bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacological attenuation of group III/IV muscle afferents improves endurance performance when oxygen delivery to locomotor muscles is preserved
Authors: Hureau Thomas J. , Weavil Joshua C. , Thurston Taylor S. , Wan Hsuan-Yu , Gifford Jayson R. , Jessop Jacob E. , Buys Michael J. , Richardson Russell S. , Amann Markus 
Published: September 2019

We sought to investigate the role of group III/IV muscle afferents in limiting endurance exercise performance, independently of their role in optimizing locomotor muscle O2 delivery. While breathing 100% O2 to ensure a similar arterial O2 content ([Formula: see text]) in both trials, eight male cyclists performed 5-km time trials under control conditions (HCTRL) and with lumbar intrathecal fentanyl (HFENT) impairing neural feedback from the lower limbs. After each time trial, common femoral artery blood flow (FBF) was quantified (Doppler ultrasound) during constant-load cycling performed at the average power of the preceding time trial. The assessment of end-tidal gases, hemoglobin content and saturation, and FBF facilitated the calculation of leg O2 delivery. Locomotor muscle activation during cycling was estimated from vastus lateralis EMG. With electrical femoral nerve stimulation, peripheral and central fatigue were quantified by pre- to postexercise decreases in quadriceps twitch torque (ΔQtw) and voluntary activation (ΔVA), respectively. FBF (~16 mL·min−1·W−1; P = 0.6), [Formula: see text] (~24 mL O2/dL; P = 0.9), and leg O2 delivery (~0.38 mL O2·min−1·W−1; P = 0.9) were not different during HCTRL and HFENT. Mean power output and time to completion were significantly improved by 9% (~310 W vs. ~288 W) and 3% (~479 s vs. ~463 s), respectively, during HFENT compared with HCTRL. Quadriceps muscle activation was 9 ± 7% higher during HFENT compared with HCTRL ( P < 0.05). ΔQtw was significantly greater in HFENT compared with HCTRL (54 ± 8% vs. 39 ± 9%), whereas ΔVA was not different (~5%; P = 0.3) in both trials. These findings reveal that group III/IV muscle afferent feedback limits whole body endurance exercise performance and peripheral fatigue by restricting neural activation of locomotor muscle. NEW & NOTEWORTHY Group III/IV muscle afferent feedback facilitates endurance performance by optimizing locomotor muscle O2 delivery but also limits performance by restricting neural drive to locomotor muscle. To isolate the performance-limiting effect of these sensory neurons, we pharmacologically attenuated their central projection during a cycling time trial while controlling for locomotor muscle O2 delivery. With no difference in leg O2 delivery, afferent blockade attenuated the centrally mediated restriction in motoneuronal output and improved cycling performance.
Combination of TMB and CNA Stratifies Prognostic and Predictive Responses to Immunotherapy Across Metastatic Cancer
Authors: Liu Li , Bai Xue , Wang Jian , Tang Xin-Ran , Wu De-Hua , Du Sha-Sha , Du Xiu-Ju , Zhang Yao-Wei , Zhu Hong-Bo , Fang Yuan , Guo Ze-Qin , Zeng Qin , Guo Xue-Jun , Liu Zhu , Dong Zhong-Yi 
Published: September 2019

Abstract

Purpose:
Although tumor mutation burden (TMB) has been well known to predict the response to immune checkpoint inhibitors (ICI), lack of randomized clinical trial data has restricted its clinical application. This study aimed to explore the significance and feasibility of biomarker combination based on TMB and copy-number alteration (CNA) for the prognosis of each tumor and prediction for ICI therapy in metastatic pan-cancer milieu.

Experimental Design:
Non-ICI–treated MSK pan-cancer cohort was used for prognosis analysis. Three independent immunotherapy cohorts, including non–small cell lung cancer (n = 240), skin cutaneous melanoma (n = 174), and mixed cancer (Dana-Farber, n = 98) patients from previous studies, were analyzed for efficacy of ICI therapy.

Results:
TMB and CNA showed optimized combination for the prognosis of most metastatic cancer types, and patients with TMBlowCNAlow showed better survival. In the predictive analysis, both TMB and CNA were independent predictive factors for ICI therapy. Remarkably, when TMB and CNA were jointly analyzed, those with TMBhighCNAlow showed favorable responses to ICI therapy. Meanwhile, TMBhighCNAlow as a new biomarker showed better prediction for ICI efficacy compared with either TMB-high or CNA-low alone. Furthermore, analysis of the non-ICI–treated MSK pan-cancer cohort supported that the joint stratification of TMB and CNA can be used to categorize tumors into distinct sensitivity to ICI therapy across pan-tumors.

