bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anti-CSF-1R emactuzumab in combination with anti-PD-L1 atezolizumab in advanced solid tumor patients naïve or experienced for immune checkpoint blockade
Authors: Gomez-Roca Carlos , Cassier Philippe , Zamarin Dmitriy , Machiels Jean-Pascal , Luis Perez Gracia Jose , Stephen Hodi F , Taus Alvaro , Martinez Garcia Maria , Boni Valentina , Eder Joseph P , Hafez Navid , Sullivan Ryan , Mcdermott David , Champiat Stephane , Aspeslagh Sandrine , Terret Catherine , Jegg Anna-Maria , Jacob Wolfgang , Cannarile Michael A , Ries Carola , Korski Konstanty , Michielin Francesca , Christen Randolph , Babitzki Galina , Watson Carl , Meneses-Lorente Georgina , Weisser Martin , Rüttinger Dominik , Delord Jean-Pierre , Marabelle Aurelien 
Published: May 2022

BackgroundThis phase 1b study (NCT02323191) evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of colony-stimulating factor-1 receptor-blocking monoclonal antibody (mAb) emactuzumab in combination with the programmed cell death-1 ligand (PD-L1)-blocking mAb atezolizumab in patients with advanced solid tumors naïve or experienced for immune checkpoint blockers (ICBs).MethodsEmactuzumab (500–1350 mg flat) and atezolizumab (1200 mg flat) were administered intravenously every 3 weeks. Dose escalation of emactuzumab was conducted using the 3+3 design up to the maximum tolerated dose (MTD) or optimal biological dose (OBD). Extension cohorts to evaluate pharmacodynamics and clinical activity were conducted in metastatic ICB-naive urothelial bladder cancer (UBC) and ICB-pretreated melanoma (MEL), non-small cell lung cancer (NSCLC) and UBC patients.ResultsOverall, 221 patients were treated. No MTD was reached and the OBD was determined at 1000 mg of emactuzumab in combination with 1200 mg of atezolizumab. Grade ≥3 treatment-related adverse events occurred in 25 (11.3%) patients of which fatigue and rash were the most common (14 patients (6.3%) each). The confirmed objective response rate (ORR) was 9.8% for ICB-naïve UBC, 12.5% for ICB-experienced NSCLC, 8.3% for ICB-experienced UBC and 5.6% for ICB-experienced MEL patients, respectively. Tumor biopsy analyses demonstrated increased activated CD8 +tumor infiltrating T lymphocytes (TILs) associated with clinical benefit in ICB-naïve UBC patients and less tumor-associated macrophage (TAM) reduction in ICB-experienced compared with ICB-naïve patients.ConclusionEmactuzumab in combination with atezolizumab demonstrated a manageable safety profile with increased fatigue and skin rash over usual atezolizumab monotherapy. A considerable ORR was particularly seen in ICB-experienced NSCLC patients. Increase ofCD8 +TILs under therapy appeared to be associated with persistence of a TAM subpopulation.
Small extracellular vesicles induce resistance to anti-GD2 immunotherapy unveiling tipifarnib as an adjunct to neuroblastoma immunotherapy
Authors: Liu Xiaoming , Wills Carson A , Chen Longgui , Zhang Jiawen , Zhao Yuanjun , Zhou Mi , Sundstrom Jeffrey M , Schell Todd , Spiegelman Vladimir S , Young Megan M , Wang Hong-Gang 
Published: May 2022

