tbuckley/cabot-search huggingface dataset:
Deletion of the SPARC acidic domain, but not the EGF-like module, affects SPARC-regulated proliferation and signaling through Hsp27 activation
Authors: Heather McClung, Sandra Rempel
Journal: Cancer Research (2008)

LB-35  Secreted Protein Acidic Rich in Cysteine (SPARC) is highly expressed in all grades of astrocytoma. We have previously shown that SPARC increases glioma invasion, while suppressing tumor growth. It is thought that these functions may be independently regulated by different domains within SPARC. To gain insight into these functions, deletion mutant constructs were created. SPARC is composed of an N-terminal acidic domain, a follistatin-like domain, containing an Epidermal Growth Factor (EGF)-like module, and a C-terminal extracellular calcium binding (EC) domain. This study focuses on the acidic domain and the EGF-like module, to determine whether either region contributes to the effects of SPARC on cell proliferation (growth curves and signaling through ERK1/2 and AKT), and/or cell migration (p38 MAPK/Hsp27 pathway). The deletion constructs, lacking either the acidic domain or the EGF-like module, were created from a parental vector encoding SPARC with a C-terminal Green Fluorescent Protein (GFP) tag. U87 cells were stably transfected with GFP vector, SPARC-GFP, or either of the deletion mutants. Clones were selected and expression and intracellular localization were determined by fluorescence imaging. The expression levels and secretion of each of the constructs were determined by Western blot analysis. Like wildtype SPARC, the intracellular localization for both constructs is perinuclear. Both mutants are secreted and are at the expected size on Western blot, which indicates that they are being expressed and processed normally. To assess the effects on proliferation, growth curves were generated by counting viable cells (trypan exclusion) on days 1, 2, 4, 6, and 8. By day 8, cells expressing the EGF-like module-deletion construct showed a decrease in proliferation compared to control cells (p
Poorly differentiated neuroendocrine carcinoma (NEC G3): Prognostic factors and potential novel targets.
Authors: Maximilian Heetfeld, Atsuko Kasajima, Arend Koch, Francesco Milone, Ingo Steffen, Manfred Dietel, Hironobu Sasano, Bertram Wiedenmann, Marianne E. Pavel
Journal: Journal of Clinical Oncology (2013)

e15071 Background: Poorly differentiated neuroendocrine carcinomas (NEC G3) represent a subgroup of neuroendocrine neoplasms with aggressive clinical behavior and poor prognosis, but showing quite variable clinical courses. In metastatic disease objective response to first-line therapy with cisplatin/ etoposide ranges between 40-67%, however median duration of response is short (4 to 9 months). There is no established second-line therapy. Methods: Clinical data of 42 patients with gastro-entero-pancreatic NEC G3 were analyzed in retrospect. In 26 cases tissue was analyzed for cell size, expression of p-mTOR and downstream effectors (p-eIF4E and p-4EBP1), somatostatin receptor (SSTR)-subtypes and growth factor receptors (EGFR and IGF-1R). Histopathological findings were analyzed using Kaplan-Meier curve, log rank test and Cox regression. Results: Patients with large cell NEC showed a more favorable survival than patients with small cell NEC. Median overall survival (mOS) was 31 versus 11 months (P=0.034). Expression of p-mTOR and p-eIF4E was seen in 64% and 24% of cases. High expression levels of p-mTOR (mOS 9 vs 25 months, P=0.026) and expression of p-eIF4E (mOS 9 vs 25 months, P=0.015) was significantly associated with shorter survival. In multivariate Cox regression p-mTOR and p-eIF4E proved to be independent prognostic factors for survival taking cell size and TNM staging into account. EGFR (cytoplasmatic and nuclear) and IGF-1R expression was found in 73.1%, 65.4% and 69.2% of the cases respectively, without significant association to survival. Expression of SSTR subtypes, Ki67 value and response to first line chemotherapy was not of prognostic value analyzed by log rank test. Conclusions: The clinical impact of cell size discrimination requires further evaluation in NEC G3. The mTOR pathway seems to play a role in tumor growth in some NEC and may represent a novel therapeutic target.
Molecular genetics and response to PCV chemotherapy in previously untreated oligodendroglial neoplasms
Authors: Carol Walker, Brian Haylock, David Husband, Kathy Joyce, Diane Fildes, Michael D. Jenkinson, Trevor Smith, John Broome, Daniel Du Plessis, Peter C. Warnke
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

