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Cyclic hibernation bouts in Daurian ground squirrels (Spermophilus dauricus) lead to repeated suppression and recovery of mitochondrial respiratory function across multiple organs, potentially impacting reactive oxygen species (ROS) dynamics. The Harderian gland (HG) plays an important role in endocrine regulation through porphyrin secretion. However, the influence of hibernation on oxidative pressure and associated antioxidant pathways in the HG remains inadequately understood. In the current study, we investigated the morphological changes, secretory activity, ROS levels, and underlying mechanisms in the HG of Daurian ground squirrels at distinct circannual stages of hibernation. Results indicated that: (1) Protoporphyrin levels in the HG increased during hibernation compared to the summer active (SA) phase, with a reduction in acinar lumen during torpor, potentially related to hibernation in a low-light environment. (2) Hydrogen peroxide (H 2 O 2 ) and malondialdehyde (MDA) content during hibernation and post-hibernation (POST) did not exceed the levels observed in SA, indicating that the HG effectively mitigated oxidative pressure and lipid peroxidation during these periods. (3) Superoxide dismutase (SOD) activity increased while glutathione peroxidase (GPx) activity decreased during Inter-bout arousal (IBA) compared to both SA and torpor, although total antioxidant capacity (T-AOC) remained stable across all stages. (4) Overall fluorescent intensity of nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) was significantly lower than in SA. These findings demonstrate that the HG in Daurian ground squirrels maintains a favorable oxidative status through the regulation of antioxidant enzyme activities during hibernation and even post-hibernation., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To investigate the biological characteristics of triple negative breast cancer (TNBC) with low expression of HER2 (HER2-low). Methods: A total of 93 TNBC cases in Shanxi Cancer Hospital from 2017 to 2019 were collected and divided into HER2-negative and HER2-low groups according to HER2 expression status. The clinicopathological features and prognostic differences between the two groups were retrospectively analyzed and compared, and genetic detection of tumor tissues was performed to clarify somatic mutation status and differences between the two groups. Results: Ninety-three patients aged 26 to 86 years were enrolled, including 60 patients in the HER2-negative group and 33 patients in the HER2-low group. The distribution of HER2-low in luminal androgen receptor (LAR) subtype (14/23, 60.87%) and non-LAR subtype (19/70, 27.14%) was significantly different ( P= 0.005). There were no significant differences in age, pT stage, histological grade, infiltration mode, lymph node metastasis and survival analysis. The expression of HER2-low in the tumor was heterogeneous, including different proportions of weak, weak to moderate intensity, and incomplete to intact membrane staining. With the change of the proportion of HER2-positive cells, the different distribution of those cells in the total tumor cells was noted, including cluster, mosaic and scattered patterns. The concentration and quality of DNA extracted from 71 of the 93 samples met the requirements for making libraries, including 43 in the HER2-negative group and 28 in the HER2-low group. Genetic mutations were mainly missense mutations, single nucleotide mutations, and point mutations in which base C was replaced by base T. There was no significant difference in genes with mutation frequency>3 times between the two groups. CTNNB1 and FGFR3 genes were only mutated in HER2-low group; while ALK, CYP2D6 and FAT1 genes were only mutated in HER2-negative group. HER2-low group included 18 HER2 1+ cases and 10 HER2 2+ cases. Genes with mutation frequency>3 times between the two groups included PIK3CA, TP53, SLX4, ATM and BRCA1. The mutation frequency of PIK3CA in HER2 2+ was significantly higher than that in HER2 1+ group ( P <0.05), and SLX4 gene was only mutated in HER2 1+ group. Conclusions: There are some differences of histological morphology and genetic variation between HER2-negative group and HER2-low group, and also differences in genetic variation between HER2 1+ and HER2 2+ in HER2-low group, which are helpful for more accurate stratification of TNBC and useful for finding the therapeutic target and precise treatment of HER2-low TNBC.

Triple-negative breast cancer (TNBC) has high heterogeneity, poor prognosis, and limited treatment success. Recently, an immunohistochemistry-based surrogate classification for the "Fudan University Shanghai Cancer Center (FUSCC) subtyping" has been developed and is considered more suitable for clinical application. Seventy-one paraffin-embedded sections of surgically resected TNBC were classified into four molecular subtypes using the IHC-based surrogate classification. Genomic analysis was performed by targeted next-generation sequencing and the specificity of the subtypes was explored by bioinformatics, including survival analysis, multivariate Cox regression, pathway enrichment, Pyclone analysis, mutational signature analysis and PHIAL analysis. AKT1 and BRCA1 mutations were identified as independent prognostic factors in TNBC. TNBC molecular subtypes encompass distinct genomic landscapes that show specific heterogeneities. The luminal androgen receptor (LAR) subtype was associated with mutations in PIK3CA and PI3K pathways, which are potentially sensitive to PI3K pathway inhibitors. The basal-like immune-suppressed (BLIS) subtype was characterized by high genomic instability and the specific possession of signature 19 while patients in the immunomodulatory (IM) subtype belonged to the PD-L1 ≥ 1% subgroup with enrichment in Notch signaling, suggesting a possible benefit of immune checkpoint inhibitors and Notch inhibitors. Moreover, mesenchymal-like (MES) tumors displayed enrichment in the receptor tyrosine kinase (RTK)-RAS pathway and potential sensitivity to RTK pathway inhibitors. The findings suggest potential treatment targets and prognostic factors, indicating the possibility of TNBC stratified therapy in the future., (© 2024. The Author(s).)

Background: Glioblastoma, a highly aggressive form of brain cancer, poses significant challenges due to its resistance to therapy and high recurrence rates. This study aimed to investigate the expression and functional implications of CDKN2A, a key tumor suppressor gene, in glioblastoma cells, building upon the existing background of knowledge in this field., Method: Quantitative reverse transcription PCR (qRT-PCR) analysis was performed to evaluate CDKN2A expression in U87 glioblastoma cells compared to normal human astrocytes (NHA). CDKN2A expression levels were manipulated using small interfering RNA (siRNA) and CDKN2A overexpression vector. Cell viability assays and carmustine sensitivity tests were conducted to assess the impact of CDKN2A modulation on glioblastoma cell viability and drug response. Sphere formation assays and western blot analysis were performed to investigate the role of CDKN2A in glioblastoma stem cell (GSC) self-renewal and pluripotency marker expression. Additionally, methylation-specific PCR (MSP) assays and demethylation treatment were employed to elucidate the mechanism of CDKN2A downregulation in U87 cells., Result: CDKN2A expression was significantly reduced in glioblastoma cells compared to NHA. CDKN2A overexpression resulted in decreased cell viability and enhanced sensitivity to carmustine treatment. CDKN2A inhibition promoted self-renewal capacity and increased pluripotency marker expression in U87 cells. CDKN2A upregulation led to elevated protein levels of p16INK4a, p14ARF, P53, and P21, which are involved in cell cycle regulation. CDKN2A downregulation in U87 cells was associated with high promoter methylation, which was reversed by treatment with a demethylating agent., Conclusion: Our findings demonstrate that CDKN2A downregulation in glioblastoma cells is associated with decreased cell viability, enhanced drug resistance, increased self-renewal capacity, and altered expression of pluripotency markers. The observed CDKN2A expression changes are mediated by promoter methylation. These results highlight the potential role of CDKN2A as a therapeutic target and prognostic marker in glioblastoma., (© 2024. The Author(s).)

