Bortezomib in previously treated phosphatase and tension homology-deficient patients with advanced intrahepatic cholangiocarcinoma: An open-label, prospective and single-centre phase II trial.

INTRODUCTION: Intrahepatic cholangiocarcinoma (ICC) is characterized by a dismal prognosis with limited therapeutic alternatives. To explore phosphatase and tension homolog (PTEN) as a biomarker for proteasome inhibition in ICC, we conducted a phase II trial to assess the second-line efficacy of bortezomib in PTEN-deficient advanced ICC patients. METHODS: A total of 130 patients with advanced ICC in our centre were screened by PTEN immunohistochemical staining between 1 July 2017, and 31 December 2021, and 16 patients were ultimately enrolled and treated with single-agent bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11 of a 21-day cycle. The primary endpoint was the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors v1.1. RESULTS: The median follow-up was 6.55 months (95% confidence interval [CI]: 0.7-19.9 months). Among the 16 enrolled patients, the ORR was 18.75% (3/16) and the disease control rate was 43.75% (7/16). The median progress-free survival was 2.95 months (95% CI: 2.1-5.1 months) and the median overall survival (mOS) was 7.2 months (95% CI: 0.7-21.6 months) in the intent-to-treat-patients. Treatment-related adverse events of any grade were reported in 16 patients, with thrombopenia being the most common toxicity. Patients with PTEN staining scores of 0 were more likely to benefit from bortezomib than those with staining scores > 0. CONCLUSIONS: Bortezomib yielded an encouraging objective response and a favourable OS as a second-line agent in PTEN-deficient ICC patients. Our findings suggest bortezomib as a promising therapeutic option for patients with PTEN-deficient ICC. HIGHLIGHTS: There is a limited strategy for the second-line option of intrahepatic cholangiocarcinoma (ICC). This investigator-initiated phase 2 study evaluated bortezomib in ICC patients with phosphatase and tension homology deficiency. The overall response rate was 18.75% and the overall survival was 7.2 months in the intent-to-treat cohort. These results justify further developing bortezomib in ICC patients with PTEN deficiency.

Diverse functions of SOX9 in liver development and homeostasis and hepatobiliary diseases.

The liver is the central organ for digestion and detoxification and has unique metabolic and regenerative capacities. The hepatobiliary system originates from the foregut endoderm, in which cells undergo multiple events of cell proliferation, migration, and differentiation to form the liver parenchyma and ductal system under the hierarchical regulation of transcription factors. Studies on liver development and diseases have revealed that SRY-related high-mobility group box 9 (SOX9) plays an important role in liver embryogenesis and the progression of hepatobiliary diseases. SOX9 is not only a master regulator of cell fate determination and tissue morphogenesis, but also regulates various biological features of cancer, including cancer stemness, invasion, and drug resistance, making SOX9 a potential biomarker for tumor prognosis and progression. This review systematically summarizes the latest findings of SOX9 in hepatobiliary development, homeostasis, and disease. We also highlight the value of SOX9 as a novel biomarker and potential target for the clinical treatment of major liver diseases.

Polypyrrole regulates Active Sites in Co-based Catalyst in Direct Borohydride Fuel Cells.

Direct borohydride fuel cells (DBFCs) convert borohydride (NaBH4) chemical energy into clean electricity. However, catalytic active site deactivation in NaBH4 solution limits their performance and stability. We propose a strategy to regulate active sites in Co-based catalysts using polypyrrole modification (Co-PX catalyst) to enhance electrochemical borohydride oxidation reaction (eBOR). As an anode catalyst, the synthesized Co-PX catalyst exhibits excellent eBOR performance in DBFCs, with current density of 280 mA ⋅ cm-2 and power density of 151 mW ⋅ cm-2, nearly twice that of the unmodified catalyst. The Co-PX catalyst shows no degradation after 120-hour operation, unlike the rapidly degrading control. In-situ electrochemical attenuated total reflection Fourier-transform infrared spectroscopy (ATR-FTIRS) and density functional theory (DFT) suggest that polypyrrole-modified carbon support regulate the charge distribution, increasing oxidation state and optimizing adsorption/desorption of intermediates. A possible reaction pathway is proposed. This work presents a promising strategy for efficient polymer-modulated catalysts in advanced DBFCs.

URI alleviates tyrosine kinase inhibitors-induced ferroptosis by reprogramming lipid metabolism in p53 wild-type liver cancers.

