Measuring Chemotherapy Response in Breast Cancer Using Optical and Ultrasound Spectroscopy

Purpose: This study comprises two subprojects. In subproject one, the study purpose was to evaluate response to neoadjuvant chemotherapy (NAC) using quantitative ultrasound (QUS) and diffuse optical spectroscopy imaging (DOS) in locally advanced breast cancer (LABC) during chemotherapy. In subproject two, DOS-based functional maps were analysed with texture-based image features to predict breast cancer response before the start of NAC. Patients and Measurements: The institution’s ethics review board approved this study. For subproject one, subjects (n=22) gave written consent before participating in the study. Participants underwent non-invasive, DOS and QUS imaging. Data were acquired at weeks 0 (i.e. baseline), 1, 4, 8 and before surgical removal of the tumour (mastectomy and/or lumpectomy); corresponding to chemotherapy schedules. QUS parameters including the midband fit (MBF), 0-MHz intercept (SI), and the spectral slope (SS) were determined from tumour ultrasound data using spectral analysis. In the same patients, DOS was used to measure parameters relating to tumour haemoglobin and tissue composition such as %Water and %Lipids. Discriminant analysis and receiver-operating characteristic (ROC) analyses were used to correlate the measured imaging parameters to Miller-Payne pathological response during treatment. Additionally, multivariate analysis was carried out for pairwise DOS and QUS parameter combinations to determine if an increase in the classification accuracy could be obtained using combination DOS and QUS parametric models. For subproject two, 15 additional patients we recruited after first giving their written informed consent. A pooled analysis was completed for all DOS baseline data (subproject 1 and subproject 2; n=37 patients). LABC patients planned for NAC had functional DOS maps and associated textural features generated. A grey-level co-occurrence matrix (texture) analysis was completed for parameters associated with haemoglobin, tissue composition, and optical properties (deoxy-haemoglobin [Hb], oxy-haemoglobin [HbO2], total haemoglobin [HbT]), %Lipids, %Water, and scattering power [SP], scattering amplitude [SA]) prior to treatment. Textural features included contrast (con), vi correlation (cor), energy (ene), and homogeneity (hom). Patients were classified as ‘responders’ or ‘non-responders’ using Miller-Payne pathological response criteria after treatment completion. In order to test if baseline univariate texture features could predict treatment response, a receiver operating characteristic (ROC) analysis was performed, and the optimal sensitivity, specificity and area under the curve (AUC) was calculated using Youden’s index (Q-point) from the ROC. Multivariate analysis was conducted to test 40 DOS-texture features and all possible bivariate combinations using a naïve Bayes model, and k-nearest neighbour (k-NN) model classifiers were included in the analysis. Using these machine-learning algorithms, the pretreatment DOS-texture parameters underwent dataset training, testing, and validation and ROC analysis were performed to find the maximum sensitivity and specificity of bivariate DOS-texture features. Results: For subproject one, individual DOS and QUS parameters, including the spectral intercept (SI), oxy-haemoglobin (HbO2), and total haemoglobin (HbT) were significant markers for response outcome after one week of treatment (p<0.01). Multivariate (pairwise) combinations increased the sensitivity, specificity and AUC at this time; the SI+HbO2 showed a sensitivity/specificity of 100%, and an AUC of 1.0 after one week of treatment. For subproject two, the results indicated that textural characteristics of pre-treatment DOS parametric maps can differentiate treatment response outcomes. The HbO2-homogeneity resulted in the highest accuracy amongst univariate parameters in predicting response to chemotherapy: sensitivity (%Sn) and specificity (%Sp) = 86.5 and 89.0%, respectively and an accuracy of 87.8%. The highest predictors using multivariate (binary) combination features were the Hb-Contrast + HbO2-Homogeneity which resulted in a %Sn = 78.0, a %Sp = 81.0% and an accuracy of 79.5% using the naïve Bayes model. Conclusion: DOS and QUS demonstrated potential as coincident markers for treatment response and may potentially facilitate response-guided therapies. Also, the results of this study demonstrated that DOS-texture analysis can be used to predict breast cancer response groups prior to starting NAC using baseline DOS measurements

Gene Expression Signature in Adipose Tissue of Acromegaly Patients.

