bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preventive effects of transcutaneous electrical acustimulation on ischemic stroke-induced constipation mediated via the autonomic pathway
Authors: Liu Zhaoxiu , Ge Yebo , Xu Feng , Xu Yuemei , Liu Yanmei , Xia Feizhen , Lin Lin , Chen Jiande D. Z. 
Published: May 2018

The aim of this study was to explore the preventive effect and possible mechanisms of transcutaneous electrical acustimulation (TEA) on stroke-induced constipation. A total of 86 ischemic stroke patients were randomly allocated to 2-wk TEA or sham-TEA group. Bowel dairy and Bristol Stool Form Scale were recorded daily. Constipation and dyspeptic symptom assessment was performed at the end of the 14-day treatment. Electrocardiogram was recorded for the assessment of autonomic function. The correlation between autonomic function at admission and stroke severity was assessed. The univariate and multivariate regression analyses were performed to investigate the risk factors for stroke-induced constipation. The cumulative incidence of stroke-induced constipation was 68.2% at the acute stage. Sympathetic nerve activity at admission was positively correlated with stroke severity ( R = 0.47, P < 0.001). Sympathetic nerve activity and stroke severity were independent risk factors for stroke-induced constipation. TEA decreased cumulative incidence of stroke-induced constipation (42.9 vs. 68.2%, P = 0.029). TEA significantly increased frequency of bowel movements (4.5 vs. 5.5, P = 0.001) and spontaneous bowel movements (3.0 vs. 4.5, P = 0.003) per week. TEA decreased straining defecations (0.2 vs. 0, P < 0.001) and laxative use (1 vs. 0, P < 0.001). TEA improved stool consistency and patients’ quality of life ( P < 0.05, resp.). TEA increased vagal activity ( P < 0.001 vs. baseline) and decreased sympathetic activity ( P < 0.001 vs. baseline). Ischemic stroke patients are predisposed to autonomic function imbalance. TEA was effective in the prevention of stroke-induced constipation, and the effect was possibly mediated via the autonomic function. NEW & NOTEWORTHY This study illustrated that the brain-gut dysfunction, primarily autonomic function imbalance, was correlated with the stroke-induced constipation. This was the first study to report that transcutaneous electrical acustimulation had a preventive effect on stroke-induced constipation, suggesting a potential novel therapy for bowel problem management. The effect was possibly mediated via the autonomic function.
Interaction between graviception and carotid baroreflex function in humans during parabolic flight-induced microgravity
Authors: Ogoh Shigehiko , Marais Michaël , Lericollais Romain , Denise Pierre , Raven Peter B. , Normand Hervé 
Published: May 2018

The aim of the present study was to assess carotid baroreflex (CBR) function during acute changes in otolithic activity in humans. To address this question, we designed a set of experiments to identify the modulatory effects of microgravity on CBR function at a tilt angle of −2°, which was identified to minimize changes in central blood volume during parabolic flight. During parabolic flight at 0 and 1 g, CBR function curves were modeled from the heart rate (HR) and mean arterial pressure (MAP) responses to rapid pulse trains of neck pressure and neck suction ranging from +40 to −80 Torr; CBR control of HR (carotid-HR) and MAP (carotid-MAP) function curves, respectively. The maximal gain of both carotid-HR and carotid-MAP baroreflex function curves were augmented during microgravity compared with 1 g (carotid-HR, −0.53 to −0.80 beats·min−1·mmHg−1, P < 0.05; carotid-MAP, −0.24 to −0.30 mmHg/mmHg, P < 0.05). These findings suggest that parabolic flight-induced acute change of otolithic activity may modify CBR function and identifies that the vestibular system contributes to blood pressure regulation under fluctuations in gravitational forces. NEW & NOTEWORTHY The effect of acute changes in vestibular activity on arterial baroreflex function remains unclear. In the present study, we assessed carotid baroreflex function without changes in central blood volume during parabolic flight, which causes acute changes in otolithic activity. The sensitivity of both carotid heart rate and carotid mean arterial pressure baroreflex function was augmented in microgravity compared with 1 g, suggesting that the vestibular system contributes to blood pressure regulation in humans on Earth.
Cardiovascular responses to exercise when increasing skin temperature with narrowing of the core-to-skin temperature gradient
Authors: Chou Ting-Heng , Allen Jakob R. , Hahn Dongwoo , Leary Brian K. , Coyle Edward F. 
Published: May 2018

