Fabrication of carbon film composites for high-strength structures

Physical and mechanical properties of fiber composite materials consisting of carbon films are described. Application of carbon film structural composites for constructing microwave filters or optical instruments is proposed. Applications in aerospace and architectural structures for high strength and low density properties are discussed

Physical properties of thin films

Studies and experiments are presented on carbon, boron, aluminum oxide, zirconium silicate, aluminum, and titanium vapor-deposited on polyimide film substrates

In-space fabrication of thin-film structures

A conceptual study of physical vapor-deposition processes for in-space fabrication of thin-film structures is presented. Potential advantages of in-space fabrication are improved structural integrity and surface reflectivity of free-standing ultra-thin films and coatings. Free-standing thin-film structures can find use as photon propulsion devices (solar sails). Other applications of the concept involve free-standing shadow shields, or thermal control coatings of spacecraft surfaces. Use of expendables (such as booster and interstage structures) as source material for the physical vapor deposition process is considered. The practicability of producing thin, textured, aluminum films by physical vapor deposition and subsequent separation from a revolving substrate is demonstrated by laboratory experiments. Heating power requirement for the evaporation process is estimated for a specific mission

The paradox of cancer genes in non-malignant conditions: implications for precision medicine.

Next-generation sequencing has enabled patient selection for targeted drugs, some of which have shown remarkable efficacy in cancers that have the cognate molecular signatures. Intriguingly, rapidly emerging data indicate that altered genes representing oncogenic drivers can also be found in sporadic non-malignant conditions, some of which have negligible and/or low potential for transformation to cancer. For instance, activating KRAS mutations are discerned in endometriosis and in brain arteriovenous malformations, inactivating TP53 tumor suppressor mutations in rheumatoid arthritis synovium, and AKT, MAPK, and AMPK pathway gene alterations in the brains of Alzheimer's disease patients. Furthermore, these types of alterations may also characterize hereditary conditions that result in diverse disabilities and that are associated with a range of lifetime susceptibility to the development of cancer, varying from near universal to no elevated risk. Very recently, the repurposing of targeted cancer drugs for non-malignant conditions that are associated with these genomic alterations has yielded therapeutic successes. For instance, the phenotypic manifestations of CLOVES syndrome, which is characterized by tissue overgrowth and complex vascular anomalies that result from the activation of PIK3CA mutations, can be ameliorated by the PIK3CA inhibitor alpelisib, which was developed and approved for breast cancer. In this review, we discuss the profound implications of finding molecular alterations in non-malignant conditions that are indistinguishable from those driving cancers, with respect to our understanding of the genomic basis of medicine, the potential confounding effects in early cancer detection that relies on sensitive blood tests for oncogenic mutations, and the possibility of reverse repurposing drugs that are used in oncology in order to ameliorate non-malignant illnesses and/or to prevent the emergence of cancer

Limits on Superconductivity-Related Magnetization in Sr2_2RuO4_4 and PrOs4_4Sb12_{12} from Scanning SQUID Microscopy

We present scanning SQUID microscopy data on the superconductors Sr2RuO4 (Tc = 1.5 K) and PrOs$_4$Sb$_{12}$ (Tc = 1.8 K). In both of these materials, superconductivity-related time-reversal symmetry-breaking fields have been observed by muon spin rotation; our aim was to visualize the structure of these fields. However in neither Sr$_2$RuO$_4$ nor PrOs$_4$Sb$_{12}$ do we observe spontaneous superconductivity-related magnetization. In Sr$_2$RuO$_4$, many experimental results have been interpreted on the basis of a $px \pm ipy$ superconducting order parameter. This order parameter is expected to give spontaneous magnetic induction at sample edges and order parameter domain walls. Supposing large domains, our data restrict domain wall and edge fields to no more than ~0.1% and ~0.2% of the expected magnitude, respectively. Alternatively, if the magnetization is of the expected order, the typical domain size is limited to ~30 nm for random domains, or ~500 nm for periodic domains.Comment: 8 pages, 7 figures. Submitted to Phys. Rev.

APOBEC-related mutagenesis and neo-peptide hydrophobicity: implications for response to immunotherapy.

Tumor-associated neo-antigens are mutated peptides that allow the immune system to recognize the affected cell as foreign. Cells carrying excessive mutation load often develop mechanisms of tolerance. PD-L1/PD-1 checkpoint immunotherapy is a highly promising approach to overcome these protective signals and induce tumor shrinkage. Yet, the nature of the neo-antigens driving those beneficial responses remains unclear. Here, we show that APOBEC-related mutagenesis - a mechanism at the crossroads between anti-viral immunity and endogenous nucleic acid editing - increases neo-peptide hydrophobicity (a feature of immunogenicity), as demonstrated by in silico computation and in the TCGA pan-cancer cohort, where APOBEC-related mutagenesis was also strongly associated with immune marker expression. Moreover, APOBEC-related mutagenesis correlated with immunotherapy response in a cohort of 99 patients with diverse cancers, and this correlation was independent of the tumor mutation burden (TMB). Combining APOBEC-related mutagenesis estimate and TMB resulted in greater predictive ability than either parameter alone. Based on these results, further investigation of APOBEC-related mutagenesis as a marker of response to anti-cancer checkpoint blockade is warranted

Socio-demographic, Clinical, and Genetic Determinants of Quality of Life in Lung Cancer Patients.

