Comprehensive genomic profiles of metastatic and relapsed salivary gland carcinomas are associated with tumor type and reveal new routes to targeted therapies.

BACKGROUND: Relapsed/metastatic salivary gland carcinomas (SGCs) have a wide diversity of histologic subtypes associated with variable clinical aggressiveness and response to local and systemic therapies. We queried whether comprehensive genomic profiling could define the tumor subtypes and uncover clinically relevant genomic alterations, revealing new routes to targeted therapies for patients with relapsed and metastatic disease. PATIENTS AND METHODS: From a series of 85 686 clinical cases, DNA was extracted from 40 µm of formalin-fixed paraffin embedded (FFPE) sections for 623 consecutive SGC. CGP was carried out on hybridization-captured, adaptor ligation-based libraries (mean coverage depth, >500×) for up to 315 cancer-related genes. Tumor mutational burden was determined on 1.1 Mb of sequenced DNA. All classes of alterations, base substitutions, short insertions/deletions, copy number changes, and rearrangements/fusions were determined simultaneously. RESULTS: The clinically more indolent SGC including adenoid cystic carcinoma, acinic cell carcinoma, polymorphous low-grade adenocarcinoma, mammary analog secretory carcinoma, and epithelial-myoepithelial carcinomas have significantly fewer genomic alterations, TP53 mutations, and lower tumor mutational burden than the typically more aggressive SGCs including mucoepidermoid carcinoma, salivary duct carcinoma, adenocarcinoma, not otherwise specified, carcinoma NOS, and carcinoma ex pleomorphic adenoma. The more aggressive SGCs are commonly driven by ERBB2 PI3K pathway genomic alterations. Additional targetable GAs are frequently seen. CONCLUSIONS: Genomic profiling of SGCs demonstrates important differences between traditionally indolent and aggressive cancers. These differences may provide therapeutic options in the future.

Blood donors' attitudes towards voluntary non-remunerated donation in Trinidad and Tobago.

OBJECTIVES: To assess the attitude towards voluntary non-remunerated blood donation among blood donors in Trinidad and Tobago (TRT). BACKGROUND: Blood donors in TRT are either family replacement (F/R, 87%) or remunerated (13%). There is chronic blood shortage and high seroreactivity for transfusion-transmissible infections (TTI) in donors. Converting existing to voluntary non-remunerated donors (VNRD) reduces the need to recruit news donors in achieving 100% VNRD. METHODS: A questionnaire-based, cross-sectional survey was conducted at two blood collection centres at an interval of 8 years. Donors were surveyed for sociodemographic characteristics, awareness of the blood shortage, previous donation behaviour, donor-beneficiary linkage if F/R, willingness to become VNRD and choice of motivators for converting to VNRD. RESULTS: A total of 400 and 595 donors respectively participated in Surveys 1 and 2, of whom 92·8 and 86·3% were F/R (P < 0·001), respectively. In both surveys, 52% of participants were unaware of an existing blood shortage (P = 0·983). Only 9·8 and 9·1% of participants expressed unwillingness to become VNRD (P = 0·720). The main motivators to convert to VNRD were reminders from the centre (84%) and extended opening hours (78%) in Survey 1 as compared to confidence that donated blood was used properly (73%) and shortened waiting times to donate (73%) in Survey 2. CONCLUSION: Despite low awareness of blood shortage, willingness to become VNRD was high among existing donors. Accountability and donor convenience underpinned the main motivators for converting to VNRD.

The association between indices of obesity and common clinical measures in adults with and without type 2 diabetes

OBJECTIVE: To determine if there are any differences in anthropometric measurements, lipid profile, blood pressure and body shape between diabetics and non-diabetics. DESIGN AND METHODS: This cross-sectional study comprised 309 subjects with 91 males and 218 females; there were 217 diabetics and 92 non-diabetics. The sample was taken from three hospitals in Trinidad. Lipid profile and blood pressure were taken from each facility’s physicians’ notes while anthropometric measurements were taken from the patients themselves. RESULTS: The diabetic group had elevated body mass index, and waist to hip ratios were significantly higher (p<0.05) when compared to non-diabetics. There was no significant difference in lipid profile and blood pressure between diabetics and non-diabetics. As age increased, the prevalence of type 2 diabetes mellitus was higher. Of the 217 diabetics, 173 were of East Indian descent. With regards to gender, more males were found to be diabetics resulting from having an android body shape as compared to females (gynoid body shape). It was deduced that waist to hip ratio was the best indicator of type 2 diabetes mellitus based on the area under the curve analysis. CONCLUSION: Of all the anthropometric measurements used, waist to hip ratio was found to be the most effective indicator of type 2 diabetes mellitus in Trinidadians, while body mass index was found to be the least.

Temozolomide resistance in glioblastoma cells occurs partly through epidermal growth factor receptor-mediated induction of connexin 43.

Glioblastoma Multiforme (GBM) is an aggressive adult primary brain tumor with poor prognosis. GBM patients develop resistance to the frontline chemotherapy, temozolomide (TMZ). As the connexins (Cx) have been shown to have a complex role in GBM, we investigated the role of Cx43 in TMZ resistance. Cx43 was increased in the TMZ-resistant low passage and cell lines. This correlated with the data in The Cancer Genome Atlas. Cx43 knockdown, reporter gene assays, chromatin immunoprecipitation assay, real-time PCR and western blots verified a role for Cx43 in TMZ resistance. This occurred by TMZ-resistant GBM cells being able to activate epidermal growth factor receptor (EGFR). In turn, EGFR activated the JNK-ERK1/2-AP-1 axis to induce Cx43. The increased Cx43 was functional as indicated by gap junctional intercellular communication among the resistant GBM cells. Cell therapy could be a potential method to deliver drugs, such as anti-EGF to tumor cells. Similar strategies could be used to reverse the expression of Cx43 to sensitize GBM cells to TMZ. The studies showed the potential for targeting EGF in immune therapy. These agents can be used in conjunction with stem cell therapy to treat GBM.

Foot-care education in patients with diabetes.

Patients with NIDDM are at risk of serious foot problems. Patient education needs to be continued long after diagnosis and initial education. The risk of complacency must be recognised, especially when there is a high rate of co-existing conditions.

Fertilization in Dictyostelium: pharmacological analyses and the presence of a substrate protein suggest protein kinase C is essential for gamete fusion.

The role of protein kinase C (PKC) during fertilization in the model eukaryote Dictyostelium discoideum was studied. Inhibition of PKC activity using staurosporine, chelerythrine, and bisindoylmaleimide resulted in a dose-dependent decrease in gamete fusion without any detectable effect on cell morphology or growth. At 1.0 microM, staurosporine led to a greater than 90% inhibition of gamete fusion. In support of this, chelerythrine and bisindoylmaleimide at 10 microM inhibited gamete cell fusion by 98 and 99%, respectively. In all cases, subsequent removal of the inhibitor allowed for the completion of sexual development in a manner indistinguishable from untreated, control cultures. In contrast, the stimulation of PKC by the addition of the phorbol ester 12-O-tetradecanoylphorbol-13-acetate at 5 nM resulted in a 56% enhancement of cell fusion. In order to identify PKC substrates that may regulate fertilization in D. discoideum, in vitro phosphorylation was carried out followed by SDS-PAGE. A number of proteins were phosphorylated, only one of which, a protein of about 50,000 M(r), appears to be a PKC substrate. In total, these results coupled with earlier work suggest that PKC functions as part of a calcium-mediated signaling pathway that regulates fertilization in D. discoideum, suggesting that the dual signaling pathway that regulates fertilization in higher eukaryotes may have evolved very early.