CDK Inhibition Reverses Acquired 5-Fluorouracil Resistance in Hepatocellular Carcinoma Cells.

Background: 5-Fluorouracil (5-FU) has been widely applied in treating cancers. However, its usage is largely limited in hepatocellular carcinoma (HCC), due to acquired resistance. Here, we aim to identify target proteins and investigate their roles in 5-FU sensitivity of HCC cells. Methods: Mass spectrometry (MS) proteomics was performed on 5-FU-resistant cell line (BEL7402/5-FU) and its parental cell line (BEL7402) with 5-FU treatment. In order to identify potential targets, we compared the proteomics between two cell line groups and used bioinformatics tools to select hub proteins from all differentially expressed proteins. Results: We finally focused on a group of cell cycle-related kinases (CDKs). By CCK8 assay, we confirmed that the CDK inhibitor significantly decreased the IC50 of 5-FU-resistant cells. Conclusions: Our study verified that CDK inhibition can reverse 5-FU resistance of HCC cells.

Effect of S-1 Plus Oxaliplatin Compared With Fluorouracil, Leucovorin Plus Oxaliplatin as Perioperative Chemotherapy for Locally Advanced, Resectable Gastric Cancer: A Randomized Clinical Trial.

IMPORTANCE: Perioperative chemotherapy is a potential treatment for locally advanced gastric cancer. However, the optimal chemotherapy regimen remains unknown. OBJECTIVE: To investigate the safety and efficacy of S-1 plus oxaliplatin (SOX) vs fluorouracil, leucovorin, and oxaliplatin (FOLFOX) as a perioperative chemotherapy regimen for patients with locally advanced gastric cancer. DESIGN, SETTING, AND PARTICIPANTS: In this phase 3, open-label, multicenter, randomized clinical trial, patients from 12 Chinese hospitals were enrolled between June 2011 and August 2016, with a last follow-up date of September 2019. The primary tumor was evaluated as either invading the serosa or the adjacent structures with or without metastatic lymph nodes, and with no evidence of distant metastases. Data were analyzed from December 2019 to June 2020. INTERVENTIONS: Patients were randomly assigned (1:1) to receive either 6 perioperative (2-4 preoperative and 2-4 postoperative) 3-week cycles of 130 mg/m2 oxaliplatin on day 1 and 80 to 120 mg/d S-1 orally daily for 2 weeks (SOX) or 130 mg/m2 oxaliplatin, 400 mg/m2 fluorouracil, 400 mg/m2 leucovorin, and 2400 mg/m2 fluorouracil as 46-hour infusion on day 1 (FOLFOX). MAIN OUTCOMES AND MEASURES: The primary end point was 3-year overall survival (OS). An absolute noninferiority margin of -8% was chosen. RESULTS: A total of 583 patients were enrolled; 293 were randomized to the SOX group and 290 were randomized to the FOLFOX group. Twelve patients (2.1%) refused preoperative chemotherapy (5 patients in the SOX group and 7 patients in the FOLFOX group), leaving a total of 288 patients in the SOX group (median [range] age, 61 [24 to 78] years; 197 men [68.4%]) and 283 patients in the FOLFOX group (median [range] age, 62 [24 to 80] years; 209 men [73.9%]) who received preoperative chemotherapy. The 3-year OS rate was 75.2% (95% CI, 70.3% to 80.5%) in the SOX group and 67.8% (95% CI, 62.5% to 73.5%) in the FOLFOX group. The absolute difference of 3-year OS rate between the 2 groups was 7.4% (95% CI, -0.1% to 14.9%), which was greater than the prespecified noninferiority margin (-8%) and showed the noninferiority of perioperative chemotherapy with SOX compared with FOLFOX. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, SOX was noninferior to FOLFOX as perioperative chemotherapy for patients with locally advanced gastric cancer and could be recommended as an alternative treatment for these patients in Asia. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01364376.

Perioperative or postoperative adjuvant oxaliplatin with S-1 versus adjuvant oxaliplatin with capecitabine in patients with locally advanced gastric or gastro-oesophageal junction adenocarcinoma undergoing D2 gastrectomy (RESOLVE): an open-label, superiority and non-inferiority, phase 3 randomised controlled trial.

