bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of key pathways, genes and immune cell infiltration in hypoxia of high-altitude acclimatization via meta-analysis and integrated bioinformatics analysis
Authors: Li Qiong , Xu Zhichao , Fang Fujin , Shen Yan , Lei Huan , Shen Xiaobing 
Published: March 2023

Background: For individuals acutely exposed to high-altitude regions, environmental hypobaric hypoxia induces several physiological or pathological responses, especially immune dysfunction. Therefore, hypoxia is a potentially life-threatening factor, which has closely related to high-altitude acclimatization. However, its specific molecular mechanism is still unclear.Methods: The four expression profiles about hypoxia and high altitude were downloaded from the Gene Expression Omnibus database in this study. Meta-analysis of GEO datasets was performed by NetworkAnalyst online tool. Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene ontology (GO) enrichment analysis, and visualization were performed using R (version 4.1.3) software, respectively. The CIBERSORT analysis was conducted on GSE46480 to examine immune cell infiltration. In addition, we experimentally verified the bioinformatics analysis with qRT-PCR.Results: The meta-analysis identified 358 differentially expressed genes (DEGs), with 209 upregulated and 149 downregulated. DEGs were mostly enriched in biological processes and pathways associated with hypoxia acclimatization at high altitudes, according to both GO and KEGG enrichment analyses. ERH, VBP1, BINP3L, TOMM5, PSMA4, and POLR2K were identified by taking intersections of the DEGs between meta-analysis and GSE46480 and verified by qRT-PCR experiments, which were inextricably linked to hypoxia. Immune infiltration analysis showed significant differences in immune cells between samples at sea level and high altitudes.Conclusion: Identifying the DEGs and pathways will improve our understanding of immune function during high-altitude hypoxia at a molecular level. Targeting hypoxia-sensitive pathways in immune cells is interesting in treating high-altitude sickness. This study provides support for further research on high-altitude acclimatization.
Non-viral TRAC-knocked-in CD19KICAR-T and gp350KICAR-T cells tested against Burkitt lymphomas with type 1 or 2 EBV infection: In vivo cellular dynamics and potency
Authors: Braun Tobias , Pruene Alina , Darguzyte Milita , vom Stein Alexander F. , Nguyen Phuong-Hien , Wagner Dimitrios L. , Kath Jonas , Roig-Merino Alicia , Heuser Michael , Riehm Lucas L. , Schneider Andreas , Awerkiew Sabine , Talbot Steven R. , Bleich André , Figueiredo Constanca , Bornhäuser Martin , Stripecke Renata 
Published: March 2023

IntroductionThe ubiquitous Epstein–Barr virus (EBV) is an oncogenic herpes virus associated with several human malignancies. EBV is an immune-evasive pathogen that promotes CD8+ T cell exhaustion and dysregulates CD4+ T cell functions. Burkitt lymphoma (BL) is frequently associated with EBV infections. Since BL relapses after conventional therapies are difficult to treat, we evaluated prospective off-the-shelf edited CAR-T cell therapies targeting CD19 or the EBV gp350 cell surface antigen.MethodsWe used CRISPR/Cas9 gene editing methods to knock in (KI) the CD19CAR.CD28z or gp350CAR.CD28z into the T cell receptor (TCR) alpha chain (TRAC) locus.ResultsApplying upscaled methods with the ExPERT ATx® MaxCyte system, KI efficacy was ~20% of the total ~2 × 108 TCR-knocked-out (KO) generated cells. KOTCRKICAR-T cells were co-cultured in vitro with the gp350+CD19+ BL cell lines Daudi (infected with type 1 EBV) or with Jiyoye (harboring a lytic type 2 EBV). Both types of CAR-T cells showed cytotoxic effects against the BL lines in vitro. CD8+ KICAR-T cells showed higher persistency than CD4+ KICAR-T cells after in vitro