bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exposure to intermittent hypoxia and sustained hypercapnia reduces therapeutic CPAP in participants with obstructive sleep apnea
Authors: El-Chami Mohamad , Sudan Sukhesh , Lin Ho-Sheng , Mateika Jason H. 
Published: July 2017

Our purpose was to determine whether exposure to mild intermittent hypoxia leads to a reduction in the therapeutic continuous positive airway pressure required to eliminate breathing events. Ten male participants were treated with twelve 2-min episodes of hypoxia ([Formula: see text] ≈50 mmHg) separated by 2-min intervals of normoxia in the presence of [Formula: see text] that was sustained 3 mmHg above baseline. During recovery from the last episode, the positive airway pressure was reduced in a stepwise fashion until flow limitation was evident. The participants also completed a sham protocol under normocapnic conditions, which mimicked the time frame of the intermittent hypoxia protocol. After exposure to intermittent hypoxia, the therapeutic pressure was significantly reduced (i.e., 5 cmH2O) without evidence of flow limitation (103.4 ± 6.3% of baseline, P = 0.5) or increases in upper airway resistance (95.6 ± 15.0% of baseline, P = 0.6). In contrast, a similar decrease in pressure was accompanied by flow limitation (77.0 ± 1.8% of baseline, P = 0.001) and an increase in upper airway resistance (167.2 ± 17.5% of baseline, P = 0.01) after the sham protocol. Consistent with the initiation of long-term facilitation of upper airway muscle activity, exposure to intermittent hypoxia reduced the therapeutic pressure required to eliminate apneic events that could improve treatment compliance. This possibility, coupled with the potentially beneficial effects of intermittent hypoxia on comorbidities linked to sleep apnea, suggests that mild intermittent hypoxia may have a multipronged therapeutic effect on sleep apnea. NEW & NOTEWORTHY Our new finding is that exposure to mild intermittent hypoxia reduced the therapeutic pressure required to treat sleep apnea. These findings are consistent with previous results, which have shown that long-term facilitation of upper muscle activity can be initiated following exposure to intermittent hypoxia in humans.
Potential involvement of lactate and interleukin-6 in the appetite-regulatory hormonal response to an acute exercise bout
Authors: Islam Hashim , Townsend Logan K. , McKie Greg L. , Medeiros Philip J. , Gurd Brendon J. , Hazell Tom J. 
Published: July 2017

High-intensity exercise suppresses appetite partly through changes in peripheral appetite-regulating hormones. Lactate and IL-6 mediate the release of these hormones in animal/cell models and may provide a mechanistic link between exercise intensity and appetite regulation. The current study examined changes in appetite-regulating hormones, lactate, and IL-6 after different intensities of running. Eight males completed four experimental sessions: 1) moderate-intensity continuous training (MICT; 65% V̇o2max); 2) vigorous-intensity continuous training (VICT; 85% V̇o2max); 3) sprint interval training (SIT; repeated “all-out” sprints); and 4) Control (CTRL; no exercise). Acylated ghrelin, active glucagon-like peptide-1 (GLP-1), total peptide YY (PYY), lactate, IL-6, and appetite perceptions were measured pre-, immediately postexercise, 30 min postexercise, and 90 min postexercise. Energy intake was recorded over 3 days. VICT and SIT suppressed ghrelin ( P < 0.001), although SIT elicited a greater ( P = 0.016 vs. MICT) and more prolonged ( P < 0.001 vs. all sessions) response. GLP-1 increased immediately after MICT ( P < 0.001) and 30 min after VICT ( P < 0.001) and SIT ( P < 0.002), while VICT elicited a greater postexercise increase in PYY vs. MICT ( P = 0.027). Postexercise changes in blood lactate and IL-6 correlated with the area under the curve values for ghrelin ( r = −0.60, P < 0.001) and GLP-1 ( r = 0.42, P = 0.017), respectively. Appetite was suppressed after exercise ( P < 0.001), although more so after VICT ( P < 0.027) and SIT ( P < 0.001) vs. MICT, and energy intake was reduced on the day after VICT ( P < 0.017 vs. MICT and CTRL) and SIT ( P = 0.049 vs. MICT). These findings support an intensity-dependent paradigm for appetite regulation following exercise and highlight the potential involvement of lactate and IL-6. NEW & NOTEWORTHY This study examines the involvement of two potential mechanisms (lactate and IL-6) that may explain the intensity-dependent effects of acute exercise on appetite-related parameters. Our findings support a clear intensity-dependent paradigm for appetite regulation following exercise, as highlighted by the change in acylated ghrelin and the suppression of appetite and energy intake after vigorous exercise (continuous and intermittent). Further, our findings extend previous work in animal/cell models by providing evidence for the potential role of lactate and IL-6 in mediating changes in appetite-related parameters following exercise in humans.
Dynamic hyperinflation and exercise limitations in obese asthmatic women
Authors: Ferreira Palmira Gabriele , Freitas Patrícia Duarte , Silva Aline Grandi , Porras Desidério Cano , Stelmach Rafael , Cukier Alberto , Fernandes Frederico Leon Arrabal , Martins Milton Arruda , Carvalho Celso R. F. 
Published: July 2017