Objective: To develop and validate a three-year risk prediction model for new-onset cardiovascular diseases (CVD) among female patients with breast cancer., Methods: Based on the data from Inner Mongolia Regional Healthcare Information Platform, female breast cancer patients over 18 years old who had received anti-tumor treatments were included. The candidate predictors were selected by Lasso regression after being included according to the results of the multivariate Fine & Gray model. Cox proportional hazard model, Logistic regression model, Fine & Gray model, random forest model, and XGBoost model were trained on the training set, and the model performance was evaluated on the testing set. The discrimination was evaluated by the area under the curve (AUC) of the receiver operator characteristic curve (ROC), and the calibration was evaluated by the calibration curve., Results: A total of 19 325 breast cancer patients were identified, with an average age of (52.76±10.44) years. The median follow-up was 1.18 [interquartile range (IQR): 2.71] years. In the study, 7 856 patients (40.65%) developed CVD within 3 years after the diagnosis of breast cancer. The final selected variables included age at diagnosis of breast cancer, gross domestic product (GDP) of residence, tumor stage, history of hypertension, ischemic heart disease, and cerebrovascular disease, type of surgery, type of chemotherapy and radiotherapy. In terms of model discrimination, when not considering survival time, the AUC of the XGBoost model was significantly higher than that of the random forest model [0.660 (95% CI : 0.644-0.675) vs . 0.608 (95% CI : 0.591-0.624), P < 0.001] and Logistic regression model [0.609 (95% CI : 0.593-0.625), P < 0.001]. The Logistic regression model and the XGBoost model showed better calibration. When considering survival time, Cox proportional hazard model and Fine & Gray model showed no significant difference for AUC [0.600 (95% CI : 0.584-0.616) vs . 0.615 (95% CI : 0.599-0.631), P =0.188], but Fine & Gray model showed better calibration., Conclusion: It is feasible to develop a risk prediction model for new-onset CVD of breast cancer based on regional medical data in China. When not considering survival time, the XGBoost model and the Logistic regression model both showed better performance; Fine & Gray model showed better performance in consideration of survival time.

Nine tetrahydrofuran lignans, including three undescribed spiro-lignans, were isolated from Isatis indigotica Fortune (Brassicaceae). Extensive spectroscopic analyses achieved the structure elucidation of these tetrahydrofuran lignans, and quantum chemical calculation combined with the MAE ΔΔδ parameter. Notably, isatispironeols A-B have a unique spiro[dienone-tetrahydrofuran] molecular core. These spiro[dienone-tetrahydrofuran] lignans showed comparable neuroprotective effects as the positive control in the H 2 O 2 -induced SH-SY5Y cells model. In addition, (-)-(7R,8S,1'R,7'R,8'R)-isatispironeol A possessed more significant AChE inhibitory activity, further interact sites were also predicted by the in silico assay., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Hyperglycemia exacerbates brain damage in cerebral ischemia/reperfusion injury. Previous study found that Lycium barbarum polysaccharides (LBP) has a neuroprotective effect on hyperglycemia-aggravated ischemic brain injury, which raising the possibility for treatment of neurodegenerative diseases. However, the underlying mechanism of LBP-induced protection by ameliorating hyperglycemia-aggravated ischemia/reperfusion injury needs to be tested. This study aimed to investigate the effects of LBP on blood-brain barrier (BBB) integrity with a hyperglycemia-aggravated cerebral ischemia/reperfusion injury model., Methods: Sprague-Dawley male rats were randomly divided into three groups: normoglycemic (NG), hyperglycemic (HG), and LBP-pretreated hyperglycemic (HG + LBP). Animals underwent middle cerebral artery occlusion (MCAO) for 30 min, followed by 1-, 3-, and 7-day of reperfusion., Results: Our results showed that the neurological deficit, infarct volume, cell apoptosis, and IgG leakage in the HG group significantly increased separately, compared with that of the NG group, (p < 0.05). Pre-treatment with LBP reversed these injury indicators (p < 0.05). And much more severe degree of swelling endothelium, swollen astrocyte, and decreased tight junctions in the micro-vessel were detected in the HG group comparing to that of the NG group. In addition, increased degree of basement membrane degradation, dissociation between the astrocyte endfeet and basement membrane, and tight junction's protein degradation was found in the HG group compared with the NG group (p < 0.05). However, when exposure to LBP therapy could reverse the above alterations (p < 0.05)., Conclusions: These results demonstrated that LBP could ameliorate hyperglycemia-exacerbated cerebral ischemia/reperfusion injury via protecting the blood-brain barrier., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2022. Published by Elsevier B.V.)

