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Robotic assisted partial nephrectomy (RPN) has emerged in urologic practice for the management of appropriately sized renal masses. We provide a 20-year comparison of the outcomes of open partial nephrectomy (OPN) versus RPN for renal cell carcinoma (RCC) at our institution. An IRB-approved retrospective review was conducted of RCC patients at a single institution from 2000 to 2022 who underwent RPN or OPN. In addition to demographics, procedural details including ischemia and operative time were collected. Oncologic outcomes were evaluated through Kaplan-Meier statistical analysis to determine recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) analysis. 849 patients underwent RPN while 385 underwent OPN. 61% were male with average age of 58.8 ± 12.8 years. Operative time was shorter in the open group (184 vs 200 min, p = 0.002), as was ischemia time (16 vs 19 min, p = 0.047). However, after 2012, RPN became more common than OPN with improving ischemia time. RPN patients had significantly improved RFS (HR 0.45, p = 0.0004) and OS (HR 0.51, p = 0.0016) when controlled for T-stage and margin status. More > pT1 masses were managed with OPN than RPN (11.2 vs 5.4%, p < 0.0001). At our institution, RPN had an increasing incidence with reduced ischemia time compared to OPN over the last 10 years. While higher stage renal masses were more often managed with OPN, selective use of RPN does offer improved oncologic outcomes. Further investigation is needed to evaluate optimization of the selection of RPN versus OPN in the nephron-sparing management of renal masses., (© 2024. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

Quantum dots (QDs) with metal fluoride surface ligands were prepared via reaction with anhydrous oleylammonium fluoride. Carboxylate terminated II-VI QDs underwent carboxylate for fluoride exchange, while InP QDs underwent photochemical acidolysis yielding oleylamine, PH 3 , and InF 3 . The final photoluminescence quantum yield (PLQY) reached 83% for InP and near unity for core-shell QDs. Core-only CdS QDs showed dramatic improvements in PLQY, but only after exposure to air. Following etching, the InP QDs were bound by oleylamine ligands that were characterized by the frequency and breadth of the corresponding ν(N-H) bands in the infrared absorption spectrum. The fluoride content (1.6-9.2 nm -2 ) was measured by titration with chlorotrimethylsilane and compared with the oleylamine content (2.3-5.1 nm -2 ) supporting the formation of densely covered surfaces. The influence of metal fluoride adsorption on the air stability of QDs is discussed.

The successful application of gradient boosting regression (GBR) in machine learning to forecast surface area, pore volume, and yield in biomass-derived activated carbon (AC) production underscores its potential for enhancing manufacturing processes. The GBR model, collecting 17 independent variables for two-step activation (2-SA) and 14 for one-step activation (1-SA), demonstrates effectiveness across three datasets-1-SA, 2-SA, and a combined dataset. Notably, in 1-SA, the GBR model yields R 2 values of 0.76, 0.90, and 0.83 for TPV, yield, and SSA respectively, and records R 2 of 0.90 and 0.91 for yield in 2-SA and combined datasets. The model highlights the significance of the soaking procedure alongside activation temperature in shaping AC properties with 1-SA or 2-SA, illustrating machine learning's potential in optimizing AC production processes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Oligonucleotides have emerged as valuable new therapeutics. Presently, oligonucleotide manufacturing consists in a series of stepwise additions until the full-length product is obtained. Deprotection of the phosphorus backbone before cleavage and deprotection (C&D) by ammonolysis is necessary to control the 3-(2-cyanoethyl) thymidine (CNET) impurity. In this study, we demonstrate that the use of piperazine as a scavenger of acrylonitrile allows phosphorus deprotection and C&D to be combined in a single step. This reduces solvent consumption, processing time, and CNET levels. Additionally, we showed that substitution of piperazine for triethylamine in the phosphorus deprotection step of supported-synthesis leads to reduced reaction times and lower levels of CNET impurities.

Brain imaging and genomics are critical tools enabling characterization of the genetic basis of brain disorders. However, imaging large cohorts is expensive and may be unavailable for legacy datasets used for genome-wide association studies (GWASs). Using an integrated feature selection/aggregation model, we developed an image-mediated association study (IMAS), which utilizes borrowed imaging/genomics data to conduct association mapping in legacy GWAS cohorts. By leveraging the UK Biobank image-derived phenotypes (IDPs), the IMAS discovered genetic bases underlying four neuropsychiatric disorders and verified them by analyzing annotations, pathways, and expression quantitative trait loci (eQTLs). A cerebellar-mediated mechanism was identified to be common to the four disorders. Simulations show that, if the goal is identifying genetic risk, our IMAS is more powerful than a hypothetical protocol in which the imaging results were available in the GWAS dataset. This implies the feasibility of reanalyzing legacy GWAS datasets without conducting additional imaging, yielding cost savings for integrated analysis of genetics and imaging., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Linkage disequilibrium (LD) is a fundamental concept in genetics; critical for studying genetic associations and molecular evolution. However, LD measurements are only reliable for common genetic variants, leaving low-frequency variants unanalyzed. In this work, we introduce cumulative LD (cLD), a stable statistic that captures the rare-variant LD between genetic regions, which reflects more biological interactions between variants, in addition to lack of recombination. We derived the theoretical variance of cLD using delta methods to demonstrate its higher stability than LD for rare variants. This property is also verified by bootstrapped simulations using real data. In application, we find cLD reveals an increased genetic association between genes in 3D chromatin interactions, a phenomenon recently reported negatively by calculating standard LD between common variants. Additionally, we show that cLD is higher between gene pairs reported in interaction databases, identifies unreported protein-protein interactions, and reveals interacting genes distinguishing case/control samples in association studies., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

