Materials for engine applications above 3000 deg F: An overview

Materials for future generations of aeropropulsion systems will be required to perform at ever-increasing temperatures and have properties superior to the current state of the art. Improved engine efficiency can reduce specific fuel consumption and thus increase range and reduce operating costs. The ultimate payoff gain is expected to come when materials are developed which can perform without cooling at gas temperatures to 2200 C (4000 F). An overview is presented of materials for applications above 1650 C (3000 F), some pertinent physical property data, and the rationale used: (1) to arrive at recommendations of material systems that qualify for further investigation, and (2) to develop a proposed plan of research. From an analysis of available thermochemical data it was included that such materials systems must be composed of oxide ceramics. The required structural integrity will be achieved by developing these materials into fiber-reinforced ceramic composites

A life in progress: motion and emotion in the autobiography of Robert M. La Follette

This article is a study of a La Follette’s Autobiography, the autobiography of the leading Wisconsin progressive Robert M. La Follette, which was published serially in 1911 and, in book form, in 1913. Rather than focusing, as have other historians, on which parts of La Follette’s account are accurate and can therefore be trusted, it explains instead why and how this major autobiography was conceived and written. The article shows that the autobiography was the product of a sustained, complex, and often fraught series of collaborations among La Follette’s family, friends, and political allies, and in the process illuminates the importance of affective ties as well as political ambition and commitment in bringing the project to fruition. In the world of progressive reform, it argues, personal and political experiences were inseparable

Fixed-dose capecitabine is feasible: results from a pharmacokinetic and pharmacogenetic study in metastatic breast cancer

The pro-drug capecitabine is approved for treatment of anthracycline- and paclitaxel-resistant metastatic breast cancer. However, toxicity and large interpatient pharmacokinetic variability occur despite body surface area (BSA)-dosing. We hypothesized that a fixed-dose schedule would simplify dosing and provide an effective and safe alternative to BSA-based dosing

The Ankyrin Repeat Domain of the TRPA Protein Painless Is Important for Thermal Nociception but Not Mechanical Nociception

The Drosophila TRPA channel Painless is required for the function of polymodal nociceptors which detect noxious heat and noxious mechanical stimuli. These functions of Painless are reminiscent of mammalian TRPA channels that have also been implicated in thermal and mechanical nociception. A popular hypothesis to explain the mechanosensory functions of certain TRP channels proposes that a string of ankyrin repeats at the amino termini of these channels acts as an intracellular spring that senses force. Here, we describe the identification of two previously unknown Painless protein isoforms which have fewer ankyrin repeats than the canonical Painless protein. We show that one of these Painless isoforms, that essentially lacks ankyrin repeats, is sufficient to rescue mechanical nociception phenotypes of painless mutant animals but does not rescue thermal nociception phenotypes. In contrast, canonical Painless, which contains Ankyrin repeats, is sufficient to largely rescue thermal nociception but is not capable of rescuing mechanical nociception. Thus, we propose that in the case of Painless, ankryin repeats are important for thermal nociception but not for mechanical nociception

Changes in breast density and circulating estrogens in postmenopausal women receiving adjuvant anastrozole

Factors associated with an increased risk of breast cancer include prior breast cancer, high circulating estrogens, and increased breast density. Adjuvant aromatase inhibitors are associated with a reduction in incidence of contralateral breast cancer. We conducted a prospective, single-arm, single-institution study to determine whether use of anastrozole is associated with changes in contralateral breast density and circulating estrogens. Eligible patients included postmenopausal women with hormone receptor-positive early-stage breast cancer who had completed local therapy, had an intact contralateral breast, and were recommended an aromatase inhibitor as their only systemic therapy. Participants received anastrozole 1 mg daily for 12 months on study. We assessed contralateral breast density and serum estrogens at baseline, 6, and 12 months. The primary endpoint was change in contralateral percent breast density from baseline to 12 months. Secondary endpoints included change in serum estrone sulfate from baseline to 12 months. Fifty-four patients were accrued. At 12 months, compared with baseline, there was a nonstatistically significant reduction in breast density (mean change: -16%, 95% CI: -30 to 2, P = 0.08) and a significant reduction in estrone sulfate (mean change: -93%, 95% CI: -94 to -91, P < 0.001). Eighteen women achieved 20% or greater relative reduction in contralateral percent density at 12 months compared with baseline; however, no measured patient or disease characteristics distinguished these women from the overall population. Large trials are required to provide additional data on the relationship between aromatase inhibitors and breast density and, more importantly, whether observed changes in breast density correlate with meaningful disease-specific outcomes

TBCRC 018: phase II study of iniparib in combination with irinotecan to treat progressive triple negative breast cancer brain metastases

