500 research outputs found
The present and future of serum diagnostic tests for testicular germ cell tumours.
Testicular germ cell tumours (GCTs) are the most common malignancy occurring in young adult men and the incidence of these tumours is increasing. Current research priorities in this field include improving overall survival for patients classified as being 'poor-risk' and reducing late effects of treatment for patients classified as 'good-risk'. Testicular GCTs are broadly classified into seminomas and nonseminomatous GCTs (NSGCTs). The conventional serum protein tumour markers α-fetoprotein (AFP), human chorionic gonadotrophin (hCG) and lactate dehydrogenase (LDH) show some utility in the management of testicular malignant GCT. However, AFP and hCG display limited sensitivity and specificity, being indicative of yolk sac tumour (AFP) and choriocarcinoma or syncytiotrophoblast (hCG) subtypes. Furthermore, LDH is a very nonspecific biomarker. Consequently, seminomas and NSGCTs comprising a pure embryonal carcinoma subtype are generally negative for these conventional markers. As a result, novel universal biomarkers for testicular malignant GCTs are required. MicroRNAs are short, non-protein-coding RNAs that show much general promise as biomarkers. MicroRNAs from two 'clusters', miR-371-373 and miR-302-367, are overexpressed in all malignant GCTs, regardless of age (adult or paediatric), site (gonadal or extragonadal) and subtype (seminomas, yolk sac tumours or embryonal carcinomas). A panel of four circulating microRNAs from these two clusters (miR-371a-3p, miR-372-3p, miR-373-3p and miR-367-3p) is highly sensitive and specific for the diagnosis of malignant GCT, including seminoma and embryonal carcinoma. In the future, circulating microRNAs might be useful in diagnosis, disease monitoring and prognostication of malignant testicular GCTs, which might also reduce reliance on serial CT scanning. For translation into clinical practice, important practical considerations now need addressing.The authors would like to acknowledge grant funding from CwCUK/GOSHCC (M.J.M. N.C. grant W1058), SPARKS (M.J.M. N.C. grant 11CAM01), CRUK (N.C. grant A13080) MRC (M.J.M. grant MC_EX_G0800464) and National Health Service funding to the Royal Marsden/Institute of Cancer Research National Institute for Health Research Biomedical Research Centre for Cancer (R.A.H.). The authors also thank the Max Williamson Fund, the Josh Carrick Foundation and The Perse Preparatory School, Cambridge for support.This is the author accepted manuscript. The final version is available fromNature Publishing Group via https://doi.org/10.1038/nrurol.2016.17
Environmental regulation induced foreign direct investment
The last decade has witnessed a renewed interest in the relationship between environmental regulations and international capital flows. However, empirical studies have so far failed to find conclusive evidence for this so-called pollution haven or race to the bottom effect where foreign direct investment (FDI) is assumed to be attracted to low regulation countries, regions or states. In this paper we present a simple theoretical framework to demonstrate that greater stringency in environmental standards can lead to a strategic increase in capital inflows which we refer to as environmental regulation induced FDI. Our result reveals a possible explanation for the mixed results in the empirical literature and provides an illustration of the conditions under which environmental regulations in the host country can affect the location decision of foreign firms
Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at â s = 8 TeV with the ATLAS detector
Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fbâ1 of â s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente
Early prediction of treatment response to high-dose salvage chemotherapy in patients with relapsed germ cell cancer using [18F]FDG PET
To assess the ability of [18F]fluorodeoxyglucose positron emission tomography for the early prediction of response in patients with relapsed metastatic germ cell tumours undergoing salvage high-dose chemotherapy. The role of positron emission tomography was compared with established means of tumour response assessment such as CT scans/MRI and serum tumour marker changes. In addition, positron emission tomography was compared with a current prognostic score which differentiates three prognostic groups with failure-free survival rates ranging from 5â50%. [18F]fluorodeoxyglucose uptake of metastases from germ cell tumours as well as CT scans and serum tumour marker were acquired after 2â3 cycles of induction chemotherapy but before the start of high-dose chemotherapy and CT scans/serum tumour marker were compared with the baseline examinations in 23 patients with relapsed germ cell tumours. To evaluate the validity of early response prediction by positron emission tomography, radiological monitoring and serum tumour marker decline, histopathologic response after resection of residual masses and/or the clinical course over 6 months after the end of treatment (relapse vs freedom of progression) were used. Overall, 10 patients (43%) achieved a marker-negative partial remission, three (13%) a marker-positive partial remission, five (22%) a disease stabilization and five (22%) progressed during treatment. Nine patients (39%) remained progression-free over 6 months following treatment, whereas 14 (61%) progressed. The outcome of high-dose chemotherapy was correctly predicted by positron emission tomography/CT scan/serum tumour marker in 91/59/48%. Eight