bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spinal AMP kinase activity differentially regulates phrenic motor plasticity
Authors: Perim Raphael Rodrigues , Fields Daryl P. , Mitchell Gordon S. 
Published: January 2020

Acute intermittent hypoxia (AIH) elicits phrenic motor plasticity via multiple distinct cellular mechanisms. With moderate AIH, phrenic motor facilitation (pMF) requires Gq protein-coupled serotonin type 2 receptor activation, ERK MAP kinase activity, and new synthesis of brain-derived neurotrophic factor. In contrast, severe AIH elicits pMF by an adenosine-dependent mechanism that requires exchange protein activated by cAMP, Akt, and mammalian target of rapamycin (mTOR) activity, followed by new tyrosine receptor kinase B protein synthesis; this same pathway is also initiated by Gs protein-coupled serotonin 7 receptors (5-HT7). Because the metabolic sensor AMP-activated protein kinase (AMPK) inhibits mTOR-dependent protein synthesis, and mTOR signaling is necessary for 5-HT7 but not 5-HT2 receptor-induced pMF, we hypothesized that spinal AMPK activity differentially regulates pMF elicited by these distinct receptor subtypes. Serotonin type 2A receptor [5-HT2A; (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride] or 5-HT7 (AS-19) receptor agonists were administered intrathecally at C4 (3 injections, 5-min intervals) while recording integrated phrenic nerve activity in anesthetized, vagotomized, paralyzed, and ventilated rats. Consistent with our hypothesis, spinal AMPK activation with 2-deoxyglucose or metformin blocked 5-HT7, but not 5-HT2A receptor-induced pMF; in both cases, pMF inhibition was reversed by spinal administration of the AMPK inhibitor compound C. Thus, AMPK differentially regulates cellular mechanisms of serotonin-induced phrenic motor plasticity. NEW & NOTEWORTHY Spinal AMP-activated protein kinase (AMPK) overactivity, induced by local 2-deoxyglucose or metformin administration, constrains serotonin 7 (5-HT7) receptor-induced (but not serotonin type 2A receptor-induced) respiratory motor facilitation, indicating that metabolic challenges might regulate specific forms of respiratory motor plasticity. Pharmacological blockade of spinal AMPK activity restores 5-HT7 receptor-induced respiratory motor facilitation in the presence of either 2-deoxyglucose or metformin, showing that AMPK is an important regulator of 5-HT7 receptor-induced respiratory motor plasticity.
Brief asphyxial state following immediate cord clamping accelerates onset of left-to-right shunting across the ductus arteriosus after birth in preterm lambs
Authors: Smolich Joseph J. , Kenna Kelly R. , Cheung Michael M. H. , Mynard Jonathan P. 
Published: January 2020

Reversal of shunting across the ductus arteriosus from right-to-left to left-to-right is a characteristic feature of the birth transition. Given that immediate cord clamping (ICC) followed by an asphyxial cord clamp-to-ventilation (CC-V) interval may augment left ventricular (LV) output and central blood flows after birth, we tested the hypothesis that an asphyxial CC-V interval accelerates the onset of postnatal left-to-right ductal shunting. High-fidelity central blood flow signals were obtained in anesthetized preterm lambs (gestation 128 ± 2 days) after ICC followed by a nonasphyxial (∼40 s, n = 9) or asphyxial (∼90 s, n = 9) CC-V interval before mechanical ventilation for 30 min after birth. Left-to-right ductal flow segments were related to aortic isthmus and descending aortic flow profiles to quantify sources of ductal shunting. In the nonasphyxial group, phasic left-to-right ductal shunting was initially minor after birth, but then rose progressively to 437 ± 164 ml/min by 15 min ( P < 0.001). However, in the asphyxial group, this shunting increased from 24 ± 21 to 199 ± 93 ml/min by 15 s after birth ( P < 0.001) and rose further to 471 ± 190 ml/min by 2 min ( P < 0.001). This earlier onset of left-to-right ductal shunting was supported by larger contributions ( P < 0.001) from direct systolic LV flow and retrograde diastolic discharge from an arterial reservoir/windkessel located in the descending aorta and its major branches, and associated with increased pulmonary arterial blood flow having a larger ductal component. These findings suggest that the duration of the CC-V interval after ICC is an important modulator of left-to-right ductal shunting, LV output and pulmonary perfusion at birth.NEW & NOTEWORTHY This birth transition study in preterm lambs demonstrated that a brief (∼90 s) asphyxial interval between umbilical cord clamping and ventilation onset resulted in earlier and greater left-to-right shunting across the ductus arteriosus after birth. This greater shunting 1) resulted from an increased left ventricular output associated with a higher systolic left-to-right ductal flow and increased retrograde diastolic discharge from a lower body arterial reservoir/windkessel, and 2) was accompanied by greater lung perfusion after birth.
Skeletal muscle V̇o2kinetics by the NIRS repeated occlusions method during the recovery from cycle ergometer exercise
Authors: Zuccarelli Lucrezia , do Nascimento Salvador Paulo Cesar , Del Torto Alessio , Fiorentino Riccardo , Grassi Bruno 
Published: January 2020

