tbuckley/cabot-search huggingface dataset:
Abstract 207: Differential Regulation of Ubiquitin-Proteasomal System in Right Ventricular Versus Left Ventricular Hypertrophy and Failure
Authors: Viswanathan Rajagopalan, Mingming Zhao, Sushma Reddy, Giovanni Fajardo, Shannamar Dewey, Aldrin Gomes, Daniel Bernstein
Journal: Circulation Research (2012)

Background: While the role of Ubiquitin-Proteasomal System (UPS) in left ventricular hypertrophy (LVH) and failure (LVF) has been controversial, the role of UPS in the right, RVH/RVF is unknown. Given the greater percent increase in RV mass and protein with RV vs. LV afterload stress, we hypothesized that UPS alterations could play an important role in RVH and RVF. Methods: Using our pulmonary artery constriction (PAC) model to induce RVH/RVF by 8d (n=13-14), UPS gene and protein expression, ubiquitination, oxidation (carbonylation), and enzyme activity were measured in PAC vs. sham controls. Proteasomal inhibitors epoxomicin (0.5 mg/kg/d) or MG132 (10 µg/kg/d) were administered from 1d before to 7d after surgery (n=3-6). Results: RVW/BW was increased by 109.3% in PAC mice. All mice developed progressive RV dilation, septal shift and decrease in RV function. UPS function, measured as 26S ß 5 chymotrypsin-like activity (71.3±3.9 vs. 100±8.3%; p&lt;0.05) and 20S ß 1 caspase-like activity (66.9±3.2 vs. 100±6.9%; p&lt;0.001), was decreased. 20S protein expression was unchanged whereas the 19S regulatory subunit Rpt5 was increased (3.3±0.5 vs. 1.4±0.2; p&lt;0.05). UCHL1 deubiquitinase (0.3±0.04 vs. 0.05±0.004; p&lt;0.0001) and Smurf1 E3 ubiquitin ligase (3369±538 vs. 1249±75.6; p&lt;0.01) were increased and both poly-ubiquitinated proteins (877600±50550 vs. 639700±45050; p&lt;0.05) and free-ubiquitins (373102±65859 vs. 177318±24188) were also increased. Carbonylation was unchanged. Pro-apoptotic Bax was increased (0.06±0.004 vs. 0.02±0.001; p&lt;0.0001), and anti-apoptotic Bcl-2 decreased (0.2±0.03 vs. 0.5±0.08; p&lt;0.05) with a 6-fold increase in Bax/Bcl-2 ratio. Proteasomal inhibition further increased free ubiquitin levels 2.6-fold (p&lt;0.0001). However, neither the degree of RVH, nor decrease in RV function was altered. Conclusion: UPS has been shown to be both activated/inhibited and cardioprotective/cardiotoxic in LVH/LVF. In RVH/RVF, despite a doubling in RV mass, UPS activity is decreased, associated with increased ubiquitinated proteins and Bax/Bcl-2 ratio. Further proteasomal inhibition does not hasten RVF, suggesting that the failing RV is resistant to further proteasomal inhibition, or a limited role for the UPS in the progression from RVH to RVF.
Transgenic drosophila as a drug-screening platform in colorectal cancer and medullary thyroid cancer.
Authors: John Michael Rozehnal, Marshall R. Posner, Celina Ang, Erdem Bangi, Caitlyn Yeykal, Ross L. Cagan, Rajan Paul Dang, Michael Donovan, Andrew V. Uzilov, Yevgeniy Antipin, Eric E. Schadt, Krzysztof Misiukiewicz
Journal: Journal of Clinical Oncology (2016)