BackgroundAnti-GD2 monoclonal antibody immunotherapy has significantly improved the overall survival rate for high-risk neuroblastoma patients. However, 40% of patients fail to respond or develop resistance to treatment, and the molecular mechanisms by which this occurs remain poorly understood. Tumor-derived small extracellular vesicles (sEVs) have emerged as critical regulators in modulating the response to immunotherapy. In this study, we investigated the role of neuroblastoma-derived sEVs in promoting resistance to the anti-GD2 monoclonal antibody dinutuximab. Moreover, to determine whether pharmacologic inhibition of sEV secretion sensitizes tumors to dinutuximab treatment, we combined dinutuximab with tipifarnib, a farnesyltransferase inhibitor that inhibits sEV secretion.MethodsWe investigated the role of neuroblastoma-derived sEVs in modulating the response to dinutuximab by utilizing the syngeneic 9464D-GD2 mouse model. The effect of neuroblastoma-derived sEVs in modulating the tumor microenvironment (TME) and host immune system were evaluated by RNA-sequencing and flow cytometry. Importantly, we used this mouse model to investigate the efficacy of tipifarnib in sensitizing neuroblastoma tumors to dinutuximab. The effect of tipifarnib on both the TME and host immune system were assessed by flow cytometry.ResultsWe demonstrated that neuroblastoma-derived sEVs significantly attenuated the efficacy of dinutuximabin vivoand modulated tumor immune cell infiltration upon dinutuximab treatment to create an immunosuppressive TME that contains more tumor-associated macrophages and fewer tumor-infiltrating NK cells. In addition, we demonstrated that neuroblastoma-derived sEVs suppress splenic NK cell maturationin vivoand dinutuximab-induced NK cell-mediated antibody-dependent cellular cytotoxicityin vitro. Importantly, tipifarnib drastically enhanced the efficacy of dinutuximab-mediated inhibition of tumor growth and prevented the immunosuppressive effects of neuroblastoma-derived sEVsin vivo.ConclusionsThese preclinical findings uncover a novel mechanism by which neuroblastoma-derived sEVs modulate the immune system to promote resistance to dinutuximab and suggest that tipifarnib-mediated inhibition of sEV secretion may serve as a viable treatment strategy to enhance the antitumor efficacy of anti-GD2 immunotherapy in high-risk neuroblastoma patients.
Gain-of-function p.F28S variant inRAC3disrupts neuronal differentiation, migration and axonogenesis during cortical development, leading to neurodevelopmental disorder
Authors: Nishikawa Masashi , Scala Marcello , Umair Muhammad , Ito Hidenori , Waqas Ahmed , Striano Pasquale , Zara Federico , Costain Gregory , Capra Valeria , Nagata Koh-ichi 
Published: May 2022

BackgroundRAC3encodes a Rho family small GTPase that regulates the behaviour and organisation of actin cytoskeleton and intracellular signal transduction. Variants inRAC3can cause a phenotypically heterogeneous neurodevelopmental disorder with structural brain anomalies and dysmorphic facies. The pathomechanism of this recently discovered genetic disorder remains unclear.MethodsWe investigated an early adolescent female with intellectual disability, drug-responsive epilepsy and white matter abnormalities. Through exome sequencing, we identified the novel de novo variant (NM_005052.3): c.83T>C (p.Phe28Ser) inRAC3. We then examined the pathophysiological significance of the p.F28S variant in comparison with the recently reported disease-causing p.Q61L variant, which results in a constitutively activated version of RAC3.ResultsIn vitro analyses revealed that the p.F28S variant was spontaneously activated by substantially increased intrinsic GTP/GDP-exchange activity and bound to downstream effectors tested, such as PAK1 and MLK2. The variant suppressed the differentiation of primary cultured hippocampal neurons and caused cell rounding with lamellipodia. In vivo analyses using in utero electroporation showed that acute expression of the p.F28S variant caused migration defects of excitatory neurons and axon growth delay during corticogenesis. Notably, defective migration was rescued by a dominant negative version of PAK1 but not MLK2.ConclusionOur results indicate that RAC3 is critical for brain development and the p.F28S variant causes morphological and functional defects in cortical neurons, likely due to the hyperactivation of PAK1.
Favourable arterial, tissue-level and venous collaterals correlate with early neurological improvement after successful thrombectomy treatment of acute ischaemic stroke
Authors: Faizy Tobias Djamsched , Mlynash Michael , Kabiri Reza , Christensen Soren , Kuraitis Gabriella , Meyer Lukas , Bechstein Matthias , Van Horn Noel , Lansberg Maarten G , Albers Greg , Fiehler Jens , Wintermark Max , Heit Jeremy J 
Published: May 2022

