bluuebunny/crossref_metadata_2025_split huggingface dataset:
Risk factors and predictive model for recurrence in papillary thyroid carcinoma: a single-center retrospective cohort study based on 955 cases
Authors: Li Yin , Tian Jiahe , Jiang Ke , Wang Zhongyu , Gao Songbo , Wei Keyang , Yang Ankui , Li Qiuli 
Published: September 2023

BackgroundThe 2015 American Thyroid Association guidelines proposed recurrence risk stratification of differentiated thyroid carcinoma, including papillary thyroid carcinoma (PTC), but this stratification excluded non–initial treatment patients with worse outcomes. This study aimed to explore the potential risk factors for recurrence in PTC and develop a predictive model for both initial and non–initial treatment of patients with PTC.MethodsA total of 955 patients were included in this study. Differences between the recurrence (−) and recurrence (+) groups were compared. The 955 patients were randomized into two groups: the training group (671 cases) and the validation group (284 cases). All variables were selected using the LASSO regression analysis. A nomogram was developed based on the results of the univariate and multivariate logistic regression analyses. The nomogram performance was evaluated using discrimination and calibration.ResultsPatients aged ≥55 years, extranodal extension (ENE), metastatic LN ratio (LNR) &gt;0.5, and non–initial treatment were identified as potential risk factors for recurrence through LASSO regression and univariate and multivariate analyses. The receiver operating characteristic curve (ROC curve) showed high efficiency, with an area under the ROC curve (AUC) of 0.819 (95% confidence interval [CI], 0.729–0.909) and 0.818 (95% CI, 0.670–0.909) in the training and validation groups, respectively. The calibration curve indicated that the nomogram had a good consistency.ConclusionIn patients with PTC, age ≥55 years, ENE, LNR &gt;0.5, and non–initial treatment are potential risk factors for recurrence. The predictive model of recurrence was confirmed to be a practical and convenient tool for clinicians to accurately predict PTC recurrence.
Implications of climate change on surface temperature in North Indian states: evidence from CMIP6 model ensembles
Authors: Awasthi Amit , Pattnayak Kanhu Charan , Tandon Aayushi , Sarkar Abhijit , Chakraborty Monojit 
Published: September 2023

Introduction: The significant impact of climate change on temperature is an important topic of discussion as it rises globally. Hence, the present study is designed to investigate the profound influence of climate change on temperature by considering the North Indian States.Methods: In this comprehensive case study, CMIP6 models are used to investigate temperature behaviour in the states of North India under 1.5°C and 2°C warming scenarios. Comparisons are made between observed surface temperature data from the Climatic Research Unit (CRU) and ensemble mean simulations from CMIP6.Results and Discussion: Results indicate that CMIP6 ensemble mean simulations effectively depict observed climatological patterns of surface temperature with negligible discrepancies. Under both the 1.5°C and 2°C warming scenarios, extreme temperatures show an increase compared to the preindustrial and present periods, suggesting an elevated risk of future severe heat events. Temperature changes relative to the preindustrial period are around 1.5°C, 3°C, and 4.5°C for the present, 1.5°C, and 2°C scenarios, respectively. Return period analysis shows a significant temperature rise of approximately 4.5° over a return time of 60 years. These findings highlight the importance of climate models, valuable for impact studies, and emphasize the need to accurately enhance future model iterations’ precision in simulating regional climates. Urgent climate change mitigation strategies are vital to curb temperature rise and mitigate potential adverse impacts on the region.Conclusion: The study provides critical insights into North India’s climate behavior, underscoring the significance of proactive measures to effectively address climate change challenges within the region.
Prospect of genetic disorders in Saudi Arabia
Authors: Alqahtani Amerh S. , Alotibi Raniah S. , Aloraini Taghrid , Almsned Fahad , Alassali Yara , Alfares Ahmed , Alhaddad Bader , Al Eissa Mariam M. 
Published: September 2023

