tbuckley/cabot-search huggingface dataset:
Increased Cardiovascular Risk Associated With E-Cigarette Use—Reply
Authors: Holly R. Middlekauff, Jesus A. Araujo
Journal: JAMA Cardiology (2017)

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Assessing the anticancer effects associated with food products and/or nutraceuticals using in vitro and in vivo preclinical development-related pharmacological tests
Authors: Florence Lefranc, Nurhayat Tabanca, Robert Kiss
Journal: Seminars in Cancer Biology (2017)

This review is part of a special issue entitled "Role of dietary pattern, foods, nutrients and nutraceuticals in supporting cancer prevention and treatment" and describes a pharmacological strategy to determine the potential contribution of food-related components as anticancer agents against established cancer. Therefore, this review does not relate to chemoprevention, which is analysed in several other reviews in the current special issue, but rather focuses on the following: i) the biological events that currently represent barriers against the treatment of certain types of cancers, primarily metastatic cancers; ii) the in vitro and in vivo pharmacological pre-clinical tests that can be used to analyse the potential anticancer effects of food-related components; and iii) several examples of food-related components with anticancer effects. This review does not represent a catalogue-based listing of food-related components with more or less anticancer activity. By contrast, this review proposes an original pharmacological strategy that researchers can use to analyse the potential anticancer activity of any food-related component-e.g., by considering the crucial characteristics of cancer biological aggressiveness. This review also highlights that cancer patients undergoing chemotherapy should restrict the use of "food complements" without supervision by a medical nutritionist. By contrast, an equilibrated diet that includes the food-related components listed herein would be beneficial for cancer patients who are not undergoing chemotherapy.
The low FODMAP diet: recent advances in understanding its mechanisms and efficacy in IBS
Authors: Heidi M Staudacher, Kevin Whelan
Journal: Gut (2017)

There is an intensifying interest in the interaction between diet and the functional GI symptoms experienced in IBS. Recent studies have used MRI to demonstrate that short-chain fermentable carbohydrates increase small intestinal water volume and colonic gas production that, in those with visceral hypersensitivity, induces functional GI symptoms. Dietary restriction of short-chain fermentable carbohydrates (the low fermentable oligosaccharide, disaccharide, monosaccharide and polyol (FODMAP) diet) is now increasingly used in the clinical setting. Initial research evaluating the efficacy of the low FODMAP diet was limited by retrospective study design and lack of comparator groups, but more recently well-designed clinical trials have been published. There are currently at least 10 randomised controlled trials or randomised comparative trials showing the low FODMAP diet leads to clinical response in 50%-80% of patients with IBS, in particular with improvements in bloating, flatulence, diarrhoea and global symptoms. However, in conjunction with the beneficial clinical impact, recent studies have also demonstrated that the low FODMAP diet leads to profound changes in the microbiota and metabolome, the duration and clinical relevance of which are as yet unknown. This review aims to present recent advances in the understanding of the mechanisms by which the low FODMAP diet impacts on symptoms in IBS, recent evidence for its efficacy, current findings regarding the consequences of the diet on the microbiome and recommendations for areas for future research.
Integrating Immunotherapy Into the Management of Renal Cell Carcinoma
Authors: Matthew Zibelman, Elizabeth R. Plimack
Journal: Journal of the National Comprehensive Cancer Network (2017)

Before 2005, systemic treatment of metastatic renal cell carcinoma (RCC) was limited to a few minimally effective options. Since then, new agents have emerged targeting the vascular endothelial growth factor and mTOR pathways, which has improved outcomes for patients. Options increased even further beginning in 2015 with 3 new agents, including the addition of nivolumab, the first immune checkpoint inhibitor to demonstrate improved survival in RCC. RCC has long been considered a malignancy with immunogenic potential, and nivolumab offers the potential for durable responses in some patients with a generally tolerable toxicity profile. With so many drugs available to clinicians and patients, properly integrating immune checkpoint blockade (ICB) into the treatment paradigm is challenging. Additionally, emerging research with other ICB agents, as well as ongoing trials of combination strategies, is likely to further impact clinical decision-making. This article attempts to provide some context to inform systemic treatment decisions in the current landscape, with a particular emphasis on the role of immunotherapy, outlines the ongoing immunotherapy research in RCC, and discusses how treatment may evolve.
Association of Glycemic Status During Progression of Chronic Kidney Disease With Early Dialysis Mortality in Patients With Diabetes
Authors: Connie M. Rhee, Csaba P. Kovesdy, Vanessa A. Ravel, Elani Streja, Steven M. Brunelli, Melissa Soohoo, Keiichi Sumida, Miklos Z. Molnar, Gregory A. Brent, Danh V. Nguyen, Kamyar Kalantar-Zadeh
Journal: Diabetes Care (2017)