co-culture with BL and upregulation of the activation/exhaustion markers PD-1, LAG-3, and TIM-3. Two preclinical in vivo xenograft models were set up with Nod.Rag.Gamma mice injected intravenously (i.v.) with 2 × 105 Daudi/fLuc-GFP or with Jiyoye/fLuc-GFP cells. Compared with the non-treated controls, mice challenged with BL and treated with CD19KICAR-T cells showed delayed lymphoma dissemination with lower EBV DNA load. Notably, for the Jiyoye/fLuc-GFP model, almost exclusively CD4+ CD19KICAR-T cells were detectable at the endpoint analyses in the bone marrow, with increased frequencies of regulatory T cells (Tregs) and TIM-3+CD4+ T cells. Administration of gp350KICAR-T cells to mice after Jiyoye/GFP-fLuc challenge did not inhibit BL growth in vivo but reduced the EBV DNA load in the bone marrow and promoted gp350 antigen escape. CD8+PD-1+LAG-3+ gp350KICAR-T cells were predominant in the bone marrow.DiscussionThe two types of KOTCRKICAR-T cells showed different therapeutic effects and in vivo dynamics. These findings reflect the complexities of the immune escape mechanisms of EBV, which may interfere with the CAR-T cell property and potency and should be taken into account for future clinical translation.
Prepackaged formula low-residue diet vs. self-prepared low-residue diet before colonoscopy: A multicenter randomized controlled trial
Authors: Pan Peng , Gu Lun , Zhao Shengbing , Wang Shuling , Ma Jiayi , Fu Hongyu , Chen Youxiang , He Shuixiang , Tian Zibin , Xu Le , Feng Zhijie , Li Yanqing , Yang Zhuo , Yang Lei , Wang Wen , Hou Qian , Liu Ting , Li Chujun , Tian Dean , Wang Xiaodi , Gao Yongmei , Shi Hanping , Bai Yu , Li Zhaoshen 
Published: March 2023

Background and aimsCompared with self-prepared LRD, a prepackaged low-residue diet (LRD) can improve patient compliance, but whether it can further improve the quality of bowel preparation is uncertain. The study aimed to compare the application of the prepackaged formula LRD with self-prepared LRD in bowel preparation for colonoscopy.MethodsA multicenter randomized controlled trial was conducted in 15 centers. The eligible subjects were randomly assigned to one of two groups: the formula LRD group and the self-prepared LRD group. On the day before the colonoscopy, subjects in the self-prepared LRD group were instructed to consume a restricted LRD prepared by themselves, while subjects in the formula LRD group were given six bags of prepackaged formula LRD and instructed to consume them according to their individual need. The primary outcome was an adequate bowel preparation rate. Secondary outcomes mainly included Boston Bowel Preparation Scale (BBPS) scores, dietary restriction compliance rate, tolerance, satisfaction, adenoma detection rate (ADR), and adverse reactions. The trial was registered at ClinicalTrials.gov under the identifier NCT03943758.ResultsA total of 550 subjects were recruited. Compared with the self-prepared LRD group, the formula LRD group showed a higher adequate bowel preparation rate (94.5 vs. 80.4%; P &lt; 0.01), BBPS scores (7.87 ± 1.13 vs. 6.75 ± 1.47; P &lt; 0.01), dietary compliance rate (92.4 vs. 78.9%; P &lt; 0.01), tolerance (P &lt; 0.01 in degree of hunger, intensity of physical strength, and negative influence on daily activities), satisfaction (8.56 ± 1.61 vs. 7.20 ± 2.02; P &lt; 0.01), and ADR (25.6 vs. 16.0%; P &lt; 0.01). There was no significant difference in adverse reactions.ConclusionCompared with self-prepared LRD, the formula LRD showed similar safety and higher bowel preparation quality, compliance, and tolerance in bowel preparation. More formula LRDs could be designed according to different dietary habits and ethnic populations, and further researches are warranted to confirm their effect.Clinical trial registrationhttps://register.clinicaltrials.gov, identifier: NCT03943758.
