Fibroblasts often constitute the majority of the stromal cells within a breast carcinoma, yet the functional contributions of these cells to tumorigenesis are poorly understood. Using a ...coimplantation tumor xenograft model, we demonstrate that carcinoma-associated fibroblasts (CAFs) extracted from human breast carcinomas promote the growth of admixed breast carcinoma cells significantly more than do normal mammary fibroblasts derived from the same patients. The CAFs, which exhibit the traits of myofibroblasts, play a central role in promoting the growth of tumor cells through their ability to secrete stromal cell-derived factor 1 (SDF-1); CAFs promote angiogenesis by recruiting endothelial progenitor cells (EPCs) into carcinomas, an effect mediated in part by SDF-1. CAF-secreted SDF-1 also stimulates tumor growth directly, acting through the cognate receptor, CXCR4, which is expressed by carcinoma cells. Our findings indicate that fibroblasts within invasive breast carcinomas contribute to tumor promotion in large part through the secretion of SDF-1.
The present study was designed to study the process of stress adaptation in roots and shoot of
Zea mays seedlings grown under hydroponic conditions during exposure to lead (Pb) (0–200
μM) for 1–7
d. ...The alterations in growth and in the level of various biochemical parameters were accessed vis-à-vis Pb accumulation. The accumulation of Pb increased in a concentration-duration-dependent manner, however its translocation from root to shoot was low. At the same time, the level of malondialdehyde (MDA) increased with increasing Pb concentration. However, growth parameters, such as dry weight and root length did not show a significant decline to any of the Pb concentrations. In addition, the level of photosynthetic pigments decreased only upon exposure to high Pb concentrations. These results suggested an alleviation of the stress that was presumably being achieved by antioxidants viz., superoxide dismutase (SOD) and catalase (CAT) as well as ascorbic acid (AsA), which increased linearly with increasing Pb levels and exposure time. However, the level of non-protein thiols (NP-SH) in roots, in general, showed a decline beyond 4
d that could be attributed to their consumption for the purpose of Pb detoxification. In conclusion,
Zea mays can be used as an indicator species for Pb, and the various antioxidants might play a key role in the detoxification of Pb induced toxic effects.
To compare arthroscopic hip surgery with physiotherapy and activity modification for improving patient reported outcome measures in patients with symptomatic femoroacetabular impingement (FAI).
Two ...group parallel, assessor blinded, pragmatic randomised controlled trial.
Secondary and tertiary care centres across seven NHS England sites.
222 participants aged 18 to 60 years with symptomatic FAI confirmed clinically and with imaging (radiography or magnetic resonance imaging) were randomised (1:1) to receive arthroscopic hip surgery (n=112) or a programme of physiotherapy and activity modification (n=110). Exclusion criteria included previous surgery, completion of a physiotherapy programme targeting FAI within the preceding 12 months, established osteoarthritis (Kellgren-Lawrence grade ≥2), and hip dysplasia (centre-edge angle <20 degrees).
Participants in the physiotherapy group received a goal based programme tailored to individual patient needs, with emphasis on improving core stability and movement control. A maximum of eight physiotherapy sessions were delivered over five months. Participants in the arthroscopic surgery group received surgery to excise the bone that impinged during hip movements, followed by routine postoperative care.
The primary outcome measure was the hip outcome score activities of daily living subscale (HOS ADL) at eight months post-randomisation, with a minimum clinically important difference between groups of 9 points. Secondary outcome measures included additional patient reported outcome measures and clinical assessment.
At eight months post-randomisation, data were available for 100 patients in the arthroscopic hip surgery group (89%) and 88 patients in the physiotherapy programme group (80%). Mean HOS ADL was 78.4 (95% confidence interval 74.4 to 82.3) for patients randomised to arthroscopic hip surgery and 69.2 (65.2 to 73.3) for patients randomised to the physiotherapy programme. After adjusting for baseline HOS ADL, age, sex, and study site, the mean HOS ADL was 10.0 points higher (6.4 to 13.6) in the arthroscopic hip surgery group compared with the physiotherapy programme group (P<0.001)). No serious adverse events were reported in either group.