patients with a favourably predicted outcome by CT scans plus serum tumour marker but a positive positron emission tomography prior to high-dose chemotherapy, failed treatment. This results in the following sensitivities/specificities for the prediction of failure of high-dose chemotherapy: positron emission tomography 100/78%; radiological monitoring 43/78%; serum tumour marker 15/100%. The positive and negative predictive values of positron emission tomography were 88 and 100%, respectively. As compared with the prognostic score, positron emission tomography was correctly positive in all patients of the three risk groups who failed treatment. In addition, a negative positron emission tomography correctly predicted a favourable outcome in the good and intermediate group. [18F]fluorodeoxyglucose positron emission tomography imaging can be used to assess response to chemotherapy in patients with relapsed germ cell tumours early in the course of treatment and may help to identify patients most likely to achieve a favourable response to subsequent high-dose chemotherapy. In patients with response to induction chemotherapy according to CT scans or serum tumour marker evaluation, positron emission tomography seems to add information to detect patients with an overall unfavourable outcome. It may also be a valuable addition to the prognostic model particularly in the good and intermediate group for further selection of patients who will profit from high-dose chemotherapy
Self-tolerance in multiple sclerosis
During the last decade, several defects in self-tolerance have been identified in multiple sclerosis. Dysfunction in central tolerance leads to the thymic output of antigen-specific T cells with T cell receptor alterations favouring autoimmune reactions. In addition, premature thymic involution results in a reduced export of naĂŻve regulatory T cells, the fully suppressive clone. Alterations in peripheral tolerance concern costimulatory molecules as well as transcriptional and epigenetic mechanisms. Recent data underline the key role of regulatory T cells that suppress Th1 and Th17 effector cell responses and whose immunosuppressive activity is impaired in patients with multiple sclerosis. Those recent observations suggest that a defect in self-tolerance homeostasis might be the primary mover of multiple sclerosis leading to subsequent immune attacks, inflammation and neurodegeneration. The concept of multiple sclerosis as a consequence of the failure of central and peripheral tolerance mechanisms to maintain a self-tolerance state, particularly of regulatory T cells, may have therapeutic implications. Restoring normal thymic output and suppressive functions of regulatory T cells appears an appealing approach. Regulatory T cells suppress the general local immune response via bystander effects rather than through individual antigen-specific responses. Interestingly, the beneficial effects of currently approved immunomodulators (interferons ÎČ and glatiramer acetate) are associated with a restored regulatory T cell homeostasis. However, the feedback regulation between Th1 and Th17 effector cells and regulatory T cells is not so simple and tolerogenic mechanisms also involve other regulatory cells such as B cells, dendritic cells and CD56bright natural killer cells
Primary caregivers, healthcare workers, teachers and community leaders' perceptions and experiences of their involvement, practice and challenges of disclosure of HIV status to children living with HIV in Malawi: A qualitative study
Background: The World Health Organisation has recommended that healthcare workers, teachers and community leaders work with parents to support children living with HIV. The aim of this study was to assess the perceptions and experiences of primary caregivers and other care providers such as healthcare workers, teachers, and community leaders regarding their involvement, practice and challenges of HIV disclosure to children aged between 6 and 12 years living with HIV in Malawi. Methods: Twelve focus group discussions and 19 one-on-one interviews involving a total of 106 participants were conducted in all three administrative regions of Malawi. The interviews and focus group discussions explored perceptions and experiences regarding involvement, practice and challenges of disclosure of HIV status to children. Data were analysed using thematic analysis. Results: Primary caregivers, healthcare workers, teachers, and community leaders all reported that the disclosure of HIV status to children was not well coordinated because each of the groups of participants was working in isolation instead of working as a team. A "working together" model emerged from the data analysis where participants expressed the need for them to work as a team in order to promote safe and effective HIV status disclosure through talking about HIV, sharing responsibility and open communication. Participants reported that by working together, the team members would ensure that the prevalence of HIV disclosure to young children increases and that there would be a reduction in any negative impact of disclosure. Conclusion: Global resources are required to better support children living with HIV and their families. Healthcare workers and teachers would benefit greatly from training in working together with families living with HIV and, specifically, training in the disclosure process. Resources, in the form of books and other educational materials, would help them explain HIV and its effective management to children and families
HLA-C and HIV-1: friends or foes?
