tbuckley/cabot-search huggingface dataset:
Diagnosis and early management of inflammatory arthritis
Authors: Joanna Ledingham, Neil Snowden, Zoe Ide
Journal: BMJ (2017)

#### What you need to know

Autoimmune inflammation affects the joints of people with inflammatory arthritis. No definitive cause has been identified, despite extensive research. An environmental trigger in a genetically predisposed individual seems to be the most likely mechanism.1

About 80-100 adults in 100 000 develop inflammatory arthritis every year.2 3 Rheumatoid arthritis is the most common inflammatory arthritis, affecting approximately 500 000 people in the UK.4 Spondylo-arthropathies, which include psoriatic arthritis, reactive arthritis, and ankylosing spondylitis, are slightly less common. In ankylosing spondylitis inflammation occurs mainly in the spine, but peripheral arthritis can occur.5 Inflammatory arthritis primarily affects people of working age, and within 10 years of diagnosis around 40% of people with rheumatoid arthritis are unable to work.6

Systematic reviews of randomised controlled trials show that early treatment can control symptoms, induce remission, minimise irreparable damage, and protect against the mortality and morbidity associated with inflammatory arthritis, especially cardiovascular. Guidelines7 and quality standards8 from the UK’s National Institute for Health and Care Excellence recommend early aggressive treatment for rheumatoid arthritis. This approach has been shown to be cost effective,9 and management principles for rheumatoid arthritis are broadly applicable to all forms of inflammatory arthritis. This clinical update, aimed at non specialists, provides information on the diagnosis and early management of inflammatory arthritis.

#### Sources and selection criteria

We performed a Pubmed search on the …
Abstract 142: Exploiting replicative vulnerabilities to counter incomplete responses to PI3K/Akt/mTOR inhibition
Authors: Sameer Chopra, Mario Niepel, Anne Jenney, Marc Hafner, Peter Sorger
Journal: Cancer Research (2017)

Abstract While a broad range of cancers harbor mutations that dysregulate PI3K-Akt-mTOR signaling, most small molecule drugs targeting this pathway have failed to demonstrate efficacy for the treatment of solid tumors. In this study, we investigated the mechanisms that account for drug efficacy and failure in PI3K-pathway dysregulated triple negative breast cancer (TNBC) cell lines using a diverse collection of 25 PI3K-Akt-mTOR inhibitors. Drug response phenotypes and changes in signaling were quantified using time-lapse imaging and quantitative single cell immunofluorescence microscopy, respectively. We identified GSK2126458 and Torin2 as having superior potency and efficacy in PI3K-pathway dysregulated TNBC. Unlike other PI3K pathway inhibitors, whose ineffectiveness arises from insufficient induction of apoptosis and variable inhibition of cell cycle progression at G1/S, GSK2126458 and Torin2 each rapidly induce caspase 3/7 activity and durably inhibit the proliferation of surviving cells. While the effectiveness of GSK2126458 in vitro appears to arise from near-complete suppression of PI3K-Akt-mTOR signaling, this approach has already proved unachievable in clinical trials. An alternative therapeutic strategy was identified by characterizing the mechanism of action of Torin2, a tool compound that inhibits both mTOR kinase and the DNA damage response kinases ATR, ATM, and DNA-PK. Unlike all other PI3K-Akt-mTOR inhibitors studied, Torin2 counters incomplete drug block at G1/S by concomitant induction of intolerable replication stress in S phase cells. The unique cell cycle pharmacology of Torin2 is recreated by combining inhibitors of mTOR and ATR/Chk1 kinases presently undergoing evaluation in clinical trials. In the context of combination therapy, where cytotoxicity arises from targeting S phase vulnerabilities rather than from PI3K-Akt-mTOR inhibition in G1, submaximal doses of mTOR kinase inhibitors are sufficient and confer benefit by preventing the outgrowth of cells that survive fractional killing from ATR/Chk1 inhibition. These findings suggest a novel strategy for mitigating the failure of precision monotherapy and have implications for the treatment of tumors where genetic lesions in the PI3K pathway co-occur with replicative vulnerabilities. Citation Format: Sameer Chopra, Mario Niepel, Anne Jenney, Marc Hafner, Peter Sorger. Exploiting replicative vulnerabilities to counter incomplete responses to PI3K/Akt/mTOR inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 142. doi:10.1158/1538-7445.AM2017-142
Abstract 800: Enhancing tumor killing abilities of NK cells by targeting CD16 shedding, and ADAM17
Authors: Hemant K. Mishra, Jianming Wu, Dan S. Kaufman, Bruce Walcheck
Journal: Cancer Research (2017)

