tbuckley/cabot-search huggingface dataset:
Development and Validation of Nomograms Predictive of Overall and Progression-Free Survival in Patients With Oropharyngeal Cancer
Authors: Carole Fakhry, Qiang Zhang, Phuc Felix Nguyen-Tân, David I. Rosenthal, Randal S. Weber, Louise Lambert, Andy M. Trotti, William L. Barrett, Wade L. Thorstad, Christopher U. Jones, Sue S. Yom, Stuart J. Wong, John A. Ridge, Shyam S.D. Rao, James A. Bonner, Eric Vigneault, David Raben, Mahesh R. Kudrimoti, Jonathan Harris, Quynh-Thu Le, Maura L. Gillison
Journal: Journal of Clinical Oncology (2017)

Purpose Treatment of oropharyngeal squamous cell carcinoma (OPSCC) is evolving toward risk-based modification of therapeutic intensity, which requires patient-specific estimates of overall survival (OS) and progression-free survival (PFS). Methods To develop and validate nomograms for OS and PFS, we used a derivation cohort of 493 patients with OPSCC with known p16 tumor status (surrogate of human papillomavirus) and cigarette smoking history (pack-years) randomly assigned to clinical trials using platinum-based chemoradiotherapy (NRG Oncology Radiation Therapy Oncology Group [RTOG] 0129 and 0522). Nomograms were created from Cox models and internally validated by use of bootstrap and cross-validation. Model discrimination was measured by calibration plots and the concordance index. Nomograms were externally validated in a cohort of 153 patients with OPSCC randomly assigned to a third trial, NRG Oncology RTOG 9003. Results Both models included age, Zubrod performance status, pack-years, education, p16 status, and T and N stage; the OS model also included anemia and age × pack-years interaction; and the PFS model also included marital status, weight loss, and p16 × Zubrod interaction. Predictions correlated well with observed 2-year and 5-year outcomes. The uncorrected concordance index was 0.76 (95% CI, 0.72 to 0.80) for OS and 0.70 (95% CI, 0.66 to 0.74) for PFS, and bias-corrected indices were similar. In the validation set, OS and PFS models were well calibrated, and OS and PFS were significantly different across tertiles of nomogram scores (log-rank P = .003;< .001). Conclusion The validated nomograms provided useful prediction of OS and PFS for patients with OPSCC treated with primary radiation-based therapy.
04.05 The metabolic checkpoint kinase mtor regulates the rheumatoid mesenchymal tissue response to inflammation
Authors: Thomas Karonitsch, Richard Kumaran Kandasamy, Barbara Herdy, Karolina Dalwigk, Birgit Niederreiter, Johannes Holinka, Florian Sevelda, Reinhard Windhager, Martin Bilban, Thomas Weichhart, Marcus Säemann, Thomas Pap, Josef Smolen, Hans P. Kiener, Giulio Superti-Furga
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> By producing cytokines, chemokines and other inflammatory factors fibroblast-like synoviocytes (FLS) frame a microenvironemt that significantly contributes to persistent synovial inflammation in rheumatoid arthritis (RA). The molecular mechanisms and pathways that regulate these responses within FLS are, however, insufficiently explored. Since mTOR is emerging as a regulator of tissue homeostasis that coordinates the cellular reponse to environmental stress, such as inflammation, we hypothesised that this kinase might also determine the FLS response to inflammation. <h3>Material and methods</h3> mTOR activation was assessed by immunhistochemistry and western blots. For functional <i>in-vitro</i> studies RA-FLS were stimulated with TNF and specific mTOR inhibitors (Torin-1, PP242 and rapamycin) were applied. Affymetrix microarrays were used for gene expression profiling. NF-κB and STAT1 pathway activation was assessed by western-blots and EMSA. <h3>Results</h3> Immunohistochemistry revealed increased mTOR activity in RA synovitis when compared to osteoarthritis. TNF stimulation of FLS <i>ex vivo</i> promoted the phosphorylation of mTOR in an AKT-dependent manner indicating that the pro-inflammatory synovial milieu may drive mTOR activation in RA. Gene expression profiling revealed a so far unknown role for mTOR in the regulation of TNF-induced gene programs: mTOR activation limits the TNF-induced expression of NF-κB-regulated genes (eg, IL6, IL8, PTGS2) by promoting the re-appearence of the NF-κB-inhibitor IκB-α. Contrary, mTOR activation augments the TNF-mediated induction of interferon regulated genes (IRGs; eg, CXCL11, TNFSF13B) by increasing the activity of the transcription factor STAT1. <h3>Conclusions</h3> The metabolic checkpoint kinase mTOR fine-tunes the induced gene expression program in FLS. Thus, mTOR emerges as crucial factor for the development of the RA-typical synovial, inflammatory microenvironment.
