tbuckley/cabot-search huggingface dataset:
Clinical and molecular comparison between short- and long-course preoperative radiotherapy for rectal cancer.
Authors: Y. Inoue, S. Saigusa, J. Hiro, Y. Toiyama, K. Tanaka, Y. Mohri, M. Kusunoki
Journal: Journal of Clinical Oncology (2011)

e14093 Background: Conventional chemoradiotherapy (CRT) or short course radiotherapy are most frequent regimens in the preoperative treatment for rectal cancer. Debate is still going on which is more effective modality to improve outcome for rectal cancer. We aim to evaluate the clinical and molecular differences between two courses retrospectively. Methods: Among 73 patients with T2-4 rectal cancer who underwent preoperative CRT, 51 patients were treated short course (5Gy×4) with immediate surgery and 22 patients with long course (45-50Gy) with delayed surgery. The 2 groups were underwent concurrent 5FU based chemotherapy. Residual cancer cells after CRT were also collected from surgical specimens. We compared gene expressions that had previously been shown to be involved in the metabolism of 5FU, radiation sensitivity, angiogenesis and epithelial-mesenchymal transition using real-time PCR. Results: There was no significant difference between 2 groups in the distribution of clinical TNM stage. Long course had a significantly higher pathological response fewer than one-third vital residual tumor cells of 56.5% than short course of 25.5% (p=0.0097). Long course had a significantly lower rate of perioperative diarrhea than the short course (18.2% vs. 49.0%, p=0.0202), but higher rate of surgical site infection (36.4% vs. 13.7%, p=0.0281). With molecular analysis, long course was found to have significantly higher intratumoral thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyl transferase (OPRT), thymidine phosphorylase (TP), excision repair cross-complementation group 1 (ERCC1), SOX2 and OCT4 expression compared with short course. After a median follow-up of 49 months, a total of 12 patients in our study population developed recurrence independent of radiation schedule. The 5-year overall survival rate was 83.3% (long) versus 83.4% (short), respectively. Conclusions: Long course is a better technique than short course for pathological effects in preoperative CRT for rectal cancer. There was no significant difference in terms of oncologic outcome, although several treatment-resistant genes had up-regulated in long course compared with short course.
Challenges Facing Early Phase Trials Sponsored by the National Cancer Institute: An Analysis of Corrective Action Plans to Improve Accrual
Authors: Holly A. Massett, Grace Mishkin, Larry Rubinstein, S. Percy Ivy, Andrea Denicoff, Elizabeth Godwin, Kate DiPiazza, Jennifer Bolognese, James A. Zwiebel, Jeffrey S. Abrams
Journal: Clinical Cancer Research (2016)

Accruing patients in a timely manner represents a significant challenge to early phase cancer clinical trials. The NCI Cancer Therapy Evaluation Program analyzed 19 months of corrective action plans (CAP) received for slow-accruing phase I and II trials to identify slow accrual reasons, evaluate whether proposed corrective actions matched these reasons, and assess the CAP impact on trial accrual, duration, and likelihood of meeting primary scientific objectives. Of the 135 CAPs analyzed, 69 were for phase I trials and 66 for phase II trials. Primary reasons cited for slow accrual were safety/toxicity (phase I: 48%), design/protocol concerns (phase I: 42%, phase II: 33%), and eligibility criteria (phase I: 41%, phase II: 35%). The most commonly proposed corrective actions were adding institutions (phase I: 43%, phase II: 85%) and amending the trial to change eligibility or design (phase I: 55%, phase II: 44%). Only 40% of CAPs provided proposed corrective actions that matched the reasons given for slow accrual. Seventy percent of trials were closed to accrual at time of analysis (phase I = 48; phase II = 46). Of these, 67% of phase I and 70% of phase II trials met their primary objectives, but they were active three times longer than projected. Among closed trials, 24% had an accrual rate increase associated with a greater likelihood of meeting their primary scientific objectives. Ultimately, trials receiving CAPs saw improved accrual rates. Future trials may benefit from implementing CAPs early in trial life cycles, but it may be more beneficial to invest in earlier accrual planning. Clin Cancer Res; 22(22); 5408-16. ©2016 AACRSee related commentary by Mileham and Kim, p. 5397.
Next-generation sequencing to identify molecular alterations in DNA repair and chromatin maintenance genes associated with pathologic complete response (pT0) to neoadjuvant accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (AMVAC) in muscle-invasive bladder cancer (MIBC).
Authors: Elizabeth R. Plimack, Roland Dunbrack, Timothy Brennan, Qiong Wei, Roman Yelensky, Ilya Serebriiskii, Jean H. Hoffman-Censits, Alexander Kutikov, R. Katherine Alpaugh, Essel Dulaimi, Rosalia Viterbo, Richard E. Greenberg, David Y. T. Chen, Costas D. Lallas, Yu-Ning Wong, Edouard John Trabulsi, Norma Alonzo Palma, Vincent A. Miller, Erica Golemis, Eric A Ross
Journal: Journal of Clinical Oncology (2014)