Background and purposeEarly neurological improvement (ENI) after thrombectomy is associated with better long-term outcomes in patients with acute ischaemic stroke due to large vessel occlusion (AIS-LVO). Whether cerebral collaterals influence the likelihood of ENI is poorly described. We hypothesised that favourable collateral perfusion at the arterial, tissue-level and venous outflow (VO) levels is associated with ENI after thrombectomy.Materials and methodsMulticentre retrospective study of patients with AIS-LVO treated by thrombectomy. Tissue-level collaterals (TLC) were measured on cerebral perfusion studies by the hypoperfusion intensity ratio. VO and pial arterial collaterals (PAC) were determined by the Cortical Vein Opacification Score and the modified Tan scale on CT angiography, respectively. ENI was defined as improvement of ≥8 points or a National Institutes of Health Stroke Scale score of 0 hour or 1 24 hours after treatment. Multivariable regression analyses were used to determine the association of collateral biomarkers with ENI and good functional outcomes (modified Rankin Scale 0–2).Results646 patients met inclusion criteria. Favourable PAC (OR: 1.9, CI 1.2 to 3.1; p=0.01), favourable VO (OR: 3.3, CI 2.1 to 5.1; p<0.001) and successful reperfusion (OR: 3.1, CI 1.7 to 5.8; p<0.001) were associated with ENI, but favourable TLC were not (p=0.431). Good functional outcomes at 90-days were associated with favourable TLC (OR: 2.2, CI 1.4 to 3.6; p=0.001), VO (OR: 5.7, CI 3.5 to 9.3; p<0.001) and ENI (OR: 5.7, CI 3.3 to 9.8; p<0.001), but not PAC status (p=0.647).ConclusionFavourable PAC and VO were associated with ENI after thrombectomy. Favourable TLC predicted longer term functional recovery after thrombectomy, but the impact of TLC on ENI is strongly dependent on vessel reperfusion.
Neurocognitive functioning and symptoms across levels of collision and contact in male high school athletes
Authors: Oldham Jessie R. , Howell David , Lanois Corey , Berkner Paul , Iverson Grant L. , Mannix Rebekah , Meehan William 
Published: May 2022

ObjectiveWe sought to determine whether male collision sport athletes perform worse on computerised neurocognitive assessments and report higher symptom burdens than athletes in contact (but not collision) sports and athletes in non-contact sports.MethodsThis cross-sectional study used data collected by the Massachusetts Concussion Management Coalition on high school boys who underwent computerised neurocognitive testing between 2009 and 2018. We divided sports participation in three different sport types: (1) collision, (2) contact, non-collision and (3) non-contact. Our outcomes included the four computerised neurocognitive composite scores (verbal memory, visual memory, visual motor speed and reaction time) and the total symptom score. The independent variable was sport type (collision, contact, non-contact), adjusted for age, concussion history and comorbidities.ResultsOf the 92 979 athletes (age: 15.59±2.08 years) included in our study, collision sport athletes performed minimally but significantly worse than other athletes on neurocognitive composite scores (verbal memory: β=−1.64, 95% CI −1.85 to –1.44; visual memory: β=−1.87, 95% CI −2.14 to –1.60; visual motor speed: β=−2.12, 95% CI −2.26 to –1.97; reaction time: β=0.02, 95% CI 0.02 to 0.02). Collision and contact sport athletes also had slightly but significantly lower total symptom scores (collision: 3.99±7.17; contact: 3.78±6.81; non-contact: 4.32±7.51, p<0.001, η2=0.001) than non-contact sport athletes.ConclusionThere are minimal observed differences in performance on neurocognitive assessments between collision sport, contact sport and non-contact sport athletes. The repetitive subconcussive head impacts associated with collision sport participation do not appear to negatively affect self-reported symptoms or neurocognitive functioning in current youth athletes.
APOE ɛ4dose associates with increased brain iron and β-amyloid via blood–brain barrier dysfunction
Authors: Uchida Yuto , Kan Hirohito , Sakurai Keita , Horimoto Yoshihiko , Hayashi Emi , Iida Akihiko , Okamura Nobuyuki , Oishi Kenichi , Matsukawa Noriyuki 
Published: May 2022

