tbuckley/cabot-search huggingface dataset:
Magnetic endoscope imaging for routine colonoscopy: impact on propofol dosage and patient safety – a randomized trial
Authors: Peter Klare, Bonnie Hartrampf, Bernhard Haller, Christoph Schlag, Fabian Geisler, Mohamed Abdelhafez, Henrik Einwächter, Monther Bajbouj, Roland Schmid, Stefan von Delius
Journal: Endoscopy (2016)

<b>Background and study aim: </b>The use of magnetic endoscope imaging (MEI) has been previously shown to facilitate colonoscopy procedures. We aimed to evaluate the benefits of MEI in terms of reduction in propofol dosage in patients undergoing routine colonoscopy. <b>Methods: </b>We conducted a randomized prospective trial in a university hospital in Germany. Endoscopists were randomly assigned 1:1 to use MEI during colonoscopy (MEI arm) <i>or</i> to conduct colonoscopy without the use of MEI (standard arm). The desired level of sedation was conscious sedation as assessed using the Observer's Assessment of Alertness and Sedation scores. After complete recovery, patient satisfaction was assessed using a numeric rating scale (NRS) ranging from 1 to 10 points. The primary outcome was total propofol dosage. Secondary outcome measures were patient satisfaction, patients' cooperation, and complication rates, as well as cecal intubation time and adenoma detection. <b>Results: </b>Among 334 randomized patients, no severe adverse events were observed. Median propofol dosage was significantly lower in the MEI arm compared with the standard arm (150 mg vs. 180 mg; <i>P</i> = 0.04). Deep sedation was observed in 7.8 % of patients in the MEI group and 3.6 % in the standard arm (<i>P</i> = 0.10). Patient satisfaction scores were higher in the MEI arm compared with standard procedures (9.0 vs. 8.5; <i>P</i> = 0.04). No significant differences in patients' cooperation, cecal intubation time, and adenoma detection were observed between the study arms. <b>Conclusion: </b>The use of MEI may be useful in reducing propofol dosage for colonoscopy and improving patient satisfaction. ClinicalTrials.gov identifier: NCT02121704.
Change in Bone Mineral Density Is an Indicator of Treatment-Related Antifracture Effect in Routine Clinical Practice
Authors: William D. Leslie, Sumit R. Majumdar, Suzanne N. Morin, Lisa M. Lix
Journal: Annals of Internal Medicine (2016)

Whether change in bone mineral density (BMD) is an accurate indicator of antifracture effect in clinical practice is unknown.To evaluate repeated BMD testing as an indicator of treatment-related fracture risk reduction.Registry-based cohort study.Manitoba, Canada.6629 women aged 40 years or older initiating osteoporosis treatment with 2 consecutive dual-energy x-ray absorptiometry scans (mean interval, 4.5 years).Change in BMD between the first and second dual-energy x-ray absorptiometry scans categorized as stable, detectable decrease, or detectable increase. Incident fractures were ascertained from health services data.During a mean of 9.2 years, 910 (13.7%) women developed incident fractures, including 198 with hip fractures. After adjustment for baseline fracture probability, women with a detectable decrease in total hip BMD compared with stable BMD had an absolute increase of 2.9% (95% CI, 1.5% to 4.4%) and 5.5% (CI, 2.8% to 8.1%) in the 5- and 10-year cumulative incidence of any fracture, respectively. In contrast, risk for any fracture in women with a detectable increase in total hip BMD was 1.3% (CI, 0.4% to 2.2%) and 2.6% (CI, 0.7% to 4.5%) lower after 5 and 10 years, respectively. Consistent results were seen for change in femoral neck and lumbar spine BMD and across a range of subgroup analyses.Lack of standardization in the BMD testing interval.Treatment-related increases in total hip BMD are associated with reduced fracture risk compared with stable BMD, whereas decreases in BMD are associated with greater risk for fractures. Monitoring BMD in clinical practice may help to identify women with a suboptimal response to osteoporosis treatment.None.
Abstract 1634: The RALA pathway drives invasion and metastasis of soft tissue sarcomas by regulating MMP14 localization and activity
Authors: Steven T. Sizemore, Fen Xia, Arnab Chakravarti
Journal: Cancer Research (2016)

