bluuebunny/crossref_metadata_2025_split huggingface dataset:
SEPT6_TRIM33 Gene Fusion and Mutated TP53 Pathway Associate With Unfavorable Prognosis in Patients With B-Cell Lymphomas
Authors: Fu Haiying , Zhou Huarong , Qiu Yanyan , Wang Jianfei , Ma Zhiming , Li Hongping , Zhang Feng , Qiu Chenxi , Shen Jianzhen , Liu Tingbo 
Published: December 2021

BackgroundMounting studies have sought to identify novel mutation biomarkers having diagnostic and prognostic potentials. Nevertheless, the understanding of the mutated pathways related to development and prognosis of B-cell lymphoma is still lacking. We aimed to comprehensively analyze the mutation alterations in genes of canonical signaling pathways and their impacts on the clinic outcomes of patients with B-cell lymphoma.MethodsCirculating cell-free DNA (cfDNA) samples from 79 patients with B-cell lymphomas were used for targeted sequencing with a 560-gene panel for depicting mutation landscapes and identifying gene fusion events. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses of mutated genes were performed. The associations of mutation status of genes and seven canonical oncogenic pathways with progression-free survival (PFS) were assessed using Kaplan-Meier test and multivariate Cox analysis. The variant allele frequencies (VAFs) of genes in TP53 and Hippo pathways in paired baseline and post-treatment samples from 18 B-cell lymphoma patients were compared. Finally, the associations of identified fusion genes, mutated genes, and pathways with treatment response were evaluated based on objective response rates (ORRs) comparisons of groups.ResultsWe identified 666 mutations from 262 genes in baseline cfDNAs from 79 B-cell lymphoma patients, and found some genes were preferentially mutated in our cohort such as GNAQ, GNAS, H3F3A, DNMT3A, HLA-A, and HLA-B. These frequently mutated genes were significantly associated with negative “regulation of gene expression, epigenetic” and virus infections such as cytomegalovirus, Epstein-Barr virus, human immunodeficiency virus 1 infections. We detected five fusion genes in at least two patients with B-cell lymphoma, and among them, TCF7L2_WT1 gene fusion was most frequently detected in 30.4% of patients (24 of 79 cases). SEPT6_TRIM33 gene fusion, mutated TP53 and Hippo pathways were significantly associated with poor PFS, and SEPT6_TRIM33 fusion gene and mutated TP53 pathway were independent prognostic factors for B-cell lymphoma. A decreased VAF of TP53 p.Y88C and LATS2 p.F972L was detected in patients with complete response to treatments. Moreover, a significant difference in ORR was observed in patients with NPM1_NR4A3 and SEPT6_TRIM33 fusions.ConclusionsSEPT6_TRIM33 gene fusion and mutated TP53 and Hippo pathways may serve as prognostic makers for B-cell lymphoma patients.
Impact of Advanced Radiotherapy on Second Primary Cancer Risk in Prostate Cancer Survivors: A Nationwide Cohort Study
Authors: Jahreiß Marie-Christina , Heemsbergen Wilma D. , van Santvoort Bo , Hoogeman Mischa , Dirkx Maarten , Pos Floris J. , Janssen Tomas , Dekker Andre , Vanneste Ben , Minken Andre , Hoekstra Carel , Smeenk Robert J. , van Oort Inge M. , Bangma Chris H. , Incrocci Luca , Aben Katja K. H. 
Published: December 2021

