bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sunitinib and Imatinib Display Differential Cardiotoxicity in Adult Rat Cardiac Fibroblasts That Involves a Role for Calcium/Calmodulin Dependent Protein Kinase II
Authors: McMullen Calum J. , Chalmers Susan , Wood Rachel , Cunningham Margaret R. , Currie Susan 
Published: February 2021

Background:Tyrosine kinase inhibitors (TKIs) have dramatically improved cancer treatment but are known to cause cardiotoxicity. The pathophysiological consequences of TKI therapy are likely to manifest across different cell types of the heart, yet there is little understanding of the differential adverse cellular effects. Cardiac fibroblasts (CFs) play a pivotal role in the repair and remodeling of the heart following insult or injury, yet their involvement in anti-cancer drug induced cardiotoxicity has been largely overlooked. Here, we examine the direct effects of sunitinib malate and imatinib mesylate on adult rat CF viability, Ca2+handling and mitochondrial function that may contribute to TKI-induced cardiotoxicity. In particular, we investigate whether Ca2+/calmodulin dependent protein kinase II (CaMKII), may be a mediator of TKI-induced effects.Methods:CF viability in response to chronic treatment with both drugs was assessed using MTT assays and flow cytometry analysis. Calcium mobilization was assessed in CFs loaded with Fluo4-AM and CaMKII activationviaoxidation was measuredviaquantitative immunoblotting. Effects of both drugs on mitochondrial function was determined by live mitochondrial imaging using MitoSOX red.Results:Treatment of CFs with sunitinib (0.1–10 μM) resulted in concentration-dependent alterations in CF phenotype, with progressively significant cell loss at higher concentrations. Flow cytometry analysis and MTT assays revealed increased cell apoptosis and necrosis with increasing concentrations of sunitinib. In contrast, equivalent concentrations of imatinib resulted in no significant change in cell viability. Both sunitinib and imatinib pre-treatment increased Angiotensin II-induced intracellular Ca2+mobilization, with only sunitinib resulting in a significant effect and also causing increased CaMKII activationviaoxidation. Live cell mitochondrial imaging using MitoSOX red revealed that both sunitinib and imatinib increased mitochondrial superoxide production in a concentration-dependent manner. This effect in response to both drugs was suppressed in the presence of the CaMKII inhibitor KN-93.Conclusions:Sunitinib and imatinib showed differential effects on CFs, with sunitinib causing marked changes in cell viability at concentrations where imatinib had no effect. Sunitinib caused a significant increase in Angiotensin II-induced intracellular Ca2+mobilization and both TKIs caused increased mitochondrial superoxide production. Targeted CaMKII inhibition reversed the TKI-induced mitochondrial damage. These findings highlight a new role for CaMKII in TKI-induced cardiotoxicity, particularly at the level of the mitochondria, and confirm differential off-target toxicity in CFs, consistent with the differential selectivity of sunitinib and imatinib.
Insulin Therapy Is Associated With an Increased Risk of Carotid Plaque in Type 2 Diabetes: A Real-World Study
Authors: Ke Jiang-Feng , Wang Jun-Wei , Zhang Zhi-Hui , Chen Ming-Yun , Lu Jun-Xi , Li Lian-Xi 
Published: February 2021

Background: Controversies concerning the association between insulin therapy and atherosclerotic lesions in type 2 diabetes mellitus (T2DM) remain to exist. The purpose of this study was to investigate whether insulin therapy in T2DM patients is linked with the increased risk of carotid atherosclerosis in real-world settings.Methods: We retrospectively enrolled 2,356 hospitalized patients with T2DM, including 1,716 subjects receiving insulin therapy and 640 subjects without receiving insulin therapy. Carotid atherosclerotic lesions including carotid intima-media thickness (CIMT), carotid plaque and carotid stenosis were assessed by Doppler ultrasonography and were compared between T2DM patients treated with and without insulin.Results: After adjusting for age and duration of diabetes, there was a significant increase in the prevalence of carotid plaque in both men (52.0 vs. 41.7%, p = 0.007) and women (49.6 vs. 39.7%, p = 0.003) receiving insulin therapy than in those without receiving insulin therapy. After further controlling for other confounding factors, compared with the patients without receiving insulin therapy, the risk of carotid plaque was still significantly increased not only in women treated with insulin (OR: 1.810; 95% CI: 1.155–2.837, p = 0.010), but also in men treated with insulin (OR: 1.867; 95% CI: 1.307–2.666; p = 0.001). Additionally, HOMA2-B% was higher in both women and men without receiving insulin therapy compared with those receiving insulin therapy (p &lt; 0.001 in both men and women), but HOMA-IR was significantly higher in patients treated with insulin than in those without receiving insulin therapy (p &lt; 0.001 in both men and women).Conclusions: Insulin therapy is associated with markedly increased risk of carotid atherosclerotic lesions in type 2 diabetes, which partly attribute to the more serious insulin resistance in T2DM patients receiving insulin therapy.
