tbuckley/cabot-search huggingface dataset:
The Addition of Bevacizumab to Oxaliplatin-Based Chemotherapy: Impact Upon Hepatic Sinusoidal Injury and Thrombocytopenia
Authors: Michael J Overman, Renata Ferrarotto, Kanwal Raghav, Binsah George, Wei Qiao, Karime K Machado, Leonard B Saltz, Thibault Mazard, J N Vauthey, Paulo M Hoff, Brian Hobbs, Evelyn M Loyer, Scott Kopetz
Journal: JNCI Journal of the National Cancer Institute (2017)

Oxaliplatin-based chemotherapy can cause hepatic sinusoidal injury (HSI), portal hypertension, and splenic sequestration of platelets. Evidence suggests that bevacizumab may protect against HSI.Two cohorts of metastatic colorectal cancer (CRC) were analyzed: a nonrandomized exploratory cohort of 184 patients treated at a single institution from 2003 to 2010 and a confirmatory cohort of 200 patients from a multi-institutional randomized trial (NO16966). All patients were treated with frontline fluoropyrimidine and oxaliplatin with or without bevacizumab. Changes in splenic volumes and platelet counts were compared by treatment, two-sided log-rank test.In the exploratory cohort, the bevacizumab-treated patients (n = 138) compared with the nonbevacizumab-treated patients (n = 46) demonstrated a longer median time to splenic enlargement (≥30%, P = .02) and reduced rate of thrombocytopenia (<150 000/mm3, P = .04). In the confirmatory cohort (106 bevacizumab arm and 94 placebo arm), the median time to a spleen enlargement of 30% or more was 7.6 vs 5.4 (P = .01), and six-month cumulative incidence of thrombocytopenia (platelets < 100 000/mm3) was 19% vs 51% (P < .001) for bevacizumab compared with placebo. The development of an increasing spleen size was associated with the risk of either grade 1 or grade 2 thrombocytopenia (P < .001). The cumulative rate of grade 1 or grade 2 thrombocytopenia was statistically less in the bevacizumab arm, with six-month grade 2 thrombocytopenia rates of 4% vs 23% (P < .001). Patients with a large spleen prior to chemotherapy initiation appeared to be at highest risk of this toxicity.In metastatic CRC, the addition of bevacizumab to oxaliplatin-based chemotherapy reduces the frequency of splenic enlargement and the rate of thrombocytopenia.
Pooled RCTs: Reanalysis accounting for screening intensity suggests that screening reduces prostate cancer mortality
Authors: Martin R. Stockler
Journal: Annals of Internal Medicine (2018)

ACP Journal Club16 January 2018Pooled RCTs: Reanalysis accounting for screening intensity suggests that screening reduces prostate cancer mortalityMartin R. Stockler, MBBS, MSc, FRACPMartin R. Stockler, MBBS, MSc, FRACPUniversity of Sydney, Sydney, New South Wales, Australia (M.R.S.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/ACPJC-2018-168-2-005 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Source CitationTsodikov A, Gulati R, Heijnsdijk EAM, et al. Reconciling the effects of screening on prostate cancer mortality in the ERSPC and PLCO Trials. Ann Intern Med. 2017;167:449-55. https://pubmed.ncbi.nlm.nih.gov/28869989Clinical Impact RatingsGIM/FP/GP: Geriatrics: Oncology: Reference1 US Preventive Services Task Force. Prostate Cancer Screening Draft Recommendations. April 2017. https://screeningforprostatecancer.org/get-the-facts/ (accessed 6 Nov 17). Google Scholar Author, Article, and Disclosure InformationAffiliations: University of Sydney, Sydney, New South Wales, Australia (M.R.S.)This article was published at Annals.org on 2 January 2018. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 16 January 2018Volume 168, Issue 2Page: JC5KeywordsBiopsyCancer screeningCancer treatmentHematologic testsIncontinenceIntent to treat analysisLung and intrathoracic tumorsMortalityProstate cancerSurgery ePublished: 16 January 2018 Issue Published: 16 January 2018 Copyright & PermissionsCopyright © 2018 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Engineering Polymersomes for Diagnostics and Therapy
Authors: Jiayu Leong, Jye Yng Teo, Vinay K. Aakalu, Yi Yan Yang, Hyunjoon Kong
Journal: Advanced Healthcare Materials (2018)

