bluuebunny/crossref_metadata_2025_split huggingface dataset:
Morphological Features and Immunohistochemical Profiling of Male Breast Gynaecomastia; A Large Tissue Microarray Study
Authors: Prasad Prakruthi , Bennett Aneliese , Speirs Val , Shaaban Abeer M. 
Published: June 2022

IntroductionGynaecomastia is the commonest male breast condition accounting for approximately 85% of male breast lesions. There is minimal information on the immunohistochemical profile of gynaecomastia. We aimed to comprehensively profile a large series of gynaecomastia samples for putative mammary diagnostic, predictive and prognostic markers.MethodsA total of 156 samples, were histologically reviewed, assembled onto tissue microarrays, and stained for oestrogen receptors (ERα, ERβ1, ERß2), progesterone receptors (total PR, PRα), androgen receptor (AR), basal &amp; luminal cytokeratins (CK5/6, CK14, CK8/18) and the proliferation marker Ki67. Relevant cut offs for marker positivity were defined based on existing literature: AR (10%), ERα and PR (Allred score &gt;3/8), ERß (10% and 20%), cytokeratins (10%) and Ki67 (10% and 20%).Results108 samples from 86 patients aged 13-75 years were available for immunohistochemical assessment. 73.1% of the lesions were AR positive, compared to 99% for ERα and 100% for both ERß1 and ERß2. 98% of samples were positive for total PR and 97.1% for PRα. 69.8% expressed CK5/6 whilst 57% were CK14 positive. A tri-layered pattern of cytokeratin expression was also observed. Ki67 positivity was low with 17.1% and 6.7% classified as Ki67 positive using 10% and 20% cut off values respectively. A significant negative correlation was found between ERα expression and patient age (rs = -0.221, p=0.023). Bivariate correlations were produced, and comparisons made with previously published data regarding the immunohistochemical status in normal female breast tissue, proliferative and neoplastic breast diseases of the female and male breast.ConclusionsHormone receptors, including oestrogen receptor α and ß isoforms as well as androgen receptors were abundantly expressed within the intraductal luminal hyperplastic epithelium in gynaecomastia supporting the hormonal role in the pathogenesis and treatment. ERα, ERβ1 and ERβ2 were expressed in a higher proportion of cells compared with their expression in the female breast benign lesions which further characterises gynaecomastia biology. The identification of a low Ki67 proliferative index and the mixed cytokeratin profile in gynaecomastia differentiates this benign condition from male breast cancer. Therefore, Ki67 and cytokeratins can help in the differential diagnosis from histological mimics in the routine diagnostic work up.
Association of Tumor Size With Prognosis in Patients With Resectable Endometrial Cancer: A SEER Database Analysis
Authors: Hou Xuefei , Yue Suru , Liu Jie , Qiu Zhiqing , Xie Liming , Huang Xueying , Li Shasha , Hu Liren , Wu Jiayuan 
Published: June 2022

This study aimed to explore the relationship between tumor size (Ts) and prognosis in endometrial cancer (EC). A total of 52,208 patients with EC who underwent total hysterectomy were selected from the Surveillance, Epidemiology, and End Results Program database. Overall survival (OS) and endometrial cancer-specific survival (ESS) were chosen as survival outcomes. The Cox proportional hazards model was used to explore the effect of Ts on prognosis. The restricted cubic splines based on the Cox regression model were used to determine the nonlinear relationship between Ts and survival. When Ts was analyzed as a categorical variable, the risk of death increased with Ts, with the highest risk in patients with Ts &gt; 9 cm with regard to all-cause death (ACD) (hazard ratio [HR] 1.317; 95% confidence interval [CI], 1.196-1.450; P &lt; 0.001) and endometrial cancer-specific death (ESD) (HR, 1.378; 95% CI, 1.226-1.549; P &lt; 0.001). As a continuous variable, Ts showed a nonlinear relationship with ACD (HR, 1.061; 95% CI, 1.053-1.069; P &lt; 0.001) and ESD (HR, 1.062; 95% CI, 1.052-1.073; P &lt; 0.001). The risk of mortality increased quickly with Ts when Ts was less than 7.5 cm and then leveled off when Ts was larger than 7.5 cm in all patients. Among patients with lymph node metastasis, the risk of poor prognosis decreased rapidly with Ts when Ts was less than 3.5 cm, and subsequently increased sharply with Ts when Ts ranged from 3.5 cm to 7.5 cm, and then increased slowly when Ts was larger than 7.5 cm (P &lt; 0.001 for nonlinearity). There was a nonlinear relationship between Ts and prognosis in patients with EC. Clinicians should not ignore the impact of small tumors on prognosis in EC patients with lymph node metastasis.
Genomic Alterations Identification and Resistance Mechanisms Exploration of NSCLC With Central Nervous System Metastases Using Liquid Biopsy of Cerebrospinal Fluid: A Real-World Study
Authors: Shen Fangfang , Liang Naixin , Fan Zaiwen , Zhao Min , Kang Jing , Wang Xifang , Hu Qun , Mu Yongping , Wang Kai , Yuan Mingming , Chen Rongrong , Guo Wei , Dong Guilan , Zhao Jun , Bai Jun 
Published: June 2022