Identification of Tumor Microenvironment-Related Prognostic Genes in Sarcoma
Authors: Dai Dongjun , Xie Lanyu , Shui Yongjie , Li Jinfan , Wei Qichun 
Published: February 2021

AimImmune cells that infiltrate the tumor microenvironment (TME) are associated with cancer prognosis. The aim of the current study was to identify TME related gene signatures related to the prognosis of sarcoma (SARC) by using the data from The Cancer Genome Atlas (TCGA).MethodsImmune and stromal scores were calculated by estimation of stromal and immune cells in malignant tumor tissues using expression data algorithms. The least absolute shrinkage and selection operator (lasso) based cox model was then used to select hub survival genes. A risk score model and nomogram were used to predict the overall survival of patients with SARC.ResultsWe selected 255 patients with SARC for our analysis. The Kaplan–Meier method found that higher immune (p = 0.0018) or stromal scores (p = 0.0022) were associated with better prognosis of SARC. The estimated levels of CD4+ (p = 0.0012) and CD8+ T cells (p = 0.017) via the tumor immune estimation resource were higher in patients with SARC with better overall survival. We identified 393 upregulated genes and 108 downregulated genes (p &lt; 0.05, fold change &gt;4) intersecting between the immune and stromal scores based on differentially expressed gene (DEG) analysis. The univariate Cox analysis of each intersecting DEG and subsequent lasso-based Cox model identified 11 hub survival genes (MYOC, NNAT, MEDAG, TNFSF14, MYH11, NRXN1, P2RY13, CXCR3, IGLV3-25, IGHV1-46, and IGLV2-8). Then, a hub survival gene-based risk score gene signature was constructed; higher risk scores predicted worse SARC prognosis (p &lt; 0.0001). A nomogram including the risk scores, immune/stromal scores and clinical factors showed a good prediction value for SARC overall survival (C-index = 0.716). Finally, connectivity mapping analysis identified that the histone deacetylase inhibitors trichostatin A and vorinostat might have the potential to reverse the harmful TME for patients with SARC.ConclusionThe current study provided new indications for the association between the TME and SARC. Lists of TME related survival genes and potential therapeutic drugs were identified for SARC.
