216 research outputs found
Cell of Origin and Genetic Alterations in the Pathogenesis of Multiple Myeloma
B cell activation and differentiation yields plasma cells with high affinity antibodies to a given antigen in a time-frame that allows for host protection. Although the end product is most commonly humoral immunity, the rapid proliferation and somatic mutation of the B cell receptor also results in oncogenic mutations that cause B cell malignancies including plasma cell neoplasms such as multiple myeloma. Myeloma is the second most common hematological malignancy and results in over 100,000 deaths per year worldwide. The genetic alterations that occur in the germinal center, however, are not sufficient to cause myeloma, but rather impart cell proliferation potential on plasma cells, which are normally non-dividing. This pre-malignant state, referred to as monoclonal gammopathy of undetermined significance or MGUS, provides the opportunity for further genetic and epigenetic alterations eventually resulting in a progressive disease that becomes symptomatic. In this review, we will provide a brief history of clonal gammopathies and detail how some of the key discoveries were interwoven with the study of plasma cells. We will also review the genetic and epigenetic alterations discovered over the past 25 years, how these are instrumental to myeloma pathogenesis, and what these events teach us about myeloma and plasma cell biology. These data will be placed in the context of normal B cell development and differentiation and we will discuss how understanding the biology of plasma cells can lead to more effective therapies targeting multiple myeloma
Wnt signaling in triple negative breast cancer is associated with metastasis
Background
Triple Negative subset of (TN) Breast Cancers (BC), a close associate of the basal-like subtype (with limited discordance) is an aggressive form of the disease which convey unpredictable, and poor prognosis due to limited treatment options and lack of proven effective targeted therapies.
Methods
We conducted an expression study of 240 formalin-fixed, paraffin-embedded (FFPE) primary biopsies from two cohorts, including 130 TN tumors, to identify molecular mechanisms of TN disease.
Results
The annotation of differentially expressed genes in TN tumors contained an overrepresentation of canonical Wnt signaling components in our cohort and others. These observations were supported by upregulation of experimentally induced oncogenic Wnt/β-catenin genes in TN tumors, recapitulated using targets induced by Wnt3A. A functional blockade of Wnt/β-catenin pathway by either a pharmacological Wnt-antagonist, WntC59, sulidac sulfide, or β-catenin (functional read out of Wnt/β-catenin pathway) SiRNA mediated genetic manipulation demonstrated that a functional perturbation of the pathway is causal to the metastasis- associated phenotypes including fibronectin-directed migration, F-actin organization, and invasion in TNBC cells. A classifier, trained on microarray data from β-catenin transfected mammary cells, identified a disproportionate number of TNBC breast tumors as compared to other breast cancer subtypes in a meta-analysis of 11 studies and 1,878 breast cancer patients, including the two cohorts published here. Patients identified by the Wnt/β-catenin classifier had a greater risk of lung and brain, but not bone metastases.
Conclusion
These data implicate transcriptional Wnt signaling as a hallmark of TNBC disease associated with specific metastatic pathways
Differential limit on the extremely-high-energy cosmic neutrino flux in the presence of astrophysical background from nine years of IceCube data
We report a quasi-differential upper limit on the extremely-high-energy (EHE)
neutrino flux above GeV based on an analysis of nine years of
IceCube data. The astrophysical neutrino flux measured by IceCube extends to
PeV energies, and it is a background flux when searching for an independent
signal flux at higher energies, such as the cosmogenic neutrino signal. We have
developed a new method to place robust limits on the EHE neutrino flux in the
presence of an astrophysical background, whose spectrum has yet to be
understood with high precision at PeV energies. A distinct event with a
deposited energy above GeV was found in the new two-year sample, in
addition to the one event previously found in the seven-year EHE neutrino
search. These two events represent a neutrino flux that is incompatible with
predictions for a cosmogenic neutrino flux and are considered to be an
astrophysical background in the current study. The obtained limit is the most
stringent to date in the energy range between and GeV. This result constrains neutrino models predicting a three-flavor
neutrino flux of $E_\nu^2\phi_{\nu_e+\nu_\mu+\nu_\tau}\simeq2\times 10^{-8}\
{\rm GeV}/{\rm cm}^2\ \sec\ {\rm sr}10^9\ {\rm GeV}$. A significant part
of the parameter-space for EHE neutrino production scenarios assuming a
proton-dominated composition of ultra-high-energy cosmic rays is excluded.Comment: The version accepted for publication in Physical Review
