Leveraging pQTL-based Mendelian randomization to identify new treatment prospects for primary biliary cholangitis and primary sclerosing cholangitis.

Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are autoimmune disorders characterized by progressive and chronic damage to the bile ducts, presenting clinicians with significant challenges. The objective of this study is to identify potential druggable targets to offer new avenues for treatment. A Mendelian randomization analysis was performed to identify druggable targets for PBC and PSC. This involved obtaining Cis-protein quantitative trait loci (Cis-pQTL) data from the deCODE database to serve as exposure. Outcome data for PBC (557 cases and 281,127 controls) and PSC (1,715 cases and 330,903 controls) were obtained from the FINNGEN database. Colocalization analysis was conducted to determine whether these features share the same associated SNPs. Validation of the expression level of druggable targets was done using the GSE119600 dataset and immunohistochemistry for clinical samples. Lastly, the DRUGBANK database was used to predict potential drugs. The MR analysis identified eight druggable targets each for PBC and PSC. Subsequent summary-data-based MR and colocalization analyses showed that LEFTY2 had strong evidence as a therapeutic candidate for PBC, while HSPB1 had moderate evidence. For PSC, only FCGR3B showed strong evidence as a therapeutic candidate. Additionally, upregulated expression of these genes was validated in PBC and PSC groups by GEO dataset and clinical samples. This study identifies two novel druggable targets with strong evidence for therapeutic candidates for PBC (LEFTY2 and HSPB1) and one for PSC (FCGR3B). These targets offer new therapeutic opportunities to address the challenging nature of PBC and PSC treatment.

A paradigm shift in cancer research based on integrative multi-omics approaches: glutaminase serves as a pioneering cuproptosis-related gene in pan-cancer.

BACKGROUND: Cuproptosis is a newly identified form of unprogrammed cell death. As a pivotal metabolic regulator, glutaminase (GLS) has recently been discovered to be linked to cuproptosis. Despite this discovery, the oncogenic functions and mechanisms of GLS in various cancers are still not fully understood. METHODS: In this study, a comprehensive omics analysis was performed to investigate the differential expression levels, diagnostic and prognostic potential, correlation with tumor immune infiltration, genetic alterations, and drug sensitivity of GLS across multiple malignancies. RESULTS: Our findings revealed unique expression patterns of GLS across various cancer types and molecular subtypes of carcinomas, underscoring its pivotal role primarily in energy and nutrition metabolism. Additionally, GLS showed remarkable diagnostic and prognostic performance in specific cancers, suggesting its potential as a promising biomarker for cancer detection and prognosis. Furthermore, we focused on uterine corpus endometrial carcinoma (UCEC) and developed a novel prognostic model associated with GLS, indicating a close correlation between GLS and UCEC. Moreover, our exploration into immune infiltration, genetic heterogeneity, tumor stemness, and drug sensitivity provided novel insights and directions for future research and laid the foundation for high-quality verification. CONCLUSION: Collectively, our study is the first comprehensive investigation of the biological and clinical significance of GLS in pan-cancer. In our study, GLS was identified as a promising biomarker for UCEC, providing valuable evidence and a potential target for anti-tumor therapy. Overall, our findings shed light on the multifaceted functions of GLS in cancer and offer new avenues for further research.

BCLAF1 binds SPOP to stabilize PD-L1 and promotes the development and immune escape of hepatocellular carcinoma.

