tbuckley/cabot-search huggingface dataset:
MMP (Matrix Metalloprotease)-9–Producing Monocytes Enable T Cells to Invade the Vessel Wall and Cause Vasculitis
Authors: Ryu Watanabe, Toshihisa Maeda, Hui Zhang, Gerald J. Berry, Markus Zeisbrich, Robert Brockett, Andrew E. Greenstein, Lu Tian, Jörg J. Goronzy, Cornelia M. Weyand
Journal: Circulation Research (2018)

Giant cell arteritis (GCA)-a primary vasculitis of medium and large arteries-is associated with vessel wall damage, elastic membrane fragmentation, and vascular remodeling. Proteinases are believed to contribute to pathogenesis by degrading extracellular matrix and causing tissue injury.The MMP (matrix metalloproteinase)-9-a type IV collagenase-is produced in the vasculitic lesions of GCA. It is unknown which pathogenic processes are MMP-9 dependent.The tissue transcriptome of GCA-affected temporal arteries contained high amounts of MMP-9 transcripts, and immunostaining for pro-MMP-9 localized the enzyme to wall-infiltrating macrophages. MMP-2 and MMP-9 transcripts were also abundant in monocytes and monocyte-derived macrophages from patients with GCA. Patient-derived monocytes outperformed healthy monocytes in passing through engineered basement membranes. GCA CD (cluster of differentiation) 4+ T cells required MMP-9-producing monocytes to penetrate through matrix built from type IV collagen. In vivo functions of MMP-9 were tested in a human artery-SCID (severe combined immunodeficiency) chimera model by blocking enzyme activity with a highly specific monoclonal antibody or by injecting rMMP-9 (recombinant MMP-9). Inhibiting MMP-9 activity profoundly suppressed vascular injury, decreased the density of inflammatory infiltrates ( P<0.001), reduced intramural neoangiogenesis ( P<0.001), and prevented intimal layer hyperplasia ( P<0.001). rMMP-9 amplified all domains of vasculitic activity, promoted assembly of T-cell infiltrates ( P<0.05), intensified formation of new microvessels ( P<0.001), and worsened intimal thickening ( P<0.001). Systemic delivery of N-acetyl-proline-glycine-proline-a matrikine produced by MMP-9-mediated gelatinolysis-had limited vasculitogenic effects.In large vessel vasculitis, MMP-9 controls the access of monocytes and T cells to the vascular wall. T cells depend on MMP-9-producing monocytes to pass through collagen IV-containing basement membrane. Invasion of vasculitogenic T cells and monocytes, formation of neoangiogenic networks, and neointimal growth all require the enzymatic activity of MMP-9, identifying this protease as a potential therapeutic target to restore the immunoprivilege of the arterial wall in large vessel vasculitis.
Variable generalization performance of a deep learning model to detect pneumonia in chest radiographs: A cross-sectional study
Authors: John R. Zech, Marcus A. Badgeley, Manway Liu, Anthony B. Costa, Joseph J. Titano, Eric Karl Oermann
Journal: PLoS Medicine (2018)

Early results in using convolutional neural networks (CNNs) on x-rays to diagnose disease have been promising, but it has not yet been shown that models trained on x-rays from one hospital or one group of hospitals will work equally well at different hospitals. Before these tools are used for computer-aided diagnosis in real-world clinical settings, we must verify their ability to generalize across a variety of hospital systems. A cross-sectional design was used to train and evaluate pneumonia screening CNNs on 158,323 chest x-rays from NIH (n=112,120 from 30,805 patients), Mount Sinai (42,396 from 12,904 patients), and Indiana (n=3,807 from 3,683 patients). In 3 / 5 natural comparisons, performance on chest x-rays from outside hospitals was significantly lower than on held-out x-rays from the original hospital systems. CNNs were able to detect where an x-ray was acquired (hospital system, hospital department) with extremely high accuracy and calibrate predictions accordingly. The performance of CNNs in diagnosing diseases on x-rays may reflect not only their ability to identify disease-specific imaging findings on x-rays, but also their ability to exploit confounding information. Estimates of CNN performance based on test data from hospital systems used for model training may overstate their likely real-world performance.
If endoscopic mucosal resection is so great for large benign colon polyps, why is so much surgery still being done?
Authors: Douglas Rex
Journal: Endoscopy (2018)

