Is there a link between overactive bladder and the metabolic syndrome in women? : A systematic review of observational studies

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.To conduct a systematic review to determine whether there is an association between metabolic syndrome (MetS) and lower urinary tract symptoms (LUTS) or overactive bladder (OAB) in women. We systematically reviewed English language observational studies on the effect of MetS (or component factors) on the presence of OAB or LUTS in women. We searched PubMed, Web of Science and The Cochrane Library with no date restrictions, checked reference lists and undertook citation searches in PubMed and Google Scholar. Studies were assessed for risk of bias. Because of heterogeneity, results were not pooled, but are reported narrativelyPeer reviewe

Histone deacetylase inhibitor trichostatin A sensitises cisplatin-resistant ovarian cancer cells to oncolytic adenovirus

Ovarian cancer is often termed a silent killer due to the late onset of symptoms. Whilst patients initially respond to chemotherapy, they rapidly develop chemo-resistance. Oncolytic adenoviruses (OAds) are promising anti-cancer agents engineered to “hijack” the unique molecular machinery of cancer cells enabling tumour-selective viral replication. This allows spread to adjacent cells and amplification of oncolysis within the tumour. OAds represent an excellent opportunity for ovarian cancer therapy via intra-peritoneal delivery, however the efficacy of OAds thus far is limited. Here, we evaluate chromatin (histone) modification in chemo-resistant cells and its relationship to Ad efficacy (wild-type or oncolytic Ad). In contrast to cisplatin-sensitive A2780 cells that show an efficient reduction of cell viability by Ad in the presence of cisplatin, cisplatin-resistant A2780/cp70 cells show diminishing Ad-mediated reduction of cell viability with escalating doses of cisplatin. Histone deacetylase (HDAC)-2 and to a lesser extent HDAC1 were up-regulated in cisplatin-resistant but not cisplatin-sensitive cells. Cisplatin-resistant cells treated with a pan-HDAC inhibitor trichostatin A (TsA) significantly enhanced Ad-mediated reduction of cell viability in the presence of cisplatin. Cells treated with TsA alone did not reduce cell viability suggesting these findings are Ad-dependent. Thus, we identify HDAC inhibition as a potential means to sensitise cisplatin-resistant ovarian cancer cells to virotherapies, an observation that may offer improved outcomes for patients with late stage, chemotherapy-resistant ovarian cancer

Targeting of low ALK antigen density neuroblastoma using AND logic-gate engineered CAR-T cells

Background aims: The targeting of solid cancers with chimeric antigen receptor (CAR) T cells faces many technological hurdles, including selection of optimal target antigens. Promising pre-clinical and clinical data of CAR T-cell activity have emerged from targeting surface antigens such as GD2 and B7H3 in childhood cancer neuroblastoma. Anaplastic lymphoma kinase (ALK) is expressed in a majority of neuroblastomas at low antigen density but is largely absent from healthy tissues. / Methods: To explore an alternate target antigen for neuroblastoma CAR T-cell therapy, the authors generated and screened a single-chain variable fragment library targeting ALK extracellular domain to make a panel of new anti-ALK CAR T-cell constructs. / Results: A lead novel CAR T-cell construct was capable of specific cytotoxicity against neuroblastoma cells expressing low levels of ALK, but with only weak cytokine and proliferative T-cell responses. To explore strategies for amplifying ALK CAR T cells, the authors generated a co-CAR approach in which T cells received signal 1 from a first-generation ALK construct and signal 2 from anti-B7H3 or GD2 chimeric co-stimulatory receptors. The co-CAR approach successfully demonstrated the ability to avoid targeting single-antigen-positive targets as a strategy for mitigating on-target off-tumor toxicity. / Conclusions: These data provide further proof of concept for ALK as a neuroblastoma CAR T-cell target

Incorporation of peptides targeting EGFR and FGFR1 into the adenoviral fibre knob domain, and their evaluation as targeted cancer therapies

Oncolytic virotherapies based on Adenovirus 5 (Ad5) hold promise as adjunctive cancer therapies; however their efficacy when delivered systemically is hampered by poor target cell specificity and pre-existing anti-Ad5 immunity. Ovarian cancer represents a promising target for virotherapy, since the virus can be delivered locally into the peritoneal cavity. Both Epidermal Growth Factor Receptor (EGFR) and Fibroblast Growth Factor Receptor 1 (FGFR1) are over-expressed in the majority of human tumours, including ovarian cancer. To generate adenoviral vectors with improved tumour specificity, we generated a panel of Ad5 vectors with altered tropism for EGFR and FGFR, rather than the natural Ad5 receptor, hCAR. We have included mutations within AB loop the viral fibre knob (KO1 mutation) to preclude interaction with, hCAR, combined with insertions in the HI loop to incorporate peptides that bind either EGFR (peptide YHWYGYTPQNVI, GE11) or FGFR1 (peptides MQLPLAT, M* and LSPPRYP, LS). Viruses were produced to high titres, and the integrity of the fibre protein was validated by Western blotting. The KO1 mutation efficiently ablated hCAR interactions, and significantly increased transduction was observed in hCARlow/EGFRhigh cell lines using Ad5.GE11, whilst transduction levels using Ad5.M* or Ad5.LS were not increased. In the presence of physiological concentrations of human blood clotting factor X (hFX), significantly increased levels of transduction via the hFX-mediated pathway were observed in cell lines, but not in primary tumour cells derived from epithelial ovarian cancer (EOC) ascites samples. Ad5 mediated transduction of EOC cells were completely abolished by the presence of 2.5% serum from patients, whilst surprisingly, incorporation of the GE11 peptide resulted in significant evasion of neutralisation in the same samples. We thus speculate that incorporation of the YHWYGYTPQNVI dodecapeptide within the fibre knob domain may provide a novel means of circumventing pre-existing Ad5 immunity that warrants further investigation

