Bone Surface Micro-Topography at Craniofacial Entheses: Insights on Osteogenic Adaptation at Muscle Insertions.

Macroscopic details of the bone-muscle interface are represented by a mosaic of calcified features inclusive of fossae, tuberosities, crests, and ridges. These features are in part of an adaptive osteogenic response to dissipate forces of localized mechanical loading. In an osteoarchaeological or paleontological context, these features are interpreted as "musculoskeletal stress markers" to infer habitual behaviors.

The superficial musculoaponeurotic system of the face: a model explored.

Regional differences in the integument of the body are explained, at least in part, by differences in fascial arrangements. In the face, where the skin is more mobile due to the action of the underlying facial muscles, fascial organisation is important for support and separation of muscle groups. This study used bequeathed cadaver material to investigate a current model of the SMAS proposed by Macchi et al.

Expression of an electrically silent voltage-gated potassium channel in the human placenta.

Human placental expression of K(V)9.3, a voltage-gated K channel linked to tissue oxygenation responses, has been suggested at the messenger RNA level but tissue localisation has not been described. We aimed to: (1) produce an antibody to human K(V)9.

Analysis of tumor burden versus progression-free survival for Phase II decision making.

Purpose: There have been recent recommendations to use percentage change in tumor burden (dTB) as a primary endpoint in randomized Phase II trials. We assessed whether dTB is better for the decision to start a Phase III trial than is progression-free survival (PFS).

Methods: We repeatedly sampled patients from six large randomized trials to obtain simulated Phase II trials.

Optimizing collection of adverse event data in cancer clinical trials supporting supplemental indications.

Purpose: Although much is known about the safety of an anticancer agent at the time of initial marketing approval, sponsors customarily collect comprehensive safety data for studies that support supplemental indications. This adds significant cost and complexity to the study but may not provide useful new information. The main purpose of this analysis was to assess the amount of safety and concomitant medication data collected to determine a more optimal approach in the collection of these data when used in support of supplemental applications.

Data submission standards and evidence requirements.

Presented are recommendations of the Data Submission Standards and Evidence Requirements panel from the Conference on Clinical Cancer Research along with the U.S. Food and Drug Administration's response to these recommendations.

Role of sensitivity analyses in assessing progression-free survival in late-stage oncology trials.

Sensitivity analysis is an important statistical technique that assesses whether the results of phase III trials are robust and likely to be generalizable. Until recently, sensitivity analyses were rarely included in phase III trials, and they remain poorly understood by many oncologists. Sensitivity analyses are critical to understanding the strength of conclusions made in the primary analysis of a late-stage clinical trial.

K+ channel inhibition modulates the biochemical and morphological differentiation of human placental cytotrophoblast cells in vitro.

Maintaining placental syncytiotrophoblast, a specialized multinucleated transport epithelium, is essential for normal human pregnancy. Syncytiotrophoblast continuously renews through differentiation and fusion of cytotrophoblast cells, under paracrine control by syncytiotrophoblast production of human chorionic gonadotropin (hCG). We hypothesized that K(+) channels participate in trophoblast syncytialization and hCG secretion in vitro.

Expression and function of potassium channels in the human placental vasculature.

In the placental vasculature, where oxygenation may be an important regulator of vascular reactivity, there is a paucity of data on the expression of potassium (K) channels, which are important mediators of vascular smooth muscle tone. We therefore addressed the expression and function of several K channel subtypes in human placentas. The expression of voltage-gated (Kv)2.

Reactivity of human placental chorionic plate vessels from pregnancies complicated by intrauterine growth restriction (IUGR).

A successful pregnancy is dependent on liberal placental perfusion via the maternal and fetal circulations. Doppler waveform analyses of umbilical arteries suggest increased resistance to flow in the fetoplacental circulation of pregnancies complicated by intrauterine growth restriction (IUGR). Neither the site nor the mediators responsible for this altered vascular reactivity are known, to date.

TASK channel expression in human placenta and cytotrophoblast cells.

Objective: The multinucleate syncytiotrophoblast is the transporting epithelium of the human placental villus, formed throughout pregnancy by fusion and differentiation of underlying mononucleate cytotrophoblast cells. Similar to other epithelia, K+ channels will impact on syncytiotrophoblast transport properties during its development and differentiation. Therefore we investigated expression and activity of the two-pore domain K+ channels TASK1 and 2 in relation to gestation and differentiation, using villous tissue from first and third trimester and cultured cytotrophoblast cells at mononucleate and multinucleate stages of culture.

Glibenclamide inhibits agonist-induced vasoconstriction of placental chorionic plate arteries.

Background: Preliminary data suggest that K(ATP) channels may be expressed in placental arteries and veins [Wareing M, Turner C, Greenwood SL, Baker PN, Fyfe GK. Expression of mRNA encoding K+ channels in chorionic plate arteries and veins. J Soc Gynecol Investig 2004;11:353A].

Expression of TASK and TREK, two-pore domain K+ channels, in human myometrium.

Two-pore domain K+ channels are an emerging family of K+ channels that may contribute to setting membrane potential in both electrically excitable and non-excitable cells and, as such, influence cellular function. The human uteroplacental unit contains both excitable (e.g.

Phase I clinical study of pertuzumab, a novel HER dimerization inhibitor, in patients with advanced cancer.