Conclusions:
The combination of TMB and CNA can jointly stratify multiple metastatic tumors into groups with different prognosis and heterogeneous clinical responses to ICI treatment. Patients with TMBhighCNAlow cancer can be an optimal subgroup for ICI therapy.
Metastatic Breast Carcinoma–Associated Fibroblasts Have Enhanced Protumorigenic Properties Related to Increased IGF2 Expression
Authors: Gui Yirui , Aguilar-Mahecha Adriana , Krzemien Urszula , Hosein Abdel , Buchanan Marguerite , Lafleur Josiane , Pollak Michael , Ferrario Cristiano , Basik Mark 
Published: September 2019

Abstract

Purpose:
The microenvironment of metastatic breast cancer is incompletely characterized, despite prior evidence that it plays a key role in the biology of metastasis. A major component of the tumor stroma is the carcinoma-associated fibroblast (CAF), which has been shown to communicate with other stromal and cancer cells to create a protumorigenic milieu. Our study was designed to characterize human CAFs from different metastatic sites.

Experimental Design:
We collected eight carcinoma-associated fibroblasts (mCAFs) from different metastatic sites and compared them with CAFs from primary tumors (pCAFs) and with normal breast fibroblasts (NFs). Molecular profiles and effects on breast cancer cell growth, on response to doxorubicin and on T-cell proliferation were compared.

Results:
We observed marked differences in mCAFs compared with pCAFs and NFs with respect to in vitro proliferation and effects on breast cancer cell migration, spheroid growth, invasion, response to doxorubicin, and in vivo tumor growth. We found marked transcriptomic differences between mCAFs and pCAFs, including increased expression of IFN-related genes and IGF2 in the former. Cluster analysis revealed two groups of mCAFs, with the liver mCAFs clustering together, with increased PDGFA expression. Treatment with an antibody against insulin-like growth factors (BI836845) inhibited growth of mixed mCAF-tumor cell xenografts in vivo. Also, mCAFs had a suppressive effect on T-cell proliferation.

Conclusions:
This is the first comparative analysis of a set of CAFs from metastatic sites in breast cancer. It revealed a marked protumorigenic effect in these mCAFs, which occurs in part through increased expression of IGF2.
Transcriptomic Heterogeneity of Androgen Receptor Activity Defines a de novo low AR-Active Subclass in Treatment Naïve Primary Prostate Cancer
Authors: Spratt Daniel E. , Alshalalfa Mohammed , Fishbane Nick , Weiner Adam B. , Mehra Rohit , Mahal Brandon A. , Lehrer Jonathan , Liu Yang , Zhao Shuang G. , Speers Corey , Morgan Todd M. , Dicker Adam P. , Freedland Stephen J. , Karnes R. Jeffery , Weinmann Sheila , Davicioni Elai , Ross Ashley E. , Den Robert B. , Nguyen Paul L. , Feng Felix Y. , Lotan Tamara L. , Chinnaiyan Arul M. , Schaeffer Edward M. 
Published: September 2019

Abstract

Purpose:
The heterogeneity of androgen receptor (AR)-activity (AR-A) is well-characterized in heavily treated metastatic castration-resistant prostate cancer (mCRPC). However, the diversity and clinical implications of AR-A in treatment-naïve primary prostate cancer is largely unknown. We sought to characterize AR-A in localized prostate cancer and understand its molecular and clinical implications.

Experimental Design:
Genome-wide expression profiles from prostatectomy or biopsy samples from 19,470 patients were used, all with independent pathology review. This was comprised of prospective discovery (n = 5,239) and validation (n = 12,728) cohorts, six retrospective institutional cohorts with long-term clinical outcomes data (n = 1,170), and The Cancer Genome Atlas (n = 333).

Results:
A low AR-active subclass was identified, which comprised 9%–11% of each cohort, and was characterized by increased immune signaling, neuroendocrine expression, and decreased DNA repair. These tumors were predominantly ERG and basal subtype. Low AR-active tumors had significantly more rapid development of recurrence or metastatic disease across cohorts, which was maintained on multivariable analysis [HR, 2.61; 95% confidence interval (CI), 1.22–5.60; P = 0.014]. Low AR-active tumors were predicted to be more sensitive to PARP inhibition, platinum chemotherapy, and radiotherapy, and less sensitive to docetaxel and androgen-deprivation therapy. This was validated clinically, in that low AR-active tumors were less sensitive to androgen-deprivation therapy (OR, 0.41; 95% CI, 0.21–0.80; P = 0.008).

