tbuckley/cabot-search huggingface dataset:
Effect of histone deacetylase inhibitor in combination with gemcitabine on pancreas cancer and cholangiocarcinoma cell line.
Authors: S. Iwahashi, M. Shimada, T. Utsunomiya, Y. Morine, S. Imura, T. Ikemoto, J. Hanaoka, Y. Saito
Journal: Journal of Clinical Oncology (2010)

e14645 Background: Histone deacetylase (HDAC) is strongly associated with epigenetic regulation and carcinogenesis, and its inhibitors (HDACIs) induce the differentiation or apoptosis of cancer cells. Valproic acid (VPA) is one of the clinically available HDACIs. On the other hand, the anticancer effects of IFNα have also been reported. Methods: Human pancreas cancer cell lines (SUIT-2, BxPC3) and a cholangiocarcinoma cell line (HuCCT1) were used. The anticancer effects of VPA combined with gemcitabine (GEM) and IFNα were examined in SUIT-2 and BxPC3, and the effects of VPA combined with GEM were studied in HuCCT1. The cell viability was evaluated by MTT assay, and the gene-expressions of P21, HDAC, VEGF, and HIF-1 were evaluated by RT-PCR. Results: Pancreas cancer cell lines: VPA (0.5mM) did not suppress the cell viability. IFNα (102E) weakly suppressed it by 28% in BxPC3 and 17% in SUIT-2. GEM (5 nM) reduced by 36% in BxPC3 and 61% in SUIT-2. The combination of GEM and IFNα showed the strong suppression by 82% in SUIT-2 and 51% in BxPC3, which was further augmented by the addition of VPA up to 88% and 67%, respectively (p < 0.05). The combination of GEM and IFNα showed the enhanced expression of p21, which was also reinforced by VPA (p < 0.01). GEM combined with VPA reduced the HDAC expressions, while such combination effects were not observed in VEGF or HIF-1 expressions.Cholangiocarcinoma cell line: GEM (5 nM) did not suppress the cell viability, GEM (10 nM) suppressed by 16%. VPA (0.5 mM) did not suppress the cell viability, while VPA (1.0 mM) weakly decreased it by 12% and VPA (5.0 mM) suppressed by 35%. GEM (5nM) and VPA (0.5 mM) reduced by 23%, which significantly augmented the anticancer effect of GEM alone or VPA alone (p < 0.01). Furthermore, GEM combined with VPA up-regulated the p21 expression compare to single agent (p < 0.05). Conclusions: VPA augmented the effects of anticancer agents in both the pancreas cancer cell lines and a cholangiocarcinoma cell line. Such effects may be owing to the up-regulated gene-expression of the cyclin dependent kinase inhibitor p21. No significant financial relationships to disclose.
Accurate Medicine: Indirect Targeting of <i>NPM1</i>-Mutated AML
Authors: Christopher S. Hourigan, Peter D. Aplan
Journal: Cancer Discovery (2016)

Acute myeloid leukemia (AML) is now recognized to be an imprecise term that refers to a range of myeloid malignancies that have different genetical etiologies, clinical characteristics, and therapeutic sensitivities. Targeting the MLL1 and DOT1L histone modification complexes, both alone and in combination, showed activity against AML driven by a mutant NPM1 protein in several preclinical models and may represent a new treatment direction for this devastating disease. Cancer Discov; 6(10); 1087-9 ©2016 AACR.See related article by Kühn and colleagues p. 1166.
ECG Challenge: August 5, 2014
Authors: Philip Podrid
Journal: Circulation (2014)

A 76-year-old man with a history of hypertension being treated with a β-blocker and diltiazem, chronic obstructive pulmonary disease, and mild mitral regurgitation presents to his primary care physician with complaints of occasional palpitations that have been present for the past 3 weeks.Physical examination demonstrates a normal blood pressure, an irregular pulse, clear lungs, and a grade 2/6 murmur consistent with mitral regurgitation.As a result of the irregular pulse, an ECG is obtained.What is the diagnosis?
Epidemiological trends in metastatic renal cell carcinoma in the era of targeted therapies: An analysis of the SEER registry.
Authors: Arpit Rao, Charles Wiggins, Richard C. Lauer
Journal: Journal of Clinical Oncology (2016)

