Circulating tumor cells (CTCs) have been shown to predict reduced survival outcomes in metastatic breast cancer.
CTCs were analyzed in 2026 patients with early breast cancer before adjuvant ...chemotherapy and in 1492 patients after chemotherapy using the CellSearch System. After immuno-magnetic enrichment for cells expressing the epithelial-cell adhesion molecule, CTCs were defined as nucleated cells expressing cytokeratin and lacking CD45. The patients were followed for a median of 35 months (range = 0-54). Kaplan-Meier analyses and the log-rank test were used for survival analyses. All statistical tests were two-sided.
Before chemotherapy, CTCs were detected in 21.5% of patients (n = 435 of 2026), with 19.6% (n = 136 of 692) of node-negative and 22.4% (n = 299 of 1334) of node-positive patients showing CTCs (P < .001). No association was found with tumor size, grading, or hormone receptor status. After chemotherapy, 22.1% of patients (n = 330 of 1493) were CTC positive. The presence of CTCs was associated with poor disease-free survival (DFS; P < .0001), distant DFS (P < .001), breast cancer-specific survival (P = .008), and overall survival (OS; P = .0002). CTCs were confirmed as independent prognostic markers in multivariable analysis for DFS (hazard ratio HR = 2.11; 95% confidence interval CI = 1.49 to 2.99; P < .0001) and OS (HR = 2.18; 95% CI = 1.32 to 3.59; P = .002). The prognosis was worst in patients with at least five CTCs per 30 mL blood (DFS: HR = 4.51, 95% CI = 2.59 to 7.86; OS: HR = 3.60, 95% CI = 1.56 to 8.45). The presence of persisting CTCs after chemotherapy showed a negative influence on DFS (HR = 1.12; 95% CI = 1.02 to 1.25; P = .02) and on OS (HR = 1.16; 95% CI = 0.99 to 1.37; P = .06) CONCLUSIONS: These results suggest the independent prognostic relevance of CTCs both before and after adjuvant chemotherapy in a large prospective trial of patients with primary breast cancer.
Avacopan for the Treatment of ANCA-Associated Vasculitis Jayne, David R.W; Merkel, Peter A; Schall, Thomas J ...
New England journal of medicine/The New England journal of medicine,
02/2021, Letnik:
384, Številka:
7
Journal Article
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The C5a receptor inhibitor avacopan was superior to a tapering schedule of prednisone with respect to remission of ANCA-associated vasculitis at 52 weeks. There were fewer glucocorticoid-associated ...adverse events in the avacopan group than in the prednisone group, and serious infections did not differ substantially between the two groups.
Pleiotropic Roles of Bile Acids in Metabolism de Aguiar Vallim, Thomas Q.; Tarling, Elizabeth J.; Edwards, Peter A.
Cell metabolism,
05/2013, Letnik:
17, Številka:
5
Journal Article
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Enzymatic oxidation of cholesterol generates numerous distinct bile acids that function both as detergents that facilitate digestion and absorption of dietary lipids, and as hormones that activate ...four distinct receptors. Activation of these receptors alters gene expression in multiple tissues, leading to changes not only in bile acid metabolism but also in glucose homeostasis, lipid and lipoprotein metabolism, energy expenditure, intestinal motility and bacterial growth, inflammation, liver regeneration, and hepatocarcinogenesis. This review covers the roles of specific bile acids, synthetic agonists, and their cognate receptors in controlling these diverse functions, as well as their current use in treating human diseases.
Circulating trimethylamine-N-oxide (TMAO) levels are strongly associated with atherosclerosis. We now examine genetic, dietary, and hormonal factors regulating TMAO levels. We demonstrate that two ...flavin mono-oxygenase family members, FMO1 and FMO3, oxidize trimethylamine (TMA), derived from gut flora metabolism of choline, to TMAO. Further, we show that FMO3 exhibits 10-fold higher specific activity than FMO1. FMO3 overexpression in mice significantly increases plasma TMAO levels while silencing FMO3 decreases TMAO levels. In both humans and mice, hepatic FMO3 expression is reduced in males compared to females. In mice, this reduction in FMO3 expression is due primarily to downregulation by androgens. FMO3 expression is induced by dietary bile acids by a mechanism that involves the farnesoid X receptor (FXR), a bile acid-activated nuclear receptor. Analysis of natural genetic variation among inbred strains of mice indicates that FMO3 and TMAO are significantly correlated, and TMAO levels explain 11% of the variation in atherosclerosis.
