tbuckley/cabot-search huggingface dataset:
Glioblastoma cell migration mediated by HGF is modulated by serum with variable participation of Met-related pseudopodial proteins
Authors: Marie Beckner, Wendy Fellows-Mayle, Naomi Agostino, Ian Pollack
Journal: Cancer Research (2007)

1357  Glioblastomas are deadly, invasive brain tumors. Once the blood brain barrier becomes defective, common in glioblastomas, blood components potentially become influencing factors on tumor invasion. Cell migration, stimulated by growth factors in tumors, is a vital step during malignant invasion that can be studied in vitro. As chemoattractants, hepatocyte growth factor/scatter factor (HGF) and fetal bovine serum, alone or combined, stimulated normoxic migration of 7 cell lines and primary glioblastoma cells aspirated from a clinical specimen. Migration in Boyden chambers was either maximally stimulated by combined HGF and serum up to 6.33-fold levels of unstimulated migration, or serum alone maximized cell motility to a lesser extent. Dose curves of serum augmented HGF-stimulated cell migration in a variable but cell-specific manner. Two glioblastoma cell lines tested displayed different sensitivities to inhibition of heat shock protein 90 (HSP90), whose clientale includes Met and many of its downstream proteins. The IC50s of radicicol, a HSP90 inhibitor, for U87 and LN229 cell migration in normoxia were 52.9 and 30.1 μM, respectively, and in glycolytic conditions (chemical hypoxia generated with sodium azide) the IC50s were 38.0 and 26.7 μM, respectively. Invasive migration of U87 cells for 7 days through cultured 1 mm rat brain slices to their bottom edges was enhanced 2.5-fold by a gradient of HGF and serum under glycolytic conditions. Basal (unstimulated) levels of Met varied 21.8-fold among whole cell lysates of motile cell lines equalized for total protein but these levels did not predict levels of cell migration. Pseudopodial lysates from U87 and LN229 cells, stimulated by HGF and serum, contained 6.37 and 5.50-fold increased phosphorylated Met, respectively, and 3.03 and 2.29-fold increased HGF, respectively, compared to unmigrated cell lysates. Levels of proteins downstream from Met, such as cortactin, Raf, Akt, and ATP citrate lyase, varied several fold in pseudopodia compared to unmigrated cells when lysates were equalized for glyceraldehyde-3-phosphate dehydrogenase (GAPDH) or total protein. Migration of glioblastoma cells to HGF, with or without serum co-stimulation, and localization of HGF and its receptor to pseudopodia indicated that Met is part of the “motogenic signature” in glioblastomas. However, cell migration mediated by HGF/Met is modulated by serum in a heterogeneous pattern and with variable participation of the downstream network of proteins in pseudopodia. Further definition of the “motogenic signature” in glioblastomas, including what can be identified in clinical samples of migrated cells and their pseudopodia, is needed to develop anti-invasion therapies that synergize with anti-HGF/Met drugs. We thank The Nick Eric Wichman Foundation, The Beez Foundation, and The Walter L. Copeland Fund of The Pittsburgh Foundation for support.
Identification of early alterations during hepatic oncogenesis in c-Myc/Tgfα transgenic mice by transcriptome analysis
Authors: Cedric Coulouarn, Valentina Factor, Pal Kaposi-Novak, Snorri Thorgeirsson
Journal: Cancer Research (2007)