2160 

Loss of chromosomes 1p and 19q has been associated with prolonged survival and chemosensitivity in oligodendroglial neoplasms, based mainly on retrospective studies, but the impact of molecular genetics in routine clinical practice is unknown. Aim. The goal was to investigate the influence of genotype on the response of primary oligodendroglial neoplasms to procarbazine, lomustine and vincristine (PCV) chemotherapy in a prospective routine clinical setting. Methods. Fifty patients with oligodendroglial neoplasms treated at a single center between 2000 and 2003 received a median of 4 cycles of PCV (range 0-6) as initial therapy. Response was assessed using Macdonald criteria and T1-weighted MR or CT images taken with contrast agents for enhancing tumors or T2-weighted MR images for non-enhancing tumors. Allelic imbalance in 1p36, 19q13, 17p13, 10p12-15 and 10q22-26 and p53 mutation (exons 5-8) were investigated using tumor samples enriched by laser capture microdissection. Results. The -1p/-19q genotype was seen in 8/13 oligodendroglioma WHO grade II, 7/20 oligoastrocytoma WHO grade II, 6/7 oligodendroglioma WHO grade III and 3/10 oligoastrocytoma WHO grade III and was inversely associated with p53 mutation and loss of 17p13. Response was significantly associated with the -1p/-19q genotype in the series as a whole (n=42; Fisher Exact: p= 0.001) and in grade II tumors (n=32; Fisher Exact: p= 0.022) . In grade III cases, response was associated with the -1p/-19q genotype without additional genetic alterations in the loci investigated (n=10; Fisher Exact: p= 0.048). Six enhancing and two non-enhancing tumors without the -1p/-19q genotype also responded. Five had p53 mutation, one had loss of 1p36 and chromosome 10 but not 19q13 and two had no detectable genetic alterations in the loci investigated. The -1p/-19q genotype had more effect on progression-free survival (PFS) than overall survival (OS) and was associated with longer PFS in univariate and multivariate analysis (Log Rank: PFS - p=0.006; OS - p=0.076; Cox Regression: PFS - p=0.001) . The -1p/-19q genotype without additional genetic alterations was associated with prolonged OS (Log Rank: p=0.003) . Conclusion. The -1p/-19q genotype was predictive of chemosensitivity in previously untreated grade II and III oligodendroglial neoplasms, but knowledge of additional genetic alterations gave improved prognostic stratification in anaplastic tumors. However 31% of cases with intact 1p/19q also benefited from PCV chemotherapy.
Factors Associated With Progression and Outcomes of Early Stage Primary Biliary Cholangitis
Authors: Nikolaos K. Gatselis, Jorn C. Goet, Kalliopi Zachou, Willem J. Lammers, Harry L.A. Janssen, Gideon Hirschfield, Christophe Corpechot, Keith D. Lindor, Pietro Invernizzi, Marlyn J. Mayo, Pier Maria Battezzati, Annarosa Floreani, Albert Pares, Vasiliki Lygoura, Frederik Nevens, Andrew L. Mason, Kris V. Kowdley, Cyriel Y. Ponsioen, Tony Bruns, Douglas Thorburn, Xavier Verhelst, Maren H. Harms, Henk R. van Buuren, Bettina E. Hansen, George N. Dalekos
Journal: Clinical Gastroenterology and Hepatology (2019)
CPX Targeting DJ-1 Triggers ROS-induced Cell Death and Protective Autophagy in Colorectal Cancer
Authors: Jing Zhou, Lu Zhang, Meng Wang, Li Zhou, Xuping Feng, Linli Yu, Jiang Lan, Wei Gao, Chundong Zhang, Youquan Bu, Canhua Huang, Haiyuan Zhang, Yunlong Lei
Journal: Theranostics (2019)

Rationale: Colorectal cancer (CRC) is one of the most common cancers worldwide. Ciclopirox olamine (CPX) has recently been identified to be a promising anticancer candidate; however, novel activities and detailed mechanisms remain to be uncovered. Methods: The cytotoxic potential of CPX towards CRC cells was examined in vitro and in vivo. The global gene expression pattern, ROS levels, mitochondrial function, autophagy, apoptosis, etc. were determined between control and CPX-treated CRC cells. Results: We found that CPX inhibited CRC growth by inhibiting proliferation and inducing apoptosis both in vitro and in vivo. The anti-cancer effects of CPX involved the downregulation of DJ-1, and overexpression of DJ-1 could reverse the cytotoxic effect of CPX on CRC cells. The loss of DJ-1 resulted in mitochondrial dysfunction and ROS accumulation, thus leading to CRC growth inhibition. The cytoprotective autophagy was provoked simultaneously, and blocking autophagy pharmacologically or genetically could further enhance the anti-cancer efficacy of CPX. Conclusion: Our study demonstrates that DJ-1 loss-induced ROS accumulation plays a pivotal role in CPX-mediated CRC inhibition, providing a further understanding for CRC treatment via modulating compensatory protective autophagy.
Whole Grains and Risk of Hepatocellular Carcinoma—Missing the Forest for the Trees?—In Reply
Authors: Wanshui Yang, Edward Giovannucci, Xuehong Zhang
Journal: JAMA Oncology (2019)

