tbuckley/cabot-search huggingface dataset:
Abstract P118: Gender Differences in Physical Activity Levels on Cardiovascular Events in Diabetes: The Strong Heart Study
Authors: Parmanand Singh, Zaid Almarzooq, Mary Roman, Richard Devereux
Journal: Circulation (2016)

Background: It has been previously shown that physical activity lowers the risk of incident diabetes in American Indians. However, in this population at high risk for cardiovascular (CV) events, it remains to be fully explored whether physical activity reduces CV death in subjects with diabetes and whether this effect is equal between genders. Objectives: To determine the inter-relationship between activity, diabetes, gender and CV death, we tested the hypotheses that, (i) activity lowers CV death in diabetes, and (ii) the CV benefit of activity is similar across genders. Methods: We examined the association between activity (leisure-time plus occupational) and CV death among 1,896 diabetic adults (mean age 56.9 ± 8) in phase I of Strong Heart Study (1989-1991. Of these, 1,254 were female (mean age 57.4 ± 8) and 642 were male (mean age 55.9 ± 8). Activity was measured as METS-hours per week on a validated survey. Regression models were used to assess for the prespecified associations and adjust for traditional CV risk factors. Kaplan-Meir analysis was used to plot survival based on activity. Results: After 14 years of follow-up (1989-1999), there were 222 CV deaths. Compared to diabetic subjects with minimal activity (quartile 1), those with higher activity levels had a lower risk of CV death (p=0.001, Fig 1A). Odds ratios were 0.60 (95% CI: 0.40-0.90; p=0.014), and 0.63 (0.41-0.95; p=0.027) for increasing activity (3rd and 4th quartiles), after adjustment for age and traditional CV risk factors. Moreover, in a subgroup analysis of female subjects with diabetes, increasing physical activity levels was significantly associated with less CV death compared to male subjects with diabetes (Fig. 1B), independent of conventional CV risk factors (p=0.003). Conclusion: In a large population study of American Indians, physical activity lowered CV death in subjects with diabetes, a finding most pronounced in females. Additional studies are needed to further investigate the pathophysiologic basis of the disparate gender response to activity.
Multi-centre clinical study of cell-free DNA mutations in benign and malignant lung lesions.
Authors: Yuancai Xie, Fenglei Yu, Xiaohua Li, Youhui Qian, Muyun Peng, Feiyue Xu, Dan Yu, Shixin Lu, Xiaonian Tu, Fengjun Cao, Xuanbin Wang, Xumei Yao, Fangsheng Cheng, Wenling Xie, Bing He, Chaoyu Liu, Jiankui He, Chuanbo Xu, Geng Tian
Journal: Journal of Clinical Oncology (2018)

e24036 Background: Cell-free circulating tumor DNA (ctDNA) for cancer detection drew significant clinical attention. Concordance of mutations in tumor tissue and ctDNA should be evaluated first. Methods: We designed andconducted a multi-center clinical trial at three (3) Tier A hospitals in China to recruit patients with occupying diseases of lung that will be treated by surgery. Patients with lung nodules or cancers of Stage I to III were eligible for inclusion. After informed consenting, samples were collected (10mL peripheral blood prior to and 10 slides of tissues during surgery) and analyzed by our proprietary Sec-Seq technique. Briefly, total cell-free DNA from plasma, genomic DNA from white blood cells and tumors were extracted; libraries constructed by custom probe hybridization; sequencing performed using NovaSeq instrument, and data analyzed by in-house bioinformatics pipeline. Results: In total, 146 patients with pulmonary space occupying lesions (111 malignant and 35 benign) pathologically diagnosed and surgically treated were included in this interim analysis. A panel of 104 genes covering 435 kb genomic regions was used. The average sequencing depth is ~35000 with ~1350 unique reads after deduplication. Detection limit for mutant allele frequency was set at 0.3% for ctDNA and 3% for tumor tissue. Among all the lung cancer patients, 94% were found to harbor at least one mutation in ctDNA or tumor tissue. When evaluating hotspots in driver genes, 46% mutations detected in tissue were also found in ctDNA. The concordance rate is 37%, 58%, 70%, and 100% for Stage I, II, III, and IV. Only two (2) Stage IV patients were enrolled accidentally due to the unavailability of pathological staging information. The most commonly mutated genes are TP53 (44%) and EGFR (35%). In the benign lesions (pneumonia and pulmonary tuberculosis), only 2 out of 35 patients (6%) had driver gene mutations in either ctDNA or tissue samples. A panel of seven (7) tumor biomarkers was also analyzed in these patients which detected only 40% of lung cancers. Conclusions: The analysis of driver gene mutations in ctDNA and tumor tissue DNA showed potentials of ctDNA in lung cancer detection and distinguishing benign from malignant lung diseases. Clinical trial information: NCT03081741.
Regulation of the oxidative processes as a possible mechanism of iron nanoparticles antitumor action.
Authors: Polina S. Kachesova, Irina A. Goroshinskaya, Vladimir B. Borodulin, Ludmila A. Nemashkalova, Anastasiya V. Chudilova, Oleg I. Kit
Journal: Journal of Clinical Oncology (2017)