3848  Hepatocellular carcinoma (HCC) is one of the most common cancers in the world, accounting for an estimated 600,000 deaths annually. Although much is known about both the etiological agents and the cellular changes that lead to HCC, the molecular pathogenesis of HCC is not well understood, partly due to the difficulty of analyzing the early stages of the disease. In this context, genetically engineered mice that recapitulate human HCC are valuable experimental models for a sequential analysis of tumor development. We previously reported that the gene expression profiles of HCCs derived from c-Myc/Tgfα transgenic mice closely reproduce those observed in a subset of human HCC with a poor prognosis (Nat. Genet., 36:1306-11, 2004). Here, we report a detailed characterization of HCC development in c-Myc/Tgfα mice starting from the early to late stages based on gene expression profiles. The tumor development in c-Myc/Tgfα mice was associated with progressive and cumulative transcriptional alterations. Already in 3 week old mice, microarray analysis revealed an induction of genes involved in replication (e.g. Mcm6, Mcm7, Myc), DNA repair (e.g. Ddb2, Rad51l1) and translation (e.g. Eef1b2, Eef2, Rpl13) characteristic of an active hepatocyte proliferation. Livers of 3 month old mice showed more extensive dysplastic changes, frequent mitosis, as well as the first signs of genomic instability along with an elevated production of reactive oxygen species. These cellular alterations coincided with an oxidative stress gene expression signature with the up-regulation of genes involved in DNA repair (e.g. Ddb2, Mlh1, Msh3, Rad51ap1), fatty acid beta-oxidation (e.g. Acaa1b, Acadm), and detoxication (e.g. Gsta1, Ugt1a9). At eight months, 100% of mice developed HCC in a background of wide-spread hepatic dysplasia. The gene expression profiles in the livers of 3 month old mice were highly similar to those of surrounding non-tumorous livers of 8 month old mice. However, the most noticeable difference was the simultaneous induction of ligands for natural killer cells (e.g. Raet1a-e) and the repression of MHC-I, specifically at 3 months. Flow cytometry experiments on purified hepatocytes confirmed these results that could be interpreted as an early mechanism of immunosurveillance to prevent the emergence and clonal expansion of progenitors for liver tumors. We conclude that tumor development in c-Myc/Tgfα mice results from a progressive accumulation of genetic alterations due to both a general metabolic disorder generating a chronic oxidative stress environment and an active hepatocyte proliferation. Moreover, our study strongly suggests that a disruption of the innate immune surveillance may contribute to a rapid selection of tumor clones at the early stages of hepatocarcinogenesis.
Selenium nanoparticles as new strategy to potentiate γδ T cell anti-tumor cytotoxicity through upregulation of tubulin-α acetylation
Authors: Yi Hu, Ting Liu, Jingxia Li, Fengyi Mai, Jiawei Li, Yan Chen, Yanyun Jing, Xin Dong, Li Lin, Junyi He, Yan Xu, Changliang Shan, Jianlei Hao, Zhinan Yin, Tianfeng Chen, Yangzhe Wu
Journal: Biomaterials (2019)

Immune cell therapy presents a paradigm for the treatment of malignant tumors. Human Vγ9Vδ2 T cells, a subset of peripheral γδ T cells, have been shown to have promising anti-tumor activity. However, new methodology on how to achieve a stronger anti-tumor activity of Vγ9Vδ2 T cells is under continuous investigation. In this work, we used selenium nanoparticles (SeNPs) to strengthen the anti-tumor cytotoxicity of Vγ9Vδ2 T cells. We found SeNPs pretreated γδ T cells had significantly stronger cancer killing and tumor growth inhibition efficacy when compared with γδ T cells alone. Simultaneously, SeNPs pretreatment could significantly upregulate the expression of cytotoxicity related molecules including NKG2D, CD16, and IFN-γ, meanwhile, downregulate PD-1 expression of γδ T cells. Importantly, we observed that SeNPs promoted tubulin acetylation modification in γδ T cells through interaction between microtubule network and lysosomes since the latter is the primary resident station of SeNPs shown by confocal visualization. In conclusion, SeNPs could significantly potentiate anti-tumor cytotoxicity of Vγ9Vδ2 T cells, and both cytotoxicity related molecules and tubulin acetylation were involved in fine-tuning γδ T cell toxicity against cancer cells. Our present work demonstrated a new strategy for further enhancing anti-tumor cytotoxicity of human Vγ9Vδ2 T cells by using SeNPs-based nanotechnology, not gene modification, implicating SeNPs-based nanotechnology had a promising clinical perspective in the γδ T cell immunotherapy for malignant tumors.
Association between breast cancer and estrogen receptor gene polymorphism PVU II
Authors: K. Neuss, D. Elling, I. Cascorbi, D. Lueftner
Journal: Journal of Clinical Oncology (2006)

