Patients with cancer may display elevated levels of B-type natriuretic peptide (BNP) and high-sensitive troponin T (hsTnT) without clinical manifestation of cardiac disease. This study aimed to ...evaluate circulating cardiovascular hormones and hsTnT and their association with mortality in cancer.
We prospectively enrolled 555 consecutive patients with a primary diagnosis of cancer and without prior cardiotoxic anticancer therapy. N-terminal pro BNP (NT-proBNP), mid-regional pro-atrial natriuretic peptide (MR-proANP), mid-regional pro-adrenomedullin (MR-proADM), C-terminal pro-endothelin-1 (CT-proET-1), copeptin, hsTnT, proinflammatory markers interleukin 6 (IL-6) and C reactive protein (CRP), and cytokines serum amyloid A (SAA), haptoglobin and fibronectin were measured. All-cause mortality was defined as primary endpoint.
During a median follow-up of 25 (IQR 16-31) months, 186 (34%) patients died. All cardiovascular hormones and hsTnT levels rose with tumour stage progression. All markers were significant predictors of mortality with HRs per IQR of 1.54 (95% CI 1.24 to 1.90, p<0.001) for NT-proBNP, 1.40 (95% CI 1.10 to 1.79, p<0.01) for MR-proANP, 1.31 (95% CI 1.19 to 1.44, p<0.001) for MR-proADM, 1.21 (95% CI 1.14 to 1.30, p<0.001) for CT-proET-1, 1.22 (95% CI 1.04 to 1.42, p=0.014) for copeptin and 1.21 (95% CI 1.13 to 1.32, p<0.001) for hsTnT, independent of age, gender, tumour entity and stage, and presence of cardiac comorbidities. NT-proBNP, MR-proANP, MR-proADM and hsTnT displayed a significant correlation with IL-6 and CRP.
Circulating levels of cardiovascular peptides like NT-proBNP, MR-proANP, MR-proADM, CT-pro-ET-1 and hsTnT were elevated in an unselected population of patients with cancer prior to induction of any cardiotoxic anticancer therapy. The aforementioned markers and copeptin were strongly related to all-cause mortality, suggesting the presence of subclinical functional and morphological myocardial damage directly linked to disease progression.
In the current classification of the World Health Organization (WHO), bone marrow mastocytosis (BMM) is a provisional variant of indolent systemic mastocytosis (ISM) defined by bone marrow ...involvement and absence of skin lesions. However, no additional diagnostic criteria for BMM have been proposed. Within the registry dataset of the European Competence Network on Mastocytosis, we compared characteristics and outcomes of 390 patients with BMM and 1175 patients with typical ISM. BMM patients were significantly older, predominantly male, had lower tryptase and lower burden of neoplastic mast cells, and displayed a higher frequency of allergic reactions, mainly triggered by Hymenoptera, than patients with typical ISM. The estimated 10-year progression-free survival of BMM and typical ISM was 95.9% and 92.6%, respectively. In BMM patients defined by WHO-based criteria, the presence of one B-Finding and tryptase level ≥125 ng/mL were identified as risk factors for progression in multivariate analyses. BMM patients without any of these risk factors were found to have better progression-free survival (p < 0.05) and better overall survival (p < 0.05) than other ISM patients. These data support the proposal to define BMM as a separate SM variant characterized by SM criteria, absence of skin lesions, absence of B-Findings, and tryptase levels <125 ng/mL.
This article contributes to the emerging discussion on the role of context in entrepreneurship as well as the development of theorizing on rural entrepreneurship. It does so by exploring the role of ...spatial context for rural entrepreneurs. Through a case study of 28 ventures, two modes of spatializing rural entrepreneurial activities are identified in the form of resource endowments and spatial bridging. Additionally, we develop a typology of rural entrepreneurs, which captures hitherto unexplored heterogeneity within this group of entrepreneurs. Spatial context is found to be of considerable significance to the rural entrepreneurial process and hence this study contributes to a micro-level understanding of place-specific entrepreneurial practices and the non-local circulation of value that can enrich local economies.