Obese individuals and patients with asthma can develop dynamic hyperinflation (DH) during exercise; however, no previous study has investigated DH as a factor associated with reduced exercise capacity in obese asthmatic women. The aim of the present study was to examine the occurrence of DH and exercise limitations in obese asthmatics. Obese grade II [obese group (Ob-G); BMI 35–39.9 kg/m2; n=36] and nonobese [nonobese group (NOb-G); BMI 18.5-29.9 kg/m2; n=18] asthmatic patients performed a cardiopulmonary test to quantify peak V̇o2 and a submaximal exercise test to assess DH. Anthropometric measurements, quadriceps endurance, and lung function were also evaluated. A forward stepwise regression was used to evaluate the association between exercise tolerance (wattage) and limiting exercise factors. Fifty-four patients completed the protocol. The Ob-G ( n = 36) presented higher peak V̇o2 values but lower power-to-weight ratio values than the NOb-G ( P <0 .05). DH was more common in the Ob-G (72.2%) than in the NOb-G (38.9%, P < 0.05). The Ob-G had a greater reduction in the inspiratory capacity (−18 vs. −4.6%, P < 0.05). Exercise tolerance was associated with quadriceps endurance ( r = 0.65; p<0.001), oxygen pulse ( r = 0.52; p=0.001), and DH ( r = −0.46, P = 0.005). The multiple regression analysis showed that the exercise tolerance could be predicted from a linear association only for muscular endurance ( r = 0.82 and r2 = 0.67). This study shows that dynamic hyperinflation is a common condition in obese asthmatics; they have reduced fitness for activities of daily living compared to nonobese asthmatics. However, peripheral limitation was the main factor associated with reduced capacity of exercise in these patients. NEW & NOTEWORTHY This is the first study to investigate the occurrence of dynamic hyperinflation (DH) in obese asthmatics. Our results demonstrate that obese asthmatics present a higher frequency and intensity of DH than nonobese asthmatics. We also show that physical deconditioning in this population is linearly associated with cardiac (O2 pulse), respiratory (DH), and peripheral muscle (resistance) limitation. However, multiple linear regression demonstrated that peripheral muscle limitation may explain the exercise limitation in this population.
Combination Therapy with NHS-muIL12 and Avelumab (anti-PD-L1) Enhances Antitumor Efficacy in Preclinical Cancer Models
Authors: Xu Chunxiao , Zhang Yanping , Rolfe P. Alexander , Hernández Vivian M. , Guzman Wilson , Kradjian Giorgio , Marelli Bo , Qin Guozhong , Qi Jin , Wang Hong , Yu Huakui , Tighe Robert , Lo Kin-Ming , English Jessie M. , Radvanyi Laszlo , Lan Yan 
Published: July 2017