643 Background: The estrogen receptor (ER) is well acknowledged as a prognostic factor in breast cancer, and it is a prerequisite to use the predictive information for hormonal therapy. We investigated whether that the different polymorphisms of the estrogen receptor could influence its expression or functionality. Methods: DNA was extracted from white blood cells of 236 breast cancer patients and 236 healthy, matched controls. The ER genotypes were determined by polymerase chain reaction (PCR) amplification followed by restriction enzyme digestion of the PCR product. Results were shown by electrophoreses. Clinical data such as histologic types, pTNM stage and patients age were available for statistical analyses. Results: We found a statistically significant correlation between the estrogen receptor polymorphism pattern and breast cancer. The receptor type PP was detected statistically significantly more often in postmenopausal breast cancer patients (PP vs pp+Pp, p =0.03). However, there was no correlation to the histobiochemical receptor status or UICC-Stadium. Conclusions: These results show an association between the estrogen receptor polymorphism and breast cancer. It seems to be that a complete lack of the p-allel is a risk factor to develop breast cancer at postmenopausal age. There was no influence on estrogen receptor expression or clinical tumor stage. Thus, we propose that there is no clinical use for estrogen receptor polymorphism analyses at this stage. No significant financial relationships to disclose.
Identification of molecular biomarkers for head and neck cancer progression
Authors: Rifat Hasina, Farhad Sigari, Winston Kuo, Leslie Martin, Mark Lingen
Journal: Cancer Research (2008)

1806  Our ability to diagnose and prevent oral cancer is hampered by a lack of unique, reliable, quantifiable, easily measured biomarkers that correlate well with disease progression. The current criteria for identifying pre-malignant lesions of the oral cavity require the identification of nuclear and/or cellular atypia. However, since morphological or cytological changes occur late in the molecular process of transformation, histologically benign appearing lesions may already have malignant potential and severely dysplastic oral lesions can undergo spontaneous regression. A method for detecting molecularly premalignant lesions at an early stage and for predicting the likelihood of their malignant progression is required. Our hypothesis is that molecular profiling in conjunction with multi-tiered high throughput validation will greatly improve diagnostic prediction compared to the cellular pattern recognition currently used. Our goal is to identify a panel of biomarkers that will allow identification of molecularly premalignant as well as histologically dysplastic lesions that are more likely to progress to cancer. In order to achieve our goal, we collected pure populations of tumor cells from 50 patients with Head and Neck Squamous Cell Carcinoma (HNSCC) and normal keratinocytes from healthy, non-smoking volunteers by laser capture microdissection. The total RNA was collected, amplified and gene expression profiling of approximately 23,000 genes using the Affymetrix gene chip platform was performed. The top 200 genes that were consistently up regulated in cancer compared to the normal references were considered for initial evaluation. Of those, 15 genes were subsequently selected as potential Oral Progression Markers (OPM) that were validated by immunohistochemical staining of custom human Tissue Micro Arrays (TMA) containing normal, dysplastic and cancer samples. This collection of OPMs may provide us with biomarkers that are capable of stratifying a given oral lesion into high and low risk categories. Furthermore, the identification of genes whose expressions are markedly altered in the majority of oral cancers when compared to normal mucosa may provide further insights into the important genotypic and phenotypic alterations that are necessary for oral cancer development.
Treatment of Critical‐Sized Calvarial Defects in Rats with Preimplanted Transplants
Authors: Baptiste Charbonnier, Mohamed Abdulla, Andrew Gorgy, Hani Shash, Zishuai Zhang, Uwe Gbureck, Ed Harvey, Nicholas Makhoul, Mirko Gilardino, Jake Barralet
Journal: Advanced Healthcare Materials (2019)

Abstract The local environment and the defect features have made the skull one of the most difficult regions to repair. Finding alternative strategies to repair large cranial defects, thereby avoiding the current limitations of autograft or polymeric and ceramic prostheses constitute an unmet need. In this study, the regeneration of an 8 mm critical‐sized calvarial defect treated by autograft or by a monetite scaffold directly placed in the defect or preimplanted (either cranial bone transplant or subcutaneous pocket) and then transplanted within the bone defect is compared. The data reveal that transplantation of preimplanted monetite transplant scaffolds greatly improves the skull vault closure compared to subcutaneously preimplanted or directly placed materials. Autografts, while clearly filling the defect volume with bone appear effective since bone volume inside the defect volume is obviously high, but are not well fused to the skull. The preimplantation site has a large influence on the regeneration of the defect. Transplantation of induced bone inside materials has the potential to reduce the need for autograft harvest without damaging the skeleton. This first demonstration indicates that cranial repair may be possible without recourse to bioactives or cultured cell therapies.
Abstract 17370: Multiple Pregnancy Factors and Later Hypertension in Swedish Women From the Vasterbotten Intervention Programme
Authors: Nisha Parikh, Margareta Norberg, Erik Ingelsson, Sven Cnattingius, Ramachandran S Vasan, Magnus Domellöf, Jan Håkan, Anna-Karin Edstedt Bonamy
Journal: Circulation (2015)