ObjectiveTo examine the effect of apolipoprotein E (APOE)ɛ4dose on blood–brain barrier (BBB) clearance function, evaluated using an advanced MRI technique and analyse its correlation with brain iron and β-amyloid accumulation in the early stages of the Alzheimer’s continuum.MethodsIn this single-centre observational prospective cohort study, 24APOE ɛ4non-carriers, 22 heterozygotes and 20 homozygotes in the early stages of the Alzheimer’s continuum were scanned with diffusion-prepared arterial spin labelling, which estimates the water exchange rate across the BBB (kw). Participants also underwent quantitative susceptibility mapping, [11C]Pittsburgh compound B-positron emission tomography and neuropsychological testing. Using an atlas-based approach, we compared the regional kwof the whole brain among the groups and analysed its correlation with the neuroradiological and neuropsychological findings.ResultsThe BBB kwvalues in the neocortices differed significantly among the groups (APOE ɛ4non-carriers>heterozygotes>homozygotes). These values correlated with brain iron levels (frontal lobe:r=−0.476, 95% CI=−0.644 to −0.264, p=0.011; medial temporal lobe:r=−0.455, 95% CI=−0.628 to −0.239, p=0.017), β-amyloid loads (frontal lobe:r=−0.504, 95% CI=−0.731 to −0.176, p=0.015; medial temporal lobe:r=−0.452, 95% CI=−0.699 to −0.110, p=0.036) and neuropsychological scores, after adjusting for age, sex andAPOE ɛ4dose.InterpretationOur results suggest that an increasedAPOE ɛ4dose is associated with decreased effective brain-waste clearance, such as iron and β-amyloid, through the BBB.
Serum GFAP differentiates Alzheimer’s disease from frontotemporal dementia and predicts MCI-to-dementia conversion
Authors: Oeckl Patrick , Anderl-Straub Sarah , Von Arnim Christine A F , Baldeiras Inês , Diehl-Schmid Janine , Grimmer Timo , Halbgebauer Steffen , Kort Anna M , Lima Marisa , Marques Tainá M , Ortner Marion , Santana Isabel , Steinacker Petra , Verbeek Marcel M , Volk Alexander E , Ludolph Albert C , Otto Markus 
Published: May 2022

ObjectiveReactive astrogliosis is a hallmark of Alzheimer’s disease (AD) and frontotemporal dementia (FTD) but differences between the diseases and time course are unclear. Here, we used serum levels of the astroglial marker glial fibrillary acidic protein (GFAP) to investigate differences in patients with AD dementia, mild cognitive impairment (MCI)-AD and behavioural variant FTD (bvFTD).MethodsThis multicentre study included serum samples from patients diagnosed with AD dementia (n=230), MCI-AD (n=111), bvFTD (n=140) and controls (n=129). A subgroup of patients with MCI-AD (n=32) was longitudinally followed-up for 3.9±2.6 years after sample collection. Serum levels of GFAP, neurofilament light chain (NfL) and pTau181 were measured by Simoa (Quanterix) and Ella (ProteinSimple).ResultsIn total, samples from 610 individuals from four clinical centres were investigated in this study. Serum GFAP levels in AD dementia were increased (median 375 pg/mL, IQR 276–505 pg/mL) compared with controls (167 pg/mL, IQR 108–234 pg/mL) and bvFTD (190 pg/mL, IQR 134–298 pg/mL, p<0.001). GFAP was already increased in the early disease phase (MCI-AD, 300 pg/mL, IQR 232–433 pg/mL, p<0.001) and was higher in patients with MCI-AD who developed dementia during follow-up (360 pg/mL, IQR 253–414 pg/mL vs 215 pg/mL, IQR 111–266 pg/mL, p<0.01, area under the curve (AUC)=0.77). Diagnostic performance of serum GFAP for AD (AUC=0.84, sensitivity 98%, specificity 60%, likelihood ratio 2.5) was comparable to serum pTau181 (AUC=0.89, sensitivity 80%, specificity 87%, likelihood ratio 6.0) but superior to serum NfL (AUC=0.71, sensitivity 92%, specificity 49%, likelihood ratio 1.8).ConclusionsOur data indicate a different type of reactive astrogliosis in AD and bvFTD and support serum GFAP as biomarker for differential diagnosis and prediction of MCI-to-dementia conversion.
Exploring in vivo multiple sclerosis brain microstructural damage through T1w/T2w ratio: a multicentre study
Authors: Margoni Monica , Pagani Elisabetta , Meani Alessandro , Storelli Loredana , Mesaros Sarlota , Drulovic Jelena , Barkhof Frederik , Vrenken Hugo , Strijbis Eva , Gallo Antonio , Bisecco Alvino , Pareto Deborah , Sastre-Garriga Jaume , Ciccarelli Olga , Yiannakas Marios , Palace Jacqueline , Preziosa Paolo , Rocca Maria A , Filippi Massimo 
Published: May 2022