OBJECTIVE Although early trials suggested that intensive glycemic targets reduce the number of complications with diabetes, contemporary trials indicate no cardiovascular benefit and potentially higher mortality risk. As patients with advanced chronic kidney disease (CKD) transitioning to treatment with dialysis were excluded from these studies, the optimal glycemic level in this population remains uncertain. We hypothesized that glycemic status, defined by hemoglobin A1c (HbA­­1c) and random glucose levels, in the pre–end-stage renal disease (ESRD) period is associated with higher 1-year post-ESRD mortality among patients with incident diabetes who have ESRD. RESEARCH DESIGN AND METHODS Among 17,819 U.S. veterans with diabetic CKD transitioning to dialysis from October 2007 to September 2011, we examined the association of mean HbA­­1c and random glucose levels averaged over the 1-year pre-ESRD transition period with mortality in the first year after dialysis initiation. All-cause mortality hazard ratios (HRs) were estimated using multivariable survival models. Secondary analyses examined cardiovascular mortality using competing risks methods. RESULTS HbA­­1c levels ≥8% (≥64 mmol/mol) were associated with higher mortality in the first year after dialysis initiation (reference value 6% to &amp;lt;7% [42–53 mmol/mol]): adjusted HRs [aHRs] 1.19 [95% CI 1.07–1.32] and 1.48 (1.31–1.67) for HbA­­1c 8% to &amp;lt;9% [64–75 mmol/mol] and ≥9% [≥75 mmol/mol], respectively). Random glucose levels ≥200 mg/dL were associated with higher mortality (reference value 100 to &amp;lt;125 mg/dL): aHR 1.34 [95% CI 1.20–1.49]). Cumulative incidence curves showed that incrementally higher mean HbA­­1c and random glucose levels were associated with increasingly higher cardiovascular mortality. CONCLUSIONS In patients with diabetes and CKD transitioning to dialysis, higher mean HbA­­1c and random glucose levels during the pre-ESRD prelude period were associated with higher 1-year post-ESRD mortality. Clinical trials are warranted to examine whether modulating glycemic status improves survival in this population.
Relationships of cyclin E with clinical outcome and biomarkers in older women with early operable primary breast cancer.
Authors: Binafsha Manzoor Syed, Andrew R. Green, Dal Morgan, Ian O. Ellis, Kelly Hunt, Khandan Keyomarsi, Kwok-Leung Cheung
Journal: Journal of Clinical Oncology (2017)

e12031 Background: Cyclin E is one of the factors responsible for transition from G1 to S phase of cell division. Cytoplasmic cyclin E has recently been shown to be associated with the greatest risk of breast cancer recurrence (Hunt KK et al. Clin Cancer Res. 2016 Nov 23). This study aimed to analyse intracellular relationships of cyclin E with clinical outcomes and with other biomarkers in a specific patient population. Methods: Over 37 years (1973-2010), 1,758 older (≥70 years) women with early operable (&lt;5cm) primary breast cancer were managed in a dedicated clinic in Nottingham. Of these 813 patients underwent primary surgery and 575 had good quality tumour samples available for tissue microarray construction and immunohistochemical studies of biomarkers. Cytoplasmic expression of cyclin E with or without nuclear expression was considered positive. Results: Cytoplasmic cyclin E expression was associated with poor clinical outcomes on multivariate analysis (see table below). Cytoplasmic cyclin E expression was significantly associated with negative ER(&lt;0.001), PR(p=0.008), CK19(p=0.009) and positive expression of Ki67(p=0.04), p53(p=0.02), CK5(p=0.001), CK17(p=0.04), LKB1(p=0.04), HER3(p=0.03) and HER4(p=0.04). No correlation was found with HER2, BRCA2, CK5/6, CK18, EGFR, CD44, MDM2, MDM4, E-Cadherin and MUC1. Conclusions: Cytoplasmic cyclin E is associated with poor clinical outcome and biomarkers of poor prognostic significance in older population with breast cancer. Cyclin E may serve as a potential therapeutic target in future. [Table: see text]
Characterization of the tumor immune microenvironment (TIM) with multiplex immunohistochemistry (mIHC) in patients with breast cancer following treatment with MK-2206.
Authors: Douglas Kanter Marks, Robyn Denise Gartrell, Margueritta El Asmar, Thomas Hart, Yan Lu, Camden Esancy, Hanina Hibshoosh, Eileen Connolly, Kevin Kalinsky, Yvonne M. Saenger
Journal: Journal of Clinical Oncology (2017)