e23160 Background: It has been shown that metal nanoparticles (NPs) can inhibit a tumor growth. Oxidative processes play important roles in tumor development and growth. The aim of this study was to determine parameters of oxidative stress in the blood of tumor-bearing animals depending on the antitumor effect of iron NPs (30-50 nm). Methods: Male rats with transplantable lymphosarcoma (LS) in the main group (n = 21) were treated with eight i.p. injections of iron NPs (total doses of 10 mg/kg bw), the control LS rats (n = 20) received saline i.p. The activity of catalase, superoxide dismutase (SOD), content of glutathione (GSH) and malondialdehyde (MDA) in the red blood cells (RBC) and ceruloplasmin oxidase activity (CP) and MDA content in blood plasma were measured. These parameters were analyzed in rats with complete tumor regression (n = 12) after NPs treated and in cases of tumor growth (n = 9). Results: In RBC of control group the level of GSH and catalase activity were increased compared to healthy rats by 24% and 14.3% (p &lt; 0.05), respectively. In spite of activation of the given antioxidant system components, the MDA content in RBC was increased by 45% (p &lt; 0.01) compared to normal values. In plasma of control group we observed an increase in MDA by 167.4% (p &lt; 0.01) and a decrease in CP by 36.8% (p &lt; 0.001). In the main group there was a decrease in blood MDA level and the antioxidant system reorganization. The degree of changes depended on the antitumor effect of NPs: rats with tumor growth showed a tendency to the decreasing MDA in RBC and normalization of plasma MDA; MDA in rats with LS regression was similar to normal values. In the main group the CP activity did not differ from the values in healthy rats. GSH increased in animals with tumor growth by 218.6% and in the animals with the effect - by 69% compared to normal values (p &lt; 0.01). SOD activity in the rats with LS growth increased by 42% and in the rats with LS regression it decreased by 30% (p &lt; 0.01). Conclusions: The data suggest the relationship between antitumor effect and modulating action on oxidative processes in LS rats treated by iron NPs. Iron NPs improved efficiency of antioxidant system in blood and contributed to suppression of oxidative stress associated with tumor growth.
GP at Hand opposes NHS England’s plan to cut funding for digital providers
Authors: Declan Murphy
Journal: BMJ (2018)

GP at Hand has opposed NHS England’s proposal to cut funding for “digital first” GP service providers that register patients from outside their geographical area, arguing that it would “strongly discourage innovation.”

The comments came in response to an NHS England consultation asking how payments to general practice might need to change to “fairly support” the rollout of digital technology.1 The consultation, which closed on 31 August, suggested that GP providers that registered patients from outside their catchment area could receive less money per patient than practices that offered a more complete service.

In a statement to The BMJ GP at Hand said that the proposed funding reductions were “unwarranted” and would “directly contradict public commitments to driving …
MET exon 14 mutations in advanced lung adenocarcinoma: Frequency and coexisting alterations.
Authors: Rossella Bruno, Cristiana Lupi, Lorenza Landi, Greta Alì, Elisa Sensi, Agnese Proietti, Riccardo Giannini, Vincenzo Condello, Maria Denaro, Mirella Giordano, Elisabetta Macerola, Anello Marcello Poma, Simona Nuti, Cristina Niccoli, Serena Pelliccioni, Marcello Tiseo, Federico Cappuzzo, Gabriella Fontanini
Journal: Journal of Clinical Oncology (2017)