Systemic anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALCL) is a group of heterogenous CD30 + T-cell non-Hodgkin lymphomas. Previous studies have highlighted the importance of JAK/STAT3 signaling activation in the molecular pathogenesis of ALK - ALCLs. In the present study, we aimed to establish a potential relationship between JAK/STAT3 signaling activation and clinicopathologic features in ALK - ALCLs, and further recognize the heterogenous nature of these neoplasms. Immunohistochemistry staining of the phosphorylated-STAT3 (p-STAT3) and dual-specificity protein phosphatase 22 ( DUSP22 ) gene rearrangement analysis were performed. Forty-five cases of ALK - ALCL were divided into 3 groups, including 9 DUSP22 -rearranged ALCLs, 21 p-STAT3 + double-negative (DN) ALCLs (both ALK and DUSP22 rearrangement negative), and 15 p-STAT3 - DN-ALCLs. Morphologically, p-STAT3 + DN-ALCLs exhibited sheet-like neoplastic cells and sometimes showed large pleomorphic cells scattered in a lymphocyte-rich background more frequently than those in other ALK - ALCLs subtypes. Phenotypically, the p-STAT3 + DN-ALCLs frequently expressed cytotoxic molecules, epithelial membrane antigen, and programmed death-ligand 1, whereas CD3 and CD5 expression was not observed. Clinically, patients with p-STAT3 + DN-ALCLs had a better prognosis than those with p-STAT3 - DN-ALCLs. These observations suggest that p-STAT3 + DN-ALCLs represent a distinct subtype of ALK - ALCLs. Identifying ALK - ALCL subtypes by using p-STAT3 staining and DUSP22 rearrangement is a promising approach that may contribute to risk stratification and better treatment decisions in the future clinical practice., Competing Interests: Conflicts of Interest and Source of Funding: Supported by the Fujian Science and Technology Program (2019Y9039 and 2021J01429). The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Seven undescribed polyketide compounds (1-4, 9-11) and six known polyketide compounds (5-8,12, 13) were isolated from Rhodiola tibetica endophytic Penicillium sp. HJT-A-10. The structural of seven undescribed polyketides metabolites were established on the basis of spectroscopic methods. The results of anti-inflammatory activity showed that compounds 1-8，10-13 had significant inhibitory effects on LPS-induced NO production in RAW 264.7 cells., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Importance: China is experiencing a sustained increase in childhood cancer. However, whether differences exist in disease burden by ethnicity remains unclear., Objective: To compare differences in cancer diagnoses and health care utilization in Inner Mongolia among children subgrouped by ethnicity (Han vs Mongolian), sex, and age., Design, Setting, and Participants: This retrospective cohort study in Inner Mongolia, China, used data on children aged 0 to 14 years with cancer from the Inner Mongolia Regional Health Information Platform, which comprises the National Basic Medical Insurance database and the Inner Mongolia cause-of-death reporting system, from January 1, 2013, to December 31, 2019. Ethnicities analyzed included Han and Mongolian; patients of other ethnicities were not included in the analysis because of the small sample size. Cancer was broadly defined as a primary malignant tumor or hematologic cancer; benign central nervous system tumors were also included. A 2-year washout period was used to exclude prevalent cases. After diagnosis, the patients were followed up until the date of death or the end of the insured status, whichever came first., Exposures: Ethnicity (Han vs Mongolian), sex (male vs female), and age (0-4, 5-9, and 10-14 years)., Main Outcomes and Measures: Crude incidence, 5-year prevalence, and survival rates at 1 year and 3 years after diagnosis; health care utilization, represented by medical costs during the first year and first 3 years after diagnosis; and hospital attendance with level (tertiary vs secondary and lower-level hospitals) and location of each unique visit., Results: From 2013 to 2019, 1 106 684 (2013), 1 330 242 (2014), 1 763 746 (2015), 2 400 343 (2016), 2 245 963 (2017), 2 901 088 (2018), and 2 996 580 (2019) children aged 0 to 14 years were registered in the NBMI database. Among the 2 996 580 children enrolled in 2019, the mean (SD) age was 6.8 (4.3) years, of whom 1 572 096 (52.5%) were male, 2 572 091 (85.8%) were Han, and 369 400 (12.3%) were Mongolian. A total of 1910 patients with cancer were identified (1048 were male [54.9%]; 1559 were Han [81.6%], and 300 were Mongolian [15.7%]). There were 764 hematologic cancers (40.0%) and 1146 solid tumors (60.0%). The overall crude incidence of cancer from 2015 to 2019 was 129.85 per million children (95% CI, 123.63-136.06), with a higher incidence among Mongolian than among Han children (155.12 [95% CI, 136.81-173.43] vs 134.39 [95% CI, 127.46-141.32]). The 5-year prevalence was 428.97 per million (95% CI, 405.52-452.42) in 2020, with a higher prevalence among Mongolian than among Han children (568.49 [95% CI, 91.62-645.36] vs 404.34 [95% CI, 379.77-428.91]). The combined 1-year (2015-2019) and 3-year (2015-2017) survival rates were 72.5% (95% CI, 67.5%-77.5%) and 66.8% (95% CI, 61.6%-71.9%), respectively. The 1-year (median [IQR], $1991 [$912-$10 181] vs $3991 [$1171-$15 425]) and 3-year (median [IQR], $2704 [$954-$13 909] vs $5375 [$1283-$22 466]) postdiagnosis costs were lower among Mongolian than among Han children. A higher proportion of Mongolian patients attended low-level hospitals (45.9% vs 17.4%)., Conclusions and Relevance: In this cohort study, Mongolian children had a higher incidence and prevalence of cancer but a lower demand for medical care, suggesting that further investigations are needed to identify mechanisms underlying ethnic disparities and ensure that care is equitable.

The molecular subtyping of triple-negative breast cancer (TNBC) is critical to guiding individualized patient treatment. In this study, we sought to characterize the clinicopathologic features of TNBC subtypes and to identify correlates of patient survival in an effort to provide a robust foundation for treatment planning. We additionally assessed PD-L1 expression in Chinese TNBC patients and evaluated the relationship between such expression and immunotherapeutic treatment outcomes. Based on analyses of histologic characteristics including apocrine differentiation, tumor-infiltrating lymphocytes, and metaplastic features, we selected immunohistochemical (IHC) markers including CD8, FOXC1, and AR for use in classifying TNBC cases. Associations between these subtypes and a range of clinicopathologic characteristics were evaluated. We classified a cohort of 93 TNBC patients into individuals with luminal androgen receptor (LAR), immunomodulatory (IM), basal-like immune-suppressed (BLIS), and mesenchymal (MES) tumor subtypes (23, 24, 39, and 7 cases, respectively). PD-L1 positivity was observed in 49.6% of cases and was more common in individuals with IM subtype disease. Mismatch repair deficiency (dMMR) was observed in just one patient. Significant differences in histologic grade, pT stage, lymphocyte distribution patterns, large scarring areas without cells in tumor of central (central scar), and PD-L1, P53, and Rb status were observed among these TNBC subtypes, whereas no such differences were observed with respect to age, invasion pattern, or pN stage. Rates of disease progression were higher at the 40-50 month follow-up time point, but there were no significant differences in recurrence-free survival or breast cancer-specific survival among these subtypes. IHC markers associated with clinicopathologic characteristics represent a powerful approach to TNBC molecular typing, providing a foundation for precision patient treatment. PD-L1 expression may represent a relevant factor in TNBC patient immunotherapeutic treatment planning, whereas dMMR is not likely to be of substantial value when evaluating immunotherapeutic efficacy in these patients., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