Disease modeling of ADAMTS9-related nephropathy using kidney organoids reveals its roles in tubular cells and podocytes
Authors: Yu Seyoung , Choi Yo Jun , Rim John Hoon , Kim Hye-Youn , Bekheirnia Nasim , Swartz Sarah Jane , Dai Hongzheng , Gu Shen Linda , Lee Soyeon , Nishinakamura Ryuichi , Hildebrandt Friedhelm , Bekheirnia Mir Reza , Gee Heon Yung 
Published: March 2023

IntroductionMutations in ADAMTS9 cause nephronophthisis-related ciliopathies (NPHP-RC), which are characterized by multiple developmental defects and kidney diseases. Patients with NPHP-RC usually have normal glomeruli and negligible or no proteinuria. Herein, we identified novel compound-heterozygous ADAMTS9 variants in two siblings with NPHP-RC who had glomerular manifestations, including proteinuria.MethodsTo investigate whether ADAMTS9 dysfunction causes NPHP and glomerulopathy, we differentiated ADAMTS9 knockout human induced pluripotent stem cells (hiPSCs) into kidney organoids. Single-cell RNA sequencing was utilized to elucidate the gene expression profiles from the ADAMTS9 knockout kidney organoids.ResultsADAMTS9 knockout had no effect on nephron differentiation; however, it reduced the number of primary cilia, thereby recapitulating renal ciliopathy. Single-cell transcriptomics revealed that podocyte clusters express the highest levels of ADAMTS9, followed by the proximal tubules. Loss of ADAMTS9 increased the activity of multiple signaling pathways, including the Wnt/PCP signaling pathway, in podocyte clusters.ConclusionsMutations in ADMATS9 cause a glomerulotubular nephropathy in kidney and our study provides insights into the functional roles of ADMATS9 in glomeruli and tubules.
Therapeutic potential of a novel peripherally restricted CB1R inverse agonist on the progression of diabetic nephropathy
Authors: Jacquot Laetitia , Pointeau Océane , Roger-Villeboeuf Célia , Passilly-Degrace Patricia , Belkaid Rim , Regazzoni Isaline , Leemput Julia , Buch Chloé , Demizieux Laurent , Vergès Bruno , Degrace Pascal , Crater Glenn , Jourdan Tony 
Published: March 2023

ObjectiveThis study assessed the efficacy of INV-202, a novel peripherally restricted cannabinoid type-1 receptor (CB1R) inverse agonist, in a streptozotocin-induced type-1 diabetes nephropathy mouse model.MethodsDiabetes was induced in 8-week-old C57BL6/J male mice via intraperitoneal injection of streptozotocin (45 mg/kg/day for 5 days); nondiabetic controls received citrate buffer. Diabetic mice were randomized to 3 groups based on blood glucose, polyuria, and albuminuria, and administered daily oral doses for 28-days of INV-202 at 0.3 or 3 mg/kg or vehicle.ResultsINV-202 did not affect body weight but decreased kidney weight compared with the vehicle group. While polyuria was unaffected by INV-202 treatment, urinary urea (control 30.77 ± 14.93; vehicle 189.81 ± 31.49; INV-202 (0.3 mg/kg) 127.76 ± 20; INV-202 (3 mg/kg) 93.70 ± 24.97 mg/24h) and albumin (control 3.06 ± 0.38; vehicle 850.08 ± 170.50; INV-202 (0.3 mg/kg) 290.65 ± 88.70; INV-202 (3 mg/kg) 111.29 ± 33.47 µg/24h) excretion both decreased compared with vehicle-treated diabetic mice. Compared with the vehicle group, there was a significant improvement in the urinary albumin to creatinine ratio across INV-202 groups. Regardless of the dose, INV-202 significantly reduced angiotensin II excretion in diabetic mice. The treatment also decreased Agtr1a renal expression in a dose-dependent manner. Compared with nondiabetic controls, the glomerular filtration rate was increased in the vehicle group and significantly decreased by INV-202 at 3 mg/kg. While the vehicle group showed a significant loss in the mean number of podocytes per glomerulus, INV-202 treatment limited podocyte loss in a dose-dependent manner. Moreover, in both INV-202 groups, expression of genes coding for podocyte structural proteins nephrin (Nphs1), podocin (Nphs2), and podocalyxin (Pdxl) were restored to levels similar to nondiabetic controls. INV-202 partially limited the proximal tubular epithelial cell (PTEC) hyperplasia and normalized genetic markers for PTEC lesions. INV-202 also reduced expression of genes contributing to oxidative stress (Nox2, Nox4, and P47phox) and inflammation (Tnf). In addition, diabetes-induced renal fibrosis was significantly reduced by INV-202.ConclusionsINV-202 reduced glomerular injury, preserved podocyte structure and function, reduced injury to PTECs, and ultimately reduced renal fibrosis in a streptozotocin-induced diabetic nephropathy mouse model. These results suggest that INV-202 may represent a new therapeutic option in the treatment of diabetic kidney disease.
