Hypoxia-inducible factor 1α/IL-6 axis in activated hepatic stellate cells aggravates liver fibrosis.

Hepatic stellate cells (HSCs) upregulate hypoxia inducible factor 1 alpha (HIF-1α) expression in response to fibrosis-induced hypoxia. The mechanism by which HIF-1α promotes liver fibrosis in HSCs is not fully understood. In this study, we found that increased expression of α-SMA, HIF-1α and IL-6, as well as colocalization of α-SMA and HIF-1α, and HIF-1α and IL-6, were observed in liver fibrotic tissues of patients and a mouse model. HIF-1α expression induced IL-6 secretion in activated HSCs and the increase could be abolished by HIF-1α suppression or HIF1A gene knockdown. HIF-1α directly bound to the hypoxia response element (HRE) region in HSC IL6/Il6 promoters. Additionally, culturing naïve CD4 T cells with supernatant from HSCs in which HIF-1α is highly expressed increased IL-17A expression, and the expression could be abolished by HIF1A knockdown in LX2. In turn, the IL-17A-enriched supernatant induced IL-6 secretion in HSCs. Together, these results show that HIF-1α upregulates IL-6 expression in HSCs and induces IL-17A secretion through directly binding to the HRE of IL6 promoter.

Surgical techniques to prevent delayed gastric emptying after pancreaticoduodenectomy.

BACKGROUND: Delayed gastric emptying (DGE) is one of the most common complications after pancreaticoduodenectomy (PD). DGE represents impaired gastric motility without significant mechanical obstruction and is associated with an increased length of hospital stay, increased healthcare costs, and a high readmission rate. We reviewed published studies on various technical modifications to reduce the incidence of DGE. DATA SOURCES: Studies were identified by searching PubMed for relevant articles published up to December 2022. The following search terms were used: "pancreaticoduodenectomy", "pancreaticojejunostomy", "pancreaticogastrostomy", "gastric emptying", "gastroparesis" and "postoperative complications". The search was limited to English publications. Additional articles were identified by a manual search of references from key articles. RESULTS: In recent years, various surgical procedures and techniques have been explored to reduce the incidence of DGE. Pyloric resection, Billroth II reconstruction, Braun's enteroenterostomy, and antecolic reconstruction may be associated with a decreased incidence of DGE, but more high-powered studies are needed in the future. Neither laparoscopic nor robotic surgery has demonstrated superiority in preventing DGE, and the use of staplers is controversial regarding whether they can reduce the incidence of DGE. CONCLUSIONS: Despite many innovations in surgical techniques, there is no surgical procedure that is superior to others to reduce DGE. Further larger prospective randomized studies are needed.

Beneficial effects of Wuzhi Capsule on tacrolimus blood concentrations in liver transplant patients with different donor-recipient CYP3A5 genotypes.

WHAT IS KNOWN AND OBJECTIVE: Tacrolimus (Tac) is an immunosuppressant that is widely used to prevent allograft rejection in patients after liver transplantation. Its metabolism mainly depends on the cytochrome P450 3A5 (CYP3A5), which has genetic polymorphisms. Recently, a Chinese herbal medicine known as Wuzhi Capsule (WZC) was shown to increase Tac blood concentrations by inhibiting the activity of CYP3A in animal studies in rats. To date, it remains unexplored whether WZC can be efficiently used to enhance the blood concentration of Tac in liver transplant patients with different donor-recipient CYP3A5 genotypes. METHODS: A total of 185 liver transplant patients were enrolled and two-way ANOVA was carried out, then they were divided into four groups according to the combinations of donor-recipient CYP3A5 phenotypes. WZC was given to patients when the dose of Tac was ≥4 mg, and the dose-adjusted C0 (C0 /D) of Tac measured twice in succession was ≤1 ng/ml/mg. The blood trough concentration of Tac (C0 ), C0 /D, and dose- and body weight-adjusted C0 (C0 /D/W) was analysed on days 7 and 14 after liver transplantation. RESULTS: The genotypes of donor and recipient or WZC had significant effects on C0, C0/D and C0/D/W. There were significant differences in the Tac blood concentrations between the groups. The recipient expression (*1)/donor expression (*1) (R+/D+) group had the lowest C0 , C0 /D and C0 /D/W among the four groups. Furthermore, a larger proportion of patients in the CYP3A5 expression groups required Tac dose adjustment to achieve a therapeutic effect and were given Tac with WZC. Notably, the use of WZC significantly increased the blood concentrations of Tac in the CYP3A5 expression groups and greater increases in the C0 /D and C0 /D/W were significantly associated with higher doses of WZC in the CYP3A5 expression groups. What is more, WZC reduced the hospitalization cost of patients to a certain extent. WHAT IS NEW AND CONCLUSION: WZC significantly increased the C0 , C0 /D and C0 /D/W in the CYP3A5 expression groups and reduced the hospitalization expenses of patients to a certain extent. What is more, greater increases in the C0 /D and C0 /D/W were significantly associated with higher doses of WZC.