Patients with symptomatic FAI referred to secondary or tertiary care achieve superior outcomes with arthroscopic hip surgery than with physiotherapy and activity modification.
ClinicalTrials.gov NCT01893034.
Abrasion of repellent-treated human skin affected the efficacy of a sustained-release insect repellent containing N,N-diethyl-3-methylbenzamide (deet) against bites of Aedes aegypti. Skin treated ...with repellent when abraded up to 30 times showed significantly lower protection than unabraded skin against mosquito bites for 10 h. The mean value of the kinetic coefficient of friction during skin abrasion by clothing (battle dress uniform fabric) for repellent-treated skin (0.159 +/- 0.003) was significantly higher than untreated skin (0.122 +/- 0.005). Repellent-treated skin appeared stickier than the untreated skin. An increase in the number of skin abrasions by clothing resulted in a reduced duration of protection against mosquito bites.
As large-scale international collaborations become the standard for astronomy research, a wealth of opportunities have emerged to create innovative education and public outreach (EPO) programming. In ...the past two decades, large collaborations have focused EPO strategies around published data products. Newer collaborations have begun to explore other avenues of public engagement before and after data are made available. We present a case study of the online EPO program of The Dark Energy Survey, currently one of the largest international astronomy collaborations actively taking data. DES EPO is unique at this scale in astronomy, as far as we are aware, as it evolved organically from scientists' passion for EPO and is entirely organized and implemented by the volunteer efforts of collaboration scientists. We summarize the strategy and implementation of eight EPO initiatives. For content distributed via social media, we present reach and user statistics over the 2016 calendar year. DES EPO online products reached ~2,500 users per post, and 94% of these users indicate a predisposition to science-related interests. We find no obvious correlation between post type and post reach, with the most popular posts featuring the intersections of science and art and/or popular culture. We conclude that one key issue of the online DES EPO program was designing material which would inspire new interest in science. The greatest difficulty of the online DES EPO program was sustaining scientist participation and collaboration support; the most successful programs are those which capitalized on the hobbies of participating scientists. We present statistics and recommendations, along with observations from individual experience, as a potentially instructive resource for scientists or EPO professionals interested in organizing EPO programs and partnerships for large science collaborations or organizations.
Coagulation factor XII (FXII) deficiency is associated with decreased neutrophil migration, but the mechanisms remain uncharacterized. Here, we examine how FXII contributes to the inflammatory ...response. In 2 models of sterile inflammation, FXII-deficient mice (F12-/-) had fewer neutrophils recruited than WT mice. We discovered that neutrophils produced a pool of FXII that is functionally distinct from hepatic-derived FXII and contributes to neutrophil trafficking at sites of inflammation. FXII signals in neutrophils through urokinase plasminogen activator receptor-mediated (uPAR-mediated) Akt2 phosphorylation at S474 (pAktS474). Downstream of pAkt2S474, FXII stimulation of neutrophils upregulated surface expression of αMβ2 integrin, increased intracellular calcium, and promoted extracellular DNA release. The sum of these activities contributed to neutrophil cell adhesion, migration, and release of neutrophil extracellular traps in a process called NETosis. Decreased neutrophil signaling in F12-/- mice resulted in less inflammation and faster wound healing. Targeting hepatic F12 with siRNA did not affect neutrophil migration, whereas WT BM transplanted into F12-/- hosts was sufficient to correct the neutrophil migration defect in F12-/- mice and restore wound inflammation. Importantly, these activities were a zymogen FXII function and independent of FXIIa and contact activation, highlighting that FXII has a sophisticated role in vivo that has not been previously appreciated.