e20656 Background: In lung cancer the evaluation of MET, a tyrosine kinase receptor involved in tumor growth and invasiveness, for copy number amplification and point mutations is relevant for prognosis and therapy. In lung adenocarcinoma (ADC) MET amplification is observed in 1-2% and MET mutations in 3-4% of cases. Mutations mainly occur in exon 14 (ex14), which encodes for the juxtamembrane negative regulatory domain, including splice site alterations and missense mutations within the exon.Commonly, MET ex14 alterations, in particular splice site ones, are mutually exclusive with other driver mutations, but co-occurrence with MET and MDM2 amplification and KRAS mutations was described. We evaluated METex14 mutation frequency and coexistence with additional driver alterations in a prospective cohort of Italian ADC patients. Methods: 315 ADC patients were tested (January-December 2016) for MET ex14 alterations by Sanger Sequencing on formalin-fixed paraffin-embedded tissues and cytological smears (tumor cells &gt; 40%). MET positive cases were screened also for other oncogenes, among which KRAS, BRAF and PIK3CA, using a MALDI-TOF platform, and for ROS1 translocations and MET amplification by FISH. Results: 16 patients (5%) were MET positive: 7 splice site mutations (43%) and 9 (57%) other alterations within ex14. Among splice site mutations 1 co-occurred with ROS1 translocation and 1 with MET amplification. Among other mutations we found 5 T1010I missense mutations: 3 co-occurring with G12D/G13C/Q61H KRAS, 1 with G469A BRAF and 1 with a MET intron 13 point mutation; 2 R988C mutations: 1 with G13C KRAS and 1 with G13C KRAS plus ROS1 translocation; 1 P1026S mutation and 1 frameshift deletion (p.A991del;R992fs*999), both with G12C KRAS. Conclusions: Splice site mutations cause MET activation by exon skipping and increase sensitivity to tyrosine-kinase inhibitors, whereas how other ex14 mutations affect MET function is not fully understood. In our cohort we found a high rate of METex14 mutations together with alterations in other oncogenes, mostly KRAS. The interaction of MET with cancer signaling pathways deserve further investigation in order to better define the role of ex14 mutations in the context of target therapy.
Triphenylphosphonium-modified mitochondria-targeted paclitaxel nanocrystals for overcoming multidrug resistance
Authors: Xue Han, Ruijuan Su, Xiuqing Huang, Yingli Wang, Xiao Kuang, Shuang Zhou, Hongzhuo Liu
Journal: Asian Journal of Pharmaceutical Sciences (2018)

Mitochondria are currently known as novel targets for treating cancer, especially for tumors displaying multidrug resistance (MDR). This present study aimed to develop a mitochondria-targeted delivery system by using triphenylphosphonium cation (TPP+)-conjugated Brij 98 as the functional stabilizer to modify paclitaxel (PTX) nanocrystals (NCs) against drug-resistant cancer cells. Evaluations were performed on 2D monolayer and 3D multicellular spheroids (MCs) of MCF-7 cells and MCF-7/ADR cells. In comparison with free PTX and the non-targeted PTX NCs, the targeted PTX NCs showed the strongest cytotoxicity against both 2D MCF-7 and MCF-7/ADR cells, which was correlated with decreased mitochondrial membrane potential. The targeted PTX NCs exhibited deeper penetration on MCF-7 MCs and more significant growth inhibition on both MCF-7 and MCF-7/ADR MCs. The proposed strategy indicated that the TPP+-modified NCs represent a potentially viable approach for targeted chemotherapeutic molecules to mitochondria. This strategy might provide promising therapeutic outcomes to overcome MDR.
A novel prognostic classifier for intrahepatic cholangiocarcinoma: Development and external and prospective validation studies.
Authors: Guang-Zhi Jin, Guan-Zhen Yu, Wen-Ming Cong
Journal: Journal of Clinical Oncology (2018)

e16102 Background: Predicting the prognosis for intrahepatic cholangiocarcinoma (ICC) is currently inadequate, and its prognostic value could be improved by the identification of suitable biomarkers. This study aimed to develop a novel prognostic classifier for patients with ICC after surgery. Methods: We screened tumour markers that over-expressed in ICC tissues using a proteomics approach. We narrowed down the tumour markers and developed prognostic classifiers based on clinical parameters and tumour markers using a Cox regression analyses from 519 patients (primary training cohort). We validated the predictive accuracy of this classifier in both the external validation cohort of 318 patients, and a prospective validation cohort of 178 patients. Results: We established classifiers based on serum CA199, serum alubumin, tumour size, tumour number, TNM, pyruvate kinase isozymes M1/M2 for overall survival (OS) and tumour size, tumour number, TNM, triosephosphate isomerise for time to recurrence (TTR). Classifiers were able to classify patients into low risk and high risk groups based on risk score. In primary training cohort, compared with patients with low risk scores, patients with high risk scores had shorter OS (p < 0.0001), and TTR (p < 0.0001). The equivalent findings were observed in the external validation cohort for OS (p < 0.0001) and TTR (p < 0.0001) and in the prospective validation cohort for OS (p < 0.0001) and TTR (p < 0.0001). ROC analyses also revealed that accuracy of the classifier was superior to that of any other independent prognostic factor for both OS and TTR in three cohorts. Two nomograms for predicts death or recurrence probability of ICC patient’s were developed, respectively. Conclusions: Our prognostic classifiers are promising predictors for survival or recurrence in ICC patients after surgical resection.
Outcomes of chemoradiotherapy neoadjuvant for esophagus cancer in Brazil.
Authors: Juliano Ce Coelho, Gustavo Vasconcelos Alves, Marcio Debiasi, Andressa Azeredo, Luiza Weis, Patricia Marks, Gabriel Sartori Pacini, Rafael Dias de Moraes, Mariane Branco, Juliana Grasselli, Rafael Zimmermann de Souza, Carolina Muller, Fábio Klamt, Gilberto Schwartsmann, Sergio Jobim Azevedo
Journal: Journal of Clinical Oncology (2016)

