tbuckley/cabot-search huggingface dataset:
Nitrite circumvents platelet resistance to nitric oxide in patients with heart failure preserved ejection fraction and chronic atrial fibrillation
Authors: Alessandra Borgognone, Eduard Shantsila, Sophie M Worrall, Eakkapote Prompunt, Thomas Loka, Brodie L Loudon, Myriam Chimen, G Ed Rainger, Janet M Lord, Ashley Turner, Peter Nightingale, Martin Feelisch, Paulus Kirchhof, Gregory Y H Lip, Steve P Watson, Michael P Frenneaux, Melanie Madhani
Journal: Cardiovascular Research (2018)

Heart failure (HF) is a pro-thrombotic state. Both platelet and vascular responses to nitric oxide (NO) donors are impaired in HF patients with reduced ejection fraction (HFrEF) compared with healthy volunteers (HVs) due to scavenging of NO, and possibly also reduced activity of the principal NO sensor, soluble guanylate cyclase (sGC), limiting the therapeutic potential of NO donors as anti-aggregatory agents. Previous studies have shown that nitrite inhibits platelet activation presumptively after its reduction to NO, but the mechanism(s) involved remain poorly characterized. Our aim was to compare the effects of nitrite on platelet function in HV vs. HF patients with preserved ejection fraction (HFpEF) and chronic atrial fibrillation (HFpEF–AF), vs. patients with chronic AF without HF, and to assess whether these effects occur independent of the interaction with other formed elements of blood. Platelet responses to nitrite and the NO donor sodium nitroprusside (SNP) were compared in age-matched HV controls (n = 12), HFpEF–AF patients (n = 29), and chronic AF patients (n = 8). Anti-aggregatory effects of nitrite in the presence of NO scavengers/sGC inhibitor were determined and vasodilator-stimulated phosphoprotein (VASP) phosphorylation was assessed using western blotting. In HV and chronic AF, both nitrite and SNP inhibited platelet aggregation in a concentration-dependent manner. Inhibition of platelet aggregation by the NO donor SNP was impaired in HFpEF-AF patients compared with healthy and chronic AF individuals, but there was no impairment of the anti-aggregatory effects of nitrite. Nitrite circumvented platelet NO resistance independently of other blood cells by directly activating sGC and phosphorylating VASP. We here show for the first time that HFpEF-AF (but not chronic AF without HF) is associated with marked impairment of platelet NO responses due to sGC dysfunction and nitrite circumvents the 'platelet NO resistance' phenomenon in human HFpEF, at least partly, by acting as a direct sGC activator independent of NO.
LPA Induces Metabolic Reprogramming in Ovarian Cancer via a Pseudohypoxic Response
Authors: Ji Hee Ha, Rangasudhagar Radhakrishnan, Muralidharan Jayaraman, Mingda Yan, Jeremy D. Ward, Kar-Ming Fung, Katherine Moxley, Anil K. Sood, Ciro Isidoro, Priyabrata Mukherjee, Yong Sang Song, Danny N. Dhanasekaran
Journal: Cancer Research (2018)