BACKGROUND: The optimal perioperative chemotherapeutic regimen for locally advanced gastric cancer remains undefined. We evaluated the efficacy and safety of perioperative and postoperative S-1 and oxaliplatin (SOX) compared with postoperative capecitabine and oxaliplatin (CapOx) in patients with locally advanced gastric cancer undergoing D2 gastrectomy. METHODS: We did this open-label, phase 3, superiority and non-inferiority, randomised trial at 27 hospitals in China. We recruited antitumour treatment-naive patients aged 18 years or older with historically confirmed cT4a N+ M0 or cT4b Nany M0 gastric or gastro-oesophageal junction adenocarcinoma, with Karnofsky performance score of 70 or more. Patients undergoing D2 gastrectomy were randomly assigned (1:1:1) via an interactive web response system, stratified by participating centres and Lauren classification, to receive adjuvant CapOx (eight postoperative cycles of intravenous oxaliplatin 130 mg/m2 on day one of each 21 day cycle plus oral capecitabine 1000 mg/m2 twice a day), adjuvant SOX (eight postoperative cycles of intravenous oxaliplatin 130 mg/m2 on day one of each 21 day cycle plus oral S-1 40-60 mg twice a day), or perioperative SOX (intravenous oxaliplatin 130 mg/m2 on day one of each 21 day plus oral S-1 40-60 mg twice a day for three cycles preoperatively and five cycles postoperatively followed by three cycles of S-1 monotherapy). The primary endpoint, assessed in the modified intention-to-treat population, 3-year disease-free survival to assess the superiority of perioperative-SOX compared with adjuvant-SOX and the non-inferiority (hazard ratio non-inferiority margin of 1·33) of adjuvant-SOX compared with adjuvant-CapOx. Safety analysis were done in patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT01534546. FINDINGS: Between Aug 15, 2012, and Feb 28, 2017, 1094 patients were screened and 1022 (93%) were included in the modified intention-to-treat population, of whom 345 (34%) patients were assigned to the adjuvant-CapOx, 340 (33%) patients to the adjuvant-SOX group, and 337 (33%) patients to the perioperative-SOX group. 3-year disease-free survival was 51·1% (95% CI 45·5-56·3) in the adjuvant-CapOx group, 56·5% (51·0-61·7) in the adjuvant-SOX group, and 59·4% (53·8-64·6) in the perioperative-SOX group. The hazard ratio (HR) was 0·77 (95% CI 0·61-0·97; Wald p=0·028) for the perioperative-SOX group compared with the adjuvant-CapOx group and 0·86 (0·68-1·07; Wald p=0·17) for the adjuvant-SOX group compared with the adjuvant-CapOx group. The most common grade 3-4 adverse events was neutropenia (32 [12%] of 258 patients in the adjuvant-CapOx group, 21 [8%] of 249 patients in the adjuvant-SOX group, and 30 [10%] of 310 patients in the perioperative-SOX group). Serious adverse events were reported in seven (3%) of 258 patients in adjuvant-CapOx group, two of which were related to treatment; eight (3%) of 249 patients in adjuvant-SOX group, two of which were related to treatment; and seven (2%) of 310 patients in perioperative-SOX group, four of which were related to treatment. No treatment-related deaths were reported. INTERPRETATION: Perioperative-SOX showed a clinically meaningful improvement compared with adjuvant-CapOx in patients with locally advanced gastric cancer who had D2 gastrectomy; adjuvant-SOX was non-inferior to adjuvant-CapOx in these patients. Perioperative-SOX could be considered a new treatment option for patients with locally advanced gastric cancer. FUNDING: National Key Research and Development Program of China, Beijing Scholars Program 2018-2024, Peking University Clinical Scientist Program, Taiho, Sanofi-Aventis, and Hengrui Pharmaceutical. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Effect of sulfur dioxide on vascular biology.

Gasotransmitters, such as nitric oxide, carbon monoxide and hydrogen sulfide, can be generated endogenously. These gasotransmitters play important roles in vascular biology, including vasorelaxation and inhibition of vascular smooth muscle cell (VSMC) proliferation. In recent years, sulfur dioxide (SO2) has been considered as a fourth gasotransmitter. SO2 is present in air pollution. Moreover, SO2 toxicity, including oxidative stress and DNA damage, has been extensively reported in previous studies. Recent studies have shown that SO2 can be endogenously generated in various organs and vascular tissues, where it regulates vascular tone, vascular smooth cell proliferation and collagen synthesis. SO2 can decrease blood pressure in rats, inhibit smooth muscle cell proliferation and collagen accumulation and promote collagen degradation, and improve vascular remodelling. SO2 can decrease cardiovascular atherosclerotic plaques by enhancing the antioxidant effect and upregulating nitric oxide/nitric oxide synthase and hydrogen sulfide/cystathionine-γ-lyase pathways. SO2 can also ameliorate vascular calcification via the transforming growth factor - ß1/Smad pathway. The effect of SO2 on vascular regulation has attracted great interest. SO2 may be a novel mediator in vascular biology.

