Use of Most Bothersome Symptom as a Coprimary Endpoint in Migraine Clinical Trials: A Post-Hoc Analysis of the Pivotal ZOTRIP Randomized, Controlled Trial.

ObjectiveTo better understand the utility of using pain freedom and most bothersome headache-associated symptom (MBS) freedom as co-primary endpoints in clinical trials of acute migraine interventions.BackgroundAdhesive dermally applied microarray (ADAM) is an investigational system for intracutaneous drug administration. The recently completed pivotal Phase 2b/3 study (ZOTRIP), evaluating ADAM zolmitriptan for the treatment of acute moderate to severe migraine, was one of the first large studies to incorporate MBS freedom and pain freedom as co-primary endpoints per recently issued guidance by the US Food and Drug Administration. In this trial, the proportion of patients treated with ADAM zolmitriptan 3.8 mg, who were pain-free and MBS-free at 2 hours post-dose, was significantly higher than for placebo.MethodsWe undertook a post-hoc analysis of data from the ZOTRIP trial to examine how the outcomes from this trial compare to what might have been achieved using the conventional co-primary endpoints of pain relief, nausea, photophobia, and phonophobia.ResultsOf the 159 patients treated with ADAM zolmitriptan 3.8 mg or placebo, prospectively designated MBS were photophobia (n = 79), phonophobia (n = 43), and nausea (n = 37). Two-hour pain free rates in those with photophobia as the MBS were 36% for ADAM zolmitriptan 3.8 mg and 14% for placebo (P = .02). Corresponding rates for those with phonophobia as the MBS were 14% and 41% (P = .05). For those whose MBS was nausea, corresponding values were 56% and 16%, respectively (P = .01). Two-hour freedom from the MBS for active drug vs placebo were 67% vs 35% (P < .01) for photophobia, 55% vs 43% (P = .45) for phonophobia, and 89% vs 58% for nausea (P = .04). MBS freedom but not pain freedom was achieved in 28%. Only 1 patient (1%) achieved pain freedom, but not MBS freedom. The proportion with both pain and MBS freedom was highest (56%) among those whose MBS was nausea.ConclusionIn this study, the use of MBS was feasible and seemed to compare favorably to the previously required 4 co-primary endpoints

Inhibiting adenoid cystic carcinoma cells growth and metastasis by blocking the expression of ADAM 10 using RNA interference

<p>Abstract</p> <p>Background</p> <p>Adenoid cystic carcinoma is one of the most common types of salivary gland cancers. The poor long-term prognosis for patients with adenoid cystic carcinoma is mainly due to local recurrence and distant metastasis. Disintegrin and metalloprotease 10 (ADAM 10) is a transmembrane protein associated with metastasis in a number of diverse of cancers. The aim of this study was to analyze the relationship between ADAM 10 and the invasive and metastatic potentials as well as the proliferation capability of adenoid cystic carcinoma cells <it>in vitro </it>and <it>in vivo</it>.</p> <p>Methods</p> <p>Immunohistochemistry and Western blot analysis were applied to detect ADAM 10 expression levels in metastatic cancer tissues, corresponding primary adenoid cystic carcinoma tissues, adenoid cystic carcinoma cell lines with high metastatic potential, and adenoid cystic carcinoma cell lines with low metastatic potential. RNA interference was used to knockdown ADAM 10 expression in adenoid cystic carcinoma cell lines with high metastatic potential. Furthermore, the invasive and metastatic potentials as well as the proliferation capability of the treated cells were observed <it>in vitro </it>and <it>in vivo</it>.</p> <p>Results</p> <p>It was observed that ADAM 10 was expressed at a significantly higher level in metastatic cancer tissues and in adenoid cystic carcinoma cell lines with high metastatic potential than in corresponding primary adenoid cystic carcinomas and adenoid cystic carcinoma cell lines with low metastatic potential. Additionally, silencing of ADAM 10 resulted in inhibition of cell growth and invasion <it>in vitro </it>as well as inhibition of cancer metastasis in an experimental murine model of lung metastases <it>in vivo</it>.</p> <p>Conclusions</p> <p>These studies suggested that ADAM 10 plays an important role in regulating proliferation and metastasis of adenoid cystic carcinoma cells. ADAM 10 is potentially an important therapeutic target for the prevention of tumor metastases in adenoid cystic carcinoma.</p

Caecilia volcani

Number of Pages: 2Integrative BiologyGeological Science

Triangle Singularities and XYZ Quarkonium Peaks

We discuss analytical properties of partial waves derived from projection of a 4-legged amplitude with crossed-channel exchanges in the kinematic region of the direct channel that corresponds to the XYZ peaks in charmonium and bottomonium. We show that in general partial waves can develop anomalous branch points in the vicinity of the direct channel physical region. In a specific case, when these branch points lie on the opposite side of the unitary cut they pinch the integration contour in a dispersion relation and if the pinch happens close to threshold, the normal threshold cusp is enhanced. We show that this effect only occurs if masses of resonances in the crossed channel are in a specific, narrow range. We estimate the size of threshold enhancements originating from these anomalous singularities in reactions where the Zc(3900) and the Zb(10610) peaks have been observed.Comment: 10 pages, 9 figures, Version v3 to appear in Phys. Lett.

Optimal entanglement witnesses based on local orthogonal observables

We show that the entanglement witnesses based on local orthogonal observables which are introduced in [S. Yu and N.-L. Liu, Phys. Rev. Lett. 95, 150504 (2005)] and [O. G\"uhne, M. Mechler, G. T\'oth and P. Adam, Phys. Rev. A 74, 010301 (2006)] in linear and nonlinear forms can be optimized, respectively. As applications, we calculate the optimal nonlinear witnesses of pure bipartite states and show a lower bound on the I-concurrence of bipartite higher dimensional systems with our method.Comment: 6 pages, 1 figure; minor changes, references adde