Persistent ER stress causes GPI anchor deficit to convert a GPI-anchored prion protein into pro-PrP via the ATF6-miR449c-5p-PIGV axis.

Endoplasmic reticulum (ER) stress and unfolded protein response are cells' survival strategies to thwart disruption of proteostasis. Tumor cells are continuously being challenged by ER stress. The prion protein, PrP, normally a glycosylphosphatidylinositol (GPI)-anchored protein exists as a pro-PrP retaining its GPI-peptide signal sequence in human pancreatic ductal cell adenocarcinoma (PDAC). Higher abundance of pro-PrP indicates poorer prognosis in PDAC patients. The reason why PDAC cells express pro-PrP is unknown. Here, we report that persistent ER stress causes conversion of GPI-anchored PrP to pro-PrP via a conserved ATF6-miRNA449c-5p-PIGV axis. Mouse neurons and AsPC-1, a PDAC cell line, express GPI-anchored PrP. However, continuous culture of these cells with the ER stress inducers thapsigargin or brefeldin A results in the conversion of a GPI-anchored PrP to pro-PrP. Such a conversion is reversible; removal of the inducers allows the cells to re-express a GPI-anchored PrP. Mechanistically, persistent ER stress increases the abundance of an active ATF6, which increases the level of miRNA449c-5p (miR449c-5p). By binding the mRNA of PIGV at its 3'-UTRs, miR449c-5p suppresses the level of PIGV, a mannosyltransferase pivotal in the synthesis of the GPI anchor. Reduction of PIGV leads to disruption of the GPI anchor assembly, causing pro-PrP accumulation and enhancing cancer cell migration and invasion. The importance of ATF6-miR449c-5p-PIGV axis is recapitulated in PDAC biopsies as the higher levels of ATF6 and miR449c-5p and lower levels of PIGV are markers of poorer outcome for patients with PDAC. Drugs targeting this axis may prevent PDAC progression.

Collagen prolyl 4-hydroxylase subunit α member-induced head and neck squamous cell carcinoma aggressiveness is antagonized by LLGL2 via reduced expression of occludin.

There are three isoforms of human collagen prolyl 4-hydroxylases (C-P4Hs), each of which has been reported to play an important role in regulating the progression of a variety of human cancers. By analyzing TGCA datasets on human head and neck squamous cell carcinoma (HNSC), we find that a higher expression of all three C-P4HAs (the α subunit of C-P4Hs) is a superior prognostic indicator than a higher expression of two or a single C-P4HA. Unexpectedly, some patients with higher levels of three C-P4HAs survive longer than patients whose tumors have lower expression of C-P4HAs. Therefore, there may be molecule(s) that can negate the deleterious effects of overexpressing C-P4HAs during cancer progression. By constructing a functional protein interaction network of C-P4HAs and analyzing molecules whose expressions are correlated significantly with that of C-P4HAs, we identify scribble cell polarity complex component 2 (LLGL2) as a factor that antagonizes the effects of overexpressed C-P4HAs on HNSC. Silencing of LLGL2 in the human oral squamous cell line Cal-27 upregulates the expression of occludin and increases cancer cell invasion and migration. In contrast, knocking down C-P4HA alone inhibits cell migration and invasion. Furthermore, simultaneously downregulating three C-P4HAs has more pronounced effects on inhibiting cell migration and invasion. Accordingly, high LLGL2 expression is also a marker indicating improved prognosis in patients with HNSC. These results suggest that the interplay between LLGL2 and C-P4HAs may be targeted to mitigate HNSC tumorigenesis and progression.

A thermoplastic microfluidic microphysiological system to recapitulate hepatic function and multicellular interactions.

