Identifying potential breath biomarkers for early diagnosis of papillary thyroid cancer based on solid-phase microextraction gas chromatography-high resolution mass spectrometry with metabolomics.

INTRODUCTION: Thyroid cancer incidence rate has increased substantially worldwide in recent years. Fine needle aspiration biopsy (FNAB) is currently the golden standard of thyroid cancer diagnosis, which however, is invasive and costly. In contrast, breath analysis is a non-invasive, safe and simple sampling method combined with a promising metabolomics approach, which is suitable for early cancer diagnosis in high volume population. OBJECTIVES: This study aims to achieve a more comprehensive and definitive exhaled breath metabolism profile in papillary thyroid cancer patients (PTCs). METHODS: We studied both end-tidal and mixed expiratory breath, solid-phase microextraction gas chromatography coupled with high resolution mass spectrometry (SPME-GC-HRMS) was used to analyze the breath samples. Multivariate combined univariate analysis was applied to identify potential breath biomarkers. RESULTS: The biomarkers identified in end-tidal and mixed expiratory breath mainly included alkanes, olefins, enols, enones, esters, aromatic compounds, and fluorine and chlorine containing organic compounds. The area under the curve (AUC) values of combined biomarkers were 0.974 (sensitivity: 96.1%, specificity: 90.2%) and 0.909 (sensitivity: 98.0%, specificity: 74.5%), respectively, for the end-tidal and mixed expiratory breath, indicating of reliability of the sampling and analysis method CONCLUSION: This work not only successfully established a standard metabolomic approach for early diagnosis of PTC, but also revealed the necessity of using both the two breath types for comprehensive analysis of the biomarkers.

Diagnosis and treatment of diabetic foot ulcer complicated with lower extremity vasculopathy: Consensus recommendation from the Chinese Medical Association (CMA), Chinese Medical Doctor Association (CMDA).

Diabetic foot ulcer complicated with lower extremity vasculopathy is highly prevalent, slow healing and have a poor prognosis. The final progression leads to amputation, or may even be life-threatening, seriously affecting patients' quality of life. The treatment of lower extremity vasculopathy is the focus of clinical practice and is vital to improving the healing process of diabetic foot ulcers. Recently, a number of clinical trials on diabetic foot ulcers with lower extremity vasculopathy have been reported. A joint group of Chinese Medical Association (CMA) and Chinese Medical Doctor Association (CMDA) expert representatives reviewed and reached a consensus on the guidelines for the clinical diagnosis and treatment of this kind of disease. These guidelines are based on evidence from the literature and cover the pathogenesis of diabetic foot ulcers complicated with lower extremity vasculopathy and the application of new treatment approaches. These guidelines have been put forward to guide practitioners on the best approaches for screening, diagnosing and treating diabetic foot ulcers with lower extremity vasculopathy, with the aim of providing optimal, evidence-based management for medical personnel working with diabetic foot wound repair and treatment.

Genome-based classification of the family Haloferacaceae and description of five novel species of Halobaculum.

The taxonomic status of some species of Halobellus, Haloferax, Halogranum, and Haloplanus within the family Haloferacaceae was elucidated by phylogenetic, phylogenomic, and comparative genomic analyses. The relative species of each genus should constitute a single species based on the overall genome-related indexes proposed for species demarcation. The cutoff values of AAI (72.1%), ANI (82.2%), and rpoB' gene similarity (90.7%) were proposed to differentiate genera within the family Haloferacaceae. According to these standards, a novel genus related to the genus Halobaculum was proposed to accommodate Halobaculum halophilum Gai3-2 T and Halobaculum salinum NJ-3-1 T. Five halophilic archaeal strains, DT31T, DT55T, DT92T, SYNS20T, and YSMS11T, isolated from a tidal flat and a marine solar saltern in China, were subjected to polyphasic classification. The phenotypic, phylogenetic, phylogenomic, and comparative genomic analyses revealed that strains DT31T (= CGMCC 1.18923 T = JCM 35417 T), DT55T (= CGMCC 1.19048 T = JCM 36147 T), DT92T (= CGMCC 1.19057 T = JCM 36148 T), SYNS20T (= CGMCC 1.62628 T = JCM 36154 T), and YSMS11T (= CGMCC 1.18927 T = JCM 34912 T) represent five novel species of the genus Halobaculum, for which the names, Halobaculum lipolyticum sp. nov., Halobaculum marinum sp. nov., Halobaculum litoreum sp. nov., Halobaculum halobium sp. nov., and Halobaculum limi sp. nov., are proposed.

