tbuckley/cabot-search huggingface dataset:
Characteristics of newly diagnosed stage IV colorectal cancer (CRC) in veterans over a 10-year period.
Authors: Neal Patel, Ying Margie Tang, Fengming Zhong, Victor Tsu-Shih Chang, Barbara Crump, Monica McPherson, Shanthi Srinivas, Basil Kasimis
Journal: Journal of Clinical Oncology (2014)

e14649 Background: We studied characteristics, comorbidity, treatment, and other survival predictors for patients (pts) with stage IV CRC. Methods: In an IRB-approved protocol, we reviewed the records of pts with newly diagnosed stage IV CRC at a VA medical center from 01/01/2003 to12/31/2012. Demographics, grade (G), ECOG performance status (PS), CEA, Hemoglobin (HGB), and Albumin (ALB) at diagnosis (dx), cause of death, sites of CRC and metastasis (mets), and treatment were studied. Comorbidity was assessed with the Charlson Comorbidity Index (CCI). Statistical analyses were performed with SAS 9.2/Stata 11.0 Results: There were 55 pts with 54 men and 1 woman. 28 pts (50.9%) were Caucasians, 25 pts (45.5%) African Americans, and 2 pts (3.6%) Hispanics. The median (M) age at dx was 65 (44-89) years (y). 48 pts (87.3%) were deceased. 42 pts (76.4%) died from CRC. 18 pts (32.7%) had rectal ca, 35 pts (63.6%) had colon ca, 2 pts (3.6%) unclear site. At dx, 47 pts (85.5%) had liver mets, 6 pts (10.9%) lung mets, and the rest had brain, bone or intra-abdominal mets. M ECOG was 1.5 (0-4). M HGB was 10.6 (6.3-15.1) gm/dl, M ALB 3.8 (1.4-4.6) gm/dl, M CEA 6.8 (0.2-6394) ng/ml. M CCI was 4.26 (0.4-13.9). 14 pts were tested for KRAS genes with 6 (42.8%) pts positive for mutations. 33 pts (60.0%) had surgery. 25 pts (75.8%) had colectomy, 6 pts (18.2%) had diverting colostomy, and 2 pts had surgery for mets. 15 pts (27.3%) had radiation. 33 pts (60.0%) received chemotherapy (chemo) including 18 (52.9%) of the 34 pts from the first 5 y and 15 (71.4%) of 21 pts from the second 5 y. 15 pts (27.3%) had 1 line of chemo, 9 pts (16.4%) 2 lines, 7 pts (12.7%) 3 lines, and 2 pts (3.6%) 4 lines. M survival was 432 days (13-2473) and is similar among races. In univariate analysis, grade (p=0.037), ECOG PS (p=0.007), CCI (p=0.000), surgery (p=0.015), and number of chemo lines (p=0.002) were significant. In multivariate analysis, surgery (p=0.047) and number of chemo lines (p=0.043) were significant for survival. Conclusions: Our study showed that surgery prolongs survival in stage IV CRC patients. Additional studies will be conducted to confirm this finding. We also showed that the number of chemo lines is significant for predicting survival. Supported by NJCCR.
New Therapeutic Approaches for Familial Hypercholesterolemia
Authors: Ezim Ajufo, Daniel J. Rader
Journal: Annual Review of Medicine (2018)

Familial hypercholesterolemia (FH) is a common genetic condition characterized by elevated plasma levels of low-density lipoprotein cholesterol (LDL-C), premature atherosclerotic cardiovascular disease, and considerable unmet medical need with conventional LDL-C-lowering therapies. Between 2012 and 2015, the US Food and Drug Administration approved four novel LDL-C-lowering agents for use in patients with FH based on the pronounced LDL-C-lowering efficacy of these medicines. We review the four novel approved agents, as well as promising LDL-C-lowering agents in clinical development, with a focus on their mechanism of action, efficacy in FH cohorts, and safety.
Chemopreventive potential of zinc in experimentally induced colon carcinogenesis
Authors: Vijayta Dani, Kim Vaiphie, Davinder Dhawan
Journal: Clinical Cancer Research (2007)