A case of adrenocortical carcinoma accompanying secondary acute adrenal hypofunction postoperation.

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare, heterogeneous malignancy with a poor prognosis. ACCs are classified as functioning and non-functioning. The pathogenesis of ACC remains elusive, and diagnosis of ACC is currently based on pathology. In the absence of other effective approaches, surgical resection is the preferred treatment option. CASE PRESENTATION: Here, we report a case of ACC in the retroperitoneum. The patient underwent radical adrenalectomy and remained disease-free throughout a 6-month follow-up. CONCLUSIONS: Radical surgical resection is an efficient therapy for ACC, and hydrocortisone can be used to alleviate symptoms of secondary acute adrenal hypofunction.

Causal effects of plasma metabolites on chronic kidney diseases and renal function: a bidirectional Mendelian randomization study.

Background: Despite the potential demonstrated by targeted plasma metabolite modulators in halting the progression of chronic kidney disease (CKD), a lingering uncertainty persists concerning the causal relationship between distinct plasma metabolites and the onset and progression of CKD. Methods: A genome-wide association study was conducted on 1,091 metabolites and 309 metabolite ratios derived from a cohort of 8,299 unrelated individuals of European descent. Employing a bidirectional two-sample Mendelian randomization (MR) analysis in conjunction with colocalization analysis, we systematically investigated the associations between these metabolites and three phenotypes: CKD, creatinine-estimated glomerular filtration rate (creatinine-eGFR), and urine albumin creatinine ratio (UACR). In the MR analysis, the primary analytical approach employed was inverse variance weighting (IVW), and sensitivity analysis was executed utilizing the MR-Egger method and MR-pleiotropy residual sum and outlier (MR-PRESSO). Heterogeneity was carefully evaluated through Cochrane's Q test. To ensure the robustness of our MR results, the leave-one-out method was implemented, and the strength of causal relationships was subjected to scrutiny via Bonferroni correction. Results: Our thorough MR analysis involving 1,400 plasma metabolites and three clinical phenotypes yielded a discerning identification of 21 plasma metabolites significantly associated with diverse outcomes. Specifically, in the forward MR analysis, 6 plasma metabolites were determined to be causally associated with CKD, 16 with creatinine-eGFR, and 7 with UACR. Substantiated by robust evidence from colocalization analysis, 6 plasma metabolites shared causal variants with CKD, 16 with creatinine-eGFR, and 7 with UACR. In the reverse analysis, a diminished creatinine-eGFR was linked to elevated levels of nine plasma metabolites. Notably, no discernible associations were observed between other plasma metabolites and CKD, creatinine-eGFR, and UACR. Importantly, our analysis detected no evidence of horizontal pleiotropy. Conclusion: This study elucidates specific plasma metabolites causally associated with CKD and renal functions, providing potential targets for intervention. These findings contribute to an enriched understanding of the genetic underpinnings of CKD and renal functions, paving the way for precision medicine applications and therapeutic strategies aimed at impeding disease progression.

Weather Translation via Weather-Cue Transferring.

In this article, the weather translation task is proposed, which aims to transfer the weather type of the image from one category to another. Weather translation is a complicated image weather editing task that changes the weather cue of an image across multiple weather types, and it is related to image restoration, image editing, and photographic style transfer tasks. Although lots of approaches have been developed for traditional image translation and restoration tasks, only few of them are capable of handling the multicategory weather types problem with a single network due to the rich categories and highly complicated semantic structures of weather images. Especially, it is difficult to change the weather cue while preserving the weather-invariant area. To solve these issues, we developed a weather-cue guided multidomain translation approach based on StarGAN v2, termed WeatherGAN. In the proposed model, the core generator is redesigned to transfer the weather cue according to the target weather type. The weather segmentation module is first introduced to acquire the weather semantic structure of images in a weakly supervised multitask manner. In addition, a weather clues module is presented to reprocess the weather segmentation into a weather-specific clues map, which identifies the weather-invariant and weather-cue areas clearly. Extensive studies and evaluations show that our approach outperforms the state of the art. The data and source code will be publicly available soon after the manuscript is accepted.

