[Non-primary solid malignancies of breast in needle core biopsy: a clinicopathological analysis of 23 cases].

Objective: To investigate the accurate diagnosis and differential diagnosis of non-primary solid malignant tumors in breast needle core biopsy. Methods: Twenty-three cases of breast, axilla or neck lymph nodes pathologically diagnosed as non-primary solid malignant tumors were collected at the First Affiliated Hospital of Nanjing Medical University, Nanjing, China from January 2013 to March 2023. The differential diagnoses and diagnostic features were analyzed, based on combining clinical data, histology, and expression characteristics of biomarkers. Results: All patients were female, with age ranging from 29 to 75 years (average 56 years). The average time from the diagnosis of primary tumor to the current diagnosis was 21 months (0 to 204 months).The primary sites included the ovary (9 cases), the lung (5 cases), the gastrointestinal tract (4 cases), the pancreas, intrahepatic bile duct, thyroid gland, nasal cavity and forearm skin (1 case each). No carcinoma in situ was found in any of the cases. The morphological differences were significant among the tumors, but similar to the primary tumors. The tumors of neuroendocrine and female reproductive tract had great morphological and immunophenotypic overlaps with breast cancer. Metastatic lung cancer cells showed obvious atypia and tumor giant cells. The morphology and immunophenotype of metastatic serous carcinoma of female reproductive system might resemble invasive micropapillary carcinoma of the breast. Metastatic adenocarcinoma of the gastrointestinal tract often had features of mucous secretion. Metastatic neuroendocrine tumors were bland in appearance and morphologically similar to solid papillary carcinoma of breast, but negative for ER. TRPS1 was mostly negative (18/23) and variably positive in ovarian (4/9) and intrahepatic bile duct (1/1) tumors. Conclusions: The diagnosis of breast needle core biopsy specimen should be combined with clinical history, imaging study, and careful examination of histological features, such as presence of in situ component, morphological similarity between the primary and metastatic tumors, and using appropriate markers to differentiate the primary from metastatic tumors.

Treatment of Benign C2 Tumors with Transoral Curettage and Posterior Instrumentation with Minimum 2-Year Follow-Up: Technical Note.

Background: Tumors of the axis (C2) are rare, which represents unique surgical challenges. Aim: To describe clinical outcomes and efficacy of transoral curettage and posterior instrumentation for treating C2 tumors, with a minimum 2-year follow-up. Setting and Design: This was a retrospective study conducted at a grade 3A hospital in China. Materials and Methods: From August 2015 to May 2017, patients diagnosed with benign C2 tumors were collected in the retrospective study. The Weinstein-Boriani-Biagini anatomic zone classification was used to characterize the tumors. The Japanese Orthopedic Association (JOA) score and the visual analog scale (VAS) pain scores were recorded pre and postoperatively. All patients were treated with posterior instrumentation and transoral curettage for tumor excision and iliac crest graft for arthrodesis. Results: Five patients were included in this report. The tumors involving C2 were all benign tumors. The JOA and VAS scores improved significantly at a 3-month follow-up, and the clinical symptoms were stable at the 12-month follow-up. Computed tomography (CT) scans at a 6-month follow-up showed solid arthrodesis in all patients. With a minimum 2-year follow-up, there was no implant loosening or tumor recurrence. Conclusion: The transoral curettage coupled with posterior instrumentation with iliac crest graft provides a reasonable option for the treatment of benign C2 tumors.

Real-world comparison of bleeding risks among non-valvular atrial fibrillation patients prescribed apixaban, dabigatran, or rivaroxaban.

