tbuckley/cabot-search huggingface dataset:
Abstract LB-168: MicroRNA-31 initiates lung tumorigenesis and promotes mutant KRAS-driven lung cancer
Authors: Mick D. Edmonds, Kelli L. Boyd, Tamara K. Moyo, Ramkrishna Mitra, Robert J. Duszynski, Maria P. Arrate, Xi Chen, Zhongming Zhao, Timothy S. Blackwell, Christine M. Eischen
Journal: Cancer Research (2016)

Abstract Lung cancer is the leading cause of cancer deaths and yet the genes that drive this malignancy are not entirely known. MicroRNA (miRNA) are important regulators of gene expression and aberrant miRNA expression has been linked to lung oncogenesis; however, little known about their contribution in tumor initiation. We’ve determined that miR-31 is overexpressed in human lung adenocarcinoma and this overexpression independently correlates with decreased patient survival. miR-31 promotes lung cell proliferation and adenocarcinoma growth in vivo. We also developed a transgenic mouse model that allows for lung-specific expression of miR-31 to test the oncogenic potential of miR-31 in the lung. Using this model, we observed that miR-31 induction results in lung hyperplasia, followed by adenoma formation and later adenocarcinoma development. We identified 6 negative regulators of RAS/MAPK signaling (RASA1, SPRED1, SPRED2, SPRY1, SPRY3, SPRY4) as direct targets of miR-31. Analysis of human lung adenocarcinoma revealed that high miR-31 expression correlated to decreased target mRNA expression. miR-31 overexpression in lung cells results in increased RAS signaling and pharmacologic inhibition of MEK ablates miR-31 induced lung cell proliferation. Induced expression of miR-31 in mice cooperated with mutant KRAS to accelerate lung tumorigenesis. Our study demonstrates for the first time that a miRNA can drive an epithelial cancer. Specifically we identified miR-31 as a driver of lung tumorigenesis that promotes mutant KRAS-mediated oncogenesis and demonstrate that miR-31 directly targets and reduces expression of negative regulators of RAS/MAPK signaling. Citation Format: Mick D. Edmonds, Kelli L. Boyd, Tamara K. Moyo, Ramkrishna Mitra, Robert J. Duszynski, Maria P. Arrate, Xi Chen, Zhongming Zhao, Timothy S. Blackwell, Christine M. Eischen. MicroRNA-31 initiates lung tumorigenesis and promotes mutant KRAS-driven lung 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 LB-168.
Temporal and spatial discordance of programmed cell death-ligand 1 expression and lymphocyte tumor infiltration between paired primary lesions and brain metastases in lung cancer
Authors: A.S. Mansfield, M.C. Aubry, J.C. Moser, S.M. Harrington, R.S. Dronca, S.S. Park, H. Dong
Journal: Annals of Oncology (2016)

BackgroundThe dynamics of PD-L1 expression may limit its use as a tissue-based predictive biomarker. We sought to expand our understanding of the dynamics of PD-L1 expression and tumor-infiltrating lymphocytes (TILs) in patients with lung cancer-related brain metastases.Experimental designPaired primary lung cancers and brain metastases were identified and assessed for PD-L1 and CD3 expression by immunohistochemistry. Lesions with 5% or greater PD-L1 expression were considered positive. Agreement statistics and the χ2 or Fisher's exact test were used for analysis.ResultsWe analyzed 146 paired lesions from 73 cases. There was disagreement of tumor cell PD-L1 expression in 10 cases (14%, κ = 0.71), and disagreement of TIL PD-L1 expression in 19 cases (26%, κ = 0.38). Most paired lesions with discordant tumor cell expression of PD-L1 were obtained 6 or more months apart. When specimens were categorized using a proposed tumor microenvironment categorization scheme based on PD-L1 expression and TILs, there were significant changes in the classifications because many of the brain metastases lacked either PD-L1 expression, tumor lymphocyte infiltration or both even when they were present in the primary lung cancer specimens (P = 0.009).ConclusionsWe identified that there are significant differences between the tumor microenvironment of paired primary lung cancers and brain metastases. When physicians decide to treat patients with lung cancer with a PD-1 or PD-L1 inhibitor, they must do so in the context of the spatial and temporal heterogeneity of the tumor microenvironment.
Abstract 687: Critical role and mechanism of WASF3 in HER2/HER3 regulation of breast cancer metastasis
Authors: yong teng, Wenhu Pi, John Cowell
Journal: Cancer Research (2016)