Interaction between programmed death-1 (PD-1) ligand 1 (PD-L1) on tumor cells and PD-1 on T cells allows tumor cells to evade T cell-mediated immune surveillance. Strategies targeting PD-1/PD-L1 have shown clinical benefits in a variety of cancers. However, limited response rates in hepatocellular carcinoma (HCC) have prompted us to investigate the molecular regulation of PD-L1. Here, we identify B cell lymphoma-2-associated transcription factor 1 (BCLAF1) as a key PD-L1 regulator in HCC. Specifically, BCLAF1 interacts with SPOP, an E3 ligase that mediates the ubiquitination and degradation of PD-L1, thereby competitively inhibiting SPOP-PD-L1 interaction and subsequent ubiquitination and degradation of PD-L1. Furthermore, we determined an SPOP-binding consensus (SBC) motif mediating the BCLAF1-SPOP interaction on BCLAF1 protein and mutation of BCLAF1-SBC motif disrupts the regulation of the SPOP-PD-L1 axis. In addition, BCLAF1 expression was positively correlated with PD-L1 expression and negatively correlated with biomarkers of T cell activation, including CD3 and CD8, as well as with the level of immune cell infiltration in HCC tissues. Besides, BCLAF1 depletion leads to a significant reduction of PD-L1 expression in vitro, and this reduction of PD-L1 promoted T cell-mediated cytotoxicity. Notably, overexpression of BCLAF1 sensitized tumor cells to checkpoint therapy in an in vitro HCC cells-Jurkat cells co-culture model, whereas BCLAF1-SBC mutant decreased tumor cell sensitivity to checkpoint therapy, suggesting that BCLAF1 and its SBC motif serve as a novel therapeutic target for enhancing anti-tumor immunity in HCC.

Impact of insomnia upon inflammatory digestive diseases and biomarkers: a two-sample mendelian randomization research on Europeans.

BACKGROUND: A number of observational studies indicate that insomnia is linked to inflammatory digestive diseases (IDDs). However, the definite relationship between insomnia and IDDs remains unclear. METHODS: We obtained the publicly available data from genome-wide association studies (GWAS) to conduct two-sample Mendelian randomization (MR) for association assessment. Five MR analysis methods were used to calculate the odds ratio (OR) and effect estimate, and the heterogeneity and pleiotropy tests were performed to evaluate the robustness of the variable instruments (IVs). RESULTS: One exposure and twenty outcome datasets based on European populations were included in this study. Using the inverse variance weighted method, we found insomnia was closely correlated with esophageal ulcer (OR = 1.011, 95%CI = 1.004-1.017, p = 0.001) and abdominal pain (effect estimate = 1.016, 95%CI = 1.005-1.026, p = 0.003). Suggestive evidence of a positively association was observed between insomnia and duodenal ulcer (OR = 1.006, 95%CI = 1.002-1.011, p = 0.009), gastric ulcer (OR = 1.008, 95%CI = 1.001-1.014, p = 0.013), rectal polyp (OR = 1.005, 95%CI = 1.000-1.010, p = 0.034), haemorrhoidal disease (OR = 1.242, 95%CI = 1.004-1.535, p = 0.045) and monocyte percentage (effect estimate = 1.151, 95%CI = 1.028-1.288, p = 0.014). No correlations were observed among other IDDs, phenotypes and biomarkers. CONCLUSIONS: Our MR study assessed the relationship between insomnia and IDDs/phenotypes/biomarkers in depth and revealed potential associations between insomnia and ulcers of the esophagus and abdominal pain.

Longitudinal surveillance of three biomarkers to predict recurrence of hepatocellular carcinoma after radical resection.