Limited real-world data are available regarding the comparative safety of non-vitamin K antagonist oral anticoagulants (NOACs). The objective of this retrospective claims observational cohort study was to compare the risk of bleeding among non-valvular atrial fibrillation (NVAF) patients prescribed apixaban, dabigatran, or rivaroxaban. NVAF patients aged ≥18 years with a 1-year baseline period were included if they were new initiators of NOACs or switched from warfarin to a NOAC. Cox proportional hazards modelling was used to estimate the adjusted hazard ratios of any bleeding, clinically relevant non-major (CRNM) bleeding, and major inpatient bleeding within 6 months of treatment initiation for rivaroxaban and dabigatran compared to apixaban. Among 60,227 eligible patients, 8,785 were prescribed apixaban, 20,963 dabigatran, and 30,529 rivaroxaban. Compared to dabigatran or rivaroxaban patients, apixaban patients were more likely to have greater proportions of baseline comorbidities and higher CHA2DS2-VASc and HAS-BLED scores. After adjusting for baseline clinical and demographic characteristics, patients prescribed rivaroxaban were more likely to experience any bleeding (HR: 1.35, 95% confidence interval [CI]: 1.26-1.45), CRNM bleeding (HR: 1.38, 95% CI: 1.27-1.49), and major inpatient bleeding (HR: 1.43, 95% CI: 1.17-1.74), compared to patients prescribed apixaban. Dabigatran patients had similar bleeding risks as apixaban patients. In conclusion, NVAF patients treated with rivaroxaban appeared to have an increased risk of any bleeding, CRNM bleeding, and major inpatient bleeding, compared to apixaban patients. There was no significant difference in any bleeding, CRNM bleeding, or inpatient major bleeding risks between patients treated with dabigatran and apixaban.

[Correlation analysis of PD-L1 expression and prognosis in triple-negative breast cancers].

Objective: To investigate the relationship between PD-L1 expression and the clinicopathologic features and prognosis in triple-negative breast carcinomas (TNBC). Methods: All 142 cases of TNBC were collected from the First Affiliated Hospital of Nanjing Medical University from February 2011 to December 2014, and the surgical excision or biopsy specimens from patients without chemotherapy and radiotherapy were included. Histopathologic analysis of stromal tumor infiltrating lymphocyte (sTIL) was performed on HE sections, and PD-L1 immunohistochemical staining was done with MaxVision. Results: The PD-L1 expression rate was 34.5% (49/142) in tumor cells, and was 62.0% (88/142) in sTIL. The PD-L1 expression in tumor cells was positively correlated with tumor size (r=0.181, P=0.031), Ki-67 index (r=0.211, P=0.012), sTIL (r=0.380, P<0.01) and PD-L1 expression in sTIL (r=0.447, P<0.01). The PD-L1 expression in sTIL was positively correlated with tumor grade (r=0.215, P=0.01), Ki-67 index (r=0.253, P=0.002) and sTIL (r=0.370, P<0.01). The high stromal CD8(+) /FOXP3(+) ratio was significantly associated with improved overall survival (χ(2)=4.186, P=0.041). The high percentage of sTIL was significantly associated with improved overall survival (χ(2)=12.427, P<0.01) and progression-free survival (χ(2)=4.057, P=0.044). Conclusions: In TNBC, PD-L1 expression is positively correlated with Ki-67 and sTIL; the stromal CD8(+) /FOXP3(+) ratio and sTIL are significantly associated with prognosis. The PD-L1 expression, stromal CD8(+) /FOXP3(+) ratio and sTIL are biologically important in TNBC, and all these correlative factors are important potential parameters in assessing immunotherapy for TNBC.

Ischemic Stroke in Nonvalvular Atrial Fibrillation at Warfarin Initiation: Assessment via a Large Insurance Database.

BACKGROUND AND PURPOSE: Stroke risk may increase shortly after warfarin initiation in nonvalvular atrial fibrillation patients. Because of the brief period and limited number of events, large samples are needed to study this effect. We compared 30-day rates of ischemic stroke between nonvalvular atrial fibrillation patients initiating warfarin to nonwarfarin comparators using an insurance claims database. METHODS: We identified nonvalvular atrial fibrillation patients via 1 inpatient/2 outpatient diagnosis claims from the MarketScan database, January 1, 2009, to December 31, 2010. We studied patients initiating warfarin using prescription claims and 1:1 matched 22 669 initiators to comparators based on age, sex, diagnosis date, and warfarin propensity score. Follow-up began on initiation date; patients were censored at discontinuation/switch of therapy, disenrollment, or end of the study. The median follow-up was 415 days. Cox regression was used to study differences in ischemic stroke risks between warfarin initiators and comparators while controlling for important prognostic factors. RESULTS: Warfarin initiators were generally similar to comparators in clinical features but had higher CHADS2 scores (1.26 versus 1.19). The first 30-day ischemic stroke rate was higher among warfarin initiators than comparators (1.47%/y (27/1836) versus 0.98%/y (18/1837); P=0.18) but lower subsequently (0.81%/y [134/16 543] versus 1.09%/y [406/37 248]; P=0.002). Multivariable regression confirmed a significant interaction between follow-up and warfarin use with the adjusted hazard ratios (95% confidence intervals) for warfarin/comparator as 1.46 (0.80-2.65) in the first 30 days and 0.70 (0.57-0.85) afterward. CONCLUSIONS: Warfarin effect was qualitatively different in the first 30 days after initiation than subsequently. This is consistent with a modest increase in stroke risk occurring briefly after starting warfarin.

