Germline mutations in CDKN2 on chromosome 9p21, which codes for the cyclin
D kinase inhibitor p16, and more rarely, mutations in the gene coding for
CDK4, the protein to which p16 binds, underlie susceptibility in some
melanoma families. We have sequenced all exons of CDKN2 and analysed the
CDK4 gene for mutations in 27 UK families showing evidence of
predisposition to melanoma. Five different germline mutations in CDKN2 were
found in six families. Three of the mutations (Met53Ile, Arg24Pro and
23ins24) have been reported previously. We have identified two novel CDKN2
mutations (88delG and Ala118Thr) which are likely to be associated with the
development of melanoma, because of their co-segregation with the disease
and their likely functional effect on the CDKN2 protein. In binding assays
the protein expressed from the previously described mutation, Met53Ile, did
not bind to CDK4/CDK6, confirming its role as a causal mutation in the
development of melanoma. Ala118Thr appeared to be functional in this assay.
Arg24Pro appeared to bind to CDK6, but not to CDK4. No mutations were
detected in exon 2 of CDK4, suggesting that causal mutations in this gene
are uncommon. The penetrance of these mutant CDKN2 genes is not yet
established, nor is the risk of non-melanoma cancer to gene carriers.
相似文献
Vaccine adjuvants are compounds that enhance/prolong the immune response to a co-administered antigen. Saponins have been widely used as adjuvants for many years in several vaccines – especially for intracellular pathogens – including the recent and somewhat revolutionary malaria and shingles vaccines. In view of the immunoadjuvant potential of Q. brasiliensis saponins, the present study aimed to characterize the QB-80 saponin-rich fraction and a nanoadjuvant prepared with QB-80 and lipids (IMXQB-80). In addition, the performance of such adjuvants was examined in experimental inactivated vaccines against Zika virus (ZIKV). Analysis of QB-80 by DI-ESI-ToF by negative ion electrospray revealed over 29 saponins that could be assigned to known structures existing in their congener Q. saponaria, including the well-studied QS-21 and QS-7. The QB-80 saponins were a micrOTOF able to self-assembly with lipids in ISCOM-like nanoparticles with diameters of approximately 43 nm, here named IMXQB-80. Toxicity assays revealed that QB-80 saponins did present some haemolytical and cytotoxic potentials; however, these were abrogated in IMXQB-80 nanoparticles. Regarding the adjuvant activity, QB-80 and IMXQB-80 significantly enhanced serum levels of anti-Zika virus IgG and subtypes (IgG1, IgG2b, IgG2c) as well as neutralized antibodies when compared to an unadjuvanted vaccine. Furthermore, the nanoadjuvant IMXQB-80 was as effective as QB-80 in stimulating immune responses, yet requiring fourfold less saponins to induce the equivalent stimuli, and with less toxicity. These findings reveal that the saponin fraction QB-80, and particularly the IMXQB-80 nanoadjuvant, are safe and capable of potentializing immune responses when used as adjuvants in experimental ZIKV vaccines. 相似文献
Secretory breast carcinoma is a rare tumor originally described in children and adolescent women with a characteristic morphology and a controversial choice of treatment. We report an additional case of a 4-year-old girl with a breast tumor diagnosed as a secretory carcinoma without involvement of the axillary lymph nodes. The therapy consisted of simple mastectomy and low axillary dissection. She presented with a local recurrence near the surgical scar 8 months later, and a wide elliptical excision of the scar and underlying tissue was performed with subsequent radiotherapy of the surgical bed. This tumor has a relatively benign behavior and rarely metastasizes. A literature review revealed only 22 cases of breast carcinoma in childhood and adolescence. ▪ 相似文献
Skin tumors induced in mice by initiation-promotion (2 microg DMBA-2 microg
TPA) protocols were found to be under multigenic control. Eighty- one N2
mice from the cross (BALB/cAnPt x SENCARA/Pt)F1 x SENCARA/Pt that were
either solidly resistant (no papillomas) or highly susceptible (> or = 7
papillomas/mouse) were subjected to a 'genome scan' using 89 microsatellite
markers to check for associations with susceptible and resistant
phenotypes. A locus on Chr 5 (Skts4) was found to control the
susceptibility of SENCARA/Pt mice and the resistance of BALB/cAnPt mice to
papilloma formation. In addition, higher than expected linkage scores were
seen for the markers D9Mit271, D11Mit268 and D12Mit56. Further work is
required to establish whether genes determining papilloma formation are
located in these regions of the genome. In general, no evidence was seen
for loss of heterozygosity in microsatellite markers on Chrs 5, 9 and 11 in
17 microdissected papillomas from (BALB/c x SENCARA)F1 hybrid mice.
