tbuckley/cabot-search huggingface dataset:
Interim safety and pharmacodynamic results for ALN-VSP02, a novel RNAi therapeutic for solid tumors with liver involvement.
Authors: J. Gollob, J. R. Infante, G. Shapiro, P. LoRusso, B. J. Dezube, J. Heymach, J. Cehelsky, R. Falzone, A. Vaishnaw, H. A. Burris
Journal: Journal of Clinical Oncology (2010)

3042 Background: Malignancies involving the liver represent a significant unmet medical need. ALN-VSP02 is a novel RNA interference (RNAi) therapeutic comprised of lipid nanoparticle-formulated small interfering RNAs (siRNAs) targeting the expression of vascular endothelial growth factor (VEGF)-A and kinesin spindle protein (KSP). Methods: A multicenter, open label, phase 1 dose escalation trial of ALN-VSP02 administered as a 15-minute iv infusion every two weeks was initiated in March 2009. Patients with advanced solid tumors are eligible if they have at least one measurable liver lesion and adequate liver function. The study uses a 3+3 design with 8 potential dose levels: 0.1, 0.2, 0.4, 0.7, 1.0, 1.25, 1.5, and 1.7 mg/kg. The primary objective is evaluation of safety and tolerability. Secondary objectives include assessment of PK and pharmacodynamic (PD) activity through DCE-MRI, biomarkers of angiogenesis, tumor biopsies, and response rate. Results: As of December 2009, 12 patients (most with colorectal cancer) have been treated on the first 4 dose levels. Forty-one doses have been administered; 0.1-0.4 mg/kg ALN-VSP02 was well- tolerated, with no hepatotoxicity. The only significant adverse event (AE) was a grade 2 infusion reaction in one patient at 0.4 mg/kg that responded to slowing of the infusion. At 0.7 mg/kg, a patient with pancreatic neuroendocrine tumor extensively involving both lobes of the liver died of hepatic failure following the second dose; this was deemed possibly related to study drug. Two additional patients treated at 0.7 mg/kg did not exhibit hepatotoxicity or any other significant AEs. PK showed Cmax and AUC that were dose proportional with no accumulation. Serial DCE-MRI scans performed 2-9 days after the first dose on 8 of the 12 patients showed a ≥40% decline in Ktrans in 12 of 15 liver tumors (80%) evaluated. This decline in blood flow was associated with extensive tumor necrosis in the patient with the neuroendocrine tumor. Conclusions: ALN-VSP02 was well-tolerated by the majority of patients across the first 4 dose levels. DCE-MRI results show preliminary evidence of an anti-VEGF effect. Accrual is continuing, and additional safety and PD data will be forthcoming. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Alnylam Pharmaceuticals Alnylam Pharmaceuticals Alnylam Pharmaceuticals Alnylam Pharmaceuticals
P1044 : Randomised, placebo-controlled clinical trial: Long-term resveratrol treatment for non-alcoholic fatty liver disease
Authors: S. Heebøll, S. Hamilton-Dutoit, Y.K. Hellberg, H. Stødkilde-Jørgensen, N. Jessen, S.B. Pedersen, H. Grønbæk
Journal: Journal of Hepatology (2015)
Gut microbiota drive the development of neuroinflammatory response in cirrhosis in mice
Authors: Dae Joong Kang, Naga S. Betrapally, Siddhartha A. Ghosh, R. Balfour Sartor, Phillip B. Hylemon, Patrick M. Gillevet, Arun J. Sanyal, Douglas M. Heuman, Daniel Carl, Huiping Zhou, Runping Liu, Xiang Wang, Jing Yang, Chunhua Jiao, Jeremy Herzog, H. Robert Lippman, Masoumeh Sikaroodi, Robert R. Brown, Jasmohan S. Bajaj
Journal: Hepatology (2016)