The clinical benefit of tyrosine kinase inhibitors (TKIs)-based systemic therapy for advanced hepatocellular carcinoma (HCC) is limited due to drug resistance. Here, we uncover that lipid metabolism reprogramming mediated by unconventional prefoldin RPB5 interactor (URI) endows HCC with resistance to TKIs-induced ferroptosis. Mechanistically, URI directly interacts with TRIM28 and promotes p53 ubiquitination and degradation in a TRIM28-MDM2 dependent manner. Importantly, p53 binds to the promoter of stearoyl-CoA desaturase 1 (SCD1) and represses its transcription. High expression of URI is correlated with high level of SCD1 and their synergetic expression predicts poor prognosis and TKIs resistance in HCC. The combination of SCD1 inhibitor aramchol and deuterated sorafenib derivative donafenib displays promising anti-tumor effects in p53-wild type HCC patient-derived organoids and xenografted tumors. This combination therapy has potential clinical benefits for the patients with advanced HCC who have wild-type p53 and high levels of URI/SCD1.

PTEN deficiency facilitates gemcitabine efficacy in cancer by modulating the phosphorylation of PP2Ac and DCK.

Gemcitabine is a nucleoside analog that has been successfully used in the treatment of multiple cancers. However, intrinsic or acquired resistance reduces the chemotherapeutic potential of gemcitabine. Here, we revealed a previously unappreciated mechanism by which phosphatase and tensin homolog (PTEN), one of the most frequently mutated genes in human cancers, dominates the decision-making process that is central to the regulation of gemcitabine efficacy in cholangiocarcinoma (CCA). By investigating a gemcitabine-treated CCA cohort, we found that PTEN deficiency was correlated with the improved efficacy of gemcitabine-based chemotherapy. Using cell-based drug sensitivity assays, cell line-derived xenograft, and patient-derived xenograft models, we further confirmed that PTEN deficiency or genetic-engineering down-regulation of PTEN facilitated gemcitabine efficacy both in vitro and in vivo. Mechanistically, PTEN directly binds to and dephosphorylates the C terminus of the catalytic subunit of protein phosphatase 2A (PP2Ac) to increase its enzymatic activity, which further dephosphorylates deoxycytidine kinase (DCK) at Ser74 to diminish gemcitabine efficacy. Therefore, PTEN deficiency and high phosphorylation of DCK predict a better response to gemcitabine-based chemotherapy in CCA. We speculate that the combination of PP2A inhibitor and gemcitabine in PTEN-positive tumors could avoid the resistance of gemcitabine, which would benefit a large population of patients with cancer receiving gemcitabine or other nucleoside analogs.

Tertiary lymphoid structures predict the prognosis and immunotherapy response of cholangiocarcinoma.

Introduction: Cholangiocarcinoma (CCA) is a malignant tumor of the biliary epithelium with a poor prognosis. The lack of biomarkers to predict therapeutic response and prognosis is one of the major challenges for CCA treatment. Tertiary lymphoid structures (TLS) provide a local and pivotal microenvironment for tumor immune responses. The prognostic value and clinical relevance of TLS in CCA remain unclear. We aimed to explore the characteristics and clinical significance of TLS in CCA. Methods: We investigated the prognostic value and clinical relevance of TLS in CCA using a surgery cohort containing 471 CCA patients (cohort 1) and an immunotherapy cohort containing 100 CCA patients (cohort 2). Hematoxylin and eosin (H&E) and immunohistochemical (IHC) staining were used to evaluate the maturity of TLS. Multiplex IHC (mIHC) was employed to characterize the composition of TLS. Results: Different maturity of TLS were observed in CCA tissue sections. Strong staining of the four-gene signature including PAX5, TCL1A, TNFRSF13C, and CD79A were found in TLS regions. A high density of intra-tumoral TLS (T-score high) were significantly correlated with longer overall survival (OS) both in CCA cohort 1 (p = 0.002) and cohort 2 (p = 0.01), whereas a high density of peri-tumoral TLS (P-score high) were associated with shorter OS in these two cohorts (p = 0.003 and p = 0.03, respectively). Conclusion: The established four-gene signature efficiently identified the TLS in CCA tissues. The abundance and spatial distribution of TLS were significantly correlated with the prognosis and immune checkpoint inhibitors (ICIs) immunotherapy response of CCA patients. The presence of intra-tumoral TLS are positive prognostic factors for CCA, which provide a theoretical basis for the future diagnosis and treatment of CCA.

