tbuckley/cabot-search huggingface dataset:
Abstract 10257: Vascular Expansion During Worsening of Heart Failure: Effects on Clinical Features and Its Determinants
Authors: Hajime Kataoka
Journal: Circulation (2015)

Introduction: During worsening heart failure (HF), it is unknown whether clinical features differ according to the level of vascular expansion, and how changes in serum substance(s) are associated with volume changes. Hypothesis: Changes in serum solutes/albumin are associated with vascular expansion and induce different clinical features during HF worsening. Methods: Data from 47 HF patients that experienced a worsening HF episode were analyzed. Each patient had at least 2 of the following HF signs: S3, rales, leg edema, body weight (BW) gain (≥1.5 kg), and ultrasound pleural effusion. Blood tests included hemoglobin (Hb), hematocrit (Ht), albumin, solutes [sodium (Na), potassium, chlorine (Cl), blood urea nitrogen, creatinine (Cr), and uric acid], and b-type natriuretic peptide (BNP). The relative change in the vascular expansion from stable to worsening HF was estimated based on changes in the plasma volume (%PV) as follows: 100 x {Hb (stable) x [1-Ht (worse)]}/ {Hb (worse) x [1-Ht (stable)]}-100. Results: When divided into two groups by the median %PV, the clinical features of the expansion group [11≤%PV (range 11 to 36%); n=24] had a lower incidence of rales (13 vs 52%, p=0.005) and a tendency toward preserved renal function defined by a decrease in serum Cr (83 vs 57%, p=0.06) as compared with the non-expansion group [%PV (range -19 to 10.8%)&lt;11;n= 23], though the increase in BW and log BNP did not differ between groups. The expansion group had a greater increase in serum Na (3.58±4.43 vs -0.11±3.31mEq, p=0.0016) and Cl (5.54±6.24 vs -0.03±4.18, p=0.0006), and a greater decrease in albumin (-0.37±0.3 vs -0.16±0.3, p=0.04) from stability to worsening HF. Logistic regression analysis revealed an independent association between the increase in %PV and the increase in the serum Cl concentration from stability to HF worsening (OR:12.5, 95%CI: 1.89-82, P=0.009). Conclusions: Vascular expansion during worsening HF is associated with changes in the serum Cl concentration. As a key osmolyte, greater accumulation of this solute in the blood vessels might act to increase or maintain intravascular volume, which induces different clinical features of HF, such as a lower incidence of rales and preserved renal function due to maintenance of the blood supply to the kidney.
Erratum: Maternal activating KIRs protect against human reproductive failure mediated by fetal HLA-C2 (Journal of Clinical Investigation (2010) 120, 11 (4102-4110) DOI: 10.1172/JCI43998)
Authors: S E Hiby, R Apps, A M Sharkey, L E Farrell, L Gardner, A Mulder, F H Claas, J J Walker, C W Redman, L Morgan, C Tower, L Regan, G E Moore, M Carrington, A Moffett
Journal: Journal of Clinical Investigation (2011)
Driving an improved CAR for cancer immunotherapy
Authors: Xiaopei Huang, Yiping Yang
Journal: Journal of Clinical Investigation (2016)

The recent clinical success of chimeric antigen receptor (CAR) T cell therapy for B cell malignancies represents a paradigm shift in cancer immunotherapy. Unfortunately, application of CAR T cell–mediated therapy for solid tumors has so far been disappointing, and the reasons for this poor response in solid tumors remain unknown. In this issue of the JCI, Cherkassky and colleagues report on their use of a murine model of human pleural mesothelioma to explore potential factors that limit CAR T cell efficacy. Their studies have uncovered the importance of the tumor microenvironment in the inhibition of CAR T cell functions, revealed a critical role for the programmed death-1 (PD-1) pathway in CAR T cell exhaustion within the tumor microenvironment, and demonstrated improved antitumor effects with a CAR T cell–intrinsic PD-1 blockade strategy using a dominant negative form of PD-1. Together, the results of this study lay the groundwork for further evaluation of mechanisms underlying CAR T cell immune evasion within the tumor microenvironment for the improvement of CAR T cell–mediated therapy for solid tumors.
Inhibition of PD-L1 by MPDL3280A and clinical activity in pts with metastatic urothelial bladder cancer (UBC).
Authors: Thomas Powles, Nicholas J. Vogelzang, Gregg Daniel Fine, Joseph Paul Eder, Fadi S. Braiteh, Yohann Loriot, Cristina Cruz Zambrano, Joaquim Bellmunt, Howard A. Burris, Siew-leng Melinda Teng, Xiaodong Shen, Hartmut Koeppen, Priti S. Hegde, Daniel S. Chen, Daniel Peter Petrylak
Journal: Journal of Clinical Oncology (2014)