BACKGROUND: Radical resection is a curative treatment for patients with hepatocellular carcinoma (HCC), but the incidence of recurrence remains high. We aimed to explore the performance of predicting HCC recurrence by longitudinal surveillance of the protein induced by vitamin K absence (PIVKA-II), alpha- fetoprotein (AFP), and lectin-reactive AFP (AFP-L3) during postoperative follow-up. METHODS: Patients who underwent radical resection for HCC at the Ningbo Medical Centre Lihuili Hospital between January 2015 and December 2020 were included. All enrolled patients regularly monitor PIVKA-II, AFP, AFP-L3 every 3 months during postoperative follow-up. The surveillance performance of PIVKA-II, AFP, AFP-L3 during follow-up for the prediction of HCC recurrence was compared in patients. The generalized estimation equation (GEE) was used to analyze the trends of the tumor biomarkers and interactions with time. Area under the receiver operator characteristic (AUROC) curves, the optimal cut-off value, the sensitivity and specificity were calculated to evaluate the performance of the three biomarkers. The recurrence-free survival (RFS) and overall survival (OS) of patients with any of the elevated biomarkers was analyzed by Kaplan-Meier curves and the log-rank test. Multivariate logistic regression models were used to analyze potential risk factors for recurrence. RESULTS: The GEE analysis indicated that PIVKA-II, AFP, AFP-L3 in the recurrence patients were higher than the no recurrence patients during follow-up, PIVKA-II and AFP showed increasing trends from 6 months before recurrence. In predicting recurrence, the AUROCs for PIVKA-II, AFP, AFP-L3 and their combination were 0.885, 0.754, 0.781 and 0.885 respectively, the optimal cut-off value for PIVKA-II, AFP, AFP-L3 was 29.5 mAU/ml, 10.7 ng/L, 1.5% respectively. The sensitivity in predicting recurrence for PIVKA-II, AFP, AFP-L3 and combination were 75.0, 54.7, 57.8 and 79.7% respectively. The RFS and the OS of patients with any of the biomarkers elevated during the follow-up was significantly shorter than that without elevated biomarkers ( P  < 0.001). Multivariate analysis showed that any of the biomarkers elevated was the independent risk factor of recurrence. CONCLUSION: Longitudinal surveillance of PIVKA-II, AFP and AFP-L3 can effectively predict recurrence of HCC after operation.

Risk factors for acute rejection in liver transplantation and its impact on the outcomes of recipients.

OBJECTIVE: To determine the risk factors for acute rejection in liver transplantation and its impact on the outcomes of the recipients. METHODS: Clinicopathological data of 290 patients who underwent liver transplantation from January 2012 to December 2021 at our center were retrospectively evaluated. Patients were grouped into an acute rejection (AR) group and a normal (NM) group based on the confirmed histopathological diagnosis of acute rejection. Univariate and multivariate logistic regression were used to determine the risk factors for acute rejection. RESULTS: 244 patients were included in the study. Acute rejection occurred in 27 (11.1%) of the patients. Warm ischemia time (P = 0.137), cold ischemia time (P = 0.064) and chronic liver failure (P = 0.001) were potential risk factors for acute rejection. Chronic liver failure (P < 0.001, OR = 8.22, 95% CI = 2.47-27.32) was the independent risk factor. There was no significant difference in overall survival between recipients with acute rejection and those without it (P = 0.985). The 1-, 3- and 5-year overall survival in the NM group was 98.1%, 85.7% and 78.6% respectively vs 88.9%, 82.5% and 82.5% respectively in the AR group. CONCLUSION: Acute rejection does not appear to affect the long-term survival of the recipients. Only chronic liver failure was an independent risk factor for acute rejection. Our findings further illustrate that contradictions still exist on which factors influence acute rejection in liver transplant recipients. SUMMARY: Clinicopathological data of 290 liver transplant recipients at our center between January 2012 and December 2021 were retrospectively evaluated to determine the risk factors for acute rejection and its impact on the outcomes of the recipients. 244 patients were included in the analysis. 27 of the 244 experienced acute rejection. Propensity score matching was performed to reduce the confounding effect. Patients were assigned to an acute rejection group (n = 27) and a normal group (n = 54). Chronic liver failure (P < 0.001, OR = 8.22, 95% CI = 2.47-27.32) was the determined to be independent risk factor for acute rejection. Acute rejection did not appear to affect the long-term survival of the recipients and there was no significant difference in overall survival between the patients with acute rejection and those without it.

Undifferentiated Pancreatic Carcinomas, Clinical Features and Therapeutic Options: What We Know.

Undifferentiated pancreatic carcinomas are rare malignant tumors of the pancreas that are very aggressive and challenging to diagnose. The WHO categorizes them into undifferentiated osteoclast-like giant cell, sarcomatoid, and rhabdoid pancreatic carcinomas. Patients present with nonspecific symptoms such as jaundice, vague abdominal or back pain and itchy skin. Their histological characteristics include positive pan-cytokeratin mononuclear pleomorphic cells, osteoclast-like giant cells and CD68. Patients may have KRAS, TP53 and SMAD4 alterations, homozygous deletions of CDKN2A and CDKN2B, as well as INI1 deficiency. Surgical resection is the only curative treatment. Patients may benefit from postoperative adjuvant therapy. There are no widely accepted guidelines specific to this type of tumor; however, some chemotherapy regimens may be promising. The patient prognosis is mostly poor, especially in patients with unresectable tumors. However, several studies have shown patients achieving long-term survival with adjuvant therapy. In conclusion, although undifferentiated pancreatic carcinoma is rare and very aggressive, there is still potential for improved patient survival with proper diagnosis and treatment.