UV-guided fractionation led to the isolation of thirteen new polyacetylenes (1-13) from the roots of Bupleurum scorzonerifolium Willd. All polyacetylenes were analyzed as racemates since the lack of optical activity and Cotton effects in the ECD spectra. The sequent chiral-phase HPLC resolution successfully gave twelve pairs of enantiomers 1a/1b and 3a/3b-13a/13b. Their structures were elucidated based on the HRESIMS and NMR data analyses. The absolute configurations were determined by the combination of Snatzke's method, electronic circular dichroism calculations, and single-crystal X-ray diffraction. Using Griess methods and MTT assays, polyacetylenes 1a, 3a, 4a/4b-12a/12b, and 13a displayed inhibitory activities against LPS-induced NO release in BV-2 microglial cells., (Copyright © 2021. Published by Elsevier Inc.)

Background: Secretory breast carcinoma is an uncommon subset of breast cancer that usually has a favorable outcome. Although initially described in children, it also occurs in adults where it may metastasize, possibly resulting in death. To date, only 20 cases of secretory breast carcinoma with distant metastases have been described., Case Presentation: A 42-year-old female presented with liver metastasis after modified radical mastectomy of the left breast in 2008 at 34 years of age. The liver metastasis was morphologically similar to the primary tumor. Pan-TRK and Fluorescence in situ hybridization showed a rearrangement in the ETV6 gene. She subsequently underwent adjuvant chemotherapy with a fatal outcome., Conclusions: Although secretory breast carcinoma is usually associated with favorable outcomes, our study and reviews provide a novel insight into the genetic spectrum and treatment of secretory breast carcinoma showing reduced expression of hormone receptors, abnormal genomic profiles, and possible poor prognosis. Targeted therapy may curb clinically aggressive cases. Additional molecular investigations are needed to determine the links between specific mutations and poor prognosis., (© 2021. The Author(s).)

Seven alkaloids including five undescribed ones (1a/1b, 2, 3 and 5) were obtained from the leaves of Isatis indigotica Fortune. Their structures were established by extensive spectroscopic analyses. The absolute configurations of compounds 1a, 1b, 3 and 5 were determined by comparison of the experimental and calculated electronic circular dichroism (ECD) spectra. Subsequently, the neuroprotective effects of all the isolates against H 2 O 2 -induced injury in SH-SY5Y cells were evaluated in vitro by MTT assay. Moreover, Annexin V-FITC/PI double staining was performed, while the activities of antioxidant enzymes (SOD, CAT and GSH-Px) for compounds 1a and 1b were measured., (Copyright © 2021 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.)

Objective: To study the expression of GATA3 and bcl-11b in peripheral T-cell lymphoma (PTCL) and their correlation with clinicopathological features. Methods: The Oncomine and GEO databases were used for analyzing the expression levels of GATA3 and bcl-11b mRNA in PTCL. Immunohistochemistry was used to detect the expression of GATA3 and bcl-11b proteins in 127 cases of PTCL diagnosed at Shanxi Provincial Cancer Hospital from January 2010 to June 2020, as well as 40 cases of lymph node with reactive hyperplasia. Results: The data in Oncomine and GEO databases showed that the expression of GATA3 and bcl-11b mRNA in PTCL was lower than that in normal tissues ( P <0.05). Immunohistochemistry showed that the positive rates of GATA3 in PTCL and lymph nodes with reactive hyperplasia were 60.6% (77/127) and 85.0% (34/40, P <0.05), respectively. The expression rates of bcl-11b in PTCL and lymph nodes with reactive hyperplasia were 55.1% (70/127) and 75.0% (30/40, P <0.05), respectively. The expression of GATA3 was related to the pathological classification of the patients with PTCL, and was inversely related to the Ann Arbor stage of the patient, while the expression of bcl-11b was inversely correlated with the IPI score of the patient ( P <0.05). The expression of GATA3 and bcl-11b was related to the patients' age, gender, LDH level, and B symptoms. Other clinicopathological characteristics were irrelevant. Spearman correlation analysis shows that the expression of GATA3 protein was associated with that of bcl-11b protein in PTCL. Conclusion: GATA3 and bcl-11b are closely related to the prognosis of PTCL, and may be important factors involved in the occurrence and development of PTCL.

Purpose: To compare the performance of three-level EuroQol five-dimensions (EQ-5D-3L) and five-level EuroQol five-dimensions (EQ-5D-5L) among common cancer patients in urban China., Methods: A hospital-based cross-sectional survey was conducted in three provinces from 2016 to 2018 in urban China. Patients with breast cancer, colorectal cancer, or lung cancer were recruited to complete the EQ-5D-3L and EQ-5D-5L questionnaires. Response distribution, discriminatory power (indicator: Shannon index [H'] and Shannon evenness index [J']), ceiling effect (the proportion of full health state), convergent validity, and health-related quality of life (HRQoL) were compared between the two instruments., Results: A total of 1802 cancer patients (breast cancer: 601, colorectal cancer: 601, lung cancer: 600) were included, with the mean age of 55.6 years. The average inconsistency rate was 4.4%. Compared with EQ-5D-3L (average: H' = 1.100, J' = 0.696), an improved discriminatory power was observed in EQ-5D-5L (H' = 1.473, J' = 0.932), especially contributing to anxiety/depression dimensions. The ceiling effect was diminished in EQ-5D-5L (26.5%) in comparison with EQ-5D-3L (34.5%) (p < 0.001), mainly reflected in the pain/discomfort and anxiety/depression dimensions. The overall utility score was 0.790 (95% CI 0.778-0.801) for EQ-5D-3L and 0.803 (0.790-0.816) for EQ-5D-5L (p < 0.001). A similar pattern was also observed in the detailed cancer-specific analysis., Conclusions: With greater discriminatory power, convergent validity and lower ceiling, EQ-5D-5L may be preferable to EQ-5D-3L for the assessment of HRQoL among cancer patients. However, higher utility scores derived form EQ-5D-5L may also lead to lower QALY gains than those of 3L potentially in cost-utility studies and underestimation in the burden of disease.

