bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel signature model based on mitochondrial-related genes for predicting survival of colon adenocarcinoma
Authors: Gao Hongli , Xing Fei 
Published: October 2022

Abstract
Background
Colon cancer is the foremost reason of cancer-related mortality worldwide. Colon adenocarcinoma constitutes 90% of colon cancer, and most patients with colon adenocarcinoma (COAD) are identified until advanced stage. With the emergence of an increasing number of novel pathogenic mechanisms and treatments, the role of mitochondria in the development of cancer, has been studied and reported with increasing frequency.

Methods
We systematically analyzed the effect of mitochondria-related genes in COAD utilizing RNA sequencing dataset from The Cancer Genome Atlas database and 1613 mitochondrial function-related genes from MitoMiner database. Our approach consisted of differentially expressed gene, gene set enrichment analysis, gene ontology terminology, Kyoto Encyclopedia of Genes and Genomes, independent prognostic analysis, univariate and multivariate analysis, Kaplan–Meier survival analysis, immune microenvironment correlation analysis, and Cox regression analysis.

Results
Consequently, 8 genes were identified to construct 8 mitochondrial-related gene model by applying Cox regression analysis, CDC25C, KCNJ11, NOL3, P4HA1, QSOX2, Trap1, DNAJC28, and ATCAY. Meanwhile, we assessed the connection between this model and clinical parameters or immune microenvironment. Risk score was an independent predictor for COAD patients’ survival with an AUC of 0.687, 0.752 and 0.762 at 1-, 3- and 5-year in nomogram, respectively. The group with the highest risk score had the lowest survival rate and the worst clinical stages. Additionally, its predictive capacity was validated in GSE39582 cohort.

Conclusion
In summary, we established a prognostic pattern of mitochondrial-related genes, which can predict overall survival in COAD, which may enable a more optimized approach for the clinical treatment and scientific study of COAD. This gene signature model has the potential to improve prognosis and treatment for COAD patients in the future, and to be widely implemented in clinical settings. The utilization of this mitochondrial-related gene signature model may be benefit in the treatments and medical decision-making of COAD.
Dynamic prediction of life-threatening events for patients in intensive care unit
Authors: Hu Jiang , Kang Xiao-hui , Xu Fang-fang , Huang Ke-zhi , Du Bin , Weng Li 
Published: October 2022

Abstract
Background
Early prediction of patients’ deterioration is helpful in early intervention for patients at greater risk of deterioration in Intensive Care Unit (ICU). This study aims to apply machine learning approaches to heterogeneous clinical data for predicting life-threatening events of patients in ICU.

Methods
We collected clinical data from a total of 3151 patients admitted to the Medical Intensive Care Unit of Peking Union Medical College Hospital in China from January 1st, 2014, to October 1st, 2019. After excluding the patients who were under 18 years old or stayed less than 24 h at the ICU, a total of 2170 patients were enrolled in this study. Multiple machine learning approaches were utilized to predict life-threatening events (i.e., death) in seven 24-h windows (day 1 to day 7) and their performance was compared.

Results
Light Gradient Boosting Machine showed the best performance. We found that life-threatening events during the short-term windows can be better predicted than those in the medium-term windows. For example, death in 24 h can be predicted with an Area Under Curve of 0.905. Features like infusion pump related fluid input were highly related to life-threatening events. Furthermore, the prediction power of static features such as age and cardio-pulmonary function increased with the extended prediction window.

Conclusion
This study demonstrates that the integration of machine learning approaches and large-scale high-quality clinical data in ICU could accurately predict life-threatening events for ICU patients for early intervention.
Identification of DNA methylation-regulated differentially expressed genes in RA by integrated analysis of DNA methylation and RNA-Seq data
Authors: Zhang Runrun , Chang Cen , Jin Yehua , Xu LingXia , Jiang Ping , Wei Kai , Xu Linshuai , Guo Shicheng , Sun Songtao , He Dongyi 
Published: October 2022

Abstract
Objective
To identify novel DNA methylation-regulated differentially expressed genes (MeDEGs) in RA by integrated analysis of DNA methylation and RNA-Seq data.

