tbuckley/cabot-search huggingface dataset:
NovoTTF-100A system (tumor treating fields) transducer array layout planning for glioblastoma: Results of a NovoTAL system user study.
Authors: Aafia Chaudhry, Laura M. Benson, Michael Varshaver, Ori Farber, Uri Weinberg, Eilon Kirson, Yoram Palti
Journal: Journal of Clinical Oncology (2015)

e13029 Background: The NovoTTF-100A System (Optune) generates Tumor Treating Fields (TTFields), an effective anti-mitotic therapy, significantly prolonging overall survival when added to standard of care in patients with newly diagnosed glioblastoma. The system locally delivers intermediate-frequency, alternating electric fields to the supratentorial brain. Patient therapy is personalized by configuring transducer array layout placement on the scalp to the tumor site using MRI measurements and the NovoTAL System. Transducer array layout mapping optimizes TTFields therapy by maximizing electric field intensity to the tumor site. This study evaluated physician performance in conducting transducer array layout mapping using the NovoTAL System compared with gold-standard mapping performed by the Novocure in-house clinical team. Methods: Fourteen physicians (7 neuro-oncologists, 4 medical oncologists, and 3 neurosurgeons) evaluated 5 blinded MRI cases of glioblastoma and performed head size and tumor location measurements using a standard Digital Imaging and Communications in Medicine reader. Concordance with Novocure measurement and intra- and inter-rater reliability were assessed using relevant correlation coefficients. The study criterion for success was a concordance correlation coefficient (CCC) > 0.80. Results: CCC for each physician versus Novocure on 20 MRI measurements was 0.96 (SD ± 0.03, range 0.90-1.00), indicating very high agreement between the 2 groups. Intra- and inter-rater reliability correlation coefficients were similarly high: 0.83 (SD ±0.15, range 0.54-1.00) and 0.80 (SD ±0.18, range 0.48-1.00), respectively. Conclusions: This user study demonstrated an excellent level of concordance between prescribing physicians and Novocure in-house clinical teams in performing transducer array layout planning. Intra-rater reliability was very high, indicating reproducible performance. Physicians prescribing TTFields, when trained on the NovoTAL System, can independently perform transducer array layout mapping required for the optimal initiation and maintenance of patients on TTFields therapy.
JAK2 E846D Germline Mutation Associated with Erythrocytosis Causes Increased and Prolonged Epo-Induced Activation of STAT5
Authors: Katarina Kapralova, Monika Horvathova, Jana Kucerova, Dagmar Pospisilova, Emilie Leroy, Stefan N. Constantinescu, Vladimir Divoky
Journal: Blood (2014)
P0628 : A high genetic heterogeneity in HBsAg can affect immunogenicity in acute hepatitis B infection
Authors: M. Aragri, N. Coppola, C. Alteri, A. Battisti, C. Sagnelli, M. Pisaturo, M.C. Bellocchi, R. Salpini, M. Starace, D. Armenia, L. Carioti, M. Pollicita, E. Sagnelli, C.F. Perno, V. Svicher
Journal: Journal of Hepatology (2015)
Similar Risk of Cardiopulmonary Adverse Events Between Propofol and Traditional Anesthesia for Gastrointestinal Endoscopy: A Systematic Review and Meta-analysis
Authors: Vaibhav Wadhwa, Danny Issa, Sushil Garg, Rocio Lopez, Madhusudhan R. Sanaka, John J. Vargo
Journal: Clinical Gastroenterology and Hepatology (2016)
Dynamin Autonomously Regulates Podocyte Focal Adhesion Maturation
Authors: Changkyu Gu, Ha Won Lee, Garrett Garborcauskas, Jochen Reiser, Vineet Gupta, Sanja Sever
Journal: Journal of the American Society of Nephrology (2016)