The decline in stroke volume (SV) during exercise in the heat has been attributed to either an increase in cutaneous blood flow (CBF) that reduces venous return or an increase in heart rate (HR) that reduces cardiac filling time. However, the evidence supporting each mechanism arises under experimental conditions with different skin temperatures (Tsk; e.g., ≥38°C vs. ≤36°C, respectively). We systematically studied cardiovascular responses to progressively increased Tsk (32°C–39°C) with narrowing of the core-to-skin gradient during moderate intensity exercise. Eight men cycled at 63 ± 1% peak oxygen consumption for 20–30 min. Tsk was manipulated by having subjects wear a water-perfused suit that covered most of the body and maintained Tsk that was significantly different between trials and averaged 32.4 ± 0.2, 35.5 ± 0.1, 37.5 ± 0.1, and 39.5 ± 0.1°C, respectively. The graded heating of Tsk ultimately produced a graded elevation of esophageal temperature (Tes) at the end of exercise. Incrementally increasing Tsk resulted in a graded increase in HR and a graded decrease in SV. CBF reached a similar average plateau value in all trials when Tes was above ~38°C, independent of Tsk. Tsk had no apparent effect on forearm venous volume (FVV). In conclusion, the CBF and FVV responses suggest no further pooling of blood in the skin when Tsk is increased from 32.4°C to 39.5°C. The decrease in SV during moderate intensity exercise when heating the skin to high levels appears related to an increase in HR and not an increase in CBF. NEW & NOTEWORTHY This study systematically investigated the effect of increasing skin temperature (Tsk) to high levels on cardiovascular responses during moderate intensity exercise. We conclude that the declines in stroke volume were related to the increases in heart rate but not the changes in cutaneous blood flow (CBF) and forearm venous volume (FVV) during moderate intensity exercise when Tsk increased from ~32°C to ~39°C. High Tsk (≥38°C) did not further elevate CBF and FVV compared with lower Tsk during moderate intensity exercise.
Aberrant Lck Signal via CD28 Costimulation Augments Antigen-Specific Functionality and Tumor Control by Redirected T Cells with PD-1 Blockade in Humanized Mice
Authors: Gulati Pratiksha , Rühl Julia , Kannan Abhilash , Pircher Magdalena , Schuberth Petra , Nytko Katarzyna J. , Pruschy Martin , Sulser Simon , Haefner Mark , Jensen Shawn , Soltermann Alex , Jungraithmayr Wolfgang , Eisenring Maya , Winder Thomas , Samaras Panagiotis , Tabor Annett , Stenger Rene , Stupp Roger , Weder Walter , Renner Christoph , Münz Christian , Petrausch Ulf 
Published: May 2018

