Vinorelbine Improves the Efficacy of Sorafenib against Hepatocellular Carcinoma: A Promising Therapeutic Approach.

Hepatocellular carcinoma (HCC) is a leading global cause of cancer-related mortality. Despite the widespread adoption of sorafenib as the standard HCC treatment, its efficacy is constrained, frequently encountering resistance. To augment the effectiveness of sorafenib, this study investigated the synergy of sorafenib and vinorelbine using 22 HCC patient-derived xenograft (PDX) models.

Everolimus Acts in Synergy with Vinorelbine to Suppress the Growth of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a challenging cancer to treat, as traditional chemotherapies have shown limited effectiveness. The mammalian target of rapamycin/sirolimus (mTOR) and microtubules are prominent druggable targets for HCC. In this study, we demonstrated that co-targeting mTOR using mTOR inhibitors (everolimus and sirolimus) along with the microtubule inhibitor vinorelbine yielded results superior to those of the monotherapies in HCC PDX models.

Generating patient-derived ascites-dependent xenograft mouse models of peritoneal carcinomatosis.

Clinically relevant animal models are crucial for effective development of therapeutics for peritoneal carcinomatosis (PC). This protocol describes the generation of patient-derived ascites-dependent xenograft (PDADX) models from the cellular component of ascites. The use of routine intraperitoneal injection of the fluid component of ascites is analogous to the biological events occurring intra-abdominally in patients with PC.

Ligand-mediated PAI-1 inhibition in a mouse model of peritoneal carcinomatosis.

Peritoneal carcinomatosis (PC) present a ubiquitous clinical conundrum in all intra-abdominal malignancies. Via functional and transcriptomic experiments of ascites-treated PC cells, we identify STAT3 as a key signaling pathway. Integrative analysis of publicly available databases and correlation with clinical cohorts (n = 7,359) reveal putative clinically significant activating ligands of STAT3 signaling.

A machine learning approach to identify predictive molecular markers for cisplatin chemosensitivity following surgical resection in ovarian cancer.

Ovarian cancer is associated with poor prognosis. Platinum resistance contributes significantly to the high rate of tumour recurrence. We aimed to identify a set of molecular markers for predicting platinum sensitivity.

Gene Expression Changes Associated with Dedifferentiation in Liposarcoma Predict Overall Survival.

Up to 10% of well-differentiated liposarcoma (WDLS) progress to dedifferentiated liposarcoma (DDLS). We aimed to identify gene expression changes associated with dedifferentiation and whether these were informative of tumour biology of DDLS. We analysed datasets from the Gene Expression Omnibus (GEO, ID = GSE30929) database to identify differentially expressed genes between WDLS ( = 52) and DDLS ( = 39).

Postoperative Inflammatory Marker Surveillance in Colorectal Peritoneal Carcinomatosis.

Background: The prognostic significance of inflammatory markers in solid cancers is well-established, albeit with considerable heterogeneity. This study sought to investigate the postoperative inflammatory marker trend in peritoneal carcinomatosis (PC), with a focus on colorectal PC (CPC), and to propose optimal surveillance periods and cutoffs.

Methods: Data were collected from a prospectively maintained database of PC patients treated at the authors' institution from April 2001 to March 2019.

Pairing a prognostic target with potential therapeutic strategy for head and neck cancer.

Objectives: We have previously identified and validated a panel of molecular prognostic markers (ATP13A3, SSR3, and ANO1) for Head and Neck Squamous Cell Carcinoma (HNSCC). The aim of this study was to investigate the consequence of ATP13A3 dysregulation on signaling pathways, to aid in formulating a therapeutic strategy targeting ATP13A3-overexpressing HNSCC.

Materials And Methods: Gene Set Enrichment Analysis (GSEA) was performed on HNSCC microarray expression data (Internal local dataset [n = 92], TCGA [n = 232], EMBL [n = 81]) to identify pathways associated with high expression of ATP13A3.

An Optimised Protocol Harnessing Laser Capture Microdissection for Transcriptomic Analysis on Matched Primary and Metastatic Colorectal Tumours.