516 Background: Clear cell RCC (ccRCC) accounts for 70-75% of all kidney and renal pelvis cancers with approximately 16% of patients presenting with distant (metastatic) disease. Five year overall survival (OS) remains dismal at 11.2% for patients with distant disease. Several tyrosine kinase inhibitors (TKI) were approved by US Food and Drug Administration for use in metastatic RCC between 2005 and 2012. While these therapies have been shown to improve outcomes in metastatic ccRCC, the long term impact remains unknown. Methods: The Surveillance, Epidemiology and End-Results (SEER) database was queried for patients aged 18 years and older diagnosed with distant stage (metastatic) ccRCC between 2001 and 2012 in the nine core SEER registries. Analyses were restricted to histologically confirmed cases. Study period was divided into 3-year intervals: 2001-03 (pre-TKI era); 2004-06 (TKI trials era); 2007-09 (early TKI era); and 2010-12 (sequential TKI era). Patients were stratified by age at diagnosis: 18-60 years, 60-69 years, and 70+ years. One, two, and three year, and median cause-specific survival were calculated by Kaplan-Meier method. Differences in cause-specific survival by time period were assessed with the Log-Rank test. Results: A total of 3,747 eligible patients were included in the analysis. For all ages combined, cause-specific survival at three years post-diagnosis was 18.8% for those diagnosed during the period 2001-03 (median 8 months), 22.7% in 2004-06 (median 10 months), 23.2% in 2007-09 (median 9 months), and 28.9% in 2010-12 (median 11.0 months) (p= 0.0004). No statistically significant improvement in survival was observed in patients aged 70 years and above (p= 0.1302). Conclusions: Our analysis quantifies the improvement in survival outcomes in metastatic ccRCC that correlate with TKI use in this setting. While there is evidence that all age groups may have benefitted from these therapies, the impact is least pronounced in patients aged 70 years and above. A SEER-Medicare analysis is planned to evaluate disparities in TKI use in this age group.
Exercise, ageing and the lung
Authors: Michael A. Roman, Harry B. Rossiter, Richard Casaburi
Journal: European Respiratory Journal (2016)

This review provides a pulmonary-focused description of the age-associated changes in the integrative physiology of exercise, including how declining lung function plays a role in promoting multimorbidity in the elderly through limitation of physical function. We outline the ageing of physiological systems supporting endurance activity: 1) coupling of muscle metabolism to mechanical power output; 2) gas transport between muscle capillary and mitochondria; 3) matching of muscle blood flow to its requirement; 4) oxygen and carbon dioxide carrying capacity of the blood; 5) cardiac output; 6) pulmonary vascular function; 7) pulmonary oxygen transport; 8) control of ventilation; and 9) pulmonary mechanics and respiratory muscle function. Deterioration in function occurs in many of these systems in healthy ageing. Between the ages of 25 and 80 years pulmonary function and aerobic capacity each decline by ∼40%. While the predominant factor limiting exercise in the elderly likely resides within the function of the muscles of ambulation, muscle function is (at least partially) rescued by exercise training. The age-associated decline in pulmonary function, however, is not recovered by training. Thus, loss in pulmonary function may lead to ventilatory limitation in exercise in the active elderly, limiting the ability to accrue the health benefits of physical activity into senescence.
A phase II evaluation of a 3-hour infusion of paclitaxel (P), cisplatin (CDDP) &amp; 5-fluorouracil (5FU) in patients with advanced or recurrent squamous cell carcinoma of the head &amp; neck (SCCHN): A Southwest Oncology Group Study
Authors: F. P. Worden, J. Moon, W. Samlowski, J. Clark, S. R. Dakhil, S. A. Taylor, S. G. Urba, M. Hussain
Journal: Journal of Clinical Oncology (2004)