See also: The size, morphology, site, and access score predicts critical outcomes of endoscopic mucosal resection in the colonEndoscopy 2018; 50(07): 684-692DOI: 10.1055/s-0043-124081
Development and validation of a radiological diagnosis model for hypersensitivity pneumonitis
Authors: Margaret L. Salisbury, Barry H. Gross, Aamer Chughtai, Mohamed Sayyouh, Ella A. Kazerooni, Brian J. Bartholmai, Meng Xia, Susan Murray, Jeffrey L. Myers, Amir Lagstein, Kristine E. Konopka, Elizabeth A. Belloli, Jamie S. Sheth, Eric S. White, Colin Holtze, Fernando J. Martinez, Kevin R. Flaherty
Journal: European Respiratory Journal (2018)

High-resolution computed tomography (HRCT) may be useful for diagnosing hypersensitivity pneumonitis. Here, we develop and validate a radiological diagnosis model and model-based points score. Patients with interstitial lung disease seen at the University of Michigan Health System (derivation cohort) or enrolling in the Lung Tissue Research Consortium (validation cohort) were included. A thin-section, inspiratory HRCT scan was required. Thoracic radiologists documented radiological features. The derivation cohort comprised 356 subjects (33.9% hypersensitivity pneumonitis) and the validation cohort comprised 424 subjects (15.5% hypersensitivity pneumonitis). An age-, sex- and smoking status-adjusted logistic regression model identified extent of mosaic attenuation or air trapping greater than that of reticulation (“MA-AT&gt;Reticulation”; OR 6.20, 95% CI 3.53–10.90; p&lt;0.0001) and diffuse axial disease distribution (OR 2.33, 95% CI 1.31–4.16; p=0.004) as hypersensitivity pneumonitis predictors (area under the receiver operating characteristic curve 0.814). A model-based score &gt;2 (1 point for axial distribution, 2 points for “MA-AT&gt;Reticulation”) has specificity 90% and positive predictive value (PPV) 74% in the derivation cohort and specificity 96% and PPV 44% in the validation cohort. Similar model performance is seen with population restriction to those reporting no exposure (score &gt;2: specificity 91%). When radiological mosaic attenuation or air trapping are more extensive than reticulation and disease has diffuse axial distribution, hypersensitivity pneumonitis specificity is high and false diagnosis risk low (&lt;10%), but PPV is diminished in a low-prevalence setting.
Davida Coady: humanitarian paediatrician, political activist, and recovering alcoholic
Authors: Ned Stafford
Journal: BMJ (2018)

As a paediatrician and then, later in her career, as an addiction treatment specialist, Davida Coady’s mission in life was to do “the greatest good for the greatest number of people,” a principle she attributed to the British philosopher John Stuart Mill.

Inspired by the life of Albert Schweitzer and his work in Africa, Coady for more than two decades risked her life flying in rickety aeroplanes to war zones and disaster areas to provide medical care—and her love—to children in nearly 35 countries in Africa, Asia, and Latin America. She also trained local healthcare workers, led infectious disease control efforts, and worked to improve nutrition. She was affiliated at various times with the Peace Corps, the World Health Organization, the World Bank, the UN High Commissioner for Refugees (UNHCR, the UN Refugee Agency), and many other voluntary agencies.



In order to promote help for children and adults in the developing world, she was often in personal contact with politicians and high level government officials, such as the late US senator Ted Kennedy, and famous human rights activists, such as actor Martin Sheen and Bianca Jagger, the Nicaragua born former wife of rock star Mick Jagger.

In Coady’s recently published memoir, The Greatest Good , which she completed while in the final stages of terminal ovarian cancer, she writes: “I have a gut feeling and a belief that one should leave the world a better place than one found it, in some ways, and that our lives are worth very little if we don’t do something to make the world better.”1

In addition to her medical work, Coady also tried to make the world a better place as a political activist. Arrested more than 50 times, she protested against nuclear proliferation, against global food giant Nestle …
Predicting low accrual in the Clinical Trials Cooperative Group Program’s phase II/III oncology trials.
Authors: Caroline Savage Bennette, Scott David Ramsey, Cara L McDermott, Josh John Carlson, Anirban Basu, David L Veenstra
Journal: Journal of Clinical Oncology (2015)

