Citations

Purpose We conducted a phase II study of combination of the anti–insulin-like growth factor 1 receptor antibody CP-751,871 with paclitaxel and carboplatin (PCI) in advanced treatment-naïve non–small-cell lung cancer (NSCLC). Patients and Methods Patients were randomly assigned (2:1) to paclitaxel 200 mg/m2, carboplatin (area under the plasma concentration-time curve of 6), and CP-751,871 10 to 20 mg/kg (PCI10, PCI20) or paclitaxel and carboplatin alone (PC) every 3 weeks for up to six cycles. PCI10-20 patients could continue CP-751,871 (figitumumab) treatment after chemotherapy discontinuation. Patients treated with PC experiencing disease progression were eligible to receive CP-751,871 at investigator's discretion. An additional nonrandomized single-arm cohort of 30 patients with nonadenocarcinoma tumor histology receiving PCI20 was enrolled on completion of the randomized study. Results A total of 156 patients were enrolled onto the randomized portion of the study. Safety and efficacy information are available for 151 patients (98 patients treated with PCI and 53 patients treated with PC). Forty-eight patients treated with PCI received PCI10 and 50 patients received PCI20 in two sequential stages. Twenty of 53 patients treated with PC received CP-751,871 after disease progression. PCI was well tolerated. Fifty-four percent of patients treated with PCI and 42% of patients treated with PC had objective responses. Sixteen of 23 patients assessable for efficacy in the nonrandomized single-arm extension cohort also responded to treatment. Of note, 14 of 18 randomly assigned and 11 of 14 nonrandomly assigned patients treated with PCI with squamous cell carcinoma histology had response to treatment, including nine objective responses in bulky disease. Responses were also observed in two patients with squamous histology receiving CP-751,871 on PC discontinuation. PCI20/PC hazard ratio for progression-free survival was 0.8 to 0.56, according to censorship. Conclusion These data suggest that PCI20 is safe and effective in patients with NSCLC.

Zusammenfassung Zilien erfüllen viele unterschiedliche Funktionen, sie dienen als Mechano-, Chemo- und Osmosensoren und spielen bei zahlreichen Signalwegen, für eine adäquate Organentwicklung, für die Aufrechterhaltung der Gewebehomöostase und bei grundsätzlichen Entwicklungsprozessen eine wichtige Rolle. Die meisten Zelltypen im Körper weisen primäre Zilien auf, motile Zilien kommen v. a. im Respirationstrakt, ependymal in den Hirnventrikeln sowie auf Eileiterepithelien vor. Mit einem Funktionsverlust der Zilien einhergehende Krankheiten werden als Ziliopathien bezeichnet. Im vorliegenden Beitrag werden einige Erkrankungen, wie die primäre ziliäre Dyskinesie (PCD) oder polyzystische Nierenerkrankungen (PKD) und hier insbesondere die ADPKD (autosomal-dominante PKD), vorgestellt. Zudem werden die bisher identifizierten Gene, die bei der Pathogenese von Ziliopathien eine Rolle spielen, vorgestellt. Dabei verursachen viele der Genmutationen mehr als nur eine Erkrankung, und viele der aufgeführten Merkmale kommen bei verschiedenen Krankheiten vor.

In this era of budgetary constraints, the biggest threat to continuing biomedical research is often seen as governmental funding cutbacks. However, a much larger threat looms—the antiscientific programs of the various so-called animal rights groups. Unless clinicians and scientists mount a concerted defense of scientific investigation, the repressive antiscience movement will win out and thrust us into a Dark Ages scenario, with only a few gallant enough to maintain scientific thought until another Enlightenment. During World War II, the German clergyman Martin Niemoeller lamented the general apathy that allowed a small group of dedicated ideologues (the Nazi hierarchy) to terrorize the Germans: "In Germany they came first for the Communists, and I didn't speak up because I wasn't a Communist. Then they came for the Jews, and I didn't speak up because I wasn't a Jew. Then they came for the trade unionists, and I didn't speak up because I wasn't a trade unionist. Then they came for the Catholics, and I didn't speak up because I was a Protestant. Then they came for me, and by that time no one was left to speak up." Not dissimilarly, the apathy of clinicians and biomedical scientists has permitted the radical animal rights movement to terrorize researchers and undermine our research freedom. In a call to action, the American Academy of Neurology has developed a statement (in association with the Foundation for Biomedical Research and other groups) on the threat to neurology research. This information was originally published in Neurology (1995;45: 609-610). In order to increase the dissemination of this important warning to clinicians and scientists everywhere, the Journal of Child Neurology in cooperation with the American Academy of Neurology is reprinting that material in this issue.

The Par-1 protein kinases are conserved from yeast to humans, where they function as key polarity determinants. The mammalian Par-1 family is comprised of 4 members (Par-1a, -b, -c, and -d). Previously, we demonstrated that atypical protein kinase C (aPKC) phosphorylates the Par-1 kinases on a conserved threonine residue (T595) to regulate localization and kinase activity. Here, we demonstrate that Par-1b is also regulated by another arm of the PKC pathway, one that involves novel PKCs (nPKC) and protein kinase D. Treatment of cells with the PKC activator phorbol-12-myristate-13-acetate (PMA) potently stimulated phosphorylation of Par-1b on serine 400 (S400), a residue that is conserved in all 4 mammalian Par-1 kinases as well as the fly ortholog. We demonstrate that PMA stimulates nPKC to activate PKD, which in turn directly phosphorylates Par-1b on S400 to positively regulate 14-3-3 binding and to negatively regulate membrane association. Thus, 2 arms of the PKC pathway regulate interactions between Par-1b and 14-3-3 proteins: one involving aPKC and the other nPKC/PKD.

