bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cross-sectional and longitudinal measures of chitinase proteins in amyotrophic lateral sclerosis and expression of CHI3L1 in activated astrocytes
Authors: Vu Lucas , An Jiyan , Kovalik Tina , Gendron Tania , Petrucelli Leonard , Bowser Robert 
Published: January 2020

ObjectiveAmyotrophic lateral sclerosis (ALS) is a complex disease with numerous pathological mechanisms resulting in a heterogeneous patient population. Using biomarkers for particular disease mechanisms may enrich a homogeneous subset of patients. In this study, we quantified chitotriosidase (Chit-1) and chitinase-3-like protein 1 (CHI3L1), markers of glial activation, in cerebrospinal fluid (CSF) and plasma and determined the cell types that express CHI3L1 in ALS.MethodsImmunoassays were used to quantify Chit-1, CHI3L1 and phosphorylated neurofilament heavy chain levels in longitudinal CSF and matching plasma samples from 118 patients with ALS, 17 disease controls (DCs), and 24 healthy controls (HCs). Immunostaining was performed to identify and quantify CHI3L1-positive cells in tissue sections from ALS, DCs and non-neurological DCs.ResultsCSF Chit-1 exhibited increased levels in ALS as compared with DCs and HCs. CSF CHI3L1 levels were increased in ALS and DCs compared with HCs. No quantitative differences were noted in plasma for either chitinase. Patients with ALS with fast-progressing disease exhibited higher levels of CSF Chit-1 and CHI3L1 than patients with slow-progressing disease. Increased numbers of CHI3L1-positive cells were observed in postmortem ALS motor cortex as compared with controls, and these cells were identified as a subset of activated astrocytes located predominately in the white matter of the motor cortex and the spinal cord.ConclusionsCSF Chit-1 and CHI3L1 are significantly increased in ALS, and CSF Chit-1 and CHI3L1 levels correlate to the rate of disease progression. CHI3L1 is expressed by a subset of activated astrocytes predominately located in white matter.
Plasma glial fibrillary acidic protein is raised in progranulin-associated frontotemporal dementia
Authors: Heller Carolin , Foiani Martha S , Moore Katrina , Convery Rhian , Bocchetta Martina , Neason Mollie , Cash David M , Thomas David , Greaves Caroline V , Woollacott Ione OC , Shafei Rachelle , Van Swieten John C , Moreno Fermin , Sanchez-Valle Raquel , Borroni Barbara , Laforce Jr Robert , Masellis Mario , Tartaglia Maria Carmela , Graff Caroline , Galimberti Daniela , Rowe James B , Finger Elizabeth , Synofzik Matthis , Vandenberghe Rik , de Mendonca Alexandre , Tagliavini Fabrizio , Santana Isabel , Ducharme Simon , Butler Christopher R , Gerhard Alex , Levin Johannes , Danek Adrian , Frisoni Giovanni , Sorbi Sandro , Otto Markus , Heslegrave Amanda J , Zetterberg Henrik , Rohrer Jonathan D 
Published: January 2020

BackgroundThere are few validated fluid biomarkers in frontotemporal dementia (FTD). Glial fibrillary acidic protein (GFAP) is a measure of astrogliosis, a known pathological process of FTD, but has yet to be explored as potential biomarker.MethodsPlasma GFAP and neurofilament light chain (NfL) concentration were measured in 469 individuals enrolled in the Genetic FTD Initiative: 114C9orf72expansion carriers (74 presymptomatic, 40 symptomatic), 119GRNmutation carriers (88 presymptomatic, 31 symptomatic), 53MAPTmutation carriers (34 presymptomatic, 19 symptomatic) and 183 non-carrier controls. Biomarker measures were compared between groups using linear regression models adjusted for age and sex with family membership included as random effect. Participants underwent standardised clinical assessments including the Mini-Mental State Examination (MMSE), Frontotemporal Lobar Degeneration-Clinical Dementia Rating scale and MRI. Spearman’s correlation coefficient was used to investigate the relationship of plasma GFAP to clinical and imaging measures.ResultsPlasma GFAP concentration was significantly increased in symptomaticGRNmutation carriers (adjusted mean difference from controls 192.3 pg/mL, 95% CI 126.5 to 445.6), but not in those withC9orf72expansions (9.0, –61.3 to 54.6),MAPTmutations (12.7, –33.3 to 90.4) or the presymptomatic groups. GFAP concentration was significantly positively correlated with age in both controls and the majority of the disease groups, as well as with NfL concentration. In the presymptomatic period, higher GFAP concentrations were correlated with a lower cognitive score (MMSE) and lower brain volume, while in the symptomatic period, higher concentrations were associated with faster rates of atrophy in the temporal lobe.ConclusionsRaised GFAP concentrations appear to be unique toGRN-related FTD, with levels potentially increasing just prior to symptom onset, suggesting that GFAP may be an important marker of proximity to onset, and helpful for forthcoming therapeutic prevention trials.
Effect of rovatirelin in patients with cerebellar ataxia: two randomised double-blind placebo-controlled phase 3 trials
Authors: Nishizawa Masatoyo , Onodera Osamu , Hirakawa Akihiro , Shimizu Yoshitaka , Yamada Masayuki 
Published: January 2020

