tbuckley/cabot-search huggingface dataset:
Randomized Phase II Trial of Ridaforolimus in Advanced Endometrial Carcinoma
Authors: Amit M. Oza, Sandro Pignata, Andres Poveda, Mary McCormack, Andrew Clamp, Benjamin Schwartz, Jonathan Cheng, Xiaoyun Li, Kristy Campbell, Pierre Dodion, Frank G. Haluska
Journal: Journal of Clinical Oncology (2015)

The prognosis for women with recurrent and metastatic endometrial cancer is poor, and improved therapies are needed. The mammalian target of rapamycin (mTOR) pathway is an important target, and mTOR inhibitors show clinical activity in endometrial cancer.An open-label, multicenter, randomized, phase II trial of oral ridaforolimus compared with progestin or investigator choice chemotherapy (comparator) was undertaken in women with metastatic or recurrent endometrial cancer who had progressive disease following one or two lines of chemotherapy and no hormonal therapy. The primary end point was progression-free survival (PFS) assessed by independent radiologic review.One hundred thirty patients were enrolled (64 received ridaforolimus and 66 received the comparator), and median age was 66 years. Treatment discontinuation as a result of adverse events was 33% with ridaforolimus versus 6% with the comparator, with common (> 10%) grade 3 toxicities being hyperglycemia, anemia, and diarrhea. Thirty-eight percent (ridaforolimus) versus 71% (comparator) of patients discontinued treatment as a result of disease progression. Median PFS at the protocol prespecified interim analysis with 58 PFS events (primary end point) was 3.6 months (95% CI, 2.7 to 7.3 months) for ridaforolimus and 1.9 months (95% CI, 1.9 to 2.3 months) for the comparator (hazard ratio, 0.53; 95% CI, 0.31 to 0.90; P = .008). PFS rate for ridaforolimus versus comparator was 48% versus 18% at 16 weeks and 38% versus 15% at 24 weeks. Objective response rate for ridaforolimus versus comparator was 0% versus 4% (P = .925), and stable disease was achieved in 35% versus 17% of patients (P = .021).Oral ridaforolimus shows encouraging activity in advanced endometrial cancer but is associated with significant toxicity. Inhibition of the PI3K/Akt/mTOR pathway may be a viable therapeutic target.
Genome-wide meta-analyses of multiancestry cohorts identify multiple new susceptibility loci for refractive error and myopia
Authors: Virginie J M Verhoeven, Pirro G Hysi, Robert Wojciechowski, Qiao Fan, Jeremy A Guggenheim, René Höhn, Stuart MacGregor, Alex W Hewitt, Abhishek Nag, Ching-Yu Cheng, Ekaterina Yonova-Doing, Xin Zhou, M Kamran Ikram, Gabriëlle H S Buitendijk, George McMahon, John P Kemp, Beate St Pourcain, Claire L Simpson, Kari-Matti Mäkelä, Terho Lehtimäki, Mika Kähönen, Andrew D Paterson, S Mohsen Hosseini, Hoi Suen Wong, Liang Xu, Jost B Jonas, Olavi Pärssinen, Juho Wedenoja, Shea Ping Yip, Daniel W H Ho, Chi Pui Pang, Li Jia Chen, Kathryn P Burdon, Jamie E Craig, Barbara E K Klein, Ronald Klein, Toomas Haller, Andres Metspalu, Chiea-Chuen Khor, E-Shyong Tai, Tin Aung, Eranga Vithana, Wan-Ting Tay, Veluchamy A Barathi, Peng Chen, Ruoying Li, Jiemin Liao, Yingfeng Zheng, Rick T Ong, Angela Döring, David M Evans, Nicholas J Timpson, Annemieke J M H Verkerk, Thomas Meitinger, Olli Raitakari, Felicia Hawthorne, Tim D Spector, Lennart C Karssen, Mario Pirastu, Federico Murgia, Wei Ang, Aniket Mishra, Grant W Montgomery, Craig E Pennell, Phillippa M Cumberland, Ioana Cotlarciuc, Paul Mitchell, Jie Jin Wang, Maria Schache, Sarayut Janmahasatian, Robert P Igo Jr, Jonathan H Lass, Emily Chew, Sudha K Iyengar, Theo G M F Gorgels, Igor Rudan, Caroline Hayward, Alan F Wright, Ozren Polasek, Zoran Vatavuk, James F Wilson, Brian Fleck, Tanja Zeller, Alireza Mirshahi, Christian Müller, André G Uitterlinden, Fernando Rivadeneira, Johannes R Vingerling, Albert Hofman, Ben A Oostra, Najaf Amin, Arthur A B Bergen, Yik-Ying Teo, Jugnoo S Rahi, Veronique Vitart, Cathy Williams, Paul N Baird, Tien-Yin Wong, Konrad Oexle, Norbert Pfeiffer, David A Mackey, Terri L Young, Cornelia M van Duijn, Seang-Mei Saw, Joan E Bailey-Wilson, Dwight Stambolian, Caroline C Klaver, Christopher J Hammond
Journal: Nature Genetics (2013)
DNMT1 and DNMT3B Modulate Distinct Polycomb-Mediated Histone Modifications in Colon Cancer
Authors: Bilian Jin, Bing Yao, Jian-Liang Li, C. Robert Fields, Amber L. Delmas, Chen Liu, Keith D. Robertson
Journal: Cancer Research (2009)

