tbuckley/cabot-search huggingface dataset:
Abstract P283: Parkin Mediates Mitophagy in Cardioprotection
Authors: Allen M Andres, Chengqun Huang, Eric P Ratliff, Genaro Hernandez, Pamela Lee, Roberta A Gottlieb
Journal: Circulation Research (2011)

Autophagy-dependent mitochondrial turnover in response to cellular stress is necessary for maintaining cellular homeostasis. However, the mechanisms that govern the selective targeting of damaged mitochondria are poorly understood. Parkin, an E3 ubiquitin ligase, has been shown to be essential for the selective clearance of damaged mitochondria. Parkin is expressed in the heart, yet its function has not been investigated in the context of cardioprotection. We previously reported that autophagy is required for cardioprotection by ischemic preconditioning (IPC). In the present study, we used simulated ischemia in vitro and IPC in hearts (in vivo and ex vivo) to investigate the role of Parkin in mediating cardioprotection. In HL-1 cells, simulated ischemia induced Parkin translocation to mitochondria and mitochondrial elimination. Mitochondrial loss was blunted in Atg5-deficient cells, revealing the requirement for autophagy in mitochondrial elimination. Consistent with previous reports implicating p62/SQSTM1 in mitophagy, we found that downregulation of p62 attenuated mitophagy and exacerbated cell death in HL-1 cardiomyocytes subjected to simulated ischemia. While wild type mice showed p62 translocation to mitochondria after IPC, Parkin knockout mice exhibited attenuated translocation of p62 to mitochondria. Importantly, ablation of Parkin in mice abolished the cardioprotective effects of IPC. These results reveal for the first time the crucial role of Parkin and mitophagy in cardioprotection.
SETD2 and histone H3 lysine 36 methylation deficiency in advanced systemic mastocytosis
Authors: G Martinelli, M Mancini, C De Benedittis, M Rondoni, C Papayannidis, M Manfrini, M Meggendorfer, R Calogero, V Guadagnuolo, M C Fontana, L Bavaro, A Padella, E Zago, L Pagano, R Zanotti, L Scaffidi, G Specchia, F Albano, S Merante, C Elena, P Savini, D Gangemi, P Tosi, F Ciceri, G Poletti, L Riccioni, F Morigi, M Delledonne, T Haferlach, M Cavo, P Valent, S Soverini
Journal: Leukemia (2017)

The molecular basis of advanced systemic mastocytosis (SM) is not fully understood and despite novel therapies the prognosis remains dismal. Exome sequencing of an index-patient with mast cell leukemia (MCL) uncovered biallelic loss-of-function mutations in the SETD2 histone methyltransferase gene. Copy-neutral loss-of-heterozygosity at 3p21.3 (where SETD2 maps) was subsequently found in SM patients and prompted us to undertake an in-depth analysis of SETD2 copy number, mutation status, transcript expression and methylation levels, as well as functional studies in the HMC-1 cell line and in a validation cohort of 57 additional cases with SM, including MCL, aggressive SM and indolent SM. Reduced or no SETD2 protein expression—and consequently, H3K36 trimethylation—was found in all cases and inversely correlated with disease aggressiveness. Proteasome inhibition rescued SETD2 expression and H3K36 trimethylation and resulted in marked accumulation of ubiquitinated SETD2 in SETD2-deficient patients but not in patients with near-normal SETD2 expression. Bortezomib and, to a lesser extent, AZD1775 alone or in combination with midostaurin induced apoptosis and reduced clonogenic growth of HMC-1 cells and of neoplastic mast cells from advanced SM patients. Our findings may have implications for prognostication of SM patients and for the development of improved treatment approaches in advanced SM.
Antipsychotic-Induced Dopamine Supersensitivity Psychosis: Pharmacology, Criteria, and Therapy
Authors: Guy Chouinard, Anne-Noël Samaha, Virginie-Anne Chouinard, Charles-Siegfried Peretti, Nobuhisa Kanahara, Masayuki Takase, Masaomi Iyo
Journal: Psychotherapy and Psychosomatics (2017)