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Epidemiology of Chlamydia trachomatis in the Middle East and north Africa: a systematic review, meta-analysis, and meta-regression
Authors: Alex Smolak, Hiam Chemaitelly, Joumana G Hermez, Nicola Low, Laith J Abu-Raddad
Journal: The Lancet Global Health (2019)

The epidemiology of Chlamydia trachomatis in the Middle East and north Africa is poorly understood. We aimed to provide a comprehensive epidemiological assessment of C trachomatis infection in the Middle East and north Africa.We did a systematic review of C trachomatis infection as well as a meta-analysis and meta-regression of C trachomatis prevalence. We searched PubMed and Embase, as well as regional and national databases up to March 13, 2019, using broad search terms with no language or year restrictions. Any document or report including biological measures for C trachomatis prevalence or incidence was eligible for inclusion. We extracted all measures of current (genital or rectal), recent, and ever infection with C trachomatis. We estimated pooled average prevalence in different populations using random-effects meta-analysis. Factors associated with prevalence and sources of between-study heterogeneity were determined using meta-regression.We identified a total of 1531 citations, of which 255 reports contributed to 552 C trachomatis prevalence measures from 20 countries. No incidence measures were identified. Pooled prevalence of current genital infection was 3·0% (95% CI 2·3-3·8) in general populations, 2·8% (1·0-5·2) in intermediate-risk populations, 13·2% (7·2-20·7) in female sex workers, 11·3% (9·0-13·7) in infertility clinic attendees, 12·4% (7·9-17·7) in women with miscarriage, 12·4% (9·4-15·7) in symptomatic women, and 17·4% (12·5-22·8) in symptomatic men. Pooled prevalence of current rectal infection was 7·7% (4·2-12·0) in men who have sex with men. Substantial between-study heterogeneity was found. Multivariable meta-regression explained 29·0% of variation. Population type was most strongly associated with prevalence. Additional associations were found with assay type, sample size, country, and sex, but not with sampling methodology or response rate (about 90% of studies used convenience sampling and >75% had unclear response rate). There was no evidence for temporal variation in prevalence between 1982 and 2018.C trachomatis prevalence in the Middle East and north Africa is similar to other regions, but higher than expected given its sexually conservative norms. High prevalence in infertility clinic attendees and in women with miscarriage suggests a potential role for C trachomatis in poor reproductive health outcomes in this region.National Priorities Research Program from the Qatar National Research Fund (a member of Qatar Foundation).
MRI lesions in the sacroiliac joints of patients with spondyloarthritis: an update of definitions and validation by the ASAS MRI working group
Authors: Walter P Maksymowych, Robert GW Lambert, Mikkel Østergaard, Susanne Juhl Pedersen, Pedro M Machado, Ulrich Weber, Alexander N Bennett, Juergen Braun, Ruben Burgos-Vargas, Manouk de Hooge, Atul A Deodhar, Iris Eshed, Anne Grethe Jurik, Kay-Geert Armin Hermann, Robert BM Landewé, Helena Marzo-Ortega, Victoria Navarro-Compán, Denis Poddubnyy, Monique Reijnierse, Martin Rudwaleit, Joachim Sieper, Filip E Van den Bosch, Désirée van der Heijde, Irene E van der Horst-Bruinsma, Stephanie Wichuk, Xenofon Baraliakos
Journal: Annals of the Rheumatic Diseases (2019)