DNA methylation patterns are established and maintained by three DNA methyltransferases (DNMT): DNMT1, DNMT3A, and DNMT3B. Although essential for development, methylation patterns are frequently disrupted in cancer and contribute directly to carcinogenesis. Recent studies linking polycomb group repression complexes (PRC1 and PRC2) to the DNMTs have begun to shed light on how methylation is targeted. We identified previously a panel of genes regulated by DNMT3B. Here, we compare these with known polycomb group targets to show that approximately 47% of DNMT3B regulated genes are also bound by PRC1 or PRC2. We chose 44 genes coregulated by DNMT3B and PRC1/PRC2 to test whether these criteria would accurately identify novel targets of epigenetic silencing in colon cancer. Using reverse transcription-PCR, bisulfite genomic sequencing, and pyrosequencing, we show that the majority of these genes are frequently silenced in colorectal cancer cell lines and primary tumors. Some of these, including HAND1, HMX2, and SIX3, repressed cell growth. Finally, we analyzed the histone code, DNMT1, DNMT3B, and PRC2 binding by chromatin immunoprecipitation at epigenetically silenced genes to reveal a novel link between DNMT3B and the mark mediated by PRC1. Taken together, these studies suggest that patterns of epigenetic modifiers and the histone code influence the propensity of a gene to become hypermethylated in cancer and that DNMT3B plays an important role in regulating PRC1 function.
Indeterminate test results of T-SPOTTM.TB performed under routine field conditions
Authors: P. Beffa, A. Zellweger, J-P. Janssens, P. Wrighton-Smith, J-P. Zellweger
Journal: European Respiratory Journal (2007)

Interferon-γ release assays for the diagnosis of tuberculosis (TB) can give indeterminate results. The prevalence of indeterminate test results (ITRs) among T-SPOT TM . TB tests was assessed. A retrospective analysis of samples processed in 2005 was performed. ITRs were assessed by age, sex, immunosuppression, distance to the laboratory and season. A subgroup of tests performed for specific indications (contact tracing, migrants with positive tuberculin skin test, TB suspects and immunosuppression) were analysed separately. Of a total of 1,429 tests, 49 (3.4%) were indeterminate. ITRs were significantly associated with old age (&gt;75 versus 5–75 yrs; odds ratio (OR) 7.97, 95% confidence interval (CI) 3.968–15.438) and the season during which samples were transported (autumn and winter versus spring and summer; OR 3.47, 95% CI 1.753–7.514). The incidence of ITR was 302 (2.0%) among TB contacts, 75 (1.6%) among immigrants, 156 (3.0%) in TB suspects and 32 (3.0%) among immunosuppressed patients. Sex, young age and distance to the laboratory were not associated with the rate of ITR. Of the 13 tests with ITR that were repeated, 10 gave a clear positive or negative result. Indeterminate test results with T-SPOT TM . TB under routine conditions were infrequent and more common in individuals aged &gt;75 yrs than in children and younger adults. The incidence of indeterminate test results was low and similar among healthy tuberculosis contacts, immigrants with a positive tuberculin skin test, tuberculosis suspects and the immunosuppressed. The conditions of transportation may influence the incidence of indeterminate test results.
Do bacteria have a role in asthma development?
Authors: J. Armann, E. von Mutius
Journal: European Respiratory Journal (2010)

