200 research outputs found
Extended abdominoperineal resection in women: the barbadian experience
BACKGROUND AND OBJECTIVES: We report our results of a selective approach to primary direct appositional vaginal repair versus transverse rectus abdominis flap repair (TRAM) in patients with extensive rectal/anal cancer or in cases with primary cancer of cervix, vagina or vulva involving the anal canal and anal sphincters. METHODS: Eighteen female patients (mean age: 62.9 years; range: 44–81 years) with a median follow-up of 14 months (range: 2–36 months) undergoing extended abdominoperineal reconstruction with total mesorectal excision between May 2002 and September 2005, were studied. RESULTS: Twelve patients underwent an extended abdominoperineal resection with hysterectomy and vaginectomy, with 6 patients undergoing primary TRAM flap reconstruction following pelvic exenteration. Exenterative procedures were performed in 2 cases of primary vaginal cancer, following Wertheim hysterectomy for carcinoma of the cervix with recurrence after radiation and in 2 further cases of anal cancer with extensive pelvic recurrence after primary chemoradiation. Fifteen cases are alive on follow-up with no evidence of disease; 2 patients who had recurrent carcinoma of the cervix and who underwent TRAM flap reconstruction, have recurrent disease after 5 and 6 months of follow-up, respectively. DISCUSSION: Our experience shows that careful primary closure of an extended abdominoperineal resection wound is effective and safe. Our one case of wound breakdown after primary repair underwent external beam and intracavitary irradiation primarily with wound breakdown of a primary repair followed by a delayed pedicled graciloplasty. TRAM flap reconstruction has been reserved in our unit for patients undergoing total pelvic extenteration. In general, we would recommend the use of TRAM flap reconstruction in younger sexually active patients where there has been external irradiation combined with brachytherapy
Telomerase activity, apoptosis and cell cycle progression in ataxia telangiectasia lymphocytes expressing TCL1
Individuals affected by ataxia telangiectasia (AT) have a marked susceptibility to cancer. Ataxia telangiectasia cells, in addition to defects in cell cycle checkpoints, show dysfunction of apoptosis and of telomeres, which are both thought to have a role in the progression of malignancy. In 1-5% of patients with AT, clonal expansion of T lymphocytes carrying t(14;14) chromosomal translocation, deregulating TCL1 gene(s), has been described. While it is known that these cells can progress with time to a frank leukaemia, the molecular pathway leading to tumorigenesis has not yet been fully investigated. In this study, we compared AT clonal cells, representing 88% of the entire T lymphocytes (AT94-1) and expressing TCL1 oncogene (ATM- TCL1 +), cell cycle progression to T lymphocytes of AT patients without TCL1 expression (ATM- TCL1-) by analysing their spontaneous apoptosis rate, spontaneous telomerase activity and telomere instability. We show that in ATM- TCL1+ lymphocytes, apoptosis rate and cell cycle progression are restored back to a rate comparable with that observed in normal lymphocytes while telomere dysfunction is maintained. © 2003 Cancer Research UK
Dynamism in the solar core
Recent results of a mixed shell model heated asymmetrically by transient
increases in nuclear burning indicate the transient generation of small hot
spots inside the Sun somewhere between 0.1 and 0.2 solar radii. These hot
bubbles are followed by a nonlinear differential equation system with finite
amplitude non-homologous perturbations which is solved in a solar model. Our
results show the possibility of a direct connection between the dynamic
phenomena of the solar core and the atmospheric activity. Namely, an initial
heating about DQ_0 ~ 10^{31}-10^{37} ergs can be enough for a bubble to reach
the outer convective zone. Our calculations show that a hot bubble can arrive
into subphotospheric regions with DQ_final ~ 10^{28} - 10^{34} ergs with a high
speed, up to 10 km s-1, approaching the local sound speed. We point out that
the developing sonic boom transforms the shock front into accelerated particle
beam injected upwards into the top of loop carried out by the hot bubble above
its forefront traveling from the solar interior. As a result, a new perspective
arises to explain flare energetics. We show that the particle beams generated
by energetic deep-origin hot bubbles in the subphotospheric layers have masses,
energies, and chemical compositions in the observed range of solar
chromospheric and coronal flares. It is shown how the emergence of a hot bubble
into subphotospheric regions offers a natural mechanism that can generate both
the eruption leading to the flare and the observed coronal magnetic topology
for reconnection. We show a list of long-standing problems of solar physics
that our model explains. We present some predictions for observations, some of
which are planned to be realized in the near future.Comment: 44 pages, 20 figure
Nanostring-based multigene assay to predict recurrence for gastric cancer patients after surgery
10.1371/journal.pone.0090133PLoS ONE93-POLN
Effect of oral contraceptive with and without associated estriol on ultrasound measurements of breast fibroadenoma: randomized clinical trial
Loss of p53 in quaking viable mice leads to Purkinje cell defects and reduced survival
The qkv mutation is a one megabase deletion resulting in
abnormal expression of the qkI gene. qkv mice exhibit
hypomyelination of the central nervous system and display rapid tremors and seizures
as adults. The qkI locus on 6q26-27 has also been implicated as a candidate
tumor suppressor gene as the qkI locus maps to a region of genetic
instability in Glioblastoma Multiforme (GBM), an aggressive brain tumor of
astrocytic lineage. As GBM frequently harbors mutations affecting p53, we
crossbred qkv and p53 mutant mice to examine whether
qkv mice on a p53−/−
background have an increased incidence of GBM.