Conclusions:
Leveraging large-scale transcriptomic data allowed the identification of an aggressive subtype of treatment-naïve primary prostate cancer that harbors molecular features more analogous to mCRPC. This suggests that a preexisting subgroup of patients may have tumors that are predisposed to fail multiple current standard-of-care therapies and warrant dedicated therapeutic investigation.
Utility of the RIG-I Agonist Triphosphate RNA for Melanoma Therapy
Authors: Helms Mike W. , Jahn-Hofmann Kerstin , Gnerlich Felix , Metz-Weidmann Christiane , Braun Monika , Dietert Gabriele , Scherer Petra , Grandien Kaj , Theilhaber Joachim , Cao Hui , Wagenaar Timothy R. , Schnurr Max M. , Endres Stefan , Wiederschain Dmitri , Scheidler Sabine , Rothenfußer Simon , Brunner Bodo , König Lars M. 
Published: September 2019

AbstractThe pattern recognition receptor RIG-I plays an important role in the recognition of nonself RNA and antiviral immunity. RIG-I's natural ligand, triphosphate RNA (ppp-RNA), is proposed to be a valuable addition to the growing arsenal of cancer immunotherapy treatment options. In this study, we present comprehensive data validating the concept and utility of treatment with synthetic RIG-I agonist ppp-RNA for the therapy of human cancer, with melanoma as potential entry indication amenable to intratumoral treatment. Using mRNA expression data of human tumors, we demonstrate that RIG-I expression is closely correlated to cellular and cytokine immune activation in a wide variety of tumor types. Furthermore, we confirm susceptibility of cancer cells to ppp-RNA treatment in different cellular models of human melanoma, revealing unexpected heterogeneity between cell lines in their susceptibility to RNA agonist features, including sequence, secondary structures, and presence of triphosphate. Cellular responses to RNA treatment (induction of type I IFN, FasR, MHC-I, and cytotoxicity) were demonstrated to be RIG-I dependent using KO cells. Following ppp-RNA treatment of a mouse melanoma model, we observed significant local and systemic antitumor effects and survival benefits. These were associated with type I IFN response, tumor cell apoptosis, and innate and adaptive immune cell activation. For the first time, we demonstrate systemic presence of tumor antigen–specific CTLs following treatment with RIG-I agonists. Despite potential challenges in the generation and formulation of potent RIG-I agonists, ppp-RNA or analogues thereof have the potential to play an important role for cancer treatment in the next wave of immunotherapy.
Morin Inhibits Proliferation and Induces Apoptosis by Modulating the miR-188-5p/PTEN/AKT Regulatory Pathway in CML Cells
Authors: Nie Zi-Yuan , Yang Lin , Liu Xiao-Jun , Yang Zhan , Yang Gao-Shan , Zhou Jing , Qin Yan , Yu Jing , Jiang Ling-Ling , Wen Jin-Kun , Luo Jian-Min 
Published: September 2019

Abstract
Increased activity of the PI3K/AKT/mTOR pathway has been observed in chronic myeloid leukemia (CML). Morin, a kind of flavonoid, exhibits a significant anticancer activity by suppressing the PI3K/AKT signaling pathway. However, the effect of morin on CML and its underlying mechanisms is poorly understood. Here, we found that morin dose dependently inhibited the proliferation of CML cell lines K562 and KCL22 and induced their apoptosis, with a significant increase in cell apoptosis upon exposure of cells to 50 μmol/L morin. Moreover, morin significantly reduced CML xenograft growth in nude mice. Mechanically, morin attenuated phosphorylated AKT level by upregulating PTEN expression, thus leading to the inhibition of AKT signaling. Knockdown of PTEN by its siRNA completely abrogated morin-induced cell apoptosis, indicating that PTEN mediates the inductive effect of morin on CML cell apoptosis. More importantly, we found that miR-188-5p was significantly upregulated in CML patients and CML cell lines. Treating CML cells with morin markedly downregulated the miR-188-5p expression level. Further, we demonstrated that miR-188-5p repressed PTEN expression by directly targeting its 3′-UTR. miR-188-5p downregulation induced by morin enhanced CML cell apoptosis by relieving miR-188-5p repression of PTEN expression. In summary, morin exerts significant anticancer efficacy in CML by regulating the miR-188-5p/PTEN axis and thus repressing the PI3K/AKT signaling.
Protective Effects of Prunasin A against the Differentiation of Osteoclasts and Destruction of Cartilage via the Receptor Activator of Nuclear Factor-Kappa-Β Ligand/Mitogen-Activated Protein Kinase/Osteoprotegerin Pathway in a Rat Model of Arthritis
Authors: Chen Tong , Zhang Bo , Lin Yuan , Pan Jiang , Zhao Xiao-Xiong , Ren Shi-Xiang 
Published: September 2019

