tbuckley/cabot-search huggingface dataset:
Abstract 4591: Differential expression of tight junction polarity genes in human colon cancer
Authors: Kathryn E. Royse, Liang Chen, Jocelyn Uriostegui, Michael Ittmann, David Y. Graham, Hashem El-Serag, Li Jiao
Journal: Cancer Research (2015)

Abstract Tight junctions perform significant and multifactorial functions in cellular polarity maintenance and paracellular transport. A number of studies have found structural disruption of epithelial colon cells can significantly impact early tumorigenesis and progression. However, little is known about the direct contribution of polarity gene expression in human colon cancer development. We compared the expression of tight junction genes in colon cancer with normal control mucosa. Total RNA was extracted from fresh frozen tissue biopsies of six white male patients (N = 3 for early stage tumore, N = 3 for late stage tumor, and N = 2 for normal adjacent controls) and four unrelated normal colon mucosa from polyp-free individuals. We used the Qiagen RT2 Profiler PCR array to determine the expression of 84 genes in the tight junction pathway. Student's t test was used to compare the expression levels between different groups (control vs. early-stage tumor and late-stage tumor) using normalized gene expression data. Functional annotation clustering of statistically significant genes by group was conducted using DAVID. Significant (P&amp;lt;0.05) down regulation of claudin (CLDN5, CLDN6, CLDN7) expression was seen in both early and late-stage tumor compared with controls, all with fold change (FC)&amp;gt; 2; while CLDN1 (FC = 15) was only significantly upregulated (P = 0.0007) in early-stage tumor. Down regulation (FC&amp;gt;2) of polarity complex gene PARD6A (P&amp;lt;.001) and associated genes (JAM2, P&amp;lt;.001 and JAM3, P &amp;lt;.001) were present in both early and late-stage tumors along with associated down-regulation of tumor suppressor PTEN (P&amp;lt;.0001). We found differential expression of tight junction genes in normal versus colon tumor. Down regulation of polarity genes is likely to affect apico-basal polarity and promote random non-coordinated migration which can lead to disruption of epithelial structure and to carcinogenic tissue infiltration. Further larger studies are warranted to investigate the role of tight junction proteins in the progression of human colon tumor. Citation Format: Kathryn E. Royse, Liang Chen, Jocelyn Uriostegui, Michael Ittmann, David Y. Graham, Hashem El-Serag, Li Jiao. Differential expression of tight junction polarity genes in human colon cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4591. doi:10.1158/1538-7445.AM2015-4591
Abstract 5255: miR-21 expression in HER2-positive breast cancer and prediction of resistance to adjuvant trastuzumab
Authors: Boye S. Nielsen, Eva Balslev, Tim S. Poulsen, Dorte Nielsen, Trine S. Moller, Christiane E. Mortensen, Kim S. Holmstrom, Estrid Hoegdall
Journal: Cancer Research (2015)