Hepatic in vitro platforms ranging from multi-well cultures to bioreactors and microscale systems have been developed as tools to recapitulate cellular function and responses to aid in drug screening and disease model development. Recent developments in microfabrication techniques and cellular materials enabled fabrication of next-generation, advanced microphysiological systems (MPSs) that aim to capture the cellular complexity and dynamic nature of the organ presenting highly controlled extracellular cues to cells in a physiologically relevant context. Historically, MPSs have heavily relied on elastomeric materials in their manufacture, with unfavorable material characteristics (such as lack of structural rigidity) limiting their use in high-throughput systems. Herein, we aim to create a microfluidic bilayer model (microfluidic MPS) using thermoplastic materials to allow hepatic cell stabilization and culture, retaining hepatic functional phenotype and capturing cellular interactions. The microfluidic MPS consists of two overlapping microfluidic channels separated by a porous tissue-culture membrane that acts as a surface for cellular attachment and nutrient exchange; and an oxygen permeable material to stabilize and sustain primary human hepatocyte (PHH) culture. Within the microfluidic MPS, PHHs are cultured in the top channel in a collagen sandwich gel format with media exchange accomplished through the bottom channel. We demonstrate PHH culture for 7 days, exhibiting measures of hepatocyte stabilization, secretory and metabolic functions. In addition, the microfluidic MPS dimensions provide a reduced media-to-cell ratio in comparison with multi-well tissue culture systems, minimizing dilution and enabling capture of cellular interactions and responses in a hepatocyte-Kupffer coculture model under an inflammatory stimulus. Utilization of thermoplastic materials in the model and ability to incorporate multiple hepatic cells within the system is our initial step towards the development of a thermoplastic-based high-throughput microfluidic MPS platform for hepatic culture. We envision the platform to find utility in development and interrogation of disease models of the liver, multi-cellular interactions and therapeutic responses.

In situ surface formation of TiO2/Ti(NO2) hybrid nanocomposites with N2 APPJ treatment for efficient C2H4 photodegradation.

TiO2/Ti(NO2) hybrid films were prepared using N2 atmospheric pressure plasma jet treatment on TiO2 coating. The film structure and morphology have been investigated using optical emission spectra, Fourier-transform infrared spectroscopy, X-ray diffraction, and X-ray photoelectron spectroscopy. The formed TiO2/Ti(NO2) photocatalystic thin films were applied for C2H4 photodegradation under UV irradiation. The results showed that the composite films exhibited superior photocatalytic activity over the untreated TiO2 film. The C2H4 concentration after 120 min varied from 12 to 6.2 mg/L, 6.7 mg/L, 7 mg/L for TiO2 with 1 min, 2 min and 3 min plasma treatment, respectively. In the banana storage experiment, the concentration of C2H4 was reduced from 15 to 9 ppm after 36 h with TiO2/Ti(NO2) nanocomposite film illuminated by UV light. The photocatalytic mechanism has been discussed. The composite film is able to more effectively separate the photo-excited electrons and holes, thus leading to the much high activity in C2H4 degradation. The current work has paved a way towards postharvest fruit preservation.

Large hepatocellular carcinomas: treatment with transarterial chemoembolization alone or in combination with percutaneous cryoablation.

PURPOSE: To evaluate the safety and efficacy of transarterial chemoembolization (TACE) combined with cryoablation (TACE-cryoablation) in large (main tumor ≥5 cm in diameter) hepatocellular carcinomas (HCCs). METHODS: From January 2010 to December 2015, 56 lesions in 56 patients were treated with combination therapy via a single TACE session followed by one to three percutaneous cryoablation sessions twice a week (TACE-cryoablation group). A total of 54 lesions in 54 patients were treated with TACE alone for two to six sessions once a month (TACE group). The decision between TACE and TACE cryoablation was based on patient choice. Outcomes of patients in two groups were compared according to the largest tumor diameter (subgroup): Group A (5 cm ≤ tumor <10 cm), Group B (10 cm ≤ tumor <15 cm), and Group C (tumor ≥15 cm). RESULTS: The mean number of cryoablation sessions per patient was 2.3 (range: 1-6). Within Group B, TACE-cryoablation significantly improved survival compared with TACE alone (11.0 vs 6.0 months; p = .008). This was also seen in Group C (8.0 vs 5.0 months; p = .001). However, no significant difference was noted in Group A (17.0 vs 13.0 months; p = .674). The complications related to TACE were comparable between the two groups. Two adverse events of grade 3 - 4 related to cryoablation occurred in two patients (3.6%). The independent prognostic factors for survival included: TACE cryoablation, AFP level, main tumor size and extrahepatic metastasis. CONCLUSIONS: TACE-cryoablation may improve overall survival in patients with HCC who presented with a tumor diameter ≥10 cm, with minimal complications, when compared with TACE alone.

