bluuebunny/crossref_metadata_2025_split huggingface dataset:
ALW peptide ameliorates lupus nephritis in MRL/lpr mice
Authors: Wang Huixia , Lu Mei , Zhai Siyue , Wu Kunyi , Peng Lingling , Yang Jie , Xia Yumin 
Published: December 2019

Abstract
Background
Lupus nephritis (LN) is a common and serious complication of systemic lupus erythematosus. Anti-double-stranded (ds) DNA immunoglobulin G (IgG) plays a pivotal role in the pathogenesis of LN. Currently, there are various therapies for patients with LN; however, most of them are associated with considerable side effects. We confirmed previously that ALW (ALWPPNLHAWVP), a 12-amino acid peptide, inhibited the binding of polyclonal anti-dsDNA antibodies to mesangial cells and isolated glomeruli in vitro. In this study, we further investigate whether the administration of ALW peptide decreases renal IgG deposition and relevant damage in MRL/lpr lupus-prone mice.

Methods
Forty female MRL/lpr mice were randomly divided into four groups. The mice were intravenously injected with D-form ALW peptide (ALW group), scrambled peptide (PLP group), and normal saline (NaCl group) or were not treated (blank group). The IgG deposition, the histopathologic changes, and the expressions of profibrotic factors were analyzed in the kidney of MRL/lpr mice.

Results
Compared with the other groups, glomerular deposition of IgG, IgG2a, IgG2b, and IgG3 was decreased in the ALW group. Moreover, ALW administration attenuated renal histopathologic changes in MRL/lpr mice, including mesangial proliferation and infiltration of inflammatory cells. Furthermore, the expressions of profibrotic cytokines, such as transforming growth factor-beta1 (TGF-β1) and platelet-derived growth factor B (PDGF-B), decreased in the serum and kidney tissue of ALW-treated mice.

Conclusions
Our study demonstrated that ALW peptide ameliorates the murine model of LN, possibly through inhibiting renal IgG deposition and relevant tissue inflammation and fibrosis.
Effects of upadacitinib on patient-reported outcomes: results from SELECT-BEYOND, a phase 3 randomized trial in patients with rheumatoid arthritis and inadequate responses to biologic disease-modifying antirheumatic drugs
Authors: Strand Vibeke , Schiff Michael , Tundia Namita , Friedman Alan , Meerwein Sebastian , Pangan Aileen , Ganguli Arijit , Fuldeore Mahesh , Song Yan , Pope Janet 
Published: December 2019

Abstract
Background
Patient-reported outcomes (PROs) are important when evaluating treatment benefits in rheumatoid arthritis (RA). We compared upadacitinib, an oral, selective JAK-1 inhibitor, with placebo to assess clinically meaningful improvements in PROs in patients with RA who have had inadequate responses to biologic disease-modifying antirheumatic drugs (bDMARD-IR).

Methods
PRO responses between upadacitinib 15 mg or 30 mg and placebo were evaluated at week 12 from the SELECT-BEYOND trial. Improvement was determined by measuring Patient Global Assessment of Disease Activity (PtGA), pain, Health Assessment Questionnaire Disability Index (HAQ-DI), Short Form-36 Health Survey (SF-36), duration and severity of morning (AM) stiffness, and Insomnia Severity Index (ISI). Least squares mean changes and percentage of patients reporting improvements ≥ minimum clinically important differences (MCID) and scores greater than or equal to normative values were determined. The number needed to treat (NNT) to achieve clinically meaningful improvements was calculated.

Results
In 498 patients, both upadacitinib doses resulted in statistically significant changes from baseline versus placebo in PtGA, pain, HAQ-DI, SF-36 Physical Component Summary (PCS), 7 of 8 SF-36 domains (15 mg), 6 of 8 SF-36 domains (30 mg), and AM stiffness duration and severity. Compared with placebo, more upadacitinib-treated patients reported improvements ≥ MCID in PtGA, pain, HAQ-DI, SF-36 PCS, 7 of 8 SF-36 domains (15 mg), 5 of 8 SF-36 domains (30 mg), AM stiffness duration and severity, and ISI (30 mg) and scores ≥ normative values in HAQ-DI and SF-36 domains. Across most PROs, NNTs to achieve MCID with upadacitinib ranged from 4 to 7 patients.

Conclusions
In bDMARD-IR RA patients, upadacitinib (15 mg or 30 mg) improved multiple aspects of quality of life, and more patients reached clinically meaningful improvements approaching normative values compared with placebo.

