tbuckley/cabot-search huggingface dataset:
Genomic profiling of malignant pleural mesothelioma with array-based comparative genomic hybridization shows frequent nonrandom chromosomal alteration regions including JUN amplification on 1p32
Authors: Tetsuo Taniguchi, Sivasundaram Karnan, Takayuki Fukui, Toshihiko Yokoyama, Hiroyuki Tagawa, Kohei Yokoi, Yuichi Ueda, Tetsuya Mitsudomi, Yoshitsugu Horio, Toyoaki Hida, Yasushi Yatabe, Masao Seto, Yoshitaka Sekido
Journal: Cancer Research (2007)

4439  Genome-wide array-based comparative genomic hybridization (CGH) analysis of malignant pleural mesotheliomas (MPMs) was performed to identify regions that display DNA copy number alterations. Seventeen primary tumors and 9 cell lines derived from 22 individuals were studied, some of them originating from the same patients. Regions of genomic aberrations observed in > 20% of individuals were 1q, 5p, 7p, 8q24, and 20p of gains, and 1p36.33, 1p36.1, 1p21.3, 3p21.3, 4q22, 4q34-qter, 6q25, 9p21.3, 10p, 13q33.2, 14q32.13, 18q, and 22q of losses. Two regions at 1p32.1 and 11q22 showed a high copy gain. The 1p32.1 region contained a protooncogene, JUN, andwe further demonstrated overexpression of JUN with real-time polymerase chain reaction (PCR) analysis. Since MPM cell lines did not overexpress JUN, our findings suggested that induction of JUN expression was involved in the development of MPM cells in vivo, which also might result in gene amplification in a subset of MPMs. Meanwhile, the most frequent alteration was the 9p21.3 deletion, which includes the p16INK4a/ p14ARF locus. With PCR analysis, we determined the extent of the homozygous deletion regions of the p16INK4a/ p14ARF locus in MPM cell lines, which indicated that the deletion regions varied among cell lines. Our results with array CGH analysis provide new insights into the genetic background of MPM, and also give some clues to manifest a new molecular target therapy for MPM.
Clinical impact of histologic subtypes and somatic mutations in peritoneal carcinomatosis from colorectal cancer.
Authors: Frederic Bibeau, Amelie Gudin, Amelie Denouel, Lise Roca, Florence Castan, Evelyne Lopez-Crapez, Alexandre Ho-pun-cheung, Pierre-Jean Lamy, Bernard Saint-Aubert, Florence Boissiere, Francois Quenet
Journal: Journal of Clinical Oncology (2013)

e14621 Background: Peritoneal carcinomatosis (PC) occurs in 10 to 15% of colorectal carcinoma (CRC). Strategies combining surgical resection and hyperthermic intraperitoneal chemotherapy have improved PC outcome. The morphologic, phenotypic and molecular spectrum of CRC PC and their clinical impact are still unknown. Methods: We selected 70 CRC PC cases operated in our institute (34 men, 36 women, median age: 61, median follow-up: 3.9 years.). The following investigations were performed: pathologic review; immunohistochemistry, focused on microsatellite instability (MSI) and CRC markers; mutational status of KRAS, BRAF and TP53. Results: 51 % of PC cases were pure or mixed mucinous carcinoma. Histologic types of PC and primary CRCwere concordant in 80% of cases. Lymphovascular and perineural infiltrations were only observed in 20 and 23% of cases, probably reflecting the preferential spread of PC by surface graft. 90% of cases displayed usual CRC phenotype: CK20+/CK7-/villine+/CDX2+. 96% of PC cases were microsatellite stable (MSS) and 58, 46 and 6% showed TP53, KRAS and BRAF mutations, respectively. No significant association was observed between the histologic type and sex, location, peritoneal index or molecular profile. Mucinous PC had a better relapse free survival (RFS) than conventional lieberkuhnian PC (P=0.04). KRAS/BRAF wild type PC had a better overall survival (OS) than KRAS or BRAF mutated PC, the latter group having the worst outcome (P&lt;0.001). Conclusions: The high rate of mucinous PC suggested a propensity for peritoneal location in primary mucinous CRC. The high rate of MSS tumors, TP53 and KRAS mutations revealed that a large part of PC could be part of the chromosomic instability molecular group. Poor RFS with lieberkuhnian PC raises the question of greater aggressiveness for this histologic type. Consistent with previous reports in metastatic CRC, poor OS was associated with KRAS and particularly BRAF mutations. These preliminary and original results may indicate a peritoneal tropism and a particular behavior for mucinous CRC and need to be prospectively confirmed to determine whether mucinous CRC and PC could benefit from particular therapeutic approaches.
Modeling Progress Toward Elimination of Hepatitis B in Australia
Authors: Karen McCulloch, Nicole Romero, Jennifer MacLachlan, Nicole Allard, Benjamin Cowie
Journal: Hepatology (2019)

