Background: Combination therapies can convert unresectable hepatocellular carcinoma (uHCC) to resectable disease, but quantifying the unbiased survival benefit attributable to conversion remains methodologically challenging. This study aimed to rigorously evaluate the prognostic association of successful conversion and compare subsequent management pathways. Methods: In this retrospective study of 362 patients with uHCC treated with lenvatinib, programmed cell death 1 (PD-1) inhibitors, and transarterial embolization (TAE)-hepatic arterial infusion chemotherapy (HAIC), we quantified the survival association of conversion using a time-dependent Cox model to address immortal time bias. Treatment pathways were categorized as surgically managed conversion (SMC), medically maintained conversion (MMC), or conversion not-achieved. We employed inverse probability of treatment weighting (IPTW) and restricted mean survival time (RMST) analysis for robust comparisons. Results: The conversion rate was 34.0% (123/362). After adjustment, successful conversion was independently associated with significantly improved overall survival [OS; hazard ratio (HR) =0.39, 95% confidence interval (CI): 0.25-0.60, P<0.001]. A distinct clinical trajectory was observed: SMC patients had the most favorable prognosis (median OS not reached), followed by MMC (median OS not reached), with conversion not-achieved patients having the poorest survival (median OS 18.4 months; P<0.001 for trend). Among converters, surgical resection was consistently associated with additional survival benefit after IPTW adjustment [OS: HR =0.28; progression-free survival (PFS): HR =0.39]. Conclusions: Successful conversion is a strong prognostic marker that identifies a pivotal window for intervention in selected patients with uHCC; within this window, surgery resection is associated with the greatest survival advantage. This study provides a methodological framework for reliably evaluating conversion therapy outcomes in real-world settings.

It has been reported that the epithelial-mesenchymal transition (EMT) plays an important role in hepatocellular carcinoma (HCC). However, the relationship between the insulin-like growth factor-1 (IGF-1) and EMT of HCC was not fully elucidated. In the present work, we found that the expression of N-cadherin, Vimentin, Snail1, Snail2, and Twist1 was positively associated with IGF-1R expression, while E-cadherin expression was negatively associated with IGF-1 expression in human HCC samples. Furthermore, we observed that IGF-1 up-regulated the expression of N-cadherin, Vimentin, Snail1, Snail2 and Twist1, and down-regulated the expression of E-cadherin. In addition, Stat5 was induced in IGF-1-treated HepG2 and Hep3B cells, and Stat5 inhibition or siRNA significantly affected IGF-1-induced EMT in HepG2 and Hep3B cells. In conclusion, IGF-1 induces EMT of HCC via Stat5 signaling pathway. Thus, IGF-1/Stat5 can be recommended as a potential and novel therapeutic strategy for HCC patients.

Spironolactone improves cardiac structure, function and prognosis in patients with heart failure and delays the progression of cardiac fibrosis. However, the exact underlying mechanism of this process remains to be elucidated. The present study therefore aimed to explore the protective effect and underlying mechanism of the aldosterone receptor antagonist, spironolactone, on myocardial fibrosis in mice with experimental autoimmune myocarditis (EAM). The EAM model was induced in BALB/c mice via immunization with murine cardiac α-myosin heavy chain sequence polypeptides. The cardiac function of the mice was assessed using echocardiography and the levels of inflammatory cytokines were quantified using ELISA. E26 transformation-specific sequence-1 (Ets-1) expression was knocked down using lentivirus-mediated small interference RNA. Total collagen deposition was assessed using Masson's trichrome and Ets-1, TGF-β1, Smad2/3, collagen I and III protein expression levels were detected using immunohistochemistry and western blotting. MMP-2 and MMP-9 mRNA expression levels and activity was determined using reverse transcription-quantitative PCR and gelatin zymography, respectively. The results of the present study demonstrated that spironolactone significantly improved myocardium hypertrophy, diastolic cardiac function and decreased myocardial inflammation and collagen deposition induced by EAM. Spironolactone treatment significantly inhibited Ets-1 and smad2/3 phosphorylation. In addition, inhibition of Ets-1 reduced the expression and activity of MMP-2 and MMP-9 and decreased cardiac fibrosis in EAM mice. The results indicated that the improvement of myocardial fibrosis by spironolactone may be associated with the TGF-β1/Smad-2/3/Ets-1 signaling pathway in EAM mice.

