bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long-term neurodevelopmental outcomes of hematopoietic stem cell transplantation for late-infantile Krabbe disease
Authors: Yoon Isabel C. , Bascou Nicholas A. , Poe Michele D. , Szabolcs Paul , Escolar Maria L. 
Published: November 2020

Abstract
Krabbe disease is a rare neurodegenerative disorder caused by a deficiency in galactocerebrosidase. The only effective treatment is hematopoietic stem cell transplantation (HSCT). Approximately 85% of Krabbe disease cases are the infantile subtypes, among which ∼20% are late infantile. Prior studies have demonstrated that HSCT is effective for early-infantile patients (0-6 months of age) who undergo transplantation while asymptomatic, compared with those receiving transplants while symptomatic. However, no studies evaluated the efficacy of HSCT for late-infantile patients (6-36 months). In this prospective, longitudinal study, patients were evaluated at a single site according to a standardized protocol. Survival analysis was performed using the Kaplan-Meier method. Differences between groups were estimated using mixed regression models to account for within-person repeated measures. Nineteen late-infantile patients underwent HSCT (March 1997 to January 2020). Compared with untreated patients, transplant recipients had a longer survival probability and improved cognitive and language function. Gross and fine motor development were most affected, with variable results. Asymptomatic patients benefitted the most from transplantation, with normal to near-normal development in all domains and some gross motor delays. Among symptomatic patients, those with disease onset at &gt;12 months of age had better cognitive outcomes than untreated patients. Those with disease onset at ≤12 months were comparable to untreated patients. We found that HSCT prolonged the lifespan and improved the functional abilities of late-infantile patients with Krabbe disease, particularly those who underwent transplantation before onset of symptoms. In addition, our findings support prior literature that reclassifies late-infantile Krabbe disease to be symptom onset at 12 to 36 months of age.
Hemolysis inhibits humoral B-cell responses and modulates alloimmunization risk in patients with sickle cell disease
Authors: Pal Mouli , Bao Weili , Wang Rikang , Liu Yunfeng , An Xiuli , Mitchell William B. , Lobo Cheryl A. , Minniti Caterina , Shi Patricia A. , Manwani Deepa , Yazdanbakhsh Karina , Zhong Hui 
Published: November 2020

Abstract
Red blood cell alloimmunization remains a barrier for safe and effective transfusions in sickle cell disease (SCD), but the associated risk factors remain largely unknown. Intravascular hemolysis, a hallmark of SCD, results in the release of heme with potent immunomodulatory activity, although its effect on SCD humoral response, specifically alloimmunization, remains unclear. Here, we found that cell-free heme suppresses human B-cell plasmablast and plasma cell differentiation by inhibiting the DOCK8/STAT3 signaling pathway, which is critical for B-cell activation, as well as by upregulating heme oxygenase 1 (HO-1) through its enzymatic byproducts, carbon monoxide and biliverdin. Whereas nonalloimmunized SCD B cells were inhibited by exogenous heme, B cells from the alloimmunized group were nonresponsive to heme inhibition and readily differentiated into plasma cells. Consistent with a differential B-cell response to hemolysis, we found elevated B-cell basal levels of DOCK8 and higher HO-1–mediated inhibition of activated B cells in nonalloimmunized compared with alloimmunized SCD patients. To overcome the alloimmunized B-cell heme insensitivity, we screened several heme-binding molecules and identified quinine as a potent inhibitor of B-cell activity, reversing the resistance to heme suppression in alloimmunized patients. B-cell inhibition by quinine occurred only in the presence of heme and through HO-1 induction. Altogether, these data suggest that hemolysis can dampen the humoral B-cell response and that B-cell heme responsiveness maybe a determinant of alloimmunization risk in SCD. By restoring B-cell heme sensitivity, quinine may have therapeutic potential to prevent and inhibit alloimmunization in SCD patients.
ISSEC: inferring contacts among protein secondary structure elements using deep object detection
Authors: Zhang Qi , Zhu Jianwei , Ju Fusong , Kong Lupeng , Sun Shiwei , Zheng Wei-Mou , Bu Dongbo 
Published: November 2020

Abstract

Background
The formation of contacts among protein secondary structure elements (SSEs) is an important step in protein folding as it determines topology of protein tertiary structure; hence, inferring inter-SSE contacts is crucial to protein structure prediction. One of the existing strategies infers inter-SSE contacts directly from the predicted possibilities of inter-residue contacts without any preprocessing, and thus suffers from the excessive noises existing in the predicted inter-residue contacts. Another strategy defines SSEs based on protein secondary structure prediction first, and then judges whether each candidate SSE pair could form contact or not. However, it is difficult to accurately determine boundary of SSEs due to the errors in secondary structure prediction. The incorrectly-deduced SSEs definitely hinder subsequent prediction of the contacts among them.