Transcriptomic analysis of cutaneous squamous cell carcinoma reveals a multi-gene prognostic signature associated with metastasis

Background: Metastasis of cutaneous squamous cell carcinoma (cSCC) is uncommon. Current staging methods are reported to have sub-optimal performances in metastasis prediction. Accurate identification of patients with tumours at high risk of metastasis would have a significant impact on management.Objective: To develop a robust and validated gene expression profile (GEP) signature for predicting primary cSCC metastatic risk using an unbiased whole transcriptome discovery-driven approach.Methods: Archival formalin-fixed paraffin-embedded primary cSCC with perilesional normal tissue from 237 immunocompetent patients (151 non-metastasising and 86 metastasising) were collected retrospectively from four centres. TempO-seq was used to probe the whole transcriptome and machine learning algorithms were applied to derive predictive signatures, with a 3:1 split for training and testing datasets.Results: A 20-gene prognostic model was developed and validated, with an accuracy of 86.0%, sensitivity of 85.7%, specificity of 86.1%, and positive predictive value of 78.3% in the testing set, providing more stable, accurate prediction than pathological staging systems. A linear predictor was also developed, significantly correlating with metastatic risk.Limitations: This was a retrospective 4-centre study and larger prospective multicentre studies are now required.Conclusion: The 20-gene signature prediction is accurate, with the potential to be incorporated into clinical workflows for cSCC

The Cd isotope composition of atmospheric aerosols from the Tropical Atlantic Ocean

Stable isotope compositions can potentially be used to trace atmospheric Cd inputs to the surface ocean and anthropogenic Cd emissions to the atmosphere. Both of these applications may provide valuable insights into the effects of anthropogenic activities on the cycling of Cd in the environment. However, a lack of constraints for the Cd isotope compositions of atmospheric aerosols is currently hindering such studies. Here we present stable Cd isotope data for aerosols collected over the Tropical Atlantic Ocean. The samples feature variable proportions of mineral dust-derived and anthropogenic Cd, yet exhibit similar isotope compositions, thus negating the distinction of these Cd sources by using isotopic signatures in this region. Isotopic variability between these two atmospheric Cd sources may be identified in other areas, and thus warrants further investigation. Regardless, these data provide important initial constraints on the isotope composition of atmospheric Cd inputs to the ocean

Impaired expression of metallothioneins contributes to allergen-induced inflammation in patients with atopic dermatitis

Regulation of cutaneous immunity is severely compromised in inflammatory skin disease. To investigate the molecular crosstalk underpinning tolerance versus inflammation in atopic dermatitis, we utilise a human in vivo allergen challenge study, exposing atopic dermatitis patients to house dust mite. Here we analyse transcriptional programmes at the population and single cell levels in parallel with immunophenotyping of cutaneous immunocytes revealed a distinct dichotomy in atopic dermatitis patient responsiveness to house dust mite challenge. Our study shows that reactivity to house dust mite was associated with high basal levels of TNF-expressing cutaneous Th17 T cells, and documents the presence of hub structures where Langerhans cells and T cells co-localised. Mechanistically, we identify expression of metallothioneins and transcriptional programmes encoding antioxidant defences across all skin cell types, that appear to protect against allergen-induced inflammation. Furthermore, single nucleotide polymorphisms in the MTIX gene are associated with patients who did not react to house dust mite, opening up possibilities for therapeutic interventions modulating metallothionein expression in atopic dermatitis

A social-ecological-technological systems framework for urban ecosystem services

As rates of urbanization and climatic change soar, decision-makers are increasingly challenged to provide innovative solutions that simultaneously address climate change impacts and risks and inclusively ensure quality of life for urban residents. Cities have turned to nature-based solutions to help address these challenges. Nature-based solutions, through the provision of ecosystem services, can yield numerous benefits for people and address multiple challenges simultaneously. Yet, efforts to mainstream nature-based solutions are impaired by the complexity of the interacting social, ecological, and technological dimensions of urban systems. This complexity must be understood and managed to ensure ecosystem-service provisioning is effective, equitable, and resilient. Here, we provide a social-ecological-technological system (SETS) framework that builds on decades of urban ecosystem services research to better understand four core challenges associated with urban nature-based solutions: multi-functionality, systemic valuation, scale mismatch of ecosystem services, and inequity and injustice. The framework illustrates the importance of coordinating natural, technological, and socio-economic systems when designing, planning, and managing urban nature-based solutions to enable optimal social-ecological outcomes

A social-ecological-technological systems framework for urban ecosystem services

As rates of urbanization and climatic change soar, decision-makers are increasingly challenged to provide innovative solutions that simultaneously address climate-change impacts and risks and inclusively ensure quality of life for urban residents. Cities have turned to nature-based solutions to help address these challenges. Nature-based solutions, through the provision of ecosystem services, can yield numerous benefits for people and address multiple challenges simultaneously. Yet, efforts to mainstream nature-based solutions are impaired by the complexity of the interacting social, ecological, and technological dimensions of urban systems. This complexity must be understood and managed to ensure ecosystem-service provisioning is effective, equitable, and resilient. Here, we provide a social-ecological-technological system (SETS) framework that builds on decades of urban ecosystem services research to better understand four core challenges associated with urban nature-based solutions: multi-functionality, systemic valuation, scale mismatch of ecosystem services, and inequity and injustice. The framework illustrates the importance of coordinating natural, technological, and socio-economic systems when designing, planning, and managing urban nature-based solutions to enable optimal social-ecological outcomes