Phase 1 Safety and Tolerability Study of BMP-7 in Symptomatic Knee Osteoarthritis

BACKGROUND: There are no proven therapies that modify the structural changes associated with osteoarthritis (OA). Preclinical data suggests that intra-articular recombinant human BMP-7 (bone morphogenetic protein-7) has reparative effects on cartilage, as well as on symptoms of joint pain. The objective of this study was to determine the safety and tolerability as well as dose-limiting toxicity and maximal tolerated dose of intra-articular BMP-7. The secondary objectives were to determine the effect on symptomatic responses through 24 weeks. METHODS: This was a Phase 1, double-blind, randomized, multi-center, placebo-controlled, single-dose escalation safety study consisting of 4 dosing cohorts in participants with knee OA. Each cohort was to consist of 8 treated participants, with treatment allocation in a 3:1 active (intra-articular BMP-7) to placebo ratio. Eligible participants were persons with symptomatic radiographic knee OA over the age of 40. The primary objective of this study was to determine the safety and tolerability of BMP-7 including laboratory assessments, immunogenicity data and radiographic assessments. Secondary objectives were to determine the proportion of participants with a 20%, 50%, and 70% improvement in the WOMAC pain and function subscales at 4, 8, 12, and 24 weeks. Other secondary outcomes included the change from baseline to 4, 8, 12, and 24 weeks for the OARSI responder criteria. RESULTS: The mean age of participants was 60 years and 73% were female. All 33 participants who were enrolled completed the study and most adverse events were mild or moderate and were similar in placebo and BMP-7 groups. The 1 mg BMP-7 group showed a higher frequency of injection site pain and there was no ectopic bone formation seen on plain x-rays. By week 12, most participants in both the BMP-7 and placebo groups experienced a 20% improvement in pain and overall the BMP-7 group was similar to placebo with regard to this measurement. In the participants who received 0.1 mg and 0.3 mg BMP-7, there was a trend toward greater symptomatic improvement than placebo. The other secondary endpoints showed similar trends including the OARSI responder criteria for which the BMP-7 groups had more responders than placebo. CONCLUSIONS: There was no dose limiting toxicity identified in this study. The suggestion of a symptom response, together with the lack of dose limiting toxicity provide further support for the continued development of this product for the treatment of osteoarthritis.ARC Future Fellowship; Stryker Biotec

Level-3 Calorimetric Resolution available for the Level-1 and Level-2 CDF Triggers

As the Tevatron luminosity increases sophisticated selections are required to be efficient in selecting rare events among a very huge background. To cope with this problem, CDF has pushed the offline calorimeter algorithm reconstruction resolution up to Level 2 and, when possible, even up to Level 1, increasing efficiency and, at the same time, keeping under control the rates. The CDF Run II Level 2 calorimeter trigger is implemented in hardware and is based on a simple algorithm that was used in Run I. This system has worked well for Run II at low luminosity. As the Tevatron instantaneous luminosity increases, the limitation due to this simple algorithm starts to become clear: some of the most important jet and MET (Missing ET) related triggers have large growth terms in cross section at higher luminosity. In this paper, we present an upgrade of the Level 2 Calorimeter system which makes the calorimeter trigger tower information available directly to a CPU allowing more sophisticated algorithms to be implemented in software. Both Level 2 jets and MET can be made nearly equivalent to offline quality, thus significantly improving the performance and flexibility of the jet and MET related triggers. However in order to fully take advantage of the new L2 triggering capabilities having at Level 1 the same L2 MET resolution is necessary. The new Level-1 MET resolution is calculated by dedicated hardware. This paper describes the design, the hardware and software implementation and the performance of the upgraded calorimeter trigger system both at Level 2 and Level 1.Comment: 5 pages, 5 figures,34th International Conference on High Energy Physics, Philadelphia, 200

Feasibility and Cardiac Safety of Trastuzumab Emtansine After Anthracycline-Based Chemotherapy As (neo) Adjuvant Therapy for Human Epidermal Growth Factor Receptor 2-Positive Early-Stage Breast Cancer

