Cystic duct cancer: Should it be deemed as a type of gallbladder cancer?

BACKGROUND According to the latest American Joint Committee on Cancer and Union for International Cancer Control manuals,cystic duct cancer(CC)is categorized as a type of gallbladder cancer(GC),which has the worst prognosis among all types of biliary cancers.We hypothesized that this categorization could be verified by using taxonomic methods.AIM To investigate the categorization of CC based on population-level data.METHODS Cases of biliary cancers were identified from the Surveillance,Epidemiology,and End Results 18 registries database.Together with routinely used statistical methods,three taxonomic methods,including Fisher’s discriminant,binary logistics and artificial neuron network(ANN)models,were used to clarify the categorizing problem of CC.RESULTS The T staging system of perihilar cholangiocarcinoma[a type of extrahepatic cholangiocarcinoma(EC)]better discriminated CC prognosis than that of GC.After adjusting other covariates,the hazard ratio of CC tended to be closer to that of EC,although not reaching statistical significance.To differentiate EC from GC,three taxonomic models were built and all showed good accuracies.The ANN model had an area under the receiver operating characteristic curve of 0.902.Using the three models,the majority(75.0%-77.8%)of CC cases were categorized as EC.CONCLUSION Our study suggested that CC should be categorized as a type of EC,not GC.Aggressive surgical attitude might be considered in CC cases,to see whether long-term prognosis could be immensely improved like the situation in EC.

Effect of oligofructose on resistance to postoperative high-fat diet-induced damage of metabolism in diabetic rats after sleeve gastrectomy

BACKGROUND Sleeve gastrectomy(SG) can induce prominent remission of type 2 diabetes mellitus.However,the long-term remission rate of diabetes usually decreases over time.Oligofructose has been verified to modulate host metabolism.The aim of this study was to explore the protective effect of oligofructose on high-fat diet(HFD)-induced metabolic dysfunction after SG.AIM To study the effect and mechanism of oligofructose on diabetic remission in diabetic rats after SG.METHODS SG and SHAM operation were performed on diabetes rats induced with an HFD,nicotinamide,and low-dose streptozotocin.Then the rats in the SHAM and SG groups were continuously provided with the HFD,and the rats in sleeve gastrectomy-oligofructose group were provided with a specific HFD containing10% oligofructose.Body weight,calorie intake,oral glucose tolerance test,homeostasis model assessment of insulin resistance,lipid profile,serum insulin,glucagon-like peptide 1(GLP-1),total bile acids,lipopolysaccharide(LPS),and colonic microbiota levels were determined and compared at the designated time points.All statistical analyses were performed using Statistic Package for Social Science version 19.0(IBM,United States),and the statistically significant difference was considered at P <0.05.RESULTS At 2 wk after surgery,rats that underwent SG exhibited improved indexes of glucose and lipid metabolism.Compared with the SG group,the rats from SGoligofructose group exhibited better parameters of glucose and lipid metabolism,lower body weight(526.86±21.51 vs 469.25±21.84,P <0.001),calorie intake(152.14±9.48 vs 129.63±8.99,P <0.001),homeostasis model assessment of insulin resistance(4.32±0.57 vs 3.46±0.52,P <0.05),and LPS levels(0.19±0.01 vs 0.16±0.01,P <0.05),and higher levels of insulin(1.17±0.17 vs 1.58±0.16,P <0.001) and GLP-1(12.39±1.67 vs 14.94±1.86,P <0.001),and relative abundances of Bifidobacterium(0.0034±0.0014 vs 0.0343±0.0064,P <0.001),Lactobacillus(0.0161±0.0037 vs 0.0357±0.0047,P <0.001),and Akkermansia muciniphila(0.0050±0.0024 vs 0.0507±0.0100,P <0.001) at the end of the study.However,no difference in total bile acids levels was observed between the two groups.CONCLUSION Oligofructose partially prevents HFD-induced glucose and lipid metabolism damage after SG,which may be due to the changes of calorie intake,insulin,GLP-1,LPS,and the gut microbiota in rats.

Robotic single-incision left hemihepatectomy for intrahepatic bile duct stones by Da Vinci single-site surgical system: A case report with video

Minimally invasive surgery is a trend in hepatobiliary surgery.A 56-year-old female patient was admitted to our institution for intrahepatic lithiasis.The CT scan showed multiple calculi in the left liver,dilation of the left intrahepatic bile duct and liver atrophy of the left lobe.Robotic single-incision left hemihepatectomy by the single-site systemwas successfully applied.With the idea of enhanced recovery after surgery,the patient was discharged on the third day after the operation without any morbidity.Robotic single-incision surgery is more frequent in gynecologic and urological surgery.As far as we know,this is the first robotic single-incision left hemihepatectomy report in the world.