In solid tumours, the abundance of macrophages is typically associated with a poor prognosis. However, macrophage clusters in tumour-cell nests have been associated with survival in some tumour types. Here, by using tumour organoids comprising macrophages and cancer cells opsonized via a monoclonal antibody, we show that highly ordered clusters of macrophages cooperatively phagocytose cancer cells to suppress tumour growth. In mice with poorly immunogenic tumours, the systemic delivery of macrophages with signal-regulatory protein alpha (SIRPα) genetically knocked out or else with blockade of the CD47-SIRPα macrophage checkpoint was combined with the monoclonal antibody and subsequently triggered the production of endogenous tumour-opsonizing immunoglobulin G, substantially increased the survival of the animals and helped confer durable protection from tumour re-challenge and metastasis. Maximizing phagocytic potency by increasing macrophage numbers, by tumour-cell opsonization and by disrupting the phagocytic checkpoint CD47-SIRPα may lead to durable anti-tumour responses in solid cancers., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Most diseases in aquaculture are caused by opportunistic pathogens. One of them, Vibrio harveyi, is a widespread Gram-negative bacterium that has become an important pathogen of aquatic species in marine environments. Here, we propose the use of the causal pie model as a framework to conceptualize the causation of vibriosis in juvenile barramundi (Lates calcarifer) and to establish an effective challenge model. In the model, a sufficient cause, or the causal pie, is a constellation of component causes that lead to an outcome (e.g. vibriosis). In the pilot study, a high cumulative mortality (63.3% ± 10.0%, mean ± SE) was observed when V. harveyi was administered by intraperitoneal injection using a high challenge dose [10 7 colony-forming units (CFU) fish -1 ], but low or no mortality was observed in fish subject to cold stress or fish with intact skin when challenged by immersion. We, therefore, tested the use of a skin lesion (induced with a 4-mm biopsy punch) combined with cold temperature stress to induce vibriosis following the causal pie model. After challenge, fish were immediately subject to cold stress (22°C) or placed at an optimal temperature of 30°C. All groups were challenged with 10 8  CFU mL -1 for 60 min. A considerably higher mortality level (72.7% ± 13.9%) was observed in fish challenged with both a skin lesion and cold stress compared with mortality in fish only having a skin lesion (14.6% ± 2.8%). V. harveyi was re-isolated from all moribund fish and was detected by species-specific real-time PCR in gills, head kidney and liver, regardless of challenge treatment confirming vibriosis as the cause of disease. Parenchymal tissues had histopathological changes consistent with vibriosis. Whole-genome sequence (WGS) is provided for the Vibrio harveyi isolate examined in this study. Overall, the causal pie model was a useful framework to conceptualize the design of the experimental challenge model, in which both cold stress and skin damage were identified as component causes of vibriosis with high mortality. This conceptual framework can be applied to other opportunistic pathogens in aquaculture or to the study of co-infections in fish., (© 2023 The Authors. Journal of Fish Diseases published by John Wiley & Sons Ltd.)

The freezing step of the lyophilization process can impact nanoparticle stability due to increased particle concentration in the freeze-concentrate. Controlled ice nucleation is a technique to achieve uniform ice crystal formation between vials in the same batch and has attracted increasing attention in pharmaceutical industry. We investigated the impact of controlled ice nucleation on three types of nanoparticles: solid lipid nanoparticles (SLNs), polymeric nanoparticles (PNs), and liposomes. Freezing conditions with different ice nucleation temperatures or freezing rates were employed for freeze-drying all formulations. Both in-process stability and storage stability up to 6 months of all formulations were assessed. Compared with spontaneous ice nucleation, controlled ice nucleation did not cause significant differences in residual moisture and particle size of freeze-dried nanoparticles. The residence time in the freeze-concentrate was a more critical factor influencing the stability of nanoparticles than the ice nucleation temperature. Liposomes freeze-dried with sucrose showed particle size increase during storage regardless of freezing conditions. By replacing sucrose with trehalose, or adding trehalose as a second lyoprotectant, both the physical and chemical stability of freeze-dried liposomes improved. Trehalose was a preferable lyoprotectant than sucrose to better maintain the long-term stability of freeze-dried nanoparticles at room temperature or 40 °C., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Xiuling Lu reports financial support was provided by Center for Pharmaceutical Processing Research., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The macrophage checkpoint interaction CD47-SIRPα is an emerging target for cancer therapy, but clinical trials of monoclonal anti-CD47 show efficacy only in liquid tumors when combined with tumor-opsonizing IgG. Here, in challenging metastatic solid tumors, CD47 deletion shows no effect on tumor growth unless combined with otherwise ineffective tumor-opsonization, and we likewise show wild-type metastases are suppressed by SIRPα-blocked macrophages plus tumor-opsonization. Lung tumor nodules of syngeneic B16F10 melanoma cells with CD47 deletion show opsonization drives macrophage phagocytosis of B16F10s, consistent with growth versus phagocytosis calculus for exponential suppression of cancer. Wild-type CD47 levels on metastases in lungs of immunocompetent mice and on human metastases in livers of immunodeficient mice show that systemic injection of antibody-engineered macrophages also suppresses growth. Such in vivo functionality can be modulated by particle pre-loading of the macrophages. Thus, even though CD47-SIRPα disruption and tumor-opsonizing IgG are separately ineffective against established metastatic solid tumors, their combination in molecular and cellular therapies prolongs survival.

Local anesthetics are voltage-gated sodium channel blockers primarily administered locally or to the innervating nerves for anesthetic or analgesic purposes. In vitro studies have found direct effects of local anesthetics on cancer cells, such as impact on cancer cell proliferation, apoptosis, migration, invasion, and chemosensitivity, by multiple mechanisms. So far, in vivo evidence regarding the effect of local anesthetics on cancer cell lines is relatively lacking. Local and regional anesthesia administration has been reported to reduce postoperative pain and opioid use in cancer treatment. Additionally, regional anesthesia may reduce the perioperative stress response. However, the clinical therapeutic application of local anesthetics in cancer remains exploratory. In this review, we will discuss the direct and indirect effects of local anesthetics on cancer cells, and discuss the current evidence related to the use of local anesthetics in the treatment of cancer., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Freeze-drying is an effective approach to improve the long-term stability of nanomedicines. Lyoprotectants are generally considered as requisite excipients to ensure that the quality of nanoparticles is maintained throughout the freeze-drying process. However, depending on the type of nanoparticles, the needs for lyoprotectants or the challenges they face during freeze-drying may be different. In this study, we compared and identified the impact of freeze-drying on key characteristics of three types of nanoparticles: solid lipid nanoparticles (SLNs), polymeric nanoparticles (PNs), and liposomes. Sucrose, trehalose, and mannitol were added to nanoparticle suspensions before freeze-drying. The same conservative freeze-drying conditions with controlled ice nucleation at -8 °C were employed for all formulations. The collapse temperatures of nanoparticle formulations were found to be the same as those of the lyoprotectant added, except PN formulation. Likely the poly(vinyl alcohol) (PVA) in the formulation induced a higher collapse temperature and retardation of drying of PNs. Freeze-drying of both SLNs and liposomes without lyoprotectants increased particle size and polydispersity, which was resolved by adding amorphous disaccharides. Regardless of the addition of lyoprotectants, freeze-drying did not alter the size of PNs possibly due to the protection from PVA. However, lyoprotectants were still necessary to shorten the reconstitution time and reduce the residual moisture. In conclusion, different types of nanoparticles face distinct challenges for freeze-drying, and lyoprotectants differentially affect various stability and quality attributes of freeze-dried nanoparticles., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Despite progress in global health, the general disease burden still disproportionately falls on low- and middle-income countries. The health needs of these countries' populations are unmet because there is a shortage in drug research and development, as well as a lack of access to essential drugs. This health disparity is especially problematic for diseases associated with poverty, namely neglected tropical diseases and microbial infections. Currently, the pharmaceutical landscape focuses on innovations determined by profit margins and intellectual property protection. To expand drug accessibility and catalyze research and development for neglected diseases, a team of researchers proposed the Health Impact Fund as a potential solution. However, the fund is predominantly considering partnerships with pharmaceutical giants in high-income countries. This commentary explores the limitations and benefits in partnering with pharmaceutical companies based in Brazil, Russia, India, and China (BRIC), with the goal of expanding the Health Impact Fund's vision to incorporate long-term, local partnerships. Identified limitations to a BRIC country partnership include lower levels of drug development expertise compared to their high-income pharmaceutical counterparts, and whether the Health Impact Fund and the participating stakeholders have the financial capability to assist in bringing a new drug to market. However, potential benefits include the creation of new incentives to fuel competitive local innovation, more equitable routes to drug discovery and development, and a product pipeline that could involve stakeholders in lower- and middle-income countries. Our commentary explores how partnership with pharmaceutical firms in BRIC countries might be advantageous for all: The Health Impact Fund, pharmaceutical companies in BRIC economies, and stakeholders in low- and middle- income countries., (© 2021. The Author(s).)

