tbuckley/cabot-search huggingface dataset:
Combined chemoimmunotherapy of castrate-resistant prostate cancer with dendritic-cell based vaccine DCVAC/Pca.
Authors: Michal Podrazil, Daniela Rozkova, Jitka Fucikova, Stanislav Katina, Radek Spisek, Jirina Bartunkova
Journal: Journal of Clinical Oncology (2014)

3095 Background: Appropriate combination of tumor mass reduction and neutralization of tumor-induced immunosuppression might potentiate the induction of anti-tumor immunity. We performed an open label, single arm Phase I/II clinical trial in patients with metastatic castrate resistant prostate cancer (mCRPC) eligible for docetaxel using autologous mature dendritic cells pulsed with killed LNCap prostate cancer cell line, DCVAC/PCa. Methods: Eligible patients had progressive mCRPC despite androgen deprivation. None of the patients received abiraterone or enzalutamide. DCVAC/PCa treatment consisted of, on average ten doses of 1x107 dendritic cells injected s.c. Treatment comprised of initial 7d administration of metronomic cyclophosphamide, and subsequent 2 doses of DCVAC/PCa. Patients then started docetaxel (75 mg/m2) and prednisone (5 mg twice daily) treatment administered every 3-weeks and DCVAC/PCa was given every 6 weeks up to a maximum number of doses manufactured from one leukapheresis. The primary end point was safety, the secondary end-point immune response. Overall survival (OS) was compared to the predicted OS according to Halabi and MSKCC nomograms. Results: Data from twenty-five patients were evaluated. The mean age at the start of immunotherapy was 67 years, median PSA 109 ng/ml and Hb 11,9 g/dl. 48% patients had GS ≥8. No serious DCVAC/PCa-related adverse events have been reported. There were no clinical or laboratory signs of autoimmunity. Median OS was 19 months (95% CI: 14.69-23.31) while the predicted median OS was 12 months (95% CI: 11.19-12.81). We observed no significant changes of the peripheral blood Tregs and MDSCs during the course of the trial. Long-term administration of DCVAC/PCa led to the induction and maintenance of the stable levels of T cells specific against multiple tumor antigens including PSA, NY-ESO1, MAGE-A1 and MAGE-A3. Conclusions: In patients with mCRPC, the alternate administration of DCVAC/PCa cancer immunotherapy and docetaxel results in the stabilization of the disease progression and longer than expected survival. Chemotherapy does not preclude the induction of tumor specific T cells. Clinical trial information: 2009-017259-24.
Long non-coding RNA CASC2 suppresses epithelial-mesenchymal transition of hepatocellular carcinoma cells through CASC2/miR-367/FBXW7 axis
Authors: Yufeng Wang, Zhikui Liu, Bowen Yao, Qing Li, Liang Wang, Cong Wang, Changwei Dou, Meng Xu, Qingguang Liu, Kangsheng Tu
Journal: Molecular Cancer (2017)

Recently, it has been reported that long non-coding RNA (lncRNA) cancer susceptibility candidate 2 (CASC2), a novel tumor suppressor, participates in regulating the carcinogenesis and suppresses tumor progression by sponging microRNAs (miRNAs). However, the expression and function of CASC2 in hepatocellular carcinoma (HCC) remain unclear. The expression of CASC2 and miR-367 in HCC specimens and cell lines were detected by real-time PCR. Western blotting and immunohistochemistry were carried out for detection of epithelial-to-mesenchymal transition (EMT) markers in HCC. Transwell assays were used to determine migration and invasion of HCC cells. A mouse model for lung metastasis was established to evaluated HCC metastasis in vivo. The correlation among CASC2, miR-367 and F-box and WD repeat domain containing 7 (FBXW7) were disclosed by a dual-luciferase reporter assay, RIP assay and biotin pull-down assay. Here, CASC2 expression was significantly downregulated in HCC tissues, especially in aggressive and recurrent cases. In accordance, CASC2 underexpression was observed in HCC cell lines compared to LO2. In vitro and in vivo experiments revealed that CASC2 inhibited migration and invasion of HCC cells. Additionally, CASC2 repressed EMT process of HCC cells. Further studies demonstrated that CASC2 could function as a competing endogenous RNA (ceRNA) by sponging miR-367 in HCC cells. Functionally, gain- and loss-of-function studies showed that miR-367 promoted migration, invasion and EMT progression of HCC cells. Moreover, further investigations disclosed that FBXW7 was a downstream target of miR-367 and CASC2 prohibited EMT progression and subsequently exerted its anti-metastatic effects via CASC2/miR-367/FBXW7 axis in HCC cells. Clinically, CASC2 underexpression and miR-367 overexpression were closely correlated with the metastasis-associated clinicopathologic features. Notably, CASC2 low-expressing and miR-367 high-expressing HCC patients showed the poorest clinical outcome. Overall, we conclude that the CASC2/miR-367/FBXW7 axis may be a ponderable and promising therapeutic target for HCC.
Quality of life (QoL) and symptoms evaluation in metastatic breast cancer (MBC) patients (pts) treated with eribulin: Preliminary results of a prospective observational study.
Authors: Teresa Gamucci, Lucia Mentuccia, Silvia Quadrini, Luca I. Moscetti, Patrizia Vici, Isabella Sperduti, Laura Pizzuti, Daniela Franco, Maria Anna Giampaolo, Maria Agnese Fabbri
Journal: Journal of Clinical Oncology (2013)