GelNB molecular coating as a biophysical barrier to isolate intestinal irritating metabolites and regulate intestinal microbial homeostasis in the treatment of inflammatory bowel disease

Inflammatory bowel disease(IBD)is a chronic,immune-mediated inflammatory disease characterized by the destruction of the structure and function of the intestinal epithelial barrier.Due to the poor remission effect and severe adverse events associated with current clinical medications,IBD remains an incurable disease.Here,we demonstrated a novel treatment strategy with high safety and effective inflammation remission via tissue-adhesive molecular coating.The molecular coating is composed of o-nitrobenzaldehyde(NB)-modified Gelatin(GelNB),which can strongly bond with-NH_(2)on the intestinal surface of tissue to form a thin biophysical barrier.We found that this molecular coating was able to stay on the surface of the intestine for long periods of time,effectively protecting the damaged intestinal epithelium from irritations of external intestinal metabolites and harmful flora.In addition,our results showed that this coating not only provided a beneficial environment for cell migration and proliferation to promote intestinal repair and regeneration,but also achieved a better outcome of IBD by reducing intestinal inflammation.Moreover,the in vivo experiments showed that the GelNB was better than the classic clinical medication-mesalazine.Therefore,our molecular coating showed potential as a promising strategy for the prevention and treatment of IBD.

Multifunctional RGD coated a single-atom iron nanozyme:A highly selective approach to inducing ferroptosis and enhancing immunotherapy for pancreatic cancer

Nanozyme is a new promising approach to cancer therapy for its ability to induce ferroptosis by activating H_(2)O_(2)via a traditional radical pathway and enhance cancer immunotherapy.However,short half-life period of hydroxyl radical(·OH)results in unsatisfied effectiveness.Herein,we synthesized a single-atom iron nanozyme(Fe-SAzyme),which can activate H_(2)O_(2)via a non-radical pathway to generate Fe-based reactive oxygen species(ROS)(O=FeO_(3)=O)for promoting the ferroptosis of pancreatic cancer cells.This Fe-SAzyme could be specifically phagocytosed by pancreatic cancer cells,increasing ROS levels and inhibiting glutathione(GSH)synthesis,which activates ferroptosis.Tumor magnetic resonance imaging(MRI)showed decreased T2 signal after intravenous injection of RGD@Fe-AC(AC=activated carbon).Moreover,RGD@Fe-AC promoted dendritic cell(DC)maturation,overcame Treg-mediated immunosuppression,activated T cells to trigger adaptive immune responses,and enhanced the efficacy ofα-PD-L1 immunotherapy.Our research demonstrated that RGD@Fe-AC provided a straightforward,easily implemented,and selective approach for pancreatic cancer treatment and immunotherapy.

Development of synthetic lethality in cancer:molecular and cellular classification

Recently,genetically targeted cancer therapies have been a topic of great interest.Synthetic lethality provides a new approach for the treatment of mutated genes that were previously considered unable to be targeted in traditional genotype-targeted treatments.The increasing researches and applications in the clinical setting made synthetic lethality a promising anticancer treatment option.However,the current understandings on different conditions of synthetic lethality have not been systematically assessed and the application of synthetic lethality in clinical practice still faces many challenges.Here,we propose a novel and systematic classification of synthetic lethality divided into gene level,pathway level,organelle level,and conditional synthetic lethality,according to the degree of specificity into its biological mechanism.Multiple preclinical findings of synthetic lethality in recent years will be reviewed and classified under these different categories.Moreover,synthetic lethality targeted drugs in clinical practice will be briefly discussed.Finally,we will explore the essential implications of this classification as well as its prospects in eliminating existing challenges and the future directions of synthetic lethality.

A novel scoring system for conversion and complication in laparoscopic liver resection

Background:Although laparoscopic liver resection(LLR)has been increasingly popular worldwide,there is lack of predictive model to evaluate the feasibility and safety of LLR.The aim of this study was to establish a scoring system for predicting the possibility of conversion and complication,which could facilitate the patient selection for clinicians and communication with patients and their relatives during the informed consent process.Methods:Consecutively 696 patients between August 1998 and December 2016 underwent LLR were recruited.The entire cohort was divided randomly into development and validation cohorts.The scoring system for conversion and complication were established according to risk factors identified from multiple logistic analysis.Subgroup analysis was performed to assess the clinical application.And the C-index and decision curve analysis(DCA)were conducted to evaluate the discrimination in comparison with other predictive models.Results:Six hundred and ninety-six patients were enrolled eventually.The rate of conversion in the development and validation cohorts was 8.3%and 10.3%,respectively.Compared with 12.6%complication rate in the development cohort,12.9%was concluded in the validation cohort.Upon on the identified risk factors,the risk stratification model was established and validated.Subsequent subgroup analysis indicated low risk patients presented superior surgical outcomes compared with high risk patients.Besides,the C-index and DCA implied our models had better capacities of predicting conversion and complication in comparison with previous scoring systems.Conclusions:This novel scoring system presents the remarkable capacities of predicting conversion,complication in LLR.And thereby,it could be a useful instrument to facilitate the patient selection for clinicians and communication with patients and their relatives during the informed consent process.