Rho family GTPases, the prototypical members of which are Cdc42, Rac1, and RhoA, are molecular switches best known for regulating the actin cytoskeleton. In addition to the canonical small GTPases, the large GTPase dynamin has been implicated in regulating the actin cytoskeleton via direct dynamin-actin interactions. The physiologic role of dynamin in regulating the actin cytoskeleton has been linked to the maintenance of the kidney filtration barrier. Additionally, the small molecule Bis-T-23, which promotes actin–dependent dynamin oligomerization and thus, increases actin polymerization, improved renal health in diverse models of CKD, implicating dynamin as a potential therapeutic target for the treatment of CKD. Here, we show that treating cultured mouse podocytes with Bis-T-23 promoted stress fiber formation and focal adhesion maturation in a dynamin-dependent manner. Furthermore, Bis-T-23 induced the formation of focal adhesions and stress fibers in cells in which the RhoA signaling pathway was downregulated by multiple experimental approaches. Our study suggests that dynamin regulates focal adhesion maturation by a mechanism parallel to and synergistic with the RhoA signaling pathway. Identification of dynamin as one of the essential and autonomous regulators of focal adhesion maturation suggests a molecular mechanism that underlies the beneficial effect of Bis-T-23 on podocyte physiology.
Treatment-free remission (TFR) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) treated with frontline nilotinib: Results from the ENESTFreedom study.
Authors: Andreas Hochhaus, Tamas Masszi, Francis J. Giles, Jerald P. Radich, David M. Ross, María Teresa Gómez Casares, Andrzej Hellmann, Jesper Stentoft, Eibhlin Conneally, Valentin García Gutierrez, Norbert Gattermann, Wieslaw Wiktor-Jedrzejczak, Philipp D. Le Coutre, Bruno Martino, Susanne Saussele, Hans D. Menssen, Weiping Deng, Nancy Krunic, Veronique Bedoucha, Giuseppe Saglio
Journal: Journal of Clinical Oncology (2016)

7001 Background: In prior clinical trials, ≈40-60% of pts with CML-CP and sustained deep molecular response (MR) maintained TFR after stopping long-term imatinib (median duration: ≈ 5-7 y). The single-arm phase 2 ENESTfreedom study (NCT01784068) is the first to specifically investigate TFR following frontline nilotinib. Methods: Pts with CML-CP with typical b2a2 or b3a2 BCR-ABL1 transcripts, ≥ 2 y of frontline nilotinib, and MR4.5 (BCR-ABL1IS ≤ 0.0032%) at prescreening were eligible. Upon enrollment, pts continued nilotinib for 1 y, with RQ-PCR assessments every 12 wk (consolidation [CONS] phase) at a central standardized laboratory. Pts with no assessment worse than MR4 (BCR-ABL1IS ≤ 0.01%), ≤ 2 assessments between MR4 and MR4.5, and MR4.5 in the last assessment of the CONS phase were eligible to stop treatment (TFR phase). Loss of major MR (MMR [BCR-ABL1IS≤ 0.1%]) triggered re-initiation of nilotinib (ReRx phase). The data cutoff for this analysis was 30 Nov 2015, when all pts who entered the TFR phase had completed 48 wk of TFR, entered the ReRx phase, or discontinued from the study. Results: A total of 215 pts entered the CONS phase. Of these, 190 stopped nilotinib and entered the TFR phase (median age at baseline: 55 y; median time from first MR4.5 to study entry: 18 mo; median nilotinib duration prior to TFR: 43 mo [range: 33-89 mo]). At wk 48 of the TFR phase, 51.6% (95% CI: 44.2-58.9%) of these 190 pts were in MMR and had not re-initiated treatment (primary endpoint). Of 86 pts who entered the ReRx phase due to loss of MMR by the data cutoff, 85 regained MMR (1 pt discontinued from the study [pt decision] without MMR 7.1 wk after entering the ReRx phase) and 76 regained MR4.5 (median time to MMR and MR4.5 among all pts who entered the ReRx phase: 7.9 wk and 13.1 wk, respectively). No new safety signals were observed on treatment. During the TFR phase, 24.7% of pts experienced musculoskeletal pain (grade 3/4 in 1.1%). Conclusions: These data demonstrate the feasibility of TFR following frontline nilotinib. Nilotinib is the first tyrosine kinase inhibitor to demonstrate successful TFR in a large proportion of eligible pts after relatively short exposure (median: ≈ 3.6 y) Clinical trial information: NCT01784068.
A multicenter, randomized, double-blinded, placebo-controlled trial of modafinil for lung cancer-related fatigue: Dose response and patient satisfaction data.
Authors: Kate Fife, Anna Spathis, Susan J. Dutton, Fiona Helen Blackhall, Ronja Bahadori, Rose Wharton, Mary O'Brien, Patrick Stone, Tim Benepal, Bee Wee
Journal: Journal of Clinical Oncology (2013)