Amino-Ligand-Coordinated Dicopper Active Sites Enable Catechol Oxidase-Like Activity for Chiral Recognition and Catalysis.

Developing highly active and selective advanced nanozymes for enzyme-mimicking catalysis remains a long-standing challenge for basic research and practical applications. Herein, we grafted a chiral histidine- (His-) coordinated copper core onto Zr-based metal-organic framework (MOF) basic backbones to structurally mirror the bimetal active site of natural catechol oxidase. Such a biomimetic fabricated process affords MOF-His-Cu with catechol oxidase-like activity, which can catalyze dehydrogenation and oxidation of o-diphenols and then transfer electrons to O2 to generate H2O2 by the cyclic conversion of Cu(II) and Cu(I). Specifically, the elaborate incorporation of chiral His arms results in higher catalytic selectivity over the chiral catechol substrates than natural enzyme. Density functional theory calculations reveal that the binding energy and potential steric effect in active site-substrate interactions account for the high stereoselectivity. This work demonstrates efficient and selective enzyme-mimicking catalytic processes and deepens the understanding of the catalytic mechanism of nanozymes.

PTEN Deficiency Facilitates Exosome Secretion and Metastasis in Cholangiocarcinoma by Impairing TFEB-mediated Lysosome Biogenesis.

BACKGROUND & AIMS: In eukaryotes, the ubiquitin-proteasome system and the autophagy-lysosome pathway are essential for maintaining cellular proteostasis and associated with cancer progression. Our previous studies have demonstrated that phosphatase and tensin homolog (PTEN), one of the most frequently mutated genes in human cancers, limits proteasome abundance and determines chemosensitivity to proteasome inhibitors in cholangiocarcinoma (CCA). However, whether PTEN regulates the lysosome pathway remains unclear. METHODS: We tested the effects of PTEN on lysosome biogenesis and exosome secretion using loss- and gain-of-function strategies in CCA cell lines. Using in vitro dephosphorylation assays, we explored the regulatory mechanism between PTEN and the key regulator of lysosome biogenesis, transcription factor EB (TFEB). Using the migration assays, invasion assays, and trans-splenic liver metastasis mouse models, we evaluated the function of PTEN deficiency, TFEB-mediated lysosome biogenesis, and exosome secretion on tumor metastasis. Moreover, we investigated the clinical significance of PTEN expression and exosome secretion by retrospective analysis. RESULTS: PTEN facilitated lysosome biogenesis and acidification through its protein phosphatase activity to dephosphorylate TFEB at Ser211. Notably, PTEN deficiency increased exosome secretion by reducing lysosome-mediated degradation of multi-vesicular bodies, which further facilitated the proliferation and invasion of CCA. TFEB agonist curcumin analog C1 restrained the metastatic phenotype caused by PTEN deficiency in mouse models, and we highlighted the correlation between PTEN deficiency and exosome secretion in clinical cohorts. CONCLUSIONS: In CCA, PTEN deficiency impairs lysosome biogenesis to facilitate exosome secretion and cancer metastasis in a TFEB phosphorylation-dependent manner.

Genomic Insights into the Radiation-Resistant Capability of Sphingomonas qomolangmaensis S5-59T and Sphingomonas glaciei S8-45T, Two Novel Bacteria from the North Slope of Mount Everest.