FRI0107 Development of a predictive model for rheumatoid arthritis mortality using random survival forest
Authors: L Rodriguez-Rodriguez, JM Lezcano, E Soudah, JΆ Jover, I González-Άlvarez, F Salazar, L Abásolo
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Different machine learning methods have been used to develop predictive models of high quality and precision [1]. Among them, Random Survival Forests (RSF) has been proposed as an alternative to traditional survival models [2], being able to overcome most of the limitation of traditional survival techniques, such as Cox proportional hazards models. <h3>Objectives</h3> Our objective was to develop and internally validate a predictive model for rheumatoid arthritis (RA) mortality using Random Survival Forests (RSF). <h3>Methods</h3> Retrospective longitudinal study involving 1,461 patients diagnosed with RA between January 1994 and August 2011, and followed at the outpatient clinic of the Rheumatology Department of the Hospital Clínico San Carlos (Madrid, Spain) until death or September 2013. Demographic and clinical-related variables collected during the first two years after disease diagnosis were used. RSF models were developed, based on 1,000 trees. 100 iterations of each model were performed to measure the mean and standard deviation (SD) of the predictive error and the integrated Brier score (IBS). Missing values were imputed using the function implemented by the <i>randomForestSRC</i> package [3]. The predictive capacity of the variables was assessed using the "variable importance" (VIMP). Two models were constructed using the log-rank (M<sub>LG</sub>) or log-rank score (M<sub>LGS</sub>) splitting rules. The model with the lowest prediction error was selected. Next, those variables with negative VIMP were excluded and a final model developed. <h3>Results</h3> 148 patients died (10.1%). M<sub>LG</sub> showed the lowest prediction error. All variables exhibited a positive VIMP. Final model showed a mean (SD) prediction error and IBS of 0.187 (0.002) and 0.150 (0.003) respectively. The most important predictor variables were age at diagnosis, median erythrocyte sedimentation rate and number of hospital admissions in the first 2 years after RA diagnosis. <h3>Conclusions</h3> We developed an accurate and precise model for RA mortality using RSF. Age and disease activity showed the highest influence in mortality. <h3>References</h3> Churpek MM, Yuen TC, Winslow C, Meltzer DO, Kattan MW, Edelson DP. Multicenter Comparison of Machine Learning Methods and Conventional Regression for Predicting Clinical Deterioration on the Wards. Crit Care Med. 2016;44: 368–74. Ishwaran H, Kogalur UB, Blackstone EH, Lauer MS. Random survival forests. Ann Appl Stat. 2008;2: 841–860. Ishwaran H, Kogalur U. Random Forests for Survival, Regression and Classification (RF-SRC) [Internet]. 2016 [cited 15 Dec 2016]. Available: https://cran.r-project.org/package=randomForestSRC. <h3>Disclosure of Interest</h3> None declared
化学予防剤の局所的配列特異的放出と治療効果を高めるための時間制御可能依存的に抗癌剤【Powered by NICT】
Authors: Pan Wen-Yu, Lin Kun-Ju, Huang Chieh-Cheng, Chiang Wei-Lun, Lin Yu-Jung, Lin Wei-Chih, Chuang Er-Yuan, Chang Yen, Sung Hsing-Wen
Journal: Biomaterials (2016)
The Association of Falling Insulin Requirements With Maternal Biomarkers and Placental Dysfunction: A Prospective Study of Women With Preexisting Diabetes in Pregnancy
Authors: Suja Padmanabhan, Vincent W. Lee, Mark Mclean, Neil Athayde, Valeria Lanzarone, Qemer Khoshnow, Michael J. Peek, N. Wah Cheung
Journal: Diabetes Care (2017)