5512 Background: Previous pilot data from a SWOG institution reported an overall response rate of 60% & a median survival of 6 months in patients (pts) with advanced/recurrent SCCHN who were treated with P, CDDP, & 5FU. To validate these results & to determine the feasibility of this combination, a phase II study was conducted by SWOG. Methods: Eligible pts had to have metastatic SCCHN or persistent/recurrent disease following definitive treatment, a Zubrod performance status ≤ 1, & adequate renal function. All pts received P (135 mg/m2) over 3 hours prior to CDDP (75 mg/m2) on day 1. 5FU (1000 mg/ m2/day) was given days 1–4 after CDDP. Chemotherapy was repeated every 21 days. Disease was assessed after every 2 cycles. Pts with partial responses (PR)/stable disease (SD) were treated until disease progression. Those with complete responses (CR) were treated with 3 additional cycles. Results: From November 2000 to May 2003, 78 pts from 34 institutions were enrolled; 74 pts were eligible (60 men; 14 women) with a median age of 59.7 years. At baseline, 20/74 pts (27%) had distant metastases, 23/74 (31%) had loco-regional disease, & 31/74 (42%) had both. Nine pts had prior chemotherapy in combination with radiation or surgery. Response was analyzed on 65 pts; 6 were excluded for lack of measurable disease at baseline. Response is pending for 3. Confirmed responses were seen in 15 pts (23%) (2 CR & 13 PR), & 9 pts (14%) had unconfirmed responses (1UCR, 8UPR); estimated response probability is 24 of 65 (95% CI: 25%–50%). Major grade 3/4 toxicities were neutropenia (35/74) (47%) & mucositis (23/74) (31%). There were 5 treatment related deaths, 2 from infection, 1 from neutropenic sepsis, 2 from other causes. The median time to follow-up was 8 months, the estimated median progression-free survival is 4 months (95%CI: 3.5–4.8), & the estimated median survival is 9 months (95%CI: 6.0–11.6). Conclusions: P, CDDP, & 5FU is active in this poor risk population, in spite of high toxicity, & appears to be associated with an improved median survival when compared with historical controls. No significant financial relationships to disclose.
Measurement of polyp size at colonoscopy: a proof-of-concept simulation study to address technology bias
Authors: Shinichiro Sakata, Felicity McIvor, Kerenaftali Klein, Andrew R L Stevenson, David G Hewett
Journal: Gut (2016)

We introduce a novel, proof-of-concept polyp measurement device for the design of future colonoscopes. In a simulation study, 50 expert endoscopists used three measurement strategies (method 1: no visual cues; method 2: a snare tip visual cue; method 3: a grid visual cue) to evaluate 120 images of 40 simulated polyps (1–10 mm) presented in random order. Measurement accuracies of each method were 20%, 33% and 90%, respectively (p<0.001). Using the proof-of-concept measurement grid (method 3), endoscopists were 99.8% accurate for high confidence classifications of polyps into clinically relevant size categories. Improvements in colonoscope design are needed to minimise human and technology biases.

There are increasing concerns about the influence of human bias on the measurement of polyp size at colonoscopy.1–3 A study of 92 124 individual colorectal polyp measurements from the UK bowel cancer screening programme showed that endoscopists, radiologists and pathologists all exhibited terminal digit preference and clustering of polyp measurements at 5mm intervals.1 Although human bias is an acknowledged contributor to the measurement error of polyps, the importance of technology bias remains understated.1–3 Figure 1 illustrates the extent of image distortion from the fish eye lens of modern colonoscopes, where objects in the centre of the display appear magnified and objects at the periphery appear small and warped. It also demonstrates how makeshift measurement tools, such as snare catheters, potentially worsen measurement error from technology bias coupled with illusions of relative size. We hypothesised that both human and technology biases could be addressed by improvements in current colonoscope technology.



Figure 1 
Three measurement conditions for a 5 mm simulated polyp taken with an Olympus CF-HQ190L colonoscope at a viewing distance of 10 mm. (A) Method 1—no visual cues, in which the polyp was photographed against a plain, orange background without any …
Critical evaluation of the Illumina MethylationEPIC BeadChip microarray for whole-genome DNA methylation profiling
Authors: Ruth Pidsley, Elena Zotenko, Timothy J. Peters, Mitchell G. Lawrence, Gail P. Risbridger, Peter Molloy, Susan Van Djik, Beverly Muhlhausler, Clare Stirzaker, Susan J. Clark
Journal: Genome biology (2016)

