tbuckley/cabot-search huggingface dataset:
PTU-065 No improvement in mortality risk nor stage of oesophago-gastric cancer in patients referred through 2ww suspected cancer pathways compared to routine referral routes
Authors: NR Lewis, J Catton, E James
Journal: Gut (2017)

Introduction  The volume of 2WW referrals continues to increase with little evidence of increased rates of cancer diagnoses or earlier stages of cancers [1]. The Cancer Plan which introduced 2WW pathways and cancer treatment targets was intended to improve outcome for patients with sooner diagnoses and earlier stages of cancer found [2]. We have observed the mortality risk and stage of oesophago-gastric (OG) cancer according to diagnostic referral route to see if 2WW pathways improve outcome for patients.  Method  OG cancers diagnosed at Nottingham University NHS Trust between 1 st Janaury 2015 – 31 st  December 2015 were identified from systematic searches of histopathological records, endoscopy database, radiological reports and registration at the Nottinghamshire OG Cancer MDT. Univariate logistic regression analysis was performed to determine the association between OG cancer mortality, stage of cancer with mode of referral. Kaplan Meier survival curves were used to describe mortality rate by stage of OG cancer and mode of referral.  Results  159 people were diagnosed with OG cancer with mean age 73.1 [SD 26.8] years. 52% (n=84) of OG cancers were diagnosed following 2WW referral with 24% (n=38) diagnosed following emergency presentation and unplanned hospitalisation. Patients diagnosed as an emergency had 4-fold increased risk of death at 1 year in comparison to those patients diagnosed along 2WW pathways (odds ratio 4.1 [95%CI 1.7, 9.7]). There was no difference in mortality risk in those referred along 2WW pathways to routine referral routes (p>0.05). Patients diagnosed as an emergency with OG cancer had 3-fold increased risk of stage 4 disease in comparison to those diagnosed along 2WW pathways (odds ratio 3.1; 95% CI 1.4, 6.8). There was no difference in the proportion of stage 4 OG cancer in those referred along 2WW pathways to routine referral routes (difference in proportion 7.0%; 95% CI −19.3, 28.2). Following review of performance status, co-morbidity and other patient factors, only 47% of patients from all routes of diagnosis were eligible for curative treatments.  Conclusion  In keeping with recent literature on other tumour sites, emergency diagnosis of OG cancers is associated with higher stage at presentation [3]. We are unable to demonstrate that diagnosis through 2WW pathways confers a lower stage at diagnosis or improved survival.  References  . https://www.england.nhs.uk/statistics/category/statistics/annual-cwt/  . https://www.england.nhs.uk/wp-content/uploads/2016/05/cancer-strategy.pdf  . Br J Cancer2016;115(7):866–75.  Disclosure of Interest  None Declared
Abstract P336: Constitutive Activation of ROCK1 in Mouse Heart Leads to Fibrotic Cardiomyopathy
Authors: Xiangsheng Yang, Qi Li, Xi Lin, Yanlin Ma, Xiaojing Yue, Zhengyin Tao, Jiang Chang
Journal: Circulation Research (2011)

