tbuckley/cabot-search huggingface dataset:
NCCTG phase II trial of bevacizumab, gemcitabine, oxaliplatin in patients with metastatic pancreatic adenocarcinoma
Authors: G. P. Kim, A. Oberg, B. Kabat, A. Sing, E. Hedrick, D. Campbell, S. Alberts
Journal: Journal of Clinical Oncology (2006)

4113 Background: The combination of gemcitabine and oxaliplatin (GemOx) is a highly active regimen in pancreatic cancer. A recent study with the biologic agent, bevacizumab, and gemcitabine has also demonstrated significant activity. A phase II study is ongoing to evaluate whether combining an active cytotoxic doublet with an effective targeted agent improves 6-month survival and is tolerable in previously untreated patients (pts) with metastatic pancreas cancer. Methods: Treatment consists of gemcitabine 1000 mg/m 2 IV over 100 minutes and bevacizumab 10 mg/kg IV given on day 1 and 15; oxaliplatin 100 mg/m 2 IV is given on day 2 and 16. A treatment cycle consists of 28 days. Eligibility includes: no prior chemotherapy, ECOG PS 0–2, bili &lt; 2× UNL, AST &lt; 5× UNL. Pts with stable full-dose anticoagulation are eligible. Bevacizumab specific exclusions include no recent stroke, heart attack, embolus, tumor invasion or significant proteinuria. CT scans are obtained every 2 cycles. Treatment continues until disease progression, toxicity or patient refusal. Results: Sixty-three patients of a planned 75 were enrolled from 7/05 to 1/06; 2 cycles of toxicity data are available on 31 of the first 32 consecutive pts. The overall grade 3+ toxicity rate is 52% (16/31); more specifically, the grade 3 toxicities were 42% (13/31) and the grade 4 rate is 10% (3/31). Grade 3 adverse events are nausea (4), vomiting (4), alk phos (3), dehydration (3), thrombosis (2), leukopenia (2), neutropenia (4), abdominal pain (2), hypokalemia (4), and one each of the following: anorexia, low consciousness, pneumonia, rectal pain, diarrhea, and proctitis. There was one patient death due to cerebral ischemia (grade 5: 1/31 or 3%). Conclusions: Early assessment of toxicity in this trial reveals a reasonably tolerable regimen. Addition of bevacizumab to GemOx appears to have grade 3/4 toxicity rates similar to historical observations (ECOG 6201). Toxicity data for all patients, after at least 2 cycles of treatment, will be presented. [Table: see text]
The Stat3/5 Signaling Biosignature in Hematopoietic Stem/Progenitor Cells Predicts Response and Outcome in Myelodysplastic Syndrome Patients Treated with Azacitidine
Authors: Paraskevi Miltiades, Eleftheria Lamprianidou, Theodoros P. Vassilakopoulos, Sotirios G. Papageorgiou, Athanasios G. Galanopoulos, Christos K. Kontos, Panagiotis G. Adamopoulos, Evangelia Nakou, Sofia Vakalopoulou, Vassilia Garypidou, Maria Papaioannou, Evdoxia Hatjiharissi, Helen A. Papadaki, Emmanuil Spanoudakis, Vassiliki Pappa, Andreas Scorilas, Constantinos Tsatalas, Ioannis Kotsianidis
Journal: Clinical Cancer Research (2015)

Azacitidine is the mainstay of high-risk myelodysplastic syndromes (MDS) therapy, but molecular predictors of response and the mechanisms of resistance to azacitidine remain largely unidentified. Deregulation of signaling via Stat3 and Stat5 in acute myeloid leukemia (AML) is associated with aggressive disease. Numerous genes involved in cell signaling are aberrantly methylated in MDS, yet the alterations and the effect of azacitidine treatment on Stat3/5 signaling in high-risk MDS have not been explored.We assessed longitudinally constitutive and ligand-induced phospho-Stat3/5 signaling responses by multiparametric flow cytometry in 74 patients with MDS and low blast count AML undergoing azacitidine therapy. Pretreatment Stat3/5 signaling profiles in CD34(+)cells were grouped by unsupervised clustering. The differentiation stage and the molecular properties of the CD34(+)G-CSF-inducible Stat3/5 double-positive subpopulation were performed by flow cytometry and quantitative real-time PCR in isolated MDS progenitors.The pretreatment Stat3/5 signaling profiles in CD34(+)cells correlated strongly with response and cytogenetics and independently predicted event-free survival. We further identified a CD34(+)G-CSF-inducible Stat3/5 double-positive subpopulation (DP subset) whose pretreatment levels were inversely associated with treatment response and cytogenetics. The kinetics of the DP subset followed the response to azacitidine and the disease course, whereas its molecular characteristics and cellular hierarchy were consistent with a leukemia propagating cell phenotype.Our findings provide a novel link among Stat3/5 signaling and MDS pathobiology and suggest that the Stat3/5 signaling biosignature may serve as both a response biomarker and treatment target.
Inhibition of protein geranylgeranylation requires p27kip1 to induce human breast cancer cell death
Authors: Aslamuzzaman Kazi, Adam Carie, Michelle Blaskovich, Cynthia Bucher, Van Thai, Stacy Moulder, Hairuo Peng, Dora Carrico, Erin Pusateri, Andrew Hamilton, Said Sebti
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