The properties of crystalline materials tend to be strongly correlated with their structures, and the prediction of crystal structure from only the composition is a coveted goal in the field of inorganic materials. However, even for the simplest compositions, such prediction relies on a complex network of interactions, including atomic or ionic radii, ionicity, electronegativity, position in the periodic table, and magnetism, to name only a few important parameters. We focus here on the AB 2 X 6 (AB 2 O 6 and AB 2 F 6 ) composition space with the specific goal of finding new oxide compounds in the trirutile family, which is known for unusual one-dimensional (1D) antiferromagnetic behavior. Through machine learning methods, we develop an understanding of how geometric and bonding constraints determine the crystallization of compounds in the trirutile structure as opposed to other ternary structures in this space. In combination with density functional theory (DFT) calculations, we predict 16 previously unreported candidate trirutile oxides. We successfully prepare one of these and show it forms in the disordered rutile structure, under the preparation conditions adopted here.

We conducted a genome-wide association study of 1320 centenarians from the New England Centenarian Study (median age = 104 years) and 2899 unrelated controls using >9 M genetic variants imputed to the HRC panel of ~65,000 haplotypes. The genetic variants with the most significant associations were correlated to 4131 proteins that were profiled in the serum of a subset of 224 study participants using a SOMAscan array. The genetic associations were replicated in a genome-wide association study of 480 centenarians and ~800 controls of Ashkenazi Jewish descent. The proteomic associations were replicated in a proteomic scan of approximately 1000 Ashkenazi Jewish participants from a third cohort. The analysis replicated a protein signature associated with APOE genotypes and confirmed strong overexpression of BIRC2 (p < 5E-16) and under-expression of APOB in carriers of the APOE2 allele (p < 0.05). The analysis also discovered and replicated associations between longevity variants and slower changes of protein biomarkers of aging, including a novel protein signature of rs2184061 (CDKN2A/CDKN2B in chromosome 9) that suggests a genetic regulation of GDF15. The analyses showed that longevity variants correlate with proteome signatures that could be manipulated to discover healthy-aging targets.

Purpose: To compare cellular uptake and cytotoxicity of fluorescein (FL)-labeled polyethylene glycols (PEGs) carrying 2 folate groups (targeted delivery vehicles [TDVs]) to non-PEGylated molecules with 1 or 2 folate groups., Materials and Methods: Three PEGylated TDVs and 2 non-PEGylated folic acid (FA)-fluorescein (FL) conjugates (FA-FL and FA-FL-FA) were synthesized. Two triple-negative breast cancer cell lines (MDA-MB-231and MDA-MB-468) were cultured to 70% confluency and incubated for 2 h in a folate-depleted medium. Folate receptor (FR) expression was confirmed by immunocytochemistry. Cellular uptake and cytotoxicity of compounds were measured by flow cytometry. Intracellular localization was confirmed using confocal microscopy., Results: MDA-MB-231 demonstrated 40% more FR staining than MD-MB-468. Intracellular localization of the 2 non-PEGylated molecules (FA-FL and FA-FL-FA) and the 3 PEGylated TDVs was confirmed with confocal microscopy. Cellular uptake was independent of concentration for FA-FL, but there was 26.8% more cytotoxicity at 30 μg/mL compared with no treatment (P ≤ .05). Uptake was > 90% for FA-FL-FA at 10 μg/mL and 30 μg/mL without significant cytotoxicity (P ≤ .005). Cellular uptake was > 80% for all TDVs. The molecule containing monodispersed PEG with M n  = 1,000 g/mol had the highest uptake in both cell lines without cytotoxicity. Maximum toxicity was demonstrated by the molecule containing PEG 2,000 only at the highest dose of 30 μg/mL (8.66% ± 3.94% cytotoxicity; cut-off was 20%)., Conclusions: The molecule containing monodispersed PEG with M n  = 1,000 g/mol and 2 FA targeting groups demonstrated better targetability and cellular uptake as a TDV., (Copyright © 2020 SIR. Published by Elsevier Inc. All rights reserved.)

Protein homeostasis, proteostasis, is essential for healthy cell functioning and is dysregulated in many diseases. Metabolic labeling with heavy water followed by liquid chromatography coupled online to mass spectrometry (LC-MS) is a powerful high-throughput technique to study proteome dynamics in vivo. Longer labeling duration and dense timepoint sampling (TPS) of tissues provide accurate proteome dynamics estimations. However, the experiments are expensive, and they require animal housing and care, as well as labeling with stable isotopes. Often, the animals are sacrificed at selected timepoints to collect tissues. Therefore, it is necessary to optimize TPS for a given number of sampling points and labeling duration and target a specific tissue of study. Currently, such techniques are missing in proteomics. Here, we report on a formula-based stochastic simulation strategy for TPS for in vivo studies with heavy water metabolic labeling and LC-MS. We model the rate constant (lognormal), measurement error (Laplace), peptide length (gamma), relative abundance of the monoisotopic peak (beta regression), and the number of exchangeable hydrogens (gamma regression). The parameters of the distributions are determined using the corresponding empirical probability density functions from a large-scale dataset of murine heart proteome. The models are used in the simulations of the rate constant to minimize the root-mean-square error (rmse). The rmse for different TPSs shows structured patterns. They are analyzed to elucidate common features in the patterns.