Abstract Engineered polymer vesicles, termed as polymersomes, confer a flexibility to control their structure, properties, and functionality. Self‐assembly of amphiphilic copolymers leads to vesicles consisting of a hydrophobic bilayer membrane and hydrophilic core, each of which is loaded with a wide array of small and large molecules of interests. As such, polymersomes are increasingly being studied as carriers of imaging probes and therapeutic drugs. Effective delivery of polymersomes necessitates careful design of polymersomes. Therefore, this review article discusses the design strategies of polymersomes developed for enhanced transport and efficacy of imaging probes and therapeutic drugs. In particular, the article focuses on overviewing technologies to regulate the size, structure, shape, surface activity, and stimuli‐ responsiveness of polymersomes and discussing the extent to which these properties and structure of polymersomes influence the efficacy of cargo molecules. Taken together with future considerations, this article will serve to improve the controllability of polymersome functions and accelerate the use of polymersomes in biomedical applications.
A pentanucleotide repeat polymorphism in the 5' control region of the apolipoprotein(a) gene is associated with lipoprotein(a) plasma concentrations in Caucasians.
Authors: M Trommsdorff, S Köchl, A Lingenhel, F Kronenberg, R Delport, H Vermaak, L Lemming, I C Klausen, O Faergeman, G Utermann
Journal: Journal of Clinical Investigation (1995)

The enormous interindividual variation in the plasma concentrations of the atherogenic lipoprotein(a) [Lp(a)] is almost entirely controlled by the apo(a) locus on chromosome 6q26-q27. A variable number of transcribed kringle4 repeats (K4-VNTR) in the gene explains a large fraction of this variation, whereas the rest is presently unexplained. We here have analyzed the effect of the K4-VNTR and of a pentanucleotide repeat polymorphism (TTTTA)n (n = 6-11) in the 5' control region of the apo(a) gene on plasma Lp(a) levels in unrelated healthy Tyroleans (n = 130), Danes (n = 154), and Black South Africans (n = 112). The K4-VNTR had a significant effect on plasma Lp(a) levels in Caucasians and explained 41 and 45% of the variation in Lp(a) plasma concentration in Tyroleans and Danes, respectively. Both, the pentanucleotide repeat (PNR) allele frequencies and their effects on Lp(a) concentrations were heterogeneous among populations. A significant negative correlation between the number of pentanucleotide repeats and the plasma Lp(a) concentration was observed in Tyroleans and Danes. The effect of the 5' PNRP on plasma Lp(a) concentrations was independent from the K4-VNTR and explained from 10 to 14% of the variation in Lp(a) concentrations in Caucasians. No significant effect of the PNRP was present in Black Africans. This suggests allelic association between PNR alleles and sequences affecting Lp(a) levels in Caucasians. Thus, in Caucasians but not in Blacks, concentrations of the atherogenic Lp(a) particle are strongly associated with two repeat polymorphisms in the apo(a) gene.
Reduced cortical oxygenation predicts a progressive decline of renal function in patients with chronic kidney disease
Authors: Menno Pruijm, Bastien Milani, Edward Pivin, Agata Podhajska, Bruno Vogt, Matthias Stuber, Michel Burnier
Journal: Kidney International (2018)