Abstract Soft tissue sarcomas (STS) are a heterogeneous group of tumors originating from mesodermal tissues such as skeletal muscle, adipose, and fibrous tissue. The propensity of STS to metastasize, particularly to the lung which occurs in approximately 20% of all cases, is the major source of mortality associated with this disease. Currently, themolecular mechanisms that drive STS metastasis are poorly understood greatly limiting our ability to determine which STS will metastasize and impeding the development of targeted therapies for the treatment of STS metastases. In this study we utilized analysis of publicly available gene expression data to identify loss of PPP2R1B expression as a strong prognosticator of STS metastasis. In vitro analyses using SW872 liposarcoma (LPS) and HT1080 fibrosarcoma cell lines determined that PPP2R1B plays an essential role in the dephosphorylation and inactivation of RALA, a major downstream effector of the Ras pathway. RALA was found to be essential for invasion of STS cells in modified Boyden chamber assays as knockdown of RALA by either siRNA or shRNA significantly decreased invasion through matrigel. Analysis of publicly available gene expression data revealed that RALA expression correlated with more aggressive LPS subtypes and was prognostic of LPS metastasis. Furthermore, we identify the transmembrane matrix metalloprotease MMP14 (MT1-MMP) as a key downstream effector of RALA mediated invasion in STS. Stable knockdown of RALA in SW872 and HT1080 cells resulted in significant mislocalization of MMP14 and reduced MMP14 enzymatic activity. MMP14 expression was also significantly prognostic of metastasis in a publically available LPS cohort. Finally, we demonstrate that a three gene signature comprised of PPP2R1B, RALA, and MMP14 can retrospectively stratify LPS patients into groups of low, moderate, or high risk for metastatic recurrence. To the best of our knowledge this is the first demonstration of a vital role for PPP2R1A and RALA in STS invasion and metastasis and these data demonstrate a novel role for RALA in the localization and activity of MMP14. In conclusion, we have identified the PPP2R1B-RALA-MMP14 axis as driver of STS metastasis with potential clinical value as both a prognostic marker and therapeutic target. Citation Format: Steven T. Sizemore, Fen Xia, Arnab Chakravarti. The RALA pathway drives invasion and metastasis of soft tissue sarcomas by regulating MMP14 localization and activity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1634.
Abstract 153: Patterns of genetic progression in high grade prostatic intraepithelial neoplasia
Authors: Seung-Hyun Jung, Sun Shin, Sug Hyung Lee, Yeun-Jun Chung
Journal: Cancer Research (2016)

Abstract High grade prostatic intraepithelial neoplasia (HGPIN) is considered a neoplastic lesion that precedes prostate cancer (PCA). Genetically, HGPIN is known to have some driver mutations such as TMPRSS2-ERG fusion and 8p loss. However, we still do not know how the whole picture of somatic mutations in HGPIN is and what are added during the progression to PCA. To identify the genomic differences between HGPIN and PCA, we analyzed 20 regions of paired HGPIN and PCA from 6 patients by whole-exome sequencing and array-comparative genomic hybridization. As expected, the number of total mutations and CNAs of HGPINs were significantly fewer than those of PCAs. Mutations in FOXA1 and CNAs (1q and 8q gains) were detected in both HGPIN and PCA (common), suggesting their roles in early PCA development. Mutations in SPOP, KDM6A, and KMT2D were PCA-specific, suggesting their roles in HGPIN progression to PCA. The 8p loss was either common or PCA-specific. HRAS and FOXA1 mutations were PIN-specific. Our data show that PCAs are direct descendants of HGPINs in most cases that require more genomic alterations to progress to PCA. The nature of heterogeneous HGPIN population that might attenuate genomic signals should further be studied. Our results provide a clue to explain the long latency from HGPIN to PCA and provide useful information for clinical decision making in the genetic diagnosis of HGPIN and PCA. Citation Format: Seung-Hyun Jung, Sun Shin, Sug Hyung Lee, Yeun-Jun Chung. Patterns of genetic progression in high grade prostatic intraepithelial neoplasia. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 153.
Quality of life in patients undergoing paclitaxel-based second-line treatment of urothelial cancer.
Authors: Guenter Niegisch, Anja Lorch, Margitta Retz, Roswitha Siener, Peter Albers
Journal: Journal of Clinical Oncology (2014)

