Severe radiation-related lymphopenia is common and associated with decreased survival in patients with several solid tumors. As the mechanisms underlying systemic lymphopenia are poorly understood, ...we developed an animal model to study the effects of brain radiation on lymphocytes and cytokines. C57 BL/6 and BALB/c mice received focal brain irradiation (4 Gy x 10 fractions or 2 Gy x 30 fractions). Weekly total lymphocyte counts (TLC), lymphocyte subsets and cytokines in blood and lymph nodes were measured. Non-irradiated lymph nodes were collected and examined before, during, and after radiation. We found that systemic TLC decreased rapidly irrespective of mouse strain or radiation schedule. 4 Gy x 10 resulted in a 42% and 75% & 70% and 49% TLC reduction in C57 BL/6 and BALB/c mice respectively. 2 Gy x 30 caused a 70% / 49% decrease in TLC in C57 BL/6 and BALB/c. Similar trends were seen for total T cells, CD4
+
, regulatory T and CD8
+
cells. Changes in lymph node architecture and cellular composition correlated with the development of systemic lymphopenia. Three weeks after radiation, TLC returned to 60-80% of baseline, preceded by increased IL-7 levels in the lymph nodes. Focal brain radiation in mice results in significant systemic lymphodepletion.
Biodiversity loss in European agricultural landscapes is progressing rapidly despite a growing number of conservation efforts. One of the reasons for this is that farmers do not have enough ...decision‐making power and do not receive adequate advice to tailor conservation measures to local conditions and regional biodiversity targets.
In this paper, we therefore address the potential and practical implementation of co‐designing conservation measures through close collaboration between farmers and other stakeholders (e.g. other practitioners, conservation experts, agricultural advisors, scientists and policymakers).
Based on interviews with four researchers from ongoing European co‐design projects, one national and one European farmers’ organizations, we discuss the challenges and provide recommendations for co‐design in the context of biodiversity conservation in agricultural landscapes.
Our aim is to reach scientists, practitioners and local decision makers working on innovative and locally adapted conservation efforts.
in German
Der Verlust der biologischen Vielfalt in europäischen Agrarlandschaften schreitet trotz einer wachsenden Zahl von Erhaltungsmaßnahmen rasch voran. Einer der Gründe dafür ist, dass die Landwirte nicht genügend Entscheidungsbefugnis haben und keine angemessene Beratung erhalten, um die Erhaltungsmaßnahmen auf die lokalen Bedingungen und regionalen Biodiversitätsziele abzustimmen.
In diesem Papier befassen wir uns daher mit dem Potenzial und den praktischen Möglichkeiten der Mitgestaltung (“Co‐Design”) von Erhaltungsmaßnahmen durch eine enge Zusammenarbeit zwischen Landwirt:innen und anderen Akteuren (z. B. anderen Praktiker:innen, Expert:innen für Naturschutz, landwirtschaftlichen Berater:innen, Wissenschaftler:innen und politischen Entscheidungsträger:innen).
Auf der Grundlage von Interviews mit vier Forscher:innen aus laufenden europäischen Co‐Design‐Projekten, einem nationalen und einem europäischen Landwirtschaftsverband erörtern wir die Herausforderungen und geben Empfehlungen für Co‐Design im Zusammenhang mit der Erhaltung der biologischen Vielfalt in Agrarlandschaften.
Unser Ziel ist es, Wissenschaftler:innen, Praktiker:innen und lokale Entscheidungsträger:innen zu erreichen, die an innovativen und lokal angepassten Maßnahmen zum Schutz der Biodiversität in Agrarlandschaften arbeiten.
Biodiversity loss in European agricultural landscapes is progressing rapidly despite a growing number of conservation efforts. In this paper, we address the potential and practical implementation of co‐designing conservation measures through close collaboration between farmers and other stakeholders (e.g. other practitioners, conservation experts, scientists and policymakers). Based on interviews with four researchers from ongoing co‐design projects and two representatives of farmers' organizations, we discuss the challenges and provide recommendations for co‐design.