Abstract Trastuzumab is established as standard care for patients with HER2-positive breast cancer both in the adjuvant and metastatic setting. However, approximately 50% of the patients do not respond to the trastuzumab therapy, and therefore new predictive biomarkers are highly warranted. MicroRNAs (miRs) constitute an interesting group of biomarkers and their cellular expression can be determined in tumor samples by in situ hybridization (ISH) analysis. miR-21 is highly prevalent and up-regulated in breast cancer and has been linked to drug resistance in clinical and in vitro settings. To determine expression patterns of miR-21 in high-grade breast cancers, we examined miR-21 expression in 22 HER2-positive tumors and 15 HER2-negative high-grade tumors by ISH. The histological examination indicated that patient samples could be divided into 3 major expression patterns: miR-21 predominantly in tumor stroma, predominantly in cancer cells or in both stromal and cancer cells. There was no obvious difference between the HER2-positive and HER2-negative tumors in terms of the miR-21 expression patterns and intensities. To explore the possibility that miR-21 expression levels and/or cellular localization could predict resistance to adjuvant trastuzumab in HER2-positive breast cancer patients, we analyzed additional 16 HER2-positive tumors from patients that were treated with trastuzumab in the adjuvant setting. Eight of the 16 patients showed clinical recurrence and were considered resistant. Examination of the miR-21 expression patterns and intensities revealed no association between the miR-21 scores in the cancer cell population (p = 0.69) or the stromal cells population (p = 0.13) and recurrent disease after adjuvant trastuzumab. Thus, our findings suggest that elevated miR-21 expression does not predict resistance to adjuvant trastuzumab. Citation Format: Boye S. Nielsen, Eva Balslev, Tim S. Poulsen, Dorte Nielsen, Trine S. Moller, Christiane E. Mortensen, Kim S. Holmstrom, Estrid Hoegdall. miR-21 expression in HER2-positive breast cancer and prediction of resistance to adjuvant trastuzumab. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5255. doi:10.1158/1538-7445.AM2015-5255
Deletion of Bak and Bax in Tie2+ BM Hematopoietic Stem Cells Induces a B Cell Lymphoproliferative Disorder.
Authors: Phuong L. Doan, J. Lauren Russell, Sarah K. Meadows, Heather A. Himburg, Pamela Daher, Nelson J. Chao, David G. Kirsch, John P. Chute
Journal: Blood (2009)
247. Characterization of Oversized rAAV Vectors for Human FVIII Gene Transfer
Authors: Sirkka Kyostio-Moore, Patricia Berthelette, Susan Piraino, Cathleen Sookdeo, Bindu Nambiar, Robert Jackson, Brenda Burnham, Catherine O'Riordan, Seng H. Cheng, Armentano Donna
Journal: Molecular Therapy (2015)

Severe hemophilia A patients with <1% coagulation activity are currently managed by infusions of recombinant factor VIII (FVIII). As periodic infusions generate trough levels of FVIII that are non-optimal, painful and debilitating joint deteriorations caused by spontaneous joint bleeds remain prevalent. Clinical trials have demonstrated that a single intravenous injection of rAAV vectors encoding FIX in hemophilia B patients can provide steady-state factor IX levels for > 4 years and consequent reduction or elimination of the need for frequent factor infusions. Similar rAAV-mediated gene transfer for hemophilia A patients is challenging due to the size of the FVIII cDNA that when combined with the necessary transcriptional elements exceeds the rAAV packaging limit of 4.7 kb. To test the feasibility of rAAV-mediated gene therapy for hemophilia A, we generated several oversized FVIII expression cassettes of different lengths and containing human B-domain deleted FVIII cDNA. These constructs were used to produce rAAV vectors by triple transfection and virus quality and yield were analyzed. Characterization of the packaged vector genomes (VGs) by Southern blot showed that the majority of genomes were 4.7 kb in size (with some being larger) and that the vector yield was affected by VG size. The vectors were also administered intravenously into C57BL/6 mice to test in vivo potency. Plasma FVIII levels were measured for 7 months post-treatment and at the end of the study, levels of FVIII mRNA and liver VG copies were quantitated. The data showed intact expression cassettes and comparable number of VG copies in liver among the vectors. Also, the higher liver mRNA levels correlated with higher plasma FVIII levels indicating that expression levels were a limiting factor. Lastly, the rAAV vector ranking was similar to ranking of plasmid expression cassettes (hydrodynamic injections) in vivo. These studies confirmed the viability of oversized rAAV vectors as an approach for the treatment of severe hemophilia A.
Abstract 1234: Impact of cancer-associated mutations on MDM2 function
Authors: Krishna M. Chauhan, Luis A. Martinez
Journal: Cancer Research (2015)

