A new minimally invasive, nonexcisional, surgical browlift technique with minimal scarring: a protocol for a prospective observational study.

Background: The aim of this study is to prospectively evaluate the new minimal invasive (MINE) browlift technique with possibly superior results and minimal visible scarring. Study design: A prospective observational study will be performed on all available data from patients who will undergo a browlift procedure in the HMC from 1 June 2021 till 31 May 2024. Our goal is to include at least 50 patients. Inclusion criteria are: patients with medical (i.e. brow ptosis and facial paralysis) or cosmetic indication, patients with sufficient understanding of the Dutch or English language and willingness to participate in extra study specific follow-up moments and filling in of questionnaires. Exclusion criteria are: less than 18 years of age and patients with previous brow or eyelid surgery. Patients will be photographed preoperatively and postoperatively using the VECTRA camera. Outcome measurements: Scarring after procedure; functionality of eyebrow movement; amount of correction in brow ptosis, measured in VECTRA; longevity of procedure in months; aesthetic result as assessed by questionnaires and adverse effects of procedure will be measured. Ethics and dissemination: The database management software 'Castor' will be used to store and collect the data from the questionnaire. The Medical Research Ethics Committee found this study not eligible to be submitted to the Dutch Medical Research Involving Human Subjects Acts (WMO). Written consent will be obtained from all patients.

Nucleolin binds to and regulates transcription of hepatitis B virus covalently closed circular DNA minichromosome.

Hepatitis B virus (HBV) remains a major public health threat with nearly 300 million people chronically infected worldwide who are at a high risk of developing hepatocellular carcinoma. Current therapies are effective in suppressing HBV replication but rarely lead to cure. Current therapies do not affect the HBV covalently closed circular DNA (cccDNA), which serves as the template for viral transcription and replication and is highly stable in infected cells to ensure viral persistence. In this study, we aim to identify and elucidate the functional role of cccDNA-associated host factors using affinity purification and protein mass spectrometry in HBV-infected cells. Nucleolin was identified as a key cccDNA-binding protein and shown to play an important role in HBV cccDNA transcription, likely via epigenetic regulation. Targeting nucleolin to silence cccDNA transcription in infected hepatocytes may be a promising therapeutic strategy for a functional cure of HBV.

[Living-donor intestinal transplantation].

Due to advances in surgical techniques, perioperative care, and new immunosuppressive agents, intestinal transplantation has become a valid therapeutic choice for chronic intestinal failure. Intestinal transplantation has been performed most commonly using deceased donation, while less than 2% of which have been from living donation. Living donor intestinal transplantation obtaining a segmental intestinal graft, usually from close relatives. Preliminary results show that acute/chronic rejection rates, postoperative opportunistic infections, and graft versus host disease are significantly reduced after living donor intestinal transplantation, contributing to improved graft and patient survivals. Due to a severe shortage of organ donation, especially in children, living donor intestinal transplantation has increasingly become an important treatment option for patients with chronic intestinal failure in China.

[Advances in combination strategies with oncolytic virotherapy].

Compared with conventional treatments, oncolytic virotherapy has the advantages of enhanced cytotoxicity, improved targeting, and minimal side effects. However, its efficacy is not as good as expected for the single drug treatment. The purpose of synergistic effect is one of the development directions of existing oncolytic virus therapy. In this paper, through a systematic review of the current preclinical and clinical trials progress of oncolytic virus combination therapy, the combined treatment strategies of oncolytic virus and immune checkpoint inhibitors, chemotherapy, targeted therapy,and cell therapy are reviewed to provide reference for further clinical application.

[Progress in perioperative management of ABO-incompatible pediatric liver transplantation].

