701 research outputs found
Prevention of an additional surgery for regional lymphadenectomy in melanoma: rapid intraoperative immunostaining of sentinel lymph node imprint smears
BACKGROUND: Sentinel lymph node (SLN) biopsy is performed at many institutions and is considered a standard of care in the management of cutaneous melanoma. The discriminatory immunostaining pattern with the 'MCW Melanoma Cocktail' (a mixture of MART-1 {1:500}, Melan- A {1:100}, and Tyrosinase {1:50} monoclonal antibodies) allows intraoperative immunocytochemical evaluation of imprint smears of SLNs for melanoma metastases. Cohesive cells of benign capsular melanocytic nevi that were also immunoreactive with the cocktail do not exfoliate easily for imprint smear detection. METHODS: We prospectively evaluated 73 lymph nodes (70 SLN & 3 non-SLN) from 41 cases (mean 1.8, 1 to 4 SLNs/case) of cutaneous melanoma using a rapid 17-minute immunostaining previously published protocol. The results were compared with permanent sections also immunostained with 'the cocktail'. RESULTS: 19.5%, 8/41 cases (12%, 9/73 lymph nodes) were positive for melanoma metastases on permanent sections immunostained with the 'MCW melanoma cocktail'. Melanoma metastases in 87.5% (7/8) of these cases were also detected in rapidly immunostained imprint smears, with 100% specificity and 90% sensitivity. None of the 7 SLNs from 7 cases with capsular nevi showed false positive results. CONCLUSION: Melanoma metastases could be detected in imprint smears immunostained with 'MCW Melanoma Cocktail' utilizing a rapid intraoperative protocol. The cohesive cells of the capsular nevi do not readily exfoliate and do not lead to false positive interpretation. In a majority of positive cases, a regional lymphadenectomy could have been completed during the same surgery for SLN biopsy and wide excision of primary melanoma site, potentially eliminating the need for an additional surgery
Monitoring SO2 emission at the Soufriere Hills Volcano: implications for changes in erruptive conditions
FLWINinfo:eu-repo/semantics/publishe
Increased entropy of signal transduction in the cancer metastasis phenotype
Studies into the statistical properties of biological networks have led to
important biological insights, such as the presence of hubs and hierarchical
modularity. There is also a growing interest in studying the statistical
properties of networks in the context of cancer genomics. However, relatively
little is known as to what network features differ between the cancer and
normal cell physiologies, or between different cancer cell phenotypes. Based on
the observation that frequent genomic alterations underlie a more aggressive
cancer phenotype, we asked if such an effect could be detectable as an increase
in the randomness of local gene expression patterns. Using a breast cancer gene
expression data set and a model network of protein interactions we derive
constrained weighted networks defined by a stochastic information flux matrix
reflecting expression correlations between interacting proteins. Based on this
stochastic matrix we propose and compute an entropy measure that quantifies the
degree of randomness in the local pattern of information flux around single
genes. By comparing the local entropies in the non-metastatic versus metastatic
breast cancer networks, we here show that breast cancers that metastasize are
characterised by a small yet significant increase in the degree of randomness
of local expression patterns. We validate this result in three additional
breast cancer expression data sets and demonstrate that local entropy better
characterises the metastatic phenotype than other non-entropy based measures.
We show that increases in entropy can be used to identify genes and signalling
pathways implicated in breast cancer metastasis. Further exploration of such
integrated cancer expression and protein interaction networks will therefore be
a fruitful endeavour.Comment: 5 figures, 2 Supplementary Figures and Table
Community-based therapy for multidrug-resistant tuberculosis in Lima, Peru.