Results
We here report an accurate approach to infer the inter-SSE contacts (thus called as ISSEC) using the deep object detection technique. The design of ISSEC is based on the observation that, in the inter-residue contact map, the contacting SSEs usually form rectangle regions with characteristic patterns. Therefore, ISSEC infers inter-SSE contacts through detecting such rectangle regions. Unlike the existing approach directly using the predicted probabilities of inter-residue contact, ISSEC applies the deep convolution technique to extract high-level features from the inter-residue contacts. More importantly, ISSEC does not rely on the pre-defined SSEs. Instead, ISSEC enumerates multiple candidate rectangle regions in the predicted inter-residue contact map, and for each region, ISSEC calculates a confidence score to measure whether it has characteristic patterns or not. ISSEC employs greedy strategy to select non-overlapping regions with high confidence score, and finally infers inter-SSE contacts according to these regions.

Conclusions
Comprehensive experimental results suggested that ISSEC outperformed the state-of-the-art approaches in predicting inter-SSE contacts. We further demonstrated the successful applications of ISSEC to improve prediction of both inter-residue contacts and tertiary structure as well.
An elderly diabetic patient with McArdle disease and recurrent rhabdomyolysis: a potential association with late hypoinsulinemia?
Authors: Chocair Pedro Renato , Mohrbacher Sara , de Menezes Neves Precil Diego Miranda , Pereira Leonardo Victor Barbosa , Oliveira Erico Souza , Nardotto Luciana Loureiro , Bales Alessandra Martins , Sato Victor Augusto Hamamoto , Silva Sabrina Neves , Ferreira Bernadete Maria Coelho , Cuvello-Neto Américo Lourenço 
Published: November 2020

Abstract

Background
McArdle disease is a myopathy caused by mutations in PYGM gene that is characterized by reduced or absent activity of myophosphorylase. Reports of patients with concomitant McArdle disease and diabetes are scarce. We report a case of a patient with a late diagnosis of McArdle disease and we postulate that symptoms may be related to hypoinsulinemia.

Case presentation
This report describes the evolution of an elderly diabetic patient with confirmed diagnosis of McArdle’s disease based on the absence of myophosphorylase activity in the analysis of muscle biopsy, and a homozygous mutation in the PYGM gene. The variant – Chr11: 64.525 (p. Asn168*fs) has not been previously described. The diagnosis of McArdle disease was confirmed after two episodes of rhabdomyolysis, at 77 and 81 years of age, as the symptoms were, until then, discrete. The “second-wind phenomenon” was not spontaneously reported, but it was confirmed when directly questioned. We postulate that the later episodes of rhabdomyolysis occurred because of a progressive decrease in insulin production with a consequent reduction in the uptake of blood glucose by muscle cells, thus compromising the cellular energy balance. To our knowledge, this is the first report of recurrent rhabdomyolysis in an elderly diabetic patient with genetically proven McArdle disease. Our initial attempt to reduce insulin resistance with metformin and pioglitazone was not effective, possibly because of inadequate insulinemia. However, an improvement was evident after the administration of low doses of intermediate-acting insulin.

Conclusions
In view of the patient’s clinical evolution, we suggest the use of medication that reduces insulin resistance for patients with McArdle disease and type 2 diabetes, pre-diabetes or even normoglycemic metabolic syndrome.
Emergency department and hospital admissions among people with dementia living at home or in nursing homes: results of the European RightTimePlaceCare project on their frequency, associated factors and costs
Authors:   on behalf of the RightTimePlaceCare Consortium, Afonso-Argilés F. Javier , Meyer Gabriele , Stephan Astrid , Comas Mercè , Wübker Ansgar , Leino-Kilpi Helena , Lethin Connie , Saks Kai , Soto-Martin Maria , Sutcliffe Caroline , Verbeek Hilde , Zabalegui Adelaida , Renom-Guiteras Anna 
Published: November 2020

Abstract

Background
Evidence is lacking on the differences between hospitalisation of people with dementia living in nursing homes and those living in the community. The objectives of this study were: 1) to describe the frequency of hospital admission among people with dementia in eight European countries living in nursing homes or in the community, 2) to examine the factors associated with hospitalisation in each setting, and 3) to evaluate the costs associated with it.