5011 Background: Metastatic UBC is associated with a poor prognosis and limited treatment options. PD-L1 expression is prevalent in this disease and may protect cancer cells from immune-mediated destruction by binding to its receptors PD-1 and B7.1. MPDL3280A is a human anti-PD-L1 mAb with an engineered Fc-domain designed for optimized efficacy and safety. Methods: In a Ph I study, UBC pts received MPDL3280A 15 mg/kg IV q3w for up to 1 y. Objective response rate (ORR; including unconfirmed responses) was assessed by RECIST v1.1. In parallel, tumor and circulating biomarkers were evaluated to study MPDL3280A immune correlates. Results: As of Sep 19, 2013, 31 UBC pts were treated with MPDL3280A. Pts were 84% male, had a median age of 66 y (42-86), 57% were ECOG PS 1 and 68% had visceral metastases. 71% received ≥ 2 prior therapies; 97% received prior platinum-based chemotherapy. Pts had received MPDL3280A for a median duration of 43 d (1-153); the majority remained on treatment as of the data cutoff. The G1-4 treatment-related AEs occurring in ≥ 2 pts were pyrexia, anemia, decreased appetite, fatigue and nausea. Related G3-4 AEs occurred in 3.2% of pts. There were no immune-related AEs. 20 PD-L1+ pts were evaluable for efficacy at time of analysis with a median follow up of 2.8 m (1.4-5). The ORR was 50% (1 CR and 9 PRs) with a median time to response of 43 d (39-82), corresponding to the first radiographic assessment. Responders included pts with visceral metastases at baseline. All responders were still responding at the time of clinical cutoff. Treatment resulted in transient increases in circulating CD8+Ki-67+ T cells and plasma proteins (eg, IL-18) upstream of IFNγ signaling, representing pharmacodynamic biomarkers of activity. Gene expression data from pretreatment tumors showed that pts who progressed had a proportionally higher myeloid gene signature (eg, IL8, CCL2). Updated data will be presented, including data from PD-L1–neg pts. Conclusions: MPDL3280A was well tolerated in this pretreated UBC population. 50% of pts treated responded to treatment. Responses were rapid and on-going. Biomarker analysis revealed pharmacodynamic markers, as well as markers of potential mechanisms of resistance to therapy. Clinical trial information: NCT01375842.
Brain-computer interface-based control of closed-loop brain stimulation: attitudes and ethical considerations
Authors: Eran Klein, Sara Goering, Josh Gagne, Conor V. Shea, Rachel Franklin, Samuel Zorowitz, Darin D. Dougherty, Alik S. Widge
Journal: Brain-Computer Interfaces (2016)

Patients who have undergone deep brain stimulation (DBS) for emerging indications have unique perspectives on ethical challenges that may shape trial design and identify key design features for BCI-driven DBS systems. DBS research in cognitive and emotional disorders has generated significant ethical interest. Much of this work has focused on developing ethical guidelines and recommendations for open-loop DBS systems. While early trials of open-loop DBS for depression gave disappointing results, research is moving toward clinical trials with closed-loop or patient-controllable DBS systems that may modulate aspects of personality and emotion. Though user-centered design is an increasingly important principle in neurotechnology, the perspectives of implanted individuals on ethical issues raised by DBS are poorly understood. We solicited those perspectives through a focus group and set of qualitative interviews of participants in trials of DBS for depression and obsessive-compulsive disorder. We identified four major themes: control over device function, authentic self, relationship effects, and meaningful consent. Each has implications for the design of closed-loop systems for non-motor disorders.
The UK ALLR3 Chemotherapy Regimen for Relapsed/Refractory Acute Lymphoblastic Leukemia of Childhood: A Multi-Institutional Retrospective Study of Treatment Related Adverse Events
Authors: Weili Sun, Alison Marie Smith, Orgal Etan, Richard Sposto, Jennifer J. Wilkes, Rebecca A Gardner, Hur Minjun, Vanessa Pineros, Emily Olson, Yijuin Tan, Susan R. Rheingold, Michael J. Burke, Alan S. Wayne
Journal: Blood (2014)
Insights into neuroepigenetics through human histone deacetylase PET imaging
Authors: Hsiao-Ying Wey, Tonya M. Gilbert, Nicole R. Zürcher, Angela She, Anisha Bhanot, Brendan D. Taillon, Fredrick A. Schroeder, Changing Wang, Stephen J. Haggarty, Jacob M. Hooker
Journal: Science Translational Medicine (2016)

