Insulin receptor-related receptor (IRR), an orphan receptor in the insulin receptor (IR) family of receptor tyrosine kinases, is primarily localized to neural crest-derived sensory neurons during ...embryonic development. Expression of IRR closely resembles that of the nerve growth factor receptor, TrkA. To analyze the signaling properties and function of IRR in PC12 cells, a TrkB/IRR hybrid receptor was used. In contrast to IR activation, brain-derived neurotrophic growth factor-mediated activation of the TrkB/IRR receptor resulted in differentiation rather than proliferation. Analysis of cytoplasmic substrates activated by the TrkB/IRR receptor indicates a signaling pathway similar to that of the IR. Mutagenesis studies further show that only TrkB/IRR receptors able to phosphorylate mitogen-activated protein kinase elicit a differentiation response. Our analysis indicates that prolonged kinetics of mitogen-activated protein kinase activation mediated by the TrkB/IRR chimeric receptor correlates with induction to differentiate.
The requirements for transformation of rat embryo fibroblasts (REFs) by transfected ras and myc oncogenes were explored. Under conditions of dense monolayer culture, neither oncogene was able to ...transform REFs on its own. However, the introduction of a ras oncogene together with a selectable neomycin resistance marker into REFs allowed killing of the normal nontransfected cells and the outgrowth of colonies of ras transformants, 10% of which survived crisis and became tumorigenic. These cells expressed <10-fold-higher levels of ras p21 than tumorigenic cells cotransfected with ras and myc oncogenes. The myc oncogene similarly was unable to induce tumorigenic conversion of REFs unless especially refractile colonies of oncogene-bearing cells, produced by use of a cotransfected selectable marker, were picked and subcultured. Tumorigenic conversion of REFs by single transfected oncogenes appears to require special culture conditions and high levels of gene expression.
The role of somatic genetic variants in the pathogenesis of intracranial-aneurysm formation is unknown. We identified a 23-year-old man with progressive, right-sided intracranial aneurysms, ...ipsilateral to an impressive cutaneous phenotype. The index individual underwent a series of genetic evaluations for known connective-tissue disorders, but the evaluations were unrevealing. Paired-sample exome sequencing between blood and fibroblasts derived from the diseased areas detected a single novel variant predicted to cause a p.Tyr562Cys (g.149505130T>C GRCh37/hg19; c.1685A>G) change within the platelet-derived growth factor receptor β gene (PDGFRB), a juxtamembrane-coding region. Variant-allele fractions ranged from 18.75% to 53.33% within histologically abnormal tissue, suggesting post-zygotic or somatic mosaicism. In an independent cohort of aneurysm specimens, we detected somatic-activating PDGFRB variants in the juxtamembrane domain or the kinase activation loop in 4/6 fusiform aneurysms (and 0/38 saccular aneurysms; Fisher’s exact test, p < 0.001). PDGFRB-variant, but not wild-type, patient cells were found to have overactive auto-phosphorylation with downstream activation of ERK, SRC, and AKT. The expression of discovered variants demonstrated non-ligand-dependent auto-phosphorylation, responsive to the kinase inhibitor sunitinib. Somatic gain-of-function variants in PDGFRB are a novel mechanism in the pathophysiology of fusiform cerebral aneurysms and suggest a potential role for targeted therapy with kinase inhibitors.
Background Activating variants in platelet-derived growth factor receptor beta (PDGFRB), including a variant we have previously described (p.Tyr562Cys g.149505130T>C GRCh37/hg19; c.1685A>G), are ...associated with development of multiorgan pathology, including aneurysm formation. To investigate the association between the allele fraction genotype and histopathologic phenotype, we performed an expanded evaluation of post-mortem normal and aneurysmal tissue specimens from the previously published index patient. Methods and Results Following death due to diffuse subarachnoid hemorrhage in a patient with mosaic expression of the above PDGFRB variant, specimens from the intracranial, coronary, radial and aortic arteries were harvested. DNA was extracted and alternate allele fractions (AAF) of
were determined using digital droplet PCR. Radiographic and histopathologic findings, together with genotype expression of
were then correlated in aneurysmal tissue and compared to non-aneurysmal tissue. The
variant was identified in the vertebral artery, basilar artery, and P1 segment aneurysms (AAF: 28.7%, 16.4%, and 17.8%, respectively). It was also identified in the coronary and radial artery aneurysms (AAF: 22.3% and 20.6%, respectively). In phenotypically normal intracranial and coronary artery tissues, the
variant was not present. The
variant was absent from lymphocyte DNA and normal tissue, confirming it to be a non-germline somatic variant. Primary cell cultures from a radial artery aneurysm localized the
variant to CD31-, non-endothelial cells. Conclusions Constitutive expression of PDGFRB within the arterial wall is associated with the development of human fusiform aneurysms. The role of targeted therapy with tyrosine kinase inhibitors in fusiform aneurysms with
mutations should be further studied.
Background
The most frequent site for the extranodal appearance of primary non-Hodgkin’s lymphomas (NHL) is the gastrointestinal (G.I.) tract. However, primary esophageal lymphoma is extremely rare. ...The purpose of the present study was to describe and analyze the demographics, clinical characteristics, histopathologic types, and long-term survival of patients with primary esophageal NHL registered in the surveillance, epidemiology, and end results (SEER) database.
Methods
Retrospective cohort study. Individuals with primary esophageal lymphoma (PEL) were identified using the international classification of disease for oncology, third edition histology codes. Patients were excluded if there was no microscopic confirmation of the neoplasm or if the diagnosis was made by autopsy or death certificate. Data on demographics, clinical characteristics, histopathology and survival were analyzed using the Kaplan–Meier method, life table, and cox proportional hazard models.
