A phase 2 study of neoadjuvant PARP inhibition followed by radical prostatectomy (RP) in patients with unfavorable intermediate-risk or high-risk prostate cancer with BRCA1/2 gene alterations (NePtune).

TPS5128 Background: Patients with localized high-risk prostate cancer have an increased risk of relapse following RP. Approximately 6% of patients with high-risk disease harbor germline alterations in the DNA repair pathway, of which BRCA1/2 alterations are the most common. Patients with germline BRCA1/2 mutations have higher rates of aggressive disease, distant metastases, and worse survival compared to non-carriers. Olaparib is a PARP inhibitor which demonstrates improved overall survival in patients with metastatic castration resistant prostate cancer with BRCA1/2 germline and somatic alterations. Additionally, olaparib has demonstrated improved invasive disease-free survival as adjuvant therapy in patients with germline BRCA1/2 HER-2 negative breast cancer. Novel, multimodal treatment strategies for patients with high-risk localized prostate cancer with germline or somatic BRCA1/2 may improve outcomes for these patients. Methods: We designed a multicenter phase 2 single arm study evaluating neoadjuvant olaparib in combination with a LHRH agonist for 6 months followed by RP. Eligible patients include those with a Gleason score ≥4+3=7, PSA >20 ng/mL or T3 disease (by DRE or prostate MRI) and lymph node <20 mm. Patients with intraductal carcinoma are eligible independent of Gleason score, PSA, or T stage. Patients must have a germline or somatic BRCA1/2pathogenic or likely pathogenic alterations identified on standard of care molecular profiling. Eligible patients receive olaparib 300 mg by mouth twice daily and a LHRH agonist for 6 months followed by RP. The primary endpoint is the rate of a pathologic complete response (pCR) or minimum residual disease (MRD, tumor ≤5 mm) as determined by central pathology review. Secondary endpoints include PSA response, surgical staging at RP, positive margin rate, time to testosterone recovery, and safety. Exploratory endpoints include quality of life assessment, proportion of downstaging on multi-parametric MRI (mpMRI), correlation of mpMRI with pathologic response, and tissue based molecular predictors of response and resistance. The sample size was estimated based a Binomial Exact test to assess the null hypothesis of the pCR/MRD rate ≤10% with one-sided 5% significance level. If the observed rate from this study is ≥32.5%, to have 90% power to conclude that the pCR/MRD rate is above 10%, a total of 30 patients will be enrolled. We can reject the null hypothesis if there are at least 7 responses. This trial is enrolling patients through the Hoosier Cancer Research Network. The study is activated at the University of California San Diego, University of Pennsylvania, and Johns Hopkins Hospital. Sites pending activation include: Memorial Sloan Kettering Cancer Center, Columbia University, and University of Buffalo. Clinical trial information: NCT05498272

Genome-Wide Mutagenesis Reveals That ORF7 Is a Novel VZV Skin-Tropic Factor

The Varicella Zoster Virus (VZV) is a ubiquitous human alpha-herpesvirus that is the causative agent of chicken pox and shingles. Although an attenuated VZV vaccine (v-Oka) has been widely used in children in the United States, chicken pox outbreaks are still seen, and the shingles vaccine only reduces the risk of shingles by 50%. Therefore, VZV still remains an important public health concern. Knowledge of VZV replication and pathogenesis remains limited due to its highly cell-associated nature in cultured cells, the difficulty of generating recombinant viruses, and VZV's almost exclusive tropism for human cells and tissues. In order to circumvent these hurdles, we cloned the entire VZV (p-Oka) genome into a bacterial artificial chromosome that included a dual-reporter system (GFP and luciferase reporter genes). We used PCR-based mutagenesis and the homologous recombination system in the E. coli to individually delete each of the genome's 70 unique ORFs. The collection of viral mutants obtained was systematically examined both in MeWo cells and in cultured human fetal skin organ samples. We use our genome-wide deletion library to provide novel functional annotations to 51% of the VZV proteome. We found 44 out of 70 VZV ORFs to be essential for viral replication. Among the 26 non-essential ORF deletion mutants, eight have discernable growth defects in MeWo. Interestingly, four ORFs were found to be required for viral replication in skin organ cultures, but not in MeWo cells, suggesting their potential roles as skin tropism factors. One of the genes (ORF7) has never been described as a skin tropic factor. The global profiling of the VZV genome gives further insights into the replication and pathogenesis of this virus, which can lead to improved prevention and therapy of chicken pox and shingles