Introduction: Pregnancy is considered a maternal cardiometabolic stress test. However, it is uncertain when considered together, which set of pregnancy characteristics independently relate to later hypertension (HTN) in women. Methods: We used Swedish Medical Birth Register data linked with the Vasterbotten Intervention Programme cohort from Northern Sweden. Using logistic regression analysis in crude and multivariable adjusted models, we related pregnancy factors in any prior pregnancy with HTN at age 40 years in parous women free of prepregnancy HTN. Pregnancy factors included parity, age at first delivery, infertility ≥ 5 years, preeclampsia, delivering a small for gestational age baby (SGA, &lt; 3rd percentile for birthweight), gestational age (shortest), placental abruption and gestational diabetes. We defined HTN as systolic BP ≥ 140 and/or DBP ≥ 90 mmHg and/or antihypertensive use. Multivariable models were adjusted for all pregnancy factors as well as for potential confounders including household income, education, smoking, alcohol intake and body mass index. Results: Among n=15,900 women, 1,535 women (9.6%) had HTN at age 40 years. In multivariable models, younger age at first birth, preeclampsia, gestational age &lt; 32 weeks and SGA, were associated with HTN (Table). Gestational diabetes and stillbirth were related to HTN in unadjusted models but not in multivariable models. Parity, infertility and placental abruption were not related to HTN at age 40 years in crude or multivariable models. Conclusions: Younger age at first birth, preeclampsia and delivering a very preterm or small for gestational age baby were independently associated with maternal hypertension at age 40 years upon accounting for sociodemographic and lifestyle factors. Our findings, if confirmed, raise the possibility that earlier and more frequent BP screening may be desirable in women with these pregnancy characteristics.
CXCL12 stimulates ADAM-mediated amphiregulin shedding in hormone-insensitive prostate cancer cells.
Authors: Sathish Kasina, Jill Macoska
Journal: Cancer Research (2008)

5103  Background: Proteolytic processing of epidermal growth factor receptor (EGFR) ligands, such as Amphiregulin (AREG), by ADAMs (A Disintegrin And Metalloprotease) can be stimulated by G protein-coupled receptor (GPCR) agonists, growth factors and cytokines. The CXC-type chemokine, CXCL12, interacts with the GPCR, CXCR4. The CXCL12/CXCR axis has also been shown to mediate gene transcription and cellular proliferation in non-transformed prostate epithelial cells, as well as motility/invasiveness in transformed cells. In this report, we investigated the ability of CXCL12 to stimulate AREG shedding in androgen-insensitive N15C6 and PC3 prostate epithelial cells, both of which respond proliferatively to sub-nanomolar levels of CXCL12 and AREG.  Methods: N15C6 or PC3 prostate epithelial cells were treated with 10pM (N15C6) or 100pM (PC3) CXCL12 in serum-free media, the media collected at 4 hrs post-treatment, concentrated, and assessed by ELISA to quantitate AREG secretion. ADAM activation was assessed at 1 and 4 hrs post-treatment with CXCL12 by Western blot analysis. Inhibitor experiments utilized a broad-spectrum metalloprotease inhibitor, o-phenanthroline (OPT) at 500uM, a selective PKC inhibitor, bisindolylmaleimide I (BIS I) at 2uM, and a selective inhibitor of the Src family of tyrosine kinases, 4-Amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]- pyrimidine (PP1) at 10uM, or vehicle control (0.1% methanol for OPT and 0.022% DMSO for BISI and PP1).  Results: These studies showed that AREG shedding was stimulated by CXCL12 in N15C6 cells, but was constitutive in PC3 prostate epithelial cells. Moreover, treatment with sub-nanomolar levels of CXCL12 stimulated a rapid and robust ADAM10 activation and a more latent and much less robust ADAM 17 activation in N15C6 cells, while PC3 cells showed only a latent and low-level activation of ADAM10 and of ADAM 17. Pre-treatment with broad-spectrum metalloprotease inhibitor, OPT blocked CXCL12-stimulated ADAM10 activation and AREG shedding in N15C6 cells. Pre-treatment with BIS I or with PP1 prior to stimulation with CXCL12 reduced AREG shedding to basal and/or below basal levels, suggesting that both PKC and Src activation are important for CXCL12/CXCR4-mediated AREG shedding in N15C6 cells. The combined data suggest a mechanism whereby CXCL12/CXCR4 interactions activate Src and PKC, which subsequently activate ADAM10, which mediates AREG cleavage and shedding in N15C6 cells.
Physical Activity and the Risk of Liver Cancer: A Systematic Review and Meta-Analysis of Prospective Studies and a Bias Analysis
Authors: Sebastian E Baumeister, Michael F Leitzmann, Jakob Linseisen, Sabrina Schlesinger
Journal: JNCI Journal of the National Cancer Institute (2019)