e12031 Background: Eribulin (E) is a nontaxane microtubule inhibitor currently indicated for third-line chemotherapy (CHT) of MBC. To evaluate its tolerability and impact on QoL and symptoms improvement in MBC pts, from April 2012, we conducted a prospective observational study. Methods: Pts pretreated with anthracycline (A) and taxane (T) who has received 2 CHT lines for MBC, scheduled to be treated with E were considered eligible. Pts complete the Edmonton Symptoms Assessment Scale (ESAS) at each cycle and the Functional Assessment of Cancer Therapy-Breast (FACT-B) every 2 cycles. Outcome of QoL included the FACT-B total score, FACT-General (FACT-G) score and the Trial Outcome Index (TOI) score. Groups of data were analyzed using ANOVA and the Friedman test. Kaplan-Meier method was used for survival calculation. Overall Survival was calculated by the Kaplan-Meier product-limit method. Results: 25 consecutive MBC pts entered the study. Median age 65 (range 31-77), PS (ECOG) 0-1 96%, 24% had triple-negative MBC, 70% ER/PgR positive and 5% HER2 positive. All pts were pretreated with A and T, 19 (76%) also with capecitabine. Median cycles 6 (range 3-13), 36% received more than 6 cycles. Five pts are to early for evaluation. Of the 20 evaluable pts main toxicity were: alopecia G1 58% and G2 42%, asthenia G2 40% peripheral neuropathy G2 25% neutropenia G2 0% and G3-G4 10%.At a median follow-up of 6 months 16% of pts achieved partial response (PR) 44% stable disease (SD) and 20% progressive disease; disease control rate (PR+SD ≥ 6 m) occurred in 40% of pts. Median PFS is 5 m (95% CI, 4-6) currently 70% of pts are alive. Data of ESAS and QoL are reported in table. Conclusions: Our preliminary results shows that treatment with E is associated with a significant improvement of ESAS scores (p=0.03) mainly in responders pts (p=0.02) and with a good maintenance of QoL with expected and manageable toxicities. Data collection is ongoing and update results will be presented. [Table: see text]
Spending on public health cut as councils look to save money
Authors: Anne Gulland
Journal: BMJ (2017)

Council spending on public health services such as sexual health clinics and treatment of substance misuse will be slashed by £85m (€95.8m; $109.5m) this financial year, according to new analysis by the King’s Fund.1

The think tank’s research, based on Department of Communities and Local Government data, shows that central government cuts have forced councils to make hard choices, with public health particularly suffering. Councils in England are planning to spend £3.4bn on public health services in 2017-18, but that sum includes money transferred from the Department of Health when councils took on some children’s services.

Taking that extra money out …
Abstract 164: MicroRNA-29c Reduces Serca2 Expression During Myocardial Hypoxia
Authors: Keith A MacCannell, Ralph V Shohet, Chad B Walton
Journal: Circulation Research (2012)