Nearly half of patients with advanced triple negative breast cancer (TNBC) develop brain metastases (BM) and most will also have uncontrolled extracranial disease. This study evaluated the safety and efficacy of iniparib, a small molecule anti-cancer agent that alters reactive oxygen species tumor metabolism and penetrates the blood brain barrier, with the topoisomerase I inhibitor irinotecan in patients with TNBC-BM. Eligible patients had TNBC with new or progressive BM and received irinotecan and iniparib every 3weeks. Time to progression (TTP) was the primary end point; secondary endpoints were response rate (RR), clinical benefit rate (CBR), overall survival (OS), toxicity, and health-related quality of life. Correlative endpoints included molecular subtyping and gene expression studies on pre-treatment archival tissues, and determination of germline BRCA1/2 status. Thirty-seven patients began treatment; 34 were evaluable for efficacy. Five of 24 patients were known to carry a BRCA germline mutation (4 BRCA1, 1 BRCA2). Median TTP was 2.14months and median OS was 7.8months. Intracranial RR was 12%, while intracranial CBR was 27%. Treatment was well-tolerated; the most common grade 3/4 adverse events were neutropenia and fatigue. Grade 3/4 diarrhea was rare (3%). Intrinsic subtyping revealed 19 of 21 tumors (79%) were basal-like, and intracranial response was associated with high expression of proliferation-related genes. This study suggests a modest benefit of irinotecan plus iniparib in progressive TNBC-BM. More importantly, this trial design is feasible and lays the foundation for additional studies for this treatment-refractory disease.Electronic supplementary materialThe online version of this article (doi:10.1007/s10549-014-3039-y) contains supplementary material, which is available to authorized users

TBCRC 018: phase II study of iniparib in combination with irinotecan to treat progressive triple negative breast cancer brain metastases

Nearly half of patients with advanced triple negative breast cancer (TNBC) develop brain metastases (BM) and most will also have uncontrolled extracranial disease. This study evaluated the safety and efficacy of iniparib, a small molecule anti-cancer agent that alters reactive oxygen species tumor metabolism and penetrates the blood brain barrier, with the topoisomerase I inhibitor irinotecan in patients with TNBC-BM. Eligible patients had TNBC with new or progressive BM and received irinotecan and iniparib every 3 weeks. Time to progression (TTP) was the primary end point; secondary endpoints were response rate (RR), clinical benefit rate (CBR), overall survival (OS), toxicity, and health-related quality of life. Correlative endpoints included molecular subtyping and gene expression studies on pre-treatment archival tissues, and determination of germline BRCA1/2 status. Thirty-seven patients began treatment; 34 were evaluable for efficacy. Five of 24 patients were known to carry a BRCA germline mutation (4 BRCA1, 1 BRCA2). Median TTP was 2.14 months and median OS was 7.8 months. Intracranial RR was 12 %, while intracranial CBR was 27 %. Treatment was well-tolerated; the most common grade 3/4 adverse events were neutropenia and fatigue. Grade 3/4 diarrhea was rare (3 %). Intrinsic subtyping revealed 19 of 21 tumors (79 %) were basal-like, and intracranial response was associated with high expression of proliferation-related genes. This study suggests a modest benefit of irinotecan plus iniparib in progressive TNBC-BM. More importantly, this trial design is feasible and lays the foundation for additional studies for this treatment-refractory disease. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10549-014-3039-y) contains supplementary material, which is available to authorized users

Effects of Environmental Enrichment on Spatial Memory and Neurochemistry in Middle-Aged Mice

The present study compared the effects of environmental enrichment on spatial memory, glutamic acid decarboxylase (GAD) activity, and synaptophysin levels in middle-aged male and female mice. Prior to testing, a subset of 18-month-old male and female C57BL/6 mice was housed with two to three toys and a running wheel in the home cage for up to 29 d. Adult mice (7 mo) of both sexes and the remaining middle-aged mice were group (social) housed, but not exposed to enriching objects. After the enrichment period, all mice were tested in a 1-day version of the Morris water maze, in which both spatial and nonspatial memory were assessed. Immediately after testing, the hippocampus and frontoparietal cortex were dissected, and GAD activity and synaptophysin levels were measured. Environmental enrichment reduced the age-related impairment in spatial acquisition and retention; relative to adult social controls, middle-aged enriched mice were unimpaired, whereas middle-aged social controls were impaired. This reduction was similar in middle-aged males and females. Enrichment did not affect cued memory in either sex. Although hippocampal GAD activity was increased by enrichment in males, all other neurochemical measurements were unaffected by enrichment or aging in either sex. These data suggest that environmental enrichment initiated at middle age can reduce age-related impairments in spatial memory in males and females, although the underlying neurobiological mechanisms of this effect remain unknown