The unfolded protein response (UPR) pathway, consisting of the evolutionarily conserved Ire1 kinase/endonuclease and the bZIP transcription factor Hxl1, is critical for the pathogenicity of ...Cryptococcus neoformans; however, its role remains unknown in other pathogenic Cryptococcus species. Here, we investigated the role of the UPR pathway in C. deuterogattii, which causes pneumonia and systemic cryptococcosis, even in immunocompetent individuals. In response to ER stress, C. deuterogattii Ire1 triggers unconventional splicing of HXL1 to induce the expression of UPR target genes such as KAR2, DER1, ALG7, and ERG29. Furthermore, C. deuterogattii Ire1 is required for growth at mammalian body temperature, similar to C. neoformans Ire1. However, deletion of HXL1 does not significantly affect the growth of C. deuterogattii at 37 °C, which is in contrast to the indispensable role of HXL1 in the growth of C. neoformans at 37 °C. Nevertheless, both C. deuterogattii ire1Δ and hxl1Δ mutants are avirulent in a murine model of systemic cryptococcosis, suggesting that a non-thermotolerance phenotypic trait also contributes to the role of the UPR pathway in the virulence of pathogenic Cryptococcus species. In conclusion, the UPR pathway plays redundant and distinct roles in the virulence of members of the pathogenic Cryptococcus species complex.
The Art of Oncology: COVID‐19 Era Reynolds, Kerry L.; Klempner, Samuel J.; Parikh, Aparna ...
The oncologist (Dayton, Ohio),
November 2020, Letnik:
25, Številka:
11
Journal Article
The clinical phenotype of somatic mutations in endometriosis is unknown. The objective was to determine whether somatic KRAS mutations were associated with greater disease burden in endometriosis ...(i.e. more severe subtypes and higher stage). This prospective longitudinal cohort study included 122 subjects undergoing endometriosis surgery at a tertiary referral center between 2013 and 2017, with 5–9 years of follow‐up. Somatic activating KRAS codon 12 mutations were detected in endometriosis lesions using droplet digital PCR. KRAS mutation status for each subject was coded as present (KRAS mutation in at least one endometriosis sample in a subject) or absent. Standardized clinical phenotyping for each subject was carried out via linkage to a prospective registry. Primary outcome was anatomic disease burden, based on distribution of subtypes (deep infiltrating endometriosis, ovarian endometrioma, and superficial peritoneal endometriosis) and surgical staging (Stages I–IV). Secondary outcomes were markers of surgical difficulty, demographics, pain scores, and risk of re‐operation. KRAS mutation presence was higher in subjects with deep infiltrating endometriosis or endometrioma lesions only (57.9%; 11/19) and subjects with mixed subtypes (60.6%; 40/66), compared with those with superficial endometriosis only (35.1%; 13/37) (p = 0.04). KRAS mutation was present in 27.6% (8/29) of Stage I cases, in comparison to 65.0% (13/20) of Stage II, 63.0% (17/27) of Stage III, and 58.1% (25/43) of Stage IV cases (p = 0.02). KRAS mutation was also associated with greater surgical difficulty (ureterolysis) (relative risk RR = 1.47, 95% CI: 1.02–2.11) and non‐Caucasian ethnicity (RR = 0.64, 95% CI: 0.47–0.89). Pain severities did not differ based on KRAS mutation status, at either baseline or follow‐up. Re‐operation rates were low overall, occurring in 17.2% with KRAS mutation compared with 10.3% without (RR = 1.66, 95% CI: 0.66–4.21). In conclusion, KRAS mutations were associated with greater anatomic severity of endometriosis, resulting in increased surgical difficulty. Somatic cancer‐driver mutations may inform a future molecular classification of endometriosis.
