Miracle-dz/UniFAR-FTUs huggingface dataset:
Photodynamic Vaccination of BALB/c Mice for Prophylaxis of Cutaneous Leishmaniasis Caused by Leishmania amazonensis

Background: Photosensitizers (PS), like porphyrins and phthalocyanines (PC) are excitable by light to generate cytotoxic singlet oxygen and other reactive oxygen species in the presence of atmospheric O2. Photodynamic inactivation of Leishmania by this means renders them non-viable, but preserves their effective use as vaccines. Leishmania can be photo-inactivated after PS-sensitization by loading via their endocytic uptake of PC or endogenous induction of transgenic mutants with delta-aminolevulinate (ALA) to accumulate cytosolic uroporphyrin I (URO). Here, PS-sensitization and photo-inactivation of Leishmania amazonensis was further examined in vitro and in vivo for vaccination against cutaneous leishmaniasis (CL). Methods and Results: Leishmania amazonensis promastigotes were photodynamically inactivated in vitro by PC-loading followed by exposure to red light (1–2 J/cm2) or ALA-induction of uroporphyrinogenic transfectants to accumulate cytosolic URO followed by longwave UV exposure. When applied individually, both strategies of photodynamic inactivation were found to significantly, albeit incompletely abolish the MTT reduction activities of the promastigotes, their uptake by mouse bone marrow-derived macrophages in vitro and their infectivity to mouse ear dermis in vivo. Inactivation of Leishmania to completion by using a combination of both strategies was thus used for the sake of safety as whole-cell vaccines for immunization of BALB/c mice. Different cutaneous sites were assessed for the efficacy of such photodynamic vaccination in vivo. Each site was inoculated first with in vitro doubly PS-sensitized promastigotes and then spot-illuminated with white light (50 J/cm2) for their photo-inactivation in situ. Only in ear dermis parasites were photo-inactivated beyond detection. Mice were thus immunized once in the ear and challenged 3 weeks later at the tail base with virulent L. amazonensis. Prophylaxis was noted in mice photodynamically vaccinated with doubly photo-inactivated parasites, as indicated by a significant delay in the onset of lesion development and a substantial decrease in the parasite loads. Conclusion: Leishmania doubly PS-sensitized and in situ photo-inactivated as described proved to be safe and effective when used for one-time immunization of ear dermis, as indicated by its significant protection of the inherently very susceptible BALB/c mice against CL.
Drug screening to target nuclear orphan receptor NR4A2 for cancer therapeutics.

Background Our previous study suggested NR4A2, a subfamily member of orphan nuclear receptors, is essential for survival of human cancer cells such as mucoepidermoid carcinoma (MEC). Methods We conducted high throughput drug screening for NR4A2 inhibitors as a novel therapeutic modality. Positive screening was performed using a luciferase reporter vector containing NR4A2 binding sequence, and a CRE-reporter control vector was used to eliminate false positives. In vitro assays for positive hits were conducted. Results A total of 23 Food and Drug Administration (FDA) and 43 Life Science Library compounds were identified, including several epidermal growth factor inhibitors and Src inhibitors. Subsequent in vitro assays confirmed that identified compounds were preferentially active in NR4A2+ cancer cells. Several candidate compounds appeared to suppress NR4A2 via inhibition of p-ERK, whereas a novel compound KU0171309 may act as a more direct inhibitor. Conclusions Further research should focus on homologue selectivity, in vivo activity, and definitively deciphering the mechanism of action of KU0171309.
Sieve estimation of Cox models with latent structures

This article considers sieve estimation in the Cox model with an unknown regression structure based on right‐censored data. We propose a semiparametric pursuit method to simultaneously identify and estimate linear and nonparametric covariate effects based on B‐spline expansions through a penalized group selection method with concave penalties. We show that the estimators of the linear effects and the nonparametric component are consistent. Furthermore, we establish the asymptotic normality of the estimator of the linear effects. To compute the proposed estimators, we develop a modified blockwise majorization descent algorithm that is efficient and easy to implement. Simulation studies demonstrate that the proposed method performs well in finite sample situations. We also use the primary biliary cirrhosis data to illustrate its application.
Human osteopontin: Potential clinical applications in cancer (Review)

