells. MUC5AC-IR800 provides distinct visualization of pancreatic cancer liver metastasis in a PDOX mouse model, demonstrating its potential utility in staging laparoscopy and fluorescence-guided surgery.

Background Cytoreductive surgery (CRS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal metastases traditionally includes omentectomy, even in the absence of visible omental metastases. We sought to determine the rate of occult histologic omental metastasis (OHOM), evaluate morbidity with omentectomy, and examine the rate of omental recurrence among patients undergoing CRS-HIPEC. Methods All CRS-HIPEC procedures from August 2007 to August 2020 were included in this single-center, retrospective, cohort study. Procedures were divided into those that included greater omentectomy (OM) and those that did not (NOM). The incidence of OHOM was evaluated specifically among the OM group with a grossly normal omentum. Multivariate regression analyses were performed to evaluate return of bowel function, ileus, and morbidity in the OM and NOM groups. Results Among 683 CRS-HIPEC procedures, 578 (84.6%) included omentectomy and 105 (15.4%) did not. The OM group had higher operative time, blood loss, peritoneal cancer index, number of visceral resections, and length of stay. In the OM group, 72 (12.5%) patients had a grossly normal omentum, and 23 (31.9%) of these had OHOM. Risk-adjusted return of bowel function, ileus, and 60-day complications were no different in the OM and NOM groups. Among 43 patients with residual omentum, 24 (55.8%) recurred, including 9 (20.9%) with omental recurrence. Conclusions Histologically occult metastasis was present in one-third of patients undergoing omentectomy during CRS-HIPEC. Omentectomy did not increase the rate of overall morbidity, and one-fifth of patients with residual omentum later developed omental recurrence. Thus, omentectomy is warranted in the absence of gross metastases during CRS-HIPEC.

Limited case series describe conflicting results regarding the safety of checkpoint inhibitors (CPI) prior to liver transplantation (LT). We reviewed single-center data on all consecutive patients who underwent LT for hepatocellular carcinoma treated with CPI between January 1, 2018, and January 30, 2021. Time from CPI to LT, immunosuppression, biopsy-proven acute cellular rejection (BPACR), graft loss and death were evaluated. Five patients with a mean age 65 (range 61-71) years underwent LT after CPI with nivolumab. Time from last CPI to LT ranged from 0.3 to 11months. Two patients with 3months from the last dose of CPI had BPACR. In conclusion, pretransplant use of CPIs, particularly within 90days of LT, was associated with BPACR and immune-mediated hepatic necrosis. Future multicenter studies should consider a sufficient interval from the last dose of CPI to LT to mitigate the risk for adverse immune-mediated outcomes and graft loss.

Appendiceal goblet cell adenocarcinoma, previously called goblet cell carcinoid and adenocarcinoma ex goblet cell carcinoid, is a rare neoplasm that occurs almost exclusively in the appendix. Several classification and grading systems have been proposed that can separate patients into prognostic groups. This review will provide an update on various classification systems with emphasis on the newly published 2019 World Health Organization Classification of Tumors, which proposed a 3-tiered grading system for appendiceal goblet cell adenocarcinoma based on the extent of low and high-grade patterns.

Background & Aims How benign liver steatosis progresses to nonalcoholic steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma (HCC) remains elusive. NASH progression entails diverse pathogenic mechanisms and relies on complex cross-talk between multiple tissues such as the gut, adipose tissues, liver, and the brain. Using a hyperphagic mouse fed with a Western diet (WD), we aimed to elucidate the cross-talk and kinetics of hepatic and extrahepatic alterations during NASH–HCC progression, as well as regression. Methods Hyperphagic mice lacking a functional Alms1 gene (Foz/Foz) and wild-type littermates were fed WD or standard chow for 12 weeks for NASH/fibrosis and for 24 weeks for HCC development. NASH regression was modeled by switching back to normal chow after NASH development. Results Foz+WD mice were steatotic within 1 to 2 weeks, developed NASH by 4 weeks, and grade 3 fibrosis by 12 weeks, accompanied by chronic kidney injury. Foz+WD mice that continued on WD progressed to cirrhosis and HCC within 24 weeks and had reduced survival as a result of cardiac dysfunction. However, NASH mice that were switched to normal chow showed NASH regression, improved survival, and did not develop HCC. Transcriptomic and histologic analyses of Foz/Foz NASH liver showed strong concordance with human NASH. NASH was preceded by an early disruption of gut barrier, microbial dysbiosis, lipopolysaccharide leakage, and intestinal inflammation. This led to acute-phase liver inflammation in Foz+WD mice, characterized by neutrophil infiltration and increased levels of several chemokines/cytokines. The liver cytokine/chemokine profile evolved as NASH progressed, with subsequent predominance by monocyte recruitment. Conclusions The Foz+WD model closely mimics the pathobiology and gene signature of human NASH with fibrosis and subsequent HCC. Foz+WD mice provide a robust and relevant preclinical model of NASH, NASH-associated HCC, chronic kidney injury, and heart failure., Supplemental Graphical Summary