Comparison between microwave ablation and lobectomy for stage I non-small cell lung cancer: a propensity score analysis.

PURPOSE: To compare the effectiveness and complication between microwave ablation and lobectomy for stage I non-small cell lung cancer. MATERIALS AND METHODS: This retrospective study was approved by two institutional ethics committees and all patients were provided with informed consent. From January 2000 to December 2010, 54 and 795 stage I patients who underwent microwave ablation and lobectomy were included in this study. A matched cohort composed of 54 and 108 patients in the microwave ablation and the lobectomy group were selected after adjustment with 1:2 propensity score matching. The overall survival and disease-free survival were evaluated. Survival curves were constructed with the Kaplan-Meier method and compared by using the log-rank test. RESULTS: The 1, 3 and 5-year Overall survive were 100, 92.6 and 50.0% for MWA group and 100, 90.7 and 46.3% for lobectomy group. The 1, 3 and 5-year disease free survival was 98.1, 79.6 and 37.0% for MWA group and 98.1, 81.5 and 29.6% for lobectomy group. There was no significant difference between two groups in overall survival (p = 0.608) and disease free survival (p = 0.672). Additionally, local or distant metastasis rate (p = 0.544) were not significantly different between two groups while the complication rate in the MWA group was significantly lower than the lobectomy group (p = 0.008). CONCLUSION: Microwave ablation has similar therapeutic effect compared with lobectomy for stage I non-small cell lung cancer, but with fewer complication and less pain.

Insulin Is Required to Maintain Albumin Expression by Inhibiting Forkhead Box O1 Protein.

Diabetes is accompanied by dysregulation of glucose, lipid, and protein metabolism. In recent years, much effort has been spent on understanding how insulin regulates glucose and lipid metabolism, whereas the effect of insulin on protein metabolism has received less attention. In diabetes, hepatic production of serum albumin decreases, and it has been long established that insulin positively controls albumin gene expression. In this study, we used a genetic approach in mice to identify the mechanism by which insulin regulates albumin gene transcription. Albumin expression was decreased significantly in livers with insulin signaling disrupted by ablation of the insulin receptor or Akt. Concomitant deletion of Forkhead Box O1 (Foxo1) in these livers rescued the decreased albumin secretion. Furthermore, activation of Foxo1 in the liver is sufficient to suppress albumin expression. These results suggest that Foxo1 acts as a repressor of albumin expression.

Feasibility and Efficacy of Microwave Ablation Combined with Iodine-125 Seed Implantation in Local Control of Recurrent Retroperitoneal Liposarcomas: Initial Clinical Experience.