Generation of large amounts of genomic data is now feasible and cost-effective with improvements in next generation sequencing (NGS) technology. Ribonucleic acid sequencing (RNA-Seq) is becoming the preferred method for comprehensively characterising global transcriptome activity. Unique to cytoreductive surgery (CRS), multiple spatially discrete tumour specimens could be systematically harvested for genomic analysis.

A set of molecular markers predicts chemosensitivity to Mitomycin-C following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal peritoneal metastasis.

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is associated with significant perioperative morbidity and mortality. We aim to generate and validate a biomarker set predicting sensitivity to Mitomycin-C to refine selection of patients with colorectal peritoneal metastasis (CPM) for this treatment. A signature predicting Mitomycin-C sensitivity was generated using data from Genomics of Drug Sensitivity in Cancer and The Cancer Genome Atlas.

Integrated Multimodal Evaluation of Genotoxicity in ZFN-Modified Primary Human Cells.

Iatrogenic adverse events in clinical trials of retroviral vector-mediated gene-corrected cells have prioritized the urgent need for more comprehensive and stringent assessment of potentially genotoxic off-target alterations and the biosafety of cells intended for therapeutic applications. Genome editing tools such as zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and clustered regularly interspaced palindromic repeats (CRISPR)-Cas9 nuclease systems are being investigated as safer and efficient alternatives for site-directed genome modification. Using site-specific integration into the AAVS1 locus of primary human cells as an example, we present an integrated approach to multimodal investigation of off-target alterations and an evaluation of potential genotoxicity induced by ZFN-mediated integration of a therapeutic transgene.

Chromosomal breaks at FRA18C: association with reduced expression, altered oncogenic signaling and increased gastric cancer survival.

Chromosomal rearrangements are common in cancer. More than 50% occur in common fragile sites and disrupt tumor suppressors. However, such rearrangements are not known in gastric cancer.

Durable engraftment of genetically modified FVIII-secreting autologous bone marrow stromal cells in the intramedullary microenvironment.

Genetically modified FVIII-expressing autologous bone marrow-derived mesenchymal stromal cells (BMSCs) could cure haemophilia A. However, culture-expanded BMSCs engraft poorly in extramedullary sites. Here, we compared the intramedullary cavity, skeletal muscle, subcutaneous tissue and systemic circulation as tissue microenvironments that could support durable engraftment of FVIII-secreting BMSC in vivo.

Unique Triphenylphosphonium Derivatives for Enhanced Mitochondrial Uptake and Photodynamic Therapy.

In this study, unique methyl-functionalized derivatives (T*PP) of the drug carrier triphenylphosphonium (TPP) that exhibit significant enhancement of the accumulation of both the cation and its conjugated cargo in cell mitochondria are designed. We show that the presence of methyl group(s) at key positions within the phenyl ring results in an increase in the hydrophobicity and solvent accessible surface area of T*PP. In particular, when the para position of the phenyl ring in T*PP is functionalized with a methyl group, the cation is most exposed to the surrounding environment, leading to a large decrease in water entropy and an increase in the level of van der Waals interaction with and partition into a nonpolar solvent.

Mitochondrial-Targeting MET Kinase Inhibitor Kills Erlotinib-Resistant Lung Cancer Cells.

Lung cancer cells harboring activating EGFR mutations acquire resistance to EGFR tyrosine kinase inhibitors (TKIs) by activating several bypass mechanisms, including MET amplification and overexpression. We show that a significant proportion of activated MET protein in EGFR TKI-resistant HCC827 lung cancer cells resides within the mitochondria. Targeting the total complement of MET in the plasma membrane and mitochondria should render these cells more susceptible to cell death and hence provide a means of circumventing drug resistance.

Multidimensional Genome-wide Analyses Show Accurate FVIII Integration by ZFN in Primary Human Cells.

Costly coagulation factor VIII (FVIII) replacement therapy is a barrier to optimal clinical management of hemophilia A. Therapy using FVIII-secreting autologous primary cells is potentially efficacious and more affordable. Zinc finger nucleases (ZFN) mediate transgene integration into the AAVS1 locus but comprehensive evaluation of off-target genome effects is currently lacking.

Characterization of Insulin-Secreting Porcine Bone Marrow Stromal Cells Ex Vivo and Autologous Cell Therapy In Vivo.