4538 Background: Neoadjuvant cisplatin based chemotherapy prior to cystectomy is standard of care for MIBC, with 30-40% expected to achieve a pT0. Biomarkers predictive of pT0 are lacking. Methods: 36 MIBC pts treated on study with 3 cycles of neoadjuvant AMVAC were included. 14/36 were pT0. DNA from pre-treatment tumor tissue underwent sequencing of 287 cancer related genes and was analyzed for presence of base substitutions, indels, copy number alterations, and selected re-arrangements. The mean number of variants and variant status for each gene were correlated with pT0 using two-sample t-test and Fisher’s exact tests. Variant data were used to create a classification tree to discriminate pts with and without pT0. Missense mutations were predicted to be deleterious/neutral using a support vector machine trained with sequence and protein structural features. Results: 747 alterations in 216 genes were detected. Pts with pT0 had more alterations (mean 25, range 11-39) than those with residual tumor (mean 18, range 8-32), p=0.01. All 13 pts with ≥ 1 variant in ATM, RB1, or FANCC achieved pT0 (positive predictive value=100%), while only 1/23 without a variant in 1 of these 3 genes achieved pT0 (negative predictive value=96%). This decision rule has a specificity of 100% and sensitivity of 93% for pT0. Permutation studies show the probability of this rule resulting in ≥ 97% accuracy by chance is ≤ 0.0001. Alterations in ATM and RB1 remained independently associated with pT0 after correction for multiple testing. All but 1 of the alterations detected in ATM, RB1 and FANCC were predicted to be deleterious. Conclusions: Alterations in ≥1 of ATM, RB1 and FANCC predict pT0 to neoadjuvant AMVAC with high sensitivity and specificity. We hypothesize that defects in these genes, which are important for maintenance of chromatin structure and DNA repair, confer sensitivity to DNA damaging chemotherapy and that the accumulation of alterations seen among pts with pT0 reflect this phenotype. Independent validation of these findings is underway. Clinical trial information: NCT01031420.
Eritoran Suppresses Colon Cancer by Altering a Functional Balance in Toll-like Receptors That Bind Lipopolysaccharide
Authors: Wei-Ting Kuo, Tsung-Chun Lee, Linda Chia-Hui Yu
Journal: Cancer Research (2016)

Colorectal carcinogenesis is affected by overexpression of the lipopolysaccharide (LPS) receptors CD14 and TLR4, which antagonize each other by affecting epithelial cell proliferation and apoptosis. Eritoran is an investigational drug for sepsis treatment that resembles the lipid A moiety of LPS and therefore acts as a TLR4 inhibitor. In the present study, we explored the potential therapeutic uses and mechanisms of action of eritoran in reducing colon cancer progression. Eritoran administration via intracolonic, intragastric, or intravenous routes significantly reduced tumor burden in a chemically induced mouse model of colorectal carcinoma. Decreased proliferation and increased apoptosis were observed in mouse tumor cells after eritoran treatment. In vitro cultures of mouse primary tumor spheroids and human cancer cell lines displayed increased cell proliferation and cell-cycle progression following LPS challenge. This effect was inhibited by eritoran and by silencing CD14 or TLR4. In contrast, apoptosis induced by eritoran was eliminated by silencing CD14 or protein kinase Cζ (PKCζ) but not TLR4. Lastly, LPS and eritoran caused hyperphosphorylation of PKCζ in a CD14-dependent and TLR4-independent manner. Blocking PKCζ activation by a Src kinase inhibitor and a PKCζ-pseudosubstrate prevented eritoran-induced apoptosis. In summary, our work offers a preclinical proof of concept for the exploration of eritoran as a clinical treatment, with a mechanistic rationale to reposition this drug to improve the management of colorectal cancer. Cancer Res; 76(16); 4684-95. ©2016 AACR.
Aortic Valve Stenosis
Authors: Amisha Patel, Ajay J. Kirtane
Journal: JAMA Cardiology (2016)

