tbuckley/cabot-search huggingface dataset:
PAK4 Phosphorylates p53 at Serine 215 to Promote Liver Cancer Metastasis
Authors: Hai-Tao Xu, Wai-Lung Lai, Heong-Fai Liu, Leo Lap-Yan Wong, Irene Oi-Lin Ng, Yick Pang Ching
Journal: Cancer Research (2016)

PAK4 kinase contributes to signaling pathways controlling cancer cell transformation, invasion, and survival, but its clinicopathological impact has begun to emerge only recently. Here we report that PAK4 overexpression in hepatocellular carcinoma (HCC) conveys aggressive metastatic properties. A novel nuclear splice isoform of PAK4 lacking exon 2 sequences was isolated as part of our studies. By stably overexpressing or silencing PAK4 in HCC cells, we showed that it was critical for their migration. Mechanistic investigations in this setting revealed that PAK4 directly phosphorylated p53 at S215, which not only attenuated transcriptional transactivation activity but also inhibited p53-mediated suppression of HCC cell invasion. Taken together, our results showed how PAK4 overexpression in HCC promotes metastatic invasion by regulating p53 phosphorylation. Cancer Res; 76(19); 5732-42. ©2016 AACR.
Validation Of Criteria For Renal Response In Patients With Multiple Myeloma (MM) Who Present With Severe Renal Dysfunction
Authors: Meletios A. Dimopoulos, Evangelos Terpos, Maria Roussou, Evangelos Eleutherakis-Papaiakovou, Maria Gavriatopoulou, Nikolaos Kanellias, Dimitrios Christoulas, Despoina Kalapanida, Despoina Mparmparoussi, Charis Matsouka, Sofoklis Kontogiannis, Evangelos Kostis, Erasmia Psimenou, Efstathios Kastritis
Journal: Blood (2013)
Abstract 1483: MT-3724, an engineered toxin body targeting CD20 for non-Hodgkin's lymphoma
Authors: Garrett L. Robinson, Sangeetha Rajagopalan, Brigitte Brieschke, Jennifer Erdman, Jane Neill, Rodney E. Flores-Lefranc, Julia Foree, William Null, Jensing Liu, Jack P. Higgins, Erin K. Willert
Journal: Cancer Research (2016)

Abstract Molecular Templates has developed engineered toxin bodies (ETBs), potent recombinant immunotoxins that combine the specificity of an antibody fragment with the powerful direct cytotoxicity of the Shiga-like toxin A subunit to specifically destroy target expressing cells. The use of other immunotoxins and antibody-drug conjugates is limited to targets with tumor-specific cell surface expression that efficiently internalize. The ETB scaffold has been designed to overcome this limitation and promote forced internalization of ETBs, a property that expands the potential targets to receptors with poor internalization kinetics. An additional benefit to ETBs is the mechanism of action (MOA) which is unique to that of other oncology treatments. CD20, a receptor that does not undergo rapid internalization, is a well characterized target for agents used to treat non-Hodgkin's lymphoma (NHL). Thus, successful CD20-targeted clinical strategies include monoclonal antibodies (mAbs) and radiolabeled mAbs that act on the cell surface. Molecular Templates’ lead compound, MT-3724, is a CD20-targeted ETB that has been engineered to force the rapid internalization of the immunotoxin after binding to CD20. MT-3724 has potent direct cell kill activity on CD20 positive lymphoma cells and is the first immunotoxin to CD20 to enter the clinic. The on-going phase I study being conducted at Memorial Sloan-Kettering Cancer Center, MD Anderson Cancer Center, and New York University Langone Medical Center has shown promising safety and efficacy in highly refractory NHL patients. Once MT-3724 is delivered to appropriate cells, the Shiga toxin A subunit inhibits protein synthesis and promotes apoptosis of tumor cells. The difference in MOA allows for activity in the refractory setting, where resistance to other treatments has emerged, and may also allow for combination therapy. Pre-clinical studies with immunomodulatory drugs (IMiDs), PI3K and Bcl-2 inhibitors that are used in treatment of NHL have shown promising results when combined with MT-3724. MT-3724 is a promising novel agent in the treatment of NHL and other CD20 positive hematological malignancies. Data around the internalization kinetics, enzymatic activity, and combination with other agents will be presented. Citation Format: Garrett L. Robinson, Sangeetha Rajagopalan, Brigitte Brieschke, Jennifer Erdman, Jane Neill, Rodney E. Flores-Lefranc, Julia Foree, William Null, Jensing Liu, Jack P. Higgins, Erin K. Willert. MT-3724, an engineered toxin body targeting CD20 for non-Hodgkin's lymphoma. [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 1483.
Abstract 3248: Over-expression of 1-ACBP, B-ACBP and PBR genes in mast cells infiltrating oesophageal squamous cell tumors
Authors: Zodwa Dlamini
Journal: Cancer Research (2016)

