tbuckley/cabot-search huggingface dataset:
Adipocytes: A Novel Target for IL-15/IL-15Rα Cancer Gene Therapy
Authors: Run Xiao, Anthony G. Mansour, Wei Huang, Logan A. Chrislip, Ryan K. Wilkins, Nicholas J. Queen, Youssef Youssef, Hsiaoyin C. Mao, Michael A. Caligiuri, Lei Cao
Journal: Molecular Therapy (2019)

IL-15 is a proinflammatory cytokine that plays an essential role in the development and activation of natural killer (NK) cells. Adipose tissue acts as an endocrine organ that secretes cytokines and is an important reservoir for lymphocytes. We hypothesized that activation of the IL-15 signaling in adipose tissue will activate and expand the NK cell population and control tumor growth. We recently developed an adipocyte-targeting recombinant adeno-associated viral (rAAV) vector with minimal off-target transgene expression in the liver. Here, we used this rAAV system to deliver an IL-15/IL-15Rα complex to the abdominal fat by intraperitoneal (i.p.) injection. Adipose IL-15/IL-15Rα complex gene transfer led to the expansion of NK cells in the adipose tissue and spleen in normal mice without notable side effects. The i.p. injection of rAAV-IL-15/IL-15Rα complex significantly suppressed the growth of Lewis lung carcinoma implanted subcutaneously and exerted a significant survival advantage in a B16-F10 melanoma metastasis model. The antitumor effects were associated with the expansion of the NK cells in the blood, spleen, abdominal fat, and tumor, as well as the enhancement of NK cell maturity. Our proof-of-concept preclinical studies demonstrate the safety and efficacy of the adipocyte-specific IL-15/IL-15Rα complex vector as a novel cancer immune gene therapy. IL-15 is a proinflammatory cytokine that plays an essential role in the development and activation of natural killer (NK) cells. Adipose tissue acts as an endocrine organ that secretes cytokines and is an important reservoir for lymphocytes. We hypothesized that activation of the IL-15 signaling in adipose tissue will activate and expand the NK cell population and control tumor growth. We recently developed an adipocyte-targeting recombinant adeno-associated viral (rAAV) vector with minimal off-target transgene expression in the liver. Here, we used this rAAV system to deliver an IL-15/IL-15Rα complex to the abdominal fat by intraperitoneal (i.p.) injection. Adipose IL-15/IL-15Rα complex gene transfer led to the expansion of NK cells in the adipose tissue and spleen in normal mice without notable side effects. The i.p. injection of rAAV-IL-15/IL-15Rα complex significantly suppressed the growth of Lewis lung carcinoma implanted subcutaneously and exerted a significant survival advantage in a B16-F10 melanoma metastasis model. The antitumor effects were associated with the expansion of the NK cells in the blood, spleen, abdominal fat, and tumor, as well as the enhancement of NK cell maturity. Our proof-of-concept preclinical studies demonstrate the safety and efficacy of the adipocyte-specific IL-15/IL-15Rα complex vector as a novel cancer immune gene therapy.
Ultrasensitive Duplex Sequencing of Pretreatment ABL1 Kinase Domain Mutations in Patients with Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia
Authors: Nicholas J Short, Hagop M. Kantarjian, Koji Sasaki, Farhad Ravandi, Jorge E. Cortes, Marina Y. Konopleva, Ghayas C. Issa, Rashmi Kanagal-Shamanna, Steven M. Kornblau, Guillermo Garcia-Manero, Victor Rivera, Rebecca E. Garris, Jesse Salk, Justin Prichard, Jerald P. Radich, Elias J. Jabbour
Journal: Blood (2018)
Abstract LB-238: Immunotransplant filters out regulatory T cells and cures large lymphoma tumors.
Authors: Joshua D Brody, Matthew J Goldstein, Ronald Levy
Journal: Cancer Research (2008)

