Ignorance based inference of optimality in thermodynamic processes

We derive ignorance based prior distribution to quantify incomplete information and show its use to estimate the optimal work characteristics of a heat engine.Comment: Latex, 10 pages, 3 figure

From Pollution to Resource: Advancing Swine Waste Treatment in the USA

Concentrated animal feeding operations (CAFOs) have led to environmental challenges, specifically waste management. Swine CAFOs generate large amounts of waste, requiring proper treatment to avoid air and water pollution. Conventional waste management technologies, such as lagoon and spray field systems, do not prevent air and water pollution impacts. Research for the past few decades led to recommendations for waste treatment technologies superior to lagoons and spray fields. Private environmental sustainability initiatives focused on reducing greenhouse gas emissions in the food supply chain have implemented biogas digester projects for capturing methane in covered swine lagoons to reduce greenhouse gas emissions. However, research indicates that methane capture alone does not solve the broader pollution issues associated with lagoon and spray field systems still in use at these CAFOs to dispose of digested effluents. The Environmentally Superior Technologies (EST) initiative in North Carolina set public standards to eliminate waste discharge, reduce atmospheric emissions, and control odors and pathogens. Research has confirmed that technologies coupling solids separation with water treatments to remove volatile organic carbon, pathogens, and reactive forms of nitrogen can meet EST standards. A designated EST—the Super Soil System—substantially reduced odor by 99.9%; pathogens by 99.99%, nutrients (phosphorus and nitrogen) by \u3e90%, and heavy metals (cooper and zinc) by 99%. The ammonia emissions were reduced by 94.4% for the warm and 99.0% for the cool season with respect to a conventional lagoon system. Corresponding greenhouse gas emission reductions were 96.7%. Components of designated EST can be applied to retrofit covered lagoons and anaerobic digestion systems with significant environmental benefits. Recommendations are proposed, based on the collective experience with EST and current trends in animal production concentration, for environmentally safe technologies to handle excess manure produced in the USA

Prognostic significance of tumor-infiltrating lymphocytes in ductal carcinoma in situ of the breast

Tumor-infiltrating lymphocytes (TILs) provide prognostic value in invasive breast cancer and guidelines for their assessment have been published. This study aims to evaluate: (a) methods of TILs assessment, and (b) their prognostic significance in breast ductal carcinoma in situ (DCIS). Hematoxylin and eosin sections from two clinically annotated DCIS cohorts; a training set (n = 150 pure DCIS) and a validation set (n = 666 comprising 534 pure DCIS and 132 cases wherein DCIS and invasive breast carcinoma were co-existent) were assessed. Seven different scoring methods were applied to the training set to identify the most optimal reproducible method associated with strongest prognostic value. Among different methods, TILs touching ducts' basement membrane or away from it by one lymphocyte cell thickness provided the strongest significant association with outcome and highest concordance rate [inter-cluster correlation coefficient = 0.95]. Assessment of periductal TILs at increasing distances from DCIS (0.2 , 0.5 , and 1 mm) as well as percent of stromal TILs were practically challenging and showed lower concordance rates than touching TILs. TILs hotspots and lymphoid follicles did not show prognostic significance. Within the pure DCIS validation set, dense TILs were associated with younger age, symptomatic presentation, larger size, higher nuclear grade, comedo necrosis and estrogen receptor negativity as well as shorter recurrence-free interval (p = 0.002). In multivariate survival analysis, dense TILs were independent predictor of shorter recurrence-free interval (p = 0.002) in patients treated with breast conservation. DCIS associated with invasive carcinoma showed denser TILs than pure DCIS (p = 9.0 × 10-13). Dense TILs is an independent prognostic variable in DCIS. Touching TILs provides a reproducible method for their assessment that can potentially be used to guide management

Antitumor Activity of Noscapine in Combination with Doxorubicin in Triple Negative Breast Cancer

The aim of this study was to investigate the anticancer activity and mechanism of action of Noscapine alone and in combination with Doxorubicin against triple negative breast cancer (TNBC).TNBC cells were pretreated with Noscapine or Doxorubicin or combination and combination index values were calculated using isobolographic method. Apoptosis was assessed by TUNEL staining. Female athymic Nu/nu mice were xenografted with MDA-MB-231 cells and the efficacy of Noscapine, Doxorubicin and combination was determined. Protein expression, immunohistochemical staining were evaluated in harvested tumor tissues. values of 36.16±3.76 and 42.7±4.3 µM respectively. The CI values (<0.59) were suggestive of strong synergistic interaction between Noscapine and Doxorubicin and combination treatment showed significant increase in apoptotic cells. Noscapine showed dose dependent reduction in the tumor volumes at a dose of 150–550 mg/kg/day compared to controls. Noscapine (300 mg/kg), Doxorubicin (1.5 mg/kg) and combination treatment reduced tumor volume by 39.4±5.8, 34.2±5.7 and 82.9±4.5 percent respectively and showed decreased expression of NF-KB pathway proteins, VEGF, cell survival, and increased expression of apoptotic and growth inhibitory proteins compared to single-agent treatment and control groups.Noscapine potentiated the anticancer activity of Doxorubicin in a synergistic manner against TNBC tumors via inactivation of NF-KB and anti-angiogenic pathways while stimulating apoptosis. These findings suggest potential benefit for use of oral Noscapine and Doxorubicin combination therapy for treatment of more aggressive TNBC