PurposeExternal Beam Radiotherapy (EBRT) techniques dramatically changed over the years. This may have affected the risk of radiation-induced second primary cancers (SPC), due to increased irradiated low dose volumes and scatter radiation. We investigated whether patterns of SPC after EBRT have changed over the years in prostate cancer (PCa) survivors.Materials and MethodsPCa survivors diagnosed between 1990-2014 were selected from the Netherlands Cancer Registry. Patients treated with EBRT were divided in three time periods, representing 2-dimensional Radiotherapy (RT), 3-dimensional conformal RT (3D-CRT), and the advanced RT (AdvRT) era. Standardized incidence ratios (SIR) and absolute excess risks (AER) were calculated to estimate relative and excess absolute SPC risks. Sub-hazard ratios (sHRs) were calculated to compare SPC rates between the EBRT and prostatectomy cohort. SPCs were categorized by subsite and anatomic region.ResultsPCa survivors who received EBRT had an increased risk of developing a solid SPC (SIR=1.08; 1.05-1.11), especially in patients aged &lt;70 years (SIR=1.13; 1.09-1.16). Pelvic SPC risks were increased (SIR=1.28; 1.23-1.34), with no obvious differences between the three EBRT eras. Non-pelvic SPC were only significantly increased in the AdvRT era (SIR=1.08; 1.02-1.14), in particular for the 1-5 year follow-up period. Comparing the EBRT cohort to the prostatectomy cohort, again an increased pelvic SPC risk was found for all EBRT periods (sHRs= 1.61, 1.47-1.76). Increased non-pelvic SPC risks were present for all RT eras and highest for the AdvRT period (sHRs=1.17, 1.06-1.29).ConclusionSPC risk in patients with EBRT is increased and remained throughout the different EBRT eras. The risk of developing a SPC outside the pelvic area changed unfavorably in the AdvRT era. Prolonged follow-up is needed to confirm this observation. Whether this is associated with increased irradiated low-dose volumes and scatter, or other changes in clinical EBRT practice, is the subject of further research.
NFAT as a Biomarker and Therapeutic Target in Non–Small Cell Lung Cancer–Related Brain Metastasis
Authors: Peng Lu , Tao Yihao , Wu Rui , Su Jing , Sun Maoyuan , Cheng Yuan , Xie Zongyi , Mao Jinning , Zhan Xiaohui , Liu Guodong 
Published: December 2021

BackgroundBrain metastases (BMs) are associated with poor prognosis and significant mortality, and approximately 25% of patients with non–small cell lung cancer (NSCLC) develop BMs. The present study was aimed to understand the relationships between BM and NSCLC and reveal potential biomarkers and therapeutic targets in NSCLC-related BM.MethodsThe differentially expressed genes (DEGs) expressed during NSCLC and BM development were predicted by bioinformatics analysis, and the expression of the upstream transcription factor nuclear factor of activated T cells (NFAT) was confirmed as a differential gene expressed in both NSCLC and BM. In addition, the expression of proteins encoded by these DEGs was verified by immunohistochemical experiments examining normal lung tissue, lung cancer tissue, and brain metastasis tissue from 30 patients with NSCLC related BM.ResultsThe co-DEGs interleukin (IL)-11, cadherin 5 (CDH5) and C-C motif chemokine 2 (CCL2) link NSCLC and BM in the Gene Expression Omnibus (GEO) database, and NFAT may target the expression of these co-DEGs. In the GEO database, NFATc1 and NFATc3 were significantly downregulated in NSCLC tissues (P &lt;.05), whereas NFATc1, NFATc2, NFATc3, and NFATc4 were significantly downregulated in BMs (P &lt;.05). Consistent findings were observed in the immunohistochemical analysis.ConclusionNFATc1 and NFATc3 may play important roles in the occurrence of NSCLC and BM by regulating IL-11, CDH5, and CCL2.
Cost-Effectiveness Analysis of Camrelizumab vs. Placebo Added to Chemotherapy as First-Line Therapy for Advanced or Metastatic Esophageal Squamous Cell Carcinoma in China
Authors: Zhang Qilin , Wu Pan , He Xucheng , Ding Yufeng , Shu Yamin 
Published: December 2021

