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De-Yi Liu,1,* Yi-Nan Li,1,* Jia-Yi Wu,1,2 Zhen-Xin Zeng,1 Yang-Kai Fu,1 Han Li,1 Xiang-Ye Ou,1 Zhi-Bo Zhang,3 Shuang-Jia Wang,4 Jun-Yi Wu,1,2 Mao-Lin Yan1,2 1Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian Province, People’s Republic of China; 2Department of Hepatobiliary Pancreatic Surgery, Fujian Provincial Hospital, Fuzhou, Fujian Province, People’s Republic of China; 3Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian Province, People’s Republic of China; 4Department of Hepato-Biliary-Pancreatic and Vascular Surgery, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jun-Yi Wu; Mao-Lin Yan, The Shengli Clinical Medical College of Fujian Medical University, Department of Hepatobiliary Pancreatic Surgery, Fujian Provincial Hospital, Dongjie Road 134, Fuzhou, Fujian Province, 350001, People’s Republic of China, Tel +86 591-88217130 ; +86 591-88217140, Fax +86 591-87557768, Email 1248087863@qq.com; yanmaolin74@163.comPurpose: The prognosis of hepatocellular carcinoma (HCC) with extrahepatic metastases (EM) is poor. The efficacy and safety of transcatheter arterial chemoembolization combined with lenvatinib plus anti-programmed cell death 1 inhibitors (triple therapy) for HCC with EM remains unclear. In this study, we aimed to determine the efficacy and safety of triple therapy in HCC patients with EM.Patients and Methods: This study retrospectively reviewed HCC patients with EM who received triple therapy and analyzed their survival rate using the Kaplan–Meier method. Univariate prognostic analysis of each data point was performed using the Log rank test, and multivariate prognostic analysis was performed using the Cox proportional risk regression model.Results: Among 60 HCC patients with EM who underwent triple therapy, the most common sites of metastasis were as follows (in descending order): the lungs (n=27), lymph nodes (n=22), and bones (n=10). After triple therapy, the median progression-free survival and median overall survival were 6 and 18.63 months, respectively. The 6-month, 1-year, and 2-year cumulative survival rates were 87.7%, 68.6%, and 26.8%, respectively. In the multivariate analysis, neutrophil-to-lymphocyte ratio (NLR) ≥ 4 and alpha-fetoprotein (AFP) level ≥ 400 ng/mL were independently associated with overall survival.Conclusion: Our findings revealed that triple therapy is an effective, well-tolerated regimen for HCC patients with EM. AFP level and NLR are prognostic risk factors for triple therapy in this patient population.Keywords: hepatocellular carcinoma, transcatheter arterial chemoembolization, lenvatinib, alpha-fetoprotein, neutrophil-to-lymphocyte ratio

Zhong-Tai Lin,1,2,* Shao-Ming Wei,1,3,* Jun-Yi Wu,1,3,* Zhi-Bo Zhang,4 Shuang-Jia Wang,5 Jian-Yin Zhou,6 Meng-Chao Luo,1,3 Zhen-Xin Zeng,1 Xiang-Ye Ou,1 Yang-Kai Fu,1 Han Li,1 De-Yi Liu,1 Jia-Yi Wu,1,3 Mao-Lin Yan1,3 1The Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian Province, People’s Republic of China; 2Department of Gastrointestinal Surgery, Fujian Provincial Hospital, Fuzhou, Fujian Province, People’s Republic of China; 3Department of Hepatobiliary Pancreatic Surgery, Fujian Provincial Hospital, Fuzhou, Fujian Province, People’s Republic of China; 4Department of Hepatopancreatobiliary Surgery, First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian Province, People’s Republic of China; 5Department of Hepato-Biliary-Pancreatic and Vascular Surgery, First Affiliated Hospital of Xiamen University, Xiamen, Fujian Province, People’s Republic of China; 6Department of Hepatobiliary Surgery, Zhongshan Hospital of Xiamen University, Xiamen, Fujian Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jia-Yi Wu; Mao-Lin Yan, The Shengli Clinical Medical College of Fujian Medical University, Department of Hepatobiliary Pancreatic Surgery, Fujian Provincial Hospital, Dongjie Road 134, Fuzhou, Fujian Province, 350001, People’s Republic of China, Tel +86 0591-88217140, Fax +86 0591-87557768, Email tyhjwjy@163.com; yanmaolin74@163.comBackground: This study aimed to assess the effect of adjuvant therapy with different durations in patients with initially unresectable hepatocellular carcinoma (uHCC) after conversion surgery.Methods: This study included 85 patients with initially uHCC who received conversion surgery between May 2019 and November 2022. They were divided into the long duration group (n = 57) and short duration group (n = 28) based on postoperative medication duration. Recurrence-free survival (RFS) and overall survival (OS) were analyzed and compared between the cohorts.Results: No significant difference in RFS or OS was found between the two groups [RFS: hazard ratio (HR) = 0.486; 95% confidence interval (CI), 0.229– 1.034, P = 0.061; OS: HR = 0.377; 95% CI, 0.119– 1.196, P = 0.098]. Patients without major pathologic response (MPR) in the long duration group had better RFS and OS results compared to those in the short duration group (RFS: HR = 0.242; 95% CI, 0.092– 0.634, P = 0.004; OS: HR = 0.264; 95% CI, 0.079– 0.882, P = 0.031). No significant difference was detected in RFS or OS between the two groups in patients with MPR (RFS: HR = 1.250; 95% CI, 0.373– 4.183, P = 0.718; OS: HR = 7.389; 95% CI, 0.147– 372.4, P = 0.317). After propensity score matching, 25 pairs of patients were selected and the results remained consistent.Conclusion: At least 6 months of adjuvant therapy may be beneficial for patients without MPR after conversion surgery. However, in patients with MPR, the effect of adjuvant therapy remains unclear. Further studies are needed to confirm the optimal duration of adjuvant therapy.Keywords: unresectable, hepatocellular carcinoma, conversion therapy, adjuvant therapy, recurrence-free survival, overall survival