BACKGROUND: Despite the prevalence of multidrug-resistant tuberculosis in nearly all low-income countries surveyed, effective therapy has been deemed too expensive and considered not to be feasible outside referral centers. We evaluated the results of community-based therapy for multidrug-resistant tuberculosis in a poor section of Lima, Peru. METHODS: We describe the first 75 patients to receive ambulatory treatment with individualized regimens for chronic multidrug-resistant tuberculosis in northern Lima. We conducted a retrospective review of the charts of all patients enrolled in the program between August 1, 1996, and February 1, 1999, and identified predictors of poor outcomes. RESULTS: The infecting strains of Mycobacterium tuberculosis were resistant to a median of six drugs. Among the 66 patients who completed four or more months of therapy, 83 percent (55) were probably cured at the completion of treatment. Five of these 66 patients (8 percent) died while receiving therapy. Only one patient continued to have positive cultures after six months of treatment. All patients in whom treatment failed or who died had extensive bilateral pulmonary disease. In a multiple Cox proportional-hazards regression model, the predictors of the time to treatment failure or death were a low hematocrit (hazard ratio, 4.09; 95 percent confidence interval, 1.35 to 12.36) and a low body-mass index (hazard ratio, 3.23; 95 percent confidence interval, 0.90 to 11.53). Inclusion of pyrazinamide and ethambutol in the regimen (when susceptibility was confirmed) was associated with a favorable outcome (hazard ratio for treatment failure or death, 0.30; 95 percent confidence interval, 0.11 to 0.83). CONCLUSIONS: Community-based outpatient treatment of multidrug-resistant tuberculosis can yield high cure rates even in resource-poor settings. Early initiation of appropriate therapy can preserve susceptibility to first-line drugs and improve treatment outcomes
DHODH modulates transcriptional elongation in the neural crest and melanoma
Melanoma is a tumour of transformed melanocytes, which are originally derived from the embryonic neural crest. It is unknown to what extent the programs that regulate neural crest development interact with mutations in the BRAF oncogene, which is the most commonly mutated gene in human melanoma1. We have used zebrafish embryos to identify the initiating transcriptional events that occur on activation of human BRAF(V600E) (which encodes an amino acid substitution mutant of BRAF) in the neural crest lineage. Zebrafish embryos that are transgenic for mitfa:BRAF(V600E) and lack p53 (also known as tp53) have a gene signature that is enriched for markers of multipotent neural crest cells, and neural crest progenitors from these embryos fail to terminally differentiate. To determine whether these early transcriptional events are important for melanoma pathogenesis, we performed a chemical genetic screen to identify small-molecule suppressors of the neural crest lineage, which were then tested for their effects on melanoma. One class of compound, inhibitors of dihydroorotate dehydrogenase (DHODH), for example leflunomide, led to an almost complete abrogation of neural crest development in zebrafish and to a reduction in the self-renewal of mammalian neural crest stem cells. Leflunomide exerts these effects by inhibiting the transcriptional elongation of genes that are required for neural crest development and melanoma growth. When used alone or in combination with a specific inhibitor of the BRAF(V600E) oncogene, DHODH inhibition led to a marked decrease in melanoma growth both in vitro and in mouse xenograft studies. Taken together, these studies highlight developmental pathways in neural crest cells that have a direct bearing on melanoma formation
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Mutations in epigenetic regulators including SETD2 are gained during relapse in pediatric acute lymphoblastic leukemia
Relapsed pediatric acute lymphoblastic leukemia (ALL) has high rates of treatment failure. Epigenetic regulators have been proposed as modulators of chemoresistance, here we sequence genes encoding epigenetic regulators in matched diagnosis-remission-relapse ALL samples. We find significant enrichment of mutations in epigenetic regulators at relapse with recurrent somatic mutations in SETD2, CREBBP, MSH6, KDM6A and MLL2, mutations in signaling factors are not enriched. Somatic alterations in SETD2, including frameshift and nonsense mutations, are present at 12% in a large de novo ALL patient cohort. We conclude that the enrichment of mutations in epigenetic regulators at relapse is consistent with a role in mediating therapy resistance