Cell therapy could potentially meet the need for pancreas and islet transplantations in diabetes mellitus that far exceeds the number of available donors. Bone marrow stromal cells are widely used in clinical trials mainly for their immunomodulatory effects with a record of safety. However, less focus has been paid to developing these cells for insulin secretion by transfection.

Multidimensional identification of tissue biomarkers of gastric cancer.

Gastric cancer remains highly fatal due to a dearth of diagnostic biomarkers for early stage disease and molecular targets for therapy. Plasma membrane proteins, including cluster of differentiation (CD) proteins and receptor tyrosine kinases (RTKs), are a rich reservoir of biomarkers. Recognizing that interrogating plasma membrane proteins individually overlooks extensive interactions among them, we have systematically investigated the membrane proteomes and transcriptomes of six gastric cancer cell lines.

Global molecular dysfunctions in gastric cancer revealed by an integrated analysis of the phosphoproteome and transcriptome.

We integrated LC-MS/MS-based and protein antibody array-based proteomics with genomics approaches to investigate the phosphoproteome and transcriptome of gastric cancer cell lines and endoscopic gastric biopsies from normal subjects and patients with benign gastritis or gastric cancer. More than 3,000 non-redundant phosphorylation sites in over 1,200 proteins were identified in gastric cancer cells. We correlated phosphoproteome data with transcriptome data sets and reported the expression of 41 protein kinases, 5 phosphatases and 65 phosphorylated mitochondrial proteins in gastric cancer cells.

Biosafety assessment of site-directed transgene integration in human umbilical cord-lining cells.

Biosafety and efficacy considerations that impede clinical application of gene therapy could be addressed by nonviral ex vivo cell therapy, utilizing transgenic cells that have been comprehensively pre-evaluated for genotoxic potential and transgene expression. We evaluated the genotoxic potential of phiC31 bacteriophage integrase-mediated transgene integration in cord-lining epithelial cells (CLECs) readily cultured from the outer membrane of human umbilical cords, by sequencing and mapping integration sites, spectral karyotyping, high-resolution genome copy number, transcriptome, and transgene copy number analyses and in vivo tumorigenicity. Of 44 independent integration events, <5% were exonic and 85% of modified cells had integrated View Article and Find Full Text PDF

The distinctive gastric fluid proteome in gastric cancer reveals a multi-biomarker diagnostic profile.

Background: Overall gastric cancer survival remains poor mainly because there are no reliable methods for identifying highly curable early stage disease. Multi-protein profiling of gastric fluids, obtained from the anatomic site of pathology, could reveal diagnostic proteomic fingerprints.

Methods: Protein profiles were generated from gastric fluid samples of 19 gastric cancer and 36 benign gastritides patients undergoing elective, clinically-indicated gastroscopy using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry on multiple ProteinChip arrays.

Nonvirally modified autologous primary hepatocytes correct diabetes and prevent target organ injury in a large preclinical model.

Background: Current gene- and cell-based therapies have significant limitations which impede widespread clinical application. Taking diabetes mellitus as a paradigm, we have sought to overcome these limitations by ex vivo electrotransfer of a nonviral insulin expression vector into primary hepatocytes followed by immediate autologous reimplantation in a preclinical model of diabetes.

Methods And Results: In a single 3-hour procedure, hepatocytes were isolated from a surgically resected liver wedge, electroporated with an insulin expression plasmid ex vivo and reimplanted intraparenchymally under ultrasonic guidance into the liver in each of 10 streptozotocin-induced diabetic Yorkshire pigs.

Analysis and functional annotation of expressed sequence tags (ESTs) from multiple tissues of oil palm (Elaeis guineensis Jacq.).

Background: Oil palm is the second largest source of edible oil which contributes to approximately 20% of the world's production of oils and fats. In order to understand the molecular biology involved in in vitro propagation, flowering, efficient utilization of nitrogen sources and root diseases, we have initiated an expressed sequence tag (EST) analysis on oil palm.

Results: In this study, six cDNA libraries from oil palm zygotic embryos, suspension cells, shoot apical meristems, young flowers, mature flowers and roots, were constructed.