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"Fishman, David"
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Paradise planned : the garden suburb and the modern city
\"From the same team that produced the monumental five-volume architectural history of New York comes the definitive work on the development of the garden suburb, a phenomenon that first emerged in England in the 1830s and still dominates residential architecture today\"-- Provided by publisher.
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microRNA-181a has a critical role in ovarian cancer progression through the regulation of the epithelial–mesenchymal transition
Ovarian cancer is a leading cause of cancer deaths among women. Effective targets to treat advanced epithelial ovarian cancer (EOC) and biomarkers to predict treatment response are still lacking because of the complexity of pathways involved in ovarian cancer progression. Here we show that miR-181a promotes TGF-β-mediated epithelial-to-mesenchymal transition via repression of its functional target, Smad7. miR-181a and phosphorylated Smad2 are enriched in recurrent compared with matched-primary ovarian tumours and their expression is associated with shorter time to recurrence and poor outcome in patients with EOC. Furthermore, ectopic expression of miR-181a results in increased cellular survival, migration, invasion, drug resistance and
in vivo
tumour burden and dissemination. In contrast, miR-181a inhibition via decoy vector suppression and Smad7 re-expression results in significant reversion of these phenotypes. Combined, our findings highlight an unappreciated role for miR-181a, Smad7, and the TGF-β signalling pathway in high-grade serous ovarian cancer.
Ovarian cancer is often diagnosed at a late stage when metastasis has already occurred. In this study, Parikh
et al.
show that mir-181a is involved in mediating the epithelial-to-mesenchymal transition in ovarian cancer, leading to activation of the TGF-β signalling pathway and metastasis.
Journal Article
Use of proteomic patterns in serum to identify ovarian cancer
New technologies for the detection of early-stage ovarian cancer are urgently needed. Pathological changes within an organ might be reflected in proteomic patterns in serum. We developed a bioinformatics tool and used it to identify proteomic patterns in serum that distinguish neoplastic from non-neoplastic disease within the ovary.
Proteomic spectra were generated by mass spectroscopy (surface-enhanced laser desorption and ionisation). A preliminary “training” set of spectra derived from analysis of serum from 50 unaffected women and 50 patients with ovarian cancer were analysed by an iterative searching algorithm that identified a proteomic pattern that completely discriminated cancer from non-cancer. The discovered pattern was then used to classify an independent set of 116 masked serum samples: 50 from women with ovarian cancer, and 66 from unaffected women or those with non-malignant disorders.
The algorithm identified a cluster pattern that, in the training set, completely segregated cancer from non-cancer. The discriminatory pattern correctly identified all 50 ovarian cancer cases in the masked set, including all 18 stage I cases. Of the 66 cases of non-malignant disease, 63 were recognised as not cancer. This result yielded a sensitivity of 100% (95% CI 93–100), specificity of 95% (87–99), and positive predictive value of 94% (84–99).
These findings justify a prospective population-based assessment of proteomic pattern technology as a screening tool for all stages of ovarian cancer in high-risk and general populations.
Journal Article
The RAB25 small GTPase determines aggressiveness of ovarian and breast cancers
High-density array comparative genomic hybridization (CGH)
1
showed amplification of chromosome 1q22 centered on the
RAB25
small GTPase
2
, which is implicated in apical vesicle trafficking
3
, in approximately half of ovarian and breast cancers.
RAB25
mRNA levels were selectively increased in stage III and IV serous epithelial ovarian cancers compared to other genes within the amplified region, implicating
RAB25
as a driving event in the development of the amplicon. Increased DNA copy number or RNA level of
RAB25
was associated with markedly decreased disease-free survival or overall survival in ovarian and breast cancers, respectively. Forced expression of
RAB25
markedly increased anchorage-dependent and anchorage-independent cell proliferation, prevented apoptosis and anoikis, including that induced by chemotherapy, and increased aggressiveness of cancer cells
in vivo
. The inhibition of apoptosis was associated with a decrease in expression of the proapoptotic molecules, BAK and BAX, and activation of the antiapoptotic phosphatidylinositol 3 kinase (PI3K) and AKT pathway, providing potential mechanisms for the effects of
RAB25
on tumor aggressiveness. Overall, these studies implicate
RAB25
, and thus the RAB family of small G proteins, in aggressiveness of epithelial cancers.
