Mutations in the tumor suppressor BRCA1 predispose women to breast and ovarian cancers. The mechanism underlying the tissue-specific nature of BRCA1's tumor suppression is obscure. We previously ...showed that the antioxidant pathway regulated by the transcription factor NRF2 is defective in BRCA1-deficient cells. Reactivation of NRF2 through silencing of its negative regulator KEAP1 permitted the survival of BRCA1-null cells. Here we show that estrogen (E2) increases the expression of NRF2-dependent antioxidant genes in various E2-responsive cell types. Like NRF2 accumulation triggered by oxidative stress, E2-induced NRF2 accumulation depends on phosphatidylinositol 3-kinase–AKT activation. Pretreatment of mammary epithelial cells (MECs) with the phosphatidylinositol 3-kinase inhibitor BKM120 abolishes the capacity of E2 to increase NRF2 protein and transcriptional activity. In vivo the survival defect of BRCA1-deficient MECs is rescued by the rise in E2 levels associated with pregnancy. Furthermore, exogenous E2 administration stimulates the growth of BRCA1-deficient mammary tumors in the fat pads of male mice. Our work elucidates the basis of the tissue specificity of BRCA1-related tumor predisposition, and explains why oophorectomy significantly reduces breast cancer risk and recurrence in women carrying BRCA1 mutations.
Insulin signalling Bevan, P
Journal of cell science,
04/2001, Letnik:
114, Številka:
Pt 8
Journal Article
Recenzirano
ABSTRACT Insulin binding to its receptor results in receptor autophosphorylation on tyrosine residues and the tyrosine phosphorylation of insulin receptor substrates (IRS-1, IRS-2 and IRS-3) by the ...insulin receptor tyrosine kinase. This allows association of IRSs with the regulatory subunit of phosphoinositide 3-kinase (PI3K) through its SRC homology 2 (SH2) domains. Once activated, the catalytic subunit phosphorylates phosphoinositides at the 3′ position of the inositol ring or proteins at serine residues. PI3K activates PtdIns(3,4)P2 / PtdIns(3,4,5)P3-dependent kinase 1 (PDK1), which activates PKB/Akt, a serine kinase. PKB in turn deactivates glycogen synthase kinase 3 (GSK-3), leading to activation of glycogen synthase and thus glycogen synthesis. Activation of PKB also results in the translocation of GLUT-4 vesicles from their intracellular pool to the plasma membrane, where they allow uptake of glucose into the cell. PKB also leads to mTOR-mediated activation of protein synthesis by PHAS/elf4 and p70s6k.
To evaluate the efficacy and tolerability of the urokinase plasminogen activator (uPA) inhibitor upamostat in combination with gemcitabine in locally advanced pancreatic adenocarcinoma (LAPC).
Within ...a prospective multicenter study, LAPC patients were randomly assigned to receive 1000 mg m(-2) of gemcitabine IV weekly either alone (arm A) or in combination with 200 mg (arm B) or 400 mg (arm C) oral upamostat daily. Efficacy endpoints of this proof-of-concept study included response rate, time to first metastasis, progression-free and overall survival (OS).
Of the 95 enroled patients, 85 were evaluable for response and 93 for safety. Median OS was 12.5 months (95% CI 8.2-18.2) in arm C, 9.7 months (95% CI 8.4-17.1) in arm B and 9.9 months (95% CI 7.4-12.1) in arm A; corresponding 1-year survival rates were 50.6%, 40.7% and 33.9%, respectively. More patients achieved a partial remission (confirmed responses by RECIST) with upamostat combination therapy (arm C: 12.9%; arm B: 7.1%; arm A: 3.8%). Overall, only 12 patients progressed by developing detectable distant metastasis (arm A: 4, arm B: 6, arm C: 2). The most common adverse events considered to be related to upamostat were asthenia, fever and nausea.
In this proof-of-concept study targeting the uPA system in LAPC, the addition of upamostat to gemcitabine was tolerated well; similar survival results were observed for the three treatment arms.
ABSTRACT
DECIPHER (https://decipher.sanger.ac.uk) is a web‐based platform for secure deposition, analysis, and sharing of plausibly pathogenic genomic variants from well‐phenotyped patients suffering ...from genetic disorders. DECIPHER aids clinical interpretation of these rare sequence and copy‐number variants by providing tools for variant analysis and identification of other patients exhibiting similar genotype–phenotype characteristics. DECIPHER also provides mechanisms to encourage collaboration among a global community of clinical centers and researchers, as well as exchange of information between clinicians and researchers within a consortium, to accelerate discovery and diagnosis. DECIPHER has contributed to matchmaking efforts by enabling the global clinical genetics community to identify many previously undiagnosed syndromes and new disease genes, and has facilitated the publication of over 700 peer‐reviewed scientific publications since 2004. At the time of writing, DECIPHER contains anonymized data from ∼250 registered centers on more than 51,500 patients (∼18000 patients with consent for data sharing and ∼25000 anonymized records shared privately). In this paper, we describe salient features of the platform, with special emphasis on the tools and processes that aid interpretation, sharing, and effective matchmaking with other data held in the database and that make DECIPHER an invaluable clinical and research resource.
DECIPHER helps the clinical community share and compare human genome variants and phenotypes in a database of thousands of anonymous consented patients worldwide. Matchmaking using DECIPHER has resulted in the discovery of many new syndromes and led to over 700 peer‐reviewed publications.