The relationship between the microbial world and asthma is not well understood. Although we know that the most potent triggers of wheezing attacks are viruses, we do not understand whether and how they contribute to disease onset and progression. Even less is known about the relationship between asthma and bacteria.

The clearest evidence stems from studying asthma exacerbations or wheezing episodes. In clinical studies viruses can be detected in up to 90% of such episodes 1, with rhinovirus being most commonly identified, followed by respiratory syncytial virus (RSV) in the first years of life. Other viruses such as parainfluenza, metapneumovirus, coronavirus, adenovirus, influenza and enteroviruses have also been implicated, mostly in older patients. In ∼10% of episodes multiple viruses were found 2. Most recently, the H1N1 virus has been reported to be more prevalent among asthmatics than other patients 3. In a recent high-risk birth cohort, children with wheezing illnesses triggered by rhinovirus infections early in life were at risk for the subsequent development of asthma up to 6 yrs of age 2.

However, it remains unclear whether viral infections are causal factors for the new onset of disease by impacting on the host's immune response or whether they merely unmask a host's underlying susceptibility to develop asthma by triggering exacerbations. It has been proposed that asthmatics may have subtle deficiencies in their immune response resulting in reduced antiviral activity and increased susceptibility for viral infections, especially of the lower respiratory tract. Corne et al. 4 recruited 76 cohabiting couples where only one partner had asthma and compared the frequency, severity and duration of rhinovirus infection between them. The authors found that asthmatics develop more severe and longer lasting respiratory symptoms following rhinovirus infections than their spouses 4. Message et al. 5 experimentally infected adult …
Carbohydrate fermentation in the human colon and its relation to acetate concentrations in venous blood.
Authors: E W Pomare, W J Branch, J H Cummings
Journal: Journal of Clinical Investigation (1985)

There is now substantial evidence that some dietary polysaccharides, notably dietary fiber, escape absorption in the small bowel and are then broken down in the large intestine of man. The main end products of this colonic digestive process, which is anerobic, are short chain fatty acids (SCFA), and acetic, propionic, and butyric acids. Although these acids are known to be absorbed from the colon, their subsequent fate and significance is unknown. We have measured venous blood SCFA levels in healthy subjects after a 16-h fast, and then following oral doses of either 50 mmol SCFA, 5, 10, or 20 g doses of the fermentable carbohydrate lactulose, or 20 g of pectin. Fasting venous blood acetate was 53.8 +/- 4.4 mumol/liter (SEM) (n = 14). Fasting arterial blood acetate, taken simultaneously with venous blood in six subjects, was higher; 125.6 +/- 13.5 mumol/liter (arterial) vs. 61.1 +/- 6.9 mumol/liter (venous). Significant levels of propionate or butyrate were not detected in any blood samples. Following an oral dose of 50 mmol mixed SCFA, venous blood acetate reached a peak of 194.1 +/- 57.9 mumol/liter at 45 min and returned to fasting levels at 2 h. Blood acetate also rose in response to lactulose, peak levels occurring 2-4 h after the dose: 5 g, 98.6 +/- 23.1 mumol/liter; 10 g, 127.3 +/- 18.2 mumol/liter; and 20 g, 181.3 +/- 23.9 mumol/liter. Pectin fermentation was much slower, with blood acetate levels starting to rise after 6 h and remaining elevated at about twice fasting levels for the subsequent 18 h. However, areas under the blood acetate curves were closely related (r = 0.97; n = 5), whatever the source of acetate. These studies show that the large intestine makes an important contribution to blood acetate levels in man and that fermentation may influence metabolic processes well beyond the wall of this organ.
Cardiac Endothelin System Impairs Left Ventricular Function in Renin-Dependent Hypertension via Decreased Sarcoplasmic Reticulum Ca <sup>2+</sup> Uptake
Authors: Lars Rothermund, Yigal M. Pinto, Berthold Hocher, Roland Vetter, Stefan Leggewie, Peter Koßmehl, Hans-Dieter Orzechowski, Reinhold Kreutz, Martin Paul
Journal: Circulation (2000)

