tbuckley/cabot-search huggingface dataset:
Abstract 2847: High complexity barcoding to study clonal dynamics in response to cancer therapy
Authors: Hyo-eun C. Bhang, David A. Ruddy, Viveksagar Krishnamurthy Radhakrishna, Rui Zhao, Iris Kao, Daniel Rakiec, Pamela Shaw, Marissa Balak, Justina X. Caushi, Elizabeth Ackley, Nicholas Keen, Michael R. Schlabach, Michael Palmer, William R. Sellers, Franziska Michor, Vesselina G. Cooke, Joshua M. Korn, Frank Stegmeier
Journal: Cancer Research (2015)

Abstract Targeted therapies, such as erlotinib and imatinib, lead to dramatic clinical responses, but the emergence of resistance presents a significant challenge. Recent studies have revealed intratumoral heterogeneity as a potential source for the emergence of therapeutic resistance. However, it is still unclear if relapse/resistance is driven predominantly by pre-existing or de novo acquired alterations. To address this question, we developed a high-complexity barcode library, ClonTracer, which contains over 27 million unique DNA barcodes and thus enables the high resolution tracking of cancer cells under drug treatment. Using this library in two clinically relevant resistance models, we demonstrate that the majority of resistant clones pre-exist as rare subpopulations that become selected in response to therapeutic challenge. Furthermore, our data provide direct evidence that both genetic and non-genetic resistance mechanisms pre-exist in cancer cell populations. The ClonTracer barcoding strategy, together with mathematical modeling, enabled us to quantitatively dissect the frequency of drug-resistant subpopulations and evaluate the impact of combination treatments on the clonal complexity of these cancer models. Hence, monitoring of clonal diversity in drug-resistant cell populations by the ClonTracer barcoding strategy described here may provide a valuable tool to optimize therapeutic regimens towards the goal of curative cancer therapies. Citation Format: Hyo-eun C. Bhang, David A. Ruddy, Viveksagar Krishnamurthy Radhakrishna, Rui Zhao, Iris Kao, Daniel Rakiec, Pamela Shaw, Marissa Balak, Justina X. Caushi, Elizabeth Ackley, Nicholas Keen, Michael R. Schlabach, Michael Palmer, William R. Sellers, Franziska Michor, Vesselina G. Cooke, Joshua M. Korn, Frank Stegmeier. High complexity barcoding to study clonal dynamics in response to cancer therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2847. doi:10.1158/1538-7445.AM2015-2847
P1286 : Low prevalence of positive viral serology for HBV and HCV among a general dutch elderly population: Results from the rotterdam study
Authors: E.P. Plompen, R. Maan, R.J. de Knegt, P. Taimr, A. Hofman, B.H. Stricker, S. Darwish Murad, H.L. Janssen
Journal: Journal of Hepatology (2015)
P-328 Which is the best first approach for liver-only synchronic metastasis rectal cancer?
Authors: I. Ghanem, M. Blazquez, O. Higuera, L. Lema, N. Rodriguez, C. Gomez-Martin, A. Mata, D. Lora, A. Custodio, J. Feliu
Journal: Annals of Oncology (2015)
Comparable activity with oral topotecan/cisplatin (TC) and IV etoposide/cisplatin (PE) as treatment for chemotherapy-naïve patients (pts) with extensive disease small cell lung cancer (ED-SCLC): Final results of a randomized phase III trial (389)
Authors: J. R. Eckardt, J. von Pawel, G. Manikhas, Z. Papai, A. Tomova, V. Tzekova, T. Crofts, S. Brannon, P. Wissel, G. Ross
Journal: Journal of Clinical Oncology (2005)

