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With improved management of patients with acute myocardial infarctions (MI), the prevalence in heart failure (HF) post-MI is expected to rise. Currently, the only successful treatments for HF are total heart transplantation and left ventricular (LV) assist devices, but their uses are limited by the availability of donor hearts and invasiveness of the procedure. In the last decade, advancements have been made towards developing injectable hydrogels for the purpose of cardiac repair. Injections of hydrogels alone have been shown to attenuate the decline in cardiac function and LV remodeling typically seen after MI in both large and small animals models. One of these hydrogels was previously developed by our lab and derived from decellularized porcine ventricular myocardium. The goal of this thesis was study to the mechanisms by which injections of the myocardial matrix hydrogel improve cardiac repair post-MI and improve upon its cardioreparative effects. To better understand how this myocardial matrix is able to induce the beneficial effects observed post-MI, a whole transcriptome microarray was performed on infarct tissue collected from matrix or saline injected infarcts. We showed through pathway analysis that the effects of the injection were dividable into several tissue level phenotypes. To better understand these in vivo phenomena, we wanted to recapitulate the observations by cell culture in vitro with the myocardial matrix. Several cell behaviors relevant to the infarct milieu were studied, including cardiac progenitor cell migration, cardiomyocyte apoptosis, cardiac fibroblast metallomatrix proteinase (MMP) production, and macrophage polarization. We demonstrated that the form of the matrix that is presented to the cells have a dramatic effect on the cellular response, whether through the 3D hydrogel or as soluble peptides released during degradation. In addition, different fractions of the degradation products also have different bioactivity. Results from these in vitro experiments suggested that the bioactivity of the myocardial matrix and its degradation products seemed to be essential to its cardioreparative effects post-MI; thus, we investigated whether this could be enhanced by prolonging the degradation rate of the hydrogel. Through these studies, we provided the first steps towards elucidating the mechanism of actions of the myocardial matrix, by defining the tissue level changes that it induces in infarcted myocardium and identifying the bioactivity in both the hydrogel form and degradation products.

Understanding complex tissues requires single-cell deconstruction of gene regulation with precision and scale. Here we present a massively parallel droplet-based platform for mapping transposase-accessible chromatin in tens of thousands of single cells per sample (scATAC-seq). We obtain and analyze chromatin profiles of over 200,000 single cells in two primary human systems. In blood, scATAC-seq allows marker-free identification of cell type-specificcis- andtrans-regulatory elements, mapping of disease-associated enhancer activity, and reconstruction of trajectories of differentiation from progenitors to diverse and rare immune cell types. In basal cell carcinoma, scATAC-seq reveals regulatory landscapes of malignant, stromal, and immune cell types in the tumor microenvironment. Moreover, scATAC-seq of serial tumor biopsies before and after PD-1 blockade allows identification of chromatin regulators and differentiation trajectories of therapy-responsive intratumoral T cell subsets, revealing a shared regulatory program driving CD8+T cell exhaustion and CD4+T follicular helper cell development. We anticipate that droplet-based single-cell chromatin accessibility will provide a broadly applicable means of identifying regulatory factors and elements that underlie cell type and function.

Hallucinations - compelling perceptions of stimuli that aren't really there - occur in many psychiatric and neurological disorders, and are triggered by certain drugs of abuse. Despite their clinical importance, the neuronal mechanisms giving rise to hallucinations are poorly understood, in large part due to the absence of animal models in which they can be induced, confirmed to be endogenously generated, and objectively analyzed. In humans, amphetamine (AMPH) and related psychostimulants taken in large or repeated doses can induce hallucinations. Here we present evidence for such phenomena in the marine mollusk Tritonia diomedea. Animals injected with AMPH were found to sporadically launch spontaneous escape swims in the absence of eliciting stimuli. Deafferented isolated brains exposed to AMPH, where real stimuli could play no role, generated sporadic, spontaneous swim motor programs. A neurophysiological search of the swim network traced the origin of these drug-induced spontaneous motor programs to spontaneous bursts of firing in the S-cells, the CNS afferent neurons that normally inform the animal of skin contact with its predators and trigger the animal's escape swim. Further investigation identified AMPH-induced enhanced excitability and plateau potential properties in the S-cells. Taken together, these observations support an argument that Tritonia's spontaneous AMPH-induced swims are triggered by false perceptions of predator contact - i.e., hallucinations-and illuminate potential cellular mechanisms for such phenomena.