e12109 Background: The PAM (PI3K/Akt/mTOR) signaling pathway has been implicated in the oncogenesis of multiple solid malignancies, including breast cancer (BC). Our aim is to characterize the TIM in a series of patients with operable stage I-III BC treated with MK-2206, an allosteric Akt inhibitor within a presurgical trial. In NCT01319539 , patients received 2 doses of MK-2206 with first dose at day -9 and second at day -2 from surgery. Methods: mIHC was performed using immune biomarkers (DAPI, CD3, CD8, CD4, FOXP3, CD68, Pancytokeratin) on full section (4uM) tissue slides from core biopsy specimens and postsurgical specimens of 10 patients - 5 treated with MK-2206, 5 paired controls. Images were taken using Vectra, a novel pathology workstation and analyzed using inForm software to perform cell classification and phenotyping. T- tests were used to compare biomarker changes before and after MK-2206. Results: Our preliminary analysis demonstrates that patients treated with MK-2206 exhibited an increase in median cytotoxic T-cells (CD3CD8+) density, as compared to the control population , which was statistically significant (87% vs.0.2%, p &lt; 0.05). We did not identify a change in macrophage (CD68) or T helper/T reg (CD4/CD4FOXP3+) density following MK-2206 treatment in this small cohort. We are currently expanding our myeloid panel as well as performing additional tissue analysis to validate our findings. As data is exploratory no correction was made for multiple comparisons. Conclusions: Tumor infiltrating lymphocytes (TILs) are both prognostic of overall survival as well as predictive of response to neoadjuvant chemotherapy in BC. At present, there are currently both FDA approved therapies, as well as agents in clinical development that exert antineoplastic activity through the PAM pathway. Investigations that endeavour to understand the impact of these therapies on the tumor immune microenvironment may lead to both an increased understanding of the bioactivity of these agents and potentially identify aspects of the immune response which can be exploited in future therapeutics.
In Vivo Analysis of Clonal Evolution of Multiple Myeloma
Authors: Yuji Mishima, Jiantao Shi, Michele Moschetta, Yujia Shen, Salomon Manier, Aldo M. Roccaro, Francois Mercier, Satoshi Takagi, Yawara Kawano, Shokichi Tsukamoto, Ilyas Sahin, Antonio Sacco, Kiyohiko Hatake, Franziska Michor, David T. Scadden, Irene M. Ghobrial
Journal: Blood (2016)
Tildrakizumab versus placebo or etanercept for chronic plaque psoriasis (reSURFACE 1 and reSURFACE 2): results from two randomised controlled, phase 3 trials
Authors: Kristian Reich, Kim A Papp, Andrew Blauvelt, Stephen K Tyring, Rodney Sinclair, Diamant Thaçi, Kristine Nograles, Anish Mehta, Nicole Cichanowitz, Qing Li, Kenneth Liu, Carmen La Rosa, Stuart Green, Alexa B Kimball
Journal: The Lancet (2017)
A phase II randomized study to compare abemaciclib plus trastuzumab with or without fulvestrant to standard of care chemotherapy plus trastuzumab in hormone receptor positive, HER2-positive advanced breast cancer (monarcHER).
Authors: Sara M. Tolaney, Nawel Bourayou, Shom Goel, Anwar Hossain, Fabrice Andre
Journal: Journal of Clinical Oncology (2017)

