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The National Comprehensive Cancer Network recommends clinical-grade genetic testing to confirm commercial results from direct-to-consumer genetic testing (DTC-GT) companies and third-party interpretation (TPI) services; however, the type of confirmatory testing that genetic counselors (GCs) recommend remains uncharacterized. Therefore, we aimed to describe GCs testing strategies for patients who have already obtained DTC-GT results (23andMe) or TPI data (Promethease) that reported a BRCA1/2 pathogenic variant. We invited GCs specializing in clinical cancer genetics to complete an online survey distributed to members of the National Society of Genetic Counselors. The survey, completed by 80 respondents, contained case scenarios featuring probands with variable personal and family histories of cancer. Our results show that the majority of participating GCs have counseled patients for their health-related commercial test results; 94% have encountered patient DTC-GT reports (3 per year), and 69% have encountered patient TPI data (2 per year). Most participating GCs would recommend confirmatory clinical-grade testing for probands with a positive 23andMe BRCA1/2 result (77/80, 96%). However, there was strong variability between the type of recommended testing. Approximately 20% recommended single-site analysis, 11%-14% recommended the three Ashkenazi Jewish BRCA1/2 founder mutations, 4% recommended BRCA1/2 testing, and 61%-64% recommended multi-gene panel testing. The most commonly recommended panels were split between a breast and gynecological cancer-focused panel and a broad pan-cancer panel. The majority of participants (98%-100%) would also recommend confirmatory testing for patients with positive TPI data for BRCA1/2. Similarly, results were mixed between those who recommended targeted, single-site analysis (10%-15%) compared to a multi-gene panel (72%-83%). These data show that while most GCs were uniform in their practice of recommending confirmatory testing, they are mixed in their approach to the specific type of testing they would select. These results may help inform counseling approaches and consensus for this expanding group of patients., (© 2021 National Society of Genetic Counselors.)

Currently, there is an incomplete understanding of the molecular pathogenesis of meningiomas, the most common primary brain tumor. Several familial syndromes are characterized by increased meningioma risk, and the genetics of these syndromes provides mechanistic insight into sporadic disease. The best defined of these syndromes is neurofibromatosis type 2, which is caused by a mutation in the NF2 gene and has a meningioma incidence of approximately 50%. This finding led to the subsequent discovery that NF2 loss-of-function occurs in up to 60% of sporadic tumors. Other important familial diseases with increased meningioma risk include nevoid basal cell carcinoma syndrome, multiple endocrine neoplasia 1 (MEN1), Cowden syndrome, Werner syndrome, BAP1 tumor predisposition syndrome, Rubinstein-Taybi syndrome, and familial meningiomatosis caused by germline mutations in the SMARCB1 and SMARCE1 genes. For each of these syndromes, the diagnostic criteria, incidence in the population, and frequency of meningioma are presented to review the relevant clinical information for these conditions. The genetic mutations, molecular pathway derangements, and relationship to sporadic disease for each syndrome are described in detail to identify targets for further investigation. Familial syndromes characterized by meningiomas often affect genes and pathways that are also implicated in a subset of sporadic cases, suggesting key molecular targets for therapeutic intervention. Further studies are needed to resolve the functional relevance of specific genes whose significance in sporadic disease remains to be elucidated.

A series of novel imidazobenzodiazepine analogs of the lead chiral ligand SH-053-2'F- S -CH 3 ( 2 ), an α2/α3/α5 (Bz)GABA (A)ergic receptor subtype selective ligand, which reversed PCP-induced prepulse inhibition (PPI) of acoustic startle, were synthesized. These chiral ( S )-CH 3 ligands are targeted for the treatment of schizophrenia and depression. These new ligands were designed by modifying the liable ester functionality in 2 to improve the metabolic stability, cytotoxicity, and activity as compared to 2 . Based on the data to date, the most promising ligands are the N -cyclopropyl amide GL-I-55 ( 8c ) and the methyl bioisostere GL-I-65 ( 9a ). The in vitro metabolic stability, cytotoxicity and in vivo locomotor effects are described in this report. Based on these results, 8c and 9a are the most promising for further in vivo pharmacology.