Shu-Qun Li,1– 3,* Jun-Yi Wu,1,2,* Jia-Yi Wu,1,2,* Huang Xie,4,* Jin-Hai Li,1,2 Zhen-Xin Zeng,1,2 Yang-Kai Fu,1,2 De-Yi Liu,1,2 Han Li,1,2 Wei-Zhao Chen,1,2 Jing-Yao Huang,4 Mao-Lin Yan1,2 1Department of Hepatobiliary Pancreatic Surgery, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian Province, 350001, People’s Republic of China; 2Department of Hepatobiliary Pancreatic Surgery, Fujian Provincial Hospital, Fuzhou, Fujian Province, 350001, People’s Republic of China; 3Department of Hepatobiliary Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi Province, 450001, People’s Republic of China; 4Department of Interventional Radiology, Fujian Medical University Union Hospital, Fuzhou, 350001, People’s Republic of China*These authors contributed equally to this workCorrespondence: Mao-Lin Yan; Jing-Yao Huang, Tel +86 591-88217130 ; +86 13705962563, Fax +86 591-87557768 ; +86 591-87113828, Email yanmaolin74@163.com; hjy999@126.comPurpose: In recent years, immune checkpoint inhibitors have been used in combination with tyrosine kinase inhibitors and local therapies, creating a new era in treating hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT). However, the benefits of this triple therapy remain unclear. Thus, this study evaluated whether the combination of transarterial chemoembolization (TACE), lenvatinib, and programmed death-1 (PD-1) inhibitors (triple therapy) was effective and safe for unresectable HCC with main trunk portal vein tumor thrombus (Vp4).Patients and Methods: This study enrolled patients receiving triple therapy at four institutions between August 2018 and April 2022. Patient characteristics and course of treatment were extracted from patient records. Tumors and tumor thrombus response were evaluated using an HCC-specific modified RECIST. Kaplan–Meier curve analysis demonstrated overall survival (OS) and progression-free survival (PFS). Adverse events (AEs) were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0.Results: Median follow-up duration was 18 (4.0– 26.3) months. Overall, 41 patients with HCC and Vp4 receiving first-line triple therapy were enrolled. The intrahepatic tumor objective response rate was 68.3%. The median OS was 21.7 (range, 2.8– 30.5) months, whereas the median PFS was 14.5 (range, 1.3– 27.6) months. Twelve patients received sequential resections. Resection was independently associated with favorable OS and PFS. Fever (31.7%), hypertension (26.8%), fatigue (24.4%), abnormal liver function (63.4%) and decreased appetite (21.9%) were the AEs frequently associated with treatment. No treatment-related mortality occurred.Conclusion: TACE plus lenvatinib and PD-1 inhibition was effective and tolerable for treating unresectable HCC with Vp4, with a high tumor response rate and favorable prognosis.Keywords: transarterial chemoembolization, lenvatinib, programmed death 1 inhibitor, hepatic cellular carcinoma, main trunk portal vein, triple therapy

Meng-Chao Luo,1,2,&ast; Jia-Yi Wu,1,3,&ast; Jun-Yi Wu,1,3 Zhong-Tai Lin,1,2 Yi-Nan Li,3 Zhen-Xin Zeng,3 Shao-Ming Wei,1,2 Mao-Lin Yan1,3 1Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian Province, 350001, People’s Republic of China; 2Department of General Surgery, Fujian Provincial Hospital, Fuzhou, Fujian Province, 350001, People’s Republic of China; 3Department of Hepatobiliary Pancreatic Surgery, Fujian Provincial Hospital, Fuzhou, Fujian Province, 350001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Mao-Lin Yan, The Shengli Clinical Medical College of Fujian Medical University, Dongjie Road 134, Fuzhou, Fujian Province, 350001, People’s Republic of China, Tel +86 591-88217130, Fax +86 591-87557768, Email yanmaolin74@163.com Shao-Ming Wei, Department of General Surgery, Fujian Provincial Hospital, Jinrong South Road 516, Fuzhou, Fujian Province, 350001, People’s Republic of China, Tel +86 591-88618707, Fax +86 591-88618900, Email 67468424@qq.comPurpose: Few reliable biomarkers for predicting the efficacy of triple therapy (lenvatinib + immune checkpoint inhibitors + transarterial chemoembolization) exist for patients with unresectable hepatocellular carcinoma (uHCC). This study explored the prognostic role of alpha-fetoprotein (AFP) and des-gamma-carboxyprothrombin (DCP) levels in patients with uHCC receiving triple therapy.Patients and Methods: This retrospective study included 93 patients with uHCC who received triple therapy at Fujian Provincial Hospital between August 2020 and November 2022. Depending on the respective baseline levels, the patients were divided into high-AFP and high-DCP groups. An early response was defined as an AFP or DCP concentration > 50% less than the baseline concentration after 6 weeks of triple therapy. The primary endpoint was the objective response rate (ORR). The secondary endpoints were progression-free survival (PFS) and overall survival (OS).Results: After 6 weeks of triple therapy, 75.3% (58/77) and 78.9% (60/76) of patients in the high-AFP and high-DCP groups achieved an objective response. Early AFP and DCP responses were positively associated with ORR (high-AFP group: odds ratio [OR]: 13.542; 95% confidence interval [CI]: 3.991– 45.950, p< 0.001; high-DCP group: OR: 17.853; 95% CI: 4.478– 71.179, p< 0.001). In the high-AFP group, the 6-month, 12-month, and 18-month PFS and OS rates were higher in the AFP responders than those in the non-responders (PFS: 66.4%, 59.6%, 48.2% vs 42.3%, 19.3%, 0%, p< 0.001; OS: 94.5%, 90.4%, 77.3% vs 75.6%, 66.2%, 49.6%, p=0.006). In the high-DCP group, the 6-month, 12-month, and 18-month PFS and OS rates were higher in the DCP responders than those in the non-responders (PFS: 67.4%, 57.7%, 39.0% vs 38.9%, 8.1%, 0%, p< 0.001; OS: 94.7%, 94.7%, 83.3% vs 77.0%, 53.9%, 36.0%, p< 0.001).Conclusion: After 6 weeks of triple therapy, an AFP or DCP reduction of > 50% predicts better treatment outcomes in uHCC patients.Keywords: unresectable hepatocellular carcinoma, alpha-fetoprotein, des-gamma-carboxyprothrombin, combination therapy, tumor response