ObjectiveThe purpose of this cost-effectiveness analysis was to estimate the effects of adding camrelizumab to standard chemotherapy as the first-line treatment in patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC) on health and economic outcomes in China.MethodsA Markov model was developed to simulate the clinical course of typical patients with advanced or metastatic ESCC in the ESCORT-1st trial. Weibull survival model was employed to fit the Kaplan-Meier progression-free survival and overall survival probabilities of the camrelizumab-chemotherapy and placebo-chemotherapy strategy, respectively. Quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICER) were estimated over a 5-year lifetime horizon. Meanwhile, one-way and probabilistic sensitivity analyses were conducted to test the uncertainty in the model.ResultsOn baseline analysis, the incremental effectiveness and cost of camrelizumab-chemotherapy versus placebo-chemotherapy were 0.15 QALYs and $7,110.56, resulting in an ICER of $46,671.10/QALY, higher than the willingness-to-pay (WTP) threshold of China ($31,498.70/QALY). The results were sensitive to the utility of PFS and cost of camrelizumab.ConclusionThe findings from the present analysis suggest that the addition of camrelizumab to chemotherapy might not be cost-effective in patients with advanced or metastatic ESCC in China.
A Novel Scoring System for Response of Preoperative Chemoradiotherapy in Locally Advanced Rectal Cancer Using Early-Treatment Blood Features Derived From Machine Learning
Authors: Kim Jaesik , Sohn Kyung-Ah , Kwak Jung-Hak , Kim Min Jung , Ryoo Seung-Bum , Jeong Seung-Yong , Park Kyu Joo , Kang Hyun-Cheol , Chie Eui Kyu , Jung Sang-Hyuk , Kim Dokyoon , Park Ji Won 
Published: December 2021

BackgroundPreoperative chemoradiotherapy (CRT) is a standard treatment for locally advanced rectal cancer (LARC). However, individual responses to preoperative CRT vary from patient to patient. The aim of this study is to develop a scoring system for the response of preoperative CRT in LARC using blood features derived from machine learning.MethodsPatients who underwent total mesorectal excision after preoperative CRT were included in this study. The performance of machine learning models using blood features before CRT (pre-CRT) and from 1 to 2 weeks after CRT (early-CRT) was evaluated. Based on the best model, important features were selected. The scoring system was developed from the selected model and features. The performance of the new scoring system was compared with those of systemic inflammatory indicators: neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, and the prognostic nutritional index.ResultsThe models using early-CRT blood features had better performances than those using pre-CRT blood features. Based on the ridge regression model, which showed the best performance among the machine learning models (AUROC 0.6322 and AUPRC 0.5965), a novel scoring system for the response of preoperative CRT, named Response Prediction Score (RPS), was developed. The RPS system showed higher predictive power (AUROC 0.6747) than single blood features and systemic inflammatory indicators and stratified the tumor regression grade and overall downstaging clearly.ConclusionWe discovered that we can more accurately predict CRT response by using early-treatment blood data. With larger data, we can develop a more accurate and reliable indicator that can be used in real daily practices. In the future, we urge the collection of early-treatment blood data and pre-treatment blood data.
Increased Levels of Plasma Extracellular Heat-Shock Proteins 60 and 70 kDa Characterized Early-Onset Neonatal Sepsis
Authors: Canul-Euan Arturo Alejandro , Zúñiga-González Gibran , Palacios-Luna Janelly Estefania , Maida-Claros Rolando , Díaz Néstor Fabián , Saltigeral-Tigeral Patricia , Karina García-May Perla , Díaz-Ruiz Oscar , Flores-Herrera Héctor 
Published: December 2021