9503 Background: Fatigue is a very common, disabling symptom in cancer, and particularly severe in lung cancer. Modafinil is a novel central nervous system stimulant, which, along with methylphenidate, is cautiously recommended by the 2013 National Comprehensive Cancer Network Guidelines for fatigue. In this phase IV randomized placebo-controlled trial, we assessed the efficacy of modafinil for managing fatigue in lung cancer. Methods: Adults with locally advanced or metastatic non small cell lung cancer (stages III and IV), ECOG performance status (PS) 0-2 and suffering from fatigue (score 5/10 or greater) were randomised 1:1 to modafinil or matched placebo, 100mg daily for 14 days and 200mg daily for a further 14 days. The primary outcome measure was change in the Functional Assessment of Chronic Illness Therapy fatigue subscale (FACIT-fatigue) at 28 days. The trial was powered to detect a 5-point difference with 80% power and 5% significance allowing for 25% attrition. Dose-response, patient satisfaction and safety were also evaluated. Results: 208 patients were recruited from 24 UK centres. Baseline characteristics were well-balanced. 160 patients completed both baseline and 28 day questionnaires and were included in the modified-ITT analysis. FACIT-fatigue mean change from baseline was modafinil=5.28, placebo=5.11, difference=0.17, (95%CI -4.17, 3.82). Adjustment for baseline fatigue and PS had no impact on outcome. No dose response was seen; the majority of improvement on all scales was seen at 14 days and sustained to 28 days. 47% of the modafinil group and 23% of the placebo group stated the study treatment was not helpful (p=0.132). Adverse events were equal. Conclusions: Both modafinil and placebo led to a clinically significant 5-point improvement in FACIT-fatigue score, but there was no significant difference between the two groups. This well-powered study suggests that there is a large placebo effect and NCCN guidelines should be reviewed. Clinical trial information: NCT00829322. [Table: see text]
Self-reported conflicts of interest (sfCOI) of authors and the interpretation of randomized phase III trials (RCT) and related editorials (REd) in cancer research.
Authors: Giovanni Mendonca Bariani, Anezka Carvalho Rubin De Celis Ferrari, Paulo Marcelo Hoff, Rachel Riechelmann
Journal: Journal of Clinical Oncology (2012)

6055 Background: Growing participation from industry in cancer research has resulted in increased reporting of COI. We aimed to test any association between author’s conclusion and sfCOI in cancer studies. Methods: All RCT and REd published in 6 major cancer journals in a 3.5 year period were selected. Two investigators blinded to COI disclosure independently analyzed each RCT and REd, classifying authors’ conclusions as highly positive, positive, neutral, negative, and highly negative with respect to author’s opinion on the experimental therapy. The agreement rate between investigators for conclusion classification was 90% (consensus was achieved for the remaining 10%). We also collected data on study results, COI and sponsorship. COI was defined as any self-reported financial tie between author and industry except for research funds. Predictors of positive/highly positive conclusions of RCT and of REd were tested separately in logistic regression multivariable models. Results: From Jan 2008 to Oct 2011, 1,485 articles were retrieved: 150 RCT and 140 REd were eligible. Among the RCT, 82 (55%) were positive, and 78 (52%) were entirely or partially funded by industry. Any sfCOI was present in 103 (69%) RCT and in 71 (47%) REd. Conclusions of REd and RCT were: 7.3% and 11.3% highly positive, 42.7% and 57.3% positive, 8.0% and 2.0% neutral, 29.3% and 18.7% negative, and 12.7% and 10.7% highly negative, respectively. Multivariable analysis showed that RCT positive result was the only significant predictor for positive conclusion by RCT authors (OR=109, 95% CI: 21-567; p&lt;0.001). The only factor associated with positive conclusions of REd authors was a positive conclusion by RCT author (OR=42, 95% CI: 7-244; p&lt;0.001). While 64 (43%) RCT reported negative results, 103 (68.7%) RCT authors interpreted studies positively. Logistic regression for discordance between RCT result and RCT conclusion did not find any association with COI. Conclusions: The interpretation of RCT results by authors was not influenced by sfCOI or trial sponsorship. Authors of REd were not influenced by study results or by their sfCOI when discussing cancer RCT.
Abstract LB-115: Mechanisms of acquired resistance to allosteric versus ATP-competitive AKT inhibition
Authors: Kristin M. Zimmerman, Brian Lee, Wei-Jen Chung, Florian Gnad, Eva Lin, Scott Martin, Kui Lin
Journal: Cancer Research (2016)