The mechanisms behind the development of hepatic encephalopathy (HE) are unclear, although hyperammonemia and systemic inflammation through gut dysbiosis have been proposed. The aim of this work was to define the individual contribution of hyperammonemia and systemic inflammation on neuroinflammation in cirrhosis using germ‐free (GF) and conventional mice. GF and conventional C57BL/6 mice were made cirrhotic using CCl 4 gavage. These were compared to their noncirrhotic counterparts. Intestinal microbiota, systemic and neuroinflammation (including microglial and glial activation), serum ammonia, intestinal glutaminase activity, and cecal glutamine content were compared between groups. GF cirrhotic mice developed similar cirrhotic changes to conventional mice after 4 extra weeks (16 vs. 12 weeks) of CCl 4 gavage. GF cirrhotic mice exhibited higher ammonia, compared to GF controls, but this was not associated with systemic or neuroinflammation. Ammonia was generated through increased small intestinal glutaminase activity with concomitantly reduced intestinal glutamine levels. However, conventional cirrhotic mice had intestinal dysbiosis as well as systemic inflammation, associated with increased serum ammonia, compared to conventional controls. This was associated with neuroinflammation and glial/microglial activation. Correlation network analysis in conventional mice showed significant linkages between systemic/neuroinflammation, intestinal microbiota, and ammonia. Specifically beneficial, autochthonous taxa were negatively linked with brain and systemic inflammation, ammonia, and with Staphylococcaceae, Lactobacillaceae , and Streptococcaceae. Enterobacteriaceae were positively linked with serum inflammatory cytokines. Conclusion : Gut microbiota changes drive development of neuroinflammatory and systemic inflammatory responses in cirrhotic animals. (H epatology 2016;64:1232‐1248)
Robot-assisted laparoscopic prostatectomy versus open radical retropubic prostatectomy: early outcomes from a randomised controlled phase 3 study
Authors: John W Yaxley, Geoffrey D Coughlin, Suzanne K Chambers, Stefano Occhipinti, Hema Samaratunga, Leah Zajdlewicz, Nigel Dunglison, Rob Carter, Scott Williams, Diane J Payton, Joanna Perry-Keene, Martin F Lavin, Robert A Gardiner
Journal: The Lancet (2016)
Abstract 3402: Ephrin B2 and Dll-4 mediated co-dependence of tumor and endothelial progenitor cells in human hepatocellular carcinoma
Authors: Rajshekhar A. Kore, Meenakshi Upreti, Azemat Jamshidi-Parsian, Rudd P.M. Dings, Issam Makhoul, Robert J. Griffin
Journal: Cancer Research (2016)

Abstract Hepatocellular carcinoma (HCC) is a highly vascularized tumor, which preferentially recruits new blood vessels from the hepatic artery to fuel its growth, through mechanisms not well understood. Here, we examined the intercellular cross-talk of HepG2 (human HCC) and endothelial progenitor cells (EPC) in transwell co-cultures to mimic initial tumor parenchyma and stroma interactions. We present evidence showing that, in culture, HepG2 cells secrete factors to induce an ‘activated’ EPC phenotype, namely, an increase in survival, growth, proliferation and migration rates. EPC cells showed a significant increase in growth (∼40%) and survival (∼80%) when co-cultured with HepG2 cells. Simultaneously, activated EPCs improved the viability of HepG2 cells. A major mediator of intercellular crosstalk are the secreted microvesicles called exosomes. Exosomes constitute a set of distinct nanovesicles (30-100 nm), endosomal in origin, constitutively secreted by many cells. They are involved in intercellular communication by transferring proteins and RNA from one cell to another. Intercellular crosstalk between these HepG2 cells and EPCs cells lead to qualitative and quantitative changes in the exosomal cargo secreted by the respective cells. The exosomal cargo constituting various proteins and genetic material have been demonstrated to be involved in processes which promote remodeling of extracellular matrix (ECM), biological adhesion and pathways modulating developmental processes and progression of inflammation, leading to cancer growth and development. In other work with glioma cell-derived exosomes has shown the presence of Ephrin A and B receptors which suggests a prominent role of secreted exosomes in stimulating and guiding tumor angiogenesis, a hallmark characteristic of glioblastoma multiforme (GBM). Additionally, our results with co-cultures of tumor and endothelial cells show that angiogenesis signaling in EPC appears to be induced by HepG2 cells via elevated endothelial Ephrin B2 and DLL-4 expression. Overall, our results demonstrate the co-dependence of HCC and EPC intercellular crosstalk, likely accomplished via secreted exosomes, in the initial stages of HCC establishment and stimulation of angiogenesis and development, thus a promising target for new clinical strategies. Citation Format: Rajshekhar A. Kore, Meenakshi Upreti, Azemat Jamshidi-Parsian, Rudd P.M. Dings, Issam Makhoul, Robert J. Griffin. Ephrin B2 and Dll-4 mediated co-dependence of tumor and endothelial progenitor cells in human hepatocellular carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3402.
Abstract 3795: Novel and selective MELK kinase inhibitors active in breast cancer cell lines
Authors: Patrizia Carpinelli, Marisa Montemartini, Nadia Amboldi, Dario Ballinari, Sabrina Cribioli, Marina Ciomei, Riccardo Colombo, Stefania Re Depaolini, Nilla Avanzi, Giulia Canevari, Walter Ceccarelli, Helena Posteri, Maria Gabriella Brasca, Daniele Donati, Eduard Rudolf Felder, Antonella Isacchi, Arturo Galvani, Alessia Montagnoli
Journal: Cancer Research (2016)

