Stereoisomer libraries: Total synthesis of all 16 stereoisomers of the pine sawfly sex pheromone by a fluorous mixture-synthesis approach

All 16 stereoisomers of the sex pheromone of pine sawfly (3,7,11-trimethylundecanol propanoate ester) have been synthesized on a 10- to 20-mg scale by a split-parallel fluorous mixture-synthesis approach. Spectral data obtained for all 32 compounds (16 alcohols and the corresponding propionates) matched well with published data, thereby validating the fluorous-tag encoding of diastereoisomers. This fluorous-tag encoding method is recommended for the efficient synthesis of multiple stereoisomers for spectroscopic studies, biological tests, or other structure-function relationships

Effects of Deliberate Ingestion of Organophosphate or Paraquat on Brain Stem Auditory-Evoked Potentials

Organophosphate (OP) and paraquat (PQ) ingestion is a serious health problem. A common pathology behind OP or PQ poisoning is the generation of reactive oxygen species (ROS) which is known to cause ototoxicity. The aim of the study was to identify the effects of deliberate ingestion of OP or PQ on brain stem auditory-evoked potentials (BAEPs). Consecutive patients with deliberate self-poisoning with OP or PQ who were admitted to a secondary and a tertiary care hospital in the Southern province of Sri Lanka and matched controls were recruited. BAEPs were performed at 1 week (first assessment) and 6 weeks (second assessment) after the exposure. Interpeak latencies of I–III, III–V, and I–V were measured. There were 70 and 28 patients in the OP and PQ arms with the mean age of 32 ± 12 and 29 ± 12 years, respectively. There were 70 controls and their mean age was 33 ± 12 years. In OP and PQ poisoning, 53/70 and 18/28 came for the second assessment, respectively. The interpeak latency was not statistically different in the controls vs the first assessment, controls vs the second assessment, and the first vs the second assessment. There were no significant lesions in the auditory pathway in OP or PQ poisoned patients. The generation of ROS within the perilymphatic space following the ingestion of OP or PQ may not be sufficient to cause lesions in the auditory pathway. Further studies with the assessment of auditory threshold are needed

α-Actinin-4 Is Essential for Maintaining the Spreading, Motility and Contractility of Fibroblasts

Background: α-actinins cross-link actin filaments, with this cross-linking activity regulating the formation of focal adhesions, intracellular tension, and cell migration. Most non-muscle cells such as fibroblasts express two isoforms, α-actinin-1 (ACTN1) and α-actinin-4 (ACTN4). The high homology between these two isoforms would suggest redundancy of their function, but recent studies have suggested different regulatory roles. Interestingly, ACTN4 is phosphorylated upon growth factor stimulation, and this loosens its interaction with actin. Methodology/Principal Findings: Using molecular, biochemical and cellular techniques, we probed the cellular functions of ACTN4 in fibroblasts. Knockdown of ACTN4 expression in murine lung fibroblasts significantly impaired cell migration, spreading, adhesion, and proliferation. Surprisingly, knockdown of ACTN4 enhanced cellular compaction and contraction force, and increased cellular and nuclear cross-sectional area. These results, except the increased contractility, are consistent with a putative role of ACTN4 in cytokinesis. For the transcellular tension, knockdown of ACTN4 significantly increased the expression of myosin light chain 2, a element of the contractility machinery. Re-expression of wild type human ACTN4 in ACTN4 knockdown murine lung fibroblasts reverted cell spreading, cellular and nuclear cross-sectional area, and contractility back towards baseline, demonstrating that the defect was due to absence of ACTN4. Significance: These results suggest that ACTN4 is essential for maintaining normal spreading, motility, cellular and nuclear cross-sectional area, and contractility of murine lung fibroblasts by maintaining the balance between transcellular contractility and cell-substratum adhesion. © 2010 Shao et al

Development of Cancer Surveillance Guidelines in Ataxia Telangiectasia: A Delphi-Based Consensus Survey of International Experts

BACKGROUND/OBJECTIVES: Ataxia telangiectasia (A-T) is a multiorgan disorder with increased vulnerability to cancer. Despite this increased cancer risk, there are no widely accepted guidelines for cancer surveillance in people affected by A-T. We aimed to understand the current international practice regarding cancer surveillance in A-T and agreed-upon approaches to develop cancer surveillance in A-T. DESIGN/METHODS: We used a consensus development method, the e-Delphi technique, comprising three rounds. Round 1 consisted of a Delphi questionnaire and a survey that collected the details of respondents\u27 professional background, experience, and current practice of cancer surveillance in A-T. Rounds 2 and 3 were designed based on previous rounds and modified according to the comments made by the panellists. The pre-specified consensus threshold was ≥75% agreement. RESULTS: Thirty-five expert panellists from 13 countries completed the study. The survey indicated that the current practice of cancer surveillance varies widely between experts and centres\u27. Consensus was reached that evidence-based guidelines are needed for cancer surveillance in people with A-T, with separate recommendations for adults and children. Statements relating to the tests that should be included, the age for starting and stopping cancer surveillance and the optimal surveillance interval were also agreed upon, although in some areas, the consensus was that further research is needed. CONCLUSION: The international expert consensus statement confirms the need for evidence-based cancer surveillance guidelines in A-T, highlights key features that the guidelines should include, and identifies areas of uncertainty in the expert community. This elucidates current knowledge gaps and will inform the design of future clinical trials

Outcome of children and adolescents with central nervous system tumors in phase I trials

Central nervous system (CNS) tumors are a leading cause of death in pediatric oncology. New drugs are desperately needed to improve survival. We evaluated the outcome of children and adolescents with CNS tumors participating in phase I trials within the Innovative Therapies for Children with Cancer (ITCC) consortium. Patients with solid tumors aged < 18 years at enrollment in their first dose-finding trial between 2000 and 2014 at eight ITCC centers were included retrospectively. Survival was evaluated using univariate/multivariate analyses. Overall, 114 patients were included (109 evaluable for efficacy). Median age was 10.2 years (range 1.0-17.9). Main diagnoses included: medulloblastoma/primitive neuroectodermal tumors (32.5%) and high-grade gliomas (23.7%). Complete/partial responses (CR/PR) were reported in 7.3% patients and stable disease (SD) in 23.9%. Performance status of 90-100%, school/work attendance, normal ALT/AST and CR/PR/SD correlated with better overall survival (OS) in the univariate analysis. No variables assessable at screening/enrollment were associated with OS in the multivariate analysis. Five patients (4.5%) were discontinued from study due to toxicity. No toxic deaths occurred. Median OS was 11.9 months with CR/PR, 14.5 months with SD and 3.7 months with progressive disease (p < 0.001). The enrollment of children and adolescents with CNS tumors in phase I trials is feasible, safe and offers potential benefit for the patients. Sustained disease stabilization has a promising role as a marker of anti-tumor activity in children with CNS tumors participating in phase I trials

Genetics of focal segmental glomerulosclerosis

The recent advances in understanding the pathophysiology of focal segmental glomerulosclerosis (FSGS) and molecular function of glomerular filtration barrier come directly from genetic linkage and positional cloning studies. The exact role and function of the newly discovered genes and proteins are being investigated by in vitro and in vivo mechanistic studies. Those genes and proteins interactions seem to change susceptibility to kidney disease progression. Better understanding of their exact role in the development of FSGS may influence future therapies and outcomes in this complex disease