Although hypoxia has been shown to reprogram cancer cells toward glycolytic shift, the identity of extrinsic stimuli that induce metabolic reprogramming independent of hypoxia, especially in ovarian cancer, is largely unknown. In this study, we use patient-derived ovarian cancer cells and high-grade serous ovarian cancer cell lines to demonstrate that lysophosphatidic acid (LPA), a lipid growth factor and GPCR ligand whose levels are substantially increased in ovarian cancer patients, triggers glycolytic shift in ovarian cancer cells. Inhibition of the G protein α-subunit Gαi2 disrupted LPA-stimulated aerobic glycolysis. LPA stimulated a pseudohypoxic response via Rac-mediated activation of NADPH oxidase and generation of reactive oxygen species, resulting in activation of HIF1α. HIF1α in turn induced expression of glucose transporter-1 and the glycolytic enzyme hexokinase-2 (HKII). Treatment of mice bearing ovarian cancer xenografts with an HKII inhibitor, 3-bromopyruvate, attenuated tumor growth and conferred a concomitant survival advantage. These studies reveal a critical role for LPA in metabolic reprogramming of ovarian cancer cells and identify this node as a promising therapeutic target in ovarian cancer.Significance: These findings establish LPA as a potential therapeutic target in ovarian cancer, revealing its role in the activation of HIF1α-mediated metabolic reprogramming in this disease. Cancer Res; 78(8); 1923-34. ©2018 AACR.
Short-Term Elevation of Fine Particulate Matter Air Pollution and Acute Lower Respiratory Infection
Authors: Benjamin D. Horne, Elizabeth A. Joy, Michelle G. Hofmann, Per H. Gesteland, John B. Cannon, Jacob S. Lefler, Denitza P. Blagev, E. Kent Korgenski, Natalie Torosyan, Grant I. Hansen, David Kartchner, C. Arden Pope
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Nearly 60% of U.S. children live in counties with particulate matter less than or equal to 2.5 μm in aerodynamic diameter (PM2.5) concentrations above air quality standards. Understanding the relationship between ambient air pollution exposure and health outcomes informs actions to reduce exposure and disease risk.To evaluate the association between ambient PM2.5 levels and healthcare encounters for acute lower respiratory infection (ALRI).Using an observational case-crossover design, subjects (n = 146,397) were studied if they had an ALRI diagnosis and resided on Utah's Wasatch Front. PM2.5 air pollution concentrations were measured using community-based air quality monitors between 1999 and 2016. Odds ratios for ALRI healthcare encounters were calculated after stratification by ages 0-2, 3-17, and 18 or more years.Approximately 77% (n = 112,467) of subjects were 0-2 years of age. The odds of ALRI encounter for these young children increased within 1 week of elevated PM2.5 and peaked after 3 weeks with a cumulative 28-day odds ratio of 1.15 per +10 μg/m3 (95% confidence interval, 1.12-1.19). ALRI encounters with diagnosed and laboratory-confirmed respiratory syncytial virus and influenza increased following elevated ambient PM2.5 levels. Similar elevated odds for ALRI were also observed for older children, although the number of events and precision of estimates were much lower.In this large sample of urban/suburban patients, short-term exposure to elevated PM2.5 air pollution was associated with greater healthcare use for ALRI in young children, older children, and adults. Further exploration is needed of causal interactions between PM2.5 and ALRI.
Skills and characteristics of the e-health literate patient
Authors: Richard Osborne, Lars Kayser
Journal: BMJ (2018)

Riggare considers what healthcare professionals could learn from e-patients.1 People and communities will inevitably embrace digital technologies, including search engines that gather both up-to-date and fallacious information. Healthcare systems and their public and private funders need to respond in an informed and structured manner. Not every current or future patient will be an e-patient, but it will soon be the norm. In …
87P Assessment of the prognostic utility of the enumeration of circulating tumour cells at the end of treatment and disease relapse in small cell lung cancer patients
Authors: A.J. Vickers, A. Xenofontos, L. Carter, R. Bernabe, M. Carter, L. Franklin, K. Morris, J. Pierce, C. Dive, F. Blackhall
Journal: Journal of Thoracic Oncology (2018)
Associations of Fitness, Physical Activity, Strength, and Genetic Risk With Cardiovascular Disease
Authors: Emmi Tikkanen, Stefan Gustafsson, Erik Ingelsson
Journal: Circulation (2018)

Background: Observational studies have shown inverse associations among fitness, physical activity, and cardiovascular disease. However, little is known about these associations in individuals with elevated genetic susceptibility for these diseases. Methods: We estimated associations of grip strength, objective and subjective physical activity, and cardiorespiratory fitness with cardiovascular events and all-cause death in a large cohort of 502 635 individuals from the UK Biobank (median follow-up, 6.1 years; interquartile range, 5.4–6.8 years). Then we further examined these associations in individuals with different genetic burden by stratifying individuals based on their genetic risk scores for coronary heart disease and atrial fibrillation. We compared disease risk among individuals in different tertiles of fitness, physical activity, and genetic risk using lowest tertiles as reference. Results: Grip strength, physical activity, and cardiorespiratory fitness showed inverse associations with incident cardiovascular events (coronary heart disease: hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.77–0.81; HR, 0.95; 95% CI, 0.93–0.97; and HR, 0.68; 95% CI, 0.63–0.74, per SD change, respectively; atrial fibrillation: HR, 0.75; 95% CI, 0.73–0.76; HR, 0.93; 95% CI, 0.91–0.95; and HR, 0.60; 95% CI, 0.56–0.65, per SD change, respectively). Higher grip strength and cardiorespiratory fitness were associated with lower risk of incident coronary heart disease and atrial fibrillation in each genetic risk score group ( P trend &lt;0.001 in each genetic risk category). In particular, high levels of cardiorespiratory fitness were associated with 49% lower risk for coronary heart disease (HR, 0.51; 95% CI, 0.38–0.69) and 60% lower risk for atrial fibrillation (HR, 0.40; 95%, CI 0.30–0.55) among individuals at high genetic risk for these diseases. Conclusions: Fitness and physical activity demonstrated inverse associations with incident cardiovascular disease in the general population, as well as in individuals with elevated genetic risk for these diseases.
Clinical and immunologic variables associated with outcomes following combination ipilimumab and nivolumab immunotherapy in melanoma.
Authors: Samuel Rosner, Erica Kwong, Katherine Panageas, Michael Andrew Postow
Journal: Journal of Clinical Oncology (2017)