Sarcoidosis is an immunologic disease of unknown etiology that manifests most frequently within the lungs or associated lymph nodes. Sarcoidosis involving the breast is seen in

Human genetic evidence has identified the voltage-gated sodium channel Na

Human genetic evidence has identified the voltage-gated sodium channel NaV1.7 as an attractive target for the treatment of pain. We initially identified naphthalene sulfonamide 3 as a potent and selective inhibitor of NaV1.7. Optimization to reduce biliary clearance by balancing hydrophilicity and hydrophobicity (Log D) while maintaining NaV1.7 potency led to the identification of quinazoline 16 (AM-2099). Compound 16 demonstrated a favorable pharmacokinetic profile in rat and dog and demonstrated dose-dependent reduction of histamine-induced scratching bouts in a mouse behavioral model following oral dosing.

Journal article A recent two-stage genome-wide association study (GWAS) identified five novel breast cancer susceptibility loci on chromosomes 9, 10, and 11. To provide more reliable estimates of the relative risk associated with these loci and investigate possible heterogeneity by subtype of breast cancer, we genotyped the variants rs2380205, rs1011970, rs704010, rs614367, and rs10995190 in 39 studies from the Breast Cancer Association Consortium (BCAC), involving 49,608 cases and 48,772 controls of predominantly European ancestry. Four of the variants showed clear evidence of association (P â ¤ 3 Ã 10(-9) ) and weak evidence was observed for rs2380205 (P = 0.06). The strongest evidence was obtained for rs614367, located on 11q13 (per-allele odds ratio 1.21, P = 4 Ã 10(-39) ). The association for rs614367 was specific to estrogen receptor (ER)-positive disease and strongest for ER plus progesterone receptor (PR)-positive breast cancer, whereas the associations for the other three loci did not differ by tumor subtype. EC Seventh Framework Programme - grant number HEALTH-F2-2009-223175 peer-reviewed

While 32 nm lithography technology is on the horizon for integrated circuit (IC) fabrication, matching the pace for miniaturization with optics has been hampered by the diffraction limit. However, development of nanoscale components and guiding methods is burgeoning through advances in fabrication techniques and materials processing. As waveguiding presents the fundamental issue and cornerstone for ultra-high density photonic ICs, we examine the current state of methods in the field. Namely, plasmonic, metal slot and negative dielectric based waveguides as well as a few sub-micrometer techniques such as nanoribbons, high-index contrast and photonic crystals waveguides are investigated in terms of construction, transmission, and limitations. Furthermore, we discuss in detail quantum dot (QD) arrays as a gain-enabled and flexible means to transmit energy through straight paths and sharp bends. Modeling, fabrication and test results are provided and show that the QD waveguide may be effective as an alternate means to transfer light on sub-diffraction dimensions.

Metastasis to the breast most commonly arises from a contralateral primary breast malignancy; however, metastatic disease can also result from extramammary malignancies by hematogenous or lymphatic dissemination. This case report reviews an unusual presentation of primary ovarian carcinoma with metastasis to an intramammary lymph node.

Female breast tissue is composed of variable proportions of fat and fibroglandular tissue, and in general, an increased ratio of fibroglandular tissue to fat corresponds to increased mammographic density. Studies suggest that mammographic density is an independent risk factor for breast cancer, and the sensitivity of mammography can be lower with heterogeneously dense or extremely dense breasts. Nineteen states have legal statutes requiring that patients be notified if they have dense breasts, including the state of Texas. Henda's law, mandated on January 1, 2012 in Texas, suggests that patients with dense breasts could benefit from additional screening tests such as breast magnetic resonance imaging (MRI). Our study examined the impact of Henda's law by comparing the number of screening breast MRIs performed for dense breasts before and after the law's implementation. Results showed a 23-fold increase in the number of dense breast MRIs in the 2 years that this new legislation was in effect. This increase could have substantial implications for the health care economy, and further studies are needed to determine the cost-effectiveness of this additional screening tool.

Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, h(l)(2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (rho = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (rho = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (rho = 0.51, SE = 0.18), and bladder and lung (rho = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.

Recent advances in somatic cell reprogramming have highlighted the plasticity of the somatic epigenome, particularly through demonstrations of direct lineage reprogramming of adult mouse and human fibroblasts to induced pluripotent stem cells (iPSCs) and induced neurons (iNs) under defined conditions. However, human cells appear to be less plastic and have a higher epigenetic hurdle for reprogramming to both iPSCs and iNs. Here, we show that SH2B adaptor protein 1β (SH2B1) can enhance neurite outgrowth of iNs reprogrammed from human fibroblasts as early as day 14, when combined with miR124 and transcription factors BRN2 and MYT1L (IBM) under defined conditions. These SH2B1-enhanced iNs (S-IBM) showed canonical neuronal morphology, and expressed multiple neuronal markers, such as TuJ1, NeuN, and synapsin, and functional proteins for neurotransmitter release, such as GABA, vGluT2, and tyrosine hydroxylase. Importantly, SH2B1 accelerated mature process of functional neurons and exhibited action potentials as early as day 14; without SH2B1, the IBM iNs do not exhibit action potentials until day 21. Our data demonstrate that SH2B1 can enhance neurite outgrowth and accelerate the maturation of human iNs under defined conditions. This approach will facilitate the application of iNs in regenerative medicine and in vitro disease modeling.

