tbuckley/cabot-search huggingface dataset:
Abstract 1958: Developing an online tool to validate survival-associated miRNAs utilizing expression data from 2,061 breast cancer patients
Authors: Balázs Győrffy, András Lánczky, Giulia Bottai, Ádám Nagy, András Szabó, Libero Santarpia
Journal: Cancer Research (2016)

Abstract Background. MicroRNAs (miRNAs) are small non-coding RNAs capable of simultaneously regulating multiple gene networks, and affecting breast cancer patients’ outcome. Here we present the development of an online tool for the real-time meta-analysis of published miRNA datasets to identify novel prognostic biomarkers in breast cancer. Methods. First, a comprehensive database was set up by searching GEO, TCGA, and PubMed repositories to identify datasets with published miRNA expression and clinical data. Due to platform differences, each dataset was processed separately. Kaplan-Meier and Cox regression analyses were performed to investigate the prognostic value of a set of dysregulated miRNAs in breast cancer. The complete analysis tool can be accessed online at: www.kmplot.com/mirna. Results. Overall, 2,061 samples from four independent datasets were integrated into the tool including the expression signature of 1,302 distinct miRNAs. In addition to overall survival data, ER status (n = 2,039), histological grade (n = 1,396) and lymph node status (n = 1,933) are also available. By using our online tool, we demonstrated the prognostic value of some of the previous reported miRNAs implicated in breast cancer. For instance, miR-29c, miR-34c, miR-101, miR-125, and miR-190b, showed a consistent prognostic value in at least three out of four breast cancer datasets. Discussion. In summary, we established the first online integrated platform for the rapid identification of the prognostic value of miRNAs in breast cancer. Citation Format: Balázs Győrffy, András Lánczky, Giulia Bottai, Ádám Nagy, András Szabó, Libero Santarpia. Developing an online tool to validate survival-associated miRNAs utilizing expression data from 2,061 breast cancer patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1958.
Chemotherapy remains an essential element of personalized care for persons with lung cancers
Authors: M.D. Hellmann, B.T. Li, J.E. Chaft, M.G. Kris
Journal: Annals of Oncology (2016)

Molecularly targeted and immunotherapies have improved the care of patients with lung cancers. These successes have rallied calls to replace or avoid chemotherapy. Yet, even in this era of precision medicine and exciting advances, cytotoxic chemotherapies remain an essential component of lung cancer treatment. In the setting of locoregional disease, chemotherapy is the only systemic therapy thus far proven to enhance curability when combined with surgery or radiation. In the metastatic setting, chemotherapy can improve the length and quality of life in many patients. Chemotherapy remains the mainstay of care for individuals whose cancers with oncogenic drivers have acquired resistance to targeted agents. Chemotherapy also has the potential to modulate the immune system to enhance the effectiveness of immune checkpoint inhibitors. In this context, chemotherapy should be framed as a critical component of the armamentarium available for optimizing cancer care rather than an unfortunate anachronism. We examine the role of chemotherapy with precision medicine in the current care of patients with lung cancers, as well as opportunities for future integration in combinations with targeted agents, angiogenesis inhibitors, immunotherapies, and antibody drug conjugates.
Adipose-Resident Group 1 Innate Lymphoid Cells Promote Obesity-Associated Insulin Resistance
Authors: Timothy E. O’Sullivan, Moritz Rapp, Xiying Fan, Orr-El Weizman, Priya Bhardwaj, Nicholas M. Adams, Thierry Walzer, Andrew J. Dannenberg, Joseph C. Sun
Journal: Immunity (2016)
Abstract 5055: SPEN stimulates primary cilia formation, cell migration and is associated with metastasis in breast cancer
Authors: Stéphanie Légaré, Catherine Chabot, Mark Basik
Journal: Cancer Research (2016)

