tbuckley/cabot-search huggingface dataset:
TNF-α and autotaxin-LPA signaling is linked in hepatitis associated hepatocellular carcinoma
Authors: Jian-Min Wu, Mary Maluccio
Journal: Cancer Research (2008)

5394  Autotaxin (ATX), known as nucleotide pyrophosphatase-phosphodiesterase-2 (ENPP2), is a secreted lysophospholipase D that hydrolyzes lysophosphatidylcholine into lysophosphatidic acid (LPA). An LPA rich microenvironment can promote inflammatory process, wound healing, and tumor progression. We have previously shown that ATX is a potential biomarker of hepatocellular carcinoma (HCC) risk in patients with hepatitis. However, the regulation and functions of ATX in hepatocellular carcinogenesis have not been studied. Known mechanisms associated with inflammation induced cancers included an increased expression of tumor necrosis factor-alpha (TNF-α), which can trigger a cascade of other cytokines that cooperate in recruiting inflammatory cells and promoting the development of cancer in chronic active hepatitis. The objective of this study was to investigate the ATX-LPA signaling pathway in HCC and identify a potential link between TNF-α and ATX-LPA signaling.  Initially, we examined the expression of ATX and LPA receptors in human hepatocyte cell lines: normal (CL48), hepatitis associated HCC (Hep3B) and HCC in the background of normal liver (HepG2). Migration assay was used to determine whether ATX functions as a chemoattractant for human hepatocytes. The effect of ATX on the expression of LPA receptors and downstream target genes such as uPA, MMP9 and VEGF was evaluated. The roles of inflammatory cytokines (TNF-α and TGF-β) on the expression of ATX were studied.  The expression of ATX between normal and hepatoma cell lines is significantly different. Quantitative real-time RT-PCR (Q-PCR) showed the endogenous expression of ATX is negligible in CL-48 and 42-fold higher in Hep3B than HepG2. Immunoblot analysis confirmed ATX is differentially expressed. LPA receptors (LPA1, LPA2 and LPA3) are overexpressed in Hep3B compared to HepG2 and CL-48. Migration assays show ATX secreted by Hep3B cells promote the migration of Hep3B and HepG2 cells, while has little effect on CL-48 cells. Treatment with 220ng/ml ATX for 20hrs increases the mRNA expression of LPA2, uPA, MMP9 and VEGF to 1.8-, 1.6-, 2-, and 1.8-fold respectively. Both Q-PCR and immunoblot results show TNF-α (10ng/ml) promotes ATX expression only in Hep3B cells (3.2 fold for mRNA expression), while TGF-β (5ng/ml) does not affect ATX expression in these three cell lines.  In conclusion: The overexpression of ATX and LPA receptors along with the induced LPA2 expression by ATX in Hep3B cells indicate ATX-LPA signaling is actively involved in human hepatitis associated HCC. The ATX-LPA signaling is linked to the invasiveness and angiogenesis of liver cancer. Pro-inflammatory cytokine TNF-α promotes ATX expression only in hepatitis associated HCC. The connection between TNF-α and ATX-LPA signaling appears to be unique to human hepatitis associated cancer.
Chronic Rhinosinusitis with Nasal Polyps
Authors: Claire Hopkins
Journal: New England Journal of Medicine (2019)

In patients with chronic rhinosinusitis with nasal polyps who have mild symptoms, intranasal glucocorticoids and saline irrigation are recommended. For more severe symptoms, short-term courses of systemic glucocorticoids may be used; if glucocorticoids are ineffective, surgery to remove polyps can be considered.
Abstract 2871: Global reduction of H3K4me3 improves chemotherapeutic efficacy for pediatric ependymomas
Authors: Guifa Xi, Nitin Wadhwani, Rintaro Hashizume, Barbara Mania-Farnell, Marcelo Bento Soares, Charles D. James, Tadanori Tomita
Journal: Cancer Research (2019)