Digital image analysis and machine learning-assisted prediction of neoadjuvant chemotherapy response in triple-negative breast cancer

Background Pathological complete response (pCR) is associated with favorable prognosis in patients with triple-negative breast cancer (TNBC). However, only 30–40% of TNBC patients treated with neoadjuvant chemotherapy (NAC) show pCR, while the remaining 60–70% show residual disease (RD). The role of the tumor microenvironment in NAC response in patients with TNBC remains unclear. In this study, we developed a machine learning-based two-step pipeline to distinguish between various histological components in hematoxylin and eosin (H&E)-stained whole slide images (WSIs) of TNBC tissue biopsies and to identify histological features that can predict NAC response. Methods H&E-stained WSIs of treatment-naïve biopsies from 85 patients (51 with pCR and 34 with RD) of the model development cohort and 79 patients (41 with pCR and 38 with RD) of the validation cohort were separated through a stratified eightfold cross-validation strategy for the first step and leave-one-out cross-validation strategy for the second step. A tile-level histology label prediction pipeline and four machine-learning classifiers were used to analyze 468,043 tiles of WSIs. The best-trained classifier used 55 texture features from each tile to produce a probability profile during testing. The predicted histology classes were used to generate a histology classification map of the spatial distributions of different tissue regions. A patient-level NAC response prediction pipeline was trained with features derived from paired histology classification maps. The top graph-based features capturing the relevant spatial information across the different histological classes were provided to the radial basis function kernel support vector machine (rbfSVM) classifier for NAC treatment response prediction. Results The tile-level prediction pipeline achieved 86.72% accuracy for histology class classification, while the patient-level pipeline achieved 83.53% NAC response (pCR vs. RD) prediction accuracy of the model development cohort. The model was validated with an independent cohort with tile histology validation accuracy of 83.59% and NAC prediction accuracy of 81.01%. The histological class pairs with the strongest NAC response predictive ability were tumor and tumor tumor-infiltrating lymphocytes for pCR and microvessel density and polyploid giant cancer cells for RD. Conclusion Our machine learning pipeline can robustly identify clinically relevant histological classes that predict NAC response in TNBC patients and may help guide patient selection for NAC treatment.publishedVersio

Efficient Non-viral Gene Delivery into Human Hematopoietic Stem Cells by Minicircle Sleeping Beauty Transposon Vectors

The Sleeping Beauty (SB) transposon system is a non-viral gene delivery platform that combines simplicity, inexpensive manufacture, and favorable safety features in the context of human applications. However, efficient correction of hematopoietic stem and progenitor cells (HSPCs) with non-viral vector systems, including SB, demands further refinement of gene delivery techniques. We set out to improve SB gene transfer into hard-to-transfect human CD34 + cells by vectorizing the SB system components in the form of minicircles that are devoid of plasmid backbone sequences and are, therefore, significantly reduced in size. As compared to conventional plasmids, delivery of the SB transposon system as minicircle DNA is 3c20 times more efficient, and it is associated with up to a 50% reduction in cellular toxicity in human CD34 + cells. Moreover, providing the SB transposase in the form of synthetic mRNA enabled us to further increase the efficacy and biosafety of stable gene delivery into hematopoietic progenitors ex vivo. Genome-wide insertion site profiling revealed a close-to-random distribution of SB transposon integrants, which is characteristically different from gammaretroviral and lentiviral integrations in HSPCs. Transplantation of gene-marked CD34 + cells in immunodeficient mice resulted in long-term engraftment and hematopoietic reconstitution, which was most efficient when the SB transposase was supplied as mRNA and nucleofected cells were maintained for 4\u20138 days in culture before transplantation. Collectively, implementation of minicircle and mRNA technologies allowed us to further refine the SB transposon system in the context of HSPC gene delivery to ultimately meet clinical demands of an efficient and safe non-viral gene therapy protocol. Ivics and collegues refined the Sleeping Beauty transposon system for gene transfer in human hematopoietic stem and progenitor cells by vectorizing the transposon components as minicircle DNA and synthetic mRNA. The advanced vector system enables efficient and safe non-viral engineering of hematopoietic cells that can be transplanted into immunodeficient mice