in press

Background: Classic galactosemia (CG) is an inborn error of galactose metabolism caused by a deficiency of the enzyme galactose-1-phosphate uridyltransferase (GALT). This enzyme causes the conversion of uridine diphosphate- glucose (UDP)-glucose and galactose-1-phosphate (Gal-1-P) to glucose-1-phosphate and UDP-galactose. The absence of this enzyme results in the accumulation of the metabolites galactitol and Gal-1-P. The CG is heterogeneous at clinical and molecular levels. Objectives: This study provides some data for the investigation of the introduction of new mutations of the GALT gene that involved the cause of galactosemia in the Iranian population. Methods: In this cross-sectional study, 31 newborns diagnosed with galactosemia were investigated for the mutations of the GALT gene in Tehran province, Iran, from March 2014 to December 2019. The polymerase chain reaction sequencing method was used to analyze the GALT gene. Results: The sequence results showed 11 pathogenic mutations on the GALT gene, including five mutations in exon 10, two mutations in exon 9, two mutations in exon 5, one mutation in exon 6, and one mutation in exon 7. Moreover, six new mutations of the GALT gene were identified in the Iranian population, namely c.442C>T (R148W), c.881T>A (F294Y), c.997C>T (R333W), c.940A>G (N314D), c.1030C>A (Q344K), and c.1018G>A (E340K). Other mutations identified in this study were c.563A>G (Q188R), c.855G>T (K285N), c.626A>C (Y209S), c.404C>T (S135L), and c.958G>A (A320T). The most common mutations in this study were p.Q188R (51.6%), K285N (9.67%), E340K (9.67%), and R148W (6.45%). Conclusions: This study identified 11 different pathogenic mutations of the GALT gene in the Iranian population with galactosemia. The identification of the mutations involved in the development of CG in the Iranian population can play an important role in early diagnosis and intervention. The GALT gene mutations identified in this study can be used as screening markers to identify Iranian children with CG.

Pancreatic cancer is a recalcitrant disease in which R0 resection is often not achieved owing to difficulty in visualization of the tumor margins and proximity of adjacent vessels. To improve outcomes, we have developed fluorescence-guided surgery (FGS) and photoimmunotherapy (PIT) using a fluorescent tumor-specific antibody.Nude mice received surgical orthotopic implantation (SOI) of the human pancreatic cancer cell line BxPC-3 expressing green fluorescent protein. An anti-carcinoembryonic antigen-related cell adhesion molecule (CEACAM) monoclonal antibody (6G5j) was conjugated to the 700-nm fluorescent dye IR700DyeDX (6G5j-IR700DX). Three weeks after SOI, 16 mice received 50 μg 6G5j-IR700DX via the tail vein 24 h before surgery and were randomized to two groups: FGS-only (n = 8) and FGS + PIT (n = 8). All tumors were imaged with the Pearl Trilogy imaging system and resected under the guidance of the FLARE imaging system. The FGS + PIT group received PIT of the post-surgical bed at an intensity of 150 mW/cmThe 6G5j-IR700DX dye illuminated the orthotopic pancreatic tumors for FGS and PIT. The metastatic recurrence rate was 100.0% for FGS-only and 25.0% for FGS + PIT (p = 0.007). The average total recurrent tumor weight was 2370.3 ± 1907.8 mg for FGS-only and 705.5 ± 1200.0 mg for FGS + PIT (p = 0.039).FGS and adjuvant PIT can be combined by using a single antibody-fluorophore conjugate to significantly reduce the frequency of pancreatic cancer recurrence.