Incidence of a First Thrombo-Embolic Event in Patients With Systemic Lupus Erythematosus and Anti-phosphatidylserine/prothrombin Antibodies: A Prospective Study
Authors: Sciascia Savino , Radin Massimo , Cecchi Irene , Rubini Elena , Foddai Silvia Grazietta , Barinotti Alice , Vaccarino Antonella , Rossi Daniela , Roccatello Dario 
Published: February 2021

Objective: This study aimed to prospectively investigate the incidence of first thromboembolic events (TEs) in a cohort of systemic lupus erythematosus (SLE) patients. The patients were positive for anti-phosphatidylserine/prothrombin (aPS/PT) antibodies and tested negative for anticardiolipin (aCL) and anti-β2–glycoprotein I (aβ2GPI) antibodies [regardless of their Lupus Anticoagulant (LA) status].Methods: Inclusion criteria included: (a) SLE with no previous TEs; (b) no concomitant anti-thrombotic therapy; (c) isolated confirmed positive test for aPS/PT.Results: From the total of 52 SLE patients (42, 80.8% women), 18 patients (34.6%) were found to be positive for aPS/PT (IgG/IgM). During a mean follow-up (3.9 ± 1.1 years), 3 TEs occurred (1.3%/year). The overall cumulative incidence of TEs was 5.8% after 2 years, and up to 16.7% when focusing on aPS/PT positive patients. All the TEs events (two cerebrovascular events and one thrombotic kidney microangiopathy) occurred in the aPS/PT positive group. When focusing on IgG aPS/PT, we found that patients who tested positive were at a significantly higher risk for TEs (crude HR 19.6, 95%; CI 1.1 to 357.6; p &lt; 0.05) compared to patients with negative aPS/PT.Conclusion: This study observed a rate of TEs of 1.3%/year, in aPS/PT positive only patients. Our prospective data suggest that aPS/PT might confer an increased risk for the development of TEs in SLE patients.
Factors Associated With Short-Term Eradication of Rectal Colonization by KPC-2 Producing Klebsiella pneumoniae in an Outbreak Setting
Authors: Pellicé Martina , Rodríguez-Núñez Olga , Rico Verónica , Agüero Daiana , Morata Laura , Cardozo Celia , Puerta-Alcalde Pedro , Garcia-Vidal Carolina , Rubio Elisa , Fernandez-Pittol Mariana J. , Vergara Andrea , Pitart Cristina , Marco Francesc , Santana Gemina , Rodríguez-Serna Laura , Vilella Ana , López Ester , Soriano Alex , Martínez Jose Antonio , Del Rio Ana 
Published: February 2021

Background: KPC-producing Klebsiella pneumoniae (KPCKP) is a threat for patients admitted to healthcare institutions.Objectives: To assess the efficacy of several decolonization strategies for KPCKP rectal carriage.Methods: Observational study performed in a 750-bed university center from July to October 2018 on the efficacy of a 10-day non-absorbable oral antibiotic (NAA) regimen (colistin 10 mg/ml, amikacin 8 mg/ml, and nystatin 30 mg/ml, 10 ml/6 h) vs. the same regimen followed by a probiotic (Vivomixx®) for 20 days in adult patients with KPCKP rectal colonization acquired during an outbreak.Results: Seventy-three patients colonized by KPCKP were included, of which 21 (29%) did not receive any treatment and 52 (71.2%) received NAA either alone (n = 26, 35.6%) or followed by a probiotic (n = 26, 35.6%). Eradication was observed in 56 (76.7%) patients and the only variable significantly associated with it was not receiving systemic antibiotics after diagnosis of rectal carriage [22/24 (91.6%) vs. 34/49 (69.3%), p = 0.04]. Eradication in patients receiving NAA plus probiotic was numerically but not significantly higher than that of controls [23/26 (88.4%) vs. 15/21 (71.4%), p = 0.14] and of those receiving only NAA (OR = 3.4, 95% CI = 0.78–14.7, p = 0.09).Conclusion: In an outbreak setting, rectal carriage of KPCKP persisted after a mean of 36 days in about one quarter of patients. The only factor associated with eradication was not receiving systemic antibiotic after diagnosis. A 10-day course of NAA had no impact on eradication. Probiotics after NAA may increase the decolonization rate, hence deserving further study.