Improving the models for prognosis of aneurysmal subarachnoid hemorrhage with the neutrophil-to-albumin ratio
Authors: Zhang Renjie , Liu Zheran , Zhang Yu , Pei Yiyan , He Yan , Yu Jiayi , You Chao , Ma Lu , Fang Fang 
Published: March 2023

ObjectiveMany peripheral inflammatory markers were reported to be associated with the prognosis of aneurysmal subarachnoid hemorrhage (aSAH). We aimed to identify the most promising inflammatory factor that can improve existing predictive models.MethodsThe study was based on data from a 10 year retrospective cohort study at Sichuan University West China Hospital. We selected the well-known SAFIRE and Subarachnoid Hemorrhage International Trialists’ (SAHIT) models as the basic models. We compared the performance of the models after including the inflammatory markers and that of the original models. The developed models were internally and temporally validated.ResultsA total of 3,173 patients were included in this study, divided into the derivation cohort (n = 2,525) and the validation cohort (n = 648). Most inflammatory markers could improve the SAH model for mortality prediction in patients with aSAH, and the neutrophil-to-albumin ratio (NAR) performed best among all the included inflammatory markers. By incorporating NAR, the modified SAFIRE and SAHIT models improved the area under the receiver operator characteristics curve (SAFIRE+NAR vs. SAFIRE: 0.794 vs. 0.778, p = 0.012; SAHIT+NAR vs. SAHIT: 0.831 vs. 0.819, p = 0.016) and categorical net reclassification improvement (SAFIRE+NAR: 0.0727, p = 0.002; SAHIT+NAR: 0.0810, p &lt; 0.001).ConclusionThis study illustrated that among the inflammatory markers associated with aSAH prognosis, NAR could improve the SAFIRE and SAHIT models for 3 month mortality of aSAH.