ABO incompatible(ABO-I) liver grafts will affect the prognosis of liver transplantation. With the improvement of perioperative treatment,including plasma exchange,rituximab,splenectomy,etc.,the prognosis of ABO-I liver transplantation has been greatly improved. Because children's immune systems are not fully developed,the perioperative management of ABO-I pediatric liver transplantation is significantly different from that of adults. Reducing the perioperative anti-donor ABO antibody titer is the key to the perioperative management of ABO-I liver transplantation. This article summarizes literatures on the perioperative management of ABO-I pediatric liver transplantation, including the perioperative anti-rejection regimen in pediatric recipients of different ages, splenectomy, postoperative monitoring and postoperative complications, etc.

Three-Dimensional Reconstruction of the Hepatitis C Virus Envelope Glycoprotein E1E2 Heterodimer by Electron Microscopic Analysis.

Despite the development of highly effective hepatitis C virus (HCV) treatments, an effective prophylactic vaccine is still lacking. HCV infection is mediated by its envelope glycoproteins, E1 and E2, during the entry process, with E2 binding to cell receptors and E1 mediating endosomal fusion. The structure of E1E2 has only been partially resolved by X-ray crystallography of the core domain of E2 protein (E2c) and its complex with various neutralizing antibodies. Structural understanding of the E1E2 heterodimer in its native form can advance the design of candidates for HCV vaccine development. Here, we analyze the structure of the recombinant HCV E1E2 heterodimer with the aid of well-defined monoclonal anti-E1 and E2 antibodies, as well as a small-molecule chlorcyclizine-diazirine-biotin that can target and cross-link the putative E1 fusion domain. Three-dimensional (3D) models were generated after extensive 2D classification analysis with negative-stain single-particle data sets. We modeled the available crystal structures of the E2c and Fabs into 3D volumes of E1E2-Fab complexes based on the shape and dimension of the domain density. The E1E2 heterodimer exists in monomeric form and consists of a main globular body, presumably depicting the E1 and E2 stem/transmembrane domain, and a protruding structure representing the E2c region, based on anti-E2 Fab binding. At low resolution, a model generated from negative-stain analysis revealed the unique binding and orientation of individual or double Fabs onto the E1 and E2 components of the complex. Cryo-electron microscopy (cryo-EM) of the double Fab complexes resulted in a refined structural model of the E1E2 heterodimer, presented here. IMPORTANCE Recombinant HCV E1E2 heterodimer is being developed as a vaccine candidate. Using electron microscopy, we demonstrated unique features of E1E2 in complex with various neutralizing antibodies and small molecule inhibitors that are important to understanding its antigenicity and induction of immune response.

[Correlation analysis between lactic, procalcitonin and disease severity in patients with imported malaria from Africa].

Objective: To explore the clinical characteristics, the correlation between lactate, procalcitonin and disease severity of imported malaria from Africa. Methods: The clinical data of 186 patients with imported malaria were collected from January 1, 2018 to April 30, 2021 in the Guangzhou Eighth People's Hospital, Guangzhou Medical University. The general conditions, clinical symptoms, laboratory tests, treatment, and prognosis of the patients were analyzed retrospectively. Receiver operating characteristic (ROC) curves were drawn to evaluate the value of relevant indicators in predicting severe malaria. Results: A total of 186 patients were divided into severe cases (n=48) and non-severe cases (n=138) in this study, of which the mean age was (38.3±10.3) years, 169(90.9%) cases were male, 17(9.1%) cases were female. The main infection species was Plasmodium falciparum, in a total of 166 cases (89.2%). The severe cases were all falciparum malarias. Compared with the non-severe group, the lactic, procalcitonin, white blood cell count and neutrophil count of the severe group were all increased, the differences were all statistically significant (all P<0.01); the percentage of monocytes, red blood cell count, hemoglobin, hematocrit and platelet count were all decreased, the difference were all statistically significant (all P<0.01). The areas under the ROC curves (AUC)(95%CI) of lactate, procalcitonin, red blood cell count, hemoglobin, hematocrit and platelet count for predicting severe malaria was 0.753(0.663-0.844), 0.755(0.670-0.841), 0.782(0.700-0.864), 0.738(0.652-0.823), 0.760(0.676-0.844), 0.778(0.699-0.857), respectively (all P<0.01). When the Youden indexes were at their maximum, the best cut-off value of lactic was 2.29 mmol/L, with sensitivity in predicting of severe malaria was 56.3%, and the specificity was 93.5%; the best cut-off value of procalcitonin was 2.12 µg/L, with sensitivity in predicting of severe malaria was 77.1%, and the specificity was 68.1%. The fatality rate of severe malaria was 4.2% (2/48). Conclusions: Anemia and thrombocytopenia are common indicators for predicting the severity of malaria. Lactic and procalcitonin also have higher predictive value for severe malaria, which could help to identify severe malaria as early as possible, improve the cure rate and reduce the risk of death.

