tbuckley/cabot-search huggingface dataset:
Trends in the incidence and survival of ovarian cancer: An analysis of the SEER database.
Authors: Rand Ladkany, Alejandro Marinos, Otavio Pereira-Rodrigues, Leila Khaddour, Daniel Isaac, Siddhartha Yadav, Dana Zakalik
Journal: Journal of Clinical Oncology (2015)

e16587 Background: Ovarian cancer is the leading cause of gynecologic cancer related deaths as well as the fifth overall cause of cancer deaths among American women. The vast majority of cases are diagnosed at an advanced stage, for which the 5-year survival rate is less than 30%. Methods: Data obtained from The National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) Program was reviewed. Adult women diagnosed with ovarian cancer between the years of 2000 and 2011 were included. The analysis focused on histologic type, histologic grade, disease stage and cause specific survival. The patients were stratified by age into three groups: patients 18 to 44 years old (Group A), patients 45 to 74 years old (Group B) and patients 75 years old and older (Group C). Results: A histologic diagnosis was available for 57 759 patients. The mean age of diagnosis was 60.7 years, with the majority of patients (67.4%) being in group B. Eighty five percent of the subjects were Caucasian. Epithelial tumors comprised 91.8% of all the cases and were the most prevalent type in all age groups. Germ cell tumors were more frequent in group A (14.0%) compared to groups B and C (0.3% and 0.1% respectively). Overall, most of the patients were diagnosed at stage III (34.5%); however there was a difference between younger and older subjects in this regard. Fifty three percent of patients in group A were diagnosed at stage I or II while 64.6% of subjects in group C were diagnosed at stage III or IV. Lastly, the 5-year cause specific survival was 75% in group A, 52% in group B and 27% in group C (p < 0.001). Conclusions: This study demonstrated that women in the younger age group were generally diagnosed at an earlier stage, which may account for the better survival compared to older patients who are diagnosed at a later stage. Although the current data does not directly address the reason for earlier diagnosis in younger patients, we can hypothesize that one of the related factors is a close gynecological follow up in women of childbearing age.
Target Site Delivery and Residence of Nanomedicines: Application of Quantitative Systems Pharmacology
Authors: Jessie L.-S. Au, Roberto A. Abbiati, M. Guillaume Wientjes, Ze Lu
Journal: Pharmacological Reviews (2019)

Quantitative systems pharmacology (QSP), an emerging field that entails using modeling and computation to interpret, interrogate, and integrate drug effects spanning from the molecule to the whole organism to forecast treatment outcomes, is expected to enhance the efficiency of drug development. Since late 2017, the U.S. Food and Drug Administration has advocated the use of an analogous approach of model-informed drug development. This review focuses on issues pertaining to nanosized medicines (NP) and the potential utility of QSP to determine NP delivery and residence at extracellular or intracellular targets in vivo. The kinetic processes governing NP disposition and transport, interactions with biologic matrix components, binding and internalization in cells, and intracellular trafficking are determined, sometimes jointly, by NP properties (e.g., dimension, materials, surface charge and modifications, shape, and geometry) and target tissue properties (e.g., perfusion status, vessel pore size and wall thickness, vessel and cell density, composition of extracellular matrix, and void volume fraction). These various determinants, together with the heterogeneous tissue structures and microenvironment factors in solid tumors, lead to environment-, spatial-, and time-dependent changes in NP concentrations that are difficult to predict. Adding to the complexity is the recent discovery that NP surface-coating protein corona, whose composition depends on NP properties and which undergoes continuous evolution with time and local protein environments, is yet another unpredictable variable. Examples are provided to demonstrate the potential utility of QSP-based multiscale modeling to capture the physicochemical and biologic processes in equations to enable computational studies of the key kinetic processes in cancer treatments.
PDLIM2 Is a Marker of Adhesion and β-Catenin Activity in Triple-Negative Breast Cancer
Authors: Orla T. Cox, Shelley J. Edmunds, Katja Simon-Keller, Bo Li, Bruce Moran, Niamh E. Buckley, Milan Bustamante-Garrido, Nollaig Healy, Ciara H. O'Flanagan, William M. Gallagher, Richard D. Kennedy, René Bernards, Carlos Caldas, Suet-Feung Chin, Alexander Marx, Rosemary O'Connor
Journal: Cancer Research (2019)