Human osteopontin (OPN) is a glycosylated phosphoprotein which is expressed in a variety of tissues in the body. In recent years, accumulating evidence has indicated that the aberrant expression of OPN is closely associated with tumourigensis, progression and most prominently with metastasis in several tumour types. In this review, we present the current knowledge on the expression profiles of OPN and its main splice variants in human cancers, as well as the potential implications in patient outcome. We also discuss its putative clinical application as a cancer biomarker and as a therapeutic target.
Retracted: In vivo and in vitro effects of PTH1‐34 on osteogenic and adipogenic differentiation of human bone marrow‐derived mesenchymal stem cells through regulating microRNA‐155

Retraction of “In vivo and in vitro effects of PTH1‐34 on osteogenic and adipogenic differentiation of human bone marrow‐derived mesenchymal stem cells through regulating microRNA‐155”, by Huan‐Sheng Han, Fang Ju, and Shuo Geng, J Cell Biochem. 2018; 3220‐3235: The above article, published online on 1 November 2017 in Wiley Online Library (https://onlinelibrary.wiley.com/doi/abs/10.1002/jcb.26478), has been retracted by agreement between the authors, the journal's Editor in Chief, Prof. Dr. Christian Behl, and Wiley Periodicals LLC. The retraction has been agreed following an investigation based allegations raised by a third party, and after the authors stated that due to statistical errors the conclusions of the articles were no longer valid.
Progressive Development of Aberrant Smooth Muscle Cell Phenotype in Abdominal Aortic Aneurysm Disease

Abdominal aortic aneurysm (AAA) is a silent, progressive disease with a high mortality and an increasing prevalence with aging. Smooth muscle cell (SMC) dysfunction contributes to gradual dilatation and eventual rupture of the aorta. Here we studied phenotypic characteristics in SMC cultured from end-stage human AAA (≥5 cm) and cells cultured from a porcine carotid artery (PCA) model of early and end-stage aneurysm. Human AAA-SMC presented a secretory phenotype and expressed elevated levels of the differentiation marker miR-145 (2.2-fold, p < 0.001) and the senescence marker SIRT-1 (1.3-fold, p < 0.05), features not recapitulated in aneurysmal PCA-SMC. Human and end-stage porcine aneurysmal cells were frequently multi-nucleated (3.9-fold, p < 0.001, and 1.8-fold, p < 0.01, respectively, vs. control cells) and displayed an aberrant nuclear morphology. Human AAA-SMC exhibited higher levels of the DNA damage marker γH2AX (3.9-fold, p < 0.01, vs. control SMC). These features did not correlate with patients' chronological age and are therefore potential markers for pathological premature vascular aging. Early-stage PCA-SMC (control and aneurysmal) were indistinguishable from one another across all parameters. The principal limitation of human studies is tissue availability only at the end stage of the disease. Refinement of a porcine bioreactor model would facilitate the study of temporal modulation of SMC behaviour during aneurysm development and potentially identify therapeutic targets to limit AAA progression.
Dickkopf homolog 3 (DKK3): A candidate for detection and treatment of cancers?

Wnt signaling is an evolutionary highly conserved pathway that is modulated by several inhibitors and activators, and plays a key role in numerous physiological processes. One of the extracellular Wnt inhibitors is the DKK (Dickkopf Homolog) family which has four members (Dkk1‐4) and a unique Dkk3‐related gene, Dkkl1 (soggy). DKK3 is a divergent member of the DKK protein family. Evidence suggests that DKK3 may serve as a potential therapeutic target in several types of human cancers. We review here the biological role of DKK3 as a tumor suppressor gene (TSG) or oncogene, and its correlation with various miRNAs. In addition, we discuss the role of polymorphisms and promoter methylation of the DKK3 gene, and of its expression in regulating cancer cell proliferation. Finally, we propose that DKK3 may be considered as both a biomarker and a therapeutic target in different cancers.
Impact of tumour thickness on survival after radical radiation and surgery in malignant pleural mesothelioma

