Cystathionine beta-synthase (CBS) is a key enzyme of the trans-sulfuration pathway that converts homocysteine to cystathionine. Loss of CBS activity due to mutation results in CBS deficiency, an inborn error of metabolism characterized by extreme elevation of plasma total homocysteine (tHcy). C57BL6 mice containing either a homozygous null mutation in the cystathionine β-synthase (Cbs ) gene or an inactive human CBS protein (Tg-G307S Cbs ) are born in mendelian numbers, but the vast majority die between 18 and 21 days of age due to liver failure.
View Article and Find Full Text PDFMeasurement of a tumor's overall genomic instability has gathered recent interest over the identification of specific genomic imbalances, as it may provide a more robust measure of tumor aggressiveness. Here we demonstrate the association of tumor genomic instability in the prediction of disease recurrence in patients with clinically localized clear cell renal cell carcinoma (ccRCC). Genomic copy number analysis was performed using SNP-based microarrays on tumors from 103 ccRCC patients.
View Article and Find Full Text PDFReceptor-interacting protein kinase 1 (RIPK1) regulates cell fate and proinflammatory signaling downstream of multiple innate immune pathways, including those initiated by TNF-α, TLR ligands, and IFNs. Genetic ablation of results in perinatal lethality arising from both RIPK3-mediated necroptosis and FADD/caspase-8-driven apoptosis. IFNs are thought to contribute to the lethality of -deficient mice by activating inopportune cell death during parturition, but how IFNs activate cell death in the absence of RIPK1 is not understood.
View Article and Find Full Text PDFPleural malignant mesothelioma is a therapy-resistant cancer affecting the serosal lining of the thoracic cavity. Mutations/deletions of , and are the most frequent genetic lesions in human malignant mesothelioma. We introduced various combinations of these deletions in the pleura of conditional knockout (CKO) mice, focusing on the contribution of loss.
View Article and Find Full Text PDFPrevious data from this group demonstrate that the murine lung metabolizes estrogen. Production of the putative carcinogen 4-hydroxyestrogen (4-OHE) is elevated within the lungs of female vs. male mice and accelerated by tobacco smoke.
View Article and Find Full Text PDFSquamous cell carcinomas of the head and neck (SCCHN) affect anatomical sites including the oral cavity, nasal cavity, pharynx, and larynx. Laryngeal cancers are characterized by high recurrence and poor overall survival, and currently lack robust molecular prognostic biomarkers for treatment stratification. Using an algorithm for integrative clustering that simultaneously assesses gene expression, somatic mutation, copy number variation, and methylation, we for the first time identify laryngeal cancer subtypes with distinct prognostic outcomes, and differing from the non-prognostic laryngeal subclasses reported by The Cancer Genome Atlas (TCGA).
View Article and Find Full Text PDFMHC-I molecules expose the intracellular protein content on the cell surface, allowing T cells to detect foreign or mutated peptides. The combination of six MHC-I alleles each individual carries defines the sub-peptidome that can be effectively presented. We applied this concept to human cancer, hypothesizing that oncogenic mutations could arise in gaps in personal MHC-I presentation.
View Article and Find Full Text PDFCDK4/6 targeting is a promising therapeutic strategy under development for various tumor types. In this study, we used computational methods and The Cancer Genome Atlas dataset analysis to identify novel miRNAs that target CDK4/6 and exhibit potential for therapeutic development in colorectal cancer. The 3'UTR of CDK4/6 mRNAs are targeted by a family of miRNAs, which includes miR-6883-5p, miR-149*, miR-6785-5p, and miR-4728-5p.
View Article and Find Full Text PDFUnlabelled: Resistance to hormonal therapies is a major clinical problem in the treatment of estrogen receptor α-positive (ERα) breast cancers. Epigenetic marks, namely DNA methylation of cytosine at specific CpG sites (5mCpG), are frequently associated with ERα status in human breast cancers. Therefore, ERα may regulate gene expression in part via DNA methylation.
View Article and Find Full Text PDFJ Inherit Metab Dis
January 2017
Cystathionine β-synthase (CBS) deficiency is a recessive inborn error of metabolism in which patients have extremely elevated plasma total homocysteine and have clinical manifestations in the vascular, visual, skeletal, and nervous systems. Homocysteine is an intermediary metabolite produced from the hydrolysis of S-adenosylhomocysteine (SAH), which is a by-product of methylation reactions involving the methyl-donor S-adenosylmethionine (SAM). Here, we have measured SAM, SAH, DNA and histone methylation status in an inducible mouse model of CBS deficiency to test the hypothesis that homocysteine-related phenotypes are caused by inhibition of methylation due to elevated SAH and reduced SAM/SAH ratio.
View Article and Find Full Text PDFThe kinase RIPK3 is a key regulator of cell death responses to a growing number of viral and microbial agents. We have found that influenza A virus (IAV)-mediated cell death is largely reliant on RIPK3 and that RIPK3-deficient mice are notably more susceptible to lethal infection by IAV than their wild-type counterparts. Recent studies demonstrate that RIPK3 also participates in regulating gene transcription programs during host pro-inflammatory and innate-immune responses, indicating that this kinase is not solely an inducer of cell death and that RIPK3-driven transcriptional responses may collaborate with cell death in promoting clearance of IAV.