BackgroundGenomic profiling of cerebrospinal fluid (CSF) can be used to detect actionable mutations and guide clinical treatment of non-small cell lung cancer (NSCLC) patients with central nervous system (CNS) metastases. Examining the performance of CSF samples in real-world settings can confirm the potential of CSF genotyping for guiding therapy in clinical practice.Patients and MethodsWe included 1,396 samples from 970 NSCLC patients with CNS metastases in real-world settings. All samples underwent targeted next-generation sequencing of 1,021 cancer-relevant genes. In total, 100 CSF samples from 77 patients who had previously received targeted treatment were retrospectively analyzed to explore the mechanisms of TKI-resistance.ResultsFor NSCLC patients with CNS metastases, CSF samples were slightly more often used for genomic sequencing in treated patients with only distant CNS metastases compared to other patients (10.96% vs. 0.81–9.61%). Alteration rates in CSF samples were significantly higher than those in plasma, especially for copy number variants (CNV). The MSAFs of CSF samples were significantly higher than those of plasma and tumor tissues (all p &lt;0.001). Remarkably, detection rates of all actionable mutations and EGFR in CSF were higher than those in plasma samples of treated patients (all p &lt;0.0001). For concordance between paired CSF and plasma samples that were simultaneously tested, the MSAF of the CSF was significantly higher than that of matched plasma cfDNA (p &lt;0.001). From multiple comparisons, it can be seen that CSF better detects alterations compared to plasma, especially CNV and structural variant (SV) alterations. CSF cfDNA in identifying mutations can confer the reason for the limited efficacy of EGFR-TKIs for 56 patients (78.87%, 56/71).ConclusionsThis real-world large cohort study confirmed that CSF had higher sensitivity than plasma in identifying actionable mutations and showed high potential in exploring underlying resistance mechanisms. CSF can be used in genomics profiling to facilitate the broad exploration of potential resistance mechanisms for NSCLC patients with CNS metastases.
Development and Validation of a DeepSurv Nomogram to Predict Survival Outcomes and Guide Personalized Adjuvant Chemotherapy in Non-Small Cell Lung Cancer
Authors: Yang Bin , Liu Chengxing , Wu Ren , Zhong Jing , Li Ang , Ma Lu , Zhong Jian , Yin Saisai , Zhou Changsheng , Ge Yingqian , Tao Xinwei , Zhang Longjiang , Lu Guangming 
Published: June 2022