Abstract The PDLIM2 protein regulates stability of transcription factors including NF-κB and STATs in epithelial and hemopoietic cells. PDLIM2 is strongly expressed in certain cancer cell lines that exhibit an epithelial-to-mesenchymal phenotype, and its suppression is sufficient to reverse this phenotype. PDLIM2 supports the epithelial polarity of nontransformed breast cells, suggesting distinct roles in tumor suppression and oncogenesis. To better understand its overall function, we investigated PDLIM2 expression and activity in breast cancer. PDLIM2 protein was present in 60% of tumors diagnosed as triple-negative breast cancer (TNBC), and only 20% of other breast cancer subtypes. High PDLIM2 expression in TNBC was positively correlated with adhesion signaling and β-catenin activity. Interestingly, PDLIM2 was restricted to the cytoplasm/membrane of TNBC cells and excluded from the nucleus. In breast cell lines, PDLIM2 retention in the cytoplasm was controlled by cell adhesion, and translocation to the nucleus was stimulated by insulin-like growth factor-1 or TGFβ. Cytoplasmic PDLIM2 was associated with active β-catenin and ectopic expression of PDLIM2 was sufficient to increase β-catenin levels and its transcriptional activity in reporter assays. Suppression of PDLIM2 inhibited tumor growth in vivo, whereas overexpression of PDLIM2 disrupted growth in 3D cultures. These results suggest that PDLIM2 may serve as a predictive biomarker for a large subset of TNBC whose phenotype depends on adhesion-regulated β-catenin activity and which may be amenable to therapies that target these pathways. Significance: This study shows that PDLIM2 expression defines a subset of triple-negative breast cancer that may benefit from targeting the β-catenin and adhesion signaling pathways.
Abstract P054: Associations Between Lifestyle Behaviors and Body Composition in 9 -11 Year Old New Zealand Children: The Moderating Effect of Parental Resilience
Authors: Lee Stoner, Rebecca Harding, Jillian Hszard, Kim Meredith-Jones, Pouya Saedi, Paula Skidmore
Journal: Circulation (2019)

Introduction: Obesity prevalence continues to rise for all age groups, particularly in those experiencing adversity or hardship. However, not all those experiencing adversity are obese. Previous research has focused on whether resilience in adults is associated with a healthy body composition, through increased ability to make healthier lifestyle choices. However, there is no research on how parental resilience relates to the lifestyle choices and body composition of their children. Hypothesis: Higher parental resilience is associated with better lifestyle (moderate to vigorous physical activity (MVPA), sedentary time, sleep duration, fruit &amp; vegetable consumption) choices and healthier body composition. Methods: This cross-sectional study recruited 408 children (9.7 [SD:0.69] y, 50% F) and their primary caregiver (41 [SD: 5.5] y, 84% F) from Otago, New Zealand. Three dependant variables were calculated: body mass index z-score (zBMI) using WHO criteria, fat mass index (FMI, kg/m 2 ) using bio-impedance analysis (BIA), and central adiposity (waist circumference, WC, cm). The four independent variables were: time (hours) spent asleep, sedentary or in MVPA using accelerometery, and fruit and vegetable dietary pattern derived from a food frequency questionnaire. Parental resilience was measured using the 10 item Conner-Davidson questionnaire. Associations between children’s lifestyle behaviours and body composition were examined using mixed effects regression models, with school as a random effect. Models were adjusted for child age, sex, ethnicity, level of deprivation, and parent age and sex. To explore the moderation effects of resiliency an interaction term was included, where resilience was split into low and high resilience by the median. Results: For the fully adjusted models, MVPA was not significantly associated with zBMI (p=0.760), FMI (p=0.984) or WC (p=0.785), nor were these relationships moderated by resiliency. Sedentary time was not associated with zBMI (p=0.447), FMI (p=0.210) or WC (p=0.380). However, resiliency moderated the association between sedentary time and WC (P=0.048), with a negative association for low resiliency (ß=-0.2, 95%CI: -1.1, 0.7), and positive association for high resiliency (ß=-1.2, 95%CI: -0.1, 2.5). Sleep duration was negatively associated with zBMI (ß=-0.1, 95%CI: -0.31, -0.0), FMI (ß=-0.3, 95%CI: -0.6, -0.1) and WC (ß=-1.1, 95%CI: =2.0, -1.6); resiliency did not moderate these relationships. Higher fruit and vegetable consumption was not associated with zBMI, but was positively associated with FMI (ß=0.2, 95%CI: 0.1, 0.3) and WC (ß=0.9, 95%CI: 0.5, 1.4); resiliency was not a significant moderator of these relationships. Conclusions: Parental resilience moderated the relationship between sedentary time and WC, with a positive relationship between sedentary time and WC for the high resiliency group.
Next Generation Sequencing (NGS) in metastatic castration resistant prostate cancer (mCRPC) to identify targets for individualized treatment: Is it feasible in daily routine?
Authors: Axel Heidenreich, David A. Pfister, Margarete Odenthal, Tim Nestler, Reinhard Büttner
Journal: Journal of Clinical Oncology (2019)