A1   Regulation of dietary factors is considered crucial for the prevention of initiating events leading to the development of colon carcinoma. Although many dietary compounds have been suggested to contribute in cancer prevention, there is strong evidence that zinc may play a pivotal role in host defense against the initiation of several malignancies including colon cancer. The present study was conducted to evaluate the modulatory effects of zinc on colonic antioxidant defense system and histoarchitecture during 1,2 dimethylhydrazine (DMH) induced colon carcinogenesis in male sparque dawley rats. The rats were segregated into four groups viz., normal control, DMH treated, zinc treated, DMH+zinc treated. Colon carcinogenesis was induced through weekly subcutaneous injections of DMH (30mg/Kg body weight) for 16 weeks. Zinc (in the form of zinc sulphate) was supplemented to rats at a dose level of 227mg/L in drinking water,  ad libitum  for the entire duration of the study. Increased tumor incidence, tumor burden was accompanied by a decrease in lipid peroxidation (LPO), glutathione-s-transferase, superoxide dismutase (SOD) and catalase. On the contrary, significantly increased levels of reduced glutathione (GSH) and glutathione reductase (GR) were observed in DMH treated rats. Administration of zinc to DMH treated rats significantly decreased the tumor incidence and tumor burden with simultaneous enhancement of LPO, SOD, CAT and GST. Further, the levels of GSH and GR were also decreased following zinc supplementation to DMH treated rats. Well-differentiated signs of dysplasia were evident in colonic tissue sections by DMH administration alone. However, zinc treatment to DMH treated rats greatly restored normalcy in the colonic histoarchitecture, with no apparent signs of neoplasia. EDXRF studies revealed a significant decrease in tissue concentrations of zinc in the colon following DMH treatment, which upon zinc supplentation were recovered to near normal levels. In conclusion, the results of this study suggest that zinc has a positive beneficial effect against chemically induced colonic preneoplastic progression in rats induced by DMH.
High dose Interleukin 2 (HD IL2) as 1<sup>st</sup> line treatment in metastatic renal cell carcinoma (mRCC): A 10-year single centre experience.
Authors: Shien Chow, Victoria Galvis, Manon Pillai, Rebecca Leach, Elizabeth Keene, Andrea Spencer-Shaw, Liptrot Tom, Jonathan Shanks, Alaaeldin Shablak, Fiona Thistlethwaithe, Robert E. Hawkins
Journal: Journal of Clinical Oncology (2016)

4555 Background: Targeted therapy has become the treatment of choice for majority of mRCC cases in recently. For most, treatment benefit is short-lived and given with palliative intent. HD IL2 is an effective treatment capable of durable remission but its unselected use was difficult due to modest response rate and considerable toxicity. Using a set pathology criteria as selection tool, we have been able to show improved outcomes in our previous report (Shablak et al 2011) . We present a 10-yr experience in our centre. Methods: Prospective pathology selection began in 2006. Tumour specimens were reviewed and stratified into Favourable or Other categories based on constitution of histology growth patterns. HD IL2 was preferentially offered to Favourable category. Outcome evaluation included response rates, survival, and treatment tolerance. Multivariate analysis were performed to explore potential prognostic and predictive factors. Results: Total patients reviewed were 145 (2003 – 2013). Among prospective cohort with Favourable pathology n = 106, overall response rate was 48.1% with CR rate of 21.6%. Median OS was 49.4 months. Factors linked to significantly better response and/or survival include > 50% alveolar growth pattern, higher cycle 1 tolerance ( > 18 doses), < 3 metastatic organ sites , and > 6/12 duration between diagnosis and start of treatment. CAIX (Carbonic anhydrase 9) is prognostic but not predictive of response. Toxicities were those expected of IL2 but was manageable on general medical wards, with no treatment-related death. Importantly most CRs were durable with 76% (23/30) remained relapse-free (median 39 months follow up). Conclusions: Our experience shows that HD IL2 remains an effective and safe treatment in well-selected cases of mRCC. Results from this large prospective series confirms similar outcomes to our previously reported retrospective series. Given the prospect of long-term remission, fit patients with Favourable histology and low disease burden should be considered for HD IL2 in experienced centre. Better understanding has been gained from this in-depth analysis especially that of possible predictors and strategies likely improve treatment outcome.
Human venous valve disease caused by mutations in <i>FOXC2</i> and <i>GJC2</i>
Authors: Oliver Lyons, Prakash Saha, Christopher Seet, Adam Kuchta, Andrew Arnold, Steven Grover, Victoria Rashbrook, Amélie Sabine, Gema Vizcay-Barrena, Ash Patel, Francesca Ludwinski, Soundrie Padayachee, Tsutomu Kume, Brenda R. Kwak, Glen Brice, Sahar Mansour, Pia Ostergaard, Peter Mortimer, Steve Jeffery, Nigel Brown, Taija Makinen, Tatiana V. Petrova, Bijan Modarai, Alberto Smith
Journal: The Journal of Experimental Medicine (2017)