Abstract WASF3 is overexpressed in high-grade breast cancer and promotes invasion and metastasis but does not affect proliferation. The HER2/ERBB2/NEU gene is also frequently overexpressed in breast cancer and has been shown to promote invasion and metastasis in these tumors. Here we show that WASF3 in present in the HER2 immunocomplex and suppression of WASF3 function leads to suppression of invasion even in the presence of HER2 expression. Overexpression of both HER2 and WASF3 in non-metastatic MCF7 breast cancer cells promotes invasion and metastasis more significantly than either gene alone. HER2 forms homodimers as well as heterodimers with other HER family members and we now show that the ability of WASF3 to promote invasion is highly dependent on the HER2/HER3 heterodimer. The engagement of WASF3 with the HER2/HER3 complex facilitates its phospho-activation and transcriptional upregulation, which is facilitated by HER2/HER3 activation of JAK/STAT signaling. In breast cancer cells overexpressing HER2, therefore, WASF3 is specifically required to facilitate the invasion/metastasis response. Targeting WASF3, therefore, could be a potential therapeutic approach to suppress metastasis of HER2-overexpressing breast tumors. Citation Format: yong teng, Wenhu Pi, John Cowell. Critical role and mechanism of WASF3 in HER2/HER3 regulation of breast cancer metastasis. [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 687.
Glycemic Control and the Risk of Tuberculosis: A Cohort Study
Authors: Pin-Hui Lee, Han Fu, Ting-Chun Lai, Chen-Yuan Chiang, Chang-Chuan Chan, Hsien-Ho Lin
Journal: PLoS Medicine (2016)

Diabetes is a well-known risk factor for tuberculosis (TB) and is increasingly prevalent in low- and middle-income countries, where the burden of TB is high. Glycemic control has the potential to modify the risk of TB. However, there are few studies on the association between glycemic control and TB risk, and the results are inconsistent.We assembled a cohort using 123,546 individuals who participated in a community-based health screening service in northern Taiwan from 5 March 2005 to 27 July 2008. Glycemic control was measured using fasting plasma glucose (FPG) at the time of screening. The cohort was followed up to 31 December 2012 for the occurrence of TB by cross-matching the screening database to the national health insurance database. Multiple imputation was used to handle missing information. During a median follow-up of 4.6 y, 327 cases of TB occurred. In the multivariable Cox regression model, diabetic patients with poor glycemic control (FPG > 130 mg/dl) had a significantly higher hazard of TB (adjusted hazard ratio [aHR] 2.21, 95% CI 1.63-2.99, p < 0.001) compared to those without diabetes. The hazard of TB in diabetic patients with good glycemic control (FPG ≤ 130 mg/dl) did not differ significantly from that in nondiabetic individuals (aHR 0.69, 95% CI 0.35-1.36, p = 0.281). In the linear dose-response analysis, the hazard of TB increased with FPG (aHR 1.06 per 10-mg/dl increase in FPG, 95% CI 1.03-1.08, p < 0.001). Assuming the observed association between glycemic control and TB was causal, an estimated 7.5% (95% CI 4.1%-11.5%) of incident TB in the study population could be attributed to poor glycemic control. Limitations of the study include one-time measurement of fasting glucose at baseline and voluntary participation in the health screening service.Good glycemic control could potentially modify the risk of TB among diabetic patients and may contribute to the control of TB in settings where diabetes and TB are prevalent.
Severely obese teens who have bariatric surgery show improved mobility and less pain
Authors: Jacqui Wise
Journal: BMJ (2016)

Severely obese teenagers who undergo bariatric surgery show improved mobility and reduced musculoskeletal pain from walking as much as two years after surgery, a study published in JAMA Pediatrics has found.1

The Teen-Longitudinal Assessment of Bariatric Surgery study included 206 adolescents, with an average age of 17 and an average body mass index of 51.7, who were undergoing …
Follicular lymphoma grade 3B includes three cytogenetically defined subgroups with primary t(14;18), 3q27 or other translocations
Authors: van den Eva Berg-de Ruiter, A Bosga-Bouwer, van Gustaaf Imhoff, R Boonstra, AY van der Veen, E Haralamabieva, van den Arie Berg, B de Jong, Krause, MC Palmer, Philippus Kluin, Sibrand Poppema
Journal: Leukemia (2003)
Abstract 17056: Nanoparticles-mediated Targeting of Pioglitazone Reduces Myocardial Ischemia-reperfusion Injury and Cardiac Remodeling by Antagonizing Monocyte-mediated Inflammation in Preclinical Animal Models
Authors: Masaki Tokutome, Tetsuya Matoba, Yasuhiro Nakano, Kaku Nakano, Kensuke Egashira
Journal: Circulation (2015)