A pan-cancer bioinformatic analysis of the carcinogenic role of SMARCA1 in human carcinomas.

SMARCA1is a mammalian imitation switch (ISWI) gene that encodes for SNF2L. SNF2L is involved in regulating cell transition from a committed progenitor state to a differentiated state. Although many papers have detailed the correlation between SMARCA1 and different cancers, no pan-cancer analysis has been conducted to date. We started by exploring the potential carcinogenic role of SMARCA1 across 33 carcinomas using the cancer genome atlas (TCGA) and the genotype-tissue expression (GTEx) databases. The expression of SMARCA1 was significantly elevated in some tumor types but not in others. There was a distinct relationship between SMARCA1 expression and patient prognosis. S116 phosphorylation levels were up-regulated in both lung adenocarcinoma and uterine corpus endometrial carcinoma. The expression level of SMARCA1 was positively correlated with cancer-associated fibroblasts infiltration in a number of tumors, such as colon adenocarcinoma, cervical squamous cell carcinoma and endocervical adenocarcinoma. It was also associated with CD8+ T-cell infiltration in head and neck squamous cell carcinoma and lung adenocarcinoma. Furthermore, SMARCA1 is involved in chromatin remodeling and protein processing-associated mechanisms. Our study presents an initial assessment and illustration of the carcinogenic role of SMARCA1 in different carcinomas.

Comprehensive bioinformatic analysis of MMP1 in hepatocellular carcinoma and establishment of relevant prognostic model.

Matrix metalloproteinase 1 (MMP1) encodes endopeptidases associated with degradation of multiple components of the extracellular matrix. This function has increasingly been considered to play a major proteolysis role in tumor invasion and metastasis. However, the relationship between MMP1 gene expression, tumor-immune microenvironment and prognosis in hepatocellular carcinoma patients remains mostly unclear. This study focused on a comprehensive analysis of MMP1 in hepatocellular carcinoma, specifically the prognosis and tumor-immune microenvironment. MMP1 expression was analyzed using TCGA database and clinical samples. MMP1 associated mechanisms, pathways, mutations and prognosis in hepatocellular carcinoma were evaluated. We also analyzed the tumor-immune microenvironment and corresponding treatments. Our research demonstrated that MMP1 expression was upregulated in patients with hepatocellular carcinoma and correlated with poor survival. A prognostic model was established and its performance evaluated. We also found and report various correlations between MMP1 and immune-related cells/genes, as well the potential therapeutic agents. These findings indicate that MMP1 can potentially be a promising prognostic biomarker and indicator of the tumor-immune microenvironment status in hepatocellular carcinoma.

Pancreatic adenocarcinoma associated immune-gene signature as a novo risk factor for clinical prognosis prediction in hepatocellular carcinoma.

Pancreatic adenocarcinoma (PAAD) has high mortality and a very poor prognosis. Both surgery and chemotherapy have a suboptimal therapeutic effect, and this caused a need to find new approaches such as immunotherapy. Therefore, it is essential to develop a new model to predict patient prognosis and facilitate early intervention. Our study screened out and validated the target molecules based on the TCGA-PAAD dataset. We established the risk signature using univariate and multivariate Cox regression analysis and used GSE62452 and GSE28735 to verify the accuracy and reliability of the model. Expanded application of PAAD-immune-related genes signature (-IRGS) on other datasets was conducted, and the corresponding nomograms were constructed. We also analyzed the correlation between immune-related cells/genes and potential treatments. Our research demonstrated that a high riskscore of PAAD-IRGS in patients with PAAD was correlated with poor overall survival, disease-specific survival and progression free interval. The same results were observed in patients with LIHC. The models constructed were confirmed to be accurate and reliable. We found various correlations between PAAD-IRGS and immune-related cells/genes, and the potential therapeutic agents. These findings indicate that PAAD-IRGS may be a promising indicator for prognosis and of the tumor-immune microenvironment status in PAAD.