The effects of gasotransmitters on bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD), which remains a major clinical problem for preterm infants, is caused mainly by hyperoxia, mechanical ventilation and inflammation. Many approaches have been developed with the aim of decreasing the incidence of or alleviating BPD, but effective methods are still lacking. Gasotransmitters, a type of small gas molecule that can be generated endogenously, exert a protective effect against BPD-associated lung injury; nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S) are three such gasotransmitters. The protective effects of NO have been extensively studied in animal models of BPD, but the results of these studies are inconsistent with those of clinical trials. NO inhalation seems to have no effect on BPD, although side effects have been reported. NO inhalation is not recommended for BPD treatment in preterm infants, except those with severe pulmonary hypertension. Both CO and H2S decreased lung injury in BPD rodent models in preclinical studies. Another small gas molecule, hydrogen, exerts a protective effect against BPD. The nuclear factor erythroid-derived 2 (Nrf2)/heme oxygenase-1 (HO-1) axis seems to play a central role in the protective effect of these gasotransmitters on BPD. Gasotransmitters play important roles in mammals, but further clinical trials are needed to explore their effects on BPD.

Potential therapeutic effect of SO2 on fibrosis.

Fibrosis is a pathological feature of most chronic diseases and leads to the dysfunction of various organs. However, there is currently no effective method for treating fibrosis. In recent years, a small gas, sulfur dioxide (SO2), which can be generated endogenously in mammals, has been found to have vasorelaxation activity, improve cardiac function and decrease myocardial injury. Endogenous SO2 also mediates the process of fibrosis. Inhibition of endogenous SO2 can aggravate small pulmonary artery remodeling and abnormal collagen accumulation. SO2 treatment significantly improves pulmonary fibrosis and pulmonary arterial remodeling. Overexpression of the key enzymes associated with endogenous SO2 generation, aspartate aminotransferase (AAT) 1 and AAT2, mimics the effect of SO2 on the down-regulation of collagen synthesis, while AAT1 or AAT2 knockdown aggravates abnormal collagen accumulation in vascular smooth muscle cells (VSMCs). SO2 also improves myocardial fibrosis induced by myocardial infarction or diabetes in rats, and inhibits myocardial fibroblast proliferation and migration by the extracellular signal-regulated protein kinase pathway. The mechanisms underlying the inhibition of fibrosis by SO2 are related to its antioxidant effect, anti-inflammation effect, improvement in cardiac function, and cell proliferation inhibition. Therefore, SO2 has a potential therapeutic effect on fibrosis.

CTGF: A potential therapeutic target for Bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease that often occurs in preterm infants. However, there is still no effective treatment for BPD. Recent studies demonstrated that connective tissue growth factor (CTGF) is involved in the development of BPD in experimental models. CTGF, also known as CCN2, is the second member of the CCN family and is necessary for normal lung development. The expression of CTGF is increased in lung tissues in infants with BPD. Hyperoxia, inflammation and mechanic ventilation increase CTGF expression which may promote fibroblast proliferation, matrix production and vascular remodeling. Conditional overexpression of CTGF in alveolar epithelial type II cells disrupts alveolarization and vascular development, induces vascular remodeling, and results in pulmonary hypertension, the pathological hallmarks of severe BPD. Further studies have shown that inhibition of CTGF by a CTGF monoclonal antibody improved alveolarization and vascular development, and decreased pulmonary vascular remodeling and pulmonary hypertension in a rodent model of BPD induced by hyperoxia. CTGF may be a novel target for BPD therapy in preterm infants.

Effects of hepatic blood inflow on liver ultrastructure and regeneration after extensive liver resection in rats with cirrhosis.

