tbuckley/cabot-search huggingface dataset:
Abstract P149: Mozobil Increases Myocardial Fibrosis via the Recruitment of Fibrocytes in the Angiotensin II--Treated Heart
Authors: Alec G Falkenham, Tim Lee, Jean Francois Legare
Journal: Circulation Research (2011)

Background: Fibroblast progenitor cells (fibrocytes) are important to the development of myocardial fibrosis and suggested to migrate to the chemokine CXCL12. CXCL12 has one primary receptor, CXCR4, to which the inhibitor Mozobil competitively binds. Mozobil has been shown to inhibit recruitment of fibrocytes to the lungs following bleomycin injury, but its affects on progenitor cells in the heart remains unclear. We hypothesized that if CXCL12 is necessary for fibrocyte recruitment, Mozobil would inhibit fibrocyte infiltration into the myocardium and consequently, decrease fibrosis. Methods: C57/Bl6 mice were treated with saline (control), AngII, or AngII+Mozobil via osmotic mini-pump. Mice were sacrificed at day 3 and tissues were collected for RNA, protein and histology. Heart sections were stained with H&amp;E and Sirius Red and analyzed for cellular infiltrate and collagen deposition, respectively. Infiltrate was measured using standardized grid counts on a single heart section. The percent area affected was the number of grids containing cellular infiltrate over the total grids containing heart tissue (∼375 grids per section). Fibrocytes were cultured from mouse peripheral blood following mobilization with Mozobil. Fibrocytes were stained for collagen-1, CD133 and CXCR4. Results: Cultured fibrocytes were positive for markers CD133 and collagen-1, as well as CXCR4. AngII infusion resulted in significant cellular infiltration, affecting 30.0 ± 4.0% (n=8) of the myocardium, relative to saline (0.3% ± 0.4; n=8). In contrast, animals receiving AngII+Mozobil had 78.9±3.1% (n=5) of the myocardium affected (p&lt;0.05). Increased infiltrate was also associated with significantly increased collagen deposition: Control (4.3% ± 0.1), AngII (11.9% ± 1.9), and AngII+Mozobil (29.0% ± 4.8). Furthermore, the infiltrate was positive for the progenitor marker CD133. Conclusion: Our findings confirm isolated fibrocytes express CXCR4. Unexpectedly however, our findings suggest CXCL12 is not required for the migration of fibrocytes to the myocardium, based on the failure of CXCR4 blockade to limit migration. Our findings suggest that increased migration into the heart may be through the increased mobilization of progenitor cells from the bone marrow.
Outcomes of advanced HL with ABVD: The University of Pennsylvania experience.
Authors: Meghna S. Trivedi, David Bajor, Tahamtan Ahmadi, Jakub Svoboda, Alison W. Loren, Stephen J. Schuster, Sunita Nasta
Journal: Journal of Clinical Oncology (2012)

e18529 Background: Hodgkin Lymphoma (HL) is considered a curable malignancy with standard therapy using the doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) regimen. Even with standard therapy, the relapse rate for patients with advanced HL (stage IIB and higher) remains significant. The International Prognostic Score (IPS) uses 7 adverse prognostic factors (serum albumin, hemoglobin, male sex, age, stage IV disease, leukocytosis, and lymphopenia) to predict outcomes in advanced HL. Methods: We performed a retrospective chart review of all patients evaluated at the University of Pennsylvania for primary HL from July 2006 to June 2011. Of 257 patients, 26 were identified as those with advanced HL who initiated ABVD treatment at the University of Pennsylvania. The study outcomes were defined by RECIST criteria. The 26 patients were stratified by IPS and outcomes were evaluated. Results: 22 of 26 patients (85%) achieved lasting complete response (CR) after receiving treatment with ABVD with a median length of follow-up of 2.93 years. Three patients had primary refractory disease. Of these patients, two (IPS 1-2) achieved CR with salvage therapy. The third patient (IPS 5) had initial partial response (PR) to ABVD then continued to have relapsed disease after 4.50 years of follow-up. One patient (IPS 5) relapsed 2.74 years after receiving ABVD and at best had PR with salvage chemotherapy. Conclusions: ABVD was effective in achieving CR; however, 4 patients were unable to achieve lasting CR from ABVD alone. Two patients with IPS of 1 and 2 eventually achieved CR from salvage therapy. Two patients with IPS of 5 were unable to achieve lasting CR. Based on this data, IPS of 5 was associated with worse outcome. Use of IPS may be helpful to identify patients needing more intensive initial therapies. [Table: see text]
CRISPR/Cas9: at the cutting edge of hepatology
Authors: Francis P Pankowicz, Kelsey E Jarrett, William R Lagor, Karl-Dimiter Bissig
Journal: Gut (2017)

Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 genome engineering has revolutionised biomedical science and we are standing on the cusp of medical transformation. The therapeutic potential of this technology is tremendous, however, its translation to the clinic will be challenging. In this article, we review recent progress using this genome editing technology and explore its potential uses in studying and treating diseases of the liver. We discuss the development of new research tools and animal models as well as potential clinical applications, strategies and challenges.
Abstract #5258: Nonradioactive quantification of phosphoinositide 3-kinase (PI3K) products from breast cancer cell lines
Authors: Kimberly Ehrmantrout, James Thompson, Paul Neilsen, Angie Branch
Journal: Cancer Research (2009)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

Phosphoinositides (PIPs) are an integral part of cell signaling pathways and are metabolized by kinases, phosphatases, and phospholipases. Phosphoinositides are produced by the activities of PI3K and serve as second messengers in cell survival, growth, motility, immune response, inflammation, and apoptosis. Conversely, abnormal production of these signaling lipids leads to proliferative, metabolic, and inflammatory disorders. It is critical to know the absolute and relative concentration of individual phosphoinositides in cell samples, but this analysis is difficult due to their low abundance and the inherent physical properties of lipids. We quantified PIPs extracted from cell lysates using direct detection on nitrocellulose membranes and in competitive ELISAs. Using specific antibodies and binding proteins we developed assays able to differentiate closely related phosphoinositides. These non radioactive assays employ synthetic di-C16 lipids as standards and are able to measure as little as 1-2 pmol of cellular PIPs. Human breast cancer cell lines MDA-MB-231 and MDA-MB-468 (PTEN deficient) were evaluated using activators and inhibitors of the PI3K pathway. We quantified PIPs from 231 and 468 cells using a biomass of several million cultured cells per assay point. We found 468 cells under hydrogen peroxide stress dramatically increased PtdIns(3,4,5)P3 and PtdIns(3,4)P2 levels while PIPn levels from 231 cells increased at a slower rate and at much lower concentrations. Levels of these two signaling PIPs were blocked by the PI3K inhibitor, wortmannin suggesting PI3K is directly involved. Lipid products of both class I and class II PI3Ks are increased by hydrogen peroxide stress in both PTEN normal and PTEN deficient breast cancer cell lines while pre-incubation with wortmannin attenuated both PtdIns(3,4)P2 and PtdIns(3,4,5)P3 increases. Hyperactivation of class I and class II PI3K in the absence of PTEN regulation (468 cells) leads to excessive 3\#8217; phosphorylated phosphoinositide levels that are known to activate Akt, leading to uncontrolled cell growth and proliferation. We expect the ability to quantify individual phosphoinositides from cells will help assign specific biological functions to these important lipid second messengers.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5258.
Safety and efficacy of sofosbuvir/velpatasvir for the treatment of chronic hepatitis C in patients aged 65 years or older: a retrospective analysis of phase 3 studies
Authors: M. Sulkowski, G. Foster, M. Shiffman, S. Byrne, J. Wolf, C. Grabowski, J. McNally, D. Brainard, K. Etzkorn, A. Sheikh, J. Feld
Journal: Journal of Hepatology (2017)
Utilization of DAA therapies ledipasvir/sofosbuvir and sofosbuvir/ velpatasvir in patients with genotype 1 HCV: real-world experience from the TRIO Network
Authors: N. Tsai, B. Bacon, M. Curry, D. Dieterich, S. Flamm, K. Kowdley, S. Milligan, Z. Younossi, N. Afdhal
Journal: Journal of Hepatology (2017)
MRI features predict survival and molecular markers in diffuse lower-grade gliomas
Authors: Hao Zhou, Martin Vallières, Harrison X Bai, Chang Su, Haiyun Tang, Derek Oldridge, Zishu Zhang, Bo Xiao, Weihua Liao, Yongguang Tao, Jianhua Zhou, Paul Zhang, Li Yang
Journal: Neuro-Oncology (2016)

