tbuckley/cabot-search huggingface dataset:
Physicians Interrupting Patients
Authors: Kari Ann Phillips, Naykky Singh Ospina
Journal: JAMA (2017)

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Quantitative assessment of gene expression variation and allele imbalance by real-time PCR with multi-gene standard
Authors: Yi-Hong Zhou, Liping Yu
Journal: Clinical Cancer Research (2007)

A32  Real-time quantitative PCR on reverse transcribed mRNA (QRT-PCR) or DNA (Q-PCR) can sensitively and reliably detect its difference in quantity among different biological samples compared to control. A select number of gene expression variables quantified by QRT-PCR assures both the quality of the data and satisfying the statistical requirements needed to produce a meaningful analysis. The comparability of data from real-time PCR remains to be challenged by lack of a standard form of calibration in order to compare data generated from different platforms. In common practice, a reference gene has been used to normalize target genes; both quantities in general rely either on PCR efficiency based methods or standard curve of serially diluted cloned DNA product of individual genes or normal DNA, thus giving rise to relative quantification. Relative quantification may not be a concern in laboratory research where a control sample is available, but is one of the hurdles in the interface of clinical oncology and research. It is important to use biomarkers in which quantification can be standardized, and the idea on use of the absolute expression ratio between a marker gene and an internal control gene may be a resolution. Our data showed that absolute ratio of mRNA quantity of target gene to reference gene in unknown samples can be achieved by referring each gene’s quantity to amplification curves of external recombinant DNA containing each gene’s amplicons - multi-gene standard. Using this method, absolute ratio of DNA quantity of target gene to reference gene can also be obtained to assess the degree of DNA copy number alteration in unbalanced loci of cancer genome. Using a standard curve to refer quantification, the quantities of mRNA or DNA in unknown sample is dependent on the input quantities of the unknown sample as well as the standard. With multi-gene standard, the ratio of two genes, however, is independent of either. In conclusion, the variation of target gene expression or allele imbalance can be sensitively and reliability quantified from calculation of the absolute ratio of target gene to reference gene using multi-gene standard in real-time PCR.
Temporal trend in dementia incidence since 2002 and projections for prevalence in England and Wales to 2040: modelling study
Authors: Sara Ahmadi-Abhari, Maria Guzman-Castillo, Piotr Bandosz, Martin J Shipley, Graciela Muniz-Terrera, Archana Singh-Manoux, Mika Kivimäki, Andrew Steptoe, Simon Capewell, Martin O’Flaherty, Eric J Brunner
Journal: BMJ (2017)

<b>Objective</b>&nbsp;To forecast dementia prevalence with a dynamic modelling approach that integrates calendar trends in dementia incidence with those for mortality and cardiovascular disease. <b>Design</b>&nbsp;Modelling study. <b>Setting</b>&nbsp;General adult population of England and Wales. <b>Participants</b>&nbsp;The English Longitudinal Study of Ageing (ELSA) is a representative panel study with six waves of data across 2002-13. Men and women aged 50 or more years, selected randomly, and their cohabiting partners were recruited to the first wave of ELSA (2002-03). 11392 adults participated (response rate 67%). To maintain representativeness, refreshment participants were recruited to the study at subsequent waves. The total analytical sample constituted 17 906 people. Constant objective criteria based on cognitive and functional impairment were used to ascertain dementia cases at each wave. <b>Main outcome measures</b>&nbsp;To estimate calendar trends in dementia incidence, correcting for bias due to loss to follow-up of study participants, a joint model of longitudinal and time-to-event data was fitted to ELSA data. To forecast future dementia prevalence, the probabilistic Markov model IMPACT-BAM (IMPACT-Better Ageing Model) was developed. IMPACT-BAM models transitions of the population aged 35 or more years through states of cardiovascular disease, cognitive and functional impairment, and dementia, to death. It enables prediction of dementia prevalence while accounting for the growing pool of susceptible people as a result of increased life expectancy and the competing effects due to changes in mortality, and incidence of cardiovascular disease. <b>Results</b>&nbsp;In ELSA, dementia incidence was estimated at 14.3 per 1000 person years in men and 17.0/1000 person years in women aged 50 or more in 2010. Dementia incidence declined at a relative rate of 2.7% (95% confidence interval 2.4% to 2.9%) for each year during 2002-13. Using IMPACT-BAM, we estimated there were approximately 767 000 (95% uncertainty interval 735 000 to 797 000) people with dementia in England and Wales in 2016. Despite the decrease in incidence and age specific prevalence, the number of people with dementia is projected to increase to 872 000, 1 092 000, and 1 205 000 in 2020, 2030, and 2040, respectively. A sensitivity analysis without the incidence decline gave a much larger projected growth, of more than 1.9 million people with dementia in 2040. <b>Conclusions</b>&nbsp;Age specific dementia incidence is declining. The number of people with dementia in England and Wales is likely to increase by 57% from 2016 to 2040. This increase is mainly driven by improved life expectancy.
MAPK-triggered chromatin reprogramming by histone deacetylase in plant innate immunity
Authors: David Latrasse, Teddy Jégu, Huchen Li, Axel de Zelicourt, Cécile Raynaud, Stéphanie Legras, Andrea Gust, Olga Samajova, Alaguraj Veluchamy, Naganand Rayapuram, Juan Sebastian Ramirez-Prado, Olga Kulikova, Jean Colcombet, Jean Bigeard, Baptiste Genot, Ton Bisseling, Moussa Benhamed, Heribert Hirt
Journal: Genome biology (2017)