Women using menopausal hormone therapy (MHT) are at increased risk of developing breast cancer (BC). To detect genetic modifiers of the association between current use of MHT and BC risk, we conducted a meta-analysis of four genome-wide case-only studies followed by replication in 11 case–control studies. We used a case-only design to assess interactions between single-nucleotide polymorphisms (SNPs) and current MHT use on risk of overall and lobular BC. The discovery stage included 2920 cases (541 lobular) from four genome-wide association studies. The top 1391 SNPs showingPvalues for interaction (Pint) −3were selected for replication using pooled case–control data from 11 studies of the Breast Cancer Association Consortium, including 7689 cases (676 lobular) and 9266 controls. Fixed-effects meta-analysis was used to derive combinedPint. No SNP reached genome-wide significance in either the discovery or combined stage. We observed effect modification of current MHT use on overall BC risk by two SNPs on chr13 nearPOMP(combinedPint≤8.9×10−6), two SNPs inSLC25A21(combinedPint≤4.8×10−5), and three SNPs inPLCG2(combinedPint≤4.5×10−5). The association between lobular BC risk was potentially modified by one SNP inTMEFF2(combinedPint≤2.7×10−5), one SNP inCD80(combinedPint≤8.2×10−6), three SNPs on chr17 nearTMEM132E(combinedPint≤2.2×10−6), and two SNPs on chr18 nearSLC25A52(combinedPint≤4.6×10−5). In conclusion, polymorphisms in genes related to solute transportation in mitochondria, transmembrane signaling, and immune cell activation are potentially modifying BC risk associated with current use of MHT. These findings warrant replication in independent studies.

To what extent are motor networks underlying rhythmic behaviors rigidly hard-wired versus fluid and dynamic entities? Do the members of motor networks change from moment-to-moment or from motor program episode-to-episode? These are questions that can only be addressed in systems where it is possible to monitor the spiking activity of networks of neurons during the production of motor programs. We used large-scale voltage-sensitive dye (VSD) imaging followed by Independent Component Analysis spike-sorting to examine the extent to which the neuronal network underlying the escape swim behavior of Tritonia diomedea is hard-wired versus fluid from a moment-to-moment perspective. We found that while most neurons were dedicated to the swim network, a small but significant proportion of neurons participated in a surprisingly variable manner. These neurons joined the swim motor program late, left early, burst only on some cycles or skipped cycles of the motor program. We confirmed that this variable neuronal participation was not due to effects of the VSD by finding such neurons with intracellular recording in dye-free saline. Further, these neurons markedly varied their level of participation in the network from swim episode-to-episode. The generality of such unreliably bursting neurons was confirmed by their presence in the rhythmic escape networks of two other molluscan species, Tritonia festiva and Aplysia californica. Our observations support a view that neuronal networks, even those underlying rhythmic and stereotyped motor programs, may be more variable in structure than widely appreciated.

As continued scaling becomes increasingly difficult, 3D integration with through silicon vias (TSVs) has emerged as a viable solution to achieve higher bandwidth and power efficiency. Mechanical stress induced by thermal mismatch between TSVs and the silicon bulk arising during wafer fabrication and 3D integration, is a key constraint. In this work, we propose a complete flow to characterize the influence of TSV stress on transistor and circuit performance. First, we analyze the thermal stress contour near the silicon surface with single and multiple TSVs through both finite element analysis (FEA) and linear superposition methods. Then, the biaxial stress is converted to mobility and threshold voltage variations depending on transistor type and geometric relation between TSVs and transistors. Next, we propose an efficient algorithm to calculate circuit variation corresponding to TSV stress based on a grid partition approach. Finally, we discuss a TSV pattern optimization strategy, and employ a series of 17-stage ring oscillators using 40 nm CMOS technology as a test case for the proposed approach.

