Utilization of services provided by village based ethnic minority midwives in mountainous villages of Vietnam

Introduction: Since 2011, the Vietnam’s Ministry of Health implemented the ethnic minority midwives (EMMs) scheme in order to increase the utilization of maternal health services by women from ethnic minorities and those living in hard-to-reach mountainous areas. This paper analyzes the utilization of antenatal, delivery, and postpartum care provided by EMMs and reports the key determinants of utilization of EMM services as perceived by service users. Methods: A structured questionnaire was administered in 2015 to all mothers (n=320) who gave birth to a live-born during a 1-year period in 31 villages which had EMM in two provinces, Dien Bien and Kon Tum. A multivariate logistic regression model was used to examine the association between all potential factors and the use of services provided by EMMs. Results: We found that EMMs provided more antenatal care and postnatal care as compared with delivery services, which corresponded to their job descriptions. The results also showed that utilization of antenatal care provided by EMMs was lower than that of postnatal care. The proportion of those who never heard about EMM was high (24%). Among the mothers who knew about EMM services, 33.4% had antenatal checkups, 20.1% were attended during home deliveries, and 57.3% had postnatal visits by an EMM. Key factors that determined the use of EMM services included knowledge of the location of EMM’s house, being aware about EMMs by health workers, trust in services provided by EMMs, and perception that many others mothers in a village also knew about EMM services. Conclusion: EMM seems to be an important mechanism to ensure assistance during home births and postnatal care for ethnic minority groups, who are often resistant to attend health facilities. Building trust and engaging with communities are the key facilitators to increase the utilization of services provided by EMMs. Communication campaigns to raise awareness about EMMs and to promote their services in the village, particularly by other health workers, represent an important strategy to further improve effectiveness of EMM scheme

Surface-enhanced Raman spectroscopy study of 4-ATP on gold nanoparticles for basal cell carcinoma fingerprint detection

The surface-enhanced Raman signals of 4-aminothiophenol (4-ATP) attached to the surface of colloidal gold nanoparticles with size distribution of 2 to 5 nm were used as a labeling agent to detect basal cell carcinoma (BCC) of the skin. The enhanced Raman band at 1075 cm-1 corresponding to the C-S stretching vibration in 4-ATP was observed during attachment to the surface of the gold nanoparticles. The frequency and intensity of this band did not change when the colloids were conjugated with BerEP4 antibody, which specifically binds to BCC. We show the feasibility of imaging BCC by surface-enhanced Raman spectroscopy, scanning the 1075 cm-1 band to detect the distribution of 4ATP-coated gold nanoparticles attached to skin tissue ex vivo

Biomechanics and the thermotolerance of development

Successful completion of development requires coordination of patterning events with morphogenetic movements. Environmental variability challenges this coordination. For example, developing organisms encounter varying environmental temperatures that can strongly influence developmental rates. We hypothesized that the mechanics of morphogenesis would have to be finely adjusted to allow for normal morphogenesis across a wide range of developmental rates. We formulated our hypothesis as a simple model incorporating time-dependent application of force to a viscoelastic tissue. This model suggested that the capacity to maintain normal morphogenesis across a range of temperatures would depend on how both tissue viscoelasticity and the forces that drive deformation vary with temperature. To test this model we investigated how the mechanical behavior of embryonic tissue (Xenopus laevis) changed with temperature; we used a combination of micropipette aspiration to measure viscoelasticity, electrically induced contractions to measure cellular force generation, and confocal microscopy to measure endogenous contractility. Contrary to expectations, the viscoelasticity of the tissues and peak contractile tension proved invariant with temperature even as rates of force generation and gastrulation movements varied three-fold. Furthermore, the relative rates of different gastrulation movements varied with temperature: the speed of blastopore closure increased more slowly with temperature than the speed of the dorsal-to-ventral progression of involution. The changes in the relative rates of different tissue movements can be explained by the viscoelastic deformation model given observed viscoelastic properties, but only if morphogenetic forces increase slowly rather than all at once. © 2014 von Dassow et al

Telomerase inhibition abolishes the tumorigenicity of pediatric ependymoma tumor-initiating cells