Abstract The primary cilium (PC) is a microtubule-based and non-motile organelle that functions as animal cells’ antennae, regulating a number of signalling pathways, including the mTOR, PDGFR and Wnt pathways, in addition to being essential for activation of the canonical Hedgehog (Hh) pathway. In breast cancer, the PC is a structure that is frequently lost due to transcription- and mutation-driven alterations in cilium-related genes. In a study aiming to delineate the hormone-independent transcriptional program regulated by SPEN, a gene that we have identified as a tumour suppressor gene in estrogen receptor (ER)-positive breast cancers, we found that SPEN was co-expressed (R&amp;gt;0.95) with a number of genes involved in ciliary biology (P = 1.64E-19), including the ciliogenic transcription factors RFX2, RFX3 and FOXJ1. Interestingly, the overexpression of SPEN resulted in the restoration of the PC in T47D cells, which have previously been shown to lack this structure. Consistent with the re-establishment of a PC in T47D cells, SPEN-overexpressing T47D cells had decreased mTOR signalling, hyperactivation of PC-dependent pathways, including the Hh and PDGFR pathways, and increased migration. Silencing SPEN expression in the non-tumorigenic MCF10A cells, which express high endogenous levels of SPEN and show a high prevalence of PC (36%), considerably decreased PC levels in MCF10A cells and was accompanied with increased mTORC1 activity as well as attenuated cell migration. We also found that SPEN silencing in MCF10A cells decreased the expression of the ciliogenic transcription factor RFX3 and that SPEN interacts with DNA upstream of RFX3 gene transcription start site in chromatin immunoprecipitation experiments. Collectively, these observations indicate that SPEN may mediate its effects, at least in part, through the transcriptional regulation of RFX3. Accordingly, RFX3 expression levels were strongly positively correlated (R = 0.55, P&amp;lt;0.0001) with SPEN levels in a cohort of 82 clinical samples from triple negative breast cancer patients. Notably, high SPEN RNA levels were also predictive of early metastasis in two independent cohorts of 77 (HR = 2.25, P = 0.03) and 170 (HR = 2.23, P = 0.004) ER-negative breast cancer patients. Together, our findings highlight a role for SPEN in the regulation of PC formation and support important functions in the inhibition of mTORC1 and activation of Hh and PDGFR pathways as well as cell migration, a process that may contribute to early metastasis in ER-negative breast cancers. Citation Format: Stéphanie Légaré, Catherine Chabot, Mark Basik. SPEN stimulates primary cilia formation, cell migration and is associated with metastasis in breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5055.
Inhibition of heat shock protein 90 (Hsp90) with the novel agent IPI-504 in metastatic GIST following failure of tyrosine kinase inhibitors (TKIs) or other sarcomas: Clinical results from phase I trial
Authors: A. J. Wagner, J. A. Morgan, R. Chugh, L. S. Rosen, S. George, M. S. Gordon, C. M. Devine, A. D. Van den Abbeele, D. Grayzel, G. D. Demetri
Journal: Journal of Clinical Oncology (2008)