Abstract CD16 consists of two isoforms (CD16a and CD16b) encoded by two highly homologous genes that differ by only 6 amino acids in their extracellular regions. CD16b is expressed by human neutrophils and CD16a by human natural killer (NK) cells. The ectodomain regions of both CD16 isoforms are cleaved proximal to the cell membrane by a proteolytic process referred to as ectodomain shedding. We demonstrate that the membrane metalloprotease ADAM17 cleaves CD16 in isolated leukocytes and in human patients. By mass spectrometry analysis, we determined 3 adjacent cleavage sites in neutrophil CD16b and one cleavage site in NK cell CD16a that occurred at the same location as the predominant cleavage site in CD16b, which is interesting considering CD16b is linked to the plasma membrane via a GPI anchor and CD16a is a transmembrane protein. Antibody-dependent cell cytotoxicity (ADCC) by NK cells is a key mechanism in the anti-cancer effects of therapeutic antibodies, and CD16a exclusively recognizes tumor-bound antibodies. Surface levels of CD16a are rapidly down-regulated upon NK cell activation by cytokines, target cell interaction, and tumor infiltration, which is associated with impaired ADCC. Thus blocking this process has important clinical significance. We contend that maintaining high surface levels of CD16a during NK cell-based immunotherapy will enhance their killing of antibody-bound tumor cells. In ongoing studies, we are examining pharmaceutical and gene-targeting means of preventing CD16a cleavage as a novel therapeutic strategy to enhance the anti-cancer effects of NK cells. Note: This abstract was not presented at the meeting. Citation Format: Hemant K. Mishra, Jianming Wu, Dan S. Kaufman, Bruce Walcheck. Enhancing tumor killing abilities of NK cells by targeting CD16 shedding, and ADAM17 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 800. doi:10.1158/1538-7445.AM2017-800
Abstract 722: Circulating EBV microRNA BART2-5p helps to diagnose nasopharyngeal carcinoma &amp;lt screen for high risk individuals precisely
Authors: Chen Jiang, Lei Li, Li Jiangchao, Shang-hang Xie, Su-mei Cao, Xin-yuan Guan
Journal: Cancer Research (2017)

Abstract Nasopharyngeal carcinoma is an EB-virus associated malignancy which is highly prevalent in Southeast Asia. If diagnosed early, the 5 year disease-free survival rate is about 90%. However, most patients have already developed local or regional invasion when diagnosed, which results in poor prognosis. So it is essential to develop biomarkers to screen high risk individuals or diagnose the disease at early stages. As nasopharyngeal carcinoma is closely related to EBV infection and microRNAs encoded by BART region (BamHI A Rightward Transcripts) is abundant in NPC, we propose to identify biomarkers from those BART microRNAs. To quantify the copy number of microRNAs in serum samples, we used Taqman Probe-based qPCR. After adding Spiked-in Control (Mixture of Cel-39,Cel-54, Cel-238) to each 100ul serum sample, we extracted total RNA and reverse transcribed microRNA into cDNA with corresponding Taqman primers. Meanwhile, microRNA mimics with known copy number were serial diluted and reverse transcribed along with the samples. qPCR was performed to quantify the level of microRNAs in these samples with diluted cDNA and Taqman Probe. All data was normalized by Spiked-in controls and exact copy number of each microRNA was calculated through the standard curve generated by the serial diluted microRNA mimics. Here, we screened 17 BART microRNAs in discovery stage and found BART 2-5p as a candidate biomarker. In training cohort consisting of 266 patients with nasopharyngeal carcinoma and controls from Hong Kong, the sensitivity, specificity and AUC is 93.2%, 89.8%,0.976 respectively. The results are similar in validation cohort 1 constituted by 376 patients and controls from Guang Zhou. To evaluate the ability of BART 2-5p to distinguish preclinical NPC patients from healthy high risk individuals, we established a nested case-control study with serum samples prospectively collected from 10 NPC patients at least one year prior to their clinical diagnosis and 92 matched healthy high risk controls from a screening scheme conducted in South China. The sensitivity and specificity is 90.0% and 31.5%. Taken together, EBV microRNA BART2-5p is a promising biomarker to improve NPC diagnosis and target preclinical patients more precisely than serologic test. Citation Format: Chen Jiang, Lei Li, Li Jiangchao, Shang-hang Xie, Su-mei Cao, Xin-yuan Guan. Circulating EBV microRNA BART2-5p helps to diagnose nasopharyngeal carcinoma &amp;lt screen for high risk individuals precisely [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 722. doi:10.1158/1538-7445.AM2017-722
Abstract 4021: Donor-specific primary monocyte-derived dendritic cell maturation model for high-throughput screening of immunostimulatory adjuvants
Authors: Qin Chen, Anthony Lawrenz, Alan Wang, Erin Kelly, Erin Harberts, Robert K. Ernst, Jay Tong
Journal: Cancer Research (2017)