An amendment to this paper has been published and can be accessed via the original article.

BACKGROUND Diabetes is related to higher risk of multiple cancers. This study aimed to explore the effect and mechanism of diabetes on liver metastasis of CRC. MATERIAL AND METHODS Overall and liver metastasis-free survival in diabetic and non-diabetic CRC patients were compared by Kaplan-Meier analysis. Expression of alphavß6 was detected by immunohistochemistry in clinical specimens. Effects of hyperglycemia on alphavß6 expression in colon cancer cells were assessed by western blot, real-time PCR, and flowcytometry. Effects of hyperglycemia on migration and invasion were demonstrated by Transwell assay. Expression and activity of MMP-9 and MMP-2 were determined by real-time PCR and gelatin zymography. Liver metastatic nodules were counted and b6 expression was detected by western blot in a liver metastasis mouse model. RESULTS CRC patients with diabetes had poorer overall and liver metastasis-free survival, and diabetes was associated with higher alphavß6 expression in CRC specimens. Hyperglycemia promoted the invasion and migration of colon cancer cells, and upregulated the expression and activity of MMP-9, which were attenuated by inhibition of alphavß6. Hyperglycemia upregulated the expression of ß6 and cell surface expression of avb6, which was reduced by ERK inhibitor. The in vitro results were confirmed in vivo in the mouse model. CONCLUSIONS Our study demonstrated the enhancing effect of hyperglycemia on liver metastasis of CRC, and showed that alphavß6 was involved in this process, suggesting that control of glucose levels and inhibition of alphavß6 can reduce the risk of liver metastasis in diabetic CRC patients.

Cancer involves the reprogramming of the body’s cells to allow them to grow, divide, and travel throughout the body. One of the processes involved – metabolic reprogramming – allows cells to use new energy sources for fuel, switching from oxidative phosphorylation to glycolysis. and enabling tumor cells to grow uncontrolled. A recent study evaluated the involvement of the tumor suppressor gene PTEN in metabolic reprogramming. Researchers compared cancerous and noncancerous liver tissue from 128 patients with hepatocellular carcinoma. They found that in cancerous liver tissue, PTEN had a reciprocal relationship with another protein, PI3K. PTEN was downregulated in HCC tissues, and its loss predicted a poor prognosis. Overexpressing PTEN blocked the switch to glycolysis, while elevated PI3K expression was observed in HCC tissues and was inhibited by PTEN overexpression. This suggests that loss of PTEN is a major event during cancer progression, enabling tumor cells to proliferate inde�nitely, making the PTEN/PI3K axis an ideal target for new avenues of HCC treatment.

Oxaliplatin is a core chemotherapeutic agent used for the treatment of colorectal liver metastasis; however, liver injury caused by oxaliplatin increases the risk of peri-operative morbidity and mortality. Magnesium isoglycyrrhizinate (MgiG) is a magnesium salt of 18-alpha glycyrrhizic acid stereo-isomer that has demonstrated liver-protective effects against toxins and hepatitis. In the present study, the liver-protective effect of MgiG against oxaliplatin-induced hepatic injury was examined in vitro and in vivo. The results demonstrated that MgiG had a protective effect against oxaliplatin-induced liver injury, as evidenced by the alleviation of hepatic pathological damage and transaminase levels. The protective effect of MgiG was demonstrated to be correlated with inhibition of oxidative stress, the interleukin-6 pathway and the coagulation system. Altogether, the present findings suggested that MgiG may have potential value in the clinical prevention and treatment of oxaliplatin-induced liver injury.