Background: Extracellular heat-shock proteins (eHsp) are highly conserved molecules that play an important role in inflammatory diseases and have been quantified in plasma from patients with infectious diseases, including sepsis. There is a constant search for dependable biochemical markers that, in combination with conventional methods, could deliver a prompt and reliable diagnosis of early-onset neonatal sepsis.Objective: We sought to assess the level of eHsp-27, eHsp-60, eHsp-70, and tumor necrosis factor-alpha (TNFα) in plasma of healthy neonates at term and infants with early-onset neonatal sepsis.Methods: This study included 34 newborns that were classified as healthy neonates at term (blood samples from the umbilical cord, n = 23) or infants with early-onset neonatal sepsis (blood samples obtained from umbilical artery by standard sterile procedures before starting a systemic antibiotic intervention, n = 11). All blood samples were centrifuged, and the plasma recovered to determine eHsp-27, eHsp-60, eHsp-70, and TNFα levels by ELISA.Results: Our results indicate that the level of eHsp-27 in healthy neonates at term was 0.045 ± 0.024 pg/ml. This value decreased 2.5-fold in infants with early-onset neonate sepsis (0.019 ± 0.006 pg/ml, p = 0.004). In contrast, the levels of eHsp-60 and eHsp-70 in healthy neonates at term were 13.69 ± 5.3 and 4.03 ± 2.6 pg/ml, respectively. These protein levels increased significantly 1.8- and 1.9-fold in the plasma of infants with early-onset neonatal sepsis (p ≤ 0.001). The level of TNFα in healthy neonates at term was 2.94 ± 0.46 pg/ml, with a 3.0-fold increase in infants with early-onset neonatal sepsis (8.96 ± 0.72 pm/ml, p ≤ 0.001). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of eHsp compared with that of C-reactive protein were 73.3, 60.0, 47.8, and 33.3%, respectively.Conclusion: This study demonstrated a consistent increase of eHsp-60 and eHsp-70 in the plasma of infants diagnosed with early-onset neonatal sepsis. These proteins showed higher sensitivity and specificity than C-reactive protein and blood culture test.
Colchicine Effectiveness and Safety in Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis
Authors: Welzel Tatjana , Ellinghaus Maren , Wildermuth Anna L. , Deschner Norbert , Benseler Susanne M. , Kuemmerle-Deschner Jasmin B. 
Published: December 2021

Introduction: Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) is the most common fever syndrome in childhood. High disease activity (DA) dramatically impacts the health-related quality of life. Thus, effective and safe treatment is crucial. Colchicine might be effective, but data are still lacking. Study aimed to assess colchicine safety and effectiveness in PFAPA.Methods: This single center study was conducted between 03/2012 and 05/2021 in PFAPA patients without variants in genetic panel testing aged ≤ 18 years fulfilling Marshall criteria and classification criteria of Gattorno et al. Exclusion criteria were elevated liver enzymes, impaired kidney function, celiac disease, lactose intolerance, previous/ongoing biologics, known colchicine-intolerance. Demographics, clinical characteristics, treatment, DA, colchicine effectiveness and safety were recorded at baseline, first and last visit. Colchicine was started at 0.5–1.0 mg/day. DA was captured by physician (PGA) and patient/parent (PPGA) global assessment on a 10 cm visual analog scale, categorized as mild (&lt;2), moderate (2–4), and high (≥5). Adverse event (AE) monitoring included gastrointestinal symptoms, liver enzyme/creatinine elevation, leukopenia, neutropenia. Primary outcome included response (R; composite of PPGA + PGA decrease ≥2) at last follow-up. Secondary outcomes were partial response (PR; PGA decrease = 1 + PPGA decrease ≥1), no response (NR; unchanged/worsened PGA/PPGA), colchicine safety, flare characteristics.Results: Twenty-seven PFAPA patients were included, 52% were female, median age was 5.8 years (1–10.75), median follow-up time was 13 months. At baseline, median PPGA was high; median PGA moderate. All patients had febrile flares. Median flare frequency was every 4–5 weeks; median duration 5–6 days. Nine patients were pre-treated with corticosteroids, increasing flare frequency in 8/9. Primary Outcome: 17 patients (63%) were responders. Secondary outcomes: PR was achieved in 15%; NR in 22% at last follow-up. DA decreased significantly (p &lt;0.0001). At last follow-up, 52% reported no flares, median flare duration decreased to 1–2 days. At first follow-up, 22% reported mild abdominal pain/diarrhea. Moderate abdominal pain/diarrhea occurred with ≥1 mg/day. Mild asymptomatic liver enzyme elevation or leucopenia were rare; no severe AE or colchicine discontinuation were observed.Conclusion: Colchicine seems to be safe, well-tolerated, and effective in PFAPA patients. It can be considered in children with moderate/high DA even those without corticosteroid-benefit.
Early Vascular Aging in Children With Tuberous Sclerosis Complex
Authors: Skrzypczyk Piotr , Wabik Anna Maria , Szyszka Michał , Józwiak Sergiusz , Bombiński Przemysław , Jakimów-Kostrzewa Aleksandra , Brzewski Michał , Pańczyk-Tomaszewska Małgorzata 
Published: December 2021