Renal tissue hypoxia is a final pathway in the development and progression of chronic kidney disease (CKD), but whether renal oxygenation predicts renal function decline in humans has not been proven. Therefore, we performed a prospective study and measured renal tissue oxygenation by blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI) in 112 patients with CKD, 47 with hypertension without CKD, and 24 healthy control individuals. Images were analyzed with the twelve-layer concentric objects method that divided the renal parenchyma in 12 layers of equal thickness and reports the mean R2* value of each layer (a high R2* corresponds to low oxygenation), along with the change in R2* between layers called the R2* slope. Serum creatinine values were collected to calculate the yearly change in estimated glomerular function rate (MDRD eGFR). Follow up was three years. The change in eGFR in CKD, hypertensive and control individuals was -2.0, 0.5 and -0.2 ml/min/1.73m<sup>2</sup>/year, respectively. In multivariable regression analysis adjusted for age, sex, diabetes, RAS-blockers, eGFR, and proteinuria the yearly eGFR change correlated negatively with baseline 24 hour proteinuria and the mean R2* value of the cortical layers, and positively with the R2* slope, but not with the other covariates. Patients with CKD and high outer R2* or a flat R2* slope were three times more likely to develop an adverse renal outcome (renal replacement therapy or over a 30% increase in serum creatinine). Thus, low cortical oxygenation is an independent predictor of renal function decline. This finding should stimulate studies exploring the therapeutic impact of improving renal oxygenation on renal disease progression.
White Blood Cell <i>BRCA1</i> Promoter Methylation Status and Ovarian Cancer Risk
Authors: Per E. Lønning, Elisabet O. Berge, Merete Bjørnslett, Laura Minsaas, Ranjan Chrisanthar, Hildegunn Høberg-Vetti, Cécile Dulary, Florence Busato, Silje Bjørneklett, Christine Eriksen, Reidun Kopperud, Ulrika Axcrona, Ben Davidson, Line Bjørge, Gareth Evans, Anthony Howell, Helga B. Salvesen, Imre Janszky, Kristian Hveem, Pål R. Romundstad, Lars J. Vatten, Jörg Tost, Anne Dørum, Stian Knappskog
Journal: Annals of Internal Medicine (2018)

The role of normal tissue gene promoter methylation in cancer risk is poorly understood.To assess associations between normal tissue BRCA1 methylation and ovarian cancer risk.2 case-control (initial and validation) studies.2 hospitals in Norway (patients) and a population-based study (control participants).934 patients and 1698 control participants in the initial study; 607 patients and 1984 control participants in the validation study.All patients had their blood sampled before chemotherapy. White blood cell (WBC) BRCA1 promoter methylation was determined by using methylation-specific quantitative polymerase chain reaction, and the percentage of methylation-positive samples was compared between population control participants and patients with ovarian cancer, including the subgroup with high-grade serous ovarian cancer (HGSOC).In the initial study, BRCA1 methylation was more frequent in patients with ovarian cancer than control participants (6.4% vs. 4.2%; age-adjusted odds ratio [OR], 1.83 [95% CI, 1.27 to 2.63]). Elevated methylation, however, was restricted to patients with HGSOC (9.6%; OR, 2.91 [CI, 1.85 to 4.56]), in contrast to 5.1% and 4.0% of patients with nonserous and low-grade serous ovarian cancer (LGSOC), respectively. These findings were replicated in the validation study (methylation-positive status in 9.1% of patients with HGSOC vs. 4.3% of control participants-OR, 2.22 [CI 1.40 to 3.52]-4.1% of patients with nonserous ovarian cancer, and 2.7% of those with LGSOC). The results were not influenced by tumor burden, storage time, or WBC subfractions. In separate analyses of young women and newborns, BRCA1 methylation was detected in 4.1% (CI, 1.8% to 6.4%) and 7.0% (CI, 5.0% to 9.1%), respectively.Patients with ovarian cancer were recruited at the time of diagnosis in a hospital setting.Constitutively normal tissue BRCA1 promoter methylation is positively associated with risk for HGSOC.Norwegian Cancer Society.
Tolerance induction to peach using glycosylated nanostructures including Pru p 3-Epitope
Authors: Maria Jose Rodriguez, Javier Ramos-Soriano, Ana Molina, Ainhoa Mascaraque, Miguel Gonzalez, Araceli Diaz-perales, James R. Perkins, Maria J. Torres, Javier Rojo, Cristobalina Mayorga
Journal: Journal of Allergy and Clinical Immunology (2018)
Comprehensive molecular profiling of advanced gastric cancer (AGC) using NGS and immunohistochemistry (IHC).
Authors: Yasutoshi Kuboki, Toru Niwa, Akiko Nagatsuma, Kohei Shitara, Nozomu Fuse, Satoshi Yamashita, Toshihiko Doi, Toshikazu Ushijima, Atsushi Ochiai, Atsushi Ohtsu
Journal: Journal of Clinical Oncology (2014)