Venous valves (VVs) prevent venous hypertension and ulceration. We report that FOXC2 and GJC2 mutations are associated with reduced VV number and length. In mice, early VV formation is marked by elongation and reorientation (“organization”) of Prox1hi endothelial cells by postnatal day 0. The expression of the transcription factors Foxc2 and Nfatc1 and the gap junction proteins Gjc2, Gja1, and Gja4 were temporospatially regulated during this process. Foxc2 and Nfatc1 were coexpressed at P0, and combined Foxc2 deletion with calcineurin-Nfat inhibition disrupted early Prox1hi endothelial organization, suggesting cooperative Foxc2–Nfatc1 patterning of these events. Genetic deletion of Gjc2, Gja4, or Gja1 also disrupted early VV Prox1hi endothelial organization at postnatal day 0, and this likely underlies the VV defects seen in patients with GJC2 mutations. Knockout of Gja4 or Gjc2 resulted in reduced proliferation of Prox1hi valve-forming cells. At later stages of blood flow, Foxc2 and calcineurin-Nfat signaling are each required for growth of the valve leaflets, whereas Foxc2 is not required for VV maintenance.
Abstract 187: Metformin Increases Degradation of Ubiquitinylated Phospholamban via Autophagy in Cardiomyocytes
Authors: Allen C Teng, Tetsuaki Miyake, Shunichi Yokoe, Liyong Zhang, Luis M Rezende, Parveen Sharma, David H MacLennan, Peter Liu, Anthony O Gramolini
Journal: Circulation Research (2015)

Phospholamban (PLN) is an effective inhibitor of the sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) in striated muscles. Here, we examined PLN stability and degradation in primary cultured mouse neonatal cardiomyocytes (CMNCs) and mouse hearts using immunoblotting, molecular imaging, and [35S]-methionine pulse-chase experiments along with lysosome (chloroquine and bafilomycin A1) and autophagic (3-methyladenine and Atg5 siRNA) antagonists. Inhibiting lysosomal and autophagic activities promoted endogenous PLN accumulation, whereas accelerating autophagy with metformin enhanced PLN degradation in CMNCs. Metabolic labeling reaffirmed that metformin promoted wild-type and R9C PLN degradation. Immunofluorescence showed that PLN and the autophagy marker, microtubule light chain 3 (LC3), became increasingly co-localized in response to chloroquine and bafilomycin treatments. Mechanistically, pentameric PLN was polyubiquitinylated at K3 residue and this modification was required for p62-mediated selective autophagy trafficking. Consistently, attenuated autophagic flux in Hace1-null mouse hearts was associated with increased PLN levels determined by immunoblot and immunofluorescence. Our study identifies a biological mechanism that traffics PLN to the lysosomes for degradation in mouse hearts.
Matrix metalloproteinase-2 knockout prevents angiotensin II-induced vascular injury
Authors: Tlili Barhoumi, Julio C Fraulob-Aquino, Muhammad Oneeb Rehman Mian, Sofiane Ouerd, Noureddine Idris-Khodja, Ku-Geng Huo, Asia Rehman, Antoine Caillon, Bianca Dancose-Giambattisto, Talin Ebrahimian, Stéphanie Lehoux, Pierre Paradis, Ernesto L Schiffrin
Journal: Cardiovascular Research (2017)

Matrix metalloproteinases (MMPs) have been implicated in the development of hypertension in animal models and humans. Mmp2 deletion did not change Ang II-induced blood pressure (BP) rise. However, whether Mmp2 knockout affects angiotensin (Ang) II-induced vascular injury has not been tested. We sought to determine whether Mmp2 knockout will prevent Ang II-induced vascular injury.A fourteen-day Ang II infusion (1000 ng/kg/min, SC) increased systolic BP, decreased vasodilatory responses to acetylcholine, induced mesenteric artery (MA) hypertrophic remodelling, and enhanced MA stiffness in wild-type (WT) mice. Ang II enhanced aortic media and perivascular reactive oxygen species generation, aortic vascular cell adhesion molecule-1 and monocyte chemotactic protein-1 expression, perivascular monocyte/macrophage and T cell infiltration, and the fraction of spleen activated CD4+CD69+ and CD8+CD69+ T cells, and Ly-6Chi monocytes. Study of intracellular signalling showed that Ang II increased phosphorylation of epidermal growth factor receptor and extracellular-signal-regulated kinase 1/2 in vascular smooth muscle cells isolated from WT mice. All these effects were reduced or prevented by Mmp2 knockout, except for systolic BP elevation. Ang II increased Mmp2 expression in immune cells infiltrating the aorta and perivascular fat. Bone marrow (BM) transplantation experiments revealed that in absence of MMP2 in immune cells, Ang II-induced BP elevation was decreased, and that when MMP2 was deficient in either immune or vascular cells, Ang II-induced endothelial dysfunction was blunted.Mmp2 knockout impaired Ang II-induced vascular injury but not BP elevation. BM transplantation revealed a role for immune cells in Ang II-induced BP elevation, and for both vascular and immune cell MMP2 in Ang II-induced endothelial dysfunction.
Combination of 177Lu-PSMA-617 and External Radiotherapy for the Treatment of Cerebral Metastases in Patients With Castration-Resistant Metastatic Prostate Cancer
Authors: Xiao Wei, Carl Schlenkhoff, Bettina Schwarz, Markus Essler, Hojjat Ahmadzadehfar
Journal: Clinical Nuclear Medicine (2017)