The first-line treatment for psychotic disorders remains antipsychotic drugs with receptor antagonist properties at D2-like dopamine receptors. However, long-term administration of antipsychotics can upregulate D2 receptors and produce receptor supersensitivity manifested by behavioral supersensitivity to dopamine stimulation in animals, and movement disorders and supersensitivity psychosis (SP) in patients. Antipsychotic-induced SP was first described as the emergence of psychotic symptoms with tardive dyskinesia (TD) and a fall in prolactin levels following drug discontinuation. In the era of first-generation antipsychotics, 4 clinical features characterized drug-induced SP: rapid relapse after drug discontinuation/dose reduction/switch of antipsychotics, tolerance to previously observed therapeutic effects, co-occurring TD, and psychotic exacerbation by life stressors. We review 3 recent studies on the prevalence rates of SP, and the link to treatment resistance and psychotic relapse in the era of second-generation antipsychotics (risperidone, paliperidone, perospirone, and long-acting injectable risperidone, olanzapine, quetiapine, and aripiprazole). These studies show that the prevalence rates of SP remain high in schizophrenia (30%) and higher (70%) in treatment-resistant schizophrenia. We then present neurobehavioral findings on antipsychotic-induced supersensitivity to dopamine from animal studies. Next, we propose criteria for SP, which describe psychotic symptoms and co-occurring movement disorders more precisely. Detection of mild/borderline drug-induced movement disorders permits early recognition of overblockade of D2 receptors, responsible for SP and TD. Finally, we describe 3 antipsychotic withdrawal syndromes, similar to those seen with other CNS drugs, and we propose approaches to treat, potentially prevent, or temporarily manage SP.
Clinical outcomes of patients with solid tumor enrolled in phase 1 clinical trials.
Authors: Aaron Cleveland Denson, TzuHua Juan, Jae K Lee, Richard D. Kim, Daniel Sullivan, Georgine Wapinsly, Barbara Bertles, Amit Mahipal
Journal: Journal of Clinical Oncology (2016)

2541 Background: Insufficient prognostic data can hamper patient enrollment into phase one clinical trials. Prior studies were limited by small numbers, selective patient population by tumor or therapy type. This study evaluated survival and prognostic factors in phase one clinical trial patients within all solid tumor types. Methods: All patients with solid tumors who participated in phase 1 therapeutic clinical trials from 1/2007 to 12/2013 at MCC were included. Data was extracted from the Oncore database and clinical charts. The primary endpoint was overall survival (OS) estimated using the Kaplan-Meir method. Results: We included 1408 patients enrolled in phase I clinical trials from 1/2007 to 12/2013 at Moffitt Cancer Center. The median age was 61 years (range 19-88) and 52% were male. Primary site of disease included Skin (26.6%), thoracic (23.5%), GI (17.5%), breast (8.7%), GU (7.2%), and others (16.3 %). Treatment types include targeted therapy (36.2%), immunotherapy (30.4%), a combination of chemo and targeted therapy (24.4%), or chemotherapy only (9%). Partial responses (PR) were seen in 6.5% of the patients, 37% had stable disease (SD) and 3.9% had a complete response (CR). Progressive disease (PD) was seen in 39% of patients. The median OS was 8.7 months (range: 0-85 months). Factors significantly associated with worse survival on multivariate analysis were history of DVT/PE , ECOG performance status ≥ 1, Liver metastasis, > 2 metastatic sites, > 2 prior systemic therapy, LDH > 618, wbc > 11. We validated the RMH prognostic score with a 95% CI of 0.361 (0.342, 0.381) as well as the MDACC prognostic score with 95% CI of 0.331 (0.313, 0.349). Serious AE (SAE) occurred in 56.6% of the patients with investigational drug related SAEs in 12% of the patients. The most common SAE included GI disorders, Surgical/Skin disorders, respiratory/thoracic/mediastinal disorders, and investigations/blood disorders. Conclusions: This is one of the largest studies to assess clinical outcomes in a phase one clinical trial population which can help improve patient selection in order to design efficient and applicable Phase 1 clinical trials.
Co-administration of RANKL and CTLA4 Antibodies Enhances Lymphocyte-Mediated Antitumor Immunity in Mice
Authors: Elizabeth Ahern, Heidi Harjunpää, Deborah Barkauskas, Stacey Allen, Kazuyoshi Takeda, Hideo Yagita, David Wyld, William C. Dougall, Michele W.L. Teng, Mark J. Smyth
Journal: Clinical Cancer Research (2017)