Background and Aims Chronic hepatitis B (CHB) is a significant global health concern, and the most prevalent blood‐borne virus in Australia. World Health Organization (WHO) member states have committed to global elimination, with targets to diagnose 90% of people living with CHB, treat 80% of those eligible, and reduce attributable deaths by 65% by the year 2030. Australia has committed to national targets of 80% diagnosed, 20% on treatment, and a 30% reduction in deaths by 2022. Approach and Results We constructed and implemented a mathematical model to estimate the burden of CHB incorporating vaccination, phases of infection, cirrhosis progression, and mortality attributed to decompensated cirrhosis and hepatocellular carcinoma and examined the population‐level impact of antiviral therapy. Diversity was integrated according to migration patterns, CHB prevalence by country of birth, Indigenous status, and age. Modelled outcomes were subjected to multivariate uncertainty analysis. Of the estimated 221,420 people living with CHB in Australia in 2017, 68% were diagnosed and 8.7% were receiving treatment (less than one‐third of those estimated to be eligible). Based on current trends, the proportion of people living with CHB who have been diagnosed will reach 71% by 2022 and 81% by 2030, and treatment uptake will rise to 11.2% by 2022 and 12.9% by 2030, resulting in a 5.7% reduction in CHB‐attributable deaths from 2015 to 2030. CHB treatment has prevented approximately 2,300 deaths in Australia between 2000 and 2017. Conclusions Australia is not on track to meet local and global targets regarding CHB. Comprehensive and regularly updated modelling approaches accounting for diversity within the population are a useful tool to measure progress and impact of interventions, and quantify further improvements required to meet elimination goals.
Body composition and association with treatment toxicity in patients with advanced renal cell carcinoma receiving targeted agents.
Authors: Kelly McCabe, Vicky Goh, Anup Vinayan, Ann Petruckevitch, Paul D. Nathan
Journal: Journal of Clinical Oncology (2013)