194 Background: Systemic of mCRPC consists of various approaches such as docetaxel, abiraterone, enzalutamide, Radium-223 and cabazitaxel. If all treatment options are exhausted, molecular profiling of biopsies from progressive metastases might enable an individualized approach with targeted therapies. It was the purpose of our study to examine (1) the feasibility of NGS in daily routine, (2) the frequency of treatable mutations and (3) the therapeutic outcome. Methods: From 1/2016 to 12/2017, 214 patients with mCRPC were treated; 52 pts progressed after exposure to all approved systemic therapies. All men underwent biopsies of the progressing lesions to perform mutational analysis via NGS using 9 Multiplex PCR amplicons (AR, ATM, BRCA1/2, CTNNB1, DLL3, PIK3CA, PTEN, RAD51C, TP53) which generation was done with a GeneRead DNAseq Custom Panel V2 (Qiagen). Creation of the library was done with the use of GeneRead DNA Library I Core, GeneRead DNA I Amp Kits and NEXTflex-96 DNA Barcode Adapter. Results: Following lesions were biopsied n = 8 (15.4%) liver, N = 4 (7.7%) lung, n = 4 (7.7%) bone, n = 36 (69.2%) lymph node. Sufficient material was received in all cases. 31 (59.7%) demonstrated wild type in all amplicons vorhanden, n = 21 (40.3%) demonstrated at least 1 potentially treatable mutation: BRCA1/2 or ATM n = 11, AR n = 7, DLL3 n = 3, p53 n = 9, Rad51C n = 4, CTNNB1 n = 4, PTEN/PIK3CA n = 4. Results were discussed in our molecular and clincical phase-I tumor board. Median overall survival oft he pateint cohort is 18.5 (6-34) months. Conclusions: NGS analysis of biopsy samples from progressing metastatic sites is feasible in mCRPC presuming an interdisciplinary setting in the diagnostic and therapy decision making process. NGS results in the identification of treatable mutations in more than one third of patients.
Network models can help focus research on the role of culture and context in psychopathology, but don't discount latent variable models
Authors: Nuwan Jayawickreme, Andrew Rasmussen, Alison Karasz, Jay Verkuilen, Eranda Jayawickreme
Journal: Behavioral and Brain Sciences (2019)

Abstract Borsboom et al. correctly note that the use of latent variable models in cross-cultural research has resulted in a futile search for universal, biological causes of psychopathology; however, this is not an inevitable outcome of such models. While network analytic approaches require further development, network models have the potential to better elucidate the role of cultural and contextual variables related to psychopathology.
Hepatitis E virus in blood donors in England, 2016 to 2017: from selective to universal screening
Authors: Heli Harvala, Patricia E Hewitt, Claire Reynolds, Callum Pearson, Becky Haywood, Kate I Tettmar, Ines Ushiro-Lumb, Susan R Brailsford, Richard Tedder, Samreen Ijaz
Journal: Eurosurveillance (2019)