First-in-human neuroepigenetic PET imaging with [ 11 C]Martinostat reveals conserved region-specific expression of class I HDACs in the healthy brain.
Interim Analysis of an Ongoing Phase Ii Trial Assessing Safety and Efficacy of R-Idea As Salvage Therapy in Patients with Relapsed/Refractory Dlbcl: an Intergroup Study of the Society of Lymphoma Treatment in Japan (Solt-J) and the West Japan Hematology/Oncology Group (Westjhog)
Authors: E. Kondo, K. Yamamoto, T. Masunari, K. Miura, J. Takizawa, Y. Masaki, T. Matsumura, Y. Hiramatsu, J. Murakami, H. Tsujimura, N. Tomita, Y. Maeda, M. Kanno
Journal: Annals of Oncology (2014)
Abstract 2344: Discovery and characterization of new original blocking antibodies targeting the CD73 immune checkpoint for cancer immunotherapy
Authors: Marc Giraudon Paoli, Severine Augier, Marilyne Royannez Blemont, Céline Rodriguez, Hélène Rispaud Blanc, Stéphanie Chanteux, Nicolas Gourdin, Laurent Gauthier, Christine Ménétrier Caux, Yannis Morel, Christophe Caux, Carine Paturel, Ivan Perrot
Journal: Cancer Research (2016)

Abstract CD73 (NT5E) is a cell membrane ectoenzyme of the NTPDase family that plays a major role in the conversion of AMP into Adenosine (Ado). Within the tumor microenvironment, accumulation of Ado causes immune suppression and dysregulation of immune cell infiltrates resulting in tumor spreading. CD73 expression in the tumor environment has been associated with poor disease outcome and/or with a pro-metastatic phenotype. Thus, targeting CD73 may promote anti-tumor immunity by reducing Ado accumulation and may block tumor cell metastasis by inhibiting CD73 on tumor cells. Here, we describe the generation and characterization of novel anti-human CD73 antibodies, intended for the treatment of a wide range of cancers. The research leading to these results has received funding from the European Community's Seventh Framework Program (FP7/2007-2013) under grant agreement n°602200. Antibodies were discovered that inhibited CD73 function by different mechanisms, including the direct blocking of CD73 enzymatic activity or the down-modulation of membrane CD73 expression. Epitope mapping revealed that antibodies acting by these different modes of action bound to distinct sites on CD73. All selected antibodies cross-react with cynomolgus CD73 protein and have strong avidity and affinity for membrane or recombinant CD73, by flow cytometry and Surface Plasmon Resonance, respectively. Antibodies that inhibit CD73 enzymatic activity strongly reduce AMP catabolism by both recombinant and cellular CD73 with IC50 in the nanomolar range. They also efficiently reverse ATP- and AMP-mediated T cell suppression in in vitro assays in presence of both CD39+ and CD73+ cells. The antibodies that induce down-modulation of cellular CD73 expression do not block recombinant CD73 enzyme activity and partially inhibit cellular CD73 activity; they reverse ATP- but not AMP-dependent T cell suppression. The antibodies displaying the most interesting features were humanized. Evaluation of their activity in animal models is ongoing. Citation Format: Marc Giraudon Paoli, Severine Augier, Marilyne Royannez Blemont, Céline Rodriguez, Hélène Rispaud Blanc, Stéphanie Chanteux, Nicolas Gourdin, Laurent Gauthier, Christine Ménétrier Caux, Yannis Morel, Christophe Caux, Carine Paturel, Ivan Perrot. Discovery and characterization of new original blocking antibodies targeting the CD73 immune checkpoint for cancer immunotherapy. [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 2344.
Safety and Activity of KOS-953 in Patients with Relapsed Refractory Multiple Myeloma (MM): Interim Results of a Phase 1 Trial.
Authors: Paul G. Richardson, Asher A. Chanan-Khan, Melissa Alsina, Deborah Doss, Beverly Landrigan, Dawn Kettner, Maher Albitar, Constantine Mitsiades, Gillian F. Cropp, Robert G. Johnson, Alison L. Hannah, Kenneth C. Anderson
Journal: Blood (2005)
Abstract 2126: Androgen receptor expression is associated with sunitinib resistance in renal cell carcinoma models
Authors: Remi M. Adelaiye-Ogala, Sreenivasulu Chintala, Ashley Orillion, Piergiorgio Pettazzoni, May Elbanna, Bennett Elzey, Kiersten Marie Miles, Chinghai Kao, Giulio F. Draetta, Roberto Pili
Journal: Cancer Research (2016)