e15608 Background: Treatment toxicity may be influenced by heterogeneity in body composition. Muscle wasting in mRCC patients treated with sorafenib is associated with increased risk of toxicity (Antoun et al, 2010). We used CT analysis to investigate changes in adipose tissue and skeletal muscle in a large cohort of mRCC patients treated with a number of targeted agents and determined whether body composition was associated with treatment toxicity. Methods: A retrospective analysis of between 2-7 sequential CT scans of 112 mRCC patients was conducted. Each patient received between 1-4 courses of therapy. In total 191 treatment episodes within this population were included; 113 courses of VEGF TKIs, 22 courses of mTOR inhibitors, 36 courses of immunotherapy and 20 episodes where no treatment was given. A validated method, using L3 as a lumbar vertebral landmark, was used to measure lumbar skeletal muscle area (cm 3 ) and adipose tissue volume (cm 3 ). Appendicular Skeletal Muscle Index (ASMI) was calculated to determine prevalence of sarcopenia within the cohort; sarcopenia was defined as ASMI &lt;7.26kg/m 2 for males and &lt;5.45kg/m 2 for females. Toxicity was assessed by Common Toxicity Criteria (CTC) scores documented in medical records. The cohort was divided into body mass index (BMI) quartiles. Results: Of the 112 participants, 74.1% of the group had a BMI &gt;25 at their first scan. Mean weight change between first and last scan was -3.89kg (SD: ±9.09). 20.5% of the cohort were sarcopenic at baseline, increasing to 38.4% at final scan. Sarcopenia was independent of weight change and was associated with increased frequency of severe (CTC grade &gt; 2) treatment toxicity (Pearson Chi Square Value: 12.82; p= 0.001). This effect persisted after adjusting for BMI quartile (odds ratio = 5.04; p=0.004). Changes in bone composition and correlation of body composition with clinical outcome will also be reported. Conclusions: Sarcopenia is common in mRCC patients and is associated with a significantly increased risk of severe treatment toxicity when receiving targeted agents. Sarcopenia was seen across all BMI quartiles and was not associated with weight change.
Changes in Plant-Based Diet Quality and Total and Cause-Specific Mortality
Authors: Megu Y. Baden, Gang Liu, Ambika Satija, Yanping Li, Qi Sun, Teresa T. Fung, Eric B. Rimm, Walter C. Willett, Frank B. Hu, Shilpa N. Bhupathiraju
Journal: Circulation (2019)

Background: Plant-based diets have been associated with lower risk of type 2 diabetes mellitus and cardiovascular disease (CVD) and are recommended for both health and environmental benefits. However, the association between changes in plant-based diet quality and mortality remains unclear. Methods: We investigated the associations between 12-year changes (from 1986 to 1998) in plant-based diet quality assessed by 3 plant-based diet indices (score range, 18–90)—an overall plant-based diet index (PDI), a healthful PDI, and an unhealthful PDI—and subsequent total and cause-specific mortality (1998–2014). Participants were 49 407 women in the Nurses’ Health Study (NHS) and 25 907 men in the Health Professionals Follow-Up Study (HPFS) who were free from CVD and cancer in 1998. Multivariable-adjusted Cox proportional-hazards models were used to estimate hazard ratios (HRs) and 95% CIs. Results: We documented 10 686 deaths including 2046 CVD deaths and 3091 cancer deaths in the NHS over 725 316 person-years of follow-up and 6490 deaths including 1872 CVD deaths and 1772 cancer deaths in the HPFS over 371 322 person-years of follow-up. Compared with participants whose indices remained stable, among those with the greatest increases in diet scores (highest quintile), the pooled multivariable-adjusted HRs for total mortality were 0.95 (95% CI, 0.90–1.00) for PDI, 0.90 (95% CI, 0.85–0.95) for healthful PDI, and 1.12 (95% CI, 1.07–1.18) for unhealthful PDI. Among participants with the greatest decrease (lowest quintile), the multivariable-adjusted HRs were 1.09 (95% CI, 1.04–1.15) for PDI, 1.10 (95% CI, 1.05–1.15) for healthful PDI, and 0.93 (95% CI, 0.88–0.98) for unhealthful PDI. For CVD mortality, the risk associated with a 10-point increase in each PDI was 7% lower (95% CI, 1–12%) for PDI, 9% lower (95% CI, 4–14%) for healthful PDI, and 8% higher (95% CI, 2–14%) for unhealthful PDI. There were no consistent associations between changes in plant-based diet indices and cancer mortality. Conclusions: Improving plant-based diet quality over a 12-year period was associated with a lower risk of total and CVD mortality, whereas increased consumption of an unhealthful plant-based diet was associated with a higher risk of total and CVD mortality.
Prospective Cohort Study Comparing Intravenous Busulfan Versus Total Body Irradiation in Cord Blood Transplantation
Authors: Baolin Tang, Xiaoyu Zhu, Changcheng Zheng, Huilan Liu, Siguo Hao, Dongping Huang, Dongjun Lin, Nainong LI, Sujun Gao, Xinquan Liang, Jianjun Li, Lulu Huang, Liangquan Geng, Kaiyang Ding, Xingbing Wang, Wen Yao, Kaidi Song, Xuhan Zhang, Xiang Wan, Lei Zhang, Juan Tong, Guangyu Sun, Zimin Sun
Journal: Blood (2018)
RAD001 (everolimus) down-regulates cyclin D3 and c-Myc and is particularly effective in the treatment of aggressive B-cell lymphomas
Authors: S. H. Kuo, C. H. Hsu, P. Y. Yeh, H. C. Hsu, M. Gao, H. J. Cheng, A. Cheng
Journal: Journal of Clinical Oncology (2006)