Asymmetric Low-Frequency Pulsed Strategy Enables Ultralong CO2 Reduction Stability and Controllable Product Selectivity.

Copper-based catalysts are widely explored in electrochemical CO2 reduction (CO2RR) because of their ability to convert CO2 into high-value-added multicarbon products. However, the poor stability and low selectivity limit the practical applications of these catalysts. Here, we proposed a simple and efficient asymmetric low-frequency pulsed strategy (ALPS) to significantly enhance the stability and the selectivity of the Cu-dimethylpyrazole complex Cu3(DMPz)3 catalyst in CO2RR. Under traditional potentiostatic conditions, Cu3(DMPz)3 exhibited poor CO2RR performance with the Faradaic efficiency (FE) of 34.5% for C2H4 and FE of 5.9% for CH4 as well as the low stability for less than 1 h. We optimized two distinguished ALPS methods toward CH4 and C2H4, correspondingly. The high selectivities of catalytic product CH4 (FECH4 = 80.3% and above 76.6% within 24 h) and C2H4 (FEC2H4 = 70.7% and above 66.8% within 24 h) can be obtained, respectively. The ultralong stability for 300 h (FECH4 > 60%) and 145 h (FEC2H4 > 50%) was also recorded with the ALPS method. Microscopy (HRTEM, SAED, and HAADF) measurements revealed that the ALPS method in situ generated and stabilized extremely dispersive and active Cu-based clusters (∼2.7 nm) from Cu3(DMPz)3. Meanwhile, ex situ spectroscopies (XPS, AES, and XANES) and in situ XANES indicated that this ALPS method modulated the Cu oxidation states, such as Cu(0 and I) with C2H4 selectivity and Cu(I and II) with CH4 selectivity. The mechanism under the ALPS methods was explored by in situ ATR-FTIR, in situ Raman, and DFT computation. The ALPS methods provide a new opportunity to boost the selectivity and stability of CO2RR.

PRMT5 regulates RNA m6A demethylation for doxorubicin sensitivity in breast cancer.

Cancer cells respond to various stressful conditions through the dynamic regulation of RNA m6A modification. Doxorubicin is a widely used chemotherapeutic drug that induces DNA damage. It is interesting to know whether cancer cells regulate the DNA damage response and doxorubicin sensitivity through RNA m6A modification. Here, we found that doxorubicin treatment significantly induced RNA m6A methylation in breast cancer cells in both a dose- and a time-dependent manner. However, protein arginine methyltransferase 5 (PRMT5) inhibited RNA m6A modification under doxorubicin treatment by enhancing the nuclear translocation of the RNA demethylase AlkB homolog 5 (ALKBH5), which was previously believed to be exclusively localized in the nucleus. Then, ALKBH5 removed the m6A methylation of BRCA1 for mRNA stabilization and further enhanced DNA repair competency to decrease doxorubicin efficacy in breast cancer cells. Importantly, we identified the approved drug tadalafil as a novel PRMT5 inhibitor that could decrease RNA m6A methylation and increase doxorubicin sensitivity in breast cancer. The strategy of targeting PRMT5 with tadalafil is a promising approach to promote breast cancer sensitivity to doxorubicin through RNA methylation regulation.

Comprehensive analysis of CDK5 as a novel biomarker for progression in esophageal cancer.

BACKGROUND: Cyclin-dependent kinase 5 (CDK5) is a member of the cyclin-dependent kinase family, and unlike the rest of the members of the family, its kinase activity is independent of cyclins. Accumulating evidence has shown that CDK5 plays a significant role in the progress of tumorigenesis except in nervous system. In particular, the expression of CDK5 and its function in esophageal cancer (ESCA) remain unknown. METHODS: With TCGA and GEO databases, CDK5 was analyzed with the expression, predicted value, clinical relationship, functional enrichment, immune cell infiltration and immune molecules in ESCA. In addition, we explored the CDK5 expression with local datasets and the influence of CDK5 on proliferation, migration and invasion behaviors of the esophageal squamous cell carcinoma (ESCC) cells in vitro and in vivo experiments. RESULTS: CDK5 expression was upregulated in ESCA, and this regulation has been verified in cell lines of ESCC. Further analysis has found that the expression of CDK5 was correlated with race, weight, BMI, histological type and tumor central location in ESCA. KEGG analysis revealed that CDK5 was involved in the progress of cancers, innate immune system and PI3K-Akt signaling pathway. CDK5 was closely related to immune cells and immune molecules in ESCA. Functional experiments confirmed CDK5 was an oncogene in ESCC by in vivo and in vitro models. CONCLUSIONS: This study shows that CDK5 is a risk factor to promote tumor progression, and Roscovitine could be one of the effective tools in the therapy of ESCA.