Near-infrared spectroscopy (NIRS) has been utilized as a noninvasive method to evaluate skeletal muscle mitochondrial function in humans, by calculating muscle V̇o2(V̇o2m) recovery (off-) kinetics following short light-intensity plantar flexion exercise. The aim of the present study was to determine V̇o2m off- kinetics following standard cycle ergometer exercise of different intensities. Fifteen young physically active healthy men performed an incremental exercise (INCR) up to exhaustion and two repetitions of constant work-rate (CWR) exercises at 80% of gas exchange threshold (GET; MODERATE) and at 40% of the difference between GET and peak pulmonary V̇o2(V̇o2p; HEAVY). V̇o2p and vastus lateralis muscle fractional O2extraction by NIRS (Δ[deoxy(Hb+Mb)]) were recorded continuously. Transient arterial occlusions were carried out at rest and during the recovery for V̇o2m calculation. All subjects tolerated the repeated occlusions protocol without problems. The quality of the monoexponential fitting for V̇o2m off-kinetics analysis was excellent (0.93≤ r2≤0.99). According to interclass correlation coefficient, the test-retest reliability was moderate to good. V̇o2m values at the onset of recovery were ~27, ~38, and ~35 times higher (in MODERATE, HEAVY, and INCR, respectively) than at rest. The time constants (τ) of V̇o2m off-kinetics were lower ( P < 0.001) following MODERATE (29.1 ± 6.8 s) vs. HEAVY (40.8 ± 10.9) or INCR (42.9 ± 10.9), suggesting an exercise intensity dependency of V̇o2m off-kinetics. Only following MODERATE the V̇o2m off-kinetics were faster than the V̇o2p off-kinetics. V̇o2m off-kinetics, determined noninvasively by the NIRS repeated occlusions technique, can be utilized as a functional evaluation tool of skeletal muscle oxidative metabolism also following conventional cycle ergometer exercise.NEW & NOTEWORTHY This is the first study in which muscle V̇o2recovery kinetics, determined noninvasively by near-infrared spectroscopy (NIRS) by utilizing the repeated occlusions method, was applied following standard cycle ergometer exercise of different intensities. The results demonstrate that muscle V̇o2recovery kinetics, determined noninvasively by the NIRS repeated occlusions technique, can be utilized as a functional evaluation tool of skeletal muscle oxidative metabolism also following conventional cycle ergometer exercise, overcoming significant limitations associated with the traditionally proposed protocol.
Effects of repeated local heat therapy on skeletal muscle structure and function in humans
Authors: Kim Kyoungrae , Reid Blake A. , Casey Caitlin A. , Bender Brooke E. , Ro Bohyun , Song Qifan , Trewin Adam J. , Petersen Aaron C. , Kuang Shihuan , Gavin Timothy P. , Roseguini Bruno T. 
Published: January 2020