Abstract Dendritic cell (DC) based immunotherapy is a promising treatment alternative for various solid tumor and hematological malignancies. DCs are capable of initiating and propagating antigen-specific adaptive immune responses through their intrinsic maturation process. Identifying novel, effective adjuvant drug candidates that can stimulate DC maturation while understanding and accounting for the variability of patient-specific DC cell responses to the immunostimulatory adjuvants is essential for development of such immunotherapies. Reliable, high throughput assay platforms that characterize patient-specific modulatory effects during the DC maturation process in vivo and in vitro are also highly desirable. In this study, we present a high throughput in vitro primary cell assay to evaluate dose-dependent DC maturation in a panel of human leukocyte antigen (HLA) typed individual donors. CD14+ monocytes from four healthy donors were isolated from leukapheresis derived peripheral blood mononuclear cells (PBMC) and cultured for seven days with GM-CSF and IL-4 to achieve differentiation to DC. Cells were then stimulated for 24 hours with lipopolysaccharide (LPS), CpG oligonucleotides, or nine different novel toll-like receptor 4 (TLR4) ligands at three concentrations. To quantify the differentiation of monocytes into DC and subsequent maturation, flow cytometry was used to measure the expression of biomarkers, MHC-II, CD40, CD80, CD83, and CD86. Greater than 99% MHC-II expression was observed across all donors and confirmed successful differentiation to DC. The TLR4 ligands showed reduced biomarker expression, as compared to pathogenic E. coli LPS but similar to PHAD, a synthetic TLR4 agonist currently used in adjuvants. While monocytes from all donors responded to the ligands tested, the intensity of activation marker expression varied among donors with LPS/TLR4 ligand induced maturation process showing 43-91% CD40 and 27-82% CD83 expression, highlighting the necessity of multi-donor screening for drug development. In conclusion, a high throughput in vitro primary monocyte derived DC differentiation assay has been developed and is commercially available to assist researchers in characterizing donor-specific DC responses to immunostimulatory adjuvants. Citation Format: Qin Chen, Anthony Lawrenz, Alan Wang, Erin Kelly, Erin Harberts, Robert K. Ernst, Jay Tong. Donor-specific primary monocyte-derived dendritic cell maturation model for high-throughput screening of immunostimulatory adjuvants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4021. doi:10.1158/1538-7445.AM2017-4021
Abstract 4111: EGFR wild type allele amplification induces acquired resistance to mutation-specific EGFR tyrosine kinase inhibitors in non-small cell lung cancer cells
Authors: Keigo Kobayashi, Shigenari Nukaga, Hiroyuki Yasuda, Keita Masuzawa, Jyunko Hamamoto, Ichiro Kawada, Katsuhiko Naoki, Sachiyo Mimaki, Shingo Matsumoto, Koichi Goto, Katsuya Tsuchihara, Tomoko Betsuyaku, Kenzo Soejima
Journal: Cancer Research (2017)