The origin of newborn hepatocytes in associating liver partition and portal vein ligation for staged hepatectomy(ALPPS)-derived regeneration

Associating liver partition and portal vein ligation for staged hepatectomy(ALPPS)has attracted interest in the field of hepatobiliary surgery worldwide(1).Given the significant improvement in morbidity and mortality,the ALPPS became safer in experienced centres,while research on the mechanism of ALPPS lags far behind clinical studies.Despite basic studies showing that activated hepatic stellates via Indian hedgehog/Gli1 pathway,mitochondria metabolism and inflammation were involved in ALPPS-derived regeneration,the cellular source of rapid self-duplication of hepatocytes during ALPPS stage I has not been well-documented(2,3).Therefore,the aim of this study was to explore the origin of newborn hepatocytes during ALPPS procedure.

CircRNA-SORE mediates sorafenib resistance in hepatocellular carcinoma by stabilizing YBX1

Sorafenib is the first-line chemotherapeutic therapy for advanced hepatocellular carcinoma(HCC).However,sorafenib resistance significantly limits its therapeutic efficacy,and the mechanisms underlying resistance have not been fully clarified.Here we report that a circular RNA,circRNA-SORE(a circular RNA upregulated in sorafenib-resistant HCC cells),plays a significant role in sorafenib resistance in HCC.We found that circRNA-SORE is upregulated in sorafenib-resistant HCC cells and depletion of circRNA-SORE substantially increases the cell-killing ability of sorafenib.Further studies revealed that circRNA-SORE binds the master oncogenic protein YBX1 in the cytoplasm,which prevents YBX1 nuclear interaction with the E3 ubiquitin ligase PRP19 and thus blocks PRP19-mediated YBX1 degradation.Moreover,our in vitro and in vivo results suggest that circRNA-SORE is transported by exosomes to spread sorafenib resistance among HCC cells.Using different HCC mouse models,we demonstrated that silencing circRNA-SORE by injection of siRNA could substantially overcome sorafenib resistance.Our study provides a proof-of-concept demonstration for a potential strategy to overcome sorafenib resistance in HCC patients by targeting circRNA-SORE or YBX1.

CRISPR-Cas9-based genome-wide screening identified novel targets for treating sorafenib-resistant hepatocellular carcinoma:a cross-talk between FGF21 and the NRF2 pathway

The treatment of hepatocellular carcinoma(HCC)has been dominated by multikinase inhibitors for more than a decade.However,drug resistance can severely restrict the efficacy of these drugs.Using CRISPR/CAS9 genome library screening,we evaluated Kelch-like ECH-associated protein 1(KEAP1)as a key regulator of sorafenib’s susceptibility in HCC.We also investigated whether KEAP1’s knockdown can stabilize nuclear factor(erythroid-derived 2)-like 2(NRF2)protein levels that led to sorafenib’s resistance,including an NRF2 inhibitor that can synergize with sorafenib to abolish HCC’s growth in vitro and in vivo.Furthermore,we clarified that fibroblast growth factor 21(FGF21)is an important downstream regulator of NRF2 in HCC.Intriguingly,we observed that FGF21 bound to NRF2 through the C-terminus of FGF21,thereby stabilizing NRF2 by reducing its ubiquitination and generating a positive feedback loop in sorafenib-resistant HCC.These findings,therefore,propose that targeting FGF21 is a promising strategy to combat HCC sorafenib’s resistance.