Abstract Background Ependymomas (EPNs) are the third most common brain tumor in children. These tumors are resistant to available chemotherapeutic treatments, therefore new effective targeted therapeutics must be identified. Increasing evidence shows epigenetic alterations including histone posttranslational modifications (PTMs), are associated with malignancy, chemotherapeutic resistance and prognosis for pediatric EPNs. In this study we examined histone PTMs in EPNs and identified potential targets to improve chemotherapeutic efficacy. Methods Global histone H3 lysine 4 trimethylation (H3K4me3) levels were detected in pediatric EPN tumor samples with immunohistochemistry and immunoblots. Candidate genes conferring therapeutic resistance were profiled in pediatric EPN tumor samples with micro-array. Promoter H3K4me3 occupancy was examined for two candidate genes, CCND1 and ERBB2, with chromatin-immunoprecipitation coupled with real-time PCR (ChIP-PCR). These methods and MTS assay were used to verify a relationship between H3K4me3 levels and CCND1 and ERBB2, and to investigate cell viability in response to chemotherapeutic drugs in primary cultured pediatric EPN cells. Results H3K4me3 levels positively correlate with WHO grade malignancy in pediatric EPNs and are associated with progression free survival in patients with posterior fossa group A EPNs (PF-EPN-A). Reduction of H3K4me3 by silencing its methyltransferase SETD1A, in primary cultured EPN cells, increased cell response to chemotherapy. Conclusions Our results support the development of a novel treatment that targets H3K4me3 to increase chemotherapeutic efficacy in pediatric PF-EPN-A tumors. Key words: promoter, H3K4me3, human SETD1A, chemotherapy, pediatric ependymoma Citation Format: Guifa Xi, Nitin Wadhwani, Rintaro Hashizume, Barbara Mania-Farnell, Marcelo Bento Soares, Charles D. James, Tadanori Tomita. Global reduction of H3K4me3 improves chemotherapeutic efficacy for pediatric ependymomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2871.
Analysis of weight loss as a prognostic factor in patients with advanced gastric cancer from the Phase 3 RAINBOW study
Authors: W. Mansoor, E. Roeland, M. Abraham, R. Wei, A. Chatterjee, A. Sashegyi, A. Desai, P. Abada, A. Chaudhry, S. Klempner
Journal: Annals of Oncology (2019)
Comparative outcome of sorafenib treatment in central Europe and Russia.
Authors: Yulia Bisovskaya, Matthias Pinter, Werner Scheithauer, Markus Peck-Radosavljevic
Journal: Journal of Clinical Oncology (2012)

e14681 Background: Sorafenib is the standard treatment for advanced stage HCC. Here we compare outcomes in 2 cohorts of HCC patients from two large oncologic referral centers in Russia (R) and Austria (A). Methods: 69 pts (19 f/50 m) with HCC (BCLC A/B/C/D 1/30/38/0) in R and 148 pts (27 f/121 m; n. s. between cohorts) with HCC (BCLC A/B/C/D 0/26/104/18) in A were treated with standard dose of sorafenib 400 mg bid until progression or death between 2006 and 01/2012. Dose reductions were due to side effects. Survival was evaluated using Kaplan-Meier analysis and compared by log-rank test. Prognostic factors evaluated were pretreatment BCLC stage, Child-Pugh stage, and etiology of liver disease (viral/non-viral). Results: BCLC-staging distribution was significantly different between R and A centers with more patients in advanced st BCLC-C in A (A 70% vs. R 55%, p&lt;0.0001). Patients also had more advanced stage liver disease in A (Child-Pugh stage A/B/C = 52/37/11%) compared to R (A/B/C = 85/15/0%; p&lt;0.0001). Overall survival in A (median 7.4 mo; 95% CI 5.5 – 9.3) compared to R (median 9 mo; 95% CI 7.6 – 10.4) was not significantly different between the two cohorts (p=0.144). When analyzed according to BCLC-stage (B and C), survival in st B pts (A 11.2 vs. R 11.0; p=0.286) as well as st C pts (A 8.9 vs. R 6.4; p=0.62) was not different between the two cohorts. When evaluated according to severity of liver disease (non-cirrhotics/Child-Pugh A and Child-Pugh B), survival in non-cirrhotics/Child-Pugh A patients (A 11.3 mo vs. R 9.0 mo; p=0.746) and Child-Pugh B patients (A 5.5 mo vs. R 3.3 mo; p=0.481) was again not different between these two cohorts. Patients with viral etiology were more common in R (48%) than in A (34%) but not significantly so (p=0.06). Survival in patients with viral (A 10.2 mo vs. R 8.7 mo; p=0.644 ) or non-viral etiology of chronic liver disease (A 6.7 mo vs. R 9.7 mo; p=0.089) was also not significantly different. Conclusions: Overall survival and survival in various subgroups analyzed was not significantly different between the two cohorts. Sorafenib treatment in Russia compared to European Institutions seems to offer a comparable benefit for patients with intermediate/advanced stage HCC, independent of severity or etiology of the underlying liver disease.
Abstract 3654: Recurrent deletions of 3q13.31 in human osteosarcoma commonly affect TUSC7 and LINC00901
Authors: Baptiste Ameline, Michal Kovac, Karim H. Saba, Maxim Barenboim, Michaela Nathrath, Karolin H. Nord, Daniel Baumhoer
Journal: Cancer Research (2019)