Deregulated metabolism is gaining recognition as a hallmark of cancer cells, and is being explored for therapeutic potential. The Warburg effect is a metabolic phenotype that occurs in 90% of tumors, ...where glycolysis is favored despite the presence of oxygen. Dichloroacetate (DCA) is a pyruvate dehydrogenase kinase (PDK) inhibitor that can reverse the Warburg effect. PENAO (4-(N-(S-penicillaminylacetyl)amino) phenylarsonous acid) is a novel anti-mitochondrial agent that targets the adenine nucleotide transporter in mitochondria and is currently in clinical trials for solid tumors. We have investigated the targeting of two aspects of metabolism, using DCA to promote mitochondrial activity combined with PENAO to inhibit mitochondrial activity, in breast and other carcinoma cell lines. PENAO was effective at low uM concentrations in luminal (T-47D) and triple negative (MDA-MB-231) breast cancer cells, in normoxia and hypoxia. The cytotoxicity of PENAO was enhanced by DCA by a mechanism involving increased reactive oxygen species in both T-47D and MDA-MB-231 cells, however further investigations found it did not always involve PDK2 inhibition or reduction of the mitochondrial membrane potential, which are the accepted mechanisms for DCA induction of apoptosis. Nevertheless, DCA sensitized all cancer cell lines tested toward apoptosis of PENAO. DCA and PENAO are both currently in clinical trials and targeting cancer metabolism with these drugs may offer options for difficult to treat cancers.
Patients with developmental disorders often harbour sub-microscopic deletions or duplications that lead to a disruption of normal gene expression or perturbation in the copy number of ...dosage-sensitive genes. Clinical interpretation for such patients in isolation is hindered by the rarity and novelty of such disorders. The DECIPHER project (https://decipher.sanger.ac.uk) was established in 2004 as an accessible online repository of genomic and associated phenotypic data with the primary goal of aiding the clinical interpretation of rare copy-number variants (CNVs). DECIPHER integrates information from a variety of bioinformatics resources and uses visualization tools to identify potential disease genes within a CNV. A two-tier access system permits clinicians and clinical scientists to maintain confidential linked anonymous records of phenotypes and CNVs for their patients that, with informed consent, can subsequently be shared with the wider clinical genetics and research communities. Advances in next-generation sequencing technologies are making it practical and affordable to sequence the whole exome/genome of patients who display features suggestive of a genetic disorder. This approach enables the identification of smaller intragenic mutations including single-nucleotide variants that are not accessible even with high-resolution genomic array analysis. This article briefly summarizes the current status and achievements of the DECIPHER project and looks ahead to the opportunities and challenges of jointly analysing structural and sequence variation in the human genome.
DECIPHER (https://www.deciphergenomics.org) is a free web platform for sharing anonymized phenotype‐linked variant data from rare disease patients. Its dynamic interpretation interfaces contextualize ...genomic and phenotypic data to enable more informed variant interpretation, incorporating international standards for variant classification. DECIPHER supports almost all types of germline and mosaic variation in the nuclear and mitochondrial genome: sequence variants, short tandem repeats, copy‐number variants, and large structural variants. Patient phenotypes are deposited using Human Phenotype Ontology (HPO) terms, supplemented by quantitative data, which is aggregated to derive gene‐specific phenotypic summaries. It hosts data from >250 projects from ~40 countries, openly sharing >40,000 patient records containing >51,000 variants and >172,000 phenotype terms. The rich phenotype‐linked variant data in DECIPHER drives rare disease research and diagnosis by enabling patient matching within DECIPHER and with other resources, and has been cited in >2,600 publications. In this study, we describe the types of data deposited to DECIPHER, the variant interpretation tools, and patient matching interfaces which make DECIPHER an invaluable rare disease resource.
The DECIPHER web platform supports the sharing and interpretation of rare disease phenotype‐linked variant data to advance diagnosis and research.
BACKGROUND:Surgical resection of persistently painful talocalcaneal tarsal coalitions may not reliably relieve symptoms in patients with large coalitions associated with excessive hindfoot valgus ...deformity and subtalar posterior facet narrowing. Since 1991, calcaneal lengthening osteotomy, with or without coalition resection, has been used at our institution to relieve symptoms and to preserve motion at the talonavicular and calcaneocuboid joints.
METHODS:We retrospectively reviewed the records for eight patients with thirteen painful talocalcaneal tarsal coalitions who had undergone a calcaneal lengthening osteotomy for deformity correction with or without coalition resection between 1991 and 2005. Preoperative and postoperative clinical, radiographic, and computed tomographic records were reviewed. The duration of clinical follow-up ranged from two to fifteen years.
RESULTS:Calcaneal lengthening osteotomy fully corrected the valgus deformity and provided short-to-intermediate term pain relief for the five patients (nine feet) in whom the talocalcaneal tarsal coalition was unresectable. The patient with resectable coalitions but excessive valgus deformities underwent calcaneal lengthening osteotomies along with coalition resections and had excellent deformity correction and pain relief in both feet. One of the two patients who underwent calcaneal lengthening osteotomy years after coalition resection had excellent correction and pain relief. The other patient had a coincident calcaneonavicular coalition and severe degenerative arthritis in the talonavicular joint. He underwent concurrent arthrodesis of the talonavicular joint and, although he had excellent deformity correction, had persistent pain. All feet underwent concurrent gastrocnemius or Achilles tendon lengthening.
CONCLUSIONS:It is generally accepted that resection is the treatment of choice for an intractably painful small talocalcaneal tarsal coalition that is associated with a wide, healthy posterior facet and minimal valgus deformity of the hindfoot. Although triple arthrodesis has been recommended for those who do not meet all three criteria, the present study suggests that an algorithmic treatment approach is justified. Treatment of the valgus deformity appears to be as important as that of the coalition. Calcaneal lengthening osteotomy with gastrocnemius or Achilles tendon lengthening is effective for correcting deformity and relieving pain in rigid flatfeet, just as it is in flexible flatfeet.
LEVEL OF EVIDENCE:Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.
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