Background —We evaluated the role of the cardiac endothelin (ET) system in compensated hypertensive left ventricular (LV) hypertrophy (LVH) and after the transition toward LV dysfunction. Methods and Results —Hypertensive transgenic rats overexpressing the Ren2 gene (Ren2 rats) were investigated between the ages of 10 and 30 weeks (Ren2-10 and Ren2-30 groups, respectively) and compared with age-matched normotensive Sprague-Dawley (SD) rats (SD-10 and SD-30 groups, respectively). Systolic blood pressure and LV weight were elevated in both Ren2 groups compared with their age-matched SD control groups ( P &lt;0.0001). In Ren2-30 rats, LV end-diastolic pressure increased and −dP/dt max decreased compared with the values in SD-30 and Ren2-10 rats ( P &lt;0.05). This was paralleled by an activation of LV mRNA expression of preproET-1 and ET-converting enzyme-1 and ET subtype A (ETA) receptor binding in Ren2-30 compared with Ren2-10 rats ( P &lt;0.001). Cardiac fibrosis was increased and sarcoplasmic reticulum (SR) Ca 2+ reuptake was reduced in Ren2-30 compared with SD-30 and Ren2-10 rats ( P &lt;0.05). Treatment of Ren2 rats with the selective ETA receptor antagonist Lu135252 between 10 and 30 weeks of age did not lower systolic blood pressure, heart weight, or cardiac fibrosis but completely prevented the deterioration of LV end-diastolic pressure and abolished alterations in −dP/dt max and SR Ca 2+ reuptake compared with no treatment in Ren2-30 and SD-30 rats ( P &lt;0.05). Conclusions —Activation of the cardiac ET system accounts at least in part for the LV dysfunction that gradually develops in LVH. The protective effect of ETA antagonism can be attributed to the improvement of diastolic LV function that is due to normalization of impaired SR Ca 2+ uptake.
Admission Troponin T Level Predicts Clinical Outcomes, TIMI Flow, and Myocardial Tissue Perfusion After Primary Percutaneous Intervention for Acute ST-Segment Elevation Myocardial Infarction
Authors: Evangelos Giannitsis, Margit Müller-Bardorff, Stephanie Lehrke, Uwe Wiegand, Ralph Tölg, Britta Weidtmann, Franz Hartmann, Gert Richardt, Hugo A. Katus
Journal: Circulation (2001)