View Article and Find Full Text PDFThe epigenetic alteration of aberrant hypermethylation in the promoter CpG island of a gene is associated with repression of transcription. In neoplastic cells, aberrant hypermethylation is well described as a mechanism of allele inactivation of particular genes with a tumor suppressor function. To investigate the role of aberrant hypermethylation in the biology and progression of urothelial cancer, we examined 101 urothelial (transitional cell) carcinomas (UC), broadly representative of the disease at presentation, with no prior immunotherapy, chemotherapy or radiotherapy, by Infinium HM27 containing 14,495 genes.
View Article and Find Full Text PDFClear cell RCC is the most common, and more likely to metastasize, of the three main histological types of RCC. Pathologic stage is the most important prognostic indicator and nuclear grade can predict outcome within stages of localized RCC. Epithelial tumors are thought to accumulate a series of genetic and epigenetic changes as they progress through well-defined clinical and histopathological changes.
View Article and Find Full Text PDFThe majority of renal cell carcinoma (RCC) is now incidentally detected and presents as small renal masses (SRMs) defined as ≤ 4 cm in size. SRMs are heterogeneous comprising several histological types of RCC each with different biology and behavior, and benign tumors mainly oncocytoma. The varied prognosis of the different types of renal tumor has implications for management options.
View Article and Find Full Text PDFObjective: The gene encoding the methionine salvage pathway methylthioadenosine phosphorylase (MTAP) is a tumor suppressor gene that is frequently inactivated in a wide variety of human cancers. In this study, we have examined if heterozygosity for a null mutation in Mtap (Mtap(lacZ)) could accelerate tumorigenesis development in two different mouse cancer models, Eμ-myc transgenic and Pten(+/-) .
Methods: Mtap Eμ-myc and Mtap Pten mice were generated and tumor-free survival was monitored over time.
Cystathionine beta-synthase (CBS) deficiency is an inborn error of metabolism characterized by extremely elevated levels of plasma total homocysteine. The vast majority of CBS-deficient patients have missense mutations located in the CBS gene that result in the production of either misfolded or unstable protein. Here, we examine the effect of proteasome inhibitors on mutant CBS function using two different mouse models of CBS deficiency.
View Article and Find Full Text PDFAlthough estrogen and the enzymes responsible for its metabolism have been detected within the lung, the ability of this tissue to metabolize estrogen has not been demonstrated previously. The goal of this study was to characterize the profile of estrogen metabolites within the murine lung and to determine the effect of tobacco smoke exposure on metabolite levels. Use of liquid chromatography-tandem mass spectrometry led to the detection of three estrogens (E1, E2 and E3) and five estrogen metabolites (2-OHE1, 4-OHE1, 4-OHE2, 2-OMeE1 and 2-OMeE2) within the perfused lung, with 4-OHE1 being the most abundant species.
View Article and Find Full Text PDFIn laboratory studies, acquired resistance to long-term antihormonal therapy in breast cancer evolves through two phases over 5 y. Phase I develops within 1 y, and tumor growth occurs with either 17β-estradiol (E(2)) or tamoxifen. Phase II resistance develops after 5 y of therapy, and tamoxifen still stimulates growth; however, E(2) paradoxically induces apoptosis.
View Article and Find Full Text PDFInterferons (IFNs) are cytokines with well-described immunomodulatory and antiviral properties, but less is known about the mechanisms by which they promote cell survival or cell death. Here, we show that IFN-γ induces RIP1 kinase-dependent necroptosis in mammalian cells deficient in NF-κB signaling. Induction of necroptosis by IFN-γ was found to depend on Jak1 and partially on STAT1.
View Article and Find Full Text PDFThe G protein-coupled receptor GPR30 binds 17beta-estradiol (E(2)) yet differs from classic estrogen receptors (ERalpha and ERbeta). GPR30 can mediate E(2)-induced nongenomic signaling, but its role in ERalpha-positive breast cancer remains unclear. Gene expression microarray data from five cohorts comprising 1,250 breast carcinomas showed an association between increased GPR30 expression and ERalpha-positive status.
View Article and Find Full Text PDFUntreated cystathionine beta-synthase (CBS) deficiency in humans is characterized by extremely elevated plasma total homocysteine (tHcy>200 microM), with thrombosis as the major cause of morbidity. Treatment with vitamins and diet leads to a dramatic reduction in thrombotic events, even though patients often still have severe elevations in tHcy (>80 microM). To understand the difference between extreme and severe hyperhomocysteinemia, we have examined two mouse models of CBS deficiency: Tg-hCBS Cbs(-/-) mice, with a mean serum tHcy of 169 microM, and Tg-I278T Cbs(-/-) mice, with a mean tHcy of 296 microM.
View Article and Find Full Text PDFPurpose: The purpose of this study was to identify patient characteristics that may be risk factors or markers of susceptibility to adverse treatment effects in cancer Phase I and II clinical trials.
Patients And Methods: A total of 459 patients enrolled in 23 therapeutic Phase I and II studies at the Fox Chase Cancer Center were included in the analysis. Patient-specific characteristics, medical and treatment history, doses of experimental agents, and graded toxicities were extracted from case report forms.
We propose two diagnostics for the statistical assessment of Hardy-Weinberg equilibrium. One diagnostic is the posterior probability of the complement of the smallest highest posterior density credible region that includes points in the parameter space consistent with the hypothesis of equilibrium. The null hypothesis of equilibrium is to be rejected if this probability is less than a pre-selected critical level.
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