ObjectiveTo identify research priorities to increase understanding of the pathogenesis, diagnosis, and improved treatment of spasmodic dysphonia.Study Design and SettingA multidisciplinary working group was formed that included both scientists and clinicians from multiple disciplines (otolaryngology, neurology, speech pathology, genetics, and neuroscience) to review currently available information on spasmodic dysphonia and to identify research priorities.ResultsOperational definitions for spasmodic dysphonia at different levels of certainty were recommended for diagnosis and recommendations made for a multicenter multidisciplinary validation study.ConclusionsThe highest priority is to characterize the disorder and identify risk factors that may contribute to its onset. Future research should compare and contrast spasmodic dysphonia with other forms of focal dystonia. Development of animal models is recommended to explore hypotheses related to pathogenesis. Improved understanding of the pathophysiology of spasmodic dysphonia should provide the basis for developing new treatment options and exploratory clinical trials.SignificanceThis document should foster future research to improve the care of patients with this chronic debilitating voice and speech disorder by otolaryngology, neurology, and speech pathology.

Background and Purpose— Evidence supports a substantial genetic contribution to the risk of intracranial aneurysm (IA). The purpose of this study was to identify chromosomal regions likely to harbor genes that contribute to the risk of IA. Methods— Multiplex families having at least 2 individuals with “definite” or “probable” IA were ascertained through an international consortium. First-degree relatives of individuals with IA who were at increased risk of an IA because of a history of hypertension or present smoking were offered cerebral magnetic resonance angiography. A genome screen was completed using the Illumina 6K SNP system, and the resulting data from 192 families, containing 1155 genotyped individuals, were analyzed. Narrow and broad disease definitions were used when testing for linkage using multipoint model-independent methods. Ordered subset analysis was performed to test for a gene×smoking (pack-years) interaction. Results— The greatest evidence of linkage was found on chromosomes 4 (LOD=2.5; 156 cM), 7 (LOD=1.7; 183 cM), 8 (LOD=1.9; 70 cM), and 12 (LOD=1.6; 102 cM) using the broad disease definition. Using the average pack-years for the affected individuals in each family, the genes on chromosomes 4 (LOD=3.5; P =0.03), 7 (LOD=4.1; P =0.01) and 12 (LOD=3.6; P =0.02) all appear to be modulated by the degree of smoking in the affected members of the family. On chromosome 8, inclusion of smoking as a covariate did not significantly strengthen the linkage evidence, suggesting no interaction between the loci in this region and smoking. Conclusions— We have detected possible evidence of linkage to 4 chromosomal regions. There is potential evidence for a gene×smoking interaction with 3 of the loci.

This paper examined the feasibility of using different optimization criteria in inverse dynamic optimization to predict antagonistic muscle forces and joint reaction forces during isokinetic flexion/extension and isometric extension exercises of the knee. Both quadriceps and hamstrings muscle groups were included in this study. The knee joint motion included flexion/extension, varus/valgus, and internal/external rotations. Four linear, nonlinear, and physiological optimization criteria were utilized in the optimization procedure. All optimization criteria adopted in this paper were shown to be able to predict antagonistic muscle contraction during flexion and extension of the knee. The predicted muscle forces were compared in temporal patterns with EMG activities (averaged data measured from five subjects). Joint reaction forces were predicted to be similar using all optimization criteria. In comparison with previous studies, these results suggested that the kinematic information involved in the inverse dynamic optimization plays an important role in prediction of the recruitment of antagonistic muscles rather than the selection of a particular optimization criterion. Therefore, it might be concluded that a properly formulated inverse dynamic optimization procedure should describe the knee joint rotation in three orthogonal planes.

Purpose Objective tumor response rates observed in phase II trials for metastatic melanoma have historically not provided a reliable indicator of meaningful survival benefits. To facilitate using overall survival (OS) or progression-free survival (PFS) as an endpoint for future phase II trials, we evaluated historical data from cooperative group phase II trials to attempt to develop benchmarks for OS and PFS as reference points for future phase II trials. Patients and Methods Individual-level and trial-level data were obtained for patients enrolled onto 42 phase II trials (70 trial arms) that completed accrual in the years 1975 through 2005 and conducted by Southwest Oncology Group, Eastern Cooperative Oncology Group, Cancer and Leukemia Group B, North Central Cancer Treatment Group, and the Clinical Trials Group of the National Cancer Institute of Canada. Univariate and multivariate analyses were performed to identify prognostic variables, and between-trial(-arm) variability in 1-year OS rates and 6-month PFS rates were examined. Results Statistically significant individual-level and trial-level prognostic factors found in a multivariate survival analysis for OS were performance status, presence of visceral disease, sex, and whether the trial excluded patients with brain metastases. Performance status, sex, and age were statistically significant prognostic factors for PFS. Controlling for these prognostic variables essentially eliminated between-trial variability in 1-year OS rates but not in 6-month PFS rates. Conclusion Benchmarks are provided for 1-year OS or OS curves that make use of the distribution of prognostic factors of the patients in the phase II trial. A similar benchmark for 6-month PFS is provided, but its use is more problematic because of residual between-trial variation in this endpoint.