ObjectiveTo investigate the efficacy of rovatirelin, a thyrotropin-releasing hormone analogue, for ataxias in patients with spinocerebellar degeneration (SCD).MethodsTwo multicentre, randomised, double-blind, placebo-controlled phase 3 studies (KPS1301, KPS1305) enrolled patients with predominant cerebellar ataxia, including SCA6, SCA31 or cortical cerebellar atrophy. KPS1301 enrolled patients with truncal ataxia and KPS1305 enrolled patients with truncal and limb ataxia. Each study included 4 weeks of pretreatment, a 28-week or 24-week treatment period and 4 weeks of follow-up. Patients were randomised (1:1:1) to rovatirelin (1.6 or 2.4 mg) or placebo in KPS1301, and randomised (1:1) to rovatirelin 2.4 mg or placebo in KPS1305. The primary endpoint was change in Scale for the Assessment and Rating of Ataxia (SARA) total scores. Pooled analysis was performed in patients who met the SARA recruitment criteria of KPS1305.ResultsFrom October 2013 to May 2014, KPS1301 enrolled 411 patients; 374 were randomised to rovatirelin 1.6 mg (n=125), rovatirelin 2.4 mg (n=126) or placebo (n=123). From November 2016 to August 2017, KPS1305 enrolled 241 patients; 203 were randomised to rovatirelin 2.4 mg (n=101) or placebo (n=102). The primary endpoint showed no significant difference between rovatirelin and placebo in these two studies. In the pooled analysis (n=278), the difference between rovatirelin 2.4 mg (n=140) and placebo (n=138) was –0.61 (–1.64 vs –1.03; 95% CI –1.16 to –0.06; p=0.029) in the adjusted mean change in the SARA total score.ConclusionsRovatirelin is a potentially effective treatment option for SCD.Trial registration numberNCT01970098;NCT02889302
Prognosis of amyotrophic lateral sclerosis patients undergoing tracheostomy invasive ventilation therapy in Japan
Authors: Hayashi Naoki , Atsuta Naoki , Yokoi Daichi , Nakamura Ryoichi , Nakatochi Masahiro , Katsuno Masahisa , Izumi Yuishin , Kanai Kazuaki , Hattori Nobutaka , Taniguchi Akira , Morita Mitsuya , Kano Osamu , Shibuya Kazumoto , Kuwabara Satoshi , Suzuki Naoki , Aoki Masashi , Aiba Ikuko , Mizoguchi Kouichi , Oda Masaya , Kaji Ryuji , Sobue Gen 
Published: January 2020

ObjectiveThe aim of this study is to describe and clarify the factors affecting the prognosis of Japanese patients with amyotrophic lateral sclerosis (ALS) undergoing tracheostomy invasive ventilation (TIV) therapy.MethodsWe conducted a prospective longitudinal observational case-control study using a multicentre registry. ALS patients who started TIV therapy after registration (TIV group) and those who did not receive TIV (non-TIV group) were included. We compared the survival time between the TIV group and the non-TIV group using a propensity score matching analysis and evaluated the prognostic factors in the TIV group.ResultsFrom February 2006 to January 2018, 190 patients in the TIV group and 1093 patients in the non-TIV group were included in this study. The mean age of disease onset and usage rate of gastrostomy and non-invasive ventilation therapy differed between the groups. In the propensity score matching analysis using known prognostic factors, the median overall survival time of the TIV group was significantly greater than that of the non-TIV group (11.33 years vs 4.61 years; p<0.001). Analysis using the Cox proportional hazard model suggested that older age of onset and respiratory onset was an independent factor for poor prognosis after starting TIV therapy.ConclusionWe showed that there was a significant difference of approximately 7 years in life expectancy between Japanese ALS patients who did and did not receive TIV therapy.
RAGE-induced ILC2 expansion in acute lung injury due to haemorrhagic shock
Authors: Zhang Kai , Jin Yue , Lai Dengming , Wang Jieyan , Wang Yang , Wu Xiaoliang , Scott Melanie , Li Yuehua , Hou Jinchao , Billiar Timothy , Wilson Mark , Shu Qiang , Fang Xiangming , Fan Jie 
Published: January 2020

