tbuckley/cabot-search huggingface dataset:
Cholesterol Accumulation in CD11c+ Immune Cells Is a Causal and Targetable Factor in Autoimmune Disease
Authors: Ayaka Ito, Cynthia Hong, Kazuhiro Oka, Jon V. Salazar, Cody Diehl, Joseph L. Witztum, Mercedes Diaz, Antonio Castrillo, Steven J. Bensinger, Lawrence Chan, Peter Tontonoz
Journal: Immunity (2016)
Risk of Myopathy Associated With DPP-4 Inhibitors in Combination With Statins: A Disproportionality Analysis Using Data From the WHO and French Spontaneous Reporting Databases
Authors: Vanessa Labat, Mickael Arnaud, Ghada Miremont-Salamé, Francesco Salvo, Bernard Bégaud, Antoine Pariente
Journal: Diabetes Care (2016)

Recently, a pharmacovigilance safety warning was released by the European Medicines Agency concerning the risk of myopathy and rhabdomyolysis associated with the use of dipeptidyl peptidase 4 (DPP-4) inhibitors (1,2). The warning was based on several cases in which DPP-4 inhibitors were used in association with statins; a drug-drug interaction was suggested (3). As statin use is likely to be common in patients with diabetes, it is important to investigate this potential serious risk and the underlying drug-drug interaction hypothesis. This need is enforced by the recent marketing in several countries of fixed combinations containing both statins and DPP-4 inhibitors (4). The aim of the study, therefore, was to assess the association between myopathy and the use of DPP-4 inhibitors, alone and in combination with statins, by analyzing data from two pharmacovigilance spontaneous reporting databases.

Data from the French Base Nationale de Pharmacovigilance (BNPV) and the World Health Organization (WHO) global individual case safety reports database, VigiBase, were analyzed for the 2009–2015 time period. Cases consisted of all reported adverse drug reactions (ADRs) of muscular injury, which were identified in both databases by using the dedicated Standardized MedDRA Queries (“myopathy/rhabdomyolysis”). All reports of other ADRs were considered noncases. The exposures of interest were the use of DPP-4 inhibitors along with statins at the time the ADR occurred, as we were investigating a potential drug-drug interaction between DPP-4 inhibitors and statins. We conducted complementary analyses considering exposures to all noninsulin antidiabetes agents other than DPP-4 inhibitors and to fibrates. As other noninsulin antidiabetes agents share indications with DPP-4 inhibitors, the …
Prognostic Role of the CD68+ Cell Count and Early Response Evaluation with Interim-PET and Levels of Plasma Thymus and Activation-Regulated Chemokine (TARC) in ABVD-Treated Classical Hodgkin Lymphoma
Authors: Stefan Hohaus, Annarosa Cuccaro, Elisa Cupelli, Salvatore Annunziata, Manuela Giachelia, Eugenio Galli, Francesca Bartolomei, Marika Picardi, Maurizio Martini, Francesco D'Alo', Maria Teresa Voso, Maria Lucia Calcagni, Vittoria Rufini, Alessandro Giordano, Giuseppe Leone, Luigi M. Maria Larocca
Journal: Blood (2014)
Expression of Master Regulators of Helper T-Cell Differentiation in Peripheral T-Cell Lymphoma, Not Otherwise Specified by Immunohistochemical Analysis.
Authors: Yosuke Matsumoto, Shigeo Horiike, Muneo Ohshiro, Mio Yamamoto, Nana Sasaki, Yasuhiko Tsutsumi, Tsutomu Kobayashi, Daisuke Shimizu, Hitoji Uchiyama, Junya Kuroda, Kenichi Nomura, Chihiro Shimazaki, Masafumi Taniwaki
Journal: Blood (2009)
Abstract 1775: Inhibition of breast cancer cell proliferation by diarylthiourea analog, SL1-18
Authors: Maryam Fallatah, Maggie C. Louie, Shengquan Liu
Journal: Cancer Research (2015)