Mount Everest provides natural advantages to finding radiation-resistant extremophiles that are functionally mechanistic and possess commercial significance. (1) Background: Two bacterial strains, designated S5-59T and S8-45T, were isolated from moraine samples collected from the north slope of Mount Everest at altitudes of 5700m and 5100m above sea level. (2) Methods: The present study investigated the polyphasic features and genomic characteristics of S5-59T and S8-45T. (3) Results: The major fatty acids and the predominant respiratory menaquinone of S5-59T and S8-45T were summed as feature 3 (comprising C16:1 ω6c and/or C16:1 ω7c) and ubiquinone-10 (Q-10). Phylogenetic analyses based on 16S rRNA sequences and average nucleotide identity values among these two strains and their reference type strains were below the species demarcation thresholds of 98.65% and 95%. Strains S5-59T and S8-45T harbored great radiation resistance. The genomic analyses showed that DNA damage repair genes, such as mutL, mutS, radA, radC, recF, recN, etc., were present in the S5-59T and S8-45T strains. Additionally, strain S5-59T possessed more genes related to DNA protection proteins. The pan-genome analysis and horizontal gene transfers revealed that strains of Sphingomonas had a consistently homologous genetic evolutionary radiation resistance. Moreover, enzymatic antioxidative proteins also served critical roles in converting ROS into harmless molecules that resulted in resistance to radiation. Further, pigments and carotenoids such as zeaxanthin and alkylresorcinols of the non-enzymatic antioxidative system were also predicted to protect them from radiation. (4) Conclusions: Type strains S5-59T (=JCM 35564T =GDMCC 1.3193T) and S8-45T (=JCM 34749T =GDMCC 1.2715T) represent two novel species of the genus Sphingomonas with the proposed name Sphingomonas qomolangmaensis sp. nov. and Sphingomonas glaciei sp. nov. The type strains, S5-59T and S8-45T, were assessed in a deeply genomic study of their radiation-resistant mechanisms and this thus resulted in a further understanding of their greater potential application for the development of anti-radiation protective drugs.

Paracoccus everestensis sp. nov., a novel bacterium with great antioxidant capacity isolated from the north slope of Mount Everest.

A bacterial strain, designated S8-55T, was isolated from moraine samples collected from the north slope of Mount Everest at an altitude of 5 500 m above sea level. The purpose of this study was to describe a novel species and its characteristics, through genome sequencing and analysis of the relationship between the members of the genus Paracoccus, and explore the antioxidant capacity of strain S8-55T. The polyphasic study confirmed the affiliation of strain S8-55T with the genus Paracoccus. Strain S8-55T was aerobic, Gram-negative and oxidase- and catalase positive. Cells were orange-pigmented, ellipsoid and had no spore formation, no flagella and no motility. Strain S8-55T grow at 10-37 °C, pH 7-11 and without NaCl. Ubiquinone 10 was its predominant respiratory menaquinone. The polar lipids of strain S8-55T were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, an unidentified phospholipid, an unidentified aminolipid and three unidentified lipids. Its major fatty acids were summed feature 8 (C18 : 1 ω7c and/or C18 : 1 ω6c). The G+C content was 64.3 mol%. The phylogenetic analysis based on the 16S rRNA sequence showed that strain S8-55T was closely related to Paracoccus angustae E6T (97.9 %), Paracoccus aerius 011410T (97.9 %) and Paracoccus hibisci THG-T2.8T (97.8 %). The average nucleotide identity values among strain S8-55T and P. angustae CCTCC AB 2015056T, P. aerius KCTC 42845T and P. hibisci CCTCC AB 2016181T were 84.1, 84.5 and 76.3 %, respectively. The genome of strain S8-55T contained antioxidant genes such as oxyR, recD, katE, recD and rpoH. Based on its morphological, physiological and chemical taxonomic characteristics, strain S8-55T (=JCM 35 227T=GDMCC 1.3026T) should be classified as a novel species of the genus Paracoccus with the proposed name Paracoccus everestensis sp. nov.

Gankyrin and TIGAR cooperatively accelerate glucose metabolism toward the PPP and TCA cycle in hepatocellular carcinoma.

Oncogene-derived metabolic reprogramming is important for anabolic growth of cancer cells, which is now considered to be not simply rely on glycolysis. Pentose phosphate pathway and tricarboxylic acid cycle also play pivotal roles in helping cancer cells to meet their anabolic and energy demands. The present work focused on gankyrin, a relatively specific oncogene in hepatocellular carcinoma (HCC), and its impact on glycolysis and mitochondrial homeostasis. Metabolomics, RNA-seq analysis, and subsequent conjoint analysis illustrated that gankyrin regulated the pentose phosphate pathway (PPP), tricarboxylic acid (TCA) cycle, and mitochondrial function and homeostasis, which play pivotal roles in tumor development. Mechanistically, gankyrin was found to modulate HCC metabolic reprogramming via TIGAR. Gankyrin positively regulated the transcription of TIGAR through Nrf2, which bound to the antioxidant response elements (AREs) in the promoter of TIGAR. Interestingly, TIGAR feedback regulated the transcription of Nrf2 and subsequently gankyrin by promoting nuclear importation of PGC1α. The loop between gankyrin, Nrf2, and TIGAR accelerated glucose metabolism toward the PPP and TCA cycle, which provided vital building blocks, such as NADPH, ATP, and ribose of tumor and further facilitated the progression of HCC.