Microstructural and Cerebral Blood Flow Abnormalities in Subjective Cognitive Decline Plus: Diffusional Kurtosis Imaging and Three-Dimensional Arterial Spin Labeling Study
Authors: Yang Zhongxian , Rong Yu , Cao Zhen , Wu Yi , Zhao Xinzhu , Xie Qiuxia , Luo Min , Liu Yubao 
Published: February 2021

Objective: To explore microstructural and cerebral blood flow (CBF) abnormalities in individuals with subjective cognitive decline plus (SCD plus) using diffusional kurtosis imaging (DKI) and three-dimensional (3D) arterial spin labeling (ASL).Methods: Twenty-seven patients with SCD plus, 31 patients with amnestic mild cognitive impairment (aMCI), and 33 elderly controls (ECs) were recruited and underwent DKI and 3D ASL using a GE 3.0-T MRI. Mean kurtosis (MK), fractional anisotropy (FA), mean diffusivity (MD), and CBF values were acquired from 24 regions of interest (ROIs) in the brain, including the bilateral hippocampal (Hip) subregions (head, body, and tail), posterior cingulate cortex (PCC), precuneus, dorsal thalamus subregions (anterior nucleus, ventrolateral nucleus, and medial nucleus), lenticular nucleus, caput nuclei caudati, white matter (WM) of the frontal lobe, and WM of the occipital lobe. Pearson's correlation analysis was performed to assess the relationships among the DKI-derived parameters, CBF values, and key neuropsychological tests for SCD plus.Results: Compared with ECs, participants with SCD plus showed a significant decline in MK and CBF values, mainly in the Hip head and PCC, and participants with aMCI exhibited more significant abnormalities in the MK and CBF values than individuals with ECs and SCD plus in multiple regions. Combined MK values showed better discrimination between patients with SCD plus and ECs than that obtained using CBF levels, with areas under the receiver operating characteristic (ROC) curve (AUC) of 0.874 and 0.837, respectively. Similarly, the AUC in discriminating SCD plus from aMCI patients obtained using combined MK values was 0.823, which was also higher than the combined AUC of 0.779 obtained using CBF values. Moreover, MK levels in the left Hip (h) and left PCC positively correlated with the auditory verbal learning test-delayed recall (AVLT-DR) score in participants with SCD plus. By contrast, only the CBF value in the left Hip head positively correlated with the AVLT-DR score.Conclusions: Our results provide new evidence of microstructural and CBF changes in patients with SCD plus. MK may be used as an early potential neuroimaging biomarker and may be a more sensitive DKI parameter than CBF at the very early stage of Alzheimer's disease (AD).
Effects of Saffron Extract Supplementation on Mood, Well-Being, and Response to a Psychosocial Stressor in Healthy Adults: A Randomized, Double-Blind, Parallel Group, Clinical Trial
Authors: Jackson Philippa A. , Forster Joanne , Khan Julie , Pouchieu Camille , Dubreuil Séverine , Gaudout David , Moras Benjamin , Pourtau Line , Joffre Florent , Vaysse Carole , Bertrand Karène , Abrous Hélène , Vauzour David , Brossaud Julie , Corcuff Jean Benoit , Capuron Lucile , Kennedy David O. 
Published: February 2021

Anxiety, stress, and low mood are closely related and may contribute to depressive symptoms. Among non-pharmacological solutions to improve subclinical mood symptoms and resilience to stress, natural products such as saffron—identified as promising following preliminary beneficial effects in major depressive disorder—represent a relevant strategy. This study aimed to assess the efficacy of 8 weeks' supplementation with 30 mg standardized saffron extract on emotional well-being in healthy adults with subclinical feelings of low mood and anxiety and/or stress and evaluate the acute effect of saffron in response to a lab-based psychosocial stressor. The study adopted a double-blind, randomized, parallel groups design in which 56 healthy male and female individuals (18–54 years) received either a saffron extract or a placebo for 8 weeks. Chronic effects of saffron on subjective anxiety, stress, and depressive feelings were assessed using a questionnaire battery [including Profile of Mood State-2, (POMS)] and acute effects in response to a lab-based psychosocial stressor were measured through psychological and physiological parameters. Urinary crocetin levels were quantified. Participants who received the saffron extract reported reduced depression scores and improved social relationships at the end of the study. Urinary crocetin levels increased significantly with saffron supplementation and were correlated with change in depression scores. The typical stress-induced decrease in heart rate variability (HRV) during exposure to the stressor was attenuated following acute saffron intake. Saffron extract appears to improve subclinical depressive symptoms in healthy individuals and may contribute to increased resilience against the development of stress-related psychiatric disorders.Clinical trials number: NCT03639831.