INTRODUCTION: The objective of the present study was to evaluate the feasibility, safety, and short-term efficacy of microwave ablation (MWA) combined with iodine-125 (125I) seed implantation in recurrent retroperitoneal liposarcomas (rRPLs). MATERIALS AND METHODS: From September 2012 to March 2015, 11 patients were enrolled in this prospective study. Eleven tumors (median, 9 cm; range, 5.5-12.5 cm) were treated with computerized tomography-guided MWA for 11 sessions and 125I seed implantation for 18 sessions. 125I seed implantation was performed 4 weeks after MWA. RESULTS: There were no procedure-related deaths. Post-MWA pain (grade ≥2) was the most common complication (6 of 11 patients, 54.5%), and fever (grade ≥2) was observed in two patients. Reversible nerve injury, defined as transient limb paresthesia or leg weakness, was observed in one patient. There were fewer complications associated with the 125I seed implantation procedure compared with the MWA procedure. All 11 patients who underwent the MWA procedure achieved a partial response (PR), according to the modified Response Evaluation Criteria in Solid Tumors, 1 month post-ablation; after 125I seed implantation was performed, a complete response was observed in three, five, and six target tumors in 3, 6, and 12 months, respectively. CONCLUSION: In selected patients with rRPLs, MWA combined with 125I seed implantation is feasible and safe with favorable local control efficacy. IMPLICATIONS FOR PRACTICE: This study evaluated the feasibility, safety, and short-term efficacy of microwave ablation (MWA) combined with iodine-125 (125I) seed implantation in recurrent retroperitoneal liposarcomas (rRPLs). Results suggest that a single session of MWA may be not sufficient in large-volume rRPLs and that as a supplement treatment, 125I seed implantation is safe and easy accessible. MWA combined with 125I seed has excellent local control effectiveness, and long-term efficacy and survival benefit still need to be more comprehensively evaluated.

Akt-mediated foxo1 inhibition is required for liver regeneration.

UNLABELLED: Understanding the hepatic regenerative process has clinical interest as the effectiveness of many treatments for chronic liver diseases is conditioned by efficient liver regeneration. Experimental evidence points to the need for a temporal coordination between cytokines, growth factors, and metabolic signaling pathways to enable successful liver regeneration. One intracellular mediator that acts as a signal integration node for these processes is the serine-threonine kinase Akt/protein kinase B (Akt). To investigate the contribution of Akt during hepatic regeneration, we performed partial hepatectomy in mice lacking Akt1, Akt2, or both isoforms. We found that absence of Akt1 or Akt2 does not influence liver regeneration after partial hepatectomy. However, hepatic-specific Akt1 and Akt2 null mice show impaired liver regeneration and increased mortality. The major abnormal cellular events observed in total Akt-deficient livers were a marked reduction in cell proliferation, cell hypertrophy, glycogenesis, and lipid droplet formation. Most importantly, liver-specific deletion of FoxO1, a transcription factor regulated by Akt, rescued the hepatic regenerative capability in Akt1-deficient and Akt2-deficient mice and normalized the cellular events associated with liver regeneration. CONCLUSION: The Akt-FoxO1 signaling pathway plays an essential role during liver regeneration.

The safety and efficacy of percutaneous intraductal radiofrequency ablation in unresectable malignant biliary obstruction: A single-institution experience.

BACKGROUND: Patients with unresectable malignant biliary obstruction have limited life expectancy because of limited stent patency and tumor progression. The aim of our study was to retrospectively evaluate the safety and efficacy of combining intraductal RFA with biliary metal stent placement for patients with malignant biliary obstruction. METHODS: Patients who received percutaneous intraductal RFA and biliary stent placement for malignant biliary obstruction between 2013 and 2015 were identified. Outcomes were stent patency, technique and clinical success rate, overall survival (OS) and complication rates. Kaplan-Meier and Cox regression analyses were used to examine the association of various factors with stent patency and OS. Complications and laboratory abnormalities were recorded. RESULTS: Fifty patients were treated with percutaneous RFA and stent placement. The rates of technical success and clinical success were 98% and 92%, respectively. The median stent patency was 7.0 (95% confidence interval [CI]: 5.3, 8.7) months and OS was 5.0 (95% CI: 4.0, 6.0) months. On univariable analysis, previously cholangitis was an independent poor prognosis factor for recurrent biliary obstruction. OS was improved in patients who received more than one intervention compared to those who received only one intervention (log-rank P = 0.007), and in those treated without versus those treated with sequential chemotherapy (log-rank P = 0.017). On multivariable analysis, the occurrence of more than one intervention (P = 0.019) had independent prognostic significance for OS. CONCLUSION: Percutaneous RFA and stent placement is a technically safe and feasible therapeutic option for the palliative treatment of malignant biliary obstruction. The long-term efficacy and safety of the procedure is promising, but further study is required via randomized and prospective trials.