Previous studies have shown that MR imaging features can be used to predict survival and molecular profile of glioblastoma. However, no study of a similar type has been performed on lower-grade gliomas (LGGs).Presurgical MRIs of 165 patients with diffuse low- and intermediate-grade gliomas (histological grades II and III) were scored according to the Visually Accessible Rembrandt Images (VASARI) annotations. Radiomic models using automated texture analysis and VASARI features were built to predict isocitrate dehydrogenase 1 (IDH1) mutation, 1p/19q codeletion status, histological grade, and tumor progression.Interrater analysis showed significant agreement in all imaging features scored (k = 0.703-1.000). On multivariate Cox regression analysis, no enhancement and a smooth non-enhancing margin were associated with longer progression-free survival (PFS), while a smooth non-enhancing margin was associated with longer overall survival (OS) after taking into account age, grade, tumor location, histology, extent of resection, and IDH1 1p/19q subtype. Using logistic regression and bootstrap testing evaluations, texture models were found to possess higher prediction potential for IDH1 mutation, 1p/19q codeletion status, histological grade, and progression of LGGs than VASARI features, with areas under the receiver-operating characteristic curves of 0.86 ± 0.01, 0.96 ± 0.01, 0.86 ± 0.01, and 0.80 ± 0.01, respectively.No enhancement and a smooth non-enhancing margin on MRI were predictive of longer PFS, while a smooth non-enhancing margin was a significant predictor of longer OS in LGGs. Textural analyses of MR imaging data predicted IDH1 mutation, 1p/19q codeletion, histological grade, and tumor progression with high accuracy.
Pazopanib and 5-FU/oxaliplatin as first-line treatment in advanced gastric cancer: PaFLO, a randomized phase II study from the AIO (Arbeitsgemeinschaft Internistische Onkologie).
Authors: Peter C. Thuss-Patience, Salah-Eddin Al-Batran, Jens T Siveke, Nils Homann, Peter Malfertheiner, Dietrich Glaeser, Alexander Stein, Ingo Tamm, Severin Daum, Jochem Potenberg, Axel Florschütz, Arndt Vogel, Karsten Ridwelski, Matthias Ritgen, Michael Geissler, Harald Schmalenberg, Peter Schlattmann, Mario Lorenz, Kirstin Breithaupt, Uwe Pichlmeier
Journal: Journal of Clinical Oncology (2015)

4033 Background: Pazopanib is an oral tyrosine kinase inhibitor which selectively inhibits angiogenesis via VEGFR-1, -2, -3, ckit and PDGF-R. Recent positive trials show that angiogenesis is an effective target in gastric cancer. In this randomized phase II trial we treated patients (pts) with FLO +/- Pazopanib. Methods: Pts with metastatic or locally advanced gastric or gastro-esophageal junction adenocarcinoma, HER2 negative and with measurable disease were randomized in a 2:1 ratio to 5-FU (2,6g/m²/24h, d1) + Leukovorin (200mg/m², d1) + Oxaliplatin (85mg/m², d1) (FLO) + Pazopanib (800mg/d d1-14, q2w) (arm A) or the same chemotherapy without Pazopanib (arm B). Analysis was planned with a Simon Minimax design with PFS rate at 6 month in arm A as the primary endpoint expecting a minimum of 40% of pts progression free. Results: 87 pts were randomized, eligible and evaluable were 51 pts in arm A and 27 in arm B. Pts characteristics in % (arm A/arm B): male: 72/63%, female: 28/37%; median age: 65/60 yrs; ECOG 0: 44/44%, 1: 50/48%, 2: 6/7%; localization GEJ: 59/30%, gastric body 41/70%; histology intestinal: 31/33%, diffuse or mixed: 28/30%, not specified: 41/37%. Treatment was tolerated well with possibly treatment related SAE in arm A in 12 of 51 pts + 4 SAE of special interest (ALT elevation) and arm B 4 of 27 pts. Median chemotherapy cycles administered were similar in both arms (8 cycles). Necessary dose reduction of chemotherapy were similar, arm A 37%, arm B 33% of pts. Pazopanib dose reductions were necessary in 22% of pts. PFS rate at 6 months was 31.4% in arm A and 25.9% arm B. Median PFS: 5.1 months arm A and 3.9 months arm B (HR 0.93, 95%CI 0.56-1.54). Median OS was 10.1 months in arm A and 7.0 months in arm B (HR 0.80, 95%CI 0.44-1.48), Median follow up is 12 months. Conclusions: Both arms had an inferior PFS than expected from the literature. Pazopanib in combination with 5-FU/Oxaliplatin showed marginal efficacy in this randomized phase II study regarding PFS. Further follow up for interesting OS data is needed. Histology specimen and multiple serum samples were collected from each pt and need to be analyzed for potential subgroups that may benefit most from Pazopanib. Clinical trial information: NCT01503372.
FOLFOX-4 + cetuximab in untreated patients with advanced colorectal cancer. A phase II study of the Gruppo Oncologico dell’Italia Meridionale (prot. GOIM 2402)
Authors: G. Colucci, F. Giuliani, R. Mattioli, C. Garufi, R. Mallamaci, G. Pezzella, M. Lopez, E. Maiello
Journal: Journal of Clinical Oncology (2006)