OBJECTIVE To investigate the association of falling insulin requirements (FIR) among women with preexisting diabetes with adverse obstetric outcomes and maternal biomarkers longitudinally in pregnancy. RESEARCH DESIGN AND METHODS A multicenter prospective cohort study of 158 women (41 with type 1 diabetes and 117 with type 2 diabetes) was conducted. Women with FIR of ≥15% from the peak total daily dose after 20 weeks' gestation were considered case subjects (n = 32). The primary outcome was a composite of clinical markers of placental dysfunction (preeclampsia, small for gestational age [≤5th centile], stillbirth, premature delivery [&amp;lt;30 weeks], and placental abruption). Maternal circulating angiogenic markers (placental growth factor [PlGF] and soluble fms-like tyrosine kinase 1 [sFlt-1]), placental hormones (human placental lactogen, progesterone, and tumor necrosis factor-α), HbA1c, and creatinine were studied serially during pregnancy. RESULTS FIR ≥15% were associated with an increased risk of the composite primary outcome (odds ratio [OR] 4.38 [95% CI 1.9–10.3]; P &amp;lt; 0.001), preeclampsia (OR 6.76 [95% CI 2.7–16.7]; P &amp;lt; 0.001), and was more common among women with type 1 diabetes (36.6 vs. 14.5%; P = 0.002). Creatinine was modestly elevated among women with FIR ≥15%; however, there was no difference in HbA1c. The ratio of sFlt-1 to PlGF was significantly higher among women with FIR at 25, 30, and 36 weeks, with differences maintained in the subgroup that developed preeclampsia. There was no difference in placental hormones between the groups. CONCLUSIONS This is the first prospective study to associate FIR with altered expression of placental antiangiogenic factors and preeclampsia. FIR are an important clinical sign, among women with preexisting diabetes, that should alert the clinician to investigate underlying placental dysfunction.
β-arrestin 2 mediates cardiac ischemia-reperfusion injury via inhibiting GPCR-independent cell survival signalling
Authors: Yimei Wang, Li Jin, Ying Song, Mao Zhang, Dan Shan, Yuli Liu, Meng Fang, Fengxiang Lv, Rui-Ping Xiao, Yan Zhang
Journal: Cardiovascular Research (2017)

Ischemic heart disease is a leading cause of morbidity and mortality worldwide. Although timely restoration of coronary blood flow (reperfusion) is the most effective therapeutics of myocardial infarction, reperfusion causes further cardiac damage, i.e. ischemia-reperfusion (I/R) injury. β-arrestins (Arrbs) have been traditionally defined as negative regulators of G protein-coupled receptor (GPCR) signalling, but recent studies have shown that they are essential for G protein-independent, GPCR-mediated biased signalling. Several ligands have been reported to be cardioprotective via Arrbs dependent pathway. However, it is unclear whether Arrbs exert receptor-independent physiological or pathological functions in the heart. Here, we sought to determine whether and how Arrbs play a role in regulating cardiomyocyte viability and myocardial remodelling following I/R injury.The expression of β-arrestin 2 (Arrb2), but not β-arrestin 1 (Arrb1), is upregulated in rat hearts subjected to I/R injury, or in cultured neonatal rat cardiomyocytes treated with hypoxia-reoxygenation (H/R) injury. Deficiency of Arrb2 in cultured neonatal rat cardiomyocytes alleviates H/R-induced cardiomyocyte death and Arrb2-/- mice are resistant to myocardial damage caused by I/R injury. In contrast, upregulation of Arrb2 triggers cardiomyocyte death and exaggerates I/R (or H/R)-induced detrimental effects. Mechanically, Arrb2 induces cardiomyocyte death by interacting with the p85 subunit of PI3K, and negatively regulating the formation of p85-PI3K/CaV3 survival complex, thus blocking activation of PI3K-Akt-GSK3β cell survival signalling pathway.We define an upregulation of Arrb2 as a pathogenic factor in cardiac I/R injury, and also reveal a novel GPCR-independent mechanism of Arrb2-mediated cell death signalling in the heart.