To study the effect of chronic excess growth hormone on adipose tissue, we performed RNA sequencing in adipose tissue biopsies from patients with acromegaly (n = 7) or non-functioning pituitary adenomas (n = 11). The patients underwent clinical and metabolic profiling including assessment of HOMA-IR. Explants of adipose tissue were assayed ex vivo for lipolysis and ceramide levels. Patients with acromegaly had higher glucose, higher insulin levels and higher HOMA-IR score. We observed several previously reported transcriptional changes (IGF1, IGFBP3, CISH, SOCS2) that are known to be induced by GH/IGF-1 in liver but are also induced in adipose tissue. We also identified several novel transcriptional changes, some of which may be important for GH/IGF responses (PTPN3 and PTPN4) and the effects of acromegaly on growth and proliferation. Several differentially expressed transcripts may be important in GH/IGF-1-induced metabolic changes. Specifically, induction of LPL, ABHD5, and NRIP1 can contribute to enhanced lipolysis and may explain the elevated adipose tissue lipolysis in acromegalic patients. Higher expression of TCF7L2 and the fatty acid desaturases FADS1, FADS2 and SCD could contribute to insulin resistance. Ceramides were not different between the two groups. In summary, we have identified the acromegaly gene expression signature in human adipose tissue. The significance of altered expression of specific transcripts will enhance our understanding of the metabolic and proliferative changes associated with acromegaly

Incorporation of Half-Cycle Theory Into Ko Aging Theory for Aerostructural Flight-Life Predictions

The half-cycle crack growth theory was incorporated into the Ko closed-form aging theory to improve accuracy in the predictions of operational flight life of failure-critical aerostructural components. A new crack growth computer program was written for reading the maximum and minimum loads of each half-cycle from the random loading spectra for crack growth calculations and generation of in-flight crack growth curves. The unified theories were then applied to calculate the number of flights (operational life) permitted for B-52B pylon hooks and Pegasus adapter pylon hooks to carry the Hyper-X launching vehicle that air launches the X-43 Hyper-X research vehicle. A crack growth curve for each hook was generated for visual observation of the crack growth behavior during the entire air-launching or captive flight. It was found that taxiing and the takeoff run induced a major portion of the total crack growth per flight. The operational life theory presented can be applied to estimate the service life of any failure-critical structural components

Lunar Return Reentry Thermal Analysis of a Generic Crew Exploration Vehicle Wall Structures

Thermostructural analysis was performed on generic crew exploration vehicle (GCEV) heat shielded wall structures subjected to reentry heating rates based on five potential lunar return reentry trajectories. The GCEV windward outer wall is fabricated with a graphite/epoxy composite honeycomb sandwich panel and the inner wall with an aluminum honeycomb sandwich panel. The outer wall is protected with an ablative Avcoat-5026-39H/CG thermal protection system (TPS). A virtual ablation method (a graphical approximation) developed earlier was further extended, and was used to estimate the ablation periods, ablation heat loads, and the TPS recession layer depths. It was found that up to 83 95 percent of the total reentry heat load was dissipated in the TPS ablation process, leaving a small amount (3-15 percent) of the remaining total reentry heat load to heat the virgin TPS and maintain the TPS surface at the ablation temperature, 1,200 F. The GCEV stagnation point TPS recession layer depths were estimated to be in the range of 0.280-0.910 in, and the allowable minimum stagnation point TPS thicknesses that could maintain the substructural composite sandwich wall at the limit temperature of 300 F were found to be in the range of 0.767-1.538 in. Based on results from the present analyses, the lunar return abort ballistic reentry was found to be quite attractive because it required less TPS weight than the lunar return direct, the lunar return skipping, or the low Earth orbit guided reentry, and only 11.6 percent more TPS weight than the low Earth orbit ballistic reentry that will encounter a considerable weight penalty to obtain the Earth orbit. The analysis also showed that the TPS weight required for the lunar return skipping reentry was much more than the TPS weight necessary for any of the other reentry trajectories considered

Displacement Theories for In-Flight Deformed Shape Predictions of Aerospace Structures

Displacement theories are developed for a variety of structures with the goal of providing real-time shape predictions for aerospace vehicles during flight. These theories are initially developed for a cantilever beam to predict the deformed shapes of the Helios flying wing. The main structural configuration of the Helios wing is a cantilever wing tubular spar subjected to bending, torsion, and combined bending and torsion loading. The displacement equations that are formulated are expressed in terms of strains measured at multiple sensing stations equally spaced on the surface of the wing spar. Displacement theories for other structures, such as tapered cantilever beams, two-point supported beams, wing boxes, and plates also are developed. The accuracy of the displacement theories is successfully validated by finite-element analysis and classical beam theory using input-strains generated by finite-element analysis. The displacement equations and associated strain-sensing system (such as fiber optic sensors) create a powerful means for in-flight deformation monitoring of aerospace structures. This method serves multiple purposes for structural shape sensing, loads monitoring, and structural health monitoring. Ultimately, the calculated displacement data can be visually displayed to the ground-based pilot or used as input to the control system to actively control the shape of structures during flight

Catalytic Enantioselective Birch–Heck Sequence for the Synthesis of Tricyclic Structures with All-Carbon Quaternary Stereocenters