Microbial-associated molecular patterns activate several MAP kinases, which are major regulators of the innate immune response in Arabidopsis thaliana that induce large-scale changes in gene expression. Here, we determine whether microbial-associated molecular pattern-triggered gene expression involves modifications at the chromatin level. Histone acetylation and deacetylation are major regulators of microbial-associated molecular pattern-triggered gene expression and implicate the histone deacetylase HD2B in the reprogramming of defence gene expression and innate immunity. The MAP kinase MPK3 directly interacts with and phosphorylates HD2B, thereby regulating the intra-nuclear compartmentalization and function of the histone deacetylase. By studying a number of gene loci that undergo microbial-associated molecular pattern-dependent activation or repression, our data reveal a mechanistic model for how protein kinase signaling directly impacts chromatin reprogramming in plant defense.
SUBSEQUENT ARM INJURY RISK FOLLOWING REHABILITATION AND RETURN TO SPORT
Authors: Ellen Shanley, Amanda Arnold, Richard Hawkins, John Tokish, Michael Kissenberth, Douglass Wyland, Charles Thigpen
Journal: British Journal of Sports Medicine (2017)

Background Reports of return to play(8–80%) and subsequent injury(15–30%) are variable following arm injuries in baseball players with no known risk factors. Objective We aimed to prospectively examine the influence of injury history, return to sport criteria, and baseball participation as risk factors in youth and adolescent baseball players returning to sport following rehabilitation. Design Prospective cohort study. Setting Youth through adolescent baseball leagues. Patients (or Participants) Injured baseball players (n=60;age=15.3±2.5 months) were followed for atleast 1 year (15.8±9.6 months) after returning to sport. Interventions (or Assessment of Risk Factors) All players' ROM, strength and outcome scores were measured and met predetermined criteria for return to sport. Players were surveyed monthly for participation, competition level, and the development of injuries. All subsequent injuries were verified as overuse time-loss injuries by team athletic trainer, physical therapist, or physician. Main Outcome Measurements Bivariate correlations were used to evaluate the relationship between injury history, return to sport criteria, and baseball participation. Forward stepwise logistic regression using significant (r&gt;.25; P &lt;0.05) associations with advancing completion level and subsequent injury were then used to calculate odds ratios and 95% confidence intervals (CIs) from the final model (α=0.05). Results Seven players reported an injury prior to the index injury. Twenty players suffered a subsequent time-loss arm injury. Development of a subsequent arm injury was correlated with previous injury(r=.45; P =0.002) and advancing one competitive level(r=.32; P =0.01). The final regression model revealed that players reporting an prior injury to the index injury were 20.5 (1.8–147.5 95% CI) times greater risk of a subsequent overuse arm injury than in players without a previous injury history. Conclusions Injury history and advancing competition levels increases the risk of a subsequent arm injury despite achievement of evidence based return to sport criteria. Clinicians should consider counseling and monitoring of youth and adolescent baseball players returning back to sport, especially after multiple arm injuries.
Umbilical cord blood stem cell derived NK cells as universal treatment for metastatic colorectal cancer using EGFR independent killing mechanisms.
Authors: John Veluchamy, Jan Spanholtz, Nina Kok, Fenna Bohme, Henk M.W. Verheul, Tanja D. de Gruijl, Hans J. Van Der Vliet
Journal: Journal of Clinical Oncology (2016)