02.21 Inhibition effects of rosiglitazone, pparγ agonist, on migration and invasion of rheumatoid arthritis-fibroblast like synoviocyte (fls) by down regulating cyr61
Authors: Eun-Jeong Kwon, Jinseok Kim, Moonjae Cho
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Peroxisome proliferator-activated receptor gamma (PPARγ) agonist has anti-inflammatory properties, which has known to reduce inflammatory cytokine production in RA. Cysteine-rich angiogenic inducer 61 (Cyr61) is associated with diseases related to chronic inflammation. Cyr61, pro-inflammatory factor, has been shown to be increased in the synovial tissues of patients with RA. However the action mechanisms between Cyr61 and PPARγ are unknown. To determine the effects of peroxisome proliferator–activated receptorγ (PPARγ) agonists on tumour necrosis factor alpha (TNF-α)- induced of FLS invasiveness phenotype and Cystein -rich angiogenic inducer 61 (Cyr61) in Rheumatoid arthritis Fibroblast-like synoviocytes (RA-FLS). <h3>Materials and methods</h3> FLS were cultured with TNF-α and Cyr61 in the presence or absence of PPARγ agonists. MMPs and CYR61 expression levels in the RA-FLS and culture medium were measured reverse transcriptase–polymerase chain reaction (RT-PCR) and western blotting. The migration and invasive phenotype of RA-FLS were determined by a scratch wound healing assay and the Boyden chamber assay. <h3>Results</h3> Cyr61 protein was expressed on RA-FLS, and its expression was increased by TNFα. Moreover, Cyr61 directly promoted RA-FLS migration (p&lt;0.01) and invasion (p&lt;0.01) compared to the untreated RA-FLS. RSG significantly decreased TNFα-induced Cyr61 expression. Furthermore, not only did RSG inhibit TNFα induced RA-FLS migration distance (p&lt;0.01) and invasion (p=0.018), but also decreased Cyr61 treated RA-FLS invasion (p&lt;0.01). <h3>Conclusion</h3> Our result show that PPARγ agonist may have beneficial effects on migration and invasion of RA-FLS via down-regulation of Cyr61. Therefore, PPARγ agonist could be a potential treatment of RA.
