Endometrial stromal sarcoma: a population-based analysis

To determine independent prognostic factors for the survival of patients with endometrial stromal sarcoma (ESS), data were abstracted from the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute from 1988 to 2003. Kaplan–Meier and Cox proportional hazards models were used for analyses. Of 831 women diagnosed with ESS, the median age was 52 years (range: 17–96 years). In total, 59.9% had stage I, 5.1% stage II, 14.9% stage III, and 20.1% had stage IV disease. Overall, 13.0, 36.1, and 34.7% presented with grades 1, 2, and 3, respectively. Patients with stage I–II vs III–IV disease had 5 years DSS of 89.3% vs 50.3% (P<0.001) and those with grades 1, 2, and 3 cancers had survivals of 91.4, 95.4, and 42.1% (P<0.001). In multivariate analysis, older patients, black race, advanced stage, higher grade, lack of primary surgery, and nodal metastasis were independent prognostic factors for poorer survival. In younger women (<50 years) with stage I–II disease, ovarian-sparing procedures did not adversely impact survival (91.9 vs 96.2%; P=0.1). Age, race, primary surgery, stage, and grade are important prognostic factors for ESS. Excellent survival in patients with grade 1 and 2 disease of all stages supports the concept that these tumors are significantly different from grade 3 tumors. Ovarian-sparing surgeries may be considered in younger patients with early-stage disease

Identification of a Vitamin-D Receptor Antagonist, MeTC7, which Inhibits the Growth of Xenograft and Transgenic Tumors In Vivo

Vitamin-D receptor (VDR) mRNA is overexpressed in neuroblastoma and carcinomas of lung, pancreas, and ovaries and predicts poor prognoses. VDR antagonists may be able to inhibit tumors that overexpress VDR. However, the current antagonists are arduous to synthesize and are only partial antagonists, limiting their use. Here, we show that the VDR antagonist MeTC7 (5), which can be synthesized from 7-dehydrocholesterol (6) in two steps, inhibits VDR selectively, suppresses the viability of cancer cell-lines, and reduces the growth of the spontaneous transgenic TH-MYCN neuroblastoma and xenografts in vivo. The VDR selectivity of 5 against RXRα and PPAR-γ was confirmed, and docking studies using VDR-LBD indicated that 5 induces major changes in the binding motifs, which potentially result in VDR antagonistic effects. These data highlight the therapeutic benefits of targeting VDR for the treatment of malignancies and demonstrate the creation of selective VDR antagonists that are easy to synthesize

Efficacy of a Non-Hypercalcemic Vitamin-D2 Derived Anti-Cancer Agent (MT19c) and Inhibition of Fatty Acid Synthesis in an Ovarian Cancer Xenograft Model

BACKGROUND:Numerous vitamin-D analogs exhibited poor response rates, high systemic toxicities and hypercalcemia in human trials to treat cancer. We identified the first non-hypercalcemic anti-cancer vitamin D analog MT19c by altering the A-ring of ergocalciferol. This study describes the therapeutic efficacy and mechanism of action of MT19c in both in vitro and in vivo models. METHODOLOGY/PRINCIPAL FINDING:Antitumor efficacy of MT19c was evaluated in ovarian cancer cell (SKOV-3) xenografts in nude mice and a syngenic rat ovarian cancer model. Serum calcium levels of MT19c or calcitriol treated animals were measured. In-silico molecular docking simulation and a cell based VDR reporter assay revealed MT19c-VDR interaction. Genomewide mRNA analysis of MT19c treated tumors identified drug targets which were verified by immunoblotting and microscopy. Quantification of cellular malonyl CoA was carried out by HPLC-MS. A binding study with PPAR-Y receptor was performed. MT19c reduced ovarian cancer growth in xenograft and syngeneic animal models without causing hypercalcemia or acute toxicity. MT19c is a weak vitamin-D receptor (VDR) antagonist that disrupted the interaction between VDR and coactivator SRC2-3. Genome-wide mRNA analysis and western blot and microscopy of MT19c treated xenograft tumors showed inhibition of fatty acid synthase (FASN) activity. MT19c reduced cellular levels of malonyl CoA in SKOV-3 cells and inhibited EGFR/phosphoinositol-3kinase (PI-3K) activity independently of PPAR-gamma protein. SIGNIFICANCE:Antitumor effects of non-hypercalcemic agent MT19c provide a new approach to the design of vitamin-D based anticancer molecules and a rationale for developing MT19c as a therapeutic agent for malignant ovarian tumors by targeting oncogenic de novo lipogenesis

The Staphylococcus aureus superantigen SElX is a bifunctional toxin that inhibits neutrophil function:SElX Inhibits Neutrophil Function

Bacterial superantigens (SAgs) cause Vβ-dependent T-cell proliferation leading to immune dysregulation associated with the pathogenesis of life-threatening infections such as toxic shock syndrome, and necrotizing pneumonia. Previously, we demonstrated that staphylococcal enterotoxin-like toxin X (SElX) from Staphylococcus aureus is a classical superantigen that exhibits T-cell activation in a Vβ-specific manner, and contributes to the pathogenesis of necrotizing pneumonia. Here, we discovered that SElX can also bind to neutrophils from human and other mammalian species and disrupt IgG-mediated phagocytosis. Site-directed mutagenesis of the conserved sialic acid-binding motif of SElX abolished neutrophil binding and phagocytic killing, and revealed multiple glycosylated neutrophil receptors for SElX binding. Furthermore, the neutrophil binding-deficient mutant of SElX retained its capacity for T-cell activation demonstrating that SElX exhibits mechanistically independent activities on distinct cell populations associated with acquired and innate immunity, respectively. Finally, we demonstrated that the neutrophil-binding activity rather than superantigenicity is responsible for the SElX-dependent virulence observed in a necrotizing pneumonia rabbit model of infection. Taken together, we report the first example of a SAg, that can manipulate both the innate and adaptive arms of the human immune system during S. aureus pathogenesis