e23164 Background: Solid tumors are typically driven by genetic changes in multiple signaling pathways. While drugging single “actionable” targets can be effective, this approach fails to address tumor complexity or whole body toxicity and often fails to provide durable response. Methods: We screen subjects with metastatic colorectal (CRC), medullary thyroid (MTC) cancers and an exploratory cohort. Available tumor tissue and a non-tumor control from the same patient are assayed by whole exome sequencing (WES), a targeted panel to guarantee sensitivity in known oncogenic hotspot regions, and a SNP microarray. Somatic tumor-specific mutations and rare germline variants are analyzed with a set of bioinformatics tools to predict their functional impact, and copy number analysis is carried out to identify amplifications or deletions. Variants predicted to be deleterious are considered for inclusion in the final avatar along with known oncogenic drivers. Candidate genes are validated by additional assays; 10-12 variants in oncogenes and/or tumor suppressors with fly orthologs are incorporated into a stable transgenic fly lineage. This fly lineage is screened against 1200 FDA-approved drugs, both in singlicate and in combination, for efficacy and toxicity. The most efficacious and least toxic drug combination are subsequently offered to study subjects in a separate clinical trial. Results: We have identified 17 candidates, 15 are currently progressing through the study (9 CRC, 4 MTC, 2 other). 7 subjects have advanced through the WES phase of the study; of these, candidate variants have been identified for 4, and a Drosophila avatar has been developed for one. Table 1 illustrates the process in these 4 patients. Conclusions: We present a method for developing patient-specific tumor models in transgenic drosophila as a drug-screening paradigm. Patient MTC-1 MTC-2 CRC-1 CRC-2 Known Drivers 1 1 16 8 Somatic Mutations 22 32 436 66 Rare Germline Variants N/A* 675 801 412 Copy Number Alteration N/A** N/A** 8 4 Total Selected for Validation 9 18 26 14 * Analysis added after this subject passed through. **CNV assays are not a part of MTC pipeline.
Preferential induction of cross-group influenza A hemagglutinin stem–specific memory B cells after H7N9 immunization in humans
Authors: Sarah F. Andrews, M. Gordon Joyce, Michael J. Chambers, Rebecca A. Gillespie, Masaru Kanekiyo, Kwanyee Leung, Eun Sung Yang, Yaroslav Tsybovsky, Adam K. Wheatley, Michelle C. Crank, Jeffrey C. Boyington, Madhu S. Prabhakaran, Sandeep R. Narpala, Xuejun Chen, Robert T. Bailer, Grace Chen, Emily Coates, Peter D. Kwong, Richard A. Koup, John R. Mascola, Barney S. Graham, Julie E. Ledgerwood, Adrian B. McDermott
Journal: Science Immunology (2017)

Antigenic drift and shift of influenza strains underscore the need for broadly protective influenza vaccines. One strategy is to design immunogens that elicit B cell responses against conserved epitopes on the hemagglutinin (HA) stem. To better understand the elicitation of HA stem-targeted B cells to group 1 and group 2 influenza subtypes, we compared the memory B cell response to group 2 H7N9 and group 1 H5N1 vaccines in humans. Upon H7N9 vaccination, almost half of the HA stem-specific response recognized the group 1 and group 2 subtypes, whereas the response to H5N1 was largely group 1-specific. Immunoglobulin repertoire analysis of HA-specific B cells indicated that the H7N9 and H5N1 vaccines induced genetically similar cross-group HA stem-binding B cells, albeit at a much higher frequency upon H7N9 vaccination. These data suggest that a group 2-based stem immunogen could prove more effective than a group 1 immunogen at eliciting broad cross-group protection in humans.
Long-Duration Complete Remissions of Diffuse Large B Cell Lymphoma after Anti-CD19 Chimeric Antigen Receptor T Cell Therapy
Authors: James N. Kochenderfer, Robert P.T. Somerville, Tangying Lu, James C. Yang, Richard M. Sherry, Steven A. Feldman, Lori McIntyre, Adrian Bot, John Rossi, Norris Lam, Steven A. Rosenberg
Journal: Molecular Therapy (2017)

T cells expressing anti-CD19 chimeric antigen receptors (CARs) can induce complete remissions (CRs) of diffuse large B cell lymphoma (DLBCL). The long-term durability of these remissions is unknown. We administered anti-CD19 CAR T cells preceded by cyclophosphamide and fludarabine conditioning chemotherapy to patients with relapsed DLBCL. Five of the seven evaluable patients obtained CRs. Four of the five CRs had long-term durability with durations of remission of 56, 51, 44, and 38 months; to date, none of these four cases of lymphomas have relapsed. Importantly, CRs continued after recovery of non-malignant polyclonal B cells in three of four patients with long-term complete remissions. In these three patients, recovery of CD19+ polyclonal B cells took place 28, 38, and 28 months prior to the last follow-up, and each of these three patients remained in CR at the last follow-up. Non-malignant CD19+ B cell recovery with continuing CRs demonstrated that remissions of DLBCL can continue after the disappearance of functionally effective anti-CD19 CAR T cell populations. Patients had a low incidence of severe infections despite long periods of B cell depletion and hypogammaglobulinemia. Only one hospitalization for an infection occurred among the four patients with long-term CRs. Anti-CD19 CAR T cells caused long-term remissions of chemotherapy-refractory DLBCL without substantial chronic toxicities. T cells expressing anti-CD19 chimeric antigen receptors (CARs) can induce complete remissions (CRs) of diffuse large B cell lymphoma (DLBCL). The long-term durability of these remissions is unknown. We administered anti-CD19 CAR T cells preceded by cyclophosphamide and fludarabine conditioning chemotherapy to patients with relapsed DLBCL. Five of the seven evaluable patients obtained CRs. Four of the five CRs had long-term durability with durations of remission of 56, 51, 44, and 38 months; to date, none of these four cases of lymphomas have relapsed. Importantly, CRs continued after recovery of non-malignant polyclonal B cells in three of four patients with long-term complete remissions. In these three patients, recovery of CD19+ polyclonal B cells took place 28, 38, and 28 months prior to the last follow-up, and each of these three patients remained in CR at the last follow-up. Non-malignant CD19+ B cell recovery with continuing CRs demonstrated that remissions of DLBCL can continue after the disappearance of functionally effective anti-CD19 CAR T cell populations. Patients had a low incidence of severe infections despite long periods of B cell depletion and hypogammaglobulinemia. Only one hospitalization for an infection occurred among the four patients with long-term CRs. Anti-CD19 CAR T cells caused long-term remissions of chemotherapy-refractory DLBCL without substantial chronic toxicities.
Targeting harmful use of alcohol for prevention and treatment of tuberculosis: a call for action
Authors: Mario Raviglione, Vladimir Poznyak
Journal: European Respiratory Journal (2017)