Abstract Maternal Embryonic Leucine zipper Kinase (MELK) is a serine-threonine kinase implicated in stem cell renewal, override of cell cycle checkpoints, pre-mRNA splicing and resistance to apoptosis, while MELK gene expression levels correlate inversely with poor prognosis in breast cancer, prostate cancer and glioblastoma patients. Moreover, recent findings underlie the oncogenic role of this kinase in triple negative breast cancer (TNBC), a category of high-grade, invasive tumors which lack expression of estrogen receptor (ER) and progesterone receptor (PR) and HER2 amplification and which is resistant to current cytotoxic and targeted therapies. Furthermore, they are highly heterogeneous with respect to genomic alterations, and common therapeutic targets are lacking, although substantial evidence implicates dysregulated kinase signaling. Here, we describe the preclinical characterization of novel, potent and selective ATP-competitive MELK kinase inhibitors identified by means of high-throughput screening of the NMS proprietary compound collection. Leading compounds possess biochemical activity against MELK in the nanomolar range with high selectivity against a panel of 60 further kinases representative of the human kinome. Amongst human tumor cell lines tested in 2-dimensional colony outgrowth assays, marked sensitivity was observed in breast cancer cell lines, with sub-micromolar anti-proliferative activity. This effect was accompanied by dose-dependent induction of apoptosis and by modulation of cellular biomarkers, consistent with a MELK-dependent mechanism of action. Overall, these data provide further evidence that MELK is a promising biological target for the development of novel anticancer therapies. Citation Format: Patrizia Carpinelli, Marisa Montemartini, Nadia Amboldi, Dario Ballinari, Sabrina Cribioli, Marina Ciomei, Riccardo Colombo, Stefania Re Depaolini, Nilla Avanzi, Giulia Canevari, Walter Ceccarelli, Helena Posteri, Maria Gabriella Brasca, Daniele Donati, Eduard Rudolf Felder, Antonella Isacchi, Arturo Galvani, Alessia Montagnoli. Novel and selective MELK kinase inhibitors active in breast cancer cell lines. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3795.
Long-term psychosocial outcomes of low-dose CT screening: results of the UK Lung Cancer Screening randomised controlled trial
Authors: Kate Brain, Kate J Lifford, Ben Carter, Olivia Burke, Fiona McRonald, Anand Devaraj, David M Hansell, David Baldwin, Stephen W Duffy, John K Field
Journal: Thorax (2016)

The UK Lung Cancer Screening (UKLS) trial is a randomised pilot trial of low-dose CT (LDCT) screening for individuals at high risk of lung cancer. We assessed the long-term psychosocial impact on individuals participating in the UKLS trial.A random sample of individuals aged 50-75 years was contacted via primary care. High-risk individuals who completed T0 questionnaires (baseline) were randomised to LDCT screening (intervention) or usual care (no screening control). T1 questionnaires were sent 2 weeks after baseline scan results or control assignment. T2 questionnaires were sent up to 2 years after recruitment. Measures included cancer distress, anxiety, depression and decision satisfaction.A total of 4037 high-risk individuals were randomised and they completed T0 questionnaires (n=2018 intervention, n=2019 control). Cancer distress was higher at T1 in intervention arm participants who received positive screening results (p≤0.001), but not at T2 (p=0.04). T2 anxiety (p≤0.001) and depression (p≤0.01) were higher in the control arm, but the absolute differences were small and not clinically relevant. At both time points, fewer control than screened participants were satisfied with their decision to participate in UKLS (p≤0.001). Regardless of trial allocation, cancer distress was higher in women (p≤0.01), participants aged ≤65 years (p≤0.001), current smokers (p≤0.001), those with lung cancer experience (p≤0.001) and those recruited from the Liverpool area (p≤0.001).Lung cancer screening using LDCT appears to have no clinically significant long-term psychosocial impact on high-risk participants. Strategies for engaging and supporting underserved groups are the key to implement routine lung cancer screening in the UK.ISRCTN 78513845; results.
Initial Combination of Empagliflozin and Metformin in Patients With Type 2 Diabetes
Authors: Samy Hadjadj, Julio Rosenstock, Thomas Meinicke, Hans J. Woerle, Uli C. Broedl
Journal: Diabetes Care (2016)