Construction of a ferroptosis-related five-lncRNA signature for predicting prognosis and immune response in thyroid carcinoma.

BACKGROUND: Thyroid carcinoma (THCA) is the most common endocrine-related malignant tumor. Despite the good prognosis, some THCA patients may deteriorate into more aggressive diseases, leading to poor survival. This may be alleviated by developing a novel model to predict the risk of THCA, including recurrence and survival. Ferroptosis is an iron-dependent, oxidative, non-apoptotic form of cell death initially described in mammalian cells, and plays an important role in various cancers. To explore the potential prognostic value of ferroptosis in THCA, ferroptosis-related long non-coding RNAs (FRLs) were used to construct model for risk prediction of THCA. METHODS: RNA-sequencing data of THCA patients and ferroptosis-related genes were downloaded from The Cancer Genome Atlas (TCGA) and FerrDb, respectively. A total of 502 patients with complete data were randomly separated into a training cohort and a validation cohort at the ratio of 2:1. The Pearson correlation coefficients were calculated to determine the correlation between ferroptosis-related genes (FRGs) and the corresponding lncRNAs, and those meeting the screening conditions were defined as FRLs. Gene Expression Omnibus (GEO) database and qRT-PCR were used to verify the expression level of FRLs in THCA tissues. Univariate and multivariate cox regression analysis were performed to construct a FRLs signature based on lowest Akaike information criterion (AIC) value in the training cohort, then further tested in the validation cohort and the entire cohort. Gene set enrichment analysis (GSEA) and functional enrichment analysis were used to analyze the biological functions and signal pathways related to differentially expressed genes between the high-risk and low-risk groups. Finally, the relative abundance of different tumor-infiltrating immune cells were calculated by CIBERSORT algorithm. RESULTS: The patients were divided into high-risk group and low-risk group based on a 5-FRLs signature (AC055720.2, DPP4-DT, AC012038.2, LINC02454 and LINC00900) in training cohort, validation cohort and entire cohort. Through Kaplan-Meier analysis and area under ROC curve (AUC) value, patients in the high-risk group exhibited worse prognosis than patients in the low-risk group. GEO database and qRT-PCR confirmed that LINC02454 and LINC00900 were up-regulated in THCA. Univariate and multivariate cox regression analyses showed that the risk score was an independent prognostic indicator. GSEA and functional enrichment analysis confirmed that immune-related pathways against cancer were significantly activated in the low-risk THCA patients. Further analysis showed that the immune cells such as plasma cells, T cells CD8 and macrophages M1, and the expression of immune checkpoint molecules, including PD-1, PD-L1, CTLA4, and LAG3, were remarkably higher in the low-risk group. CONCLUSION: Our study used the TCGA THCA dataset to construct a novel FRLs prognostic model which could precisely predict the prognosis of THCA patients. These FRLs potentially mediate anti-tumor immunity and serve as therapeutic targets for THCA, which provided the novel insight into treatment of THCA.

Family socioeconomic status and mental health in Chinese adolescents: the multiple mediating role of social relationships.

BACKGROUND: The purpose of this study is to explore whether social relationships of family and school contexts mediate the influence of socioeconomic status (SES) on Chinese adolescents' mental health. METHODS: A school-based study was conducted among a sample aged 13-18 in East China (n = 6902). We used scales for measuring social relationships and self-rated mental health. Family SES was computed from subjective socioeconomic status, education and occupation of parents.The mediation model was tested by using Path Analysis in IBM SPSS-Amos. RESULTS: The results showed that SES can significantly influence adolescent mental health through parent-child relationship, student-teacher relationship and student-student relationship. The total effect, direct effect and total indirect effect were -0.209 (95% CI = -0.299, -0.136), -0.090 (95% CI = -0.174, -0.007), -0.119 (95% CI = -0.187, -0.078) for boys, and -0.337 (95% CI = -0.478, -0.230), -0.132 (95% CI = -0.283, 0.010), -0.205 (95% CI = -0.351, -0.085) for girls. CONCLUSION: The link between SES and adolescent mental health can be explained by social relationships. Focusing on the parent-child, student-student and student-teacher relationship interventions may contribute to improving the mental health of Chinese adolescents, especially in low socioeconomic groups, as well as female students.