Two commonly observed charge transport mechanisms in single-molecule junctions are coherent tunneling and incoherent hopping. It has been generally believed that tunneling processes yield temperature-independent conductance behavior and hopping processes exhibit increasing conductance with increasing temperature. However, it has recently been proposed that tunneling can also yield temperature-dependent transport due to the thermal broadening of the Fermi energy of the contacts. In this work, we examine a series of rigid, planar furan oligomers that are free from a rotational internal degree of freedom to examine the temperature dependence of tunneling transport directly over a wide temperature range (78-300 K). Our results demonstrate conductance transition from a temperature-independent regime to a temperature-dependent regime. By examining various hopping and tunneling models and the correlation between the temperature dependence of conductance and molecular orbital energy offset from the Fermi level, we conclude thermally assisted tunneling is the dominant cause for the onset of temperature-dependent conductance in these systems.

Enhancing the gating performance of single-molecule conductance is significant for realizing molecular transistors. Herein, we report a new strategy to improve the electrochemical gating efficiency of single-molecule conductance with fused molecular structures consisting of heterocyclic rings of furan, thiophene, or selenophene. One order magnitude of gating ratio is achieved within a potential window of 1.2 V for the selenophene-based molecule, which is significantly greater than that of other heterocyclic and benzene ring molecules. This is caused by the different electronic structures of heterocyclic molecules and transmission coefficients T ( E ), and preliminary resonance tunneling is achieved through the highest occupied molecular orbital at high potential. The current work experimentally shows that electrochemical gating performance can be significantly modulated by the alignment of the conducting orbital of the heterocyclic molecule relative to the metal Fermi energy.

Disturbed blood flow has been recognized to promote platelet aggregation and thrombosis via increasing accumulation of von Willebrand factor (VWF) at the arterial post-stenotic sites. The mechanism underlying the disturbed-flow regulated endothelial VWF production remains elusive. Here we described a mouse model, in which the left external carotid artery (LECA) is ligated to generate disturbed flow in the common carotid artery. Ligation of LECA increased VWF accumulation in the plasma. Carotid arterial thrombosis was induced by ferric chloride (FeCl 3 ) application and the time to occlusion in the ligated vessels was reduced in comparison with the unligated vessels. In vitro , endothelial cells were subjected to oscillatory shear (OS, 0.5 ± 4 dynes/cm 2 ) or pulsatile shear (PS, 12 ± 4 dynes/cm 2 ). OS promoted VWF secretion as well as the cell conditioned media-induced platelet aggregation by regulating the intracellular localization of vesicle-associated membrane protein 3 (VAMP3) and synaptosomal-associated protein 23 (SNAP23). Disruption of vimentin intermediate filaments abolished the OS-induced translocation of SNAP23 to the cell membrane. Knockdown of VAMP3 and SNAP23 reduced the endothelial secretion of VWF. Systemic inhibition of VAMP3 and SNAP23 by treatment of mice with rapamycin significantly ameliorated the FeCl 3 -induced thrombogenesis, whereas intraluminal overexpression of VAMP3 and SNAP23 aggravated it. Our findings demonstrate VAMP3 and SNAP23 as potential targets for preventing the disturbed flow-accelerated thrombus formation., (Copyright © 2020 Zhu, Jiang, Liu, Xi, Wang, Yang, Yao, Pang, Han, Zhang, Sun and Zhou.)

Objective: To investigate the expression of CDK6 and FOXM1 in peripheral T-cell lymphoma (PTCL), and its correlation with clinicopathologic features and patient prognosis. Methods: The Oncomine was used for data mining and analyzing the expression levels of CDK6 and FOXM1 in PTCL. Immunohistochemistry (IHC) of EnVision method was used to detect the expression of CDK6 and FOXM1 proteins in 166 cases of PTCL diagnosed at Shanxi Provincial Cancer Hospital from January 2016 to December 2018, and 30 cases of lymph node with reactive hyperplasia as control. Results: Among the PTCL patients, 104 were male and 62 were female, aged from 3 to 85 years, with an average age of 53 years. Analyses of the Oncomine 4.5 database showed that mRNA expression of CDK6 and FOXM1 in PTCL tissues was significantly higher than that in normal tissue ( P< 0.05). IHC staining showed the positive rates of CDK6 and FOXM1 proteins in PTCL tissues were 27.7% (46/166) and 80.7% (134/166), respectively. The expression was mainly present in the nuclei of tumor cells, showing a diffuse, strongly positive pattern. The positive rates of CDK6 and FOXM1 proteins among the 30 cases of lymph-node reactive hyperplasia were 0 (0/30) and 30% (9/30), respectively. The expression of FOXM1 was mainly found in the lymphoid follicle germinal center, and not present in the T-zone cells. CDK6 protein, FOXM1 protein and the co-expression of CDK6 and FOXM1 proteins in PTCL were associated with higher Ann Arbor staging and international prognostication index score ( P< 0.05), and inversely associated with overall survival ( P< 0.05). Meanwhile, CDK6 protein expression was positively correlated with FOXM1 protein expression ( P< 0.05). Conclusions: CDK6 and FOXM1 may be new targets for the diagnosis and treatment of PTCL. The overexpression of CDK6 may lead to enhanced function of the transcription factor FOXM1, while the overexpression of CDK6 and FOXM1 also promotes the development and progression of PTCL.

In the current study, four pairs of new enantiomeric alkaloids (1a/1b-4a/4b) were obtained from the leaves of Isatis indigotica Fortune Ex Land. Their structures were elucidated through spectroscopic methods and quantum mechanical calculations. Biologically, all isolates were evaluated for their neuroprotective effects against H 2 O 2 -induced SH-SY5Y cell injury. As a result, 1a and 1b exhibited enantioselective neuroprotective effects, further Annexin V-FITC/PI analysis showed that apoptosis ratios of 1a and 1b were reduced to 20.93% and 17.87%, respectively., Competing Interests: Conflict of interest The authors declare that there are no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Mutations of PIK3CA have recently been shown to play an important role in the pathogenesis and progression of breast neoplasms. The prevalence of PIK3CA in Chinese breast cancer patients may be underestimated. Therefore, we investigated the distribution of somatic PIK3CA mutation in Chinese breast cancer patients and explored their role in tumor phenotypes., Methods: Mutational analysis of PIK3CA was done in 113 primary breast cancers of Chinese women used Amplification refractory mutation system (ARMS). The relationship of PIK3CA mutations with several clinicopathologic characteristics was analyzed., Results: PIK3CA gene mutation was identified in 43(38.05%) cases and has a more significant difference between exon 9 and 20. HER2 gene amplification was 32.6% in 43 cases of PIK3CA mutation, but 37.1% in 70 cases of non-mutation (χ 2 = 0.245, P > 0.05). There was no significant correlation of the age distribution, lymph node status, histological tumor grading, ER and/or PR and P53 between 2 groups (P > 0.05)., Conclusion: A high frequency of somatic PIK3CA mutation was detected in Chinese breast cancer patients, especially in exon 20. The relationship between PIK3CA gene mutation and clinical pathological features of breast cancer needs to be further studied in a large series of patients. PIK3CA mutations seem to have the potential to be used in target treatment and as an indicator of prognosis.