Tuberculosis remains a global health problem, with an estimated 10.4 million cases and 1.8 million deaths resulting from the disease in 2015. The most lethal and disabling form of tuberculosis is ...tuberculous meningitis (TBM), for which more than 100,000 new cases are estimated to occur per year. In patients who are co-infected with HIV-1, TBM has a mortality approaching 50%. Study of TBM pathogenesis is hampered by a lack of experimental models that recapitulate all the features of the human disease. Diagnosis of TBM is often delayed by the insensitive and lengthy culture technique required for disease confirmation. Antibiotic regimens for TBM are based on those used to treat pulmonary tuberculosis, which probably results in suboptimal drug levels in the cerebrospinal fluid, owing to poor blood-brain barrier penetrance. The role of adjunctive anti-inflammatory, host-directed therapies - including corticosteroids, aspirin and thalidomide - has not been extensively explored. To address this deficit, two expert meetings were held in 2009 and 2015 to share findings and define research priorities. This Review summarizes historical and current research into TBM and identifies important gaps in our knowledge. We will discuss advances in the understanding of inflammation in TBM and its potential modulation; vascular and hypoxia-mediated tissue injury; the role of intensified antibiotic treatment; and the importance of rapid and accurate diagnostics and supportive care in TBM.
There is mounting evidence for the contribution of apoE to the pathophysiology of Alzheimer disease (AD). Studies also indicate that plasma apoE levels may reflect disease status, suggesting that ...apoE is a potential AD biomarker. However, while some studies of apoE levels in plasma have presented correlations with AD pathology, others have not. Thus, there is a lack of consensus as to the suitability of plasma apoE as an AD biomarker. The major objective of this cross-sectional study was to investigate total plasma apoE as well as levels of the apoE4 form in a large, highly characterized cohort which included both healthy controls and participants with early-stage AD.
Total apoE and apoE4 were measured in 1,079 individuals drawn from the highly characterized Australian Imaging, Biomarkers and Lifestyle (AIBL) study. Total and isoform-specific plasma apoE levels were then compared with cerebral Aβ load, as assessed by PET using Pittsburgh compound B (PiB).
Total apoE and apoE4 levels were found to be significantly lower in patients with AD in the entire cohort, and decrease with Aβ load in the PiB-PET subset. ApoE levels were significantly lower among ε4 homozygous individuals. In APOE ε3/ε4 heterozygote carriers, apoE4 levels decrease, indicating that apoE3 levels increase with disease.
Analysis of cross-sectional data from the AIBL study indicates that plasma apoE levels are altered in AD and correlate with AD pathology level. The significance of these findings will be determined in the AIBL longitudinal study of aging.
Ripretinib (DCC-2618) was designed to inhibit the full spectrum of mutant KIT and PDGFRA kinases found in cancers and myeloproliferative neoplasms, particularly in gastrointestinal stromal tumors ...(GISTs), in which the heterogeneity of drug-resistant KIT mutations is a major challenge. Ripretinib is a “switch-control” kinase inhibitor that forces the activation loop (or activation “switch”) into an inactive conformation. Ripretinib inhibits all tested KIT and PDGFRA mutants, and notably is a type II kinase inhibitor demonstrated to broadly inhibit activation loop mutations in KIT and PDGFRA, previously thought only achievable with type I inhibitors. Ripretinib shows efficacy in preclinical cancer models, and preliminary clinical data provide proof-of-concept that ripretinib inhibits a wide range of KIT mutants in patients with drug-resistant GISTs.
•Ripretinib broadly inhibits primary and drug-resistant KIT/PDGFRA mutants•KIT/PDGFRA inhibitor of all known activation loop mutations•In drug-resistant cancers, ripretinib blocks kinase signaling and tumor growth•Circulating tumor DNA data confirm broad inhibition of mutant KIT in GIST patients
To overcome the often multi-subclonal mutations in treatment-resistant GIST, Smith et al. design ripretinib, which targets a broad spectrum of KIT and PDGFRA mutants. Ripretinib shows efficacy in KIT and PDGFRA mutant cancer models and reduces circulating tumor DNA mutant allele frequency in two GIST patients.
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