BackgroundType 2 immune dysfunction contributes to acute lung injury and lethality following haemorrhagic shock (HS) and trauma. Group 2 innate lymphoid cells (ILC2s) play a significant role in the regulation of type 2 immune responses. However, the role of ILC2 in post-HS acute lung injury and the underlying mechanism has not yet been elucidated.ObjectiveTo investigate the regulatory role of ILC2s in HS-induced acute lung injury and the underlying mechanism in patients and animal model.MethodsCirculating markers of type 2 immune responses in patients with HS and healthy controls were characterised. Using a murine model of HS, the role of high-mobility group box 1 (HMGB1)-receptor for advanced glycation end products (RAGE) signalling in regulation of ILC2 proliferation, survival and function was determined. And the role of ILC2 in inducing type 2 immune dysfunction was assessed as well.ResultsThe number of ILC2s was significantly increased in the circulation of patients with HS that was correlated with the increase in the markers of type 2 immune responses in the patients. Animal studies showed that HMGB1 acted via RAGE to induce ILC2 accumulation in the lungs by promoting ILC2 proliferation and decreasing ILC2 death. The expansion of ILC2s resulted in type 2 cytokines secretion and eosinophil infiltration in the lungs, both of which contributed to lung injury after HS.ConclusionsThese results indicate that HMGB1-RAGE signalling plays a critical role in regulating ILC2 biological function that aggravates type 2 lung inflammation following HS.
Impact of respiratory muscle training on respiratory muscle strength, respiratory function and quality of life in individuals with tetraplegia: a randomised clinical trial
Authors: Boswell-Ruys Claire L , Lewis Chaminda R H , Wijeysuriya Nirupama S , McBain Rachel A , Lee Bonsan Bonne , McKenzie David K , Gandevia Simon C , Butler Jane E 
Published: January 2020

BackgroundRespiratory complications remain a leading cause of morbidity and mortality in people with acute and chronic tetraplegia. Respiratory muscle weakness following spinal cord injury-induced tetraplegia impairs lung function and the ability to cough. In particular, inspiratory muscle strength has been identified as the best predictor of the likelihood of developing pneumonia in individuals with tetraplegia. We hypothesised that 6 weeks of progressive respiratory muscle training (RMT) increases respiratory muscle strength with improvements in lung function, quality of life and respiratory health.MethodsSixty-two adults with tetraplegia participated in a double-blind randomised controlled trial. Active or sham RMT was performed twice daily for 6 weeks. Inspiratory muscle strength, measured as maximal inspiratory pressure (PImax) was the primary outcome. Secondary outcomes included lung function, quality of life and respiratory health. Between-group comparisons were obtained with linear models adjusting for baseline values of the outcomes.ResultsAfter 6 weeks, there was a greater improvement in PImax in the active group than in the sham group (mean difference 11.5 cmH2O (95% CI 5.6 to 17.4), p<0.001) and respiratory symptoms were reduced (St George Respiratory Questionnaire mean difference 10.3 points (0.01–20.65), p=0.046). Significant improvements were observed in quality of life (EuroQol-Five Dimensional Visual Analogue Scale 14.9 points (1.9–27.9), p=0.023) and perceived breathlessness (Borg score 0.64 (0.11–1.17), p=0.021). There were no significant improvements in other measures of respiratory function (p=0.126–0.979).ConclusionsProgressive RMT increases inspiratory muscle strength in people with tetraplegia, by a magnitude which is likely to be clinically significant. Measurement of baseline PImax and provision of RMT to at-risk individuals may reduce respiratory complications after tetraplegia.Trial registration numberAustralian New Zealand Clinical Trials Registry (ACTRN 12612000929808).
Time to exhaustion during cycling is not well predicted by critical power calculations
Authors: Pallarés Jesus G. , Lillo-Bevia Jose R. , Morán-Navarro Ricardo , Cerezuela-Espejo Victor , Mora-Rodriguez Ricardo 
Published: January 2020