[Outcome of pediatric-to-adult liver transplantation:a single-center study in China].

Objective: To explore the outcome of the pediatric-to-adult liver transplantation, including postoperative complications and relevant factors which affecting graft survival. Methods: Data of 55 patients undergoing pediatric-to-adult liver transplantation at the First Affiliated Hospital of Zhejiang University between January 2015 and August 2021 were retrospectively analyzed. The donors consisted of 34 males and 21 females, and the age was (11.8±4.7) years (range: 1 to 17 years). Among the cases,17 cases (30.9%) were donation of brain death,32 cases (58.2%) were donation of cardiac death, and 6 cases (10.9%) were donation after brain death plus cardiac death. The recipients consisted of 32 males and 23 females, and the age was (51.6±10.1) years (range: 27 to 70 years). Among the recipients,10 cases (18.2%) were ABO-incompatible liver transplantation.The influencing factors of early graft survival were analyzed by Student t test,Mann-Whitney U test or χ2 test,respectively.Survival curve was drawn by Kaplan-Meier method.Logistic multivariate analysis was used to analyze the independent relevant factors of early postoperative graft loss. Results: Up to October 31,2021,the follow-up time (M(IQR)) was 36.0(43.1)months(range:5.9 to 81.7 months).There were 13 cases with graft loss (two of them underwent re-transplantation due to acute liver failure).The monofactor analysis indicated that cold ischemia time and donor-recipient blood group matching were the relevant factors affecting the early graft survival rate(both P<0.05).Logistic multivariate analysis showed that cold ischemia time and history of recipient gastrointestinal bleeding were independent relevant factors(both P<0.05).Postoperative hepatic artery thrombosis occurred in 3 cases(5.5%), portal vein thrombosis diagnosed in 4 cases(7.3%), portal vein stenosis occurred in 2 cases(3.6%),biliary complications diagnosed in 7 cases(12.7%), and small liver syndrome was found in 8 cases(14.5%). Conclusions: Adult liver transplantation with pediatric donor liver is an effective method to treat end-stage liver disease.Cold ischemia time and history of recipient gastrointestinal bleeding were independent relevant factors for the early graft survival.

[Review of risk evaluation scores for benign end stage liver diseases recipients].

Liver transplant is an unreplaceable method for benign end-stage liver disease. The risk evaluation for the waiting list recipients and for post-transplant survival could provide practical indication for organ allocation. In recent years, there are two major kinds of evaluation scores. The first kind of evaluation scores is based on model for end-stage liver disease(MELD) score,including SOFT/P-SOFT score,UCLA-FRS score and BAR score. The other evaluation system is based on the concept of acute-on-chronic liver failure,including CLIF-C-ACLF score,TAM score,AARC-ACLF score and COSSH-ACLF score. The scores based on ACLF have been shown superior power in predicting waiting list survival and post-transplant prognosis than MELD. This article reviews the two kinds of evaluation scores,aiming for the better allocation policy and the better prognosis of benign end-stage liver disease.

[Review of risk evaluation scores for benign end stage liver diseases recipients].