The seeds of divergence: the economy of French North America, 1688 to 1760

Generally, Canada has been ignored in the literature on the colonial origins of divergence with most of the attention going to the United States. Late nineteenth century estimates of income per capita show that Canada was relatively poorer than the United States and that within Canada, the French and Catholic population of Quebec was considerably poorer. Was this gap long standing? Some evidence has been advanced for earlier periods, but it is quite limited and not well-suited for comparison with other societies. This thesis aims to contribute both to Canadian economic history and to comparative work on inequality across nations during the early modern period. With the use of novel prices and wages from Quebec—which was then the largest settlement in Canada and under French rule—a price index, a series of real wages and a measurement of Gross Domestic Product (GDP) are constructed. They are used to shed light both on the course of economic development until the French were defeated by the British in 1760 and on standards of living in that colony relative to the mother country, France, as well as the American colonies. The work is divided into three components. The first component relates to the construction of a price index. The absence of such an index has been a thorn in the side of Canadian historians as it has limited the ability of historians to obtain real values of wages, output and living standards. This index shows that prices did not follow any trend and remained at a stable level. However, there were episodes of wide swings—mostly due to wars and the monetary experiment of playing card money. The creation of this index lays the foundation of the next component. The second component constructs a standardized real wage series in the form of welfare ratios (a consumption basket divided by nominal wage rate multiplied by length of work year) to compare Canada with France, England and Colonial America. Two measures are derived. The first relies on a “bare bones” definition of consumption with a large share of land-intensive goods. This measure indicates that Canada was poorer than England and Colonial America and not appreciably richer than France. However, this measure overestimates the relative position of Canada to the Old World because of the strong presence of land-intensive goods. A second measure is created using a “respectable” definition of consumption in which the basket includes a larger share of manufactured goods and capital-intensive goods. This second basket better reflects differences in living standards since the abundance of land in Canada (and Colonial America) made it easy to achieve bare subsistence, but the scarcity of capital and skilled labor made the consumption of luxuries and manufactured goods (clothing, lighting, imported goods) highly expensive. With this measure, the advantage of New France over France evaporates and turns slightly negative. In comparison with Britain and Colonial America, the gap widens appreciably. This element is the most important for future research. By showing a reversal because of a shift to a different type of basket, it shows that Old World and New World comparisons are very sensitive to how we measure the cost of living. Furthermore, there are no sustained improvements in living standards over the period regardless of the measure used. Gaps in living standards observed later in the nineteenth century existed as far back as the seventeenth century. In a wider American perspective that includes the Spanish colonies, Canada fares better. The third component computes a new series for Gross Domestic Product (GDP). This is to avoid problems associated with using real wages in the form of welfare ratios which assume a constant labor supply. This assumption is hard to defend in the case of Colonial Canada as there were many signs of increasing industriousness during the eighteenth and nineteenth centuries. The GDP series suggest no long-run trend in living standards (from 1688 to circa 1765). The long peace era of 1713 to 1740 was marked by modest economic growth which offset a steady decline that had started in 1688, but by 1760 (as a result of constant warfare) living standards had sunk below their 1688 levels. These developments are accompanied by observations that suggest that other indicators of living standard declined. The flat-lining of incomes is accompanied by substantial increases in the amount of time worked, rising mortality and rising infant mortality. In addition, comparisons of incomes with the American colonies confirm the results obtained with wages— Canada was considerably poorer. At the end, a long conclusion is provides an exploratory discussion of why Canada would have diverged early on. In structural terms, it is argued that the French colony was plagued by the problem of a small population which prohibited the existence of scale effects. In combination with the fact that it was dispersed throughout the territory, the small population of New France limited the scope for specialization and economies of scale. However, this problem was in part created, and in part aggravated, by institutional factors like seigneurial tenure. The colonial origins of French America’s divergence from the rest of North America are thus partly institutional

Design of thin-film AlN actuators for 4-inch transparent plates for haptic applications

International audienceNumerous applications require tactile interfaces today. In particular, many customers' applications such as Smartphone, tablet PC or touch pad can be concerned by high performances, low voltage haptic interfaces which allow the user to interact with its environment by the sense of touch. This technology is already used but with limitations such as high power consumption and limited feedback effect (simple vibration). We chose to work on the squeeze-film effect. It consists in changing the friction between the finger and a plate resonator. It provides high granularity level of haptic sensation. This paper deals with the design of high performances actuators in order to promote the squeeze-film effect on a 4-inch plate (diagonal of the plate). Using predictive models, we select the best design, able to generate the highest substrate displacement amplitude as possible. We built demonstrators using a generic technology based on thin-film AlN actuators. Electromechanical characterization is ongoing before the integration of the thin-film actuator plate in a haptic demonstrator in a close future

Micro-patterning of NdFeB and SmCo magnet films for integration into Micro- Electro-Mechanical-Systems

The integration of high performance RE-TM (NdFeB and SmCo) hard magnetic films into Micro-Electro-Mechanical-Systems (MEMS) requires their patterning at the micron scale. In this paper we report on the applicability of standard micro-fabrication steps (film deposition onto topographically patterned substrates, wet etching and planarization) to the patterning of 5 µm thick RE-TM films. While NdFeB comprehensively fills micron scaled trenches in patterned substrates, SmCo deposits are characterized by poor filling of the trench corners, which poses a problem for further processing by planarization. The hal-00438119, version 1- 2 Dec 2009 magnetic hysteresis loops of both the NdFeB and SmCo patterned films are comparable to those of non-patterned films prepared under the same deposition/annealing conditions. A micron-scaled multipole magnetic field pattern is directly produced by the unidirectional magnetization of the patterned films. NdFeB and SmCo show similar behavior when wet etched in an amorphous state: etch rates of approximately 1.25µm/minute and vertical side walls which may be attributed to a large lateral over-etch of typically 20 µm. Chemical-Mechanical Planarization (CMP) produced material removal rates of 0.5-3µm/min fo