Abstract Background: The potency of transferring ex vivo activated tumor-infiltrating lymphocytes into lymphodepleted recipients has been demonstrated in clinical trials, though the use of in vivo vaccine-primed anti-tumor lymphocytes could make this approach sufficiently feasible for broad clinical application. We previously described a vaccination maneuver against murine B-cell lymphoma combining chemotherapy (CTX) and intra-tumoral injection of an immunostimulant CpG, which induced T-cell immunity and eradicated established tumors. An ongoing clinical trial of this maneuver has demonstrated complete and partial responses in lymphoma patients, though immune-regulatory factors such as regulatory T cells (Tregs) and limiting amounts of “homeostatic” cytokines might block even more powerful antitumor immunity. Transfer of tumor-specific lymphocytes into lymphodepleted recipients may eliminate these immune-regulatory obstacles. Methods: Splenocytes and bone marrow from CpG/CTX vaccinated mice were transplanted into lethally irradiated recipients, i.e., “immunotransplant.” Recipients received high dose tumor challenge with A20 murine B-cell lymphoma and followed clinically for tumor growth and for tumor-specific CD8 T cell IFNγ responses by multi-color flow cytometry. Results: We observed selective filtering against Tregs, doubling of the transferred Teffector:Treg ratio, and preferential expansion of transferred tumor-specific CD8 T cells in immunotransplant recipients. Immunotransplant cures large subcutaneous (&amp;gt;100 mm2) and metastatic tumors in 100% of recipients and enhances tumor-specific T cell memory. The addition of a vaccine “boost” to the immunotransplant maneuver results in an additional 3-fold increase in tumor-specific immunity and the use of cured recipients as subsequent donors in serial immunotransplant experiments demonstrated even greater tumor protection. Conclusions: As hematopoietic stem cell transplantation is a standard therapy for lymphoma patients, pre-transplant vaccination followed by post-transplant transfer of tumor-specific T cells could be tested in clinical trials. Our model suggests that this immunotransplant approach would allow the benefit of cancer vaccines to be revealed and might lead to cure of otherwise resistant malignancies.
Gemcitabine, Dexamethasone, Cisplatin +/- Rituximab (GDP +/- R) Is Highly Effective As a Mobilization Regimen in Relapsed or Refractory Lymphoma (COLLYM STUDY)
Authors: Jean-Philippe Adam, Vincent T. Taillefer, Marianne Emond, Marie-Hélène Leblanc, Olivier Besner-Morin, Stephane Doucet
Journal: Blood (2018)
Suboptimality in perceptual decision making and beyond
Authors: Hilary C. Barth, Sara Cordes, Andrea L. Patalano
Journal: Behavioral and Brain Sciences (2018)

Abstract We concur with the authors’ overall approach and suggest that their analysis should be taken even further. First, the same points apply to areas beyond perceptual decision making. Second, the same points apply beyond issues of optimality versus suboptimality.
Association Between Self-rated Health, Coronary Artery Calcium Scores, and Atherosclerotic Cardiovascular Disease Risk
Authors: Olusola A. Orimoloye, Mohammadhassan Mirbolouk, S. M. Iftekhar Uddin, Zeina A. Dardari, Michael D. Miedema, Mouaz H. Al-Mallah, Joseph Yeboah, Ron Blankstein, Khurram Nasir, Michael J. Blaha
Journal: JAMA Network Open (2019)

The interplay of self-rated health (SRH), coronary artery calcium (CAC) scores, and cardiovascular risk is poorly described.
Abstract P021: Hemoglobin A1c (HbA1c) and the Risk of Ischemic Stroke Among Women
Authors: Sally N Adebamowo, Jennifer K Pai, Monik C Jiménez, Kathryn M Rexrode
Journal: Circulation (2016)

Background: Poor glucose control as indicated by elevated levels of hemoglobin A1c (HbA1c) among those with diabetes is a risk factor for stroke; however, whether HbA1c is independently associated with risk of stroke among those without diabetes remains unclear. Methods: Among 32,826 participants in the Nurses’ Health Study who provided blood samples in 1989-1990, ischemic strokes were identified and confirmed by medical records through 2010. Participants with a history of diabetes or HbA1c ≥ 6.5% at baseline were excluded from the analyses. We conducted a nested case-control analysis of 378 cases, matched to controls (1:1) on age, menopausal status, use of postmenopausal hormones, ancestry, date of blood draw, fasting status and smoking status. The study population was categorized into quartiles based on the baseline HbA1c distribution among the controls Conditional and unconditional logistic regression models were used to estimate the multivariable adjusted (alcohol intake, body mass index [BMI], physical activity, aspirin use, C-reactive protein [CRP] levels, history of hypertension, coronary heart disease [CHD] and total/high density lipoprotein cholesterol) association of HbA1c and the risk of ischemic stroke; results were similar, thus we present results for unconditional analyses. Results: The mean age at baseline was 60.8 years and the median time to stroke was 9.0 years. In univariate analyses, median HbA1c levels did not differ between stroke cases compared to controls (median of 5.5 for both groups; p-value=0.91). The relative risk (RR) of ischemic stroke was 0.91 (95% confidence interval (CI), 0.57 - 1.45), p-trend = 0.55, among those in the highest quartile compared to the lowest. There was no evidence of effective modification of the association between HbA1c and ischemic stroke by age, BMI, smoking, hypertension or CRP. Conclusions: In this population of women without diabetes at baseline, HbA1c was not significantly associated with increased risk of total ischemic stroke.
Gabriel Weston: The different time zones of doctors and patients
Authors: Gabriel Weston
Journal: BMJ (2019)

I accompanied a friend to dialysis this week. She’s gone on alternate days for the past 20 years, while, in all my years as a doctor, I’d never been to one of these centres.

