Molecular diagnosis of multiple endocrine neoplasia type 2A

Objective. To identify by means of genetic analyses individuals who are at risk of developing medullary thyroid cancer that is a component of multiple endocrine neoplasia.Subjects. A three-generation kindred with clinically and biochemically diagnosed medUllary thyroid cancer.Method. Identification of a heterozygote mutation by nucleic acid sequencing and restriction analyses.Results. A heterozygote T → C (Cys → Arg) mutation at codon 618 in exon 10 of the RET proto-oncogene was identified in 4 family members who had previously been diagnosed with medullary thyroid cancer. The same mutation was also found in one of the proband's presymptomatic children who subsequently underwent a preemptive thyroidectomy. The genetic diagnosis was confirmed by histology. No mutations were detected in any other family members.Conclusion. Identification of heterozygote germline mutations in multiple endocrine neoplasia is direct, highly accurate and cost-effective. This study demonstrates that, appropriately used, molecular diagnosis can supersede conventional biochemical methods in the management of patients with inherited cancers

The relationship between anti-HPV-16 IgG seropositivity and cancer of the cervix, anogenital organs, oral cavity and pharynx, oesophagus and prostate in a black South African population

BACKGROUND: Human papillomavirus type 16 (HPV-16) infection is an important cause of cervical cancer, other anogenital cancers and, possibly, some oral and pharyngeal cancers. The association of HPV-16 with oesophageal and with prostate cancers has not been firmly established. METHODS: We analysed sera from 3,757 HIV seronegative black South Africans using an anti-HPV IgG enzyme-linked immunosorbent assay (ELISA). The subjects were recruited from 1995 to 2000 as part of an ongoing cancer case control study. Cases were patients with newly diagnosed cancers of the cervix (n = 946), other anogenital organs (n = 80), the oral cavity and pharynx (n = 102), the oesophagus (n = 369) or the prostate (n = 205). The comparison group consisted of 2,055 age and sex-matched patients randomly selected from the same data base, diagnosed at the same hospitals, but with a vascular disease or with a cancer unrelated to HPV infection. Subjects' sera were randomly and blindly allocated onto ELISA plates. Optical density (OD) levels of anti-HPV-16 IgG of > 0.45 and ≥ 0.767 were taken to be cut-offs for negative, medium and high antibody levels. RESULTS: After adjustment for potential confounders, cancer types that showed a statistically significant association with increased anti-HPV-16 IgG antibody (Ab) levels were cancer of the cervix (OR for medium Ab levels = 1.6, and for high = 2.4, p < 0.0001), cancers of other anogenital organs (OR for medium or high Ab levels = 2.5, p = 0.002), and cancer of the oesophagus (OR for medium Ab = 1.3, and high Ab levels = 1.6 p = 0.002). Cancers of the oral cavity and pharynx showed a borderline significant association in the unadjusted model (p = 0.05) but after adjustment for confounding the trend in relation to Ab levels was positive but not statistically significant (OR for medium Ab = 1.1, and high Ab = 1.5 p = 0.13). Prostate cancer was not associated with HPV-16 seropositivity (OR for medium Ab level = 1.4, and for high Ab level = 1.3, p = 0.3). CONCLUSION: If there is indeed an association between HPV-16 and oesophageal and possibly also some oral cavity and pharyngeal cancers, then emerging HPV vaccines may also reduce, at least in part, the incidence of these leading cancer types

Comparison of hormonal receptor and HER-2 status between breast primary tumours and relapsing tumours: clinical implications of progesterone receptor loss

Differences in hormone receptor and HER-2 status between primary tumour and corresponding relapse could have a substantial impact on clinical management of patients. The aim of this study was to evaluate change in expression of hormone receptors and HER-2 status between primary tumour and corresponding local recurrence or distant metastasis. We analysed 140 primary tumours and related recurrent or metastatic samples. Hormone receptors status was evaluated by immunohistochemistry, while HER-2 status by immunohistochemistry and silver in situ hybridisation. A change in HER-2 was rare; 3.7% of cases by immunohistochemistry and only 0.7% by silver in situ hybridisation analysis. A change in estrogen and progesterone receptors was seen in 6.4% and 21.4% of cases, respectively. Estrogen receptor change was not affected by adjuvant therapy, whereas progesterone receptor was influenced by adjuvant chemotherapy associated to hormone therapy (P = 0.0005). A change in progesterone receptor was more frequent in distant metastases than in local recurrences (P = 0.03). In the setting of estrogen receptor positive tumours, patients with progesterone receptor loss in local recurrence had a statistically significant lower median metastasis free survival compared to others patients; progesterone receptor positive, 112 months; progesterone receptor negative, 24 months (P = 0.005). A change between primary tumour and corresponding relapse is frequent for progesterone receptor, infrequent for estrogen receptor and rare for HER-2. In cases with changes in HER-2, it is worthwhile reassessing HER-2 status with both immunohistochemistry and in situ hybridisation analysis. Progesterone receptor loss seems to be influenced by therapy and to correlate with a worse prognosis

Early phase of plasticity-related gene regulation and SRF dependent transcription in the hippocampus