Introduction: Rare diseases (RDs) create a massive burden for governments and families because sufferers of these diseases are required to undergo long-term treatment or rehabilitation to maintain a normal life. In Saudi Arabia (SA), the prevalence of RDs is high as a result of cultural and socio-economic factors. This study, however, aims to shed light on the genetic component of the prevalence of RDs in SA.Methodology: A retrospective study was conducted between September 2020 and December 2021 at King Saud Medical City, a tertiary hospital of the Ministry of Health (MOH), SA. A total of 1080 individuals with 544 potentially relevant variants were included. The index was 738, and the samples were tested in a commercialized laboratory using different molecular techniques, including next-generation sequencing.Result: A total of 867 molecular genetics tests were conducted on 738 probands. These tests included 610 exome sequencing (ES) tests, four genome sequencing (GS) tests, 82 molecular panels, 106 single nucleotide polymorphism (SNP) array, four methylation studies, 58 single-gene studies and three mitochondrial genome sequencing tests. The diagnostic yield among molecular genetics studies was 41.8% in ES, 24% in panels, 12% in SNP array and 24% in single gene studies. The majority of the identified potential variants (68%) were single nucleotide variants (SNV). Other ascertained variants included frameshift (11%), deletion (10%), duplication (5%), splicing (9%), in-frame deletion (3%) and indels (1%). The rate of positive consanguinity was 56%, and the autosomal recessive accounted for 54%. We found a significant correlation between the ES detection rate and positive consanguinity. We illustrated the presence of rare treatable conditions in DNAJC12, SLC19A3, and ALDH7A1, and the presence of the founder effect variant in SKIC2. Neurodevelopmental disorders were the main phenotype for which genetics studies were required (35.7%).Conclusion: This is the sixth-largest local study reporting next-generation sequencing. The results indicate the influence of consanguineous marriages on genetic disease and the burden it causes for the Kingdom of SA. This study highlights the need to enrich our society’s knowledge of genetic disorders. We recommend utilising ES as a first-tier test to establish genetic diagnosis in a highly consanguineous population.
TRAIL promotes the polarization of human macrophages toward a proinflammatory M1 phenotype and is associated with increased survival in cancer patients with high tumor macrophage content
Authors: Gunalp Sinem , Helvaci Derya Goksu , Oner Aysenur , Bursalı Ahmet , Conforte Alessandra , Güner Hüseyin , Karakülah Gökhan , Szegezdi Eva , Sag Duygu 
Published: September 2023

BackgroundTNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily that can either induce cell death or activate survival pathways after binding to death receptors (DRs) DR4 or DR5. TRAIL is investigated as a therapeutic agent in clinical trials due to its selective toxicity to transformed cells. Macrophages can be polarized into pro-inflammatory/tumor-fighting M1 macrophages or anti-inflammatory/tumor-supportive M2 macrophages and an imbalance between M1 and M2 macrophages can promote diseases. Therefore, identifying modulators that regulate macrophage polarization is important to design effective macrophage-targeted immunotherapies. The impact of TRAIL on macrophage polarization is not known.MethodsPrimary human monocyte-derived macrophages were pre-treated with either TRAIL or with DR4 or DR5-specific ligands and then polarized into M1, M2a, or M2c phenotypes in vitro. The expression of M1 and M2 markers in macrophage subtypes was analyzed by RNA sequencing, qPCR, ELISA, and flow cytometry. Furthermore, the cytotoxicity of the macrophages against U937 AML tumor targets was assessed by flow cytometry. TCGA datasets were also analyzed to correlate TRAIL with M1/M2 markers, and the overall survival of cancer patients.ResultsTRAIL increased the expression of M1 markers at both mRNA and protein levels while decreasing the expression of M2 markers at the mRNA level in human macrophages. TRAIL also shifted M2 macrophages towards an M1 phenotype. Our data showed that both DR4 and DR5 death receptors play a role in macrophage polarization. Furthermore, TRAIL enhanced the cytotoxicity of macrophages against the AML cancer cells in vitro. Finally, TRAIL expression was positively correlated with increased expression of M1 markers in the tumors from ovarian and sarcoma cancer patients and longer overall survival in cases with high, but not low, tumor macrophage content.ConclusionsTRAIL promotes the polarization of human macrophages toward a proinflammatory M1 phenotype via both DR4 and DR5. Our study defines TRAIL as a new regulator of macrophage polarization and suggests that targeting DRs can enhance the anti-tumorigenic response of macrophages in the tumor microenvironment by increasing M1 polarization.
The interplay between neoantigens and immune cells in sarcomas treated with checkpoint inhibition
Authors: Anzar Irantzu , Malone Brandon , Samarakoon Pubudu , Vardaxis Ioannis , Simovski Boris , Fontenelle Hugues , Meza-Zepeda Leonardo A. , Stratford Richard , Keung Emily Z. , Burgess Melissa , Tawbi Hussein A. , Myklebost Ola , Clancy Trevor 
Published: September 2023