Purpose: Novel partners for established immune checkpoint inhibitors in the treatment of cancer are needed to address the problems of primary and acquired resistance. The efficacy of combination RANKL and CTLA4 blockade in antitumor immunity has been suggested by recent case reports in melanoma. Here, we provide a rationale for this combination in mouse models of cancer.Experimental Design: The efficacy and mechanism of a combination of RANKL and CTLA4 blockade was examined by tumor-infiltrating lymphocyte analysis, tumor growth, and metastasis using a variety of neutralizing antibodies and gene-targeted mice.Results: RANKL blockade improved the efficacy of anti-CTLA4 mAbs against solid tumors and experimental metastases, with regulatory T-cell (Treg)-depleting anti-CTLA4 mAbs of the mouse IgG2a isotype showing greatest combinatorial activity. The optimal combination depended on the presence of activating Fc receptors and lymphocytes (NK cells for metastatic disease and predominantly CD8+ T cells for subcutaneous tumor control), whereas anti-RANKL alone did not require FcR. The significantly higher T-cell infiltration into solid tumors post anti-RANKL and anti-CTLA4 was accompanied by increased T-cell effector function (cytokine polyfunctionality), and anti-RANKL activity occurred independently of Treg depletion. The majority of RANKL expression in tumors was on T cells whereas RANK-expressing cells were mostly tumor-associated macrophages (TAM), with some expression also observed on dendritic cells (DC) and myeloid-derived suppressor cells (MDSC).Conclusions: These results provide a rationale for the further investigation of RANKL-RANK interactions in tumor immunity and a basis for development of translational markers of interest in human clinical trials. Clin Cancer Res; 23(19); 5789-801. ©2017 AACR.
RNA-Seq analysis of glioma tumors to reveal targetable gene fusions.
Authors: Deepa Suresh Subramaniam, Joanne Xiu, Shwetal Mehta, Zoran Gatalica, Jeffrey Swensen, Nader Sanai, Amy B. Heimberger
Journal: Journal of Clinical Oncology (2017)