Abstract Purpose: Third-generation EGFR-tyrosine kinase inhibitors (TKIs) are mutation-specific inhibitors that generally have minimal effects on wild type protein. The mechanisms underlying acquired resistance to third-generation EGFR-TKIs remain relatively uncharacterized. The purpose of this study is to clarify the mechanisms of acquired resistance to third-generation EGFR-TKIs in order to improve the prognosis of lung cancer patients harboring EGFR mutations. Experimental design: We established third-generation EGFR-TKIs resistant cells using a dose-escalation method. The PC9 (EGFR E746-A750del) and H1975 (EGFR L858R+T790M) human NSCLC cell lines were cultured with rociletinib (CO-1686) or osimertinib (AZD9291) for several months. Their resistance to a third-generation EGFR-TKIs was confirmed by the MTS cell proliferation assay. To clarify the heterogeneity of potential resistance mechanisms, those resistant cell lines were subcloned to isolate resistant clones. DNA isolated from the parental and resistant cell clones was then subjected to whole exome sequencing. Copy number alterations and several genetic alterations potentially relevant to EGFR-TKIs sensitivity were detected. Results: We identified Src-AKT pathway contribute to acquired resistance. In addition, we identified that EGFR wild type allele, but not mutation allele, amplification induced acquired resistance. It mirrors the decreased inhibitory pressure for wild type EGFR by mutation-specific EGFR-TKIs. Conclusion: We provide evidence of wild type allele-mediated resistance, a novel concept of acquired resistance, occurring in response to mutation-specific inhibitor therapy in cancer treatment. 1833 /2600characters Citation Format: Keigo Kobayashi, Shigenari Nukaga, Hiroyuki Yasuda, Keita Masuzawa, Jyunko Hamamoto, Ichiro Kawada, Katsuhiko Naoki, Sachiyo Mimaki, Shingo Matsumoto, Koichi Goto, Katsuya Tsuchihara, Tomoko Betsuyaku, Kenzo Soejima. EGFR wild type allele amplification induces acquired resistance to mutation-specific EGFR tyrosine kinase inhibitors in non-small cell lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4111. doi:10.1158/1538-7445.AM2017-4111
Abstract 240: Dietary patterns and risk of colorectal neoplasia in Puerto Rican Hispanics: A case control study
Authors: Julyann Perez-Mayoral, Sachelly Julian, Marievelisse Soto-Salgado, Michael J. Gonzalez, Marcia Cruz-Correa
Journal: Cancer Research (2017)

Abstract Colorectal cancer (CRC) is the leading cause of cancer death in Puerto Rico and second cause of death in the US. It is well accepted that modifiable lifestyle habits such as diet, contribute to CRC development. Diet could reduce up to 70% of CRC cases. Dietary patterns vary according to race/ethnicity. Puerto Rican Hispanics (PRH) have been shown to have a distinct diet compared to US non-Hispanic Whites (NHW). According to the BRFSS, only 17.7% of PRH and 23.4% of NHW consume fruit and vegetables five times per day. The objective of this study was to describe the association of specific food groups consumption with the risk of colorectal neoplasia (CRN: polyps and/or CRC) in PRH. The validated Colon Cancer Family Registry food frequency questionnaire was administered to healthy individuals (controls) and individuals with CRN (cases) recruited through the Puerto Rico Colorectal Cancer Registry (PURIFICAR). Models adjusted by age, gender, educational attainment and family history of CRC were fitted to estimate the odds ratios (OR) with 95% confidence intervals (CI) through a polytomous logistic regression models comparing cases and controls. A total of 577 subjects were included in the study (controls=254; polyps=50; and CRC=273). The frequency of consumption of fruits, low fat dairy products, eggs, pasta/rice, non-fried chicken, and seafood were significantly different between controls and CRN cases (p&amp;lt;0.05). Adjusted models showed that a higher consumption of fruits (OR≥once per day=0.29) and full-fat dairy products (OR≥once per day=0.22) were associated with decreased risk of polyps (p&amp;lt;0.05). A frequency of consumption of 2-4 times per week, when compared to ≤ 1 per week, of full-fat dairy products (OR2-4 times per week=0.51), seafood (OR2-4 times per week=0.49), and red meats (OR2-4 times per week=0.56) was associated with a decreased risk of CRC (p&amp;lt;0.05). Our results showed that a higher consumption of fruits and full-fat dairy products significantly reduce the risk of polyps in PRH. In addition, consumption of seafood, full-fat dairy, and red meats up to 4 times per week may reduce the risk of CRC in PRH. Educational interventions for cancer prevention in PRH should incorporate nutritional information tailor to our community. Citation Format: Julyann Perez-Mayoral, Sachelly Julian, Marievelisse Soto-Salgado, Michael J. Gonzalez, Marcia Cruz-Correa. Dietary patterns and risk of colorectal neoplasia in Puerto Rican Hispanics: A case control study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 240. doi:10.1158/1538-7445.AM2017-240
Comparison of a structured home-based rehabilitation programme with conventional supervised pulmonary rehabilitation: a randomised non-inferiority trial
Authors: Elizabeth J Horton, Katy E Mitchell, Vicki Johnson-Warrington, Lindsay D Apps, Louise Sewell, Mike Morgan, Rod S Taylor, Sally J Singh
Journal: Thorax (2017)