The aim of the present study was to investigate the effects of hepatic blood inflow on liver function, liver ultrastructure and the regeneration of future liver remnant (FLR) following major hepatectomy in rats with liver cirrhosis. A rat model of cirrhosis was established through intraperitoneal injection of carbon tetrachloride for 8 consecutive weeks. Extensive liver resection and different blood inflow models by portal vein (PV) and/or hepatic artery (HA) stenosis were conducted on the cirrhosis rats. Animal models were constructed as follows: Control (group A), low-flow PV + high-flow HA (group B), low-flow PV + low-flow HA (group C), high-flow PV + high-flow HA (group D) and high-flow PV + low-flow HA (group E). Hepatic blood inflow was detected by laser speckle contrast analysis, liver function and pathological changes were analyzed, Masson staining was used to identify the fibrosis of the liver and Periodic acid-Schiff staining was used to identify glycogen synthesis and hepatocyte function. The liver cell ultrastructure was evaluated by transmission electron microscopy, and the expression of Ki-67 in hepatocytes and the weight of the FLR were recorded to determine the regeneration of the FLR. Five days after major hepatectomy and liver blood inflow modulation, pathological examination of the livers from groups B and C revealed less congestion and less extensive hepatocellular injury. The serum alanine aminotransferase level of group B at 1, 3 and 5 days after hepatectomy and blood inflow modulation was 460.9±31.7, 331.0±22.0 and 285.6±15.8 U/l, respectively (control group: 676.9±41.7, 574.9±28.0 and 436.1±32.7 U/l, respectively; P<0.05); the total bilirubin of group B at 1, 3 and 5 days was 20.4±1.5, 16.1±1.0 and 13.5±0.6 µmol/l, respectively (control group: 30.3±1.4, 26.5±0.8 and 22.1±1.2 µmol/l, respectively; P<0.05). The size of the endoplasmic reticulum in the low-flow PV groups increased significantly and the mitochondrial swelling was alleviated. The positive rate of Ki-67 in the hepatocytes of groups B, C and D was 23.9±3.6, 15.7±2.3 and 12.9±2.4%, respectively (control group: 10.1±2.1%, P<0.05), and the positive rate of Ki-67 in group E was 6.1±1.4% (compared with that of the control group, P<0.05). The remnant liver weight of group B was 15.4±1.0 g (compared with that of the control group, P<0.05). Therefore, decreased portal blood flow combined with increased hepatic arterial blood flow alleviated the congestion in the liver following major hepatectomy in cirrhotic rats, improved the pathological status and liver function, increased the expression of Ki-67 and promoted liver regeneration.

Sulfur dioxide ameliorates rat myocardial fibrosis by inhibiting endoplasmic reticulum stress.

Myocardial remodeling occurs after myocardial infarction (MI), the leading cause of mortality worldwide. Although myocardial fibrosis plays an important role in the process of myocardial remodeling, there is not yet an effective method of reducing it. The aim of the present study was to determine the effects of sulfur dioxide (SO2) on myocardial fibrosis and the possible mechanisms of these effects. SO2 treatment reduced the extent of myocardial fibrosis and post-MI levels of collagens I and III in the left-ventricular myocardium. SO2 also improved MI-induced thinning of the left ventricular wall while enlarging the left ventricular internal diameter. SO2 was able to reduce matrix metalloproteinase (MMP)-9 activity and increase tissue matrix metalloproteinase inhibitor (TIMP)-1 content in myocardium after MI. However, the mechanism underlying these effects of SO2 on myocardial fibrosis are unknown. Western blot analysis of endoplasmic reticulum (ER) stress-related proteins showed that glucose-regulated protein 78, C/EBP homologous protein, caspase-12, and phosphorylated eukaryotic initiation factor 2α expression levels were significantly increased in MI rats and decreased by SO2 treatment. The ER stress promoter dithiothreitol reversed these effects of SO2. In conclusion, SO2 alleviated myocardial fibrosis in MI rats through a mechanism related to inhibition of excessive ER stress.

The significance of prophylactic transarterial chemoembolization after radical resection of small hepatocellular carcinoma: A retrospective analysis.