► Hepatic FMO3 synthesizes TMAO from TMA ► In vivo overexpression or silencing of FMO3 increases or decreases plasma TMAO levels, respectively ► FMO3 expression is repressed by testosterone and induced by bile acids via the nuclear receptor FXR ► Natural variations of TMAO levels in mice contribute to atherosclerosis susceptibility
Abstract The fourth edition of the World Health Organization (WHO) classification of urogenital tumours (WHO “blue book”), published in 2016, contains significant revisions. These revisions were ...performed after consideration by a large international group of pathologists with special expertise in this area. A subgroup of these persons met at the WHO Consensus Conference in Zurich, Switzerland, in 2015 to finalize the revisions. This review summarizes the most significant differences between the newly published classification and the prior version for renal, penile, and testicular tumours. Newly recognized epithelial renal tumours are hereditary leiomyomatosis and renal cell carcinoma (RCC) syndrome–associated RCC, succinate dehydrogenase–deficient RCC, tubulocystic RCC, acquired cystic disease–associated RCC, and clear cell papillary RCC. The WHO/International Society of Urological Pathology renal tumour grading system was recommended, and the definition of renal papillary adenoma was modified. The new WHO classification of penile squamous cell carcinomas is based on the presence of human papillomavirus and defines histologic subtypes accordingly. Germ cell neoplasia in situ (GCNIS) of the testis is the WHO-recommended term for precursor lesions of invasive germ cell tumours, and testicular germ cell tumours are now separated into two fundamentally different groups: those derived from GCNIS and those unrelated to GCNIS. Spermatocytic seminoma has been designated as a spermatocytic tumour and placed within the group of non–GCNIS-related tumours in the 2016 WHO classification. Patient summary The 2016 World Health Organization (WHO) classification contains new renal tumour entities. The classification of penile squamous cell carcinomas is based on the presence of human papillomavirus. Germ cell neoplasia in situ of the testis is the WHO-recommended term for precursor lesions of invasive germ cell tumours.
In viscous, organic-rich aerosol particles containing iron, sunlight may induce anoxic conditions that stabilize reactive oxygen species (ROS) and carbon-centered radicals (CCRs). In laboratory ...experiments, we show mass loss, iron oxidation and radical formation and release from photoactive organic particles containing iron. Our results reveal a range of temperature and relative humidity, including ambient conditions, that control ROS build up and CCR persistence in photochemically active, viscous organic particles. We find that radicals can attain high concentrations, altering aerosol chemistry and exacerbating health hazards of aerosol exposure. Our physicochemical kinetic model confirmed these results, implying that oxygen does not penetrate such particles due to the combined effects of fast reaction and slow diffusion near the particle surface, allowing photochemically-produced radicals to be effectively trapped in an anoxic organic matrix.
Abstract It has been 12 yr since the publication of the last World Health Organization (WHO) classification of tumours of the prostate and bladder. During this time, significant new knowledge has ...been generated about the pathology and genetics of these tumours. Intraductal carcinoma of the prostate is a newly recognized entity in the 2016 WHO classification. In most cases, it represents intraductal spread of aggressive prostatic carcinoma and should be separated from high-grade prostatic intraepithelial neoplasia. New acinar adenocarcinoma variants are microcystic adenocarcinoma and pleomorphic giant cell adenocarcinoma. Modifications to the Gleason grading system are incorporated into the 2016 WHO section on grading of prostate cancer, and it is recommended that the percentage of pattern 4 should be reported for Gleason score 7. The new WHO classification further recommends the recently developed prostate cancer grade grouping with five grade groups. For bladder cancer, the 2016 WHO classification continues to recommend the 1997 International Society of Urological Pathology grading classification. Newly described or better defined noninvasive urothelial lesions include urothelial dysplasia and urothelial proliferation of uncertain malignant potential, which is frequently identified in patients with a prior history of urothelial carcinoma. Invasive urothelial carcinoma with divergent differentiation refers to tumours with some percentage of “usual type” urothelial carcinoma combined with other morphologies. Pathologists should mention the percentage of divergent histologies in the pathology report. Patient summary Intraductal carcinoma of the prostate is a newly recognized entity in the 2016 World Health Organization classification. Better defined noninvasive urothelial lesions include urothelial dysplasia and urothelial proliferation of uncertain malignant potential.