Liver transplant is an unreplaceable method for benign end-stage liver disease. The risk evaluation for the waiting list recipients and for post-transplant survival could provide practical indication for organ allocation. In recent years, there are two major kinds of evaluation scores. The first kind of evaluation scores is based on model for end-stage liver disease(MELD) score,including SOFT/P-SOFT score,UCLA-FRS score and BAR score. The other evaluation system is based on the concept of acute-on-chronic liver failure,including CLIF-C-ACLF score,TAM score,AARC-ACLF score and COSSH-ACLF score. The scores based on ACLF have been shown superior power in predicting waiting list survival and post-transplant prognosis than MELD. This article reviews the two kinds of evaluation scores,aiming for the better allocation policy and the better prognosis of benign end-stage liver disease.

[Gastrointestinal reconstruction by intestinal auto-transplantation after radical resection of neoplasms involving superior mesenteric artery: a preliminary consideration].

When abdominal neoplasms originating from the pancreas or nearby organs locally involving the superior mesenteric artery (SMA), complete resection is still the only hope for cure. However, SMA resection and reconstruction is a complex surgical procedure associated with high postoperative morbidity and mortality. Intestinal autotransplantation has recently emerged in clinical practice as a treatment option for selected patients with neoplasms involving the SMA. The original procedure involved en bloc removal of a tumor together with the intestine, ex vivo resection and reconstruction of gastrointestinal tract by an intestinal autograft. To further refine this complex procedure, a modified method was developed in which a segmental bowel autograft is selected and harvested first during the initial stage of the operation, and radical resection of the neoplasm is carried out thereafter. The modification would better protect a healthy bowel autograft from potential damage due to prolonged warm ischemia and allow the subsequent lengthy process of dissection to be performed in an unrushed manner. Furthermore, this alteration would better adhere to the general principles of minimal tumor manipulation during operation and potentially decrease the risks of tumor implantation during in vitro organ perfusion. Although intestinal autotransplantation has expanded eligibility for resection of otherwise unresectable lesions involving the SMA, its operative complexity, high risks, and post-operative complications largely limit its clinical applications.

Genetically edited hepatic cells expressing the NTCP-S267F variant are resistant to hepatitis B virus infection.

The sodium-dependent taurocholate co-transporting polypeptide (NTCP)-S267F variant is known to be associated with a reduced risk of hepatitis B virus (HBV) infection and disease progression. The NTCP-S267F variant displays diminished function in mediating HBV entry, but its function in HBV infection has not been fully established in more biologically relevant models. We introduced the NTCP-S267F variant and tested infectivity by HBV in genetically edited hepatic cells. HepG2-NTCP clones with both homozygous and heterozygous variants were identified after CRISPR base editing. NTCP-S267F homozygous clones did not support HBV infection. The heterozygote clones behaved similarly to wild-type clones. We generated genetically edited human stem cells with the NTCP-S267F variant, which differentiated equally well as wild-type into hepatocyte-like cells (HLCs) expressing high levels of hepatocyte differentiation markers. We confirmed that HLCs with homozygous variant did not support HBV infection, and heterozygous variant clones were infected with HBV equally as well as the wild-type cells. In conclusion, we successfully introduced the S267F variant by CRISPR base editing into the NTCP/SLC10A gene of hepatocytes, and showed that the variant is a loss-of-function mutation. This technology of studying genetic variants and their pathogenesis in a natural context is potentially valuable for therapeutic intervention against HBV.

[Progress and perspectives on adjuvant therapy after curative resection of hepatocellular carcinoma].