Purpose Trastuzumab emtansine (T-DM1), an antibody-drug conjugate comprising the cytotoxic agent DM1, a stable linker, and trastuzumab, has demonstrated substantial activity in human epidermal growth factor receptor 2 (HER2) -positive metastatic breast cancer, raising interest in evaluating the feasibility and cardiac safety of T-DM1 in early-stage breast cancer (EBC). Patients and Methods Patients (N = 153) with HER2-positive EBC and prechemotherapy left ventricular ejection fraction (LVEF) \u3e= 55% received (neo) adjuvant doxorubicin plus cyclophosphamide or fluorouracil plus epirubicin plus cyclophosphamide followed by T-DM1 for four cycles. Patients could then receive three to four cycles of optional docetaxel with or without trastuzumab. T-DM1 was then resumed with optional radiotherapy (sequential or concurrent) for 1 year (planned) of HER2-directed therapy. The coprimary end points were rate of prespecified cardiac events and safety. Results Median follow-up was 24.6 months. No prespecified cardiac events or symptomatic congestive heart failures were reported. Four patients (2.7%) had asymptomatic LVEF declines (\u3e= 10 percentage points from baseline to LVEF\u3c 50%), leading to T-DM1 discontinuation in one patient. Of 148 patients who received \u3e= one cycle of T-DM1, 82.4% completed the planned 1-year duration of HER2-directed therapy. During T-DM1 treatment, 38.5% and 2.7% of patients experienced grade 3 and 4 adverse events, respectively. Approximately 95% of patients receiving T-DM1 plus radiotherapy completed \u3e= 95% of the planned radiation dose with dela

Influence of oral processing on appetite and food intake - A systematic review and meta-analysis.

Food delivers energy, nutrients and a pleasurable experience. Slow eating and prolonged oro-sensory exposure to food during consumption can enhance the processes that promote satiation. This systematic review and meta-analysis investigated the effects of oral processing on subjective measures of appetite (hunger, desire to eat) and objectively measured food intake. The aim was to investigate the influence of oral processing characteristics, specifically "chewing" and "lubrication", on "appetite" and "food intake". A literature search of six databases (Cochrane library, PubMed, Medline, Food Science and Technology Abstracts, Web of Science, Scopus), yielded 12161 articles which were reduced to a set of 40 articles using pre-specified inclusion and exclusion criteria. A further two articles were excluded from the meta-analysis due to missing relevant data. From the remaining 38 papers, detailing 40 unique studies with 70 subgroups, raw data were extracted for meta-analysis (food intake n = 65, hunger n = 22 and desire to eat ratings n = 15) and analyzed using random effects modelling. Oral processing parameters, such as number of chews, eating rate and texture manipulation, appeared to influence food intake markedly but appetite ratings to a lesser extent. Meta-analysis confirmed a significant effect of the direct and indirect aspects of oral processing that were related to chewing on both self-reported hunger (-0.20 effect size, 95% confidence interval CI: -0.30, -0.11), and food intake (-0.28 effect size, 95% CI: -0.36, -0.19). Although lubrication is an important aspect of oral processing, few studies on its effects on appetite have been conducted. Future experiments using standardized approaches should provide a clearer understanding of the role of oral processing, including both chewing and lubrication, in promoting satiety

Braided racks, Hurwitz actions and Nichols algebras with many cubic relations

We classify Nichols algebras of irreducible Yetter-Drinfeld modules over groups such that the underlying rack is braided and the homogeneous component of degree three of the Nichols algebra satisfies a given inequality. This assumption turns out to be equivalent to a factorization assumption on the Hilbert series. Besides the known Nichols algebras we obtain a new example. Our method is based on a combinatorial invariant of the Hurwitz orbits with respect to the action of the braid group on three strands.Comment: v2: 35 pages, 6 tables, 14 figure

Survival, pathologic response, and genomics in CALGB 40601 (Alliance), a neoadjuvant Phase III trial of paclitaxel-trastuzumab with or without lapatinib in HER2-positive breast cancer