Glass and glass-ceramic samples of metastable lithium thiophosphates with compositions of 70Li 2 S-30P 2 S 5 and Li 7 P 3 S 11 were controllably prepared by using a rapid assisted-microwave procedure in under 30 min. The rapid preparation times and weak coupling of the evacuated silica ampules with microwave radiation ensure minimal reactivity of the reactants and the container. The microwave-prepared samples display comparable conductivity values with more conventionally prepared (melt quenched) glass and glass-ceramic samples, on the order of 0.1 and 1 mS cm -1 at room temperature, respectively. Rietveld analysis of synchrotron X-ray diffraction data acquired with an internal standard quantitatively yields phase amounts of the glassy and amorphous components, establishing the tunable nature of the microwave preparation. X-ray photoelectron spectroscopy and Raman spectroscopy confirm the composition and the appropriate ratios of isolated and corner-sharing tetrahedra in these semicrystalline systems. Solid-state 7 Li nuclear magnetic resonance (NMR) spectroscopy resolves the seven crystallographic Li sites in the crystalline compound into three main environments. The diffusion behavior of these Li environments as obtained from pulsed-field gradient NMR methods can be separated into one slow and one fast component. The rapid and tunable approach to the preparation of high quality "Li 7 P 3 S 11 " samples presented here coupled with detailed structural and compositional analysis opens the door to new and promising metastable solid electrolytes.

Protein homeostasis (proteostasis) is a result of a dynamic equilibrium between protein synthesis and degradation. It is important for healthy cell/organ functioning and is often associated with diseases such as neurodegenerative diseases and non-Alcoholic Fatty Liver disease. Heavy water metabolic labeling, combined with liquid-chromatography and mass spectrometry (LC-MS), is a powerful approach to study proteostasis in vivo in high throughput. Traditionally, intact peptide signals are used to estimate stable isotope incorporation in time-course experiments. The time-course of label incorporation is used to extract protein decay rate constant (DRC). Intact peptide signals, computed from integration in chromatographic time and mass-to-charge ratio (m/z) domains, usually, provide an accurate estimate of label incorporation. However, sample complexity (co-elution), limited dynamic range, and low signal-to-noise ratio (S/N) may adversely interfere with the peptide signals. These artifacts complicate the DRC estimations by distorting peak shape in chromatographic time and m/z domains. Fragment ions, on the other hand, are less prone to these artifacts and are potentially well suited in aiding DRC estimations. Here, we show that the label incorporation encoded into the isotope distributions of fragment ions reflect the isotope enrichment during the metabolic labeling with heavy water. We explore the label incorporation statistics for devising practical approaches for DRC estimations.

A major hallmark of cancer is a perturbed metabolism resulting in high demand for various metabolites, glucose being the most well studied. While glucose can be converted into pyruvate for ATP production, the serine synthesis pathway (SSP) can divert glucose to generate serine, glycine, and methionine. In the process, the carbon unit from serine is incorporated into the one-carbon pool which makes methionine and maintains S-adenosylmethionine levels, which are needed to maintain the epigenetic landscape and ultimately controlling what genes are available for transcription. Alternatively, the carbon unit can be used for purine and thymidylate synthesis. We present here an approach to follow the flux through this pathway in cultured human cells using stable isotope enriched glucose and gas chromatography mass spectrometry analysis of serine, glycine, and methionine. We demonstrate that in three different cell lines this pathway contributes only 1-2% of total intracellular methionine. This suggests under high extracellular methionine conditions, the predominance of carbon units from this pathway are used to synthesize nucleic acids., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Rickettsiae can cause life-threatening infections in humans. Macrophages are one of the initial targets for rickettsiae after inoculation by ticks. However, it remains poorly understood how rickettsiae remain free in macrophages prior to establishing their infection in microvascular endothelial cells. Here, we demonstrated that the concentration of Rickettsia australis was significantly greater in infected tissues of Atg5 flox/flox mice than in the counterparts of Atg5 flox/flox Lyz- Cre mice, in association with a reduced level of interleukin-1β (IL-1β) in serum. The greater concentration of R. australis in Atg5 flox/flox bone marrow-derived macrophages (BMMs) than in Atg5 flox/flox Lyz- Cre BMMs in vitro was abolished by exogenous treatment with recombinant IL-1β. Rickettsia australis induced significantly increased levels of light chain 3 (LC3) form II (LC3-II) and LC3 puncta in Atg5 -competent BMMs but not in Atg5 -deficient BMMs, while no p62 turnover was observed. Further analysis found the colocalization of LC3 with a small portion of R. australis and Rickettsia -containing double-membrane-bound vacuoles in the BMMs of B6 mice. Moreover, treatment with rapamycin significantly increased the concentrations of R. australis in B6 BMMs compared to those in the untreated B6 BMM controls. Taken together, our results demonstrate that Atg5 favors R. australis infection in mouse macrophages in association with a suppressed level of IL-1β production but not active autophagy flux. These data highlight the contribution of Atg5 in macrophages to the pathogenesis of rickettsial diseases., (Copyright © 2018 Bechelli et al.)

Developments in computational chemistry, bioinformatics, and laboratory evolution have facilitated the de novo design and catalytic optimization of enzymes. Besides creating useful catalysts, the generation and iterative improvement of designed enzymes can provide valuable insight into the interplay between the many phenomena that have been suggested to contribute to catalysis. In this work, we follow changes in conformational sampling, electrostatic preorganization, and quantum tunneling along the evolutionary trajectory of a designed Kemp eliminase. We observe that in the Kemp Eliminase KE07, instability of the designed active site leads to the emergence of two additional active site configurations. Evolutionary conformational selection then gradually stabilizes the most efficient configuration, leading to an improved enzyme. This work exemplifies the link between conformational plasticity and evolvability and demonstrates that residues remote from the active sites of enzymes play crucial roles in controlling and shaping the active site for efficient catalysis.