10503 Background: Laboratory studies have demonstrated that inhibition of the Hsp90 chaperone protein results in selective destruction of the mutated KIT kinase in human GIST cell lines across multiple genotypes which confer TKI resistance. Other histopathologic subtypes of soft tissue sarcoma (STS) are also sensitive in vitro. To test this clinically, we conducted a phase I trial of IPI-504, a water-soluble Hsp90 inhibitor, for patients (pts) with metastatic, TKI-resistant GIST or metastatic STS. Methods: Pts with metastatic, TKI-resistant GIST or advanced/metastatic STS received IPI-504 in 21 day cycles (IV in 250 cc of normal saline over 30 min) either twice weekly for 2 weeks followed by 1 week off treatment (Schedule A) or twice weekly continuously for 3 weeks (Schedule B). Serial monitoring with 18FDG-PET imaging at baseline, day 11, and day 21, as well as PK profiling of IPI-504 and its major active metabolites (17-AAG and 17-AG) were performed. Results: 54 pts (38 GIST; 16 STS) have been entered at 5 dose levels (90 mg/m2 IPI-504 [n=6], 150 [6], 225 [9], 300 [3], 400 [23] 500 [7]). The GIST pts had progressed despite prior imatinib and sunitinib in 100% and 95% respectively, as well as other agents in 38%. 45/54 pts received Schedule A. The maximum tolerated dose (MTD) was 400 mg/m2 on Schedule A based on 2 DLTs (G3 headache, G3 myalgia) observed at the 500 mg/m2 dose level. In the 18 GIST pts assessed by PET, 22% had a PET partial response and an additional 66% had stable disease according to the EORTC PET response criteria. Although no RECIST- defined responses were observed, 29/37 (78%) evaluable pts had a best response of SD. Conclusions: IPI-504 has been well-tolerated overall and shows promising early evidence of activity in the treatment of pts with TKI-resistant GIST. The MTD for twice-weekly IPI-504 for 2 weeks with 1 week off treatment is 400 mg/m2; expansion of this cohort is ongoing. Targeting Hsp90 represents a novel therapeutic strategy for patients with metastatic GIST. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Infinity Pharmaceuticals Amgen, Ariad, Bayer, Genentech™ BioOncology, GlaxoSmithKline, Human Genome Sciences, Infinity Pharmaceuticals, Johnson & Johnson, Novartis, Pfizer Oncology, PharmaMar Infinity Pharmaceuticals Novartis, Pfizer Oncology, PharmaMar Amgen, Ariad, ArQule, Bristol-Myers Squibb, Exelixis, Genentech™ BioOncology, Infinity Pharmaceuticals, Johnson & Johnson, Novartis, OSI Oncology, Pfizer Oncology, PharmaMar Ariad, GlaxoSmithKline, Infinity Pharmaceuticals, Johnson & Johnson, Novartis, Pfizer Oncology, PharmaMar
Role of T Cell-Derived IL-21 in the Proliferation of Chronic Lymphocytic Leukemia Cells,
Authors: Maria F. Pascutti, Jacqueline M. Tromp, Margot Jak, Ingrid A.M. Derks, Rene A.W. van Lier, Steven T. Pals, Marinus H.J. Van Oers, Arnon P Kater, Eric Eldering
Journal: Blood (2011)
Low Serum Total Protein and Unfavorable Pathological Subtype Are Independent Unfavorable Factors in Peripheral T-Cell Lymphoma (PTCL) Treated in Prospective Clinical Tirals; Japan Clinical Oncology Group (JCOG) 0108A Study.
Authors: Yoshitoyo Kagami, Tomohiro Kinoshita, Takashi Watanabe, Kuniaki Itoh, Harumi Kaba, Kenichi Yoshimura, Motoko Yamaguchi, Mitsutoshi Kurosawa, Kunihiro Tsukasaki, Masaharu Kasai, Kensei Tobinai, Yoshihiro Matsuno, Kiyoshi Mukai, Tomomitsu Hotta, Masanori Shimoyama
Journal: Blood (2007)
Abstract NG01: Accumulation of somatic mutations in normal and cancerous tissues with age
Authors: Margaret L. Hoang, Isaac Kinde, Cristian Tomasetti, Thomas Rosenquist, Arthur P. Grollman, Kenneth W. Kinzler, Bert Vogelstein, Nickolas Papadopoulos
Journal: Cancer Research (2016)

Abstract Fundamental theories in carcinogenesis and aging evoke the accumulation of rare somatic mutations in normal tissues over time. However, absence of a simple and systematic method to characterize somatic mutations in normal tissues precludes the understanding of their functional consequences. We present Bottleneck Sequencing System (BotSeqS), a next-generation sequencing method that quantitates rare somatic point mutations simultaneously across the mitochondrial and nuclear genomes. BotSeqS combines molecular barcoding with a simple dilution step immediately before library amplification. Using BotSeqS, we determine the mutation frequencies and spectra in normal brain, kidney, and colon from a total of 34 individuals ranging from &amp;lt; 1 to 98 years old. We show an age and tissue-dependent accumulation of rare point mutations and demonstrate that the somatic mutational burden in normal tissues can vary by several orders of magnitude depending on biological and environmental factors. For example, individuals with defects in the mismatch repair machinery or exposure to environmental carcinogens (smoking, aristolochic acid) show significant increases in mutational frequencies and altered mutational spectra compared to controls. We further show major differences between the mutational patterns of the mitochondrial and nuclear genomes in normal tissues. Lastly, we find that the mutational spectra of normal tissues were different from each other but similar to cancers from the same tissue type, suggesting that the differential mutational spectra observed in cancers are tissue-specific rather than cancer-specific. This technology can provide insights into the number and nature of genetic alterations in normal tissues and can be used to address a variety of fundamental questions about the genomes of diseased tissues. Citation Format: Margaret L. Hoang, Isaac Kinde, Cristian Tomasetti, Thomas Rosenquist, Arthur P. Grollman, Kenneth W. Kinzler, Bert Vogelstein, Nickolas Papadopoulos. Accumulation of somatic mutations in normal and cancerous tissues with age. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr NG01.
Abstract 348: Small molecule Axl Ig1-Gas6 inhibitors block Gas6-inducible Axl signaling and suppress tumorigenicity
Authors: Nitu Bansal, Stanley Kimani, Kamlendra Singh, Thomas Comollo, Sushil Kumar, Vladyslav Kholodovych, Youyi Peng, William Welsh, Bertino Joseph, Raymond B. Birge
Journal: Cancer Research (2016)