Over the past few years, the increasing role of risk factors and determinants of tuberculosis (TB) has been sufficiently elucidated [1, 2]. A number of noncommunicable conditions that are associated with TB have been identified [3]. These are particularly important at the start of the new millennium, as more and more low- and middle-income countries have entered a phase of epidemiological transition characterised by growing epidemics of noncommunicable diseases and conditions replacing infectious diseases as the main causes of ill health and deaths [4, 5]. Harmful use of alcohol favors development of tuberculosis and poor outcomes <http://ow.ly/oWKs30cyHcx>
Gonadotropin-releasing Hormone Agonists, Orchiectomy, and Risk of Cardiovascular Disease: Semi-ecologic, Nationwide, Population-based Study
Authors: Frederik Birkebæk Thomsen, Fredrik Sandin, Hans Garmo, Ingela Franck Lissbrant, Göran Ahlgren, Mieke Van Hemelrijck, Jan Adolfsson, David Robinson, Pär Stattin
Journal: European Urology (2017)

In observational studies, men with prostate cancer treated with gonadotropin-releasing hormone (GnRH) agonists had a higher risk of cardiovascular disease (CVD) compared to men who had undergone orchiectomy. However, selection bias may have influenced the difference in risk.To investigate the association of type of androgen deprivation therapy (ADT) with risk of CVD while minimising selection bias.Semi-ecologic study of 6556 men who received GnRH agonists and 3330 men who underwent orchiectomy as primary treatment during 1992-1999 in the Prostate Cancer Database Sweden 3.0.We measured the proportion of men who received GnRH agonists as primary treatment in 580 experimental units defined by healthcare provider, diagnostic time period, and age at diagnosis. Incident or fatal CVD events in units with high and units with low use of GnRH agonists were compared. Net and crude probabilities were also analysed.The risk of CVD was similar between units with the highest and units with the lowest proportion of GnRH agonist use (relative risk 1.01, 95% confidence interval [CI] 0.93-1.11). Accordingly, there was no difference in the net probability of CVD after GnRH agonist compared to orchiectomy (hazard ratio 1.02, 95% CI 0.96-1.09). The 10-yr crude probability of CVD was 0.56 (95% CI 0.55-0.57) for men on GnRH agonists and 0.52 (95% CI 0.50-0.54) for men treated with orchiectomy. The main limitation was the nonrandom allocation to treatment, with younger men with lower comorbidity and less advanced cancer more likely to receive GnRH agonists.Our data do not support previous observations that GnRH agonists increase the risk of CVD in comparison to orchiectomy.We found a similar risk of cardiovascular disease between medical and surgical treatment as androgen deprivation therapy for prostate cancer.
Ibrutinib treatment improves T cell number and function in CLL patients
Authors: Meixiao Long, Kyle Beckwith, Priscilla Do, Bethany L. Mundy, Amber Gordon, Amy M. Lehman, Kami J. Maddocks, Carolyn Cheney, Jeffrey A. Jones, Joseph M. Flynn, Leslie A. Andritsos, Farrukh Awan, Joseph A. Fraietta, Carl H. June, Marcela V. Maus, Jennifer A. Woyach, Michael A. Caligiuri, Amy J. Johnson, Natarajan Muthusamy, John C. Byrd
Journal: Journal of Clinical Investigation (2017)