PURPOSE: To clarify the necessity of prophylactic transarterial chemoembolization (pTACE) after radical resection for small hepatocellular carcinoma (sHCC) (<3.0 cm) and identify prognostic determinants. MATERIALS AND METHODS: Consecutive 161 patients with sHCC in Zhejiang Cancer Hospital from May 2009 to May 2014 were retrospectively studied. In these patients, 87 patients only received radical resection alone (control group), while other 74 patients received pTACE after radical resection (pTACE group). The overall survival (OS) and recurrence-free survival (RFS) were evaluated by Kaplan-Meier method and the related factors on OS and RFS were analyzed by Cox regression analysis. RESULTS: The median OS for all patients was 33.6 months. The median OS in the pTACE and control group was 34.1 and 33.4 months, respectively (P = 0.508). The 1-, 3-, and 5-year survival rates were 91.9%, 73.4%, and 42.7% in the pTACE group and 93.1%, 77.9%, and 51.4% in the control group, respectively. The median RFS in pTACE and control group was 21.6 and 31.3 months (P = 0.002), respectively. The 1-, 3-, and 5-year RFS rate in pTACE group and control group was 81.0%, 47.4%, and 27.6% and 86.9%, 71.7%, and 49.9%, respectively. Preoperative gamma-glutamyl transferase (GGT) serum level ≥60 U/L (hazard ratio [HR] = 2.603, 95% confidence interval [CI] =1.506-4.501, P = 0.001) and recurrence (HR = 6.034, 95% CI = 2.931-12.421, P = 0.003) were independent prognostic determinants associated with poor prognosis in multivariate analysis. Resection followed by pTACE (HR = 2.046, 95% CI = 1.262-3.319, P = 0.004) and preoperative GGT serum level ≥60 U/L (HR = 1.864, 95% CI = 1.152-3.017, P = 0.011) were independent prognostic factors associated with higher rate of recurrence. CONCLUSIONS: Instead of improving the survival time, postoperative pTACE increased the rate of recurrence in sHCC patients. Preoperative GGT serum level ≥60 U/L and recurrence were independent prognostic determinants associated with poor prognosis.

Tumor repressor gene chondroadherin oppose migration and proliferation in hepatocellular carcinoma and predicts a good survival.

The molecular that used as prognosis and potential therapy target is urgently needed in hepatocellular carcinoma (HCC). In current work, we found the expression of CHAD (chondroadherin) was significantly reduced in hepatocellular carcinoma compared to the normal tissue, on both mRNA and protein levels, in three independent datasets. Survival analysis was implemented on these datasets, and low expression of CHAD was found to be significantly associated with poor survival. Furthermore, metastasis-averse HCC and metastasis-incline HCC group comparison, and protein abundance evaluation of normal-tumor-portal vein tumor thrombus pairs indicate that metastatic tendentiousness is reduced along with CHAD abundance. Correlation analysis was also carried out and CHAD was shown to be significantly associated with differentiation and metastasis. Multivariable cox regression analysis showed that CHAD expression is more important for prognosis, compared to the other clinical indicators. To facilitate the utilization of CHAD clinically, a nomogram was plotted to estimate the three-year survival rate. Functional assays testing the migration and proliferation ability following knock down of CHAD in two cell lines, SMMC7721 and HCCLM3, were performed and discovered that reduction of CHAD level significantly enhance both proliferation and migration in both cell lines. Gene Set Enrichment Analysis (GSEA) comparing the CHAD-low and CHAD-high group showed that KEGG signaling pathways including "focal adhesion", "ECM receptor interaction", and "regulation of actin cytoskeleton" were significantly enriched. In conclusion, as a potential prognostic biomarker, tumor suppressor gene CHAD represses migration and proliferation of hepatocellular carcinoma cells, probability via mediating cell-cell adhesion.

Sulfur dioxide: foe or friend for life?

Sulfur dioxide (SO2) is a toxic gas and air pollutant. The toxic effects of SO2 have been extensively studied. Oxidative damage due to SO2 can occur in multiple organs. Inhaled SO2 can also cause chromosomal aberrations, DNA damage and gene mutations in mammals. However, SO2 can also be generated from the sulfur-containing amino acid, L-cysteine. Recent studies have shown that SO2 has a vasorelaxant effect, and ameliorates pulmonary hypertension and vascular remodeling. SO2 can also reduce lung injury and myocardial injury in rats. In addition, SO2 reduces myocardial ischemia-reperfusion injury and atherosclerotic lesions. Therefore, SO2 exerts both detrimental and protective effects in mammals. Is SO2 a foe or friend for life?.