Methods
The present study is a secondary data analysis of the RightTimePlaceCare European project. A cross-sectional survey was conducted with data collected from people with dementia living at home or who had been admitted to a nursing home in the last 3 months, as well as from their caregivers. Data on hospital admissions at 3 months, cognitive and functional status, neuropsychiatric symptoms, comorbidity, polypharmacy, caregiver burden, nutritional status, and falls were assessed using validated instruments. Multivariate regression models were used to investigate the factors associated with hospital admission for each setting. Costs were estimated by multiplying quantities of resources used with the unit cost of each resource and inflated to the year 2019.

Results
The study sample comprised 1700 people with dementia living in the community and nursing homes. Within 3 months, 13.8 and 18.5% of people living in nursing homes and home care, respectively, experienced ≥1 hospital admission. In the nursing home setting, only polypharmacy was associated with a higher chance of hospital admission, while in the home care setting, unintentional weight loss, polypharmacy, falls, and more severe caregiver burden were associated with hospital admission. Overall, the estimated average costs per person with dementia/year among participants living in a nursing home were lower than those receiving home care.

Conclusion
Admission to hospital is frequent among people with dementia, especially among those living in the community, and seems to impose a remarkable economic burden. The identification and establishment of an individualised care plan for those people with dementia with polypharmacy in nursing homes, and those with involuntary weight loss, accidental falls, polypharmacy and higher caregiver burden in the home care setting, might help preventing unnecessary hospital admissions.
Association of Ambient air Pollution with risk of preeclampsia during pregnancy: a retrospective cohort study
Authors: Jia Lu , Liu Qing , Hou Huiqing , Guo Guangli , Zhang Ting , Fan Songli , Wang Li 
Published: November 2020

Abstract

Background
Ambient air pollution is becoming a serious environmental problem in China. The results were inconsistent on that air pollution was a risk factor of preeclampsia in pregnancy.

Methods
Total 116,042 pregnant women were enrolled from 22 hospitals in 10 cities of Hebei Province, China from January 1, 2015 to December 31, 2017. The parturients were divided into preeclampsia group (PE group) and non-preeclampsia group (non-PE group). The data of air pollutants, namely, particulate matter (PM)2.5, PM10, NO2, SO2, CO, O3 were collected from China Environmental Inspection Station.

Results
Among the 116,042 pregnant women, 2988 (2.57%) pregnant women were diagnosed with preeclampsia. The concentrations of exposed PM2.5, PM10, NO2 and O3 in the PE group were significantly higher than those in the non-PE group, and they were risk factors of the PE group in the first and second trimester of pregnancy respectively. The concentrations of exposed SO2 and CO in PE patients and non-PE women were not different, but high concentration of these air pollutants were risk factors to PE in the second trimester.

Conclusion
The exposure to PM2.5, PM10, NO2, O3 were risk factors for preeclampsia in the first and second trimester of pregnancy, while only at high level, SO2 and CO were risk factors for preeclampsia in the second trimester of pregnancy.
circCUL2 regulates gastric cancer malignant transformation and cisplatin resistance by modulating autophagy activation via miR-142-3p/ROCK2
Authors: Peng Lei , Sang Huaiming , Wei Shuchun , Li Yuanyuan , Jin Duochen , Zhu Xudong , Li Xuan , Dang Yini , Zhang Guoxin 
Published: November 2020

Abstract

Background
Circular RNAs (circRNAs) are a class of noncoding RNAs (ncRNAs) and can modulate gene expression by binding to miRNAs; further, circRNAs have been shown to participate in several pathological processes. However, the expression and biological function of circCUL2 in gastric cancer (GC) remains largely unknown.

Methods
circRNA microarrays and quantitative real-time PCR (qRT-PCR) were used to identify differentially expressed circRNAs in GC tissues and cell lines. circCUL2 knockdown and overexpression were performed to indicate the functional role of circCUL2 in vitro and in vivo. The expression and regulation of circCUL2, miR-142-3p and ROCK2 were evaluated using fluorescence in situ hybridization (FISH), dual-luciferase assays, RNA pull-down assays, RNA immunoprecipitation (RIP) and rescue experiments. Furthermore, the regulation of cisplatin sensitivity and autophagy by circCUL2/miR-142-3p/ROCK2 was demonstrated by cellular apoptosis assays, western blot, immunofluorescence and transmission electron microscopy analyses.