Trial registration
The trial is registered with ClinicalTrials.gov (NCT02706847), registered 6 March 2016.
Sonographic features of carotid artery dissection due to extension of aortic dissection: a case report
Authors: Boßelmann Christian , Poli Sven 
Published: December 2019

Abstract
Background
Carotid artery dissection due to extension of aortic dissection (CAEAD) is a severe complication of acute aortic dissection. The risk of ischemic stroke is increased. Early sonographic detection and repeat evaluation are necessary to guide clinical management.

Case presentation
A 58-year-old male patient presents with sudden, tearing retrosternal pain. Point-of-care carotid ultrasound is used to establish the diagnosis of CAEAD. We describe a number of sonographic features and compare ultrasound to other imaging modalities.

Conclusions
Bedside carotid ultrasound enables rapid, sensitive and safe hemodynamic assessment, especially in critically ill patients.
Physiological serum total bilirubin concentrations were inversely associated with diabetic peripheral neuropathy in Chinese patients with type 2 diabetes: a cross-sectional study
Authors: Yan Pijun , Zhang Zhihong , Miao Ying , Xu Yong , Zhu Jianhua , Wan Qin 
Published: December 2019

Abstract
Background
Although bilirubin has been generally regarded as a waste with potential neurotoxicity at high levels, a few clinical studies suggest a potential protective role of physiological serum total bilirubin (TBIL) concentrations in diabetic peripheral neuropathy (DPN). However, the pathological mechanisms underlying the relationship remain poorly understood. The objective of this study was to explore the relationship between serum TBIL and DPN, and clinical and laboratory parameters.

Methods
Serum TBIL was measured in 1342 patients with type 2 diabetes mellitus (T2DM). The relationship between TBIL and DPN and other parameters was analyzed.

Results
Serum TBIL levels were significantly lower in T2DM patients with DPN, and were independently and negatively associated with vibration perception thresholds (VPT) (P < 0.01 or P < 0.05). Moreover, serum TBIL was negatively associated with neutrophil and white blood cell counts, fibrinogen, and the prevalence of hypertension, diabetic foot ulceration, peripheral arterial disease, diabetic nephropathy and diabetic retinopathy (P < 0.01 or P < 0.05). Additionally, serum TBIL was an independent decisive factor for the presence of DPN after multivariate adjustment. Compared to the highest quartile of TBIL, the lower quartiles were associated with a significantly increased risk of DPN (P < 0.01). Last but most importantly, the analysis of receiver operating characteristic curves revealed that the best cutoff value for serum TBIL to predict DPN was 10.75 μmol/L (sensitivity 54.6% and specificity 62.9%).

Conclusions
These findings suggest that lower physiological serum TBIL may be associated with the presence of DPN due to its decreased anti-inflammatory and vascular protective effects.
Body mass index is associated with epigenetic age acceleration in the visceral adipose tissue of subjects with severe obesity
Authors: de Toro-Martín Juan , Guénard Frédéric , Tchernof André , Hould Frédéric-Simon , Lebel Stéfane , Julien François , Marceau Simon , Vohl Marie-Claude 
Published: December 2019

Abstract
Background
There is solid evidence that obesity induces the acceleration of liver epigenetic aging. However, unlike easily accessible blood or subcutaneous adipose tissue, little is known about the impact of obesity on epigenetic aging of metabolically active visceral adipose tissue (VAT). Herein, we aimed to test whether obesity accelerates VAT epigenetic aging in subjects with severe obesity.

Results
A significant and positive correlation between chronological age and epigenetic age, estimated with a reduced version of the Horvath’s epigenetic clock, was found in both blood (r = 0.78, p = 9.4 × 10−12) and VAT (r = 0.80, p = 1.1 × 10−12). Epigenetic age acceleration, defined as the residual resulting from regressing epigenetic age on chronological age, was significantly correlated with body mass index (BMI) in VAT (r = 0.29, p = 0.037). Multivariate linear regression analysis showed that, after adjusting for chronological age, sex and metabolic syndrome status, BMI remained significantly associated with epigenetic age acceleration in VAT (beta = 0.15, p = 0.035), equivalent to 2.3 years for each 10 BMI units. Binomial logistic regression showed that BMI-adjusted epigenetic age acceleration in VAT was significantly associated with a higher loss of excess body weight following biliopancreatic diversion with duodenal switch surgery (odds ratio = 1.21; 95% CI = 1.04–1.48; p = 0.03).