Abstract The PI3K/AKT signaling pathway mediates a variety of cellular processes including metabolism, glucose uptake, angiogenesis, growth, survival and proliferation. Increased activity of this pathway is observed in many cancer types and is associated with tumor invasiveness, survival, and proliferation. Various regulators of this pathway are being investigated as therapeutic targets in oncology, including the AKT kinases. Two distinct classes of AKT inhibitors (AKTi) are being evaluated as therapeutic agents in the clinic: allosteric inhibitors (e.g. MK-2206) and ATP-competitive inhibitors (e.g. Ipatasertib/GDC-0068). In an effort to elucidate pathway alterations in response to these inhibitors and, ultimately, to improve therapeutic outcome, we are currently evaluating mechanisms of acquired resistance to both AKT inhibitor classes. The establishment of clonal cell populations resistant to either MK-2206 or GDC-0068 and subsequent characterization of alterations in these lines revealed various genetic and non-genetic variations associated with AKTi resistance. Here, we will present findings on biological mechanisms that contribute to acquired AKTi resistance in prostate and ovarian cancer cell line models. Citation Format: Kristin M. Zimmerman, Brian Lee, Wei-Jen Chung, Florian Gnad, Eva Lin, Scott Martin, Kui Lin. Mechanisms of acquired resistance to allosteric versus ATP-competitive AKT inhibition. [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 LB-115.
Abstract 4571: Semaphorin/plexin signalling promotes nucleocytoplasmic trafficking of nuclear receptors
Authors: Magali Williamson, John R. Masters
Journal: Cancer Research (2016)

Abstract Androgen receptor (AR) signalling is critical to prostate cancer progression and androgen deprivation therapy (ADT) is the first line of treatment for metastatic prostate cancer. Acquired resistance to ADT results from androgen-independent reactivation of the AR pathway primarily. Prostate tumours also bypass androgen blockade by the upregulation of the glucocorticoid receptor (GR). Both AR and GR are nuclear receptors that bind their respective ligands in the cytoplasm and then translocate to the nucleus where they act as transcription factors. Plexins are cell surface receptors for semaphorins. PlexinB1 is overexpressed and mutated in several cancers including prostate cancer and deletion of the plexinB1 gene reduces metastasis in mouse models, indicating an oncogenic role for plexinB1 in prostate cancer. We have found that activation of plexinB1 by semaphorin4D (Sema4D) results in AR phosphorylation at serine 81, activation of AR-transcriptional activity and increased expression of androgen-responsive genes, effects reversed by plexinB1 knockdown. PlexinB1 activation increases the translocation of both AR-GFP constructs and endogenous AR to the nucleus in prostate cancer cells. Furthermore knockdown of AR in the prostate cancer cell line LNCaP reduces Sema4D-induced anchorage-independent growth of these cells. To determine if the Sema4D/plexinB1 signalling pathway also affects translocation of other nuclear receptors to the nucleus, we have also studied the effect of Sema4D treatment on nuclear trafficking of the glucocorticoid receptor (GR). Prostate cancer cells were transfected with a GR-GFP construct and the subcellular localisation of GR-GFP was monitored upon Sema4D treatment by immunocytochemistry and confocal microscopy. The nuclear translocation of endogenous GR was also assessed following Sema4D stimulation by immunocytochemistry and subcellular fractionation studies. We found that activation of plexinB1 by Sema4D results in a significant increase in the percentage of cells with nuclear GR-GFP and in the nuclear localisation of endogenous GR in prostate cancer cells. These findings show that plexinB1 activation has a role in the trafficking and activation of nuclear receptors and so may have a role in resistance to ADT in late stage prostate cancer. Citation Format: Magali Williamson, John R. Masters. Semaphorin/plexin signalling promotes nucleocytoplasmic trafficking of nuclear receptors. [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 4571.
Abstract 4780: RXDX-107 exhibits multiple mechanisms of intracellular delivery and results in extensive drug-induced interstrand crosslinks in solid tumor preclinical models
Authors: Leenus Martin, Roopal Patel, Michael Johnson, Jerry Cao, Peter Chua, Colin Walsh, Jennifer Oliver, Pratik Multani, Robert Wild, Ralph Lin, Gary G. Li
Journal: Cancer Research (2016)