Purpose: Epithelial neoplasms of the appendix are difficult to study preclinically given their low incidence, frequent mucinous histology, and absence of a comparable organ in mice for disease modeling. Although surgery is an effective treatment for localized disease, metastatic disease has a poor prognosis as existing therapeutics borrowed from colorectal cancer have limited efficacy. Recent studies reveal that appendiceal cancer has a genomic landscape distinct from colorectal cancer and thus preclinical models to study this disease are a significant unmet need. Experimental Design: We adopted an ex vivo slice model that permits the study of cellular interactions within the tumor microenvironment. Mucinous carcinomatosis peritonei specimens obtained at surgical resection were cutoff using a vibratome to make 150-μm slices cultured in media. Results: Slice cultures were viable and maintained their cellular composition regarding the proportion of epithelial, immune cells, and fibroblasts over 7 days. Within donor specimens, we identified a prominent and diverse immune landscape and calcium imaging confirmed that immune cells were functional for 7 days. Given the diverse immune landscape, we treated slices with TAK981, an inhibitor of SUMOylation with known immunomodulatory functions, in early-phase clinical trials. In 5 of 6 donor samples, TAK981-treated slices cultures had reduced viability, and regulatory T cells (Treg). These data were consistent with TAK981 activity in purified Tregs using an in vitro murine model. Conclusions: This study demonstrates an approach to study appendiceal cancer therapeutics and pathobiology in a preclinical setting. These methods may be broadly applicable to the study of other malignancies.

Indocyanine green has been used for fluorescence-guided surgery of liver metastasis and labeling of liver segments. However, indocyanine green is nonspecific, and indocyanine green labeling does not always clearly outline tumor margins. In addition, it is difficult to distinguish between a tumor and its adjacent liver segment colored with indocyanine green alone. In the present study, we performed fluorescence-guided surgery in an orthotopic colon-cancer liver metastasis mouse model by labeling the metastatic liver tumor with an anti-carcinoembryonic antigen fluorescent antibody and with indocyanine green restricted to the adjacent liver segment.A liver metastasis model was established with human LS174T colon cancer tumor fragments. To label the tumor, mice received SGM-101, an anti-carcinoembryonic antigen antibody conjugated to a near-infrared fluorophore (700 nm), currently in clinical trials, 3 days before surgery. Indocyanine green (800 nm) was injected after ligation of the tumor-bearing Glissonean pedicle with fluorescence labeling restricted to the liver segment adjacent to the tumor. Bright-light surgery and fluorescence-guided surgery were performed to resect the liver metastasis. To assess recurrence, mice underwent necropsy 3 weeks after surgery and the tumor was weighed.Fluorescence-guided anatomic left lateral lobectomy and fluorescence-guided partial liver resection were both performed with color-coded double labeled imaging. Tumor weight 3 weeks after surgery was significantly lower with fluorescence-guided surgery compared to bright-light surgery (38 ± 57 mg vs 836 ± 668 mg, P = .011) for partial liver resection.The present study provides a proof-of-concept that color-coded and double labeling of the tumor and adjacent liver segment has the potential to improve liver metastasectomy.

Smooth muscle tumors represent the second most common mural mesenchymal neoplasm in the gastrointestinal tract, but established criteria for prognostic assessment of these tumors are lacking. A large cohort of surgically resected intramural gastrointestinal smooth muscle tumors from 31 institutions was analyzed to identify potential prognostic features. Pathologic features were assessed by expert gastrointestinal and/or soft tissue pathologists at each center. Immunohistochemical confirmation was required. A total of 407 cases from the esophagus (n = 97, 24%), stomach (n = 180, 44%), small bowel (n = 74, 18%), and colorectum (n = 56, 14%) were identified. Patients ranged in age from 19 to 92 years (mean 55 years), with a slight female predominance (57%). Mean tumor size was 5.4 cm, with the largest tumor measuring 29 cm. Disease progression following surgery, defined as local recurrence, metastasis, or disease-related death, occurred in 56 patients (14%). Colorectal tumors were most likely to progress, followed by small bowel and gastric tumors. None of the esophageal tumors in this series progressed. Receiver operator characteristic analysis identified optimal cutoffs of 9.8 cm and 3 mitoses/5 mm2 for discriminating between progressive and non-progressive tumors. Histologic features strongly associated with progression by univariate analysis included moderate-to-severe atypia, high cellularity, abnormal differentiation (defined as differentiation not closely resembling that of normal smooth muscle), tumor necrosis, mucosal ulceration, lamina propria involvement, and serosal involvement (P 10 cm and/or showing ≥3 mitoses/5 mm2 may behave aggressively, and therefore close clinical follow-up is recommended in these cases.