BACKGROUND. Ibrutinib has been shown to have immunomodulatory effects by inhibiting Bruton's tyrosine kinase (BTK) and IL-2–inducible T cell kinase (ITK). The relative importance of inhibiting these 2 kinases has not been examined despite its relevance to immune-based therapies.
Desialylation of Megakaryocytes Diminishes Platelet Production By Disrupting Megakaryocyte Adhesion, Migration and Proplatelet Formation in Chronic Immune Thrombocytopenia
Authors: Qian-Ming Wang, Jia-Min Zhang, Xiao-Lu Zhu, Hai-Xia Fu, Meng Lv, Yuan Kong, Ying-Jun Chang, Lan-Ping Xu, Kai-Yan Liu, Xiao-Jun Huang, Xiao-Hui Zhang
Journal: Blood (2016)
Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder
Authors: Elaine T Lim, Mohammed Uddin, Silvia De Rubeis, Yingleong Chan, Anne S Kamumbu, Xiaochang Zhang, Alissa M D'Gama, Sonia N Kim, Robert Sean Hill, Arthur P Goldberg, Christopher Poultney, Nancy J Minshew, Itaru Kushima, Branko Aleksic, Norio Ozaki, Mara Parellada, Celso Arango, Maria J Penzol, Angel Carracedo, Alexander Kolevzon, Christina M Hultman, Lauren A Weiss, Menachem Fromer, Andreas G Chiocchetti, Christine M Freitag, George M Church, Stephen W Scherer, Joseph D Buxbaum, Christopher A Walsh
Journal: Nature Neuroscience (2017)
Comparison of combination anti-EGFR and anti-VEGFR2 therapy to MTD standard chemotherapeutic regimens
Authors: Erik Corcoran, Jessica Kearney, Dhanvanthri Deevi, Margarita Camara, David Surguladze, Daniel Hicklin, James Tonra
Journal: Cancer Research (2007)

4097  The initial aim of targeted therapy was to achieve anticancer effects comparable to cytotoxic therapies, with more limited toxicity to normal tissue. Combining targeted therapies currently offers the best chance of achieving this goal. Here we have compared the efficacy of a combination of IgG1 monoclonal antibodies targeting EGFR (cetuximab) and VEGFR2 (DC101) to a maximum tolerated dose (MTD) of standard chemotherapeutic combination used in the clinic. Cetuximab+DC101 was compared to Irinotecan/5-FU/Leucovorin (IFL) and 5-FU/Leucovorin/oxaliplatin (FOLFOX) in 5 subcutaneous xenograft models of colon cancer. The combination targeted therapy approach had greater efficacy than FOLFOX and IFL in the DLD-1 and HCT-8 models, and very similar efficacy in the GEO and HCT-116 model. In the KM-12 model, cetuximab+DC101 matched the efficacy of FOLFOX but was less efficacious than IFL. In an orthotopic model where luciferase expressing HT-29 cells were injected into the rectal lining, cetuximab+DC101 matched the ability of FOLFOX and IFL to inhibit primary tumor growth and lymph node metastasis. Cetuximab+DC101 was also compared to MTD gemcitabine in 3 subcutaneous xenograft models of pancreatic cancer. The combination targeted therapy approach achieved significantly greater efficacy than gemcitabine in the BxPC-3 model, and similar efficacy in the HPAC and Mia Paca-2 models. In an orthotopic model in which luciferase expressing L3.7Pl cells were injected into the tail of the pancreas, cetuximab+DC101 achieved greater inhibition than gemcitabine in terms of primary tumor growth inhibition and a trend for reduction in liver metastasis. Thus combination targeted therapy with VEGFR2 and EGFR monoclonal antibodies has the potential to reduce the use of more toxic cancer treatments while still maintaining maximal therapeutic benefits.
Receptor activity of GPCR mas is suppressed by C-terminal GFP tagging
Authors: Jing Xin Sun, Sau Tuen Lee, Wing Hung Ko, Wing Tai Cheung
Journal: Cancer Research (2008)