The Mechanisms of Systemic Inflammatory and Immunosuppressive Acute-on-Chronic Liver Failure and Application Prospect of Single-Cell Sequencing.

Acute-on-chronic liver failure (ACLF) is a complex clinical syndrome, and patients often have high short-term mortality. It occurs with intense systemic inflammation, often accompanied by a proinflammatory event (such as infection or alcoholic hepatitis), and is closely related to single or multiple organ failure. Liver inflammation begins when innate immune cells (such as Kupffer cells (KCs)) are activated by binding of pathogen-associated molecular patterns (PAMPs) from pathogenic microorganisms or damage-associated molecular patterns (DAMPs) of host origin to their pattern recognition receptors (PRRs). Activated KCs can secrete inflammatory factors as well as chemokines and recruit bone marrow-derived cells such as neutrophils and monocytes to the liver to enhance the inflammatory process. Bacterial translocation may contribute to ACLF when there are no obvious precipitating events. Immunometabolism plays an important role in the process (including mitochondrial dysfunction, amino acid metabolism, and lipid metabolism). The late stage of ACLF is mainly characterized by immunosuppression. In this process, the dysfunction of monocyte and macrophage is reflected in the downregulation of HLA-DR and upregulation of MER tyrosine kinase (MERTK), which weakens the antigen presentation function and reduces the secretion of inflammatory cytokines. We also describe the specific function of bacterial translocation and the gut-liver axis in the process of ACLF. Finally, we also describe the transcriptomics in HBV-ACLF and the recent progress of single-cell RNA sequencing as well as its potential application in the study of ACLF in the future, in order to gain a deeper understanding of ACLF in terms of single-cell gene expression.

Hepatic epithelioid hemangioendothelioma: Update on diagnosis and therapy.

With an estimated incidence of only 1-2 cases in every 1 million people, hepatic epithelioid hemangioendothelioma (HEHE) is a rare vascular endothelial cell tumor occurring in the liver and consisting of epithelioid and histiocyte-like vascular endothelial cells in mucus or a fibrotic matrix. HEHE is characterized as a low-to-moderate grade malignant tumor and is classified into three types: solitary, multiple, and diffuse. Both the etiology and characteristic clinical manifestations of HEHE are unclear. However, HEHE has a characteristic appearance on imaging including ultrasound, magnetic resonance imaging, and positron emission tomography/computerized tomography. Still, its diagnosis depends mainly on pathological findings, with immunohistochemical detection of endothelial markers cluster of differentiation 31 (CD31), CD34, CD10, vimentin, and factor VIII antigen as the basis of diagnosis. Hepatectomy and/or liver transplantation are the first choice for treatment, but various chemotherapeutic drugs are reportedly effective, providing a promising treatment option. In this review, we summarize the literature related to the diagnosis and treatment of HEHE, which provides future perspectives for the clinical management of HEHE.

Fast-growing epithelioid hemangioendothelioma of the liver: A case report.

RATIONALE: Hepatic epithelioid hemangioendothelioma (HEH) is a rare vascular tumor of the liver with malignant potential. It can be of solitary type, multifocal type, or diffuse type. Although there are some characteristic features on radiologic imaging, the definitive diagnosis of HEH is based on histopathology. The surgical treatment of HEH includes liver resection and transplant. PATIENT CONCERNS: A middle-aged woman presented with easy fatiguability and anorexia for 1 month was found to have multifocal lesions on radiological imaging. DIAGNOSIS: HEH was diagnosed by needle biopsy. It can be seen from imaging that this case is a multifocal form. The largest lesion increased from 3 to 3.3 cm within 2 months, with an increase of 9.45%; no other relevant literatures have been reported. INTERVENTIONS: The possibility of liver transplantation was suggested to the patient. However, the patient refused transplantation and was successfully treated by radical right hepatectomy and resection of the left lobe lesion. OUTCOMES: She remained disease-free throughout a year follow-up period. CONCLUSION: HEH is a rare disease with characteristic radiological and pathological features. Although liver transplantation is the preferred treatment for multifocal HEH, surgical excision represents one alternative when the lesions can be guaranteed to be completely excised.