Effect of Race and Ethnicity on Antihypertensive Medication Utilization Among Women in the United States: Study of Women's Health Across the Nation (SWAN).

BACKGROUND: Antihypertensive medication use may vary by race and ethnicity. Longitudinal antihypertensive medication use patterns are not well described in women. METHODS AND RESULTS: Participants from the Study of Women's Health Across the Nation (SWAN), a prospective cohort of women (n=3302, aged 42-52), who reported a diagnosis of hypertension or antihypertensive medication use at any annual visit were included. Antihypertensive medications were grouped by class and examined by race/ethnicity adjusting for potential confounders in logistic regression models. A total of 1707 (51.7%) women, mean age 50.6 years, reported hypertension or used antihypertensive medications at baseline or during follow-up (mean 9.1 years). Compared with whites, blacks were almost 3 times as likely to receive a calcium channel blocker (odds ratio, 2.92; 95% CI, 2.24-3.82) and twice as likely to receive a thiazide diuretic (odds ratio, 2.38; 95% CI, 1.93-2.94). Blacks also had a higher probability of reporting use of ≥2 antihypertensive medications (odds ratio, 1.95; 95% CI, 1.55-2.45) compared with whites. Use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and thiazide diuretics increased over time for all racial/ethnic groups. Contrary to our hypothesis, rates of ß-blocker usage did not decrease over time. CONCLUSIONS: Among this large cohort of multiethnic midlife women, use of antihypertensive medications increased over time, with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers becoming the most commonly used antihypertensive medication, even for blacks. Thiazide diuretic utilization increased over time for all race/ethnic groups as did use of calcium channel blockers among blacks; both patterns are in line with guideline recommendations for the management of hypertension.

[Epidemiological analysis of malaria prevalence in Jiangsu Province in 2015].

Objective To understand the malaria epidemic situation and characteristics in Jiangsu Province in 2015, so as to provide the evidence for malaria elimination. Methods The data of malaria cases in Jiangsu Province in 2015 were collected from China's routine diseases surveillance information system. Results Totally 405 imported cases were reported in Jiangsu Province in 2015, and the cases increased by 14.08% compared with those in 2014. All the malaria cases were imported, and 5 cases (1.23%) were from Southeast Asia and 400 (98.77%) were from 25 African countries or regions. The imported malaria cases were reported in 13 cities across Jiangsu Province, where Taizhou, Lianyungang, Nantong, Huaian and Yangzhou cities accounted for 68.64% of all the cases in the province. Jiangsu Institute of Parasitic Diseases (JIPD) reference lab checked all the cases and classified 299 falciparum malaria cases, 13 vivax malaria cases, 18 quartan malaria cases, 71 ovale malaria cases, and 4 mixed Plasmodium infection cases. Conclusions In Jiangsu Province, there are no local malaria cases for 4 consecutive years, but the imported cases are on the rise. Compared to 2014, the imported vivax cases increased significantly in 2015. It should be the key points to strengthen the surveillance of imported malaria cases, improve malaria diagnosis and treatment abilities for all levels of medical institutions, and promote the abilities of Plasmodium check, and focus survey and disposal of all Center for Disease Control (CDC) staffs across Jiangsu Province.

[Diagnostic knowledge and skills of parasitic diseases based on competition of professional personnel in Jiangsu Province, China].