Tumour thickness was assessed to determine if this parameter could refine patients' selection for multimodality therapy in malignant pleural mesothelioma. We reviewed 65 consecutive treatment-naïve malignant pleural mesothelioma patients undergoing surgery for mesothelioma after radiation therapy (SMART). Total tumour thickness was determined by measuring the maximal thickness on nine predefined sectors on the chest wall, mediastinum and diaphragm. After a median follow-up of 19 months, 40 patients (62%) developed recurrence and 36 died (55%). Total tumour thickness, ranging between 2.4 and 21 cm (median 6.9 cm), correlated with tumour volume (p<0.0001, R2=0.29) and maximum standardised uptake value (p=0.006, R2=0.11). Total tumour thickness had a significant impact on overall survival and disease-free survival in univariate analysis. In multivariate analysis, total tumour thickness remained an independent predictor of survival (p=0.02, hazard ratio (HR) 1.12, 95% CI 1.02–1.23) and disease-free survival (p=0.01, HR 1.13, 95% CI 1.03–1.24) along with epithelial histologic subtype (p<0.0001, HR 0.25, 95% CI 0.13–0.50) and pN2 disease (p=0.03, HR 2.15, 95% CI 1.07–4.33). Diaphragmatic tumour thickness correlated best with time to recurrence (p=0.002, R2=0.22) and time to death (p=0.003, R2=0.2). The impact of tumour thickness on survival and disease-free survival independent of histologic subtypes and nodal disease is extremely encouraging. This parameter could potentially be used to refine the clinical staging of malignant pleural mesothelioma and optimise patient selection for radical treatment. Tumour thickness is an independent predictor of outcome after radical treatment for malignant pleural mesothelioma http://ow.ly/KCbT306wDBN
A novel mechanism of action of HER2 targeted immunotherapy is explained by inhibition of NRF2 function in ovarian cancer cells

Nuclear erythroid related factor-2 (NRF2) is known to promote cancer therapeutic detoxification and crosstalk with growth promoting pathways. HER2 receptor tyrosine kinase is frequently overexpressed in cancers leading to uncontrolled receptor activation and signaling. A combination of HER2 targeting monoclonal antibodies shows greater anticancer efficacy than the single targeting antibodies, however, its mechanism of action is largely unclear. Here we report novel actions of anti-HER2 drugs, Trastuzumab and Pertuzumab, involving NRF2. HER2 targeting by antibodies inhibited growth in association with persistent generation of reactive oxygen species (ROS), glutathione (GSH) depletion, reduction in NRF2 levels and inhibition of NRF2 function in ovarian cancer cell lines. The combination of antibodies produced more potent effects than single antibody alone; downregulated NRF2 substrates by repressing the Antioxidant Response (AR) pathway with concomitant transcriptional inhibition of NRF2. We showed the antibody combination produced increased methylation at the NRF2 promoter consistent with repression of NRF2 antioxidant function, as HDAC and methylation inhibitors reversed such produced transcriptional effects. These findings demonstrate a novel mechanism and role for NRF2 in mediating the response of cancer cells to the combination of Trastuzumab and Pertuzumab and reinforce the importance of NRF2 in drug resistance and as a key anticancer target.
Potential Adverse Effects of Broad-Spectrum Antimicrobial Exposure in the Intensive Care Unit

Abstract Background The potential adverse effects of empiric broad-spectrum antimicrobial use among patients with suspected but subsequently excluded infection have not been fully characterized. We sought novel methods to quantify the risk of adverse effects of broad-spectrum antimicrobial exposure among patients admitted to an intensive care unit (ICU). Methods Among all adult patients admitted to ICUs at a single institution, we selected patients with negative blood cultures who also received ≥1 broad-spectrum antimicrobials. Broad-spectrum antimicrobials were categorized in ≥1 of 5 categories based on their spectrum of activity against potential pathogens. We performed, in serial, 5 cohort studies to measure the effect of each broad-spectrum category on patient outcomes. Exposed patients were defined as those receiving a specific category of broad-spectrum antimicrobial; nonexposed were all other patients in the cohort. The primary outcome was 30-day mortality. Secondary outcomes included length of hospital and ICU stay and nosocomial acquisition of antimicrobial-resistant bacteria (ARB) or Clostridium difficile within 30 days of admission. Results Among the study cohort of 1918 patients, 316 (16.5%) died within 30 days, 821 (42.8%) had either a length of hospital stay >7 days or an ICU length of stay >3 days, and 106 (5.5%) acquired either a nosocomial ARB or C. difficile. The short-term use of broad-spectrum antimicrobials in any of the defined broad-spectrum categories was not significantly associated with either primary or secondary outcomes. Conclusions The prompt and brief empiric use of defined categories of broad-spectrum antimicrobials could not be associated with additional patient harm.
Regional Homogeneity

