Identification of new subtypes and potential genetic signatures in triple-negative breast cancer using weighted gene co-expression network analysis.

OBJECTIVE: Triple-negative breast cancer (TNBC) is a heterogeneous disease with aggressive behavior and poor prognosis. Here, we used gene expression profiling to define new subtypes of TNBC, which may improve prevention and treatment through personalized medicine. MATERIALS AND METHODS: Gene expression profiles from the public datasets GSE76250, GSE61724, GSE61723, and GES76275 were subjected to co-expression analysis to identify differentially expressed genes (DEGs) between TNBC and non-TNBC tissues. Consistency clustering was used to define TNBC subtypes, whose correlation with gene modules was analyzed. Enrichment analysis was used to identify module genes' biological functions and pathways. Single-sample gene set enrichment analysis was used to assess immune cell infiltration in the different TNBC subtypes, and the ChAMP package was used to examine methylation sites in TNBC. RESULTS: A total of 4,958 DEGs in TNBC were identified, which showed the same expression differences across all datasets as in the dataset GSE76250 and clustered into 9 co-expression modules. TNBC samples clustered into two subtypes based on nine hub genes from the modules. Class I showed the most significant correlation with module 1, whose genes were related mainly to interleukin-1 response, while class II showed the most significant correlation with module 6, whose genes were related mainly to the transforming growth factor-ß pathway. Class I was significantly enriched in cell cycle and DNA replication, and tumors of this subtype showed lower immune cell infiltration than class II tumors. Tumor infiltration by Th2 cells correlated positively with the expression of MCM10 and negatively with the expression of PREX2. A greater methylation of CIDEC, DLC1, EDNRB, EGR2 and SRPK1 correlated with better prognosis. CONCLUSIONS: Class I TNBC, for which a useful biomarker is MCM10, may be associated with a worse prognosis than class II TNBC, for which PREX2 may serve as a biomarker.

HMGB1 affects the development of pulmonary arterial hypertension via RAGE.

OBJECTIVE: To investigate the effect of high-mobility group box 1 (HMGB1) on the proliferation, migration and inflammatory response of human pulmonary artery smooth muscle cells (HPASMCs) and human pulmonary artery endothelial cells (HPAECs) through the receptor for advanced glycation end products (RAGE) and to investigate the mechanism of action underlying the effect of HMGB1 on pulmonary arterial hypertension. MATERIALS AND METHODS: The effect of HMGB1 on the proliferation of the two cell types was examined using the MTT assay under environmental hypoxia (incubation with 1.5% oxygen) to simulate the condition of pulmonary arterial hypertension in the body. The effect of HMGB1 on HPAEC migration was observed using the scratch assay. The effect of HMGB1 on the inflammatory mediators IL-6 and CXCL8 in the two cell types was assessed using qPCR (Real-time Quantitative PCR) and ELISA, and the RAGE mRNA and protein expression levels were also examined. RESULTS: Hypoxia promoted the proliferation of both cell types but inhibited the migration of HPAECs. HMGB1 had no obvious effect on the proliferation and migration of the cells. Both hypoxia and HMGB1 promoted the expression of the pro-inflammatory factors IL-6 and CXCL8. HMGB1 significantly promoted RAGE expression compared to the normal control group. CONCLUSIONS: HMGB1 affects the functions of HPASMCs and HPAECs through RAGE and may affect the course of pulmonary arterial hypertension.

Drug-drug interaction between valproic acid and meropenem: a retrospective analysis of electronic medical records from neurosurgery inpatients.