7003 Background: TC is a tolerable regimen and requires fewer clinic visits for drug administration (Proc. ASCO 2004). A randomized phase III study comparing TC vs PE, the current standard of care, was conducted to compare safety and efficacy in this setting. Methods: Chemotherapy-naïve patients with ED-SCLC and performance status (PS) ECOG 0, 1, or 2 stratified by gender, PS, LDH, and country were randomized to receive either oral topotecan (d1–5: 1.7 mg/m2)/cisplatin (d5: 60 mg/m2) (TC) or IV etoposide (d1–3: 100 mg/m2)/cisplatin (d1: 80 mg/m2) (PE). The initial TC dose regimen, T=2.0 mg/m2/day, was reduced due to excessive, serious neutropenia, diarrhea and typhilitis. Following this amendment, a complete, randomized population at the reduced T dose, 1.7 mg/m2/day, was recruited. Primary endpoint was overall survival. Results: Between 5/2001 and 12/2002, 859 patients were recruited, 784 into the T(1.7)C and PE arms (ITT). Baseline characteristics were balanced. Median number of cycles (range) for TC was 5 (1–9), PE 6 (1–8). TC and PE were well tolerated. Hematologic toxicity, TC vs PE: G4 neutropenia (26, 56.8%), Gr 4 thrombocytopenia (8.7, 5.7%), Gr 3/4 anemia (37.3, 21.1%), fever/infection with Gr 4 neutropenia (3.9, 8.9%), sepsis (4.2, 2.1%). Nonhematologic toxicity: Gr 3 nausea (3.9, 7.3%) Gr 3/4 vomiting (4.5, 9.4%), Gr 3/4 diarrhea (5.8, 2.3%) Gr 3/4 anorexia (3.7, 0.5%). Conclusions: This is one of the largest studies conducted in ED-SCLC. TC and PE show comparable activity and tolerability in the therapy-naïve setting. TC vs PE: Efficacy results TC (95% CI) n=389 PE (95% CI) n=395 Hazards Ratio (95% CI) Log-rank P value Median survival (wks) 39.3 (37.4,42.4) 40.3 (37.1,43.6) Overall survival 1.06 (0.91,1.24) P=0.4734 1-yr survival (%) 31.4 (26.7,37.0) 31.4 (26.8,30.0) Median time to progression (wks) 24.1 (22.1,25.7) 25.1 (24.1,26.9) Time to progression 1.19 (1.03,1.38) P=0.02 Complete response/partial response 25/220 21/251 Overall response rate (%) 63.0 (58.2,67.8) 68.9 (64.3,73.4) Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline
Massive parallel RNA sequencing of highly purified mesenchymal elements in low-risk MDS reveals tissue-context-dependent activation of inflammatory programs
Authors: S Chen, N A Zambetti, E M J Bindels, K Kenswill, A M Mylona, N M Adisty, R M Hoogenboezem, M A Sanders, E M P Cremers, T M Westers, J H Jansen, A A van de Loosdrecht, M H G P Raaijmakers
Journal: Leukemia (2016)

Massive parallel RNA sequencing of highly purified mesenchymal elements in low-risk MDS reveals tissue-context-dependent activation of inflammatory programs
Chronic conditions and lifestyle behavior after cancer: The differences between 2,103 cancer cases and 4,185 age and gender matched controls.
Authors: Bogda Koczwara, Michelle Miller, Richard John Woodman, John Coveney, Sue Booth, James Dollman, Catherine Mackenzie, Narelle Berry
Journal: Journal of Clinical Oncology (2013)

9585 Background: Weight gain and inactivity after cancer are associated with poorer cancer outcomes and may predispose to chronic conditions but the prevalence of these among cancer survivors is not well defined. The objectives of this cross-sectional study were to determine whether those with history of cancer have a greater prevalence of chronic conditions and whether their lifestyle behaviours differ from cancer free controls. Methods: Cross-sectional self-reported data were obtained from adult telephone survey respondents between January 2010 and March 2012. Age and gender matched individuals who did not report a cancer diagnosis were randomly selected from the same data source as controls. Data reported included rates of cardiovascular disease, hypertension, hyperlipidaemia, diabetes, and osteoporosis, lifestyle behaviours (diet, physical activity and smoking), obesity, psychological distress and self-reported health. Between-group differences were assessed using McNemar’s test. Results: 2,103 cases and 4,185 controls were included in the analyses. Cancer cases had a higher prevalence than controls for all chronic conditions: cardiovascular disease 22.1% vs 18.4%, p=0.001; hypertension 53.3% vs 50%, p=0.015; hyperlipidaemia 47.8% vs 41.8%, p&lt;0.001; diabetes 16% vs 13%, p=0.006; osteoporosis 13% vs 11%, p=0.013. There were no differences in diet, exercise or obesity. Cancer cases were more likely to report “very high” psychological distress (2.9% vs 1.7%, p=0.005) and “poor-fair” self-rated health (33.5% vs 22.9%, p&lt;0.001). Conclusions: Despite similar diet and exercise habits and levels of obesity the prevalence of chronic conditions was significantly higher amongst those with history of cancer compared to controls. Further research is warranted to explain this increased predisposition to chronic conditions.
Second-Generation HSP90 Inhibitor Onalespib Blocks mRNA Splicing of Androgen Receptor Variant 7 in Prostate Cancer Cells
Authors: Roberta Ferraldeschi, Jonathan Welti, Marissa V. Powers, Wei Yuan, Tomoko Smyth, George Seed, Ruth Riisnaes, Somaieh Hedayat, Hannah Wang, Mateus Crespo, Daniel Nava Rodrigues, Ines Figueiredo, Susana Miranda, Suzanne Carreira, John F. Lyons, Swee Sharp, Stephen R. Plymate, Gerhardt Attard, Nicola Wallis, Paul Workman, Johann S. de Bono
Journal: Cancer Research (2016)