Abstract TAM receptors (Tyro-3, Axl, and Mer) are a family of three homologous receptor tyrosine kinases (RTKs) expressed predominantly on myeloid-derived hematopoietic cells and epithelial cells which function as inhibitory receptors that dampen inflammatory responses and maintain tissue tolerance. Additionally, all three TAMs have been implicated in various human malignancies, where level of expression is often associated with more aggressive staging of the cancers, poorer predicted patient survival, as well as drug-resistant cancers. Over the past several years, considerable effort has been made to generate small molecule tyrosine kinase inhibitors and biological therapeutics (such as monoclonal antibodies and soluble extracellular receptor traps) targeting TAM receptors in human cancers. Early preclinical studies show promising anti-tumor activities using either kinase inhibitors or monoclonal antibodies against Axl and Mer, although cross-reactivity with other tyrosine kinase inhibitors is associated with off-target specificities. Here, we report the development and characterization of a series of small molecule inhibitors that target the interface between the Ig1 domain of Axl and Gas6, and inhibit native receptors and Axl reporter lines with sub-micro-molar affinities. Additionally, these compounds inhibit Gas6 inducible motility and invasion in Axl-expressing cell lines, and suppress tumor growth in xenograft models of non small cell lung cancer. Together, these observations demonstrate that Axl can be targeted by small molecules that bind to the Ig1 domain/Gas6 interaction, and validate Ig1 inhibitors as novel agents for treatment of cancer. Citation Format: Nitu Bansal, Stanley Kimani, Kamlendra Singh, Thomas Comollo, Sushil Kumar, Vladyslav Kholodovych, Youyi Peng, William Welsh, Bertino Joseph, Raymond B. Birge. Small molecule Axl Ig1-Gas6 inhibitors block Gas6-inducible Axl signaling and suppress tumorigenicity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 348.
Open contracting for health services
Authors: Andrew Jack
Journal: BMJ (2016)

More transparency could reduce corruption and get better value for money explains Andrew Jack 

How much of the huge amount spent worldwide every year on health commodities and services actually reaches patients? Procurement and contracting are highly vulnerable to corruption. “Open contracting” aims to make the processes used to purchase government goods and services transparent by publishing the details of contracts online. These can be easily accessed and analysed by the public, private sectors, and civil society. Backers of the approach say that it makes purchases more efficient and fair by boosting competition and accountability and reducing the scope for corruption. It can also help to demonstrate good practices to countries with less experience.

Open Contracting, a US non-profit group that advocates for and advises on the approach, estimates that around …
Abstract 4071: Targeted disruption of T-cell protein tyrosine phosphatase in mouse epidermis reveals its critical role in chemically-induced skin carcinogenesis
Authors: Hyunseung Lee, Mihwa Kim, Liza D. Morales, Thomas J. Slaga, John DiGiovanni, Dae J. Kim
Journal: Cancer Research (2016)

Abstract Environmental factors such as chemical toxicants contribute to the development of skin cancer by creating mutations in housekeeping genes and proto-oncogenes which disrupt intracellular signaling mechanisms. One vital signaling mechanism is tyrosine phosphorylation signaling. Phosphotyrosine signaling is regulated by the counter-activities of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Recently we reported TC-PTP (PTPN2) is critical regulator of STAT3 signaling in mouse keratinocytes. To assess the role of TC-PTP in skin carcinogenesis, we generated epidermal-specific TC-PTP-deficient (K14Cre.PTPN2fl/fl) transgenic mice. Loss of TC-PTP led to a desensitization to tumor initiator 7,12-dimethylbenz[a]anthracene (DMBA)-induced apoptosis both in vivo epidermis and in vitro keratinocytes. TC-PTP deficiency in epidermis resulted in a significant increase in epidermal thickness and hyperproliferation (assessed by bromodeoxyuridine (BrdU) labeling index) compared to control mice following treatment with the tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA). Consistently, primary keratinocytes derived from TC-PTP-deficient mice showed a faster growth rate. To further investigate the role of TC-PTP in skin carcinogenesis, TC-PTP-deficient mice were subjected to two-stage skin carcinogenesis analysis. TC-PTP-deficient mice showed a shortened latency of tumor development and significantly increased numbers of tumors compared to control mice, demonstrating TC-PTP deficiency predisposes mice to skin carcinogenesis. The data reveals TC-PTP may be a novel potential target for the prevention of skin cancer due to its role in the regulation of proliferation and apoptosis in epidermis. Citation Format: Hyunseung Lee, Mihwa Kim, Liza D. Morales, Thomas J. Slaga, John DiGiovanni, Dae J. Kim. Targeted disruption of T-cell protein tyrosine phosphatase in mouse epidermis reveals its critical role in chemically-induced skin carcinogenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4071.
Abstract 4773: Gene-targeted apoptosis as a novel therapeutic strategy for HER2-positive breast cancer
Authors: Faye A. Rogers, Meetu Kaushik
Journal: Cancer Research (2016)