Methods
The transcription and DNA methylation profiles of 9 RA and 15 OA synovial tissue were generated by RNA-Seq and Illumina 850K DNA methylation BeadChip. Gene set enrichment analysis (GSEA) and Weighted gene co-expression network analysis (WGCNA) were used to analyze methylation-regulated expressed genes by R software. The differentially expressed genes (DEGs), differentially methylated probes (DMPs), differentially methylated genes (DMGs) were analyzed by DESeq and ChAMP R package. The functional correlation of MeDEGs was analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). The protein–protein interaction (PPI) network of MeDEGs was constructed by STRING and Reactome FI Cytoscape Plugin. Correlation analysis between methylation level and mRNA expression was conducted with R software.

Results
A total of 17,736 genes, 25,578 methylated genes and 755,852 methylation probes were detected. A total of 16,421 methylation-regulated expressed genes were obtained. The GSEA showed that these genes are associated with activation of immune response, adaptive immune response, Inflammatory response in C5 (ontology gene sets). For KEGG analysis, these genes are associated with rheumatoid arthritis, NF-kappa B signaling pathway, T cell receptor signaling pathway. The WGCNA showed that the turquoise module exhibited the strongest correlation with RA (R = 0.78, P = 1.27 × 10− 05), 660 genes were screened in the turquoise module. A total of 707 MeDEGs were obtained. GO analysis showed that MeDEGs were enriched in signal transduction, cell adhesion for BP, enriched in plasma membrane, integral component of membrane for CC, and enriched in identical protein binding, calcium ion binding for MF. The KEGG pathway analysis showed that the MeDEGs were enriched in calcium signaling pathway, T cell receptor signaling pathway, NF-kappa B signaling pathway, Rheumatoid arthritis. The PPI network containing 706 nodes and 882 edges, and the enrichment p value < 1.0 × 10− 16. With Cytoscape, based on the range of more than 10 genes, a total of 8 modules were screened out. Spearman correlation analysis showed RGS1(cg10718027), RGS1(cg02586212), RGS1(cg10861751) were significantly correlated with RA.

Conclusions
RGS1 can be used as novel methylated biomarkers for RA.
Simplified regimen of combined low-dose rituximab for autoimmune encephalitis with neuronal surface antibodies
Authors: Du Ying , Zhao Chao , Liu Juntong , Li Chuan , Yan Qi , Li Lin , Hao Yunfeng , Yao Dan , Si Huaxing , Zhao Yingjun , Zhang Wei 
Published: October 2022

Abstract
Background
Autoimmune encephalitis (AE) with neuronal surface antibodies (NSAbs) presents pathogenesis mediated by B cell-secreting antibodies. Rituximab is a second-line choice for the treatment for AE with NSAbs, which can cause B cell depletion via targeting CD20. However, the optimal protocol and dosage of rituximab combined with first-line therapy for NSAbs-associated AE remains unclear so far. In this study, we explored the efficacy and safety of low-dose rituximab combined with first-line treatment for NSAbs-associated AE.

Methods
Fifty-nine AE patients with NSAbs were enrolled, and retrospectively divided into common first-line therapy (41 patients) and combined low-dose rituximab (100 mg induction weekly with 3 circles, followed by 100 mg reinfusion every 6 months) with first-line therapy (18 patients). Outcome measures included changes in the Clinical Assessment Scale for Autoimmune Encephalitis (CASE) score (primary endpoint), changes in the modified Rankin Scale (mRS), the Mini-mental State Examination (MMSE), the patient and caregiver Neuropsychiatric Inventory (NPI) score at each visit (baseline, discharge, 6 months, 12 months and last follow-up) between two groups (secondary endpoint), as well as oral prednisone dosage, relapse and adverse effects during follow-up.