e15508 Background: Efficacy of palliative 2nd line treatment in patients (pts) suffering from advanced urothelial cancer (UC) is limited. Accordingly, careful observation of patient-reported quality-of-life (QoL) and treatment related changes of QoL is mandatory. Therefore, we searched to evaluate “typical” ailments and treatment related changes in QoL in these pts. Methods: Results of the EORTC QLQ C30 questionnaire (C30) were reviewed in 129 pts included in two prospective trials on paclitaxel-based treatment of cisplatin-resistant advanced UC (gemcitabine/paclitaxel: 102 pts [AB 20/99]; paclitaxel/everolimus: 27pts [AB 35/09]). Pts with completed C30 before start of treatment and available data on treatment response were eligible for analysis. Global health status (QL), functional scales (FSc) and symptom scales (SSc) were compared to published (EORTC 2008) normative data for patients suffering from metastatic/recurrent cancers (MET). Treatment related changes of QoL were evaluated. For statistical evaluation two-way analysis of variance (ANOVA) incl. Bonferroni´s post test was used. Results: 87 pts were eligible for analysis (62 male, 25 female, median age 65 [inter-quartile-range 60-71] years). Compared to MET data, impaired emotional FSc (-13 [95% confidence interval [CI] 6-23] points, p<0.001) and higher pain SSc (+14 [CI 6-23] points, p<0.001) were the most relevant differences. QL and further FSc/SSc were comparable or presented with only minor differences. Pain SSc was significantly lower after 2 and 3 treatment cycles (47,9 [SD 3,8] vs. 29,9 [SD 4,3], p<.001) but returned to baseline values during the following cycles. Further changes of QL, FSc or SSc during treatment were not observed. Comparing responders (n=28) and non-responders (n=59), no differences in QL, FSc and SSc were observed both at baseline and during treatment. Conclusions: Due to impaired QoL comparable to other pts suffering from recurrent/metastatic cancers, a comprehensive palliative care of pts undergoing 2ndline treatment for UC is inalienable. Special emphasis should be attributed to relevant pain and emotional problems. Despite significant treatment related side-effects, pts did not report major impairment of QoL.
A Molecular Model to Predict Durable Remission after First Line Fludarabine-Cyclophosphamide-Rituximab Treatment in Chronic Lymphocytic Leukemia
Authors: Davide Rossi, Lodovico Terzi di Bergamo, Annalisa Chiarenza, Pietro Bulian, Carlo Visco, Francesca Romana Mauro, Fortunato Morabito, Agostino Cortelezzi, Francesco Zaja, Francesco Forconi, Luca Laurenti, Ilaria Del Giudice, Lorenzo De Paoli, Iolanda Vincelli, Gian Matteo Rigolin, Roberto Marasca, Omar Perbellini, Carol Moreno, Giovanni Del Poeta, Massimo Massaia, Pier Luigi Zinzani, Marco Montillo, Antonio Cuneo, Robin Foà, Valter Gattei, Gianluca Gaidano
Journal: Blood (2014)
Abstract CT115: Pharmacokinetics of standard versus short high-dose dexamethasone therapy in childhood acute lymphoblastic leukemia: results from the UKALL 2011 trial
Authors: Rosanna K. Jackson, Julie AE Irving, Gareth J. Veal
Journal: Cancer Research (2016)

Abstract Dexamethasone (Dex) is a key component of ALL therapy, with glucocorticoid sensitivity strongly linked to prognosis. However, it also contributes to life threatening toxicities. The ongoing UKALL 2011 trial is investigating a new schedule of Dex (10mg/m2 × 14 days vs 6mg/m2 × 28 days), in an attempt to bring about a more rapid cytoreduction whilst limiting toxicities associated with long term steroid exposure. There are limited data regarding Dex pharmacokinetics, however large variability has been reported in children with ALL (Yang et al. 2008). For Dex pharmacokinetic studies, blood samples were collected up to 8h post oral administration on one of the first and last three days of induction chemotherapy. Plasma Dex levels were analysed using a validated LC-MS method, with a range of 5-250ng/ml, and non-compartmental pharmacokinetic analysis was performed. Pharmacokinetic parameters from day one sampling are shown below. Exposure, as defined by AUC0-12h, and Cmax were significantly higher on the short arm (p = 0.0002 and 0.0007, respectively). However there was substantial overlap between the two arms, with a number of patients on the standard arm exhibiting higher exposures than those on short therapy, despite having a longer duration of treatment. This is reflected in the AUC0-12h ranges observed on the two arms (short: 202-1606; standard: 38-1009 hr*ng/mL). Pharmacokinetic profiles also differed between the two days of treatment, with AUC0-12h being significantly higher at the end of induction chemotherapy (n = 37, study day 1: 655 ± 322; study day 2: 894 ± 496 hr*ng/mL, p = 0.003). Based on these preliminary data it will be important to consider pharmacokinetic variability when analysing the results generated from the UKALL 2011 trial. Further evaluation of relationships between pharmacokinetic variation, dose scheduling and clinical outcome may enable better stratification of Dex therapy for future patients. Dexamethasone pharmacokinetics in short and standard therapy arms following day one samplingPharmacokinetic parameters (mean ± SD)Half life (hr)Tmax (hr)Cmax(ng/mL)Clearance(L/hr/m2)AUC0-12h(hr*ng/mL)Short (n=43)3.96 ± 3.21.9 ± 1.0128 ± 558.1 ± 5.3692 ± 325Standard (n=33)3.68 ± 2.11.7 ± 1.187 ± 419.2 ± 12.7443 ± 202 Citation Format: Rosanna K. Jackson, Julie AE Irving, Gareth J. Veal. Pharmacokinetics of standard versus short high-dose dexamethasone therapy in childhood acute lymphoblastic leukemia: results from the UKALL 2011 trial. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT115.
Stimulation of lipogenesis by pharmacological activation of the liver X receptor leads to production of large, triglyceride-rich VLDL particles
Authors: A Grefhorst, BM Elzinga, PJ Voshol, Torsten Plosch, T Kok, Vincent Bloks, van der Fjodor Sluijs, JA Romijn, Henkjan Verkade, Folkert Kuipers
Journal: Circulation (2002)
Abstract 4428: Nestin suppression attenuates invasive potential of endometrial cancer cells by down regulating TGF-β signaling pathway
Authors: Amber A. Bokhari, Batsukh Dorjbal, Tabari M. Baker, Sana Waheed, Christopher M. Zahn, Chad A. Hamilton, George L. Maxwell, Viqar Syed
Journal: Cancer Research (2016)