The present study evaluated the protective effects of pseurotin A against inflammation and the destruction of cartilage in a rat model of rheumatoid arthritis (RA). RA was induced by intradermal injections of Freund’s complete adjuvant (1 mg/mL), and the treatment with pseurotin A (50 and 100 mg/kg, p.o.) was administered over 1 week. The effects of pseurotin A were assessed by estimating hind paw volume (HPV) and determining the levels of inflammatory mediators in the serum and synovial fluid of collagen-induced arthritis (CIA)-induced RA rats. Western blot and histopathological assays were performed to assess changes in synovial tissues. Additionally, in vitro analyses of receptor activator of nuclear factor-kappa-Β ligand (RANKL)-stimulated RAW264.7 cells treated with pseurotin A at different concentrations (1, 10, and 100 µg/mL) were conducted to assess the effects of pseurotin A on apoptosis ratio, real-time polymerase chain reaction data, and tartrate-resistant acid phosphatase staining. Compared to the RA group, treatment with pseurotin A significantly decreased HPV and reduced the levels of inflammatory mediators in the synovial fluid and blood. Additionally, pseurotin A ameliorated the protein expressions of osteoprotegerin, nuclear factor of activated T-cells, nuclear factor-kappa beta (NF-κB), IκBα, extracellular signal regulated kinase, and P38 as well as histopathological changes in the synovial tissue of CIA-induced RA rats. The in vitro findings revealed that pseurotin A treatment did not alter the apoptosis ratio in RANKL-stimulated RAW264.7 cells but significantly reduced the mRNA expressions of calcitonin receptor, NF-κB, and matrix metallopeptidase-9. The present findings suggest that pseurotin A ameliorated the differentiation of osteoclasts and the destruction of cartilage in RA rats via regulation of the mitogen-activated protein kinase/RANKL/NF-kB pathway.
Mammals of Tengchong Section of Gaoligongshan National Nature Reserve in Yunnan Province, China
Authors: Li Fei , Huang Xiang-Yuan , Zhang Xing-Chao , Zhao Xing-Xi , Yang Jian-Huan , Chan Bosco Pui Lok 
Published: September 2019

We conducted field surveys on the mammalian diversity in the Tengchong Section of Gaoligongshan National Nature Reserve in Yunnan Province, China, using camera trap and transect method between April 2014 and May 2018. A total of 46 identifiable mammal species were recorded, including one new record for China and nine new species for the Tengchong County. Of the 46 species, nine are globally threatened (three Endangered and six Vulnerable) and six are Near Threatened on the IUCN Red List of Threatened Species. Species richness of most mammal groups in Tengchong remains high compared to similar sites in neighbouring countries; however, encounter rates for species vulnerable to high hunting pressures were quite low and large carnivores, except the Asiatic Black Bear, were either extirpated or at critically low numbers. Future surveys should cover a wider elevation range and a variety of microhabitats to increase the probability of detecting the species not yet recorded. To enhance the conservation value of the reserve for the diverse mammalian community, poaching and livestock grazing should be further controlled; in addition, protection and restoration of low-altitude forests should be encouraged. Monitoring and research on selected flagship species should also be conducted.
A preliminary report on butterfly fauna (Insecta: Lepidoptera) of Tengchong Section of Gaoligongshan National Nature Reserve, China
Authors: Lo Yik Fui Philip , Bi Zheng 
Published: September 2019

The butterfly fauna of Tengchong Section of Gaoligongshan National Nature Reserve, western Yunnan, China was investigated during a series of field surveys conducted between April 2014 and May 2018. A total of 216 butterfly species were recorded (Hesperiidae 41, Papilionidae 20, Pieridae 21, Lycaenidae 45, and Nymphalidae 89), of which 179 represent new records for Tengchong. Significant findings include paratype materials of a recently described genus and a subspecies, respectively, as well as three national and five provincial new records. Several obscure species were rediscovered during the survey, including two taxa that have not been recorded since their descriptions, Celaenorrhinus morena Evans, 1949 and Thoressa pedla pedla (Evans, 1956). The result of the survey is presented herein with notes on some little-known species. Additionally, past records on Tengchong butterfly fauna were reviewed and a name is treated as nomen nudum.
Carotid Plaque Neovascularization Detected With Superb Microvascular Imaging Ultrasound Without Using Contrast Media
Authors: Zamani Mahtab , Skagen Karolina , Scott Helge , Lindberg Beate , Russell David , Skjelland Mona 
Published: September 2019