5642 

Decreased levels of the CDK inhibitor p27Kip1 are associated with poor prognosis in breast cancer patients. We designed a novel tetrapeptide mimic inhibitor of geranylgeranyltransferase I (GGTase I), GGTI-2418, that significantly induces breast tumor cell death by increasing the protein levels of p27Kip1. GGTI-2418, inhibits GGTase I competitively (Ki = 4.4 ± 1.6nM) and selectively (5600 fold) over farnesyltransferase. In human breast cancer cell lines, GGTI-2417 a methyl ester prodrug of GGTI-2418 induces p27Kip1 levels, tumor cell death and G/G1 accumulation. p27Kip1 knockout cells and p27kip1 siRNA experiments demonstrated that GGTI-2417-induced breast tumor cell death requires p27Kip1. In nude mouse xenografts, GGTI-2418 suppresses the growth of human breast tumors. In transgenic mice where breast tumors are driven by the oncogene ErbB2, GGTI-2418 induces significant tumor regression.
Addressing the Core of Carcinogenesis: How a Mitochondrial Mutation Leads to Metabolic Remodeling in Familial Cancers
Authors: Antonio De Flora, Silvio De Flora
Journal: JNCI Journal of the National Cancer Institute (2015)

Appropriate knowledge of the metabolic properties of cancer cells compared with normal ones is a major prerequisite in order to elucidate the mechanisms responsible for abnormal cell proliferation and dysregulated biomass production.A relevant paradigm is the not-yet-fully-perfected basis of the Warburg effect and of the underlying pathways of glucose and glutamine utilization in tumor cells (1).On the other hand, peculiarities in cancer cell metabolism are the result of both germline and somatic mutations, but little is known in general on how these mutations translate into cancer-specific phenotypes, mostly to selected enzyme deficiencies or to imbalances in the regulation and the coordination of metabolic fluxes in tumor cells.This limitation reflects a still-insufficient integration of emerging data from high-throughput technologies and of the various steps of experimental analysis that characterize the "omics" field.While a general advancement in the area is legitimately expected from the development of computational tools (1), it is well documented that wet science, eg, genome-wide association studies and metabolic approaches, is strictly required.To this purpose, it is interesting to note that, for example, cancer-causing mutations associated with enzyme deficiencies are generally investigated according to the following multistep strategy:
Four-Week Studies of Oral Hypoxia-Inducible Factor–Prolyl Hydroxylase Inhibitor GSK1278863 for Treatment of Anemia
Authors: Louis Holdstock, Amy M. Meadowcroft, Rayma Maier, Brendan M. Johnson, Delyth Jones, Anjay Rastogi, Steven Zeig, John J. Lepore, Alexander R. Cobitz
Journal: Journal of the American Society of Nephrology (2015)