Aortic Valve StenosisAortic stenosis is a narrowing of the aortic valve, the outflow valve of the heart between the left ventricle (main pumping chamber) and the aorta (major blood vessel carrying blood to the body).
Effects of long-term testosterone administration on cognition in older men with low or low-to-normal testosterone concentrations: a prespecified secondary analysis of data from the randomised, double-blind, placebo-controlled TEAAM trial
Authors: Grace Huang, Whitney Wharton, Shalender Bhasin, S Mitchell Harman, Karol M Pencina, Panayiotis Tsitouras, Zhuoying Li, Kathleen A Hally, Sanjay Asthana, Thomas W Storer, Shehzad Basaria
Journal: The Lancet Diabetes & Endocrinology (2016)
How do training and competition workloads relate to injury? The workload—injury aetiology model
Authors: Johann Windt, Tim J Gabbett
Journal: British Journal of Sports Medicine (2016)

Injury aetiology models that have evolved over the previous two decades highlight a number of factors which contribute to the causal mechanisms for athletic injuries. These models highlight the pathway to injury, including (1) internal risk factors (eg, age, neuromuscular control) which predispose athletes to injury, (2) exposure to external risk factors (eg, playing surface, equipment), and finally (3) an inciting event, wherein biomechanical breakdown and injury occurs. The most recent aetiological model proposed in 2007 was the first to detail the dynamic nature of injury risk, whereby participation may or may not result in injury, and participation itself alters injury risk through adaptation. However, although training and competition workloads are strongly associated with injury, existing aetiology models neither include them nor provide an explanation for how workloads alter injury risk. Therefore, we propose an updated injury aetiology model which includes the effects of workloads. Within this model, internal risk factors are differentiated into modifiable and non-modifiable factors, and workloads contribute to injury in three ways: (1) exposure to external risk factors and potential inciting events, (2) fatigue, or negative physiological effects, and (3) fitness, or positive physiological adaptations. Exposure is determined solely by total load, while positive and negative adaptations are controlled both by total workloads, as well as changes in load (eg, the acute:chronic workload ratio). Finally, we describe how this model explains the load-injury relationships for total workloads, acute:chronic workload ratios and the training load-injury paradox.
A Long Tail of Sub-Clonal TP53 Mutations Emerged By Ultra-Deep Sequencing of Newly Diagnosed Multiple Myeloma (MM)
Authors: Marina Martello, Barbara Santacroce, Angela Flores Dico, Enrica Borsi, Torsten Haferlach, Flavio Mignone, Igor Saggese, Elena Zamagni, Paola Tacchetti, Lucia Pantani, Annamaria Brioli, Beatrice Anna Zannetti, Serena Rocchi, Katia Mancuso, Nicoletta Testoni, Giulia Marzocchi, Gaia Ameli, Annalisa Pezzi, Michele Cavo, Giovanni Martinelli, Carolina Terragna
Journal: Blood (2014)
Abstract 1370: Biochemical and Proteomic Approach to the Study of the Experimental Diabetic Myocardium
Authors: Oscar Lorenzo, Sara Ares, Irene Zubiri, Emilio Camafeita, Belen Picatoste, Juan Antonio Lopez, Jesus Egido, Jose Tunon
Journal: Circulation (2009)