Risk Factors of Early Liver Metastasis for Pancreatic Ductal Adenocarcinoma after Radical Resection.

Background: Liver metastasis arises in many postoperative patients with PDAC, occurring in the early stage appears to lead to a very poor prognosis. Objective: We aimed to analyze the risk factors for early liver metastasis after radical resection for patients with pancreatic ductal adenocarcinoma (PDAC) and to indicate the poor prognosis of early liver metastasis. Methods: Patients who underwent pancreatectomy for PDAC at the Ningbo Medical Centre Lihuili Hospital between January 2015 and June 2021 were included. The exclusion criteria were death within 30 days after the operation, complications with other malignancies, and a positive final resection margin (R1). Liver metastasis and its occurrence time were recorded, and risk factors for early (≤6 months) liver metastasis were analyzed by logistic regression models. The prognosis of patients with early liver metastasis and different recurrence patterns was analyzed by Kaplan-Meier curves and the log-rank test. Results: From the identified cohort of 184 patients, 172 patients were included for further analysis. 55 patients developed early liver metastasis within 6 months after the operation. Univariate analysis showed that CA125 ≥ 30 IU/ml, tumor size ≥ 4 cm, poor tumor differentiation, and portal vein/superior mesenteric vein (PV/SMV) reconstruction were risk factors, and multivariate analysis showed that poor tumor differentiation and PV/SMV reconstruction were independent risk factors for early liver metastasis. The prognosis of liver metastasis was the worst among the different recurrence patterns. Early liver metastasis indicates a poor prognosis in patients with PDAC. Conclusions: Poor differentiation and PV/SMV reconstruction are independent risk factors for early liver metastasis in patients with PDAC, and early liver metastasis indicates a poor prognosis.

Expression of SET domain bifurcated histone lysine methyltransferase 1 and its clinical prognostic significance in hepatocellular carcinoma.

BACKGROUND: To detect the expression of histone methyltransferase SETDB1 in hepatocellular carcinoma, and to analyze the relationship between SETDB1 expression and tumor size, microvascular invasion, pTNM stage, gender, age, tumor number, tumor differentiation, and other clinicopathological characteristics. METHODS: Immunohistochemical method was used to detect the expression of SETDB1 proteins in liver cancer tissues and adjacent tissues of 100 cases. The qRT-PCR method was used to detect the expression of SETDB1 mRNA in hepatocellular carcinoma and adjacent tissues of 64 cases. RESULTS: The expression of SETDB1 protein and mRNA in hepatocellular carcinoma was higher than that of adjacent normal liver tissue (p < 0.05). High protein expression of SETDB1 was associated with tumor size, MVI presence, and pTNM stage (p < 0.05). Univariate analysis revealed that the tumor size, tumor differentiation, MVI grade, and pTNM stage were correlated with DFS, while tumor size, MVI grade, pTNM stage, and SETDB1 protein expression were correlated with OS. Multivariate analysis showed that the combination of MVI grade and pTNM stage has statistical significance in predicting prognosis, while SETDB1 protein expression was not significant prognosis factor. CONCLUSIONS: SETDB1 has a certain role in HCC progression and may act as a prognostic predictor concerning the survival of HCC patients.

Efficacy and safety of sirolimus early conversion protocol in liver transplant patients with hepatocellular carcinoma: A single-arm, multicenter, prospective study.