相似文献
Determining the factors associated with NCCLs and DH in populations could guide the implementation of specific preventive measures. This study evaluated the clinical features and factors associated with non‐carious cervical lesions (NCCLs) and dentin hypersensitivity (DH) in a Brazilian population. The participants were 118 patients at the Dentistry Clinic of our dental school. They completed an interview to obtain personal information and determine the possible factors associated with NCCLs and DH. Clinical examination was undertaken to record the NCCLs, shape of the lesion and certain occlusal factors. DH was diagnosed by air and probe tests. Data were analysed with the multilevel Poisson regression and prevalence ratios, and the respective 95% confidence intervals were calculated. The prevalence of NCCLs and DH among patients was 67·8% and 51·7%, respectively. Of a total number of 2902 teeth examined, 9·65% had NCCLs and 5·82% were sensitive to air. The most affected teeth for both conditions were the premolars. Most of the NCCLs were wedge‐shaped and located in the maxilla. The factors associated with NCCLs and DH were age and presence of premature occlusal contacts. NCCLs were also significantly associated with consumption of wine and alcoholic beverages, and DH with consumption of acidic fruits and juices. NCCLs were a common finding, with higher frequency in more advanced age groups, the maxilla and premolars. A significant association occurred between NCCLs, premature contacts and consumption of wine and alcoholic beverages. DH was associated with NCCLs, premature contacts and with the consumption of acidic fruits and juices. 相似文献
Introduction: Epigenetic mechanisms of gene regulatory control play fundamental roles in developmental morphogenesis, and, as more recently appreciated, are heavily implicated in the onset and progression of neoplastic disease, including cancer. Many epigenetic mechanisms are therapeutically targetable, providing additional incentive for understanding of their contribution to cancer and other types of neoplasia.
Areas covered: The Jumonji-domain histone demethylase (JHDM) family exemplifies many of the above traits. This review summarizes the current state of knowledge of the functions and pharmacologic targeting of JHDMs in cancer and other neoplastic processes, with an emphasis on diseases affecting the pediatric population.
Expert opinion: To date, the JHDM family has largely been studied in the context of normal development and adult cancers. In contrast, comparatively few studies have addressed JHDM biology in cancer and other neoplastic diseases of childhood, especially solid (non-hematopoietic) neoplasms. Encouragingly, the few available examples support important roles for JHDMs in pediatric neoplasia, as well as potential roles for JHDM pharmacologic inhibition in disease management. Further investigations of JHDMs in cancer and other types of neoplasia of childhood can be expected to both enlighten disease biology and inform new approaches to improve disease outcomes. 相似文献
This study aimed to determine the inter-rater and intrarater reliability, agreement, and minimal detectable change (MDC) of the neck muscle strength test using a handheld dynamometer in healthy women and women with headaches.
Methods
Neck muscle strength in maximal voluntary contraction was measured using the Lafayette Manual Muscle Testing attached to a nonelastic belt in 25 women with migraines and in 25 healthy women. Three repetitions of flexion, extension, and lateral flexion were performed. The tests were performed by 2 examiners on the same day, with a 10-minute interval, and by 1 examiner, with a 1-week interval. The reliability was verified by the intraclass correlation coefficient, the agreement determined by standard error measurement, and the MDC calculated.
Results
The protocol exhibited moderate to excellent intrarater and inter-rater reliabilities in both groups (intraclass correlation coefficientrange, 0.53-0.90). The standard error measurement ranged from 0.43 to 1.81 and the MDC from 1.49 up to 4.61.
Conclusion
Quantification of neck muscle strength using the handheld dynamometer with an attached nonelastic belt exhibited moderate to excellent intra- and inter-rater reliability in women with and without migraines. Moreover, the standard error measurement and MDC were proven to be useful in the interpretation of data and in guiding clinical decisions. 相似文献