Abstract MDM2 is an E3 ubiquitin ligase that functions as a negative regulator of the tumor suppressor p53. MDM2 can promote the ubiquitination and proteasomal degradation through 26S proteasome. In addition to p53, MDM2 can ubiquitinate and promote the degradation of other proteins including SLUG, PCNA, and TERT. Although MDM2 has a well accepted role as an oncogene in human cancer, it also exhibits the ability to suppress the SLUG-driven epithelial mesenchymal transition (EMT) that is a key component of the metastasis process. The fact that MDM2 is required to suppress the SLUG-driven epithelial mesenchymal transition (EMT) led us to speculate that mutations in the MDM2 gene might impair the proteasomal degradation of key regulatory proteins that control biological events and thereby contribute to tumorogenesis. Here, we studied twenty-one somatic point mutants in MDM2 that occur in human cancer. We find that seven of these MDM2 mutants have lost the capacity to degrade p53. Of these mutants, three have lost the capacity to polyubiquitinate and two do not interact with p53. Additionally, we found that two of the mutants exhibit enhanced ability to degrade p53. We also assessed whether these mutants impacted the ability of mdm2 to degrade SLUG. Although previous studies have shown that MDM2 needs to form a trimeric complex with p53 and SLUG in order for degradation of the latter, we find that MDM2 efficiently degraded SLUG in the absence of p53. Furthermore, MDM2 mutants that do not interact with p53 still retain the ability to degrade SLUG. Our study indicates that mutations in MDM2 can yield mutant proteins that exhibit distinct capacities to degrade its substrates. Further, in vitro and in vivo studies will address the impact of these mutations on the oncogenic properties of MDM2. Citation Format: Krishna M. Chauhan, Luis A. Martinez. Impact of cancer-associated mutations on MDM2 function. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1234. doi:10.1158/1538-7445.AM2015-1234
Abstract 723: GRB7 promotes doxorubicin resistance in triple-negative breast cancer cells via multiple signaling pathways
Authors: Kristopher A. Lofgren, Verónica Calvo, Orsi Giricz, Paraic A. Kenny
Journal: Cancer Research (2015)

Abstract Triple-negative breast cancer (TNBC) lacks expression of the estrogen and progesterone steroid receptors and HER2; thus TNBC patients cannot benefit from the recent successes of targeted therapies, and instead rely on cytotoxic chemotherapeutic cocktails. As such, tumor recurrence is high and patient prognosis is poor. GRB7 is a soluble adaptor protein required for cell migration, invasion, and proliferation in TNBC. We have previously reported that a high GRB7 mRNA level was the strongest predictor of tumor recurrence in a cohort of 246 TNBC patients treated with doxorubicin. GRB7 was confirmed in a smaller, independent cohort as an indicator of poor prognosis. After the observation of both decreased doxorubicin sensitivity and elevated GRB7 expression levels in TNBC tumors, we hypothesized that GRB7 was mediating a signaling pathway critical for drug resistance and cell survival. The current study utilizes isogenic MDA-MB-231 breast cancer cell lines to examine the impact of altered GRB7 levels on TNBC cell signaling and chemosensitivity. Through stable overexpression and knock-down of GRB7, we have identified multiple downstream kinases with altered phosphorylation in basal growth conditions (Akt, Erk, and Jnk) that remain responsive to EGF stimulation. Treatment of TNBC cell lines with G7-18NATE, a specific peptide inhibitor of GRB7, sensitized TNBC cells to doxorubicin. Therefore, we created stable cell lines with constitutively active Akt and Map2k1 and the overexpression of MKK7 in order to determine whether the activation of these kinases individually have novel roles in GRB7-mediated chemoresistance and TNBC cell biology associated with the malignant phenotype, such as cell migration and invasion. This study provides a strong rationale for targeting GRB7 or GRB7-dependent pathways in combination with cytotoxic chemotherapy for GRB7-high TNBC patients. Delineating the signaling events downstream of GRB7 in TNBC could provide further insight into improving the therapeutic index with combinatorial approaches. Citation Format: Kristopher A. Lofgren, Verónica Calvo, Orsi Giricz, Paraic A. Kenny. GRB7 promotes doxorubicin resistance in triple-negative breast cancer cells via multiple signaling pathways. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 723. doi:10.1158/1538-7445.AM2015-723
Abstract 324: High throughput triculture: A breast cancer spheroid model for drug screening
Authors: Gabriel J. Benton, Gerald DeGray, Irina Arnaoutova, Hynda K. Kleinman, Jay George
Journal: Cancer Research (2015)