Mammalian target of rapamycin (mTOR) inhibitor as an attractive drug target with promising antitumor effects has been widely investigated. High quality clinical trial has been conducted in liver transplant (LT) recipients in Western countries. However, the pertinent studies in Eastern world are paucity. Therefore, we designed a clinical trial to test whether sirolimus can improve recurrence-free survival (RFS) in hepatocellular carcinoma (HCC) patients beyond the Milan criteria after LT. This is an open-labeled, single-arm, prospective, multicenter, and real-world study aiming to evaluate the clinical outcomes of early switch to sirolimus-based regimens in HCC patients after LT. Patients with a histologically proven HCC and beyond the Milan criteria will be enrolled. The initial immunosuppressant regimens are center-specific for the first 4-6 weeks. The following regimens integrated sirolimus into the regimens as a combination therapy with reduced calcineurin inhibitors based on the condition of patients and centers. The study is planned for 4 years in total with a 2-year enrollment period and a 2-year follow-up. We predict that sirolimus conversion regimen will provide survival benefits for patients particular in the key indicator RFS as well as better quality of life. If the trial is conducted successfully, we will have a continued monitoring over a longer follow-up time to estimate indicator of overall survival. We hope that the outcome will provide better evidence for clinical decision-making and revising treatment guidelines based on Chinese population data. Trial register: Trial registered at http://www.chictr.org.cn: ChiCTR2100042869.

A Meta-Analysis and Systematic Review of Normothermic and Hypothermic Machine Perfusion in Liver Transplantation.

BACKGROUND: The gap between the demand and supply of donor livers is still a considerable challenge. Since static cold storage is not sufficient in marginal livers, machine perfusion is being explored as an alternative. The objective of this study was to assess (dual) hypothermic oxygenated machine perfusion (HOPE/D-HOPE) and normothermic machine perfusion (NMP) in contrast to static cold storage (SCS). METHODS: Three databases were searched to identify studies about machine perfusion. Graft and patient survival and postoperative complications were evaluated using the random effects model. RESULTS: the incidence of biliary complications was lower in HOPE vs. SCS (OR: 0.59, 95% CI: 0.36-0.98, p = 0.04, I2: 0%). There was no significant difference in biliary complications between NMP and SCS (OR: 0.76, 95% CI: 0.41-1.40, p = 0.38, I2: 55%). Graft and patient survival were significantly better in HOPE than in SCS (HR: 0.40, 95% CI: 0.23-0.71, p = 0.002, I2: 0%) and (pooled HR: 0.43, 95% CI: 0.20-0.93, p = 0.03, I2: 0%). Graft and patient survival were not significantly different between NMP and SCS. CONCLUSION: HOPE/D-HOPE and NMP are promising alternatives to SCS for donor liver preservation. They may help address the widening gap between the demand for and availability of donor livers by enabling the rescue and transplantation of marginal livers.

Therapeutic effectiveness and safety of sintilimab-dominated triple therapy in unresectable hepatocellular carcinoma.

Immune checkpoint inhibitor therapy has shown promising results in patients with unresectable hepatocellular carcinoma. This study aimed to evaluate the effectiveness and safety of sintilimab, a programmed cell death protein-1 (PD-1) blockade, combined with sorafenib and transhepatic arterial chemotherapy and embolization in this patient population, compared with sintilimab monotherapy and sintilimab-sorafenib duotherapy. This was a 22 months single center retrospective cohort study in China. 80 patients with unresectable hepatocellular carcinoma were included, with diagnosis confirmed by either histologic, cytologic or diagnostic imaging analysis. The patients were divided into three groups based on therapeutic regimen: sintilimab monotherapy (sintilimab group, n = 22), sintilimab-sorafenib duotherapy (duplex group, n = 23), sintilimab-sorafenib and transcatheter arterial chemoembolization combined therapy (triple group, n = 35). The principal evaluation criteria were overall survival and progression free survival in the population, assessed according to response evaluation criteria in solid tumors, version 1.1 (RECIST 1.1). Secondary evaluation criteria were safety, objective response rate and disease control rate. From March 1st, 2019 to December 31, 2020, 80 patients with unresectable hepatocellular carcinoma were included and divided into three treatment groups (22 received sintilimab monotherapy, 23 received sintilimab-sorafenib duotherapy, and 35 received sintilimab-sorafenib combined with transcatheter arterial chemoembolization). The median overall survival of all patients was 11.0 months (95% CI 7.7-14.3). Median overall survival was 13.0 months (95% CI NE-NE), 9.0 months(95% CI 6.3-11.7)and 3.0 months (95% CI 1.9-4.1, p < 0.0001) in the triple therapy, duplex and sintilimab groups respectively, while the corresponding median progression-free survival were 5.0 months (95% CI 2.9-7.1, p < 0.001), 4.0 months (95% CI 2.8-5.2) and 2.0 months (95% CI 1.7-2.3). Disease control and clinical benefits rates were higher in the triple therapy group (80%, 95% CI 63.1-91.6, p < 0.001; 54.3%, 95% CI 36.6-71.2, p < 0.01) compared to the sintilimab group. Median duration of disease control was 4.0 months (95% CI NE-NE, p < 0.01) in the triple therapy group, longer than that of the duplex group (2.0 months, 95% CI 0.9-3.1) and sintilimab group (2.0 months, 95% CI 0.8-3.2). Grade 3 or 4 treatment-related adverse events occurred in 26.3% of 80 patients with hypertension was the most common event observed (38, 47.5%), however, other severe toxic effects were infrequent. Sintilimab combined with sorafenib and transcatheter arterial chemoembolization might have more beneficial effects on overall and progression-free survival and on the duration of disease control outcomes than both sintilimab monotherapy and sintilimab-sorafenib duotherapy in patients with unresectable hepatocellular carcinoma. This triple therapy model might represent an innovative and effective option for inoperable liver cancer.