IntroductionSarcomas are comprised of diverse bone and connective tissue tumors with few effective therapeutic options for locally advanced unresectable and/or metastatic disease. Recent advances in immunotherapy, in particular immune checkpoint inhibition (ICI), have shown promising outcomes in several cancer indications. Unfortunately, ICI therapy has provided only modest clinical responses and seems moderately effective in a subset of the diverse subtypes.MethodsTo explore the immune parameters governing ICI therapy resistance or immune escape, we performed whole exome sequencing (WES) on tumors and their matched normal blood, in addition to RNA-seq from tumors of 31 sarcoma patients treated with pembrolizumab. We used advanced computational methods to investigate key immune properties, such as neoantigens and immune cell composition in the tumor microenvironment (TME).ResultsA multifactorial analysis suggested that expression of high quality neoantigens in the context of specific immune cells in the TME are key prognostic markers of progression-free survival (PFS). The presence of several types of immune cells, including T cells, B cells and macrophages, in the TME were associated with improved PFS. Importantly, we also found the presence of both CD8+ T cells and neoantigens together was associated with improved survival compared to the presence of CD8+ T cells or neoantigens alone. Interestingly, this trend was not identified with the combined presence of CD8+ T cells and TMB; suggesting that a combined CD8+ T cell and neoantigen effect on PFS was important.DiscussionThe outcome of this study may inform future trials that may lead to improved outcomes for sarcoma patients treated with ICI.
Non-classical HLA-E restricted CMV 15-mer peptides are recognized by adaptive NK cells and induce memory responses
Authors: Martín Almazán Nerea , Sala Benedetta Maria , Sandalova Tatyana , Sun Yizhe , Resink Tom , Cichocki Frank , Söderberg-Nauclér Cecilia , Miller Jeffrey S. , Achour Adnane , Sarhan Dhifaf 
Published: September 2023

IntroductionHuman cytomegalovirus (HCMV) reactivation causes complications in immunocompromised patients after hematopoietic stem cell transplantation (HSCT), significantly increasing morbidity and mortality. Adaptive Natural Killer (aNK) cells undergo a persistent reconfiguration in response to HCMV reactivation; however, the exact role of aNK cell memory in HCMV surveillance remains elusive.MethodsWe employed mass spectrometry and computational prediction approaches to identify HLA-E-restricted HCMV peptides that can elucidate aNK cell responses. We also used the K562 cell line transfected with HLA-E0*0103 for specific peptide binding and blocking assays. Subsequently, NK cells were cocultured with dendritic cells (DCs) loaded with each of the identified peptides to examine aNK and conventional (c)NK cell responses.ResultsHere, we discovered three unconventional HLA-E-restricted 15-mer peptides (SEVENVSVNVHNPTG, TSGSDSDEELVTTER, and DSDEELVTTERKTPR) derived from the HCMV pp65-protein that elicit aNK cell memory responses restricted to HCMV. aNK cells displayed memory responses towards HMCV-infected cells and HCMV-seropositive individuals when primed by DCs loaded with each of these peptides and predicted 9-mer versions. Blocking the interaction between HLA-E and the activation NKG2C receptor but not the inhibitory NKG2A receptor abolished these specific recall responses. Interestingly, compared to the HLA-E complex with the leader peptide VMAPRTLIL, HLA-E complexes formed with each of the three identified peptides significantly changed the surface electrostatic potential to highly negative. Furthermore, these peptides do not comprise the classical HLA-E-restriction motifs.DiscussionThese findings suggest a differential binding to NKG2C compared to HLA-E complexes with classical leader peptides that may result in the specific activation of aNK cells. We then designed six nonameric peptides based on the three discovered peptides that could elicit aNK cell memory responses to HCMV necessary for therapeutic inventions. The results provide novel insights into HLA-E-mediated signaling networks that mediate aNK cell recall responses and maximize their reactivity.
A comprehensive pan-cancer analysis of CDH5 in immunological response
Authors: Li Yuantao , Wu Qikai , Lv Jiancheng , Gu Junwei 
Published: September 2023