Abstract Resistance to available hormone therapies in prostate cancer has been associated with alternative splicing of androgen receptor (AR) and specifically, the expression of truncated and constitutively active AR variant 7 (AR-V7). The transcriptional activity of steroid receptors, including AR, is dependent on interactions with the HSP90 chaperone machinery, but it is unclear whether HSP90 modulates the activity or expression of AR variants. Here, we investigated the effects of HSP90 inhibition on AR-V7 in prostate cancer cell lines endogenously expressing this variant. We demonstrate that AR-V7 and full-length AR (AR-FL) were depleted upon inhibition of HSP90. However, the mechanisms underlying AR-V7 depletion differed from those for AR-FL. Whereas HSP90 inhibition destabilized AR-FL and induced its proteasomal degradation, AR-V7 protein exhibited higher stability than AR-FL and did not require HSP90 chaperone activity. Instead, HSP90 inhibition resulted in the reduction of AR-V7 mRNA levels but did not affect total AR transcript levels, indicating that HSP90 inhibition disrupted AR-V7 splicing. Bioinformatic analyses of transcriptome-wide RNA sequencing data confirmed that the second-generation HSP90 inhibitor onalespib altered the splicing of at least 557 genes in prostate cancer cells, including AR. These findings indicate that the effects of HSP90 inhibition on mRNA splicing may prove beneficial in prostate cancers expressing AR-V7, supporting further clinical investigation of HSP90 inhibitors in malignancies no longer responsive to androgen deprivation. Cancer Res; 76(9); 2731–42. ©2016 AACR.
Expression and prognostic value of TRAIL receptors R1 and R2 in early stage breast cancer
Authors: M. M. McCarthy, K. A. Divito, R. L. Camp, M. Sznol, D. L. Rimm, H. M. Kluger
Journal: Journal of Clinical Oncology (2005)

9528 Background: Identifying molecular markers that predict outcome in early stage breast cancer may improve selection of patients for adjuvant therapy, and could reveal important targets or pathways for therapeutic intervention. TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) receptors R1 and R2 are cell surface receptors that transmit apoptotic signals and cause cell death. TRAIL R1 and R2 activation has been shown to induce apoptosis in breast cancer cells, and agents that activate these receptors are in clinical development. Therefore, we sought to determine the expression and prognostic value of TRAIL R1 and R2 in early stage breast cancer. Methods: Tissue microarrays containing specimens from 431 breast cancer patients with 20-year follow-up were employed and evaluated with our AQUA system for automated quantitative analysis. The system uses cytokeratin to define pixels as breast cancer (tumor mask) within the array spot, and measures intensity of TRAIL receptor expression using Cy5 conjugated antibodies within the mask. We also studied 220 unmatched normal breast specimens for TRAIL R1 and R2 expression. Scores were correlated with clinical and pathological variables. Results: Expression of TRAIL R1 was not associated with survival. High TRAIL R2 expression strongly correlated with decreased survival by Cox univariate analysis (P=0.0018). On multivariate analysis, high TRAIL R-2 expression maintained its independence as a predictive marker, as did nodal status and tumor size. TRAIL R2 expression was stronger in malignant specimens than in normal breast epithelium by unpaired t-tests (P<0.0001). Conclusions: High TRAIL R2 expression was independently associated with worse survival in breast cancer. The results require prospective confirmation. The biological basis and the sensitivity of high TRAIL R2 expressing cells to TRAIL agonists and/or chemotherapy are subject to further investigation. High TRAIL R2 expression in early stage breast cancer may identify a subset of patients requiring more aggressive or pathway-targeted adjuvant treatment. Our results also suggest that clinical trials involving TRAIL R2 agonists should stratify patients based on TRAIL R2 expression. No significant financial relationships to disclose.
Soundings: Quaint or what?
Authors: Liam Farrell
Journal: BMJ (2000)

The hills are beautiful at this time of the year; the verdant meadows tranquil but for the racket of bumblebees frenziedly rogering the butterflies among the dandelions and the Great God Pan making lewd suggestions to the wood nymphs; whinbushes golden and so lush with spines that if you threw in a herbalist she would squeal for weeks; snow white lily-of-the-valley coating the glensides like talcum powder down the natal cleft of a big fat man, as Wordsworth might have said if he had had medical training.