Hypoxia-inducible factor prolyl hydroxylase inhibitors stabilize levels of hypoxia-inducible factor that upregulate transcription of multiple genes associated with the response to hypoxia, including production of erythropoietin. We conducted two phase 2a studies to explore the relationship between the dose of the hypoxia-inducible factor-prolyl hydroxylase inhibitor GSK1278863 and hemoglobin response in patients with anemia of CKD (baseline hemoglobin 8.5-11.0 g/dl) not undergoing dialysis and not receiving recombinant human erythropoietin (nondialysis study) and in patients with anemia of CKD (baseline hemoglobin 9.5-12.0 g/dl) on hemodialysis and being treated with stable doses of recombinant human erythropoietin (hemodialysis study). Participants were randomized 1:1:1:1 to a once-daily oral dose of GSK1278863 (0.5 mg, 2 mg, or 5 mg) or control (placebo for the nondialysis study; continuing on recombinant human erythropoietin for the hemodialysis study) for 4 weeks, with a 2-week follow-up. In the nondialysis study, GSK1278863 produced dose-dependent effects on hemoglobin, with the highest dose resulting in a mean increase of 1 g/dl at week 4. In the hemodialysis study, treatment with GSK1278863 in the 5-mg arm maintained mean hemoglobin concentrations after the switch from recombinant human erythropoietin, whereas mean hemoglobin decreased in the lower-dose arms. In both studies, the effects on hemoglobin occurred with elevations in endogenous erythropoietin within the range usually observed in the respective populations and markedly lower than those in the recombinant human erythropoietin control arm in the hemodialysis study, and without clinically significant elevations in plasma vascular endothelial growth factor concentrations. GSK1278863 was generally safe and well tolerated at the doses and duration studied. GSK1278863 may prove an effective alternative for managing anemia of CKD.
Invasive mediastinal staging is irrelevant for PET/CT positive N2 lung cancer if the primary tumour and ipsilateral lymph nodes are resectable
Authors: Eric Lim, Philip J McElnay, Gaetano Rocco, Alessandro Brunelli, Gilbert Massard, Alper Toker, Bernward Passlick, Gonzalo Varela, Walter Weder
Journal: The Lancet Respiratory Medicine (2015)
High frequency CD8+PD-1+ TCR clonotypes isolated from fresh melanomas display anti-tumor activity
Authors: Pasetto Anna, Alena Gros, Paul F Robbins, Todd D Prickett, Drew C Deniger, Rodrigo Matus-Nicodemus, Maria R Parkhurst, Jessica S Crystal, Kasia Trebska-Mcgowan, Steven A Rosenberg
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Adoptive transfer of T cell receptor (TCR) redirected T cells has traditionally targeted shared tumor-specific antigens restricted to common major histocompatibility complexes with the rationale of treating a large population of patients. Recently, tumor infiltrating lymphocytes (
A novel long noncoding RNA Lnc‐HC binds hnRNPA2B1 to regulate expressions of Cyp7a1 and Abca1 in hepatocytic cholesterol metabolism
Authors: Xi Lan, Jidong Yan, Juan Ren, Bo Zhong, Jing Li, Yue Li, Li Liu, Jing Yi, Qingzhu Sun, Xudong Yang, Jian Sun, Liesu Meng, Wenhua Zhu, Rikard Holmdahl, Dongmin Li, Shemin Lu
Journal: Hepatology (2015)

Cholesterol metabolism disorder in hepatocytes predicts a higher risk of metabolic syndrome (MetS). Long noncoding RNAs (lncRNAs) have emerged as critical players in cellular cholesterol metabolism, but their functions are not systematically clarified. Here, we have identified a novel lncRNA named lnc‐HC negatively regulating cholesterol metabolism within hepatocytes through physical interaction with hnRNPA2B1. By further binding to the target messenger RNA of Cyp7a1 or Abca1 , the lnc‐HC ‐hnRNPA2B1 complex decreases expressions of the two genes that are implicated in cellular cholesterol excretion. lnc‐HC knockdown can strongly recover the cholesterol disorder in vivo . In the upstream pathway, lnc‐HC is up‐regulated by high cholesterol by the transcription activator, CCAAT/enhancer‐binding protein beta. Conclusion: These findings suggest a subtle feed‐forward regulation of lnc‐HC in cholesterol metabolism and define a novel line of evidence by which lncRNAs modulate the metabolic system at the post‐transcriptional level. (H epatology 2016;64:58‐72)
Abstract 1280: Clinical features of transcriptional factor Helios expression on regulatory T cells in patients with non-small cell lung cancer
Authors: Satoshi Muto, Yuki Owada, Takuya Inoue, Yuzuru Watanabe, Takumi Yamaura, Mitsuro Fukuhara, Naoyuki Okabe, Yuki Matsumura, Takeo Hasegawa, Jun Osugi, Mika Hoshino, Mitsunori Higuchi, Hiroyuki Suzuki, Mitsukazu Gotoh
Journal: Cancer Research (2015)