BackgroundCadherin 5 (CDH5) functions critically in maintaining cell adhesion and integrity of endothelial and vascular cells. The expression of CDH5 is abnormal in tumor cells, which may have great potential to serve as a new immune checkpoint. The current pan-cancer analysis was performed to better understand the role of CDH5 in tumor.MethodsThe clinical significance and immunological function of CDH5 in pan-cancers were comprehensively analyzed based on the correlations between CDH5 and clinicopathologic features, prognosis values, tumor mutation burden (TMB), microsatellite instability (MSI), immune cells infiltration and immune response genes using 33 datasets from The Cancer Genome Atlas (TCGA). We further confirmed the expression of CDH5 in bladder cancer (BCa) tissues and cell lines. The CD8+ T cells were screened from peripheral blood of healthy controls and activated. BCa cell-CD8+ T cell co-culture assay and ELISA assay were carried out to verify the immunological function of CDH5.ResultsThe expression of CDH5 was down-regulated in 8 types of tumors including in BCa but up-regulated in 4 types of tumors. CDH5 was significantly correlated with tumor stage in 6 types of tumors. In addition, CDH5 was positively or negatively correlated with tumor prognosis. Furthermore, CDH5 was closely associated with TMB in 15 types of tumors and with MSI in 9 types of tumors. KEGG-GSEA and Hallmarks-GSEA analyses results indicated that CDH5 was positively related to immune response in most tumor types. In many tumors, CDH5 showed a positive correlation with immune cell infiltration. Enrichment analyses demonstrated that CDH5 was significantly related to the expression of many immunomodulators and chemokines. Further experiments showed that CDH5 was low-expressed in BCa tissues and cell lines in comparison to adjacent normal tissues and normal urothelial cell line, but it was positively associated with a better prognosis of BCa patients. The results of in vitro co-culture assay and ELISA assay demonstrated that CDH5 could promote the function of CD8+ T cells in TME of BCa.ConclusionIn summary, CDH5 was positively associated with a favorable prognosis and effective immune response in tumors, showing a great potential to serve as a novel tumor biomarker and immune checkpoint.
Immune monitoring of SARS-CoV-2-specific T cell and B cell responses in patients with multiple sclerosis treated with ocrelizumab
Authors: Groß-Albenhausen Elina , Weier Alicia , Velten Markus , Heider Thorsten , Chunder Rittika , Kuerten Stefanie 
Published: September 2023

IntroductionSince the development of the coronavirus disease (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), there has been significant interest in determining the effectiveness of SARS-CoV-2 vaccines in patients under immunomodulatory or immunosuppressive therapies. The aim of this study was to evaluate the impact of ocrelizumab, a monoclonal anti-CD20 antibody, on SARS-CoV-2-specific T cell and B cell responses in patients with relapsing-remitting multiple sclerosis (RRMS).MethodsTo this end, peripheral blood mononuclear cells (PBMCs) were isolated from n = 23 patients with RRMS. Of these patients, n = 17 were tested before (time point t0) and one month after (time point t1) their first dose of ocrelizumab. In addition, we studied n = 9 RRMS patients that got infected with SARS-CoV-2 over the course of ocrelizumab therapy (time point t2). PBMCs were also isolated from n = 19 age- and gender-matched healthy controls (HCs) after vaccination or infection with SARS-CoV-2, respectively. Interferon-γ (IFN-γ)/interleukin-2 (IL-2) and granzyme B (GzB)/perforin (PFN) double-color enzyme-linked immunospot (ELISPOT) assays or single-color ELISPOT assays were performed to measure SARS-CoV-2 antigen-specific T cell and B cell responses. Anti-viral antibody titers were quantified in the serum by chemiluminescence immunoassay.ResultsOur data indicate a significant difference in the SARS-CoV-2 specific IFN-γ (P = 0.0119) and PFN (P = 0.0005) secreting T cell compartment in the MS cohort at t0 compared to HCs. Following the first dose of ocrelizumab treatment, a significant decrease in the number of SARS-CoV-2 spike protein-specific B cells was observed (P = 0.0012). Infection with SARS-CoV-2 in MS patients under ocrelizumab therapy did not significantly alter their existing immune response against the virus. Kaplan-Meier survival analysis suggested that the spike S1 protein-specific immunoglobulin (Ig)G response might be a key parameter for predicting the probability of (re)infection with SARS-CoV-2.DiscussionOur results call for a critical discussion regarding appropriate vaccination intervals and potential biomarkers for the prediction of (re)infection with SARS-CoV-2 in patients with MS receiving ocrelizumab.Unique identifierDRKS00029110; URL: http://apps.who.int/trialsearch/.
Modulation of intestinal IL-37 expression and its impact on the epithelial innate immune response and barrier integrity
Authors: Kröhn Laura , Azabdaftari Aline , Heuberger Julian , Hudert Christian , Zilbauer Matthias , Breiderhoff Tilman , Bufler Philip 
Published: September 2023