Abstract RXDX-107 is a dodecanol alkyl ester of bendamustine, which is then encapsulated in human serum albumin (HSA) to form nanoparticles. Bendamustine is an alkylating agent that induces interstrand DNA crosslinks (ICLs) and causes cell death via several pathways, including intrinsic apoptosis. The activity of bendamustine in the treatment of solid tumor malignancies has not been impressive, possibly due to the pharmacokinetic and limited biodistribution properties of bendamustine. RXDX-107 was designed to improve tissue biodistribution over bendamustine, which may result in superior efficacy and tolerability in patients with solid tumors. In preclinical studies, RXDX-107 displayed significant anti-tumor activity in multiple solid tumor cell lines, cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models of advanced solid tumors, such as breast, lung, and ovarian cancer. In this study, we further evaluated the mechanism of action of RXDX-107, particularly the means of entry and accumulation of drug into tumor cells. We have developed a novel analytical method to precisely quantify both dodecanol alkyl ester of bendamustine and released bendamustine in tissue culture medium and cells. Our data demonstrate that RXDX-107 is transported into cells in three active forms. Firstly, RXDX-107 slowly releases bendamustine into the extracellular medium, and released bendamustine then enters into cells. Secondly, the dodecanol alkyl ester of bendamustine is transported into cells and causes ICLs. And lastly, by measuring macropinocytosis, we also determined that human serum albumin nanoparticles mediate the intracellular entry of RXDX-107. Each of these mechanisms results in the formation of ICLs. In addition, comet assay data demonstrate that RXDX-107 displayed stronger induction of ICLs than bendamustine, and the induced ICLs persist over 48 hours in multiple solid tumor cell lines. Taken together, our data demonstrate that RXDX-107 enters and accumulates into cells via multiple mechanisms, and causes extensive and superior ICLs compared to bendamustine in several solid tumor cell lines, thereby providing a strong rationale for further investigation of this agent in solid tumor indications. Citation Format: Leenus Martin, Roopal Patel, Michael Johnson, Jerry Cao, Peter Chua, Colin Walsh, Jennifer Oliver, Pratik Multani, Robert Wild, Ralph Lin, Gary G. Li. RXDX-107 exhibits multiple mechanisms of intracellular delivery and results in extensive drug-induced interstrand crosslinks in solid tumor preclinical models. [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 4780.
Abstract 4575: Altered catalytic properties of a subset of Met cytoplasmic domain variants occurring in renal cell carcinoma
Authors: Dinuka De Silva, Young Lee, Arpita Roy, Donald P. Bottaro
Journal: Cancer Research (2016)

Abstract TCGA provisional data of papillary renal cell carcinoma (PRCC) kidney cancer, a malignant hereditary cancer syndrome, reveals that 23% of patients (n = 161) have MET gene amplification and/or mRNA up-regulation (2-fold or greater; RNA-Seq V2) and 10% of patients possess MET mutations. The Met tyrosine kinase is the cell surface receptor for hepatocyte growth factor (HGF). HGF stimulation induces Met protein autophosphorylation and consequently enhances epithelial cell motility, morphogenesis, and proliferation. Chronic and/or overstimulation of Met contributes to tumor growth and metastasis. We determined Km and Vmax for ATP binding to full-length Met protein isolated from the PRCC derived cell line ACHN, which possesses the MET mutation T992I (numbered per SWISSPROT accession P08581) in the juxtamembrane domain, and the clear cell RCC derived cell line Caki-1, which possesses the MET V1220I mutation in the kinase domain. Catalytic constants were determined using two-site immunoassays for total Met and phospho-Met. Both variants were associated with increased Vmax relative to wild type Met protein isolated from B5/589 breast epithelial cells. The observed increased catalytic activity of receptor variants may confer a higher overall rate of signaling at lower ATP concentrations, potentially contributing to enhanced tumor cell motility and proliferation in both papillary and clear cell RCC. Citation Format: Dinuka De Silva, Young Lee, Arpita Roy, Donald P. Bottaro. Altered catalytic properties of a subset of Met cytoplasmic domain variants occurring in renal cell 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 4575.