Abstract Breast cancer is the most common malignancy that occurs in women in the US and has the second highest cancer-associated mortality rate. Depending on the expression of estrogen receptor α (ERα), breast cancer can be classified as ER positive or negative. Current drugs used to treat ER+ cancers include selective estrogen receptor modulators (SERMs) and selective estrogen receptor down-regulators (SERDs). Unfortunately, prolonged exposure to these drugs often leads to the development of acquired resistance. Consequently, there is a great need to develop alternative therapeutic options. Flexible heteroarotinoids (Flex-Hets) are compounds derived from retinoids that have been shown to display anti-cancer activity. These compounds tend to exhibit lower toxicity in comparison to their retinoid precursor. The objective of this study is to investigate the anti-cancer effects of SL1-18 — a novel heteroarotinoid — on ER+ breast cancer. Our data suggest that treatment of MCF-7 with SL1-18 inhibit cell growth with a GI50 of 5μM. In order to understand the mechanism of action, we evaluated the effects of SL1-18 on the expression of cell cycle regulators, and our results suggest that SL1-18 decreases the expression of cyclin A, cyclin B, cyclin D1 and cdk2. Furthermore, cell cycle analysis revealed that SL1-18 reduces the number of cells going through the S phase when compared to mock-treated controls. Taken together, these preliminary results suggest that the SL1-18 may be a potent inhibitor of breast cancer cell growth, but further research is necessary to determine its mechanism of action. Citation Format: Maryam Fallatah, Maggie C. Louie, Shengquan Liu. Inhibition of breast cancer cell proliferation by diarylthiourea analog, SL1-18. [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 1775. doi:10.1158/1538-7445.AM2015-1775
42. Differential Transduction Profiles of AAV Vectors in a Mouse Model of Human Glycosylation
Authors: Lavanya Rao, Blake H. Albright, Travis Corriher, Giridhar Murlidharan, Aravind Asokan
Journal: Molecular Therapy (2015)

Recent studies have demonstrated that AAV gene transfer efficiency and tropism, particularly with regard to the liver, can vary markedly across animal species. A mechanistic understanding of such host-specific AAV transduction profiles is essential for translating preclinical studies to the clinic. In this regard, virus-glycan interactions are key determinants of tissue tropism displayed by various AAV vectors. It is now known that AAV serotypes 1, 4, 5 and 6 utilize glycans terminating in sialic acid (Sia) as a primary receptor. Amongst various forms of Sia, N-glycolylneuraminic acid (Neu5Gc) is the most prevalent in most mammals; however humans are unable to synthesize Neu5GC from its precursor, N-acetylneuraminic acid (Neu5AC), due to a loss-of-function mutation. Consequently, Neu5AC is the predominant Sia in humans. In the current study, we first observed that metabolic incorporation of the nonhuman Sia, Neu5GC selectively reduces transduction efficiency of AAV1 and 6 in vitro. Utilizing a mouse model genetically engineered to express only the human-specific Sia, Neu5AC, we assessed the effects of sialic acid composition on the tropism and biodistribution of various AAV serotypes. Post systemic administration in humanized mice, modest differences in transduction were noted in case of serotypes 4 and 6, without changes to endogenous tissue tropism. Interestingly, AAV9, which utilizes galactose (Gal) showed an increase in transduction across multiple organs. Further, AAV9, which tends to transduce both neuronal and glial cell populations upon intracranial injection in normal mice, showed a transduction pattern restricted to neurons in humanized mice. These results suggest AAV vector biology may differ across species at both the cellular and tissue levels. These findings could have important implications towards the design and interpretation of pre-clinical studies/data leading to clinical translation.
SURG-38. DIRECT EVIDENCE OF PLASTICITY WITHIN PRIMARY MOTOR AND SENSORY CORTICES VIA DIRECT ELECTRICAL STIMULATION IN GLIOBLASTOMA PATIENTS UNDERGOING REPEAT AWAKE CRANIOTOMY
Authors: William Gibb, Nathan Kong
Journal: Neuro-Oncology (2016)