Recent studies have shown that diffusion on the surface of organic glasses can be many orders of magnitude faster than bulk diffusion. Developing new probes that can readily measure surface diffusion can help study the effect of parameters such as chemical structure, intermolecular interaction, molecules' shape and size on the enhanced surface diffusion. In this study, we develop a novel probe that significantly simplifies these types of studies. Tobacco mosaic virus (TMV) is used as probe particle to measure surface diffusion coefficient of molecular glass N,N'-bis(3-methylphenyl)-N,N'-diphenylbenzidine (TPD). The evolution of the meniscus formed around TMV is probed as a function of time at various temperatures. TMV has a well-defined, mono-dispersed, cylindrical shape, with a large aspect-ratio (average diameter of 16.6 nm, length of 300 nm). As such, the shape of the meniscus around the center of TMV is semi-two dimensional, which compared to using a nanosphere as probe, increases the driving force for meniscus formation and simplifies the analysis of surface diffusion. We show that under these conditions, after a short transient time the shape of the meniscus is self-similar, allowing accurate determination of the surface diffusion coefficient. Measurements at various temperatures are then performed to investigate the temperature dependence of the surface diffusion coefficient. It is found that surface diffusion is greatly enhanced in TPD and has a lower activation barrier compared to the bulk counterpart. These observations are consistent with previous studies of surface diffusion on molecular glasses, demonstrating the accuracy of this method.

We detail the formation and properties associated with stable glasses (SG) formed by a series of structural analogues of 1,3-bis(1-naphthyl)-5-(2-naphthyl)benzene (α,α,β-TNB), a well-studied SG former. Five compounds with similar structural properties were synthesized and physical vapor-deposited with a constant deposition rate at various substrate temperatures (Tdep) in the range between 0.73 Tg and 0.96 Tg. These molecules include α,α,β-TNB, 3,5-di(naphthalen-1-yl)-1-phenylbenzene (α,α-P), 9-(3,5-di(naphthalen-1-yl)phenyl)anthracene (α,α-A), 9,9'-(5-(naphthalen-2-yl)-1,3-phenylene)dianthracene (β-AA), and 3,3',5,5'-tetra(naphthalen-1-yl)-1,1'-biphenyl (α,α,α,α-TNBP). Ellipsometry was used to study the transformations from the as-deposited glasses into ordinary glasses (OG). The stability of each film was evaluated by measuring the fictive temperature (Tf) and density difference between the as-deposited glass and OG. It is demonstrated that all five molecules can form SGs upon vapor deposition in this temperature range. In-depth studies on the dependence of the stability of as-deposited glasses upon Tdep were performed with three molecules, α,α,β-TNB, α,α-P, and α,α-A. The general trends of stability were comparable at the same Tdep/Tg for these three compounds. Similar to previous studies on α,α,β-TNB, vapor-deposited glasses of α,α-P and α,α-A formed the most stable structures around Tdep = 0.8-0.85 Tg. The most stable glass of each molecule showed the lowest thermal expansion coefficient compared to OG and a positive optical birefringence. However, the SGs of α,α-A were less stable compared to α,α-P and α,α,β-TNB at the relative Tdep/Tg. Based on Arrhenius extrapolation of the aging time, as a measure of stability, the most stable α,α-A glass was only aged for a few years as opposed to hundreds or thousands of years for other glasses. We hypothesize that the reduced stability is due to slower mobility at the free surface of α,α-A glass compared to the other two molecules.

The pitting of nuclear steam generator tubing alloys 600, 690 and 800 was studied at 60 °C using dilute thiosulfate solutions containing excess sulfate or (for Alloy 600) chloride. A potentiostatic scratch method was used. In sulfate solutions, all alloys pitted at low potentials, reflecting their lack of protective Mo. The alloys demonstrated the most severe pitting at a sulfate : thiosulfate concentration ratio of ∼40. Alloy 600 pitted worst at a chloride : thiosulfate ratio of ∼2000. The results are interpreted through the mutual electromigration of differently charged anions into a pit nucleus, and differences in the major alloy component.

The present experiments were undertaken to examine whether oxytocin cells in the paraventricular nucleus receive synaptic inputs from the contralateral supraoptic or paraventricular nucleus. Using urethane-anesthetized lactating rats, extracellular action potentials were recorded from single oxytocin or vasopressin cells in the paraventricular nucleus. Electrical stimulation was applied to the contralateral supraoptic nucleus or paraventricular nucleus, and responses of oxytocin or vasopressin cells were analyzed by peri-stimulus time histogram or by change in firing rate of oxytocin or vasopressin cells. Electrical stimulation of the contralateral supraoptic nucleus or paraventricular nucleus did not cause antidromic excitation in oxytocin or vasopressin cells but caused orthodromic responses. Although analysis by peri-stimulus time histogram showed that electrical stimulation of the contralateral supraoptic nucleus or paraventricular nucleus caused orthodromic excitation in both oxytocin and vasopressin cells, the proportion of excited oxytocin cells was greater than that of vasopressin cells. Train stimulation applied to the contralateral supraoptic nucleus or paraventricular nucleus at 10 Hz increased firing rates of oxytocin cells and decreased those of vasopressin cells. The results of the present experiments suggest that oxytocin cells in the paraventricular nucleus receive mainly excitatory synaptic inputs from the contralateral supraoptic nucleus and paraventricular nucleus. Receipt these synaptic inputs to oxytocin cells may contribute to the synchronized activation of oxytocin cells during the milk ejection reflex., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Purpose: The human kallikrein-2 (hK2) protein and two single nucleotide polymorphism (SNPs) (rs2664155, rs198977) of the gene are associated with prostate cancer risk. We examined whether hK2 protein and gene SNPs predict prostate cancer at the time of repeat biopsy., Methods: We prospectively offered a repeat biopsy to men with a negative prostate biopsy performed for a PSA >4.0 ng/mL or abnormal Digital Rectal Exam (DRE) between 2001-2005. We genotyped and measured serum hK2 levels in 941 men who underwent a repeat prostate biopsy. Logistic regression analyses were conducted to determine the significance of KLK2 SNPs and hK2 levels for predicting cancer at repeat biopsy., Results: Of the 941 patients, 180 (19.1%) were found to have cancer. The rs198977 SNP was positively associated with cancer at repeat biopsy (OR variant T allele = 1.8, 95% CI: 1.04-3.13, p = 0.049). When combined, the odds ratio for prostate cancer for patients with high hK2 levels and the variant T-allele of rs198977 was 3.77 (95% CI: 1.94-7.32, p < 0.0001), compared to patients with low hK2 levels and the C-allele. The addition of hK2 levels and KLK2 rs198977 to the baseline predictive model did not significantly increase the area under the curve from a baseline model of 0.67 to 0.69 (p = 0.6)., Conclusions: The KLK2 SNP rs198977 was positively associated with hK2 levels and predicts prostate cancer at the time of repeat prostate biopsy. Further characterization of the KLK2 gene will be needed to determine its clinical utility.

