Cancer-associated fibroblasts expressing fibroblast activation protein and podoplanin in non-small cell lung cancer predict poor clinical outcome

BACKGROUND: Cancer-associated fibroblasts (CAFs) are a dominant cell type in the stroma of non-small cell lung cancer (NSCLC). Fibroblast heterogeneity reflects subpopulations of CAFs, which can influence prognosis and treatment efficacy. We describe the subtypes of CAFs in NSCLC.METHODS: Primary human NSCLC resections were assessed by flow cytometry and multiplex immunofluorescence for markers of fibroblast activation which allowed identification of CAF subsets. Survival data were analysed for our NSCLC cohort consisting of 163 patients to understand prognostic significance of CAF subsets.RESULTS: We identified five CAF populations, termed CAF S1-S5. CAF-S5 represents a previously undescribed population, and express FAP and PDPN but lack the myofibroblast marker αSMA, whereas CAF-S1 populations express all three. CAF-S5 are spatially further from tumour regions then CAF-S1 and scRNA data demonstrate an inflammatory phenotype. The presence of CAF-S1 or CAF-S5 is correlated to worse survival outcome in NSCLC, despite curative resection, highlighting the prognostic importance of CAF subtypes in NSCLC. TCGA data suggest the predominance of CAF-S5 has a poor prognosis across several cancer types.CONCLUSION: This study describes the fibroblast heterogeneity in NSCLC and the prognostic importance of the novel CAF-S5 subset where its presence correlates to worse survival outcome.</p

Mobile applications for weather and climate information: their use and potential for smallholder farmers

Mobile phones are increasingly being used to provide smallholder farmers with agricultural and related information. There is currently great interest in their scope to communicate climate and weather information. Farmers consistently identify demand for weather information and whilst ICTs may be one way of delivering this at scale there are concerns that this should not be seen as a panacea. At a time when there have been a range of initiatives and projects that have been implemented this paper seeks to draw lessons and identify key considerations to inform the development of future mobile applications to provide climate services to smallholder farmers. A literature review, interviews with key informants and experts and 15 case study reviews were conducted. This focused principally on Sub Saharan Africa but included some examples from India. Despite numerous initiatives few have developed fully beyond the pilot stage and few have been evaluated. Some of the provision to date has been of questionable value to farmers. A key observation is that relatively little attention has been paid in design, to the needs for and use of both the information and technology by farmers, and few attempts made to differentiate provision according to gender and other demographic variables. Other factors contributing to success included communications approaches, which are interactive and/or involve trusted intermediaries who can add context to and help interpret more complex information. Providing weather information alongside other services as ‘bundles’ and in conjunction with complementary communications approaches appears to work well. An important challenge is how to meet farmers’ needs for location specific, timely and relevant information in economically sustainable ways. More widely there are challenges in achieving successful business models and potential conflicts between initiatives driven by mobile network operators and public goals. The study identified areas of considerable potential which include: the use of increasingly available mobile data connections to ensure locally relevant content is available to farmers in timely fashion (including both historical climate information and forecasts); development of participatory decision making tools to enable farmers to interpret information for their own contexts and consider implications and management options; use of visual applications and participatory video on mobile devices to enhance learning and advisory services for farmers; the potential for increased feedback between farmers and service providers as well as increased knowledge sharing between farmers provided by the use of social media

Perilipin A is essential for the translocation of hormone-sensitive lipase during lipolytic activation

Akey step in lipolytic activation of adipocytes is the translocation of hormone-sensitive lipase (HSL) from the cytosol to the surface of the lipid storage droplet. Adipocytes from perilipin-null animals have an elevated basal rate of lipolysis compared with adipocytes from wild-type mice, but fail to respond maximally to lipolytic stimuli. This defect is downstream of the β-adrenergic receptor–adenylyl cyclase complex. Now, we show that HSL is basally associated with lipid droplet surfaces at a low level in perilipin nulls, but that stimulated translocation from the cytosol to lipid droplets is absent in adipocytes derived from embryonic fibroblasts of perilipin-null mice. We have also reconstructed the HSL translocation reaction in the nonadipocyte Chinese hamster ovary cell line by introduction of GFP-tagged HSL with and without perilipin A. On activation of protein kinase A, HSL-GFP translocates to lipid droplets only in cells that express fully phosphorylatable perilipin A, confirming that perilipin is required to elicit the HSL translocation reaction. Moreover, in Chinese hamster ovary cells that express both HSL and perilipin A, these two proteins cooperate to produce a more rapidly accelerated lipolysis than do cells that express either of these proteins alone, indicating that lipolysis is a concerted reaction mediated by both protein kinase A–phosphorylated HSL and perilipin A

Phototherapeutic Induction of Immunogenic Cell Death and CD8+ T Cell-Granzyme B Mediated Cytolysis in Human Lung Cancer Cells and Organoids