Results
The level of circCUL2, which is stable and cytoplasmically localized, was significantly reduced in GC tissues and cells. Overexpressed circCUL2 inhibited malignant transformation in vitro and tumorigenicity in vivo. In the AGS and SGC-7901 cell lines, circCUL2 sponged miR-142-3p to regulate ROCK2, thus modulating tumor progression. Furthermore, in the AGS/DDP and SGC-7901/DDP cell lines, circCUL2 regulated cisplatin sensitivity through miR-142-3p/ROCK2-mediated autophagy activation.

Conclusion
circCUL2 may function as a tumor suppressor and regulator of cisplatin sensitivity through miR-142-3p/ROCK2-mediated autophagy activation, which could be a key mechanism and therapeutic target for GC.
The PVT1 lncRNA is a novel epigenetic enhancer of MYC, and a promising risk-stratification biomarker in colorectal cancer
Authors: Shigeyasu Kunitoshi , Toden Shusuke , Ozawa Tsuyoshi , Matsuyama Takatoshi , Nagasaka Takeshi , Ishikawa Toshiaki , Sahoo Debashis , Ghosh Pradipta , Uetake Hiroyuki , Fujiwara Toshiyoshi , Goel Ajay 
Published: November 2020

Abstract
Accumulating evidence suggests that dysregulation of transcriptional enhancers plays a significant role in cancer pathogenesis. Herein, we performed a genome-wide discovery of enhancer elements in colorectal cancer (CRC). We identified PVT1 locus as a previously unrecognized transcriptional regulator in CRC with a significantly high enhancer activity, which ultimately was responsible for regulating the expression of MYC oncogene. High expression of the PVT1 long-non-coding RNA (lncRNA) transcribed from the PVT1 locus was associated with poor survival among patients with stage II and III CRCs (p < 0.05). Aberrant methylation of the PVT1 locus inversely correlated with the reduced expression of the corresponding the PVT1 lncRNA, as well as MYC gene expression. Bioinformatic analyses of CRC-transcriptomes revealed that the PVT1 locus may also broadly impact the expression and function of other key genes within two key CRC-associated signaling pathways – the TGFβ/SMAD and Wnt/β-Catenin pathways. We conclude that the PVT1 is a novel oncogenic enhancer of MYC and its activity is controlled through epigenetic regulation mediated through aberrant methylation in CRC. Our findings also suggest that the PVT1 lncRNA expression is a promising prognostic biomarker and a potential therapeutic target in CRC.
Functionally enhanced placenta-derived mesenchymal stem cells inhibit adipogenesis in orbital fibroblasts with Graves’ ophthalmopathy
Authors: Kim Jae Yeon , Park Sohae , Lee Hyun-Jung , Lew Helen , Kim Gi Jin 
Published: November 2020

Abstract

Background
Placenta-derived mesenchymal stem cells (PD-MSCs) have unique immunomodulatory properties. Phosphatase of regenerating liver-1 (PRL-1) regulates the self-renewal ability of stem cells and promotes proliferation. Graves’ ophthalmopathy (GO) is an autoimmune inflammatory disease of the orbit and is characterized by increased orbital levels of adipose tissue. Here, we evaluated the therapeutic mechanism for regulation of adipogenesis by PRL-1-overexpressing PD-MSCs (PD-MSCsPRL-1, PRL-1+) in orbital fibroblast (OF) with GO patients.

Methods
PD-MSCs isolated from human placenta were transfected with the PRL-1 gene using nonviral transfection method. Primary OFs were isolated from orbital adipose tissue specimens from GO patients. After maturation as adipogenic differentiation, normal and GO-derived OFs were cocultured with naïve and PD-MSCsPRL-1. We analyzed the protein levels of adipogenesis markers and their signaling pathways in OFs from GO patients.

Results
The characteristics of PD-MSCsPRL-1 were similar to those of naïve cells. OFs from GO patients induced adipocyte differentiation and had significantly decreased a lipid accumulation after coculture with PD-MSCsPRL-1 compared to naïve cells. The mRNA and protein expression of adipogenic markers was decreased in PD-MSCsPRL-1. Insulin-like growth factor-binding proteins (IGFBPs) secreting PD-MSCsPRL-1 downregulated the phosphorylated PI3K/AKT/mTOR expression in OFs from GO patients. Interestingly, IGFBP2, − 4, − 6, and − 7 expression in PD-MSCsPRL-1, which was mediated by integrin alpha 4 (ITGA4) and beta 7 (ITGB7), was higher than that in naïve cells and upregulated phosphorylated FAK downstream factor.