2019 Background: Fusions involving oncogenes have been reported in gliomas and may serve as novel therapeutic targets. We aim to use RNA-sequencing to interrogate a large cohort of gliomas for targetable genetic fusions. Methods: Gliomas were profiled using the ArcherDx FusionPlex Assay at a CLIA-certified lab (Caris Life Sciences) and 52 gene targets were analyzed. Fusions with preserved kinase domains were investigated. Results: Among 404 gliomas tested, 39 (9.7%) presented potentially targetable fusions, of which 24/226 (11%) of glioblastoma (GBM), 5/42 (12%) of anaplastic astrocytoma (AA), 2/25 (8%) of grade II astrocytoma and 3 of 7 (43%) of pilocytic astrocytoma (PA) harbored targetable fusions. In GBMs, 1 of 15 (6.7%) IDH-mutated tumors had a fusion while 22 of 175 (12.6%) IDH-wild type tumors had fusions. 46 oligodendroglial tumors were profiled and no fusions were seen, which was lower than frequency of fusions in astrocytic tumors (34/300, p = 0.0236). The most frequent fusions seen involved FGFR3 (N = 12), including 10 FGFR3-TACC3 (1 AA, 6 GBM and 3 glioma NOS); 1 FGFR3-NBR1 (AA) and 1 FGFR3-BRAP (GBM). 11 fusions involving MET were seen, 10 in GBM and 1 in AA. The most common MET fusion was PTPRZ1-MET (1 in AA and 4 in GBM), followed by ST7-MET (N = 3, GBM), CAPZA2-Met (N = 2, GBM) and TPR-MET (N = 1, GBM). 8 NTRK fusions were seen; 1 involving NTRK1 (BCAN-NTRK1, PA), 6 NTRK2 (1 NOS1AP-NTRK2 in AA; GKAP1-NTRK2, KCTD8-NTRK2, TBC1D2-NTRK2 and SOSTM1-NTRK2, 1 each in GBM and 1 VCAN-NTRK2 in grade II astrocytoma) and 1 NTRK3 (EML4-NTRK3 in GBM). EGFR fusions (2 EGFR-SEPT14 and 1 EGFR-VWC2) were seen in 3 GBMs, BRAF in 3 (1 KIAA1549-BRAF, 1 LOC100093631-BRAF in PA and 1 ZSCAN23-BRAF in glioma NOS) and PDGFRA (RAB3IP-PDGFRA, in GBM) in 1. C11orf95-RELA fusions were seen in 2 of 3 grade III ependymomas but not in the 2 grade II ependymomas. Conclusions: We report targetable fusion genes involving NTRK, MET, EGFR, FGFR3, BRAF and PDGFRA including novel fusions that haven’t been previously described in gliomas (e.g., EGFR-VWC2; FGFR3-NBR1). Fusions were seen in over 10% of astrocytic tumors, while none was seen oligodendrogliomas. Identification of such kinase-associated fusion transcripts may allow us to exploit therapeutic opportunities with targeted therapies in gliomas.
Post Transplant Cyclophosphamide (PTCy) with Anti-Thymocyte Globulin (ATG) Effectively Reduces the Severe (Grade III-IV) Acute Graft-Versus-Host Disease (GVHD) When Compared to ATG Alone in Matched Unrelated Donor (MUD) Allogeneic Hematopoietic Cell Transplants
Authors: Uday Deotare, David Loach, Fotios V. Michelis, Dennis D. Kim, Santhosh Thyagu, Jeffrey H. Lipton, Hans A. Messner, Auro Viswabandya
Journal: Blood (2016)
Abstract 273: P2Y2 Receptor-Mediated Lymphotoxin-α Secretion Regulates ICAM-1 Expression in Smooth Muscle Cells
Authors: Cheikh Seye, Wilbert Derbigny, Shaomin Qian
Journal: Circulation Research (2012)

Rationale: Single nucleotide polymorphism (SNP) in the LGASL2 galectin-2 (Gal-2) gene leads to altered secretion of lymphotoxin-α (LT-α) and is associated with coronary artery disease. Objective:Our aim was to determine whether factors other than genetic variations in LGASL2 regulate LT-α release and to define the role of this pro-inflammatory in vascular smooth muscle cells (SMC). Methods and results: The proinflammatory cytokine lymphotoxin-alpha (LTA) is thought to contribute to the pathogenesis of atherosclerosis. However, the mechanisms that regulate its expression in VSMC are poorly understood. The ability of exogenous nucleotides to stimulate LTA production was evaluated in VSMC by ELISA. The P2Y 2 nucleotide receptor (P2Y 2 R) agonist UTP stimulates a strong and sustained release of LTA from wild-type but not P2Y 2 R -/- SMC. Assessment of LTA gene transcription by LTA promoter-luciferase construct indicated that LTA levels are controlled at the level of transcription. We show using RNAi techniques that knockdown of the actin-binding protein filamin-A (FLNa) severely impaired nucleotide-induced Rho activation and consequent Rho-mediated LTA secretion. Re-introduction of FLNa in FLNa RNAi SMC rescued UTP-induced LTA expression. In addition, we found UTP-stimulated LTA secretion is not sensitive to brefeldin A (BFA), which blocks the formation of vesicles involved in protein transport from the ER to the Golgi apparatus, suggesting that P2Y 2 R/filamin-mediated secretion of LTA is independent of the ER/Golgi secretory vesicle route. Furthermore, UTP selectively induces ICAM-1 expression in WT but not SMC expressing a truncated P2Y 2 R deficient in LTA secretion. Conclusion: These data suggest that P2Y 2 R recruits FLNa to provide a cytoskeletal scaffold necessary for Rho signaling pathway upstream of LTA release and subsequent stimulation of ICAM-1 expression on VSMC.
Multiplatform profiling of rare pancreatic carcinoma subtypes to identify potential actionable targets.
Authors: Erkut Borazanci, Sherri Z. Millis, Josiah Winkler, Ramesh K. Ramanathan, Daniel D. Von Hoff
Journal: Journal of Clinical Oncology (2014)