To explore the potential risk factors related to gastrointestinal cancer in northern China.A total of 3314 cases of gastrointestinal cancer (esophageal, gastric, pancreatic and biliary) and 2223 controls (including healthy individuals, glioma and thyroid cancer) were analyzed by case-control study. Multivariable logistic regression analysis was applied to evaluate the association between different cancers and hepatitis B surface antigen, sex, age, blood type, diabetes, or family history of cancer.Type 2 diabetes was significantly associated with gastric, biliary and pancreatic cancer with an OR of 2.0-3.0. Blood type B was significantly associated with esophageal cancer [odd ratio (OR) = 1.53, 95% confidence interval (CI) = 1.10-2.14] and biliary cancer (OR = 1.49, 95% CI = 1.09-2.05). The prevalence of type 2 diabetes was significantly higher in gastric, biliary and pancreatic cancers compared with other groups, with ORs ranging between 2.0 and 3.0. Family history of cancer was strongly associated with gastrointestinal compared with other cancers.Blood type B individuals are susceptible to esophageal and biliary cancer. Type 2 diabetes is significantly associated with gastric, biliary and especially pancreatic cancer.

The radial scar (RS) or complex sclerosing lesion (CSL) of the breast represents a management dilemma on diagnosis at breast core needle biopsy because of the risk of associated malignancy identified only upon surgical excision. To determine our experience, we retrospectively reviewed core needle biopsies performed at the Darlene G. Cass Breast Imaging Center from 2006 to 2011, identifying 67 patients with RS or CSL, and correlated histology at excisional biopsy with core biopsy results. Of the 67 cases, 6 (9%) were associated with malignancy at surgical excision. The average size of the RS or CSL was 1.42 cm. In conclusion, RS or CSL diagnosed at core needle biopsy still warrants surgical excision because of the significant percentage (9%) of cases with associated malignancy.

Utilizing linear mixed oligopoly model, this paper explores the magnitude of the maximum-revenue tariff, optimum-welfare tariff, and revenue-constrained optimal tariff that is especially designed for the consideration of the bureaucratic inefficiency. In particular, the tariff ranking issue is examined under both cases of Cournot competition and domestic public leadership. We found that, under Cournot competition, the optimum-welfare tariff is the highest and it is followed by the revenue-constrained optimal tariff while the maximum-revenue tariff is the lowest. But, under Stackelberg public leadership, if the domestic private firms are fewer than the foreign firms, the maximum-revenue tariff becomes the highest and the optimum-welfare exceeds the revenue-constrained optimal tariff.

BACKGROUND: Somatic mutations in phosphoinositide-3-kinase catalytic subunit alpha (PIK3CA) are frequent in breast tumours and have been associated with oestrogen receptor (ER) expression, human epidermal growth factor receptor-2 overexpression, lymph node metastasis and poor survival. The goal of this study was to evaluate the association between inherited variation in this oncogene and risk of breast cancer. METHODS: A single-nucleotide polymorphism from the PIK3CA locus that was associated with breast cancer in a study of Caucasian breast cancer cases and controls from the Mayo Clinic (MCBCS) was genotyped in 5436 cases and 5280 controls from the Cancer Genetic Markers of Susceptibility (CGEMS) study and in 30 949 cases and 29 788 controls from the Breast Cancer Association Consortium (BCAC). RESULTS: Rs1607237 was significantly associated with a decreased risk of breast cancer in MCBCS, CGEMS and all studies of white Europeans combined (odds ratio (OR) = 0.97, 95% confidence interval (CI) 0.95-0.99, P = 4.6 x 10(-3)), but did not reach significance in the BCAC replication study alone (OR = 0.98, 95% CI 0.96-1.01, P = 0.139). CONCLUSION: Common germline variation in PIK3CA does not have a strong influence on the risk of breast cancer British Journal of Cancer (2011) 105, 1934 - 1939. doi: 10.1038/bjc.2011.448 www.bjcancer.com Published online 27 October 2011 (C) 2011 Cancer Research UK

Esophageal adenocarcinoma risk in Barrett's esophagus (BE) is increased 30- to 125-fold versus the general population. Among all BE patients, however, neoplastic progression occurs only once per 200 patient-years. Molecular biomarkers are therefore needed to risk-stratify patients for more efficient surveillance endoscopy and to improve the early detection of progression. We therefore performed a retrospective, multicenter, double-blinded validation study of eight BE progression prediction methylation biomarkers. Progression or nonprogression were determined at 2 years (tier 1) and 4 years (tier 2). Methylation was assayed in 145 nonprogressors and 50 progressors using real-time quantitative methylation-specific PCR. Progressors were significantly older than nonprogressors (70.6 versus 62.5 years; P < 0.001). We evaluated a linear combination of the eight markers, using coefficients from a multivariate logistic regression analysis. Areas under the ROC curve (AUC) were high in the 2-year, 4-year, and combined data models (0.843, 0.829, and 0.840; P < 0.001