Tumor recurrence after curative resection of hepatocellular carcinoma(HCC) is a major challenge to patient survival. Postoperative adjuvant therapy has been proved to be an effective method in tackling tumor recurrence. However,its role in HCC remains unclear. First,there are many differences between Chinese and foreign guidelines in recommendations on adjuvant therapy of HCC. Chinese guidelines have made many recommendations on various modalities of adjuvant therapy of HCC,including anti-viral therapy,transarterial chemoembolization,and herbs. On the contrary,foreign guidelines don't make any recommendation on adjuvant therapy of HCC,except for anti-viral therapy. Second,clear definition of patients who have a higher risk of tumor recurrence is still unknown. In other words,patients who will benefit from adjuvant therapy is unclear. Although various kinds of adjuvant therapies have been proved to be efficient in preventing tumor recurrence and prolonging patient survival,a standard protocol is still lacking. There are many ongoing clinical trials investigating the value of adjuvant therapy in HCC. Emerging evidences will answer questions on the role of adjuvant therapy and how to perform it.

PADI4, negatively regulated by miR-335-5p, participates in regulating the proliferation, migration, invasion and radiosensitivity of nasopharyngeal carcinoma cells.

Peptidyl arginine deiminase 4 (PADI4), an enzyme that converts arginine residues to citrulline residues in the presence of calcium ions, affects the biochemical activities of proteins. The biological function of PADI4 as well as its mechanism in nasopharyngeal carcinoma (NPC) necessitates further investigation. PADI4 expression in NPC tissues and cells was detected using Western blot. qRT-PCR was used to determine the expression of miR-335-5p and PADI4 mRNA in NPC tissues and cells. BrdU assay and CCK-8 assay were employed to detect cell proliferation. Cell migration and invasion were evaluated using Transwell assay. NPC cells were exposed to different doses of radiation in vitro, and then colony formation assays were used to detect colony survival. The target relationship between miR-335-5p and PADI4 was verified using Western blot, qRT-PCR, and dual-luciferase reporter gene assays. Compared with normal mucosal epithelial tissues and cell lines, the expression level of PADI4 in NPC tissues and cells was significantly up-regulated. PADI4 overexpression promoted the proliferation, migration, and invasion of NPC cells. Under radiation, NPC cell survival was significantly promoted by the up-regulation of PADI4. Conversely, knock-down of PADI4 suppressed the above-mentioned malignant phenotypes. MiR-335-5p could bind with the 3' UTR of PADI4 mRNA, and suppressed the expression of PADI4. PADI4 down-regulated the expression of p21 and activated the mTOR signaling pathway. PADI4, which is negatively regulated by miR-335-5p, promotes the proliferation, migration, invasion and radioresistance of NPC cells by regulating the p21 and mTOR signaling pathways.

Randomized Trial of a Vaccine Regimen to Prevent Chronic HCV Infection.

BACKGROUND: A safe and effective vaccine to prevent chronic hepatitis C virus (HCV) infection is a critical component of efforts to eliminate the disease. METHODS: In this phase 1-2 randomized, double-blind, placebo-controlled trial, we evaluated a recombinant chimpanzee adenovirus 3 vector priming vaccination followed by a recombinant modified vaccinia Ankara boost; both vaccines encode HCV nonstructural proteins. Adults who were considered to be at risk for HCV infection on the basis of a history of recent injection drug use were randomly assigned (in a 1:1 ratio) to receive vaccine or placebo on days 0 and 56. Vaccine-related serious adverse events, severe local or systemic adverse events, and laboratory adverse events were the primary safety end points. The primary efficacy end point was chronic HCV infection, defined as persistent viremia for 6 months. RESULTS: A total of 548 participants underwent randomization, with 274 assigned to each group. There was no significant difference in the incidence of chronic HCV infection between the groups. In the per-protocol population, chronic HCV infection developed in 14 participants in each group (hazard ratio [vaccine vs. placebo], 1.53; 95% confidence interval [CI], 0.66 to 3.55; vaccine efficacy, -53%; 95% CI, -255 to 34). In the modified intention-to-treat population, chronic HCV infection developed in 19 participants in the vaccine group and 17 in placebo group (hazard ratio, 1.66; 95% CI, 0.79 to 3.50; vaccine efficacy, -66%; 95% CI, -250 to 21). The geometric mean peak HCV RNA level after infection differed between the vaccine group and the placebo group (152.51×103 IU per milliliter and 1804.93×103 IU per milliliter, respectively). T-cell responses to HCV were detected in 78% of the participants in the vaccine group. The percentages of participants with serious adverse events were similar in the two groups. CONCLUSIONS: In this trial, the HCV vaccine regimen did not cause serious adverse events, produced HCV-specific T-cell responses, and lowered the peak HCV RNA level, but it did not prevent chronic HCV infection. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT01436357.).