Hippocampal organotypic cultures are a highly reliable in vitro model for studying neuroplasticity: in this paper, we analyze the early phase of the transcriptional response induced by a 20 \ub5M gabazine treatment (GabT), a GABA-Ar antagonist, by using Affymetrix oligonucleotide microarray, RT-PCR based time-course and chromatin-immuno-precipitation. The transcriptome profiling revealed that the pool of genes up-regulated by GabT, besides being strongly related to the regulation of growth and synaptic transmission, is also endowed with neuro-protective and pro-survival properties. By using RT-PCR, we quantified a time-course of the transient expression for 33 of the highest up-regulated genes, with an average sampling rate of 10 minutes and covering the time interval [10 3690] minutes. The cluster analysis of the time-course disclosed the existence of three different dynamical patterns, one of which proved, in a statistical analysis based on results from previous works, to be significantly related with SRF-dependent regulation (p-value<0.05). The chromatin immunoprecipitation (chip) assay confirmed the rich presence of working CArG boxes in the genes belonging to the latter dynamical pattern and therefore validated the statistical analysis. Furthermore, an in silico analysis of the promoters revealed the presence of additional conserved CArG boxes upstream of the genes Nr4a1 and Rgs2. The chip assay confirmed a significant SRF signal in the Nr4a1 CArG box but not in the Rgs2 CArG box

Search for gravitational waves associated with gamma-ray bursts detected by Fermi and Swift during the LIGO–Virgo run O3b

We search for gravitational-wave signals associated with gamma-ray bursts (GRBs) detected by the Fermi and Swift satellites during the second half of the third observing run of Advanced LIGO and Advanced Virgo (2019 November 1 15:00 UTC–2020 March 27 17:00 UTC). We conduct two independent searches: a generic gravitational-wave transients search to analyze 86 GRBs and an analysis to target binary mergers with at least one neutron star as short GRB progenitors for 17 events. We find no significant evidence for gravitational-wave signals associated with any of these GRBs. A weighted binomial test of the combined results finds no evidence for subthreshold gravitational-wave signals associated with this GRB ensemble either. We use several source types and signal morphologies during the searches, resulting in lower bounds on the estimated distance to each GRB. Finally, we constrain the population of low-luminosity short GRBs using results from the first to the third observing runs of Advanced LIGO and Advanced Virgo. The resulting population is in accordance with the local binary neutron star merger rate

P53 codon 72 polymorphism and BRCA 1 and 2 mutations in ovarian epithelial malignancies in black South Africans.

Mutations in the BRCA and p53 tumor suppressor genes are implicated in the oncogenesis of ovarian tumors although their exact roles remain unclear. Despite recognized ethnic differences in the frequency of ovarian cancer and in genetic polymorphisms between populations, studies carried out so far have focused almost entirely on Caucasian subjects. In this study, undertaken at King Edward VIII Hospital, Durban, South Africa, we examined blood and/or primary epithelial ovarian tumor tissue from 75 black South African women for the presence of the three most commonly occurring BRCA 1 and 2 mutations (185delAG, 5382insC and 6174delT). The p53 codon 72 allele status was also examined and results were compared to a reference cohort comprising 340 ethnically matched subjects. None of the BRCA 1 or 2 mutations were detected in the patient group. The codon 72 Arg allele frequency in lymphocytic DNA was not significantly different compared with the control group. In contrast, in ovarian tumor DNA, the Arg allele was found significantly more frequently than in the controls; this was observed in terms of both Arg allele frequency (45% vs. 31%; P = 0.017) and Arg homozygosity (20% vs. 9%; P = 0.039). Tumors with the more aggressive serous papillary cystadenomatous histology had a markedly higher Arg frequency (45%) than the mucinous cystadenomas (25%). The higher frequency of the Arg allele detected in this study in black South Africans with ovarian tumors suggests a possible role in malignant transformation and may constitute a risk factor for ovarian and other epithelial cancers through mechanisms yet to be elucidated

P53 codon 72 polymorphism and BRCA 1 and 2 mutations in ovarian epithelial malignancies in black South Africans.

Mutations in the BRCA and p53 tumor suppressor genes are implicated in the oncogenesis of ovarian tumors although their exact roles remain unclear. Despite recognized ethnic differences in the frequency of ovarian cancer and in genetic polymorphisms between populations, studies carried out so far have focused almost entirely on Caucasian subjects. In this study, undertaken at King Edward VIII Hospital, Durban, South Africa, we examined blood and/or primary epithelial ovarian tumor tissue from 75 black South African women for the presence of the three most commonly occurring BRCA 1 and 2 mutations (185delAG, 5382insC and 6174delT). The p53 codon 72 allele status was also examined and results were compared to a reference cohort comprising 340 ethnically matched subjects. None of the BRCA 1 or 2 mutations were detected in the patient group. The codon 72 Arg allele frequency in lymphocytic DNA was not significantly different compared with the control group. In contrast, in ovarian tumor DNA, the Arg allele was found significantly more frequently than in the controls; this was observed in terms of both Arg allele frequency (45% vs. 31%; P = 0.017) and Arg homozygosity (20% vs. 9%; P = 0.039). Tumors with the more aggressive serous papillary cystadenomatous histology had a markedly higher Arg frequency (45%) than the mucinous cystadenomas (25%). The higher frequency of the Arg allele detected in this study in black South Africans with ovarian tumors suggests a possible role in malignant transformation and may constitute a risk factor for ovarian and other epithelial cancers through mechanisms yet to be elucidated