Iron Overload Is Highly Prevalent in All Disease Severity States in Pyruvate Kinase Deficiency (PKD)
Authors: Eduard J van Beers, Wilma Barcellini, Stefan W. Eber, Janet L Kwiatkowski, Jennifer A Rothman, Ellis J Neufeld, Mukta Sharma, D Holmes Morton, Bertil Glader, Nina Kollmar, Hassan M. Yaish, Jenny M. Despotovic, Christine M. Knoll, Yves D. Pastore, Kevin Kuo, Peter E. Newburger, Marcin W Wlodarski, Alexis A. Thompson, Yaddanapudi Ravindranath, Winfred C. Wang, Heng Wang, Joachim B. Kunz, Vicky R. Breakey, Melissa J. Rose, Melissa Rhodes, Heather A Bradeen, Sujit Sheth, Dongjing Guo, Wendy B. London, Rachael F. Grace
Journal: Blood (2016)
Individualized Adaptive Stereotactic Body Radiotherapy for Liver Tumors in Patients at High Risk for Liver Damage
Authors: Mary Feng, Krithika Suresh, Matthew J. Schipper, Latifa Bazzi, Edgar Ben-Josef, Martha M. Matuszak, Neehar D. Parikh, Theodore H. Welling, Daniel Normolle, Randall K. Ten Haken, Theodore S. Lawrence
Journal: JAMA Oncology (2017)

Patients with preexisting liver dysfunction could benefit the most from personalized therapy for liver tumors to balance maximal tumor control and minimal risk of liver failure. We designed an individualized adaptive trial testing the hypothesis that adapting treatment based on change in liver function could optimize the therapeutic index for each patient.To characterize the safety and efficacy of individualized adaptive stereotactic body radiotherapy (SRBT) for liver tumors in patients who have preexisting liver dysfunction.From 2010 to 2014, 90 patients with intrahepatic cancer treated with prior liver-directed therapy were enrolled in this large phase 2, single-arm, clinical trial at an academic medical center. All patients had at least 1 year of potential follow-up.Using indocyanine green retention at 15 minutes (ICGR15) as a direct biomarker of liver function and a Bayesian adaptive model, planned SBRT was individually modified midway through the course of therapy to maintain liver function after the complete course.The primary outcome was local control; the secondary outcome was safety and overall survival.Patients were 34 to 85 years of age, and 70% (63) were male. Ninety patients (69 [77%] with hepatocellular carcinoma, 4 [4%] with intrahepatic cholangiocarcinoma, and 17 [19%] with metastatic) received treatment to 116 tumors. Sixty-two patients (69%) had cirrhosis, 21 (23%) were Child-Pugh (CP) grade B. The median tumor size was 3 cm; 16 patients (18%) had portal vein involvement. Sixty-two (69%) received all 5 fractions (47 full dose, 15 dose-reduced owing to rising ICGR15). Treatment was well tolerated, with a lower than expected complication rate without adaptation: 6 (7%) experienced a 2-point decline in CP 6 months post-SBRT. The 1- and 2-year local control rates were 99% (95% CI, 97%-100%) and 95% (95% CI, 91%-99%), respectively.We demonstrated that the treatment strategy of individualized adaptive therapy based on a direct biomarker of liver function can be used to achieve both high rates of local control and a high degree of safety without sacrificing either. Individualized adaptive radiotherapy may represent a new treatment paradigm in which dose is based on individual, rather than population-based, tolerance to treatment.clinicaltrials.gov Identifier: NCT01522937.
子宮炎の治療とウシ子宮における広域スペクトル抗菌活性のin vivo評価のためのキトサン微粒子の応用【Powered by NICT】
Authors: Jeon Soo Jin, Ma Zhengxin, Kang Minyoung, N Galvao Klibs, Jeong Kwangcheol Casey
Journal: Biomaterials (2016)
The Risk of Tumour Recurrence in Patients Undergoing Renal Transplantation for End-stage Renal Disease after Previous Treatment for a Urological Cancer: A Systematic Review
Authors: Romain Boissier, Vital Hevia, Harman Max Bruins, Klemens Budde, Arnaldo Figueiredo, Enrique Lledó-García, Jonathon Olsburgh, Heinz Regele, Claire Fraser Taylor, Rhana Hassan Zakri, Cathy Yuhong Yuan, Alberto Breda
Journal: European Urology (2017)
Varus Thrust and Incident and Progressive Knee Osteoarthritis
Authors: Leena Sharma, Alison H. Chang, Rebecca D. Jackson, Michael Nevitt, Kirsten C. Moisio, Marc Hochberg, Charles Eaton, C. Kent Kwoh, Orit Almagor, Jane Cauley, Joan S. Chmiel
Journal: Arthritis & Rheumatology (2017)