Pediatric ependymomas are highly recurrent tumors resistant to conventional chemotherapy. Telomerase, a ribonucleoprotein critical in permitting limitless replication, has been found to be critically important for the maintenance of tumor-initiating cells (TICs). These TICs are chemoresistant, repopulate the tumor from which they are identified, and are drivers of recurrence in numerous cancers. In this study, telomerase enzymatic activity was directly measured and inhibited to assess the therapeutic potential of targeting telomerase. Telomerase repeat amplification protocol (TRAP) (n = 36) and C-circle assay/telomere FISH/ATRX staining (n = 76) were performed on primary ependymomas to determine the prevalence and prognostic potential of telomerase activity or alternative lengthening of telomeres (ALT) as telomere maintenance mechanisms, respectively. Imetelstat, a phase 2 telomerase inhibitor, was used to elucidate the effect of telomerase inhibition on proliferation and tumorigenicity in established cell lines (BXD-1425EPN, R254), a primary TIC line (E520) and xenograft models of pediatric ependymoma. Over 60 % of pediatric ependymomas were found to rely on telomerase activity to maintain telomeres, while no ependymomas showed evidence of ALT. Children with telomerase-active tumors had reduced 5-year progression-free survival (29 +/- A 11 vs 64 +/- A 18 %; p = 0.03) and overall survival (58 +/- A 12 vs 83 +/- A 15 %; p = 0.05) rates compared to those with tumors lacking telomerase activity. Imetelstat inhibited proliferation and self-renewal by shortening telomeres and inducing senescence in vitro. In vivo, Imetelstat significantly reduced subcutaneous xenograft growth by 40 % (p = 0.03) and completely abolished the tumorigenicity of pediatric ependymoma TICs in an orthotopic xenograft model. Telomerase inhibition represents a promising therapeutic approach for telomerase-active pediatric ependymomas found to characterize high-risk ependymomas.Canadian Institutes of Health Research [MOP 82727]info:eu-repo/semantics/publishedVersio

Epigenetic polypharmacology: from combination therapy to multitargeted drugs

The modern drug discovery process has largely focused its attention in the so-called magic bullets, single chemical entities that exhibit high selectivity and potency for a particular target. This approach was based on the assumption that the deregulation of a protein was causally linked to a disease state, and the pharmacological intervention through inhibition of the deregulated target was able to restore normal cell function. However, the use of cocktails or multicomponent drugs to address several targets simultaneously is also popular to treat multifactorial diseases such as cancer and neurological disorders. We review the state of the art with such combinations that have an epigenetic target as one of their mechanisms of action. Epigenetic drug discovery is a rapidly advancing field, and drugs targeting epigenetic enzymes are in the clinic for the treatment of hematological cancers. Approved and experimental epigenetic drugs are undergoing clinical trials in combination with other therapeutic agents via fused or linked pharmacophores in order to benefit from synergistic effects of polypharmacology. In addition, ligands are being discovered which, as single chemical entities, are able to modulate multiple epigenetic targets simultaneously (multitarget epigenetic drugs). These multiple ligands should in principle have a lower risk of drug-drug interactions and drug resistance compared to cocktails or multicomponent drugs. This new generation may rival the so-called magic bullets in the treatment of diseases that arise as a consequence of the deregulation of multiple signaling pathways provided the challenge of optimization of the activities shown by the pharmacophores with the different targets is addressed

CP-31398, a putative p53-stabilizing molecule tested in mammalian cells and in yeast for its effects on p53 transcriptional activity

BACKGROUND: CP-31398 is a small molecule that has been reported to stabilize the DNA-binding core domain of the human tumor suppressor protein p53 in vitro. The compound was also reported to function as a potential anti-cancer drug by rescuing the DNA-binding activity and, consequently, the transcription activation function of mutant p53 protein in mammalian tissue culture cells and in mice. RESULTS: We performed a series of gene expression experiments to test the activity of CP-31398 in yeast and in human cell cultures. With these cell-based assays, we were unable to detect any specific stimulation of mutant p53 activity by this compound. Concentrations of CP-31398 that were reported to be active in the published work were highly toxic to the human H1299 lung carcinoma and Saos-2 cell lines in our experiments. CONCLUSION: In our experiments, the small molecule CP-31398 was unable to reactivate mutant p53 protein. The results of our in vivo experiments are in agreement with the recently published biochemical analysis of CP-31398 showing that this molecule does not bind p53 as previously claimed, but intercalates into DNA

Species Used for Drug Testing Reveal Different Inhibition Susceptibility for 17beta-Hydroxysteroid Dehydrogenase Type 1