qkv/v;
p53−/− mice had a reduced survival rate
compared to p53−/− littermates, and the cause of
death of the majority of the mice remains unknown. In addition, immunohistochemistry
revealed Purkinje cell degeneration in the cerebellum. These results suggest that
p53 and qkI are genetically linked for neuronal maintenance and
survival
Targeting HER2/neu with a fully human IgE to harness the allergic reaction against cancer cells
Breast and ovarian cancer are two of the leading causes of cancer deaths among women in the United States. Overexpression of the HER2/neu oncoprotein has been reported in patients affected with breast and ovarian cancers, and is associated with poor prognosis. To develop a novel targeted therapy for HER2/neu expressing tumors, we have constructed a fully human IgE with the variable regions of the scFv C6MH3-B1 specific for HER2/neu. This antibody was expressed in murine myeloma cells and was properly assembled and secreted. The Fc region of this antibody triggers in vitro degranulation of rat basophilic cells expressing human FcεRI (RBL SX-38) in the presence of murine mammary carcinoma cells that express human HER2/neu (D2F2/E2), but not the shed (soluble) antigen (ECDHER2) alone. This IgE is also capable of inducing passive cutaneous anaphylaxis in a human FcεRIα transgenic mouse model, in the presence of a cross-linking antibody, but not in the presence of soluble ECDHER2. Additionally, IgE enhances antigen presentation in human dendritic cells and facilitates cross-priming, suggesting that the antibody is able to stimulate a secondary T-cell anti-tumor response. Furthermore, we show that this IgE significantly prolongs survival of human FcεRIα transgenic mice bearing D2F2/E2 tumors. We also report that the anti-HER2/neu IgE is well tolerated in a preliminary study conducted in Macaca fascicularis (cynomolgus) monkeys. In summary, our results suggest that this IgE should be further explored as a potential therapeutic against HER2/neu overexpressing tumors, such as breast and ovarian cancers.Fil: Daniels, Tracy R.. University of California at Los Angeles; Estados UnidosFil: Leuchter, Richard K.. University of California at Los Angeles; Estados UnidosFil: Quintero, Rafaela. University of California; Estados UnidosFil: Helguera, Gustavo Fernando. University of California at Los Angeles; Estados Unidos. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Rodríguez, José A.. University of California at Los Angeles; Estados UnidosFil: Martínez Maza, Otoniel. University of California at Los Angeles; Estados UnidosFil: Schultes, Birgit C.. Advanced Immune Therapeutics, Inc.; Estados Unidos. Momenta Pharmaceuticals, Inc.; Estados UnidosFil: Nicodemus, Christopher F.. Advanced Immune Therapeutics, Inc.; Estados UnidosFil: Penichet, Manuel L.. University of California at Los Angeles; Estados Unido
A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing
PURPOSE: Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. METHODS: Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. RESULTS: We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). CONCLUSION: The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock
TRPC5 ion channel permeation promotes weight gain in hypercholesterolaemic mice
Transient Receptor Potential Canonical 5 (TRPC5) is a subunit of a Ca2+-permeable non-selective cationic channel which negatively regulates adiponectin but not leptin in mice fed chow diet. Adiponectin is a major anti-inflammatory mediator and so we hypothesized an effect of TRPC5 on the inflammatory condition of atherosclerosis. Atherosclerosis was studied in aorta of ApoE−/− mice fed western-style diet. Inhibition of TRPC5 ion permeation was achieved by conditional transgenic expression of a dominant negative ion pore mutant of TRPC5 (DNT5). Gene expression analysis in adipose tissue suggested that DNT5 increases transcript expression for adiponectin while decreasing transcript expression of the inflammatory mediator Tnfα and potentially decreasing Il6, Il1β and Ccl2. Despite these differences there was mild or no reduction in plaque coverage in the aorta. Unexpectedly DNT5 caused highly significant reduction in body weight gain and reduced adipocyte size after 6 and 12 weeks of western-style diet. Steatosis and circulating lipids were unaffected but mild effects on regulators of lipogenesis could not be excluded, as indicated by small reductions in the expression of Srebp1c, Acaca, Scd1. The data suggest that TRPC5 ion channel permeation has little or no effect on atherosclerosis or steatosis but an unexpected major effect on weight gain
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