Background: Monocyte-mediated inflammation is a major mechanism of myocardial ischemia-reperfusion (IR) injury and cardiac remodeling. However, no anti-inflammatory therapy has been developed for clinical myocardial IR injury. Pioglitazone, a peroxisome proliferator-activated receptor (PPAR)γ agonist, has unique anti-inflammatory effects on monocyte/macrophage. Here we tested the hypothesis that nanoparticle-mediated targeting of pioglitazone into cardiomyocytes and inflammatory monocytes ameliorates IR injury and cardiac remodeling in preclinical animal models. Methods and Results: We formulated poly (lactic acid/glycolic acid) nanoparticle containing pioglitazone (Pio-NPs). In mouse IR model, nanoparticles were delivered predominantly to circulating monocytes and to cardiomyocytes and macrophages in the IR heart. Intravenous treatment with Pio-NPs containing ≥0.1 mg/kg of pioglitazone at the time of reperfusion reduced IR injury, which was canceled by the pretreatment with PPARγ antagonist GW9662 (Fig. A). In contrast, pioglitazone solution at doses up to 3.0 mg/kg showed no therapeutic effects (Fig. A). Pio-NPs reduced inflammatory gene expression and inhibited the recruitment of Ly6Chigh inflammatory monocytes into IR heart (Fig. B). Pio-NPs showed no therapeutic effects in mice lacking CCR2. In a mouse model of myocardial infarction, intravenous treatment with Pio-NPs for 3 days after LAD ligation attenuated cardiac remodeling, improved cardiac function, and reduced recruitment of macrophage and polarization of macrophages toward M2 phenotype (Fig. C, D). Finally, in a mini-pig model of myocardial IR injury, Pio-NPs induced cardioprotection from IR injury, indicating the pre-clinical proof of concept. Conclusion: Nanoparticle-mediated targeting of pioglitazone into cardiomyocytes and monocytes can be developed as a novel modality that offers organ protection by antagonizing monocyte-mediated inflammation in acute MI.
Biomarkers in Colorectal Cancer Screening
Authors: Minhhuyen T. Nguyen, David S. Weinberg
Journal: Journal of the National Comprehensive Cancer Network (2016)

Colorectal cancer (CRC) is the third most common cause of cancer death in men and women in the United States. The main goals of screening are to prevent carcinogenesis (via adenoma detection and removal) and detect cancer at an early, curable stage. CRC mortality is steadily dropping in the United States, partly because of greater screening utilization. However, nearly 1 in 3 average-risk people are not up to date with standard CRC screening recommendations. This review surveys a wide range of CRC biomarkers in various stages of development, which may offer attractive risk stratification tools; a few have reached the commercial stage. If widely accepted, these tools may contribute to shift CRC screening practices away from 1-step colonoscopy to a 2-step risk stratification process of predictive biomarker measurements followed by colonoscopy for lower-risk patients with a positive result. Such strategies could potentially increase the rate of CRC screening.
Abstract 5139: Adjuvant immunotherapy targeting CSF1R to limit metastatic progression
Authors: Justin Evans, Amber J. Giles, Meera Murgai, Miki Kasai, Caitlin Reid, Rosandra Natasha Kaplan
Journal: Cancer Research (2016)