Human serum albumin (HSA) is a potent inhibitor of Aβ self-association and this novel, to our knowledge, function of HSA is of potential therapeutic interest for the treatment of Alzheimer's disease. It is known that HSA interacts with Aβ oligomers through binding sites evenly partitioned across the three albumin domains and with comparable affinities. However, as of this writing, no information is available on the HSA-Aβ interactions beyond domain resolution. Here, we map the HSA-Aβ interactions at subdomain and peptide resolution. We show that each separate subdomain of HSA domain 3 inhibits Aβ self-association. We also show that fatty acids (FAs) compete with Aβ oligomers for binding to domain 3, but the determinant of the HSA/Aβ oligomer interactions are markedly distinct from those of FAs. Although salt bridges with the FA carboxylate determine the FA binding affinities, hydrophobic contacts are pivotal for Aβ oligomer recognition. Specifically, we identified a site of Aβ oligomer recognition that spans the HSA (494-515) region and aligns with the central hydrophobic core of Aβ. The HSA (495-515) segment includes residues affected by FA binding and this segment is prone to self-associate into β-amyloids, suggesting that sites involved in fibrilization may provide a lead to develop inhibitors of Aβ self-association., (Copyright © 2013 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Aim: (1) Investigate incidence, magnitude and bacterial diversity of bacteraemia due to flossing compared with scaling and root planing (SRP) and (2) Identify any associations with clinical parameters., Materials and Methods: Full-mouth flossing and single quadrant SRP were performed at separate visits for 30 patients with chronic periodontitis. Baseline blood samples and at 30 s and 10 min. after completion of flossing, 5 min. after initiation of SRP and 30 s and 10 min. after completion of SRP were obtained. Total bacteraemia and viridans streptococcal bacteraemia (VSB) were investigated., Results: Total bacteraemia incidence was 30% for flossing and 43.3% for SRP (no significant difference; p = 0.21). Flossing and SRP caused the same incidence of VSB (26.7%). Flossing caused a higher mean magnitude of total bacteraemia than SRP (7.4 ± 16.2 CFU/ml versus 2 ± 3.4 CFU/ml), but the difference was not significant (p = 0.2). Flossing caused a higher mean magnitude of VSB than SRP (1.2 ± 1.6 CFU/ml versus 0.4 ± 0.2 CFU/ml), but the difference was not significant (p = 0.09). Viridans streptococci comprised 11.4% of flossing bacteraemia isolates and 7.6% in SRP. No correlations were found between clinical parameters and incidence or magnitude of bacteraemia following flossing. Gingival inflammation was significantly associated with incidence of total bacteraemia (p = 0.01) and VSB (p = 0.001) following SRP. No correlations were found for any parameter and magnitude of total bacteraemia or VSB following SRP., Conclusions: No differences were found between flossing and SRP in the incidence or magnitude of total bacteraemia or VSB. This finding is important in the ongoing re-evaluation of antibiotic prophylaxis to prevent infective endocarditis., (© 2012 John Wiley & Sons A/S.)

Autologous stem cell therapy has not been as effective as forecasted from preclinical studies. Patient age was reported as an important contributing factor. The goal of this study was to uncover age-dependent mechanisms of stem cell dysfunction and to investigate possible means to restore the cellular function. Bone marrow mesenchymal stem cells (MSCs) were isolated from cardiovascular patients. Cell proliferation and number of colonies were inversely correlated with patient age. Myogenic differentiation of MSCs in culture was induced with 5-azacytidine. Differentiation correlated with age, with less differentiation in MSCs from aged patients. We performed real-time PCR to identify genes in the WNT/β-catenin signaling network and found that transcript levels of CTNNB1, LEF1, FZD8, WNT3A, and SFRP4 were negatively correlated with age, whereas FOSL1, LRP6, and FZD6 were positively correlated with age. Protein evaluation showed that β-catenin nuclear translocation correlated with age and was lower in aged MSCs. Aged MSCs treated with lithium chloride-to increase the bioavailability of β-catenin-recovered their capacity for myogenic differentiation through myocyte enhancer factor 2C but not with the knockdown of β-catenin using small-interfering RNA. This study may be the first to relate reduced nuclear β-catenin bioavailability in MSCs from aged patients. Most important, this abnormality was potentially recoverable, providing a target for improving the function of bone marrow stem cells and their clinical utility in aged patients., (Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Purpose: To identify and examine polymorphisms of genes associated with aggressive and clinical significant forms of prostate cancer among a screening cohort., Experimental Design: We conducted a genome-wide association study among patients with aggressive forms of prostate cancer and biopsy-proven normal controls ascertained from a prostate cancer screening program. We then examined significant associations of specific polymorphisms among a prostate cancer screened cohort to examine their predictive ability in detecting prostate cancer., Results: We found significant associations between aggressive prostate cancer and five single nucleotide polymorphisms (SNPs) in the 10q26 (rs10788165, rs10749408, and rs10788165, p value for association 1.3 × 10(-10 ) to 3.2 × 10(-11) ) and 15q21 (rs4775302 and rs1994198, p values for association 3.1 × 10(-8 ) to 8.2 × 10(-9)) regions. Results of a replication study done in 3439 patients undergoing a prostate biopsy, revealed certain combinations of these SNPs to be significantly associated not only with prostate cancer but with aggressive forms of prostate cancer using an established classification criterion for prostate cancer progression (odds ratios for intermediate to high-risk disease 1.8-3.0, p value 0.003-0.001). These SNP combinations were also important clinical predictors for prostate cancer detection based on nomogram analysis that assesses prostate cancer risk., Conclusions: Five SNPs were found to be associated with aggressive forms of prostate cancer. We demonstrated potential clinical applications of these associations.

Cardiac safety testing of lead drug candidates is an important part of the drug discovery and development process. All new chemical entities need to be subjected to extensive preclinical assessment for cardiac liability, especially for a potentially fatal form of ventricular arrhythmia referred to as Torsades de Pointes. We have developed an innovative label-free, real-time system, the xCELLigence RTCA Cardio System, which is designed to monitor contractility of cardiomyocytes based on impedance measurement. The assay is performed using specially designed microtiter plates that are integrated with gold microelectrodes. The system was validated using mouse embryonic stem cell-derived cardiomyocytes, human-induced pluripotent stem cell-derived cardiomyocytes, and rat neonatal primary cardiomyocytes by applying a variety of tool compounds and drugs with known mechanisms of action. Our data show that the time resolution in the assay can provide important information about compound action. Furthermore, the impedance-based beating profile in response to compound treatment can provide mechanistic toxicity information regarding the target being modulated and may be able to flag pro-arrhythmic compounds. We believe the real-time and kinetic aspect of this technology combined with beat-to-beat measurement of cardiomyocyte contraction would make this instrument an important part of preclinical cardiac safety assessment., (Copyright © 2011 Society for Laboratory Automation and Screening. Published by Elsevier Inc. All rights reserved.)