Much effort has been made to understand the organizational principles of human brain function using functional magnetic resonance imaging (fMRI) methods, among which resting-state fMRI (rfMRI) is an increasingly recognized technique for measuring the intrinsic dynamics of the human brain. Functional connectivity (FC) with rfMRI is the most widely used method to describe remote or long-distance relationships in studies of cerebral cortex parcellation, interindividual variability, and brain disorders. In contrast, local or short-distance functional interactions, especially at a scale of millimeters, have rarely been investigated or systematically reviewed like remote FC, although some local FC algorithms have been developed and applied to the discovery of brain-based changes under neuropsychiatric conditions. To fill this gap between remote and local FC studies, this review will (1) briefly survey the history of studies on organizational principles of human brain function; (2) propose local functional homogeneity as a network centrality to characterize multimodal local features of the brain connectome; (3) render a neurobiological perspective on local functional homogeneity by linking its temporal, spatial, and individual variability to information processing, anatomical morphology, and brain development; and (4) discuss its role in performing connectome-wide association studies and identify relevant challenges, and recommend its use in future brain connectomics studies.
Microplastics alter composition of fungal communities in aquatic ecosystems

Despite increasing concerns about microplastic (MP) pollution in aquatic ecosystems, there is insufficient knowledge on how MP affect fungal communities. In this study, we explored the diversity and community composition of fungi attached to polyethylene (PE) and polystyrene (PS) particles incubated in different aquatic systems in north-east Germany: the Baltic Sea, the River Warnow and a wastewater treatment plant. Based on next generation 18S rRNA gene sequencing, 347 different operational taxonomic units assigned to 81 fungal taxa were identified on PE and PS. The MP-associated communities were distinct from fungal communities in the surrounding water and on the natural substrate wood. They also differed significantly among sampling locations, pointing towards a substrate and location specific fungal colonization. Members of Chytridiomycota, Cryptomycota and Ascomycota dominated the fungal assemblages, suggesting that both parasitic and saprophytic fungi thrive in MP biofilms. Thus, considering the worldwide increasing accumulation of plastic particles as well as the substantial vector potential of MP, especially these fungal taxa might benefit from MP pollution in the aquatic environment with yet unknown impacts on their worldwide distribution, as well as biodiversity and food web dynamics at large.
Bioresorbable optical fiber Bragg gratings.

We demonstrate, for the first time, an inscription and wet dissolution study of Bragg gratings in a bioresorbable calcium-phosphate glass optical fiber. Bragg gratings, with average refractive index changes of 5.8×10-4, were inscribed using 193 nm excimer laser radiation. Results on the dissolution of the irradiated fiber in simulated physiological conditions are presented after immersing a tilted Bragg grating in a phosphate buffered saline solution for 56 h; selective chemical etching effects are also reported. The investigations performed pave the way toward the use of such phosphate glass fiber Bragg gratings for the development of soluble photonic sensing probes for the efficient in vivo monitoring of vital mechanical or chemical parameters.
Quercetin-mediated synthesis of graphene oxide–silver nanoparticle nanocomposites: a suitable alternative nanotherapy for neuroblastoma