UBQLN1 mediates sorafenib resistance through regulating mitochondrial biogenesis and ROS homeostasis by targeting PGCip in hepatocellular carcinoma

The treatment for hepatocellular carcinoma(HCC)is promising in recent years,but still facing critical challenges.The first targeted therapy,sorafenib,prolonged the overall survival by months.However,resistance often occurs,largely limits its efficacy.Sorafenib was found to target the electron transport chain complexes,which results in the generation of reactive oxygen species(ROS).To maintain sorafenib resistance and further facilitate tumor progression,cancer cells develop strategies to overcome excessive ROS production and obtain resistance to oxidative stress-induced cell death.In the present study,we investigated the roles of ROS in sorafenib resistance,and found suppressed ROS levels and reductive redox states in sorafenib-resistant HCC cells.Mitochondria in sorafenib-resistant cells maintained greater functional and morphological integrity under the treatment of sorafenib.However,cellular oxygen consumption rate and mitochondria DNA content analyses revealed fewer numbers of mitochondria in sorafenib-resistant cells.Further investigation attributed this finding to decreased mitochondrial biogenesis,likely caused by the accelerated degradation of peroxisome proliferator-activated receptor y coactivator ip(PGC1P).Mechanistic dissection showed that upregulated UBQLN1 induced PGCip degradation in a ubiquitination-independent manner to attenuate mitochondrial biogenesis and ROS production in sorafenib-resistant cells under sorafenib treatment.Furthermore,clinical investigations further indicated that the patients with higher UBQLN1 levels experienced worse recurrence-free survival.In conclusion,we propose a novel mechanism involving mitochondrial biogenesis and ROS homeostasis in sorafenib resistance,which may offer new therapeutic targets and strategies for HCC patients.

一项基于肿瘤基因数据库关于综合分析缺氧导致的肝细胞癌的蛋白预测标志物miR-210变化的研究（英文）

目的:研究肝癌细胞缺氧微环境导致miR-210表达变化与肿瘤进展、预后等相关性。创新点:首次阐明了miR-210表达与肝癌预后及缺氧相关基因的关系。方法:选取肿瘤基因数据库(TCGA)中424位肝癌患者的miR-210表达水平、临床病理参数及缺氧相关基因(HIFla、HIF3a、PTPN1和BNIP3)表达量,研%miR-210与肝癌预后及缺氧基因之间的相关性。结论:miR-210的表达与肝细胞癌进展分期呈正相关,它的高表达预示更低的无瘤生存率。因此,推测miR-210可能与肿瘤细胞缺氧相关性死亡有关。

DDB1-and CUL4-associated factor 8 plays a critical role in spermatogenesis

Cullin-RING E3 ubiquitin ligase(CRL)-4 is a member of the large CRL family in eukaryotes.It plays important roles in a wide range of cellular processes,organismal development,and physiological and pathological conditions.DDB1-and CUL4-associated factor 8(DCAF8)is a WD40 repeat-containing protein,which serves as a substrate receptor for CRL4.The physiological role of DCAF8 is unknown.In this study,we constructed Dcaf8 knockout mice.Homozygous mice were viable with no noticeable abnormalities.However,the fertility of Dcaf8-deficient male mice was markedly impaired,consistent with the high expression of DCAF8 in adult mouse testis.Sperm movement characteristics,including progressive motility,path velocity,progressive velocity,and track speed,were significantly lower in Dcaf8 knockout mice than in wild-type(WT)mice.However,the total motility was similar between WT and Dcaf8 knockout sperm.More than 40%of spermatids in Dcaf8 knockout mice showed pronounced morphological abnormalities with typical bent head malformation.The acrosome and nucleus of Dcaf8 knockout sperm looked similar to those of WT sperm.In vitro tests showed that the fertilization rate of Dcaf8 knockout mice was significantly reduced.The results demonstrated that DCAF8 plays a critical role in spermatogenesis,and DCAF8 is a key component of CRL4 function in the reproductive system.

CircRNA-SORE mediates sorafenib resistance inhepatocellular carcinoma by stabilizing YBX1

Sorafenib is the first-line chemotherapeutic therapy for advanced hepatocellular carcinoma(HCC).However,sorafenib resistance significantly limits its therapeutic efficacy,and the mechanisms underlying resistance have not been fully clarified.Here we report that a circular RNA,circRNA-SORE(a circular RNA upregulated in sorafenib-resistant HCC cells),plays a significant role in sorafenib resistance in HCC.We found that circRNA-SORE is upregulated in sorafenib-resistant HCC cells and depletion of circRNA-SORE substantially increases the cell-killing ability of sorafenib.Further studies revealed that circRNA-SORE binds the master oncogenic protein YBX1 in the cytoplasm,which prevents YBX1 nuclear interaction with the E3 ubiquitin ligase PRP19 and thus blocks PRP19-mediated YBX1 degradation.Moreover,our in vitro and in vivo results suggest that circRNA-SORE is transported by exosomes to spread sorafenib resistance among HCC cells.Using different HCC mouse models,we demonstrated that silencing circRNA-SORE by injection of siRNA could substantially overcome sorafenib resistance.Our study provides a proof-of-concept demonstration for a potential strategy to overcome sorafenib resistance in HCC patients by targeting circRNA-SORE or YBX1.