Background and AimsIntestinal epithelial cells separate the luminal flora from lamina propria immune cells and regulate innate immune responses in the gut. An imbalance of the mucosal immune response and disrupted intestinal barrier integrity contribute to the evolution of inflammatory bowel diseases. Interleukin (IL)-37 has broad anti- inflammatory activity and is expressed by the human intestinal epithelium. Mice ectopically expressing human IL-37 show reduced epithelial damage and inflammation after DSS-induced colitis. Here, we investigated the impact of IL-37 on the innate immune response and tight junction protein expression of mouse intestinal organoids and the modulation of IL37 expression in human intestinal organoids.MethodsMurine intestinal organoids were generated from IL-37tg and wildtype mice. Human ileal organoids were generated from healthy young donors.ResultsExpression of transgene IL-37 or recombinant IL-37 protein did not significantly reduce overall proinflammatory cytokine mRNA expression in murine intestinal organoids. However, higher IL37 expression correlated with a reduced proinflammatory cytokine response in murine colonic organoids. IL37 mRNA expression in human ileal organoids was modulated by proinflammatory cytokines showing an increased expression upon TNF-α-stimulation and decreased expression upon IFN-gamma stimulation. Transgene IL-37 expression did not rescue TNF-α-induced changes in morphology as well as ZO-1, occludin, claudin-2, and E-cadherin expression patterns of murine jejunal organoids.ConclusionsWe speculate that the anti-inflammatory activity of IL-37 in the intestine is mainly mediated by lamina propria immune cells protecting intestinal epithelial integrity.
Etiologic characteristics revealed by mNGS-mediated ultra-early and early microbiological identification in airway secretions from lung transplant recipients
Authors: Zhang Xiaoqin , Tang Xuemei , Yi Xiaoli , Lei Yu , Lu Sen , Li Tianlong , Yue Ruiming , Pan Lingai , Feng Gang , Huang Xiaobo , Wang Yiping , Cheng Deyun 
Published: September 2023

BackgroundPost-operative etiological studies are critical for infection prevention in lung transplant recipients within the first year. In this study, mNGS combined with microbial culture was applied to reveal the etiological characteristics within one week (ultra-early) and one month (early) in lung transplant recipients, and the epidemiology of infection occurred within one month.MethodsIn 38 lung transplant recipients, deep airway secretions were collected through bronchofiberscope within two hours after the operation and were subjected to microbial identification by mNGS and microbial culture. The etiologic characteristics of lung transplant recipients were explored. Within one month, the infection status of recipients was monitored. The microbial species detected by mNGS were compared with the etiological agents causing infection within one month.ResultsThe detection rate of mNGS in the 38 airway secretions specimens was significantly higher than that of the microbial culture (P&lt;0.0001). MNGS identified 143 kinds of pathogenic microorganisms; bacterial pathogens account for more than half (72.73%), with gram-positive and -negative bacteria occupying large proportions. Fungi such as Candida are also frequently detected. 5 (50%) microbial species identified by microbial culture had multiple drug resistance (MDR). Within one month, 26 (68.42%) recipients got infected (with a median time of 9 days), among which 10 (38.46%) cases were infected within one week. In the infected recipients, causative agents were detected in advance by mNGS in 9 (34.62%) cases, and most of them (6, 66.67%) were infected within one week (ultra-early). In the infection that occurred after one week, the consistency between mNGS results and the etiological agents was decreased.ConclusionBased on the mNGS-reported pathogens in airway secretions samples collected within two hours, the initial empirical anti-infection regimes covering the bacteria and fungi are reasonable. The existence of bacteria with MDR forecasts the high risk of infection within 48 hours after transplant, reminding us of the necessity to adjust the antimicrobial strategy. The predictive role of mNGS performed within two hours in etiological agents is time-limited, suggesting continuous pathogenic identification is needed after lung transplant.