Heterozygosity for Pten Promotes Tumorigenesis in a Mouse Model of Medulloblastoma
BACKGROUND: Recent publications have described an important role for cross talk between PI-3 kinase and sonic hedgehog signaling pathways in the pathogenesis of medulloblastoma. METHODOLOGY/PRINCIPAL FINDINGS: We crossed mice with constitutive activation of Smoothened, SmoA1, with Pten deficient mice. Both constitutive and conditional Pten deficiency doubled the incidence of mice with symptoms of medulloblastoma and resulted in decreased survival. Analysis revealed a clear separation of gene signatures, with up-regulation of genes in the PI-3 kinase signaling pathway, including downstream activation of angiogenesis in SmoA1+/-; Pten +/- medulloblastomas. Western blotting and immunohistochemistry confirmed reduced or absent Pten, Akt activation, and increased angiogenesis in Pten deficient tumors. Down-regulated genes included genes in the sonic hedgehog pathway and tumor suppressor genes. SmoA1+/-; Pten +/+ medulloblastomas appeared classic in histology with increased proliferation and diffuse staining for apoptosis. In contrast, Pten deficient tumors exhibited extensive nodularity with neuronal differentiation separated by focal areas of intense staining for proliferation and virtually absent apoptosis. Examination of human medulloblastomas revealed low to absent PTEN expression in over half of the tumors. Kaplan-Meier analysis confirmed worse overall survival in patients whose tumor exhibited low to absent PTEN expression. CONCLUSIONS/SIGNIFICANCE: This suggests that PTEN expression is a marker of favorable prognosis and mouse models with activation of PI-3 kinase pathways may be important tools for preclinical evaluation of promising agents for the treatment of medulloblastoma
Ten-eleven translocation protein 1 modulates medulloblastoma progression
Background: Medulloblastoma (MB) is the most common malignant pediatric brain tumor that originates in the cerebellum and brainstem. Frequent somatic mutations and deregulated expression of epigenetic regulators in MB highlight the substantial role of epigenetic alterations. 5-hydroxymethylcytosine (5hmC) is a highly abundant cytosine modification in the developing cerebellum and is regulated by ten-eleven translocation (TET) enzymes.
Results: We investigate the alterations of 5hmC and TET enzymes in MB and their significance to cerebellar cancer formation. We show total abundance of 5hmC is reduced in MB, but identify significant enrichment of MB-specific 5hmC marks at regulatory regions of genes implicated in stem-like properties and Nanog-binding motifs. While TET1 and TET2 levels are high in MBs, only knockout of Tet1 in the smoothened (SmoA1) mouse model attenuates uncontrolled proliferation, leading to a favorable prognosis. The pharmacological Tet1 inhibition reduces cell viability and platelet-derived growth factor signaling pathway-associated genes.
Conclusions: These results together suggest a potential key role of 5hmC and indicate an oncogenic nature for TET1 in MB tumorigenesis, suggesting it as a potential therapeutic target for MBs
TNPO2 variants associate with human developmental delays, neurologic deficits, and dysmorphic features and alter TNPO2 activity in Drosophila
Transportin-2 (TNPO2) mediates multiple pathways including non-classical nucleocytoplasmic shuttling of >60 cargoes, such as developmental and neuronal proteins. We identified 15 individuals carrying de novo coding variants in TNPO2 who presented with global developmental delay (GDD), dysmorphic features, ophthalmologic abnormalities, and neurological features. To assess the nature of these variants, functional studies were performed in Drosophila. We found that fly dTnpo (orthologous to TNPO2) is expressed in a subset of neurons. dTnpo is critical for neuronal maintenance and function as downregulating dTnpo in mature neurons using RNAi disrupts neuronal activity and survival. Altering the activity and expression of dTnpo using mutant alleles or RNAi causes developmental defects, including eye and wing deformities and lethality. These effects are dosage dependent as more severe phenotypes are associated with stronger dTnpo loss. Interestingly, similar phenotypes are observed with dTnpo upregulation and ectopic expression of TNPO2, showing that loss and gain of Transportin activity causes developmental defects. Further, proband-associated variants can cause more or less severe developmental abnormalities compared to wild-type TNPO2 when ectopically expressed. The impact of the variants tested seems to correlate with their position within the protein. Specifically, those that fall within the RAN binding domain cause more severe toxicity and those in the acidic loop are less toxic. Variants within the cargo binding domain show tissue-dependent effects. In summary, dTnpo is an essential gene in flies during development and in neurons. Further, proband-associated de novo variants within TNPO2 disrupt the function of the encoded protein. Hence, TNPO2 variants are causative for neurodevelopmental abnormalities
