bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single-cell protein activity analysis reveals a novel subpopulation of chondrocytes and the corresponding key master regulator proteins associated with anti-senescence and OA progression
Authors: Guang Zhao , Min Zhang , Jun-Tan Li , Tian-Xu Dou , Xiang Gao 
Published: March 2023

BackgroundOsteoarthritis (OA) is a prevalent senescence-related disease with substantial joint pain, loss of joint function, and cartilage degeneration. Because of the paucity of single-cell studies of OA and the gene dropout problem of single-cell RNA sequencing, it is difficult to acquire an in-depth understanding of the molecular characteristics of various chondrocyte clusters.MethodsHere, we aimed to provide new insights into chondrocyte senescence and a rationale for the development of effective intervention strategies for OA by using published single-cell RNA-sequencing data sets and the metaVIPER algorithm (Virtual Inference of Protein activity by Enriched Regulon). This algorithm was employed to present a proteome catalog of 62,449 chondrocytes from the cartilage of healthy individuals and OA patients at single-cell resolution. Furthermore, histopathologic analysis was carried out in cartilage samples from clinical patients and experimental mouse models of OA to validate above results.ResultsWe identified 16 protein-activity-based chondrocyte clusters as well as the underlying master regulators in each cluster. By assessing the enrichment score of each cluster in bulk RNA-sequencing data, followed by gene-set variation analysis, we preliminarily identified a novel subpopulation of chondrocytes (cluster 3). This clinically relevant cluster was predicted to be the main chondrocyte cluster responsible for maintaining cellular homeostasis and anti-senescence. Specifically, we uncovered a set of the key leading-edge proteins of cluster 3 by validating the robustness of the above results using another human chondrocyte single-cell RNA-sequencing data set, consisting of 24,675 chondrocytes. Furthermore, cartilage samples from clinical patients and experimental mouse models of OA were used to evaluate the expression patterns of these leading-edge proteins, and the results indicated that NDRG2, TSPYL2, JMJD6 and HMGB2 are closely associated with OA pathogenesis and might play critical roles in modulating cellular homeostasis and anti-senescence in chondrocytes.ConclusionOur study revealed a novel subpopulation of chondrocytes that are critical for anti-progression of OA and the corresponding master regulator proteins, which might serve as therapeutic targets in OA.
Genetic deletion of HVEM in a leukemia B cell line promotes a preferential increase of PD-1- stem cell-like T cells over PD-1+ T cells curbing tumor progression
Authors: del Rio Maria-Luisa , de Juan Carla Yago-Diez , Roncador Giovanna , Caleiras Eduardo , Álvarez-Esteban Ramón , Pérez-Simón José Antonio , Rodriguez-Barbosa Jose-Ignacio 
Published: March 2023

IntroductionA high frequency of mutations affecting the gene encoding Herpes Virus Entry Mediator (HVEM, TNFRSF14) is a common clinical finding in a wide variety of human tumors, including those of hematological origin.MethodsWe have addressed how HVEM expression on A20 leukemia cells influences tumor survival and its involvement in the modulation of the anti-tumor immune responses in a parental into F1 mouse tumor model of hybrid resistance by knocking-out HVEM expression. HVEM WT or HVEM KO leukemia cells were then injected intravenously into semiallogeneic F1 recipients and the extent of tumor dissemination was evaluated.ResultsThe loss of HVEM expression on A20 leukemia cells led to a significant increase of lymphoid and myeloid tumor cell infiltration curbing tumor progression. NK cells and to a lesser extent NKT cells and monocytes were the predominant innate populations contributing to the global increase of immune infiltrates in HVEM KO tumors compared to that present in HVEM KO tumors. In the overall increase of the adaptive T cell immune infiltrates, the stem cell-like PD-1- T cells progenitors and the effector T cell populations derived from them were more prominently present than terminally differentiated PD-1+ T cells.ConclusionsThese results suggest that the PD-1- T cell subpopulation is likely to be a more relevant contributor to tumor rejection than the PD-1+ T cell subpopulation. These findings highlight the role of co-inhibitory signals delivered by HVEM upon engagement of BTLA on T cells and NK cells, placing HVEM/BTLA interaction in the spotlight as a novel immune checkpoint for the reinforcement of the anti-tumor responses in malignancies of hematopoietic origin.
Combined therapy with methotrexate nanoconjugate and dendritic cells with downregulated IL-10R expression modulates the tumor microenvironment and enhances the systemic anti-tumor immune response in MC38 murine colon carcinoma
Authors: Szczygieł Agnieszka , Węgierek-Ciura Katarzyna , Wróblewska Anna , Mierzejewska Jagoda , Rossowska Joanna , Szermer-Olearnik Bożena , Świtalska Marta , Anger-Góra Natalia , Goszczyński Tomasz M. , Pajtasz-Piasecka Elżbieta 
Published: March 2023

