The t Complex Distorter 2 Candidate Gene, Dnahc8, Encodes at Least Two Testis-Specific Axonemal Dynein Heavy Chains That Differ Extensively at Their Amino and Carboxyl Termini

AbstractHomozygosity for the t haplotype allele of the testis-specifically expressed axonemal dynein heavy chain (axDHC) gene, Dnahc8, has been linked to male sterility resulting from aberrant sperm motility. However, the near absence of Dnahc8 expression has been associated with male sterility resulting from an early breakdown in sperm flagellar development. Although axDHCs are integral participants in flagellar motility, a role in flagellar morphogenesis has never been attributed to a member of this highly conserved gene family. To gain a better understanding of this presumed novel role for Dnahc8, we have studied the organization and expression of full-length Dnahc8+ and Dnahc8t transcripts. Our results demonstrate the existence of at least two alternatively spliced, testis-specific Dnahc8 mRNAs transcribed from both the + and t alleles. A highly expressed isoform encodes a protein with significant homology nearly throughout to the γ heavy chain of the Chlamydomonas axonemal outer arm dynein, while a more poorly expressed isoform codes for a protein whose sequence diverges significantly from that of other axDHCs at both its N and C termini. While in situ hybridization studies demonstrate that both mRNA species accumulate exclusively in mid to late spermatocytes, each isoform shows spatial independence. Additional experiments demonstrate the existence of a testis-expressed mRNA with no significant open reading frame, a portion of which is antisense to the 5′-untranslated region of the highly divergent Dnahc8 isoform. The cumulative data imply that Dnahc8 may have acquired functional plasticity in the testis through the tightly controlled expression of both typical and unusual isoforms

Assessing the molecular genetics of attention networks

BACKGROUND: Current efforts to study the genetic underpinnings of higher brain functions have been lacking appropriate phenotypes to describe cognition. One of the problems is that many cognitive concepts for which there is a single word (e.g. attention) have been shown to be related to several anatomical networks. Recently, we have developed an Attention Network Test (ANT) that provides a separate measure for each of three anatomically defined attention networks. RESULTS: In this study we have measured the efficiency of neural networks related to aspects of attention using the ANT in a population of 200 adult subjects. We then examined genetic polymorphisms in four candidate genes (DRD4, DAT, COMT and MAOA) that have been shown to contribute to the risk of developing various psychiatric disorders where attention is disrupted. We find modest associations of several polymorphisms with the efficiency of executive attention but not with overall performance measures such as reaction time. CONCLUSIONS: These results suggest that genetic variation may underlie inter-subject variation in the efficiency of executive attention. This study also shows that genetic influences on executive attention may be specific to certain anatomical networks rather than affecting performance in a global or non-specific manner. Lastly, this study further validates the ANT as an endophenotypic assay suitable for assessing how genes influence certain anatomical networks that may be disrupted in various psychiatric disorders

Phase II Trial of Cediranib in Combination With Cisplatin and Pemetrexed in Chemotherapy-Naïve Patients With Unresectable Malignant Pleural Mesothelioma (SWOG S0905).

PurposeAntiangiogenic agents combined with chemotherapy have efficacy in the treatment of unresectable malignant pleural mesothelioma (MPM). Cediranib (AstraZeneca, Cheshire, United Kingdom), a vascular endothelial growth factor receptor and platelet-derived growth factor receptor inhibitor, demonstrated therapeutic potential in a prior phase I trial. We evaluated a phase II trial for efficacy.Patients and methodsSWOG S0905 (ClinicalTrials.gov identifier: NCT01064648) randomly assigned cediranib or placebo with platinum-pemetrexed for six cycles followed by maintenance cediranib or placebo in unresectable chemotherapy-naïve patients with MPM of any histologic subtype. Primary end point was Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 progression-free survival (PFS). Secondary end points included overall survival, PFS by modified RECIST v1.1, response (modified RECIST and RECIST v1.1), disease control, and safety/toxicity. The trial was designed to detect a difference in RECIST v1.1 PFS at the one-sided 0.1 level using a stratified log-rank test.ResultsNinety-two eligible patients were enrolled (75% epithelioid and 25% biphasic or sarcomatoid). The cediranib arm had more grade 3 and 4 diarrhea, dehydration, hypertension, and weight loss. Cediranib improved PFS by RECIST v1.1 (hazard ratio, 0.71; 80% CI, 0.54 to 0.95; P = .062; 7.2 months v 5.6 months) and increased modified RECIST v1.1 response (50% v 20%; P = .006). By modified RECIST v1.1, cediranib numerically increased PFS (hazard ratio, 0.77; 80% CI, 0.59 to 1.02; P = .12; median, 6.9 months v 5.6 months). No significant difference in overall survival was observed.ConclusionThe addition of cediranib to platinum-pemetrexed improved PFS by RECIST v1.1 and response rate by modified RECIST in patients with unresectable MPM. Whereas adding antiangiogenics to chemotherapy has been a successful strategy for some patients, the cediranib toxicity profile and small incremental survival benefit precludes additional development in MPM