Abstract Oesophageal cancer ranks as the sixth most common malignancy in the world, and recent evidence has shown that its incidence is increasing. ACBPs (Acyl-coA binding proteins) act as intracellular carrier-proteins for medium to long chain acyl-coA, mediating fatty acid transport to the mitochondrion for ß-oxidation. ACBPs are also believed to be putative ligands of PBR (peripheral benzodiazepine receptor), and bound to this receptor facilitate mitochondrial membrane permeabilization giving the notion that favours apoptosis. The main aim of the study was to establish the expression patterns of 1-ACBP, B-ACBP, and PBR in oesophageal cancer, and to link their roles with the disease. Probes specific to the genes encoding 1-ACBP, B-ACBP, and PBR were PCR amplified and cloned into pGEM-T easy vectors using gene specific primers. The cloned products were sequenced and screened against the GENBANK database (NCBI) to verify the identity and orientation of cloned products within the vector. Antisense and sense probes were then generated using T7 or SP6 RNA polymerase after digestion with either Pst1 or Apa1, respectively. In situ hybridization and quantitative real-time PCR methods were performed to determine localization and the expression levels of the three genes in oesophageal cancer. All three genes illustrated substantial up-regulation within the malignant tissue sections as compared to normal oesophageal sections, all three transcripts localized specifically to plasma cells and lymphocytes in diseased and normal tissue section. In the diseased tissue B-ACBP and 1-ACBP mRNA localized to endothelial cells of blood vessels in the submucosa. B-ACBP also localized to the nucleus of squamous epithelial cells. PBR localization was indicated in tumour islands of invasive tissue sections. Quantitative RT-PCR also indicated that the expression levels of PBR were higher as compared to the ACBP genes expression in tumours. These results show that 1-ACBP, B-ACBP and PBR play a role in the pathogenesis of oesophageal tumours and also suggest the interaction between these genes with the immune system and that was also confirmed using bioinformatics analysis. Citation Format: Zodwa Dlamini. Over-expression of 1-ACBP, B-ACBP and PBR genes in mast cells infiltrating oesophageal squamous cell tumors. [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 3248.
Abstract LB-093: Vaccine based immunotherapy regimen (VBIR) for the treatment of prostate cancer
Authors: Helen Cho, Paul Cockle, Binder Joe, Weeratna Risini, Phil White, Karin Jooss
Journal: Cancer Research (2016)

Abstract A successful cancer vaccine will activate the host immune system to induce a balanced T- and B-cell response to tumor-specific antigens that can lead to tumor regression. Effective cancer vaccines will need to overcome several challenges to accomplish this goal, such as to break tolerance to the tumor associated antigens which are mostly self antigens, induce and maintain high tumor-specific T-cell titers to keep the immune pressure on the tumor as well as to overcome the immune suppressive tumor microenvironment to keep the T-cells active at the tumor site. We have applied the lessons learned in the field to the development of a multi-component cancer immunotherapy regimen that has entered clinical testing at the beginning of 2016 for the treatment of patients with prostate cancer. The vaccine regimen consists of a chimpanzee adenovirus prime vaccination administered intramuscularly followed by DNA boost vaccinations delivered with an electroporation device and with each vaccination low dose of an anti-CTLA4 antibody is administered locally, in close proximity of the vaccine draining lymph nodes. The adenovirus and DNA express the three prostate cancer antigens PSA, PSMA and PSCA. Lastly, sutent or anti-PD-1 is added to the regimen to counter the immune suppressive tumor microenvironment by lowering myeloid derived suppressor cells (by sutent doses that are lower than the approved clinical dose) or interfering with the PD-L1/PD-1 signaling pathway (by anti-PD-1). Data will be presented in tumor-bearing mice and non human primates (NHPs) demonstrating the attributes of the heterologous prime/boost vaccine with local anti-CTLA4 that induces potent, polyclonal and functional tumor-antigen specific T- and B cell responses that are maintained at high levels for up to a year in NHPs. We could also demonstrate that low dose of sutent is highly effective at lowering MDSCs in tumors and the periphery of tumor bearing mice, resulting in significantly enhanced potency of a heterologous prime/boost cancer vaccine. Lastly, our data suggest that - in the context of active vaccination - local delivery of anti-CTLA4 is superior to systemic delivery of the immune modulator at enhancing vaccine induced T-cell responses, thereby broadening the therapeutic window of the immune modulator. Citation Format: Helen Cho, Paul Cockle, Binder Joe, Weeratna Risini, Phil White, Karin Jooss. Vaccine based immunotherapy regimen (VBIR) for the treatment of prostate cancer. [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-093.
Abstract 996: STAT3 modulates HOTAIR transcription to influence HNSCC growth in vitro and in vivo
Authors: Xuan Zhou
Journal: Cancer Research (2016)