3559 Background: Cetuximab is an IgG monoclonal antibody targeting the EGFR showing to be effective both as single agent or in combination with Irinotecan (CPT-11) or Irinotecan/FU/FA in patients (pts) with EGFR-expressing metastatic colorectal cancer (CRC) in the first and second/subsequent-line setting. The current trial was designed to evaluate the efficacy and the safety of Cetuximab plus Folfox-4 as first -line treatment. The main objective was the percentage of confirmed objective response rate. Methods: Chemonaivepts with non-resectable metastatic CRC and expressing EGFR were treated with Cetuximab (400 mg/m 2 week 1 and 250 mg/m 2 weekly thereafter) plus Folfox-4 (every 2 weeks: Oxaliplatin 85 mg/m 2 , day 1; FA 100 mg/m 2 2h, simultaneously with OH-P, and FU 400 mg/m 2 iv bolus followed by 600 mg/m 2 iv for 22h on days 1 and 2). The first evaluation of disease status (Recist criteria) was performed after the first 4 cycles and confirmed after one month. The treatment was continued until a maximum of 12 cycles of chemotherapy; the maintenaice with Cetuximab was permitted. Preliminary results: On the 65 screened pts, 47 (72%) had EGFR-expressing metastatic disease and were enrolled. Their main characteristics were: median Ecog PS 0; median age 66 yrs (range 43–74); main sites of disease: liver 31, lung 12, lymph-nodes 3, others 8. To date twenty-two pts are evaluable for activity and 27 for toxicity; 2 pts are not evaluable and 25 are too early. We observed 16 PR (72.7%), 5 NC (22.7%) and 1 PD (4.6%) for an ORR of 72.7% and a TGCR of 95.4%; the confirmed PR were 15 (68%). To date 2 pts undergone surgery of their metastases both for lung. The main adverse events grade 3/4 (NCI criteria) were: acne-like rush 18.5%, diarrea 7%, nausea/vomiting 4% and anemia 4%. Conclusions: Our preliminary results confirm that the combination of Cetuximab plus Folfox-4 has an high activity and a good safety profile in advanced CRC pts. The study is ongoing. No significant financial relationships to disclose.
The UICC Cervical Cancer Initiative: A comprehensive program for cervical cancer prevention worldwide including a fellowship program
Authors: J. Harford
Journal: Journal of Clinical Oncology (2009)