e14525 Background: Resistance to epidermal growth factor receptor (EGFR) targeting therapy is a major limitation in metastatic colorectal cancer (mCRC). Moreover, NK cells in solid tumor patients are often dysfunctional and low in number. Adoptive NK cell therapy could overcome those limitations and toxicities related to anti-EGFR therapies. In this study, cytotoxicity of allogeneic NK cell products like activated peripheral blood NK cells (PBNK) and oNKord, an alternate source of umbilical cord blood stem cell derived NK cells, has been investigated against colon cancer cells. Methods: Flow cytometry based NK cell cytotoxicity assays were performed, PBNK were co-cultured with various colon cancer cell lines coated or non-coated with cetuximab and their cytotoxicity was compared with oNKord. Results: Cetuximab as monotherapy was ineffective in killing EGFR+ RASmut, EGFR+ BRAFmut and EGFR- RASwt cells, whereas activated PBNK were able to initiate lysis of colon cancer cells. Cytotoxicity was further potentiated significantly (p < 0.01) upon coating colon cancer cells with cetuximab, including EGFR+ primary colon tumors (n = 5; 3 RASwt, 2 RASmut) with a cytotoxicity of 36 ± 5%, p < 0.05. More importantly, a significant (p < 0.01) higher cytotoxicity was induced by oNKord in EGFR+ RASmut (38 ± 4% vs 61 ± 5%), EGFR+ BRAFmut (36 ± 4% vs 59 ± 3% ) and EGFR- RASwt (42 ± 8% vs 67 ± 7% ) colon cancer cells compared to PBNK + cetuximab conditions. Conclusions: Activated NK cells are able to eliminate colon cancer cell lines and primary colon tumor cells.oNKord showed enhanced anti-tumor cytotoxicity against colon cancer independent of EGFR, RAS and BRAF status. As oNKord has proven safety in a phase I clinical trial in acute myeloid leukemia (AML), a fast translation towards clinical proof of concept in mCRC is feasible. A clinical study to further develop oNKord immunotherapy in mCRC patients has been planned to start this year.
Real-world dosing of regorafenib in metastatic colorectal cancer (mCRC): Interim analysis from the prospective, observational CORRELATE study
Authors: Manuel O’Connor Juan, Leopold Öhler, Werner Scheithauer, Jean-Philippe Metges, Louis-Marie Dourthe, Willem de Groot Jan, Josef Thaler, Kun-Huei Yeh, Jen-Kou Lin, Alfredo Falcone, Cornelis J.A. Punt, Jan Kalinovsky, Sabine Fiala-Buskies, Andres Cervantes, Lone N. Petersen, Michel Ducreux
Journal: Annals of Oncology (2017)
<i>Notes from the Field:</i> Late-Onset Infant Group B Streptococcus Infection Associated with Maternal Consumption of Capsules Containing Dehydrated Placenta — Oregon, 2016
Authors: Genevieve L. Buser, Sayonara Mató, Alexia Y. Zhang, Ben J. Metcalf, Bernard Beall, Ann R. Thomas
Journal: MMWR Morbidity and Mortality Weekly Report (2017)
Bringing Lung Function Prediction Equations to Diverse Populations
Authors: Joshua M. Galanter
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Finally, we must rise to the challenge of risk stratification.Not all children with asthma have attacks.In both the PROSE trial ( 9) and a previous omalizumab study (6), children with the highest levels of exhaled nitric oxide and peripheral blood eosinophils had the best response, and the peripheral blood eosinophil count is a promising marker in pediatrics (15).Personalizing treatment for asthma attacks must be the next goal, especially if omalizumab treatment is extended into the preschool years.
LION: Lymphadenectomy in ovarian neoplasms—A prospective randomized AGO study group led gynecologic cancer intergroup trial.
Authors: Philipp Harter, Jalid Sehouli, Domenica Lorusso, Alexander Reuss, Ignace Vergote, Christian Marth, Jae Weon Kim, Francesco Raspagliesi, Boern Lampe, Fabio Landoni, Werner Meier, David Cibula, Alexander Mustea, Sven Mahner, Ingo B. Runnebaum, Barbara Schmalfeldt, Alexander Burges, Rainer Kimmig, Uwe A. G. Wagner, Andreas Du Bois
Journal: Journal of Clinical Oncology (2017)