Abstract Background Squamous cell carcinoma is the most common cancer type of head and neck (HNSCC) with poor prognosis. Signal transducer and activator of transcription 3 (STAT3) activation is involved in HNSCC carcinogenesis as a transcript factor. A new class of transcripts, long noncoding RNAs (lncRNAs), has been recently found to be pervasively transcribed in the genome. HOTAIR, lncRNA Hox transcript antisense intergenic RNA, has been characterized as a novel hall marker to predict poor prognosis in HNSCC. HOTAIR regulates downstream target gene transcription by recruiting polycomb repressive complex 2 (PRC2) to the cell nucleus and triggers triple methylation of H3K27. Methods RNA sequencing, qPCR and CHIP assay were used to determine HOTAIR is a down-stream gene of STAT3. MTT and western blot were employed to examine the regulatory mechanism between STAT3 and HOTAIR in HNSCC cancers in vitro. Additionally, a cell derived xenograft tumor model was used to further validate the anti tumor effect of targeting STAT3/HOTAIR axis in vivo. Results STAT3 depleted HNSCC cell showed decreased HOTAIR expression by qPCR assay. CHIP assay indicated STAT3 bind to the promoter region of HOTAIR encoding gene. Combined inhibition of STAT3 and HOTAIR significantly inhibited cell proliferation, sensitive to cisplatin in HNSCC. Up-regulating HOTAIR partially compensated anti-tumor effect of targeting STAT3 in HNSCC. Conclusion Our data suggested that HOTAIR overexpression is depended on constitutive STAT3 activation in HNSCC and targeting STAT3/HOTAIR axis showed significant therapeutic potential in vitro and in vivo. Citation Format: Xuan Zhou. STAT3 modulates HOTAIR transcription to influence HNSCC growth in vitro and in vivo. [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 996.
Self‐expanding metal stent should be considered in patients with cirrhosis and uncontrolled variceal bleeding
Authors: Astrid Marot, Eric Trépo, Christopher Doerig, Christophe Moreno, Pierre Deltenre
Journal: Hepatology (2016)