AIM:To prospectively evaluate the effect of local wound infiltration with ropivacaine on postoperative pain relief and stress response reduction after open hepatectomy.METHODS:A total of 56 patients undergoing open hepatectomy were randomly divided into two groups: a ropivacaine group (wound infiltration with ropivacaine solution) and a control group (infiltration with isotonic saline solution). A visual analog scale (VAS) at rest and on movement was used to measure postoperative pain for the first 48 h after surgery. Mean arterial pressure (MAP), heart rate (HR), time to bowel recovery, length of hospitalization after surgery, cumulative sufentanil consumption, and incidence of nausea and vomiting were compared between the two groups. Surgical stress hormones (epinephrine, norepinephrine, and cortisol) were detected using enzyme-linked immunosorbent assay, and the results were compared.RESULTS:VAS scores both at rest and on movement at 24 h and 48 h were similar between the two groups. Significantly lower VAS scores were detected at 0, 6, and 12 h in the ropivacaine group compared with the control group (P < 0.05 for all). MAP was significantly lower at 6, 12, and 24 h (P < 0.05 for all); HR was significantly lower at 0, 6, 12, and 24 h (P < 0.05 for all); time to bowel recovery and length of hospitalization after surgery (P < 0.05 for both) were significantly shortened; and cumulative sufentanil consumption was significantly lower at 6, 12, 24, and 36 h (P < 0.05 for all) in the ropivacaine group than in the control group, although the incidence of nausea and vomiting showed no significant difference between the two groups. The levels of epinephrine, norepinephrine, and cortisol were significantly lower in the ropivacaine group than in the control group at 24 and 48 h (P < 0.01 for all).CONCLUSION:Local wound infiltration with ropivacaine after open hepatectomy can improve postoperative pain relief, reduce surgical stress response, and accelerate postoperative recovery.

BACKGROUND:Both phosphorylated signal transducer and activator of transcription 3(pStat-3) and integrin αvβ6 can play vital role in the development and progression of cancer. However, little is known about their expression correlation and clinical significance in gallbladder cancer(GBC).OBJECTIVE:The aim of our present study was to investigate the expression of pStat-3 and integrin αvβ6, two proteins' correlation and their clinical significance in GBC tissues.RESULTS:The expression of pStat-3 and integrin αvβ6 were both significantly associated with T stage, lymph node metastasis status, TNM stage (P=0.008, P=0.000, P=0.000 and P=0.036, P=0.001,P=0.000,respectively). IHC and Western blot showed their expressions in GBC tissues were higher than that in paraneoplastic tissues. Moderate positive correlation existed between the two proteins (r =0.349, P <0.001). The survival analysis by Kaplan-Meier and Cox regression model showed that GBC patients with pStat-3 or integrin αvβ6 positive expression had a significantly poorer 2-year survival rate (P = 0.002 and 0.000, the log-rank test, respectively), and either marker could act as unfavorable independent prognostic factors(RR=1.907, P=0.021 and RR=2.046, P=0.038).MATERIALS AND METHODS:The expression levels of pStat-3 and integrin αvβ6 were analyzed in GBC cancerous and paraneoplastic tissues of 97 cases via immunohistochemistry(IHC) and further validated by western blot method. Besides, SPSS software was used to observe their clinical significance as well as the two proteins' correlation.CONCLUSION:pStat-3 and integrin αvβ6 were indicators of tumor's progression and poor prognosis of patients with GBC. And the further study involving them may provide a helpful therapeutic target in prevention and treatment of GBC patients.