TPS1109 Background: Inhibition of CDK4 in preclinical models, demonstrated efficacy in HER2+ breast cancer and enhanced activity of HER2-targeted therapy suggesting a crosstalk between HER2 signaling and the cyclin D/CDK4 signaling pathway in which CDK4 &amp; CDK6 inhibitors may re-sensitize resistant tumors to HER2 blockade.Abemaciclib is a selective inhibitor of CDK4 &amp; CDK6 inhibitor that demonstrates single-agent anti-tumor activity on a continuous dosing schedule in women with hormone receptor positive (HR+) advanced breast cancer. Triple regimens with abemaciclib have been tolerable. Methods: monarcHER is an ongoing Phase 2, open-label, study in postmenopausal women with HR+, HER2+ locally advanced or metastatic breast cancer. Eligible patients (pts) are those previously treated with ≥2 HER2-directed therapies in advanced disease setting; T-DM1 and a taxane in any disease setting; no prior treatment with fulvestrant or any CDK4 &amp; CDK6 inhibitor or with ECOG PS ≤1; LVEF ≥50%; no visceral crisis and no CNS metastases that are untreated, symptomatic or requiring steroids. Pts are randomized 1:1:1 to Arm A (abemaciclib [150mg PO Q12H] plus trastuzumab [IV infusion Q3 weeks] plus fulvestrant [IM injection on D1, 15, 29 then Q4 weeks]), Arm B (abemaciclib plus trastuzumab), or Arm C (trastuzumab plus SOC single-agent chemotherapy of physician’s choice); stratified based on number of prior systemic regimens (excluding single agent endocrine therapy) and disease status (measurable vs nonmeasurable). The primary objective evaluates investigator-assessed progression-free survival (PFS). Secondary objectives include overall survival, objective response rate, duration of response, disease control rate, clinical benefit rate, safety and tolerability, efficacy, health outcomes and pharmacokinetics. Analysis is planned at 165 PFS events, providing ≥80% power to detect superiority of Arm A and Arm B over Arm C, assuming a hazard ratio of 0.67 at a one-sided alpha of 0.10. First pt visit occurred in May 2016; with a target enrollment of 225 pts. Contact information: 1-877-CTLILLY (1-877-285-4559) Clinical trial information: NCT02675231.
MDU ceases to cover private spinal surgery
Authors: Nigel Hawkes
Journal: BMJ (2017)

The Medical Defence Union, which claims to be Britain’s largest provider of medical indemnity cover to doctors, is withdrawing support for spinal surgery in private hospitals, blaming the prohibitive cost of claims.

The decision will not affect such operations in the NHS, which runs its own indemnity scheme, but NHS consultants who also work in the private sector will have to find a new provider for cover when their existing contract with MDU runs out. Without indemnity cover they will be unable to work in the private sector.

Fiona Booth, chief executive of the Association of Independent Healthcare Organisations, told The BMJ , “Private hospitals do not employ consultants but offer them practising privileges. Every hospital will have its own set of terms and conditions, but all will include the obligation to hold medical indemnity …
Reuse of Pacemakers
Authors: Santiago Nava, José L. Morales, Manlio F. Márquez, Fausto Barrera, Jorge Gómez, Luis Colín, Josep Brugada, Pedro Iturralde
Journal: Circulation (2013)

In developing economies, there are patients in whom pacemaker implantation is delayed because they cannot afford one. Reused devices have been a solution. To address concerns about safety, a cohort of consecutive patients implanted with a reused pacemaker was compared with a control group.A cohort of 603 consecutive patients from 2000 to 2010 was studied in an ambispective noninferiority study. The study group patients (n=307) received resterilized pacemakers, and the control group patients (n=296) received a new pacemaker. A combined end point of 3 major outcomes-unexpected battery depletion, infection, and device dysfunction-was analyzed. A total of 85 pacemakers had to be explanted, 31 in the control group (10.5%) and 54 in the study group (17.6%; relative risk, 1.68; 95% confidence interval, 1.1-2.5; P=0.02). Forty-three reached the primary end point, 16 in the control group (5.5%) and 27 in the study group (7.2%; relative risk, 1.3; 95% confidence interval, 0.70-2.45; P=0.794). In terms of individual outcomes, 5 new pacemakers (1.7%) and 11 resterilized pacemakers (3.6%) had unexpected battery depletion (relative risk, 2.12; 95% confidence interval, 0.75-6; P=0.116); 3.7% new pacemakers and 3.2% reused pacemakers had a procedure-related infection (relative risk, 0.87; 95% confidence interval, 0.38-2.03; P=0.46); and 1 pacemaker in the study group malfunctioned.Pacemaker reuse is feasible and safe and is a viable option for patient with bradyarrhythmias. Other than the expected shorter battery life, reuse of pacemaker generators is not inferior to the use of new devices.
Improving Gene Therapy Efficiency through the Enrichment of Human Hematopoietic Stem Cells
Authors: Katelyn E. Masiuk, Devin Brown, Jennifer Laborada, Roger P. Hollis, Fabrizia Urbinati, Donald B. Kohn
Journal: Molecular Therapy (2017)