Two castration-resistant prostate cancer patients, both with cerebral and visceral and lymphatic metastases, received multiple cycles of Lu-PSMA-617 treatments. The prognosis of both cases is dependent on brain metastases. Between Lu-PSMA-617 treatment cycles, local radiotherapy was also applied to the brain metastases. Prior to the combined therapy, all systemic metastases, including cerebral lesions, showed PSMA expression using Ga-PSMA PET/CT. Under the combined therapy, all the metastases, particularly the cerebral lesions, showed significant regression in size and PSMA expression over time.
Therapeutic and Prognostic Implications of BRAF V600E in Pediatric Low-Grade Gliomas
Authors: Alvaro Lassaletta, Michal Zapotocky, Matthew Mistry, Vijay Ramaswamy, Marion Honnorat, Rahul Krishnatry, Ana Guerreiro Stucklin, Nataliya Zhukova, Anthony Arnoldo, Scott Ryall, Catriona Ling, Tara McKeown, Jim Loukides, Ofelia Cruz, Carmen de Torres, Cheng-Ying Ho, Roger J. Packer, Ruth Tatevossian, Ibrahim Qaddoumi, Julie H. Harreld, James D. Dalton, Jean Mulcahy-Levy, Nicholas Foreman, Matthias A. Karajannis, Shiyang Wang, Matija Snuderl, Amulya Nageswara Rao, Caterina Giannini, Mark Kieran, Keith L. Ligon, Maria Luisa Garre, Paolo Nozza, Samantha Mascelli, Alessandro Raso, Sabine Mueller, Theodore Nicolaides, Karen Silva, Romain Perbet, Alexandre Vasiljevic, Cécile Faure Conter, Didier Frappaz, Sarah Leary, Courtney Crane, Aden Chan, Ho-Keung Ng, Zhi-Feng Shi, Ying Mao, Elizabeth Finch, David Eisenstat, Bev Wilson, Anne Sophie Carret, Peter Hauser, David Sumerauer, Lenka Krskova, Valerie Larouche, Adam Fleming, Shayna Zelcer, Nada Jabado, James T. Rutka, Peter Dirks, Michael D. Taylor, Shiyi Chen, Ute Bartels, Annie Huang, David W. Ellison, Eric Bouffet, Cynthia Hawkins, Uri Tabori
Journal: Journal of Clinical Oncology (2017)

Purpose BRAF V600E is a potentially highly targetable mutation detected in a subset of pediatric low-grade gliomas (PLGGs). Its biologic and clinical effect within this diverse group of tumors remains unknown. Patients and Methods A combined clinical and genetic institutional study of patients with PLGGs with long-term follow-up was performed (N = 510). Clinical and treatment data of patients with BRAF V600E mutated PLGG (n = 99) were compared with a large international independent cohort of patients with BRAF V600E mutated-PLGG (n = 180). Results BRAF V600E mutation was detected in 69 of 405 patients (17%) with PLGG across a broad spectrum of histologies and sites, including midline locations, which are not often routinely biopsied in clinical practice. Patients with BRAF V600E PLGG exhibited poor outcomes after chemotherapy and radiation therapies that resulted in a 10-year progression-free survival of 27% (95% CI, 12.1% to 41.9%) and 60.2% (95% CI, 53.3% to 67.1%) for BRAF V600E and wild-type PLGG, respectively ( P < .001). Additional multivariable clinical and molecular stratification revealed that the extent of resection and CDKN2A deletion contributed independently to poor outcome in BRAF V600E PLGG. A similar independent role for CDKN2A and resection on outcome were observed in the independent cohort. Quantitative imaging analysis revealed progressive disease and a lack of response to conventional chemotherapy in most patients with BRAF V600E PLGG. Conclusion BRAF V600E PLGG constitutes a distinct entity with poor prognosis when treated with current adjuvant therapy.
Surveillance for Silicosis Deaths Among Persons Aged 15–44 Years — United States, 1999–2015
Authors: Jacek M. Mazurek, John M. Wood, Patricia L. Schleiff, David N. Weissman
Journal: MMWR Morbidity and Mortality Weekly Report (2017)