Conclusions
Epigenetic age acceleration increases with BMI in VAT, but not in blood, as previously reported in liver. These results suggest that obesity is associated with epigenetic age acceleration of metabolically active tissues. Further studies that deepen the physiological relevance of VAT epigenetic aging will help to better understand the onset of metabolic syndrome and weight loss dynamics following bariatric surgery.
The timeline of epigenetic drug discovery: from reality to dreams
Authors: Ganesan A. , Arimondo Paola B. , Rots Marianne G. , Jeronimo Carmen , Berdasco María 
Published: December 2019

AbstractThe flexibility of the epigenome has generated an enticing argument to explore its reversion through pharmacological treatments as a strategy to ameliorate disease phenotypes. All three families of epigenetic proteins—readers, writers, and erasers—are druggable targets that can be addressed through small-molecule inhibitors. At present, a few drugs targeting epigenetic enzymes as well as analogues of epigenetic modifications have been introduced into the clinic use (e.g. to treat haematological malignancies), and a wide range of epigenetic-based drugs are undergoing clinical trials. Here, we describe the timeline of epigenetic drug discovery and development beginning with the early design based solely on phenotypic observations to the state-of-the-art rational epigenetic drug discovery using validated targets. Finally, we will highlight some of the major aspects that need further research and discuss the challenges that need to be overcome to implement epigenetic drug discovery into clinical management of human disorders. To turn into reality, researchers from various disciplines (chemists, biologists, clinicians) need to work together to optimise the drug engineering, read-out assays, and clinical trial design.
Early detection of the major male cancer types in blood-based liquid biopsies using a DNA methylation panel
Authors: Constâncio Vera , Nunes Sandra P. , Moreira-Barbosa Catarina , Freitas Rui , Oliveira Jorge , Pousa Inês , Oliveira Júlio , Soares Marta , Dias Carlos Gonçalves , Dias Teresa , Antunes Luís , Henrique Rui , Jerónimo Carmen 
Published: December 2019

AbstractBackgroundLung (LC), prostate (PCa) and colorectal (CRC) cancers are the most incident in males worldwide. Despite recent advances, optimal population-based cancer screening methods remain an unmet need. Due to its early onset, cancer specificity and accessibility in body fluids, aberrant DNA promoter methylation might be a valuable minimally invasive tool for early cancer detection. Herein, we aimed to develop a minimally invasive methylation-based test for simultaneous early detection of LC, PCa and CRC in males, using liquid biopsies.ResultsCirculating cell-free DNA was extracted from 102 LC, 121 PCa and 100 CRC patients and 136 asymptomatic donors’ plasma samples. Sodium-bisulfite modification and whole-genome amplification was performed. Promoter methylation levels ofAPCme, FOXA1me, GSTP1me, HOXD3me,RARβ2me, RASSF1Ame, SEPT9meandSOX17mewere assessed by multiplex quantitative methylation-specific PCR.SEPT9meandSOX17mewere the only biomarkers shared by all three cancer types, although they detected CRC with limited sensitivity. A “PanCancer” panel (FOXA1me, RARβ2meandRASSF1Ame) detected LC and PCa with 64% sensitivity and 70% specificity, complemented with “CancerType” panel (GSTP1meandSOX17me) which discriminated between LC and PCa with 93% specificity, but with modest sensitivity. Moreover, aHOXD3meandRASSF1Amepanel discriminated small cell lung carcinoma from non-small cell lung carcinoma with 75% sensitivity, 88% specificity, 6.5 LR+ and 0.28 LR–. AnAPCmeandRASSF1Amepanel independently predicted disease-specific mortality in LC patients.ConclusionsWe concluded that a DNA methylation-based test in liquid biopsies might enable minimally invasive screening of LC and PCa, improving patient compliance and reducing healthcare costs. Moreover, it might assist in LC subtyping and prognostication.
Plasma Aβ42/40 ratio alone or combined with FDG-PET can accurately predict amyloid-PET positivity: a cross-sectional analysis from the AB255 Study
Authors:   The AB255 Study Group, Pérez-Grijalba Virginia , Arbizu Javier , Romero Judith , Prieto Elena , Pesini Pedro , Sarasa Leticia , Guillen Fernando , Monleón Inmaculada , San-José Itziar , Martínez-Lage Pablo , Munuera Josep , Hernández Isabel , Buendía Mar , Sotolongo-Grau Oscar , Alegret Montserrat , Ruiz Agustín , Tárraga Lluis , Boada Mercè , Sarasa Manuel 
Published: December 2019