BackgroundUnderstanding the negative impact of the tumor microenvironment on the creation of an effective immune response has contributed to the development of new therapeutic anti-cancer strategies. One such solution is combined therapy consisting of chemotherapeutic administration followed by dendritic cell (DC)-based vaccines. The use of cytostatic leads to the elimination of cancer cells, but can also modulate the tumor milieu. Moreover, great efforts are being made to increase the therapeutic outcome of immunotherapy, e.g. by enhancing the ability of DCs to generate an efficient immune response, even in the presence of immunosuppressive cytokines such as IL-10. The study aimed to determine the effectiveness of combined therapy with chemotherapeutic with immunomodulatory potential – HES-MTX nanoconjugate (composed of methotrexate (MTX) and hydroxyethyl starch (HES)) and DCs with downregulated expression of IL-10 receptor stimulated with tumor antigens (DC/shIL-10R/TAg) applied in MC38 murine colon carcinoma model.MethodsWith the use of lentiviral vectors the DCs with decreased expression of IL-10R were obtained and characterized. During in vivo studies MC38-tumor bearing mice received MTX or HES-MTX nanoconjugate as a sole treatment or combined with DC-based immunotherapy containing unmodified DCs or DCs transduced with shRNA against IL-10R (or control shRNA sequence). Tumor volume was monitored during the experiment. One week after the last injection of DC-based vaccines, tumor nodules and spleens were dissected for ex vivo analysis. The changes in the local and systemic anti-tumor immune response were estimated with the use of flow cytometry and ELISA methods.Results and conclusionsIn vitro studies showed that the downregulation of IL-10R expression in DCs enhances their ability to activate the specific anti-tumor immune response. The use of HES-MTX nanoconjugate and DC/shIL-10R/TAg in the therapy of MC38-tumor bearing mice resulted in the greatest tumor growth inhibition. At the local anti-tumor immune response level a decrease in the infiltration of cells with suppressor activity and an increase in the influx of effector cells into MC38 tumor tissue was observed. These changes were crucial to enhance the effective specific immune response at the systemic level, which was revealed in the greatest cytotoxic activity of spleen cells against MC38 cells.
Precision (repeatability and reproducibility) of papillary and peripapillary vascular density measurements using optical coherence tomography angiography in children
Authors: Chen Ruru , Liu Xinyu , Yao Mingyu , Zou Zhilin , Chen Xinyi , Li Zheng , Chen Xin , Su Mengjuan , Lian Hengli , Lu Weiwei , Yang Yizhou , McAlinden Colm , Wang Qinmei , Chen Shihao , Huang Jinhai 
Published: March 2023

ImportanceOptical coherence tomography angiography (OCTA) has been widely applied into children, however, few studies have assessed the repeatability and reproducibility of papillary and peripapillary VD in healthy children.ObjectiveTo assess the precision of papillary and peripapillary vascular density (VD) measurements using optical coherence tomography angiography (OCTA) and analyze the effects of the signal strength index (SSI) and axial length (AL) on precision estimates.Design, setting, and participantsThis was a prospective observational study. Seventy-eight children aged 6–16 years underwent 4.5 × 4.5 mm OCTA (RTVue XR Avanti) disc scans: two scans by one examiner (repeatability) and two additional scans by another examiner (reproducibility). Within-subject standard deviation (Sw), test-retest reproducibility (TRT), within-subject coefficient of variation (CoV), intraclass correlation coefficient (ICC), and Bland–Altman analysis were performed.Main outcomes and measuresIn repeatability measurement, the fluctuation ranges (minimum to maximum) of VD between intraexaminer A/B in Sw, TRT, CoV, and ICC were (1.05–2.17)% / (1.16–2.32)%, (2.9–6)% / (3.21–6.44)%, (1.9–4.47)% / (2.08–5)%, and (0.588–0.783)% / (0.633–0.803)%, respectively. In reproducibility measurement, the fluctuation ranges of VD in Sw, TRT, CoV, and ICC were 1.11–2.13%, 3.07–5.91%, 1.99–4.41%, and 0.644–0.777%, respectively. VD was negatively correlated with SSI in most sectors of the peripapillary (e.g., inferior nasal, temporal inferior, temporal superior, superior temporal, and superior nasal). AL was positively correlated with inferior temporal VD and negatively correlated with superior nasal VD.Conclusion and relevanceOptical coherence tomography angiography showed moderate-to-good repeatability and reproducibility for papillary and peripapillary perfusion measurements in healthy children. The SSI value affects most of the peripapillary VD, while AL affects only the temporal inferior and nasal superior peripapillary VD.
Effect of anesthesia assistance on the detection rate of precancerous lesions and early esophageal squamous cell cancer in esophagogastroduodenoscopy screening: A retrospective study based on propensity score matching
Authors: Liang Min , Xu Chunhong , Zhang Xinyan , Zhang Zongwang , Cao Junli 
Published: March 2023