Management of gliomas includes aggressive surgical resection while minimizing morbidity; brain plasticity can aid in achieving both goals. Recent evidence in low-grade gliomas suggests that significant plasticity can occur, allowing for preservation of neurologic function despite tumors in/near regions classically considered eloquent. However, data in tumor and stroke cohorts argue that plasticity may be less robust within primary cortices (e.g. M1/S1/V1) and in more rapidly-acquired insults (e.g. glioblastoma, stroke). In this study, we examine plasticity within primary sensory (S1) and motor (M1) cortices in glioblastoma patients undergoing repeat intra-operative direct electrical stimulation (DES) under awake conditions. This retrospective analysis included five patients with glioblastoma in/near M1/S1 that underwent two awake surgeries, each with DES-based sensory and motor mapping. Inter-surgery interval was 216 ± 41 days. Plasticity was defined as a change in mapping result (gain, loss, or change of function) within M1/S1 at second operation or absence of typical mapping result without a change in the patient’s sensory/motor exam. Four of five patients (80%) exhibited at least one site of plasticity within M1 or S1. Out of 41 total sites stimulated in both surgeries, 9 S1 (22%) and 11 M1 (27%) sites demonstrated plasticity, with gain of function (negative→positive) and loss of function (positive→negative) equally distributed. Change of function (e.g. hand motor to forearm motor) and cross-modal (e.g. motor→sensory) plasticity sites were also observed (10% of total sites). The current study provides direct evidence of multiple patterns of plasticity within the primary sensorimotor cortices of the adult brain over a relatively short time scale (months). Further, these data suggest that even in patients with high-grade gliomas near primary brain regions, significant functional reorganization is possible. A better fundamental understanding of the factors promoting/inhibiting plasticity may aid in treatment of patients with brain tumors and other neurologic disorders.
Abstract 4177: Simultaneous activation of C-X-C chemokine receptor 4 and cannabinoid receptor 2 results in decreased angiogenesis
Authors: Kisha A. Scarlett, Brittney Sandifer, Christopher J. Coke, Cimona V. Hinton
Journal: Cancer Research (2015)

Abstract Tumor angiogenesis is a complex process modulated by numerous signaling molecules and pathways that influence cell migration, invasion, survival and tube formation. The expression of the G-protein-coupled receptor (GPCR) C-X-C Chemokine Receptor 4 (CXCR4) has been correlated with the increased angiogenic potential of cancer cells. The ligand-specific binding of CXCL12 to CXCR4 increases tumor angiogenesis by upregulating the expression of vascular endothelial growth factor (VEGF) at both mRNA and protein levels. Thus, modulating the CXCR4/CXCL12 signaling axis provides an attractive target for the inhibition of tumor angiogenesis and cancer progression. Recent studies have suggested that in addition to its palliative properties, cannabis may have anti-proliferative and anti-metastatic effects by acting through the GPCR, cannabinoid receptor 2 (CB2R). GPCR heterodimerization has emerged as a means by which new signaling entities can be created with respect to agonist binding. Preliminary co-immunoprecipitation data from our lab indicates that agonist-bound CXCR4 and agonist-bound CB2R interact at the cell membrane and that receptor interaction mitigates the effects of CXCL12-mediated CXCR4 signaling. Here we show that co-stimulation of prostate cancer cells with CXCR4 and CB2R-specific agonists results in decreased VEGF expression in vitro. Furthermore, treatment of human endothelial cells with conditioned medium collected from co-stimulated prostate cancer cells decreased endothelial cell migration in wound healing and invasion assays, and decreased endothelial cell tubulogenesis. Taken together, these results demonstrate that desensitization of CXCR4 signaling through association with CB2R is a novel anti-angiogenic strategy and reinforces the clinical relevance of cannabinoids in cancer treatment. Note: This abstract was not presented at the meeting. Citation Format: Kisha A. Scarlett, Brittney Sandifer, Christopher J. Coke, Cimona V. Hinton. Simultaneous activation of C-X-C chemokine receptor 4 and cannabinoid receptor 2 results in decreased angiogenesis. [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 4177. doi:10.1158/1538-7445.AM2015-4177
Unmet need in rheumatology: reports from the Targeted Therapies meeting 2019
Authors: Kevin L Winthrop, Michael E Weinblatt, Joan Bathon, Gerd R Burmester, Philip J Mease, Leslie Crofford, Vivian Bykerk, Maxime Dougados, James Todd Rosenbaum, Xavier Mariette, Joachim Sieper, Fritz Melchers, Bruce N Cronstein, Ferry C Breedveld, Joachim Kalden, Josef S Smolen, Daniel Furst
Journal: Annals of the Rheumatic Diseases (2019)

Objectives To detail the greatest areas of unmet scientific and clinical needs in rheumatology. Methods The 21st annual international Advances in Targeted Therapies meeting brought together more than 100 leading basic scientists and clinical researchers in rheumatology, immunology, epidemiology, molecular biology and other specialties. During the meeting, breakout sessions were convened, consisting of 5 disease-specific groups with 20–30 experts assigned to each group based on expertise. Specific groups included: rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, systemic lupus erythematosus and other systemic autoimmune rheumatic diseases. In each group, experts were asked to identify unmet clinical and translational research needs in general and then to prioritise and detail the most important specific needs within each disease area. Results Overarching themes across all disease states included the need to innovate clinical trial design with emphasis on studying patients with refractory disease, the development of trials that take into account disease endotypes and patients with overlapping inflammatory diseases, the need to better understand the prevalence and incidence of inflammatory diseases in developing regions of the world and ultimately to develop therapies that can cure inflammatory autoimmune diseases. Conclusions Unmet needs for new therapies and trial designs, particularly for those with treatment refractory disease, remain a top priority in rheumatology.
451. Robust Manufacture of CAR-T Cells
Authors: Pradip Bajgain, John Wilson, Dan Welch, Helen E. Heslop, Cliona M. Rooney, Malcolm K. Brenner, Ann M. Leen, Juan F. Vera
Journal: Molecular Therapy (2016)