Abstract
Purpose: Combination therapy of adoptively transferred redirected T cells and checkpoint inhibitors aims for higher response rates in tumors poorly responsive to immunotherapy like malignant pleural mesothelioma (MPM). Only most recently the issue of an optimally active chimeric antigen receptor (CAR) and the combination with checkpoint inhibitors is starting to be addressed.
Experimental Design: Fibroblast activation protein (FAP)–specific CARs with different costimulatory domains, including CD28, Δ-CD28 (lacking lck binding moiety), or 4-1BB were established. CAR-T cells were characterized in vitro and antitumor efficacy was tested in vivo in a humanized mouse model in combination with PD-1 blockade. Finally, the Δ-CD28 CAR was tested clinically in a patient with MPM.
Results: All the three CARs demonstrated FAP-specific functionality in vitro. Gene expression data indicated a distinct activity profile for the Δ-CD28 CAR, including higher expression of genes involved in cell division, glycolysis, fatty acid oxidation, and oxidative phosphorylation. In vivo, only T cells expressing the Δ-CD28 CAR in combination with PD-1 blockade controlled tumor growth. When injected into the pleural effusion of a patient with MPM, the Δ-CD28 CAR could be detected for up to 21 days and showed functionality.
Conclusions: Overall, anti-FAP-Δ-CD28/CD3ζ CAR T cells revealed superior in vitro functionality, better tumor control in combination with PD-1 blockade in humanized mice, and persistence up to 21 days in a patient with MPM. Therefore, further clinical investigation of this optimized CAR is warranted. Clin Cancer Res; 24(16); 3981–93. ©2018 AACR.
TAS6417, A Novel EGFR Inhibitor Targeting Exon 20 Insertion Mutations
Authors: Hasako Shinichi , Terasaka Miki , Abe Naomi , Uno Takao , Ohsawa Hirokazu , Hashimoto Akihiro , Fujita Ryoto , Tanaka Kenji , Okayama Takashige , Wadhwa Renu , Miyadera Kazutaka , Aoyagi Yoshimi , Yonekura Kazuhiko , Matsuo Kenichi 
Published: May 2018

Abstract
Activating mutations in the EGFR gene are important targets in cancer therapy because they are key drivers of non–small cell lung cancer (NSCLC). Although almost all common EGFR mutations, such as exon 19 deletions and the L858R point mutation in exon 21, are sensitive to EGFR-tyrosine kinase inhibitor (TKI) therapies, NSCLC driven by EGFR exon 20 insertion mutations is associated with poor clinical outcomes due to dose-limiting toxicity, demonstrating the need for a novel therapy. TAS6417 is a novel EGFR inhibitor that targets EGFR exon 20 insertion mutations while sparing wild-type (WT) EGFR. In cell viability assays using Ba/F3 cells engineered to express human EGFR, TAS6417 inhibited EGFR with various exon 20 insertion mutations more potently than it inhibited the WT. Western blot analysis revealed that TAS6417 inhibited EGFR phosphorylation and downstream molecules in NSCLC cell lines expressing EGFR exon 20 insertions, resulting in caspase activation. These characteristics led to marked tumor regression in vivo in both a genetically engineered model and in a patient-derived xenograft model. Furthermore, TAS6417 provided a survival benefit with good tolerability in a lung orthotopic implantation mouse model. These findings support the clinical evaluation of TAS6417 as an efficacious drug candidate for patients with NSCLC harboring EGFR exon 20 insertion mutations. Mol Cancer Ther; 17(8); 1648–58. ©2018 AACR.
Tumor-Specific Inhibition ofIn SituVaccination by Distant Untreated Tumor Sites
Authors: Morris Zachary S. , Guy Emily I. , Werner Lauryn R. , Carlson Peter M. , Heinze Clinton M. , Kler Jasdeep S. , Busche Sara M. , Jaquish Abigail A. , Sriramaneni Raghava N. , Carmichael Lakeesha L. , Loibner Hans , Gillies Stephen D. , Korman Alan J. , Erbe Amy K. , Hank Jacquelyn A. , Rakhmilevich Alexander L. , Harari Paul M. , Sondel Paul M. 
Published: May 2018