ObjectivesTo evaluate white matter and grey matter T1-weighted (w)/T2w ratio (T1w/T2w ratio) in healthy controls and patients with multiple sclerosis, and its association with clinical disability.MethodsIn this cross-sectional study, 270 healthy controls and 434 patients with multiple sclerosis were retrospectively selected from 7 European sites. T1w/T2w ratio was obtained from brain T2w and T1w scans after intensity calibration using eyes and temporal muscle.ResultsIn healthy controls, T1w/T2w ratio increased until 50–60 years both in white and grey matter. Compared with healthy controls, T1w/T2w ratio was significantly lower in white matter lesions of all multiple sclerosis phenotypes, and in normal-appearing white matter and cortex of patients with relapsing-remitting and secondary progressive multiple sclerosis (p≤0.026), but it was significantly higher in the striatum and pallidum of patients with relapsing-remitting, secondary progressive and primary progressive multiple sclerosis (p≤0.042). In relapse-onset multiple sclerosis, T1w/T2w ratio was significantly lower in white matter lesions and normal-appearing white matter already at Expanded Disability Status Scale (EDSS) <3.0 and in the cortex only for EDSS ≥3.0 (p≤0.023). Conversely, T1w/T2w ratio was significantly higher in the striatum and pallidum for EDSS ≥4.0 (p≤0.005). In primary progressive multiple sclerosis, striatum and pallidum showed significantly higher T1w/T2w ratio beyond EDSS=6.0 (p≤0.001). In multiple sclerosis, longer disease duration, higher EDSS, higher brain lesional volume and lower normalised brain volume were associated with lower lesional and cortical T1w/T2w ratio and a higher T1w/T2w ratio in the striatum and pallidum (β from −1.168 to 0.286, p≤0.040).ConclusionsT1w/T2w ratio may represent a clinically relevant marker sensitive to demyelination, neurodegeneration and iron accumulation occurring at the different multiple sclerosis phases.
MR T2-relaxation time as an indirect measure of brain water content and disease activity in NMOSD
Authors: Cacciaguerra Laura , Pagani Elisabetta , Radaelli Marta , Mesaros Sarlota , Martinelli Vittorio , Ivanovic Jovana , Drulovic Jelena , Filippi Massimo , Rocca Maria A 
Published: May 2022