Abstract Nestin, an intermediate filament protein and a stem cell marker is expressed in several cancers. Little is known about the expression level and role of Nestin in endometrial cancer. Compared to immortalized endometrial epithelial cell line EM-E6/E7/TERT, endometrial cancer lines express high to moderate levels of Nestin. Endometrial tumors and tumor cell lines have a cancer stem-like cells population expressing CD133. The AN3CA and KLE cells showed more CD133+ cells and expressed Nestin at higher levels than Ishikawa cells. Knockdown of Nestin in AN3CA and KLE, and overexpression in Ishikawa cells was associated respectively with attenuation and enhancement of CD133+ cells. Knockdown of Nestin increased cells in G0/G1 phase and decreased in S phase, whereas overexpression decreased cells in G0/G1 phase and increased in S phase of cell cycle. Nestin knockdown cells showed increased expression of p21, p27 and PNCA and decreased expression of cyclin-D1 and D3. Nestin overexpression revealed an inverse expression pattern of cell cycle regulatory proteins. Nestin knockdown inhibited cancer cell growth and invasive potential by down regulating TGF-β signaling components, MMP-2, MMP-9, vimentin, SNAIL, SLUG, Twist, N-cadherin, and upregulating E-cadherin. Conversely, Nestin overexpression enhanced cell invasiveness by upregulating TGF-β signaling components, MMP-2, MMP-9, mesenchymal markers and downregulaing epithelial marker, E-cadherin. Nestin knockdown inhibited and overexpression promoted invadopodia formation and pFAK expression. Knockdown of Nestin significantly reduced tumor volume in vivo. Finally, progesterone and a nitric oxide donor inhibited Nestin expression in endometrial cancer cells. These results suggest that Nestin can be a therapeutic target for cancer treatment. Citation Format: Amber A. Bokhari, Batsukh Dorjbal, Tabari M. Baker, Sana Waheed, Christopher M. Zahn, Chad A. Hamilton, George L. Maxwell, Viqar Syed. Nestin suppression attenuates invasive potential of endometrial cancer cells by down regulating TGF-β signaling pathway. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4428.
Liquid Biopsy Receives Approval
Authors: Rebecca Voelker
Journal: JAMA (2016)

The first blood-based genetic test—known as a liquid biopsy—that detects epidermal growth factor receptor (EGFR) gene mutations in non–small cell lung cancers has received FDA approval. The cobas EGFR Mutation Test v2 is a companion diagnostic for the cancer drug erlotinib.
Risk for Hospital Contact With Infection in Patients With Splenectomy
Authors: Reimar W. Thomsen, W. Marieke Schoonen, Dóra K. Farkas, Anders Riis, Jacob Jacobsen, Jon P. Fryzek, Henrik Toft Sørensen
Journal: Annals of Internal Medicine (2009)

Investigators compared the risk for infections that required hospital care in all 3812 patients in Denmark who underwent splenectomy from 1996 to 2005 with that in 3 groups: the general population,...
High cost of new drugs
Authors: Mariana Mazzucato
Journal: BMJ (2016)

Why government must negotiate a better deal for publicly funded research 

The investigation by The BMJ and Cambridge and Bath universities into the availability of breakthrough hepatitis C drugs raises important questions for NHS England about access to lifesaving drugs.1 However, the main question is why medicines are so expensive in the first place. The pricing strategy of Gilead for sofosbuvir (Sovaldi) and ledipasvir-sofosbuvir (Harvoni) raises questions that go well beyond the UK.