AbstractPurpose: To determine whether combination therapy with NHS-muIL12 and the anti-programmed death ligand 1 (PD-L1) antibody avelumab can enhance antitumor efficacy in preclinical models relative to monotherapies.Experimental Design: BALB/c mice bearing orthotopic EMT-6 mammary tumors and μMt− mice bearing subcutaneous MC38 tumors were treated with NHS-muIL12, avelumab, or combination therapy; tumor growth and survival were assessed. Tumor recurrence following remission and rechallenge was evaluated in EMT-6 tumor-bearing mice. Immune cell populations within spleen and tumors were evaluated by FACS and IHC. Immune gene expression in tumor tissue was profiled by NanoString® assay and plasma cytokine levels were determined by multiplex cytokine assay. The frequency of tumor antigen–reactive IFNγ-producing CD8+ T cells was evaluated by ELISpot assay.Results: NHS-muIL12 and avelumab combination therapy enhanced antitumor efficacy relative to either monotherapy in both tumor models. Most EMT-6 tumor–bearing mice treated with combination therapy had complete tumor regression. Combination therapy also induced the generation of tumor-specific immune memory, as demonstrated by protection against tumor rechallenge and induction of effector and memory T cells. Combination therapy enhanced cytotoxic NK and CD8+ T-cell proliferation and T-bet expression, whereas NHS-muIL12 monotherapy induced CD8+ T-cell infiltration into the tumor. Combination therapy also enhanced plasma cytokine levels and stimulated expression of a greater number of innate and adaptive immune genes compared with either monotherapy.Conclusions: These data indicate that combination therapy with NHS-muIL12 and avelumab increased antitumor efficacy in preclinical models, and suggest that combining NHS-IL12 and avelumab may be a promising approach to treating patients with solid tumors. Clin Cancer Res; 23(19); 5869–80. ©2017 AACR.
Bevacizumab Induces Acute Hypoxia and Cancer Progression in Patients with Refractory Breast Cancer: Multimodal Functional Imaging and Multiplex Cytokine Analysis
Authors: Ueda Shigeto , Saeki Toshiaki , Osaki Akihiko , Yamane Tomohiko , Kuji Ichiei 
Published: July 2017

Abstract
Purpose: Bevacizumab, an antibody against endothelial growth factor, is a key but controversial drug in the treatment of metastatic breast cancer. We, therefore, aimed to determine the intrinsic resistance to bevacizumab at the physiologic and molecular levels in advanced breast cancer using PET, dynamic contrast-enhanced MRI, diffuse optical spectroscopic imaging (DOSI), and multiplex cytokine assays.
Experimental Design: In total, 28 patients diagnosed with advanced stage III/IV breast cancer receiving single-agent bevacizumab for 1 week followed by paclitaxel combined with bevacizumab underwent 18F-fluorodeoxyglucose (FDG)-PET, 18F-fluoromisonidazole (FMISO)-PET, and MRI at both baseline and two courses after treatment initiation. Hemodynamic measurement using DOSI and blood sample collection were performed at baseline and multiple times during the first week after the initiation of single-agent bevacizumab. We distinguished nonresponders from responders by serial FDG-PET based on their glycolytic changes to chemotherapy.
Results: Nonresponders showed significantly higher hypoxic activity on FMISO-PET and less tumor shrinkage than responders. Hemodynamic parameters showed higher tumor blood volume and a remarkable decrease in the tissue oxygen level in nonresponders compared with responders after the infusion of single-agent bevacizumab. Multiplex cytokine assays revealed increased plasma levels of both proangiogenic and hypoxia-related inflammatory cytokines in nonresponders and decreased levels in responders.
Conclusions: Nonresponders exhibited a higher degree of angiogenesis with more severe hypoxia than responders during bevacizumab treatment. These findings demonstrated that the addition of bevacizumab to paclitaxel treatment under hypoxic conditions could be ineffective and may result in acute hypoxia and increased cytokine secretion associated with cancer progression. Clin Cancer Res; 23(19); 5769–78. ©2017 AACR.
High Level of Tobacco Carcinogen–Derived DNA Damage in Oral Cells Is an Independent Predictor of Oral/Head and Neck Cancer Risk in Smokers
Authors: Khariwala Samir S. , Ma Bin , Ruszczak Chris , Carmella Steven G. , Lindgren Bruce , Hatsukami Dorothy K. , Hecht Stephen S. , Stepanov Irina 
Published: July 2017

AbstractExposure to tobacco-specific nitrosamines (TSNA) and polycyclic aromatic hydrocarbons (PAH) is recognized to play an important role in the development of oral/head and neck squamous cell cancer (HNSCC). We recently reported higher levels of TSNA-associated DNA adducts in the oral cells of smokers with HNSCC as compared with cancer-free smokers. In this study, we further investigated the tobacco constituent exposures in the same smokers to better understand the potential causes for the elevated oral DNA damage in smokers with HNSCC. Subjects included cigarette smokers with HNSCC (cases, n = 30) and cancer-free smokers (controls, n = 35). At recruitment, tobacco/alcohol use questionnaires were completed, and urine and oral cell samples were obtained. Analysis of urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and N'-Nitrosonornicotine (NNN; TSNA biomarkers), 1-hydroxypyrene (1-HOP, a PAH), cotinine, 3′-hydroxycotinine, and the nicotine metabolite ratio (NMR) were performed. Cases and controls differed in mean age, male preponderance, and frequency of alcohol consumption (but not total alcoholic drinks). Univariate analysis revealed similar levels of NNN, 1-HOP, and cotinine between groups but, as reported previously, significantly higher DNA adduct formation in the cases. Multiple regression adjusting for potential confounders showed persistent significant difference in DNA adduct levels between cases and controls [ratio of geometric means, 20.0; 95% CI, 2.7–148.6). Our cohort of smokers with HNSCC demonstrates higher levels of TSNA-derived oral DNA damage in the setting of similar exposure to nicotine and tobacco carcinogens. Among smokers, DNA adduct formation may act as a predictor of eventual development of HNSCC that is independent of carcinogen exposure indicators. Cancer Prev Res; 10(9); 507–13. ©2017 AACR.See related editorial by Johnson and Bauman, p. 489
The Path of Most Resistance: Transdifferentiation Underlies Exceptional Nonresponses to Androgen Receptor Pathway Inhibition in Prostate Cancer
Authors: Sinha Seema , Nelson Peter S. 
Published: July 2017