Objective To understand the integrated ability of parasitic disease prevention and control of professional personnel of Jiangsu Province through the contest. Methods Totally 56 players from the whole province were selected, and all the players participated in the contest. The theory knowledge and skill scores were collected and the statistical analyses were conducted. Results The average theoretical score of the participants was 88.86±15.56 and the passing rate was 91.1%. The average skill operating score was 69.16±16.01 and the passing rate was 67.9%. The average Plasmodium microscopy score was 16.54±8.09 and the passing rate was 50%. The average helminth egg microscopy score was 34.27±10.66 and the passing rate was 67.9%. There were statistical differences among the age groups and different levels of schistosomiasis endemic situation (F = 5.10, 6.39, both P < 0.01). The theoretical knowledge including schistosomiasis, malaria, hydatid disease and others and the score rates were 91.07%, 90.94%, 85.83% and 90.93%, respectively. The hydatid disease score rate was lower (χ2 = 19.17, P < 0.01). The radar chart displayed that the score rates of tabletting and microscopy test in Kato-Katz film production, malaria blood film production and microscopy test were all low. Conclusion In Jiangsu Province, the participants have higher score in the theory test. However, they have lower skill test score, especially in the parasite species identification. The operational skills still need to be strengthened for center for disease control (CDC) participants.

Duration of the menopausal transition is longer in women with young age at onset: the multiethnic Study of Women's Health Across the Nation.

OBJECTIVE: The menopausal transition (MT) is a critical period associated with physiologic changes that influence women's long-term health and longevity. Information is, however, limited regarding factors that influence age at the onset of the MT and its duration (ie, time from MT onset to the final menstrual period). METHODS: We analyzed data for 1,145 women from four sites of the Study of Women's Health Across the Nation who participated in the menstrual calendar substudy, had the start of the MT identified, and had no missing covariate information. Participants included from four racial/ethnic groups: African American, white, Chinese, and Japanese. Women completed daily menstrual calendars from 1996 to 2006 and questions on hormone therapy use monthly. Baseline measures included education, economic strain, and menstrual cycle characteristics. Annual measures included height, weight, and smoking status. Cox proportional hazards models were used to analyze the data. RESULTS: The adjusted median duration of the MT ranged from 4.37 years among the oldest age-at-onset quartile to 8.57 years among the youngest age-at-onset quartile (P < 0.001). Cigarette smoking was associated with an earlier onset (P < 0.001) and a shorter duration (P < 0.001). African American women had a longer duration (P = 0.012) than white women. Body mass index was associated with a later onset of the MT (P = 0.001) but not its duration. CONCLUSIONS: The duration of the MT was largely influenced by the age at which it began: earlier onset was associated with a longer transition. This finding provides a strong rationale for developing improved markers of the onset of the early MT.

Longitudinal analysis of changes in weight and waist circumference in relation to incident vasomotor symptoms: the Study of Women's Health Across the Nation (SWAN).

OBJECTIVE: Greater body mass index (BMI) and body fat are associated with vasomotor symptoms (VMS). Thus, weight loss may prevent VMS. We analyzed whether concurrent BMI or waist circumference and/or changes in weight or waist circumference predicted incident VMS and whether these relations differed by menopause stage or race/ethnicity. METHODS: Data from 10 follow-up visits for 1,546 participants in the Study of Women's Health Across the Nation who reported no VMS at baseline were modeled for time to first symptomatic visit in relation to concurrent BMI and waist circumference and change in weight and waist circumference during early and late menopause using discrete survival analyses, adjusting for covariates. RESULTS: Greater concurrent BMI and waist circumference were significantly related to greater any and frequent (≥6 d in the last 2 wk) incident VMS in early menopause and lower VMS risk in late menopause. Percentage weight change since baseline and since the prior visit was unrelated to incident any VMS in either menopause stage. Percentage weight change since baseline had a significant shallow U-shaped association with incident frequent VMS in early menopause (P = 0.02), a shallow inverse U-shape in late menopause (P = 0.02), and a significant interaction with menopause stage (P = 0.004) but not with race/ethnicity. Recent weight change was unassociated with incident VMS in either menopause stage. Results were similar for waist change. CONCLUSIONS: Concurrent BMI and waist circumference were positively related to incident VMS in early menopause and negatively related in late menopause. Maintaining healthy weight in early menopause may help prevent VMS.

Change in sexual functioning over the menopausal transition: results from the Study of Women's Health Across the Nation.