Abstract Introduction Foxp3+ regulatory T cells (Tregs) have been thought to have at least two subsets: natural Tregs (nTregs) and induced Tregs (iTregs). Recently, expression of the transcription factor Helios, a member of the Ikaros gene family, has been expected to be a molecular marker of nTregs, but this is still controversial. To date, several in vitro studies and animal model studies regarding Helios have been reported, but there has been no examination of the clinical impact of Helios expression on Tregs in patients with lung cancer to date. Methods A total of 45 non-small cell lung cancer (NSCLC) patients who underwent surgical resection and 19 advanced/recurrent NSCLC patients was evaluated. Peripheral blood mononuclear cells (PBMCs) taken from these patients were examined by flow-cytometry. Of these 45 patients, 18 who were evaluable for tumor tissue underwent immunohistochemical investigation for tumor-infiltrating lymphocytes. Results Helios-negative Tregs of CD4+ T cells were significantly higher not only in all cancer patients (2.4%), but also in stage IA patients (2.6%) as compared with normal controls (1.5%, p&amp;lt;0.001). Patients who had a lower level of Helios-negative Tregs in tumor-infiltrating lymphocytes had significantly longer survival (p = 0.038). Discussion Helios-negative Tregs may be involved in immune suppression, even in early-stage NSCLC. The frequency of Helios-negative Tregs could be a useful prognostic biomarker in patients with NSCLC. The biological functions of Helios-negative Tregs in immune suppression should be further examined. Baseline demographicsCharacteristicN (%)Age (y)Mean±SD67±8SexFemale27 (42)Male37 (58)Pathological stageIA22 (34)IB16 (25)IIA4 (6)IIB3 (5)III0 (0)IV (Recurrence included)Chemotherapy1st-line6 (9)2nd-line6 (9)3rd or later-line7 (11)Pathological classificationAdenocarcinoma51 (80)Squamous cell carcinoma10 (16)Others3 (5)EGFR mutationPositive22 (34)Negative31 (48)Unknown11 (17) Citation Format: Satoshi Muto, Yuki Owada, Takuya Inoue, Yuzuru Watanabe, Takumi Yamaura, Mitsuro Fukuhara, Naoyuki Okabe, Yuki Matsumura, Takeo Hasegawa, Jun Osugi, Mika Hoshino, Mitsunori Higuchi, Hiroyuki Suzuki, Mitsukazu Gotoh. Clinical features of transcriptional factor Helios expression on regulatory T cells in patients with non-small cell lung cancer. [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 1280. doi:10.1158/1538-7445.AM2015-1280
Prostaglandin-dependent modulation of dopaminergic neurotransmission elicits inflammation-induced aversion in mice
Authors: Michael Fritz, Anna M. Klawonn, Anna Nilsson, Anand Kumar Singh, Joanna Zajdel, Daniel Björk Wilhelms, Michael Lazarus, Andreas Löfberg, Maarit Jaarola, Unn Örtegren Kugelberg, Timothy R. Billiar, David J. Hackam, Chhinder P. Sodhi, Matthew D. Breyer, Johan Jakobsson, Markus Schwaninger, Günther Schütz, Jan Rodriguez Parkitna, Clifford B. Saper, Anders Blomqvist, David Engblom
Journal: Journal of Clinical Investigation (2015)

Systemic inflammation causes malaise and general feelings of discomfort. This fundamental aspect of the sickness response reduces the quality of life for people suffering from chronic inflammatory diseases and is a nuisance during mild infections like common colds or the flu. To investigate how inflammation is perceived as unpleasant and causes negative affect, we used a behavioral test in which mice avoid an environment that they have learned to associate with inflammation-induced discomfort. Using a combination of cell-type–specific gene deletions, pharmacology, and chemogenetics, we found that systemic inflammation triggered aversion through MyD88-dependent activation of the brain endothelium followed by COX1-mediated cerebral prostaglandin E2 (PGE2) synthesis. Further, we showed that inflammation-induced PGE2 targeted EP1 receptors on striatal dopamine D1 receptor–expressing neurons and that this signaling sequence induced aversion through GABA-mediated inhibition of dopaminergic cells. Finally, we demonstrated that inflammation-induced aversion was not an indirect consequence of fever or anorexia but that it constituted an independent inflammatory symptom triggered by a unique molecular mechanism. Collectively, these findings demonstrate that PGE2-mediated modulation of the dopaminergic motivational circuitry is a key mechanism underlying the negative affect induced by inflammation.
Number needed to treat: enigmatic results for exacerbations in COPD
Authors: Sally Lettis, Oliver Keene
Journal: European Respiratory Journal (2015)