Background: Diabetes mellitus (DM) may affect directly the heart. The acute effect of DM on the myocardium has been described. However, the effect of long-standing DM and of coexisting hypertension...
Outcome of Down Syndrome (DS) Children with Acute Myeloid Leukemia (AML) or Myelodysplasia (MDS) Treated with a Uniform Prospective Clinical Trial - Initial Report of the COG Trial A2971.
Authors: Alan S. Gamis, Todd A. Alonzo, Joanne M. Hilden, Robert B. Gerbing, Thomas W. Loew, Lois Hathaway, Loris McGavran, Dorothy Barnard, Jeffrey W. Taub, Yaddanapudi Ravindranath, Franklin O. Smith, Robert Arceci
Journal: Blood (2006)
Syndromic surveillance based on emergency department activity and crude mortality: two examples
Authors: L Josseran, Javier Nicolau, N Caillère, P Astagneau, G Brücker
Journal: Eurosurveillance (2006)

Recent public health crises have shown the need for readily available information allowing proper management by decision-makers. One way of obtaining early information is to involve data providers who already record routine data for their own use. We describe here the results of a pilot network carried out by the InVS (Institut national de veille sanitaire) which gathered data available in real time from hospital emergency departments and register offices. Emergency departments data were registered from patients' computerized medical files. Mortality data were received from the national institute of statistics (Insee). Data were transmitted automatically on a daily basis. Influenza data from outbreaks in 2004/05 and 2005/06 were compared with data from the sentinel network for the same periods. Environmental health data were compared with meteorological temperatures recorded in Paris between June and August 2006. A mortality analysis was conducted on a weekly basis. Correlation between influenza data from emergency departments and data from Sentiweb (sentinel network) was significant (p<0.001) for both outbreaks. In 2005 and 2006, the outbreaks were described similarly by both sources with identification of the start of the outbreaks by both systems during the same weeks. As for data related to heat, a significant correlation was observed between some diagnoses and temperature increases. For both types of phenomena, mortality increased significantly with one to two weeks lag. To our knowledge, this is the first time that a study using real time morbidity and mortality data is conducted. These initial results show how these data complement each other and how their simultaneous analysis in real time makes it possible to quickly measure the impact of a phenomenon.
Improved treatment outcome of MDR-TB in Eastern Taiwan: Reducing default rate by DOTS Plus
Authors: Chih Bin Lin, Jen-Jyh Lee, Hung-Chieh Sun
Journal: European Respiratory Journal (2013)

Multidrug-resistant tuberculosis (MDR-TB) is an increasing global problem. Meta-analysis by Orenstein et al. about treatment outcome of MDR TB worldwide was: 62% successful, 11% death and 12% defaulted. Report by Chiang et al. about treatment without DOTS-Plus showed an outcome for 299 MDR-TB patients in Taiwan as follows: 51.2% treatment success, 9.4% died, and 29.1% defaulted.  Our aim was to assess treatment outcome of MDR-TB patients after introduction of “DOTS-Plus strategy” in Eastern Taiwan, following WHO guidelines.  We reviewed all patients who began treatment with DOTS-Plus for MDR-TB in Eastern Taiwan, between May 1st, 2007 and November 30th, 2012.  Out of a total of 135 bacteriologically confirmed MDR-TB cases, 13 were still in treatment. Among 122 patients with final outcomes, 54 (44.26%) were new cases, 47 (38.52%) have been previously treated with first line anti-TB drugs, 21 (17.21%) with secondary second line drugs. The mean age was 49.7 years (range 12 to 93) and 94 (77.05%) were male. Three (2.46%) patients received surgical intervention. Finally, 84 (68.85%) patients were cured, 11 (9.02%) completed therapy, 18 (14.75%) died, 1 (0.82%) defaulted, treatment failed in 8 (6.56%) and treatment success in 95 (77.87%).  Treatment success rate for MDR-TB patients in Eastern Taiwan has improved since implementing “DOTS-Plus regimen” in May 2007 compared not only to Taiwan9s prior rate but also to world-wide values. The default rate was reduced from 29.1% to 0.82% in Taiwan, with world-wide value at 12%.Treating MDR-TB patients under “DOTS-Plus regimen” can improve the treatment success rate in Eastern Taiwan, and especially by reduce default rate.
Soundings: The skier's tale
Authors: Kevin Barraclough
Journal: BMJ (2002)

Someone once pointed out that an excessive fear of death substantially impairs the quality of your life. The same could be said for the quality of your skiing. If, like me, you are an extremely poor skier then, at the top of that icy red run, you see only fear. The scintillating light of sun on alpine peaks is invisible, shrouded in the miasma of concern for your immediate future. Thoughts that should be soaring from this perspective on the top of the world remain fixedly locked on the safety of your anterior cruciate ligaments.