BackgroundEsophagogastroduodenoscopy (EGD) screening is vital for the early diagnosis of esophageal squamous cell cancer (ESCC). However, improvement in the detection rate of precancerous lesions and early ESCC with anesthesia assistance (AA) has not yet been investigated. This retrospective study aimed to evaluate the effect of AA on the detection rate of precancerous lesions and early ESCC in patients undergoing EGD screening and identify risk factors affecting the detection rate.MethodsWe reviewed patients’ electronic medical records who underwent EGD screening between May 2019 and August 2020. Patients were divided into two groups based on whether they received AA: those in Group A underwent EGD screening with AA, and patients in Group O underwent EGD screening without AA. Propensity score matching (PSM) was used to account for differences in baseline characteristics. Detection rates of precancerous lesions and early ESCC were compared between the two groups following PSM. Binary logistic regression was used to identify risk factors affecting the detection rate.ResultsThe final analysis included 21,835 patients (Group A = 13,319, Group O = 8,516) from 28,985 patients who underwent EGD screening during the study period. Following PSM, 6009 patients remained in each group for analysis. There was no significant difference in the detection rate of precancerous lesions and early ESCC between Groups A and O (1.1% vs. 0.8%, p &gt; 0.05). Binary logistic regression showed that age (50–59 years, 60–69 years and 70–79 years), higher endoscopist seniority, high-definition (HD) endoscopy, narrow-band imaging (NBI), and number of endoscopic images were all independent risk factors that affected the detection rate of precancerous lesions and early ESCC.ConclusionThere was no statistically significant difference in the detection rate of precancerous lesions and early ESCC between patients who underwent EGD screening with and without AA. All independent risk factors that affected the detection rate of precancerous lesions and early ESCC included the following: age (50–59 years, 60–69 years and 70–79 years), higher endoscopist seniority, HD endoscopy, NBI, and number of endoscopic images. Endoscopists should consider all these factors as much as possible when performing EGD screening.
Association of geriatric nutritional risk index with all-cause hospital mortality among elderly patients in intensive care unit
Authors: Peng Jiang-Chen , Zhu Yi-Wei , Xing Shun-Peng , Li Wen , Gao Yuan , Gong Wen-Wen 
Published: March 2023

BackgroundMalnutrition is associated with poor outcomes for geriatric patients in intensive care unit (ICU). It is important to identify patients at risk of malnutrition and provide individual nutrition support. The assessment of malnutrition risk is not easy for these patients due to their cognitive impairment. Geriatric nutrition risk index (GNRI) is a simple and objective scoring tool to evaluate the risk of malnutrition in elderly patients. In this study, we aimed to see whether GNRI score was appropriate to predict clinical outcomes among geriatric patients in the setting of ICU.Materials and methodsElderly patients with age ≥ 65 years were extracted from Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Categories based on GNRI were classified as major risk (GNRI &lt;82), moderate risk (GNRI 82 to &lt;92), low risk (GNRI 92 to ≤98), and no risk (GNRI &gt;98). The primary outcome was all-cause hospital mortality. Multivariable Cox proportional hazards regression models and restricted cubic spline were used to investigate associations of GNRI with hospital mortality, respectively. A two-piecewise linear regression model was applied to examine the inflection point of GNRI on hospital mortality. To reduce selection bias, propensity score matching (PSM) was used in a 1:1 ratio.ResultsA total of 3,696 geriatric patients were finally included with median age 75 (69, 81) years. The prevalence of major risk was 28.6%. In the fully adjusted model, GNRI categories featured a negative trend with hospital mortality (p for trend = 0.037). Restricted cubic spline analysis demonstrated an L-shaped relationship between GNRI and hospital mortality before and after matching. The inflection point was 78.7. At the left side of inflection point, GNRI levels were significantly negatively associated with hospital mortality (HR = 0.96, 95% CI: 0.94–0.98; p &lt; 0.001) and featured no significant relations at the right side. Multiple linear regression also showed that GNRI was negatively associated with length of stay in hospital.ConclusionThe major risk of malnutrition defined by GNRI was able to predict poor prognosis for geriatric patients admitted to ICU.
Diagnostic performance of transperineal prostate targeted biopsy alone according to the PI-RADS score based on bi-parametric magnetic resonance imaging
Authors: Noh Tae Il , Shim Ji Sung , Kang Seok Ho , Cheon Jun , Kang Sung Gu 
Published: March 2023