WHAT IS KNOWN AND OBJECTIVE: A series of studies have indicated that valproic acid (VPA) plasma concentration decreased rapidly when used concomitantly with carbapenem antibiotics, including meropenem (MEPM), imipenem and panipenem, which may increase the risk of seizure breakthrough. However, the cause for the change in VPA pharmacokinetics is unclear. A retrospective analysis of VPA therapeutic drug monitoring (TDM) records was performed to investigate this VPA pharmacokinetics drug-drug interaction. METHODS: Three hundred and eighty one VPA TDM records from the Department of Neurosurgery of Xiangya Hospital from January 2012 to December 2014 were collected. The VPA TDM records were categorized by VPA and MEPM daily dosages in grams/day (g/day). A comparison of VPA plasma levels among different groups was performed to investigate the change in VPA level in this drug interaction. RESULTS AND DISCUSSION: Remarkable decreases in VPA plasma level were observed when the drug was used concomitantly with MEPM in both 1.2 g/d and 1.6 g/d VPA groups (67·3 ± 4·6 µg/mL, n = 21 vs. 15·3 ± 1·9 µg/mL, n = 15, P < 0·001; 67·6 ± 1·2 µg/mL vs. 18·1 ± 2·6 µg/mL, n = 38, P < 0·001). No significant difference in VPA plasma concentrations was observed between the 1·2 g/day VPA + MEPM, 1·6 g/day VPA + MEPM and 2·0 g/day VPA + MEPM groups (15·3 ± 1·9 µg/mL, n = 15 vs. 18·1 ± 2·6 µg/mL, n = 38 vs. 9·0 ± 3·0 µg/mL, n = 7; P = 0·252). The decrease in VPA concentration was independent of MEPM daily dose (14·0 ± 5·1 µg/mL, n = 4 for high MEPM daily dose vs. 16·5 ± 1·9 µg/mL, n = 56 for low MEPM daily dose; P = 0·729). After discontinuation of MEPM for more than 7 days, VPA plasma concentration recovered to a value comparable to that before MPEM initiation (69·7 ± 4·2 µg/mL, n = 21 vs. 51·2 ± 8·1 µg/mL, n = 9; P = 0·48). WHAT IS NEW AND CONCLUSION: This is the first study using a large number of VPA TDM records to investigate the change in VPA levels caused by concomitant use of MEPM. Our results imply that the decrease in drug concentration cannot be reversed by increasing VPA dose. Moreover, MEPM daily dose did not influence the drop in VPA plasma level. At least 7 days are required for the recovery of VPA plasma concentration after discontinuation of MEPM.

[Prediction of occupational allergic contact dermatitis induced by formaldehyde by IL17/IL22 secretion cell rest combined with patch test].

Objective: To investigate the possible role of IL17-and IL22-secreting cells combined with patch test for the prediction of formaldehyde-induced occupational allergic contact dermatitis(OACD). Methods: From October 2014 to October 2016, totally 131 formaldehyde-exposed workers(49 cases with inflammatory skin lesions,82 ones without inflammatory skin lesions)and 63 non-exposed health controls were recruited. Patch-test was performed in 49 cases of formaldehyde-exposed workers with inflammatory skin lesions. Circulating IL17+and IL22+Tcell subsets were assessed by flow cytometry(FCM). Results: Among 49 cases of formaldehyde-exposed workers with inflammatory skin lesions,32 cases were with positive patch-test while 17 cases with negative patch-test. The proportions of circulating CD3+CD8-IL17+ and CD3+CD8-IL22+ cells from patch-test(+) formaldehyde-exposed workers were significantly higher than that of patch-test(-)group, formaldehyde-exposed workers without skin lesions and non-exposed controls(P<0.05). The proportions of circulating CD3+CD8-IL17+ and CD3+CD8-IL22+cells from patch-test(-)group and formaldehyde-exposed workers without skin lesions were also higher than that of non-exposed controls(P<0.05). But there was no significant difference between patch-test(-)group and formaldehyde-exposed workers without skin lesions(P>0.05). Peripheral CD3+CD8+IL17+and CD3+CD8+IL22+cells were also detected in spite of small amounts. The percentages of CD3+CD8+IL17+and CD3+CD8+IL22+ cells inperipheral blood from patch-test(+)formaldehyde-exposed workers were enhanced significantly, compared to patch-test(-)group, formaldehyde-exposed workers without skin lesions and non-exposed controls(P<0.05). The proportions of circulating CD3+CD8+IL17+ and CD3+CD8+IL22+ cells from patch-test(-)group and formaldehyde-exposed workers without skin lesions were significantly higher than that of non-exposed controls(P<0.05). But there was no significant difference between patch-test(-) group and formaldehyde-exposed workers without skin lesions(P>0.05). Conclusion: The proportions of circulating IL17+ and IL22+T cells(both CD8-and CD8+)are enhanced in formaldehyde-exposed workers at proposed OEL, possibly involved in the development of formaldehyde-induced OACD.The detection of IL17-and IL22-secreting cells combined with formaldehyde patch test help to screen the workers with allergy property and prevent OACD.