e15229 Background: Adenosquamous (AS), mucinous adenocarcinoma (MA), anaplastic (AP), acinar cell (Ac), and squamous (Sq) are rare exocrine pancreas cancer subtypes. Very little molecular analysis has been done in these tumor subtypes. No standard therapy exists for patients with these malignancies. Methods: Of 2400 pancreatic cancers referred to Caris Life Sciences globally, 116 cases were found to be rare subtypes (shown below) based on pathology and clinical history. Specific testing was performed per physician request, including sequencing (Sanger or NGS), protein expression (immunohistochemistry), and gene amplification (CISH or FISH). Results: IHC, Sequencing, and ISH analysis are shown in the accompanying table. Conclusions: Thisanalysisshows heretofore unsuspected leads to be considered for treatments of these rare variants of exocrine pancreas cancer. It is surprising to see the spectrum of different profiles among these tumor subtypes, including amplification of EGFR in of four of the subtypes. Profiling also shows possible roles of more traditional chemotherapies such as temozolomide (due to low MGMT), doxorubicin and etoposide (TOP2A inhibitors), nab-paclitaxel (SPARC inhibition), and platinum therapies (agents that target ERCC1). While the sample size is small, the heterogeneity in profiling results within each exocrine pancreas cancer subtype indicates that molecular profiling may be appropriate to provide maximum information regarding patient’s tumor. IHC percent positive N AR ERCC1 MGMT PDGFR PGP PR RRM1 SPARC TOP2A TOPO1 TS AS 19 0 31 82 20 14 6 41 42 79 35 35 MA 53 0 44 73 18 60 2 14 35 31 48 1 AP 12 0 57 29 50 20 0 11 36 43 25 11 Ac 22 5 32 67 33 32 43 19 24 50 32 24 Sq 10 0 40 86 0 43 0 17 67 33 43 33 N cMET Sequencing percent mutated ISH +/N EGFR KRAS PIK3CA SMAD4 TP53 EGFR Med Age M:F AS 4 0 0 100 0 0 75 0/6 60 14:5 MA 6 0 0 79 8 33 33 2/19 63 24:29 AP 2 0 0 100 0 0 3/4 58 9:3 Ac 3 33 0 0 0 33 33 2/13 58 15:7 Sq 3 0 0 100 0 0 100 2/3 68 7:3
Is in patient ulrsound (US) scan always necessary in patients with alcohlolic liver disease (ALD)) or can we be more selective?
Authors: J Gasem, P Kelly, R Walker
Journal: Endoscopy (2005)

Aim: 1- To look at patients with ALD and to identify in what proportion in- patient US scan affected the management of the patient. 2- To compare the clinical presentation of patients in whom it did not, to attempt to determine patients who are likely to benefit from in-patient US scan.
An update on imaging the biliary tract: comparable roles of ultrasonography and magnetic resonance
Authors: HJ Khan, M Tower, FO Cunningham, JP McGrath
Journal: Endoscopy (2006)