Although adoptive transfer of chimeric antigen receptor (CAR)-modified T cells has produced promising clinical responses, the broader application of this therapy has been hindered by prolonged and complicated cell production methods. In the current work, we have overcome this limitation through the incorporation of a gas permeable culture device (G-Rex) to support T cell expansion. This culture system consists of a suite of devices, all of which contain a gas permeable silicone membrane, which allows gas exchange to occur at the base. This configuration allows for the culture of T cells with an unconventionally large volume of media per unit of surface area (10ml of media/cm2), thereby supporting uninterrupted cell growth without media exchange. Importantly, this system is simple to use and can be placed in a regular incubator as the G-Rex does not require active agitation or perfusion. To evaluate the utility of this system for the expansion of CAR T cells, we transduced healthy donor-derived primary T cells with a CAR targeting the prostate cancer antigen - PSCA (previously generated and characterized by our group). Three days after retroviral transduction, transgenic CAR T cells (transduction efficiency of 83.6±6%) from 3 donors were transferred to G-Rex100M devices (surface area of 100cm2) in 1000ml of complete T cell media (10ml/cm2) at low (total of 25E+06 CAR T cells), intermediate (50E+06 CAR T cells) and high (100E+06 CAR T cells) cell densities (250E+03 cells/cm2, 500E+03 cells/cm2 and 1000E+03 cells/cm2, respectively). Subsequently, the cell cultures were monitored by glucose and lactic acid assessment. After 10 days of culture, the average fold-expansion was similar for all conditions (24.3±10.4, 35.5±7.8, 29.8±2.1 for low, intermediate, and high cell densities, respectively). Interestingly though, the donor-to-donor variability was decreased significantly at the higher cell density (SD of 10.4, 7.8, and 2.1 for cell densities of 250E+03 cells/cm2, 500E+03 cells/cm2 and 1000E+03 cells/cm2, respectively), highlighting the importance of identifying the optimal seeding density to support robust manufacture. Notably, no media replenishment was required and the only culture manipulation performed was the addition of IL2 (50U/ml) 3 times/week. Importantly, T cells manufactured using this optimized method expressed higher levels of central memory and activation markers (CD62L and CD25) and demonstrated superior anti-tumor activity when compared to cells maintained in conventional tissue-culture plates. To further simplify the manufacturing process, we have now developed a semi-automated, closed system (GatheRex) for cell collection, which can be paired with G-Rex and allows collection of cells in a small volume (100ml) in under five minutes.
Abstract 654: PG-101 in combination with docetaxel or Herceptin improves breast cancer survival
Authors: Madhuri Wadehra, Meagan Kiyohara, Christen Dillard, Negin Ashki, Christie Qin
Journal: Cancer Research (2015)