Ulinastatin exhibits anti-inflammatory activity and protects the heart from ischemia/reperfusion injury. However, whether ulinastatin has a protective effect in diabetic cardiomyopathy is yet to be elucidated. The aim of the present study was to investigate the protective effects of ulinastatin against diabetic cardiomyopathy and its underlying mechanisms. A C57/BL6J mice model of diabetic cardiomyopathy was used and mice were randomly assigned to three groups: Control group, diabetes mellitus (DM) group and DM + ulinastatin treatment group. Cardiac function was assessed using echocardiography and the level of inflammatory cytokine high mobility group box 1 (HMGB1) expression was measured using histopathological examination and reverse transcription-quantitative polymerase chain reaction. The levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6 were measured using western blotting and ELISA. The apoptosis rate in the myocardium was assessed by TUNEL assay. Caspase-3 activation, expression of B-cell lymphoma 2 (Bcl-2) and Bcl-2 associated × (Bax) were measured using western blotting, as was the activity of the mitogen activated protein kinase (MAPK) signaling pathway. The results indicated that ulinastatin significantly improved cardiac function in mice with DM. Ulinastatin treatment significantly downregulated HMGB1, TNF-α and IL-6 expression (P<0.05) and significantly reduced the percentage of apoptotic cardiomyocytes (P<0.05) via reduction of caspase-3 activation and the ratio of Bax/Bcl-2 in diabetic hearts (P<0.05). In addition, ulinastatin attenuated the activation of the MAPK signaling pathway. In conclusion, ulinastatin had a protective effect against DM-induced cardiac dysfunction in a mouse model. This protective effect may be associated with the anti-inflammatory and anti-apoptotic abilities of ulinastatin via the MAPK signaling pathway.

Liu, Enyu MD; Vasan, Robin V. MD; Kuehn, Florian MD; Zhang, Zongli MD; Zhao, ChuanZong MD; Wang, Ben MD Author Information

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most deadly cancers and is expected to become the second leading cause of cancer death by 2030. Despite extensive efforts to improve surgical treatment, limited progress has been made. Increasing evidence indicates that integrin β6 plays a crucial role in carcinoma invasion and metastasis. However, the expression and role of β6 in PDAC remain largely unknown. In the present study, we investigated the expression of β6 in PDAC and its potential value as a prognostic factor and therapeutic target. β6 upregulation was identified as an independent unfavorable prognostic indicator. Integrin β6 markedly promoted the proliferation and invasion of pancreatic carcinoma cells and induced ETS1 phosphorylation in an ERK-dependent manner, leading to the upregulation of matrix metalloprotease-9, which is essential for β6-mediated invasiveness of pancreatic carcinoma cells. Accordingly, small interfering RNA-mediated silencing of integrin β6 markedly suppressed xenograft tumor growth in vivo. Taken together, our results suggest that integrin β6 plays important roles in the progression of pancreatic carcinoma and contributes to reduced survival times, and may serve as a novel therapeutic target for the treatment of PDAC.

Background: Since the advent of four-port laparoscopic cholecystectomy (LC), many modifications have been made that aimed to improve cosmesis and patient prognosis. Here we compared a variety of surgical outcomes such as quality of life three months after surgery between three-port LC and conventional four-port LC. Methods: This study presents an analysis of 245 patients with cholelithiasis who were between 31 and 78 years of age and who underwent elective LC between May 2013 and December 2014. Patients were randomized to undergo either the three-port LC or four-port LC surgery. Operation and hospitalization details were collected. Cosmetic outcome and quality of life of patients were assessed by the validated Patient Scar Questionnaire and MOS-24 questionnaire, respectively, 3 months after surgery. Results: 245 patients were included, and a complete follow-up was possible for 216 patients (88%). The average length of hospital stay, as well as time needed for return to normal activity and work, was significantly shorter in the three-port group than in the four-port group. No significant differences were observed for operating time and bleeding volume. The average hospitalization cost was lower, and, more importantly, patients had a significantly better cosmetic outcome and quality of life scores at 3 months in the three-port group. Conclusion: Three-port LC was as effective as the conventional four-port LC, and it shortened hospital stay, reduced hospitalization cost, and accelerated patient recovery. Moreover, the cosmetic outcome and quality of life were better.