Alcoholic liver disease (ALD) is a leading cause of cirrhosis in the United States, which is characterized by extensive deposition of extracellular matrix proteins and formation of a fibrous scar. Hepatic stellate cells (HSCs) are the major source of collagen type 1 producing myofibroblasts in ALD fibrosis. However, the mechanism of alcohol‐induced activation of human and mouse HSCs is not fully understood. We compared the gene‐expression profiles of primary cultured human HSCs (hHSCs) isolated from patients with ALD (n = 3) or without underlying liver disease (n = 4) using RNA‐sequencing analysis. Furthermore, the gene‐expression profile of ALD hHSCs was compared with that of alcohol‐activated mHSCs (isolated from intragastric alcohol‐fed mice) or CCl4‐activated mouse HSCs (mHSCs). Comparative transcriptome analysis revealed that ALD hHSCs, in addition to alcohol‐activated and CCl4‐activated mHSCs, share the expression of common HSC activation (Col1a1 [collagen type I alpha 1 chain], Acta1 [actin alpha 1, skeletal muscle], PAI1 [plasminogen activator inhibitor‐1], TIMP1 [tissue inhibitor of metalloproteinase 1], and LOXL2 [lysyl oxidase homolog 2]), indicating that a common mechanism underlies the activation of human and mouse HSCs. Furthermore, alcohol‐activated mHSCs most closely recapitulate the gene‐expression profile of ALD hHSCs. We identified the genes that are similarly and uniquely up‐regulated in primary cultured alcohol‐activated hHSCs and freshly isolated mHSCs, which include CSF1R (macrophage colony‐stimulating factor 1 receptor), PLEK (pleckstrin), LAPTM5 (lysosmal‐associated transmembrane protein 5), CD74 (class I transactivator, the invariant chain), CD53, MMP9 (matrix metallopeptidase 9), CD14, CTSS (cathepsin S), TYROBP (TYRO protein tyrosine kinase‐binding protein), and ITGB2 (integrin beta‐2), and other genes (compared with CCl4‐activated mHSCs). Conclusion: We identified genes in alcohol‐activated mHSCs from intragastric alcohol‐fed mice that are largely consistent with the gene‐expression profile of primary cultured hHSCs from patients with ALD. These genes are unique to alcohol‐induced HSC activation in two species, and therefore may become targets or readout for antifibrotic therapy in experimental models of ALD., We identified genes in alcohol‐activated mHSCs from IG alcohol‐fed mice that are largely consistent with the gene‐expression profile of primary cultured hHSCs from patients with ALD. These genes are unique to alcohol‐induced HSC activation in two species, and therefore may become targets or readout for antifibrotic therapy in experimental models of ALD.

Sterol deficiency triggers SCAP-mediated SREBP activation, whereas hypernutrition together with ER stress activates SREBP1/2 via caspase-2. Whether these pathways interact and how they are selectively activated by different dietary cues are unknown. Here, we reveal regulatory crosstalk between the two pathways that controls the transition from hepatosteatosis to steatohepatitis. Hepatic ER stress elicited by NASH-inducing diets activates IRE1 and induces expression of the PIDDosome subunits caspase-2, RAIDD, and PIDD1, along with INSIG2, an inhibitor of SCAP-dependent SREBP activation. PIDDosome assembly activates caspase-2 and sustains IRE1 activation. PIDDosome ablation or IRE1 inhibition blunt steatohepatitis and diminish INSIG2 expression. Conversely, while inhibiting simple steatosis, SCAP ablation amplifies IRE1 and PIDDosome activation and liver damage in NASH-diet-fed animals, effects linked to ER disruption and preventable by IRE1 inhibition. Thus, the PIDDosome and SCAP pathways antagonistically modulate nutrient-induced hepatic ER stress to control non-linear transition from simple steatosis to hepatitis, a key step in NASH pathogenesis.