Objective: To understand the consistency of ALK Ventana-D5F3 immunohistochemistry (IHC) interpretation in Chinese lung adenocarcinoma among histopathologists from different hospitals, and to recommend solution for the problems found during the interpretation of ALK IHC in real world, with the aim of the precise selection of patients who can benefit from ALK targeted therapy. Methods: This was a multicenter and retrospective study. A total of 109 lung adenocarcinoma cases with ALK Ventana-D5F3 IHC staining were collected from 31 lung cancer centers in RATICAL research group from January to June in 2018. All cases were scanned into digital imaging with Ventana iSCANcoreo Digital Slide Scanning System and scored by 31 histopathologists from different centers according to ALK binary (positive or negative) interpretation based on its manufacturer's protocol. The cases with high inconsistency rate were further analyzed using FISH/RT-PCR/NGS. Results: There were 49 ALK positive cases and 60 ALK negative cases, confirmed by re-evaluation by the specialist panel. Two cases (No. 2302 and No.2701) scored as positive by local hospitals were rescored as negative, and were confirmed to be negative by RT-PCR/FISH/NGS. The false interpretation rate of these two cases was 58.1% (18/31) and 48.4% (15/31), respectively. Six out of 31 (19.4%) pathologists got 100% accuracy. The minimum consistency between every two pathologists was 75.8%.At least one pathologist gave negative judgement (false negative) or positive judgement (false positive) in the 49 positive or 60 negative cases, accounted for 26.5% (13/49), 41.7% (25/60), respectively, with at least one uncertainty interpretation accounted for 31.2% (34/109). Conclusion: There are certain heterogeneities and misclassifications in the real world interpretation of ALK-D5F3 IHC test, which need to be guided by the oncoming expert consensus based on the real world data.

Six pairs of alkaloid enantiomers including 11 new alkaloids (1A: /1B: -5A: /5B, 6A: ) were isolated from the leaves of Isatis tinctoria . Their structures were established by extensive spectroscopic analyses. Enantiomers were separated successfully by chiral chromatographic column and the absolute configurations of all isolates were determined by comparison of experimental and calculated electronic circular dichroism spectra. The isolated alkaloids were evaluated for their neuroprotective activities against H 2 O 2 -induced cell injury in human neuroblastoma SH-SY5Y cells. The results showed that 5A/5B: and 6A/6B: exhibited potent neuroprotective activities at 50 µM compared with the H 2 O 2 -treated group., Competing Interests: The authors declare that they have no conflict of interest., (Georg Thieme Verlag KG Stuttgart · New York.)

Five pairs of enantiomeric compounds (1a/1b-5a/5b) including seven undescribed compounds (1a/1b-3a/3b, 4b) along with two known ones (. and .) have been isolated from corn silk (Stigma maydis). Racemic mixtures of these enantiomers were separated by HPLC with different types of chiral columns. Their structures were elucidated based on comprehensive spectroscopic analyses together with quantum chemical calculations of 13 C NMR data and electronic circular dichroism (ECD) curves. All the isolates were evaluated for their inhibition ability of self-induced Aβ 1-42 aggregation. Among them, compounds 4a (88.36%), 4b (74.66%) and . (85.65%) showed stronger inhibitory activity than the positive control curcumin (61.90%). The different inhibition profiles of enantiomers 4a and 4b were explained by docking simulation studies., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: To evaluate the efficacy of reinforcement on duodenal stump using single purse-string suture during laparoscopic radical gastrectomy for gastric cancer in preventing duodenal stump leakage. Methods: A descriptive cohort study was conducted to retrospectively collect clinical data of 211 patients with gastric adenocarcinoma who underwent laparoscopic radical gastrectomy with Roux-en-Y or Billroth Ⅱ reconstruction and reinforcement on duodenal stump using laparoscopic single purse-string suture in Zhongshan Hospital of Fudan University between January 2013 and December 2016. Of 211 patients, 136 were male and 75 were female with mean age of (57.5±11.1)(24 to 87) years. Tumors locating at gastric upper 1/3, middle 1/3 and low 1/3 were found in 62, 68 and 81 patients respectively. Eighty-three cases underwent total gastrectomy, 128 underwent distal subtotal gastrectomy, 107 underwent Roux-en-Y reconstruction and 104 underwent Billroth II reconstruction. The procedure of reinforcement on duodenal stump using single purse-string suture during laparoscopic radical gastrectomy was as follows: (1) after cutting the duodenal stump to about 2.0 cm in length, use a 3-0 single-strand absorbable suture to make a muscle layer purse at a distance of 1.0 to 1.5 cm from the duodenal stump; (2) use the purse line to make a slipknot; (3) push the duodenum stump into the purse with a needle holder or grasper; (4) tighten the knot of the purse string, and then make 4 to 5 knots for reinforcement. Postoperative complications were defined and graded according to the Clavien-Dindo grading criteria, and the incidence of early complications was recorded. Clinicopathologic features and postoperative outcomes were analyzed. Results: All patients completed operations successfully. The mean time of laparoscopic single purse-string suture was (5.1±1.6) (3.6 to 10.2) minutes. Postoperative early complication occurred in 31 cases (14.7%), of whom 27 cases developed surgery-related complications (12.8%), including 7 cases (3.3%) of peritoneal infection, 6 (2.8%) of pancreatic leakage, 4 (1.9%) of wound infection, 4 (1.9%) of gastroplegia, 2 (0.9%) of peritoneal hemorrhage, 2 (0.9%) of intestinal obstruction, 2 (0.9%) of lymphatic leakage, and no duodenal stump leakage; while 4 cases (1.9%) developed internal non-surgical complication, including 3 cases (1.4%) of pulmonary infection and 1 (0.5%) of cardiovascular event. The patient with peritoneal hemorrhage was healed after re-operation and all other patients were discharged uneventfully after conservative treatment. Four cases (1.9%) developed complications beyond grade III a of Clavien-Dindo criteria. Conclusion: Reinforcement on duodenal stump using laparoscopic single purse-string suture during laparoscopic radical gastrectomy with Roux-en-Y or Billroth II reconstruction is simple and effective, and can prevent the risk of development of duodenal stump leakage.