OBJECTIVE: The aim of the study was to identify whether there is a decline in sexual functioning related to the menopausal transition or to hysterectomy. METHODS: In a cohort of 1,390 women aged 42 to 52, with intact uterus and at least one ovary, not using hormone therapy, and pre- or early perimenopausal at baseline, we fit piecewise linear growth curves to 5,798 repeated measurements (seven visits spanning 14.5 y) of a sexual functioning score (range, 5-25) as a function of time relative to date of final menstrual period (FMP) or hysterectomy. RESULTS: Mean sexual functioning at baseline in women with a dateable FMP was 18.0 (SD, 3.4). There was no change in sexual function until 20 months before the FMP. From 20 months before until 1 year after the FMP, sexual function decreased by 0.35 annually (95% CI, -0.44 to -0.26) and continued to decline more than 1 year after the FMP, but at a slower rate (-0.13 annually, 95% CI, -0.17 to -0.10). The decline was smaller in African Americans and larger in Japanese than whites. Vaginal dryness, lubricant use, depressive symptoms, or anxiety did not explain decline in sexual function. Women who had a hysterectomy before the FMP did not show a decline in sexual function before hysterectomy, but scores declined afterward (0.21 annually, 95% CI, -0.28 to -0.14). CONCLUSIONS: Decline in sexual function became apparent 20 months before FMP and slowed 1 year after FMP through 5 years afterward. A decline in sexual function was observed immediately after hysterectomy and persisted for the 5 years of observation.

[CD8 and FOXP3 expression in stromal tumor-infiltrating lymphocytes of triple-negative breast carcinomas: a clinicopathologic study].

OBJECTIVE: To investigate the relationship between stromal tumor-infiltrating lymphocytes (TIL) and CD8 or FOXP3 positive lymphocytes in triple-negative breast carcinoma. METHODS: A total of 160 triple-negative breast carcinomas were collected from the First Affiliated Hospital of Nanjing Medical University during 2012 to 2014. All were surgical excision or biopsy specimens from patients without prior chemotherapy and radiotherapy. Histopathologic analysis of stromal TIL was performed on hematoxylin and eosin-stained sections, and MaxVision immunohistochemical method was used for detection of CD8 and FOXP3 protein expression. RESULTS: Stromal TILs were positively correlated with Ki-67 labeling index (P=0.002). The density of CD8(+) cytotoxic T-lymphocyte (CTL) was negatively correlated with tumor size (P=0.009), and positively correlated with Ki-67 index (P=0.021). The density of FOXP3(+) regulatory T-lymphocyte (Treg) was inversely correlated with the patient age (P=0.030), and positively correlated with histological grade (P=0.026). Stromal TILs were positively correlated with the density of CD8(+) CTL (P=0.014). CONCLUSIONS: The percentage of stromal TILs and density of CD8(+) CTL are associated with tumor cell proliferation of triple-negative breast cancers. The density of FOXP3(+) Treg is significantly associated with poor prognosis. Stromal TIL is positively correlated with the density of CD8(+) CTL. Stromal TIL may provide a potential marker for pathological diagnosis and a target for guiding adjuvant therapy in patients with triple-negative breast cancers.

Characterizing the trajectories of vasomotor symptoms across the menopausal transition.

OBJECTIVE: The aim of the study was to investigate the heterogeneity of temporal patterns of vasomotor symptoms (VMS) over the menopausal transition and identify factors associated with these patterns in a diverse sample of women. METHODS: The Study of Women's Health Across the Nation is a multisite longitudinal study of women from five racial/ethnic groups transitioning through the menopause. The analytic sample included 1,455 women with nonsurgical menopause and a median follow-up of 15.4 years. Temporal patterns of VMS and associations with serum estradiol and follicle-stimulating hormone, race/ethnicity, body mass index, and demographic and psychosocial factors were examined using group-based trajectory modeling. RESULTS: Four distinct trajectories of VMS were found: onset early (11 years before the final menstrual period) with decline after menopause (early onset, 18.4%), onset near the final menstrual period with later decline (late onset, 29.0%), onset early with persistently high frequency (high, 25.6%), and persistently low frequency (low, 27.0%). Relative to women with persistently low frequency of VMS, women with persistently high and early onset VMS had a more adverse psychosocial and health profile. Black women were overrepresented in the late onset and high VMS subgroups relative to white women. Obese women were underrepresented in the late onset subgroup. In multivariable models, the pattern of estradiol over the menopause was significantly associated with the VMS trajectory. CONCLUSIONS: These data distinctly demonstrate heterogeneous patterns of menopausal symptoms that are associated with race/ethnicity, reproductive hormones, premenopause body mass index, and psychosocial characteristics. Early targeted intervention may have a meaningful impact on long-term VMS.