Potential conflict of interest: Dr. Moreno consults for and received grants from Gilead, Janssen, and AbbVie. He consults for MSD, Bristol‐Myers Squibb, and Novartis. He received grants from Astellas and Roche. TO THE EDITOR: We read the article by Escorsell et al.1 with great interest. This is the first randomized, controlled trial comparing self‐expanding metal stent (SEMS) and balloon tamponade in acute refractory variceal bleeding in patients with cirrhosis. Although this study showed that SEMSs have greater efficacy in the control of bleeding and present less serious adverse events than does balloon tamponade, it failed to demonstrate a survival benefit. Even if randomized, controlled trials are considered the best way to assess the impact of an intervention, this is probably not the case when SEMSs are used to control acute refractory variceal bleeding for the following reasons. First, blinding the therapeutic intervention was not possible. Second, the investigators used patients treated with balloon tamponade as controls despite high rates of serious adverse events and rebleeding after balloon deflation. Thus, patients treated with balloon tamponade were not perfect controls. Third, patients enrolled in this study likely differed from the average patient seen in daily practice. This statement is supported by the 11 exclusion criteria mentioned in the study design and by the low number of patients included during a 3‐year period, despite the many centers participating in the study. This is a clear limitation of this study that reduces the robustness of the conclusions. In the specific setting of acute refractory variceal bleeding, the results from observational studies may seem more relevant to clinical practice.2 In line with this comment, a recent meta‐analysis (which already included Escorsell's results) assessed the usefulness of SEMS in patients with cirrhosis and severe or refractory variceal bleeding.3 This meta‐analysis showed that failure to control bleeding occurred in 18% of cases. Fewer than 40% of patients treated with SEMS died after 30 days and only 12% died from recurrent bleeding. Even if these results are not a proof that SEMS reduce mortality, this percentage compares favorably to the mortality rates reported in previous studies. Furthermore, a significant percentage of patients had access to transjugular intrahepatic portosystemic shunt (26%) or to liver transplantation (10%), which underlines that SEMS can also serve as a bridge to a more definitive treatment. Overall, we believe that SEMS should be considered in patients with cirrhosis and uncontrolled variceal bleeding. How early SEMS should be placed during the course of acute variceal bleeding to achieve better control of bleeding and prevention of rebleeding before the development of more‐severe liver dysfunction remains to be assessed.
Pulmonary Arterial Hypertension in Idiopathic Myelofibrosis Is Associated with an Alterated Angiogenic Status.
Authors: Agostino Cortelezzi, Nicoletta Del Papa, Rossella Calori, Maria Cristina Pasquini, Michela Cortiana, Ilaria Silvestris, Giuseppe Gritti, Fabiola B. Sozzi, Paola Bianchi, Giorgio Lambertenghi Deliliers
Journal: Blood (2006)
Frequency, Type, and Volume of Leisure-Time Physical Activity and Risk of Coronary Heart Disease in Young Women
Authors: Andrea K. Chomistek, Beate Henschel, A. Heather Eliassen, Kenneth J. Mukamal, Eric B. Rimm
Journal: Circulation (2016)

Background: The inverse association between physical activity and coronary heart disease (CHD) risk has primarily been shown in studies of middle-aged and older adults. Evidence for the benefits of frequency, type, and volume of leisure-time physical activity in young women is limited. Methods: We conducted a prospective analysis among 97 230 women aged 27 to 44 years at baseline in 1991. Leisure-time physical activity was assessed biennially by questionnaire. Cox proportional hazards models were used to examine the associations between physical activity frequency, type, and volume, and CHD risk. Results: During 20 years of follow-up, we documented 544 incident CHD cases. In multivariable-adjusted models, the hazard ratio (95% confidence interval) of CHD comparing ≥30 with &lt;1 metabolic equivalent of task-hours/wk of physical activity was 0.75 (0.57–0.99) ( P , trend=0.01). Brisk walking alone was also associated with significantly lower CHD risk. Physical activity frequency was not associated with CHD risk when models also included overall activity volume. Finally, the association was not modified by body mass index (kg/m 2 ) ( P , interaction=0.70). Active women (≥30 metabolic equivalent of task-hours/wk) with body mass index&lt;25 kg/m 2 had 0.52 (95% confidence interval, 0.35–0.78) times the rate of CHD in comparison with women who were obese (body mass index≥30 kg/m 2 ) and inactive (physical activity &lt;1 metabolic equivalent of task-hours/wk). Conclusions: These prospective data suggest that total volume of leisure-time physical activity is associated with lower risk of incident CHD among young women. In addition, this association was not modified by weight, emphasizing that it is important for normal weight, overweight, and obese women to be physically active.
Radial Artery as a Coronary Artery Bypass Conduit
Authors: Mario Gaudino, Paolo Tondi, Umberto Benedetto, Valentina Milazzo, Roberto Flore, Franco Glieca, Francesca Romana Ponziani, Nicola Luciani, Leonard N. Girardi, Filippo Crea, Massimo Massetti
Journal: Journal of the American College of Cardiology (2016)
Contemporary use of lymph node dissection at nephroureterectomy in treating upper tract urothelial carcinoma: A US population-based analysis.
Authors: Yu-Wei Chen, Francisco Gelpi-Hammerschmidt, Chao-Ping Wu, Joaquim Bellmunt, Steven L. Chang
Journal: Journal of Clinical Oncology (2015)