Rationale: Gaps in our understanding of glutamatergic signaling may be key obstacles in accurately modeling complex CNS diseases. System xc (-) is an example of a poorly understood component of glutamate homeostasis that has the potential to contribute to CNS diseases., Objectives: This study aims to determine whether system xc (-) contributes to behaviors used to model features of CNS disease states., Methods: In situ hybridization was used to map mRNA expression of xCT throughout the brain. Microdialysis in the prefrontal cortex was used to sample extracellular glutamate levels; HPLC was used to measure extracellular glutamate and tissue glutathione concentrations. Acute administration of sulfasalazine (8-16 mg/kg, IP) was used to decrease system xc (-) activity. Behavior was measured using attentional set shifting, elevated plus maze, open-field maze, Porsolt swim test, and social interaction paradigm., Results: The expression of xCT mRNA was detected throughout the brain, with high expression in several structures including the basolateral amygdala and prefrontal cortex. Doses of sulfasalazine that produced a reduction in extracellular glutamate levels were identified and subsequently used in the behavioral experiments. Sulfasalazine impaired performance in attentional set shifting and reduced the amount of time spent in an open arm of an elevated plus maze and the center of an open-field maze without altering behavior in a Porsolt swim test, total distance moved in an open-field maze, or social interaction., Conclusions: The widespread distribution of system xc (-) and involvement in a growing list of behaviors suggests that this form of nonvesicular glutamate release is a key component of excitatory signaling.

Rationale: Aspects of schizophrenia, including deficits in sensorimotor gating, have been linked to glutamate dysfunction and/or oxidative stress in the prefrontal cortex. System xc(-), a cystine-glutamate antiporter, is a poorly understood mechanism that contributes to both cellular antioxidant capacity and glutamate homeostasis., Objectives: Our goal was to determine whether increased system xc(-) activity within the prefrontal cortex would normalize a rodent measure of sensorimotor gating., Methods: In situ hybridization was used to map messenger RNA (mRNA) expression of xCT, the active subunit of system xc(-), in the prefrontal cortex. Prepulse inhibition was used to measure sensorimotor gating; deficits in prepulse inhibition were produced using phencyclidine (0.3-3 mg/kg, sc). N-Acetylcysteine (10-100 μM) and the system xc(-) inhibitor (S)-4-carboxyphenylglycine (CPG, 0.5 μM) were used to increase and decrease system xc(-) activity, respectively. The uptake of (14)C-cystine into tissue punches obtained from the prefrontal cortex was used to assay system xc(-) activity., Results: The expression of xCT mRNA in the prefrontal cortex was most prominent in a lateral band spanning primarily the prelimbic cortex. Although phencyclidine did not alter the uptake of (14)C-cystine in prefrontal cortical tissue punches, intraprefrontal cortical infusion of N-acetylcysteine (10-100 μM) significantly reduced phencyclidine- (1.5 mg/kg, sc) induced deficits in prepulse inhibition. N-Acetylcysteine was without effect when coinfused with CPG (0.5 μM), indicating an involvement of system xc(-)., Conclusions: These results indicate that phencyclidine disrupts sensorimotor gating through system xc(-) independent mechanisms, but that increasing cystine-glutamate exchange in the prefrontal cortex is sufficient to reduce behavioral deficits produced by phencyclidine.

In forty-five Holstein Frisian dairy cows (1-6 weeks post partum; mean age: 5.1 +/- 1.2 years) the serum total bile acid concentrations (SBA) were measured enzymatically. In all cows a left sided abomasal displacement was corrected surgically by right side laparotomy and omentopexy three days before investigation. The liver fat content was determined in all cows histologically. Liver failure was assumed if typical clinical signs (ataxia, general depression, recumbency or coma), an increased venous plasma ammonia level (> 35 mumol/l) and a decreased plasma amino acid index (< 4.0) were found. Cows without liver failure (N = 29) were grouped according to the liver fat content as cows with mild (N = 5), moderate (N = 19) or severe hepatosteatosis (N = 5). Histological examination of liver biopsies in cows with liver failure (N = 16) revealed in twelve cases a severe fatty liver and in four cases a hydropic degeneration of the liver tissue. Although in cows without liver failure mean SBA concentrations were higher in the group with moderate (47.3 +/- 30.9 mumol/l) or severe fatty liver (32.9 +/- 21.7 mumol/l) than in that with mild lipidosis (18.0 (16.8 mumol/l), differences were not significant. The mean SBA concentration in cows with liver failure (70.5 +/- 49.5 mumol/l) was only significantly (p < 0.05) increased compared to cows with uncomplicated mild hepatic lipidosis. In conclusion, the determination of SBA concentrations is of little value in the recognition of fatty liver or even liver failure due to the considerable variance of SBA concentrations in dairy cows.

Application of a HPLC-technique according to MURACA & BLANCKAERT (1983) for accurate determination of the relative amounts of unconjugated bilirubin and its sugar mono- and diconjugates in bovine plasma is described and the results are compared with those of the conventional diazo-method. The diazo-assay yielded values for total and unconjugated bilirubin which were considerably higher than those obtained by the HPLC-technique. This is probably due to unidentified diazo-positive compounds distinct from bilirubin. The direct-reacting fraction in the diazo-assay showed little or no agreement with the fraction of total ester conjugates determined by HPLC. Results indicate that the diagnostical value of bilirubin subfractioning by the diazo-method as a liver function test in cattle must be reconsidered.