Comparison of intraluminal radiofrequency ablation and stents vs. stents alone in the management of malignant biliary obstruction.

PURPOSE: To retrospectively evaluate the added benefit of adding intraluminal radiofrequency ablation (RFA) to biliary metal stent placement for patients with malignant biliary obstruction (MBO). METHODS: From November 2013 to December 2015, 89 patients with MBO who had undergone percutaneous intraluminal RFA and stent placement (RFA-stent group, n = 50) or stent placement only (stent group, n = 39) were included. Outcomes were compared according to the type of tumour: cholangiocarcinoma or non-cholangiocarcinoma. RESULTS: Primary and secondary stent patency (PSP, SSP) were significantly higher for the RFA-stent group than the stent group (PSP: 7.0 months vs. 5.0 months, p = 0.006; SSP: 10.0 months vs. 5.6 months, p < 0.001), with overall survival being comparable (5.0 months vs. 4.7 months, p = 0.068). In subgroup analysis, RFA-stent showed significant PSP benefits compared to stent alone in patients with cholangiocarcinoma (7.4 months vs. 4.3 months; p = 0.009), but with comparable outcomes in patients with non-cholangiocarcinoma (6.3 months vs. 5.2 months; p = 0.266). The SSP was improved in both subgroups (cholangiocarcinoma, 12.6 months vs. 5.0 months, p < 0.001; non-cholangiocarcinoma, 10.3 months vs. 5.5 months, p = 0.013). Technical success and clinical success were not significantly different between the two groups. The rate of complication was higher for the RFA-stent group, but tolerable when compared to the stent group. CONCLUSIONS: Although survival was comparable between the groups, RFA-stent confers therapeutic benefits to patients with MBO in terms of stent patency compared to stent placement alone, especially in those with cholangiocarcinoma.

Feasibility and Clinical Value of CT-guided (125)I Brachytherapy for Bilateral Lung Recurrences from Colorectal Carcinoma.

PURPOSE: To prospectively evaluate the feasibility and clinical value of computed tomography (CT)-guided iodine 125 ((125)I) brachytherapy to treat bilateral lung recurrences from colorectal carcinoma. MATERIALS AND METHODS: This study was approved by Sun Yat-sen University Cancer Center Institutional Review Board and all patients provided informed written consent. Seventy-two patients with bilateral lung recurrences from colorectal carcinoma were enrolled and randomly divided into two groups. Thirty-three were percutaneously treated with CT-guided (125)I brachytherapy (group A) and the other 39 were only given symptomatic and supportive treatments (group B). Follow-up contrast agent-enhanced CT scans were reviewed and efficacy of treatment was evaluated. (125)I brachytherapy was considered a success if it achieved the computerized treatment planning system criteria 1 month after procedure. Analyses included Kaplan-Meier, Mantel-Cox log-rank test, and Cox proportional hazards regression. RESULTS: In group A, 37 (125)I brachytherapy procedures were performed in 33 patients with 126 lung metastatic lesions and the success rate was 87.9% (29 of 33 patients). The local control rate of 3, 6, 12, 24, and 36 months was 75.8%, 51.5%, 33.3%, 24.2%, and 9.1%, respectively. A small amount of pulmonary hematoma occurred in five patients, and six patients presented with pneumothorax with pulmonary compression of 30%-40%. No massive bleeding or radiation pneumonitis occurred. The mean overall survival (OS) of group A was significantly longer than that of group B, and (125)I brachytherapy was an independent factor that affected the OS (group A, 18.8 months; group B, 8.6 months; hazard ratio, 0.391 [95% confidence interval: 0.196, 0.779]; P = .008). CONCLUSION: CT-guided (125)I brachytherapy is feasible and safe for the treatment of bilateral lung recurrences from colorectal carcinoma.

Osteopontin enhances the expression of HOTAIR in cancer cells via IRF1.