Aims: Ultrasonography (US) provides cost effective tool as compared to MRI in diagnosis of hepatobiliary biliary pathology. The aim of this study was to provide an update on the comparable roles of US and MRI in a group of patients with suspected biliary tract disease over a 4-year period.
Stearoyl-CoA desaturase regulates sorafenib resistance via modulation of ER stress-induced differentiation
Authors: Mark Kin Fai Ma, Eunice Yuen Ting Lau, Doris Hoi Wing Leung, Jessica Lo, Nicole Pui Yu Ho, Lily Kwan Wai Cheng, Stephanie Ma, Chi Ho Lin, John A. Copland, Jin Ding, Regina Cheuk Lam Lo, Irene Oi Lin Ng, Terence Kin Wah Lee
Journal: Journal of Hepatology (2017)
Human Immunodeficiency Virus-1 (HIV-1)-Tat Protein Promotes Migration of Acquired Immunodeficiency Syndrome–Related Lymphoma Cells and Enhances Their Adhesion to Endothelial Cells
Authors: Renato G.S. Chirivi, Giulia Taraboletti, Maria Rosa Bani, Luca Barra, Giampiero Piccinini, Mauro Giacca, Federico Bussolino, Raffaella Giavazzi
Journal: Blood (1999)
The relationship between cytokine profile and gender, age, and subtype, in patients with irritable bowel syndrome (IBS)
Authors: P Scully, S O'Brien, EM Quigley, PWN Keeling, TG Dinan
Journal: Endoscopy (2006)

Aims: IBS is considered to be a multi-factorial disorder and it has been postulated that an abnormal pattern of cytokine expression may play a role in its onset. In this study we compared cytokine plasma levels in IBS patients with those of and age- and sex-matched controls.
Cervical and breast cancer mortality trends in neighboring countries with different screening policies.
Authors: Philippe Autier, Cécile Pizot, Mathieu Boniol, Peter Boyle
Journal: Journal of Clinical Oncology (2016)

1571 Background: Cervical cancer mortality has decreased in most high income countries while breast cancer mortality started to decline decades later. Screening effectiveness was assessed in 4 pairs of neighboring European countries where nationwide screening programs have been implemented and who have comparable socio-economic status and access to high quality medical care, through the analysis of cancer mortality trends after screening introduction. Methods: Age-standardised mortality rates of cervical and breast cancer were calculated using data in the WHO database. Changes in mortality trends were assessed through percent change over the period 1962-1985 for cervical cancer and 1989-2012 for breast cancer. Information on the introduction, organization and participation of screening were available in the literature. Results: In Sweden, Finland, the Netherlands and Northern Ireland, where screening was adopted earlier, cervical cancer mortality decreased rapidly over the 23-years with reductions of -51.9%, -64.5%, -54.5% and -39.9% respectively. In Norway, Denmark, Belgium and Ireland, neighboring countries that implemented screening programs more than 10 years later, cervical cancer mortality decreased slowly with declines of -22.8%, -46.6%, -27.0% and -13.4% respectively. For breast cancer, mortality trends in neighboring countries remained similar regardless of screening programs. Norway (-38.1% ) and Denmark (34.9%), the late adopters, had steeper reductions in mortality than the early adopters, Finland (19.4%) and Sweden (-26.6%). Quite similar changes in breast cancer mortality where observed in Belgium (-36.3%) and The Netherlands (-32.4% respectively) despite the late introduction of screening programs and low participation in Belgium. The same pattern was observed in Northern Ireland (-35.0%) and Ireland (34.9). Conclusions: Trends in cervical cancer mortality are in agreement with the implementation of screening: the earlier the adoption of population-based screening, the quicker and greater were the drops in cervical cancer mortality. In contrast, early adoption of population-based mammography screening had no influence on the trends of breast cancer mortality.