The therapeutic effect of KSP inhibitors in preclinical models of cholangiocarcinoma.

Cholangiocarcinoma (CCA) is an epithelial malignancy with a dismal prognosis owing to limited treatment options. Here, we identified several compound candidates against CCA using a high-throughput drug screen with approved or emerging oncology drugs, among which kinesin spindle protein (KSP) inhibitors showed potent cytotoxic effects on CCA cells. Treatment with KSP inhibitors SB743921 and ARRY520 caused significant tumor suppression in CCA xenograft models in vivo. Mechanistically, KSP inhibitors led to the formation of abnormal monopolar spindles, which further resulted in the mitotic arrest and cell death of CCA cells both in vivo and in vitro. KEGG pathway analysis of transcriptional data confirmed this finding. Moreover, our clinical data as well as the TCGA database showed KIF11 expression was abundant in most CCA tumor specimens and associated with poor outcomes of CCA patients. Our results demonstrate that the therapeutic regimen of KSP inhibitors could be a promising treatment strategy in CCA.

Single-Atom Iron Enables Strong Low-Triggering-Potential Luminol Cathodic Electrochemiluminescence.

The conventional cathodic electrochemiluminescence (ECL) always requires a more negative potential to trigger strong emission, which inevitably damages the bioactivity of targets and decreases the sensitivity and specificity. In this work, iron single-atom catalysts (Fe-N-C SACs) were employed as an efficient co-reaction accelerator for the first time to achieve the impressively cathodic emission of a luminol-H2O2 ECL system at an ultralow potential. Benefiting from the distinct electronic structure, Fe-N-C SACs exhibit remarkable properties for the activation of H2O2 to produce massive reactive oxygen species (ROS) under a negative scanning potential from 0 to -0.2 V. The ROS can oxidize the luminol anions into luminol anion radicals, avoiding the tedious electrochemical oxidation process of luminol. Then, the in situ-formed luminol anion radicals will directly react with ROS for the strong ECL emission. As a proof of concept, sensitive detection of the carcinoembryonic antigen was realized by glucose oxidase-mediated ECL immunoassay, shedding light on the superiority of SACs to construct efficient cathodic ECL systems with low triggering potential.

Sphingomonas radiodurans sp. nov., a novel radiation-resistant bacterium isolated from the north slope of Mount Everest.

A bacterial strain, designated S9-5T, was isolated from moraine samples collected from the north slope of Mount Everest at an altitude of 5 500 m above sea level. A polyphasic study confirmed the affiliation of the strain with the genus Sphingomonas. Strain S9-5T was an aerobic, Gram-stain-negative, non-spore-forming, non-motile and rod-shaped bacterium that could grow at 10-40 °C, pH 5-8 and with 0-9 % (w/v) NaCl. Q-10 was its predominant respiratory menaquinone. Diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, an unidentified phospholipid, an unidentified aminophospholipid and eight unidentified lipids comprised the polar lipids of strain S9-5T. Its major fatty acids were summed feature 8 (C18 : 1 ω7c and/or C18 : 1 ω6c) and C16 : 0. The G+C content was 65.75mol%. Phylogenetic analysis based on 16S rRNA sequences showed that strain S9-5T was phylogenetically closely related to Sphingomonas panaciterrae DCY91T (98.17 %), Sphingomonas olei K-1-16T (98.11 %) and Sphingomonas mucosissima DSM 17494T (97.39 %). The average nucleotide identity values among strain S9-5T and Sphingomonas panaciterrae DCY91T, Sphingomonas olei K-1-16T and Sphingomonas mucosissima DSM 17494T were 78.82, 78.87 and 78.29 %, respectively. Based on the morphological, physiological and chemotaxonomic data, strain S9-5T (=JCM 34750T=GDMCC 1.2714T) should represent a novel species of the genus Sphingomonas, for which we propose the name Sphingomonas radiodurans sp. nov.

Circulating tumor cells: A surrogate to predict the effect of treatment and overall survival in gastric adenocarcinoma.

