Identification of DYNLT1 associated with proliferation, relapse, and metastasis in breast cancer

BackgroundBreast cancer (BC) is the most common malignant disease worldwide. Although the survival rate is improved in recent years, the prognosis is still bleak once recurrence and metastasis occur. It is vital to investigate more efficient biomarkers for predicting the metastasis and relapse of BC. DYNLT1 has been reported that participating in the progression of multiple cancers. However, there is still a lack of study about the correlation between DYNLT1 and BC.MethodsIn this study, we evaluated and validated the expression pattern and prognostic implication of DYNLT1 in BC with multiple public cohorts and BC tumor microarrays (TMAs) of paraffin-embedded tissues collected from the Affiliated Hospital of Jining Medical University. The response biomarkers for immune therapy, such as tumor mutational burden (TMB), between different DYNLT1 expression level BC samples were investigated using data from the TCGA-BRCA cohort utilizing public online tools. In addition, colony formation and transwell assay were conducted to verify the effects of DYNLT1 in BC cell line proliferation and invasion.ResultsThe results demonstrated that DYNLT1 overexpressed in BC and predicted poor relapse-free survival in our own BC TMA cohort. In addition, DYNLT1 induced BC development by promoting MDA-MB-231 cell proliferation migration, and metastasis.ConclusionAltogether, our findings proposed that DYNLT1 could be a diagnostic and prognostic indicator in BC

Continuous-Flow Oxidation of Amines Based on Nitrogen-Rich Heterocycles: A Facile and Sustainable Approach for Promising Nitro Derivatives

The oxidation of amines based on nitrogen-rich heterocycles is one of the appealing alternatives for promising nitro derivatives. Herein, we present a continuous-flow process to achieve oxidation of these amines to their nitro derivatives, taking advantage of hydrogen peroxide as an environmentally benign and inexpensive oxidant. Facile and sustainable access to valuable nitro compounds was ensured. The utility of the present continuous-flow oxidation process was demonstrated by synthesizing promising energetic compounds 5-amino-3-nitro-1,2,4-triazole (ANTA) and 1-methyl-3,4,5-trinitropyrazole (MTNP) on a multigram scale

Pharmacokinetic and Drug–Drug Interaction Profiles of the Combination of Tezacaftor/Ivacaftor

Drug–drug interaction (DDI) studies are described for tezacaftor/ivacaftor, a new cystic fibrosis transmembrane conductance regulator modulator therapy for the treatment of cystic fibrosis. Three phase I DDI studies were conducted in healthy subjects to characterize the DDI profile of tezacaftor/ivacaftor with cytochrome P450 (CYP)3A substrates, CYP3A inhibitors, and a permeability glycoprotein (P‐gp) substrate. The effects of steady‐state tezacaftor/ivacaftor on the pharmacokinetics (PKs) of digoxin (a P‐gp substrate), midazolam, and ethinyl estradiol/norethindrone (CYP3A substrates) were evaluated. Effects of strong (itraconazole) and moderate (ciprofloxacin) CYP3A inhibitors on tezacaftor/ivacaftor PKs were also determined. Tezacaftor/ivacaftor increased digoxin area under the curve (AUC) by 30% but did not affect midazolam, ethinyl estradiol, or norethindrone exposures. Itraconazole increased the AUC of tezacaftor 4‐fold and ivacaftor 15.6‐fold. Ciprofloxacin had no significant effect on tezacaftor or ivacaftor exposure. Coadministration of tezacaftor/ivacaftor may increase exposure of sensitive P‐gp substrates. Tezacaftor/ivacaftor is unlikely to impact exposure of drugs metabolized by CYP3A, including hormonal contraceptives. Strong CYP3A inhibitors significantly increase the exposures of tezacaftor and ivacaftor

Combined effects of smoking and systolic blood pressure on risk of coronary heart disease: a cohort study in Chinese women

Objectives: To quantify the combined effects of systolic blood pressure (SBP) and cigarette smoking on incident coronary heart disease (CHD) in women.Methods: Overall, 86,338 women aged ≥40 years were enrolled in 1991. The follow-up evaluation was conducted in 1999–2000, with a response rate of 92.9%.Results: A total of 829 CHD events (fatal and nonfatal) were observed among the participants who were free of cardiovascular diseases (CVD) at baseline. Higher SBP was significantly associated with more risk of CHD in both nonsmokers and current smokers (all p < 0.0001 for linear trends). Comparing with never smoking, both low and high levels of cigarettes smoked per day (1–7, and ≥8 cigarettes per day) and pack-years (<10, and ≥10 pack-years) were associated with increased risk of CHD in those with normal and high SBP. The multivariate adjusted relative risks (RRs) of CHD were 2.54 (95% confidence interval [CI] 2.00-3.23), 1.28 (1.01-1.63), and 1.57 (1.33-1.86) for current smokers with high SBP, current smokers with normal SBP, and nonsmokers with high SBP, respectively, compared with nonsmokers with normal SBP. The present study identified a statistically significant additive interaction between these two factors on CHD.Conclusions: Our study indicated that the combined effects of cigarette smoking and high SBP could be expected to have extra adverse effects on CHD in women, which highlights the importance of multifactorial interventions to decrease the risk of CHD, for example, quitting smoking and treatment of high blood pressure in Chinese women

Blocking the recruitment of naive CD4+ T cells reverses immunosuppression in breast cancer

The origin of tumor-infiltrating Tregs, critical mediators of tumor immunosuppression, is unclear. Here, we show that tumor-infiltrating naive CD4+ T cells and Tregs in human breast cancer have overlapping TCR repertoires, while hardly overlap with circulating Tregs, suggesting that intratumoral Tregs mainly develop from naive T cells in situ rather than from recruited Tregs. Furthermore, the abundance of naive CD4+ T cells and Tregs is closely correlated, both indicating poor prognosis for breast cancer patients. Naive CD4+ T cells adhere to tumor slices in proportion to the abundance of CCL18-producing macrophages. Moreover, adoptively transferred human naive CD4+ T cells infiltrate human breast cancer orthotopic xenografts in a CCL18-dependent manner. In human breast cancer xenografts in humanized mice, blocking the recruitment of naive CD4+ T cells into tumor by knocking down the expression of PITPNM3, a CCL18 receptor, significantly reduces intratumoral Tregs and inhibits tumor progression. These findings suggest that breast tumor-infiltrating Tregs arise from chemotaxis of circulating naive CD4+ T cells that differentiate into Tregs in situ. Inhibiting naive CD4+ T cell recruitment into tumors by interfering with PITPNM3 recognition of CCL18 may be an attractive strategy for anticancer immunotherapy