Sulfur dioxide: a physiologic endothelium-derived relaxing factor.

The gasotransmitter nitric oxide was classified as the first endothelium-derived relaxant factor, and opened a new era in cardiovascular research. Another small gas, sulfur dioxide (SO2), can also be generated endogenously in mammals. Recent studies have shown that SO2 may play important roles in the cardiovascular system. At low concentrations, the vasodilatory effect of SO2 is endothelium-dependent. The vasodilation induced by an endothelium-derived relaxant factor is achieved by the opening of potassium channels, and hyperpolarization of the membranes of vascular smooth muscle cells. This feature is in accordance with that of SO2. The vasodilatory effect of SO2 is related to the opening of adenosine triphosphate-sensitive potassium channels and high-conductance calcium-activated potassium channels. The 3'-5'-cyclic guanosine monophosphate pathway and activation of nitric oxide synthase are also involved in the endothelium-derived relaxant factor effect of SO2. The vasodilatory effect of gaseous SO2 is much stronger than that of its derivatives (bisulfite and sulfite). It is suggested that SO2 may be a candidate endothelium-derived relaxant factor, which could lead to a new era of research into cardiovascular disease in mammals.

Lentivirus-mediated inhibition of USP39 suppresses the growth of gastric cancer cells via PARP activation.

Gastric cancer (GC) is the second most common cause of cancer-associated mortality worldwide. Ubiquitin-specific peptidase 39 (USP39) has important roles in mRNA processing and has been reported to be involved in the growth of breast cancer cells. However, the roles of USP39 in GC have remained to be investigated, which was the aim of the present study. A lentivirus expressing short hairpin RNA targeting USP39 was constructed and transfected into MGC80­3 cells. Suppression of USP39 expression significantly decreased the proliferation and colony forming ability of MGC80­3 cells as indicated by an MTT and a clonogenic assay, respectively. In addition, flow cytometric cell cycle analysis revealed that depression of USP39 induced G2/M­phase arrest, while an intracellular signaling array showed that the cleavage of PARP at Asp214 was increased following USP39 knockdown. These results suggested that USP39 is involved in the proliferation of GCs and may be utilized as a molecular target for GC therapy.

The significance of transarterial chemoembolization combined with systemic chemotherapy for patients with KRAS wild-type unresectable metachronous colorectal carcinoma with liver metastases.

PURPOSE: The purpose of this study was to assess the survival benefits of transarterial chemoembolization (TACE) combined with systemic chemotherapy as the first-line treatment for metachronous unresectable colorectal carcinoma with liver metastases (CLMs) and to identify prognostic determinants. PATIENTS AND METHODS: One hundred and fifty-four patients with KRAS wild-type metachronous unresectable CLMs were retrospectively collected from January 2006 to December 2014. Patients were divided into four groups according to treatment modality: 43 patients with chemotherapy alone (Group A), 39 patients with chemotherapy plus TACE (Group B), 38 patients with chemotherapy plus cetuximab (Group C), and 34 patients with chemotherapy plus TACE and cetuximab (Group D). We compared the rate of patients converted to resection for liver metastases (LMs), overall survival among these groups, and assessed prognostic factors. RESULTS: The median interval time from resection of primary tumor to the diagnosis of CMLs was 12.0 months. The 1-, 3-, and 5-year survival rates and median survival time (MST) for all patients were 83.1%, 24.7%, 5.8%, and 22.9 months, respectively. Survival rates were significantly different in four groups at 1 year, 3 years, and 5 years with the MST of 17.5, 28.4, 18.9, and 30.3 months, respectively (P < 0.0001). The R0 resection rates for LMs were 7.0% in Group A, 30.8% in Group B, 10.5% in Group C, and 32.4% in Group D, which were statistically significantly different (P = 0.004). Univariate analysis revealed that posttreatment carcinoembryonic antigen serum level, tumor node (TN) stage, resection of LMs, tumor response, and treatment group were the significant prognostic factors. After adjusting the covariates in multivariate analysis, TN stage (hazard ratio [HR] = 1.394, 95% confidence interval [CI] = 1.027-1.893,P = 0.033), tumor response (HR = 2.901, 95% CI = 2.105-3.999,P < 0.0001), and treatment group (HR = 0.726, 95% CI = 0.594-0.887,P= 0.002) remained independent prognostic determinants. CONCLUSION: For patients with initially unresectable KRAS wild-type CLMs, chemotherapy plus TACE improved the resectability of LMs and survival compared with chemotherapy alone or chemotherapy plus cetuximab.