Objectives The Assessment of SpondyloArthritis international Society (ASAS) MRI working group (WG) was convened to generate a consensus update on standardised definitions for MRI lesions in the sacroiliac joint (SIJ) of patients with spondyloarthritis (SpA), and to conduct preliminary validation. Methods The literature pertaining to these MRI lesion definitions was discussed at three meetings of the group. 25 investigators (20 rheumatologists, 5 radiologists) determined which definitions should be retained or required revision, and which required a new definition. Lesion definitions were assessed in a multi-reader validation exercise using 278 MRI scans from the ASAS classification cohort by global assessment (lesion present/absent) and detailed scoring (inflammation and structural). Reliability of detection of lesions was analysed using kappa statistics and the intraclass correlation coefficient (ICC). Results No revisions were made to the current ASAS definition of a positive SIJ MRI or definitions for subchondral inflammation and sclerosis. The following definitions were revised: capsulitis, enthesitis, fat lesion and erosion. New definitions were developed for joint space enhancement, joint space fluid, fat metaplasia in an erosion cavity, ankylosis and bone bud. The most frequently detected structural lesion, erosion, was detected almost as reliably as subchondral inflammation (κappa/ICC:0.61/0.54 and 0.60/0.83) . Fat metaplasia in an erosion cavity and ankylosis were also reliably detected despite their low frequency (κappa/ICC:0.50/0.37 and 0.58/0.97). Conclusion The ASAS-MRI WG concluded that several definitions required revision and some new definitions were necessary. Multi-reader validation demonstrated substantial reliability for the most frequently detected lesions and comparable reliability between active and structural lesions.
Molecular gene expression profiling to predict the tissue of origin and direct site-specific therapy in patients (pts) with carcinoma of unknown primary site (CUP): Results of a prospective Sarah Cannon Research Institute (SCRI) trial.
Authors: Frank A. Greco, Mark S. Rubin, Ralph V. Boccia, Michael A. Scola, David R. Spigel, Samuel Raby, Thabiso W. Chirwa, Raven Quinn, Catherine A. Schnabel, Mark G. Erlander, John D. Hainsworth
Journal: Journal of Clinical Oncology (2012)

10530 Background: Tumor profiling is an emergent technique to determine tissue of origin in CUP patients. However, the value of these predictions in improving treatment efficacy is unknown. In this prospective trial, we used tumor profiling results to direct site-specific therapy for CUP pts. Methods: A 92-gene RT-PCR assay (CancerTYPE ID; bioTheranostics, Inc.) was performed on tumor biopsies from previously untreated CUP pts who consented. When a tissue of origin was predicted, pts who were treatment candidates were assigned standard site-specific first-line therapy. Results: Between 10/08 and 12/11, 289 pts were enrolled, 252 had successful assays performed, and 247 (98%) had a tissue of origin predicted. 224 pts were eligible for treatment; 197 pts received assay-directed treatment. 120 of 224 treated pts (54%) had assay diagnoses of tumor types known to derive substantial benefit from standard site-specific treatment (bladder 27, colorectal 26, NSCLC 24, breast 10, ovary 10, kidney 9, prostate 4, germ cell 4, others 6 (3 sites), while 104 pts (46%) had assay diagnoses of relatively resistant tumors (biliary tract 45, pancreas 12, gastroesophageal 10, liver 7, sarcoma 5, cervix 5, others 20 (8 sites). Median OS for all treated pts was 10.8 months (mos); OS for 197 pts with assay-directed treatment was 12.2 mos (versus 6.0 mos for 27 pts receiving empiric therapy). Median OS was better in the 120 pts with assay diagnoses of more responsive tumor types (12.8 vs 7.4 mos; p = .027). Median OS (mos) in specific subgroups: pancreas 9, kidney 12, colon 12, NSCLC 16, ovary 30. Conclusions: This is the first prospective trial in which molecular profiling has directed site-specific therapy in CUP pts. Assay-directed therapy in 197 pts produced a median OS (12.2 mos) that compares favorably with previous empiric CUP therapy. CUP pts predicted to have more responsive tumor types had longer survival compared to less responsive types, suggesting accurate identification by the assay. These results strengthen the rationale for molecular profiling in CUP management.
NCIC IND.190: A phase I trial of MK-0646 in combination with cisplatin and etoposide in extensive-stage small cell lung cancer (ES SCLC).
Authors: Peter Michael Ellis, Frances A. Shepherd, Scott Andrew Laurie, Glenwood D. Goss, Martin Sebastian Olivo, Jean Powers, Wendy Walsh, Lesley Seymour, Penelope Ann Bradbury
Journal: Journal of Clinical Oncology (2012)