Background: Helicobacter pylori are a persistent colonizer of the human gastric mucosa, which can lead to the development of peptic ulcer disease and gastric adenocarcinomas. However, H. pylori can asymptomatically colonize a host for years. One factor that has been hypothesized to contribute to such persistence is the production of Lewis (Le) antigens in the lipopolysaccharide layer of the bacterial outer membrane as a form of molecular mimicry, because humans also express these antigens on their gastric mucosa. Humans and H. pylori both are polymorphic for Le expression, which is driven in H. pylori by variation at the Le synthesis loci. In this report, we sought to characterize Le genotypic and phenotypic variation in geographically diverse H. pylori isolates., Materials and Methods: From patients undergoing endoscopy in 29 countries, we determined Le phenotypes of 78 H. pylori strains and performed genotyping of the galT and β-(1,3)galT loci in 113 H. pylori strains., Results: Le antigen phenotyping revealed a significant (p < .0001) association between type 1 (Le(a) and Le(b) ) expression and strains of East Asian origin. Genotyping revealed a significant correlation between strain origin and the size of the promoter region upstream of the Le synthesis gene, galT (p < .0001)., Conclusion: These results indicate that the heterogeneity of human Le phenotypes is reflected in their H. pylori colonizing strains and suggest new loci that can be studied to assess the variation of Le expression., (© 2011 Blackwell Publishing Ltd.)

This study was a preliminary investigation into a seated unloading movement strategy for the lumbar spine using the upper extremities. With the economic burden of LBP estimated in the billions worldwide, and also with a trend towards more jobs related to sitting, a simple distraction exercise coined chair-care is presented. An attempt to objectify using stadiometry was used to measure standing height changes after 15 min of sitting and after the exercise. The results showed significant standing height gains post-exercise when compared to post-sitting and initial standing (2.4 and 2.7 mm, respectively). No significant standing height changes were seen after 15 min of sitting. It is therefore likely that this simple seated exercise creates standing height gains of the spine. Proposed mechanisms are discussed with an emphasis on spinal hydraulics and intervertebral disc nutrition. Reproducible studies are required., (Copyright 2008 Elsevier Ltd. All rights reserved.)

Introduction: This study surveyed the residents of the rural and remote communities in the Bella Coola Valley, British Columbia, on their alcohol drinking habits and on their opinions as to which of a list of health issues were the most important considerations for the well-being of the community., Methods: People aged 17 years and older living in the Bella Coola Valley were asked to complete a detailed Health and Quality of Life Survey during the period August 2001 to May 2002. This included two separate mailouts. Alcohol drinking habits; and ratings on whether or not people believed that alcohol abuse, drug abuse, family violence, unemployment, sexual abuse and racial discrimination were surveyed., Results: A total of 674 adults age 17 years and older (39% response rate) completed an 11-page questionnaire. Results from the survey indicate that unemployment, alcohol abuse and drug abuse are seen as the most important community health problems by the majority of residents. Eighty-eight percent of respondents agree or strongly agree that unemployment is a problem; for alcohol abuse it was 83%, for drug abuse 77%, for both family violence and sexual abuse 58%, and for racial discrimination it was 53%. Patterns of drinking habits vary considerably between Aboriginal peoples and non-Aboriginal people. More Aboriginal respondents abstained from drinking alcoholic beverages (54%) than non-Aboriginal respondents (22%). Among the Aboriginal peoples who did drink alcohol, there were relatively more heavy drinkers (36%) compared with non-Aboriginal people (7%). There were more heavy drinkers among men than among women., Conclusion: Patterns of drinking habits vary between men and women and between Aboriginal and non-Aboriginal people. The majority of residents agree that alcohol is a problem in these communities. Unemployment, drug abuse, family violence, sexual abuse and racial discrimination are also believed to be important issues for the Bella Coola Valley. This information should be used to set priorities for future health and wellness programs.

Introduction: The current study quantifies visits to salaried physicians working in a geographically remote health care facility in British Columbia in 2001., Methods: A retrospective chart review was conducted of patients residing in the Bella Coola Valley and attending the Bella Coola General Hospital/Medical Clinic (BCGH/Medical Clinic) in 2001. Visits to family physicians at this clinic, visits to the BCGH emergency department, hospital admissions, smoking rates and chronic disease prevalence rates were quantified., Results: An estimated 2378 patients made 7747 BCGH/Medical Clinic family physician visits, and 4474 "other" visits in 2001. These "other" visits included emergency department visits (n = 1736), hospital admissions (n = 245) and prescription visits (n = 2252). Twenty-six percent (n = 622) of the population did not see a family physician at all in 2001, and 15% of the population accounted for 52% of all visits. Women had a higher number of visits than men; pregnant women had a higher number of visits than non-pregnant women, and the Aboriginal population saw family physicians more often than did non-Aboriginal people (p < 0.001). Those who had a chronic illness (e.g., diabetes) saw family physicians more frequently than did people who did not have that particular chronic illness (p < 0.01). The Aboriginal population used the BCGH/Medical Clinic and emergency department more frequently than did the non-Aboriginal population. BCGH/Medical Clinic physicians had an average of 75 patient visits per week. An additional 22 "visits" per week were for writing prescription refills with the patient not present., Conclusion: Older people, people with chronic disease, women and Aboriginal peoples more frequently visited the family physicians. Salaried physicians working in geographically isolated communities appeared to behave in ways that minimized contact (e.g., used the phone, wrote prescriptions without patient being present) and maximized time efficiency for both themselves and their patients.

Introduction: North American rural residents have higher rates of chronic disease and they report being ill more frequently compared to their urban counterparts. We recently studied health-related quality in residents living in the isolated, rural community of Bella Coola, Canada., Objective: To assess health-related quality of life parameters in adults suffering from chronic disease and living in the rural, remote community of Bella Coola., Methods: Design, mixed methods: (1) mailed health-related survey; (2) retrospective chart review., Study Population: people aged 17 years and older living in the Bella Coola Valley and having a chart at the Bella Coola Medical Clinic as of September 2001 were asked to complete a detailed health-related quality of life survey during the period August to December 2001., Main Outcome Measures: demographics (age, sex, weight [BMI], ethnicity). Health-related quality of life was measured using the MOS 36-item Short Form Health Survey (SF-36), and the US Centers for Disease Control healthy day's items. Chronic diseases studied included diabetes mellitus, hypertension, chronic obstructive lung disease, coronary artery disease, hyperlipidemia, depression/anxiety, cancer, osteoarthritis, inflammatory arthritis and chronic back/neck pain., Results: Response rate to the survey was 38% (675/1770). Compared to total clinic population relatively more female (57% vs 49%), non-Aboriginal (63% vs 57%) and older people (48.9 vs 43.5 years) answered the survey. The most prevalent chronic diseases among the survey respondents were hypertension (17%), depression/anxiety (13%), hyperlipidemia (11%), chronic back/neck pain (11%), and osteoarthritis (9%). Linear regression analysis was performed for each of the SF-36 domains and CDC healthy day items. The presence of chronic disease is associated with significant differences in HRQOL item scores and the greater the number chronic diseases present the worse the HRQOL item scores., Conclusion: People living in the rural remote community of Bella Coola who have chronic disease experience significant impairment in their health-related quality of life. The greater the number of coexisting chronic diseases a person has, the more likely that poor HRQOL scores will be reported.