Results
Compared with traditional first-line therapy group, for primary outcome, CASE scores at last follow-up were significantly improved in combined rituximab group, as well as markedly improving changes of CASE scores between baseline and each visit. While changes of mRS, MMSE and NPI scores, as secondary endpoint, were all markedly accelerating improvement between baseline and each visit, as well as both oral prednisone dosage and relapse were also greatly reduced during follow-up. Meanwhile, longitudinal analysis in combination of rituximab cohort also revealed persistently marked amelioration in a series of scales from baseline even more than 1 year. Moreover, analysis in rituximab subgroup showed no difference in any clinical outcomes between combination with single first-line and with repeated first-line treatment (≥ 2 times), while compared to delayed combination with rituximab (> 3 months), early initiation of combination (≤ 3 months) might achieve better improvements in CASE and MMSE assessment even 1 year later. No rituximab-correlated serious adverse events have been reported in our patients.

Conclusions
Our simplified regimen of combined low-dose rituximab firstly showed significantly accelerating short-term recovery and long-term improvement for AE with NSAbs, in parallel with markedly reduced prednisone dosage and clinical relapses. Moreover, opportunity of protocol showed earlier initiation (≤ 3 months) with better long-term improvement.
Comparing biological effectiveness guided plan optimization strategies for cranial proton therapy: potential and challenges
Authors: Hahn Christian , Heuchel Lena , Ödén Jakob , Traneus Erik , Wulff Jörg , Plaude Sandija , Timmermann Beate , Bäumer Christian , Lühr Armin 
Published: October 2022

Abstract
Background
To introduce and compare multiple biological effectiveness guided (BG) proton plan optimization strategies minimizing variable relative biological effectiveness (RBE) induced dose burden in organs at risk (OAR) while maintaining plan quality with a constant RBE.

Methods
Dose-optimized (DOSEopt) proton pencil beam scanning reference treatment plans were generated for ten cranial patients with prescription doses ≥ 54 Gy(RBE) and ≥ 1 OAR close to the clinical target volume (CTV). For each patient, four additional BG plans were created. BG objectives minimized either proton track-ends, dose-averaged linear energy transfer (LETd), energy depositions from high-LET protons or variable RBE-weighted dose (DRBE) in adjacent serially structured OARs. Plan quality (RBE = 1.1) was assessed by CTV dose coverage and robustness (2 mm setup, 3.5% density), dose homogeneity and conformity in the planning target volumes and adherence to OAR tolerance doses. LETd, DRBE (Wedenberg model, α/βCTV = 10 Gy, α/βOAR = 2 Gy) and resulting normal tissue complication probabilities (NTCPs) for blindness and brainstem necrosis were derived. Differences between DOSEopt and BG optimized plans were assessed and statistically tested (Wilcoxon signed rank, α = 0.05).

Results
All plans were clinically acceptable. DOSEopt and BG optimized plans were comparable in target volume coverage, homogeneity and conformity. For recalculated DRBE in all patients, all BG plans significantly reduced near-maximum DRBE to critical OARs with differences up to 8.2 Gy(RBE) (p < 0.05). Direct DRBE optimization primarily reduced absorbed dose in OARs (average ΔDmean = 2.0 Gy; average ΔLETd,mean = 0.1 keV/µm), while the other strategies reduced LETd (average ΔDmean < 0.3 Gy; average ΔLETd,mean = 0.5 keV/µm). LET-optimizing strategies were more robust against range and setup uncertaintes for high-dose CTVs than DRBE optimization. All BG strategies reduced NTCP for brainstem necrosis and blindness on average by 47% with average and maximum reductions of 5.4 and 18.4 percentage points, respectively.

Conclusions
All BG strategies reduced variable RBE-induced NTCPs to OARs. Reducing LETd in high-dose voxels may be favourable due to its adherence to current dose reporting and maintenance of clinical plan quality and the availability of reported LETd and dose levels from clinical toxicity reports after cranial proton therapy. These optimization strategies beyond dose may be a first step towards safely translating variable RBE optimization in the clinics.
Dissecting super-enhancer driven transcriptional dependencies reveals novel therapeutic strategies and targets for group 3 subtype medulloblastoma
Authors: Li Meng , Han Yujie , Wang Chaochen , Kang Wenfeng , Jiang Wenyan , Zhang Lei , Tang Yujie 
Published: October 2022

Abstract
Background
Medulloblastoma is the most common malignant pediatric brain tumor and group 3 subtype medulloblastoma (G3-MB) exhibits the worst prognosis. Super enhancers (SEs) are large clusters of enhancers that play important roles in cancer through transcriptional control of cell identity genes, oncogenes and tumor-dependent genes. Dissecting SE-driven transcriptional dependencies of cancer leads to identification of novel oncogenic mechanisms, therapeutic strategies and targets.