This study reviews the literature related to regional entrepreneurship. It identifies the main topical perspectives, advancements and shortcomings, discusses several research gaps and proposes ways ...forward. The literature review is based on 170 peer-reviewed articles in the leading journals of entrepreneurship and regional science. The findings reveal that major debates occur within the disciplines of regional economics, sociology and economic geography, but discussions across disciplines are scant. While regional economists tend to overlook the role of contextualized agency, and thus neglect processes that may influence entrepreneurs' acting in distinctive localities, entrepreneurship scholars tend to overlook the role of the spatial and proximate contextual conditions in the entrepreneurial process. Future research should intensify its efforts on the interrelation between entrepreneurial agency and regional structuring in order to expand current understandings of which types of entrepreneurship prevail in different localities.
In multicellular organisms, temporal and spatial regulation of cell proliferation is central for generating organs with defined sizes and morphologies. For establishing and maintaining the ...post‐mitotic quiescent state during cell differentiation, it is important to repress genes with mitotic functions. We found that three of the Arabidopsis MYB3R transcription factors synergistically maintain G2/M‐specific genes repressed in post‐mitotic cells and restrict the time window of mitotic gene expression in proliferating cells. The combined mutants of the three repressor‐type MYB3R genes displayed long roots, enlarged leaves, embryos, and seeds. Genome‐wide chromatin immunoprecipitation revealed that MYB3R3 binds to the promoters of G2/M‐specific genes and to E2F target genes. MYB3R3 associates with the repressor‐type E2F, E2FC, and the RETINOBLASTOMA RELATED proteins. In contrast, the activator MYB3R4 was in complex with E2FB in proliferating cells. With mass spectrometry and pairwise interaction assays, we identified some of the other conserved components of the multiprotein complexes, known as DREAM/dREAM in human and flies. In plants, these repressor complexes are important for periodic expression during cell cycle and to establish a post‐mitotic quiescent state determining organ size.
Synopsis
Activator and DREAM‐like repressor R1R2R3‐Myb transcription factors act coordinately to regulate mitotic target genes and organ growth in Arabidopsis thaliana.
R1R2R3‐Mybs with repressor functions maintain G2/M‐specific genes repressed in post‐mitotic cells and restrict mitotic gene expression in proliferating cells.
Transcriptional cell cycle regulation at G2/M impacts on plant organ growth.
R1R2R3‐Myb activators and repressors form distinct multi‐protein complexes.
Repressive R1R2R3‐Mybs are similar to the DREAM/dREAM complexes in human and fly.
Activator and DREAM‐like repressor R1R2R3‐Myb transcription factors act coordinately to regulate mitotic target genes and organ growth in Arabidopsis thaliana.
euromodulation is among the fastest-growing areas of medicine, involving many diverse specialties and affecting hundreds of thousands of patients with numerous disorders worldwide. It can briefly be ...described as the science of how electrical, chemical, and mechanical interventions can modulate the nervous system function. A prominent example of neuromodulation is deep brain stimulation (DBS), an intervention that reflects a fundamental shift in the understanding of neurological and psychiatric diseases: namely as resulting from a dysfunctional activity pattern in a defined neuronal network that can be normalized by targeted stimulation. The application of DBS has grown remarkably and more than 130,000 patients worldwide have obtained a DBS intervention in the past 30 years—most of them for treating movement disorders. This Frontiers Research Topics provides an overview on the current discussion beyond basic research in DBS and other brain stimulation technologies. Researchers from various disciplines, who are working on broader clinical, ethical and social issues related to DBS and related neuromodulation technologies, have contributed to this research topic.
Ovarian cancer is typically accompanied by the occurrence of malignant ascites containing large number of macrophages. It has been suggested that these tumor‐associated macrophages (TAMs) are skewed ...to alternative polarization (M2) and thereby play an essential role in therapy resistance and metastatic spread. In our study, we have investigated the nature, regulation and clinical correlations of TAM polarization in serous ovarian cancer. Macrophage polarization markers on TAMs and ascites cytokine levels were analyzed for 30 patients and associated with relapse‐free survival (RFS) in a prospective study with 20 evaluable patients. Surface expression of the M2 marker CD163 on TAMs was inversely associated with RFS (p < 0.01). However, global gene expression profiles determined for 17 of these patients revealed a mixed‐polarization phenotype unrelated to the M1/M2 classification. CD163 surface expression also correlated with the ascites levels of IL‐6 and IL‐10 (p < 0.05), both cytokines induced CD163 expression, and their ascites levels showed a clear inverse association with RFS (p < 0.01). These findings define a subgroup of patients with high CD163 expression, high IL‐6 and/or IL‐10 levels and poor clinical outcome.