BACKGROUND: Circulating tumor cells and serum tumor markers have been found significant in predicting outcome for several malignancies. However, their role in gastric cancer is not fully clarified. We conducted a retrospective study to explore the prognostic value of circulating tumor cells and their applicability in assessing the treatment efficacy in gastric cancers. METHODS: From September 2015 to December 2018, 116 patients with newly pathologically diagnosed gastric adenocarcinoma were enrolled. At both baseline and two courses after chemotherapy, the data of circulating tumor cells and serum tumor markers, such as CEA, CA72-4, CA19-9, CA50, and CA242, were collected. The relationships between the change trend of circulating tumor cells and the treatment efficacy were analyzed after chemotherapy, with a paired t-test. Univariate and multivariable analysis were used to find prognostic factors for overall survival (OS). RESULTS: We found there is a significant difference between the circulating tumor cells-positive and circulating tumor cells-negative before and after therapy (mOS 12.6 vs. 31.6 months, P<0.001; mOS 12.4 vs. 24.2 months, P=0.002), respectively. Also, differentiation, pre-therapeutic circulating tumor cells and therapeutic response were independent predictors of overall survival. Following two courses of chemotherapy, the number of circulating tumor cells increased obviously in the progressive disease group (P=0.002), while they decreased in the non-progressive disease group (P=0.02). Thus, the change in the circulating tumor cells count had a close association with the therapeutic response (P=0.004). CONCLUSION: Generally, circulating tumor cells provide a novel tool to evaluate the outcomes of gastric cancer patients. Since the change of circulating tumor cells was highly related to treatment response, it may be an auxiliary to assess the effect of chemotherapy, leading an earlier adjustment of following regimens.

PTEN deficiency facilitates the therapeutic vulnerability to proteasome inhibitor bortezomib in gallbladder cancer.

Gallbladder cancer (GBC) is an aggressive malignancy of biliary tract with poor prognosis. Although several studies have shown the frequency of relevant genetic alterations, there are few genetic models or translational studies that really benefit for GBC treatment in the era of precision medicine. By targeted sequencing and immunohistochemistry staining, we identified that phosphate and tension homology deleted on chromosome ten (PTEN) was frequently altered in GBC specimens, and loss of PTEN expression was independently correlated with poor survival outcomes. Further drug screening assays revealed proteasome inhibitor bortezomib as a promising agent for GBC treatment, and knockdown of PTEN increased bortezomib efficacy both in vivo and in vitro. Therapeutic evaluation of patient derived xenografts (PDXs) strongly supported the utilization of bortezomib in PTEN deficient GBC. Mechanically, functional PTEN inhibited ARE-dependent transcriptional activity, the same machinery regulating the transcription of proteasome subunits, thus PTEN suppressed proteasome activity and bortezomib sensitivity. Through siRNA screening, we identified the ARE-related transcriptional suppressor BACH1 involved in PTEN-mediated proteasome inhibition and regulated by PTEN-AKT1 axis. In summary, our study indicates that proteasome activity represents a prime therapeutic target in PTEN-deficient GBC tumors, which is worthy of further clinical validation.

The efficacy and safety of irinotecan ±â€Šbevacizumab compared with oxaliplatin ±â€Šbevacizumab for metastatic colorectal cancer: A meta-analysis.

BACKGROUND: Irinotecan (IRI)-based and oxaliplatin (OXA)-based regimens are available for the treatment of metastatic colorectal cancer (mCRC). Several studies have published inconsistent results in their comparisons of the efficacy and toxicity of IRI ±â€Šbevacizumab and OXA ±â€Šbevacizumab. This meta-analysis was performed to evaluate the efficacy and safety of these 2 regimens in patients with mCRC. METHODS: We searched several databases to identify relevant studies, including PubMed, EMBASE, and the Cochrane Controlled Trials Register. The primary endpoints were overall survival (OS) and time to progression (TTP). The secondary comparisons were overall response rate (ORR) and toxicity. In addition, the hazard ratio (HR) or risk ratio (RR) values with their corresponding 95% confidence intervals (CIs) were extracted from these studies. RESULTS: Pooled data of 13 studies demonstrated no significant differences in OS (HR = 0.96, 95% CI: 0.86-1.08, P = .53) and TTP (HR = 0.88, 95% CI: 0.72-1.08, P = .24) between the 2 groups. However, the ORR (RR = 0.87, 95% CI: 0.78-0.97, P = .02) was clearly improved in the OXA ±â€Šbevacizumab arm. Higher incidences of grade 3/4 nausea (RR = 1.63, 95% CI: 1.28-2.07, P < .001), vomiting (RR = 1.40, 95% CI: 1.09-1.81, P = .01), diarrhea (RR = 1.44, 95% CI: 1.23-1.70, P < .001), and anemia (RR = 4.13, 95% CI: 2.75-6.22, P < .001) were observed in the IRI group. However, the incidences of grade 3/4 neutropenia (RR = 0.75, 95% CI: 0.68-0.83, P < .001), thrombocytopenia (RR = 0.43, 95% CI: 0.26-0.73, P = .002), and paresthesia/neurological disturbances (RR = 0.04, 95% CI: 0.02-0.07, P < .001) were higher in the OXA group. CONCLUSION: This meta-analysis confirmed that the OXA ±â€Šbevacizumab regimen as a maintenance therapy significantly improved the ORR in patients with mCRC. Exhibiting strong efficacy and safety, the OXA and OXA plus bevacizumab regimens are preferred as first-line treatments for mCRC.