A pair of new cycloneolignan enantiomers (1a and 1b) were isolated from the leaves of Isatis indigotica Fortune. Their structures were elucidated by extensive spectroscopic data analysis, including 1D and 2D NMR, HRESIMS, MS/MS analysis, together with theoretical electronic circular dichroism (ECD) calculations. Compounds 1a and 1b were then evaluated for their neuroprotective effects against MPP + -induced SH-SY5Y cell injury. As a result, compounds 1a (77.64%) and 1b (78.62%) exhibited moderate neuroprotective activity at the concentration of 12.5 µM compared with that of MPP + treated group (62.00% at 1 mM) by MTT assay. Furthermore, Annexin V-FITC/PI analysis showed that apoptosis ratios of 1a and 1b were reduced to 10.99% and 9.31%, respectively., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The relationship between survivin and extranodal, nasal-type natural killer/T cell lymphoma (ENKTCL) was unclearly established yet. We here studied the potential prognostic roles of survivin and its implication as a target in ENKTCL therapy., Methods: ENKTCL patients' peripheral blood were collected and tested by ELISA. ENKTCL cell lines were cultured with or without survivin inhibitor and tested by MTT and Flow cytometry. According to the gene expression profiles from the ArrayExpress Archive under E-TABM-702, survivin co-regulated cluster was established by Coupled Two-way Clustering Algorithm., Results: Seventeen point six percent of total 17 ENKTCL patients were serum survivin-positive. These patients had poorer outcome than that of negative cases (P<0.01). Analysis of survivin co-regulation genes in ENKTCL revealed that survivin was significantly involved in pluripotency, drug resistance, cell cycle and proliferation, indicating that it should be one of key regulators in ENKTCL and might be a latent therapeutic target. Our results just showed that YM155, a survivin inhibitor, had strong anti-tumor effect on ENKTCL cell lines in a dose dependent manner. It increased sub-G1 phase population and reduced G1- and G2-M phase populations (P<0.05). In addition, combining YM155 with DDP induced a larger decrease in cell viability than either agent alone and had a higher inhibition rate than Bliss index, suggesting their synergistic inhibition., Conclusions: We concluded that survivin was a potential prognostic marker and a critical regulatory molecule in the pathological process of ENKTCL. It would be a promising target in drugs discovery for ENKTCL therapy., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Objective: To investigate the expression of B7H3 and B7H4 in T lymphoblastic lymphoma/leukemia (T-LBL/ALL) in correlation with clinicopathological parameters and patient prognosis. Methods: Immunohistochemistry (IHC) was used to detect the expression of B7H3 and B7H4 protein in 100 cases of T-LBL/ALL(test group) and 30 cases of lymph node reactive hyperplasia (LH) (control group), diagnosed at Shanxi Cancer Hospital from January 2001 to June 2017. Real-time RT-PCR was used to detect the mRNA expression of B7H3 and B7H4 in 50 cases of T-LBL/ALL and 30 cases of LH (control group). Results: There were 79 males,21 females. Immunohistochemical results showed that the expression rates of B7H3 and B7H4 were 23%(23/100) and 54%(54/100), respectively. By real-time RT-PCR, the relative expression of B7H3 mRNA in the T-LBL/ALL group was 2.5 times of that of the LH group. The expression levels of B7H4 mRNA in T-LBL/ALL group and LH group were extremely low.Single factor analysis showed that B7H3 protein expression in T-LBL/ALL group was associated with B symptoms and primary nodal disease ( P< 0.05). B7H4 protein expression was associated with mediastinal broadening and bone marrow involvement ( P< 0.05). B7H3 protein, B7H3 mRNA, B7H4 protein expression and IPI score were associated with prognosis ( P< 0.05), and the combined expression of B7H3 and B7H4 was associated with T-LBL/ALL prognosis ( P< 0.05). Multivariate Cox regression analysis showed that overexpression of B7H3 mRNA was an independent risk factor for the prognosis of patients with T-LBL/ALL ( P< 0.05). Conclusion: Expression of B7H3 and B7H4 is closely corelated with clinicopathological parameters and prognosis of patients with T-LBL/ALL, suggesting that B7H3 and B7H4 expression play an important role in the development of T-LBL/ALL.

Correction for 'Bioactive spiropyrrolizidine oxindole alkaloid enantiomers from Isatis indigotica fortune' by Si-Fan Liu et al., Org. Biomol. Chem., 2018, 16, 9430-9439.

Four pairs of new spiropyrrolizidine oxindole enantiomers (1a/1b-4a/4b) were isolated from the leaves of Isatis indigotica Fortune. Their structures and absolute configurations were elucidated by a combination of NMR spectroscopic analyses, experimental and calculated electronic circular dichroism (ECD) and the assistance of quantum chemical predictions (QCP) of 13C NMR chemical shifts. Notably, all the isolated spiropyrrolizidine oxindoles are reported as natural products for the first time. The biosynthetic pathway of these unique structures was proposed to be formed by cycloaddition reaction. In addition, all the compounds were evaluated for their inhibitory effects on β-amyloid aggregation by ThT assay, and the optically pure compounds 1a/1b and 2a/2b exhibited better Aβ1-42 aggregation inhibition potency (85.8% and 73.6%, 71.5% and 75.8%, respectively) at a concentration of 20 μM, compared with the positive control curcumin (57.0%). The difference of the inhibitory pattern caused by chirality was also explained by molecular docking studies.