Silicosis is usually a disease of long latency affecting mostly older workers; therefore, silicosis deaths in young adults (aged 15-44 years) suggests acute or accelerated disease.* To understand the circumstances surrounding silicosis deaths among young persons, CDC analyzed the underlying and contributing causes† of death using multiple cause-of-death data (1999-2015) and industry and occupation information abstracted from death certificates (1999-2013). During 1999-2015, among 55 pneumoconiosis deaths of young adults with International Classification of Diseases, Tenth Revision (ICD-10) code J62 (pneumoconiosis due to dust containing silica),§ 38 (69%) had code J62.8 (pneumoconiosis due to other dust containing silica), and 17 (31%) had code J62.0 (pneumoconiosis due to talc dust) listed on their death certificate. Decedents whose cause of death code was J62.8 most frequently worked in the manufacturing and construction industries and production occupations where silica exposure is known to occur. Among the 17 decedents who had death certificates listing code J62.0 as cause of death, 13 had certificates with an underlying or a contributing cause of death code listed that indicated multiple drug use or drug overdose. In addition, 13 of the 17 death certificates listing code J62.0 as cause of death had information on decedent's industry and occupation; among the 13 decedents, none worked in talc exposure-associated jobs, suggesting that their talc exposure was nonoccupational. Examining detailed information on causes of death (including external causes) and industry and occupation of decedents is essential for identifying silicosis deaths associated with occupational exposures and reducing misclassification of silicosis mortality.
Genotoxic and mutagenic properties of acrylamide and glycidamide in human lymphocytes and V79-cells.
Authors: Matthias Baum, Evelyne Fauth, Silke Fritzen, Armin Herrmann, Peter Mertes, Melanie Rudolphi, Heinrich Zankl, Gerhard Eisenbrand
Journal: Cancer Research (2004)

3196   Acrylamide (AA) can be formed in heated foodstuffs in substantial amounts depending on the heating conditions and the concentration of precursors. AA has carcinogic potential as demonstrated in animal experiments. However, the mechanism of carcinogenicity and its relevance for the human situation is still under debate. There is substantial evidence that glycidamide (2,3-epoxypropanamide, GA), that is generated in vivo primarily by CYP450 2E1 mediated metabolism, is the ultimate carcinogen by covalent interaction with DNA. The extent of DNA damage is supposed to be mainly governed by kinetics of activating and desactivating metabolic pathways. We therefore used human blood as a model system to study dose response dependent DNA damage and induction of micronuclei in lymphocytes. DNA-damage was monitored by single cell gel electrophoresis, expressed as tail intensity (TI). Blood was freshly collected from donors, heparinized and incubated for 1, 2, or 4 hours with acrylamide (1000, 3000, 4500 or 6000 μM) or glycidamide (100, 300, 1000 or 3000μM). Acrylamide compared to the solvent-control did not induce significant DNA-damage under the used conditions, whereas GA started to induce significant DNA-damage at 300 μM, 4h. To investigate the induction of micronuclei (MN) in lymphocytes, blood was treated with cytochalasin b and then incubated with AA (500, 1000, 2500, and 5000μM) or GA (50, 100, 250, and 1000μM) for 23 hours. Acrylamide did not enhance the MN frequencies in lymphocytes significantly. Glycidamide exerted slightly enhanced MN frequencies at about 1000μM. Furthermore, induction of mutations at the hypoxanthine phosphoribosyl transferase locus (HPRT) was investigated in V79-cells. Cells were incubated with AA (100, 1000, 5000, 10 000 μM) or GA (400, 800, 1200, 2000 μM) for 24 hours. Selection for HPRT mutants was performed with 6-thioguanine. After a period of 10 to 13 days, mutation frequencies (MF) as mutants per 1 million cells were determined. AA did not induce HPRT-mutations at all concentrations tested. With GA an elevated mutation frequence was seen at 800 μM (MF: 14±8; solvent-control MF: 4±2), 1200 μM (MF: 24±5) and 2000μM (MF: 31±9). These results demonstrate that AA has no genotoxic or mutagenic potential under our testing conditions, whereas glycidamide is genotoxic and mutagenic. Future reserach is aimed at determination of hemoglobine adducts by AA/GA in this system to arrive at a biomarker guided dosimetry of genotoxic effects and by this to improve the basis for risk assessment. (This work was supported by AiF 108 ZBG/5)