Objectives: Experimental data indicate that activating mutations in the mTOR (mammalian target of rapamycin) pathway may lead to abnormal arterial wall structure. Vascular anomalies like arterial stenoses are reported in pediatric patients with tuberous sclerosis complex (TSC). In addition, large renal lesions (angiomyolipoma—AML and cysts) are risk factors for arterial hypertension in adult patients with TSC. This study aimed to assess blood pressure, including central blood pressure and arterial damage (early vascular aging—EVA) in children with TSC.Materials and Methods: In a group of 33 pediatric patients with TSC (11.13 ± 4.03 years, 15 boys, 18 girls), we evaluated peripheral and central office blood pressure, 24-h ambulatory blood pressure, and arterial damage: aortic pulse wave velocity (aPWV) [m/s], [Z-score], augmentation index (AIx75HR [%]), common carotid artery intima-media thickness (cIMT) [mm], [Z-score], stiffness of common carotid artery (E-tracking), renal lesions in magnetic resonance and ultrasonography, and selected biochemical parameters. The control group consisted of 33 healthy children (11.23 ± 3.28 years, 15 boys, 18 girls).Results: In TSC group 7 (21.2%) children had arterial hypertension, 27 (81.8%) children had renal angiomyolipomas, 26 (78.8%)—renal cysts, and 4 (12.1%) patients were treated with mTOR inhibitors (2 patients with everolimus and 2 patients with sirolimus) at the moment of evaluation. Children with TSC had higher central systolic blood pressure (AoSBP) (98.63 ± 9.65 vs. 90.45 ± 6.87 [mm Hg], p &lt; 0.001), cIMT (0.42 ± 0.05 vs. 0.39 ± 0.03 [mm], p = 0.011), cIMT Z-score (0.81 ± 1.21 vs. 0.16 ± 0.57, p = 0.007), aPWV (4.78 ± 0.81 vs. 4.25 ± 0.56 [m/s], p = 0.003) and aPWV Z-score (−0.14 ± 1.15 vs. −0.96 ± 0.87, p = 0.002) compared to healthy children, without differences in AIx75HR (8.71 ± 15.90 vs. 5.24 ± 11.12 [%], p = 0.319) and stiffness of common carotid artery. In children with TSC AoSBP correlated positively with serum cystatin C concentration (r = 0.377, p = 0.030) and with maximum diameter of renal cyst (R = 0.419, p = 0.033); mean arterial pressure (MAP) 24 h Z-score correlated with serum cystatin C concentration (R = 0.433, p = 0.013); and aPWV Z-score with daily urinary albumin loss [mg/24 h] (R = 0.412, p = 0.029).Conclusions: Children with tuberous sclerosis complex are at risk of elevated central blood pressure and early vascular aging. In children with TSC, blood pressure and arterial stiffness are related to renal involvement.
Morphological Analysis of Nose in Patients of Tessier No. 0 Cleft With a Bifid Nose in China
Authors: Wang Xin , Wang Huan , You Jianjun , Zheng Ruobing , Xu Yihao , Zhang Xulong , Guo Junsheng , Fan Fei 
Published: December 2021