Background: Our previous study demonstrated that genetic deletion of ROCK1 inhibited stress-induced cardiac fibrosis and ROCK1 was cleaved by caspase 3 into a constitutively active Rho kinase isoform, ROCKΔ1 that led to increase in Rho kinase activity in human failing hearts. However, the function of truncated ROCK1 accumulated in human failing myocardium and the molecular signaling linked between ROCKΔ1 and cardiac remodeling remain obscure. Methods and Results: To recapitulate this human pathophysiological situation and define the pathogenic role of ROCKΔ1 in heart, we generated transgenic mice expressing ROCKΔ1 in heart. Significant increase in Rho kinase activity was achieved. The mice developed fibrotic cardiomyopathy along with upregulation of TGFβ1 and NF-κB signaling. Significant increases in fibrotic factors were observed. Echocardiography revealed diastolic dysfunction in the transgenic heart. The transgenic mice were predisposed to angiotensin II treatment that led to massive fibrotic cardiomyopathy. Rho kinase inhibitor Fasudil treatment attenuated the fibrotic maladaption. To elucidate the molecular mechanism underlying ROCKΔ1-mediated fibrotic cardiomyopathy, wild-type cardiac fibroblasts were co-cultured with transgenic cardiomyocytes. Large amount of fibroblasts were activated and induced to express α-SMA by the transgenic cardiomyocytes but not by the wild-type control cardiomyocytes. Addition of Rho kinase, TGFβR1 and NF-κB inhibitors to the culture media attenuated the fibroblast activation. The results suggested that the pro-fibrotic TGFβ and NF-κB signaling are responsible for ROCKΔ1-mediated fibrotic cardiomyopathy. Finally, we demonstrated TGFβ1 was a SRF (serum response factor) new target gene. EMSA, luciferase and CHIP assay revealed SRF binding to TGFβ1 promoter. Genetic deletion of SRF in mouse heart resulted in marked decrease in TGFβ1 expression. Conclusions: Our studies demonstrated the pro-fibrotic role of truncated ROCK1 in vivo and provided an animal model that recapitulated human heart failure. The results elucidated that activation of NF-κB and TGFβ1 signaling contributed to Rho kinase-mediated fibrotic cardiomyopathy, the later was regulated by SRF.
Abstract 17231: Contact-Mediated Interaction Between Pulmonary Artery Endothelial and Smooth Muscle Cells Promotes a BMPR2-β-catenin-Notch1 Signal Causing Hyperpolarization of Endothelial Mitochondria and a Stalk Cell-like Phenotype
Authors: Kazuya Miyagawa, Caiyun G Li, Jan K Hennigs, Shalina Taylor, Jan-Renier Moonen, Silin Sa, Lingli Wang, Aiqin Cao, Marlene Rabinovitch
Journal: Circulation (2015)

Background: Pulmonary arterial hypertension (PAH) is characterized by endothelial (EC) apoptosis related to loss of distal (D) pulmonary arteries (PA) and abnormal proliferation of smooth muscle-like cells (SMC). These features are mediated by impaired cell metabolism. We observed mitochondrial dysfunction in human PAEC with reduced or mutant BMPR2, the gene associated with familial PAH. Deletion of BMPR2 in murine EC causes failure to regenerate DPA and to recover from hypoxia induced pulmonary hypertension. Loss of BMPR2 in PASMC results in mitochondrial dysfunction associated with enhanced proliferation. Since metabolites and other factors are often transferred by cell contact, we investigated how PASMC-PAEC contact impacts PAEC mitochondrial and cellular function, and could be perturbed by a BMPR2 mutation in PAEC and/or PASMC. Methods and Results: We used a co-culture system in which PAEC and PASMC from lungs of donor control (c-) or PAH patients with a BMPR2 mutation (m-) were either seeded on opposite sides of a 1μm pore insert or separated to assess non-contact mediated responses. When c-PAEC contacted c-PASMC, PAEC mitochondrial membrane potential (Δψ) increased 6-fold compared to mono-cultured or non-contact co-cultured cells (p &lt; 0.001). These PAEC exhibited a significant increase in proliferation (3-fold increase by Ki-67 staining, p&lt;0.01) and survival (73% reduction in caspase activity, p &lt; 0.001); however we observed a decrease in migration and angiogenic capacity in modified Boyden chamber and matrigel assays (52% and 60% reduction, p &lt; 0.001, respectively). We related the increase in Δψ and the above ‘stalk cell-like’ phenotype to an increase in Notch1 intracellular domain (2.5-fold increase, p &lt; 0.001), as they were abrogated by the gamma secretase inhibitor, and enhanced by the co-transcriptional activator β-catenin (4-fold increase, p &lt; 0.001). When m-PAEC and m-PASMC were used in contact cultures, these features were not observed. Conclusions: PASMC in contact with PAEC increase Δψ and produce a Notch and β-catenin mediated stalk cell-like EC phenotype. These features are lost when BMPR2 is deficient in both PAEC and PASMC suggesting that BMPR2-mediated PASMC-EC contact allows PAEC to survive and regenerate in response to damage.
Comparative eligibility of metastatic pancreatic adenocarcinoma (MPA) patients for first-line palliative intent FOLFIRINOX (FIO) versus nab-paclitaxel plus gemcitabine (NG).
Authors: Winson Y. Cheung, Daniel John Renouf, Howard John Lim, Renata D'Alpino Peixoto
Journal: Journal of Clinical Oncology (2014)