Abstract Background Physical inactivity is an established risk factor for several cancers of the digestive system and female reproductive organs, but the evidence for liver cancers is less conclusive. Methods The aim of this study was to synthesize prospective observational studies on the association of physical activity and liver cancer risk by means of a systematic review and meta-analysis. We searched Medline, Embase, and Scopus from inception to January 2019 for prospective studies investigating the association of physical activity and liver cancer risk. We calculated mean hazard ratios (HRs) and 95% confidence intervals (CIs) using a random-effects model. We quantified the extent to which an unmeasured confounder or an unaccounted selection variable could shift the mean hazard ratio to the null. Results Fourteen prospective studies, including 6,440 liver cancers, were included in the systematic review and meta-analysis. The mean hazard ratio for high compared with low physical activity was 0.75 (95% CI = 0.63 to 0.89; 95% prediction interval = 0.52 to 1.07; I² = 64.2%). We estimated that 67.6% (95% CI = 56.6% to 78.5%) of all true effect estimates would have a hazard ratio less than 0.8. Bias analysis suggested than an unobserved confounder would have to be associated with a 1.99-fold increase in the risk of physical activity or liver cancer to explain away the observed mean hazard ratio. An unaccounted for selection variable would have to be related to exposure and endpoint with a relative risk of 1.58 to explain away the mean hazard ratio. Conclusions Physical activity is inversely related to the risk of liver cancer. Further studies with objectively measured physical activity and quasi-experimental designs addressing confounding are needed.
Gene expression profiling (GEP)-defined risk and molecular subgroups assessed at baseline and at relapse: Collective impact on post-relapse survival of multiple myeloma (MM) treated with total therapies 2 and 3
Authors: B. Nair, J. Shaughnessy, Y. Alsayed, J. Haessler, F. van Rhee, K. Hollmig, M. Pineda-Roman, J. Crowley, B. Barlogie
Journal: Journal of Clinical Oncology (2009)

8589 Background: GEP-defined risk has evolved as the most robust predictor of overall and event-free survival (OS, EFS) in MM with TT2 and TT3 protocols, distinguishing 85% with low-risk (LR) and 15% with high-risk (HR). Upon relapse, the original risk designation may change typically in the direction LR to HR. Here we examine, among patients with available GEP data at baseline (BL) and relapse (REL), the contributions of both observations on post-relapse survival (PRS). Methods: Paired REL-BL GEP data were available in 77 patients, while information on metaphase cytogenetic abnormalities (CA) was obtained in 76 patients at both time-points. Results: PRS was significantly affected by both BL and REL HR status so that, among the 52 patients with LR at BL, HR status at REL conferred significantly poorer outcome compared to those with LR at REL (p=0.0005) with 30-mo estimates of 71% v 13%; likewise, among the 25 patients with HR at baseline, HR present also at relapse further diminished PRS (p=0.09) with 30-mo estimates in both settings of less than 20%. Similar considerations for CA status revealed, among the 29 patients without CA at BL, marked attrition of PRS with CA v no CA at REL with 30-mo estimates of 29% v 81% (p=0.04); for the 47 patients with CA at BL, CA also at REL further diminished the poor PRS from 46% to 22% (p=0.06). When all standard BL and REL prognostic factors were examined in a multivariate model, GEP-derived HR contributed to poor PRS both when present at BL (HR=2.79, p=0.005) and at REL (HR=2.77, p=0.002), in addition to CA at BL (HR=2.44, p=0.018). Conclusions: In estimating PRS in TT protocols, genetic characteristics at BL (HR, CA) have enduring adverse consequences aggravated further by HR status at REL. Therefore, in HR/CA BL settings, aiming at REL prevention appears as the best overall treatment strategy. [Table: see text]