3506  Orphan G protein-coupled receptor (GPCR) mas was initially isolated from a human epidermal carcinoma. Previous study from our lab has identified a surrogate ligand MBP7 (mas binding peptide 7) for mas, and indicated GFP tagging may affect the receptor activity of mas [Bikkavilli RK, et al. Biochem Pharmacol. 71(2006) 319-337]. To further functionally characterize receptor activity of mas, we established three stable CHO cell lines expressing native mas, mas-GFP and mas-(Gly10Ser5)-GFP. Phages expressing a surrogate peptide ligand for mas displayed punctate binding and were internalized in all the three cell lines expressing native mas and GFP-tagged variants. However, number of phages being internalized in cells expressing mas-GFP was substantially less than that of cells expressing mas-(Gly10Ser5)-GFP and native mas. In parallel, biotinylation experiment quantitatively showed that the extent of mas-(Gly10Ser5)-GFP internalization was higher than that of mas-GFP. Consistent with internalization assay, calcium mobilization stimulated by MBP7 was also different in cell lines expressing native mas and GFP tagged variants. In cells expressing native mas, MBP7 induced a rapid increase of calcium and then the cellular calcium level returned to a basal level within five minutes. Instead, a sustained high level of intracellular calcium was observed in cells expressing mas-(Gly10Ser5)-GFP. By contrast, only a transient and delayed rising of intracellular calcium level was detected in cells expressing mas-GFP. These results suggested that C-terminal GFP-tagging reduced the receptor activity of mas.
Probing the AML Surfaceome for Chimeric Antigen Receptor (CAR) Targets
Authors: Fabiana Perna, Samuel Berman, Jorge Mansilla-Soto, Mohamad Hamieh, Rupa Juthani, Rajesh Soni, Justin Eyquem, Ronald Hendrickson, Cameron Brennan, Michel Sadelain
Journal: Blood (2016)
Randomized phase II study of PEGPH20 plus nab-paclitaxel/gemcitabine (PAG) vs AG in patients (Pts) with untreated, metastatic pancreatic ductal adenocarcinoma (mPDA).
Authors: Sunil R. Hingorani, Andrea J. Bullock, Tara Elisabeth Seery, Lei Zheng, Darren Sigal, Paul S. Ritch, Fadi S. Braiteh, Mark Zalupski, Nathan Bahary, William Proctor Harris, Jie Pu, Carrie Aldrich, Sihem Khelifa, Xionghua W. Wu, Joaquina Baranda, Ping Jiang, Andrew Eugene Hendifar
Journal: Journal of Clinical Oncology (2017)

4008 Background: Hyaluronan (HA) accumulation in the tumor microenvironment produces elevated tumor pressure, vascular compression, and reduced drug delivery. PEGPH20 degrades HA, increasing the access and therapeutic index of anticancer agents. Methods: In Stage 1 of this phase II study, pts with untreated mPDA were randomized 1:1 to PAG (P; 3 µg/kg IV 2x/wk x 3 wks in C1, then 1x/wk x 3 wks in C2+, plus AG) vs AG every 28 days. An imbalance in thromboembolic (TE) events in the PAG arm led to a clinical hold (~40% of pts discontinued PEGPH20), exclusion of pts at high risk for TE events and enoxaparin prophylaxis in both study arms. In Stage 2, randomization was 2:1 to PAG vs AG. Tumor HA was tested using a novel assay (VENTANA HA RxDx). Primary endpoints were PFS (evaluable pts) and TE event rate (Stage 2). Secondary endpoints were PFS by HA level and ORR. Results: 279 pts were randomized; 231 are evaluable for efficacy. Of 246 pts with HA data, 84 (34%) were HA-High. As of December 16, 2016, the primary PFS endpoint was statistically significant for PAG vs AG (HR 0.73, 95% CI 0.53-1.00; p = 0.048) (Table). PFS in HA-High pts was also statistically significant in the PAG vs AG arm (HR 0.51; 95% CI 0.26-1.00; p = 0.048). ORR in HA-High pts was 46% (PAG) vs 34% (AG). Overall survival in HA-High pts (exploratory) was 11.5 months (mo) (PAG) and 8.5 mo (AG) (HR 0.96, 95% CI 0.57-1.61). TE events were similar (PAG 14% vs AG 10%) following enoxaparin initiation. All grade treatment-related AE included peripheral edema (PAG 63% vs AG 26%), muscle spasms (56% vs 3%), neutropenia (34% vs 19%), and myalgia (26% vs 7%). Conclusions: Randomized Phase II study met both primary endpoints (PFS and TE event rate), with the largest improvement in the secondary endpoint of PFS in HA-High pts. These data support HA as a potential predictive biomarker for patient selection of PEGPH20, currently investigated in the ongoing global Phase III HALO 301 study with PFS and OS as co-primary endpoints. Clinical trial information: NCT01839487. [Table: see text]
Mechanical Thrombectomy After Intravenous Thrombolysis vs Mechanical Thrombectomy Alone in Acute Stroke—Reply
Authors: Jonathan M. Coutinho, Vitor M. Pereira
Journal: JAMA Neurology (2017)

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