SIMPLE SUMMARY: Immunogenic cancer cell death and photodynamic therapy play an important emerging role in cancer treatment. Understanding mechanisms involved in tumor killing via immune cells in response to photodynamic therapy is important for developing new anticancer approaches. In this study, we report that methylene blue photodynamic therapy decreases the proliferation of lung cancer cells and patient derived non-small cell lung cancer organoids via immunogenic cells death and granzyme B mediated cytolysis. ABSTRACT: Augmenting T cell mediated tumor killing via immunogenic cancer cell death (ICD) is the cornerstone of emerging immunotherapeutic approaches. We investigated the potential of methylene blue photodynamic therapy (MB-PDT) to induce ICD in human lung cancer. Non-Small Cell Lung Cancer (NSCLC) cell lines and primary human lung cancer organoids were evaluated in co-culture killing assays with MB-PDT and light emitting diodes (LEDs). ICD was characterised using immunoblotting, immunofluorescence, flow cytometry and confocal microscopy. Phototherapy with MB treatment and low energy LEDs decreased the proliferation of NSCLC cell lines inducing early necrosis associated with reduced expression of the anti-apoptotic protein, Bcl2 and increased expression of ICD markers, calreticulin (CRT), intercellular cell-adhesion molecule-1 (ICAM-1) and major histocompatibility complex I (MHC-I) in NSCLC cells. MB-PDT also potentiated CD8(+) T cell-mediated cytolysis of lung cancer via granzyme B in lung cancer cells and primary human lung cancer organoids

Influence of melt feeding scheme and casting parameters during direct-chill casting on microstructure of an AA7050 billet

© The Minerals, Metals & Materials Society and ASM International 2012Direct-chill (DC) casting billets of an AA7050 alloy produced with different melt feeding schemes and casting speeds were examined in order to reveal the effect of these factors on the evolution of microstructure. Experimental results show that grain size is strongly influenced by the casting speed. In addition, the distribution of grain sizes across the billet diameter is mostly determined by melt feeding scheme. Grains tend to coarsen towards the center of a billet cast with the semi-horizontal melt feeding, while upon vertical melt feeding the minimum grain size was observed in the center of the billet. Computer simulations were preformed to reveal sump profiles and flow patterns during casting under different melt feeding schemes and casting speeds. The results show that solidification front and velocity distribution of the melt in the liquid and slurry zones are very different under different melt feeding scheme. The final grain structure and the grain size distribution in a DC casting billet is a result of a combination of fragmentation effects in the slurry zone and the cooling rate in the solidification range

Livelihood responses to Lantana camara invasion and biodiversity change in southern India: application of an asset function framework

Natural resources play key roles as assets in the livelihoods of rural communities. However, the benefits of these assets in livelihoods are frequently conceived narrowly as income generating or vulnerability reducing. We contend that they have other important roles to play in poverty reduction and livelihood change. In this paper we use a case study of two ethnic communities in a village in southern India to investigate livelihood responses to change in forest biodiversity through an examination of changes in attributes of natural assets resulting from the invasion of Lantana camara and wider socio-economic change. The invasion of forest by Lantana has contributed to changes in the attributes and functions of four key natural assets: forest grazing, bamboo for basketry, Phoenix loureie for brooms, and wild yams. We observe that differences in households’ and individuals’ ability to substitute important functions of lost or declining assets affect their ability to adapt to changes in resource availability and attributes. Analysing changes in asset attributes for different user groups allows the social effects of environmental change to be disaggregated

Downregulation of Mcl-1 has anti-inflammatory pro-resolution effects and enhances bacterial clearance from the lung

Phagocytes not only coordinate acute inflammation and host defense at mucosal sites, but also contribute to tissue damage. Respiratory infection causes a globally significant disease burden and frequently progresses to acute respiratory distress syndrome, a devastating inflammatory condition characterized by neutrophil recruitment and accumulation of protein-rich edema fluid causing impaired lung function. We hypothesized that targeting the intracellular protein myeloid cell leukemia 1 (Mcl-1) by a cyclin-dependent kinase inhibitor (AT7519) or a flavone (wogonin) would accelerate neutrophil apoptosis and resolution of established inflammation, but without detriment to bacterial clearance. Mcl-1 loss induced human neutrophil apoptosis, but did not induce macrophage apoptosis nor impair phagocytosis of apoptotic neutrophils. Neutrophil-dominant inflammation was modelled in mice by either endotoxin or bacteria (Escherichia coli). Downregulating inflammatory cell Mcl-1 had anti-inflammatory, pro-resolution effects, shortening the resolution interval (R(i)) from 19 to 7 h and improved organ dysfunction with enhanced alveolar–capillary barrier integrity. Conversely, attenuating drug-induced Mcl-1 downregulation inhibited neutrophil apoptosis and delayed resolution of endotoxin-mediated lung inflammation. Importantly, manipulating lung inflammatory cell Mcl-1 also accelerated resolution of bacterial infection (R(i); 50 to 16 h) concurrent with enhanced bacterial clearance. Therefore, manipulating inflammatory cell Mcl-1 accelerates inflammation resolution without detriment to host defense against bacteria, and represents a target for treating infection-associated inflammation