AbstractIn situ vaccination is an emerging cancer treatment strategy that uses local therapies to stimulate a systemic antitumor immune response. We previously reported an in situ vaccination effect when combining radiation (RT) with intratumor (IT) injection of tumor-specific immunocytokine (IC), a fusion of tumor-specific antibody and IL2 cytokine. In mice bearing two tumors, we initially hypothesized that delivering RT plus IT-IC to the “primary” tumor would induce a systemic antitumor response causing regression of the “secondary” tumor. To test this, mice bearing one or two syngeneic murine tumors of B78 melanoma and/or Panc02 pancreatic cancer were treated with combined external beam RT and IT-IC to the designated “primary” tumor only. Primary and secondary tumor response as well as animal survival were monitored. Immunohistochemistry and quantitative real-time PCR were used to quantify tumor infiltration with regulatory T cells (Treg). Transgenic “DEREG” mice or IgG2a anti–CTLA-4 were used to transiently deplete tumor Tregs. Contrary to our initial hypothesis, we observed that the presence of an untreated secondary tumor antagonized the therapeutic effect of RT + IT-IC delivered to the primary tumor. We observed reciprocal tumor specificity for this effect, which was circumvented if all tumors received RT or by transient depletion of Tregs. Primary tumor treatment with RT + IT-IC together with systemic administration of Treg-depleting anti–CTLA-4 resulted in a renewed in situ vaccination effect. Our findings show that untreated tumors can exert a tumor-specific, Treg-dependent, suppressive effect on the efficacy of in situ vaccination and demonstrate clinically viable approaches to overcome this effect. Untreated tumor sites antagonize the systemic and local antitumor immune response to an in situ vaccination regimen. This effect is radiation sensitive and may be mediated by tumor-specific regulatory T cells harbored in the untreated tumor sites. Cancer Immunol Res; 6(7); 825–34. ©2018 AACR.
The Clinical Activity of PD-1/PD-L1 Inhibitors in Metastatic Non–Clear Cell Renal Cell Carcinoma
Authors: McKay Rana R. , Bossé Dominick , Xie Wanling , Wankowicz Stephanie A.M. , Flaifel Abdallah , Brandao Raphael , Lalani Aly-Khan A. , Martini Dylan J. , Wei Xiao X. , Braun David A. , Van Allen Eliezer , Castellano Daniel , De Velasco Guillermo , Wells J. Connor , Heng Daniel Y. , Fay Andre P. , Schutz Fabio A. , Hsu JoAnn , Pal Sumanta K. , Lee Jae Lyun , Hsieh James J. , Harshman Lauren C. , Signoretti Sabina , Motzer Robert J. , Feldman Darren , Choueiri Toni K. 
Published: May 2018

Abstract
Programmed death 1 (PD-1) and PD ligand 1 (PD-L1) inhibitors have shown activity in metastatic clear cell renal cell carcinoma (ccRCC). Data on the activity of these agents in patients with non–clear cell RCC (nccRCC) or patients with sarcomatoid/rhabdoid differentiation are limited. In this multicenter analysis, we explored the efficacy of PD-1/PD-L1 inhibitors in patients with nccRCC or sarcomatoid/rhabdoid differentiation. Baseline and follow-up demographic, clinical, treatment, and radiographic data were collected. The primary endpoint was objective response rate. Secondary endpoints include time-to-treatment failure (TTF), overall survival (OS), and biomarker correlates. Forty-three patients were included: papillary (n = 14; 33%), chromophobe (n = 10; 23%), unclassified (n = 9; 21%), translocation (n = 3; 7%), and ccRCC with sarcomatoid differentiation (n = 7, 16%). Of those 43 patients, 11 patients (26%) had sarcomatoid and/or rhabdoid differentiation (n = 7 with ccRCC; n = 4 nccRCC). Overall, 8 patients (19%) objectively responded, including 4 patients (13%) who received PD-1/PD-L1 monotherapy. Responses were observed in patients with ccRCC with sarcomatoid and/or rhabdoid differentiation (n = 3/7, 43%), translocation RCC (n = 1/3, 33%), and papillary RCC (n = 4/14, 29%). The median TTF was 4.0 months [95% confidence interval (CI), 2.8–5.5] and median OS was 12.9 months (95% CI, 7.4–not reached). No specific genomic alteration was associated with clinical benefit. Modest antitumor activity for PD-1/PD-L1–blocking agents was observed in some patients with nccRCC. Further prospective studies are warranted to investigate the efficacy of PD-1/PD-L1 blockade in this heterogeneous patient population. Cancer Immunol Res; 6(7); 758–65. ©2018 AACR.
Minimally Invasive Delivery of Hydrogel-Encapsulated Amiodarone to the Epicardium Reduces Atrial Fibrillation
Authors: Garcia Jose R. , Campbell Peter F. , Kumar Gautam , Langberg Jonathan J. , Cesar Liliana , Deppen Juline N. , Shin Eric Y. , Bhatia Neal K. , Wang Lanfang , Xu Kai , Schneider Frank , Robinson Brian , García Andrés J. , Levit Rebecca D. 
Published: May 2018