目的:探讨丹参酮ⅡA磺酸钠注射液对行肝门阻断术患者血流动力学及血液流变学影响.方法:选取我院肝胆外科收治的原发性肝癌患者92例,随机数字表达法分为2组,其中对照组46例,全麻行肝癌根治术治疗;实验组46例,在手术前7d予以丹参酮ⅡA磺酸钠注射液,80 mg注入150mL0.9％氯化钠注射液中,日一次静滴,连续治疗7d.分别观察两组患者肝门阻断前及阻断后1 min,5 min,10 min,20 min和解除阻断后30 min血流动力学及血液流变学.结果:①实验组患者肝门阻断后10 min和阻断20 min两个时间段的心率(Heart rate,HR)明显低于对照组同时间段HR,平均动脉压(Mean arterial pressure,MAP)、心排出量(Cardiac output,CO)、左室做功指数(The left ventricular work index,LCWI)明显高于对照组同时间段,差异有统计学意义(P＜0.05).②实验组患者肝门阻断后10 min和阻断20 min两个时间段的全血高切粘度、全血低切粘度、血浆比粘度和纤维蛋白定量明显低于对照组同时间段,差异有统计学意义(P＜0.05).结论:丹参酮ⅡA磺酸钠注射液能够明显改善肝门阻断术引起的血流动力学及血液流变学各项指标,从而保证原发性肝癌手术过程中肝脏的供血量,防止血液凝聚导致的血栓形成.

目的:分析和总结胰腺癌的手术治疗经验,结合相关资料探讨胰腺癌可切除性的评估标准.方法:对2007年1月至2012年1月手术治疗胰腺癌患者的诊断和治疗进行回顾性分析.结合患者病程、临床症状和体征、肿瘤TSN分期和影像学检查等资料,随访患者是否死亡及死亡时间、原因等数据,对胰腺癌的可切除性进行评估.结果:89例胰腺癌中,50例首发症状为上腹部疼痛和/或上腹部饱胀不适.25例为皮肤巩膜黄染、皮肤瘙痒和茶色尿等症状.肿瘤分期为Ⅰ、Ⅱ期和术前影像学检查中提示肿瘤未侵犯血管和无远处转移的患者切除率较高.结论:术前影像学检查及肿瘤TSN分期可用于胰腺癌可切除性评估.

BACKGROUND:The bedside index of severity in acute pancreatitis (BISAP) is a new, convenient, prognostic multifactor scoring system. As there were no studies designed to validate this system according to the latest Atlanta classification in China and more data are needed before clinical application, we compared BISAP, the Acute Physiology and Chronic Health Evaluation (APACHE) II and Ranson scoring systems in predicting the severity, pancreatic necrosis and mortality of acute pancreatitis (AP) using the latest 2012 Atlanta classification in a tertiary care center in China. METHODS:The medical records of all patients with AP admitted to our hospitals between January 2010 and June 2013 were reviewed retrospectively. Severe AP was defined as the persistence of organ failure for more than 48 h. The capacity of the BISAP, APACHE II and Ranson's score system to predict severity, pancreatic necrosis and mortality was evaluated using linear-by-linear association. The predictive accuracy of the BISAP, APACHE II and Ranson's score was measured as the area under the receiver operating characteristic curve (AUC). RESULTS:Of 155 patients enrolled in the study, 16.7% were classified as having severe AP, and six (3.2%) died. There were statistically significant trends for increasing severity (P < 0.001), PNec (P < 0.001) and mortality (P < 0.001) with increasing BISAP. The AUC for severity predicted by BISAP was 0.793 (95% confidence interval [CI] 0.700-0.886), APACHE II 0.836 (95% CI 0.744-0.928) and by Ranson score was 0.903 (95% CI 0.814-0.992). The AUC for PNec predicted by BISAP was 0.834 (95% CI 0.739-0.929), APACHE II 0.801 (95% CI 0.691-0.910) and by Ranson score was 0.840 (95% CI 0.741-0.939). The AUC for mortality predicted by BISAP was 0.791 (95% CI 0.593-0.989), APACHE II 0.812 (95% CI 0.717-0.906) and by Ranson score was 0.904 (95% CI 0.829-0.979). CONCLUSIONS:BISAP score may be a valuable source for risk stratification and prognostic prediction in Chinese patients with AP. A prospective and multicenter validation study is required to confirm our results and further our recognition of BISAP scores in AP.