COMT val158met Genotype Affects Recruitment of Neural Mechanisms Supporting Fluid Intelligence

Fluid intelligence (gf) influences performance across many cognitive domains. It is affected by both genetic and environmental factors. Tasks tapping gf activate a network of brain regions including the lateral prefrontal cortex (LPFC), the presupplementary motor area/anterior cingulate cortex (pre-SMA/ACC), and the intraparietal sulcus (IPS). In line with the “intermediate phenotype” approach, we assessed effects of a polymorphism (val158met) in the catechol-O-methyltransferase (COMT) gene on activity within this network and on actual task performance during spatial and verbal gf tasks. COMT regulates catecholaminergic signaling in prefrontal cortex. The val158 allele is associated with higher COMT activity than the met158 allele. Twenty-two volunteers genotyped for the COMT val158met polymorphism completed high and low gf versions of spatial and verbal problem-solving tasks. Our results showed a positive effect of COMT val allele load upon the blood oxygen level–dependent response in LPFC, pre-SMA/ACC, and IPS during high gf versus low gf task performance in both spatial and verbal domains. These results indicate an influence of the COMT val158met polymorphism upon the neural circuitry supporting gf. The behavioral effects of val allele load differed inside and outside the scanner, consistent with contextual modulation of the relation between COMT val158met genotype and gf task performance

Phase I Trial of Arginine Deprivation Therapy with ADI-PEG 20 Plus Docetaxel in Patients with Advanced Malignant Solid Tumors

PURPOSE: This phase I study examined the toxicity and tolerability, of pegylated arginine deiminase (ADI-PEG 20) in combination with docetaxel in patients with advanced solid malignancies. EXPERIMENTAL DESIGN: Eligible patients had histologically proven advanced solid malignancies, with any number of prior therapies, zubrod performance status 0–2 and adequate organ function. Patients received ADI-PEG 20 weekly intramuscular injection ranging from 4.5–36 mg/m(2), and up to ten doses of docetaxel 75 mg/m(2) every three weeks. Primary endpoints were safety, toxicity and a recommended phase II dose. Circulating arginine levels were measured prior to each cycle. Tumor response was measured as a secondary endpoint every six weeks on study. RESULTS: Eighteen patients received a total of 116 cycles of therapy through four dose levels of ADI-PEG 20. A single dose-limiting toxicity (grade 3 urticarial rash) was observed at the 1(st) dose level, with no additional dose-limiting toxicities observed. Hematologic toxicities were common with 14 patients experiencing at least one grade 3–4 leukopenia. Fatigue was the most prevalent toxicity reported by 16 patients. Arginine was variably suppressed with ten patients achieving at least a 50% reduction in baseline values. In 14 patients with evaluable disease, four partial responses (including two patients with PSA response) were documented and seven patients had stable disease. CONCLUSIONS: ADI-PEG 20 demonstrated reasonable toxicity in combination with docetaxel. Promising clinical activity was noted and expansion cohorts are now accruing for both castrate resistant prostate cancer and non-small cell lung cancer at a recommended phase II dose of 36 mg/m(2)

Tumor BRCA1, RRM1 and RRM2 mRNA Expression Levels and Clinical Response to First-Line Gemcitabine plus Docetaxel in Non-Small-Cell Lung Cancer Patients

Overexpression of RRM1 and RRM2 has been associated with gemcitabine resistance. BRCA1 overexpression increases sensitivity to paclitaxel and docetaxel. We have retrospectively examined the effect of RRM1, RRM2 and BRCA1 expression on outcome to gemcitabine plus docetaxel in advanced non-small-cell lung cancer (NSCLC) patients. = 0.001). Low BRCA1 expression was the only factor significantly associated with longer time to progression in 31 patients receiving cisplatin-based second-line therapy.The mRNA expression of BRCA1, RRM1 and RRM2 is potentially a useful tool for selecting NSCLC patients for individualized chemotherapy and warrants further investigation in prospective studies