The cardiac response to a hypoxic challenge is coordinated by the transcription factor Hypoxia Inducible Factor-1 (HIF-1), which drives the transcription of a large number of genes pertinent to angiogenesis, metabolism, and calcium cycling. Expression of HIF-1alpha that has been mutated to remove oxygen regulation recapitulates many of the changes in gene expression seen in hypoxia. It also results in reversible cardiac dysfunction associated with marked decrease of Sarco-Endoplasmic Reticulum Calcium-Dependent ATP-ase (SERCA2). This decrease in SERCA was more rapid and more substantial than a moderate decrease seen in the mRNA for this protein. In this study, we tested the hypothesis that the decrease in SERCA2 is mediated by the up-regulation of microRNA (miRNA) in the heart. We identified 30 miRNAs that are dysregulated upon induction of oxygen stable HIF1 expression. Three of these have evident binding sites in the 3’ untranslated region of the SERCA2 gene. Transient co-transfection of a mimic molecule for these three miRs with a luciferase reporter construct that includes the 3’ UTR of SERCA2 showed that mi-29c produced a substantial decrease in reporter expression. This effect is abolished by the mutagenesis of the predicted target site within the 3’UTR. Similarly, transfection of this mimic molecule into a cell line that expresses SERCA2 results in a reduction in SERCA2 protein levels. An antagomir to this miR rescues the reduction in SERCA seen with HIF expression. We conclude that miR-29c, is responsible for an important portion of the down-regulation of SERCA2, and thus the contractile dysfunction, seen in hypoxia.
Optimal Medical Therapy for Known Coronary Artery Disease
Authors: Raymond J. Gibbons, Todd D. Miller
Journal: JAMA Cardiology (2017)

<h3>Importance</h3> This review examines the current state-of-the-art optimal medical therapy (OMT) for patients with known coronary artery disease. This therapy, which is sometimes labeled as<i>secondary prevention</i>, is effective in preventing recurrent events and is recommended by the American College of Cardiology Foundation/American Heart Association guidelines. Optimal medical therapy is of recognized public health benefit. <h3>Observations</h3> The available evidence from broad patient populations, contemporary randomized trials, and multiple recent studies with pharmacy records indicates that the delivery of OMT is far from ideal. We suggest approaches for quality improvement, including better patient education, the increased use of interventions that are known to improve compliance, and the use of performance measures focused on long-term OMT in outpatient care. <h3>Conclusions and Relevance</h3> Improvement in the delivery of OMT to patients with coronary artery disease is one possible step to help the United States reduce the recently reported increase in death rate from heart disease.
Intratumor heterogeneity in non-small cell lung cancer inferred by multi-region exome sequencing
Authors: Bruin, N McGranahan, L Yates, M Jamal-Hanjani, M Salm, R Mitter, S Shafi, N Murugaesu, A Rowan, M Gerlinger, D Wedge, S Horswell, I Varela, W Tom, C Parikh, T Harkins, C Lee, N Matthews, A Stewart, P Campbell, C Swanton
Journal: Cancer Research (2014)
Role of Consolidation High Dose Chemotherapy (HDC) with Autologous Stem Cell Transplant (ASCT) Support in Patients with Peripheral T-Cell Lymphoma Who Achieved Complete Remission (CR1) Following First Line Induction Chemotherapy
Authors: Lay Poh Khoo, Tiffany Tang, Suk Teng Chin, Jeslin Ha, Colin Phipps, Yuh Shan Lee, Mohamad Farid, Kevin Tay, Miriam Tao, Richard Hong Hui Quek, Soon Thye Lim
Journal: Blood (2016)
HER2 amplification and gene signal distribution in gastroesophageal cancer.
Authors: Jan Trøst Jørgensen, Karsten Bork Nielsen, Gitte Kjærsgaard, Anna Jepsen, Jens Mollerup
Journal: Journal of Clinical Oncology (2017)

e15600 Background: HER2 serves as an important therapeutic target in gastroesophageal cancer. Differences in HER2 gene signal distribution patterns can be observed at the tissue level, but how it influences the HER2 amplification status has not been studied so far. Here, we investigated the link between HER2 amplification and the different types of gene signal distribution. Methods: Tumor samples from 140 patients with gastroesophageal adenocarcinoma where analyzed using the HER2 IQFISH pharmDx™ assay. Specimens covered non-amplified and amplified cases with a preselected high proportion of HER2 amplified cases. Based on the HER2/CEN-17 ratio, specimens were categorized into amplified or non-amplified. The signal distribution patterns were divided into homogeneous, heterogeneous focal or heterogeneous mosaic. The study was conducted based on anonymized specimens with limited access to clinicopathological data. Results: Among the 140 analyzed specimens 83 had a heterogeneous HER2 signal distribution, with 62 being focal and 21 of the mosaic type. The remaining 57 specimens had a homogeneous signal distribution. HER2 amplification was observed in 63 of the 140 specimens, and nearly all (93.7%) were found among specimens with a heterogeneous focal signal distribution (p &lt; 0.0001). The mean HER2/CEN-17 ratio for the focal heterogeneous group was 8.75 (CI95%: 6.87 – 10.63), compared to 1.53 (CI95%: 1.45 – 1.61) and 1.70 (CI95%: 1.22 – 2.18) for the heterogeneous mosaic and homogeneous groups, respectively, (p &lt; 0.0001). Conclusions: A clear relationship between HER2 amplification and the focal heterogeneous signal distribution was demonstrated in tumor specimens from patients with gastroesophageal cancer. Furthermore, we raise the hypothesis that the signal distribution patterns observed with FISH might be related to different subpopulations of HER2 positive tumor cells.
Improving Adherence to Long-term Opioid Therapy Guidelines to Reduce Opioid Misuse in Primary Care
Authors: Jane M. Liebschutz, Ziming Xuan, Christopher W. Shanahan, Marc LaRochelle, Julia Keosaian, Donna Beers, George Guara, Kristen O’Connor, Daniel P. Alford, Victoria Parker, Roger D. Weiss, Jeffrey H. Samet, Julie Crosson, Phoebe A. Cushman, Karen E. Lasser
Journal: JAMA Internal Medicine (2017)