Later, as duty free whisky loosens the knotted cables of body and mind, a certain perspective returns, sharpened by the thrill of survival. You remember your equally inept friends in the ski school who form, in adversity, an almost Chaucerian pageant of humanity.

Before you in the crocodile down the mountain, locked in iron snow ploughs even more rigid than your own, is someone whom life defeats. You can watch her close in the walls of her universe to shut out the sense of vertigo. These dizzy perspectives of an unfamiliar world are to her merely frightening rather than liberating.

Then there are those whom the parallel turn defeats but who press on stubbornly, encased in a permanent salopette of snow. Gravity, like death, will win out in the end, but not without a titanic struggle.

And then there is the pessimist who weighs down the group with his own certain knowledge of the malevolence of fate. But this cloud is dissipated by the woman who wears her fear on her sleeve for all to see and be comforted by, but who disguises her courage in a blizzard of self deprecating humour.

The week ends and these people, whose lives you have briefly shared, move away to their own realities, distant from your own. The communal experience of fear and shin pain has sharpened the usual ambiguous intimacy of holiday friendships. As both observer and participant in these minor trials, you find yourself wondering what sort of patients these people will be when faced in the future with the inevitable significant illness. With a certain hubris you feel that you could infer their sickness behaviour with some precision. And the most curious thing is that sometimes your intuitions will be right and often they will be wrong.
Effects of Prenatal PM10 Exposure on Fetal Cardiovascular Malformations in Fuzhou, China: A Retrospective Case–Control Study
Authors: Chao-Bin Liu, Xin-Ru Hong, Miao Shi, Xiao-Qiu Chen, Hui-Juan Huang, Jin-Hua Chen, Kai Yang, Su-Qing Chen, Han-Qiang Chen, Hai-Dong Kan, Qing-Hua Sun
Journal: Environmental Health Perspectives (2016)

Maternal exposure to ambient air pollution has been associated with an increased risk of congenital heart defects in offspring; however, the results are inconsistent.We investigated whether there is an association between prenatal exposure to particulate matter with diameter ≤10μm (PM10) during early pregnancy and fetal cardiovascular malformations.The gravidae from a hospital-based case–control study in Fuzhou, China, during 2007–2013 were assigned 10-d or 1-mo averages of daily PM10 using an air monitor–based inverse distance weighting method during early pregnancy. A total of 662 live-birth or selectively terminated cases and 3,972 live-birth controls were enrolled. The exposure was considered as a categorical variable. A multivariable logistic regression model was constructed to quantify the adjusted odds ratios (aORs) of the exposure to PM10 and the risks of fetal cardiovascular malformations.PM10 levels were positively associated with the risks of atrial septal defect (aORs ranging from 1.29 to 2.17), patent ductus arteriosus [aORs = 1.54, 1.63; 95% confidence intervals (CIs): 1.17, 2.23; 1.06, 3.24], overall fetal cardiovascular malformations (aOR = 1.28; 95% CI: 1.03, 1.61), ventricular septal defect (aOR = 1.19; 95% CI: 1.00, 1.43), and tetralogy of Fallot (aOR = 1.44; 95% CI: 1.01, 2.19) in the various observed periods scaled by 10 d or 1 mo in the first and second gestation months. The strongest associations were observed for exposure to PM10 in the second quartile, whereas the associations were attenuated when higher concentrations of PM10 in the third and fourth quartiles of the exposure were evaluated. No correlations of PM10 levels with these cardiovascular malformations in the other time periods of gestation were observed.Our findings suggest some positive associations between maternal exposure to ambient PM10 during the first two months of pregnancy and fetal cardiovascular malformations. https://doi.org/10.1289/EHP289.