5500 Background: So far, there is no level-1 evidence regarding the role of systematic pelvic and para-aortic lymphadenectomy (LNE) in patients with advanced ovarian cancer (AOC) with macroscopic complete resection und clinically negative lymph nodes (LN). Therefore, surgical management regarding LNE worldwide is very heterogeneous. Methods: Prospective randomized trial including patients with newly diagnosed AOC FIGO IIB-IV with macroscopic complete resection and pre- and intra-operatively clinical negative LN were randomized intra-operatively to LNE versus no-LNE. All centers had to qualify regarding surgical skills before participation in this trial. The primary endpoint was overall survival. Results: 647 patients were randomized between 12/08 and 1/12 to LNE (n=323) or no-LNE (n=324). The median number of removed LN in patients randomized to LNE was 57 (pelvic 35 and para-aortic22). Post-op platinum-taxane based chemotherapy was applied in 85% of the patients in the no-LNE arm and 80% in the LNE arm. Microscopic metastases were diagnosed in 56% of the pts in the LNE arm. Median OS in the no-LNE arm was 69 months and 66 months in the LNE arm (HR 1.06, 95%CI 0.83-1.34, p=0.65) and the median PFS was 26 months in both arms (HR 1.11, 95%CI 0.92-1.34 p=0.30). Surgery in the LNE arm was 64 minutes longer (means: 352 vs 288 min), resulted in a higher median blood loss (650 vs 500 ml), and a higher transfusion rate (67% vs 59%). Furthermore, serious post-operative complications occurred more frequently in the LNE arm (e.g. rate of re-laparotomies 12.1% vs 5.9% [p=0.006], hospital re-admittance rate 8.0% vs 3.1% [p=0.006] and deaths within 60 days after surgery 3.1 vs 0.9% [p=0.049]). Conclusions: Systematic pelvic and para-aortic LNE in patients with AOC with both intra-abdominal complete resection and clinically negative LN neither improve overall nor progression-free survival despite detecting (and removing) sub-clinical retroperitoneal lymph node metastases in 56% of the patients. Our data indicate that systematic LNE of clinical negative LN in patients with AOC and complete resection should be omitted to reduce post-operative morbidity and mortality. Clinical trial information: NCT00712218.
Low density array profiling of head and neck squamous cell carcinoma utilizing a 25-gene signature can reliably identify hypoxic tumors
Authors: A Williamson, Gnj Betts, S Patiar, HR Valentine, JJ Irlam, A Ramachandran, A Merve, JJ Homer, C Moller-Levet, FM Buffa, G Hall, CJ Miller, AL Harris, Cml West
Journal: Cancer Research (2012)
A multicenter randomized controlled trial (RCT) of adjuvant chemotherapy (CT) in nasopharyngeal carcinoma (NPC) with residual plasma EBV DNA (EBV DNA) following primary radiotherapy (RT) or chemoradiation (CRT).
Authors: Anthony T. C. Chan, Edwin Pun Hui, Roger K.C. Ngan, Stewart Yuk Tung, Ashley Chi Kin Cheng, Wai Tong Ng, Victor HF Lee, Brigette Ma, Hoi Ching Cheng, Frank C.S. Wong, Herbert H. F. Loong, Macy Tong, Daren MC Poon, Anil Tejbhan Ahuja, Ann Dorothy King, Ki Wang, Frankie Mo, Benny C.Y. Zee, Allen K.C. Chan, YM Dennis Lo
Journal: Journal of Clinical Oncology (2017)