Three to 5 cycling tests to exhaustion allow prediction of time to exhaustion (TTE) at power output based on calculation of critical power (CP). We aimed to determine the accuracy of CP predictions of TTE at power outputs habitually endured by cyclists. Fourteen endurance-trained male cyclists underwent 4 randomized cycle-ergometer TTE tests at power outputs eliciting (i) mean Wingate anaerobic test (WAnTmean), (ii) maximal oxygen consumption, (iii) respiratory compensation threshold (VT2), and (iv) maximal lactate steady state (MLSS). Tests were conducted in duplicate with coefficient of variation of 5%–9%. Power outputs were 710 ± 63 W for WAnTmean, 366 ± 26 W for maximal oxygen consumption, 302 ± 31 W for VT2 and 247 ± 20 W for MLSS. Corresponding TTE were 00:29 ± 00:06, 03:23 ± 00:45, 11:29 ± 05:07, and 76:05 ± 13:53 min:s, respectively. Power output associated with CP was only 2% lower than MLSS (242 ± 19 vs. 247 ± 20 W; P < 0.001). The CP predictions overestimated TTE at WAnTmean (00:24 ± 00:10 mm:ss) and MLSS (04:41 ± 11:47 min:s), underestimated TTE at VT2 (–04:18 ± 03:20 mm:ss; P < 0.05), and correctly predicted TTE at maximal oxygen consumption. In summary, CP accurately predicts MLSS power output and TTE at maximal oxygen consumption. However, it should not be used to estimate time to exhaustion in trained cyclists at higher or lower power outputs (e.g., sprints and 40-km time trials). Novelty CP calculation enables to predict TTE at any cycling power output. We tested those predictions against measured TTE in a wide range of cycling power outputs. CP appropriately predicted TTE at maximal oxygen consumption intensity but err at higher and lower cycling power outputs.
Eddington-inspired-Born–Infeld tensorial instabilities neutralized in a quantum approach
Authors: Albarran Imanol , Bouhmadi-López Mariam , Chen Che-Yu , Chen Pisin 
Published: January 2020

AbstractThe recent direct detection of gravitational waves has highlighted the huge importance of the tensorial modes in any extended gravitational theory. One of the most appealing approaches to extend gravity beyond general relativity is the Eddington-inspired-Born–Infeld gravity which is formulated within the Palatini approach. This theory can avoid the Big Bang singularity in the physical metric although a Big Bang intrinsic to the affine connection is still there, which in addition couples to the tensorial sector and might jeopardize the viability of the model. In this paper, we suggest that a quantum treatment of the affine connection, or equivalently of its compatible metric, is able to rescue the model. We carry out such an analysis and conclude that from a quantum point of view such a Big Bang is unharmful. We expect therefore that the induced tensorial instability, caused by the Big Bang intrinsic to the affine connection, can be neutralized at the quantum level.
A Quantitative Centrosomal Amplification Score Predicts Local Recurrence of Ductal Carcinoma In Situ
Authors: Mittal Karuna , Toss Michael S. , Wei Guanhao , Kaur Jaspreet , Choi Da Hoon , Melton Brian D. , Osan Remus M. , Miligy Islam M. , Green Andrew R. , Janssen Emiel A.M. , Søiland Håvard , Gogineni Keerthi , Manne Upender , Rida Padmashree , Rakha Emad A. , Aneja Ritu 
Published: January 2020

Abstract

Purpose:
The purpose of this study is to predict risk of local recurrence (LR) in ductal carcinoma in situ (DCIS) with a new visualization and quantification approach using centrosome amplification (CA), a cancer cell–specific trait widely associated with aggressiveness.

Experimental Design:
This first-of-its-kind methodology evaluates the severity and frequency of numerical and structural CA present within DCIS and assigns a quantitative centrosomal amplification score (CAS) to each sample. Analyses were performed in a discovery cohort (DC, n = 133) and a validation cohort (VC, n = 119).

Results:
DCIS cases with LR exhibited significantly higher CAS than recurrence-free cases. Higher CAS was associated with a greater risk of developing LR (HR, 6.3 and 4.8 for DC and VC, respectively; P &lt; 0.001). CAS remained an independent predictor of relapse-free survival (HR, 7.4 and 4.5 for DC and VC, respectively; P &lt; 0.001) even after accounting for potentially confounding factors [grade, age, comedo necrosis, and radiotherapy (RT)]. Patient stratification using CAS (P &lt; 0.0001) was superior to that by Van Nuys Prognostic Index (VNPI; HR for CAS = 6.2 vs. HR for VNPI = 1.1). Among patients treated with breast-conserving surgery alone, CAS identified patients likely to benefit from adjuvant RT.