Prescription opioid misuse is a national crisis. Few interventions have improved adherence to opioid-prescribing guidelines.To determine whether a multicomponent intervention, Transforming Opioid Prescribing in Primary Care (TOPCARE; http://mytopcare.org/), improves guideline adherence while decreasing opioid misuse risk.Cluster-randomized clinical trial among 53 primary care clinicians (PCCs) and their 985 patients receiving long-term opioid therapy for pain. The study was conducted from January 2014 to March 2016 in 4 safety-net primary care practices.Intervention PCCs received nurse care management, an electronic registry, 1-on-1 academic detailing, and electronic decision tools for safe opioid prescribing. Control PCCs received electronic decision tools only.Primary outcomes included documentation of guideline-concordant care (both a patient-PCC agreement in the electronic health record and at least 1 urine drug test [UDT]) over 12 months and 2 or more early opioid refills. Secondary outcomes included opioid dose reduction (ie, 10% decrease in morphine-equivalent daily dose [MEDD] at trial end) and opioid treatment discontinuation. Adjusted outcomes controlled for differing baseline patient characteristics: substance use diagnosis, mental health diagnoses, and language.Of the 985 participating patients, 519 were men, and 466 were women (mean [SD] patient age, 54.7 [11.5] years). Patients received a mean (SD) MEDD of 57.8 (78.5) mg. At 1 year, intervention patients were more likely than controls to receive guideline-concordant care (65.9% vs 37.8%; P < .001; adjusted odds ratio [AOR], 6.0; 95% CI, 3.6-10.2), to have a patient-PCC agreement (of the 376 without an agreement at baseline, 53.8% vs 6.0%; P < .001; AOR, 11.9; 95% CI, 4.4-32.2), and to undergo at least 1 UDT (74.6% vs 57.9%; P < .001; AOR, 3.0; 95% CI, 1.8-5.0). There was no difference in odds of early refill receipt between groups (20.7% vs 20.1%; AOR, 1.1; 95% CI, 0.7-1.8). Intervention patients were more likely than controls to have either a 10% dose reduction or opioid treatment discontinuation (AOR, 1.6; 95% CI, 1.3-2.1; P < .001). In adjusted analyses, intervention patients had a mean (SE) MEDD 6.8 (1.6) mg lower than controls (P < .001).A multicomponent intervention improved guideline-concordant care but did not decrease early opioid refills.clinicaltrials.gov Identifier: NCT01909076.
Effects of Klotho on fibrosis and cancer: A renal focus on mechanisms and therapeutic strategies
Authors: Rik Mencke, Hannes Olauson, Jan-Luuk Hillebrands
Journal: Advanced Drug Delivery Reviews (2017)

Klotho is a membrane-bound protein predominantly expressed in the kidney, where it acts as a permissive co-receptor for Fibroblast Growth Factor 23. In its shed form, Klotho exerts anti-fibrotic effects in several tissues. Klotho-deficient mice spontaneously develop fibrosis and Klotho deficiency exacerbates the disease progression in fibrotic animal models. Furthermore, Klotho overexpression or supplementation protects against fibrosis in various models of renal and cardiac fibrotic disease. These effects are mediated at least partially by the direct inhibitory effects of soluble Klotho on TGFβ1 signaling, Wnt signaling, and FGF2 signaling. Soluble Klotho, as present in the circulation, appears to be the primary mediator of anti-fibrotic effects. Similarly, through inhibition of the TGFβ1, Wnt, FGF2, and IGF1 signaling pathways, Klotho also inhibits tumorigenesis. The Klotho promoter gene is generally hypermethylated in cancer, and overexpression or supplementation of Klotho has been found to inhibit tumor growth in various animal models. This review focuses on the protective effects of soluble Klotho in inhibiting renal fibrosis and fibrosis in distant organs secondary to renal Klotho deficiency. We also discuss the structure-function relationships of Klotho domains and biological effects in the context of potential targeted treatment strategies.
Single-Subject Studies in Translational Nutrition Research
Authors: Nicholas J. Schork, Laura H. Goetz
Journal: Annual Review of Nutrition (2017)