It ran like clockwork. My friend was allocated a bed and weighed. Numbers were punched into the machine directing four litres to be drawn off at a rate of 380 mL/min, a bag of dialysis fluid was popped in, and her neck line was hooked up. Within moments of her arriving, a pie chart on the monitor showed that the first fraction of her four hour session had elapsed. Swaddled in …
Integrative Next Generation Sequencing of Myeloproliferative Neoplasms and Correlation of Genetic Variations to Disease Severity
Authors: Malathi Kandarpa, Kristen Pettit, Yi-Mi Wu, Qing Li, Robert Lonigro, Dan Robinson, Luke F. Peterson, Philip S Boonstra, Arul Chinnaiyan, Moshe Talpaz
Journal: Blood (2018)
Abstract 17311: How You “Place It” Matters: The Impact of Inflow and Outflow VAD Cannulation Orientation on Overall System Thrombogenicity
Authors: Wei-Che Chiu, Phat Tran, Danny Bluestein, Marvin J Slepian
Journal: Circulation (2013)

Purpose: VADs are burdened with an incidence of thromboembolic events. Limited surgical guidance exists as to optimized orientation of VADs during surgical implantation as to radial orientation of ...
Scotland already has world leading mortality review system
Authors: C George M Fernie
Journal: BMJ (2019)

Fletcher and colleagues discuss the belated introduction of medical examiners1—I gave evidence for the BMA to the Luce review on death certification back in 2002. 

Despite alluding to medical examiners being established “in pilot sites across the UK,” this article fails to recognise the innovative development of proportionate scrutiny introduced throughout Scotland in 2015. Encompassing both general practice and secondary care, the Death …
Prior dengue virus infection and risk of Zika: A pediatric cohort in Nicaragua
Authors: Aubree Gordon, Lionel Gresh, Sergio Ojeda, Leah C. Katzelnick, Nery Sanchez, Juan Carlos Mercado, Gerardo Chowell, Brenda Lopez, Douglas Elizondo, Josefina Coloma, Raquel Burger-Calderon, Guillermina Kuan, Angel Balmaseda, Eva Harris
Journal: PLoS Medicine (2019)

Zika virus (ZIKV) emerged in northeast Brazil in 2015 and spread rapidly across the Americas, in populations that have been largely exposed to dengue virus (DENV). The impact of prior DENV infection on ZIKV infection outcome remains unclear. To study this potential impact, we analyzed the large 2016 Zika epidemic in Managua, Nicaragua, in a pediatric cohort with well-characterized DENV infection histories.Symptomatic ZIKV infections (Zika cases) were identified by real-time reverse transcription PCR and serology in a community-based cohort study that follows approximately 3,700 children aged 2-14 years old. Annual blood samples were used to identify clinically inapparent ZIKV infections using a novel, well-characterized serological assay. Multivariable Poisson regression was used to examine the relation between prior DENV infection and incidence of symptomatic and inapparent ZIKV infection. The generalized-growth method was used to estimate the effective reproduction number. From January 1, 2016, to February 28, 2017, 560 symptomatic ZIKV infections and 1,356 total ZIKV infections (symptomatic and inapparent) were identified, for an overall incidence of 14.0 symptomatic infections (95% CI: 12.9, 15.2) and 36.5 total infections (95% CI: 34.7, 38.6) per 100 person-years. Effective reproduction number estimates ranged from 3.3 to 3.4, depending on the ascending wave period. Incidence of symptomatic and total ZIKV infections was higher in females and older children. Analysis of the effect of prior DENV infection was performed on 3,027 participants with documented DENV infection histories, of which 743 (24.5%) had experienced at least 1 prior DENV infection during cohort follow-up. Prior DENV infection was inversely associated with risk of symptomatic ZIKV infection in the total cohort population (incidence rate ratio [IRR]: 0.63; 95% CI: 0.48, 0.81; p < 0.005) and with risk of symptomatic presentation given ZIKV infection (IRR: 0.62; 95% CI: 0.44, 0.86) when adjusted for age, sex, and recent DENV infection (1-2 years before ZIKV infection). Recent DENV infection was significantly associated with decreased risk of symptomatic ZIKV infection when adjusted for age and sex, but not when adjusted for prior DENV infection. Prior or recent DENV infection did not affect the rate of total ZIKV infections. Our findings are limited to a pediatric population and constrained by the epidemiology of the site.These findings support that prior DENV infection may protect individuals from symptomatic Zika. More research is needed to address the possible immunological mechanism(s) of cross-protection between ZIKV and DENV and whether DENV immunity also modulates other ZIKV infection outcomes such as neurological or congenital syndromes.
Choose and Use Your Chemical Probe Wisely to Explore Cancer Biology
Authors: Julian Blagg, Paul Workman
Journal: Cancer Cell (2017)