Conclusions:
CAS predicted 10-year LR risk for patients who underwent surgical management alone and identified patients who may be at low risk of recurrence, and for whom adjuvant RT may not be required. CAS demonstrated the highest concordance among the known prognostic models such as VNPI and clinicopathologic variables such as grade, age, and comedo necrosis.
Targeting Super-Enhancer–Associated Oncogenes in Osteosarcoma with THZ2, a Covalent CDK7 Inhibitor
Authors: Zhang Jiajun , Liu Weihai , Zou Changye , Zhao Zhiqiang , Lai Yuanying , Shi Zhi , Xie Xianbiao , Huang Gang , Wang Yongqian , Zhang Xuelin , Fan Zepei , Su Qiao , Yin Junqiang , Shen Jingnan 
Published: January 2020

Abstract

Purpose:
Malignancy of cancer cells depends on the active transcription of tumor-associated genes. Recently, unique clusters of transcriptional enhancers, termed super-enhancers, have been reported to drive the expression of genes that define cell identity. In this study, we characterized specific super-enhancer–associated genes of osteosarcoma, and explored their potential therapeutic value.

Experimental Design:
Super-enhancer regions were characterized through chromatin immunoprecipitation sequencing (ChIP-seq). RT-qPCR was used to detect the mRNA level of CDK7 in patient specimens and confirm the regulation of sensitive oncogenes by THZ2. The phosphorylation of the initiation-associated sites of RNA polymerase II (RNAPII) C-terminal repeat domain (CTD) was measured using Western blotting. Microarray expression analysis was conducted to explore transcriptional changes after THZ2 treatment. A variety of in vitro and in vivo assays were performed to assess the effects of CDK7 knockdown and THZ2 treatment in osteosarcoma.

Results:
Super-enhancers were associated with oncogenic transcripts and key genes encoding cell-type–specific transcription factors in osteosarcoma. Knockdown of transcription factor CDK7 reduced phosphorylation of the RNAPII CTD, and suppressed the growth and metastasis of osteosarcoma. A new specific CDK7 inhibitor, THZ2, suppressed cancer biology by inhibition of transcriptional activity. Compared with typical enhancers, osteosarcoma super-enhancer–associated oncogenes were particular vulnerable to this transcriptional disruption. THZ2 exhibited a powerful anti-osteosarcoma effect in vitro and in vivo.

Conclusions:
Super-enhancer–associated genes contribute to the malignant potential of osteosarcoma, and selectively targeting super-enhancer–associated oncogenes with the specific CDK7 inhibitor THZ2 might be a promising therapeutic strategy for patients with osteosarcoma.
A Phase I Study of Ruxolitinib, Lenalidomide, and Steroids for Patients with Relapsed/Refractory Multiple Myeloma
Authors: Berenson James R. , To Jennifer , Spektor Tanya M. , Martinez Daisy , Turner Carley , Sanchez Armando , Ghermezi Matthew , Eades Benjamin M. , Swift Regina A. , Schwartz Gary , Eshaghian Shahrooz , Stampleman Laura , Moss Robert A. , Lim Stephen , Vescio Robert 
Published: January 2020

Abstract

Purpose:
Ruxolitinib with lenalidomide and dexamethasone shows antimyeloma effects in vitro and in vivo. MUC1 leads to lenalidomide resistance in multiple myeloma cells, and ruxolitinib blocks its expression. Thus, ruxolitinib may restore sensitivity to lenalidomide. Therefore, a phase I trial was conducted to determine the safety and efficacy of ruxolitinib with lenalidomide and methylprednisolone for patients with relapsed/refractory multiple myeloma (RRMM) who had been treated with lenalidomide/steroids and a proteasome inhibitor and showed progressive disease at study entry.

Patients and Methods:
A traditional 3+3 dose escalation design was used to enroll subjects in four cohorts with planned total enrollment of 28 patients. Subjects received ruxolitinib twice daily, lenalidomide daily on days 1–21 of a 28-day cycle, and methylprednisolone orally every other day. Primary endpoints were safety, clinical benefit rate (CBR), and overall response rate (ORR).

Results:
Twenty-eight patients were enrolled. The median age was 67 years and received a median of six prior treatments including lenalidomide and steroids to which 93% were refractory. No dose-limiting toxicities occurred. The CBR and ORR were 46% and 38%, respectively. All 12 responding patients were refractory to lenalidomide. Grade 3 or grade 4 adverse events (AE) included anemia (18%), thrombocytopenia (14%), and lymphopenia (14%). Most common serious AEs included sepsis (11%) and pneumonia (11%).

Conclusions:
This phase I trial demonstrates that a JAK inhibitor, ruxolitinib, can overcome refractoriness to lenalidomide and steroids for patients with RRMM. These results represent a promising novel therapeutic approach for treating multiple myeloma (ClinicalTrials.gov number, NCT03110822).