Liver transplant is indicated with curative intent for patients with early-stage hepatocellular carcinoma (HCC). The radiologic T category is used to determine candidacy and priority of patients on the waiting list. After transplant, the explant liver pathologic TNM stage is used as a predictor of postoperative outcomes and overall prognosis. Although the comparison of radiologic and pathologic T categories for concordance is often considered to be straightforward, the staging conventions significantly differ. Not accounting for these differences is in part the reason for the high rates of radiologic-pathologic discordance reported in the literature, with inconsistent terminology being an additional source of confusion when evaluating concordance. These factors may affect the understanding of important radiopathologic phenotypes of disease and the adequate investigation of their prognostic capabilities. The aims of this article are to provide an overview of the pathologic and radiologic TNM staging systems for HCC while describing staging procedures, emphasize the differences between these staging systems to highlight the limitations of radiologic-pathologic stage correlation, present a review of the literature on the prognostic value of individual features used for HCC staging; and signal significant aspects of preoperative risk stratification that could be improved to positively impact posttransplant outcomes.

Novel graphitic carbon nitride-multi wall carbon nanotubes based nanocomposites decorated with different mass fraction (x = 10–50) of bio ultrasound synthesized ZnO-NPs were fabricated. The characterization of g-C3N4/MWCNT/ZnO (x) was performed in detail using a wide range of methods such as FT-IR, XRD, FE-SEM, EDS, XPS, DRS, HRTEM and N2 physisorption. Efficiency of ultrasound wave accelerated photodegradation of anxiolytic drug Alprazolam by advanced oxidation processes (AOP) was investigated in the presence of g-C3N4/MWCNT/ZnO. AOP was studied under different kind of irradiation (UVA, Vis and SSI) and photocatalyst (with different weight ratio of ZnO to g-C3N4/MWCNT), loading of photocatalyst, pH, as well as the presence of alcoholic •OH scavenger. By evaluating the effect of kinds of irradiation and photocatalysts, it was demonstrated that the UVA/g-C3N4/MWCNT/ZnO (x = 30) combination is a efficacious system for ALP removal. The dose of g-C3N4/MWCNT/ZnO (x = 30) was 1.0 mg/mL and the pH 7 was chosen as the optimal condition. The influence of •OH scavengers on the sonophotocatalysis shows that the ultrasound removal of ALP was accomplished mainly via •OH radicals.

Although hepatocellular cancer (HCC) usually occurs in the setting of liver fibrosis, the causal relationship between liver fibrosis and HCC is unclear. in vivo and in vitro models of HCC involving Col(r/r) mice (that produce a collagenase-resistant type I collagen) or wild-type (WT) mice were used to assess the relationship between type I collagen, liver fibrosis, and experimental HCC. HCC was either chemically induced in WT and Col(r/r) mice or Hepa 1-6 cells were engrafted into WT and Col(r/r) livers. The effect of hepatic stellate cells (HSCs) from WT and Col(r/r) mice on the growth of Hepa 1-6 cells was studied by using multicellular tumor spheroids and xenografts. Collagen type I deposition and fibrosis were increased in Col(r/r) mice, but they developed fewer and smaller tumors. Hepa 1-6 cells had reduced tumor growth in the livers of Col(r/r) mice. Although Col(r/r) HSCs exhibited a more activated phenotype, Hepa 1-6 growth and malignancy were suppressed in multicellular tumor spheroids and in xenografts containing Col(r/r) HSCs. Treatment with vitronectin, which mimics the presence of degraded collagen fragments, converted the Col(r/r) phenotype into a WT phenotype. Although Col(r/r) mice have increased liver fibrosis, they exhibited decreased HCC in several models. Thus, increased liver type I collagen does not produce increased experimental HCC.