Patient reported health-related quality of life (QOL) is a major component of the overall well-being of cancer patients, with links to prognosis. In 6,420 lung cancer patients, we identified patient characteristics and genetic determinants of QOL. Patient responses from the SF-12 questionnaire was used to calculate normalized Physical Component Summary (PCS) and Mental Component Summary (MCS) scores. Further, we analyzed 218 single nucleotide polymorphisms (SNPs) in the p38 MAPK signaling pathway, a key mediator of response to cellular and environmental stress, as genetic determinants of QOL in a subset of the study population (N = 641). Trends among demographic factors for mean PCS and MCS included smoking status (PCS Ptrend < 0.001, MCS Ptrend < 0.001) and education (PCS Ptrend < 0.001, MCS Ptrend < 0.001). Similar relationships were seen for MCS. The homozygous rare genotype of MEF2B: rs2040562 showed an increased risk of a poor MCS (OR: 3.06, 95% CI: 1.05-8.92, P = 0.041). Finally, survival analysis showed that a low PCS or a MCS was associated with increased risks of five-year mortality (HR = 1.63, 95% CI: 1.51-1.77, HR = 1.23, 95% CI: 1.16-1.32, respectively) and there was a significant reduction in median survival time (Plog-rank < 0.001). These findings suggest that multiple factors contribute to QOL in lung cancer patients, and baseline QOL can impact survival

The role of drug resistance in poor viral suppression in rural South Africa: findings from a population-based study.

BACKGROUND:Understanding factors driving virological failure, including the contribution of HIV drug resistance mutations (DRM), is critical to ensuring HIV treatment remains effective. We examine the contribution of drug resistance mutations for low viral suppression in HIV-positive participants in a population-based sero-prevalence survey in rural South Africa. METHODS:We conducted HIV drug resistance genotyping and ART analyte testing on dried blood spots (DBS) from HIV-positive adults participating in a 2014 survey in North West Province. Among those with virologic failure (> 5000 copies/mL), we describe frequency of DRM to protease inhibitors (PI), nucleoside reverse transcriptase inhibitors (NRTI), and non-nucleoside reverse transcriptase inhibitors (NNRTI), report association of resistance with antiretroviral therapy (ART) status, and assess resistance to first and second line therapy. Analyses are weighted to account for sampling design. RESULTS:Overall 170 DBS samples were assayed for viral load and ART analytes; 78.4% of men and 50.0% of women had evidence of virologic failure and were assessed for drug resistance, with successful sequencing of 76/107 samples. We found ≥1 DRM in 22% of participants; 47% were from samples with detectable analyte (efavirenz, nevirapine or lopinavir). Of those with DRM and detectable analyte, 60% showed high-level resistance and reduced predicted virologic response to ≥1 NRTI/NNRTI typically used in first and second-line regimens. CONCLUSIONS:DRM and predicted reduced susceptibility to first and second-line regimens were common among adults with ART exposure in a rural South African population-based sample. Results underscore the importance of ongoing virologic monitoring, regimen optimization and adherence counseling to optimize durable virologic suppression

A synthetic-lethality RNAi screen reveals an ERK-mTOR co-targeting pro-apoptotic switch in PIK3CA+ oral cancers.

mTOR inhibition has emerged as a promising strategy for head and neck squamous cell carcinomas (HNSCC) treatment. However, most targeted therapies ultimately develop resistance due to the activation of adaptive survival signaling mechanisms limiting the activity of targeted agents. Thus, co-targeting key adaptive mechanisms may enable more effective cancer cell killing. Here, we performed a synthetic lethality screen using shRNA libraries to identify druggable candidates for combinatorial signal inhibition. We found that the ERK pathway was the most highly represented. Combination of rapamycin with trametinib, a MEK1/2 inhibitor, demonstrated strong synergism in HNSCC-derived cells in vitro and in vivo, including HNSCC cells expressing the HRAS and PIK3CA oncogenes. Interestingly, cleaved caspase-3 was potently induced by the combination therapy in PIK3CA+ cells in vitro and tumor xenografts. Moreover, ectopic expression of PIK3CA mutations into PIK3CA- HNSCC cells sensitized them to the pro-apoptotic activity of the combination therapy. These findings indicate that co-targeting the mTOR/ERK pathways may provide a suitable precision strategy for HNSCC treatment. Moreover, PIK3CA+ HNSCC are particularly prone to undergo apoptosis after mTOR and ERK inhibition, thereby providing a potential biomarker of predictive value for the selection of patients that may benefit from this combination therapy