Treatment-Emergent Neuroendocrine Prostate Cancer: A Clinicopathological and Immunohistochemical Analysis of 94 Cases
Authors: Zhang Qingfu , Han Yunan , Zhang Yao , Liu Dan , Ming Jian , Huang Bo , Qiu Xueshan 
Published: February 2021

PurposeThis study aimed to evaluate the pathological characteristics, immunophenotype, and prognosis of treatment-emergent neuroendocrine prostate cancer (T-NEPC).Materials and MethodsWe collected 231 repeated biopsy specimens of castration-resistant prostate cancer (CRPC) cases between 2008 and 2019. We used histopathological and immunohistochemical evaluations of Synaptophysin (SYN), ChromograninA (CgA), CD56, androgen receptor (AR), and prostate-specific antigen (PSA) to screen out T-NEPC cases. Multivariate analyses were performed to identify factors in the prognosis of T-NEPC. Further, the results were verified in the Surveillance, Epidemiology, and End Results (SEER) program.ResultsAmong the 231 CRPC cases, 94 (40.7%) cases were T-NEPC. T-NEPC were more likely to present with negative immunohistochemistry for AR (30.9%) and PSA (47.9%) than that of CRPC (8.8% and 17.5%, respectively). Kaplan-Meier analysis revealed that patients with T-NEPC (median overall survival [OS]: 17.6 months, 95% CI: 15.3–19.9 months) had significantly worse survival compared with usual CRPC patients (median OS: 23.6 months, 95% CI: 21.3-25.9 months, log-rank P = 0.001), especially in metastasis cases (median OS: 15.7 months, 95% CI: 13.3-18.0 months) and patients with small cell carcinoma component (median OS: 9.7 months, 95% CI: 8.2–11.2 months). Prostate adenocarcinoma with diffuse NE differentiation (median OS: 18.8 months, 95% CI: 15.3–22.3 months) had poor outcome than those with usual CRPC (P = 0.027), while there was no significant change in the focal NE differentiation (median OS: 22.9 months, 95% CI: 18.1–27.7 months, P = 0.136). In the unadjusted model, an excess risk of overall death was observed in T-NEPC with PSA negative (HR = 2.86, 95% CI = 1.39–6.73). Among 476 NEPC cases in the SEER database from 2004 to 2017, we observed a higher hazard of overall death in patients aged 65 years and older (HR = 1.35, 95% CI = 1.08–1.69), patients with PSA ≤ 2.5 ng/ml (HR = 1.90, 95%CI = 1.44–2.52), patients with PSA 2.6–4.0 ng/ml (HR = 2.03, 95%CI = 1.38–2.99), stage IV tumor (HR = 2.13, 95%CI = 1.47–3.08) and other races (HR = 1.85, 95%CI = 1.17–2.94) in total NEPC, adjusting for confounders. Similar hazard ratios were observed in pure NEPC, while there was no significant results among prostate adenocarcinoma with NE differentiation tumors.ConclusionT-NEPC was associated with an unfavorable prognosis, negative immunohistochemistry for PSA in T-NEPC and serum PSA level ≤ 4 ng/ml had a worse prognosis. Urologists and pathologists should recognize the importance of the second biopsy in CRPC to avoid unnecessary diagnosis and treatment delays.