7093 Background: Increased serum levels of insulin like growth factor (IGF), plus overexpression of the IGF-receptor (IGFR) are implicated in SCLC cell growth and proliferation, making suppression of the IGFR a potential therapeutic target. MK-0646 is a monoclonal antibody directed against the IGFR. The aim of this study was to determine the recommended phase II dose (RP2D) of cisplatin, etoposide plus MK-0646. Methods: We conducted a phase I study of two dose levels of MK-0646 (DL1 5mg/kg, DL2 10mg/kg IV weekly) in combination with cisplatin (25mg/m 2 ) and etoposide (100mg/m 2 ) IV D1-3, q21d, for patients with chemotherapy-naive ES SCLC, PS 0-2. Patients with treated stable brain metastases were eligible. Patients completing 4-6 cycles of combination therapy could continue single agent MK-0646 until disease progression. Primary outcome was determination of the RP2D. Secondary outcomes included ORR (RECIST 1.1), and toxicity (CTCAEv3). Results: A total of 12 patients were treated (DL1 – 3, DL2 – 9). The median age was 63 years (48-70), with 6 males and 6 females. Most subjects were good ECOG PS (PS 1 – 8, PS 2 – 4) and had 4 or more sites of disease (n=8). No DLTs were observed in DL1 or DL2. In an expanded DL2 cohort, 1 patient died from neutropenic sepsis during cycle 1. The median number of treatment cycles of chemotherapy was 4 (DL1) or 5 (DL2) and MK-0646 was 6 (DL1&amp;2). Dose delays were observed for chemotherapy (DL1 - 2, DL2 – 6) and MK-0646 (DL1 – 3, DL2 – 7). The confirmed ORR was 72.7% (PR 8, SD 2, PD 1, non-evaluable 1). Grade ≥3 toxicities (any cycle) occurring in more than 1 patient included: neutropenia (92%); thrombocytopenia (25%); leukopenia (50%); anemia (17%); fatigue (33%); joint pain (17%); thrombosis (25%). Grade 2 or 3 hyperglycemia was observed in 1 of 3 (DL1) and 5 of 9 (DL2). Eight SAEs were observed in 3 patients (thrombosis, febrile neutropenia, infection, syncope, fatigue 2, dyspnea, back pain). Conclusions: MK-0646 can be combined at full dose with standard doses of cisplatin and etoposide (25mg/m 2 and 100mg/m 2 D1-3) with a RP2D of MK-0646 10mg/kg/week. The observed toxicities are consistent with that expected from cisplatin and etoposide except for hyperglycemia, which appears dose dependent.
Combination of bortezomib with a FLT3 inhibitor potentiates inhibition of proliferation and apoptosis of AML in vitro
Authors: P. C. Cheng, J. Crane, T. Hunter
Journal: Journal of Clinical Oncology (2009)

e14551 Background: FLT3 receptor tyrosine kinase activating mutations contribute to leukemogenesis and poor prognosis in approximately 30% of acute myeloid leukemia (AML). An internal tandem duplication (ITD) mutation in the juxtamembrane domain of FLT3 results in loss of autoinhibition that leads to constitutive, ligand-independent activation of the receptor, with subsequent activation of multiple downstream signaling pathways, including RAS/MAPK and STAT5. Early phase clinical trials of FLT3 inhibitors show a lack of durability of responses, suggesting combination therapy may work better. Methods: In the course of conducting a synthetic lethality screen with a FLT3 inhibitor on the Ba/F3 murine cell line stably expressing human FLT3 or FLT3-ITD, we identified bortezomib, a proteasome inhibitor, as having potent activity against FLT3-ITD cells. The effects of drugs on proliferation, apoptosis, and phosphosignaling were quantified in Ba/F3 cells and in the HL60 (WT FLT3) and MV4–11 (FLT3-ITD) human cell lines, using an MTS- based colorimetric assay, caspase 3 and 7 activity assays, and immunoblotting, respectively. Results: A highly potent and specific FLT3 inhibitor was shown to have an IC50 of 1.9 nM, inhibiting proliferation, inducing apoptosis, and abrogating downstream STAT5 and ERK phosphorylation in FLT3-ITD cells. The IC50 of bortezomib for FLT3-ITD cells was 10 nM as compared to an IC50 of 40 nM for WT FLT3 cells. Surprisingly, bortezomib abrogated tyrosine phosphorylation of FLT3, STAT5, and ERK within 60 min of adding drug. When the FLT3 inhibitor and bortezomib were used at IC25 concentrations, a more pronounced inhibition of cell proliferation was observed when they were used in combination than with either alone. Conclusions: Bortezomib preferentially kills FLT3- ITD cells, showing a four-fold more potent inhibition of cell proliferation, induces apoptosis, and abrogates activation of FLT3 and its downstream effector pathways. The combination of proteasome inhibition with FLT3 inhibition results in enhanced cytotoxicity. The mechanism by which bortezomib affects the FLT3-ITD signaling axis and the possible synergy with FLT3 inhibitors remains to be elucidated. No significant financial relationships to disclose.