Background Somatic mutations of mitochondrial DNA (mtDNA) are common in many human cancers. We have described an oligonucleotide microarray ("MitoChip") for rapid sequencing of the entire mitochondrial genome (Zhou et al, J Mol Diagn 2006), facilitating the analysis of mtDNA mutations in preneoplastic lesions. We examined 14 precancerous lesions, including seven Barrett esophagus biopsies, with or without associated dysplasia; four colorectal adenomas; and three inflammatory colitis-associated dysplasia specimens. In all cases, matched normal tissues from the corresponding site were obtained as germline control. MitoChip analysis was performed on DNA obtained from cryostat-embedded specimens. Results A total of 513,639 bases of mtDNA were sequenced in the 14 samples, with 490,224 bases (95.4%) bases assigned by the automated genotyping software. All preneoplastic lesions examined demonstrated at least one somatic mtDNA sequence alteration. Of the 100 somatic mtDNA alterations observed in the 14 cases, 27 were non-synonymous coding region mutations (i.e., resulting in an amino acid change), 36 were synonymous, and 37 involved non-coding mtDNA. Overall, somatic alterations most commonly involved the COI, ND4 and ND5 genes. Notably, somatic mtDNA alterations were observed in preneoplastic lesions of the gastrointestinal tract even in the absence of histopathologic evidence of dysplasia, suggesting that the mitochondrial genome is susceptible at the earliest stages of multistep cancer progression. Conclusion Our findings further substantiate the rationale for exploring the mitochondrial genome as a biomarker for the early diagnosis of cancer, and confirm the utility of a high-throughput array-based platform for this purpose from a clinical applicability standpoint.

Objectives This study evaluated the use of an injectable hydrogel derived from ventricular extracellular matrix (ECM) for treating myocardial infarction (MI) and its ability to be delivered percutaneously. Background Injectable materials offer promising alternatives to treat MI. Although most of the examined materials have shown preserved or improved cardiac function in small animal models, none have been specifically designed for the heart, and few have translated to catheter delivery in large animal models. Methods We have developed a myocardial-specific hydrogel, derived from decellularized ventricular ECM, which self-assembles when injected in vivo. Female Sprague-Dawley rats underwent ischemia reperfusion followed by injection of the hydrogel or saline 2 weeks later. The implantation response was assessed via histology and immunohistochemistry, and the potential for arrhythmogenesis was examined using programmed electrical stimulation 1 week post-injection. Cardiac function was analyzed with magnetic resonance imaging 1 week pre-injection and 4 weeks post-MI. In a porcine model, we delivered the hydrogel using the NOGA-guided MyoStar catheter (Biologics Delivery Systems, Irwindale, California), and utilized histology to assess retention of the material. Results We demonstrate that injection of the material in the rat MI model increases endogenous cardiomyocytes in the infarct area and maintains cardiac function without inducing arrhythmias. Furthermore, we demonstrate feasibility of transendocardial catheter injection in a porcine model. Conclusions To our knowledge, this is the first in situ gelling material to be delivered via transendocardial injection in a large animal model, a critical step towards the translation of injectable materials for treating MI in humans. Our results warrant further study of this material in a large animal model of MI and suggest this may be a promising new therapy for treating MI.

Background Resveratrol, a phytoalexin found in grapes and red wine, exhibits diverse pharmacological activities. However, relatively little is known about whether resveratrol modulates the ion channels in cortical neurons. The large-conductance calcium-activated potassium channels (BKCa) and voltage-gated sodium channels were expressed in cortical neurons and play important roles in regulation of neuronal excitability. The present study aimed to determine the effects of resveratrol on BKCa currents and voltage-gated sodium currents in cortical neurons. Results Resveratrol concentration-dependently increased the current amplitude and the opening activity of BKCa channels, but suppressed the amplitude of voltage-gated sodium currents. Similar to the BKCa channel opener NS1619, resveratrol decreased the firing rate of action potentials. In addition, the enhancing effects of BKCa channel blockers tetraethylammonium (TEA) and paxilline on action potential firing were sensitive to resveratrol. Our results indicated that the attenuation of action potential firing rate by resveratrol might be mediated through opening the BKCa channels and closing the voltage-gated sodium channels. Conclusions As BKCa channels and sodium channels are critical molecular determinants for seizure generation, our findings suggest that regulation of these two channels in cortical neurons probably makes a considerable contribution to the antiseizure activity of resveratrol.