17573 Background: Aggressive B-cell lymphoma is recently found to be associated with constitutive activation of the PI3K/Akt pathway, and thereby is relatively resistant to apoptosis. Furthermore, activation of the PI3K/Akt signaling pathway can result in the upregulation of cyclin D3 and c-Myc through inhibition of the cap-independent RNA translation. Since mTOR is closely associated with the regulation of the translation process, and is a downstream mediator of the PI3K/Akt signalling pathway, this study aimed to examine if RAD001, an inhibitor of mTOR, can be effective in the treatment of aggressive B-cell lymphoma. Methods: Pfeiffer (diffuse large cell lymphoma), Ramos (EBV (−) Burkitt’s lymphoma), Raji (EBV (+) Burkitt’s lymphoma), and MC116 (EBV (−) undifferentiated lymphoma) cell lines were used in this study. Expression of pAkt, p70S6 kinase, pp70 S6 kinase, 4E-BP1, p4E-BP1, cyclin D3, and c-Myc was measured by immunoblotting. Results: Akt was constitutively activated in all four lymphoma cell lines. Downstream effectors of PI3/Akt signaling pathway, including p70S6 kinase and 4E-BP1, were also phosphorylated in these lymphoma cell lines. RAD001 downregulated p70S6 kinase and 4E-BP1, and the IC50s of growth suppression ranged from 5 to 50 nM, without significant difference between EBV (+) and EBV (−) cell lines. The IC50s of these lymphoma cell lines appeared to be much lower than those obtained from the carcinoma cell lines, suggesting that lymphomas may be particularly sensitive to growth inhibition by RAD001. RAD001 blocked cell cycle progression in G0/G1 phase in all four lymphoma cell lines while there was no significant increase in sub-G1 phases, suggesting that apoptosis was not the major mechanism of RAD001-induced growth inhibition. In addition, in parallel with the RAD001-induced growth inhibition, a dose-dependent down-regulation of the expression of cyclin D3 and c-Myc was demonstrated. Conclusions: The mechanism of action is at least partly due to downregulation of cyclin D3 and c-Myc, and subsequent G0/G1 block. Since overexpression of cyclin D3 and c-Myc is also closely associated with chemoresistance of aggressive B-cell lymphoma, RAD001 may be a useful adjunct in the treatment of this group of tumors. No significant financial relationships to disclose.
Transcriptional silencing of Chfr predicts clinical outcome to chemoradiotherapy in head and neck cancer
Authors: Nelofer Syed, Paul Smith, Alexandra Sullivan, Marlene Attard, Paul Farrell, Helen Wong, Marco Merlano, Gianmauro Numico, John A. Green, Milena Gasco, Tim Crook
Journal: Cancer Research (2005)