What's new?
The peritoneal environment plays a critical role in the spread of ovarian cancer, ultimately becoming a malignant ascites, rich in tumor‐associated macrophages (TAMs), in advanced stages of disease. TAMs in this context have been implicated in therapy resistance and metastatic spread, though their function remains unclear. Here, TAMs from malignant ascites in patients with serous ovarian carcinoma were found to express a mixed‐polarization phenotype and highly variable levels of the surface marker CD163. Elevated CD163 was associated with early disease relapse and increased IL‐6 and IL‐10 levels. Further investigation of these changes in surface marker expression could provide insight into mechanisms of progression in ovarian cancer.
Unlike most other primary epidermal growth factor receptor (
) mutations in non-small cell lung cancer (NSCLC), exon 20 insertions, comprising approximately 4% to 10% of all
mutations, are generally ...considered to be resistant to EGFR tyrosine kinase inhibitors (TKIs). However,
exon 20 insertions are structurally and pharmacologically heterogeneous, with variability in their position and size having implications for response to different EGFR TKIs. The second-generation ErbB family blocker, afatinib, is approved for the first-line treatment of
mutation-positive NSCLC and has been shown to have a broad inhibitory profile against common and uncommon
mutations. Here, we describe a patient with bilateral multifocal lung adenocarcinoma harboring a very rare
exon 20 insertion (c.2317_2319dup3; p.H773dup), who has been receiving treatment with afatinib for 4.5 years. To our knowledge, this is the first report describing long-term benefit for a patient treated with afatinib with this rare exon 20 insertion. We are aware of two further cases with this rare
mutation. One patient, also reported here, has early-stage lung adenocarcinoma and has not yet received systemic therapy for NSCLC. The other patient received afatinib in the context of a global compassionate use program and had progressive disease. Our findings may be of clinical relevance for patients carrying tumors with this rare mutation as epidemiological evidence suggests that p.H773dup may function as a driver mutation in NSCLC. Together with previous preclinical and clinical evidence for the activity of afatinib against certain
exon 20 insertions, these findings warrant further investigation.
Plant cells divide their cytoplasmic content by forming a new membrane compartment, the cell plate, via a rerouting of the secretory pathway toward the division plane aided by a dynamic cytoskeletal ...apparatus known as the phragmoplast. The phragmoplast expands centrifugally and directs the cell plate to the preselected division site at the plasma membrane to fuse with the parental wall. The division site is transiently decorated by the cytoskeletal preprophase band in preprophase and prophase, whereas a number of proteins discovered over the last decade reside continuously at the division site and provide a lasting spatial reference for phragmoplast guidance. Recent studies of membrane fusion at the cell plate have revealed the contribution of functionally conserved eukaryotic proteins to distinct stages of cell plate biogenesis and emphasize the coupling of cell plate formation with phragmoplast expansion. Together with novel findings concerning preprophase band function and the setup of the division site, cytokinesis and its spatial control remain an open-ended field with outstanding and challenging questions to resolve.
This volume offers the first comprehensive look at the role of women in the monarchies of the ancient Mediterranean. It consistently addresses certain issues across all dynasties: title; role in ...succession; the situation of mothers, wives, and daughters of kings; regnant and co-regnant women; and role in cult and in dynastic image, and examines a sampling of the careers of individual women while placing them within broader contexts. Written by an international group of experts, this collection is based on the assumption that women played a fundamental role in ancient monarchy, that they were part of, not apart from it, and that it is necessary to understand their role to understand ancient monarchies. This is a crucial resource for anyone interested in the role of women in antiquity.
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