Methods
Integrative SE analyses of primary tissues and patient-derived tumor cell lines of G3-MB were performed to extract the conserved SE-associated gene signatures and their oncogenic potentials were evaluated by gene expression, tumor-dependency and patient prognosis analyses. SE-associated subtype-specific upregulated tumor-dependent genes, which were revealed as members of SE-driven core transcriptional regulatory network of G3-MB, were then subjected to functional validation and mechanistic investigation. SE-associated therapeutic potential was further explored by genetic or pharmaceutical targeting of SE complex components or SE-associated subtype-specific upregulated tumor-dependent genes individually or in combination, and the underlying therapeutic mechanisms were also examined.

Results
The identified conserved SE-associated transcripts of G3-MB tissues and cell lines were enriched of subtype-specifically upregulated tumor-dependent genes and MB patients harboring enrichment of those transcripts exhibited worse prognosis. Fourteen such conserved SE-associated G3-MB-specific upregulated tumor-dependent genes were identified to be members of SE-driven core transcriptional regulatory network of G3-MB, including three well-recognized TFs (MYC, OTX2 and CRX) and eleven newly identified downstream effector genes (ARL4D, AUTS2, BMF, IGF2BP3, KIF21B, KLHL29, LRP8, MARS1, PSMB5, SDK2 and SSBP3). An OTX2-SE-ARL4D regulatory axis was further revealed to represent a subtype-specific tumor dependency and therapeutic target of G3-MB via contributing to maintaining cell cycle progression and inhibiting neural differentiation of tumor cells. Moreover, BET inhibition with CDK7 inhibition or proteasome inhibition, two combinatory strategies of targeting SE complex components (BRD4, CDK7) or SE-associated effector gene (PSMB5), were shown to exhibit synergistic therapeutic effects against G3-MB via stronger suppression of SE-associated transcription or higher induction of ER stress, respectively.

Conclusions
Our study verifies the oncogenic role and therapeutic potential of SE-driven transcriptional dependencies of G3-MB, resulting in better understanding of its tumor biology and identification of novel SE-associated therapeutic strategies and targets.
Patient-specific modeling of stroma-mediated chemoresistance of pancreatic cancer using a three-dimensional organoid-fibroblast co-culture system
Authors: Schuth Sebastian , Le Blanc Solange , Krieger Teresa G. , Jabs Julia , Schenk Miriam , Giese Nathalia A. , Büchler Markus W. , Eils Roland , Conrad Christian , Strobel Oliver 
Published: October 2022

Abstract
Background
Cancer-associated fibroblasts (CAFs) are considered to play a fundamental role in pancreatic ductal adenocarcinoma (PDAC) progression and chemoresistance. Patient-derived organoids have demonstrated great potential as tumor avatars for drug response prediction in PDAC, yet they disregard the influence of stromal components on chemosensitivity.

Methods
We established direct three-dimensional (3D) co-cultures of primary PDAC organoids and patient-matched CAFs to investigate the effect of the fibroblastic compartment on sensitivity to gemcitabine, 5-fluorouracil and paclitaxel treatments using an image-based drug assay. Single-cell RNA sequencing was performed for three organoid/CAF pairs in mono- and co-culture to uncover transcriptional changes induced by tumor-stroma interaction.

Results
Upon co-culture with CAFs, we observed increased proliferation and reduced chemotherapy-induced cell death of PDAC organoids. Single-cell RNA sequencing data evidenced induction of a pro-inflammatory phenotype in CAFs in co-cultures. Organoids showed increased expression of genes associated with epithelial-to-mesenchymal transition (EMT) in co-cultures and several potential receptor-ligand interactions related to EMT were identified, supporting a key role of CAF-driven induction of EMT in PDAC chemoresistance.