Extended pancreato-duodenectomy coupled with adjuvant chemotherapy for SMARCB1/INI1 deficient pancreatic carcinoma: A case report and literature review.

INTRODUCTION: SMARCB1/INI1 gene deletion appears to be associated with a rare, malignant and aggressive form of pancreatic carcinoma whose diagnosis is challenging. Our objective is to illustrate that the tumor may masquerade as a duodenal papillary carcinoma, be difficulty to identify on diagnostic imaging and that making an accurate diagnosis may be challenging, however surgical resection may be possible. CASE REPORT: We present a case of a 24-year old male patient presenting with jaundice and itchy skin, elevated TBIL, AST, ALP and CA125. A 2.2 × 1.7 cm pancreatic nodule, later diagnosed as a SMARCB1/INI deficient pancreatic carcinoma was detected on Endoscopic Ultrasound - Fine Needle Aspiration (EUS-FNA). The patient was successfully treated with extended pancreato-duodenectomy coupled with adjuvant chemotherapy, a 7 × 5 × 5 cm tumor resected. DISCUSSION: SMARCB1/INI deficient pancreatic carcinoma has been reported in couple of other articles. However, unlike other cases, in our case identification and accurate assessment of the tumor was particularly difficulty both on imaging and during operation. Our patient has thus far had a positive outcome with no recurrence. CONCLUSION: For rare forms of pancreatic carcinoma, identification and assessment of the tumor size may be challenging on imaging and during operation. However, careful assessment should be performed before ruling out surgical resection. Furthermore, adjuvant chemotherapy may be beneficial to the patient.

[Increasing the thermostability of glutamate decarboxylase from Lactobacillus brevis by introducing proline].

Glutamate decarboxylase, a unique pyridoxal 5'-phosphate-dependent enzyme, catalyzes α-decarboxylation of L-glutamate to γ-aminobutyrate. However, glutamate decarboxylase from different sources has the common problem of poor thermostability that affects its application in industry. In this study, proline was introduced at 13 different positions in glutamate decarboxylase by using the design strategy of homologous sequence alignment between Thermococcus kodakarensis and Lactobacillus brevis CGMCC No.1306. A mutant enzyme G364P with higher thermostability was obtained. Compared to the wild type, thermostability of the mutant G364P was significantly improved, the half-life time (t1/2) at 55 °C and the semi-inactivation temperature (T50 ¹5) of the mutant G364P increased 19.4 min and 5.3 °C, respectively, while kcat/Km of the mutant enzyme remained nearly unchanged. Further analysis of their thermostability by molecular dynamics simulations were performed. The root mean square deviation of G364P and root mean square fluctuation in the loop region including G364 were lower than the wild type at 313 K for 10 ns, and G364P increased one hydrophobic interaction in the loop region. It proves that mutation of flexible 364-Gly to rigid proline endows glutamate decarboxylase with enhanced thermostability.