e15264 Background: The ACCORD and MPACT trials demonstrated superiority of FIO and NG over gemcitabine alone, respectively, in the treatment of MPA. In the absence of a direct comparison between these regimens, it is unclear whether FIO or NG is superior. Because both trials had stringent yet different inclusion criteria, our aim was to determine the proportion of MPA patients (pts) who would be potentially eligible for first-line palliative intent FIO vs. NG in routine clinical practice. Methods: Consecutive pts diagnosed with MPA from 2000 to 2011, referred to any 1 of 5 regional cancer centers in British Columbia, Canada and who initiated palliative chemotherapy with gemcitabine were reviewed. Clinicopathological variables and treatment outcomes were retrospectively collected and compared among groups. For this study, eligibility criteria for each regimen were based on those described in the respective phase III trials. Results: A total of 473 pts were identified: median age was 66 years (range 34–89) and 258 (55%) were men. Only 25% of pts would be eligible for FIO as compared to 45% for NG. The main reasons for ineligibility to FIO were age >/= 75 years (19%), ECOG performance status (PS) >/= 2 (57%), and bilirubin > 1.5 times upper limit of normal (ULN) range (18%). The main reasons for ineligibility to NG were ECOG PS >/= 3 (15%), bilirubin > ULN (25%), and cardiac dysfunction (14%). Median overall survival (OS) for the entire cohort treated with gemcitabine was 5.8 months (95% CI 5.4-6.2). On univariate analyses, eligible pts for FIO had longer median OS than ineligible pts (8.6 vs. 4.7 months, p<0.001). Pts eligible for NG also had longer median OS than those deemed ineligible (6.7 vs 4.9 months, p=0.008). After accounting for ECOG PS in the multivariate model, eligibility for either FIO or NG no longer predicted for better OS. Conclusions: In this population-based analysis, almost twice as many MPA pts would be eligible for NG than FIO. The longer OS observed in the FIO-eligible population likely reflects the exclusion of ECOG PS 2 pts. Accurate assessment of PS in MPA pts can facilitate treatment decision making and help with the selection between FIO and NG.
Multiple Cancers of the Human Gastrointestinal Tract
Authors: Warren, Shields
Journal: JNCI Journal of the National Cancer Institute (1945)

Journal Article Multiple Cancers of the Human Gastrointestinal Tract Get access Shields Warren Shields Warren assistant professor of pathology Harvard Medical School Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 5, Issue 5, April 1945, Page 375, https://doi.org/10.1093/jnci/5.5.375 Published: 01 April 1945
Acute myeloid leukemia transforms the bone marrow niche into a leukemia-permissive microenvironment through exosome secretion
Authors: B Kumar, M Garcia, L Weng, X Jung, J L Murakami, X Hu, T McDonald, A Lin, A R Kumar, D L DiGiusto, A S Stein, V A Pullarkat, S K Hui, N Carlesso, Y-H Kuo, R Bhatia, G Marcucci, C-C Chen
Journal: Leukemia (2017)

Little is known about how leukemia cells alter the bone marrow (BM) niche to facilitate their own growth and evade chemotherapy. Here, we provide evidence that acute myeloid leukemia (AML) blasts remodel the BM niche into a leukemia growth-permissive and normal hematopoiesis-suppressive microenvironment through exosome secretion. Either engrafted AML cells or AML-derived exosomes increased mesenchymal stromal progenitors and blocked osteolineage development and bone formation in vivo. Preconditioning with AML-derived exosomes 'primed' the animals for accelerated AML growth. Conversely, disruption of exosome secretion in AML cells through targeting Rab27a, an important regulator involved in exosome release, significantly delayed leukemia development. In BM stromal cells, AML-derived exosomes induced the expression of DKK1, a suppressor of normal hematopoiesis and osteogenesis, thereby contributing to osteoblast loss. Conversely, treatment with a DKK1 inhibitor delayed AML progression and prolonged survival in AML-engrafted mice. In addition, AML-derived exosomes induced a broad downregulation of hematopoietic stem cell-supporting factors (for example, CXCL12, KITL and IGF1) in BM stromal cells and reduced their ability to support normal hematopoiesis. Altogether, this study uncovers novel features of AML pathogenesis and unveils how AML cells create a self-strengthening leukemic niche that promotes leukemic cell proliferation and survival, while suppressing normal hematopoiesis through exosome secretion.
Postdiagnosis Statin Use and Mortality in Danish Patients With Prostate Cancer
Authors: Signe Benzon Larsen, Christian Dehlendorff, Charlotte Skriver, Susanne Oksbjerg Dalton, Christina Gade Jespersen, Michael Borre, Klaus Brasso, Mette Nørgaard, Christoffer Johansen, Henrik Toft Sørensen, Jesper Hallas, Søren Friis
Journal: Journal of Clinical Oncology (2017)