Osteopontin (OPN), a secreted phosphoglycoprotein, plays important roles in tumor growth, invasion, and metastasis for many types of cancers. The long, noncoding RNA HOTAIR has been strongly associated with the invasion and metastasis of cancer cells. In this study, we found that recombinant human OPN could induce HOTAIR expression in a time- and dose-dependent manner, and our data also showed that OPN transcriptionally activated the expression of HOTAIR in cancer cells. Furthermore, through chromatin immunoprecipitation and luciferase activity assays, we found that IRF1 could bind to the HOTAIR promoter region and decrease its transcriptional activity, and cellular overexpression of IRF1 downregulated the level of HOTAIR. The receptor CD44 has also been verified as a regulator of OPN-induced HOTAIR expression. Interestingly, our data demonstrated that OPN could regulate PI3K/AKT and IRF1 expression and signaling, thereby influencing the expression of HOTAIR. In hepatocellular carcinoma samples, levels of HOTAIR correlated with the expression of OPN and IRF1. We therefore conclude that OPN, as an extracellular matrix protein, can stimulate the expression of HOTAIR by attenuating the inhibitory effect of IRF1, and this results in promotion of the invasion and metastasis of cancer cells.

Combination of radiofrequency ablation with transarterial chemoembolization for hepatocellular carcinoma: an up-to-date meta-analysis.

The aim of this meta-analysis was to compare the effectiveness of combination of radiofrequency ablation (RFA) and transarterial chemoembolization (TACE) with that of RFA alone in patients with hepatocellular carcinoma (HCC). Randomized controlled trials comparing RFA plus TACE with RFA alone for HCC were included into this meta-analysis, and the search strategy followed the requirement of the Cochrane Library Handbook. Overall survival rate and recurrence-free survival rate were analyzed and compared by using Review Manager (version 5). We identified 7 randomized controlled trials comprising 571 patients who were treated by RFA plus TACE versus RFA alone for HCC. Meta-analyses showed that the combination of RFA and TACE was associated with a significantly higher overall survival rates (OR1 year = 2.39, 95 % CI, 1.35-4.21, P = 0.003; OR3 years = 1.85, 95 %CI 1.26-2.71, P = 0.002), and recurrence-free survival rate (OR1 year = 2.00, 95 % CI 1.26-3.18, P = 0.003; OR3 years = 2.13, 95 %CI 1.41-3.20, P < 0.001). Additionally, the quality of the evidence was high for the 1- and 3-year survival rate; no evidence of publication bias was observed. The combination of RFA with TACE can improve the overall survival rate and the recurrence-free survival rate for patients with HCC.

DEB-TACE versus cTACE for unresectable HCC with B1-type bile duct invasion after successful biliary drainage: A propensity score matching analysis.

BACKGROUND: Transarterial chemoembolization (TACE) is the standard treatment for intermediate-stage hepatocellular carcinoma (HCC). Given the lack of specific recommendations for conventional TACE (cTACE) and drug-eluting bead TACE (DEB-TACE) in patients having unresectable HCC with tumor infiltrating the common hepatic duct or the first-order branch of the bile ducts (B1-type bile duct invasion; B1-BDI) after biliary drainage, we retrospectively compared the safety and efficacy of DEB-TACE with cTACE in this patient population. MATERIALS AND METHODS: Using data from five tertiary medical centers (January 2017-December 2021), we compared complications, overall survival (OS), time to progression (TTP), and tumor response rate between patients having unresectable HCC with B1-BDI who underwent DEB-TACE or cTACE after successful biliary drainage. X-tile software calculated the pre-TACE total bilirubin (TBil) cutoff value, indicating optimal timing for sequential TACE after drainage. Propensity score matching (PSM) was performed. RESULTS: The study included 108 patients with unresectable HCC (B1-BDI) who underwent DEB-TACE and 114 who received cTACE as initial treatment. After PSM (n = 53 for each group), the DEB-TACE group had a longer TTP (8.9 vs. 6.7 months, p = 0.038) and higher objective response rate (64.2% vs. 39.6%, p = 0.011) than did the cTACE group, although OS was comparable (16.7 vs. 15.3 months, p = 0.115). The DEB-TACE group exhibited fewer post-procedural increments in the mean albumin-bilirubin score, TBil, and alanine aminotransferase (ALT), along with a significantly lower incidence of serious adverse events within 30 days (hepatic failure, ALT increase, and TBil increase) than the cTACE group (all p < 0.05). The pre-TACE TBil cutoff value was 99 µmol/L; patients with higher values (>99 µmol/L) had poorer OS in both groups (p < 0.05). CONCLUSION: DEB-TACE is safe and effective after successful biliary drainage in unresectable HCC with B1-BDI, potentially better than cTACE in terms of liver toxicity, TTP, and ORR. Lowering TBil below 99 µmol/L through successful drainage may create ideal conditions for sequential TACE.

BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module.

Engulfment and subsequent degradation of apoptotic cells is an essential step that occurs throughout life in all multicellular organisms. ELMO/Dock180/Rac proteins are a conserved signalling module for promoting the internalization of apoptotic cell corpses; ELMO and Dock180 function together as a guanine nucleotide exchange factor (GEF) for the small GTPase Rac, and thereby regulate the phagocyte actin cytoskeleton during engulfment. However, the receptor(s) upstream of the ELMO/Dock180/Rac module are still unknown. Here we identify brain-specific angiogenesis inhibitor 1 (BAI1) as a receptor upstream of ELMO and as a receptor that can bind phosphatidylserine on apoptotic cells. BAI1 is a seven-transmembrane protein belonging to the adhesion-type G-protein-coupled receptor family, with an extended extracellular region and no known ligands. We show that BAI1 functions as an engulfment receptor in both the recognition and subsequent internalization of apoptotic cells. Through multiple lines of investigation, we identify phosphatidylserine, a key 'eat-me' signal exposed on apoptotic cells, as a ligand for BAI1. The thrombospondin type 1 repeats within the extracellular region of BAI1 mediate direct binding to phosphatidylserine. As with intracellular signalling, BAI1 forms a trimeric complex with ELMO and Dock180, and functional studies suggest that BAI1 cooperates with ELMO/Dock180/Rac to promote maximal engulfment of apoptotic cells. Last, decreased BAI1 expression or interference with BAI1 function inhibits the engulfment of apoptotic targets ex vivo and in vivo. Thus, BAI1 is a phosphatidylserine recognition receptor that can directly recruit a Rac-GEF complex to mediate the uptake of apoptotic cells.

CHAC1 inactivation is effective to preserve muscle glutathione but is insufficient to protect against muscle wasting in cachexia.

Muscle wasting is one of the main characteristics of cachexia associated with cancer and other chronic diseases and is often exacerbated by antineoplastic agents. Increased oxidative stress is associated with muscle wasting, along with depletion of glutathione, the most abundant endogenous antioxidant. Therefore, boosting endogenous glutathione has been proposed as a therapeutic strategy to prevent muscle wasting. Here, we tested this hypothesis by inactivating CHAC1, an intracellular glutathione degradation enzyme. We found CHAC1 expression is increased under multiple muscle wasting conditions in animal models, including fasting, cancer cachexia, and chemotherapy. The elevation of muscle Chac1 expression is associated with reduced glutathione level. CHAC1 inhibition via CRSPR/Cas9 mediated knock-in of an enzyme inactivating mutation demonstrates a novel strategy to preserve muscle glutathione levels under wasting conditions but fails to prevent muscle wasting in mice. These results suggest that preserving intracellular glutathione level alone may not be sufficient to prevent cancer or chemotherapy induced muscle wasting.

Sorafenib plus drug-eluting bead transarterial chemoembolization for early intrahepatic stage-progressed advanced hepatocellular carcinoma refractory to conventional transarterial chemoembolization.