Clinical and prognosis value of the number of metastatic lymph nodes in patients with papillary thyroid carcinoma.

OBJECTIVE: It has been reported that papillary thyroid carcinoma (PTC) patients with lymph node metastasis (LNM) are largely associated with adverse outcomes. The present study aimed to assess the correlation between the number of metastatic lymph nodes (NMLNs) and clinical prognosis in patients with PTC. METHODS: We retrospectively reviewed the medical records of patients with PTC who underwent initial thyroid cancer surgery in Renmin Hospital of Wuhan University between 2017 and 2019. A total of 694 patients with PTC and cervical lymph node dissection as well as a total checked number of lymph nodes ≥ 5 were involved in this study. The clinicopathological characteristics of patients were compared according to NMLNs, the number of central cervical lymph nodes (CLNs) and the number of lateral lymph nodes (LLNs). RESULTS: NMLNs > 5, CLNs > 5 and LLNs > 5 were 222 (32.0%), 159 (24.3%) and 70 (10.1%) seen in the analyzed samples, respectively. Young patients, patients with larger tumor diameter, bilaterality, multifocality and gross extrathyroidal extension (ETE) were more inclined to NMLNs > 5, CLNs > 5 and LLNs > 5 (P < 0.05). It was found that the recurrence-free survival among pN1 patients was significantly discrepant between different groups (NMLNs ≤ 5/5: P = 0.001; LLNs ≤ 5/5: P < 0.001). In multivariate logistic regression analysis, patients aged < 55 years (OR = 1.917), primary tumor size > 10 mm (OR = 2.131), bilaterality (OR = 1.889) and tumor gross ETE (OR = 2.759) were independent predictors for high prevalence of total NMLNs > 5 (P < 0.05). Specially, patients aged < 55 years (OR = 2.864), primary tumor size > 10 mm (OR = 2.006), and tumor gross ETE (OR = 2.520) were independent predictors for high prevalence of CLNs > 5 (P < 0.01); Bilaterality (OR = 2.119), CLNs > 5 (OR = 6.733) and tumor gross ETE (OR = 4.737) were independent predictors for high prevalence of LLNs > 5 (P < 0.05). CONCLUSIONS: In conclusion, it is evident that NMLNs is related to the invasive clinicopathological features and adverse outcome of patients with PTC which should be correctly evaluated to provide an appropriate guidance for reasonable treatment and careful follow-up.

Clinical Outcomes of Proximal Gastrectomy versus Total Gastrectomy for Proximal Gastric Cancer: A Systematic Review and Meta-Analysis.

INTRODUCTION: The extent of optimal gastric resection for proximal gastric cancer (PGC) continues to remain controversial, and a final consensus is yet to be met. The current study aimed to compare the perioperative outcomes, postoperative complications, and overall survival (OS) of proximal gastrectomy (PG) versus total gastrectomy (TG) in the treatment of PGC through a meta-analysis. METHODS: We systematically searched PubMed, Embase, The Cochrane Library, and Web of Science for articles published in English since database establishment to October 2019. Evaluated endpoints were perioperative outcomes, postoperative complications, and long-term survival outcomes. RESULTS: A total of 2,896 patients in 25 full-text articles were included, of which one was a prospective randomized study, one was a clinical phase III trial, and the rest were retrospective comparative studies. The PG group showed a higher incidence of anastomotic stenosis (OR = 2.21 [95% CI: 1.08-4.50]; p = 0.03) and reflux symptoms (OR = 3.33 [95% CI: 1.85-5.99]; p < 0.001) when compared with the TG group, while no difference was found in PG patients with double-tract reconstruction (DTR). The retrieved lymph nodes were clearly more in the TG group (WMD = -10.46 [95% CI: -12.76 to -8.17]; p < 0.001). The PG group was associated with a better 5-year OS relative to TG with 11 included studies (OR = 1.35 [95% CI: 1.03-1.77]; p = 0.03). After stratification for early gastric cancer and PG with DTR groups, however, there was no significant difference between the 2 groups (OR = 1.35 [95% CI: 0.59-2.45]; p = 0.62). CONCLUSION: In conclusion, PG was associated with a visible improved long-term survival outcome for all irrespective of tumor stage, while a similar 5-year OS for only early gastric cancer patients between the 2 groups. Future randomized clinical trials of esophagojejunostomy techniques, such as DTR following PG, are expected to prevent postoperative complications and assist surgeons in the choice of surgical approach for PGC patients.