55 Background: Prior studies have shown routine laboratory parameters such as lymphocytes (lymphs) and eosinophils (eos) are associated with outcome in patients (pts) treated with ipilimumab (ipi) or programmed death-1 (PD-1) agents as single drugs. Less is known about these parameters as potential biomarkers for pts treated with ipi + nivolumab (nivo) in combination. Methods: After IRB approval, a single institution, retrospective review was performed of pts with melanoma who received ipi + nivo on phase I-III clinical trials (n=122) as well as via commercial use (n=87). Prior to treatment initiation, routine laboratory parameters were investigated and correlated with overall survival (OS) and disease response by RECIST 1.1 (partial or complete response vs. stable/progressive disease). Absolute as well as relative frequencies of cell counts were examined. Kaplan-Meier estimators and Cox regression were performed. Results: 209 pts, 85 (41%) women and 124 (59%) men, with a median age of 60.5 years were analyzed. Median OS was 44.4 months, 95% CI (32.9, not reached). 23 pts had a complete response (CR) and 87 pts had a partial response (PR), while 39 pts had stable disease (SD) and 49 pts had progressive disease (PD). By univariate analysis, significant favorable factors for OS included: low absolute monocytes, low absolute/relative neutrophils, high relative eos, and high relative lymphs. Low LDH and the neutrophil to lymph ratio were also associated with better OS. None of these factors were significantly associated with response by RECIST 1.1. Conclusions: Routinely assessed laboratory parameters were associated with OS but not disease response among pts receiving ipi + nivo. Some of these factors were similar to those which previously correlated with OS after ipi or nivo as single-agents, suggesting they may be prognostic. Given the ongoing randomized phase III study of ipi + nivo and nivo vs. ipi, there is an opportunity to examine whether these factors are relevant in refining which pts obtain the greatest benefit from ipi + nivo vs. single agent therapy.
Silencing the Snail-Dependent RNA Splice Regulator ESRP1 Drives Malignant Transformation of Human Pulmonary Epithelial Cells
Authors: Tonya C. Walser, Zhe Jing, Linh M. Tran, Ying Q. Lin, Natalie Yakobian, Gerald Wang, Kostyantyn Krysan, Li X. Zhu, Sherven Sharma, Mi-Heon Lee, John A. Belperio, Aik T. Ooi, Brigitte N. Gomperts, Jerry W. Shay, Jill E. Larsen, John D. Minna, Long-sheng Hong, Michael C. Fishbein, Steven M. Dubinett
Journal: Cancer Research (2018)

Abstract Epithelial-to-mesenchymal transition (EMT) is organized in cancer cells by a set of key transcription factors, but the significance of this process is still debated, including in non–small cell lung cancer (NSCLC). Here, we report increased expression of the EMT-inducing transcription factor Snail in premalignant pulmonary lesions, relative to histologically normal pulmonary epithelium. In immortalized human pulmonary epithelial cells and isogenic derivatives, we documented Snail-dependent anchorage-independent growth in vitro and primary tumor growth and metastatic behavior in vivo. Snail-mediated transformation relied upon silencing of the tumor-suppressive RNA splicing regulatory protein ESRP1. In clinical specimens of NSCLC, ESRP1 loss was documented in Snail-expressing premalignant pulmonary lesions. Mechanistic investigations showed that Snail drives malignant progression in an ALDH+CD44+CD24− pulmonary stem cell subset in which ESRP1 and stemness-repressing microRNAs are inhibited. Collectively, our results show how ESRP1 loss is a critical event in lung carcinogenesis, and they identify new candidate directions for targeted therapy of NSCLC. Significance: This study defines a Snail-ESRP1 cancer axis that is crucial for human lung carcinogenesis, with implications for new intervention strategies and translational opportunities. Cancer Res; 78(8); 1986–99. ©2018 AACR.
Prognostic factors influencing survival in small bowel neuroendocrine tumors with liver metastasis.
Authors: Nicholas Manguso, Attiya Harit, Nicholas N. Nissen, James Mirocha, Andrew Eugene Hendifar, Farin F. Amersi
Journal: Journal of Clinical Oncology (2017)