Objective: To determine the prevalence of depression-anxiety disorders and the degree to which physicians prescribed antidepressants for Aboriginal and non-Aboriginal populations living in a remote rural community in British Columbia in 2001., Methods: To obtain data for our main outcome measures, we retrospectively reviewed the charts of 2375 patients living in the Bella Coola Valley as of September 2001 and attending the Bella Coola Medical Clinic., Results: The 2001 prevalence rate of depression-anxiety disorders in the Bella Coola Valley was 7.5% (177/2375). Depression was the most common problem (86%) in these patients. Women had a higher rate of depression-anxiety disorders (10.3%) than did men (4.7%) (P < 0.001). Non-Aboriginal people had a slightly higher rate (8.5%) than did Aboriginal people (6.3%); however, the difference was not statistically significant. Antidepressant medications were commonly prescribed for chronic pain and insomnia. The general pattern of antidepressant medication use in 2001 among both Aboriginal and non-Aboriginal people living in the Bella Coola Valley was as follows: peak use of antidepressants was in the middle to late years; the rate for women was roughly double the rate for men; and proportionately more Aboriginal people, especially the women, were taking antidepressants., Conclusions: Depression-anxiety disorder prevalence rates for Aboriginal and non-Aboriginal populations are similar. When using antidepressant medication prescriptions as a community health indicator, health care administrators should be aware that antidepressant medications are commonly prescribed for conditions other than depression-anxiety disorder.

Background: Mammographic breast density is a significant risk factor for breast cancer. Women with dense tissue accounting for more than 60-75% of the area of the breast have a 4- to 6-fold increase in their risk of breast cancer, compared to women with little or no breast density. A high circulating level of insulin-like growth factor-I (IGF-I) and low IGF binding protein 3 (IGFBP-3) level have been associated with increased breast density in premenopausal women. Genetic polymorphisms in the IGF1 and IGFBP3 genes may influence breast and serum levels of these growth factors. The aims of this study were to determine whether polymorphic variations in the IGF1 and IGFBP3 genes are associated with breast density, and serum IGF-I and IGFBP-3 levels, and whether serum IGF-I and IGFBP-3 levels are associated with mammographic density., Methods: A total of 441 white women, recruited from Women's College Hospital (Toronto, Ontario), enrolled in this study. Each woman completed a questionnaire, detailing information on age, menstrual history, hormone use, diet, and medical and mammography history. Blood samples were taken for DNA extraction to genotype the subjects for polymorphic variants in the two candidate genes, and for measurement of circulating levels of IGF-I and IGFBP-3. Mammographic films were retrieved from Women's College Hospital and digitized using a laser film scanner. The digitized images were assessed for breast density using a computer-assisted method., Results: There was a positive association between serum IGFBP-3 levels and the number of A alleles at a previously described polymorphic locus in the promoter region of the IGFBP3 gene among premenopausal women (P = 0.01). There was also a positive trend in the mean percentage of breast density by the number of A alleles of the IGFBP3 gene among premenopausal women (P = 0.0005). Women with two A alleles had a 5-fold increase in the odds of having a percentage of breast density greater or equal to 28%, compared with women with no A allele (P = 0.002). However, there was no association between serum IGF-I and IGFBP-3 levels and breast density among premenopausal women (P > 0.05)., Conclusions: This is the first study to report a strong relationship between a polymorphic gene locus (IGFBP3) and mammographic breast density. However, we could not confirm an association between serum IGF-I levels and breast density among premenopausal women, as demonstrated in previous studies.

Up to one-third of women with breast cancer have a family history of breast cancer, and approximately 5% of cases are attributed to mutations in high-risk breast cancer susceptibility genes, such as BRCA1 and BRCA2. It is believed that genes of lower penetrance, but of greater prevalence, may also modulate a woman's risk of breast cancer. We studied the association of breast cancer and the trinucleotide repeat polymorphism (CAGn) in exon 1 of the androgen receptor gene (AR) in 299 cases of breast cancer and in 229 hospital-based controls from The Philippines. Women for whom the mean length of the CAG repeat allele was < or = 25 units had approximately one-half of the risk of breast cancer compared with women with a mean repeat length of > or = 26 [odds ratio (OR), 0.47; 95% confidence interval (CI), 0.28-0.8). The association with breast cancer risk was particularly strong among older women (> or = 50 years; OR, 0.2; 95% CI, 0.04-0.94). The association was also observed for the longer of the two AR alleles; there was a 5% increase in breast cancer risk for each unit increase in CAG repeat number. These findings support the theory that short trinucleotide repeat genotypes of the AR gene protect against breast cancer.

We introduce a new type of x-ray telescope design, an equal-curvature telescope. We simply add a second-order axial sag to the base grazing-incidence cone-cone telescope. The radius of curvature of the sag terms is the same on the primary surface and on the secondary surface. The design is optimized such that the on-axis image spot at the focal plane is minimized. The on-axis rms spot diameter of two telescopes that we studied is less than 0.2 arc sec. The off-axis performance is comparable with that of equivalent Wolter type 1 telescopes.

Bloom syndrome is an autosomal recessive disorder whose characteristics include an increased risk for many types of cancers. In contrast to the homozygous mutations of Bloom syndrome, heterozygous carriers of BLM mutations may be at increased risk for developing colorectal cancer. We have screened 2,333 Jewish individuals, including 497 individuals with colorectal cancer, 125 with adenomatous polyps, 767 with noncolorectal cancers and 944 controls for the truncating BLM(Ash) founder mutation. The BLM(Ash) mutation was carried by 0.80% of individuals with colorectal neoplasia, 0.87% of those with any type of cancer and 0.85% of controls. In addition to case-control data, we found no evidence to support a significant relationship between increased cancer risk and heterozygous BLM(Ash) mutations with respect to age of cancer diagnosis, tumor multiplicity or family cancer history.