6522 Background: Although general barriers to clinical trial accrual are well described, the extent to which trial-level factors differentially influence accrual to individual trials has not been comprehensively studied. Our objective was to study the empirical relationship and predictive properties of a broad set of putative risk factors for low accrual among NCI's Clinical Trials Cooperative Group Program (CTCG), now the National Clinical Trials Network. Methods: Data from 787 phase II/III adult CTCG trials that opened 2000-2011 were used to develop a logistic regression model to predict low accrual, defined as trials that closed with or were accruing at < 50% of target; 46 trials opened 2012-2013 were used for validation. Candidate predictors of accrual were identified from a literature review and expert interviews. Model performance was evaluated by calibration and discrimination via the area under the curve (AUC). Results: The multivariable model (Table) had good calibration and discrimination to predict trials with low accrual (AUC in trials launched in 2012-2013: 0.73; 95% CI: 0.58, 0.88). Results were robust to different definitions of accrual success and model selection strategies. Conclusions: Prospectively, a prediction tool based on multiple trial-level risk factors may help quantify the risk of low accrual for cooperative group trials. Such a tool could inform trial design, aid prioritization decisions, and help target limited resources to support accrual where most needed. Multivariable model to predict low accrual in CTCG phase II/III trials. Risk Factor Odds Ratio 95% CI Annual incidence of clinical condition(s), per 10,000 0.98 0.95, 1.00 Common solid tumor setting (prostate, breast, lung, colon) 2.11 1.14, 3.88 # Competing trials/10,000 eligible patients 1.86 1.31, 2.66 >1 condition evaluated 1.88 1.17, 3.03 Enrollment as % of eligible population, per % 2.67 1.36, 5.25 Investigational new drug (IND) 0.21 0.09, 0.51 Interaction term (Phase III x IND) 3.41 1.02, 11.45 Metastatic setting 1.46 0.81, 2.63 Phase III (vs II) 2.63 1.52, 4.54 Radiation therapy 2.01 1.26, 3.21 Sample size, per 100 0.96 0.93, 1.00 Targeted therapy 0.54 0.34, 0.87 Tissue sample required to assess eligibility 1.33 0.88, 2.02
Geographic Variation in Pediatric Cancer Incidence — United States, 2003–2014
Authors: David A. Siegel, Jun Li, S. Jane Henley, Reda J. Wilson, Natasha Buchanan Lunsford, Eric Tai, Elizabeth A. Van Dyne
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

Approximately 15,000 persons aged <20 years receive a cancer diagnosis each year in the United States (1). National surveillance data could provide understanding of geographic variation in occurrence of new cases to guide public health planning and investigation (2,3). Past research on pediatric cancer incidence described differences by U.S. Census region but did not provide state-level estimates (4). To adequately describe geographic variation in cancer incidence among persons aged <20 years in the United States, CDC analyzed data from United States Cancer Statistics (USCS) during 2003-2014 and identified 171,432 cases of pediatric cancer during this period (incidence = 173.7 cases per 1 million persons). The cancer types with the highest incidence rates were leukemias (45.7), brain tumors (30.9), and lymphomas (26.2). By U.S. Census region, pediatric cancer incidence was highest in the Northeast (188.0) and lowest in the South (168.0), whereas by state (including the District of Columbia [DC]), rates were highest in New Hampshire, DC, and New Jersey. Among non-Hispanic whites (whites) and non-Hispanic blacks (blacks), pediatric cancer incidence was highest in the Northeast, and the highest rates among Hispanics were in the South. The highest rates of leukemia were in the West, and the highest rates of lymphoma and brain tumors were in the Northeast. State-based differences in pediatric cancer incidence could guide interventions related to accessing care (e.g., in states with large distances to pediatric oncology centers), clinical trial enrollment, and state or regional studies designed to further explore variations in cancer incidence.
Changes of microbiome profile during nivolumab treatment in NSCLC patients.
Authors: Andrea Botticelli, Lorenza Putignani, Ilaria Zizzari, Federica Del Chierico, Sofia Reddel, Francesca DI Pietro, Andrea Quagliarello, Concetta Elisa Onesti, Giusti Raffaele, Federica Mazzuca, Marianna Nuti, Paolo Marchetti
Journal: Journal of Clinical Oncology (2018)