2159  Several genes encode proteins which function as mitotic stress checkpoints, including Chfr (checkpoint with forkhead associated and ring finger). Chfr is subject to methylation-dependent silencing in a number of human cancers. Here, we show that RNAi-dependent silencing of Chfr confers increased in vitro cellular sensitivity to cisplatin and irradiation, in addition to taxanes, whereas sensitivity to anthracyclines is unaffected. To investigate the potential clinical significance of this observation, we examined promoter methylation of Chfr in 79 cases of locally advanced head and neck squamous cell carcinomas (HNSCC) treated with chemoradiation. Using methylation specific PCR and bisulphite sequencing, we detected CpG methylation in the transcriptional regulatory elements of Chfr in 47/79 cases. Methylation of Chfr was also detectable in pre-malignant dysplasias, implying that methylation-dependent silencing is an early event in tumourigenesis in subset of HNSCC. Silencing of Chfr occurred irrespective of HPV and p53 status. Complete response (CR) to chemoradiotherapy was higher in cases with methylation of Chfr (p=
Effectiveness of seasonal influenza vaccine in preventing laboratory-confirmed influenza in primary care in the United Kingdom: 2014/15 end of season results
Authors: Richard Pebody, Fiona Warburton, Nick Andrews, Joanna Ellis, Beatrix von Wissmann, Chris Robertson, Ivelina Yonova, Simon Cottrell, Naomh Gallagher, Helen Green, Catherine Thompson, Monica Galiano, Diogo Marques, Rory Gunson, Arlene Reynolds, Catherine Moore, David Mullett, Sameera Pathirannehelage, Matthew Donati, Jillian Johnston, Simon de Lusignan, Jim McMenamin, Maria Zambon
Journal: Eurosurveillance (2015)

The 2014/15 influenza season in the United Kingdom (UK) was characterised by circulation of predominantly antigenically and genetically drifted influenza A(H3N2) and B viruses. A universal paediatric influenza vaccination programme using a quadrivalent live attenuated influenza vaccine (LAIV) has recently been introduced in the UK. This study aims to measure the end-of-season influenza vaccine effectiveness (VE), including for LAIV, using the test negative case-control design. The overall adjusted VE against all influenza was 34.3% (95% confidence interval (CI) 17.8 to 47.5); for A(H3N2) 29.3% (95% CI: 8.6 to 45.3) and for B 46.3% (95% CI: 13.9 to 66.5). For those aged under 18 years, influenza A(H3N2) LAIV VE was 35% (95% CI: -29.9 to 67.5), whereas for influenza B the LAIV VE was 100% (95% CI:17.0 to 100.0). Although the VE against influenza A(H3N2) infection was low, there was still evidence of significant protection, together with moderate, significant protection against drifted circulating influenza B viruses. LAIV provided non-significant positive protection against influenza A, with significant protection against B. Further work to assess the population impact of the vaccine programme across the UK is underway.
Cannabis based drugs: GPs should be able to prescribe to improve access, NICE says
Authors: Ingrid Torjesen
Journal: BMJ (2019)

GPs and other prescribers such as pharmacists and nurses should be able to take on prescribing of cannabis based medicinal products once it has been initiated by specialists in expert centres, the UK National Institute for Health and Care Excellence has proposed in draft guidance.1

Expanding prescribing as part of a shared care agreement, after specialists have assessed patients and initiated treatment with cannabis based products, would improve patients’ access to products, allow a more holistic approach to care, and may reduce costs to the NHS, says NICE.

The guideline was fast tracked after cannabis based products were reclassified last year to allow specialist doctors to prescribe them in exceptional cases where patients’ clinical needs could not be met by licensed drugs.1

The only licensed cannabis based drug that NICE recommends is nabilone as an add-on treatment for adults with nausea and vomiting induced by chemotherapy whose symptoms have not responded to conventional drugs. …
The Prospective Association Between Inflammation and Depressive Symptoms in Type 2 Diabetes Stratified by Sex
Authors: Calum D. Moulton, John C. Pickup, Anna S. Rokakis, Stephanie A. Amiel, Khalida Ismail, Daniel Stahl
Journal: Diabetes Care (2019)