Trajectories of estradiol and follicle-stimulating hormone over the menopause transition and early markers of atherosclerosis after menopause.

AIM: The purpose of this study was to assess associations between distinct patterns of circulating estradiol (E2) and follicle-stimulating hormone (FSH) over the menopause transition (MT) and subclinical measures of atherosclerosis after menopause. METHODS AND RESULTS: Four temporal patterns of E2 decline (Low: low before and after final menstrual period (FMP); Medium: medium before and high after FMP; High-early decline: high prior to FMP and early decline thereafter; High-late decline: high prior to FMP and late decline thereafter) and three of FSH rise (Low, Medium, High) over 9.6 years across FMP were identified and linked to carotid intima-media-thickness (IMT), adventitial diameter (AD), and presence of carotid plaque (cPlaque) measured after menopause at the 12th annual visit (visit 12). Participants were 856 women (age at visit 12 = 59.5 ± 2.7 years) from the Study of Women's Health Across the Nation (SWAN), who never reported a stroke or a heart attack. In models adjusted for visit 12 or baseline cardiovascular disease (CVD) risk factors, odds of having any cPlaque were ∼43% lower among women with the High-early decline E2 trajectory compared to women with the Low E2 trajectory. In contrast, women with the Medium E2 trajectory had significantly higher IMT than those with the Low E2 trajectory adjusting for visit 12 CVD risk factors. Interestingly, adjusting for baseline CVD risk factors attenuated this association. The Low FSH group had lower IMT than the Medium and High FSH groups (p ≤ 0.05) in all models. CONCLUSION: During MT, women are subjected to hormonal alterations that could potentially increase their risk of developing CVD after menopause.

Varying patterns of brachial artery flow-mediated dilatation in women with polycystic ovary syndrome and controls: An application of the group-based trajectory modeling.

PURPOSE: To identify changing patterns of absolute change in brachial artery lumen diameter (LD) after reactive hyperemia in women with polycystic ovary syndrome (PCOS) and controls and to quantify the association of PCOS status and participants' factors with these patterns. METHODS: Brachial flow-mediated dilation was measured in 128 women with PCOS and 148 controls aged 30-60 years. Group-based trajectory modeling was used to investigate absolute change in LD every 30 seconds for 2 minutes after occluding cuff deflation. Multinomial logistic regression was used to identify factors associated with trajectories. RESULTS: Three patterns emerged, namely nondilators (42.2%), dilators (44.6%), and enhanced dilators (13.0%). The proportion of women with PCOS did not differ across groups. Independently of age and PCOS status, larger baseline LD (odds ratio; 95% confidence interval: 2.51; 1.29, 4.89) and lower insulin levels (0.70; 0.52, 0.93) were associated with nondilators rather than with dilators. Higher total cholesterol was associated with dilators in women with PCOS but with nondilators in controls. CONCLUSIONS: Trajectory modeling identified distinct patterns of change in LD and factors associated with the endothelial response. This method may be a useful tool to understand the brachial flow-mediated vasodilator response.

SL4, a chalcone-based compound, induces apoptosis in human cancer cells by activation of the ROS/MAPK signalling pathway.