Abstract The ability to target HER2-driven breast cancers using anticancer agents with mechanisms of actions that are independent of the HER2 cellular growth function, represents a powerful new tool to circumvent drug resistance experienced with traditional HER2-targeted therapies. We have discovered that manipulation of the balance between the DNA repair response and apoptotic pathways provides an alternative strategy to induce targeted apoptosis in HER2-amplified breast cancers. Our recent finding that triplex-induced DNA damage can activate apoptosis in human cells has yielded the opportunity to develop a new class of HER2-targeted therapies. Here, we have uncovered the novel finding that triplex-induced apoptosis only occurs when multiple triplex structures are formed, while NER (nucleotide excision repair)-dependent repair prevails in the presence of one or two structures. With this in mind, we have designed sequence-specific DNA-binding molecules that create chromosomal triplex structures and activate tumor-specific apoptosis through the induction of excessive DNA damage at the HER2 locus. Importantly, this only occurs in malignant cells with multiple copies of the HER2 gene. We have evaluated the efficacy of the HER2-targeted triplex-forming molecules using cell growth and apoptosis assays and demonstrate that these molecules are particularly effective in eliciting tumor specific apoptosis in HER2-amplified breast cancer cell lines. Furthermore, these molecules have the ability to suppress the growth and metastasis of human HER2-positive breast cancers in a xenograft mouse model. Moreover, we demonstrate that the NER protein, XPD mediates the survival-death decision in response to triplex-induced DNA damage via a p53-independent mechanism that involves phosphorylation of the H2AX tyrosine 142 residue, which stimulates the signaling pathway to recruit pro-apoptotic factors to the damage site. Our results establish an alternative and novel method to specifically target HER2-positive breast cancers by exploiting the cell's own DNA damage response machinery. This study introduces a new paradigm for gene-targeted drugs that can be used in the treatment of HER2-positive and drug-resistant breast cancers with minimal potential for toxicity to normal tissue. Citation Format: Faye A. Rogers, Meetu Kaushik. Gene-targeted apoptosis as a novel therapeutic strategy for HER2-positive breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4773.
Abstract 2026: DEC1 negatively regulates AMPK activity via LKB1
Authors: Fuyuki Sato, Yasuteru Muragaki
Journal: Cancer Research (2016)

Abstract Basic helix-loop-helix (bHLH) transcription factor DEC1 (bHLHE40/Stra13/Sharp2) is one of the clock genes that show a circadian rhythm in various tissues. AMP-activated protein kinase (AMPK) activity plays important roles in metabolism and in cell death induced by glucose depletion. Recent reports have shown that AMPK activity exhibited a circadian rhythm. However, how the circadian rhythm of AMPK activity is regulated is not known. The aim of this study is the direct correlation between DEC1 expression and AMPK activity. DEC1 protein and AMPK activity showed a circadian rhythm in the mouse liver with different peak levels. A medium change and serum shock led to rhythmic patterns of DEC1 protein and AMPK activity levels in WI-38 cells, and their peak levels occurred at different times. However, changing the medium did not induce circadian rhythms of DEC1 protein or AMPK activity levels in MCF-7 and U2OS cells, in which the intensities of these levels had inversely correlated patterns. Knocking down DEC1 expression increased AMPK activity, whereas DEC1 overexpression decreased it. DEC1 bound to the E-box of the LKB1 promoter, decreasing the LKB1 activity and total protein levels. In addition, knocking down DEC1 expression inhibited cell death under the condition of glucose depletion, increasing the activity of both AMPK and LKB1. Taken together, our results showed that the levels of DEC1 protein and AMPK activity were affected even long after the medium change and that the rhythmic patterns of these levels were inversely correlated. We concluded that DEC1 negatively regulated AMPK activity via LKB1. Citation Format: Fuyuki Sato, Yasuteru Muragaki. DEC1 negatively regulates AMPK activity via LKB1. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2026.