PURPOSE CALGB 40601 assessed whether dual versus single human epidermal growth factor receptor 2 (HER2) -targeting drugs added to neoadjuvant chemotherapy increased pathologic complete response (pCR). Here, we report relapse-free survival (RFS), overall survival (OS), and gene expression signatures that predict pCR and survival. PATIENTS AND METHODS Three hundred five women with untreated stage II and III HER2-positive breast cancer were randomly assigned to receive weekly paclitaxel combined with trastuzumab plus lapatinib (THL), trastuzumab (TH), or lapatinib (TL). The primary end point was pCR, and secondary end points included RFS, OS, and gene expression analyses. mRNA sequencing was performed on 264 pretreatment samples. RESULTS One hundred eighteen patients were randomly allocated to THL, 120 to TH, and 67 to TL. At more than 7 years of follow-up, THL had significantly better RFS and OS than did TH (RFS hazard ratio, 0.32; 95% CI, 0.14 to 0.71; P 5.005; OS hazard ratio, 0.34; 95% CI, 0.12 to 0.94; P 5.037), with no difference between TH and TL. Of 688 previously described gene expression signatures, significant associations were found in 215 with pCR, 45 with RFS, and only 22 with both pCR and RFS (3.2%). Specifically, eight immune signatures were significantly correlated with a higher pCR rate and better RFS. Among patients with residual disease, the immunoglobulin G signature was an independent, good prognostic factor, whereas the HER2-enriched signature, which was associated with a higher pCR rate, showed a significantly shorter RFS. CONCLUSION In CALGB 40601, dual HER2-targeting resulted in significant RFS and OS benefits. Integration of intrinsic subtype and immune signatures allowed for the prediction of pCR and RFS, both overall and within the residual disease group. These approaches may provide means for rational escalation and de-escalation treatment strategies in HER2-positive breast cancer

Epigenetic alterations differ in phenotypically distinct human neuroblastoma cell lines

<p>Abstract</p> <p>Background</p> <p>Epigenetic aberrations and a CpG island methylator phenotype have been shown to be associated with poor outcomes in children with neuroblastoma (NB). Seven cancer related genes (<it>THBS-1, CASP8, HIN-1, TIG-1, BLU, SPARC</it>, and <it>HIC-1</it>) that have been shown to have epigenetic changes in adult cancers and play important roles in the regulation of angiogenesis, tumor growth, and apoptosis were analyzed to investigate the role epigenetic alterations play in determining NB phenotype.</p> <p>Methods</p> <p>Two NB cell lines (tumorigenic LA1-55n and non-tumorigenic LA1-5s) that differ in their ability to form colonies in soft agar and tumors in nude mice were used. Quantitative RNA expression analyses were performed on seven genes in LA1-5s, LA1-55n and 5-Aza-dC treated LA1-55n NB cell lines. The methylation status around <it>THBS-1, HIN-1, TIG-1 </it>and <it>CASP8 </it>promoters was examined using methylation specific PCR. Chromatin immunoprecipitation assay was used to examine histone modifications along the <it>THBS-1 </it>promoter. Luciferase assay was used to determine <it>THBS-1 </it>promoter activity. Cell proliferation assay was used to examine the effect of 5-Aza-dC on NB cell growth. The soft agar assay was used to determine the tumorigenicity.</p> <p>Results</p> <p>Promoter methylation values for <it>THBS-1</it>, <it>HIN-1</it>, <it>TIG-1</it>, and <it>CASP8 </it>were higher in LA1-55n cells compared to LA1-5s cells. Consistent with the promoter methylation status, lower levels of gene expression were detected in the LA1-55n cells. Histone marks associated with repressive chromatin states (H3K9Me3, H3K27Me3, and H3K4Me3) were identified in the <it>THBS-1 </it>promoter region in the LA1-55n cells, but not the LA1-5s cells. In contrast, the three histone codes associated with an active chromatin state (acetyl H3, acetyl H4, and H3K4Me3) were present in the <it>THBS-1 </it>promoter region in LA1-5s cells, but not the LA1-55n cells, suggesting that an accessible chromatin structure is important for <it>THBS-1 </it>expression. We also show that 5-Aza-dC treatment of LA1-55n cells alters the DNA methylation status and the histone code in the <it>THBS-1 </it>promoter modifies cell morphology, and inhibits their ability to form colonies in soft agar.</p> <p>Conclusion</p> <p>Our results suggest that epigenetic aberrations contribute to NB phenotype, and that tumorigenic properties can be inhibited by reversing the epigenetic changes with 5-Aza-dC.</p