A novel technique of inserting pancreaticogastrostomy with duct-to-mucosa anastomosis can potentially reduce postoperative pancreatic fistula.

BACKGROUND: We describe our novel technique of inserting pancreaticogastrostomy (IPG) after pancreaticoduodenectomy. In our technique, the seromuscular and mucosal layers of the posterior gastric wall are separated to create a mucosal pouch. A duct-to-mucosa anastomosis is performed through a small incision in the mucosal layer. An inner suture at the seromuscular-mucosal margin incorporating the pancreatic parenchyma and an outer suture on the exterior margin of the seromuscular layer to wrap the pouch around the pancreas are placed to complete the IPG. MATERIALS AND METHODS: We examined the clinicopathological features and outcomes of 259 patients who underwent pancreaticoduodenectomy between January 2010 and April 2014. RESULTS: One hundred forty-three (55.2%) patients underwent IPG, while 116 (44.8%) had conventional pancreaticojejunostomy. Most preoperative and intraoperative parameters were comparable. Overall morbidity in the IPG group was 28.7%. The rate of grade A postoperative pancreatic fistula (POPF) was 7.0%, and the rates of grade B and C POPF were 0.7% and 0.0%, respectively. The corresponding rates of grade A, B, and C fistulae were 5.2%, 8.6%, and 5.2%, respectively. CONCLUSIONS: In selected patients, our novel technique can be performed safely and may reduce the rates of POPF.

[Enhancing glutamate decarboxylase activity by site-directed mutagenesis: an insight from Ramachandran plot].

Glutamate decarboxylase (GAD) can catalyze the decarboxylation of glutamate into γ-aminobutyrate (GABA) and is the only enzyme of GABA biosynthesis. Improving GAD activity and thermostability will be helpful for the highly efficient biosynthesis of GABA. According to the Ramachandran plot information of GAD 1407 three-dimensional structure from Lactobacillus brevis CGMCC No. 1306, we identified the unstable site K413 as the mutation target, constructed the mutant GAD by site-directed mutagenesis and measured the thermostability and activity of the wide type and mutant GAD. Mutant K413A led to a remarkably slower inactivation rate, and its half-life at 50 °C reached 105 min which was 2.1-fold higher than the wild type GAD1407. Moreover, mutant K413I exhibited 1.6-fold higher activity in comparison with the wide type GAD1407, although it had little improvement in thermostability of GAD. Ramachandran plot can be considered as a potential approach to increase GAD thermostability and activity.

Mucin-producing intrahepatic biliary papillomatosis.

PURPOSE: Mucin-producing intrahepatic biliary papillomatosis (MPIBP) is an uncommon tumor. The purpose of this study was to evaluate the clinical, radiological, and histopathological characteristics of MPIBP, and its prognosis. METHODS: A retrospective analysis was conducted of 11 patients who underwent surgery for MPIBP. The clinical features and radiological, pathological, and operative findings were reviewed, and the survival rates were determined. RESULTS: Repeated episodes of fever and epigastric pain with or without jaundice were the common clinical manifestations. Radiologically, all patients showed diffuse bile duct dilatation with cystic change in intrahepatic bile duct. All patients underwent a hepatic resection with or without an extrahepatic bile duct resection. No in-hospital mortality occurred. All patients survived without any signs of recurrence (median 12 +/- 7 months); three patients, including two patients who underwent a palliative resection, had an attack of cholangitis, which was effectively treated with antibiotics. CONCLUSIONS: A diagnosis of MPIBP is usually made in patients with biliary dilatation following a radiologic study. Magnetic resonance cholangiopancreatography is more valuable than other modalities in diagnosis. Mucin-producing intrahepatic biliary papillomatosis is a premalignant disease with high malignant potential. The prognosis of MPIBP is excellent if an aggressive resection is performed. A combination of cholangioscopy and frozen sections during the operation is beneficial for a radical successful surgical resection.