There is a great deal of interest in personalized, individualized, or precision interventions for disease and health-risk mitigation. This is as true of nutrition-based intervention and prevention strategies as it is for pharmacotherapies and pharmaceutical-oriented prevention strategies. Essentially, technological breakthroughs have enabled researchers to probe an individual's unique genetic, biochemical, physiological, behavioral, and exposure profile, allowing them to identify very specific and often nuanced factors that an individual might possess, which may make it more or less likely that he or she responds favorably to a particular intervention (e.g., nutrient supplementation) or disease prevention strategy (e.g., specific diet). However, as compelling and intuitive as personalized nutrition might be in the current era in which data-intensive biomedical characterization of individuals is possible, appropriately and objectively vetting personalized nutrition strategies is not trivial and requires novel study designs and data analytical methods. These designs and methods must consider a very integrated use of the multiple contemporary biomedical assays and technologies that motivate them, which adds to their complexity. Single-subject or N-of-1 trials can be used to assess the utility of personalized interventions and, in addition, can be crafted in such a way as to accommodate the necessarily integrated use of many emerging biomedical technologies and assays. In this review, we consider the motivation, design, and implementation of N-of-1 trials in translational nutrition research that are meant to assess the utility of personalized nutritional strategies. We provide a number of example studies, discuss appropriate analytical methods given the complex data they generate and require, and consider how such studies could leverage integration of various biomarker assays and clinical end points. Importantly, we also consider the development of strategies and algorithms for matching nutritional needs to individual biomedical profiles and the issues surrounding them. Finally, we discuss the limitations of personalized nutrition studies, possible extensions of N-of-1 nutritional intervention studies, and areas of future research.
Small Cell, Large Impact
Authors: Amishi Bajaj
Journal: JAMA Oncology (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Twenty-Year Progression Rate to Clinical Onset According to Autoantibody Profile, Age, and <i>HLA-DQ</i> Genotype in a Registry-Based Group of Children and Adults With a First-Degree Relative With Type 1 Diabetes
Authors: Frans K. Gorus, Eric V. Balti, Anissa Messaaoui, Simke Demeester, Annelien Van Dalem, Olivier Costa, Harry Dorchy, Chantal Mathieu, Luc Van Gaal, Bart Keymeulen, Daniël G. Pipeleers, Ilse Weets
Journal: Diabetes Care (2017)

We investigated whether islet autoantibody profile, HLA-DQ genotype, and age influenced a 20-year progression to diabetes from first autoantibody positivity (autoAb+) in first-degree relatives of patients with type 1 diabetes.Persistently islet autoAb+ siblings and offspring (n = 462) under 40 years of age were followed by the Belgian Diabetes Registry. AutoAbs against insulin (IAA), GAD (GADA), IA-2 antigen (IA-2A), and zinc transporter 8 (ZnT8A) were determined by radiobinding assay.The 20-year progression rate of multiple-autoAb+ relatives (n = 194) was higher than that for single-autoAb+ participants (n = 268) (88% vs. 54%; P < 0.001). Relatives positive for IAA and GADA (n = 54) progressed more slowly than double-autoAb+ individuals carrying IA-2A and/or ZnT8A (n = 38; P = 0.001). In multiple-autoAb+ relatives, Cox regression analysis identified the presence of IA-2A or ZnT8A as the only independent predictors of more rapid progression to diabetes (P < 0.001); in single-autoAb+ relatives, it identified younger age (P < 0.001), HLA-DQ2/DQ8 genotype (P < 0.001), and IAA (P = 0.028) as independent predictors of seroconversion to multiple positivity for autoAbs. In time-dependent Cox regression, younger age (P = 0.042), HLA-DQ2/DQ8 genotype (P = 0.009), and the development of additional autoAbs (P = 0.012) were associated with more rapid progression to diabetes.In single-autoAb+ relatives, the time to multiple-autoAb positivity increases with age and the absence of IAA and HLA-DQ2/DQ8 genotype. The majority of multiple-autoAb+ individuals progress to diabetes within 20 years; this occurs more rapidly in the presence of IA-2A or ZnT8A, regardless of age, HLA-DQ genotype, and number of autoAbs. These data may help to refine the risk stratification of presymptomatic type 1 diabetes.