Seven new N-acylanthranilic acid derivatives (1-3, 4a/4b, 5a/5b) including two pairs of enantiomers (4a/4b and 5a/5b) were isolated from the leaves of Isatis indigotica Fortune. Their chemical structures were elucidated by extensive spectroscopic data analyses. The absolute configurations of compounds 4a/4b and 5a/5b were determined by comparison of the experimental and calculated ECD spectra. All compounds were tested for their anti-Aβ 1-42 aggregation activity. As a result, compounds 1 (72.1%), 2 (79.8%) and 5a (81.8%) showed stronger inhibitory activity than the positive control curcumin (67.0%). By the comparison between 5a (81.8%) and 5b (63.1%), it was found that stereochemical configurations may affect Aβ 1-42 aggregation activity, which was discussed through the molecular docking results of compounds 5a and 5b., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Rubus ideaus L., a member of the Rosaceae family, is popular for its distinctive flavor and attractive red color. In order to explore the functional factors possibly presented in the fruit, seven new benzofuran neolignans (1a/1b-3a/3b and 4b), together with one known neolignan 4a, were isolated from the fruit of R. ideaus. Compounds 1a/1b-4a/4b as four pairs of enantiomers were separated on a chiral chromatographic column. Their structures including absolute configurations were elucidated by extensive spectroscopic data analyses, including UV, IR, HRESIMS, NMR, and comparing their experimental electronic circular dichroism (ECD) spectra with calculated ECD spectra. Additionally, all these enantiomeric compounds were evaluated for their antioxidant, neuroprotective, and anti-Aβ 1-42 aggregation activities., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: To study the expression of SOX11 in the patients with mantle cell lymphoma (MCL) and explore the clinical values of SOX11 in MCL., Patients and Methods: In the paraffin-embedded MCL tissues of 75 patients diagnosed in the Department of Hematology, Shanxi Tumor Hospital, were performed the immunohistochemical labeling of Ki67 and SOX11 by the EnVision method. Meanwhile, the expression of SOX11 mRNA was also detected by reverse transcriptase-polymerase chain reaction (RT-PCR), and the association of SOX11 with such prognostic indexes as pathological typing, staging, immunophenotyping, and MIPI was analyzed using the statistical method., Results: The immunohistochemistry showed that 97% of cases expressed SOX11 positive, and the RT-PCR results showed that the expression of SOX11 mRNA in the MCL patients was significantly higher than those with reactive hyperplasia lymphoid [3.097 (1.311, 6.216) and 1.058 (0.302, 2.623, respectively (p<0.05). Higher expression of SOX11 mRNA was positively correlated with some good prognostic factors such as ECOG<2, no bone marrow involvement and low-risk according to the International Prognostic Index (IPI). The comparison of the survival curves between group SOX11 mRNA

Neurotrophic factors (NTFs) are well known to serve critical functions in neural survival, neurite growth and cell differentiation in vivo and in vitro . Previous progress has indicated that nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), two NTF family members, may be involved in the process of tumor progression. In the present study, the expression of NGF and BDNF was detected using immunohistochemistry on 70 adult astrocytoma samples collected from distinct locations as well as of various pathological grades, with an additional 15 samples being collected from normal adult brain tissue to be used as controls. NGF and BDNF were identified to be expressed in all samples, and their positive cell expression rates in astrocytomas demonstrated a significant increase compared with that in the normal controls (P<0.05), particularly in grade III (P<0.05). In addition, the expression of NGF and BDNF exhibited a gradual decrease ranging from the temporal lobe, parietal lobe and cerebellum to the frontal lobe (P<0.05). The results of the present study suggest that the expression of NGF and BDNF is increased in astrocytomas, which is associated with the pathological grade and the astrocytoma location.

Enantiomers account for quite a large percentage of compounds in natural products. Our team is interested in the separation and biological activity of racemic compounds. In this report, four pairs of prenylated flavan enantiomers [(±)-1-(±)-4], including five new compounds, were isolated from the stem and root bark of Daphne giraldii, and separated successfully by using chiral chromatographic column. Their planar structures and absolute configurations were established by comprehensive spectroscopic analyses as well as circular dichroism (CD) spectroscopy. The isolates had a selective cytotoxicity towards hepatic carcinoma cell lines. Among them, new compound (+)-4 showed a more potent inhibitory effect on Hep3B cells with an IC 50 value of 30.3 μM, compared with its racemic mixture 4. Therefore, the action mechanism of (+)-4in vitro was subsequently investigated. The morphological observation and Western blot analysis demonstrated that (+)-4 could markedly induce apoptosis through intrinsic and extrinsic pathways, and also cause autophagy by increasing the phosphorylation of AMP-activated protein kinase (AMPK) in Hep3B cells. After treatment with the autophagic inhibitor bafilomycin A1 (Baf A1), (+)-4-induced apoptosis increased significantly, suggesting that the autophagy induced by (+)-4 performed a protective effect on apoptotic cell death., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Objective: To investigate the significance of CXCL12/CXCR4 expression in T lymphoblastic lymphoma/leukemia (T-LBL/ALL) and its prognostic significance. Methods: Using immunohistochemical EnVision method, CXCL12, CXCR4 and Ki-67 expression were evaluated in 72 cases of T-LBL/ALL and 30 selected cases of lymph node reactive hyperplasia (LH) as control. In addition, CXCL12 and CXCR4 mRNA expression levels were examined by real-time reverse transcription polymerase chain reaction (real-time RT-PCR) method. Results: Immunohistochemical results showed that the expression rates of CXCL12 and CXCR4 in T-LBL/ALL were 84.7%(61/72) and 91.6%(66/72), respectively, and these were not different from the expression in the LH control group. The expression indexes of Ki-67 <80% and ≥80% were 25 cases (34.7%, 25/72) and 47 cases (65.3%, 47/72), respectively. Real-time quantitative PCR demonstrated that CXCL12 and CXCR4 mRNA expression in T-LBL/ALL was 62.4% and 71.5%, respectively, and was statistically different ( P <0.05) from that of the control group. Single factor analysis found that CXCL12 mRNA expression in T-LBL/ALL was positively correlated with Ann Arbor staging and KPS score ( P <0.05); CXCL12 protein expression was positively correlated with splenomegaly ( P <0.05); CXCR4 mRNA expression was positively correlated with the IPI score, clinical symptoms, mediastinal widening and bone marrow involvement ( P <0.05); CXCR4 protein expression was positively correlated with mediastinal widening ( P <0.05); CXCL12 mRNA expression was positively correlated with CXCL12 protein and CXCR4 protein expression ( P <0.05), but not the CXCR4 mRNA and protein levels. There was no correlation between CXCL12 and CXCR4 protein expression and CXCR4 mRNA expression. Multivariate COX regression analysis showed that high expression of CXCR4 protein, hepatosplenomegaly and bone marrow involvement were risk factors for T-LBL/ALL outcome. Conclusions: CXCL12/CXCR4 expression is associated with disease progress, mediastinal widening, bone marrow involvement and adverse outcome in T-LBL/ALL. CXCL12/CXCR4 axis plays an essential role in the occurrence and development of T-LBL/ALL. However, CXCL12 and CXCR4 protein expression are not entirely reflected by mRNA transcription levels, and there may be other molecules involved in CXCL12/CXCR4 expression and regulation. With CXCR4 antagonists undergoing clinical trials, targeting the CXCL12/CXCR4 axis may be a promising treatment strategy for T-LBL/ALL.