N-Terminal PreS1 Sequence Regulates Efficient Infection of Cell-Culture-Generated Hepatitis B Virus.

BACKGROUND AND AIMS: An efficient cell-culture system for hepatitis B virus (HBV) is indispensable for research on viral characteristics and antiviral reagents. Currently, for the HBV infection assay in cell culture, viruses derived from HBV genome-integrated cell lines of HepG2.2.15 or HepAD-38 are commonly used. However, these viruses are not suitable for the evaluation of polymorphism-dependent viral characteristics or resistant mutations against antiviral reagents. HBV obtained by the transient transfection of the ordinary HBV molecular clone has limited infection efficiencies in cell culture. APPROACH AND RESULTS: We found that an 11-amino-acid deletion (d11) in the preS1 region enhances the infectivity of cell-culture-generated HBV (HBVcc) to sodium taurocholate cotransporting polypeptide-transduced HepG2 (HepG2/NTCP) cells. Infection of HBVcc derived from a d11-introduced genotype C strain (GTC-d11) was ~10-fold more efficient than infection of wild-type GTC (GTC-wt), and the number of infected cells was comparable between GTC-d11- and HepG2.2.15-derived viruses when inoculated with the same genome equivalents. A time-dependent increase in pregenomic RNA and efficient synthesis of covalently closed circular DNA were detected after infection with the GTC-d11 virus. The involvement of d11 in the HBV large surface protein in the enhanced infectivity was confirmed by an HBV reporter virus and hepatitis D virus infection system. The binding step of the GTC-d11 virus onto the cell surface was responsible for this efficient infection. CONCLUSIONS: This system provides a powerful tool for studying the infection and propagation of HBV in cell culture and also for developing the antiviral strategy against HBV infection.

Asymptomatic COVID-19 infection in patients with cancer at a cancer-specialized hospital in Wuhan, China - Preliminary results.

OBJECTIVE: Patients with cancer are usually immunosuppressive and susceptible to COVID-19 infection. Asymptomatic COVID-19 cases are infective and cannot be identified by symptom-based screening. There is an urgent need to control virus spread by asymptomatic carriers at cancer centres. We aim to describe the characteristics, screening methods, and outcomes of cancer patients with asymptomatic COVID-19 infection and to further explore anti-tumour treatment for this population. PATIENTS AND METHODS: We reviewed patients with cancer who were admitted to Hubei Cancer Hospital in Wuhan from February 1, 2020, to April 4, 2020. We collected demographic data, laboratory findings, treatment information, nucleic acid and serum test results, chest computed tomography (CT) information and survival status of cancer patients diagnosed with asymptomatic COVID-19 infection. RESULTS: A total of 16 cancer patients with asymptomatic COVID-19 infection were confirmed. The most common cancer type was breast cancer. The blood cell counts of most patients were in the normal range. Lymphocytes of 100% of asymptomatic carriers were in the normal range. Thirteen (81.3%) patients were positive for virus-specific IgM antibodies, and three (18.8%) were positive by PCR; only one (6.3%) patient showed novel coronavirus pneumonia features on CT. Three (18.3%) patients died, and the cause of death was considered malignancy caused by delaying anti-tumour treatment. CONCLUSIONS: Our study shows that the lymphocytes of 100% of asymptomatic carriers were in the normal range. This result indicates that the host immunity of asymptomatic carriers is not significantly disrupted by COVID-19. Single PCR detection is not sufficient to screen among asymptomatic individuals, and a combination of PCR tests, serological tests and CT is of great importance. Unless the tumour is life-threatening or rapidly progressing, we advise restarting active anti-tumour therapy after PCR tests become negative.