e15020 Background: Immune Checkpoint Inhibitors (ICIs) are improving the survival of cancer patients, however only the 20-30% of treated patients present long term benefits. Hence in the context of multiple treatment possibilities, the identification of predictive markers of response and toxicity is a challenging approach for drug selection in order to obtain the best clinical benefit. The changes occurring in the microbiota composition has been proposed as a mechanism potentially influencing the response and the toxicity to immunotherapy Methods: The microbiome composition was studied in an age-matched control-case study of 11 patients affected by non-small cell lung cancer (NSCLC) treated with Nivolumab versus 11 healthy controls (CTRLs). The stool samples of NSCLC patients were collected at cycle 1, 3 and 5. The microbiome analysis was performed by targeted-metagenomics of the 16S rRNA locus (V3-V4 region) on an Illumina MiSeq Platform. Non-parametrical statistical analyses were performed to assess microbial OTUs distribution and a- and b-diversity indexes were computed to describe the microbial ecology Results: Microbiota meta-taxonomy was described for the NSCLC patients versus CTRLs and at each time-course of the Nivolumab treatment (C1-C5). In NSCLC patients Rikenellaceae, Prevotella, Streptococcus, Lactobacillus (p < 0.05), Bacteroides plebeius, Oscillospira, Enterobacteriaceae (p < 0.05) appeared increased compared to CTRLs. Not responders had Ruminococcus bromii, Dialister, Sutterella more abundant than responder patients to therapy (p < 0.05). Slightly increased in responders appeared Akkermansia muciniphila, Bifidobacterium longum and Faecalibacterium prausnitzii (p < 0.05). Propionibacterium acnes, Veillonella, Staphylococcus aureus, Peptostreptococcus appeared significantly over-expressed, while Clostridium perfringens was significantly reduced at the C1 compared to the C3 time-point of the treatment. Conclusions: Nivolumab seems to influence the microbiome composition during treatment. Moreover our data confirm significant role of specific gut microbiota bacteria in influencing cancer development and response to immunotherapy.
Abstract 2333: Genetic characterization of programmed cell death in aneuploid yeast cells
Authors: Megan Onyundo, Matthew Sanborn, Victoria Timmel, Nicanor Austriaco
Journal: Cancer Research (2018)

Abstract Aneuploidy is the genetic state of a cell that has a chromosomal number that is not an exact multiple of the haploid complement. It is a leading cause of spontaneous abortions and of mental retardation in humans, and is a characteristic defect in cancer. Yeast cells that are aneuploid manifest a diversity of phenotypes including cell cycle defects, genomic instability, protein imbalance, chaperone stress and proteotoxicity. We are investigating the links between aneuploidy on the budding yeast, Saccharomyces cerevisiae and programmed cell death. We have shown that aneuploid yeast cells are more sensitive to ethanol-induced cell death. In addition, we have also shown that caloric restriction protects aneuploid yeast from program cell death. [In addition to funding from the RI-INBRE Program, our laboratory is supported by grant NIGMS R15 GM110578, awarded to N. Austriaco.] Citation Format: Megan Onyundo, Matthew Sanborn, Victoria Timmel, Nicanor Austriaco. Genetic characterization of programmed cell death in aneuploid yeast cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2333.
Abstract 1254: Metformin's potential as a breast cancer preventative agent by altering epigenetic patterns
Authors: Caitriona Tyndall, Charlene Lam, Marc Gunter, James Flanagan
Journal: Cancer Research (2018)

Abstract Metformin is one of the most commonly prescribed Type II Diabetes Mellitus (T2DM) drugs and has been shown in diabetic long-term users to reduce the likelihood of breast cancer by 56%. Breast cancer is the most commonly diagnosed cancer in the UK accounting for 55,000 new cases per year. It has been estimated that as much as 27% of cases could be prevented based on current knowledge. This study aims to investigate the novel hypothesis that metformin acts as a preventative agent by altering epigenetic patterns in non-cancerous breast epithelial cells and the T2DM environment, namely hyperinsulinemia and hyperglycaemia, potentially modulates this. Crystal Violet cell viability assay and Western Blot for p-AMPK, a known target for metformin, were performed to assess the response of two non-cancerous breast epithelial cells lines, MCF10A and MCF12A, to metformin in a range of insulin and glucose concentrations. Western blot was performed to assess changes in histone post-translational modifications (PTMs), such as H2K27ac and H3K27me3, following 3-days treatment with metformin at 2.5mM and 5mM. Additionally, we conducted an Illumina MethylationEPIC Array on MCF10A and MCF12A cell lines treated for 3-days with 2.5mM and 5mM metformin. Pyrosequencing assay was used to further validate interesting CpG sites. Our findings suggest non-cancerous breast epithelial cells, MCF10A and MCF12A cell lines, are sensitive to metformin following 3 and 7-days treatment. Further to this, our data suggests the T2DM environment impacts the effectiveness of metformin where low glucose and high insulin significantly increase metformin effectiveness in MCF10A and MCF12 cell lines following 3-day treatment, respectively. Metformin treatment leads to the activation of p-AMPK in normal breast epithelial cells. Analysis of Illumina MethylationEPIC array suggests metformin in hyperglycaemic and hyperinsulinemic conditions induces differential DNA methylation changes in MCF10A and MCF12A non-cancerous breast epithelial cell lines and the effects are dose dependent. Of the 850,000 probes, 13 CpG sites in MCF10A and 5 CpG sites in MCF12A showed significant changes in methylation following metformin treatment (p&amp;lt;0.001). In summary, this study has shown a potential mechanism of metformin action through altering of epigenetic patterns in non-cancerous breast epithelial cells. Future work aims to further explore epigenetic changes induced by metformin in the context of the T2DM environment and whether these changes could potentially predict reduced breast cancer risk. Citation Format: Caitriona Tyndall, Charlene Lam, Marc Gunter, James Flanagan. Metformin's potential as a breast cancer preventative agent by altering epigenetic patterns [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1254.
KEYNOTE-061: Phase 3 study of pembrolizumab vs paclitaxel for previously treated advanced gastric or gastroesophageal junction (G/GEJ) cancer
Authors: K. Shitara, M. Özgüroğlu, Y J Bang, M. Di Bartolomeo, M. Mandalà, M H Ryu, L. Fornaro, T. Olesiński, C. Caglevic, H. Chung, K. Muro, E. Gökkurt, W. Mansoor, R. McDermott, E. Schacham-Shmueli, X. Chen, S P Kang, C. Mayo, A. Ohtsu, C. Fuchs
Journal: Annals of Oncology (2018)