6002 Background: The benefit of adjuvant CT in NPC is unclear. Post-RT EBV DNA predicts poor survival and may be a biomarker of subclinical residual disease. We conducted a biomarker driven RCT using post-RT EBV DNA to select high risk NPC patients (pts) for adjuvant CT while sparing low risk pts from unnecessary toxicity. Methods: Eligible pts had biopsy proven NPC of AJCC (6th Ed) stage IIB-IVB, detectable EBV DNA ( &gt; 0 copy/ml) at 6-8 weeks post-RT, no persistent locoregional disease or distant metastasis, ECOG 0 or 1, and adequate organ function. Pts were randomized with stratification for primary therapy (RT Vs CRT) and tumor stage (II/III Vs IV) to arm A (adjuvant cisplatin 40 mg/m2 and gemcitabine 1000 mg/m2, both given on D1+8 q3w x 6 cycles) or arm B (clinical follow-up). Primary endpoint was relapse free survival (RFS). With a hazard ratio (HR) of 2, 100 pts were required with a power of 0.8 and an alpha at 0.05. Results: From 9/2006 to 7/2015, 789 pts consented for EBV DNA screening, 218 (27.6%) pts had detectable EBV DNA, and 104 (13.2%) pts were randomized (arm A: 52; arm B: 52). The two arms were well balanced in baseline characteristics. 84.6% received prior neoadjuvant and/or concurrent CT and all received curative RT. Staging distribution: IIB 27.9%, III 37.5%, IVA 19.2%, IVB 15.4%. 8 pts refused adjuvant CT after randomization. Overall 69% and 50% completed 3 and 6 cycles of adjuvant CT respectively. After median follow up of 6.5 years (yr), the 3-yr and 5-yr survival outcomes were summarized in Table. Conclusions: In NPC pts who had residual EBV DNA after curative RT/CRT, adjuvant CT with cisplatin-gemcitabine did not improve survival. Clinical trial information: NCT00370890. [Table: see text]
Effects of Long-Term Ruxolitinib (RUX) on Bone Marrow (BM) Morphology in Patients with Myelofibrosis (MF) Enrolled in the COMFORT-I Study
Authors: Hans Michael Kvasnicka, Juergen Thiele, Carlos E. Bueso-Ramos, William Sun, Ahmad Naim, Smitha Svaraman, Jessy Gao, Jason R. Gotlib, Vikas Gupta, Kim-Hien Dao, Moshe Talpaz, Elliott F. Winton, Jimmie H. Harvey, Srdan Verstovsek
Journal: Blood (2016)
Effect of the Addition of Cetuximab to Paclitaxel, Cisplatin, and Radiation Therapy for Patients With Esophageal Cancer
Authors: Mohan Suntharalingam, Kathryn Winter, David Ilson, Adam P. Dicker, Lisa Kachnic, André Konski, A. Bapsi Chakravarthy, Christopher J. Anker, Harish Thakrar, Naomi Horiba, Ajay Dubey, Joel S. Greenberger, Adam Raben, Jeffrey Giguere, Kevin Roof, Gregory Videtic, Jondavid Pollock, Howard Safran, Christopher H. Crane
Journal: JAMA Oncology (2017)

The role of epidermal growth factor receptor (EGFR) inhibition in chemoradiation strategies in the nonoperative treatment of patients with esophageal cancer remains uncertain. To evaluate the benefit of cetuximab added to concurrent chemoradiation therapy for patients undergoing nonoperative treatment of esophageal carcinoma. A National Cancer Institute (NCI) sponsored, multicenter, phase 3, randomized clinical trial open to patients with biopsy-proven carcinoma of the esophagus. The study accrued 344 patients from 2008 to 2013. Patients were randomized to weekly concurrent cisplatin (50 mg/m2), paclitaxel (25 mg/m2), and daily radiation of 50.4 Gy/1.8 Gy fractions with or without weekly cetuximab (400 mg/m2 on day 1 then 250 mg/m2 weekly). Overall survival (OS) was the primary endpoint, with a study designed to detect an increase in 2-year OS from 41% to 53%; 80% power and 1-sided α = .025. Between June 30, 2008, and February 8, 2013, 344 patients were enrolled. This analysis used all data received at NRG Oncology through April 12, 2015. Sixteen patients were ineligible, resulting in 328 evaluable patients, 159 in the experimental arm and 169 in the control arm. Patients were well matched between the treatment arms for patient and tumor characteristics: 263 (80%) with T3 or T4 disease, 215 (66%) N1, and 62 (19%) with celiac nodal involvement. Incidence of grade 3, 4, or 5 treatment-related adverse events at any time was 71 (46%), 35 (23%), or 6 (4%) in the experimental arm and 83 (50%), 28 (17%), or 2 (1%) in the control arm, respectively. A clinical complete response (cCR) rate of 81 (56%) was observed in the experimental arm vs 92 (58%) in the control arm (Fisher exact test, P = .66). No differences were seen in cCR between treatment arms for either histology (adenocarcinoma or squamous cell). Median follow-up for all patients was 18.6 months. The 24- and 36-month local failure for the experimental arm was 47% (95% CI, 38%-57%) and 49% (95% CI, 40%-59%) vs 49% (95% CI, 41%-58%) and 49% (95% CI, 41%-58%) for the control arm (HR, 0.92; 95% CI, 0.66-1.28; P = .65). The 24- and 36-month OS rates for the experimental arm were 45% (95% CI, 37%-53%) and 34% (95% CI, 26%-41%) vs 44% (95% CI, 36%-51%) and 28% (95% CI, 21%-35%) for the control arm (HR, 0.90; 95% CI, 0.70-1.16; P = .47). The addition of cetuximab to concurrent chemoradiation did not improve OS. These phase 3 trial results point to little benefit to current EGFR-targeted agents in an unselected patient population, and highlight the need for predictive biomarkers in the treatment of esophageal cancer. clinicaltrials.gov Identifier: NCT00655876.