The purpose of the present study was to examine the effects of repeated exposure to local heat therapy (HT) on skeletal muscle function, myofiber morphology, capillarization, and mitochondrial content in humans. Twelve young adults (23.6 ± 4.8 yr, body mass index 24.9 ± 3.0 kg/m2) had one randomly selected thigh treated with HT (garment perfused with water at ~52°C) for 8 consecutive weeks (90 min, 5 days/wk) while the opposite thigh served as a control. Biopsies were obtained from the vastus lateralis muscle before and after 4 and 8 wk of treatment. Knee extensor strength and fatigue resistance were also assessed using isokinetic dynamometry. The changes in peak isokinetic torque were higher ( P = 0.007) in the thigh exposed to HT than in the control thigh at weeks 4 (control 4.2 ± 13.1 Nm vs. HT 9.1 ± 16.1 Nm) and 8 (control 1.8 ± 9.7 Nm vs. HT 7.8 ± 10.2 Nm). Exposure to HT averted a temporal decline in capillarization around type II fibers ( P < 0.05), but had no effect on capillarization indexes in type I fibers. The content of endothelial nitric oxide synthase was ~18% and 35% higher in the thigh exposed to HT at 4 and 8 wk, respectively ( P = 0.003). Similarly, HT increased the content of small heat shock proteins HSPB5 ( P = 0.007) and HSPB1 ( P = 0.009). There were no differences between thighs for the changes in fiber cross-sectional area and mitochondrial content. These results indicate that exposure to local HT for 8 wk promotes a proangiogenic environment and enhances muscle strength but does not affect mitochondrial content in humans.NEW & NOTEWORTHY We demonstrate that repeated application of heat therapy to the thigh with a garment perfused with warm water enhances the strength of knee extensors and influences muscle capillarization in parallel with increases in the content of endothelial nitric oxide synthase and small heat shock proteins. This practical method of passive heat stress may be a feasible tool to treat conditions associated with capillary rarefaction and muscle weakness.
Development and Validation of a 34‐Gene Inherited Cancer Predisposition Panel Using Next‐Generation Sequencing
Authors: Rosenthal Sun Hee , Sun Weimin , Zhang Ke , Liu Yan , Nguyen Quoclinh , Gerasimova Anna , Nery Camille , Cheng Linda , Castonguay Carolyn , Hiller Elaine , Li James , Elzinga Christopher , Wolfson David , Smolgovsky Alla , Chen Rebecca , Buller-Burckle Arlene , Catanese Joseph , Grupe Andrew , Lacbawan Felicitas , Owen Renius 
Published: January 2020

The use of genetic testing to identify individuals with hereditary cancer syndromes has been widely adopted by clinicians for management of inherited cancer risk. The objective of this study was to develop and validate a 34‐gene inherited cancer predisposition panel using targeted capture‐based next‐generation sequencing (NGS). The panel incorporates genes underlying well‐characterized cancer syndromes, such as BRCA1 and BRCA2 (BRCA1/2), along with more recently discovered genes associated with increased cancer risk. We performed a validation study on 133 unique specimens, including 33 with known variant status; known variants included single nucleotide variants (SNVs) and small insertions and deletions (Indels), as well as copy‐number variants (CNVs). The analytical validation study achieved 100% sensitivity and specificity for SNVs and small Indels, with 100% sensitivity and 98.0% specificity for CNVs using in‐house developed CNV flagging algorithm. We employed a microarray comparative genomic hybridization (aCGH) method for all specimens that the algorithm flags as CNV‐positive for confirmation. In combination with aCGH confirmation, CNV detection specificity improved to 100%. We additionally report results of the first 500 consecutive specimens submitted for clinical testing with the 34‐gene panel, identifying 53 deleterious variants in 13 genes in 49 individuals. Half of the detected pathogenic/likely pathogenic variants were found in BRCA1 (23%), BRCA2 (23%), or the Lynch syndrome‐associated genes PMS2 (4%) and MLH1 (2%). The other half were detected in 9 other genes: MUTYH (17%), CHEK2 (15%), ATM (4%), PALB2 (4%), BARD1 (2%), CDH1 (2%), CDKN2A (2%), RAD51C (2%), and RET (2%). Our validation studies and initial clinical data demonstrate that a 34‐gene inherited cancer predisposition panel can provide clinically significant information for cancer risk assessment.
Macrophage Syk–PI3Kγ Inhibits Antitumor Immunity: SRX3207, a Novel Dual Syk–PI3K Inhibitory Chemotype Relieves Tumor Immunosuppression
Authors: Joshi Shweta , Liu Kevin X. , Zulcic Muamera , Singh Alok R. , Skola Dylan , Glass Christopher K. , Sanders P. Dominick , Sharabi Andrew B. , Pham Timothy V. , Tamayo Pablo , Shiang Daniel , Dinh Huy Q. , Hedrick Catherine C. , Morales Guillermo A. , Garlich Joseph R. , Durden Donald L. 
Published: January 2020