Label-free, sensitive colorimetric detection of mercury(II) by target-disturbed in situ seeding growth of gold triangular nanoprisms.

Gold nanomaterials have been used extensively in colorimetric detection of mercuric ions (Hg2+) due to their shape- and size-dependent, ultrastrong localized surface plasmon resonance (LSPR). Conventional detection was performed by first synthesizing the nanomaterials, and then applying them to signal-transducing reactions. We herein report a convenient method for detecting Hg2+ based on gold triangular nanoprisms (AuTNPs). During the seeding-growth process, Hg2+ added to the growth solution was co-reduced and deposited on the high-energy facets of the gold seeds, affecting the deposition patterns of the subsequently generated Au0 and ultimately leading to the formation of defective AuTNPs. Morphological changes were reflected by the in-plane dipole LSPR wavelength shift, which was proportionally related to the concentration of Hg2+. To improve the selectivity, the interference from Ag+ was eliminated by a stepwise preparation-selective precipitation approach. Under the optimized conditions, Hg2+ could be selectively detected with 20 min, with a detection limit of 0.12 nM. Finally, the method was successfully applied to detecting trace Hg2+ in fortified drinking, mineral and rain water samples, with recoveries ranging from 95.17% to 110.6%.

Germline mutations in 40 cancer susceptibility genes among Chinese patients with high hereditary risk breast cancer.

Multigene panel testing of breast cancer predisposition genes have been extensively conducted in Europe and America, which is relatively rare in Asia however. In this study, we assessed the frequency of germline mutations in 40 cancer predisposition genes, including BRCA1 and BRCA2, among a large cohort of Chinese patients with high hereditary risk of BC. From 2015 to 2016, consecutive BC patients from 26 centers of China with high hereditary risk were recruited (n = 937). Clinical information was collected and next-generation sequencing (NGS) was performed using blood samples of participants to identify germline mutations. In total, we acquired 223 patients with putative germline mutations, including 159 in BRCA1/2, 61 in 15 other BC susceptibility genes and 3 in both BRCA1/2 and non-BRCA1/2 gene. Major mutant non-BRCA1/2 genes were TP53 (n = 18), PALB2 (n = 11), CHEK2 (n = 6), ATM (n = 6) and BARD1 (n = 5). No factors predicted pathologic mutations in non-BRCA1/2 genes when treated as a whole. TP53 mutations were associated with HER-2 positive BC and younger age at diagnosis; and CHEK2 and PALB2 mutations were enriched in patients with luminal BC. Among high hereditary risk Chinese BC patients, 23.8% contained germline mutations, including 6.8% in non-BRCA1/2 genes. TP53 and PALB2 had a relatively high mutation rate (1.9 and 1.2%). Although no factors predicted for detrimental mutations in non-BRCA1/2 genes, some clinical features were associated with mutations of several particular genes.

A gold nanorod-based plasmonic platform for multi-logic operation and detection.

A multi-logic gate platform was designed based on morphological changes of gold nanorods (AuNRs) resulted from the iodine-mediated etching. By utilizing the anti-etching effects of mercapto compounds and Au-Hg amalgams as well as the etch-promoting effect of Cu2+, we successfully built five logic gates, namely, AND, NOR, XNOR, YES and IMPLY, along with a three-input combinational logic gate XNOR-IMPLY. The platform was versatile and easy to use, did not require complex surface modification or separation/purification steps as the conventional AuNR-based logic gates did. The logic operations, accompanied by distinct color changes, enabled multi-task detection by naked-eye for 'have' or 'none' discrimination or highly sensitive and selective analysis by spectroscopy with wide linear ranges.

Small molecule HDAC inhibitors: Promising agents for breast cancer treatment.