Abstract Many drugs that show promise in preclinical evaluation fail miserably during clinical trials, and the inability of current preclinical models to properly predict drug response may be attributed to oversimplified or non-existent tumor microenvironments. To provide a more physiologically predictive model for drug screening, we have developed an in vitro, 384 well, triculture system that presents key chemical (i.e. low pH, low glucose, low oxygen), extracellular matrix (ECM), and cellular (tumor cells, stromal cells and endothelial cells) attributes of tumor tissues. By using ECM proteins, we can promote the proper physiology for each of these cell types in triculture. To evaluate interactions between each cell type, they are fluorescently labeled with fluorophores with different excitation and emission spectra; MCF7 and MDA-MB-231 human breast cancer cell lines express a red fluorescence protein, while human umbilical vein endothelial cells (HUVECs) and human adipose-derived mesenchymal stem cells (hMSCs) are labeled with stable lipophilic membrane dyes. Breast tumor microtissues spontaneously assemble when breast cancer cells are co-cultured with hMSCs under low adhesion conditions. Once formed, these microtissues are deposited onto preformed tubule networks comprised of HUVECs and hMSCs and are embedded within a hydrogel composed of ECM proteins. Cellular interactions and dissemination are monitored via fluorescence microscopy, and cell proliferation of the breast cancer cells is quantified using a fluorescence plate reader. The breast cancer cells exhibit cell-cell interactions with endothelial tubules and stromal cells, forming microtissues. Furthermore, the response to anti-cancer drugs, paclitaxel and fluorouracil, in an in vitro triculture system is similar to the response for the same drugs in xenografts model, unlike 2D or 3D monoculture. This high throughput triculture cancer model will provide more insight into pathological mechanisms and can better predict response to anti-cancer drug treatment. Citation Format: Gabriel J. Benton, Gerald DeGray, Irina Arnaoutova, Hynda K. Kleinman, Jay George. High throughput triculture: A breast cancer spheroid model for drug screening. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 324. doi:10.1158/1538-7445.AM2015-324
Commentary: “The political response has been dismal”
Authors: Sarah Wollaston
Journal: BMJ (2017)

The current pressures in the NHS can be traced back to 2009 and what became known as the Nicholson challenge. In the aftermath of the economic crash this ushered in an unprecedented period of efficiency savings against a headwind of rapidly rising demand and costs. The incoming coalition government then imposed a disruptive and demoralising reorganisation that distracted from the key challenges. Rather than seizing the opportunity to integrate health and social care and to design a sustainable long term financial settlement, the Health and Social Care Act 2012 led to greater fragmentation at a time when our demographic changes demanded a different approach.

In the decade to 2015, the number of people living to age 85 and beyond increased by 31%.1 That is a cause for celebration, but there has been a striking failure to plan for what this means for health and social care. The same is true for the rapidly rising cost of preventable conditions and expensive new drugs and technologies.

Over the last parliament, funding for the NHS increased annually by an average of just 1.1%, …
Abstract 3698: The landscape of published cancer meta-analyses: a descriptive look from 2008-2013
Authors: Ximena V. Qadir, Mindy Clyne, Tram K. Lam, Muin J. Khoury, Sheri D. Schully
Journal: Cancer Research (2015)