Abstract
Macrophages (MΦ) play a critical role in tumor growth, immunosuppression, and inhibition of adaptive immune responses in cancer. Hence, targeting signaling pathways in MΦs that promote tumor immunosuppression will provide therapeutic benefit. PI3Kγ has been recently established by our group and others as a novel immuno-oncology target. Herein, we report that an MΦ Syk–PI3K axis drives polarization of immunosuppressive MΦs that establish an immunosuppressive tumor microenvironment in in vivo syngeneic tumor models. Genetic or pharmacologic inhibition of Syk and/or PI3Kγ in MΦs promotes a proinflammatory MΦ phenotype, restores CD8+ T-cell activity, destabilizes HIF under hypoxia, and stimulates an antitumor immune response. Assay for transposase-accessible Chromatin using Sequencing (ATAC-seq) analyses on the bone marrow–derived macrophages (BMDM) show that inhibition of Syk kinase promotes activation and binding of NF-κB motif in SykMC-KO BMDMs, thus stimulating immunostimulatory transcriptional programming in MΦs to suppress tumor growth. Finally, we have developed in silico the “first-in-class” dual Syk/PI3K inhibitor, SRX3207, for the combinatorial inhibition of Syk and PI3K in one small molecule. This chemotype demonstrates efficacy in multiple tumor models and represents a novel combinatorial approach to activate antitumor immunity.
Black Raspberry Inhibits Oral Tumors in Mice Treated with the Tobacco Smoke Constituent Dibenzo(def,p)chrysene Via Genetic and Epigenetic Alterations
Authors: Chen Kun-Ming , Sun Yuan-Wan , Kawasawa Yuka Imamura , Salzberg Anna C. , Zhu Junjia , Gowda Krishne , Aliaga Cesar , Amin Shantu , Atkins Hannah , El-Bayoumy Karam 
Published: January 2020

Abstract

We previously reported that the environmental pollutant and tobacco smoke constituent dibenzo[def,p]chrysene (DBP) induced DNA damage, altered DNA methylation and induced oral squamous cell carcinoma (OSCC) in mice. In the present study, we showed that 5% dietary black raspberry (BRB) significantly reduced (P &lt; 0.05) the levels of DBP-DNA adducts in the mouse oral cavity with comparable effect to those of its constitutes. Thus, only BRB was selected to examine if aberrant DNA methylation induced by DBP can be altered by BRB. Using comparative genome-wide DNA methylation analysis, we identified 479 hypermethylated and 481 hypomethylated sites (q &lt; 0.01, methylation difference &gt;25%) between the oral tissues of mice treated with DBP and fed control diet or diet containing BRB. Among the 30 differential methylated sites (DMS) induced by DBP, we found DMS mapped to Fgf3, Qrich2, Rmdn2, and Cbarp were hypermethylated by BRB whereas hypomethylated by DBP at either the exact position or proximal sites; DMS mapped to Vamp3, Ppp1rB1, Pkm, and Zfp316 were hypomethylated by BRB but hypermethylated by DBP at proximal sites. In addition to Fgf3, 2 DMS mapped to Fgf4 and Fgf13 were hypermethylated by BRB; these fibroblast growth factors are involved in regulation of the epithelial–mesenchymal transition (EMT) pathway as identified by IPA. Moreover, BRB significantly reduced (P &lt; 0.05) the tumor incidence from 70% to 46.7%. Taken together, the inhibitory effects of BRB on DNA damage combined with its effects on epigenetic alterations may account for BRB inhibition of oral tumorigenesis induced by DBP.

Significance:
We provided mechanistic insights that can account for the inhibition of oral tumors by BRB, which could serve as the framework for future chemopreventive trials for addicted smokers as well as non- or former smokers who are exposed to environmental carcinogens.
Availability of home palliative care services and dying at home in conditions needing palliative care: A population-based death certificate study
Authors: Nakanishi Miharu , Ogawa Asao , Nishida Atsushi 
Published: January 2020

Background: Avoiding inappropriate care transition and enabling people with chronic diseases to die at home have become important health policy issues. Availability of palliative home care services may be related to dying at home. Aim: After controlling for the presence of hospital beds and primary care physicians, we examined the association between availability of home palliative care services and dying at home in conditions requiring such services. Design: Death certificate data in Japan in 2016 were linked with regional healthcare statistics. Setting/participants: All adults (18 years or older) who died from conditions needing palliative care in 2016 in Japan were included. Results: There were 922,756 persons included for analysis. Malignant neoplasm (37.4%) accounted for most decedents, followed by heart disease including cerebrovascular disease (31.4%), respiratory disease (14.7%) and dementia/Alzheimer’s disease/senility (11.5%). Of decedents, 20.8% died at home or in a nursing home and 79.2% died outside home (hospital/geriatric intermediate care facility). Death at home was more likely in health regions with fewer hospital beds and more primary care physicians, in total and per condition needing palliative care. Number of home palliative care services was negatively associated with death at home. The adjustment for home palliative care services disappeared in heart disease including cerebrovascular disease and reversed in respiratory disease. Conclusion: Specialised home palliative care services may be suboptimal, and primary care services may serve as a key access point in providing baseline palliative care to people with conditions needing palliative care. Therefore, primary care services should aim to enhance their palliative care workforce.
Endovascular Thrombectomy for Stroke Effectiveness Study—An Audit From a Small Tertiary Care Center
Authors: Virani Karim , Hu Sherry , Christian Christine , Simpkin Wendy , Phillips Stephen , Shankar Jai Jai Shiva 
Published: January 2020