Background: Pembrolizumab showed promising antitumor activity and a manageable safety profile in patients with pretreated G/GEJ cancer in KEYNOTE-012 and KEYNOTE-059. KEYNOTE-061 (NCT02370498) was a global, open-label phase 3 study of pembrolizumab vs paclitaxel for previously treated advanced G/GEJ adenocarcinoma that progressed after first-line chemotherapy containing platinum and fluoropyrimidine. Methods: Eligible patients were randomized in a 1:1 ratio to pembrolizumab 200 mg Q3W or paclitaxel 80 mg/m2 on days 1, 8, and 15 of 4-week cycles. Randomization was stratified by geographic region, TTP on first-line therapy, and PD-L1 combined positive score (CPS). Primary end points were OS (efficacy boundary, one-sided P = 0.0135) and PFS in the CPS ≥1 population. Differences in OS and PFS were assessed using the stratified log-rank test. Results: Of the 592 patients enrolled, 395 had PD-L1 CPS ≥1: 196 assigned to pembrolizumab, 199 to paclitaxel. After median follow-up of 8 mo, 7.8% of patients completed or remained on pembrolizumab. Median OS was 9.1 mo (95% CI 6.2-10.7) with pembrolizumab vs 8.3 mo (95% CI 7.6-9.0) with paclitaxel (HR 0.82, 95% CI 0.66-1.03; one-sided P = 0.042). 12-mo OS rates were 39.8% vs 27.1%; 18-mo rates were 25.7% vs 14.8%. There was no improvement in PFS (median 1.5 mo with pembrolizumab vs 4.1 mo with paclitaxel; HR 1.27 [95% CI 1.03-1.57]) or ORR (15.8% vs 13.6%), but pembrolizumab responses were more durable (median 18.0 mo vs 5.2 mo; duration ≥12 mo 59.5% vs 29.5%). The pembrolizumab treatment effect for OS was more evident in patients with ECOG PS 0 (median OS 12.3 mo vs 9.3 mo; HR 0.69, 95% CI 0.49-0.97). In post-hoc analysis, the pembrolizumab treatment effect for OS was also greater in patients with CPS ≥10 (median OS 10.4 mo vs 8.0 mo; HR 0.64, 95% CI 0.41-1.02) and in patients with MSI-H tumors, regardless of CPS (median OS not reached vs 8.1 mo; HR 0.42, 95% CI 0.13–1.31). In all patients, grade 3-5 drug-related AE incidence was 14.3% with pembrolizumab vs 34.8% with paclitaxel; 3.1% vs 5.4% discontinued due to drug-related AEs. Conclusions: Pembrolizumab did not significantly improve OS vs paclitaxel in patients with previously treated G/GEJ cancer and PD-L1 CPS ≥1, although a benefit for pembrolizumab emerged with long-term follow-up. Pembrolizumab had a better safety profile than paclitaxel. The pembrolizumab treatment effect was more evident in patients with ECOG PS 0, those with greater PD-L1 expression, and those with MSI-H tumors. Trials of pembrolizumab as monotherapy and as part of combination therapy for G/GEJ cancer are ongoing.