Pre-neoplastic alterations define CLL DNA methylome and persist through disease progression and therapy
Most human cancers converge to a deregulated methylome with reduced global levels and elevated methylation at select CpG islands. To investigate the emergence and dynamics of the cancer methylome, we characterized genome-wide DNA methylation in preneoplastic monoclonal B-cell lymphocytosis (MBL) and chronic lymphocytic leukemia (CLL), including serial samples collected across disease course. We detected the aberrant tumor-associated methylation landscape at CLL diagnosis and found no significant differentially methylated regions in the high-count MBL-to-CLL transition. Patient methylomes showed remarkable stability with natural disease and posttherapy progression. Single CLL cells were consistently aberrantly methylated, indicating a homogeneous transition to the altered epigenetic state and a distinct expression profile together with MBL cells compared with normal B cells. Our longitudinal analysis reveals the cancer methylome to emerge early, which may provide a platform for subsequent genetically driven growth dynamics, and, together with its persistent presence, suggests a central role in disease onset. SigNifiCANCe: DNA methylation data from a large cohort of patients with MBL and CLL show that epigenetic transformation emerges early and persists throughout disease stages with limited subsequent changes. Our results indicate an early role for this aberrant landscape in the normal-to-preneoplastic transition that may reflect a pan-cancer mechanism
A dominant-negative effect drives selection of TP53 missense mutations in myeloid malignancies
TP53, which encodes the tumor suppressor p53, is the most frequently mutated gene in human cancer. The selective pressures shaping its mutational spectrum, dominated by missense mutations, are enigmatic, and neomorphic gain-of-function (GOF) activities have been implicated. We used CRISPR-Cas9 to generate isogenic human leukemia cell lines of the most common TP53 missense mutations. Functional, DNA-binding, and transcriptional analyses revealed loss of function but no GOF effects. Comprehensive mutational scanning of p53 single-amino acid variants demonstrated that missense variants in the DNA-binding domain exert a dominant-negative effect (DNE). In mice, the DNE of p53 missense variants confers a selective advantage to hematopoietic cells on DNA damage. Analysis of clinical outcomes in patients with acute myeloid leukemia showed no evidence of GOF for TP53 missense mutations. Thus, a DNE is the primary unit of selection for TP53 missense mutations in myeloid malignancies
The Vehicle, Spring 2013
Vol. 54, Issue 1
Table of Contents
About Face!: A Confederacy of ClichesKaren Neuberg page 8
HopeJames Coxpage 9
IN or OUTTaryn DeVriespage 12
The Imagination of a ChildMaxwell Collinspage 16
How Free to be a TreeLeann Kirchnerpage 18
CrowsValentina Canopage 19
Old West PhotosFred Pollackpage 20
Lava LampFred Pollackpage 21
Mort MotGerry Mark Nortonpage 23
If ILaura Adrianpage 24
Finding my MonkeyDavid Lewitzkypage 25
Slow DragDavid Lewitzkypage 26
Political ScienceElizabeth Marlowpage 27
...Were Punctuated By...Elizabeth Marlowpage 28
St. E Pt 1Elizabeth Marlowpage 29
The Steamboat CaptainElizabeth Marlowpage 30
Pretty EyesRyan Sheapage 31
The World is RoundRyan Sheapage 32
End SongsJason Graffpage 33
The Sensitive Youth Grows UpRichard King Perkins IIpage 41
Colors and LightKyle Owenspage 42
RE-TARDKarlyn Thayerpage 44
Where Is Waldo?Riley Parishpage 57
Beneath Shifting SoundsHolly Daypage 58
Talking Shop with Mike Kardospage 60
Winnie Davis Neely Award winner:
Paper CutsGregory Robert Petersonpage 68
Paper-Mache PoetryGregory Robert Petersonpage 69
James K. Johnson Award winners:
ValveChristopher Robinsonpage 72
Dear MotherEliot Thompsonpage 76
Why Are There Bars on the WindowsEliot Thompsonpage 77
To Be a ScholarEliot Thompsonpage 79
OccidentalEliot Thompsonpage 80
Falling is for the ClumsyEliot Thompsonpage 81
Scary MonstersC. David Banyaipage 83
I Called My Grandmother DollyRashelle Spearpage 90
Tender FleshH R Greenpage 92
Faking ItShelby Koehnepage 95
Contributor\u27s notespage 101https://thekeep.eiu.edu/vehicle/1095/thumbnail.jp
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