Differentiating neurosarcoidosis from multiple sclerosis using combined analysis of basic CSF parameters and MRZ reaction
Authors: Vlad Benjamin , Neidhart Stephan , Hilty Marc , Ziegler Mario , Jelcic Ilijas 
Published: March 2023

BackgroundNeurosarcodosis is one of the most frequent differential diagnoses of multiple sclerosis (MS) and requires central nervous system (CNS) biopsy to establish definite diagnosis according to the latest consensus diagnostic criteria. We here analyzed diagnostic values of basic cerebrospinal fluid (CSF) parameters to distinguish neurosarcoidosis from MS without CNS biopsy.MethodsWe retrospectively assessed clinical, radiological and laboratory data of 27 patients with neurosarcoidosis treated at our center and compared following CSF parameters with those of 138 patients with relapsing-remitting MS: CSF white cell count (WCC), CSF/serum albumin quotient (Qalb), intrathecal production of immunoglobulins including oligoclonal bands (OCB), MRZ reaction, defined as a polyspecific intrathecal production of IgG reactive against ≥2 of 3 the viruses measles (M), rubella (R), and zoster (Z) virus, and CSF lactate levels. Additional inflammatory biomarkers in serum and/or CSF such as neopterin, soluble interleukin-2 receptor (sIL-2R) and C-reactive protein (CRP) were assessed.ResultsThere was no significant difference in the frequency of CSF pleocytosis, but a CSF WCC &gt; 30/μl was more frequent in patients with neurosarcoidosis. Compared to MS, patients with neurosarcoidosis showed more frequently an increased Qalb and CSF lactate levels as well as increased serum and CSF levels of sIL-2R, but a lower frequency of intrathecal IgG synthesis and positive MRZ reaction. Positive likelihood ratio (PLR) of single CSF parameters indicating neurosarcoidosis was highest, if (a) CSF WCC was &gt;30/μl (PLR 7.2), (b) Qalb was &gt;10 × 10−3 (PLR 66.4), (c) CSF-specific OCB were absent (PLR 11.5), (d) CSF lactate was elevated (PLR 23.0) or (e) sIL-2R was elevated (PLR&gt;8.0). The combination of (a) one of three following basic CSF parameters, i.e., (a.1.) CSF WCC &gt;30/ul, or (a.2.) QAlb &gt;10 × 10−3, or (a.3.) absence of CSF-specific OCB, and (b) absence of positive MRZ reaction showed the best diagnostic accuracy (sensitivity and specificity each &gt;92%; PLR 12.8 and NLR 0.08).ConclusionCombined evaluation of basic CSF parameters and MRZ reaction is powerful in differentiating neurosarcoidosis from MS, with moderate to severe pleocytosis and QAlb elevation and absence of intrathecal IgG synthesis as useful rule-in parameters and positive MRZ reaction as a rule-out parameter for neurosarcoidosis.
Clinical value of 18F-FDG PET/CT to predict MYCN gene, chromosome 1p36 and 11q status in pediatric neuroblastoma and ganglioneuroblastoma
Authors: Ren Jiazhong , Fu Zheng , Zhao Yaqing 
Published: March 2023

ObjectiveTo explore the value of 18F-2-fluoro-2-deoxyglucose (FDG) positron emission tomography (PET)/computed tomography(CT) in MYCN gene and chromosome 1p36 and 11 statuses in newly diagnosed pediatric NB(neuroblastoma) and GNB(ganglioneuroblastoma).MethodsWe retrospectively analyzed newly diagnosed patients with 48 NB and 12 with GNB in our hospital. The data obtained from the clinical medical records included age, sex, pathologic type, and laboratory parameters such as lactate dehydrogenase (LDH), neuron-specific enolase (NSE) and the status of MYCN gene and chromosome 1p36 and 11q. The bone conditions were also obtained in the examination of bone marrow biopsy. Primary tumors were manually segmented to measure the maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), tumor volume(MTV) and total lesion glycolysis(TLG) and the maximal length of the lesion in the axial image(LEGmax).ResultsThe differences in bone marrow involvement and lymph node metastases in patients with chromosome 11q deletions were statistically significant (all p &lt; 0.05). Chromosome 11q deletion was an independent factor affecting bone marrow involvement (OR=17.796, p=0.011). The levels of NSE, LDH, LEGmax and SUVmax, SUVmean, MTV, TLG all predicted MYCN gene amplification (all p &lt; 0.05). The levels of LDH, LEGmax and MTV, TLG all predicted deletions in chromosomes 1p36 (all p &lt; 0.05), while NSE, SUVmax and SUVmean did not (all p &gt; 005).ConclusionThe LDH levels, LEGmax, MTV and TLG can effectively predict the status of the MYCN oncogene and chromosome 1p36 in pediatric neuroblastoma and ganglioneuroblastoma. Those patients with chromosome 11q deletions are more likely to develop bone marrow involvement and lymph node metastases, showing a worse progression-free survival.