OBJECTIVE We tested whether inflammation is associated with worsening depressive symptoms in type 2 diabetes and examined whether sex moderated this association. RESEARCH DESIGN AND METHODS In a prospective cohort study of people with newly diagnosed type 2 diabetes, we measured depressive symptoms over a 2-year follow-up using the Patient Health Questionnaire-9 (PHQ-9). The independent variable was a composite inflammation burden score at diagnosis of diabetes, derived from hs-CRP, white cell count, interleukin (IL)-1β, IL-1 receptor antagonist, monocyte chemotactic protein-1, and vascular endothelial growth factor concentrations. General linear models assessed 1) the association between overall inflammation burden and estimated marginal mean PHQ-9 score (ln transformed) at 2 years and 2) whether sex interacted with elevated inflammation burden (above-median score) in predicting change in PHQ-9 score. Models were adjusted for age, ethnicity, BMI, blood pressure, cholesterol, HbA1c, antidepressants, anti-inflammatory medications, and baseline ln PHQ-9 score. RESULTS Of 1,174 people with complete inflammation data, mean (SD) age was 56.7 (11.0) years and 46.1% were of nonwhite ethnicity and 44.1% female. After full adjustment, inflammation burden was not associated with worsening ln PHQ-9 score (P = 0.65). However, female sex interacted with elevated inflammation in predicting higher 2-year ln PHQ-9 score (β = 0.32, P = 0.005), showing that the difference by inflammation burden in females was 0.32 larger than in males. In post hoc comparisons, ln PHQ-9 score was higher in females than males with elevated inflammation (P = 0.003) but not with low inflammation (P = 0.34) burden. CONCLUSIONS In type 2 diabetes, female sex confers specific vulnerability to the effects of inflammation on depressive symptoms.
PTU-079 Over-age self referrals in the english bowel cancer screening programme – are they the worried well or the symptomatic needing something more?
Authors: CJ Chapman, A Field, RF Logan
Journal: Gut (2017)

Introduction  The English Bowel Cancer screening programme has been in operation in England since 2006. Subjects aged 60–74 and who are registered with an NHS general practice are invited to complete a guaiac faecal occult blood test (FOBt) every two years until they reach 75. People found to have abnormal tests are then referred to for further assessment, with most going on to have a colonoscopy.  Over the age of 75, individuals can ‘self-refer’ into the programme. The size of the population >75 is increasing, and is more health conscious. We were therefore interested in understanding the demographics of this group of individuals.  Method  The number of people aged 75 and over, who requested kits within the Eastern hub area of the BCSP, was interrogated. Data was analysed according to age, gender, positivity of the test, fitness for colonoscopy and cancers and adenomas detected.  Results  Between 2010 and 2015 over 30 000 tests were completed by subjects with ages ranging from 75% to 98. 54% of individuals were male compared to 49% in 60–74 age group. Numbers of people who self-refer are increasing annually but still represent less than 2% of all tests performed.  Positivity in the over 75’s was 3.3% compared to 2% in the 60–74 age range. Cancer detection rates were higher in these individuals than in the younger age groups (cancer: 16% vs 8.5%).  Conclusion  Whilst numbers of over age referrals are on the increase they remain a small proportion of the subject screened by the BCSP. As might be expected from an older population a higher cancer and adenoma detection rate was observed. If uptake continues to increase, it is likely to impact on the colonoscopy services in England.  Disclosure of Interest  None Declared
Genetic Heterogeneity of t(8;21)(q22;q22.1) Acute Myeloid Leukemia Revealed By High-Throughput Targeted Sequencing
Authors: Nikolaus Jahn, Mridul Agrawal, Anna Dolnik, Sibylle Cocciardi, Laura K. Schmalbrock, Tamara J. Blätte, Verena I. Gaidzik, Peter Paschka, Daniela Weber, Ekaterina Panina, Thomas Michael Schroeder, Mohammed Amen Wattad, Michael Pfreundschuh, Heinz A. Horst, Felicitas Thol, Michael Heuser, Arnold Ganser, Richard F. Schlenk, Hartmut Döhner, Lars Bullinger, Konstanze Dohner
Journal: Blood (2017)