Background and Purpose—
A significant proportion of ischemic strokes are caused by emboli from unstable carotid artery plaques with intraplaque neovascularization (IPN) as a key feature of plaque instability. IPN is not detectable with conventional Doppler ultrasound. Contrast-enhanced ultrasound (CEUS) can visualize IPN, but its use is limited in clinical practice because it requires an intravenous injection of contrast. Superb microvascular imaging (SMI) without contrast uses an algorithm to remove clutter and motion wall artifacts while preserving low-velocity blood flow signals, enabling visualization of IPN. Our aim was to assess the feasibility of SMI for the detection of IPN.

Methods—
Thirty-one patients with >50% carotid stenosis were included: 22 patients were symptomatic and 9 asymptomatic. All patients underwent conventional carotid ultrasound, CEUS, SMI, and blood tests. CEUS and SMI findings were compared and correlated to histological plaque assessments after endarterectomy.

Results—

There was significant positive correlation between an IPN visual 5-level classification of SMI and a semiquantitative analysis of CEUS (
P
<0.001,
r
=0.911). Plaques with higher SMI grades had higher numbers of neovessels quantified at histology (
P
=0.041,
r
=0.460). Hypoechoic plaques had higher grades of IPN on both CEUS and SMI (
P
<0.001). Higher visual IPN counts on SMI were associated with (1) increased areas of inflammation (
P
=0.043,
r
=0.457), (2) combined rank scores of granulation tissue, inflammation and lipids (
P
=0.02,
r
=0.494) at histology, and (3) higher peak-intensity values on quantitative CEUS (
P
=0.042,
r
=0.514).

Conclusions—
SMI ultrasound can detect neovascularization with accuracy comparable to CEUS, suggesting SMI to be a promising noninvasive alternative to CEUS for the assessment of carotid plaque stability.
Cardiometabolic Health and Longitudinal Progression of White Matter Hyperintensity
Authors: Scharf Eugene L. , Graff-Radford Jonathan , Przybelski Scott A. , Lesnick Timothy G. , Mielke Michelle M. , Knopman David S. , Preboske Gregory M. , Schwarz Christopher G. , Senjem Matthew L. , Gunter Jeffrey L. , Machulda Mary , Kantarci Kejal , Petersen Ronald C. , Jack Clifford R. , Vemuri Prashanthi 
Published: September 2019

Background and Purpose—
White matter hyperintensity (WMH) burden is associated with stroke and cognitive decline. Risk factors associated with the longitudinal progression of WMH in the general population have not been systematically investigated. To investigate the primary midlife and current cardiometabolic risk factors associated with changes in WMH over time in a population cohort.

Methods—
This cohort study included participants enrolled in the Mayo Clinic Study of Aging, a longitudinal population-based study in Olmsted County, Minnesota with at least 2 consecutive WMH assessments on fluid-attenuated inversion recovery-magnetic resonance images (n=554, ≥60 years with midlife assessments) with relevant baseline laboratory measures of interest. Linear mixed model regression was used to determine the important components of cardiometabolic risk profile at baseline that were associated with future progression of WMH. These analyses were controlled for age and sex. Sensitivity analyses were conducted using stratification by sex. The main outcome measure was percent change in WMH normalized to total intracranial volume. Three sets of models were constructed to evaluate individual (1) midlife risk factors, (2) current risk factors including the presence of metabolic syndrome and its constituents, and (3) baseline measurements of continuous laboratory measures of cardiometabolic risk.

Results—

Age was the strongest predictor of progression in WMH (
P
<0.001). Baseline hypertension (
P
<0.001), midlife hypertension (
P
=0.003), and baseline fasting glucose in males (
P
=0.01) were predictive of WMH change. The presence of metabolic syndrome was not associated with progressive WMH. In sensitivity analyses, associations between hypertension and WMH progression were stronger in females. Baseline serum glucose was associated with increase in WMH but was not significant in females in the stratified analysis. Other continuous laboratory measures of vascular risk were not associated with progressive WMH.

Conclusions—
Midlife and current hypertension in all participants and fasting glucose in males were associated with quantitative changes in white matter. Prospective clinical studies should determine optimal blood pressure to reduce stroke and cognitive impairment during aging.