PURPOSE: To investigate the effectiveness and safety of the combination of sorafenib and drug-eluting bead transarterial chemoembolization (DEB-TACE) in the treatment of early intrahepatic stage-progressed advanced hepatocellular carcinoma (ISPA-HCC). METHODS: This study was approved by the ethics committees of six tertiary medical centers in China. Between October 2017 and October 2020, 213 patients with advanced HCC received either sorafenib combined with on-demand DEB-TACE (DTS group, n = 103) or sorafenib monotherapy (S group, n = 110). Overall survival (OS), time to progression (TTP), local tumor response, and adverse events (AEs) were compared between the two groups. RESULTS: The incidences of nause/vomiting, abdonimal pain, hyperbilirubinemia, fever and ALT/AST increasing were higher in the DTS group. The post-treatment partial response, objective response, and disease control rates were significantly higher in the DTS group than in the S group (51.5% vs. 23.6%; 56.3% vs. 25.5%; 77.7% vs. 56.4%, respectively). The median OS was significantly longer in the DTS group than in the S group [16.3 vs. 10.0 months; hazard ratio (HR) = 0.43; P < 0.001], as was the TTP (6.7 vs. 4.3 months; HR = 0.60; P = 0.001). In the DTS group, patients who received ≥ 2 sessions of DEB-TACE benefited more than those who received two sessions of DEB-TACE. Multivariate analysis revealed that the α-fetoprotein level and treatment allocation were independent predictors of OS and TTP. CONCLUSION: The combination of sorafenib and DEB-TACE is safe and effective for the treatment of early ISPA-HCC.

Development and validation of a nomogram for predicting survival time and making treatment decisions for clinical stage IA NSCLC based on the SEER database.

Background: The aim of this study was to establish and validate a nomogram model for accurate prediction of patients' survival with T1aN0M0 none small cell lung cancer (NSCLC). Methods: The patients, diagnosed with the stage IA NSCLC from 2004-2015, were identified from the Surveillance, Epidemiology and End Results (SEER) database. The variables with a P-value < 0.05 in a multivariate Cox regression were selected to establish the nomogram. The discriminative ability of the model was evaluated by the concordance index (C-index). The proximity of the nomogram prediction to the actual risk was depicted by a calibration plot. The clinical usefulness was estimated by the decision curve analysis (DCA). Survival curves were made with Kaplan-Meier method and compared by Log-Rank test. Results: Eight variables, including treatment, age, sex, race, marriage, tumor size, histology, and grade were selected to develop the nomogram model by univariate and multivariate cox regression. The C-index was 0.704 (95% CI, 0.694-0.714) in the training set and 0.713 (95% CI, 0.697-0.728) in the test set, which performed significantly better than 8th edition AJCC TNM stage system (0.550, 95% CI, 0.408-0.683, P < 0.001). The calibration curve showed that the prediction ability of 3-years and 5-years survival rate demonstrated a high degree of agreement between the nomogram model and the actual observation. The DCA curves also proved that the nomogram-assisted decisions could improve patient outcomes. Conclusion: We established and validated a prognostic nomogram to predict 3-years and 5-years overall survival in stage IA NSCLC.

Unconventional Rac-GEF activity is mediated through the Dock180-ELMO complex.

Mammalian Dock180 and ELMO proteins, and their homologues in Caenorhabditis elegans and Drosophila melanogaster, function as critical upstream regulators of Rac during development and cell migration. The mechanism by which Dock180 or ELMO mediates Rac activation is not understood. Here, we identify a domain within Dock180 (denoted Docker) that specifically recognizes nucleotide-free Rac and can mediate GTP loading of Rac in vitro. The Docker domain is conserved among known Dock180 family members in metazoans and in a yeast protein. In cells, binding of Dock180 to Rac alone is insufficient for GTP loading, and a Dock180 ELMO1 interaction is required. We can also detect a trimeric ELMO1 Dock180 Rac1 complex and ELMO augments the interaction between Dock180 and Rac. We propose that the Dock180 ELMO complex functions as an unconventional two-part exchange factor for Rac.