OBJECTIVES: SL4, a chalcone-based compound, exhibits clearly inhibitory effects on HIF-1 and has been shown to effectively suppress tumour invasion and angiogenesis in vitro and in vivo. Here, studies were conducted to determine SL4's anti-apoptotic effects and its underlying mechanisms, in human cancer cells. MATERIALS AND METHODS: Cytotoxicity, apoptotic induction and its involved mechanisms of SL4 were investigated using normal cells, cancer cells and mouse xenograft models. The role of reactive oxygen species (ROS) and mitogen-activated protein kinase (MAPK) signalling in SL4-induced apoptosis was explored by manipulating specific scavenger or signalling inhibitors, in cultured cells. RESULTS: SL4 significantly inhibited cell population growth of human cancer cell lines but exhibited lower cytotoxicity against normal cells. In addition, SL4 effectively induced apoptosis of Hep3B and MDA-MB-435 cells by activating procaspase-8, -9 and -3, and down-regulating expression levels of XIAP, but did not affect HIF-1 apoptosis-related targets, Survivin and Bcl-XL. Further study showed that SL4 also reduced mitochondrial membrane potential and promoted generation of ROS. ROS generation and apoptotic induction by SL4 were blocked by NAC, a scavenger of ROS, suggesting SL4-induced apoptosis via ROS accumulation. We also found that MAPKs, JNK and p38, but not ERK1/2, to be critical mediators in SL4-induced apoptosis. SP600125 and SB203580, specific inhibitors of JNK kinase and p38 kinase, significantly retarded apoptosis induced by SL4. Moreover, anti-oxidant NAC blocked activation of JNK and p38 induced by SL4, indicating that ROS may act as upstream signalling of JNK and p38 activation. It is noteworthy that animal studies revealed dramatic reduction (49%) in tumour volume after 11 days SL4 treatment. CONCLUSIONS: These data demonstrate that SL4 induced apoptosis in human cancer cells through activation of the ROS/MAPK signalling pathway, suggesting that it may be a novel lead compound, as a cancer drug candidate, with polypharmacological characteristics.

Ectopic adiposity is associated with autonomic risk factors and subclinical cardiovascular disease in young adults.

OBJECTIVE: To examine the relationship between ectopic adiposity and markers of cardiometabolic risk, autonomic control, and subclinical cardiovascular disease (CVD). METHODS: Cross-sectional analyses were performed in 324 subjects with overweight and obesity. Single-slice CT images were analyzed to calculate thigh muscle attenuation (MA), a measure of ectopic adiposity. Autonomic control was assessed using low-frequency to respiratory-frequency heart rate variability (LFa/RFa ratio). Carotid intima-media thickness (IMT) was a marker of subclinical CVD. RESULTS: Among overweight participants, those with low MA had lower HDL-c, higher LFa/RFa ratio, and subcutaneous thigh fat compared to high MA individuals despite no difference in visceral fat or insulin resistance. Significant associations were not observed in the class I obese group. In the class II obese group, those with high MA had higher triglycerides and insulin levels, yet there was no difference in visceral fat compared to the low MA group. Mean IMT was significantly higher in the low MA compared to the high MA overweight group (0.63 mm vs. 0.58 mm, P = 0.04) but was similar between the low and high MA class II obese groups. CONCLUSIONS: Excess ectopic adiposity in muscle tissue is associated with metabolic and autonomic risk factors and subclinical CVD, most notably in overweight individuals, independent of insulin resistance and visceral abdominal fat.

Nulliparity is associated with less healthy markers of subclinical cardiovascular disease in young women with overweight and obesity.

OBJECTIVE: Higher parity is associated with increased subclinical cardiovascular disease (CVD) in mid-life and older women and with increased CVD risk overall. The relationship between parity, subclinical CVD, and infertility in young women with overweight and obesity has been infrequently evaluated. METHODS: Reproductive histories were obtained in 191 (66%) young women with overweight and obesity (BMI 25-39.9 kg/m(2) ) participating in a weight loss trial. Baseline carotid intima-media thickness (IMT) and inter-adventitial diameter (IAD) were assessed via B-mode ultrasound. Linear regression was used to estimate the relationship between parity and carotid measures, adjusted for demographic, cardiovascular, and reproductive risk factors. RESULTS: Nulliparous women (n = 70, age 34.9 ± 7.1) had increased common carotid IAD (0.230 mm, SE 0.08, P = 0.003) and mean common carotid artery (CCA) IMT (0.031 mm, SE 0.01, P = 0.007) compared with parous women (n = 102, age 39.5 ± 4.9), persisting after adjustment for age, race, and CVD risk factors. No other reproductive factors were statistically significantly associated. CONCLUSIONS: Nulliparity is associated with markers of less healthy carotid arteries in a sample of disease-free 25- to 45-year-old women with overweight or obesity. This may represent a beneficial effect of pregnancy or indicate overall better health in women with overweight/obesity who are capable of childbearing.