The major histocompatibility complex class I protein HLA-C plays a crucial role as a molecule capable of sending inhibitory signals to both natural killer (NK) cells and cytotoxic T lymphocytes (CTL) via binding to killer cell Ig-like receptors (KIR). Recently HLA-C has been recognized as a key molecule in the immune control of HIV-1. Expression of HLA-C is modulated by a microRNA binding site. HLA-C alleles that bear substitutions in the microRNA binding site are more expressed at the cell surface and associated with the control of HIV-1 viral load, suggesting a role of HLA-C in the presentation of antigenic peptides to CTLs. This review highlights the role of HLA-C in association with HIV-1 viral load, but also addresses the contradiction of the association between high cell surface expression of an inhibitory molecule and strong cell-mediated immunity. To explore additional mechanisms of control of HIV-1 replication by HLA-C, we address specific features of the molecule, like its tendency to be expressed as open conformer upon cell activation, which endows it with a unique capacity to associate with other cell surface molecules as well as with HIV-1 proteins
Functional Expression of the Extracellular Calcium Sensing Receptor (CaSR) in Equine Umbilical Cord Matrix Size-Sieved Stem Cells
The present study investigates the effects of high external calcium concentration ([Ca(2+)](o)) and the calcimimetic NPS R-467, a known calcium-sensing receptor (CaSR) agonist, on growth/proliferation of two equine size-sieved umbilical cord matrix mesenchymal stem cell (eUCM-MSC) lines. The involvement of CaSR on observed cell response was analyzed at both the mRNA and protein level.A large (>8 ”m in diameter) and a small (<8 ”m) cell line were cultured in medium containing: 1) low [Ca(2+)](o) (0.37 mM); 2) high [Ca(2+)](o) (2.87 mM); 3) NPS R-467 (3 ”M) in presence of high [Ca(2+)](o) and 4) the CaSR antagonist NPS 2390 (10 ”M for 30 min.) followed by incubation in presence of NPS R-467 in medium with high [Ca(2+)](o). Growth/proliferation rates were compared between groups. In large cells, the addition of NPS R-467 significantly increased cell growth whereas increasing [Ca(2+)](o) was not effective in this cell line. In small cells, both higher [Ca(2+)](o) and NPS R-467 increased cell growth. In both cell lines, preincubation with the CaSR antagonist NPS 2390 significantly inhibited the agonistic effect of NPS R-467. In both cell lines, increased [Ca(2+)](o) and/or NPS R-467 reduced doubling time values.Treatment with NPS R-467 down-regulated CaSR mRNA expression in both cell lines. In large cells, NPS R-467 reduced CaSR labeling in the cytosol and increased it at cortical level.In conclusion, calcium and the calcimimetic NPS R-467 reduce CaSR mRNA expression and stimulate cell growth/proliferation in eUCM-MSC. Their use as components of media for eUCM-MSC culture could be beneficial to obtain enough cells for down-stream purposes
Pure seminoma: A review and update
Pure seminoma is a rare pathology of the young adult, often discovered in the early stages. Its prognosis is generally excellent and many therapeutic options are available, especially in stage I tumors. High cure rates can be achieved in several ways: standard treatment with radiotherapy is challenged by surveillance and chemotherapy. Toxicity issues and the patients' preferences should be considered when management decisions are made. This paper describes firstly the management of primary seminoma and its nodal involvement and, secondly, the various therapeutic options according to stage
Management of patients with advanced prostate cancer: recommendations of the St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) 2015.
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