Purpose Increasing evidence indicates that statin use may reduce mortality from prostate cancer. In this work, we examined whether postdiagnosis statin use was associated with reduced cancer-specific mortality or all-cause mortality among patients with prostate cancer in Denmark. Material and Methods From nationwide Danish registries, we identified all patients with incident prostate adenocarcinoma from 1998 to 2011 and retrieved data on tumor and patient characteristics, drug use, and primary treatment. We defined postdiagnosis use (two or more prescriptions) of statins as a time-varying covariate with 1-year lag. Cox proportional hazards regression models used to compute hazard ratios (HRs) for prostate cancer-specific mortality and all-cause mortality through 2013 associated with postdiagnosis statin use. In secondary and sensitivity analyses, we assessed statin use within exposure periods of 1 year or 5 years after prostate cancer diagnosis and evaluated the influence of prediagnosis statin use. Results Among 31,790 patients, 7,365 died of prostate cancer and 11,811 died from other causes during a median follow-up of 2.8 years (interquartile range, 1.3 to 5.1 years) from 1 year after diagnosis. Postdiagnosis statin use was associated with adjusted HRs of 0.83 (95% CI, 0.77 to 0.89) for prostate cancer mortality and 0.81 (95% CI, 0.76 to 0.85) for all-cause mortality. Similar results were observed in 1-year and 5-year sensitivity analyses. No substantial effect measure modification was found with estimated dose or type of statin, clinical stage, Gleason score, or with prediagnosis statin use; however, patients who were diagnosed early in the study period or who underwent radical prostatectomy or endocrine therapy exhibited slightly lower HRs for prostate cancer mortality with postdiagnosis statin use than did those in the overall analyses. Conclusion Postdiagnosis statin use was associated with reduced mortality from prostate cancer; however, it remains to be established whether this association is causal.
効率的な膵癌プローブとしてLyP‐1で固定された磁気メソ多孔性ナノ粒子【Powered by NICT】
Authors: Jiang Yongjian, Liu Shaojun, Zhang Yu, Li Hengchao, He Hang, Dai Juntao, Jiang Tao, Ji Weihang, Geng Daoying, A Elzatahry Ahmed, Alghamdi Abdulaziz, Fu Deliang, Deng Yonghui, Zhao Dongyuan
Journal: Biomaterials (2017)
Development of trastuzumab-resistance in BT-474 breast cancer cells following prolonged estrogen-deprivation in vivo
Authors: Ginny Li, Shota Yamamoto, Jun Guo, Lisa Crocker, Gail Lewis Phillips
Journal: Cancer Research (2007)