Background:
Atrial fibrillation (AF) is the most common cardiac arrhythmia. Although treatment options for AF exist, many patients cannot be maintained in normal sinus rhythm. Amiodarone is an effective medication for AF but has limited clinical utility because of off-target tissue toxicity.

Methods:
Here, we use a pig model of AF to test the efficacy of an amiodarone-containing polyethylene glycol–based hydrogel. The gel is placed directly on the atrial epicardium through the pericardial space in a minimally invasive procedure using a specially designed catheter.

RESULTS:
Implantation of amiodarone-containing gel significantly reduced the duration of sustained AF at 21 and 28 days; inducibility of AF was reduced 14 and 21 days post-delivery. Off-target organ drug levels in the liver, lungs, thyroid, and fat were significantly reduced in animals treated with epicardial amiodarone gel compared with systemic controls in small-animal distribution studies.

Conclusions:
The pericardium is an underutilized therapeutic site and may be a new treatment strategy for AF and other cardiovascular diseases.
Independent Prognostic Value of Serum Soluble ST2 Measurements in Patients With Heart Failure and a Reduced Ejection Fraction in the PARADIGM-HF Trial (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure)
Authors: O’Meara Eileen , Prescott Margaret F. , Claggett Brian , Rouleau Jean L. , Chiang Lu-May , Solomon Scott D. , Packer Milton , McMurray John J.V. , Zile Michael R. 
Published: May 2018

Background:
Soluble ST2 (sST2) is associated with cardiac remodeling and fibrosis. In chronic heart failure, the predictive value of sST2 has not been evaluated in a model that includes both NT-proBNP (N-terminal pro-B-type natriuretic peptide) and hs-TnT (high-sensitivity cardiac troponin T), in a trial in which treatment had a major impact. Therefore, the effects of treatment on sST2 levels in PARADIGM-HF trial (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure), the relationships between sST2 and outcomes, and the prognostic utility of various sST2 partition values were examined.

Methods and Results:

Baseline (n=2002), 1-month (n=1936), and 8-month postrandomization (n=1758) sST2 levels were compared between treatment groups (sacubitril/valsartan versus enalapril). Relationships between baseline sST2 and (1) heart failure hospitalization, (2) cardiovascular death, and (3) combined heart failure hospitalization and cardiovascular death were assessed using restricted cubic spline models. Adjusted Cox proportional hazards models were used to examine the impact of sST2 change from baseline to 1 month on the hazard of experiencing each outcome. Sacubitril/valsartan led to more reductions and fewer increases in sST2 levels versus enalapril. After adjusting for other predictors, including NT-proBNP and hs-TnT, baseline sST2 remained an independent predictor of outcomes. Associations between baseline sST2 and outcomes were linear. sST2 increases at 1 month were associated with worse subsequent outcomes and decreased with better outcomes (
P
=0.001, 0.012, and 0.009 for the 3 outcomes, respectively).

Conclusions:
Sacubitril/valsartan resulted in greater reductions and less increases in sST2 levels than enalapril. No specific threshold was associated with risk, as linear relationships between baseline sST2 and outcomes were observed. Changes in sST2 from baseline to 1 month were independently associated with the risk of outcomes.