Abstract Background: Osteosarcoma, the most common primary tumor of bone, generally harbors complex structural rearrangements. In this study, we identified frequent mono- and bi-allelic deletions of the two long non-coding RNAs TUSC7 and LINC00901, both located on the long arm of chromosome 3 (3q13.31). Their precise biological function remain largely unknown, although it was suggested that TUSC7 may participate in micro-RNA trapping and thereby could be involved in tumor suppressor gene regulation. Moreover, the presence of a TP53 responsive element upstream of their coding region suggests an involvement in the convoluted TP53 signaling pathway. Methods: Whole genome sequencing data (n=104) and Affymetrix Cytoscan arrays (n=52) were used to derive copy-number profiles of each tumor and interrogated for LINC00901 and TUSC7 deletions. These findings were validated in an independent set of 102 formalin-fixed and paraffin-embedded tissue samples using RNA in situ hybridization techniques. Results: Mono- and bi-allelic deletions were detected in 68 (43.5%) sequenced and array-profiled osteosarcomas. Of these, 34 tumors (50%) acquired deletions in both genes whilst additional focal deletions of TUSC7 and LINC00901 were acquired in 11 (16%) and 19 (28%), respectively. The four remaining cases (6%) revealed copy number losses within the intergenic region between TUSC7 and LINC00901. In addition, reduced amounts or complete losses of hybridisation signals were detected in similar proportions in the independent set of FFPE samples. Conclusions: We identified recurrent 3q13.31 deletions in 68/156 (43,5%) human osteosarcomas which seems remarkable in a tumor well known for its high amount of genomic complexity and intertumoral heterogeneity. TUSC7 and LINC00901 might act as downstream effectors of the TP53 pathway and could be functionally equivalent to TP53 inactivation in case of copy number loss. To further elucidate the consequences of 3q13.31 aberrations we aim to correlate our findings with transcriptome data which is currently ongoing. Citation Format: Baptiste Ameline, Michal Kovac, Karim H. Saba, Maxim Barenboim, Michaela Nathrath, Karolin H. Nord, Daniel Baumhoer. Recurrent deletions of 3q13.31 in human osteosarcoma commonly affect TUSC7 and LINC00901 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3654.
Abstract 2183: Protective autophagy elicited by RAF®MEK®ERK inhibition suggests a treatment strategy for pancreatic cancer
Authors: Conan G. Kinsey, Soledad A. Camolotto, Amelie M. Boespflug, Katrin P. Guillen, Mona Foth, Amanda Truong, Sophia S. Schuman, Jill E. Shea, Michael T. Seipp, Jeffrey T. Yap, Lance D. Burrell, David H. Lum, Jonathan R. Whisenant, G. Weldon Gilcrease, Courtney C. Cavalieri, Kaitrin M. Rehbein, Stephanie L. Cutler, Kajsa E. Affolter, Alana L. Welm, Bryan E. Welm, Courtney L. Scaife, Eric L. Snyder, Martin McMahon
Journal: Cancer Research (2019)

Abstract Pancreatic ductal adenocarcinoma was responsible for ~43,000 deaths in the USA in 2017 and is the epitome of a recalcitrant cancer driven by an, as yet, pharmacologically intractable oncoprotein, KRAS. Although the clinical picture remains grim, the mechanisms by which key alterations in tumor suppressors and proto-oncogenes contribute to PDA have been dissected. Downstream of KRAS, the RAF→MEK→ERK signaling pathway plays a central role in pancreatic carcinogenesis. However, to date, pharmacological inhibition of this pathway has provided no clinical benefit to PDA patients. Here we show that inhibition of KRAS→RAF→MEK→ERK signaling in PDA cell lines elicits autophagy, a process of cellular recycling that protects pancreatic cancer cells from the potentially cytotoxic effects of KRAS pathway inhibition. Furthermore, combined inhibition of MEK1/2 plus autophagy displays synergistic anti-proliferative effects against PDA cell lines in vitro, and promotes regression of xenografted patient-derived PDA tumors in mice. Finally, treatment of a PDA patient with the combination of trametinib plus hydroxychloroquine resulted in a partial, but nonetheless striking disease response. These data suggest that this combination therapy may represent a novel strategy to target RAS-driven cancers such as PDA. Citation Format: Conan G. Kinsey, Soledad A. Camolotto, Amelie M. Boespflug, Katrin P. Guillen, Mona Foth, Amanda Truong, Sophia S. Schuman, Jill E. Shea, Michael T. Seipp, Jeffrey T. Yap, Lance D. Burrell, David H. Lum, Jonathan R. Whisenant, G. Weldon Gilcrease, Courtney C. Cavalieri, Kaitrin M. Rehbein, Stephanie L. Cutler, Kajsa E. Affolter, Alana L. Welm, Bryan E. Welm, Courtney L. Scaife, Eric L. Snyder, Martin McMahon. Protective autophagy elicited by RAF®MEK®ERK inhibition suggests a treatment strategy for pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2183.
Dual functionalized liposomes for efficient co-delivery of anti-cancer chemotherapeutics for the treatment of glioblastoma
Authors: Sushant Lakkadwala, Bruna dos Santos Rodrigues, Chengwen Sun, Jagdish Singh
Journal: Journal of Controlled Release (2019)