Background Standardised home-based pulmonary rehabilitation (PR) programmes offer an alternative model to centre-based supervised PR for which uptake is currently poor. We determined if a structured home-based unsupervised PR programme was non-inferior to supervised centre-based PR for participants with COPD. Methods A total of 287 participants with COPD who were referred to PR (187 male, mean (SD) age 68 (8.86) years, FEV 1 % predicted 48.34 (17.92)) were recruited. They were randomised to either centre-based PR or a structured unsupervised home-based PR programme including a hospital visit with a healthcare professional trained in motivational interviewing, a self-management manual and two telephone calls. Fifty-eight (20%) withdrew from the centre-based group and 51 (18%) from the home group. The primary outcome was dyspnoea domain in the chronic respiratory disease questionnaire (Chronic Respiratory Questionnaire Self-Report; CRQ-SR) at 7 weeks. Measures were taken blinded. We undertook a modified intention-to-treat (mITT) complete case analysis, comparing groups according to original random allocation and with complete data at follow-up. The non-inferiority margin was 0.5 units. Results There was evidence of significant gains in CRQ-dyspnoea at 7 weeks in both home and centre-based groups. There was inconclusive evidence that home-based PR was non-inferior to PR in dyspnoea (mean group difference, mITT: −0.24, 95% CI −0.61 to 0.12, p=0.18), favouring the centre group at 7 weeks. Conclusions The standardised home-based programme provides benefits in dyspnoea. Further evidence is needed to definitively determine if the health benefits of the standardised home-based programme are non-inferior or equivalent to supervised centre-based rehabilitation. Trial registration number ISRCTN81189044.
Abstract 2566: Positive cross-regulatory loop links ZBTB7A to estrogen receptor alpha expression in breast cancer
Authors: Mary Ellen Molloy, Monika Lewinska, ThanhThao Nguyen, Zhi-Min Yuan
Journal: Cancer Research (2017)

Abstract In breast development and tumorigenesis the biological functions of estrogen are mediated by estrogen receptor alpha (ERα). Approximately 70% of breast cancers are classified as ERα positive and are therefore candidates to receive various forms of endocrine therapy. De novo or acquired resistance to endocrine therapies limits their clinical effectiveness. Identification of novel targets is critical to combat disease progression. Our lab has recently discovered that ZBTB7A suppresses glycolysis by transcriptionally repressing key genes within the glycolytic pathway in various cancer types (Liu, X.S., et al. 2014). Currently, ZBTB7A is proposed to be an oncogene in breast cancer (Zu, X., et al. 2011), however its function in ERα positive breast cancers has yet to be fully addressed. Using publically available datasets, we found that in luminal breast cancers relapse free survival was improved for patients whose tumors expressed high levels of ZBTB7A. Gene expression analysis of TCGA datasets revealed that ZBTB7A and ERα are highly correlated in human breast tumors prompting us to evaluate their potential cross regulation. ERα mRNA and protein levels were significantly decreased upon ZBTB7A silencing both in MCF-7 and T47D breast cancer cell lines. Upon estradiol stimulation, ZBTB7A silencing reduced ERα target gene expression and estrogen response element driven luciferase reporter activity. Additionally, silencing of ZBTB7A inhibited estradiol-induced proliferation and decreased sensitivity to tamoxifen in MCF-7 and T47D cells. These data suggest that ZBTB7A may be required to mediate the pro-proliferative signal of estradiol through its regulation of ERα expression in breast cancer cell lines. To evaluate the potential regulation of ERα on ZBTB7A, ERα was silenced and ZBTB7A mRNA and protein expression were determined. ERα silencing had no effect on ZBTB7A mRNA levels, but led to decreased ZBTB7A protein expression. These effects on ZBTB7A protein expression were attenuated by the presence of the proteasomal inhibitor MG132. Together, these data suggest a model in which ZBTB7A promotes ERα expression at the transcript level while ERα stabilizes ZBTB7A post-transcriptionally conferring a positive feedback loop and sensitivity to estradiol and endocrine therapies. ZBTB7A may contribute to the transcriptional program maintaining a hormone and endocrine therapy responsive phenotype in breast cancer. Citation Format: Mary Ellen Molloy, Monika Lewinska, ThanhThao Nguyen, Zhi-Min Yuan. Positive cross-regulatory loop links ZBTB7A to estrogen receptor alpha expression in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2566. doi:10.1158/1538-7445.AM2017-2566