11027 Background: In advanced gastric cancer, most of clinical trials are designed based on IHC/in situ hybridization in tissue. However, NGS screening allowed us to comprehensively profile tumor gene status recently. Our goal is to profile both gene alterations and conventional biomarker in gastric cancer for potential molecular targeted therapy. Methods: Formalin-fixed, paraffin-embedded (FFPE) tumor samples from 121 patients with stage III/IV gastric cancer who underwent gastrectomy were examined for HER2, EGFR, c-MET and FGFR2 expression using IHC. In addition, genomic DNA was extracted from each FFPE sample and a total of 15,991 regions in 409 cancer-related genes were sequenced to detect mutations using the Ion AmpliSeq Library kit 2.0 and Comprehensive Cancer Panel. In addition, to evaluate copy number variation of a gene, relative reading depth to the reference (RRDR) of an individual gene was calculated. Amplification was defined as an RRDR greater than 2. Results: The most frequently mutated genes were TP53 (36.4%). In addition, mutations in oncogenes such as PIK3CA (7.4%), ROS1 (4.1%), HER2 (4.1%), MET (1.7%) and ALK (1.7%) were detected. The most frequently amplified gene was SRC (20.7%). Amplification was also detected for other genes such as HER2 (14.9%), CCNE1 (13.2%), CCND1 (9.1%), EGFR (7.4%), KRAS (7.4%), MET (6.6%), RET (3.3%) and FGFR2 (2.5%). The rate of over-expression (IHC 3+) was as follows: HER2 (16.5%), EGFR (23.1%), MET (9.9%) and FGFR2 (14.0%). Most of the cases with HER2 over-expression had HER2 amplification. On the other hand, in a few cases with EGFR/c-MET/FGFR2 over-expression, amplification of these genes was not detected. Over-expression cases with EGFR or FGFR2 had other various gene alterations such as PIK3CA mutations and/or KRAS alterations. In contrast, HER2 or c-MET over-expression cases were mutually exclusive with respect to PIK3CA mutations. Conclusions: We identified several possible candidate genes that could be targets for personalized therapy. Comprehensive analyses including IHC will be necessary to design the optimal therapy with which to treat the right population of patients in future clinical trials.
Computational chemical biology and drug design: Facilitating protein structure, function, and modulation studies
Authors: Mingyue Zheng, Jihui Zhao, Chen Cui, Zunyun Fu, Xutong Li, Xiaohong Liu, Xiaoyu Ding, Xiaoqin Tan, Fei Li, Xiaomin Luo, Kaixian Chen, Hualiang Jiang
Journal: Medicinal Research Reviews (2018)

Over the past quarter of a century, there has been rapid development in structural biology, which now can provide solid evidence for understanding the functions of proteins. Concurrently, computational approaches with particular relevance to the chemical biology and drug design (CBDD) field have also incrementally and steadily improved. Today, these methods help elucidate detailed working mechanisms and accelerate the discovery of new chemical modulators of proteins. In recent years, integrating computational simulations and predictions with experimental validation has allowed for more effective explorations of the structure, function and modulation of important therapeutic targets. In this review, we summarize the main advancements in computational methodology development, which are then illustrated by several successful applications in CBDD. Finally, we conclude with a discussion of the current major challenges and future directions in the field.
Cytoplasmic ERß expression to predict efficacy and survival of EGFR-TKI in EGFR-mutant NSCLC.
Authors: Zhijie Wang, Jie Wang, Xiaodong Wang, Zhirong Shen, Xiaosheng Ding, Hua Bai, Jianchun Duan, Tongtong An, Yuyan Wang, Minglei Zhuo, Shuhang Wang, Meina Wu
Journal: Journal of Clinical Oncology (2013)