Glioblastoma is a hostile brain tumor associated with high infiltration leading to poor prognosis. Anti-cancer chemotherapeutic agents have limited access into the brain due to the presence of the blood brain barrier (BBB). In this study, we designed a dual functionalized liposomal delivery system, surface modified with transferrin (Tf) for receptor mediated transcytosis and a cell penetrating peptide-penetratin (Pen) for enhanced cell penetration. We loaded doxorubicin and erlotinib into liposomes to enhance their translocation across the BBB to glioblastoma tumor. In vitro cytotoxicity and hemocompatibility studies demonstrated excellent biocompatibility for in vivo administration. Co-delivery of doxorubicin and erlotinib loaded Tf-Pen liposomes revealed significantly (p < 0.05) higher translocation (~15%) across the co-culture endothelial barrier resulting in regression of tumor in the in vitro brain tumor model. The biodistribution of Tf-Pen liposomes demonstrated ~12 and 3.3 fold increase in doxorubicin and erlotinib accumulation in mice brain, respectively compared to free drugs. In addition, Tf-Pen liposomes showed excellent antitumor efficacy by regressing ~90% of tumor in mice brain with significant increase in the median survival time (36 days) along with no toxicity. Thus, we believe that this study would have high impact for treating patients with glioblastoma.
Role of portal venous platelet activation in patients with decompensated cirrhosis and TIPS
Authors: Alexander Queck, Roberto Carnevale, Frank Erhard Uschner, Robert Schierwagen, Sabine Klein, Christian Jansen, Carsten Meyer, Michael Praktiknjo, Daniel Thomas, Christian Strassburg, Stefan Zeuzem, Francesco Violi, Jonel Trebicka
Journal: Gut (2019)

We read with interest the recent study by Lv et al ,1 who pointed out that transjugular intrahepatic portosystemic shunt (TIPS) placement is feasible for prevention of variceal rebleeding in the majority of cirrhotic patients with portal vein thrombosis and that it is more effective than endoscopic band ligation plus propranolol. Moreover, association with a higher probability of portal vein recanalisation and a lower risk of subsequent rethrombosis was described. However, even after TIPS, in eight out of 24 patients, either portal or superior mesenteric vein thrombosis persisted or reoccurred. While development and progression of splanchnic venous thrombotic events implicate disease progression in cirrhosis,2 their pathogenesis remains unclear. According to Virchow’s triad, pathological coagulation/platelets, decreased flow and impaired vascular wall are the drivers of thrombosis. In TIPS, flow is restored and, to a large extent, also the shear stress (the vascular wall compenent) due to decompression of portal hypertension. However, the prothrombotic milieu (platelet and plasmatic coagulation) has not been investigated to date. One hypothesis for this is the platelet …
Abstract 14136: A Shift of Energy Substrates From Fatty Acid to Glucose Exacerbates Cardiac Dysfunction During Pressure Overload in Mice Deficient in Fatty Acid Binding Protein 4 and 5
Authors: Yogi Umbarawan, Tatsuya Iso, Mas Rizky Aa Syamsunarno, Norimichi Koitabashi, Hiroaki Sunaga, Hiroki Matsui, Masahiko Kurabayashi
Journal: Circulation (2016)

Fatty acid (FA) is central energy substrate for the heart while glucose utilization is dynamically regulated in response to pressure-overload. We recently reported that capillary endothelial FABP4/...
Abstract 2046: Egr-1 promotes bone marrow fibrosis in primary myelofibrosis
Authors: Rekha M. Rao, Amar Kumar, Pratikkumar Vekaria, Abdulraheem Yacoub, Barry Skikne, Joseph McGuirk
Journal: Cancer Research (2019)