Effects of Antiviral Therapy on HBV Reactivation and Survival in Hepatocellular Carcinoma Patients Undergoing Hepatic Artery Infusion Chemotherapy
Authors: Liu Shousheng , Lai Jinfa , Lyu Ning , Xie Qiankun , Cao Huijiao , Chen Dabiao , He Meng , Zhang Bei , Zhao Ming 
Published: February 2021

BackgroundThis study aimed to investigate the influence of hepatic artery infusion chemotherapy (HAIC) on hepatitis B virus (HBV) reactivation in hepatitis B surface antigen (HBsAg) positive patients with primary hepatocellular carcinoma (HCC) as well as evaluate the role of antiviral prophylaxis in these patients.MethodsWe enrolled 170 HBsAg-positive advanced HCC patients receiving HAIC using mFOLFOX regimen, of which 137 patients received antiviral prophylaxis. Risk factors for HBV reactivation were analyzed. The overall survival (OS) from the first application of HAIC were compared between antiviral and non-antiviral groups.ResultsA total of 25 patients (14.7%) developed HBV reactivation after HAIC, of which 16 patients received antiviral treatment and nine patients did not. The incidence of HBV reactivation was 11.7% (16/137) in antiviral group and 27.3% (9/33) in non-antiviral group respectively. No antiviral prophylactic was the only significant risk factor for HBV reactivation (OR=12.35, 95% confidence interval (CI) 4.35–33.33, p&lt;0.001). Patients in antiviral group received more cycles of HAIC compared with non-antiviral group (3.11 ± 1.69 vs 1.75 ± 1.18, p&lt;0.05) at the time of HBV reactivated. Seven of the 25 HBV reactivation patients developed hepatitis. OS in antiviral group was significantly longer than that of non-antiviral group (median 16.46 vs 10.68 months; HR=0.57; 95% CI, 0.36–0.91; p&lt;0.05).ConclusionsHBV reactivation is more prone to occur in the HBsAg-positive HCC patients undergoing HAIC without antiviral prophylaxis. Regular monitoring of HBV DNA and antiviral prophylaxis are suggested to prevent HBV reactivation as well as prolong the OS of these patients.Name of the Trial RegisterHAIC Using Oxaliplatin Plus Fluorouracil/Leucovorin for Patients with Locally Advanced HCC.Clinical Trial Registrationhttps://www.clinicaltrials.gov/, identifier NCT 02436044
The Predictive Value of Tumor Volume and Its Change on Short-Term Outcome for Esophageal Squamous Cell Carcinoma Treated With Radiotherapy or Chemoradiotherapy
Authors: Liang Shuai , Li Chengming , Gao Zhenhua , Shang Dongping , Yu Jinming , Meng Xue 
Published: February 2021

ObjectivesTo investigate the tumor volume and its change on short-term outcome in esophageal squamous cell carcinoma (ESCC) patients who underwent definitive radiotherapy or chemoradiotherapy.Methods and MaterialsAll data were retrospectively collected from 418 ESCC patients who received radiotherapy or chemoradiotherapy at our institution between 2015 and 2019. Short-term outcome using the treatment response evaluation was assessed according to the RECIST 1.1. The tumor volume change rate (TVCR) was defined as follows: TVCR = {1 − [gross tumor volume (GTV) at shrinking irradiation field planning)]/(GTV at the initial treatment planning)} ×100%. Chi square test was used to compare the clinic characteristics in different TVCR groups, and the difference between initial GTV (GTVi) and shrinking GTV (GTVs) was compared using Wilcoxon’s sign rank test. Logistic regression analysis and Spearman correlation was performed.ResultsThere was a significant decrease in GTVi compared to GTVs (P &lt; 0.001). In univariate analysis, age, cT-stage, TNM stage, treatment modality, GTVi, and TVCR were associated with short-term outcome (all P&lt; 0.05). In multivariate analysis, gender and TVCR were statistically significant (P = 0.010, &lt;0.001) with short-term outcome, and the combined predictive value of gender and TVCR exceeded that of TVCR (AUC, 0.876 vs 0.855).ConclusionsTVCR could serve to forecast short-term outcome of radiotherapy or chemoradiotherapy in ESCC. It was of great significance to guide the individualized treatment of ESCC.