PurposeTo compare the diagnostic performance of transperineal targeted biopsy (TB) or systematic biopsy (SB) alone based on combined TB+SB and radical prostatectomy (RP) specimen for detecting prostate cancer (PCa) according to the prostate imaging reporting and data system (PI-RADS) score. Materials and methodsThis study included 1077 men who underwent transperineal bi-parametric (bp) magnetic resonance imaging (MRI)–ultrasound (US) fusion TB+SB (bpMRI-US FTSB) between April 2019 and March 2022. To compare the performance of each modality (TB, SB, and combined TB+SB) with the RP specimen (as the standard) for detecting PCa and clinically significant PCa (csPCa), receiver operating characteristic (ROC) curves were plotted.ResultsPCa was detected in 581 of 1077 men (53.9%) using bpMRI-US FTSB. CsPCa was detected in 383 of 1077 men (35.6%), 17 of 285 (6.0%) with PI-RADS 0 to 2, 35 of 277 (12.6%) with PI-RADS 3, 134 of 274 (48.9%) with PI-RADS 4, and 197 of 241 (81.7%) with PI-RADS 5, respectively. The additional diagnostic value of TB vs. SB compared to combined TB+SB for diagnosing csPCa were 4.3% vs. 3.2% (p=0.844), 20.4% vs 5.1% (p&lt;0.001), and 20.3% vs. 0.7% (p&lt;0.001) with PI-RADS 3, 4, and 5, respectively. TB alone showed no significant difference in diagnostic performance for csPCa with combined TB+SB based on RP specimens in patients with PI-RADS 5 (p=0.732).ConclusionA need for addition of SB to TB in patients with PI-RADS 3 and 4 lesions, however, TB alone may be performed without affecting the management of patients with PI-RADS 5.
Case Report: Clinical response to anaplastic lymphoma kinase inhibitor-based targeted therapy in uterine inflammatory myofibroblastic tumor harboring ALK-IGFBP5 fusion
Authors: Zhao Ting , Zhang Xiaowei , Liu Xin , Ren Min , Cheng Yufan , Wang Jian , Luo Zhiguo 
Published: March 2023

BackgroundAn inflammatory myofibroblastic tumor (IMT) is a mesenchymal tumor with a prevalence ranging from 0.04% to 0.7% worldwide, in which the lung is the most common predilection site, accounting for 33% of cases, followed by the abdomen, pelvis, mesentery, and uterus. Approximately 50% of uterine IMTs present as anaplastic lymphoma kinase (ALK) positive along with ALK gene fusion, which lays a solid foundation for the development of ALK-based target therapy to optimize treatment strategies.Case presentationHerein we describe a 57-year-old woman who presented with a slow-growing mass in the uterus for over 10 years and then received surgical resection because of significant progressive enlargement of the mass during follow-up. She was diagnosed with uterine leiomyosarcoma (LMS) with no further interventions until recurrence. We revised the diagnosis to uterine IMT based on diffuse ALK expression, ALK-IGFBP5 gene fusion, and the morphologic features of the tumors by pathology consultation. Based on these, we recommended an ALK tyrosine kinase inhibitor (TKI) treatment, crizotinib (250 mg bid), and she achieved a complete response (CR) with at least 18 months of progression-free survival (PFS). We monitored the dynamics of target lesions and peripheral blood cells at regular intervals through CT scans and routine blood tests during the treatment process. We present patient responses to ALK inhibitor-based targeted therapy with uterine IMT harboring ALK-IGFBP5 fusion, and the neutrophil-to-lymphocyte ratio (NLR) may be an effective indicator to predict prognosis.
Case report: A case of epidermolysis bullosa complicated with pyloric atresia and a literature review
Authors: Luo Caiyun , Yang Liucheng , Huang Zhaorong , Su Yuqian , Lu Yi , Yu Daiyue , Zhang Mengzhen , Wu Kai 
Published: March 2023