Suissa [1] provides the event-based number needed to treat (NNT) for a reduction in exacerbations with fluticasone/salmeterol compared with placebo for the TORCH (Towards a Revolution in COPD Health) trial by period of follow-up (0–1 years after treatment, 1–2 years after treatment and 2–3 years after treatment) [2]. These NNT data are misleading as they fail to recognise that in chronic obstructive pulmonary disease (COPD) trials, patients who exacerbate are more likely to withdraw from the trial than patients with no exacerbations. Keene et al. [3] show that for the TRISTAN (TRial of Inhaled STeroids ANd long-acting β2 agonists) trial, the exacerbation rate is more than three per year among placebo patients withdrawing prior to 1 year compared with an exacerbation rate of one per year for patients completing a year of placebo treatment. In the TORCH trial, 25% of the placebo group withdrew compared with 15% of the fluticasone/salmeterol arm during the first year of follow-up; therefore, patients entering the second year of the trial on placebo and on fluticasone/salmeterol were no longer directly comparable. This is not accounted for in the calculation of exacerbation rates or NNT during years 2 and 3, as presented in table 2 of the study by Suissa [1]. NNT calculations during years 2 and 3 are misleading as they don–t account for differential withdrawal in year 1 <http://ow.ly/UeS61>
Prevalence of extended-spectrum beta-lactamase producing Escherichia coli in community-onset urinary tract infections in France in 2013
Authors: D. Martin, S. Fougnot, F. Grobost, S. Thibaut-Jovelin, F. Ballereau, T. Gueudet, D. de Mouy, J. Robert, F. Alexandre, P. Andorin, F. Artur, H. Banctel, J. Bayette, F. Bonfils, D. Boraud, S. Camiade, J. Caillon, N. Capron, N. Chatelain, B. Coudé du Foresto, G. Cous, V. Desroys du Roure, H.-P. Doermann, A. Dubouix, S. Fougnot, J.-L. Galinier, G. Grandjean, D. Grisard, F. Grobost, T. Gueudet, P. Hance, A. Holstein, M.-F. Jendrysik, E. Jobert, J.-R. Kamdem-Djoko, D. Lair, J.-M. Le Bris, N. Lecordier, S. Liébault, N. Lièvre, J. Nalpas, G. Payro, B. Poirey, E. Pradier, L. Prots, J.-P. Rault, M.-L. Roche, J. Thierry, H. Valade, P. Versini, A. Vrain, Ph Weber
Journal: Journal of Infection (2015)
Trastuzumab-induced cardiotoxicity in early breast cancer: Evaluation of possible risk and protective factors.
Authors: Alberto Farolfi, Elisabetta Melegari, Michele Aquilina, Emanuela Scarpi, Toni Ibrahim, Roberta Maltoni, Samanta Sarti, Lorenzo Cecconetto, Elisabetta Pietri, Anna Fedeli, Marina Faedi, Oriana Nanni, Dino Amadori, Andrea Rocca
Journal: Journal of Clinical Oncology (2012)

e11054 Background: Adjuvant trastuzumab improves survival in early breast cancer (EBC) patients (pts). However, trastuzumab-induced cardiotoxicity (TIC) renders it necessary to identify possible risk and protective factors. Methods: A retrospective study was conducted in which medical charts of pts treated with adjuvant trastuzumab were reviewed. Hypertension, smoking history, dysthyroidism, obesity, hypercholesterolemia, diabetes mellitus and anthracycline cumulative dose were considered as potential risk factors. The relationship between the use of beta-blockers (BB), angiotensin-converting enzyme inhibitors (ACEI) and/or angiotensin receptor blockers (ARB) (either started before or during adjuvant therapy) and TIC development was also evaluated. TIC was defined as an absolute left ventricular ejection fraction (LVEF) decrease ≥15 points from baseline or an absolute LVEF &lt;50%. The term heart failure (HF) referred to the New York Heart Association classification III or IV. Logistic regression was used to assess relative risks. Results: A total of 179 HER2-positive EBC pts (median 54 years, range 30-84) were evaluated. 154 (86%) were treated with anthracycline-based adjuvant chemotherapy. 78 (44%) did not show any risk factors, whereas 101 (56%) had at least one: hypertension (24%), smoking habit (16%), dysthyroidism (18%), obesity (12%), hypercholesterolemia (9%) and diabetes mellitus (4%). Among the 179 EBC pts, 78 (44%, 95% confidence intervals (CI) 37-51%) experienced TIC during their 12-month trastuzumab treatment and only 4 (2%, 95% CI 0-4%) developed HF. 14 pts stopped trastuzumab due to TIC. None of the risk factors described above was correlated with TIC development. A previous anthracycline cumulative dose &gt; 240 mg/m 2 conferred an odds ratio of 3.07 compared with treatmemt with lower doses (95% CI 1.29-7.27, p=0.0011). BB, ACEI and/or ARB neither reduced nor increased the risk of TIC. Conclusions: TIC is a frequent, albeit generally mild, adverse event in clinical practice. Closer collaboration between cardiologists and oncologists is needed to better define risk and protective factors of cardiotoxicity in order to avoid trastuzumab-therapy discontinuation.