905  Amplification and overexpression of the HER2/ErbB2 receptor tyrosine kinase occur in 25-30% of breast cancer patients and are correlated with poor clinical outcome. The humanized HER2 antibody, trastuzumab, was developed as a targeted therapeutic for HER2-positive breast cancer. Although trastuzumab has clinical activity both as a single agent and in combination with chemotherapy, lack of response to trastuzumab can occur either at the initiation of treatment (innate resistance) or following prolonged exposure (acquired resistance). Understanding the mechanisms underlying response to trastuzumab therapy continues to be an important area of study. BT-474 cells are HER2-amplified, trastuzumab-sensitive breast cancer cells and provide a good model for studying trastuzumab activity both in vitro and in vivo. While adapting BT-474 cells to grow in vivo in the absence of exogenous estrogen supplementation, we discovered that the estrogen-deprived BT-474 line we developed was un-responsive to trastuzumab. This cell line, named BT-474 EEI (exogenous estrogen independent) maintains 3+ HER2 expression (as measured by IHC on xenograft tumors and by FACS or Western analysis on cultured cells) and retains sensitivity to trastuzumab-DM1 immunoconjugate, erlotinib and chemotherapeutic drugs. Expression of ER-α is slightly elevated in BT-474 EEI cells compared to the parental line, likely a consequence of adaptation to low estrogen conditions. In fact, the proliferative response to 17β-estradiol in vitro is greatly enhanced in the BT-474 EEI cells. Both IGF-1R and IRS-1 are up-regulated in BT-474 EEI cells. In addition, the EEI cells show increased expression of HER/ErbB receptor ligands, notably amphiregulin, HB-EGF, epiregulin, and TGF-α. Expression of EGFR, however, is reduced compared to the parental cells. Moreover, basal levels of phosphorylated HER/ErbB receptors (EGFR, HER2 and HER3) are decreased in BT-474 EEI. We also examined signaling through the MAPK and AKT pathways. In contrast to BT-474 cells, which display high basal phospho-AKT, the BT-474 EEI cells show decreased constitutive AKT activation. However, heregulin-induced AKT phosphorylation is equivalent in both cell types. No detectable differences in signaling through the MAPK or mTOR pathways were observed. In summary, the BT-474 EEI cell line displays similar characteristics described in models of acquired trastuzumab resistance (i.e. increased IGF-1R and HER/erbB ligands), yet offers a unique system for studying mechanisms of non-response to trastuzumab . Experiments are currently underway to determine which molecular alterations contribute to the lack of response to trastuzumab observed in BT-474 EEI cells.
Revisiting gene mutations and prognosis of ex-M6a-acute erythroid leukemia with regard to the new WHO classification
Authors: N Cervera, N Carbuccia, M-J Mozziconacci, J Adélaïde, S Garnier, A Guille, A Murati, M Chaffanet, N Vey, D Birnbaum, V Gelsi-Boyer
Journal: Blood Cancer Journal (2017)

HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not.The documents may come from teaching and research institutions in France or abroad, or from public or private research centers.L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés. Revisiting gene mutations and prognosis of ex-M6a-acute erythroid leukemia with regard to the new WHO classification
A human APOC3 missense variant and monoclonal antibody accelerate apoC-III clearance and lower triglyceride-rich lipoprotein levels
Authors: Sumeet A Khetarpal, Xuemei Zeng, John S Millar, Cecilia Vitali, Amritha Varshini Hanasoge Somasundara, Paolo Zanoni, James A Landro, Nicole Barucci, William J Zavadoski, Zhiyuan Sun, Hans de Haard, Ildikó V Toth, Gina M Peloso, Pradeep Natarajan, Marina Cuchel, Sissel Lund-Katz, Michael C Phillips, Alan R Tall, Sekar Kathiresan, Paul DaSilva-Jardine, Nathan A Yates, Daniel J Rader
Journal: Nature Medicine (2017)

Recent large-scale genetic sequencing efforts have identified rare coding variants in genes in the triglyceride-rich lipoprotein (TRL) clearance pathway that are protective against coronary heart disease (CHD), independently of LDL cholesterol (LDL-C) levels. Insight into the mechanisms of protection of these variants may facilitate the development of new therapies for lowering TRL levels. The gene APOC3 encodes apoC-III, a critical inhibitor of triglyceride (TG) lipolysis and remnant TRL clearance. Here we report a detailed interrogation of the mechanism of TRL lowering by the APOC3 Ala43Thr (A43T) variant, the only missense (rather than protein-truncating) variant in APOC3 reported to be TG lowering and protective against CHD. We found that both human APOC3 A43T heterozygotes and mice expressing human APOC3 A43T display markedly reduced circulating apoC-III levels. In mice, this reduction is due to impaired binding of A43T apoC-III to lipoproteins and accelerated renal catabolism of free apoC-III. Moreover, the reduced content of apoC-III in TRLs resulted in accelerated clearance of circulating TRLs. On the basis of this protective mechanism, we developed a monoclonal antibody targeting lipoprotein-bound human apoC-III that promotes circulating apoC-III clearance in mice expressing human APOC3 and enhances TRL catabolism in vivo. These data reveal the molecular mechanism by which a missense variant in APOC3 causes reduced circulating TG levels and, hence, protects from CHD. This protective mechanism has the potential to be exploited as a new therapeutic approach to reduce apoC-III levels and circulating TRL burden.