Abstract Background: Androgen receptor (AR) expression has been reported in renal cell carcinoma but its biological role remains elusive. Sunitinib is a potent anti-angiogenic drug approved for the treatment of advanced renal cell carcinoma (RCC). However, eventually RCC tumors develop drug resistance. We have hypothesized that tumor cells resistance to sunitinib is associated with kinome reprograming and anti-apoptotic genes upregulation. To date, there is no report on the association between AR expression and resistance to TKI such as sunitinib in RCC. Our study was designed to investigate the role of AR in sunitinib resistance in RCC. We used our previously reported sunitinib resistant ccRCC cells and patient derived xenograft models. Methods: Human RCC cell lines; 786-0, 786-0R (sunitinib resistant), C2, C2R (sunitinib resistant), ACHN and Caki 2 were utilized to determine sensitivity or resistance to sunitinib. Patient derived xenograft (PDX) models of advance and metastatic RCC and RCC cell lines, sensitive and resistant tumors were used to detect AR expression by qRT-PCR, immunohistochemistry and Western blot analysis. Reverse phase protein array (RPPA) was used to assess 249 protein including AR in sunitinib sensitive and resistant tumors. Results: Our qRT-PCR data showed an increase by 1000 folds in mRNA levels of AR in our sunitinib resistant cell lines. Similarly, RPPA data revealed AR to be increased in sunitinib resistant RCC PDX tumors. This observation was confirmed by Western blot analysis. Conclusion: Overall our data suggest the potential role of AR and its association with resistance to sunitinib. Ongoing studies are testing the in vitro and in vivo combination treatment of RCC models with sunitinib and AR antagonists. Citation Format: Remi M. Adelaiye-Ogala, Sreenivasulu Chintala, Ashley Orillion, Piergiorgio Pettazzoni, May Elbanna, Bennett Elzey, Kiersten Marie Miles, Chinghai Kao, Giulio F. Draetta, Roberto Pili. Androgen receptor expression is associated with sunitinib resistance in renal cell carcinoma 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 2126.
Abstract 729: Novel role of CB2R in tuning breast tumor microenvironment, EGF/EGFR and IGF-I/IGF-IR pathways
Authors: Mohamad Elbaz, Mohd Nasser, Janani Ravi, Dinesh Ahirwar, Ramesh Ganju
Journal: Cancer Research (2016)