This study compared the efficacy and safety of initial combinations of empagliflozin + metformin with empagliflozin and metformin monotherapy in patients with type 2 diabetes.The study randomized 1,364 drug-naïve patients (HbA1c >7.5 to ≤12% [>58 to ≤108 mmol/mol]) for 24 weeks to empagliflozin 12.5 mg b.i.d. + metformin 1,000 mg b.i.d., empagliflozin 12.5 mg b.i.d. + metformin 500 mg b.i.d., empagliflozin 5 mg b.i.d + metformin 1,000 mg b.i.d., empagliflozin 5 mg b.i.d. + metformin 500 mg b.i.d., empagliflozin 25 mg q.d., empagliflozin 10 mg q.d., metformin 1,000 mg b.i.d., or metformin 500 mg b.i.d. The primary end point was change from baseline in HbA1c at week 24.At week 24, reductions in HbA1c (mean baseline 8.6-8.9% [70-73 mmol/mol]) were -1.9 to -2.1% with empagliflozin + metformin twice-daily regimens, -1.4% with both empagliflozin once-daily regimens, and -1.2 to -1.8% with metformin twice-daily regimens. Reductions in HbA1c were significantly greater with empagliflozin + metformin twice-daily regimens than with empagliflozin once-daily regimens (P < 0.001) and with metformin twice-daily regimens (P < 0.01). Reductions in weight at week 24 were significantly greater with empagliflozin + metformin twice-daily regimens (range -2.8 to -3.8 kg) than with metformin twice-daily regimens (-0.5 to -1.3 kg) (P < 0.001 for all). Adverse event (AE) rates were similar across groups (56.7-66.3%). No hypoglycemic AEs required assistance.Initial combinations of empagliflozin + metformin for 24 weeks significantly reduced HbA1c versus empagliflozin once daily and metformin twice daily, without increased hypoglycemia, reduced weight versus metformin twice daily, and were well tolerated.
Contribution of a functional polymorphism in HOTAIR to the susceptibility of gastric cancer in a Turkish population: A case-control study.
Authors: Ahmet Taner Sümbül, Suleyman Bayram
Journal: Journal of Clinical Oncology (2015)

e15100 Background: HOX transcript antisense intergenicRNA (HOTAIR), as a long non-coding RNA (lncRNA), can regulate gene expression through reprograms chromatin states and epigenetic modifications. Accumulating evidence indicates that overexpression of HOTAIR plays a critical role in cancer development, progression and metastasis. Recently, a naturally occurring C/T single nucleotide polymorphism (SNP) in the intronic enhancer of HOTAIR, HOTAIR rs920778, has been reported to influence HOTAIR expression and genetic susceptibility of esophageal squamous cell carcinoma. The aim of the present study was to investigate whether HOTAIRrs920778 polymorphism could be involved in the risk of gastric cancer (GC) susceptibility. Methods: The genotype frequency of HOTAIRrs920778 polymorphism was determined by using TaqMan Real-Time Polymerase Chain Reaction (PCR) method in 104 subjects with GC and 209 cancer-free control subjects matched on age and gender. Results: No statistically significant differences were found in the allele or genotype distributions of the HOTAIR rs920778 polymorphism among GC and cancer-free control subjects (P > 0.05). Conclusions: Our results demonstrate for the first time that the HOTAIR rs920778 polymorphism has not been in any major role in genetic susceptibility to gastric carcinogenesis, at least in the population studied here. Independent studies are needed to validate our findings in a larger series, as well as in patients of different ethnic origins.
P0866 : Comparative efficacy and tolerability of daclatasvir + sofosbuvir versus sofosbuvir + ribavirin for hepatitis C genotype 3: A matching-adjusted indirect comparison
Authors: E. Swallow, J. Song, Y. Yuan, A. Kalsekar, C. Kelley, F. Mu, S. Kim, S. Noviello, J. Signorovitch
Journal: Journal of Hepatology (2015)
Abstract 1840: Metabolomic profiling of gastrointestinal stromal tumor (GIST) T1 cell lines in response to imatinib therapy
Authors: Vered Marks, Gregory Tiesi, Ana Paz Mejia, Jonathan Trent, Jamie Walls, Alan Livingstone, Danny Yakoub
Journal: Cancer Research (2015)