Abstract Cancer epidemiology has undergone rapid growth in the past two decades. This rapid expansion of scientific literature in cancer epidemiology has required scientists to increasingly look towards meta-analyses to help navigate the “sea of literature”. Knowledge integration has facilitated the movement of translation of scientific findings into clinical applications, evidence-based recommendations and population health impact. Performing meta-analysis has allowed scientists to filter through large datasets and translate these scientific or clinical findings effectively. To our knowledge, there has never been a systematic attempt to compile meta-analyses in cancer. Here, we describe the landscape of cancer meta-analyses including publication production stratified by year, cancer outcome measures, study design, cancer type, journal and country leaders in the field. To ascertain human cancer meta-analytical studies published in the scientific literature during the years 2008 through 2013, we searched PubMed using a text query and the Human Genome Epidemiology (HuGE) Navigator. Two reviewers read through abstracts to determine whether the articles met inclusion criteria. Articles were included if there was a meta-analytical analysis of a human cancer measurement and met one of the following outcome criteria: 1) risk of disease, 2) diagnostic measure, 3) prognostic measure, 4) treatment of disease, including long-term survival and/or adverse events and 5) screening for disease. Coding of articles involved extracting information from the Medline version of each PubMed article reference (i.e. Journal title, year of publication, first author location and cancer-site mesh terms), and by manually reviewing abstracts for classification on the human cancer outcome measurement and other manually coded information. A total of 4,007 cancer meta-analyses were captured by PubMed from 2008 to 2013. Our systematic review of cancer meta-analyses publications indicates a rapid growth of cancer meta-analyses worldwide with 20% production in the past 6-year time period. Furthermore, PLoS One and Asian Pacific Journal of Cancer Prevention were recorded as the top two publishers in the research field. Genomic, clinical and modifiable cancer risk factors were captured as the top leading cancer meta-analyses studies. Observational studies were captured as the leading meta-analyses study design. In the past five years there was an increased wide distribution of meta-analyses on all cancer types. Citation Format: Ximena V. Qadir, Mindy Clyne, Tram K. Lam, Muin J. Khoury, Sheri D. Schully. The landscape of published cancer meta-analyses: a descriptive look from 2008-2013. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3698. doi:10.1158/1538-7445.AM2015-3698
A Humanized HLA-DR Antibody (HU1D10, Apolizumab) in Combination with G-CSF (Filgrastim) for the Treatment of Non-Hodgkin’s Lymphoma: A Pilot Study.
Authors: Juergen Rech, Roland Repp, Dorit Rech, Bernhard Stockmeyer, Michael Dechant, Gerald Niedobitek, Tilman Pearce, Georg Weiner, Martin Gramatzki, Thomas Valerius
Journal: Blood (2005)
Effect of bendamustine on apoptosis and colony-initiating precursors in Hodgkin lymphoma cells.
Authors: R. De Filippi, D. Aldinucci, D. Galati, A. Esposito, C. Borghese, S. Crisci, G. Abagnale, E. Morelli, F. Frigeri, G. Corazzelli, A. Pinto
Journal: Journal of Clinical Oncology (2011)

e18559 Background: Hodgkin lymphoma (HL) recurring after stem cell transplantation is incurable and active agents are needed in this setting. Bendamustine is a bi-functional alkylator active in non-Hodgkin lymphoma. Activity of bendamustine towards tumor cells of HL has never been previously described. Methods: A panel of human cell lines (L1236, L428, KMH2, HDLM2, L540), validated models for HL, was studied. Cells were exposed to increasing concentrations of bendamustine (12.5 to 100 µmol/L) and analyzed for proliferation, apoptosis and cell cycle changes. Effect of bendamustine on HL clonogenic precursors was assessed by primary/secondary methylcellulose assays and colony cells characterization (CD30, aldehyde dehydrogenase [ALDH] or Hoechst [Hcst]-33342). Results: Bendamustine displayed a significant time- and dose-dependent antiproliferative effect on all HL cell lines, with an observed IC50 between 25-50 µmol/L at 48 hrs. In all lines, at least 50% of cells showed Annexin-V binding following 24 hrs of exposure to concentrations lower than 100 µmol/L, with 70% to 90% of apoptotic cells at longer times (48-72 hrs). Sensitivity to Bendamustine of HL cells was independent from the presence of p53 mutations. In all HL lines, exposure to a concentration as low as 25 µmol/L induced >50% of cells to accumulate in the G2/M phase of the cell cycle with presence of tetraploid nuclei witnessing mitotic defects. Finally, a 24 hr-exposure to very low concentrations (IC50: 17-38 µmol/L) of bendamustine was able to inhibit primary colony formation in all HL cell lines irrespective of p53 status. Intriguingly, a significantly lower concentration of the agent (IC50: 3.1-15.0 µmol/L) was able to suppress formation of secondary colonies, which were sustained, in L428 and KMH2 cells, by CD30+/ALDH)hi or Hcsthi precursor cells. Conclusions: Bendamustine displays marked antiproliferative and pro-apototic effects on cultured HL cells, irrespective of p53 status, by promoting G2/M arrest and changes compatible with mitotic catastrophe. HL colony-initiating precursors are highly sensitive to extremely low concentrations of the agent. Clinical testing of bendamustine in HL both as single agent and in combination is warranted.