A Review of Artificial Lateral Line in Sensor Fabrication and Bionic Applications for Robot Fish.

Lateral line is a system of sense organs that can aid fishes to maneuver in a dark environment. Artificial lateral line (ALL) imitates the structure of lateral line in fishes and provides invaluable means for underwater-sensing technology and robot fish control. This paper reviews ALL, including sensor fabrication and applications to robot fish. The biophysics of lateral line are first introduced to enhance the understanding of lateral line structure and function. The design and fabrication of an ALL sensor on the basis of various sensing principles are then presented. ALL systems are collections of sensors that include carrier and control circuit. Their structure and hydrodynamic detection are reviewed. Finally, further research trends and existing problems of ALL are discussed.

Tectonic 1 accelerates gastric cancer cell proliferation and cell cycle progression in vitro.

Hedgehog (Hh) pathway is important in development and cancer. Hh signaling is constitutively active in gastric cancer. Recently, tectonic 1 (TCTN1) was identified as one regulator of the Hh pathway. In the present study, the biological role of TCTN1 was examined in gastric cancer via an RNA interference lentivirus system. The constructed lentivirus efficiently suppressed TCTN1 expression in three gastric cancer cell lines. The proliferation of gastric cancer cells was significantly inhibited in TCTN1 knockdown cells, as determined by 3­(4,5­dimethylthiazol­2­yl)­2,5­diphenyltetrazolium bromide and colony formation assays. Furthermore, in order to determine the underlying mechanism, the cell cycle progression of MGC80­3 cells was analyzed by flow cytometry. Knockdown of TCTN1 led to cell cycle arrest at the G2/M phase, which contributed to inhibition of growth. In conclusion, the results demonstrated that TCTN1 was essential in the growth of gastric cancer cells in vitro, suggesting TCTN1 as a potential target candidate for the treatment of gastric cancer.

Signal pathways involved in the biological effects of sulfur dioxide.

Gasotransmitters, such as nitric oxide, carbon monoxide and hydrogen sulfide, play important roles in life and have attracted great interest in scientists. In recent years, sulfur dioxide (SO2) has also been found to play important roles in mammals. The redox pathway is involved in the biological effects of SO2, such as the protective effect on myocardial ischemia reperfusion, myocardial injury, pulmonary hypertension and atherosclerosis. Ion channels, such as L-type calcium and adenosine triphosphate-sensitive potassium channels, as well as 3'-5'-cyclic guanosine monophosphate and 3'-5'-cyclic adenosine monophosphate pathways are also involved in the vasorelaxant effect of SO2. The mitogen-activated protein kinase pathway plays roles in vascular remodeling during pulmonary hypertension and vascular smooth muscle cell proliferation. Understanding these signaling mechanisms would help to clarify the pathophysiological effect and therapeutic potential of SO2.

Surgical treatment of huge hepatocarcinoma with invasion or severe adhesion of diaphragm using the technique of orthotopic liver resection.

BACKGROUND/AIMS: To explore the clinical application and significance of the technique of orthotopic liver resection. METHODOLOGY: From January 2004 to December 2011, five patients with huge hepatocellular carcinoma with invasion or severe adhesion of diaphragm were undergone right semi-liver resection using the technique of orthotopic liver resection. The right hemi-liver was isolated from the first liver portal, second liver portal and third liver portal, then isolated from the normal liver, finally the tumor and the invaded diaphragm were resected or removed from the severe adhesion. The approach to hepatic resection involved routine use of Peng's multifunctional operative dissector, selective control of in and out-flow of liver, control of inferior vena cava (IVC) and liver hanging maneuver, anterior approach, etc. RESULTS: The operations were successfully performed in 5 patients. Operative time was 120, 180, 150, 150 and 160 min, respectively. The amount of blood loss were 350, 350, 400, 450, 600 ml, respectively. Postoperative complications were pleural effusion in 3 cases, and other 2 cases recovered without complications. CONCLUSIONS: Although the technique of orthotopic liver resection has a high technical requirement for surgeons, it provides a surgical method and operative opportunity for the patients whose tumor has invaded diaphragm or has been severe adhesion with diaphragm and conventional liver resection cannot be performed.