Abstract Background: There is a growing need for novel drugs to treat drug resistant GIST. The aim of this study was to evaluate chronological metabolic changes in GIST cells treated with imatinib mesylate. Methods: Human GIST T1 cells were incubated with imatinib 0.5 mM. Metabolomic profiling was performed in extracted cell pellets at 12, 24 and 48 hours, after viability and cell counting was done, and compared with controls via acquisition of 1H-NMR spectra using a 500MHz spectrometer equipped with a 5mm TCI 500S2 H-C/N-D-05 Z cryoprobe head at 298 K. Standard, one-dimensional NOESYpr1D pre-saturation pulse program was used. Spectra were further processed in an NMR suite processor; Partial Least Squares Discriminant Analysis (PLS-DA) model was used for characterization of chronological biochemical differences. Results: By 48 hours of exposure of cells to imatinib, glucose initially increased then significantly decreased with gradual decrease of lactate production and minimal changes in pyruvate and succinate denoting shifting from cytosolic to mitochondrial glycolysis, this was echoed with consumption of glutamine and glutamate. Glutathione and cell membrane phospholipids as phosphocholine gradually decreased by a factor of 1.6 for each, suggesting inhibited growth and invasiveness. Aspartate, myo-inositol, glycerophosphocholine and taurine gradually increased by a factor of 1.6, 1.7, 2.6 and 1.3, respectively. Tyrosine, valine and leucine showed minimal changes. Cell viability was directly correlated to changes in choline, creatine phosphate, myo-inositol and taurine (Pearson's R &amp;gt;0.65). PLS-DA model suggested that changes in myoinositol, glycerophosphocholine, glutamate, aspartate, phosphcholine and glutathione were the metabolites mostly influencing the differential chronological global metabolic profiles of the cells with continued exposure to imatinib (R2X = 0.76, R2Y = 0.60, Q2(cum) = 0.20). Conclusion: Metabolomic profiling of GIST cells exposed to signal transduction modulators supplements molecular findings and provides further mechanistic insights into longitudinal changes of the mitochondrial and glycolytic pathways of oncogenesis, it can potentially provide novel as well as complementary therapeutic targets. Citation Format: Vered Marks, Gregory Tiesi, Ana Paz Mejia, Jonathan Trent, Jamie Walls, Alan Livingstone, Danny Yakoub. Metabolomic profiling of gastrointestinal stromal tumor (GIST) T1 cell lines in response to imatinib therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1840. doi:10.1158/1538-7445.AM2015-1840
Abstract 2863: Mechanisms underlying estrogen-induced inflammation in estrogen-deprived breast cancer cells
Authors: Ping Fan, Fadeke A. Agboke, Amit Kumar Tyagi, V. Craig Jordan
Journal: Cancer Research (2016)

Abstract Inflammation is critical for estrogen (E2) to undertake apoptosis in E2-deprived breast cancer cells. However, it remains unclear how E2 induces inflammation. Here, we demonstrate that E2 increases lipid metabolism and accumulates unfolded proteins in the endoplasmic reticulum in E2-deprived breast cancer cells. These two major alterations result in different inflammatory responses. E2 rapidly increases lipid metabolism related genes such as fatty acid desaturase 1 (FADS1) and CCAAT/enhancer binding protein beta (CEBPB) to modulate adipose inflammation related factors, e.g. IL6/IL6R after two hours treatment, which regulate the cellular proliferation or differentiation. Simultaneously, accumulation of the unfolded protein activates unfolded protein response (UPR) sensors, protein kinase RNA-like endoplasmic reticulum kinase (PERK) and inositol-requiring protein 1 alpha (IRE1α) within few hours after exposure to E2. Importantly, inhibition of PERK, rather than IRE1α, is able to completely prevent E2 from induction of late event inflammatory genes associated with apoptosis, such as tumor necrosis factor (TNF) superfamily members, BCL2L11 (Bim), and HMOX1,which are activated by E2 after 48 hours. Consistently, nuclear factor-kappa B (NF-κB) is activated when TNFα is maximal after E2 treatment. Further examination revealed that an anti-inflammatory agent, dexamethasone (Dex), activates glucocorticoid receptor (GR) transcriptional activity and blocks E2-induced apoptosis. These effects can be reversed by the knockdown of GR. A notable mechanistic change is that Dex effectively blocks the phosphorylation of PERK and produces equivalent inhibitory effects on the apoptosis-associated inflammatory genes as the PERK inhibitor. However, Dex has an additional potential to activate lipid metabolism and are additive with E2 to elevate FADS1 and adipokine IL6/IL6R. All of these data, for the first time, describe the mechanisms underlying E2-induced inflammation in E2-deprived breast cancer. It provides important information to restrict the clinical use of glucocorticoids, which will undermine the beneficial effects of E2-induced apoptosis in estrogen deprived breast cancer patients. Citation Format: Ping Fan, Fadeke A. Agboke, Amit Kumar Tyagi, V. Craig Jordan. Mechanisms underlying estrogen-induced inflammation in estrogen-deprived breast cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2863.