ObjectiveThis article aims to explore the diagnosis, molecular characteristics, treatment, and prognosis of epidermolysis bullosa with pyloric atresia (EB-PA).MethodsThe clinical manifestations, diagnosis and treatment, and genetic characteristics of a patient with EB-PA admitted to our hospital were analysed. The disease subtypes, concomitant abnormalities, molecular characteristics, and prognosis of patients with EB-PA were summarized by searching the EB-PA-related literature since 2011.ResultsWe present a very low birth weight female infant with skin blisters and pyloric obstruction. Exome sequencing revealed heterozygous mutations in the ITGB4 gene: c.794dupC (p. S265fs*5) and c.2962G &gt; A (p.A988T). This infant was diagnosed with EB-PA. Coverage of the wounds and Penicillin were used to prevent infection, but the patient eventually developed severe sepsis. A literature review was carried out including 49 cases of EB-PA; among these cases, 34 were preterm infants, weighing between 930 and 3,640 g. Of these EB-PA patients, 28 had accompanying malformations, including urinary system malformations and aplasia cutis congenita (ACC). Thirty-two patients identified the subtype of EB-PA, of whom 25 were diagnosed with junctional epidermolysis bullosa (JEB), 6 with epidermolysis bullosa simplex (EBS), and 1 with dystrophic epidermolysis bullosa (DEB). Genetic testing was conducted on 23 patients, of whom 15 carried Integrin Beta-4 (ITGB4) gene mutations and one JEB patient carried an Integrin Alpha-6 (ITGA6) gene mutation; 4 of the 5 EBS patients had Plectin (PLEC) gene mutations, and the other had an ITGB4 mutation. ITGB4 mutation cases involved 29 mutation sites, primarily concentrated in the region encoding the integrin beta subunit; PLEC mutation cases involved 7 mutation sites. Among all cases, 43 underwent pyloric atresia surgery, of whom 24 died postoperatively, and 6 without surgery therapy died within a short period.ConclusionEB-PA is a rare genetic disorder characterized by increased skin fragility and PA involving mutations in the ITGB4, PLEC, or ITGA6 genes. EB-PA has a high incidence of complications and mortality, surgery and supportive therapy are currently the most common treatment options.
Optic disc and retinal vascular features in first 6 years of Chinese children
Authors: Liu Guina , Jiang Anna , Cao Le , Ling Saiguang , Wang Xi , Bu Shaochong , Lu Fang 
Published: March 2023

PurposeRetinal microvasculature plays an important role in children's fundus lesions and even in their later life. However, little was known on the features of normal retina in early life. The purpose of this study was to explore the normal retinal features in the first 6 years of life and provide information for future research.MethodsChildren, aged from birth to 6 years old and diagnosed with various unilateral ocular diseases were included. Venous phase fundus fluorescein angiography images with the optic disc at the center were collected. Based on the ResUNet convolutional neural network, optic disc and retinal vascular features in the posterior retina were computed automatically.ResultsA total of 146 normal eyes of 146 children were included. Among different age groups, no changes were shown in the optic disc diameter (y = −0.00002x + 1.362, R2 = 0.025, p = 0.058). Retinal vessel density and fractal dimension are linearly and strongly correlated (r = 0.979, p &lt; 0.001). Older children had smaller value of fractal dimension (y = −0.000026x + 1.549, R2 = 0.075, p = 0.001) and narrower vascular caliber if they were less than 3 years old (y = −0.008x + 84.861, R2 = 0.205, p &lt; 0.001). No differences were in the density (y = −0.000007x + 0.134, R2 = 0.023, p = 0.067) and the curvature of retinal vessels (lnC = −0.00001x − 4.657, R2 = 0.001, p = 0.667).ConclusionsAge and gender did not impact the optic disc diameter, vessel density, and vessel curvature significantly in this group of children. Trends of decreased vessel caliber in the first 3 years of life and decreased vessel complexity with age were observed. The structural characteristics provide information for future research to better understand the developmental origin of the healthy and diseased retina.