The BMJ ’s investigation is just an example of a more general problem. What is the right price to pay for a particular drug, and how should this be determined?

Pharmaceutical innovation should be structured so that it focuses on unmet health needs globally and delivers therapeutic advances that are affordable and accessible to all,2 not just profitable for manufacturers. This requires an approach that directs effort towards therapeutic innovations rather than “me too” drugs, and a financing and pricing structure which is transparent, focused on access, and reflects the collective investment and risk taking involved.

Drug companies have often …
Paraneoplastic pemphigus with anti-BP180 autoantibodies and Castleman disease
Authors: L. Maier, A. Udvardi, M. Hertl, R. Eming, E. Schmidt, D. Zillikens, B. Volc-Platzer
Journal: British Journal of Dermatology (2016)

Paraneoplastic pemphigus (PNP) is commonly associated with IgG-autoantibodies against desmoglein 1 and 3, plakins (desmoplakin I and II, envoplakin, periplakin), desmocollins 1-3, BP2301 and α2-macroglobulin-like-1 (A2ML1)2. The major autoantigen of bullous pemphigoid (BP), pemphigoid gestationis and lichen planus pemphigoides (LPP) is the NC16A domain of BP1803.

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Abstract 4085: Notch1 signaling determines melanoma-regulating role of tumor stromal fibroblasts
Authors: Hongwei Shao, Ranran Kong, Mecker Moller, Massimiliano L. Ferrari, Leiming Zhang, Freddy Radtke, Anthony J. Capobianco, Zhao-Jun Liu
Journal: Cancer Research (2016)

Abstract Objectives. Tumor stromal fibroblasts are crucial in regulating tumor growth, invasion and metastasis, yet the molecular mechanisms that determine the tumor regulatory role of stromal fibroblasts remains unknown. Here, we uncover the Notch1 signaling pathway as a molecular determinant that controls the tumor regulatory role of tumor stromal fibroblasts in melanoma growth and invasion. Methods. Murine melanoma cells B16-F10, stably transduced with Luciferase 2 (Luc2)/lentivirus, were xenografted on the skin of two new mouse lines: the Gain-Of-Function of Notch1 (GOFNotch1: Fsp1.Cre+/-;ROSALSL-N1IC+/+) and Loss-Of-Function of Notch1 (LOFNotch1: Fsp1.Cre+/-;Notch1LoxP/LoxP+/+), respectively. GOFctrl (FSP1.Cre-/-;ROSALSL-N1IC+/+) and LOFctrl (FSP1.Cre-/-; Notch1LoxP/LoxP+/+) mice were used as control. Tumor growth was measured based on tumor weight and melanoma local invasion were examined by H&amp;E staining of resected tumor tissue. Results. Using a mouse melanoma model in which exogenous melanoma cells were grafted on the skin of two lines of mice where the genetic activation or inactivation of Notch1 signaling specifically occurs in natural host stromal fibroblasts, we demonstrated that Notch1 pathway activity could determine the tumor-promoting or tumor-suppressing phenotype in tumor stromal fibroblasts. Tumor stromal fibroblasts carrying elevated Notch1 activity significantly inhibited melanoma growth and invasion, while those with a null Notch1 promoted melanoma invasion. Conclusions. These findings identify the Notch1 pathway as a molecular determinant that controls the regulatory role of tumor stromal fibroblasts in melanoma skin growth and invasion, unveiling Notch1 signaling as a potential therapeutic target for melanoma and potentially other solid tumors. Citation Format: Hongwei Shao, Ranran Kong, Mecker Moller, Massimiliano L. Ferrari, Leiming Zhang, Freddy Radtke, Anthony J. Capobianco, Zhao-Jun Liu. Notch1 signaling determines melanoma-regulating role of tumor stromal fibroblasts. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4085.
The First In Vitro and In Vivo Assessment Of Anfibatide, a Novel Glycoprotein Ib Antagonist, In Mice and In a Phase I Human Clinical Trial
Authors: Yan Hou, Xi Lei, Benjamin Xiaoyi Li, Xiangrong Dai, Zhongqiang Yang, Fang Qian, Guohui Zhang, Zhengyu Xu, Jing Liu, Chaofan Liang, Yanan Zhao, Jie Shen, Hui Zhou, Yiming Wang, Alexandra H. Marshall, Heyu Ni
Journal: Blood (2013)