BackgroundHigh-mobility group box 1 (HMGB1) is an important mediator of the inflammatory response. Its expression is increased in diabetic cardiomyopathy (DCM), but its role is unclear. We investigated the potential role and mechanism of HMGB1 in diabetes-induced myocardial fibrosis and dysfunction in mice.MethodsIn vivo, type 1 diabetes was induced by streptozotocin (STZ) in mice. HMGB1 expression was knocked down by lentivirus-mediated short-hairpin RNA (shRNA). Cardiac function was assessed by echocardiography. Total collagen deposition was assessed by Masson's trichrome and Picrosirius red staining. HMGB1, collagen I and III, and transforming growth factor β1 (TGF-β1) expression was quantified by immunostaining and western bolt analysis. In vitro, isolated neonatal cardiac fibroblasts were treated with high glucose (HG) or recombinant HMGB1 (rHMGB1). Pharmacologic (neutralizing anti-HMGB1 antibody) or genetic (shRNA-HMGB1) inhibition of HMGB1 was used to investigate the role of HMGB1 in HG-induced functional changes of cardiac fibroblasts.ResultsIn vivo, HMGB1 was diffusely expressed in the myocardium of diabetic mice. HMGB1 silencing ameliorated left ventricular dysfunction and remodeling and decreased collagen deposition in diabetic mice. In vitro, HG induced HMGB1 translocation and secretion in both viable cardiomyocytes and fibroblasts. Administration of rHMGB1 dose-dependently increased the expression of collagens I and III and TGF-β1 in cardiac fibroblasts. HMGB1 inhibition reduced HG-induced collagen production, matrix metalloproteinase (MMP) activities, proliferation, and activated mitogen-activated protein kinase signaling in cardiac fibroblasts.ConclusionsHMGB1 inhibition could alleviate cardiac fibrosis and remodeling in diabetic cardiomyopathy. Inhibition of HMGB1 might have therapeutic potential in the treatment of the disease.

目的：探讨去甲斑蝥素抑制结肠癌细胞上皮-间质转化的分子机制,为中药抗癌机制的研究奠定基础.方法：将HT-29结肠癌细胞经NCTD处理后,光镜下观察细胞形态学变化;流式细胞术检测处理前后细胞表面上皮表型及间质表型标志物的变化情况;Western Blotting分析常见调控细胞EMT过程信号传导通路中关键分子及其磷酸化状态的变化;转录因子活化技术观察核因子磷酸化状态的变化.结果：显微镜下观察发现,经NCTD处理后,结肠癌细胞EMT过程受到抑制;流式细胞术证实肿瘤细胞整合素ovβ6表达降低,同时上皮表型标志物表达升高,间质表型标志分子表达减少;Western Blotting分析常见调控细胞EMT过程信号传导通路中仅有ERK及p-ERK表达水平降低,其他关键蛋白无明显变化;转录因子活化技术发现利用siRNA技术干扰整合素αvβ6后,ERK下游的核转录因子中仅有ETS-1磷酸化水平改变,Western Blotting分析证实经NCTD处理后出现与干扰αvβ6表达造成的一致性改变.结论：去甲斑蝥素通过阻断α v β 6-ERK-ETS1信号通路抑制结肠癌细胞上皮-间质转化过程,从而发挥抗癌作用.

Both transcriptional factor Ets-1 and integrin αvβ6 play an important role in the development and progression of cancer. The aim of our study was to investigate the expression of Integrin αvβ6 and Ets-1, two proteins’ correlation and their clinical significance in colorectal cancerous tissues.