e15688 Background: Management of liver metastasis in patients with small bowel neuroendocrine tumors (SBNET) remains unclear. Complete surgical resection improves long term survival however factors that influence overall prognosis are not clear. Methods: Database review identified 301 patients diagnosed with SBNET from 1990 to 2013. Only patients with known liver metastasis who underwent resection of the primary tumor were included. Outcomes among patients who underwent complete surgical resection, incomplete debulking of liver metastasis, and resection of the primary tumor alone were compared. The Kaplan-Meier method was used for survival estimates and Cox regression was used to identify predictors of death. Results: 111 patients met study criteria. Median age was 59 years (range 16-80); 49% were male. The terminal ileum (47/111, 42%) was the most common primary tumor location. The median number of liver lesions was 8.5 (range 1-31) and median lesions resected was 1 (range 0-31). In addition to resection of the primary tumor, 36 patients (32%) had no liver resection (NR), 41 (36.9%) had complete resection of liver disease (R0) and 34 (30%) had incomplete resection of liver metastasis (R1). 58 patients (36%) had one or more wedge resections, 12 (10.8%) underwent segmentectomy and 5 (4.5%) had a lobectomy. 33 (29.7%) patients underwent post-operative chemoembolization, 25 (22.5%) had radioembolization and 23 (20.7%) had radiofrequency ablation. The R1 group differed from the R0 group in median size of primary tumor (2.5 cm R1 vs 1.6 cm R0, p = 0.05) and median number of positive lymph nodes (5.0 R1 vs 3.0 R0, p = 0.05). The 5-year OS was 80.9%, 81.1% and 100% for NR, R1 and R0 groups respectively (p = 0.01). 10-year OS did not differ between groups (72.8% NR vs 81.1% R1vs 82.5% NR, p = 0.31). Cox regression showed post-operative administration of chemotherapy (HR = 3.68, p &lt; 0.01) and higher tumor grade (HR = 18.4, p = 0.02) increased risk of death. Conclusions: In patients with SBNET with liver metastasis, higher tumor grade and post-operative chemotherapy increased risk of death. However, resection of the primary tumor along with liver metastasis improves the 5-year OS with complete cytoreduction providing the most benefit.
Feasibility study of multiple HLA-class IA restricted peptide vaccines (KRM-19) for metastatic triple negative breast cancer (TNBC).
Authors: Uhi Toh, Shuko Saku, Nobutaka Iwakuma, Mina Okabe, Shigeki Shichijo, Akira Yamada, Kyogo Itoh, Yoshito Akagi
Journal: Journal of Clinical Oncology (2017)

164 Background: Our previous phase II clinical trial has indicated that the therapeutic selected personalized peptide vaccines (PPV) were effective for boosting anticancer immunity and the immune response after PPV was associated with the clinical outcome as a prognostic factor for metastatic breast cancer (mBC). Based on the data from the PPV studies, we have conducted an early phase II study to evaluate the safety and the efficacy of a new regimen using multiple peptide vaccines (KRM-19) for pts with metastatic TNBC. Methods: KRM-19 consisted of 19 mixed peptides which were chosen from the previously reported 31 PPVs according to their anti-tumor immunologic effect and safety profile for mBC pts. All patients had histologically confirmed measurable ER-PgR-Her2- mBC and their human leukocyte antigen (HLA)-A molecules should be each of -A2, A3, A11, A24, A26, A31, or A33. KRM-19 (19mg/ml) was administrated subcutaneously in order with schedule of every week for a total of 6 doses. The concurrent conventional chemo- and/or endocrine therapy was not permitted for the combination, but was available for post-study treatment. Measurement of peptide-specific cytotoxic T lymphocyte (CTL) and IgG responses were conducted before and after vaccination. Levels of IgG reactive to each of the 19 peptides in the pre- and post-vaccination plasma were measured using the LUMINEX system at every 6 vaccinations. Peptide-specific CTL responses were examined by INF-ɤ ELISPOT. Clinical response was evaluated by RECIST criteria. Results: 10 patients with refractory metastatic TNBC received all 6 vaccines and 10/10 patients experienced Grade 1-2 skin reaction at injection site, 5/10 pts had Grade 2-3 liver function disorder, 3/10 and 1/10 pts had Grade 2 bone marrow suppression and nausea, respectively. The clinical responses were assessed in 8 pts included 1 PR case, 4 SD cases, and 3 PD cases. The evaluation of other clinical and immunologic data is underway. Conclusions: Subcutaneous KRM-19 vaccine administration was safe and resulted in a 12.5% objective response and 62.5% clinical benefit rate in TNBC pts, warranting further larger scale study. Clinical trial information: UMIN000014616.
Palliative care and end-of-life health care utilization of pancreatic cancer patients at an urban safety-net hospital.
Authors: Nizar Bhulani, M. Elizabeth Paulk, Arjun Gupta, Kiauna Donnell, Valorie Harvey, Joan Cox, John Vernon Cox, Sirisha Karri, Udit N. Verma, Aravind Sanjeevaiah, Naga Koteswari Cheedella, Leticia Khosama, Yull Edwin Arriaga, Samira K. Syed, Syed Mohammad Ali Kazmi, Adam Korenke, Muhammad Shaalan Beg
Journal: Journal of Clinical Oncology (2018)