Journal Article
Reproductive risk factors for ovarian cancer in carriers of BRCA1 or BRCA2 mutations: a case-control study
Several of the known risk factors for ovarian cancer are thought to act through their effects on ovulation and the menstrual cycle, such as parity, breastfeeding, and use of oral contraceptives. We aimed to assess the effect of these three risk factors, and of tubal ligation, on the risk of ovarian cancer in women who carry a mutation in the
BRCA1 or
BRCA2 genes.
We did a matched case-control study in women who were found to carry a pathogenetic mutation in
BRCA1 or
BRCA2. Participants were derived from a population-based study of ovarian cancer in Ontario, Canada, and from an international registry of mutation carriers based in Toronto, ON, Canada. All participants completed a written questionnaire that detailed their reproductive history. Women with invasive ovarian cancer and controls were matched on year of birth, country of residence, mutation (
BRCA1 or
BRCA2), and history of breast cancer. The odds ratios and 95% CI for ovarian cancer were estimated with respect to use of oral contraceptives, parity, breastfeeding, and tubal ligation.
Questionnaires were completed by 799 women with a history of invasive ovarian cancer (670 with
BRCA1 mutations, 128 with
BRCA2 mutations, and one with a mutation in both genes), and controls were 2424 women without ovarian cancer (2043 with
BRCA1 mutations, 380 with
BRCA2 mutations, and one with a mutation in both genes). Use of oral contraceptives reduced the risk of ovarian cancer in carriers of
BRCA1 mutations (odds ratio 0·56 [95% CI 0·45–0·71]; p<0·0001) and carriers of
BRCA2 mutations (0·39 [0·23–0·66]; p=0·0004). Parity was associated with a reduced risk for carriers of
BRCA1 mutations (0·67 [0·46–0·96]; p=0·03), but with an increased risk for those with
BRCA2 mutations (2·74 [1·18–6·41]; p=0·02). Breastfeeding was associated with a reduced risk for carriers of
BRCA1 mutations (0·74 [0·56–0·97]; p=0·03). An effect of similar magnitude was seen for carriers of
BRCA2 mutations (0·72 [0·41–1·29]; p=0·27), but this was not statistically significant. The association with tubal ligation was not significant for carriers of
BRCA1 mutations (0·80 [0·59–1·08]; p=0·15), or for carriers of
BRCA2 mutations (0·63 [0·34–1·15]; p=0·13).
Oral contraceptives could be used as a means to prevent ovarian cancer in carriers of
BRCA1 and
BRCA2 mutations. The possible adverse effect of parity on ovarian-cancer risk in women with a
BRCA2 mutation needs further study.
Journal Article
Roles of LPA in ovarian cancer development and progression
Lysophosphatidic acid (LPA), a bioactive phospholipid, stimulates survival, proliferation, adhesion, migration and invasion of ovarian cancer cells through the activation of G-protein-coupled plasma membrane receptors. LPA and its receptors are aberrantly expressed in ovarian cancer, with high levels predominantly found in malignant ascites and in the plasma of ovarian cancer patients. LPA signals multiple intracellular pathways, such as Ras/MEKK1-–MAPK and PI3K/Akt, to promote growth factors and protease expression, and induce angiogenesis and tumor cell invasion through the extracellular matrix and across the basement membrane. Only a small portion of this intricate lipid-signaling cascade has been characterized thus far. We believe that elucidation of this complex transduction network will provide further opportunities to understand the mechanism of ovarian carcinogenesis, invasion and metastasis.