AbstractBackgroundTo facilitate population screening and clinical trials of disease-modifying therapies for Alzheimer’s disease, supportive biomarker information is necessary. This study was aimed to investigate the association of plasma amyloid-beta (Aβ) levels with the presence of pathological accumulation of Aβ in the brain measured by amyloid-PET. Both plasma Aβ42/40 ratio alone or combined with an FDG-PET-based biomarker of neurodegeneration were assessed as potential AD biomarkers.MethodsWe included 39 cognitively normal subjects and 20 patients with mild cognitive impairment from the AB255 Study who had undergone PiB-PET scans. Total Aβ40 and Aβ42 levels in plasma (TP42/40) were quantified using ABtest kits. Subjects were dichotomized as Aβ-PET positive or negative, and the ability of TP42/40 to detect Aβ-PET positivity was assessed by logistic regression and receiver operating characteristic analyses. Combination of plasma Aβ biomarkers and FDG-PET was further assessed as an improvement for brain amyloidosis detection and diagnosis classification.ResultsEighteen (30.5%) subjects were Aβ-PET positive. TP42/40 ratio alone identified Aβ-PET status with an area under the curve (AUC) of 0.881 (95% confidence interval [CI] = 0.779–0.982). Discriminating performance of TP42/40 to detect Aβ-PET-positive subjects yielded sensitivity and specificity values at Youden’s cutoff of 77.8% and 87.5%, respectively, with a positive predictive value of 0.732 and negative predictive value of 0.900. All these parameters improved after adjusting the model for significant covariates. Applying TP42/40 as the first screening tool in a sequential diagnostic work-up would reduce the number of Aβ-PET scans by 64%. Combination of both FDG-PET scores and plasma Aβ biomarkers was found to be the most accurate Aβ-PET predictor, with an AUC of 0.965 (95% CI = 0.913–0.100).ConclusionsPlasma TP42/40 ratio showed a relevant and significant potential as a screening tool to identify brain Aβ positivity in preclinical and prodromal stages of Alzheimer’s disease.
Characterization of the selective in vitro and in vivo binding properties of crenezumab to oligomeric Aβ
Authors: Meilandt William J. , Maloney Janice A. , Imperio Jose , Lalehzadeh Guita , Earr Tim , Crowell Susan , Bainbridge Travis W. , Lu Yanmei , Ernst James A. , Fuji Reina N. , Atwal Jasvinder K. 
Published: December 2019

Abstract
Background
Accumulation of amyloid β (Aβ) in the brain is proposed as a cause of Alzheimer’s disease (AD), with Aβ oligomers hypothesized to be the primary mediators of neurotoxicity. Crenezumab is a humanized immunoglobulin G4 monoclonal antibody that has been shown to bind to synthetic monomeric and aggregated Aβ in vitro; however, less is known about the binding characteristic in vivo. In this study, we evaluated the binding patterns of crenezumab to synthetic and native forms of Aβ both in vitro and in vivo.

Methods
Crenezumab was used to immunoprecipitate Aβ from synthetic Aβ preparations or brain homogenates from a PS2APP mouse model of AD to determine the forms of Aβ that crenezumab interacts with. Following systemic dosing in PS2APP or nontransgenic control mice, immunohistochemistry was used to localize crenezumab and assess its relative distribution in the brain, compared with amyloid plaques and markers of neuritic dystrophies (BACE1; LAMP1). Pharmacodynamic correlations were performed to investigate the relationship between peripheral and central target engagement.

Results
In vitro, crenezumab immunoprecipitated Aβ oligomers from both synthetic Aβ preparations and endogenous brain homogenates from PS2APP mice. In vivo studies in the PS2APP mouse showed that crenezumab localizes to regions surrounding the periphery of amyloid plaques in addition to the hippocampal mossy fibers. These regions around the plaques are reported to be enriched in oligomeric Aβ, actively incorporate soluble Aβ, and contribute to Aβ-induced neurotoxicity and axonal dystrophy. In addition, crenezumab did not appear to bind to the dense core region of plaques or vascular amyloid.