(Cancer Cell 32, 9–25; July 10, 2017) In the originally published version of this article, the authors mistakenly depicted an incorrect chemical structure for BI2536 in Figure 5C. The original version had the position of an ethyl substituent and a carbonyl group switched. The figure has now been updated with the correct chemical structure and is shown here and in the article online. This transcriptional error does not affect the conclusions in the Perspective. The authors apologize for this error and any confusion that it may have caused.Figure 5Thio-2, Lowering Lipophilicity and Pharmacophore Crossing (original)View Large Image Figure ViewerDownload Hi-res image Download (PPT) Choose and Use Your Chemical Probe Wisely to Explore Cancer BiologyBlagg et al.Cancer CellJuly 10, 2017In BriefSmall-molecule chemical probes or tools have become progressively more important in recent years as valuable reagents to investigate fundamental biological mechanisms and processes causing disease, including cancer. Chemical probes have also achieved greater prominence alongside complementary biological reagents for target validation in drug discovery. However, there is evidence of widespread continuing misuse and promulgation of poor-quality and insufficiently selective chemical probes, perpetuating a worrisome and misleading pollution of the scientific literature. We discuss current challenges with the selection and use of chemical probes, and suggest how biologists can and should be more discriminating in the probes they employ. Full-Text PDF Open Access
PDK1 Mediates <i>NOTCH1</i>-Mutated Head and Neck Squamous Carcinoma Vulnerability to Therapeutic PI3K/mTOR Inhibition
Authors: Vaishnavi Sambandam, Mitchell J. Frederick, Li Shen, Pan Tong, Xiayu Rao, Shaohua Peng, Ratnakar Singh, Tuhina Mazumdar, Chenfei Huang, Qiuli Li, Curtis R. Pickering, Jeffery N. Myers, Jing Wang, Faye M. Johnson
Journal: Clinical Cancer Research (2019)

Abstract Purpose: Head and neck squamous cell carcinoma (HNSCC) is driven largely by the loss of tumor suppressor genes, including NOTCH1, but lacks a biomarker-driven targeted therapy. Although the PI3K/mTOR pathway is frequently altered in HNSCC, the disease has modest clinical response rates to PI3K/mTOR inhibitors and lacks validated biomarkers of response. We tested the hypothesis that an unbiased pharmacogenomics approach to PI3K/mTOR pathway inhibitors would identify novel, clinically relevant molecular vulnerabilities in HNSCC with loss of tumor suppressor function. Experimental Design: We assessed the degree to which responses to PI3K/mTOR inhibitors are associated with gene mutations in 59 HNSCC cell lines. Apoptosis in drug-sensitive cell lines was confirmed in vitro and in vivo. NOTCH1 pathway components and PDK1 were manipulated with drugs, gene editing, knockdown, and overexpression. Results: PI3K/mTOR inhibition caused apoptosis and decreased colony numbers in HNSCC cell lines harboring NOTCH1 loss-of-function mutations (NOTCH1MUT) and reduced tumor size in subcutaneous and orthotopic xenograft models. In all cell lines, NOTCH1MUT was strongly associated with sensitivity to six PI3K/mTOR inhibitors. NOTCH1 inhibition or knockout increased NOTCH1WT HNSCC sensitivity to PI3K/mTOR inhibition. PDK1 levels dropped following PI3K/mTOR inhibition in NOTCH1MUT but not NOTCH1WT HNSCC, and PDK1 overexpression rescued apoptosis in NOTCH1MUT cells. PDK1 and AKT inhibitors together caused apoptosis in NOTCH1WT HNSCC but had little effect as single agents. Conclusions: Our findings suggest that NOTCH1MUT predicts response to PI3K/mTOR inhibitors, which may lead to the first biomarker-driven targeted therapy for HNSCC, and that targeting PDK1 sensitizes NOTCH1WT HNSCC to PI3K/mTOR pathway inhibitors.
The effect of adjuvant chemotherapy for stage III colon cancer in elderly patients.
Authors: Naomi Hayashi
Journal: Journal of Clinical Oncology (2019)