Results
179 patients were included (68% males, median age 66 years IQR 46–79). The overall survival at 1, 5 and 10 years was 65% (95% CI 57.9–72.3%), 49% (95% CI 42.1–57.3%), and 31% (95% CI 24.5–38.6%), respectively. On univariate analyses, individuals with extranodal marginal zone lymphoma (MZL) had a significantly higher overall survival when compared to patients with diffuse large B cell lymphoma (HR 0.29; 95% CI 0.11–0.73.
p
= 0.008). Furthermore, patients whose cancer was diagnosed after 1997 showed an improved overall survival (HR 0.40; 95% CI 0.26–0.61.
p
< 0.001) when compared to those diagnosed before 1997.
Conclusions
In this large population-based series, diagnosis after 1997 (year of rituximab approval by the FDA) and MZL subtype were associated with improved survival outcomes in patients with PEL.
Most World Health Organization (WHO) grade I meningiomas carry a favorable prognosis. Some become clinically aggressive with recurrence, invasion, and resistance to conventional therapies (grade 1.5; ...recurrent/progressive WHO grade I tumors requiring further treatment within 10 years). We aimed to identify biomarker signatures in grade 1.5 meningiomas where histopathology and genetic evaluation has fallen short.
Mass spectrometry (MS)-based phosphoproteomics and peptide chip array kinomics were used to compare grade I and 1.5 tumors. Ingenuity Pathway Analysis (IPA) identified alterations in signaling pathways with validation by Western blot analysis. The selected biomarker was evaluated in an independent cohort of 140 samples (79/140 genotyped for meningioma mutations) by tissue microarray and correlated with clinical variables.
The MS-based phosphoproteomics revealed differential Ser/Thr phosphorylation in 32 phosphopeptides. The kinomic profiling by peptide chip array identified 10 phosphopeptides, including a 360% increase in phosphorylation of RB1, in the 1.5 group. IPA of the combined datasets and Western blot validation revealed regulation of AKT and cell-cycle checkpoint cascades. RB1 hyperphosphorylation at the S780 site distinguished grade 1.5 meningiomas in an independent cohort of 140 samples and was associated with decreased progression/recurrence-free survival. Mutations in
and
E17K did not predict RB1 S780 staining or progression in grade 1.5 meningiomas.
RB1 S780 staining distinguishes grade 1.5 meningiomas, independent of histology, subtype, WHO grade, or genotype. This promising biomarker for risk stratification of histologically bland WHO grade I meningiomas provides insight into the pathways of oncogenesis driving these outlying clinically aggressive tumors.
En este estudio se evaluó la actividad antibacteriana de una cepa de Enterococcus mundtii tw278 productora de bacteriocina aislada del contenido intestinal de Hemiodema spectabilis (pepino de mar), ...recolectado en la costa patagónica de la Argentina. La cepa se identificó mediante pruebas bioquímicas y análisis filogenético del gen ARNr 16S. Además, se detectó el gen estructural que codifica para la mundticina KS mediante técnicas de PCR. La investigación de los factores de virulencia reveló que la cepa de E. mundtii tw278 no presentó actividad gelatinasa ni hemolítica y fue susceptible a todos los antibióticos analizados, excepto la cefalotina. La máxima actividad inhibitoria se logró al final de la fase logarítmica cuando se utilizó el caldo MRS como medio de cultivo a 35 °C. Luego de 12 h de incubación, el sobrenadante libre de células (SLC) alcanzó un título de 163 840 unidades arbitrarias por mililitro contra la cepa indicadora de Listeria innocua ATCC 33090. El SLC exhibió actividad contra todas las cepas de Listeria ensayadas, Enterococcus faecalis ATCC 29212, enterococos resistentes a vancomicina (Van A, Van B y Van C), Lactobacillus plantarum TwLb 5 y Vibrio anguilarum V10. Este sería el primer estudio que informa el aislamiento de una cepa bacteriocinogénica de E. mundtii aislada del contenido intestinal de Hemiodema spectabilis.
This paper presents the design and construction of a land wheeled autonomous mini-robot (LWAMR) for in-door surveillance. The LWAMR is able to be autonomous by using a position, speed and distance ...sensor. In addition, it is capable to send images and video in real time by using a spy cam, which is controlled by a servomechanism. Details of the design, control algorithm, communication, and human machine interface (HMI) are given. HMI was implemented in LabVIEW and it is used for monitoring remotely the LWAMR health and surveillance. Communication between the HMI and the LWAMR system was carried out by means of RF transceiver. Results show the effective implementation of this kind of LWAMR system. Advantages of the presented LWAMR are: low cost, versatility, modularity, robustness and remote (or not) operation by using a mobile device HMI.
Neurotrophic factors are essential for neuronal survival and function. Recent data have demonstrated that the product of the tyrosine kinase trk proto-oncogene binds NGF and is a component of the ...high affinity NGF receptor. Analysis of the trkB gene product, gp145trkB, in NIH 3T3 cells indicates that this tyrosine kinase receptor is rapidly phosphorylated on tyrosine residues upon exposure to the NGF-related neurotrophic factors BDNF and NT-3. Furthermore, gp145trkB specifically binds BDNF and NT-3 in NIH 3T3 cells and in hippocampal cells, but does not bind NGF. Thus, the trk family of receptors are likely to be important signal transducers of NGF-related trophic signals in the formation and maintenance of neuronal circuits.
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