Abstract Metastasis is often considered a late stage event, although the first changes in the metastatic site occur very early during localized primary tumor development. Although understanding of these initiating events is limited, immune suppression plays an essential role in allowing for the outgrowth of disseminating tumor cells. Targeting this immune suppressive milieu can hold promise to effectively inhibit metastatic progression. Colony stimulating factor-one (CSF-1) is overexpressed by many diverse tumor types and can induce expansion and recruitment of CSF-1 receptor (CSF-1R) expressing cells. CSF-1R is expressed on a multitude of myeloid cells including inflammatory monocytes, myeloid derived suppressor cells and macrophages, which are key immune suppressive cells in a primary tumor site. Using a metastatic rhabdomyosarcoma model, we have identified expansion of immune suppressive myeloid cells in the early metastatic microenvironment. PLX3397, which is small molecular inhibitor that selectively targets CSF-1R, Kit and Oncogenic FLT3, was used to determine the impact of targeting this immune suppressive microenvironment in limiting metastatic progression. PLX3397 and GW2580, a selective CSF1R inhibitor, reduce the immune suppressive capacity of bone marrow-derived monocytes on activated T cells. Adjuvant therapy with PLX3397 in resected rhabdomyosarcoma reduces metastatic spread. Targeting CSF-1R is associated with an expansion of CD11C expressing antigen presenting cells in the metastatic tissue and in combination with PD-1 blockade improves anti-tumor immunity. Continued investigation of combination immunotherapy with metastatic microenvironment targeting in the adjuvant setting holds promise to limit metastatic spread. Citation Format: Justin Evans, Amber J. Giles, Meera Murgai, Miki Kasai, Caitlin Reid, Rosandra Natasha Kaplan. Adjuvant immunotherapy targeting CSF1R to limit metastatic progression. [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 5139.
Combining genomewide association study and lung <scp>eQTL</scp> analysis provides evidence for novel genes associated with asthma
Authors: M. A. Nieuwenhuis, M. Siedlinski, M. van den Berge, R. Granell, X. Li, M. Niens, P. van der Vlies, J. Altmüller, P. Nürnberg, M. Kerkhof, O. C. van Schayck, R. A. Riemersma, T. van der Molen, J. G. de Monchy, Y. Bossé, A. Sandford, C. A. Bruijnzeel‐Koomen, R. Gerth van Wijk, N. H. ten Hacken, W. Timens, H. M. Boezen, J. Henderson, M. Kabesch, J. M. Vonk, D. S. Postma, G. H. Koppelman
Journal: Allergy (2016)

Genomewide association studies (GWASs) of asthma have identified single-nucleotide polymorphisms (SNPs) that modestly increase the risk for asthma. This could be due to phenotypic heterogeneity of asthma. Bronchial hyperresponsiveness (BHR) is a phenotypic hallmark of asthma. We aim to identify susceptibility genes for asthma combined with BHR and analyse the presence of cis-eQTLs among replicated SNPs. Secondly, we compare the genetic association of SNPs previously associated with (doctor's diagnosed) asthma to our GWAS of asthma with BHR.A GWAS was performed in 920 asthmatics with BHR and 980 controls. Top SNPs of our GWAS were analysed in four replication cohorts, and lung cis-eQTL analysis was performed on replicated SNPs. We investigated association of SNPs previously associated with asthma in our data.A total of 368 SNPs were followed up for replication. Six SNPs in genes encoding ABI3BP, NAF1, MICA and the 17q21 locus replicated in one or more cohorts, with one locus (17q21) achieving genomewide significance after meta-analysis. Five of 6 replicated SNPs regulated 35 gene transcripts in whole lung. Eight of 20 asthma-associated SNPs from previous GWAS were significantly associated with asthma and BHR. Three SNPs, in IL-33 and GSDMB, showed larger effect sizes in our data compared to published literature.Combining GWAS with subsequent lung eQTL analysis revealed disease-associated SNPs regulating lung mRNA expression levels of potential new asthma genes. Adding BHR to the asthma definition does not lead to an overall larger genetic effect size than analysing (doctor's diagnosed) asthma.
Abstract 2757: Mcl-1 dictates DNA double-strand break repair pathway choice
Authors: Guo Chen, Ke Xu, Maohua Xie, Taofeek K. Owonikoko, Suresh S. Ramalingam, Paul W. Doetsch, Xingming Deng
Journal: Cancer Research (2016)

Abstract DNA double-strand breaks (DSBs) are mainly repaired by homologous recombination (HR) and non-homologous end-joining (NHEJ) pathways. The choice of pathway is a critical aspect of DSB repair that is poorly understood. We show that Mcl-1 acts as a functional switch in pathway choice between HR and NHEJ. Mcl-1 is cell cycle-regulated, with expression peaking in S/G2 phase via reduction of its ubiquitination when HR occurs. Mcl-1 depletion reduces HR and enhances NHEJ. Mcl-1 overexpression results in a net increase in HR over NHEJ. Mcl-1 promotes HR-dependent DSB repair following DNA replication stress, which contributes to maintenance of genomic integrity. Mcl-1 directly interacts with Ku via its BH1 and BH3 domains. This interaction is required for Mcl-1 to inhibit Ku-mediated NHEJ, and promote Mre11 complex-mediated DNA resection and HR-dependent DSB repair. Thus, Mcl-1, in addition to its antiapoptotic function, plays an unexpected role in directing DSB repair pathway choice by skewing the balance toward HR during cell cycle progression. Citation Format: Guo Chen, Ke Xu, Maohua Xie, Taofeek K. Owonikoko, Suresh S. Ramalingam, Paul W. Doetsch, Xingming Deng. Mcl-1 dictates DNA double-strand break repair pathway choice. [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 2757.
Sixty seconds on . . . the NHS “reset”
Authors: Gareth Iacobucci
Journal: BMJ (2016)

Yes, I’m afraid so. It may be summer, but those at NHS England never rest.