To determine if varus thrust, a bowing out of the knee during gait (i.e., the first appearance or worsening of varus alignment during stance), is associated with incident and progressive knee osteoarthritis (OA), we undertook an Osteoarthritis Initiative ancillary study. We further considered hypothesized associations adjusted for static alignment, anticipating some attenuation.Gait was observed for the presence of thrust by 1 of 2-3 examiners per study site at 4 sites. In eligible knees, incident OA was defined as subsequent incident Kellgren/Lawrence grade ≥2, whole- and partial-grade medial joint space narrowing (JSN), and annualized loss of joint space width (JSW); progression was defined as medial JSN and JSW loss. Outcome measures were assessed for up to 7 years of follow-up. Analyses were knee-level, using multivariable logistic and linear regression with generalized estimating equations to account for between-limb correlation.The incident OA sample included 4,187 knees (2,610 persons); the progression sample included 3,421 knees (2,284 persons). In knees with OA, thrust was associated with progression as assessed by each outcome measure, with adjustment for age, sex, body mass index, and pain on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale. In knees without OA, varus thrust was not associated with incident OA or other outcomes. After adjustment for alignment, the thrust-progression association was attenuated, but an independent association persisted for partial-grade JSN and JSW loss outcome models. WOMAC pain and alignment were consistently associated with all outcome measures. Within the stratum of varus knees, thrust was associated with an increased risk of progression.Varus thrust visualized during gait is associated with knee OA progression and should be a target of intervention development.
TLR2 Plays a Key Role in Platelet Hyperreactivity and Accelerated Thrombosis Associated With Hyperlipidemia
Authors: Sudipta Biswas, Alejandro Zimman, Detao Gao, Tatiana V. Byzova, Eugene A. Podrez
Journal: Circulation Research (2017)

Platelet hyperreactivity, which is common in many pathological conditions, is associated with increased atherothrombotic risk. The mechanisms leading to platelet hyperreactivity are complex and not yet fully understood.Platelet hyperreactivity and accelerated thrombosis, specifically in dyslipidemia, have been mechanistically linked to the accumulation in the circulation of a specific group of oxidized phospholipids (oxPCCD36) that are ligands for the platelet pattern recognition receptor CD36. In the current article, we tested whether the platelet innate immune system contributes to responses to oxPCCD36 and accelerated thrombosis observed in hyperlipidemia.Using in vitro approaches, as well as platelets from mice with genetic deletion of MyD88 (myeloid differentiation factor 88) or TLRs (Toll-like receptors), we demonstrate that TLR2 and TLR6 are required for the activation of human and murine platelets by oxPCCD36. oxPCCD36 induce formation of CD36/TLR2/TLR6 complex in platelets and activate downstream signaling via TIRAP (Toll-interleukin 1 receptor domain containing adaptor protein)-MyD88-IRAK (interleukin-1 receptor-associated kinase)1/4-TRAF6 (TNF receptor-associated factor 6), leading to integrin activation via the SFK (Src family kinase)-Syk (spleen tyrosine kinase)-PLCγ2 (phospholipase Cγ2) pathway. Intravital thrombosis studies using ApoE-/- mice with genetic deficiency of TLR2 or TLR6 have demonstrated that oxPCCD36 contribute to accelerated thrombosis specifically in the setting of hyperlipidemia.Our studies reveal that TLR2 plays a key role in platelet hyperreactivity and the prothrombotic state in the setting of hyperlipidemia by sensing a wide range of endogenous lipid peroxidation ligands and activating innate immune signaling cascade in platelets.
More patients are surviving heart failure, audit finds
Authors: Zosia Kmietowicz
Journal: BMJ (2017)

The death rate among people admitted to hospital with heart failure in England and Wales fell to 8.9% in 2015-16, down from 9.6% the previous year, saving about 500 lives, show figures from the National Heart Failure Audit.1

The audit was based on an analysis of 66 695 admissions to hospital where the patient’s main diagnosis was heart failure, and it used data from 82% of all heart failure …