Dry eye disease (DED) is a prevalent and intractable ocular disease induced by a variety of causes. Elevated sphingomyelin (SM) levels and pro-inflammatory cytokines were detected on the ocular surface of DED patients, particularly in the meibomian glands. Sphingomyelin synthase 2 (SMS2), one of the proteins involved in SM synthesis, would light a novel way of developing a DED therapy strategy. Herein, we report the design and optimization of a series of novel thiophene carboxamide derivatives to afford 14l with an improved highly potent inhibitory activity on SM synthesis (IC_{50, SMS2} = 28 nmol/L). Moreover, 14l exhibited a notable protective effect of anti-inflammation and anti-apoptosis on human corneal epithelial cells (HCEC) under TNF-α-hyperosmotic stress conditions in vitro, with an acceptable ocular specific distribution (corneas and meibomian glands) and pharmacokinetics (PK) profiles (t _{1/2, cornea} = 1.11 h; t _{1/2, meibomian glands} = 4.32 h) in rats. Furthermore, 14l alleviated the dry eye symptoms including corneal fluorescein staining scores and tear secretion in a dose-dependent manner in mice. Mechanically, 14l reduced the mRNA expression of Tnf-α, Il-1β and Mmp-9 in corneas, as well as the proportion of very long chain SM in meibomian glands. Our findings provide a new strategy for DED therapy based on selective SMS2 inhibitors.

Objectives:To investigate the clinical characteristics and prognosis of patients with pulmonary arterial hypertension(PAH)concomitant with obstructive sleep apnea(OSA).Methods:We analyzed the data of 208 patients diagnosed with PAH in the Pulmonary Vascular Diseases Ward of our hospital from September 2019 to August 2024,who underwent sleep breathing monitoring and echocardiography during hospitalization.Three clusters were identified:Cluster 1(n=121)had no OSA and mildly elevated N-terminal pro-B-type natriuretic peptide(NT-proBNP),Cluster 2(n=71)exhibited mild OSA and mildly elevated NT-proBNP,and Cluster 3(n=16)presented with moderate to severe OSA along with significantly elevated NT-proBNP.Results:The mean age of this patient cohort was(39±12)years,mean body mass index was(21.74±3.67)kg/m2,and 27.9%patients were male.Sixty-five patients(31.3%)had OSA.The echocardiographic indicators reflecting the structural function of the heart chambers and hemodynamic parameters in patients with PAH showed a significant correlation with nocturnal hypoxia.Compared to Cluster 1,patients in Cluster 2 and Cluster 3 had wider pulmonary arteries and inferior vena cava diameters,larger right ventricular diameters,higher pulmonary artery pressure,higher pulmonary vascular resistance,and lower cardiac index(all P<0.05).Cluster 3 patients had a significantly higher risk of death(log-rank P=0.022).Conclusions:Thirty-one percent of PAH patients in this study had concomitant OSA.PAH patients with significantly elevated NT-proBNP and comorbid moderate-to-severe OSA had a significantly higher risk of death compared to those with only mild or without OSA without significantly elevated NT-proBNP.Management strategies that address both PAH and OSA might be effective in improving the outcomes of these patients.

Objectives:To investigate the clinical characteristics and prognosis of patients with pulmonary arterial hypertension(PAH)concomitant with obstructive sleep apnea(OSA).Methods:We analyzed the data of 208 patients diagnosed with PAH in the Pulmonary Vascular Diseases Ward of our hospital from September 2019 to August 2024,who underwent sleep breathing monitoring and echocardiography during hospitalization.Three clusters were identified:Cluster 1(n=121)had no OSA and mildly elevated N-terminal pro-B-type natriuretic peptide(NT-proBNP),Cluster 2(n=71)exhibited mild OSA and mildly elevated NT-proBNP,and Cluster 3(n=16)presented with moderate to severe OSA along with significantly elevated NT-proBNP.Results:The mean age of this patient cohort was(39±12)years,mean body mass index was(21.74±3.67)kg/m2,and 27.9%patients were male.Sixty-five patients(31.3%)had OSA.The echocardiographic indicators reflecting the structural function of the heart chambers and hemodynamic parameters in patients with PAH showed a significant correlation with nocturnal hypoxia.Compared to Cluster 1,patients in Cluster 2 and Cluster 3 had wider pulmonary arteries and inferior vena cava diameters,larger right ventricular diameters,higher pulmonary artery pressure,higher pulmonary vascular resistance,and lower cardiac index(all P<0.05).Cluster 3 patients had a significantly higher risk of death(log-rank P=0.022).Conclusions:Thirty-one percent of PAH patients in this study had concomitant OSA.PAH patients with significantly elevated NT-proBNP and comorbid moderate-to-severe OSA had a significantly higher risk of death compared to those with only mild or without OSA without significantly elevated NT-proBNP.Management strategies that address both PAH and OSA might be effective in improving the outcomes of these patients.