Abstract Cannabinoid receptor-2 (CB2R) is an integral part of the endocannabinoid system. It is upregulated in the primary breast cancer lesions and in different types of immune cells however; its functional role in breast tumorigenesis is not well understood. The present study was aimed at evaluating the mechanistic anti-tumor role of CB2R activation on breast cancer cells and immune cells within the breast tumor microenvironment. First, we analyzed the anti-tumorigenic mechanisms of CB2R activation in ERá- and ERá+ breast cancer cells. Our studies showed that CB2R specific agonist (JWH-015) inhibits EGF and IGF-I-induced migration and invasion of ERá+ and ERá- breast cancer cells. At the molecular level, JWH-015 inhibits EGFR and IGF-IR activation and their downstream targets STAT3, AKT, ERK, NF-kB and MMP-9/MMP-2. Interestingly, We found that JWH-015 significantly reduces breast cancer growth in vivo and the tumors that were derived from CB2R agonist treatment showed reduced activation of EGFR and IGF-IR and their downstream targets compared to control group. Since CB2R is overexpressed in immune cells, we assessed for the role of CB2R activation on modulation of immune cells present in tumor stroma. We observed increased tumor weight, more myeloid derived suppressor cells (MDSCs) (CD11b+/Gr-1+) and less CD3+/CD8+ cells in orthotopically injected CB2R knock out mice compared to wild type mice. Furthermore, we found that JWH-015-treated wild type mice have reduced tumor growth and metastasis, more CD3+/CD8+ cells and less MDSCs within the tumor stroma. For the first time, we show that CB2R activation might suppress breast tumor growth and metastasis through novel mechanisms of inhibiting EGFR and IGF-IR signaling axes on tumor cells and modulating the immune cells’ compositions within the breast tumor microenvironment. Citation Format: Mohamad Elbaz, Mohd Nasser, Janani Ravi, Dinesh Ahirwar, Ramesh Ganju. Novel role of CB2R in tuning breast tumor microenvironment, EGF/EGFR and IGF-I/IGF-IR pathways. [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 729.
F-18 Fluorothymidine (FLT) Imaging of the Bone Marrow Compartment in Rats Following Whole Body Irradiation, Stem Cell Transplantation and Spontaneous Recovery.
Authors: Jennifer L. Holter, Vibhudutta Awasthi, Kristin Thorp, Anderson Stacy, Sandra Bryant, Robert B. Epstein
Journal: Blood (2009)
Safety and Efficacy of Self-Expanding TAVR in Patients With Aortoventricular Angulation
Authors: Jeffrey J Popma, Michael J Reardon, Steven J Yakubov, James B Hermiller, J Kevin Harrison, Thomas G Gleason, John V Conte, G Michael Deeb, Stanley Chetcuti, Jae K Oh, Michael J Boulware, Jian Huang, David H Adams
Journal: JACC. Cardiovascular imaging (2016)
Meta-analysis of risk for lymphoma with immunomodulators for inflammatory bowel disease.
Authors: D. S. Kotlyar, C. Brensinger, J. D. Lewis, W. Blonski, M. Van Domselaar, D. L. Porter, S. Sandilya, G. R. Lichtenstein
Journal: Journal of Clinical Oncology (2010)

e18517 Background: Inflammatory bowel disease (IBD) treatment includes immunomodulators (Kandiel 2005 PMID: 16009685). Here we pooled studies examining immunomodulators as a risk factor for lymphoma to increase the power of risk estimates. Methods: We searched MEDLINE for: lymphoproliferative and thiopurines; and azathioprine and lymphoma. Included citations were cohort studies examining IBD (ulcerative colitis and Crohn's disease), evaluated cancer as an outcome, and pts. received AZA, and/or 6-MP. Pooled standardized incidence rates (SIRs) and 95% confidence intervals (CIs) were estimated by summing observed and expected numbers of lymphomas. CIs assumed a Poisson distribution. To examine for heterogeneity, the deviance statistic from Poisson regression models was examined. Results: There were 414 citations, and 406 were excluded. In referral centers (n=6), the SIR = 4.43. (95% CI: 2.53-7.21). In population-based studies (n=2), the SIR = 4.27 (95% CI: 2.52-6.75).There was no significant difference between the SIRs of the two groups (p=0.91). Conclusions: Referral bias has not been assessed in prior studies; here we find no significant difference between referral center and population-based studies. Of 12,938 patients, the SIR in patients with IBD on immunomodulators is approximatley fourfold compared to controls. Referral center studies (test for heterogeneity: p value = 0.0702) Study Obs. Expected SIR 95% CI No. of pts. Connell (PMID: 7910274) 0 0.52 0 NA 755 Farrell (PMID: 10986211) 2 0.05 37.5 (3.53-137) 238 Fraser (PMID:12144571) 3 0.65 4.64 (0.87-13.7) 626 Kinlen (Am J Med 1985;78:44-9) 2 0.16 12.5 (1.18-46.0) 321 Korelitz (PMID: 10566724) 3 0.61 4.91 (0.93-14.5) 486 Van Domselaar (PMID: 19889478) 5 1.35 3.70 (1.33-8.12) 371 Combined 15 3.39 4.43 (2.53-7.21) 2,797 Population-based studies (test for heterogeneity: p-value = 0.2003) Study Obs. Expected SIR 95% CI No. of pts. Lewis PMID: 11677199 1 0.64 1.56 (0.0006-8.96) 1,465 Beaugerie PMID: 19837455 17 3.58 4.75 (2.76-7.62) 8,676 Combined 18 4.22 4.27 (2.52-6.75) 10,141 Combined data (referral SIR [4.43] vs. the population studies SIR [4.27]; p value=0.91) Obs. Expected SIR 95% CI No. of pts. All studies 33 7.83 4.34 (3.00-6.07) 12,938 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Prometheus, Salix Prometheus, Salix