Background: Portal vein tumor thrombus (PVTT) seriously affects the prognosis of hepatocellular carcinoma (HCC). However, whether bile duct tumor thrombus (BDTT) significantly affects the prognosis of HCC as much as PVTT remains unclear. We aimed to compare the long-term surgical outcomes of HCC with macroscopic PVTT (macro-PVTT) and macroscopic BDTT (macro-BDTT)., Methods: The data of HCC patients with macro-BDTT or macro-PVTT who underwent hemihepatectomy were retrospectively reviewed. A propensity score matching (PSM) analysis was performed to reduce the baseline imbalance. The recurrence-free survival (RFS) and overall survival (OS) rates were compared between the cohorts., Results: Before PSM, the PVTT group had worse RFS and OS rates than the BDTT group (P = 0.043 and P = 0.008, respectively). Multivariate analyses identified PVTT (hazard ratio [HR] = 1.835, P = 0.016) and large HCC (HR = 1.553, P = 0.039) as independent risk factors for poor OS and RFS, respectively. After PSM, the PVTT group had worse RFS and OS rates than the BDTT group (P = 0.037 and P = 0.004, respectively). The 3- and 5-year OS rates were significantly higher in the BDTT group (59.5% and 52.1%, respectively) than in the PVTT group (33.3% and 20.2%, respectively)., Conclusion: Aggressive hemihepatectomy provides an acceptable prognosis for HCC patients with macro-BDTT. Furthermore, the long-term surgical outcomes of HCC patients with macro-BDTT were significantly better than those of HCC patients with macro-PVTT., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Wei, Fu, Zeng, Huang, Lv, Chen, Wei, Zhang, Zhou, Wu and Yan.)

Introduction: Transarterial chemoembolization combined with lenvatinib and PD-1 inhibitor (triple therapy) has displayed encouraging clinical outcomes for unresectable hepatocellular carcinoma (uHCC). We aimed to explore the prognostic value of pathological response (PR) in patients with initially uHCC who underwent conversion surgery following triple therapy and identify predictors of major pathological response (MPR)., Methods: A total of 76 patients with initially uHCC who underwent conversion surgery following triple therapy were retrospectively analyzed. PR was calculated as the proportion of nonviable tumor cell surface area of the whole tumor bed surface area. MPR was identified when PR was ≥90%. Pathological complete response (pCR) was defined as the absence of viable tumor cells., Results: MPR and pCR were identified in 53 (69.7%) and 25 (32.9%) patients, respectively. The 1- and 2-year overall survival in patients with MPR were significantly higher than in those without MPR (100.0% and 91.3% vs. 67.7% and 19.4%; p < 0.001). The corresponding recurrence-free survival was also improved in patients with MPR compared to those without (75.9% and 50.8% vs. 22.3% and 11.2%; p < 0.001). Similar results were observed among patients with pCR and those without. Patients who achieved MPR without pCR exhibited survival rates comparable to those of patients who achieved pCR. Baseline neutrophil-to-lymphocyte ratio ≥2.6 ( p = 0.016) and preoperative alpha-fetoprotein level ≥400 ng/mL ( p = 0.015) were independent predictors of MPR., Conclusion: The presence of MPR or pCR could improve prognosis in patients with initially uHCC who underwent conversion surgery following triple therapy. The PR may become a surrogate marker for predicting the prognosis of these patients., Competing Interests: The authors have no conflicts of interest to declare., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Background: The long-term prognosis after surgery of patients with hepatocellular carcinoma (HCC) and extrahepatic bile duct tumor thrombus (Ex-BDTT) remains unknown. We aimed to identify the surgical outcomes of patients with HCC and Ex-BDTT., Methods: A total of 138 patients with Ex-BDTT who underwent hepatectomy with preservation of the extrahepatic bile duct from five large hospitals in China between January 2009 and December 2017 were included. The Cox proportional hazards model was used to analyze overall survival (OS) and recurrence-free survival (RFS)., Results: With a median follow-up of 60 months (range, 1-127.8 months), the median OS and RFS of the patients were 28.6 and 8.9 months, respectively. The 1-, 3-, and 5-year OS rates of HCC patients with Ex-BDTT were 71.7%, 41.2%, and 33.5%, respectively, and the corresponding RFS rates were 43.5%, 21.7%, and 20.0%, respectively. Multivariate analysis identified that major hepatectomy, R0 resection, and major vascular invasion were independent prognostic factors for OS and RFS. In addition, preoperative serum total bilirubin ≥ 4.2 mg/dL was an independent prognostic factor for RFS., Conclusion: Major hepatectomy with preservation of the extrahepatic bile duct can provide favorable long-term survival for HCC patients with Ex-BDTT., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Huang, Zeng, Wu, Li, Wang, Fu, Wu, Wei, Lv, Chen, Huang, Cheng and Yan.)