Background Graphene and graphene-related materials have gained substantial interest from both academia and industry for the development of unique nanomaterials for biomedical applications. Graphene oxide (GO) and silver nanoparticles (AgNPs) are a valuable platform for the development of nanocomposites, permitting the combination of nanomaterials with different physical and chemical properties to generate novel materials with improved and effective functionalities in a single platform. Therefore, this study was conducted to synthesize a graphene oxide–silver nanoparticle (GO-AgNPs) nanocomposite using the biomolecule quercetin and evaluate the potential cytotoxicity and mechanism of GO-AgNPs in human neuroblastoma cancer cells (SH-SY5Y). Methods The synthesized GO-AgNPs were characterized using various analytical techniques. The potential toxicities of GO-AgNPs were evaluated using a series of biochemical and cellular assays. The expression of apoptotic and anti-apoptotic genes was measured by quantitative real-time reverse transcription polymerase chain reaction. Further, apoptosis was confirmed by caspase-9/3 activity and a terminal deoxynucleotidyl transferase dUTP nick end labeling assay, and GO-AgNPs-induced autophagy was also confirmed by transmission electron microscopy. Results The prepared GO-AgNPs exhibited significantly higher cytotoxicity toward SH-SY5Y cells than GO. GO-AgNPs induced significant cytotoxicity in SH-SY5Y cells by the loss of cell viability, inhibition of cell proliferation, increased leakage of lactate dehydrogenase, decreased level of mitochondrial membrane potential, reduced numbers of mitochondria, enhanced level of reactive oxygen species generation, increased expression of pro-apoptotic genes, and decreased expression of anti-apoptotic genes. GO-AgNPs induced caspase-9/3-dependent apoptosis via DNA fragmentation. Finally, GO-AgNPs induced accumulation of autophagosomes and autophagic vacuoles. Conclusion In this study, we developed an environmentally friendly, facile, dependable, and simple method for the synthesis of GO-AgNPs nanocomposites using quercetin. The synthesized GO-AgNPs exhibited enhanced cytotoxicity compared with that of GO at very low concentrations. This study not only elucidates the potential cytotoxicity against neuroblastoma cancer cells, but also reveals the molecular mechanism of toxicity.
Green Tea Catechins and Vitamin E Inhibit Angiogenesis of Human Microvascular Endothelial Cells Through Suppression of IL-8 Production

Epidemiological and animal studies have indicated that consumption of green tea and high vitamin E intake are associated with a reduced risk of developing certain forms of cancer. However, the inhibitory mechanism of green tea catechins and vitamin E in angiogenesis, an important process in tumor growth, has not been well established. In the present study, α-tocopherol and several major catechins of green tea (catechin, epicatechin, epicatechin gallate, epigallocatechin, and epigallocatechin gallate) were tested for their ability to inhibit tube formation in vitro using a model in which human microvascular endothelial cells were exposed to a constant rate of a physiologically low level of H2O2. In this model, the production of interleukin (IL)-8 by human microvascular endothelial cells at a low level of H2O2was required for angiogenesis, as assessed by tube formation in three-dimensional gel in culture. Vitamin E (d-α-tocopherol, 40 μM) in the culture media significantly reduced IL-8 production and angiogenesis. Among the green tea catechins, epigallocatechin (0.5-1 μM) was the most effective in reducing IL-8 production and inhibiting angiogenesis. These results suggest that consumption of green tea catechins or supplemental intake of vitamin E may have preventive effects on tumor development, mediated, at least in part, through inhibition of angiogenesis via suppression of IL-8 production.
Because difficulty is not the same for everyone: the impact of complexity in working memory is associated with cannabinoid 1 receptor genetic variation in young adults

ABSTRACT Individual differences in working memory ability are mainly revealed when a demanding challenge is imposed. Here, we have associated cannabinoid 1 (CB1) receptor genetic variation rs2180619 (AA, AG, GG), which is located in a potential CNR1 regulatory sequence, with performance in working memory. Two-hundred and nine Mexican-mestizo healthy young participants (89 women, 120 men, mean age: 23.26 years, SD = 2.85) were challenged to solve a medium (2-back) vs. a high (3-back) difficulty N-back tasks. All subjects responded as expected, performance was better with the medium than the high demand task version, but no differences were found among genotypes while performing each working memory (WM) task. However, the cost of the level of complexity in N-back paradigm was double for GG subjects than for AA subjects. It is noteworthy that an additive-dosage allele relation was found for G allele in terms of cost of level of complexity. These genetic variation results support that the endocannabinoid system, evaluated by rs2180619 polymorphism, is involved in WM ability in humans.