Targeted therapies for gastrointestinal stromal tumor (GIST) are modestly effective, but GIST cannot be cured with single agent tyrosine kinase inhibitors. In this study, we sought to identify new therapeutic targets in GIST by investigating the tumor microenvironment. Here, we identified a paracrine signaling network by which cancer-associated fibroblasts (CAFs) drive GIST growth and metastasis. Specifically, CAFs isolated from human tumors were found to produce high levels of platelet-derived growth factor C (PDGFC), which activated PDGFC-PDGFRA signal transduction in GIST cells that regulated the expression of SLUG, an epithelial-mesenchymal transition (EMT) transcription factor and downstream target of PDGFRA signaling. Together, this paracrine induce signal transduction cascade promoted tumor growth and metastasis in vivo. Moreover, in metastatic GIST patients, SLUG expression positively correlated with tumor size and mitotic index. Given that CAF paracrine signaling modulated GIST biology, we directly targeted CAFs with a dual PI3K/mTOR inhibitor, which synergized with imatinib to increase tumor cell killing and in vivo disease response. Taken together, we identified a previously unappreciated cellular target for GIST therapy in order to improve disease control and cure rates.

Background: Emergence and prevalence of Methicillin-Resistant Staphylococcus aureus (MRSA) has become a major universal health concern, limiting therapeutic options. Methods: In the North side of Iran, during the years 2015 to 2017, a total number of 37 MRSA isolates, including 19 clinical isolates from hospitalized patients and 18 colonizing isolates from health care workers were identified from three hospitals, in Gorgan, North of Iran. Antimicrobial susceptibility test was performed using the disk diffusion method and E-test. The presence of virulence and antibiotic resistance determinants were evaluated by PCR. The genotypic characterization was further analyzed using multi-locus sequence, spa, SCCmec, and agr typing.Results: The frequency of MRSA among S. aureus isolates was 38.14% (37/97). The most frequent S. aureus resistant isolates were found to be obstinate against penicillin (98%) and gentamicin (82.5%). Additionally, the lowest resistance rates were found against daptomycin (0%), vancomycin (2.7%), and quinupristin-dalfopristin (5.4%). All MRSA isolates were susceptible to daptomycin with MIC50/MIC90 of 0.25/0.5 µg/ml. One isolate belonging to the ST239-SCCmecIII/t037 clone (MIC≥16μg/ml) was resistant to vancomycin. All but one isolate that shares the ST22-SCCmec IV/t790 strain were positive for both tsst and pvl genes. The most predominant MRSA isolates (27%) were associated with the ST239-SCCmec III/t037 clone; and followed by ST239-SCCmec III/t924 (16.2%).Conclusions: In our study, circulating MRSA strains were genetically diverse with a high prevalence of the ST239-SCCmecIII/t037 clone. These findings emphasize the need for future and continuous surveillance studies on MRSA to prevent the dissemination of multidrug resistance and existing MRSA clones in an effective manner.

Liver disease (hepatic disease) adversely affects the normal function of the liver and causes liver problems. Drug-induced liver injury (DILI) can be predicted by primary human hepatocytes. However, the sources of hepatocytes for large-scale drug toxicity screening are limited. To solve this problem, pluripotent stem cells (PSCs), mesenchymal stem cells (MSCs), and hepatic stem cells (HSCs) have emerged as attractive cell sources for cell-based therapies. Human PSCs, including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have the ability to undergo self-renewal and differentiate into lineages of ectoderm, mesoderm, and endoderm. Human PSC can be used for the generation of hepatocytes to facilitate the development of novel drugs for the treatment of severe liver diseases. The therapeutic potential of PSC-derived hepatocytes for liver failure have been identified to enhance the development of chemically defined and xenogenic- free 3D culture methods. To date, several hepatic differentiation strategies and various extracellular matrix (ECM) components have been employed to produce hepatocytes or hepatic-like cells (HLCs) in vitro. In this review, we focused on the potential of Matrigel, collagen type 1, Ro- Gel, and laminin as ECM on the differentiation and function of hESC- and hiPSC-derived hepatocytes. The hepatic differentiation of human ESCs and iPSCs would offer an ideal tool for cell therapy and liver diseases.