And the people; slow, sullen, and yet dull, we are so rural that cows are considered effete, stylised, and possibly homosexual, and the only thing we milk is the social security system. We are unsentimental about nature; we can't eat the scenery, we say, though judging from our dental appearance some of us have tried, so we augment our incomes by smuggling and blackmailing small furry animals.

Hunt saboteurs find us unsympathetic, although we dislike fat upper class bastards on horseback just as much as they do; if a fox could eat you, we assure them, it would, and it wouldn't care if it had to hunt you bare arsed across the hills to do it. As for tree huggers, the day a tree hugs you back, you'll be sorry. According to a local folksong, French kiss an oak tree and you end up with a mouthful of gloopy sap.

We are shy and terse, and we follow the Bible's teaching: “Never let your left hand know what your right hand is doing,” it advises, to which I add, especially when it involves bodily organs. One of the joys of visiting other countries is engaging in discourse with the locals and learning about their culture, so tourists here are fucked.

Up here the police enjoy all the esteem of a dead goat, and a doctor's life accordingly becomes more diverting.

“My brother's cut himself, I want you to come out and stitch him up.”

I explained that such a brutal injury would need to attend the surgery. 

“There's no one for to drive him.”

I remained firm, and eventually the real reason emerged.

“We can't bring him in, he's threatening us with a knife.”

 We are unsentimental  about nature
Cell-Mediated Cytotoxicity to Muscle in Polymyositis
Authors: R. L. Dawkins, F. L. Mastaglia
Journal: New England Journal of Medicine (1973)

Immunologic injury to cultures of skeletal muscle was studied in patients with polymyositis by means of a 51Cr release method that allows quantitation of myocyte injury. Lymphocyte-mediated myotoxicity was elevated in a group of nine patients with active disease (p<0.001) but was normal in four patients with inactive disease. There was no evidence of antibody-mediated cytotoxicity. Lymphocyte-mediated myotoxicity in the active group was analyzed in relation to treatment and immunosuppression in six of the nine patients. Seven tests on patients on immunosuppressive therapy gave normal lymphocyte-mediated myotoxicity values of 1.0 ± 4.2 per cent (mean ± S.D.), whereas eight tests on patients who were on less than immunosuppressive therapy yielded elevated lymphocyte-mediated myotoxicity: 24.4 ± 10.6 per cent, with a significant difference between these two groups (p < 0.001). These data suggest that the pathogenesis of polymyositis involves a cell-mediated immunologic reaction directed against skeletal muscle, and that immunosuppressive therapy may exert its clinical effect by decreasing lymphocyte myotoxicity.
Holism and holistic
Authors: Graham Russell
Journal: BMJ (2016)

Holistic is a term widely applied in science in general, including medicine, where it refers to managing the “whole person,” not just the symptoms or a disease. Holistic is a neologism introduced by Jan Christian Smuts—a South African soldier, statesman, and philosopher—in his 1926 treatise Holism and Evolution .1 Smuts visualised the universe as three “wholes”—matter, …
Abstract 1256: Reperfusion But Not Ischemia Initiates Autophagy And Inhibition Of Autophagy Protects The Heart From Reperfusion Injury
Authors: Huihua Wang, Jinkun Xi, Guang Cheng, Guillaume Chanoit, Robert A Mueller, Edward A Norfleet, Zhelong Xu
Journal: Circulation (2007)