Carbon capture, utilization, and storage (CCUS) technology is widely recognized as a key solution for mitigating global climate change. Consequently, it has received significant attention from countries worldwide. However, carbon dioxide corrosion poses a significant challenge to CCUS and represents a bottleneck to the large-scale development and application of this technology. To mitigate this issue, this review starts with a discussion of corrosion problems in CCUS. Later, the fundamentals of the carbon dioxide corrosion mechanism are introduced. Then, the influences of various factors that affect the corrosion are highlighted, such as water content, pH, flow rate, etc. Afterward, we summarize the commonly used methods for corrosion protection, with a particular focus on inhibitor, given their eco-friendly and effective nature. Lastly, challenges and prospects are discussed to motivate future studies on developing novel, high-performance green inhibitor and studying the corresponding protection mechanisms, hoping to make some contributions to carbon emission reduction., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)

Apart from cancer, metabolic reprogramming is also prevalent in other diseases, such as bacterial infections. Bacterial infections can affect a variety of cells, tissues, organs, and bodies, leading to a series of clinical diseases. Common Pathogenic bacteria include Helicobacter pylori, Salmonella enterica, Mycobacterium tuberculosis, Staphylococcus aureus, and so on. Amino acids are important and essential nutrients in bacterial physiology and support not only their proliferation but also their evasion of host immune defenses. Many pathogenic bacteria or opportunistic pathogens infect the host and lead to significant changes in metabolites, especially the proteinogenic amino acids, to inhibit the host's immune mechanism to achieve its immune evasion and pathogenicity. Here, we review the regulation of host metabolism, while host cells are infected by some common pathogenic bacteria, and discuss how amino acids of metabolic reprogramming affect bacterial infections, revealing the potential adjunctive application of amino acids alongside antibiotics., (© 2023. The Author(s).)

Background: Diabetic skin ulcers, a significant global healthcare burden, are mainly caused by the inhibition of cell proliferation and impaired angiogenesis. XB130 is an adaptor protein that regulates cell proliferation and migration. However, the role of XB130 in the development of diabetic skin ulcers remains unclear., Aim: To investigate whether XB130 can regulate the inhibition of proliferation and vascular damage induced by high glucose. Additionally, we aim to determine whether XB130 is involved in the healing process of diabetic skin ulcers, along with its molecular mechanisms., Methods: We conducted RNA-sequencing analysis to identify the key genes involved in diabetic skin ulcers. We investigated the effects of XB130 on wound healing using histological analyses. In addition, we used reverse transcription-quantitative polymerase chain reaction, Western blot, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining, immunofluorescence, wound healing, and tubule formation experiments to investigate their effects on cellular processes in human umbilical vein endothelial cells (HUVECs) stimulated with high glucose. Finally, we performed functional analysis to elucidate the molecular mechanisms underlying diabetic skin ulcers., Results: RNA-sequencing analysis showed that the expression of XB130 was up-regulated in the tissues of diabetic skin ulcers. Knockdown of XB130 promoted the healing of skin wounds in mice, leading to an accelerated wound healing process and shortened wound healing time. At the cellular level, knockdown of XB130 alleviated high glucose-induced inhibition of cell proliferation and angiogenic impairment in HUVECs. Inhibition of the PI3K/Akt pathway removed the proliferative effects and endothelial protection mediated by XB130., Conclusion: The findings of this study indicated that the expression of XB130 is up-regulated in high glucose-stimulated diabetic skin ulcers and HUVECs. Knockdown of XB130 promotes cell proliferation and angiogenesis via the PI3K/Akt signalling pathway, which accelerates the healing of diabetic skin ulcers., Competing Interests: Conflict-of-interest statement: All the authors have declared no conflict of interest., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