ObjectiveSince astrocytes at the blood–brain barrier are targeted by neuromyelitis optica spectrum disorder (NMOSD), this study aims to assess whether patients with NMOSD have a subclinical accumulation of brain water and if it differs according to disease activity.MethodsSeventy-seven aquaporin-4-positive patients with NMOSD and 105 healthy controls were enrolled at two European centres. Brain dual-echo turbo spin-echo MR images were evaluated and maps of T2 relaxation time (T2rt) in the normal-appearing white matter (NAWM), grey matter and basal ganglia were obtained. Patients with a clinical relapse within 1 month before or after MRI acquisition were defined ‘active’. Differences between patients and controls were assessed using z-scores of T2rt obtained with age-adjusted and sex-adjusted linear models from each site. A stepwise binary logistic regression was run on clinical and MRI variables to identify independent predictors of disease activity.ResultsPatients had increased T2rt in both white and grey matter structures (p range: 0.014 to <0.0001). Twenty patients with NMOSD were defined active. Despite similar clinical and MRI features, active patients had a significantly increased T2rt in the NAWM and grey matter compared with those clinically stable (p range: 0.010–0.002). The stepwise binary logistic regression selected the NAWM as independently associated with disease activity (beta=2.06, SE=0.58, Nagelkerke R2=0.46, p<0.001).ConclusionsIn line with the research hypothesis, patients with NMOSD have increased brain T2rt. The magnitude of this alteration might be useful for identifying those patients with active disease.
TEARS: a longitudinal investigation of the prevalence, psychological associations and trajectory of poststroke emotionalism
Authors: Broomfield Niall McIntyre , West Robert , Barber Mark , Quinn Terence J , Gillespie David , Walters Matthew , House Allan 
Published: May 2022

ObjectiveThere are few longitudinal studies of poststroke emotionalism (PSE) and our understanding of the psychological associations of PSE is limited, constraining assessment of existing interventions and the development of new therapies. This study aimed to assess the prevalence and course of PSE over the first year poststroke, and its psychological associations.MethodsConsenting stroke survivors who were physically and cognitively able to participate were assessed within 2 weeks, 6 and 12 months of stroke to determine PSE point prevalence using a diagnostic, semistructured PSE interview (Testing Emotionalism After Recent Stroke-Diagnostic Interview). At the same assessments, neuropsychological and disability status were determined using Hospital Anxiety and Depression Scale, Abbreviated Mental Test, National Institute of Health Stroke Scale, Barthel Index and Euro-Qol.ResultsTwo hundred and seventy seven stroke survivors were recruited between 1 October 2015 and 30 September 2018. Diagnostic data were available at baseline for 228 of 277 cohort participants. Point prevalence for PSE was 27.2% at 2 weeks; estimated prevalence at 6 months adjusted for baseline was 19.9% and at 12 months 22.3%. PSE was associated with symptoms of anxiety and event-related distress.InterpretationPSE affects at least one in five stroke patients acutely following their stroke, and continues to affect one in eight longer term. PSE is associated with anxiety and event-related distress but is not simply a manifestation of mood disorder over time. Such psychological correlates may have implications for longer term social rehabilitation.
Muscle biochemical and pathological diagnosis in Pompe disease
Authors: Saito Yoshihiko , Nakamura Kimitoshi , Fukuda Tokiko , Sugie Hideo , Hayashi Shinichiro , Noguchi Satoru , Nishino Ichizo 
Published: May 2022

Background and objectivesPompe disease is reportedly less prevalent in Japan than in neighbouring countries, raising a possibility that some patients may be overlooked. Therefore, all muscle biopsy samples received at our institute were screened for Pompe disease to determine the accuracy of the disease prevalence.MethodsThe acid α-glucosidase (GAA) activity was assayed using 10 µm frozen muscle sections from 2408 muscle biopsies received between July 2015 and January 2018. Genetic analysis was performed for samples with decreased activity. The number of myopathologically diagnosed patients was retrospectively assessed.ResultsThe GAA activity was distributed similarly to previous results from dried blood spot screening. GAA activity measured using muscle sections corresponded to that measured using muscle blocks. Of 163 patients with GAA activity <3 nmol/hour/mg protein, 43 (26%) patients had homozygous pseudodeficiency alleles inGAA(p.G576S and p.E689K). In the retrospective analysis, the number of patients diagnosed with Pompe disease via muscle biopsies decreased to zero over time.DiscussionMuscle pathology is an accurate method to diagnose Pompe disease. It is unlikely that a significant number of patients with Pompe disease are overlooked. Pathological variants were rare, and the majority carried a pseudodeficiency allele, which further supports our conclusion.