Abstract
Summary: In this issue of Cancer Discovery, Zou and colleagues describe a mechanism involving cellular transdifferentiation that promotes exceptional resistance to antiandrogen therapy in prostate cancer. A background of coinactivation of Trp53 and Pten increased the frequency of the transdifferentiated neuroendocrine phenotype. These findings have implications for developing approaches to repress cellular plasticity and overcome treatment resistance. Cancer Discov; 7(7); 673–4. ©2017 AACR.
See related article by Zou et al., p. 736.
A randomised trial on the effect of anti-platelet therapy on the systemic inflammatory response in human endotoxaemia
Authors: Kiers Dorien , van der Heijden Wouter A. , van Ede Lisa , Gerretsen Jelle , de Mast Quirijn , van der Ven Andre J. , el Messaoudi Saloua , Rongen Gerard A. , Gomes Marc , Kox Matthijs , Pickkers Peter , Riksen Niels P. 
Published: July 2017

SummaryThe use of acetylsalicylic acid (ASA) is associated with improved outcome in patients with sepsis, and P2Y12 inhibitors have been suggested to also have immunomodulatory effects. Therefore, we evaluated the effects of clinically relevant combinations of antiplatelet therapy on the immune response in experimental endotoxaemia in humans in vivo. Forty healthy subjects were randomised to seven days of placebo, placebo with ASA, ticagrelor and ASA, or clopidogrel and ASA treatment. Systemic inflammation was elicited at day seven by intravenous administration of Escherichia coli endotoxin. ASA treatment profoundly augmented the plasma concentration of pro-inflammatory cytokines, but did not affect anti-inflammatory cytokines. Addition of either P2Y12 antagonist to ASA did not affect any of the circulating cytokines, except for an attenuation of the ASA-induced increase in TNFα by ticagrelor. Systemic inflammation increased plasma adenosine, without differences between groups, and although P2Y12 inhibition impaired platelet reactivity, there was no correlation with cytokine responses.Note: This work was performed at the Radboud University Medical Center, Nijmegen, The Netherlands.Supplementary Material to this article is available online at www.thrombosis-online.com.
Plasma carboxypeptidase U (CPU, CPB2, TAFIa) generation during in vitro clot lysis and its interplay between coagulation and fibrinolysis
Authors: Leenaerts Dorien , Aernouts Jef , Van Der Veken Pieter , Sim Yani , Lambeir Anne-Marie , Hendriks Dirk 
Published: July 2017

SummaryCarboxypeptidase U (CPU, CPB2, TAFIa) is a basic carboxypeptidase that is able to attenuate fibrinolysis. The inactive precursor procarboxypeptidase U is converted to its active form by thrombin, the thrombin-thrombomodulin complex or plasmin. The aim of this study was to investigate and characterise the time course of CPU generation in healthy individuals. In plasma of 29 healthy volunteers, CPU generation was monitored during in vitro clot lysis. CPU activity was measured by means of an enzymatic assay that uses the specific substrate Bz-o-cyano-Phe-Arg. An algorithm was written to plot the CPU generation curve and calculate the parameters that define it. In all individuals, CPU generation was biphasic. Marked inter-individual differences were present and a reference range was determined. The endogenous CPU generation potential is the composite effect of multiple factors. With respect to the first CPU activity peak characteristics, we found correlations with baseline proCPU concentration, proCPU Thr325Ile polymorphism, time to clot initiation and the clot lysis time. The second CPU peak related with baseline proCPU levels and with the maximum turbidity of the clot lysis profile. In conclusion, our method offers a technique to determine the endogenous CPU generation potential of an individual. The parameters obtained by the method quantitatively describe the different mechanisms that influence CPU generation during the complex interplay between coagulation and fibrinolysis, which are in line with the threshold hypothesis.Supplementary Material to this article is available online at www.thrombosis-online.com.
Prasugrel in critically ill patients
Authors: Schoergenhofer Christian , Hobl Eva-Luise , Staudinger Thomas , Speidl Walter , Heinz Gottfried , Siller-Matula Jolanta , Zauner Christian , Reiter Birgit , Kubica Jacek , Jilma Bernd 
Published: July 2017