Lentiviral vector (LV)-based hematopoietic stem cell (HSC) gene therapy is becoming a promising clinical strategy for the treatment of genetic blood diseases. However, the current approach of modifying 1 × 108 to 1 × 109 CD34+ cells per patient requires large amounts of LV, which is expensive and technically challenging to produce at clinical scale. Modification of bulk CD34+ cells uses LV inefficiently, because the majority of CD34+ cells are short-term progenitors with a limited post-transplant lifespan. Here, we utilized a clinically relevant, immunomagnetic bead (IB)-based method to purify CD34+CD38- cells from human bone marrow (BM) and mobilized peripheral blood (mPB). IB purification of CD34+CD38- cells enriched severe combined immune deficiency (SCID) repopulating cell (SRC) frequency an additional 12-fold beyond standard CD34+ purification and did not affect gene marking of long-term HSCs. Transplant of purified CD34+CD38- cells led to delayed myeloid reconstitution, which could be rescued by the addition of non-transduced CD38+ cells. Importantly, LV modification and transplantation of IB-purified CD34+CD38- cells/non-modified CD38+ cells into immune-deficient mice achieved long-term gene-marked engraftment comparable with modification of bulk CD34+ cells, while utilizing ∼7-fold less LV. Thus, we demonstrate a translatable method to improve the clinical and commercial viability of gene therapy for genetic blood cell diseases.
Abstract AP10: A NOVEL PAN–ALDH1A INHIBITOR INDUCES NECROPTOSIS IN OVARIAN CANCER STEM–LIKE CELLS AND SYNERGIZES WITH CHEMOTHERAPY TO IMPROVE OUTCOMES
Authors: Ilana Chefetz, Linda Hong, Kun Yang, Brandt Huddle, Charles Landen, Thomas Hurley, Scott D. Larsen, Ronald J. Buckanovich
Journal: Clinical Cancer Research (2017)

Abstract BACKGROUND: We recently demonstrated that Aldehyde dehydrogenase (ALDH) activity and the stem cell marker CD133 can be used to define an ovarian cancer cell differentiation hierarchy. We demonstrated that even small increases in multipotent ALDHbrightCD133+ cancer stem–like cells (CSC) significantly increase chemotherapy resistance and tumor initiation capacity. ALDH1A family members (ALDH1A1, 1A2, and 1A3) have been implicated as the primary enzymes identifying CSC and have been strongly linked with chemotherapy resistance. Given the expression of ALDH1A family members in CSC and their role in chemotherapy resistance we hypothesized they could be important therapeutic targets. METHODS AND RESULTS: We developed a panel of novel ALDH inhibitors (ALDHi). We identified a DEAB analog 673540 (673A) which inhibits all three ALDH1A1 enzymes (IC50 ~220nM). Pan–ALDH1A inhibition, induced necroptotic cell death specifically in ALDHbright and CD133+ ovarian CSC. 673A induced necroptosis was driven by the induction of the mitochondrial uncoupling proteins, UCP1 and UCP3, and reduction in OXPHOS capacity. Necroptosis was caspase and RIP1 independent, but is associated with MLKL translocation to membrane, and DRP1 activation and translocation to mitochondria. 673A therapy was highly synergistic with chemotherapy, reducing tumor initiation capacity, and resulting in a 60% tumor cure rate in multiple tumor models in–vivo. CONCLUSIONS: ALDHi are highly active in experimental models of ovarian cancer. As ALDHi induce metabolic necroptosis, ALDHi are active in apoptosis resistant ovarian cancer cell lines. These studies support the development of ALDHi as novel therapeutics for ovarian cancer. Citation Format: Ilana Chefetz, Linda Hong, Kun Yang, Brandt Huddle, Charles Landen, Thomas Hurley, Scott D. Larsen, and Ronald J. Buckanovich. A NOVEL PAN–ALDH1A INHIBITOR INDUCES NECROPTOSIS IN OVARIAN CANCER STEM–LIKE CELLS AND SYNERGIZES WITH CHEMOTHERAPY TO IMPROVE OUTCOMES [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr AP10.