Steroid-related cancers can be treated by inhibitors of steroid metabolism. In searching for new inhibitors of human 17beta-hydroxysteroid dehydrogenase type 1 (17β-HSD 1) for the treatment of breast cancer or endometriosis, novel substances based on 15-substituted estrone were validated. We checked the specificity for different 17β-HSD types and species. Compounds were tested for specificity in vitro not only towards recombinant human 17β-HSD types 1, 2, 4, 5 and 7 but also against 17β-HSD 1 of several other species including marmoset, pig, mouse, and rat. The latter are used in the processes of pharmacophore screening. We present the quantification of inhibitor preferences between human and animal models. Profound differences in the susceptibility to inhibition of steroid conversion among all 17β-HSDs analyzed were observed. Especially, the rodent 17β-HSDs 1 were significantly less sensitive to inhibition compared to the human ortholog, while the most similar inhibition pattern to the human 17β-HSD 1 was obtained with the marmoset enzyme. Molecular docking experiments predicted estrone as the most potent inhibitor. The best performing compound in enzymatic assays was also highly ranked by docking scoring for the human enzyme. However, species-specific prediction of inhibitor performance by molecular docking was not possible. We show that experiments with good candidate compounds would out-select them in the rodent model during preclinical optimization steps. Potentially active human-relevant drugs, therefore, would no longer be further developed. Activity and efficacy screens in heterologous species systems must be evaluated with caution

Decreased expression of 17β-hydroxysteroid dehydrogenase type 1 is associated with DNA hypermethylation in colorectal cancer located in the proximal colon

<p>Abstract</p> <p>Background</p> <p>The importance of 17β-estradiol (E2) in the prevention of large bowel tumorigenesis has been shown in many epidemiological studies. Extragonadal E2 may form by the aromatase pathway from androstenedione or the sulfatase pathway from estrone (E1) sulfate followed by E1 reduction to E2 by 17-β-hydroxysteroid dehydrogenase (HSD17B1), so <it>HSD17B1 </it>gene expression may play an important role in the production of E2 in peripheral tissue, including the colon.</p> <p>Methods</p> <p><it>HSD17B1 </it>expression was analyzed in colorectal cancer cell lines (HT29, SW707) and primary colonic adenocarcinoma tissues collected from fifty two patients who underwent radical colon surgical resection. Histopathologically unchanged colonic mucosa located at least 10-20 cm away from the cancerous lesions was obtained from the same patients. Expression level of <it>HSD17B1 </it>using quantitative PCR and western blot were evaluated. DNA methylation level in the 5' flanking region of <it>HSD17B1 </it>CpG rich region was assessed using bisulfite DNA sequencing and HRM analysis. The influence of DNA methylation on HSD17B1 expression was further evaluated by ChIP analysis in HT29 and SW707 cell lines. The conversion of estrone (E1) in to E2 was determined by electrochemiluminescence method.</p> <p>Results</p> <p>We found a significant decrease in HSD17B1 transcript (<it>p </it>= 0.0016) and protein (<it>p </it>= 0.0028) levels in colorectal cancer (CRC) from the proximal but not distal colon and rectum. This reduced <it>HSD17B1 </it>expression was associated with significantly increased DNA methylation (<it>p </it>= 0.003) in the CpG rich region located in the 5' flanking sequence of the <it>HSD17B1 </it>gene in CRC in the proximal but not distal colon and rectum. We also showed that 5-dAzaC induced demethylation of the 5' flanking region of <it>HSD17B1</it>, leading to increased occupation of the promoter by Polymerase II, and increased transcript and protein levels in HT29 and SW707 CRC cells, which contributed to the increase in E2 formation.</p> <p>Conclusions</p> <p>Our results showed that reduced <it>HSD17B1 </it>expression can be associated with DNA methylation in the 5' flanking region of <it>HSD17B1 </it>in CRC from the proximal colon.</p

Discrete seasonal hydroclimate reconstructions over northern Vietnam for the past three and a half centuries

We present a 350-year hydroclimatic year (HY) index for northern Vietnam derived from three discrete seasonal reconstructions from tree rings: an index of autumn rainfall from the earlywood widths of Chinese Douglas fir (Pseudotsuga sinensis), the first such record from this species, and two nearby published Palmer Drought Severity Index (PDSI) reconstructions from cypress (Fokienia hodginsii) tree rings for spring and summer, respectively. Autumn rainfall over the study region constitutes only around 9% of the annual total, but its variability is strongly linked to the strength of the atmospheric gradient over Asia during the transition from the boreal summer to winter monsoons. Deficit or surplus of autumn rainfall enhances or mitigates, respectively, the impact of the annual winter dry season on trees growing on porous karst hillsides. The most protracted HY drought (dry across all seasons) occurred at the turn of the twentieth century at a time of relative quiet, but a mid-to-late eighteenth century multi-year HY drought coincided with a period of great societal turmoil across mainland Southeast Asia and the Tay Son Rebellion in northern Vietnam. A mid-nineteenth century uprising accompanied by a smallpox epidemic, crop failure and famine, occurred during the worst autumn drought of the past two and a half centuries but only moderate drought in spring and summer. The “Great Vietnamese Famine” of the mid-twentieth century was dry only in autumn, with a wet spring and an average summer