e15568 Background: The neoadjuvant chemoradiotherapy in the treatment of patients with esophageal or esophagogastric-junction cancer is established as the best treatment to surgical patients. This therapy improves long-term survival, but patients from Brazil are underrepresented in clinical trials and data on real life outcomes are lacking. Methods: From January 2012 to December 2015, all patients treated with neoadjuvant carboplatin/paclitaxel with concurrent radiotherapy at two University Hospitals in South of Brazil were identified by electronic database. Medical records were reviewed and demographic data, tumor and treatment characteristics were collected. OS and PFS were estimated by Kaplan-Meier curves. Statistical analysis was performed with SPSS 22. Results: Fifty-three patients were collected for this analysis. Patient characteristics revealed a mean age of 59.25 ± 9.03 years, 74% male, a positive smoking history in 91%, a positive history of alcohol consumption in 60%, ECOG performance status of 0-1 in 94%, loss of more than 10% of body weight in 43% and stage I, II and III in 8%, 48% and 44%, respectively. Forty-four patients (83%) had squamous cell, 8 (15%) adenocarcinoma and 1 (2%) other histology. Thirty-eight patients (72%) were submitted to surgery, 17 (32%) achieved a complete response (CR) and 12 (22%) a partial response. twenty-two patients (41%) have died with an OS of 24.46 months. In multivariable analysis, histology (adenocarcinoma) was independently associated with worst prognostic in OS, HR of 4.21 (95% IC, 1.07 to 16.82). Conclusions: To our knowledge, this is the first report of patients from Brazil treated with concurrent chemoradiation as a neoadjuvant strategy. However, the pathological CR rate and the findings of patients with squamous histology have a better prognosis is consistent with previous studies. Clearly the population in this study is different from CROSS trial. In our population, most patients has squamous cell cancer, over 90% are smokers and most of them show considerable use of alcohol. Even using the same inclusion criteria of CROSS trial, we had worse outcomes in terms of OS compared with the original study. More patients from Latin America should be included in large esophageal cancer studies.
Colorectal cancer sidedeness and its association with survival and tumor biology in operable patients.
Authors: Joseph Chan, Connie Irene Diakos, David Lok Hang Chan, Alexander Engel, Nick Pavlakis, Anthony J Gill, Stephen John Clarke
Journal: Journal of Clinical Oncology (2017)

e15110 Background: Recent data from patients with metastatic disease enrolled on trials of systemic chemotherapy have suggested that the sidedness of colorectal cancer(CRC) is associated with survival differences with better response seen with right sided tumours. The biological explanation for these differences has not been confirmed and there have been concerns that the differences relate predominantly to patient selection in clinical trial design. This study examines survival differences by side in sequential patients with newly diagnosed, operable CRC. Methods: Data for 3281 consecutive patients from the Northern Sydney Local Health District from 1998 to 2012 who underwent surgical resection of their CRC were retrospectively collected. Survival was assessed by log-rank test, association between sidedness and tumor biology by chi squared analysis and multivariate analysis by Cox regression. Results: Overall, there was a survival difference between left and right sided colon cancer and rectal cancer (p &lt; 0.022). However, stage for stage, only stage 3 patients demonstrated a survival difference with right sided colon cancers (median OS 67.1 months, p = 0.009) but not left sided colon cancers (70.4 months p = 0.132) having inferior survival compared to rectal cancers (83.2 months). In terms of biological associations, right sided tumors were more associated with advanced age (p &lt; 0.001), female gender (p &lt; 0.001), more advanced T and m stage (p &lt; 0.001), high grade (p &lt; 0.001), thin walled vessel invasion (p &lt; 0.001), discontinuous extratumoral nodules (DETN) (p &lt; 0.001), peritumoral lymphocytic response (p = 0.002), BRAFV600E mutation (p &lt; 0.001), mismatch repair deficiency (p &lt; 0.001), low lymphocyte-to-monocyte ratio (LMR) (p &lt; 0.001) and high neutrophil-to-lymphocyte ratio (p &lt; 0.001). In multivariate analysis, age (p &lt; 0.001), T stage and m stage (p = 0.001), grade (p = 0.002), extra venous permeation(p = 0.034), DETN (p = 0.09), MMR-BRAF combined status (p = 0.001) and LMR (p &lt; 0.001) remained independently significant. Conclusions: There appears to be a difference in survival related to tumor site only in stage 3 CRC. Differences in tumor biology could account for these findings.
Differences in biomarker testing and first-line treatment outcome in chronic lymphocytic leukemia patients in the US and EU5.
Authors: Chitra Karki, Emily Zacherle, Samantha Martino, Valerie Wriede, Bijal Shah-Manek
Journal: Journal of Clinical Oncology (2018)