Obesity modulates the association between systolic blood pressure and albuminuria

Background. Obesity is associated with albuminuria and incident kidney disease. Increased vulnerability of the glomerular microcirculation to elevated systemic blood pressure is postulated to contribute to adverse effects of obesity on the kidney. We therefore hypothesized that obesity would modulate the association between systolic blood pressure (sBP) and albuminuria. Methods. The relationship between obesity and albuminuria [fractional albumin excretion (FEalb) or albumin:creatinine ratio (ACR)] was modelled using linear/logistic regression in the US National Health and Nutrition Examination Survey 1999–2010 cohorts (N = 23 710). Associations between sBP and albuminuria were examined across strata of waist circumference and body mass index (BMI) using interaction terms. Results. Obesity was associated with albuminuria through an interaction with sBP. Among participants in the 4th/5th quintiles of waist circumference each 10 mmHg increase in sBP was accompanied by approximately double the increment in FEalb observed among those in quintile 2 (14% versus 7%, P 110 mmHg in quintile 5 of waist circumference, in quintile 2 FEalb did not increase until sBP was  >130 mmHg. Findings were consistent when defining obesity by BMI or waist circumference and when quantifying albuminuria by ACR or FEalb. Assessing albuminuria as the odds ratio of ACR >30 mg/g also gave similar results. Conclusion. The interaction between sBP and obesity supports the premise that obesity sensitizes the kidney to increased systemic blood pressure

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Supplementary Material for: Pulmonary Hypertension in Renal Disease: Epidemiology, Potential Mechanisms and Implications

Pulmonary hypertension (PH) is highly prevalent in end-stage renal disease. Several observational studies, based on an echocardiographic diagnosis of PH, have suggested a prevalence of 30-60% and an association with increased mortality and poorer outcome following renal transplantation. The pathogenesis of PH in this population remains poorly understood. Reported associations include arteriovenous fistulae, cardiac dysfunction, fluid overload, bone mineral disorder and non-biocompatible dialysis membranes. However, due to the small numbers, the cross-sectional nature of the majority of studies in this field, and the reliance on echocardiography for the diagnosis of PH, no consistent association with any individual risk factor has been demonstrated. There is no difference in prevalence between patients receiving different dialysis modalities and emerging evidence suggests that the onset of the condition may precede dialysis treatment in many patients. Furthermore, little is known about the impact of the ‘uraemic vasculopathy' on the pulmonary vasculature. Given the similarities between vascular changes in uraemia and those seen in pulmonary arterial hypertension, it is possible that a pulmonary vasculopathy may be present in a proportion of patients. There is a need for better understanding of the natural history and the pathogenesis of the condition which would help to individualise treatment of PH in end-stage renal disease. To enable such understanding, prospective adequately powered studies with an integrated investigational approach including right heart catheterisation are needed

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Not AvailableIndia is going to be urban nation which shall be adding 404 million people to its urban population between 2014 and 2050. The annual growth in urban population in India between 2010 and 2015 was 1.1% the highest among the major economies, according to the UN World Urbanisation Prospects Report 2014. Indian cities are already contributing more than 62% to our national GDP. This increasing population in urban areas and increased saying with flowers shall create the huge demand for the floricultural products in urban and peri-urban parts of many cities of India. To cater the need of flowers in urban areas, the flower markets are an important aspect of floriculture industry. Proper marketing facilities shall bridge the gap between producers and consumers and thereby fetching better returns to the farmers. Therefore efforts were made by our team to study the Gultekdi Market of Agricultural Produce Marketing Committee (APMC), Pune wherein traders and flower marketing patterns was studied. During survey, direct personal interviews were conducted at flower market and at flower shops. This was done with the aid of a questionnaire of open- end questions. Based on the data collected from 65 traders for their educational qualifications it was observed that most of respondents had attained higher secondary school education (41%), those who had attained secondary school education were 27%, the least had attained only post graduate (9%) and 20% had attained graduation. 100% of the respondents were men with variable ages. 31-40 years old were the majority with 32.30% followed by 41-50 years old with 29.23% and 51-60 with 20.00% whereas, the least were above 61 years old which constituted 6.15% followed by 21-30 with 12.30%. In APMC traders are creating jobs for youth and farmers. Based on the survey scoring was given and efforts were made to identify the major difficulties. The price fluctuation is major issue for traders and about 64% traders said its major difficulty for them. Whereas, lack of storage facility at market place is another issue which was raised by 54% of traders interviewed. Among traders, knowledge about market is also major challenge and about 50% of traders facing problem in everyday business. Based on the data obtained about 84% respondent provide guidance about planting time of flower crops and 83% respondents give information about trending varieties in the market. Such information shall be highly useful for the farmers for getting better returns and planning of crop calendar.Not Availabl