ObjectiveTo develop and validate a DeepSurv nomogram based on radiomic features extracted from computed tomography images and clinicopathological factors, to predict the overall survival and guide individualized adjuvant chemotherapy in patients with non-small cell lung cancer (NSCLC).Patients and MethodsThis retrospective study involved 976 consecutive patients with NSCLC (training cohort, n=683; validation cohort, n=293). DeepSurv was constructed based on 1,227 radiomic features, and the risk score was calculated for each patient as the output. A clinical multivariate Cox regression model was built with clinicopathological factors to determine the independent risk factors. Finally, a DeepSurv nomogram was constructed by integrating the risk score and independent clinicopathological factors. The discrimination capability, calibration, and clinical usefulness of the nomogram performance were assessed using concordance index evaluation, the Greenwood-Nam-D’Agostino test, and decision curve analysis, respectively. The treatment strategy was analyzed using a Kaplan–Meier curve and log-rank test for the high- and low-risk groups.ResultsThe DeepSurv nomogram yielded a significantly better concordance index (training cohort, 0.821; validation cohort 0.768) with goodness-of-fit (P&lt;0.05). The risk score, age, thyroid transcription factor-1, Ki-67, and disease stage were the independent risk factors for NSCLC.The Greenwood-Nam-D’Agostino test showed good calibration performance (P=0.39). Both high- and low-risk patients did not benefit from adjuvant chemotherapy, and chemotherapy in low-risk groups may lead to a poorer prognosis.ConclusionsThe DeepSurv nomogram, which is based on the risk score and independent risk factors, had good predictive performance for survival outcome. Further, it could be used to guide personalized adjuvant chemotherapy in patients with NSCLC.
A Nomogram Model to Predict Early Recurrence of Patients With Intrahepatic Cholangiocarcinoma for Adjuvant Chemotherapy Guidance: A Multi-Institutional Analysis
Authors: Li Qi , Zhang Jian , Chen Chen , Song Tianqiang , Qiu Yinghe , Mao Xianhai , Wu Hong , He Yu , Cheng Zhangjun , Zhai Wenlong , Li Jingdong , Zhang Dong , Geng Zhimin , Tang Zhaohui 
Published: June 2022

BackgroundThe influence of different postoperative recurrence times on the efficacy of adjuvant chemotherapy (ACT) for intrahepatic cholangiocarcinoma (ICC) remains unclear. This study aimed to investigate the independent risk factors and establish a nomogram prediction model of early recurrence (recurrence within 1 year) to screen patients with ICC for ACT.MethodsData from 310 ICC patients who underwent radical resection between 2010 and 2018 at eight Chinese tertiary hospitals were used to analyze the risk factors and establish a nomogram model to predict early recurrence. External validation was conducted on 134 patients at the other two Chinese tertiary hospitals. Overall survival (OS) and relapse-free survival (RFS) were estimated by the Kaplan–Meier method. Multivariate analysis was conducted to identify independent risk factors for prognosis. A logistic regression model was used to screen independent risk variables for early recurrence. A nomogram model was established based on the above independent risk variables to predict early recurrence.ResultsACT was a prognostic factor and an independent affecting factor for OS and RFS of patients with ICC after radical resection (p &lt; 0.01). The median OS of ICC patients with non-ACT and ACT was 14.0 and 15.0 months, and the median RFS was 6.0 and 8.0 months for the early recurrence group, respectively (p &gt; 0.05). While the median OS of ICC patients with non-ACT and ACT was 41.0 and 84.0 months, the median RFS was 20.0 and 45.0 months for the late recurrence group, respectively (p &lt; 0.01). CA19-9, tumor size, major vascular invasion, microvascular invasion, and N stage were the independent risk factors of early recurrence for ICC patients after radical resection. The C-index of the nomogram was 0.777 (95% CI: 0.713~0.841) and 0.716 (95%CI: 0.604~0.828) in the training and testing sets, respectively.ConclusionThe nomogram model established based on the independent risk variables of early recurrence for curatively resected ICC patients has a good prediction ability and can be used to screen patients who benefited from ACT.
S645C Point Mutation Suppresses Degradation of EGFR to Promote Progression of Glioblastoma
Authors: Huang Wenda , Zou Ling , Hao Zhaonian , Wang Baofeng , Mao Feng , Duan Qiuhong , Guo Dongsheng 
Published: June 2022

BackgroundThe tightly controlled activity of EGFR is important for the homeostasis of self-renewal of human tissue. Mutations in the extracellular domain of EGFR are frequent and function as a novel mechanism for oncogenic EGFR activation in GBM, and impact the response of patients to small-molecule inhibitors.MethodsWe constructed glioblastoma cell lines stably expressing wild-type EGFR and the mutant of EGFR S645C. We detected cell growth in vitro and in vivo. We evaluated the anti-tumor activity and effectiveness of gefitinib and osimertinib in cells.ResultsIn the present study, we identified an oncogenic substituted mutation of EGFR—S645C. The mutation can promote the proliferation and colony formation of glioblastoma in vitro and in vivo. Mechanistically, the EGFR S645C mutation potentially changes the formation of hydrogen bonds within dimerized EGFR and inhibits the degradation of EGFR to prolong downstream signaling. The mutation induces resistance to gefitinib but presents an opportunity for osimertinib treatment.ConclusionThe study indicated a novel oncogenic mutation and advises on the precise treatment of individual patients with the EGFR S645C mutation.
Preoperative Prediction of the Aggressiveness of Oral Tongue Squamous Cell Carcinoma with Quantitative Parameters from Dual-Energy Computed Tomography
Authors: Yang Xieqing , Hu Huijun , Zhang Fang , Li Dongye , Yang Zehong , Shi Guangzi , Lu Guoxiong , Jiang Yusong , Yang Lingjie , Wang Yu , Duan Xiaohui , Shen Jun 
Published: June 2022