Background Numerous investigations have previously evaluated the association of interleukin (IL) 4 gene polymorphisms and the risk of asthma, conferring inconsistent results. To resolve the incongruent outcomes yielded from different single studies, we conducted the most up-to-date meta-analysis of IL4 gene −589C/T (rs2243250) polymorphism and susceptibility to asthma. Methods A systematic literature search was performed in ISI web of science, Scopus, Medline/PubMed databases prior to September 2020, and the pooled odds ratio (OR) and their corresponding 95% CI were calculated to determine the association strength. Results Literature search led to retrieving of 49 publications (55 case-control studies) containing 9572 cases and 9881 controls. It was revealed that IL4 gene −589C/T polymorphism increased the risk of asthma across all genetic models, including dominant model (OR = 1.22), recessive model (OR = 1.17), allelic model (OR = 1.21), and TT vs. CC model (OR = 1.34), but not the CT vs. TT model. The subgroup analysis by age indicated that IL4 gene -589C/T polymorphism was significantly associated with asthma risk in both pediatrics and adults. Additionally, the subgroup analysis by ethnicity revealed significant association in Asian, American, and Europeans. Finally, subgroup analysis by East Asian and non-East Asian populations indicated significant associations. Conclusions The current meta-analysis revealed that IL4 gene -589C/T polymorphism was a susceptibility risk in both pediatrics and adults in the whole and different ethnic groups.

Tissue resident macrophages and recruited monocyte-derived macrophages contribute to host defense but also play pathological roles in a diverse range of human diseases. Multiple macrophage phenotypes are often represented in a diseased tissue, but we lack a deep understanding of the mechanisms that control diversification. Here we use a combination of genetic, genomic, and imaging approaches to investigate the origins and epigenetic trajectories of hepatic myeloid cells during diet-induced non-alcoholic steatohepatitis (NASH). The NASH diet induces striking changes in Kupffer cell enhancers and gene expression, resulting in partial loss of Kupffer cell identity, induction of Trem2 and Cd9 expression, and cell death. Kupffer cell loss is compensated by gain of adjacent monocyte derived macrophages that exhibit convergent epigenomes, transcriptomes and functions. NASH-induced changes in Kupffer cell enhancers are driven by AP-1 and Egr factors that reprogram the Kupffer cell specific functions of Liver X receptors. These findings reveal mechanisms by which disease-associated environmental signals instruct resident and recruited macrophages to acquire distinct programs of gene expression and corresponding phenotypes.

MnS2, MnS2/Chitosan‑sodium Alginate (MnS2/CS-NaAlg) and MnS2/Chitosan-Calcium Alginate (MnS2/CS-CaAlg) nanocomposites were prepared via the chemical procedure. The characterization was performed by various instruments such as energy dispersive X-ray spectrometer (EDX), scanning electron microscopy (SEM), X-ray diffraction (XRD) elemental map analysis, Fourier transform infrared spectrometry (FT-IR), Brunauer–Emmett–Teller (BET) surface area measurements, UV–Vis absorption spectra and X-ray absorption spectroscopy. The mean crystallite sizes of MnS2, MnS2/CS-NaAlg and MnS2/CS-CaAlg are 60.12, 71.25 and 74.54 nm, respectively. From Kubelka–Munk equation, the energy band gaps of MnS2, MnS2/CS-NaAlg and MnS2/CS-CaAlg are estimated to be 2.83, 2.71 and 2.41 eV, respectively. The investigation of photocatalysis properties was performed by degradation of tramadol under UV light illumination. The optimum of experimental variables such as pH and time on photo-degradation were found 3 and 60 min, respectively. The results show that the efficiency photocatalysis of MnS2/CS-NaAlg and MnS2/CS-CaAlg nanocomposites under was higher than MnS2. The antibacterial and fungicidal property of MnS2/CS-NaAlg and MnS2/CS-CaAlg nanocomposites was investigated and demonstrates good efficiency in antimicrobial efficiency compared to MnS2. The MnS2, MnS2/CS-NaAlg and MnS2/CS-CaAlg have been shown excellent mechanical and antioxidant properties.