IntroductionHepatitis E virus (HEV), the most common cause of acute hepatitis in many European countries, is transmitted through consumption of processed pork but also via blood transfusion and transplantation. HEV infection can become persistent in immunocompromised individuals.AimWe aimed to determine the incidence and epidemiology of HEV infection in English blood donors since the introduction of donation screening in 2016.MethodsBetween March 2016 and December 2017, 1,838,747 blood donations were screened for HEV RNA. Donations containing HEV RNA were further tested for serological markers, RNA quantification and viral phylogeny. Demographics, travel and diet history were analysed for all infected donors.ResultsWe identified 480 HEV RNA-positive blood donations during the 22-month period, most (319/480; 66%) donors were seronegative. Viral loads ranged from 1 to 3,230,000 IU/ml. All sequences belonged to genotype 3, except one which likely represents a new genotype. Most viraemic donors were over 45 years of age (279/480; 58%), donors aged between 17 and 24 years had a seven-times higher incidence of HEV infection than other donors between March and June 2016 (1:544 donations vs 1:3,830). HEV-infected blood donors were evenly distributed throughout England. Screening prevented 480 HEV RNA-positive blood donations from reaching clinical supply.ConclusionHEV screening of blood donations is a vital step in order to provide safer blood for all recipients, but especially for the immunosuppressed. The unusually high rates of HEV infection in young blood donors may provide some insight into specific risks associated with HEV infection in England.
Abstract P053: The Frequency of High Glycemic Load Meals is Predictive of Cardiovascular Risk Factors in Children at Risk for Obesity After 2 Years
Authors: Karine Suissa, Andrea Benedetti, Mélanie Henderson, Katherine Gray-Donald, Gilles Paradis
Journal: Circulation (2019)

Introduction: Consuming a daily diet of high glycemic load (GL) carbohydrates has potential long-term effects on obesity and cardiovascular health. However, it is possible that the GL of certain meals (breakfast, lunch and supper) have different effects. Few studies have examined the effect of meal-specific GL and frequency of high GL meals on adiposity and cardiovascular health in children. We hypothesized that the number of high GL meals per day, and secondarily, the meal-specific GL, would predict cardiovascular risk factors in children after two years of follow-up. Methods: We used data from the QUALITY cohort which recruited 630 children, ages 8-10 years at baseline with at least one obese parent. Three separate 24-hour dietary recalls were administered by a dietitian at baseline and individual meal-specific GL scores were calculated using the International table of GI. CV risk factors measured at 2 years of follow-up included continuous values of BMI z-score, percent fat mass, triglycerides, LDL and HDL cholesterol, and systolic (SBP) and diastolic (DBP) blood pressure obtained through direct measurement (blood pressure, blood lipids, anthropometrics) or questionnaires (socio-economic characteristics). Linear regressions between meal-specific GL categorized as high ( 2 33) vs. low (&lt;33) and CV risk factors were estimated, adjusting for important confounders, including underreporting, as well as anthropometric, socio-economic and dietary factors. Secondary analysis consisted of linear regression with number of high GL meals as an ordinal exposure variable. Results: Mean age at baseline was 9.6 years, with 33% of children overweight or obese. Breakfast, lunch and supper glycemic load were positively associated with each other. A higher number of high GL meals was positively associated with BMI z-score (β=0.18, 95%CI: 0.06, 0.30), percent fat mass (β=1.74, 95%CI: 0.52, 2.96) and triglycerides (β=0.08, 95%CI: 0.03, 0.14) and negatively associated with HDL (β=-0.04, 95%CI: -0.07, -0.01). Our secondary analysis revealed that High breakfast GL was positively associated with increased triglycerides (β=0.14, 95%CI: 0.05, 0.23) after 2 years but not adiposity, HDL, LDL and blood pressure. High GL lunch (β=0.27, 95%CI: 0.08, 0.46) and supper (β=0.22, 95%CI: 0.02, 0.41) were associated with higher BMI z-score after 2 years. Conclusion: In conclusion, consuming more than one high GL meal per day is associated with greater BMI and unhealthy lipid profile after 2 years.
Patient-reported psychosocial distress in adolescents and young adults with germ cell tumors.
Authors: Maryam Soleimani, Cheryl Ho, Christian K. Kollmannsberger, Alan Bates, Bonnie Leung
Journal: Journal of Clinical Oncology (2019)