e19512 Background: Studies have demonstrated that biomarker testing in chronic lymphocytic leukemia (CLL) is a major determinant of diagnosis and response to therapy. The objective of this study was to evaluate biomarker testing rates and response to 1st line (1L) therapy between CLL patients in the US and 5 European countries (EU5) using real world data from Ipsos’ Global Oncology Monitor. Methods: A multi-center retrospective medical chart review of CLL patients in the US (n = 2,139) and EU5 (France, Germany, Italy, Spain, UK; n = 1,232) was conducted between 7/2016 and 6/2017. Physicians randomly selected patient charts currently on an anti-cancer regimen and extracted data on patient demographics, biomarker status, and 1L therapy response. Chi-square tests and t-tests were used for statistical comparisons. Results: There were no significant differences in mean age or gender between patients from US and EU5 (p > 0.05). Diabetes, renal function disorder, cardiovascular disease, and hypertension were more common among US vs. EU5 patients (p < 0.05 for all). More EU5 patients (6%) had lymphoid type cancer (US 4%; p = 0.01), but there were no differences in the proportion of patients with mixed cell, B-cell, or T-cell type cancer between groups (p > 0.05 for all). There were no differences in testing rate (US 94% vs. EU5 93%) or positivity for CD-20 (92% vs. 93%; p > 0.05 for both). More patients were tested (80% vs. 68%) and tested positive (42% vs. 22%) for CD-38 in the EU5 (p < 0.0001 for both). Among CD-20 and CD-38+ patients, there was no difference in complete response (CR) or partial response (PR) after 1st-line therapy between the US and EU5 (p > 0.05 for all). However, among CD-20+ patients more patients in the EU5 achieved very good PR (28% vs. 23%), while more US patients had stable disease (8% vs. 4%), local recurrence (3% vs. < 1%), and distant progression (6% vs. 3%; p < 0.05 for all). These differences were not evident between CD38+ patient groups. Conclusions: While biomarker testing had no apparent impact on treatment response, the current study suggests that US patients have more severe disease which may potentially explain why first-line therapy outcomes were worse for CLL patients in the US vs. EU5.
PTMD: A Database of Human Disease-Associated Post-Translational Modifications
Authors: Haodong Xu, Yongbo Wang, Shaofeng Lin, Wankun Deng, Di Peng, Qinghua Cui, Yu Xue
Journal: Genomics Proteomics & Bioinformatics (2018)

Abstract Various posttranslational modifications (PTMs) participate in nearly all aspects of biological processes by regulating protein functions, and aberrant states of PTMs are frequently implicated in human diseases. Therefore, an integral resource of PTM–disease associations (PDAs) would be a great help for both academic research and clinical use. In this work, we reported PTMD, a well-curated database containing PTMs that are associated with human diseases. We manually collected 1950 known PDAs in 749 proteins for 23 types of PTMs and 275 types of diseases from the literature. Database analyses show that phosphorylation has the largest number of disease associations, whereas neurologic diseases have the largest number of PTM associations. We classified all known PDAs into six classes according to the PTM status in diseases and demonstrated that the upregulation and presence of PTM events account for a predominant proportion of disease-associated PTM events. By reconstructing a disease–gene network, we observed that breast cancers have the largest number of associated PTMs and AKT1 has the largest number of PTMs connected to diseases. Finally, the PTMD database was developed with detailed annotations and can be a useful resource for further analyzing the relations between PTMs and human diseases. PTMD is freely accessible at http://ptmd.biocuckoo.org.