Identification of biomarkers and their functions in dasatinib-resistant pancreatic cancer using bioinformatics analysis.

Dasatinib is a tyrosine kinase inhibitor, which inhibits tumor proliferation by blocking SRC pathways and is considered as a potential treatment of various epithelial neoplasms, including pancreatic cancer. However, dasatinib efficacy is largely limited due to drug resistance. In the present study, bioinformatics strategies were used to investigate the potential mechanisms of dasatinib-resistance in pancreatic cancer. The gene expression profiles of the Panc0403, Panc0504, Panc1005 (dasatinib-sensitive), SU8686, MiaPaCa2 and Panc1 (acquired dasatinib-resistant) cell lines were obtained from the gene expression omnibus database. The differentially expressed genes (DEGs) were then selected using R software. In addition, gene ontology (GO) and pathway enrichment analysis were performed through the Database for Annotation, Visualization and Integrated Discovery. A protein-protein interaction (PPI) network was constructed and analyzed to determine the hub genes using the Search Tool for the Retrieval of Interacting Genes database. A total of 472 DEGs, including vimentin, transmembrane 4 l six family member 18 and S100 calcium binding protein P, were identified. Enrichment analysis by GO function demonstrated that DEGs were associated with extracellular components, signal regulation and binding factors. The analysis of the Kyoto Encyclopedia of Genes and Genomes demonstrated that several adenocarcinoma pathways were enriched, including the phosphoinositide 3-kinases/protein kinase B and mitogen-activated protein kinase signaling pathways. Some hub genes were highlighted following the PPI network construction, including Rac family small GTPase 1, laminin subunit α3, integrin subunit ß4, integrin subunit α2, collagen type VI α1 chain, collagen type I α2 chain, arrestin ß1 and synaptotagmin 1, which may be associated with pancreatic adenocarcinoma prognosis. A total of five out of eight hub genes were highly associated with the overall survival rate (P<0.05). In conclusion, the present study reported novel insights into the mechanisms of dasatinib resistance. Identification of these hub genes may be considered as potential novel treatment targets for dasatinib-resistance in pancreatic cancer.

Complete genomic sequence analysis of a highly virulent isolate revealed a novel strain of Sugarcane mosaic virus.

Sugarcane mosaic virus (SCMV) is the most prevalent virus causing maize dwarf mosaic disease in northern China. A SCMV isolate, BD8, was obtained from the maize showing dwarf and mosaic symptoms in Baoding, China. The complete genomic sequence of BD8 is 9,576 nucleotides (nt) excluding the poly(A) tail. It contains one single open reading frame of 9,192 nt and encodes a large polyprotein of 3,063 amino acids (aa), flanked by a 5'-untranslated region (UTR) of 148 nt and a 3'-UTR of 236 nt. The entire genomic sequence of BD8 shares identities of 79.1-80.8% with those of other 13 SCMV isolates available in the GenBank at nt level, while their CP genes share identities of 76.9-82.6 and 82.8-86.9% at nt and aa levels, respectively. Phylogenetic analysis of the complete genomic sequences reveals that SCMV can be clustered to four groups: group I includes isolates from maize, group II consists of isolates from sugarcane or maize, groups III and IV contain single isolate of AU-A (AJ278405) and BD8, respectively. Thus, BD8 represents a new strain of SCMV. Furthermore analysis of the CP gene sequences of more isolates shows that BD8 is clustered to a group with the isolates from Thailand and Vietnam, which implies that isolates of this strain have been distributed in South Asia. In the greenhouse, BD8 can cause severe symptoms in all the 12 maize varieties tested with high incidence, indicating that BD8 is highly virulent.