e19067 Background: Estrogen receptor pathway has been reported to be interacted with epidermal growth factor receptor (EGFR) signal pathway. This study focused on the impact of intracellular ERβ localization (cytoplasmic or nuclear) on efficacy of EGFR-TKI. Methods: Tumor tissue specimens from 149 stage IV NSCLC patients treated with EGFR-TKI were analyzed using immunohistochemistry (IHC) for ER expression (ERα or β) and their associations with clinicopathological variables and clinical outcomes. Significance of cyto-ERβ expression was further examined in NSCLC cell lines. Results: The expression of ERα and ERβ was detected in 15% and 28.9% of the patients, respectively. Cyto-ERβ positive cases showed shortened PFS compared with negative ones (3.1 months vs. 7.3 months, p=0.061). In the EGFR-mutant subgroup, differences of PFS were enlarged with significant statistics (4.7 months vs. 10.9 months, p=0.042). COX’s proportional hazard model showed that female, EGFR mutation and c-ERβ status were independent predictors for PFS. PC-9 cells present ERβ in cytoplasma and nucleus. Estrodial (E2) induced PC-9 cells moderately resistant to erlotinib with a 3-fold increase of IC50, and the resistance can be reversed by ER blocker (fulvestrant) or siRNA directed to ESR2. The E2 function was accomplished by nongenomic activation (MAPK phosphorylation) caused by E2 via cyto-ERβ. Combination treatment with erlotinib and fulvestrant turned out to be far more effective than either treatment alone in PC-9 cells. Conclusions: Cyto-ERβ expression may predict relatively poor efficacy to EGFR-TKI compared with non- cyto-ERβ expression in NSCLC patients harboring EGFR mutation.
A multidimensional assessment of the burden of psoriasis: results from a multinational dermatologist and patient survey
Authors: C.E.M. Griffiths, S.-J. Jo, L. Naldi, R. Romiti, E. Guevara-Sangines, T. Howe, G. Pietri, I. Gilloteau, C. Richardson, H. Tian, M. Augustin
Journal: British Journal of Dermatology (2018)

Psoriasis is a chronic, immune‐mediated disease, characterized by symptoms that include itching and skin pain and is often associated with comorbidities. Patients have a substantial detriment to quality of life (QoL) and work productivity with associated cost burden. To investigate the incremental burden of comorbidities, itch and affected body areas among systemic eligible patients with psoriasis, using a multinational survey of dermatologists and their patients with psoriasis. Multinational data from the Growth from Knowledge (GfK) Disease Atlas Global Real‐World Evidence program were used. Eligible patients were identified as those who were currently having or had ever had moderate‐to‐severe psoriasis, and must have been receiving prescription treatments at the time of the survey. Multivariable regression analyses were conducted to assess the incremental burden among psoriasis patients with physical and psychological comorbidities, itch and affected visible and sensitive body areas vs. psoriasis patients without these conditions, respectively. The study enrolled 3821 patients with psoriasis, from nine countries, with an average Psoriasis Area and Severity Index score of 6·4. The presence of comorbidities was associated with a significant increase in the likelihood of skin pain, lower QoL, greater work impairment and increased usage of medical resources (except in psoriasis patients with obesity and type 2 diabetes). Psoriasis patients suffering from itch and those with visible and sensitive affected body areas also had impaired QoL vs. those without these conditions. Psoriasis patients with physical and psychological comorbidities, itch and affected visible and sensitive body areas had lower QoL and greater work impairment compared to those without these conditions.
Late hepatitis B reactivation following direct‐acting antiviral–based treatment of recurrent hepatitis C in an anti‐HBc–positive liver transplant recipient
Authors: Julien Vionnet, Manuel Pascual, Barbara Testoni, Christophe Combet, Sébastien Godat, Sandrine Vijgen, Vincent Aubert, Laura Rubbia‐Brandt, Fabien Zoulim, Darius Moradpour
Journal: Hepatology (2017)