The treatment of malignant tumors has entered the era of immunotherapy, and immune checkpoint inhibitors (ICIs) have brought significant benefits to patients. However, some patients are required to discontinue treatment with ICIs owing to factors such as disease progression and intolerable side effects. Faced with limited subsequent treatment options and complex medical needs, we searched PubMed, Embase, Cochrane library, and the NIH clinical trials database and found that ICI rechallenge could be a relevant clinical strategy. The factors that could affect the rechallenge efficacy include the patients' characteristics, therapeutic strategy selection, and the timing of treatment. Multiple factors are used to identify target population, of which clinical features and PD-L1 expression are more potential. Both single ICI rechallenge and combination therapy may have survival benefits. Patients who have tolerated initial immunotherapy well could undergo ICI rechallenge, while patients who have experienced grade 3 or higher immune-related adverse events should be carefully assessed prior to rechallenge. Interventions and the interval between two courses of ICI will clearly have an impact on the efficacy of subsequent treatment. Preliminary data evaluation supports further investigation on ICI rechallenge to identify the factors that could contribute to its efficacy., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: It is unclear whether associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) can be performed in hepatitis B virus-related hepatocellular carcinoma (HCC) patients with cirrhosis. We explored the efficacy of ALPPS in HCC patients., Methods: Data of 54 patients who underwent ALPPS between August 2014 and July 2020 at three centers were collected. Adverse factors affecting their prognosis were analyzed and subsequently compared with 184 patients who underwent transcatheter arterial chemoembolization (TACE)., Results: Overall survival rates of the ALPPS group at 1, 3, and 5 years were 70.6%, 38.4%, and 31.7%, respectively; corresponding disease-free survival rates were 50.5%, 22.4%, and 19.2%, respectively. The ALPPS group had a significantly greater long-term survival rate than the TACE group (before propensity score matching, P < 0.001; after propensity score matching, P = 0.002). Multivariate analysis demonstrated that multifocal lesions (P = 0.018) and macroscopic vascular invasion (P = 0.001) were prognostic factors for HCC patients who underwent ALPPS. After the propensity score matching, the multifocal lesions (P = 0.031), macroscopic vascular invasion (P = 0.003), and treatment type (ALPPS/TACE) (P = 0.026) were the factors adversely affecting the prognosis of HCC patients., Conclusion: ALPPS was feasible in hepatitis B virus-related HCC patients with cirrhosis and resulted in better survival than TACE., (Copyright © 2022 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Introduction: The actual rate of conversion surgery and its prognostic advantages remain unclear. This study aimed to assess the outcomes of salvage surgery after conversion therapy with triple therapy (transcatheter arterial chemoembolization [TACE] combined with lenvatinib plus anti-PD-1 antibodies) in patients with initially unresectable hepatocellular carcinoma (uHCC)., Methods: Patients with initially uHCC who received at least one cycle of first-line triple therapy and salvage surgery at five major cancer centers in China were included. The primary endpoints were overall survival (OS) and recurrence-free survival (RFS) rates after salvage surgery. The secondary endpoints were perioperative complications, 90-day mortality, and pathological tumor response., Results: Between June 2018 and December 2021, 70 patients diagnosed with uHCC who underwent triple therapy and salvage surgery were analyzed: 39 with Barcelona Clinic Liver Cancer (BCLC) stage C, 22 with BCLC stage B, and 9 with BCLC stage A disease. The median interval between the start of triple therapy and salvage surgery was 4.3 months (range, 1.7-14.2 months). Pathological complete response and major pathological response were observed in 29 (41.4%) and 59 (84.3%) patients, respectively. There were 2 cases of perioperative mortality (4.3%) and 5 cases of severe perioperative complications (7.1%). With a median follow-up of 12.9 months after surgery (range, 0.3-36.8 months), the median OS and RFS were not reached. The 1- and 2-year OS rates were 97.1% and 94.4%, respectively, and the corresponding RFS rates were 68.9% and 54.4%, respectively., Conclusion: First-line combination of TACE, lenvatinib, and anti-PD-1 antibodies provides a better chance of conversion therapy in patients with initially uHCC. Furthermore, salvage surgery after conversion therapy is effective and safe and has the potential to provide excellent long-term survival benefits., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2022 by The Author(s). Published by S. Karger AG, Basel.)

The intracellular EscE protein tightly controls the secretion of the type III secretion system (T3SS) middle and late substrates in Edwardsiella piscicida. However, the regulation of secretion by EscE is incompletely understood. In this work, we reveal that EscE interacts with EsaH and EsaG. The crystal structures of the EscE-EsaH complex and EscE-EsaG-EsaH complex were resolved at resolutions of 1.4 Å and 1.8 Å, respectively. EscE and EsaH form a hydrophobic groove to engulf the C-terminal region of EsaG (56 to 73 amino acids [aa]), serving as the cochaperones of T3SS needle protein EsaG in E. piscicida . V61, K62, M64, and M65 of EsaG play a pivotal role in maintaining the conformation of the ternary complex of EscE-EsaG-EsaH, thereby maintaining the stability of EsaG. An in vivo experiment revealed that EscE and EsaH stabilize each other, and both of them stabilize EsaG. Meanwhile, either EscE or EsaH can be secreted through the T3SS. The secondary structure of EsaH lacks the fourth and fifth α helices presented in its homologs PscG, YscG, and AscG. Insertion of the α4 and α5 helices of PscG or swapping the N-terminal 25 aa of PscG with those of EsaH starkly decreases the protein level of the chimeric EsaH, resulting in instability of EsaG and deactivation of the T3SS. To the best of our knowledge, these data represent the first reported structure of the T3SS needle complex of pathogens from Enterobacteriaceae and the first evidence for the secretion of T3SS needle chaperones. IMPORTANCE Edwardsiella piscicida causes severe hemorrhagic septicemia in fish. Inactivation of the type III secretion system (T3SS) increases its 50% lethal dose (LD 50 ) by ~10 times. The secretion of T3SS middle and late substrates in E. piscicida is tightly controlled by the intracellular steady-state protein level of EscE, but the mechanism is incompletely understood. In this study, EscE was found to interact with and stabilize EsaH in E. piscicida . The EscE-EsaH complex is structurally analogous to T3SS needle chaperones. Further study revealed that EscE and EsaH form a hydrophobic groove to engulf the C-terminal region of EsaG, serving as the cochaperones stabilizing the T3SS needle protein EsaG. Interestingly, both EscE and EsaH are secreted. Our study reveals that the EscE-EsaH complex controls T3SS protein secretion by stabilizing EsaG, whose secretion in turn leads to the secretion of the middle and late T3SS substrates.

Objective: To analyze the current status of clinical trial registration of Traditional Chinese Medicine (TCM) for the treatment of neurological diseases., Methods: Interventional clinical trials of TCM treatment for ischemic stroke, hemorrhagic stroke, vascular cognitive impairment, tension-type headache before September 22, 2020 on the platform of Chinese Clinical Trial Registry (ChiCTR), and ClinicalTrials.gov were searched. Two researchers independently selected the literature and extracted data., Results: A total of 180 interventional clinical trials were included for analysis. Out of 180 trials, 127 were from ChiCTR and 53 from ClinicalTrials.gov. The countries primary sponsoring the included trials were China (176, 97.8%), and the common categories of primary sponsors were hospital (131, 72.8%). Among the study design, the largest proportion of allocation was randomized (172, 95.6%), interventional model assignment was parallel (163, 90.6%), masking was double blind 49 (27.2%), and the sample size was ≤ 400 (144, 80.0%). The trials were most carried out at a single center (102, 56.7%). Among the included studies, 112 (62.2%) registered on ChiCTR attached the ethical approval documents. In terms of trial stages, 50 (27.7%) studies were in phase IV. The mostly used intervention was Chinese herbal medicines (99, 55%), acupuncture (68, 37.8%) was the second. By searching the registration number on China National Knowledge Infrastructure Database and PubMed, 38 (21.1%) registered trials were published, including 25 protocol studies and 14 research results with one (NCT02275949) published both the protocol and the results., Conclusions: Irregular and inadequate reporting, untimely update and publication, insufficient information on traditional medicine unique characteristics, and lack of international collaborations are the problems existing in the interventional clinical registration trials of traditional medicine treatment on neurological diseases. More efforts need to be made from the above aspects to standardize and improve the registration of traditional medicine trials.