Conclusions
Crenezumab binds to multiple forms of amyloid β (Aβ), particularly oligomeric forms, and localizes to brain areas rich in Aβ oligomers, including the halo around plaques and hippocampal mossy fibers, but not to vascular Aβ. These insights highlight a unique mechanism of action for crenezumab of engaging Aβ oligomers.
An additional challenge for head and neck radiologists: anatomic variants posing a surgical risk – a pictorial review
Authors: Farina Davide , Lombardi Davide , Bertuletti Martina , Palumbo Giovanni , Zorza Ivan , Ravanelli Marco 
Published: December 2019

AbstractAnatomic variants in the head and neck are quite numerous and occur frequently: a minority of them increase the risk of complications during surgical procedures and may be visualized on cross-sectional images. As some of these complications are potentially fatal, awareness (and accurate reporting) of such variants is a basic responsibility of radiologists, particularly when surgery in the pertinent anatomic area is under consideration.
Successful resuscitation from prolonged hypothermic cardiac arrest without extracorporeal life support: a case report
Authors: Kuhnke Melanie , Albrecht Roland , Schefold Joerg C. , Paal Peter 
Published: December 2019

Abstract
Background
We report a case of successful prolonged cardiopulmonary resuscitation (5 hours and 44 minutes) following severe accidental hypothermia with cardiac arrest treated without rewarming on extracorporeal life support.

Case presentation
A 52-year-old Italian mountaineer, was trapped in a crevasse and rescued approximately 7 hours later by a professional rescue team. After extrication, he suffered a witnessed cardiac arrest with ventricular fibrillation. Immediate defibrillation and cardiopulmonary resuscitation were started. His core temperature was 26.0 °C. Due to weather conditions, air transport to an extracorporeal life support center was not possible. Thus, he was rewarmed with conventional rewarming methods in a rural hospital. Auto-defibrillation occurred at a core temperature of 29.8 °C after 5 hours and 44 minutes of continued cardiopulmonary resuscitation. With a core temperature of 33.4 °C, he was finally admitted to a level 1 trauma center and extracorporeal life support was no longer required. Seven weeks following the accident, he was discharged home with complete neurological recovery.

Conclusions
Successful rewarming from severe hypothermia without extracorporeal life support use as performed in this case suggests that patients with primary hypothermic cardiac arrest have a chance of a favorable neurological outcome even after several hours of cardiac arrest when cardiopulmonary resuscitation and conventional rewarming are performed continuously. This may be especially relevant in remote areas, where extracorporeal life support rewarming is not available.
Synergistic modulation of signaling pathways to expand and maintain the bipotency of human hepatoblasts
Authors: Pan Tingcai , Chen Yan , Zhuang Yuanqi , Yang Fan , Xu Yingying , Tao Jiawang , You Kai , Wang Ning , Wu Yuhang , Lin Xianhua , Wu Feima , Liu Yanli , Li Yingrui , Wang Guodong , Li Yin-xiong 
Published: December 2019

Abstract
Background
The limited proliferative ability of hepatocytes is a major limitation to meet their demand for cell-based therapy, bio-artificial liver device, and drug tests. One strategy is to amplify cells at the hepatoblast (HB) stage. However, expansion of HBs with their bipotency preserved is challenging. Most HB expansion methods hardly maintain the bipotency and also lack functional confirmation.

Methods
On the basis of analyzing and manipulating related signaling pathways during HB (derived from human induced pluripotent stem cells, iPSCs) differentiation and proliferation, we established a specific chemically defined cocktails to synergistically regulate the related signaling pathways that optimize the balance of HB proliferation ability and stemness maintenance, to expand the HBs and investigate their capacity for injured liver repopulation in immune-deficient mice.

Results
We found that the proliferative ability progressively declines during HB differentiation process. Small molecule activation of Wnt or inhibition of TGF-β pathways promoted HB proliferation but diminished their bipotency, whereas activation of hedgehog (HH) signaling stimulated proliferation and sustained HB phenotypes. A cocktail synergistically regulating the BMP/WNT/TGF-β/HH pathways created a fine balance for expansion and maintenance of the bipotency of HBs. After purification, colony formation, and expansion for 20 passages, HBs retained their RNA profile integrity, normal karyotype, and ability to differentiate into mature hepatocytes and cholangiocytes. Moreover, upon transplantation into liver injured mice, the expanded HBs could engraft and differentiate into mature human hepatocytes and repopulate liver tissue with restoring hepatocyte mass.

Conclusion
Our data contribute to the understanding of some signaling pathways for human HB proliferation in vitro. Simultaneous BMP/HGF induction, activation of Wnt and HH, and inhibition of TGF-β pathways created a reliable method for long-term stable large-scale expansion of HBs to obtain mature hepatocytes that may have substantial clinical applications.

Graphical abstract