Effect of blood glucose level on standardized uptake value (SUV) in F-18- FDG PET-scan : a systematic review and meta-analysis of 20,807 individual SUV measurements
Objectives To evaluate the effect of pre-scan blood glucose levels (BGL) on standardized uptake value (SUV) in F-18-FDG-PET scan. Methods A literature review was performed in the MEDLINE, Embase, and Cochrane library databases. Multivariate regression analysis was performed on individual datum to investigate the correlation of BGL with SUVmax and SUVmean adjusting for sex, age, body mass index (BMI), diabetes mellitus diagnosis, F-18-FDG injected dose, and time interval. The ANOVA test was done to evaluate differences in SUVmax or SUVmean among five different BGL groups (200 mg/dl). Results Individual data for a total of 20,807 SUVmax and SUVmean measurements from 29 studies with 8380 patients was included in the analysis. Increased BGL is significantly correlated with decreased SUVmax and SUVmean in brain (p <0.001, p <0.001,) and muscle (p <0.001, p <0.001) and increased SUVmax and SUVmean in liver (p = 0.001, p = 0004) and blood pool (p=0.008, p200 mg/dl had significantly lower SUVmax. Conclusion If BGL is lower than 200mg/dl no interventions are needed for lowering BGL, unless the liver is the organ of interest. Future studies are needed to evaluate sensitivity and specificity of FDG-PET scan in diagnosis of malignant lesions in hyperglycemia.Peer reviewe
Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed
Genetic studies on telomere length are important for understanding age-related diseases. Prior GWAS for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally-diverse individuals (European, African, Asian and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n=109,122 individuals. We identified 59 sentinel variants (p-value OBFC1indicated the independent signals colocalized with cell-type specific eQTLs for OBFC1 (STN1). Using a multi-variant gene-based approach, we identified two genes newly implicated in telomere length, DCLRE1B (SNM1B) and PARN. In PheWAS, we demonstrated our TL polygenic trait scores (PTS) were associated with increased risk of cancer-related phenotypes
Investigation of two Fermi-LAT gamma-ray blazars coincident with high-energy neutrinos detected by IceCube
After the identification of the gamma-ray blazar TXS 0506+056 as the first
compelling IceCube neutrino source candidate, we perform a systematic analysis
of all high-energy neutrino events satisfying the IceCube realtime trigger
criteria. We find one additional known gamma-ray source, the blazar GB6
J1040+0617, in spatial coincidence with a neutrino in this sample. The chance
probability of this coincidence is 30% after trial correction. For the first
time, we present a systematic study of the gamma-ray flux, spectral and optical
variability, and multi-wavelength behavior of GB6 J1040+0617 and compare it to
TXS 0506+056. We find that TXS 0506+056 shows strong flux variability in the
Fermi-LAT gamma-ray band, being in an active state around the arrival of
IceCube-170922A, but in a low state during the archival IceCube neutrino flare
in 2014/15. In both cases the spectral shape is statistically compatible () with the average spectrum showing no indication of a significant
relative increase of a high-energy component. While the association of GB6
J1040+0617 with the neutrino is consistent with background expectations, the
source appears to be a plausible neutrino source candidate based on its
energetics and multi-wavelength features, namely a bright optical flare and
modestly increased gamma-ray activity. Finding one or two neutrinos originating
from gamma-ray blazars in the given sample of high-energy neutrinos is
consistent with previously derived limits of neutrino emission from gamma-ray
blazars, indicating the sources of the majority of cosmic high-energy neutrinos
remain unknown.Comment: 22 pages, 11 figures, 2 Table
Searching for eV-scale sterile neutrinos with eight years of atmospheric neutrinos at the IceCube neutrino telescope
We report in detail on searches for eV-scale sterile neutrinos, in the
context of a 3+1 model, using eight years of data from the IceCube neutrino
telescope. By analyzing the reconstructed energies and zenith angles of 305,735
atmospheric and events we construct confidence
intervals in two analysis spaces: vs.
under the conservative assumption ; and
vs. given sufficiently large that
fast oscillation features are unresolvable. Detailed discussions of the event
selection, systematic uncertainties, and fitting procedures are presented. No
strong evidence for sterile neutrinos is found, and the best-fit likelihood is
consistent with the no sterile neutrino hypothesis with a p-value of 8\% in the
first analysis space and 19\% in the second.Comment: This long-form paper is a companion to the letter "An eV-scale
sterile neutrino search using eight years of atmospheric muon neutrino data
from the IceCube Neutrino Observatory". v2: update other experiments contours
on results plo
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