SummaryWhile prasugrel is indicated for the treatment of myocardial infarction, its effects in the most severely affected patients requiring intensive care is unknown, so that we measured the antiplatelet effects and sparse pharmacokinetics of prasugrel in critically ill patients. Twenty-three patients admitted to medical intensive care units, who were treated with 10 mg prasugrel once daily, were included in this prospective trial. Critically ill patients responded poorly to daily prasugrel treatment: adenosine diphosphate (ADP)-induced aggregation in whole blood classified 65 % (95 % confidence intervals (CI) 43–84 %) of patients as having high on treatment platelet reactivity, platelet function under high shear rates even 74 % (95 %CI 52–90 %). There was only limited additional inhibition provided 2 hours after the next dose of prasugrel. In contrast, insufficient inhibition of the target was only seen in 26 % (95 %CI 10–48 %) of patients as measured by the vasodilator-stimulated phosphoprotein phosphorylation (VASP-P) assay. Low effective plasma levels of prasugrel active metabolite were measured at trough [0.5 (quartiles 0.5–1.1) ng/ml at baseline], and 2 hours after intake [5.7 (3.8–9.8) ng/ml], but showed coefficients of variation of ~70 %. In sum, inhibition of platelet aggregation by prasugrel is not uniform but highly variable in critically ill patients, similar to clopidogrel in a general population. The pharmacokinetic measurements indicate that poor absorption/metabolism of prasugrel may partly contribute while inflammation induced heightened intrinsic platelet reactivity may also play a role.Supplementary Material to this article is available online at www.thrombosis-online.com.Note: This work was performed at the Medical University of Vienna, Austria.
Effect Modification of Chronic Kidney Disease on the Association of Circulating and Imaging Cardiac Biomarkers With Outcomes
Authors: Gregg L. Parker , Adams‐Huet Beverley , Li Xilong , Colbert Gates , Jain Nishank , de Lemos James A. , Hedayati S. Susan 
Published: July 2017

Background

Cardiac troponin T and brain natriuretic peptide (
BNP
) are elevated in >50% of dialysis patients and are associated with poor outcomes. Few data investigated these associations in earlier chronic kidney disease (CKD).

Methods and Results

We studied whether
CKD
modified associations of elevated
BNP
, N‐terminal‐pro‐
BNP
, high‐sensitivity cardiac troponin T, coronary artery calcification, and left ventricular hypertrophy with all‐cause death and cardiovascular death/events in 3218 multiethnic individuals followed for 12.5 years, and whether biomarkers added prognostic information to traditional cardiovascular risk factors in
CKD
. Of the cohort, 279 (9%) had
CKD
. There were 296 deaths and 218 cardiovascular deaths/events. Of non‐
CKD
individuals, 7% died and 6% had cardiovascular death/event versus 32% and 30% of
CKD
participants,
P
<0.001 for both. The interaction between
BNP
and
CKD
on death was significant (
P
=0.01): the adjusted hazard ratio in
CKD
was 2.05, 95%
CI
(1.34, 3.14), but not significant in non‐
CKD
, 1.04 (0.76, 1.41).
CKD
modified the association of high‐sensitivity cardiac troponin T with cardiovascular death/event, adjusted hazard ratio 3.34 (1.56, 7.18) in
CKD
versus 1.65 (1.16, 2.35) in non‐
CKD
, interaction
P
=0.09. There was an interaction between N‐terminal‐pro‐
BNP
and
CKD
for death in those without prior cardiovascular disease. Addition of each biomarker to traditional risk factors improved risk prediction, except coronary artery calcification was not discriminatory for cardiovascular death/event in CKD.

Conclusions

Cardiac biomarkers, with the exception of coronary artery calcification, prognosticated outcomes in early‐stage
CKD
as well as, if not better than, in non‐
CKD
individuals, even after controlling for estimated glomerular filtration rate, and added to information obtained from traditional cardiovascular risk factors alone.