ObjectivesTo determine whether quantitative parameters derived from dual-energy computed tomography (DECT) were predictive of the aggressiveness of oral tongue squamous cell carcinoma (OTSCC) including the pathologic stages, histologic differentiation, lymph node status, and perineural invasion (PNI).MethodsBetween August 2019 and March 2021, 93 patients (mean age, 54.6 ± 13.8 years; 66 men) with pathologically diagnosed OTSCC were enrolled in this prospective study. Preoperative DECT was performed and quantitative parameters (e.g., slope of the spectral Hounsfield unit curve [λHu], normalized iodine concentration [nIC], normalized effective atomic number [nZeff], and normalized electron density [nRho]) were measured on arterial phase (AP) and venous phase (VP) DECT imaging. Quantitative parameters from DECT were compared between patients with different pathologic stages, histologic differentiation, lymph node statuses, and perineural invasion statuses. Logistic regression analysis was utilized to assess independent parameters and the diagnostic performance was analyzed by the receiver operating characteristic curves (ROC).ResultsλHu and nIC in AP and λHu, nZeff, and nIC in VP were significantly lower in stage III–IV lesions than in stage I–II lesions (p &lt; 0.001 to 0.024). λHu in VP was an independent predictor of tumor stage with an odds ratio (OR) of 0.29, and area under the curve (AUC) of 0.80. λHu and nIC were higher in well-differentiated lesions than in poorly differentiated lesions (p &lt; 0.001 to 0.021). The nIC in VP was an independent predictor of histologic differentiation with OR of 0.31, and AUC of 0.78. λHu and nIC in VP were lower in OTSCCs with lymph node metastasis than those without metastasis (p &lt; 0.001 to 0.005). λHu in VP was the independent predictor of lymph node status with OR of 0.42, and AUC of 0.74. No significant difference was found between OTSCCs without PNI and those with PNI in terms of the quantitative DECT parameters.ConclusionDECT can be a complementary means for the preoperative prediction of the aggressiveness of OTSCC.
The Longitudinal Impact of Maternal Depression and Neighborhood Social Context on Adolescent Mental Health
Authors: Lew Daphne , Xian Hong , Loux Travis , Shacham Enbal , Scharff Darcell 
Published: June 2022

PurposeMaternal depression and neighborhood characteristics are known to be associated both with each other and with adolescent mental health outcomes. These exposures are also subject to change throughout the life of a child. This study sought to identify multi-trajectories of maternal depression (MD) and self-reported neighborhood collective efficacy (NCE) over a 12-year period and determine whether these trajectories are differentially associated with adolescent mental health.MethodsData from the Fragile Families and Child Wellbeing study, a longitudinal cohort study of new parents and their children, were used. Maternal depression (MD) and self-reported NCE when the child was 3, 5, 9, and 15 years of age were the primary exposures of interest. Adolescent depression and anxiety symptomology when the child was 15 years of age were the primary outcomes. Primary analyses were conducted using multi-trajectory modeling and linear regressions.ResultsFive multi-trajectories were identified, two of which were characterized by no MD but either high or low NCE, and three of which were characterized by similarly moderate levels of NCE but either increasing, decreasing, or consistently high MD. Children of mothers with increasing or consistently high depressive symptomology and moderate NCE had significantly higher depression and anxiety scores compared to children of mothers with no depressive symptomology and high NCE.ConclusionAdolescents with consistent and proximal exposure to MD are most likely to suffer from adverse mental health and should be provided with appropriate support systems to mitigate these outcomes.
Rescue Paracetamol in Postoperative Pain Management in Extremely Low Birth Weight Neonates Following Abdominal Surgery: A Single Unit Retrospective Study
Authors: Cihlarova Hana , Bencova Lenka , Zlatohlavkova Blanka , Allegaert Karel , Pokorna Pavla 
Published: June 2022