A new enantioselective desymmetrizing Mizoroki–Heck reaction is reported. The process affords high yields and enantioselectivities of tricyclic structures containing all-carbon quaternary stereocenters. The substrates for the reaction are efficiently synthesized from Birch reduction–alkylation of benzoic acid and benzoate esters

Catalytic Enantioselective Birch–Heck Sequence for the Synthesis of Tricyclic Structures with All-Carbon Quaternary Stereocenters

A new enantioselective desymmetrizing Mizoroki–Heck reaction is reported. The process affords high yields and enantioselectivities of tricyclic structures containing all-carbon quaternary stereocenters. The substrates for the reaction are efficiently synthesized from Birch reduction–alkylation of benzoic acid and benzoate esters

SCPS-TP, TCP, and Rate-Based Protocol Evaluation

Tests were performed at Glenn Research Center to compare the performance of the Space Communications Protocol Standard Transport Protocol (SCPS TP, otherwise known as "TCP Tranquility") relative to other variants of TCP and to determine the implementation maturity level of these protocols, particularly for higher speeds. The testing was performed over reasonably high data rates of up to 100 Mbps with delays that are characteristic of near-planetary environments. The tests were run for a fixed packet size, but for variously errored environments. This report documents the testing performed to date

In vivo regulatory phosphorylation of the phosphoenolpyruvate carboxylase AtPPC1 in phosphate-starved Arabidopsis thaliana

PEPC [PEP(phosphoenolpyruvate) carboxylase] is a tightly controlled cytosolic enzyme situated at a major branchpoint in plant metabolism. Accumulating evidence indicates important functions for PEPC and PPCK (PEPC kinase) in plant acclimation to nutritional Pi deprivation. However, little is known about the genetic origin or phosphorylation status of native PEPCs from −Pi (Pi-deficient) plants. The transfer of Arabidopsis suspension cells or seedlings to −Pi growth media resulted in: (i) the marked transcriptional upregulation of genes encoding the PEPC isoenzyme AtPPC1 (Arabidopsis thaliana PEPC1), and PPCK isoenzymes AtPPCK1 and AtPPCK2; (ii) >2-fold increases in PEPC specific activity and in the amount of an immunoreactive 107-kDa PEPC polypeptide (p107); and (iii) In vivo p107 phosphorylation as revealed by immunoblotting of clarified extracts with phosphosite-specific antibodies to Ser-11 (which could be reversed following Pi resupply). Approx. 1.3 mg of PEPC was purified 660-fold from −Pi suspension cells to apparent homogeneity with a specific activity of 22.3 units · mg−1 of protein. Gel filtration, SDS/PAGE and immunoblotting demonstrated that purified PEPC exists as a 440-kDa homotetramer composed of identical p107 subunits. Sequencing of p107 tryptic and Asp-N peptides by tandem MS established that this PEPC is encoded by AtPPC1. Pi-affinity PAGE coupled with immunoblotting indicated stoichiometric phosphorylation of the p107 subunits of AtPPC1 at its conserved Ser-11 phosphorylation site. Phosphorylation activated AtPPC1 at pH 7.3 by lowering its Km(PEP) and its sensitivity to inhibition by L-malate and L-aspartate, while enhancing activation by glucose 6-phosphate. Our results indicate that the simultaneous induction and In vivo phosphorylation activation of AtPPC1 contribute to the metabolic adaptations of −Pi Arabidopsis

Assessing the Criteria for Definition of Perimembranous Ventricular Septal Defects in Light of the Search for Consensus

Background: Discussions continue as to whether ventricular septal defects are best categorized according to their right ventricular geography or their borders. This is especially true when considering the perimembranous defect. Our aim, therefore, was to establish the phenotypic feature of the perimembranous defect, and to establish the ease of distinguishing its geographical variants. Methods and results: We assessed unrepaired isolated perimembranous ventricular defects from six historic archives, subcategorizing them using the ICD-11 coding system. We identified 365 defects, of which 94 (26%) were deemed to open centrally, 168 (46%) to open to the outlet, and 84 (23%) to the inlet of the right ventricle, with 19 (5%) being confluent. In all hearts, the unifying phenotypic feature was fibrous continuity between the leaflets of the mitral and tricuspid valves. This was often directly between the valves, but in all instances incorporated continuity through the atrioventricular portion of the membranous septum. In contrast, we observed fibrous continuity between the leaflets of the tricuspid and aortic valves in only 298 (82%) of the specimens. When found, discontinuity most commonly was seen in the outlet and central defects. There were no discrepancies between evaluators in distinguishing the borders, but there was occasional disagreement in determining the right ventricular geography of the defect. Conclusions: The unifying feature of perimembranous defects, rather than being aortic-to-tricuspid valvar fibrous continuity, is fibrous continuity between the leaflets of the atrioventricular valves. While right ventricular geography is important in classification, it is the borders which are more objectively defined