TCERG1L allelic variation is associated with cisplatin-induced hearing loss in childhood cancer, a PanCareLIFE study.

In children with cancer, the heterogeneity in ototoxicity occurrence after similar treatment suggests a role for genetic susceptibility. Using a genome-wide association study (GWAS) approach, we identified a genetic variant in TCERG1L (rs893507) to be associated with hearing loss in 390 non-cranial irradiated, cisplatin-treated children with cancer. These results were replicated in two independent, similarly treated cohorts (n = 192 and 188, respectively) (combined cohort: P = 5.3 × 10-10, OR 3.11, 95% CI 2.2-4.5). Modulating TCERG1L expression in cultured human cells revealed significantly altered cellular responses to cisplatin-induced cytokine secretion and toxicity. These results contribute to insights into the genetic and pathophysiological basis of cisplatin-induced ototoxicity

Monoallelic Expression of Multiple Genes in the CNS

The inheritance pattern of a number of major genetic disorders suggests the possible involvement of genes that are expressed from one allele and silent on the other, but such genes are difficult to detect. Since DNA methylation in regulatory regions is often a mark of gene silencing, we modified existing microarray-based assays to detect both methylated and unmethylated DNA sequences in the same sample, a variation we term the MAUD assay. We probed a 65 Mb region of mouse Chr 7 for gene-associated sequences that show two distinct DNA methylation patterns in the mouse CNS. Selected genes were then tested for allele-specific expression in clonal neural stem cell lines derived from reciprocal F1 (C57BL/6×JF1) hybrid mice. In addition, using a separate approach, we directly analyzed allele-specific expression of a group of genes interspersed within clusters of OlfR genes, since the latter are subject to allelic exclusion. Altogether, of the 500 known genes in the chromosomal region surveyed, five show monoallelic expression, four identified by the MAUD assay (Agc1, p (pink-eyed dilution), P4ha3 and Thrsp), and one by its proximity to OlfR genes (Trim12). Thrsp (thyroid hormone responsive SPOT14 homolog) is expressed in hippocampus, but the human protein homolog, S14, has also been implicated in aggressive breast cancer. Monoallelic expression of the five genes is not coordinated at a chromosome-wide level, but rather regulated at individual loci. Taken together, our results suggest that at least 1% of previously untested genes are subject to allelic exclusion, and demonstrate a dual approach to expedite their identification

Optimising the Nadroparin Dose for Thromboprophylaxis During Hemodialysis by Developing a Population Pharmacodynamic Model Using Anti-Xa Levels

INTRODUCTION: The optimal nadroparin dose in patients undergoing hemodialysis is difficult to determine in clinical practice. Anti-Xa levels ≥ 0.4 IU/mL and 70%) of peak anti-Xa levels < 2.0 IU/mL. CONCLUSION: Mainly patients receiving hemodiafiltration and those receiving hemodialysis with a high LBM can benefit from a higher nadroparin dose than currently used in clinical practice, while having anti-Xa levels < 2.0 IU/mL

Development and Evaluation of a Prediction Model for Underestimated Invasive Breast Cancer in Women with Ductal Carcinoma In Situ at Stereotactic Large Core Needle Biopsy

<div><p>Background</p><p>We aimed to develop a multivariable model for prediction of underestimated invasiveness in women with ductal carcinoma in situ at stereotactic large core needle biopsy, that can be used to select patients for sentinel node biopsy at primary surgery.</p> <p>Methods</p><p>From the literature, we selected potential preoperative predictors of underestimated invasive breast cancer. Data of patients with nonpalpable breast lesions who were diagnosed with ductal carcinoma in situ at stereotactic large core needle biopsy, drawn from the prospective COBRA (Core Biopsy after RAdiological localization) and COBRA2000 cohort studies, were used to fit the multivariable model and assess its overall performance, discrimination, and calibration.</p> <p>Results</p><p>348 women with large core needle biopsy-proven ductal carcinoma in situ were available for analysis. In 100 (28.7%) patients invasive carcinoma was found at subsequent surgery. Nine predictors were included in the model. In the multivariable analysis, the predictors with the strongest association were lesion size (OR 1.12 per cm, 95% CI 0.98-1.28), number of cores retrieved at biopsy (OR per core 0.87, 95% CI 0.75-1.01), presence of lobular cancerization (OR 5.29, 95% CI 1.25-26.77), and microinvasion (OR 3.75, 95% CI 1.42-9.87). The overall performance of the multivariable model was poor with an explained variation of 9% (Nagelkerke’s <i>R</i>^<i>2</i>), mediocre discrimination with area under the receiver operating characteristic curve of 0.66 (95% confidence interval 0.58-0.73), and fairly good calibration.</p> <p>Conclusion</p><p>The evaluation of our multivariable prediction model in a large, clinically representative study population proves that routine clinical and pathological variables are not suitable to select patients with large core needle biopsy-proven ductal carcinoma in situ for sentinel node biopsy during primary surgery.</p> </div

TCERG1L allelic variation is associated with cisplatin-induced hearing loss in childhood cancer, a PanCareLIFE study

In children with cancer, the heterogeneity in ototoxicity occurrence after similar treatment suggests a role for genetic susceptibility. Using a genome-wide association study (GWAS) approach, we identified a genetic variant in TCERG1L to be associated with hearing loss in 390 non-cranial irradiated, cisplatin-treated children with cancer. These results were replicated in two independent, similarly treated cohorts. Modulating TCERG1L expression in cultured human cells revealed significantly altered cellular responses to cisplatin-induced cytokine secretion and toxicity. These results contribute to insights into the genetic and pathophysiological basis of cisplatin-induced ototoxicity.</p