Cancer-associated fibroblasts (CAF) may exert tumor-promoting and tumor-suppressive functions, but the mechanisms underlying these opposing effects remain elusive. Here, we sought to understand these ...potentially opposing functions by interrogating functional relationships among CAF subtypes, their mediators, desmoplasia, and tumor growth in a wide range of tumor types metastasizing to the liver, the most common organ site for metastasis. Depletion of hepatic stellate cells (HSC), which represented the main source of CAF in mice and patients in our study, or depletion of all CAF decreased tumor growth and mortality in desmoplastic colorectal and pancreatic metastasis but not in nondesmoplastic metastatic tumors. Single-cell RNA-Seq in conjunction with CellPhoneDB ligand-receptor analysis, as well as studies in immune cell-depleted and HSC-selective knockout mice, uncovered direct CAF-tumor interactions as a tumor-promoting mechanism, mediated by myofibroblastic CAF-secreted (myCAF-secreted) hyaluronan and inflammatory CAF-secreted (iCAF-secreted) HGF. These effects were opposed by myCAF-expressed type I collagen, which suppressed tumor growth by mechanically restraining tumor spread, overriding its own stiffness-induced mechanosignals. In summary, mechanical restriction by type I collagen opposes the overall tumor-promoting effects of CAF, thus providing a mechanistic explanation for their dual functions in cancer. Therapeutic targeting of tumor-promoting CAF mediators while preserving type I collagen may convert CAF from tumor promoting to tumor restricting.
Immune response dynamics in coronavirus disease 2019 (COVID-19) and their severe manifestations have largely been studied in circulation. Here, we examined the relationship between immune processes ...in the respiratory tract and circulation through longitudinal phenotypic, transcriptomic, and cytokine profiling of paired airway and blood samples from patients with severe COVID-19 relative to heathy controls. In COVID-19 airways, T cells exhibited activated, tissue-resident, and protective profiles; higher T cell frequencies correlated with survival and younger age. Myeloid cells in COVID-19 airways featured hyperinflammatory signatures, and higher frequencies of these cells correlated with mortality and older age. In COVID-19 blood, aberrant CD163+ monocytes predominated over conventional monocytes, and were found in corresponding airway samples and in damaged alveoli. High levels of myeloid chemoattractants in airways suggest recruitment of these cells through a CCL2-CCR2 chemokine axis. Our findings provide insights into immune processes driving COVID-19 lung pathology with therapeutic implications for targeting inflammation in the respiratory tract.
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•Airways show localized immune responses correlating to age and outcome in COVID-19•Airway T cells are activated and resident, while myeloid cells are hyperinflammatory•Aberrant CD163hi and HLA-DRlo monocytes predominate in COVID-19 blood•Monocytes infiltrate airways and lung alveoli potentially through a CCL2-CCR2 axis
Through longitudinal profiling of paired airways and blood from patients with severe COVID-19, Szabo et al. reveal airway immune responses that correlate with age and outcome. They further identify coordinate roles for T and myeloid cells in the respiratory tract and circulation in perpetuating lung pathology and disease pathogenesis.
This account presents information on all aspects of the biology of Fraxinus excelsior L. (Ash) that are relevant to understanding its ecological characteristics and behaviour. The main topics are ...presented within the standard framework of the Biological Flora of the British Isles: distribution, habitat, communities, responses to biotic factors, responses to environment, structure and physiology, phenology, floral and seed characters, herbivores and disease, history, and conservation. Fraxinus excelsior is a large forest tree, native throughout the main islands of Britain and much of mainland Europe. Seedlings are shade tolerant, but adults are not so it tends to be an intermediate successional species, invading gaps in mixed stands rather than forming extensive pure stands. Ash grows on a wide range of soils but is commonest on nutrientârich soils with a high base status and pHÂ >Â 4.2, and is at its best on dry calcareous screes and fertile alluvial soils. Fraxinus excelsior is trioecious or subdioecious with male, hermaphrodite and female flowers and trees. Seed production is prolific with periodic higher producing mast years. Seeds are primarily windâdispersed, but they can float and be moved considerable distances along waterways. Germination is delayed by dormancy until usually the second spring after being shed. Ash is tolerant of drought, but intolerant of spring frosts and so is predicted to fare well under current climate change scenarios, and indeed has recently been expanding in range in Europe. However, ash health and survival is currently seriously compromised by ash dieback caused by the fungus Hymenoscyphus fraxineus (Chalara fraxinea) that has the potential to kill all but a very few resistant trees. Moreover, the emerald ash borer beetle Agrilus planipennis, a serious pest of ash species in N. America, has reached Europe (though not yet the British Isles) and poses an equally if not more serious longâterm threat to ash.
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