521 Background: Germ cell tumours are the most common cancer of male adolescents and young adults (AYA, age 18-39). Men in this age group have been healthy much of their lives, and are at a stage of personal and professional growth, consequently a diagnosis of cancer can cause significant psychosocial distress. We evaluated patient reported psychosocial distress and hypothesized that AYA compared to older patients experienced more anxiety and distress in emotional, practical and physical domains. Methods: All patients referred to BC Cancer complete the Psychosocial Screen for Cancer (PSSCAN-R) at first consultation. This is a validated screening questionnaire for distress. Components include a screen for subclinical/clinical symptoms of depression and anxiety and the Canadian Problem Checklist (CPC) with 6 domains of concern: emotional, informational, practical, spiritual, social/family and physical. Results: Data was collected for 349 patients from 2011-2015. Baseline characteristics: 227 (65%) AYA, median age 33 (range 18-83), 41 (11%) metastatic disease at diagnosis. The top 3 AYA concerns were work/school (38.3%), financial (34.8%), frustration and anger (26%). AYA patients scored positive for subclinical/clinical anxiety more commonly than their older counterparts (39.4% vs. 27.9%, p = 0.028). AYA patients with subclinical/clinical anxiety symptoms experienced more fears and worries (41.5%), concerns regarding work/school (38%), lack of understanding of their disease (37.9%), finances (35.3%) and frustration and anger (26.3%) than AYA patients who do not express anxiety symptoms. Conclusions: The results of this study indicate that AYA with testicular cancer have unique needs and experience significantly more self-reported anxiety symptoms with emotional, informational, and practical concerns. Programs tailored to address needs of AYA patients may help reduce anxiety and improve the cancer experience. The results of this study are valuable to stakeholders for allocation of resources to address psychosocial parameters of distress in this patient group.
Association of Tramadol With All-Cause Mortality Among Patients With Osteoarthritis
Authors: Chao Zeng, Maureen Dubreuil, Marc R. LaRochelle, Na Lu, Jie Wei, Hyon K. Choi, Guanghua Lei, Yuqing Zhang
Journal: JAMA (2019)

<h3>Importance</h3> An American Academy of Orthopaedic Surgeons guideline recommends tramadol for patients with knee osteoarthritis, and an American College of Rheumatology guideline conditionally recommends tramadol as first-line therapy for patients with knee osteoarthritis, along with nonsteroidal anti-inflammatory drugs. <h3>Objective</h3> To examine the association of tramadol prescription with all-cause mortality among patients with osteoarthritis. <h3>Design, Setting, and Participants</h3> Sequential, propensity score–matched cohort study at a general practice in the United Kingdom. Individuals aged at least 50 years with a diagnosis of osteoarthritis in the Health Improvement Network database from January 2000 to December 2015, with follow-up to December 2016. <h3>Exposures</h3> Initial prescription of tramadol (n = 44 451), naproxen (n = 12 397), diclofenac (n = 6512), celecoxib (n = 5674), etoricoxib (n = 2946), or codeine (n = 16 922). <h3>Main Outcomes and Measures</h3> All-cause mortality within 1 year after initial tramadol prescription, compared with 5 other pain relief medications. <h3>Results</h3> After propensity score matching, 88 902 patients were included (mean [SD] age, 70.1 [9.5] years; 61.2% were women). During the 1-year follow-up, 278 deaths (23.5/1000 person-years) occurred in the tramadol cohort and 164 (13.8/1000 person-years) occurred in the naproxen cohort (rate difference, 9.7 deaths/1000 person-years [95% CI, 6.3-13.2]; hazard ratio [HR], 1.71 [95% CI, 1.41-2.07]), and mortality was higher for tramadol compared with diclofenac (36.2/1000 vs 19.2/1000 person-years; HR, 1.88 [95% CI, 1.51-2.35]). Tramadol was also associated with a higher all-cause mortality rate compared with celecoxib (31.2/1000 vs 18.4/1000 person-years; HR, 1.70 [95% CI, 1.33-2.17]) and etoricoxib (25.7/1000 vs 12.8/1000 person-years; HR, 2.04 [95% CI, 1.37-3.03]). No statistically significant difference in all-cause mortality was observed between tramadol and codeine (32.2/1000 vs 34.6/1000 person-years; HR, 0.94 [95% CI, 0.83-1.05]). <h3>Conclusions and Relevance</h3> Among patients aged 50 years and older with osteoarthritis, initial prescription of tramadol was associated with a significantly higher rate of mortality over 1 year of follow-up compared with commonly prescribed nonsteroidal anti-inflammatory drugs, but not compared with codeine. However, these findings may be susceptible to confounding by indication, and further research is needed to determine if this association is causal.