In recent years the Illumina HumanMethylation450 (HM450) BeadChip has provided a user-friendly platform to profile DNA methylation in human samples. However, HM450 lacked coverage of distal regulatory elements. Illumina have now released the MethylationEPIC (EPIC) BeadChip, with new content specifically designed to target these regions. We have used HM450 and whole-genome bisulphite sequencing (WGBS) to perform a critical evaluation of the new EPIC array platform. EPIC covers over 850,000 CpG sites, including >90 % of the CpGs from the HM450 and an additional 413,743 CpGs. Even though the additional probes improve the coverage of regulatory elements, including 58 % of FANTOM5 enhancers, only 7 % distal and 27 % proximal ENCODE regulatory elements are represented. Detailed comparisons of regulatory elements from EPIC and WGBS show that a single EPIC probe is not always informative for those distal regulatory elements showing variable methylation across the region. However, overall data from the EPIC array at single loci are highly reproducible across technical and biological replicates and demonstrate high correlation with HM450 and WGBS data. We show that the HM450 and EPIC arrays distinguish differentially methylated probes, but the absolute agreement depends on the threshold set for each platform. Finally, we provide an annotated list of probes whose signal could be affected by cross-hybridisation or underlying genetic variation. The EPIC array is a significant improvement over the HM450 array, with increased genome coverage of regulatory regions and high reproducibility and reliability, providing a valuable tool for high-throughput human methylome analyses from diverse clinical samples.
Low Toxicity Profile of the Combination of Bendamustine Plus Rituximab (BR) in Elderly FRAIL Patients with Newly Diagnosed DLBCL
Authors: Michele Spina, Stefano Luminari, Flavia Salvi, Francesco Passamonti, Alberto Fabbri, Umberto Vitolo, Maria Giuseppina Cabras, Maurizio Miglino, Francesco Merli, Pier Paolo Fattori, Anna Marina Liberati, Alfonso Zaccaria, Patrizia Tosi, Rosanna Ciancia, Emanuela Anna Pesce, Sergio Storti
Journal: Blood (2014)
Docetaxel (DOC) with concurrent radiation (CRT) and bevacizumab (BEV) or erlotinib (ERL) for locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN).
Authors: Panayiotis Savvides, Sabarish Ayyappan, Min Yao, Rod Rezaee, Chad Zender, Jay Wasman, Pingfu Fu, Mitchell Machtay, Pierre Lavertu, Michael K. Gibson
Journal: Journal of Clinical Oncology (2014)

6070 Background: Cisplatin (CIS) may not be the optimal radiosensitizer when combined with targeted agents in CRT regimens. RTOG 0234, a randomized phase II trial of postoperative radiation (RT) plus DOC or CIS plus cetuximab for high-risk LA-HNSCC showed an impressive improvement in overall survival and disease-free survival of DOC versus CIS (79% versus 69% and 66% versus 57% respectively). DOC-based CRT backbone regimens are worth further study in the organ preservation setting. To facilitate and accelerate evaluation of additional targeted agents, we summarized our experience in DOC-based chemo-RT using two consecutive phase II clinical trials with either BEV or ERL. Methods: 73 patients with LA-SCCHN (stage III- IVb) treated with RT (70 or 70.2-72Gy, 1.8-2Gy/day), weekly DOC (20 mg/m2) and targeted therapy [BEV (5 mg/kg/qow) or ERL (150 mg/day)] were included. DOC dose was based on a phase I clinical trial of RT + DOC + ERL (Savvides P. Phase I study of ERL, DOC and RT in LA-SCCHN. AACR 2007.). Results: Patients with a median age 57 (range 35-75), primary site of LA-SCCHN [oropharynx (n=49), larynx (n=17), hypopharynx (n=2) and oral cavity (n=5)]. Efficacy data have been previously presented separately for the 2 trials (Savvides P. Phase II study of ERL, DOC and RT in LA-SCCHN. AHNS 2010.), (Galanopoulos N. Phase II study of BEV, DOC and RT in LA-SCCHN. ASTRO 2011.). Delivery of planned treatment was achieved in both trials; median total radiation therapy dose 70 Gy, median duration 53 days. DOC median dose intensity (MDI) 20mg/m2/qw, x8 doses; BEV MDI 5mg/kg/qow, x4 doses and ERL MDI 150mg/qd.No increased SAEs, compared to historical controls. BEV/ERL related events limited to 2 G4 bleeding episodes and 1 G3 episode of thrombosis (BEV); 4 G4 skin rash episodes and 1 G5 event (death not treatment related) (ERL). Conclusions: Weekly DOC at 20 mg/m2/wk with RT and either BEV or ERL is feasible and safe for definitive treatment of patients with LA-SCCHN and should serve as the backbone for evaluation of novel targeted agents. Supported in part by Genentech, NIH grants CA62502 and M01 RR-000080. Clinical trial identifier: NCT00049283; NCT00281840.
New Insight into Epstein-Barr Virus-Associated Biological Behavior of Aggressive Natural Killer Cell Leukemia
Authors: Hongsheng Zhou, Chanxin Yin, Yongjian Deng, Xiaolei Xue, Xiangzhao Li, Ying Tian, Hongsheng Li, Libin Liao, Dan Fang, Min Dai, Qiang Wang, Na Xu, Fen Huang, Zhiping Fan, Yu Zhang, Yongqiang Wei, Dan Xu, Qianli Jiang, Xiaoli Liu, Jing Sun, Qifa Liu, Bing Xu, Ru Feng, Bing Z Carter, Fanyi Meng
Journal: Blood (2014)
HN5: A phase I/II study of erlotinib as adjuvant therapy in patients treated by chemoradiation therapy (CRT) for locally advanced SCCHN.
Authors: D. Soulieres, B. Fortin, E. Winquist, D. Charpentier, E. Harnett, W. Walsh, W. Parulekar
Journal: Journal of Clinical Oncology (2010)