Conclusion
In summary, IGFBPs secreting PD-MSCPRL-1 inhibit adipogenesis in OFs from GO patients by upregulating phosphorylated FAK and downregulating PI3K/AKT/mTOR signaling pathway. The functional enhancement of PD-MSCs by nonviral gene modification provides a novel therapeutic strategy for the treatment of degenerative diseases.
Melphalan induces cardiotoxicity through oxidative stress in cardiomyocytes derived from human induced pluripotent stem cells
Authors: Liu Rui , Li Dong , Sun Fangxu , Rampoldi Antonio , Maxwell Joshua T. , Wu Ronghu , Fischbach Peter , Castellino Sharon M. , Du Yuhong , Fu Haian , Mandawat Anant , Xu Chunhui 
Published: November 2020

Abstract

Background
Treatment-induced cardiotoxicity is a leading noncancer-related cause of acute and late onset morbidity and mortality in cancer patients on antineoplastic drugs such as melphalan—increasing clinical case reports have documented that it could induce cardiotoxicity including severe arrhythmias and heart failure. As the mechanism by which melphalan impairs cardiac cells remains poorly understood, here, we aimed to use cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) to investigate the cellular and molecular mechanisms of melphalan-induced cardiotoxicity.

Methods
hiPSC-CMs were generated and treated with clinically relevant doses of melphalan. To characterize melphalan-induced cardiotoxicity, cell viability and apoptosis were quantified at various treatment durations. Ca2+ transient and contractility analyses were used to examine the alterations of hiPSC-CM function. Proteomic analysis, reactive oxygen species detection, and RNA-Sequencing were conducted to investigate underlying mechanisms.

Results
Melphalan treatment of hiPSC-CMs induced oxidative stress, caused Ca2+ handling defects and dysfunctional contractility, altered global transcriptomic and proteomic profiles, and resulted in apoptosis and cell death. The antioxidant N-acetyl-l-cysteine attenuated these genomic, cellular, and functional alterations. In addition, several other signaling pathways including the p53 and transforming growth factor-β signaling pathways were also implicated in melphalan-induced cardiotoxicity according to the proteomic and transcriptomic analyses.

Conclusions
Melphalan induces cardiotoxicity through the oxidative stress pathway. This study provides a unique resource of the global transcriptomic and proteomic datasets for melphalan-induced cardiotoxicity and can potentially open up new clinical mechanism-based targets to prevent and treat melphalan-induced cardiotoxicity.
Galectin-9 is required for endometrial regenerative cells to induce long-term cardiac allograft survival in mice
Authors: Zhao Yiming , Li Xiang , Yu Dingding , Hu Yonghao , Jin Wang , Qin Yafei , Kong Dejun , Wang Hongda , Li Guangming , Alessandrini Alessandro , Wang Hao 
Published: November 2020

Abstract
Background
Endometrial regenerative cells (ERCs), a novel type of mesenchymal-like stem cells, were identified as an attractive candidate for immunoregulation and induction of cardiac allograft tolerance. However, the underlying mechanisms of ERCs in immune regulation still remain largely unclear. The present study is designed to determine whether the expression of Galectin-9 (Gal-9), a soluble tandem-repeat member of the galectin family, is crucial for ERC-based immunomodulation.

Methods
In this study, we measured Gal-9 expression on ERCs and then co-cultured Gal-9-ERCs, ERCs, and ERCs+lactose (Gal-9 blocker) with activated C57BL/6-derived splenocytes. Furthermore, we performed mouse heart transplantation between BALB/c (H-2d) donor and C57BL/6 (H-2b) recipient. ERCs were administrated 24 h after the surgery, either alone or in combination with rapamycin.

Results
Our data demonstrate that ERCs express Gal-9, and this expression is increased by IFN-γ stimulation in a dose-dependent manner. Moreover, both in vitro and in vivo results show that Gal-9-ERC-mediated therapy significantly suppressed Th1 and Th17 cell response, inhibited CD8+ T cell proliferation, abrogated B cell activation, decreased donor-specific antibody production, and enhanced the Treg population. The therapeutic effect of ERCs was further verified by their roles in prolonging cardiac allograft survival and alleviating graft pathological changes.

Conclusions
Taken together, these data indicate that Gal-9 is required for ERC-mediated immunomodulation and prevention of allograft rejection.