Background — In ST-segment elevation myocardial infarction, a troponin T ≥0.1 μg/L on admission indicates poorer prognosis despite early reperfusion. To evaluate the underlying reason, we studied the value of cardiac troponin T (cTnT) for prediction of outcomes, epicardial blood flow, and myocardial reperfusion after primary percutaneous intervention. Methods and Results — Patients (n=140) admitted within 12 hours after onset of symptoms were stratified by admission cTnT. Epicardial and myocardial reperfusion were graded by the TIMI score and by measurement of relative increases of myoglobin, cTnT, and creatine kinase (CK)-MB 60 minutes after recanalization, respectively. cTnT was positive in 64 patients (45.7%) and was associated with longer median time intervals to admission (5.5 versus 3.5 hours, P &lt;0.001) and higher mortality rates after 30 days (12.5% versus 3.9%, P =0.06) and 9 months (14% versus 3.9%, P =0.005). cTnT independently predicted a 3.2-fold risk for incomplete epicardial reperfusion ( P =0.03). In addition, cTnT ≥0.1 μg/L was associated with more severely impaired myocardial perfusion despite normal epicardial flow, as indicated by lower 60-minute ratios of myoglobin (2.6 versus 7.6, P =0.007), cTnT (6.6 versus 29.2, P &lt;0.001), and CK-MB (3.5 versus 21.4, P =0.002) and a tendency for less resolution of ST-segment elevations (54% versus 60%, P =0.08). Conclusions — cTnT predicts poorer clinical outcomes, lower rates of postprocedural TIMI 3 flow, and more severely compromised myocardial perfusion despite normal epicardial flow. Thus, a cTnT-positive patient may require more aggressive adjunctive therapy when treated by percutaneous coronary intervention. The impact of preexisting or evolving microvascular dysfunction and the effect of therapies that target myocardial perfusion require further prospective evaluation.
Radiotherapy in Older Women With Low-Risk Breast Cancer: Why Did Practice Not Change?
Authors: Sharon H. Giordano
Journal: Journal of Clinical Oncology (2012)

Radiotherapy after breast-conserving surgery reduces the risk of breast cancer recurrence and death as a result of breast cancer. In the most recent update of the Early Breast Cancer Trialists’ Group metaanalysis, radiotherapy lowered the risk of breast cancer recurrence by about one half and lowered the risk of breast cancer death by one sixth. 1,2 However, the absolute benefit of radiotherapy depended on the baseline risk of recurrence and was smaller in patients with a lower risk of recurrence. This concept raises the question of whether radiotherapy after breast-conserving surgery can be safely omitted if the absolute risk of recurrence is low. The CALGB 9343 trial directly addressed this question in the subset of older women with low-risk breast cancer. 2 This study enrolled more than 600 women age 70 years and older who had clinical stage 1 estrogen receptor–positive breast cancer and who were treated with breast-conserving surgery. Patients were randomly assigned to tamoxifen alone or tamoxifen plus radiotherapy. This study showed that there was no significant difference in the rates of subsequent mastectomy, distant metastases, or overall survival between the two groups. At the time of the initial study publication in 2004, the median follow-up was five years and the rate of local or regional recurrence was 1% in the group that received radiation and 4% in the group that did not. With longer follow-up of 10.5 years, the only significantly different outcome was local recurrence with a difference of 2% in the irradiated group and 9% in those women who did not receive adjuvant radiotherapy. 3 On the basis of these findings, the National Comprehensive
A Model of Human Tumor Dormancy: An Angiogenic Switch From the Nonangiogenic Phenotype
Authors: George N. Naumov, Elise Bender, David Zurakowski, Soo-Young Kang, David Sampson, Evelyn Flynn, Randolph S. Watnick, Oddbjorn Straume, Lars A. Akslen, Judah Folkman, Nava Almog
Journal: JNCI Journal of the National Cancer Institute (2006)