The excretory-secretory products released by the liver fluke Fasciola gigantica (FgESPs) play important roles in regulating the host immune response during the infection. Identification of hepatic miRNAs altered by FgESPs may improve our understanding of the pathogenesis of F. gigantica infection. In this study, we investigated the alterations in the hepatic microRNAs (miRNAs) in mice treated with FgESPs using high-throughput small RNA (sRNA) sequencing and bioinformatics analysis. The expression of seven miRNAs was confirmed by quantitative stem-loop reverse transcription quantitative PCR (qRT-PCR). A total of 1,313 miRNAs were identified in the liver of mice, and the differentially expressed (DE) miRNAs varied across the time lapsed post exposure to FgESPs. We identified 67, 154 and 53 dysregulated miRNAs at 1, 4 and 12 weeks post-exposure, respectively. 5 miRNAs (miR-126a-3p, miR-150-5p, miR-155-5p, miR-181a-5p and miR-362-3p) were commonly dysregulated at the three time points. We also found that most of the DE miRNAs were induced by FgESPs in the mouse liver after 4 weeks of exposure. These were subjected to Gene Ontology (GO) enrichment analysis, which showed that the predicted targets of the hepatic DE miRNAs of mice 4 weeks of FgESPs injection were enriched in GO terms, including cell membrane, ion binding, cellular communication, organelle and DNA damage. KEGG analysis indicated that the predicted targets of the most downregulated miRNAs were involved in 15 neural activity-related pathways, 6 digestion-related pathways, 20 immune response-related pathways and 17 cancer-related pathways. These data provide new insights into how FgESPs can dysregulate hepatic miRNAs, which play important roles in modulating several aspects of F. gigantica pathogenesis., Competing Interests: The authors have declared that no competing interests exist.

Harvested banana fruit ripened under warm temperatures above 24 °C remain green peel, leading to severe economic loss. E3 ubiquitin-ligases, as the major components in the ubiquitination pathway, have been implicated to play important roles in temperature-stress responses. However, the molecular mechanism underlying high temperature-triggered stay-green ripening bananas in association with E3 ubiquitin-ligases, remains largely unknown. In this study, a RING-type E3 ubiquitin ligase termed MaLUL2 , was isolated and characterized from banana fruit. The MaLUL2 gene contains 1095 nucleotides and encodes a protein with 365 amino acids. The MaLUL2 protein contains a domain associated with RING2 (DAR2) and a RING domain, which are the typical characteristics of RING-type E3 ligases. MaLUL2 expression was up-regulated during high temperature-induced green ripening. Subcellular localization showed that MaLUL2 localized in the nucleus, cytoplasm, and plasma membrane. MaLUL2 displayed E3 ubiquitin ligase activity in vitro. More importantly, transient overexpression of MaLUL2 in banana fruit peel increased the level of ubiquitination in vivo and led to a stay-green phenotype, accompanying with decreased expression of chlorophyll catabolic genes. Collectively, these findings suggest that MaLUL2 might act as a negative regulator of chlorophyll degradation and provide novel insights into the regulatory mechanism of high temperature-induced green ripening bananas.

The plant hormone jasmonic acid (JA) has been recognized as an important promoter of leaf senescence in plants. However, upstream transcription factors (TFs) that control JA biosynthesis during JA-promoted leaf senescence remain unknown. In this study, we report the possible involvement of a TEOSINTE BRANCHED1/CYCLOIDEA/PCF (TCP) TF BrTCP7 in methyl jasmonate (MeJA)-promoted leaf senescence in Chinese flowering cabbage. Exogenous MeJA treatment reduced maximum quantum yield (Fv/Fm) and total chlorophyll content, accompanied by the increased expression of senescence marker and chlorophyll catabolic genes, and accelerated leaf senescence. To further understand the transcriptional regulation of MeJA-promoted leaf senescence, a class I member of TCP TFs BrTCP7 was examined. BrTCP7 is a nuclear protein and possesses trans-activation ability through subcellular localization and transcriptional activity assays. A higher level of BrTCP7 transcript was detected in senescing leaves, and its expression was up-regulated by MeJA. The electrophoretic mobility shift assay and transient expression assay showed that BrTCP7 binds to the promoter regions of a JA biosynthetic gene BrOPR3 encoding OPDA reductase3 (OPR3) and a chlorophyll catabolic gene BrRCCR encoding red chlorophyll catabolite reductase (RCCR), activating their transcriptions. Taken together, these findings reveal that BrTCP7 is associated with MeJA-promoted leaf senescence at least partly by activating JA biosynthesis and chlorophyll catabolism, thus expanding our knowledge of the transcriptional mechanism of JA-mediated leaf senescence.