Objective: Facial cleft involves complex malformations. No study assessed the facial deformity of Tessier No. 0 cleft with a bifid nose. Thus, we used anthropometric measurements to access the nose in patients.Methods: A total of 24 bifid nose deformities underwent surgery at our institution between 2010 and 2019. Standardized photographs were taken preoperatively and postoperatively. Landmarks were identified on these images; measurements for nasal analysis were performed and compared with the established Chinese norms. Surgical method differences were also analyzed.Results: The median follow-up time was 2.51 years. Postoperatively, there is a significant difference in comparison with preoperative in the nasal index, medial canthus and nose width index, nasolabial angle, nasofacial angle, ala length and nasal bridge length index, nasal tip protrusion and nasal width index, and nasal width and ala length index. Furthermore, the medial canthus and nose width index, and nasal width and ala length index were significantly larger in ordinary people, while ala length and nasal bridge length index and nasal tip protrusion and nasal width index were smaller. After surgery, most angles and index were standard except the nasolabial angle in the females, and ala length and nasal bridge length index in the males. Moreover, as for the group of costal cartilage transplantation, most index and angles have improved after surgery including nasolabial angle, nasofacial angle, ala length and nasal bridge length index, nasal tip protrusion and nasal width index, and nasal width and ala length index. However, only nasal tip protrusion and nasal width index, columella length and nasal tip protrusion index, and nasal width and ala length index in the silicone prosthesis group implantation has significance. Costal cartilage transplantation can also better improve ala length and nasal bridge length index than the silicone prosthesis implantation.Conclusion: Most defects can be repaired with surgery, but the outcome has a lack of evaluation. Thus, anthropometric assessment can serve as a material for nasal and reconstructive surgery.
A Case Report and Literature Review of a Novel Mutation in the MAGED2 Gene of a Patient With Severe Transient Polyhydramnios
Authors: Wu Xiaoxia , Huang Le , Luo Caiqun , Liu Yang , Niu Jianmin 
Published: December 2021

Background: Polyhydramnios occurs frequently during pregnancy. Mutations in the MAGED2 gene can cause X-linked acute early-onset polyhydramnios with a severe but transient form of antenatal Bartter's syndrome.Case Presentation: Here, we report a new novel frameshift mutation c.733_734delCT (p. Leu245GlufsTer4) in the MAGED2 gene (NM_177433.1) that caused prenatal polyhydramnios, but did not cause polyuria after birth. Follow-up was conducted for 2 months, and the baby's growth and development were normal, without polyuria and renal impairment. In addition, we identified all individuals with MAGED2 mutations reported in the literature before March 2021.Conclusion: We report a new case with a novel variant of the MAGED2 gene that caused severe hydramnios but with a good result and summary clinical characteristics in a newborn with antenatal Bartter's syndrome caused by an MAGED2 mutation. Good prenatal diagnosis and genetic consultation can improve pregnancy monitoring and newborn management.
Growth Hormone Secretagogue Receptor 1A Antagonist JMV2959 Effectively Prevents Morphine Memory Reconsolidation and Relapse
Authors: Zhao Jing , Du Xinyu , Chen Mingzhu , Zhu Shimin 
Published: December 2021

Relapse to drug seeking after prolonged abstinence is a major problem in the clinical treatment of drug addiction. The use of pharmacological interventions to disrupt established drug reward memories is a promising strategy for the treatment of drug addiction. A growth hormone secretagogue receptor 1 A antagonist, JMV2959, has been shown to reduce morphine-induced conditioned place preference (CPP) in rats within hours of intervention; thus, JMV2959 is a potential candidate for drug addiction treatment. However, the effect of JMV2959 on reconsolidation to disrupt drug seeking remains unknown. In this study, we assessed the effect of JMV2959 on morphine induced memory reconsolidation to inhibit drug seeking after drug withdrawal. Our results showed that the administration of JMV2959 (6 mg/kg) significantly reduced environmental cue induced CPP, which suggested a preventive effect of JMV2959 on morphine induced memory reconsolidation. Additionally, JMV2959 administration significantly altered the locomotor activity and food and water intake but did not significantly alter the natural reward preference. We concluded that JMV2959 may be an effective candidate to treat drug addiction.