Background: Microscopic human cancers can remain dormant for life. Tumor progression depends on sequential events, including a switch to the angiogenic phenotype, i.e., initial recruitment of new vessels. We previously demonstrated that human tumors contain tumor cell populations that are heterogeneous in angiogenic activity. Here, we separated angiogenic from nonangiogenic human tumor cell populations and compared their growth. Methods: Severe combined immunodeficient (SCID) mice were inoculated with nonangiogenic human MDA-MB-436 breast adenocarcinoma, KHOS-24OS osteosarcoma, or T98G glioblastoma cells. Most of the resulting tumors remained microscopic (<1 mm diameter), but some eventually became angiogenic and enlarged and were used to isolate angiogenic tumor cells. Angiogenic and nonangiogenic tumor cells were inoculated into SCID mice, and time to the development of palpable tumors was determined. Cell proliferation was assayed in vitro by growth curves and in vivo by staining for proliferating cell nuclear antigen or Ki67. Microscopic tumors from both tumor cell populations were examined for histologic evidence of vascular development 14 days after inoculation in mice. Expression of the angiogenesis inhibitor thrombospondin-1 was examined by immunoblotting. Results: Nonangiogenic tumors of each tumor type developed palpable tumors after means of 119 days (range: 53–185 days) for breast cancer, 238 days (184–291 days) for osteosarcoma, and 226 days (150–301 days) for glioblastoma. Angiogenic cells developed palpable tumors within 20 days after inoculation. However, nonangiogenic and angiogenic cells of each tumor type had similar proliferation rates. Fourteen days after tumor cell inoculation, tumors from angiogenic cells showed evidence of functional vasculature. In contrast, nonangiogenic tumors remained microscopic in size with absent or nonfunctional vasculature. Thrombospondin-1 expression was statistically significantly lower (by five- to 23-fold, depending on tumor type) in angiogenic than nonangiogenic cells. Conclusions: This model provides a conceptual framework and a reproducible in vivo system to study unresolved central questions in cancer biology regarding the initiation, reversibility, and molecular regulation of the timing of the angiogenic switch.
Airway mucosa: secretory cells, mucus and mucin genes
Authors: PK Jeffery, D Li
Journal: European Respiratory Journal (1997)

The airway mucosa is lined by a continuous epithelium comprised of multiple cell phenotypes, several of which are secretory. Secretions produced by these cells mix with a variety of macromolecules, ions and water to form a respiratory tract fluid that protects the more distal airways and alveoli from injury and infection. The present article highlights the structure of the mucosa, particularly its secretory cells, gives a synopsis of the structure of mucus, and provides new information on the localization of mucin (MUC) genes that determine the peptide sequence of the protein backbone of the glycoproteins, which are a major component of mucus. Airway secretory cells comprise the mucous, serous, Clara and dense-core granulated cells of the surface epithelium, and the mucous and serous acinar cells of the submucosal glands. Several transitional phenotypes may be found, especially during irritation or disease. Respiratory tract mucins constitute a heterogeneous group of high molecular weight, polydisperse richly glycosylated molecules: both secreted and membrane-associated forms of mucin are found. Several mucin (MUC) genes encoding the protein core of mucin have been identified. We demonstrate the localization of MUC gene expression to a number of distinct cell types and their upregulation both in response to experimentally administered lipopolysaccharide and cystic fibrosis.
Learning from death: a hospital mortality reduction programme
Authors: John Wright, Bob Dugdale, Ian Hammond, Brian Jarman, Maria Neary, Duncan Newton, Chris Patterson, Lynne Russon, Philip Stanley, Rose Stephens, Erica Warren
Journal: Journal of the Royal Society of Medicine (2006)

ProblemThere are wide variations in hospital mortality. Much of this variation remains unexplained and may reflect quality of care. Strategies for changeAudit of hospital deaths to inform an evidence-based approach to identify processes of care to target for the hospital strategy. Establishment of a hospital mortality reduction group with senior leadership and support to ensure the alignment of the hospital departments to achieve a common goal. Robust measurement and regular feedback of hospital deaths using statistical process control charts and summaries of death certificates and routine hospital data. Whole system working across a health community to provide appropriate end of life care. Training and awareness in processes of high quality care such as clinical observation, medication safety and infection control. EffectsHospital standardized mortality ratios fell significantly in the 3 years following the start of the programme from 94.6 (95% confidence interval 89.4, 99.9) in 2001 to 77.5 (95% CI 73.1, 82.1) in 2005. This translates as 905 fewer hospital deaths than expected during the period 2002–2005. Lessons learntImproving the safety of hospital care and reducing hospital deaths provides a clear and well supported goal from clinicians, managers and patients. Good leadership, good information, a quality improvement strategy based on good local evidence and a community-wide approach may be effective in improving the quality of processes of care sufficiently to reduce hospital mortality.