Several lines of evidence have implicated the involvement of the phytohormone gibberellin (GA) in modulating leaf senescence in plants. However, upstream transcription factors (TFs) that regulate GA biosynthesis in association with GA-mediated leaf senescence remain elusive. In the current study, we report the possible involvement of a TEOSINTE BRANCHED1/CYCLOIDEA/PCF (TCP) TF BrTCP21 in GA-delayed leaf senescence in Chinese flowering cabbage. Exogenous GA 3 treatment maintained a higher value of maximum PSII quantum yield (Fv/Fm) and total chlorophyll content, accompanied by the repression of the expression of senescence-associated genes and chlorophyll catabolic genes, which led to the delay of leaf senescence. A class I member of TCP TFs BrTCP21, was further isolated and characterized. The transcript level of BrTCP21 was low in senescing leaves, and decreased following leaf senescence, while GA 3 could keep a higher expression level of BrTCP21 . BrTCP21 was further found to be a nuclear protein and exhibit trans-activation ability through transient-expression analysis in tobacco leaves. Intriguingly, the electrophoretic mobility shift assay (EMSA) and transient expression assay illustrated that BrTCP21 bound to the promoter region of a GA biosynthetic gene BrGA20ox3 , and activated its transcription. Collectively, these observations reveal that BrTCP21 is associated with GA-delayed leaf senescence, at least partly through the activation of the GA biosynthetic pathway. These findings expand our knowledge on the transcriptional mechanism of GA-mediated leaf senescence.

Dual pH- and thermo-responsive polysulfone (PSf) membranes with three-dimensionally interconnected networks are fabricated by introducing poly(acrylic acid-co-N-isopropylacrylamide) (P(AA-NIPAm)) into the membrane surfaces and pore walls during membrane formation via a vapor-liquid induced phase separation (V-LIPS) process. After introducing the copolymers of P(AA-NIPAm), the fabricated membranes exhibit impressive open network pores on the surfaces, meanwhile their cross-sectional structure turns from classical asymmetric finger-like structure into bi-continuous nanopores throughout the whole thickness of membrane, due to high solution viscosity and low mass transfer rate of VIPS process. Furthermore, pure water permeation tests show that the pure water permeation (L p ) and the molecular weight cutoff (MWCO) of the fabricated PSf/P(AA-NIPAm) membranes increases sharply as the solution pH decreases from 12.5 to 1.5 and the feed temperature increases from 25 to 50 °C, attributing to the increasing pore size. With the decreasing mass ratio of AA to NIPAm, the pH-responsive coefficient decreases, while the temperature- responsive coefficient increases. In particular, for the fabricated membrane with the mass ratio of AA to NIPAm of 3 to 2, L p changes from ∼16.0 to ∼821.4 L m -2  h -1  bar -1 and MWCO increases from ∼223.1 to ∼1493.2 kDa, as the filtration experiments are operated with feed pH and temperature of 12.5/25 °C and 1.5/50 °C respectively. The results proposed in this study provide a novel mode for design and development dual responsive porous membranes in situ, which will enable good separation of various materials and expand the scope of membrane applications., (Copyright © 2018 Elsevier Inc. All rights reserved.)

We previously observed that disruption of FK506-binding protein 12.6 (FKBP12.6) gene resulted in cardiac hypertrophy in male mice. Studies showed that overexpression of FKBP12.6 attenuated thoracic aortic constriction (TAC)-induced cardiac hypertrophy in mice, whereas the adenovirus-mediated overexpression of FKBP12.6 induced hypertrophy and apoptosis in cultured neonatal cardiomyocytes, indicating that the role of FKBP12.6 in cardiac hypertrophy is still controversial. In this study, we aimed to investigate the roles and mechanisms of FKBP12.6 in angiotensin II (AngII)-induced cardiac hypertrophy using various transgenic mouse models in vivo and in vitro. FKBP12.6 knockout (FKBP12.6 -/- ) mice and cardiac-specific FKBP12.6 overexpressing (FKBP12.6 TG) mice were infused with AngII (1500 ng/kg/min) for 14 days subcutaneously by implantation of an osmotic mini-pump. The results showed that FKBP12.6 deficiency aggravated AngII-induced cardiac hypertrophy, while cardiac-specific overexpression of FKBP12.6 prevented hearts from the hypertrophic response to AngII stimulation in mice. Consistent with the results in vivo, overexpression of FKBP12.6 in H9c2 cells significantly repressed the AngII-induced cardiomyocyte hypertrophy, seen as reductions in the cell sizes and the expressions of hypertrophic genes. Furthermore, we demonstrated that the protection of FKBP12.6 on AngII-induced cardiac hypertrophy was involved in reducing the concentration of intracellular Ca 2+ ([Ca 2+ ]i), in which the protein significantly inhibited the key Ca 2+ /calmodulin-dependent signalling pathways such as calcineurin/cardiac form of nuclear factor of activated T cells 4 (NFATc4), calmodulin kinaseII (CaMKII)/MEF-2, AKT/Glycogen synthase kinase 3β (GSK3β)/NFATc4 and AKT/mTOR signalling pathways. Our study demonstrated that FKBP12.6 protects heart from AngII-induced cardiac hypertrophy through inhibiting Ca 2+ /calmodulin-mediated signalling pathways., (© 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

In situ pegylated (PEGylated) microporous membranes have been extensively reported using poly(ethylene glycol) (PEG)-based polymers as blending additives. Alternatively, free standing PEGylated polysulfone (PSf) membranes with excellent hydrophilicity and antifouling ability were directly fabricated from polysulfone/poly(ethylene glycol) methyl ether methacrylate (PSf/PEGMA) solutions after in situ cross-linking polymerization without any treatment via vapor induced phase separation (VIPS) process for the first time. The microstructures and performances of the resulting membranes shifted regularly by adjusting exposure time of the liquid film in humid air. With increasing exposure time, plenty of worm-like networks formed and distributed on membrane surfaces, meanwhile cross-sectional morphology changed from asymmetric finger-like microporous structure to symmetric cellular-like structure, resulting in better mechanical stability. As the exposure time raised from 0 to 5 min, the surface coverage of carboxyl groups increased from ∼1.1 to 4.0 mol%, leading to the decrease in water contact angle from ∼63 to 27° and the increase in water flux from ∼110 to 512 L m -2  h -1 . In addition, at prolonged exposure time, increasing hydrophilic PEG chains migrated to membrane surfaced and repelled the adsorption and deposition of protein, resulting in better antifouling ability. The findings of this study offer a facile and high efficient strategy for flexible design and fabrication of the in situ PEGylated membranes with desirable structures and performances in large scale., (Copyright © 2018 Elsevier Inc. All rights reserved.)