Direct‐acting antivirals (DAAs) have changed the landscape of hepatitis C virus (HCV) treatment, but chronic hepatitis C (CHC) remains a leading indication for liver transplantation (LT). Hepatitis B virus (HBV) reactivation has been reported in HBV‐HCV‐coinfected patients treated with DAAs. We report on a case of late HBV reactivation after DAA‐based treatment of recurrent hepatitis C in an antibody against hepatitis B core antigen (anti‐HBc)‐positive LT recipient. (Hepatology 2018;67:791‐793).
Comparison of PEF vs. FEV 1 Endpoints in Trials with Tiotropium in Adults and Adolescents with Moderate or Severe Symptomatic Asthma
Authors: David M.G. Halpin, J. Mark FitzGerald, Michael Engel, Petra Moroni-Zentgraf, Ralf Sigmund, Eli O. Meltzer, Thomas B. Casale
Journal: Journal of Allergy and Clinical Immunology (2018)
Cognitive Effects of Cancer and Cancer Treatments
Authors: Tim A. Ahles, James C. Root
Journal: Annual Review of Clinical Psychology (2018)

As the population of cancer survivors has grown into the millions, there has been increasing emphasis on understanding how the late effects of treatment affect survivors' ability to return to work/school, their capacity to function and live independently, and their overall quality of life. This review focuses on cognitive change associated with cancer and cancer treatments. Research in this area has progressed from a pharmacotoxicology perspective to a view of the cognitive change as a complex interaction of aspects of the treatment, vulnerability factors that increase risk for posttreatment cognitive decline, cancer biology, and the biology of aging. Methodological advances include the development of (a) measurement approaches that assess more fine-grained subcomponents of cognition based on cognitive neuroscience and (b) advanced statistical approaches. Conceptual issues that arise from this multidimensional perspective are described in relation to future directions, understanding of mechanisms, and development of innovative interventions.
Depressed mood is associated with loss of productivity in allergic rhinitis
Authors: A. P. Campbell, L. P. Hoehle, K. M. Phillips, D. S. Caradonna, S. T. Gray, A. R. Sedaghat
Journal: Allergy (2018)

Abstract Allergic rhinitis ( AR ) is associated with significant decreases in quality of life and productivity losses. We hypothesized that symptoms of AR may differentially associate with lost productivity due to AR . We performed a cross‐sectional cohort study of 105 prospectively recruited patients with persistent AR . AR control, severity of depressed mood, and sinonasal symptoms were assessed with the Rhinitis Control Assessment Test ( RCAT ), Patient Health Questionnaire ( PHQ ‐2), and the 22‐item Sinonasal Outcome Test ( SNOT ‐22), respectively. Lost productivity was assessed by asking the number of days of work/school missed due to AR in the last 3 months. Patients missed a mean of 1.5 days ( SD :2.9) of work or school. Lost productivity was associated with PHQ ‐2 (adjusted linear regression coefficient [β] = .68, 95% CI : 0.20‐1.15, P = .007) analysis but not SNOT ‐22 or RCAT scores. Productivity losses due to AR are associated with severity of depressed mood rather than classic nasal or extra‐nasal symptoms of AR .
Exhalation Delivery Systems (EDS) Greatly Increase Topical Delivery to Target Sites for Chronic Rhinosinusitis (CRS) Compared to Nasal Sprays or Pressurized MDIs (pMDI)
Authors: Per G. Djupesland, John C. Messina, Ramy A. Mahmoud
Journal: Journal of Allergy and Clinical Immunology (2018)