Abstract Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) characterized by JAK-STAT-activated proliferation of leukemia cells and progressive bone marrow fibrosis. However little is known about the bone marrow stromal cell (BMSC) intrinsic factors that work in concert with leukemia stem cells (LSCs) to promote fibrosis of the bone marrow in PMF. In this study we developed an in vitro model to simulate bone marrow fibrosis in PMF by exposing cultured BMSC, HS-5 cells to PMF-patient plasma. We observed that exposure of BMSCs to PMF plasma but not normal serum increased total cellular and mitochondrial reactive oxygen species (ROS), as well as Early growth response 1 (Egr-1) and its target gene expression in BMSCs. Egr-1 is a transcription factor that upregulates fibrosis-associated genes, and is acutely induced by numerous cytokines (e.g. TGF-β, PDGFα) that are elevated in PMF. Utilizing this model, we performed RNA sequencing of HS-5 cells exposed to PMF plasma. We observed that PMF plasma exposure alters pathways responsible for multiple DNA damage responses, G1/s cell cycle checkpoint regulation and protein homeostasis. Since PMF progression is associated with enhanced oxidative stress which induces both DNA damage and Egr-1 expression, we determined the effect of anti-oxidants on the induction Egr-1 and fibrosis associated genes in BMSCs following treatment with PMF plasma. We report that treatment with N-acetyl-cysteine (a ROS scavenger) and mitotempo (a mitochondrial ROS scavenger) abrogated the up-regulation of PMF plasma-induced fibrosis-associated genes in BMSCs. Additionally, knockdown of Egr-1 in BMSCs resulted in the down-regulation of collagen 1A1 and connective tissue growth factor (CTGF) following exposure to PMF plasma. These findings suggest that PMF plasma induces ROS and promotes the upregulation of pro-fibrotic genes in an Egr-1-dependent manner in PMF. Our studies suggest that inhibition of ROS and Egr-1-induced gene transcription could be used as a strategy to alleviate bone marrow fibrosis; a disease complication in PMF for which there are no approved therapies. Citation Format: Rekha M. Rao, Amar Kumar, Pratikkumar Vekaria, Abdulraheem Yacoub, Barry Skikne, Joseph McGuirk. Egr-1 promotes bone marrow fibrosis in primary myelofibrosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2046.
Changes in hospital safety following penalties in the US Hospital Acquired Condition Reduction Program: retrospective cohort study
Authors: Roshun Sankaran, Devraj Sukul, Ushapoorna Nuliyalu, Baris Gulseren, Tedi A Engler, Emily Arntson, Hanna Zlotnick, Justin B Dimick, Andrew M Ryan
Journal: BMJ (2019)

Abstract Objective To evaluate the association between hospital penalization in the US Hospital Acquired Condition Reduction Program (HACRP) and subsequent changes in clinical outcomes. Design Regression discontinuity design applied to a retrospective cohort from inpatient Medicare claims. Setting 3238 acute care hospitals in the United States. Participants Medicare fee-for-service beneficiaries discharged from acute care hospitals between 23 July 2014 and 30 November 2016 and eligible for at least one targeted hospital acquired condition (n=15 470 334). Intervention Hospital receipt of a penalty in the first year of the HACRP. Main outcome measures Episode level count of targeted hospital acquired conditions per 1000 episodes, 30 day readmissions, and 30 day mortality. Results Of 724 hospitals penalized under the HACRP in fiscal year 2015, 708 were represented in the study. Mean counts of hospital acquired conditions were 2.72 per 1000 episodes for penalized hospitals and 2.06 per 1000 episodes for non-penalized hospitals; 30 day readmissions were 14.4% and 14.0%, respectively, and 30 day mortality was 9.0% for both hospital groups. Penalized hospitals were more likely to be large, teaching institutions, and have a greater share of patients with low socioeconomic status than non-penalized hospitals. HACRP penalties were associated with a non-significant change of −0.16 hospital acquired conditions per 1000 episodes (95% confidence interval −0.53 to 0.20), −0.36 percentage points in 30 day readmission (−1.06 to 0.33), and −0.04 percentage points in 30 day mortality (−0.59 to 0.52). No clear patterns of clinical improvement were observed across hospital characteristics. Conclusions Penalization was not associated with significant changes in rates of hospital acquired conditions, 30 day readmission, or 30 day mortality, and does not appear to drive meaningful clinical improvements. By disproportionately penalizing hospitals caring for more disadvantaged patients, the HACRP could exacerbate inequities in care.