1547 Background: HPV vaccines and new screening tools have the potential to make cervical cancer largely a disease of the past. The UICC Cervical Cancer Initiative (CCI) is a comprehensive program that aims to increase awareness and education, and support screening, vaccination, and treatment via four key components: advocacy; public information; professional education; and pilot projects. CCI is global in scope, but emphasis is placed on resource-poor settings where mortality and morbidity rates from cervical cancer and HPV-related infections are highest. Lack of appropriate professional knowledge has recurrently been identified as one of the major hindrances to national cancer control programs and lack of access to diagnosis and treatment. Methods: A comprehensive educational package developed by a task force of experts will serve as a basis for train the trainer courses. CCI curriculum materials are practical and reader-friendly with an interdisciplinary approach. UICC has developed a dedicated fellowship program to support the implementation of the CCI. Special attention is given to south-to-south knowledge transfer by encouraging workshops within regions and in local languages. Professional education is one of the key components of UICC projects in Tanzania and Nicaragua, which aim to showcase the impact of comprehensive education on cervical cancer control. The fellowships support these efforts via opportunities for appropriate training of health practitioners, policy-makers, educators, researchers, and technicians. Results: See www.uicc.org for information about study grants, training workshops, technology transfer, and training for nurses, investigators, and pathologists. Expert reviewers ensure each project is judged according to preset criteria. Conclusions: Knowledge transfer between professionals and a lay audience is critical for long-term sustainability. The UICC cervical cancer curriculum supported by a dedicated fellowship program and a train the trainer approach is one route to achieving success. Key factors include: identification of host institutions and reviewers, continual funding, evaluation and implementation plans per trainee, as well as a sharing best practice forum. No significant financial relationships to disclose.
Comparison of efficacy and safety of ombitasvir/paritaprevir/ ritonavir and dasabuvir ± ribavirin between Asian and western HCV GT1b-infected patients
Authors: L. Wei, Y. Luo, W.-L. Chuang, S.W. Paik, M.-L. Yu, L.M. Fredrick, A. Campbell, R. Trinh, J. Enejosa, N.S. Shulman, J. Heo, N. Mobashery
Journal: Journal of Hepatology (2017)
Evaluation of spleen length progression rate as a surrogate marker of clinical outcome in patients with Primary Sclerosing Cholangitis
Authors: F. Jung, M. Peiseler, R. Zenouzi, M. Sebode, J. Hartl, S. Hübener, C. Weiler-Normann, A. Lohse, C. Schramm, H. Ehlken
Journal: Journal of Hepatology (2017)
Liver-targeting with the novel nucleotide prodrug MIV-818 designed for the treatment of liver cancers
Authors: R. Bethell, K. Tunblad, B. Rizoska, A. Linqvist, S. Juric, F. Öberg, B. Classon, A. Eneroth, J. Öhd, M. Albertella
Journal: Journal of Hepatology (2017)
Efficacy and safety of ombitasvir/paritaprevir/ritonavir and dasabuvir with ribavirin in Asian patients with genotype 1b chronic hepatitis C virus infection and compensated cirrhosis: ONYX-II post-treatment week 24 results
Authors: L. Wei, G.-Q. Wang, Y. Luo, C.-J. Chu, S.W. Paik, J. Hou, J. Cheng, Q. Xie, Z. Duan, J.-H. Kao, B. Fu, L. Fredrick, N. Mobashery, J. Heo
Journal: Journal of Hepatology (2017)
SOF/VEL/VOX results in high SVR12 rates when administered for 12 weeks in DAA-experienced patients or for 8 Weeks in DAA-naïve patients: an integrated analysis of the POLARIS-1, POLARIS-2, POLARIS-3 and POLARIS-4 studies
Authors: S.K. Roberts, C.L. Cooper, E. Lawitz, K.R. Reddy, A.J. Thompson, S. Zeuzem, I.M. Jacobson, P. Ruane, R.H. Hyland, L.M. Stamm, L. Han, D.M. Brainard, N. Bräu, T. Asselah, B.E. Willems, S. Flamm, M. Bourlière, G.R. Foster, E.J. Gane, M. Manns, S.C. Gordon, K. Kowdley
Journal: Journal of Hepatology (2017)
Notch-Regulated Enhancers in B-Cell Lymphoma Activate MYC and Potentiate B-Cell Receptor Signaling
Authors: Russell J.H. Ryan, Jelena Petrovic, Dylan Rausch, Caleb Lareau, Winston Lee, Laura Donohue, Amanda L. Christie, Shawn Gillespie, Michael J. Kluk, Valentina Nardi, Robert B. Faryabi, Ephraim P. Hochberg, David M. Weinstock, Bradley E. Bernstein, Jon C. Aster, Warren S. Pear
Journal: Blood (2016)
HER2 Reactivation through Acquisition of the HER2 L755S Mutation as a Mechanism of Acquired Resistance to HER2-targeted Therapy in HER2+ Breast Cancer
Authors: Xiaowei Xu, Carmine De Angelis, Kathleen A. Burke, Agostina Nardone, Huizhong Hu, Lanfang Qin, Jamunarani Veeraraghavan, Vidyalakshmi Sethunath, Laura M. Heiser, Nicholas Wang, Charlotte K.Y. Ng, Edward S. Chen, Alexander Renwick, Tao Wang, Sarmistha Nanda, Martin Shea, Tamika Mitchell, Mahitha Rajendran, Ian Waters, Daniel J. Zabransky, Kenneth L. Scott, Carolina Gutierrez, Chandandeep Nagi, Felipe C. Geyer, Gary C. Chamness, Ben H. Park, Chad A. Shaw, Susan G. Hilsenbeck, Mothaffar F. Rimawi, Joe W. Gray, Britta Weigelt, Jorge S. Reis-Filho, C. Kent Osborne, Rachel Schiff
Journal: Clinical Cancer Research (2017)

Resistance to anti-HER2 therapies in HER2
Distracted Driving With Attention-Deficit/Hyperactivity Disorder
Authors: Vishal Madaan, Daniel J. Cox
Journal: JAMA Psychiatry (2017)

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