e15634 Background: Nephroureterectomy (NU) is the current gold-standard in the management of upper tract urothelial carcinoma (UTUC). Our study aims to describe the current trend of lymph node dissection (LND) at NU, the factors associated with LND use and whether NU with LND is associated with a reduction in cancer-specific mortality (CSM) for patients with UTUC. Methods: We identified patients diagnosed with non-metastatic UTUC from 2004-2011 in the Surveillance, Epidemiology and End Results Program (SEER). A multivariable logistic regression was used to model the predictors for undergoing a LND ( ≥ 3 lymph node removed, covariates adjusted including age, sex, race, marital status, year of diagnosis, tumor site, tumor grade and t stage). We estimated the 5-year cumulative CSM for the NU with LND cohort vs.NU alone cohort; a multivariable Cox regression model (covariates adjusted including LND ,tumor site, tumor grade, t stage, age, sex, race, marital status and year of diagnosis) was used to estimate the predictors for CSM. Results: The study cohort included 1,445 non-metastatic UTUC patients treated with NU. The contemporary trend of LND at NU was low (N = 166, 11.5%), versus NU alone (N = 1279, 88.5%). Patients with T4 stage (AOR: 2.77, 95% CI: 1.45-5.30) and younger age ( < 60) were more likely to receive LND (AOR: 2.22, 95%CI: 1.44-3.44). The 5-year CSM for NU with LND cohort and NU alone cohort were 26% and 28%, respectively without statistical significance (Gray’s test:p-value: 0.58). After adjusting for baseline characteristics, LND was not associated with reduced CSM (AHR: 0.99, 95% CI: 0.80-1.23). Of the 166 patients who received LND at NU, 43.4% had pathologically positive lymph nodes, which were associated with higher risk of CSM (AHR: 2.94, 95%CI: 1.80-4.80). Conclusions: In the United States, LND is relatively uncommon at the time of NU in the management of patients with UTUC however it is also not associated with a reduced CSM rate. Nevertheless, pathologically positive lymph node status was an independent predictor for CSM suggesting LND serves an essential staging procedure in this patient population.
Recombinant Thrombomodulin for the Treatment of Transplantation-Associated Coagulopathy after Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Kazuyoshi Ishii, Shosaku Nomura, Tomoki Ito, Yuta Katayama, Taiichi Kyo, Shuichi Ota, Masanori Seki, Shigeru Chiba, Yoshinobu Maeda, Mitsune Tanimoto, Takayuki Ikezoe, Hideo Yagi, Yoji Ishida, Naohito Fujishima, Kenichi Sawada
Journal: Blood (2014)
a drug burden index to define the functional burden of medications in older people. Commentary : A step forward
Authors: Joseph Agostini, Sarah N Hilmer, Ronald I Shorr, Douglas C Bauer, Darrell R Abernethy, Donald E Mager
Journal: JAMA Internal Medicine (2007)

Background: Older people carry a high burden of illness for which medications are indicated, along with increased risk of adverse drug reactions. We developed an index to determine drug burden based on pharmacologic principles. We evaluated the relationship of this index to physical and cognitive performance apart from disease indication. Methods: Data from the Health, Aging, and Body Composition Study on 3075 well-functioning community-dwelling persons aged 70 to 79 years were analyzed by multiple linear regression to assess the cross-sectional association of drug burden index with a validated composite continuous measure for physical function, and with the Digit Symbol Substitution Test for cognitive performance. Results: Use of anticholinergic and sedative medications was associated with poorer physical performance score (anticholinergic exposure, 2.08 vs 2.21, P<.001; sedative exposure, 2.09 vs 2.19, P<.001) and cognitive performance on the Digit Symbol Substitution Test (anticholinergic exposure, 34.5 vs 35.5, P=.045; sedative exposure, 34.0 vs 35.5, P=.01). Associations were strengthened when exposure was calculated by principles of dose response. An increase of 1 U in drug burden index was associated with a deficit of 0.15 point (P<.001) on the physical function scale and 1.5 points (P=.01) on the Digit Symbol Substitution Test. These values were more than 3 times those associated with a single comorbid illness. Conclusions: The drug burden index demonstrates that anticholinergic and sedative drug exposure is associated with poorer function in community-dwelling older people. This pharmacologic approach provides a useful evidence-based tool for assessing the functional effect of exposure to medications in this population.
VELCADE/Dexamethasone (Vel/Dex) Versus VAD as Induction Treatment Prior to Autologous Stem Cell Transplantation (ASCT) in Newly Diagnosed Multiple Myeloma (MM): An Interim Analysis of the IFM 2005-01 Randomized Multicenter Phase III Trial.
Authors: Jean-Luc Harousseau, Gerald Marit, Denis Caillot, Philippe Casassus, Thierry Facon, Mohamad Mohty, Frederic Maloisel, Herve Maisonneuve, Carine Chaleteix, Lofti Benboubker, Dixie-Lee Esseltine, Michel Attal
Journal: Blood (2006)