[Advances in perioperative systemic therapy for hepatocellular carcinoma].

The low surgical resection rate and high postoperative recurrence rate of hepatocellular carcinoma(HCC) are urgent clinical problems to be solved. Therefore, it is important to develop effective perioperative treatment. In recent years, a growing number of studies have shown that systemic therapy is expected to break through the limitations of traditional local treatment and play an important role in preoperative treatment. For example, some novel targeted agents and immunocheckpoint inhibitors have shown excellent potential as neoadjuvant treatment for HCC. Meanwhile, researchers have explored the application of systemic therapy as adjuvant therapy, but due to different criteria for patient selection, no consensus is reached on its efficacy. By far, there is no standard procedure for the application of systemic therapy in HCC perioperative period, little is known about the efficacy and safety of targeted drugs and immunotherapy. This article discusses the feasibility of systemic therapy as neoadjuvant and adjuvant treatment of HCC, as well as its adverse events, with an aim to provide new horizons of HCC systemic therapy in the perioperative period.

Metabolic Profiling Reveals Aggravated Non-Alcoholic Steatohepatitis in High-Fat High-Cholesterol Diet-Fed Apolipoprotein E-Deficient Mice Lacking Ron Receptor Signaling.

Non-alcoholic steatohepatitis (NASH) represents the progressive sub-disease of non-alcoholic fatty liver disease that causes chronic liver injury initiated and sustained by steatosis and necroinflammation. The Ron receptor is a tyrosine kinase of the Met proto-oncogene family that potentially has a beneficial role in adipose and liver-specific inflammatory responses, as well as glucose and lipid metabolism. Since its discovery two decades ago, the Ron receptor has been extensively investigated for its differential roles on inflammation and cancer. Previously, we showed that Ron expression on tissue-resident macrophages limits inflammatory macrophage activation and promotes a repair phenotype, which can retard the progression of NASH in a diet-induced mouse model. However, the metabolic consequences of Ron activation have not previously been investigated. Here, we explored the effects of Ron receptor activation on major metabolic pathways that underlie the development and progression of NASH. Mice lacking apolipoprotein E (ApoE KO) and double knockout (DKO) mice that lack ApoE and Ron were maintained on a high-fat high-cholesterol diet for 18 weeks. We observed that, in DKO mice, the loss of ligand-dependent Ron signaling aggravated key pathological features in steatohepatitis, including steatosis, inflammation, oxidation stress, and hepatocyte damage. Transcriptional programs positively regulating fatty acid (FA) synthesis and uptake were upregulated in the absence of Ron receptor signaling, whereas lipid disposal pathways were downregulated. Consistent with the deregulation of lipid metabolism pathways, the DKO animals exhibited increased accumulation of FAs in the liver and decreased level of bile acids. Altogether, ligand-dependent Ron receptor activation provides protection from the deregulation of major metabolic pathways that initiate and aggravate non-alcoholic steatohepatitis.

[Developments and controversies in neoadjuvant therapy for resectable pancreatic cancer].

Neoadjuvant therapy has been proved beneficial in patients with non-metastatic pancreatic cancer and it has received unprecedented attention in past years. However, the clinical value of neoadjuvant therapy in resectable pancreatic cancer patients remains controversial.Although the NCCN guideline has recommended that resectable pancreatic cancer patients with high-risk factors should be given preoperative neoadjuvant therapy, there is no consensus on specific criteria, treatment options, treatment duration and timing of surgery.More high-level evidences are strongly required.Recently, the development of new technologies such as liquid biopsy and radiomics analysis for pancreatic cancer will also help to address some clinical problems.This article reviewed the developments and controversies in neoadjuvant therapy for resectable pancreatic cancer.