In this study, we evaluate the impact of whole genome and transcriptome analysis (WGTA) on predictive molecular profiling and histologic diagnosis in a cohort of advanced malignancies. WGTA was used ...to generate reports including molecular alterations and site/tissue of origin prediction. Two reviewers analyzed genomic reports, clinical history, and tumor pathology. We used National Comprehensive Cancer Network (NCCN) consensus guidelines, Food and Drug Administration (FDA) approvals, and provincially reimbursed treatments to define genomic biomarkers associated with approved targeted therapeutic options (TTOs). Tumor tissue/site of origin was reassessed for most cases using genomic analysis, including a machine learning algorithm (Supervised Cancer Origin Prediction Using Expression SCOPE) trained on The Cancer Genome Atlas data. WGTA was performed on 652 cases, including a range of primary tumor types/tumor sites and 15 malignant tumors of uncertain histogenesis (MTUH). At the time WGTA was performed, alterations associated with an approved TTO were identified in 39 (6%) cases; 3 of these were not identified through routine pathology workup. In seven (1%) cases, the pathology workup either failed, was not performed, or gave a different result from the WGTA. Approved TTOs identified by WGTA increased to 103 (16%) when applying 2021 guidelines. The histopathologic diagnosis was reviewed in 389 cases and agreed with the diagnostic consensus after WGTA in 94% of non‐MTUH cases (n = 374). The remainder included situations where the morphologic diagnosis was changed based on WGTA and clinical data (0.5%), or where the WGTA was non‐contributory (5%). The 15 MTUH were all diagnosed as specific tumor types by WGTA. Tumor board reviews including WGTA agreed with almost all initial predictive molecular profile and histopathologic diagnoses. WGTA was a powerful tool to assign site/tissue of origin in MTUH. Current efforts focus on improving therapeutic predictive power and decreasing cost to enhance use of WGTA data as a routine clinical test.
Knowledge of the presence of cirrhosis is important for the management of patients with chronic hepatitis C (CHC). Most models for predicting cirrhosis were derived from small numbers of patients and ...included subjective variables or laboratory tests that are not readily available. The aim of this study was to develop a predictive model of cirrhosis in patients with CHC based on standard laboratory tests. Data from 1,141 CHC patients including 429 with cirrhosis were analyzed. All biopsies were read by a panel of pathologists (blinded to clinical features), and fibrosis stage was determined by consensus. The cohort was divided into a training set (n = 783) and a validation set (n = 358). Variables that were significantly different between patients with and without cirrhosis in univariate analysis were entered into logistic regression models, and the performance of each model was compared. The area under the receiver-operating characteristic curve of the final model comprising platelet count, AST/ALT ratio, and INR in the training and validation sets was 0.78 and 0.81, respectively. A cutoff of less than 0.2 to exclude cirrhosis would misclassify only 7.8% of patients with cirrhosis, while a cutoff of greater than 0.5 to confirm cirrhosis would misclassify 14.8% of patients without cirrhosis. The model performed equally well in fragmented and nonfragmented biopsies and in biopsies of varying lengths. Use of this model might obviate the requirement for a liver biopsy in 50% of patients with CHC. In conclusion, a model based on standard laboratory test results can be used to predict histological cirrhosis with a high degree of accuracy in 50% of patients with CHC.
Arthrochalasia type Ehlers-Danlos Syndrome (EDS) is a connective tissue disease characterized by severe generalized joint hypermobility, congenital bilateral hip dislocations, and recurrent joint ...subluxations and dislocations. Only one study has reported bone fragility resulting in fractures. The genetic abnormality underlying this disorder is a variant in the
gene causing entire or partial loss of exon 6, resulting in defective type 1 collagen synthesis.
We report a female infant born at 35 weeks of gestation presenting with pathologic skull fracture following vaginal delivery. Genetic testing revealed a pathogenic variant in the
gene (c.472-1G > C), consistent with arthrochalasia type EDS, reported previously.
This report adds pathologic fractures to the phenotypic breadth of this type of EDS and reinforces the importance of including the condition on the differential diagnosis when early onset non-accidental injury or trauma is being considered.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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