BackgroundIntravenous paracetamol added to morphine reduces postoperative morphine consumption in (near)term neonates. However, there are only sparse data on intravenous paracetamol as multimodal strategy in extremely low birth weight (ELBW) neonates.ObjectivesThis study aims to assess the effects of rescue intravenous paracetamol on postoperative pain management (≤48 h postoperatively) in relation to both analgesic efficacy (validated pain assessment, drug consumption, adequate rescue medication) and safety (hypotension and bradycardia). This rescue practice was part of a standardized pain management approach in a single neonatal intensive care unit (NICU).MethodsA single-center retrospective observational study included 20 ELBW neonates, who underwent major abdominal surgery. The primary endpoints of the postoperative study period were pain intensity, over-sedation, time to first rescue analgesic dose, and the effect of paracetamol on opiate consumption. Secondary endpoints were safety parameters (hypotension, bradycardia). And as tertiary endpoints, the determinants of long-term outcome were evaluated (i.e., duration of mechanical ventilation, intraventricular hemorrhage - IVH, periventricular leukomalacia - PVL, postnatal growth restriction, stage of chronic lung disease – CLD or neurodevelopmental outcome according to Bayley-II Scales of Infant Development at 18–24 months).ResultsAll neonates received continuous opioids (sufentanil or morphine) and 13/20 also intravenous paracetamol as rescue pain medication during a 48-h postoperative period. Although opioid consumption was equal in the non-paracetamol and the paracetamol group over 48 h, the non-paracetamol group was characterized by oversedation (COMFORTneo &lt; 9), a higher incidence of severe hypotension, and younger postnatal age (p &lt; 0.05). All long-term outcome findings were similar between both groups.ConclusionsOur study focused on postoperative pain management in ELBW neonates, and showed that intravenous paracetamol seems to be safe. Prospective validation of dosage regimens of analgesic drugs is needed to achieve efficacy goals.
Metformin Improves the Senescence of Renal Tubular Epithelial Cells in a High-Glucose State Through E2F1
Authors: Liang Dan , Li Zhiyang , Feng Zhaowei , Yuan Zhiping , Dai Yunli , Wu Xin , Zhang Fan , Wang Yuanyuan , Zhou Yuxia , Liu Lingling , Shi Mingjun , Xiao Ying , Guo Bing 
Published: June 2022

Diabetic kidney disease is a major cause of chronic kidney condition and the most common complication of diabetes. The cellular senescence participates in the process of diabetic kidney disease, but the specific mechanism is not yet clear. Cell cycle-related protein E2F transcription factor 1 (E2F1) is a member of the E2F transcription factor family, it plays a key role in cellular damage under HG conditions. In this study, we explored whether metformin improves a high-glucose-induced senescence and fibrosis of renal tubular epithelial cells through cell cycle-related protein E2F1. In the in vivo experiments, the recombinant adeno-associated virus (AAV-shE2F1) knockdown E2F1 gene was injected into the tail vein of 16-weeks-old db/db mice for 8 weeks. The 16-week-old db/db mice were administered metformin (260 mg/kg/d) continuously for 8 weeks. The normal control group (NC) and diabetic model group (DM) were set up simultaneously. Mice renal tubular epithelial cells (mRTECs) were cultured in vitro. The cells were randomly divided into the following groups: normal glucose (NG, containing 5.5 mmol/L glucose), high glucose group (HG, containing 30 mmol/L glucose), NG/HG metformin intervention group (NG/HG + Met), NG/HG negative control siRNA transfection group (NG/HG + Control), NG/HG E2F1 siRNA transfection group (NG/HG + siRNA E2F1), HG metformin intervention and overexpression E2F1 plasmid transfection group (HG + Met + overexpress-E2F1). The expression of related indexes were detected by Western blot, real-time polymerase chain reaction (PCR), immunohistochemistry, and immunofluorescence. The results showed that E2F1 knockdown or metformin reduces the degree of renal fibrosis, DNA damage, and cellular senescence in the DM group; metformin also reduced the expression of E2F1. If E2F1 was overexpressed, the effects of metformin in delaying fibrosis and reducing DNA damage and cellular senescence could be weakened. Thus, metformin alleviates high-glucose-induced senescence and fibrosis of renal tubular epithelial cells by downregulating the expression of E2F1.