Conclusions
Our results demonstrate the potential of personalized PDAC co-cultures models not only for drug response profiling but also for unraveling the molecular mechanisms involved in the chemoresistance-supporting role of the tumor stroma.
Analgesic efficacy of local versus proximal nerve blocks after hallux valgus surgery: a systematic review
Authors: Ravanbod Hamid Reza 
Published: October 2022

AbstractBackgroundHallux valgus (HV) surgery is an orthopaedic procedure that commonly causes mild to moderate postoperative pain. Effective management of this pain has become an important element of modern hallux valgus surgical treatment. A local anaesthetic (LA) with an antinociceptive effect can control this pain. However, relatively few papers have evaluated this strategy in depth. The objective of the current systematic review was to address this demand by comparing the efficacy of proximal and local blocks in controlling postoperative pain following hallux valgus surgery.Main textOvid‐MEDLINE, Cochrane Central, PubMed, Web of Science (WOS), Scopus, and Embase were searched from their inceptions through December 29, 2021. Observational and clinical trial publications in peer‐reviewed English‐language journals with a sample size of at least 20 were included. The trials involved adults over 18 who could describe their discomfort and had a bunionectomy. The included studies were evaluated using the Cochrane risk of bias 2 method. Descriptive analysis synthesised the results.Among the 439 articles identified, five studies compromising 459 participants were included. Ankle blocks were superior to control in two studies (P = 0.001, P < 0.001) and superior to local blocks in one study (P < 0.001). Additionally, one study showed that popliteal and ankle blocks administered with lidocaine or levobupivacaine were equivalent (P = 0.123 and P = 0.055, respectively). However, one of these five included studies indicated that ankle blocks were not effective (P = 0.123) in reducing postoperative pain.ConclusionsThe key findings presented herein suggest that regional blocks effectively reduce postoperative pain and that an ankle block has more supportive evidence for its effectiveness. However, an adequate assessment of the effectiveness of various administrative routes was challenging due to the lack of reliable evidence. This needs to be addressed in future studies.Trial registrationPROSPERO registration: CRD42022307974.
Hao-Fountain syndrome and genital disorders: report of a new possible association
Authors: Zampieri Nicola , Pulvirenti Rebecca , Pedrazzoli Eleonora , Camoglio Francesco Saverio 
Published: October 2022

Abstract
Background
Hao-Fountain syndrome is a neurodevelopmental disorder characterized by global developmental delay, variably impaired intellectual development with significant speech delay and, in some males patients, it has been reported an association with hypogonadism. At present less than 50 cases are reported in literature.

Case presentation
We report a case of this rare syndrome in a young female with isolated tubal torsion; our patients had different hospitalizations without treatment but during the last episode we decide to perform an abdominal surgical explortion. This is the first case in Literature with a new USP7 mutation.

Conclusions
This case opens new perspective in this rare syndrome and a review approach to isolated tubal torsion. These symptoms should be always well checked.
Personalized Disease Prevention (PDP): study protocol for a cluster-randomized clinical trial
Authors: Taksler Glen B. , Le Phuc , Hu Bo , Alberts Jay , Flynn Allen J. , Rothberg Michael B. 
Published: October 2022

Abstract
Background
The US Preventive Services Task Force recommends 25 primary preventive services for middle-aged adults, but it can be difficult to do them all.

Methods
The Personalized Disease Prevention (PDP) cluster-randomized clinical trial will evaluate whether patients and their providers benefit from an evidence-based decision tool to prioritize preventive services based on their potential to improve quality-adjusted life expectancy. The decision tool will be individualized for patient risk factors and available in the electronic health record. This Phase III trial seeks to enroll 60 primary care providers (clusters) and 600 patients aged 40–75 years. Half of providers will be assigned to an intervention to utilize the decision tool with approximately 10 patients each, and half will be assigned to usual care. Mixed-methods follow-up will include collection of preventive care utilization from electronic health records, patient and physician surveys, and qualitative interviews. We hypothesize that quality-adjusted life expectancy will increase by more in patients who receive the intervention, as compared with controls.

Discussion
PDP will test a novel, holistic approach to help patients and providers prioritize the delivery of preventive services, based on patient risk factors in the electronic health record.

Trial registration
ClinicalTrials.gov NCT05463887. Registered on July 19, 2022.