489 Background: There has been an increase in Palliative care utilization in cancer patients. We examined trends of palliative care and intensive care utilization in pancreatic cancer patients in an urban setting safety net hospital. Methods: This is a retrospective analysis of pancreatic cancer patients seen at the Parkland Health and Hospital System between January 1999 and September 2016. Cancer cases and receipt of palliative care were identified from prospectively maintained registries. Health care utilization including intensive care unit (ICU) was reviewed. All statistical analysis was done using IBM SPSS version 24. Results: We identified 455 new diagnoses of pancreatic cancer, mean age 61 years, 227 (50%) female and 228 (50%) white. Of these, 277 (61%) received palliative care ever. Patient who received palliative care were more likely to be younger (mean age, 59.3+-12 vs 62.8 +- 12 years) and have stage 4 disease vs stage 1-3 disease (p 0.006, and p 0.003 respectively). There was no statistically significant difference in palliative care utilization between gender and ethnicity groups. 140 patients had a DNR order and 29 required ICU admission at any point. A first contact with palliative care consult was obtained &lt; = 7 days before death for 29 (10%) patients, &lt; = 30 days before death for 86 (31%) patients, 30-60 days before death for 50 (18%) and more than 60 days before death for 141 (51%) patients. Patients receiving palliative care were more likely to have a DNR status (p &lt; 0.001) but had no difference in ICU use within the last 30 days of life (p 0.285). Conclusions: The rate of palliative care in patients with pancreatic cancer in this cohort from a safety net hospital is higher than nationally reported studies. Most patients received palliative care &gt; 30 days before death. While patients received early palliative care, it did not result in reduced ICU care. Factors influencing ICU care utilization near the end of life need further study.
Breast Cancer in Relation to Nursing and Menopausal History2
Authors: Brian MacMahon, Manning Feinleib
Journal: JNCI Journal of the National Cancer Institute (1960)

Journal Article Breast Cancer in Relation to Nursing and Menopausal History Get access Brian MacMahon, Brian MacMahon Search for other works by this author on: Oxford Academic PubMed Google Scholar Manning Feinleib Manning Feinleib Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 24, Issue 3, March 1960, Pages 733–753, https://doi.org/10.1093/jnci/24.3.733 Published: 01 March 1960 Article history Received: 28 August 1959 Published: 01 March 1960
A ternary-complex of a suicide gene, a RAGE-binding peptide, and polyethylenimine as a gene delivery system with anti-tumor and anti-angiogenic dual effects in glioblastoma
Authors: Eunji Choi, Jungju Oh, Dahee Lee, Jaewon Lee, Xiaonan Tan, Minkyung Kim, Gyeungyun Kim, Chunxian Piao, Minhyung Lee
Journal: Journal of Controlled Release (2018)
CNS myeloid cells critically regulate heat hyperalgesia
Authors: Stefanie Kälin, Kelly R. Miller, Roland E. Kälin, Marina Jendrach, Christian Witzel, Frank L. Heppner
Journal: Journal of Clinical Investigation (2018)

Activation of non-neuronal microglia is thought to play a causal role in spinal processing of neuropathic pain. To specifically investigate microglia-mediated effects in a model of neuropathic pain and overcome the methodological limitations of previous approaches exploring microglia function upon nerve injury, we selectively ablated resident microglia by intracerebroventricular ganciclovir infusion into male CD11b-HSVTK–transgenic mice, which was followed by a rapid, complete, and persistent (23 weeks) repopulation of the CNS by peripheral myeloid cells. In repopulated mice that underwent sciatic nerve injury, we observed a normal response to mechanical stimuli, but an absence of thermal hypersensitivity ipsilateral to the injured nerve. Furthermore, we found that neuronal expression of calcitonin gene–related peptide (CGRP), which is a marker of neurons essential for heat responses, was diminished in the dorsal horn of the spinal cord in repopulated mice. These findings identify distinct mechanisms for heat and mechanical hypersensitivity and highlight a crucial contribution of CNS myeloid cells in the facilitation of noxious heat.