Purpose: Endovascular thrombectomy (EVT) treatment for acute ischemic stroke is now recommended as a standard of care. However, implementing EVT in routine clinical practice poses many challenges, even in countries with advanced health-care systems. The aim of the current study is to delineate if EVT at our institution is an effective treatment for acute ischemic stroke. Methods: All patients who underwent EVT at our institution between December 2011 and July 2017 were retrospectively assessed from our prospective registry. Clinical and imaging (including the Alberta Stroke Program Early CT [ASPECT] score, single-phase computed tomography angiography, and computed tomography perfusion) criteria were utilized to determine EVT suitability. Primary outcomes included modified Rankin score (mRS) at 90 days and recanalization determined by the modified Treatment in Cerebral Infarction score. Effectiveness was assessed by comparing our cohort with patients receiving EVT in the ESCAPE (Endovascular Treatment for Small Core and Proximal Occlusion Ischemic Stroke) trial. Results: Eighty-eight patients presented to our hospital after a median of 87 minutes last seen normal. Of these, median ASPECT score was 9. A majority (72%) also received intravenous alteplase. Successful recanalization (≥TICI 2b) was achieved in 79%. At 90 days, 48% (36/75) were functionally independent (mRS score of 0-2) and 28% (21/75) were disabled (mRS score of 3-5); 24% (18/75) died (mRS of 6) within 90 days. Conclusions: An audit of our initial experience with EVT for the treatment of acute ischemic stroke in a small tertiary care center yielded similar results compared to the ESCAPE trial, which is encouraging for implementing this treatment in routine clinical practice.
A Single-Institute Experience With Radioactive Seed Localization of Breast Lesions—A Retrospective Study
Authors: Jumaa Klaudia , Johani Badria Al , Brackstone Muriel , Kornecki Anat 
Published: January 2020

Objectives: To assess the benefits associated with radioactive seed localization (RSL) in comparison to conventional wire localization (WL) for nonpalpable breast lesions. Methods: Radioactive seed localization was initiated at our institution in July 2013. Retrospective review of all WL performed between June 2012 and July 2013 (2013) and all RSL performed during June 2015 and July 2016 (2016). Patients who received neoadjuvant therapy or did not undergo their planned surgeries and WL performed in 2016 were excluded. The following data were collected: final pathology, resection margins for malignant lesions, time to surgery, seed migration, and number of localized lumpectomies performed by each surgeon. Results: A total of 292 WL procedures (288 women) in 2013 and 194 RSL procedures (186 women) in 2016 were eligible for the study. All WLs were inserted the day of surgery. Mean time from RSL insertion to surgery was 4.0 ± 2.8 days (range: 1-17 days). There was no difference in specimen size for malignant lesions (6.8 ± 2.8 cm for WL and 6.9 ± 2.9 cm for RSL; P = .5). Specimen radiographs were obtained in 233 (80%) of 292 WL compared to 194 (100%) of 194 RSL ( P < .001). For malignant lesions, positive margins were present in 34 (17.2%) of 198 with WL compared to 15 (10.3%) of 146 with RSL ( P < .001). Close margins (≤1 mm) were present in 31 (15.6%) of 198 with WL compared to 1 (0.6%) of 146 with RSL ( P < .001). The seed fell out of the specimen during surgery in 6 (3.1%) of 194. No seed loss was recorded. The surgeons (n = 4) who transitioned to RSL increased the number of surgeries per month from a mean of 4.4 ± 2.6 in 2013 to 6.9 ± 3.5 in 2016, equivalent to a 41% increase ( P = .003). Conclusions: The use of RSL, as compared to conventional WL, resulted in a reduction in the number of pathologically involved surgical margins and was associated with an increased number of surgeries. Furthermore, RSL can be performed up to 14 days prior to surgery, which may improve scheduling flexibility in the radiology department.