Roads to interdisciplinarity - working at the nexus among food systems, nutrition and health: 1st annual Agriculture, Nutrition and Health (ANH) Academy Week, Addis Ababa (Ethiopia), 20-24 June 2016

The development agenda over the next 15 years will be framed by the Sustainable Development Goals (SDGs), of which more than half relate either directly or indirectly to the agricultural sector, highlighting its importance in economic growth and development of low- and middle-income countries (LMICs) (FAO 2015). It is therefore imperative that agricultural systems are better understood, so that they may be strengthened and optimised to deliver outcomes in line with the SDGs. The interface between agriculture, nutrition and health is particularly multifaceted and complex, and the development of successful strategies will require an integrated and multi-sectoral approach (Dorward and Dangour 2012; Jones and Ejeta 2016). ‘Agri-health’ is an evolving paradigm seeking to unify research approaches and methodologies between agriculture and health. Research within the field encapsulates a broad range of disciplines, locations and actors, and aligns these into a common research agenda. In doing so, agri-health aims to transcend barriers imposed by the longstanding institutional and disciplinary silos. Much progress has been made in recent years in this regard (Harris et al. 2013; Kanter et al. 2014; Picchioni et al. 2015). However, more coordinated efforts are required to generate consensus and target strategic priorities amongst the many existing information gaps (Webb and Kennedy 2014). Understanding the linkages between complex issues such as globalisation, climate change, food systems, and evolving burdens of malnutrition is central to agri-health research. The Leverhulme Centre for Integrative Research on Agriculture and Health (LCIRAH) was created in 2010 with a key focus on agri-health interdisciplinary research. LCIRAH includes experts from across the member colleges of the University of London: the London School of Hygiene and Tropical Medicine (LSHTM), the School of Oriental and African Studies (SOAS), and the Royal Veterinary College (RVC). The Agriculture, Nutrition and Health Academy (ANH Academy), was established in 2015 as a platform to facilitate learning, knowledge sharing, capacity building and collaborative partnerships among the growing global community of researchers, practitioners and policy makers working within agri-health. It was developed with support from the Innovative Metrics and Methods for Agriculture and Nutrition Actions (IMMANA) research programme,Footnote1 led by LCIRAH and Tufts University, in partnership with the CGIAR Programme on Agriculture for Nutrition and Health (A4NH). Within this scope, the ANH Academy hosts an annual ANH Academy Week, building on the legacy of five agri-health research conferences organised by LCIRAH; as well as events and activities coordinated under the CGIAR A4NH. The inaugural ANH Academy Week took place in Addis Ababa, Ethiopia, in June 2016 and included two days of interactive ‘learning labs’ (training sessions on skills and methods across a broad range of disciplines in agri-health), followed by a three-day research conference. The conference included a mix of abstract-driven sessions, round table discussions, and keynote speeches from across the spectrum of agriculture, nutrition and health disciplines, and a wide range of countries. Hawkes et al. (2012) developed a conceptual framework (Fig. 2, hereafter referred to as the Framework), outlining the key pathways through which agriculture may affect nutritional status in Low and Middle Income Countries (LMICs), as well as broader drivers of these pathways. Drawing on this Framework, this paper aims to provide an analytical synthesis of the ANH Academy week by mapping the research and debates presented during the conference

T cells drive negative feedback mechanisms in Cancer Associated Fibroblasts, promoting expression of co-inhibitory ligands, CD73 and IL-27 in non-small cell lung cancer

The success of immune checkpoint therapy shows tumor-reactive T cells can eliminate cancer cells but are restrained by immunosuppression within the tumor micro-environment (TME). Cancer associated fibroblasts (CAFs) are the dominant stromal cell in the TME and co-localize with T cells in non-small cell lung cancer. We demonstrate the bidirectional nature of CAF/T cell interactions; T cells promote expression of co-inhibitory ligands, MHC molecules and CD73 on CAFs, increasing their production of IL-6 and eliciting production of IL-27. In turn CAFs upregulate co-inhibitory receptors on T cells including the ectonucleotidase CD39 promoting development of an exhausted but highly cytotoxic phenotype. Our results highlight the bidirectional interaction between T cells and CAFs in promoting components of the immunosuppressive CD39, CD73 adenosine pathway and demonstrate IL-27 production can be induced in CAF by activated T cells