The burden and scope of childhood cancer in displaced patients in Jordan: The King Hussein Cancer Center and Foundation Experience
Authors: Rihani Rawad , Jeha Sima , Nababteh Mayse , Rodriguez-Galindo Carlos , Mansour Asem , Sultan Iyad 
Published: March 2023

IntroductionJordan hosts one of the highest numbers of refugees per capita in the world, with the Syrian crisis leading to an influx of displaced persons to the already vulnerable population. However, limited resources and a lack of cancer-care strategies have made it difficult for refugees in Jordan to access quality cancer care. The King Hussein Cancer Center (KHCC) and Foundation (KHCF) have played a pivotal role in providing financial and medical support for displaced children with cancer, treating 968 non-Jordanian children with cancer between 2011-2022, with a median age of 6 years. Of these, 84% were fully funded by KHCF, and nationalities included Syrians (29%), Palestinians (26%), Iraqis (23%), and Yemenis (17%). Cancer diagnoses included solid tumors (44%), leukemia (23%), lymphoma (13%), bone sarcomas (9.5%), and retinoblastoma (9.1%). The median cost of treatment was JOD 18,000 (USD 25,352), with a total estimated cost of JOD 23.8 million (USD 33.5 million). More recently, in partnership with St. Jude Children’s Research Hospital (SJCRH), two successive humanitarian funds (HF) were established to optimize cancer care for displaced children in Jordan.ResultsBetween February 2018 and September 2022, 51 children were fully treated on KHCC-SJCRH-HF, with a median age of 6 years and nationalities including Syrians (80%), Iraqis (6%), and Yemenis (8%). The most common cancer diagnoses were leukemia (41%), lymphoma (25%), solid tumors (24%), retinoblastoma (6%), and brain tumors (4%). Of these, 94% are alive and 51% are still receiving coverage. The median coverage for patients was JOD 21,808 (USD 30,715), and the total cost of treatment on KHCC/KHCF-SJCRH/American Lebanese Syrian-Associated Charities HF1 and HF2 was JOD 1.44 million (USD 1.97 million) and JOD 1.18 million (USD 1.67 million), respectively.ConclusionThis experience highlights the high burden of displaced children with cancer in Jordan, and the importance of local foundations like KHCC/KHCF and partnerships with international partners like SJCRH in providing lifesaving humanitarian initiatives and quality cancer care. Innovative cancer-care delivery models and sustainable financing are essential to ensure continuous coverage and access to cancer care for displaced persons in Jordan.
URB2 as an important marker for glioma prognosis and immunotherapy
Authors: Fang Chaoyou , Zhang Zeyu , Han Yongquan , Xu Houshi , Zhu Zhengyang , Du Yichao , Hou Pinpin , Yuan Ling , Shao Anwen , Zhang Anke , Lou Meiqing 
Published: March 2023

Introduction: Glioma is the most common primary brain tumor and primary malignant tumor of the brain in clinical practice. Conventional treatment has not significantly altered the prognosis of patients with glioma. As research into immunotherapy continues, glioma immunotherapy has shown great potential.Methods: The clinical data were acquired from the Chinese Glioma Genome Atlas (CGGA) database and validated by the Gene Expression Omnibus (GEO) database, The Cancer Genome Atlas (TCGA) dataset, Clinical Proteomic Tumor Analysis Consortium (CPTAP) database, and Western blot (WB) analysis. By Cox regression analyses, we examined the association between different variables and overall survival (OS) and its potential as an independent prognostic factor. By constructing a nomogram that incorporates both clinicopathological variables and the expression of URB2, we provide a model for the prediction of prognosis. Moreover, we explored the relationship between immunity and URB2 and elucidated its underlying mechanism of action.Results: Our study shows that URB2 likely plays an oncogenic role in glioma and confirms that URB2 is a prognostic independent risk factor for glioma. Furthermore, we revealed a close relationship between immunity and URB2, which suggests a new approach for the immunotherapy of glioma.Conclusion: URB2 can be used for prognosis prediction and immunotherapy of glioma.