In the present study, intestinal tight junctions (TJs) and Kupffer cell polarization were investigated in an alcoholic steatohepatitis (ASH) mouse model to uncover the potential side effects of overexposure to fish oil or omega-3 fatty acids. The mice were fed ad libitum with a liquid diet containing ethanol and fish oil. In the meantime, ethanol was given every 5-7 days by gavage to simulate binge drinking. After the 7 th binge, steatosis, necrosis, inflammatory infiltration, and bridging fibrosis were observed in the liver by histological staining. After the 13 th binge, the inducers, markers and other downstream genes/proteins of the Kupffer cell M1/M2 phenotype in the liver, serum, and small intestine were analysed. The results suggested that a chronic high dosage of fish oil alone reduced the mRNA levels of most genes tested and showed a tendency to damage the intestinal zonula occludens-1 localization and reduce the number of M2 Kupffer cells. Meanwhile, the combination of fish oil and ethanol damaged the intestinal TJs, resulting in an increased endotoxin level in the liver. Gut-derived endotoxin polarized Kupffer cells to the M1 phenotype, whereas the number of cells with the M2 phenotype (markers: CD163 and CD206) was decreased. Interleukin-4 (IL-4), an M2 Kupffer cell inducer, was also decreased. Moreover, in vitro experiments showed that IL-4 reversed eicosapentaenoic acid-induced CD163 and CD206 mRNA suppression in RAW 264.7 cells. Overall, our results showed that a chronic high dosage of fish oil exacerbated gut-liver axis injury in alcoholic liver disease in mice, and endotoxin/IL-4-induced Kupffer cell polarization imbalance might play an important role in that process.

Edwardsiella tarda is an important Gram-negative pathogen that employs a type III secretion system (T3SS) to deliver effectors into host cells to facilitate bacterial survival and replication. These effectors are translocated into host cells through a translocon complex composed of three secreted proteins, namely, EseB, EseC, and EseD. The secretion of EseB and EseD requires a chaperone protein called EscC, whereas the secretion of EseC requires the chaperone EscA. In this study, we identified a novel protein (EseE) that also regulates the secretion of EseC. An eseE deletion mutant secreted much less EseC into supernatants, accompanied by increased EseC levels within bacterial cells. We also demonstrated that EseE interacted directly with EseC in a pulldown assay. Interestingly, EseC, EseE, and EscA were able to form a ternary complex, as revealed by pulldown and gel filtration assays. Of particular importance, the deletion of eseE resulted in decreased levels of EseB and EseD proteins in both the bacterial pellet and supernatant fraction. Furthermore, real-time PCR assays showed that EseE positively regulated the transcription of the translocon operon escC-eseE, comprising escC, eseB, escA, eseC, eseD, and eseE These effects of EseE on the translocon components/operon appeared to have a functional consequence, since the ΔeseE strain was outcompeted by wild-type E. tarda in a mixed infection in blue gourami fish. Collectively, our results demonstrate that EseE not only functions as a chaperone for EseC but also acts as a positive regulator controlling the expression of the translocon operon escC-eseE, thus contributing to the pathogenesis of E. tarda in fish., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Background: Based on registries, the European experience has been that <50% of patients are treated according to protocols and/or benefit from the minimum required surgery for ovarian cancer. The French Cancer Plan 2009-2013 considers the definition of qualitative indicators in ovarian cancer surgery in France. This endeavour was undertaken by the French Society of Gynaecologic Oncology (SFOG) in partnership with the French National College of Obstetricians and Gynecologists and all concerned learned societies in a multidisciplinary mindset., Methods: The quality indicators for the initial management of patients with ovarian cancer were based on the standards of practice determined from scientific evidence or expert consensus., Results: The indicators were divided into structural indicators, including material (equipment), human (number and qualification of staff), and organizational resources, process indicators, and outcome indicators., Conclusions: The enforcement of a quality assurance programme in any country would undoubtedly promote improvement in the quality of care for ovarian cancer patients and would result in a dramatic positive impact on their survival. Such a policy is not only beneficial to the patient, but is also profitable for the healthcare system.

Telomere extension by telomerase is essential for chromosome stability and cell vitality. Here, we report the identification of a splice variant of mammalian heterogeneous nuclear ribonucleoprotein A2 (hnRNP A2), hnRNP A2*, which binds telomeric DNA and telomerase in vitro. hnRNP A2* colocalizes with telomerase in Cajal bodies and at telomeres. In vitro assays show that hnRNP A2* actively unfolds telomeric G-quadruplex DNA, exposes 5 nt of the 3' telomere tail and substantially enhances the catalytic activity and processivity of telomerase. The expression level of hnRNP A2* in tissues positively correlates with telomerase activity, and overexpression of hnRNP A2* leads to telomere elongation in vivo. Thus, hnRNP A2* plays a positive role in unfolding telomere G-quadruplexes and in enhancing telomere extension by telomerase.