Abstract Background: Breast cancer is a heterogeneous disease with several subtypes which dictate which course of treatment each patient will receive. However, resistance remains a significant challenge. In triple negative breast cancer (TNBC), an aggressive histological subtype with limited treatment options and very poor prognosis, resistance to current standard therapies such as taxanes severely limits the available options for previously treated patients. This problem also occurs with targeted therapies. Trastuzumab is the standard of care for HER2+ tumors. However, de novo or acquired Trastuzumab resistance is a major limitation for its clinical efficacy. Thus, there remains an urgent unmet need for improved targeted agents for this patient population. Methods: To this end, we define another marker epithelial membrane protein-2 (EMP2) as a novel target for Trastuzumab and taxane resistant tumors. EMP2 expression was determined using standard immunohistochemistry. We have recently developed a novel IgG1 monoclonal antibody to EMP2 termed PG-101. Acquired Trastuzumab and docetaxel resistant tumors were treated with PG-101 using human xenograft models. Results: EMP2 is an oncogenic protein whose expression has been shown to correlate with tumor progression as well as the formation of breast cancer stem cells. In this study, we present evidence that EMP2 is highly expressed in acquired resistant tumor cells both in culture as well as in patient samples. We also tested the efficacy of PG-101 in combination with docetaxel, and we have evidence that the combination significantly improves tumor-free survival. Moreover, preliminary data also strongly suggests that PG-101 can be used as an adjuvant therapy for docetaxel and Trastuzumab resistant tumors whereby PG-101 reduced both tumor load in both models in vivo. Conclusions: Given that EMP2 is also overexpressed in endometrial and ovarian cancers, our data collectively suggest that PG-101 therapy has the potential to revolutionize the outcomes for women with cancer. Citation Format: Madhuri Wadehra, Meagan Kiyohara, Christen Dillard, Negin Ashki, Christie Qin. PG-101 in combination with docetaxel or Herceptin improves breast cancer survival. [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 654. doi:10.1158/1538-7445.AM2015-654
Race-Related Differences in Left Ventricular Structural and Functional Remodeling in Response to Increased Afterload
Authors: Miguel M. Fernandes-Silva, Amil M. Shah, Sheila Hegde, Alexandra Goncalves, Brian Claggett, Susan Cheng, Wilson Nadruz, Dalane W. Kitzman, Suma H. Konety, Kunihiro Matsushita, Thomas Mosley, Carolyn S.P. Lam, Barry A. Borlaug, Scott D. Solomon
Journal: JACC Heart Failure (2016)
Abstract 1592: CXCR4 pathways in CTCs: from bioinformatics to immunophenotype
Authors: G. Kallergi, V. Tsintari, S. Sfakianakis, M. Zervakis, D. Mavroudis, V. Georgoulias
Journal: Cancer Research (2015)

Abstract Introduction: Bioinformatics’ analysis regarding gene expression in Normal tissue vs cancer tissue, Normal blood vs cancer patients’ blood and Normal blood vs cancer tissue revealed a subgroup of 24 genes which potentially could be overexpressed in CTCs. Among these genes are: CXCR4, a chemokine receptor which is involved in tumor metastasis and, JUNB a transcription factor participating in CXCR4 pathway. The objective of this study was to confirm the results of bioinformatics’ analysis in samples from breast cancer patients and therefore to evaluate the expression of CXCR4 and JUNB in CTCs. Methods: Triple staining immunofluoresence with panytokeratin/CXCR4/JUNB antibodies were performed in SKBR3, MDA-MB231, MCF7 and Hela cell lines. The same experiments were performed in PBMCs from normal (n = 10.) subjects and in PBMCs (n = 55) from untreated metastatic breast cancer patients. Results: Since CXCR4, as a chemokine receptor is also expressed on hematopoietic cells, its expression on CTCs was quantified using the ARIOL system. We used cell lines and both normal vs patients’ PBMCs in order to establish an expression pattern of both molecules. Quantification experiments among cell lines revealed that CXCR4 was overexpressed in SKBR3 following the subsequent hierarchy SKBR3&amp;gt;MCF7&amp;gt;MDA-MB231&amp;gt;Hela. Accordingly, the expression pattern of JUNB in cell lines was SKBR3&amp;gt;Hela&amp;gt;MCF7&amp;gt;MDA-MB231 with higher expression in SKBR3 and lower in MDA-MB 231. Statistical analysis revealed significant differences in the expression of both molecules between healthy donors’ PBMCs and patient's PBMCs. Subsequently, CTCs were detected in 17 out of 55 screened patients (31%). Mean intensity of CTCs for CXCR4 was 34.38 and it was higher than Hela and lower than SKBR3. Patients with CXCR4-positive CTCs (with mean expression higher than 95% of normal PBMCs) were 53%. In addition 84% of the examined CTCs had expression profile higher than normal PBMCs. JUNB expression in CTCs (above 95% of normal PBMCs) was identified in 76.92% of patients. JUNB mean expression in CTCs was 26.1 and it was lower than SKBR3 and higher than MCF7. Furthermore 64.3% of the total CTCs have expression higher than Normal PBMCs. Conclusion: CXCR4 and JUNB are highly expressed in CTCs derived from breast cancer patients, in agreement to bioinformatics’ analysis. Quantification of immunofluoresence potentially delineates a subgroup of patients with high expression of CXCR4 and JUNB that could benefit from target therapies. Citation Format: G. Kallergi, V. Tsintari, S. Sfakianakis, M. Zervakis, D. Mavroudis, V. Georgoulias. CXCR4 pathways in CTCs: from bioinformatics to immunophenotype. [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 1592. doi:10.1158/1538-7445.AM2015-1592