Sustained remission of rheumatoid arthritis with a specific serotonin reuptake inhibitor antidepressant: a case report and review of the literature

<p>Abstract</p> <p>Introduction</p> <p>The mainstay of pharmacologic therapy for rheumatoid arthritis includes the use of disease-modifying agents like sulfasalazine and methothrexate, and more recently, anti-tumor necrosis factor-α agents. Depression remains a major co-morbidity in patients with rheumatoid arthritis and is thought to contribute to disability and mortality in these patients. Evidence now suggests that a biologic link exists between substrates responsible for inflammatory conditions and mood disorders. Most of this evidence comes from preclinical studies. Nevertheless, more research into this area is helping us to understand the possible mechanisms through which these conditions interact with each other.</p> <p>Case presentation</p> <p>We describe a 60-year-old Indian man with rheumatoid arthritis diagnosed 15 years ago who had minimal response to multiple therapies with disease-modifying agents and whose arthritis symptoms surprisingly remitted when he was started on a specific serotonin reuptake inhibitor antidepressant, three years ago, for co-morbid major depression. This remission has been maintained with this medication, and the patient is currently not taking any antirheumatoid medications.</p> <p>Conclusion</p> <p>Possible mechanisms linking substrates of mood disorders and inflammation are reviewed in this case report, particularly the serotonergic system. Evidence seems to suggest a significant interaction between the serotonergic systems and inflammation. This interaction seems to be bidirectional. An understanding of this relation is most important to gain insight not only into pathophysiological mechanisms underlying this condition, but also into how treatments for these conditions may complement each other and possibly provide greater therapeutic options in both of these disabling conditions.</p

Formaldehyde, glyoxal, and methylglyoxal in air and cloudwater at a rural mountain site in central Virginia

As part of the Shenandoah Cloud and Photochemistry Experiment (SCAPE), we measured formaldehyde (HCHO), glyoxal (CHOCHO), and methylglyoxal (CH3C(O)CHO) concentrations in air and cloudwater at Pinnacles (elevation 1037 m) in Shenandoah National Park during September 1990. Mean gas‐phase concentrations of HCHO and CHOCHO were 980 and 44 pptv, respectively. The concentration of CH3C(O)CHO rarely exceeded the detection limit of 50 pptv. Mean cloudwater concentrations of HCHO and CHOCHO were 9 and 2 μM, respectively; the mean CH3C(O)CHO concentration was below its detection limit of 0.3 μM. The maximum carbonyl concentrations were observed during stagnation events with high O3, peroxides, and CO. Outside of these events the carbonyls did not correlate significantly with O3, CO, or NOy. Carbonyl concentrations and concentration ratios were consistent with a major source for the carbonyls from isoprene oxidation. Oxidation of CH4 supplies a significant background of HCHO. The carbonyl concentrations were indistinguishable in two size fractions of cloudwater having a cut at d=18 μm. Gas‐ and aqueous‐phase concentrations of HCHO from samples collected during a nighttime cloud event agree with thermodynamic equilibria within a factor of 2. Samples collected during a daytime cloud event show HCHO supersaturation by up to a factor of 4. Positive artifacts in the cloudwater samples due to hydrolysis of hydroxymethylhydroperoxide (HOCH2OOH) could perhaps account for this discrepancy

Caracterização do perfil comportamental e de competência social de indivíduos com a síndrome del22q11.2

Resumo:OBJETIVO:caracterizar os problemas comportamentais e de competência social de indivíduos com a síndrome del22q11.2 e compará-los com indivíduos com desenvolvimento típico, segundo informação dos pais.MÉTODOS:participaram desta pesquisa 24 pais de indivíduos de ambos os gêneros, entre seis e 18 anos, sendo 12 indivíduos com a síndrome del22q11.2 (grupo amostral) e 12 indivíduos com desenvolvimento típico (grupo controle). Foi aplicado o inventário comportamental "Child Behavior Checklist (CBCL)".RESULTADOS:oito dos 12 indivíduos com a síndrome foram classificados como "clínico" nas escalas de comportamento e Problemas Internalizantes; cinco dos 12 indivíduos do grupo amostral foram classificados como "clínico" quanto às escalas de comportamento e Problemas Externalizantes. Nas habilidades de competência social, dez dos 12 indivíduos do grupo amostral foram classificados como "clínico".CONCLUSÃO:indivíduos com diagnóstico da síndrome del22q11.2 apresentaram, segundo opinião dos pais, problemas comportamentais e de competência social, em diferentes graus de comprometimento. Quando realizada a comparação entre os grupos pode-se observar diferenças estatisticamente significantes em variáveis dos comportamentos externalizantes e dos comportamentos internalizantes. Desta forma, concluí-se que o grupo amostral apresenta comportamentos mais alterados quando comparados ao grupo controle