Purpose: Pertuzumab, a recombinant humanized monoclonal antibody (2C4), binds to extracellular domain II of the HER-2 receptor and blocks its ability to dimerize with other HER receptors. Pertuzumab represents a new class of targeted therapeutics known as HER dimerization inhibitors. A clinical study was conducted to investigate safety and pharmacokinetics of pertuzumab and to perform a preliminary assessment of HER dimerization inhibition as a treatment strategy.

Localization of TASK and TREK, two-pore domain K+ channels, in human cytotrophoblast cells.

Objective: Two-pore domain K+ channels (K2P), an emerging K+ channel subfamily, contribute to setting membrane potential in both electrically excitable and nonexcitable cells and, as such, influence cellular function. The multinucleate syncytiotrophoblast of human placenta, formed from the fusion of mononucleate cytotrophoblast cells, is a transporting epithelium whose function likely depends on the activity of K+ channels. We have therefore investigated the gene expression of two members of this family, TASK and TREK, in cultured human cytotrophoblast cells, and have also investigated protein expression in cytotrophoblast cells and placenta.

Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer.

Background: Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, has shown promising preclinical and clinical activity against metastatic colorectal cancer, particularly in combination with chemotherapy.

Methods: Of 813 patients with previously untreated metastatic colorectal cancer, we randomly assigned 402 to receive irinotecan, bolus fluorouracil, and leucovorin (IFL) plus bevacizumab (5 mg per kilogram of body weight every two weeks) and 411 to receive IFL plus placebo. The primary end point was overall survival.

A randomized controlled trial evaluating the efficacy and safety of intermittent 3-, 4-, and 5-day cycles of intravenous recombinant human interleukin-2 combined with antiretroviral therapy (ART) versus ART alone in HIV-seropositive patients with 100-300 CD4+ T cells.

The effect of length of therapy on the safety and efficacy profile of continuous intravenous (CIV) interleukin-2 (IL-2) in combination with antiretroviral therapy (ART) was evaluated in 81 HIV-seropositive patients with CD4(+) T-cell counts of 100-300/mm(3). Patients were randomized to CIV IL-2 (12 mIU/day) for 3, 4, or 5 days plus ART every 8 weeks for six cycles, or to ART alone. The mean percent increase in CD4(+) T-cell counts was 24.

Phase Ib trial of intravenous recombinant humanized monoclonal antibody to vascular endothelial growth factor in combination with chemotherapy in patients with advanced cancer: pharmacologic and long-term safety data.

Purpose: Tumor angiogenesis mediated by vascular endothelial growth factor (VEGF) is inhibited by the recombinant humanized (rhu) monoclonal antibody (MAb) rhuMAbVEGF, which has synergy with chemotherapy in animal models. The present study was designed to assess the safety and pharmacokinetics of weekly intravenous (IV) rhuMAbVEGF with one of three standard chemotherapy regimens.

Patients And Methods: Twelve adult patients were enrolled four on each combination.

Recombinant human thrombopoietin clinical development.

Patients undergoing anticancer therapy are often at risk for developing severe and/or prolonged posttreatment thrombocytopenia. This can be associated with significant bleeding; currently, it is treated with supportive platelet transfusions. Frequent platelet transfusions can cause alloimmunization which requires HLA-matched donors and more frequent blood transfusions, and transmission of both viral and bacterial infections via platelet transfusions remains a concern.

Pooled analysis of 3 randomized, controlled trials of interleukin-2 therapy in adult human immunodeficiency virus type 1 disease.

We collected human immunodeficiency virus (HIV) disease progression, survival, most recent CD4 cell count, and plasma HIV RNA levels from patients (n=157) who participated in randomized clinical trials of interleukin (IL)-2 that commenced before 1995. Data were available for 155 (99%) patients. Statistical analyses were based on the intention-to-treat principle.

Structure and regulation of amiloride-sensitive sodium channels.

Amiloride-sensitive Na+ channels constitute a new class of proteins known as the ENaC-Deg family of ion channels. All members in this family share a common protein structure but differ in their ion selectivity, their affinity for the blocker amiloride, and in their gating mechanisms. These channels are expressed in many tissues of invertebrate and vertebrate organisms where they serve diverse functions varying from Na+ absorption across epithelia to being the receptors for neurotransmitters in the nervous system.

Long-term survival update for high-dose recombinant interleukin-2 in patients with renal cell carcinoma.

Purpose: To update response duration and survival data for patients with metastatic renal cell carcinoma treated with high-dose interleukin (IL)-2.

Patients And Methods: Two hundred fifty-five assessable patients were entered onto seven phase II clinical trials. Recombinant IL-2 600,000 or 720,000 IU/kg was administered by 15-minute intravenous infusion every 8 hours for up to 14 consecutive doses over 5 days as clinically tolerated with maximal support.

The second hydrophobic domain contributes to the kinetic properties of epithelial sodium channels.

The epithelial sodium channel (ENaC) is the prototype of a new class of ion channels known as the ENaC/Deg family. The hallmarks of ENaC are a high selectivity for Na(+), block by amiloride, small conductance, and slow kinetics that are voltage-independent. We have investigated the contribution of the second hydrophobic domain of each of the homologous subunits alpha, beta, and gamma to the kinetic properties of ENaC.