Clinical Trial Registration

: URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT01035255.
Prognostic Significance of Creatinine Increases During an Acute Heart Failure Admission in Patients With and Without Residual Congestion
Authors: Metra Marco , Cotter Gad , Senger Stefanie , Edwards Christopher , Cleland John G. , Ponikowski Piotr , Cursack Guillermo C. , Milo Olga , Teerlink John R. , Givertz Michael M. , O’Connor Christopher M. , Dittrich Howard C. , Bloomfield Daniel M. , Voors Adriaan A. , Davison Beth A. 
Published: May 2018

Background:
The importance of a serum creatinine increase, traditionally considered worsening renal function (WRF), during admission for acute heart failure has been recently debated, with data suggesting an interaction between congestion and creatinine changes.

Methods and Results:

In post hoc analyses, we analyzed the association of WRF with length of hospital stay, 30-day death or cardiovascular/renal readmission and 90-day mortality in the PROTECT study (Placebo-Controlled Randomized Study of the Selective A1 Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized With Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function). Daily creatinine changes from baseline were categorized as WRF (an increase of 0.3 mg/dL or more) or not. Daily congestion scores were computed by summing scores for orthopnea, edema, and jugular venous pressure. Of the 2033 total patients randomized, 1537 patients had both available at study day 14. Length of hospital stay was longer and 30-day cardiovascular/renal readmission or death more common in patients with WRF. However, these were driven by significant associations in patients with concomitant congestion at the time of assessment of renal function. The mean difference in length of hospital stay because of WRF was 3.51 (95% confidence interval, 1.29–5.73) more days (
P
=0.0019), and the hazard ratio for WRF on 30-day death or heart failure hospitalization was 1.49 (95% confidence interval, 1.06–2.09) times higher (
P
=0.0205), in significantly congested than nonsignificantly congested patients. A similar trend was observed with 90-day mortality although not statistically significant.

Conclusions:
In patients admitted for acute heart failure, WRF defined as a creatinine increase of ≥0.3 mg/dL was associated with longer length of hospital stay, and worse 30- and 90-day outcomes. However, effects were largely driven by patients who had residual congestion at the time of renal function assessment.

Clinical Trial Registration

: URL:
https://www.clinicaltrials.gov
. Unique identifiers: NCT00328692 and NCT00354458.
Remote Left Ventricular Hemodynamic Monitoring Using a Novel Intracardiac Sensor
Authors: Mondritzki Thomas , Boehme Philip , White Jason , Park Jin Woo , Hoffmann Jessica , Vogel Julia , Kolkhof Peter , Walsh Stuart , Sandner Peter , Bischoff Erwin , Dinh Wilfried , Hüser Jörg , Truebel Hubert 
Published: May 2018

Background—
Heart failure (HF) remains the most common reason for hospital admission in patients aged >65 years. Despite modern drug therapy, mortality and readmission rates for patients hospitalized with HF remain high. This necessitates further research to identify early patients at risk for readmission to limit hospitalization by timely adjustment of medical therapy. Implantable devices can monitor left ventricular (LV) hemodynamics and remotely and continuously detect the early signs of decompensation to trigger interventions and reduce the risk of hospitalization for HF. Here, we report the first preclinical study validating a new batteryless and easy to implant LV-microelectromechanical system to assess LV performance.

Methods and Results—
A miniaturized implantable wireless pressure sensor was adapted for implantation in the LV apex. The LV-microelectromechanical system sensor was tested in a canine model of HF. The wireless pressure sensor measurements were compared with invasive left heart catheter-derived measurements at several time points. During different pharmacological challenge studies with dobutamine or vasopressin, the device was equally sensitive compared with invasive standard procedures. No adverse events or any observable reaction related to the implantation and application of the device for a period of 35 days was observed.

Conclusions—
Our miniaturized wireless pressure sensor placed in the LV (LV-microelectromechanical system) has the potential to become a new telemetric tool to earlier identify patients at risk for HF decompensation and to guide the treatment of patients with HF.