Integrated Chinese Herbal Medicine and Western Medicine on the Survival in Patients with Colorectal Cancer: A Retrospective Study of Medical Records.

Recent studies suggested that Traditional Chinese Medicine could play a beneficial role in conventional cancer treatment. The aim of this retrospective cohort study was to investigate the effect of Chinese herbal medicine (CHM) combined with Western medicine on the survival of patients with colorectal cancer. A retrospective cohort study was conducted on patients with newly diagnosed colorectal cancer identified from the Dalin Tzu Chi Hospital Cancer Registry Database in 2004-2014. Combining with the medical records of the study hospital, patients were classified into CHM users and CHM nonusers. Kaplan-Meier analyses and Cox proportional hazards regression analyses were used to investigate the survival between CHM users and CHM nonusers. A total of 535 patients with colorectal cancer were included in the study with 147 of them were CHM users. The log-rank test for Kaplan-Meier survival curve revealed a statistically significant difference between the survival of CHM users and CHM nonusers (P=0.006). Results from multivariate Cox regression analysis showed that CHM use was significantly associated with better survival (adjusted hazard ratio = 0.54, 95% CI = 0.38 to 0.77). In addition, the CHM formulae Jia Wei Xiao Yao San, Zhi Bah Di Huang Wan, Ping Wei San, and Qui Pi Tang were significantly associated with better survival. In conclusion, findings from this retrospective cohort study indicated that integrated CHM and Western medicine could improve survival in patients with colorectal cancer. Additional research on integrating TCM with Western medicine to improve cancer survival is warranted.

Hem-o-lok clip found in the common bile duct 3 years after laparoscopic cholecystectomy and surgical exploration.

Endoscopic retrograde cholangiopancreatography (ERCP) with stone extraction is a common and preferred choice for gallstone disease. Laparoscopic common bile duct exploration (LCBDE) and laparoscopic cholecystectomy (LC) are being increasingly used for managing choledocholithiasis and cholecystolithiasis. We report a case of a Hem-o-lok clip that was dropped into the common bile duct (CBD) after LC and surgical common bile duct exploration (CBDE). An 84-year-old man presented with right upper quadrant pain and jaundice for 2 months, and chills and hyperpyrexia for 1 day. The patient had received ERCP and surgical CBDE at a local hospital 3 years previously. The patient first received ERCP and endoscopic nasobiliary drainage (ENBD). When laboratory tests were normal, the patient then received LCBDE. During exploration, stones and a Hem-o-lok clip in the CBD were removed. The patient made good progress after LCBDE + T-tube placement and was discharged from hospital. The findings from this case suggest the following: 1) an appropriate therapy method should be considered for certain gallstone diseases, especially for choledocholithiasis and cholecystolithiasis; and 2) a Hem-o-lok clip should be carefully used during laparoscopic or robot-assisted surgery and the Hem-o-lok clip should not be in close proximity to the incision on the CBD.

Occurrence of signet-ring cell carcinoma with cholangiocarcinoma 25 years after choledochal cyst excision: A case report.

RATIONALE: Choledochal cysts are a risk factor for the development of cholangiocarcinoma. Hence, complete surgical excision is the preferred treatment in most cases. However, cholangiocarcinoma still can develop from the remnant biliary system after surgical excision. Signet-ring cell carcinoma is a rare type of cancer of the biliary system, and the occurrence of signet-ring cell carcinoma after surgical excision of choledochal cysts has not been reported in the English literature to date. PATIENT CONCERNS: We report a case of a 32-year-old woman who presented with a 1-month history of abdominal pain,obstructive jaundice, itching, and fever. The patient had undergone choledochal cyst excision and Roux-en-Y hepatico-jejunostomy 25 years previously and had now developed signet-ring cell carcinoma along with cholangiocarcinoma at the anastomotic site. DIAGNOSES:: signet-ring cell carcinoma along with cholangiocarcinoma. INTERVENTIONS: Interventions included laparotomy with evacuation,blood transfusion,and other adjuvant therapy. OUTCOMES: The patient died five months later. LESSONS: Surgery is the best treatment for CCCs, and the surgeon should try to remove as much as of the bile duct cyst as possible.