611 Background: Adjuvant chemotherapy (ACT) has been recommended for stage III colon cancer patients in NCCN guidelines. However, the benefit of ACT is still controversial in elderly patients. Methods: We retrospectively included stage III colon cancer patients with aged over 70 that were operated between 2008 and 2015 in Tosei general hospital from Japan. We calculated 3 years recurrence rate and performed a multivariate analysis to estimate the risk of recurrence. The model was adjusted by including the following 7 confounders: Age, ECOG-PS (0-1 or ≥ 2), tumor site (right or left), T stage (T1-3 or T4 ), N stage (N1 or N2), pathological type (por-sig or other), and complete ACT (yes or no). No complete ACT was defined as discontinuation ACT and surgery alone. Results: 182 patients were identified (87 patients aged &lt; 70 and 95 patients aged ≥ 70). ACT was performed in 58 patients (61.1%) and complete rate was 67.2% in elderly patients. The median follow up was 36.0 months. 29 patients (30.0%) had relapse. 3 years recurrence rate was 24.3% and 37.8% with complete ACT or no complete ACT (p = 0.29). In multivariate analysis, N2 was only the risk of recurrence (HR 6.95, p &lt; 0.01). In further analysis, addition of oxaliplatin was significant risk factor of recurrence in elderly patients (HR 10.4, p &lt; 0.01). On the other hand, in young patients, no complete ACT was only risk of recurrence (p = 0.01). 3 years survival rate was 89.1% and 81.0% with complete ACT or no complete ACT (p = 0.27). Conclusions: The multivariate analysis showed that ACT did not reduce the risk of recurrence in elderly patients. Moreover, addition of oxaliplatin suggested not only futile but harmful in those patients. These results support the previous reports (MOSAIC study and PETACC-8 trial) that microsatellite instability and RAS status may affect the effect of oxaliplatin.
Abstract B005: Ginger consumption inhibits β-arrestin-2 expression and functions in melanoma and prostate cancer cells
Authors: Tonelia A. Mowart, Timothy Adekoya, Nikia Smith, Tonya S. Lane, Ricardo M. Richardson
Journal: Cancer Research (2018)

Abstract Ginger active components are widely known for being a potent antioxidant and recently as a potential anticancer agent. [6]-Gingerol, the most abundant and pungent bioactive component of ginger, was shown to inhibit angiogenesis and tumorigenesis in xenograph models of both prostate cancer (PCa) and melanoma. To date, the precise mechanism(s) for the antitumor effect of ginger is not well understood. The adaptor proteins, β-arrestins, have been shown to modulate tumor development and metastasis in both PCa and melanoma. In this study, we sought to determine the role of [6]-gingerol in β-arrestin (βarr) 1 and 2-mediated PCa and melanoma development, progression, and metastasis. To that end, the PCa cells PC-3 and the melanoma B16-F10 cells were treated with different concentrations of [6]-gingerol for 48 hours. Cell lysates were assayed by Western blot analysis for βarr-1 and βarr-2, CXCR1, and CXCR2 expression, as well as MAP kinase and transcription factors activation. The data demonstrated that pretreatment with [6]-gingerol caused a dose-dependent inhibition of βarr-2, but not βarr-1, in both cell lines, which correlated with significant decrease in Akt and NF-κB activation. [6]-Gingerol pretreatment decreased CXCR1 and CXCR2 expression, CXCL-8-induced intracellular calcium mobilization; and delayed wound closure. [6]-Gingerol exposure also decreased PC-3 and B16 metastasis in zebrafish. Altogether the data indicated that the protective effect of [6]-gingerol in tumorigenesis is likely mediated via a βarr-2-dependent mechanism. Citation Format: Tonelia A. Mowart, Timothy Adekoya, Nikia Smith, Tonya S. Lane, Ricardo M. Richardson. Ginger consumption inhibits β-arrestin-2 expression and functions in melanoma and prostate cancer cells [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B005.