OBJECTIVE To study the effect of Osthole on the proliferation and apoptosis in human nasopharyngeal carcinoma(NPC) cell, and to explore new treatment measures for nasopharyngeal carcinoma. METHODS Human NPC cell line CNE2 was treated with various concentrations of Osthole. MTT assay was used to investigate the cell viability, and apoptosis was detected by flow cytometry in CNE2 cells. Furthermore, the mRNA and protein expression levels of Bcl-2, Bax were determined by RT-PCR and western blot respectively. RESULTS Osthole induced significantly inhibitory effect on CNE2 cells at 24 h, 48 h and 72 h, and it was related with time and dose(P＜0.01). Following treatment of Osthole for 48 h, CNE2 cells showed significantly higher apoptosis rate than controls(P＜0.01). Meanwhile, both the mRNA and protein levels of Bax in Osthole-treated CNE2 cells were significantly higher than that of controls, while the level of Bcl-2 was downregulated, both of which changed with dose(P＜0.01). CONCLUSION The present study implied that Osthole can effectively inhibit proliferation and induce apoptosis in NPC cell lines CNE2.

Objective To explore the association between blood cadmium levels (BCLs) and clinicopathological characteristics of patients with breast cancer.Methods The clinicopathological characteristics and blood specimens of 186 patients diagnosed with breast cancer were collected between July and December 2009.BCLs were detected by graphite-furnace atomizer absorption spectrophotometer.Mann-Whitney U test and Kruskal-Wallis H test were used to compare the BCLs of patients with different clinical characteristics.Spearman rank correlation analysis was used to evaluate the relationships between BCLs and some indices of clinical characteristics.Results The BCLs was 2.280 (1.579) μg/L.The BCLs were significantly different in patients with different age and body mass index (BMI) (Z =-2.075,P =0.038;x2 =7.429,P =0.023).Also,there were significant differences in different T stages (x2 =10.137,P =0.017),M stages (Z =-2.225,P =0.026),clinical stages (x2 =16.060,P =0.001) and human epidermal growth factor receptor-2 (HER-2) status (Z=-2.072,P=0.038).Excepting for age (r =0.126,P =0.066),BCLs were positively associated with BMI,T stage,M stage,clinical stage and HER-2 status (r=0.159,P =0.030;r =0.171,P=0.020;r =0.166,P =0.044;r=0.154,P =0.040;r =0.152,P =0.038).Conclusion The BCLs are associated with some clinicopathological characteristics of breast cancer,and high blood cadmium burden may promote the development of breast cancer.

Objective To evaluate the protein expression of chromosome 2 open reading frame 40 (C2orf40) in nasopharyngeal carcinoma (NPC) tissues and cells,and to explore its association with cell differentiation and clinicopatho]ogical features.Methods A total of 122 patients with NPC between January 2001 and December 2003 were enrolled in Cancer Hospital of Shantou University Medical College.The paraffinembedded tissue sections and medical records were collected.Twenty-five samples with chronic nasopharyngitis were used as controls.Tumor and control tissues from biopsies underwent immunohistochemical staining for C2orf40.C2orf40 expression was analyzed with clinicopathological variables.Besides,the protein expressions of C2orf40 were measured by Western blotting in three NPC cell lines,including CNE1,CNE2 and C666-1.Results Ninety-six percent (24/25) of control tissues showed positive expression,among which 88.0％ showed dense staining.Otherwise,only 58.3％ (71/122) of NPC samples were positive for C2orf40 protein and 82.0％ showed weak staining.There was significantly difference between the two groups (U =255.500,P ＜ 0.001).It was inversely related to lymph nodes status (r =-0.058,P ＜ 0.001) and clinical stage (r =-0.202,P =0.026) by Spearman rank correlation test.In vitro,higher level of C2orf40 protein was found in well differentiated CNE1 cells,while lower levels were found in poorly differentiated cell lines CNE2 and C666-1.Conclusion Down-regulated C2orf40 expression is correlated with tunor cell differentiation,lymph nodes metastasis and clinical stage,and may be a molecular event in the occurrence and development of NPC.C2orf40 is likely to be a potential target of anticancer therapy.