Breast cancer, a heterogeneous disease, is the most frequently diagnosed cancer and the second leading cause of cancer-related death among women worldwide. Recently, epigenetic abnormalities have emerged as an important hallmark of cancer development and progression. Given that histone deacetylases (HDACs) are crucial to chromatin remodeling and epigenetics, their inhibitors have become promising potential anticancer drugs for research. Here we reviewed the mechanism and classification of histone deacetylases (HDACs), association between HDACs and breast cancer, classification and structure-activity relationship (SAR) of HDACIs, pharmacokinetic and toxicological properties of the HDACIs, and registered clinical studies for breast cancer treatment. In conclusion, HDACIs have shown desirable effects on breast cancer, especially when they are used in combination with other anticancer agents. In the coming future, more multicenter and randomized Phase III studies are expected to be conducted pushing promising new therapies closer to the market. In addition, the design and synthesis of novel HDACIs are also needed.

Intraoperative rapid aspiration cytological method for parathyroid glands identification and protection.

To explore new methods for intraoperative identification of parathyroid glands, 86 thyroid cancer patients, admitted to Xijing hospital from July 2017 to July 2018, were included. During lymph node dissection, parathyroid glands were firstly judged by clinician eyeballing, based on his clinical experience. Then, cytological detection was used for rapid identification via Diff-quik staining. PTH monitoring was performed by PTH detection kit. Finally, frozen pathology was examined and regarded as the golden standard. In this study, 172 suspicious parathyroid glands were observed. According to frozen pathology outcome, the accuracy, sensitivity and specificity of clinician eyeballing were calculated as 63.3%, 100%, and 13.9%. Kappa test showed poor consistency (kappa = 0.156), AUC area was 0.569 ± 0.045, 95%CI = (0.480-0.658), p = 0.123. For cytological and PTH detection, the accuracy, sensitivity and specificity were 91.7% vs. 92.3%, 93.6% vs. 93.8% and 89.0% vs. 90.3%. Kappa value was 0.829 vs. 0.842, indicating good consistency. AUC area was 0.908 ± 0.027 vs. 0.918 ± 0.025, 95%CI = (0.856-0.960) vs. (0.869-0.966), p < 0.001, indicating higher diagnositic value. Besides, compared with frozen pathology, cytological detection was easily and rapid. The time-taking between frozen pathology and cytological detection or PTH detection were 39.0 ± 6.59 min vs. 5.02 ± 0.78 min and 39.0 ± 6.59 min vs. 6.1 ± 1.23 min, p < 0.001. In conclusion, intra-operative cytological detection maybe potential for in-situ preservation of parathyroid glands.

PRMT5 determines the sensitivity to chemotherapeutics by governing stemness in breast cancer.

PURPOSE: Acquired resistance to chemotherapeutic agents in breast cancer is a major clinical challenge. Recent studies have shown that the emergence of cancer stem cells contributes to the development of drug resistance, and the protein arginine methyltransferase 5 (PRMT5) was crucial for the maintenance of stemness. However, the roles of PRMT5 in breast cancer cell stemness and the development of cancer drug resistance have not been clarified. In this study, we investigated the effect of PRMT5 on the sensitivity to doxorubicin and cell stemness in breast cancer. METHODS: PRMT5 expression was assessed in a panel of breast cancer cell lines (MDA-MB-231, MCF7, T-47D, BT-474, Au-565) and normal mammal epithelial cells (MCF10A). For knockdown of PRMT5 expression, two pairs of shRNAs as well as a control shRNA were utilized. Meanwhile, the wild-type PRMT5 and its catalytically dead counterpart (R368A) were stably overexpressed in MDA-MB-231 and MCF7 cells. The sensitivity to doxorubicin was determined by MTT assays, TUNEL assays, and Western blot analyses. To evaluate the degree of cell stemness, CD24/CD44-sorting and mammosphere formation experiments were performed. RESULTS: We demonstrated that PRMT5 regulates OCT4/A, KLF4, and C-MYC in breast cancer to govern stemness and affects the doxorubicin resistance of breast cancer. CONCLUSION: Our study suggests that PRMT5 may play an important role in the doxorubicin resistance of breast cancer.

A new diterpenoid from the leaves of Platycladus orientalis.

A new diterpenoid, 17-methyl-8, 13-labdadien-15, 16-olid-19-oic acid methyl ester (1), along with two known compounds 2 and 3, were isolated from the leaves of Platycladus orientalis (L.) Franco. The structures were confirmed based on the analysis of HR-MS, 1D-NMR, and 2D-NMR spectra and the configuration of 1 was confirmed by the single-crystal X-ray diffraction.

Activation of hypoxia-inducible factor-1α by prolonged in vivo hyperinsulinemia treatment potentiates cancerous progression in estrogen receptor-positive breast cancer cells.