The exact role of autophagy in myocardial ischemia/reperfusion injury remains unknown. We aimed to test if and how autophagy contributes to the pathogenesis of ischemia/reperfusion injury in the heart. Isolated rat hearts were subjected to 30 min regional ischemia followed by 2 h of reperfusion or sham operation. Myocardial biopsies were taken from ischemic area. Ischemia did not increase the LC3-II to LC3-I ratio (LC3-II/LC3-I), an established marker of autophagy, compared to the sham group. In contrast, LC3-II/LC3-I was markedly increased upon reperfusion (1.4, 2.2, 2.9, and 2.2-fold increases at 10, 30, 60, and 120 min of reperfusion; n = 6)). These observations suggest that reperfusion but not ischemia triggers autophagy. In support of this finding, electron microscopic analysis revealed a significant increase in the number of cytoplasmic autophagosome in myocardium upon reperfusion but not during ischemia. To confirm that the above observations were of autophagic origin, we tested if 3-methyladenine ...
TCTAP C-133 Severe Catheter Kinking and Entrapment During Trans-brachial Angiography: Percutaneous Retrieval with a Slender Approach
Authors: Sho Hashimoto, Akihiko Takahashi, Norimasa Taniguchi, Takeshi Yamada, Yukio Mizuguchi, Shunsuke Nakajima, Tetsuya Hata
Journal: Journal of the American College of Cardiology (2016)
Effects of Tributyltin Chloride on Cybrids with or without an ATP Synthase Pathologic Mutation
Authors: Ester López-Gallardo, Laura Llobet, Sonia Emperador, Julio Montoya, Eduardo Ruiz-Pesini
Journal: Environmental Health Perspectives (2016)

The oxidative phosphorylation system (OXPHOS) includes nuclear chromosome (nDNA)- and mitochondrial DNA (mtDNA)-encoded polypeptides. Many rare OXPHOS disorders, such as striatal necrosis syndromes, are caused by genetic mutations. Despite important advances in sequencing procedures, causative mutations remain undetected in some patients. It is possible that etiologic factors, such as environmental toxins, are the cause of these cases. Indeed, the inhibition of a particular enzyme by a poison could imitate the biochemical effects of pathological mutations in that enzyme. Moreover, environmental factors can modify the penetrance or expressivity of pathological mutations.We studied the interaction between mitochondrially encoded ATP synthase 6 (p.MT-ATP6) subunit and an environmental exposure that may contribute phenotypic differences between healthy individuals and patients suffering from striatal necrosis syndromes or other mitochondriopathies.We analyzed the effects of the ATP synthase inhibitor tributyltin chloride (TBTC), a widely distributed environmental factor that contaminates human food and water, on transmitochondrial cell lines with or without an ATP synthase mutation that causes striatal necrosis syndrome. Doses were selected based on TBTC concentrations previously reported in human whole blood samples.TBTC modified the phenotypic effects caused by a pathological mtDNA mutation. Interestingly, wild-type cells treated with this xenobiotic showed similar bioenergetics when compared with the untreated mutated cells.In addition to the known genetic causes, our findings suggest that environmental exposure to TBTC might contribute to the etiology of striatal necrosis syndromes.López-Gallardo E, Llobet L, Emperador S, Montoya J, Ruiz-Pesini E. 2016. Effects of tributyltin chloride on cybrids with or without an ATP synthase pathologic mutation. Environ Health Perspect 124:1399-1405; http://dx.doi.org/10.1289/EHP182.
Efficacy and Safety of Imatinib on Top of BFM-Like Chemotherapy in Pediatric Patients with Ph+/BCR-ABL+ Acute Lymphoblastic Leukemia (Ph+ALL). the EsPhALL Study
Authors: Andrea Biondi, Martin Schrappe, Paola Di Lorenzo, Anders Castor, Giovanna Lucchini, Virginie Gandemer, Rob Pieters, Jan Stary, Gabriele Escherich, Myriam Campbell, Ci Kong-Li, Ajay J Vora, Gudmar Lonnerholm, Maurizio Arico‘, Jochen Harbott, Vaskar Saha, Maria Grazia Valsecchi
Journal: Blood (2011)
Psoriasis, Type 2 Diabetes Mellitus, and Obesity
Authors: Joel M. Gelfand
Journal: JAMA Dermatology (2016)

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Multivariate Analysis Reveals a miRNA Profile Correlated To Karyotype and Outcome In Pediatric B-Cell Precursor ALL
Authors: Marina Lipkin Vasquez, Stefano Volinia, Cecilia Fernandez, Nicola Zanesi, Grazia Fazio, Ilana Renault Zalcberg, Ramiro Garzon, Giovanni Cazzaniga, Andrea Biondi, Carlo M. Croce
Journal: Blood (2013)