Skin Impedance Measurements for Acupuncture Research: Development of a Continuous Recording System

Skin impedance at acupuncture points (APs) has been used as a diagnostic/therapeutic aid for more than 50 years. Currently, researchers are evaluating the electrophysiologic properties of APs as a possible means of understanding acupuncture's mechanism. To comprehensively assess the diagnostic, therapeutic and mechanistic implications of acupuncture point skin impedance, a device capable of reliably recording impedances from 100 kΩ to 50 MΩ at multiple APs over extended time periods is needed. This article describes design considerations, development and testing of a single channel skin impedance system (hardware, control software and customized electrodes). The system was tested for accuracy against known resistors and capacitors. Two electrodes (the AMI and the ORI) were compared for reliability of recording over 30 min. Two APs (LU 9 and PC 6) and a nearby non-AP site were measured simultaneously in four individuals for 60 min. Our measurement system performed accurately (within 5%) against known resistors (580 kΩ–10 MΩ) and capacitors (10 nF–150 nF). Both the AMI electrode and the modified ORI electrode recorded skin impedance reliably on the volar surface of the forearm (r = 0.87 and r = 0.79, respectively). In four of four volunteers tested, skin impedance at LU 9 was less than at the nearby non-AP site. In three of four volunteers skin impedance was less at PC 6 than at the nearby non-AP site. We conclude that our system is a suitable device upon which we can develop a fully automated multi-channel device capable of recording skin impedance at multiple APs simultaneously over 24 h

Physics at a Neutrino Factory

In response to the growing interest in building a Neutrino Factory to produce high intensity beams of electron- and muon-neutrinos and antineutrinos, in October 1999 the Fermilab Directorate initiated two six-month studies. The first study, organized by N. Holtkamp and D. Finley, was to investigate the technical feasibility of an intense neutrino source based on a muon storage ring. This design study has produced a report in which the basic conclusion is that a Neutrino Factory is technically feasible, although it requires an aggressive R&D program. The second study, which is the subject of this report, was to explore the physics potential of a Neutrino Factory as a function of the muon beam energy and intensity, and for oscillation physics, the potential as a function of baseline.Comment: 133 pages, 64 figures. Report to the Fermilab Directorate. Available from http://www.fnal.gov/projects/muon_collider/ This version fixes some printing problem

Identification of a unique intervillous cellular signature in chronic histiocytic intervillositis

Introduction: Chronic histiocytic intervillositis (CHI) is a rare histopathological lesion in the placenta characterized by an infiltrate of CD68+ cells in the intervillous space. CHI is associated with adverse pregnancy outcomes such as miscarriage, fetal growth restriction, and (late) intrauterine fetal death. The adverse pregnancy outcomes and a variable recurrence rate of 25–100% underline its clinical relevance. The pathophysiologic mechanism of CHI is unclear, but it appears to be immunologically driven. The aim of this study was to obtain a better understanding of the phenotype of the cellular infiltrate in CHI. Method: We used imaging mass cytometry to achieve in-depth visualization of the intervillous maternal immune cells and investigated their spatial orientation in situ in relation to the fetal syncytiotrophoblast. Results: We found three phenotypically distinct CD68+HLA-DR+CD38+ cell clusters that were unique for CHI. Additionally, syncytiotrophoblast cells in the vicinity of these CD68+HLA-DR+CD38+ cells showed decreased expression of the immunosuppressive enzyme CD39. Discussion: The current results provide novel insight into the phenotype of CD68+ cells in CHI. The identification of unique CD68+ cell clusters will allow more detailed analysis of their function and could result in novel therapeutic targets for CHI