Despite numerous epidemiological data linking type 2 diabetes mellitus (T2DM) and breast cancer (BCa), there is limited experimental evidence of this association. The clinically relevant question is at what stage diabetes may exert its tumor-promoting activity. Moreover, identification of major pathophysiological pathways underlying this activity should provide valuable information for treatment. In the present study, the BCa cells isolated from long-term T2DM-treated tumors from diabetic nude mice were found to have increased cell proliferation, invasiveness and docetaxel (DTX) resistance. Importantly, this stimulatory effect was only observable in estrogen receptor (ER)-positive BCa cells. Mechanistically, T2DM-elicited hyperinsulinemia induced HIF-1α expression by reducing its ubiquitination, which was accompanied with upregulated oxidative stress. Furthermore, in vivo inhibition of HIF-1α expression effectively reversed the above-mentioned tumor-promoting activity and partially attenuated T2DM-elicited oxidative stress. Altogether, the results provide novel and compelling experimental evidence that (i) prolonged exposure to T2DM promotes BCa progression; (ii) the hyperinsulinemia/HIF-1α/oxidative stress cascade is the major mediator of this effect.

Regulation of cancerous progression and epithelial-mesenchymal transition by miR-34c-3p via modulation of MAP3K2 signaling in triple-negative breast cancer cells.

Emerging but limited data have evidenced an essential involvement of microRNAs (miRNAs) in the development and progression of triple negative breast cancer (TNBC), which empowers these small regulators as an innovative therapeutic approach, especially for this unique tumor subgroup still lacking an efficient and specific therapeutic target. Herein, we reported the down-regulation of miR-34c-3p level in TNBC tissues, and its expression was closely associated with estrogen receptor alpha (ERα), but not other receptors, in well-characterized breast cancer (BCa) cells. Functionally, ectopic expression of miR-34c-3p inhibited migration, invasion and epithelial-mesenchymal transition (EMT) in TNBC cells. From a mechanistic standpoint, bioinformatics coupled with luciferase and gain-of-function, loss-of-function assays showed that miR-34c-3p may regulate TNBC progression by directly targeting the 3'-untranslated region (UTR) of mitogen-activated protein kinase kinase kinase 2 (MAP3K2). Consistently, MAP3K2 overexpression could effectively rescue miR-34c-3p mimics-induced suppression of cell invasion and EMT. In light of these findings, miR-34c-3p may function as a tumor suppressor in regulating of TNBC invasiveness and EMT through negatively modulating MAP3K2 pathway. Future endeavor in this field may help to identify a novel biomarker to predict prognosis and response to therapy in TNBC.

Elevated expression of protein arginine methyltransferase 5 predicts the poor prognosis of breast cancer.

Protein arginine methyltransferase 5 is one of the type II protein arginine methyltransferase family members that can symmetrically dimethylate arginine residues on target proteins in both the cytoplasm and the nucleus. Protein arginine methyltransferase 5 was reported to be an oncoprotein that participates in tumor progression through both epigenetic silencing and organelle biogenesis. So far, it has been implicated in various cancers, but its expression pattern in breast cancer has not been elucidated thoroughly. We analyzed the protein arginine methyltransferase 5 expression patterns in several breast cancer samples and tissue arrays to better characterize its contribution to breast cancer. Primary breast tumors showed increased protein arginine methyltransferase 5 expression compared with adjacent normal tissues in both the fresh tissue samples and tissue arrays. Also, there was a tendency that metastatic lymph nodes demonstrated enhanced protein arginine methyltransferase 5 expression compared to primary sites. Moreover, we found a significant correlation between protein arginine methyltransferase 5 and Ki-67, with higher Ki-67 and protein arginine methyltransferase 5 expressions in primary breast tumors compared with normal breast tissues. Moreover, the Cancer Genome Atlas cohort analysis revealed that high protein arginine methyltransferase 5 messenger RNA expression was associated with an unfavorable prognosis in human epidermal growth factor receptor 2 (HER-2) positive and triple negative breast cancer patients. Finally, the roles and mechanisms of protein arginine methyltransferase 5 in the proliferation, cell cycle progression, and apoptosis of MDA-MB-231 cells were assessed using protein arginine methyltransferase 5 and shPRMT5 transfection. In conclusion, we proposed that protein arginine methyltransferase 5 is an independent prognostic biomarker for breast cancer, and targeting protein arginine methyltransferase 5 might be a promising strategy for breast cancer treatment.