The long-term effects of interferon treatment on cell lines that maintain human papillomavirus type 31 (HPV-31) episomes have been examined. High doses and prolonged interferon treatment resulted in growth arrest of HPV-positive cells, with a high percentage of cells undergoing apoptosis. These effects were not seen with interferon treatment of either normal human keratinocytes or cells derived from HPV-negative squamous carcinomas, which exhibited only slight decreases in their rates of growth. Within 2 weeks of the initiation of treatment, a population of HPV-31-positive cells that were resistant to interferon appeared consistently and reproducibly. The resistant cells had growth and morphological characteristics similar to those of untreated cells. Long-term interferon treatment of HPV-positive cells also resulted in a reduction in HPV episome levels but did not significantly decrease the number of integrated copies of HPV. Cells that maintained HPV genomes lacking E5 were sensitive to interferon, while cells expressing only the E6/E7 genes were resistant. In contrast, cells that expressed E2 from a tetracycline-inducible promoter were found to be significantly more sensitive to interferon treatment than parental cells. This suggests that at least a portion of the sensitivity to interferon could be mediated through the E2 protein. These studies indicate that cells maintaining HPV episomes are highly sensitive to interferon treatment but that resistant populations arise quickly.Human papillomaviruses (HPV) are small double-stranded DNA viruses that infect epithelial tissues. More than 85 subtypes have been identified, and each of these types exhibits strict tissue specificity (13). About one-third of HPV types infect the anogenital epithelia and induce the most common form of sexually transmitted disease (71). HPV infect cells in the basal layer of epithelia and establish a latent infection in these cells. Production of HPV virions, however, requires infected cells to migrate away from the basal layer and undergo differentiation (28,31,71). The HPV that infect the anogenital region can be divided into high-risk and low-risk HPV types depending on their association with malignancy. The low-risk HPVs, such as HPV type 6 (HPV-6) and HPV-11, cause hyperproliferative lesions of external genitalia and are rarely associated with malignancies. In contrast, the high-risk HPVs, , are the etiological agents of cervical cancer (28,31,35,71). The difference in clinical outcome between low-and high-risk HPV infections has been an area of major research interest.The genomes of all genital HPV types encode 8 to 10 proteins. In the high-risk HPVs, E6 and E7 function as oncogenes. E6 binds to the cellular ubiquitin ligase, E6AP, which then targets p53 for degradation (29,53,54,67). In addition, E6 activates the expression of htert, the catalytic subunit of telomerase. E7 binds to and inhibits the activity of retinoblastoma protein, pRB, and promotes the constitutive activation of E2F family members (9,16,38,44). The E1 and E2 g...
Papillomaviruses (PVs) are a family of small DNA viruses that infect epithelial tissue at various anatomical locations. Over 85 PV types that are specific for humans (HPVs) have been identified, and they show a high degree of sequence and functional conservation. A subset of HPVs infect the genital epithelia and are broadly divided into two categories: low-risk viruses that cause benign hyperproliferative lesions, and highrisk types that can potentially progress to neoplastic transformation (23).High-risk HPV types include HPV
Fanconi–Bickel syndrome (FBS, OMIM #227810) is a rare autosomal recessive disorder of carbohydrate transport originally described in 1949 [Fanconi and Bickel(1949);Helv Paediatr Acta 4: 359–396]. FBS is caused by mutations in the glucose and galactose transporter gene SLC2A2 (HGNC ID11006) [Santeret al.(1997); Nat Genet 17: 324–326] and is characterized by hepatic glycogen accumulation with hepatomegaly, fasting hypoglycemia, short stature, impaired glucose tolerance, hyperlipidemia, and tubular nephropathy. Although the described complications would not seem to preclude fertility in FBS patients, there has been no report of reproduction in affected individuals to date. We have followed a female with FBS for at least 20 years. She received a clinical diagnosis in adolescence, with recent molecular confirmation of two mutations in trans in the SLC2A2 gene. She has had glucosuria, proteinuria, impaired tubular reabsorption of phosphate, osteopenia, and hypercholesterolemia throughout her life, without any documented episodes of hypoglycemia. Hepatomegaly was initially noticed in infancy and resolved in late adolescence. She became pregnant at 31 years of age, had gestational diabetes treated with diet, and delivered a healthy boy. She had impaired glucose tolerance after her pregnancy.Her adult height was at the lower end of her target height range, and she had evidence of localized osteopenia at the left distal radius on DXA scan. This report describes the clinical history of an affected individual and highlights the importance of continued follow-up in order to extend our understanding of the history of this rare metabolic disorder.
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