Journal Article
Analysis of Albumin-Associated Peptides and Proteins from Ovarian Cancer Patients
Background: Albumin binds low–molecular-weight molecules, including proteins and peptides, which then acquire its longer half-life, thereby protecting the bound species from kidney clearance. We developed an experimental method to isolate albumin in its native state and to then identify [mass spectrometry (MS) sequencing] the corresponding bound low–molecular-weight molecules. We used this method to analyze pooled sera from a human disease study set (high-risk persons without cancer, n= 40; stage I ovarian cancer, n = 30; stage III ovarian cancer, n = 40) to demonstrate the feasibility of this approach as a discovery method. Methods: Albumin was isolated by solid-phase affinity capture under native binding and washing conditions. Captured albumin-associated proteins and peptides were separated by gel electrophoresis and subjected to iterative MS sequencing by microcapillary reversed-phase tandem MS. Selected albumin-bound protein fragments were confirmed in human sera by Western blotting and immunocompetition. Results: In total, 1208 individual protein sequences were predicted from all 3 pools. The predicted sequences were largely fragments derived from proteins with diverse biological functions. More than one third of these fragments were identified by multiple peptide sequences, and more than one half of the identified species were in vivo cleavage products of parent proteins. An estimated 700 serum peptides or proteins were predicted that had not been reported in previous serum databases. Several proteolytic fragments of larger molecules that may be cancer-related were confirmed immunologically in blood by Western blotting and peptide immunocompetition. BRCA2, a 390-kDa low-abundance nuclear protein linked to cancer susceptibility, was represented in sera as a series of specific fragments bound to albumin. Conclusion: Carrier-protein harvesting provides a rich source of candidate peptides and proteins with potential diverse tissue and cellular origins that may reflect important disease-related information.
Journal Article
Postanesthesia Care for the Elderly Patient
As the general population lives longer, the perioperative physician is more likely to encounter disease states that increase in incidence in an aging population. This review focuses on anesthetic considerations for rational drug choices during the perioperative care of elderly patients. The primary aim of the review was to identify intraoperative and postanesthetic considerations for diseases associated with advancing age; it includes highlights of the commonly impaired major organs (eg, cardiovascular, pulmonary, neurologic, renal, hepatic systems). We also outline an approach to frequent issues that arise in the immediate postsurgical period while caring for these patients.
A systematic review was performed on aspects of the perioperative and postoperative periods that relate to the elderly. A list of pertinent key words was derived from the authors, and a PubMed database search was performed.
The anesthesiologist must account for changes in various organ systems that affect perioperative care, including the cardiovascular, pulmonary, renal, hepatic, and central nervous systems. The pharmacokinetic principles frequently differ and are often unpredictable because of anatomic changes and decreased renal and hepatic function. The most important pharmacodynamic consideration is that elderly patients tend to exhibit an exaggerated hypoactivity after anesthesia.
Before surgery, it is essential to identify those patients at risk for delirium and other commonly encountered postanesthesia scenarios. Failure to manage these conditions appropriately can lead to an escalation of care and prolonged hospitalization.
Journal Article
Tubal ligation and risk of ovarian cancer in carriers of BRCA1 or BRCA2 mutations: a case-control study
In several case-control and prospective studies, tubal ligation has been associated with a decreased risk of invasive epithelial ovarian cancer. We aimed to assess the potential of tubal ligation in reducing the risk of ovarian cancer in women who carry predisposing mutations in the BRCA1 or BRCA2 genes.
We did a matched case-control study among women from Canada, the USA, and the UK who had undergone genetic testing and who carried a pathogenic mutation in BRCA1 or BRCA2. Cases were 232 women with a history of invasive ovarian cancer, and controls were 232 women without ovarian cancer, and who had both ovaries intact. Cases and controls were matched for year of birth, country of residence, and mutation (BRCA1 or BRCA2). The odds ratio for developing ovarian cancer was estimated for tubal ligation, adjusting for oral contraceptive use, parity, history of breast cancer, and ethnic group.
In an unadjusted analysis among BRCA1 carriers, significantly fewer cases than controls had ever had tubal ligation (30 of 173 [18%] vs 60 of 173 [35%], odds ratio 0·37 [95% CI 0·21–0·63]; p=0·0003). After adjustment for oral contraceptive use, parity, history of breast cancer and ethnic group, the odds ratio was 0·39 (p=0·002). Combination of tubal ligation and past use of an oral contraceptive was associated with an odds ratio of 0·28 (0·15–0·52). No protective effect of tubal ligation was seen among carriers of the BRCA2 mutation.
Tubal ligation is a feasible option to reduce the risk of ovarian cancer in women with BRCA1 mutations who have completed childbearing.
Journal Article