5562 Background: Treatment of locally advanced SCCHN usually includes primary/post-op concomitant CRT. Disease recurs in a significant proportion of pts within 2y. SCCHN is known to overexpress EGFR. Single agents targeting EGFR have demonstrated activity in metastatic SCCHN and were well tolerated. No specific data exists regarding the sequential therapy of erlotinib immediately after CRT. Previous reports in NSCLC suggest an added toxicity/death of EGFR-TKI after CRT. The objective of the present trial was to evaluate toxicity and feasibility of adjuvant erlotinib therapy after CRT for locally advanced SCCHN. Methods: Pts with locally advanced SCCHN in complete or excellent PR (based on clinical/radiological evaluation) after radical radiotherapy and concomitant platinum based chemotherapy were eligible. Erlotinib was started within 12 weeks of completion of CRT. The first 6 pts were to be treated with erlotinib at 100 mg daily for 24 weeks and, after demonstration of tolerable toxicities at this level, the next 13 pts were treated at 150 mg daily for 24 weeks. Pts were evaluated monthly during therapy and every 3 months thereafter to evaluate efficacy. Blood and urine samples were collected throughout the study for evaluation of biomarkers that could predict recurrence (data not presented in this abstract). Results: 19 pts were recruited to this trial (17M, 2F). Baseline staging prior to CRT was stage III—5 pts, stage IVA—10 pts, and stage IVB—4 pts. ECOG PS was 0 in 7 pts and 1 in 12 pts at study entry. At 100 mg daily, no pt had grade 3 or greater toxicity. For the 150mg daily cohort, 3 pts had grade 3 toxicities (stomatitis, pain, rash). The dose of 4 pts was reduced to 100mg due to skin toxicity. 15 pts completed therapy, while 3 pts stopped at their request and 1 for other reason. 3 pts have had disease recurrence, and with a median follow-up of 47 months (range, 10-68 months). PFS has not been reached. Estimated 4Y PFS is 83% (95%CI: 54-94%). Conclusions: Erlotinib was generally well tolerated and appears feasible as adjuvant therapy following CRT in pts with locally advanced SCCHN. This approach should be considered for a phase III trial. Supported by CCSRI Grant#15469 and Roche Canada. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche
NHS to pilot ways to stop sending mental health patients long distances for treatment
Authors: Gareth Iacobucci
Journal: BMJ (2016)

NHS England is to test new approaches to delivering mental health services in a bid to end the practice of patients being sent a long way from their home for inpatient treatment.

Six pilot sites will be tasked with redesigning young people’s mental health services and secure mental health services, with the aim of reducing psychiatric hospital admissions, shortening inpatient stays in hospital, and eliminating “clinically inappropriate” placements out of patients’ local area.

The number of mental health patients sent out of area for treatment has risen in recent years because of a shortage of inpatient beds, causing much difficulty for patients, their families, and clinicians.

NHS England said that the £1.8m (€2.1m; $2.3m) investment spread across the six sites would help reduce the need to send vulnerable people across the country to be treated.

NHS mental health trusts, independent …
Association of host genome with intestinal microbial composition in a large healthy cohort
Authors: Williams Turpin, Osvaldo Espin-Garcia, Wei Xu, Mark S Silverberg, David Kevans, Michelle I Smith, David S Guttman, Anne Griffiths, Remo Panaccione, Anthony Otley, Lizhen Xu, Konstantin Shestopaloff, Gabriel Moreno-Hagelsieb, Andrew D Paterson, Kenneth Croitoru
Journal: Nature Genetics (2016)