Spot on. NHS finances have never been worse. Hospitals and other trusts recorded an eye watering cumulative deficit of £2.8bn (€3.28bn; $3.65bn) in 2015-16, the largest ever. More than two thirds of NHS trusts failed to balance their books last year, hence the …
Should Markus Rehm be permitted to compete in the long jump at the Olympic Games?
Authors: Emma M Beckman, Mark J Connick, Mike J McNamee, Richard Parnell, Sean M Tweedy
Journal: British Journal of Sports Medicine (2016)

On 30 May 2016, Markus Rehm (MR), the outstanding Paralympic long jumper whose personal best would have won gold at the London Olympics,1 announced his desire to participate in the 2016 Rio Olympic Games to the world's media. Critically, MR, who is a unilateral below-knee amputee, uses a long jump-specific prosthesis (LJSP) and he supported his case for inclusion using results of a scientific study in which he participated.2

According to the IAAF rules, the use of a mechanical aid is not permitted unless the athlete can establish that ‘on the balance of probabilities’, its use would not provide an overall competitive advantage over an athlete not using such an aid.3 On 17 June the IAAF President stated: “…at this stage he [MR] has not been able to do that [prove no advantage]”.4

At the time of writing the International Association of Athletic Federations (IAAF) had not expanded on their announcement. However, given the importance of MR's case for athletics stakeholders and for sport in general, the scientific report …
Abstract 4395: Tissue stiffness and hypoxia regulate breast cancer stem cells through ILK
Authors: Mei-Fong Pang, Melody Stallings-Mann, Michael J. Siedlik, Victor D. Varner, Siyang Han, Derek C. Radisky, Celeste M. Nelson
Journal: Cancer Research (2016)

Abstract The mechanical and chemical properties of the cellular microenvironment can influence the phenotype of cancer cells. The hypoxic conditions within solid breast tumors can contribute to invasiveness and the formation of breast cancer stem cells (CSCs). Integrin-linked kinase (ILK) is a critical mediator for mechanotransduction, a process that converts exogenous mechanical stimuli into biochemical signals. Yet, it is unclear how the physical properties of the tumor microenvironment, including matrix stiffness and hypoxia, integrate to direct the formation of the breast CSC niche. Using an innovative engineered culture model, we found that stiff and hypoxic microenvironments activate integrin signaling and a stem-like gene signature in breast cancer cells, suggesting that integrin signaling, matrix mechanics and oxygen tension cooperatively promote the formation of breast CSCs. Stiff and hypoxic microenvironments promote integrin signaling and the expression of CSC markers including CD44 and Nanog. Knocking down ILK reverts the CSC phenotype of invasive breast cancer cells on stiff matrix, and abrogates their ability to form mammospheres and colonies in soft agar. In contrast, ectopic expression of ILK enhances CSC properties. ILK promotes integrin signaling and the CSC phenotype through the PI3K/Akt pathway. Stiff microenvironments promote tumor formation and metastasis in ovo. ILK depletion significantly abrogates the tumorigenenic and metastatic potential of invasive breast cancer cells in ovo. Importantly, we found that breast cancer cells expressing ILK and the CSC marker CD44 were only present in the regions of tumors predicted to be stiff in breast cancer patient samples. Our data suggest that ILK act as an essential mechanosensor that regulates breast CSC phenotype in response to matrix mechanics and oxygen tension to regulate the formation of breast CSCs. Citation Format: Mei-Fong Pang, Melody Stallings-Mann, Michael J. Siedlik, Victor D. Varner, Siyang Han, Derek C. Radisky, Celeste M. Nelson. Tissue stiffness and hypoxia regulate breast cancer stem cells through ILK. [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 4395.
LBA-01 Safety and efficacy of cobimetinib (cobi) and atezolizumab (atezo) in a Phase 1b study of metastatic colorectal cancer (mCRC)
Authors: J. Bendell, K. Tae Won, C. Cheng Ean, B. Yung-Jue, C. Lee, J. Desai, J. Lewin, J. Wallin, M. Das Thakur, G. Mwawasi, E. Cha, J. Infante
Journal: Annals of Oncology (2016)