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In this case–control study, we assessed differences in daily spiritual experiences between patients with breast cancer diagnoses and healthy controls in relation to other breast cancer risk factors. The participants were 201 newly diagnosed Polish patients with breast cancer (58 ± 6 years) and 201 age-matched healthy controls. Spiritual experiences were assessed using the Daily Spiritual Experiences Scale (DSES). Adjusted odds ratios (OR) and 95% confidence intervals (CI) of the DSES score for breast cancer diagnosis were calculated with logistic regression. The DSES score was significantly higher in the healthy controls than in the cases. After controlling for alcohol use, education, BMI, and rural residence, higher spirituality was associated with a lower risk of breast cancer (OR 0.98, 95% CI 0.97–1.00). Two DSES item scores differed significantly between cases and controls, being lower in breast cancer cases: "I am spiritually touched by the beauty of creation" (p = 0.01) and "I feel selfless caring for others" (p = 0.049). After controlling for other variables (i.e., hormone replacement therapy, family history, breastfeeding, and diet quality), the DSES score was statistically non-significant (OR 0.99, 95% CI 0.97–1.006). Therefore, the original relationship DSES score and breast cancer was quite weak. Although the study found little relationship between the analyzed variables, presented differences in spirituality may differentiate the patterns of spiritual well-being among breast cancer patients; however, more data are needed from longitudinal study designs to establish causal inferences. [ABSTRACT FROM AUTHOR]

Transport infrastructure is not currently the domain of activity of solely the public sector. Governments entrust the provision of services or realization of investment tasks to private entities and the form of involvement of private investors may be the public-private partnership PPP. Successful implementation of the PPP projects requires appropriate economic, legal, institutional and social conditions. The article identifies these determinants based on the literature on the subject and then their analysis in relation to conditions of operation and market development of the PPP projects in the area of transport infrastructure in Poland. The analysis covered the years 2009-2018 and was conducted against the background of development of the PPP market in selected EU countries. [ABSTRACT FROM AUTHOR]

Presents a study that investigated proximity rapid thermal diffusion using phosphorus spin-on dopants (SOD). Analysis of the process kinetics; Factor which control the process at low diffusion temperature; Diffusion of dopant and its concentration distribution in the SOD.

Rapid thermal diffusion (RTD) of phosphorus has been investigated using a spin-on dopant (SOD) deposited on a silicon wafer and placed as a dopant source in proximity to a processed Si wafer. In such a process, the efficiency of doping is affected by the amount of P supplied from the SOD to the processed wafer. Doping in RTD is controlled by the thickness of the SOD and its structure, which depends on low-temperature baking. Experimental results of secondary-ion-mass spectroscopy analyses and sheet resistance indicate that diffusion coefficients of phosphorus in the SOD during RTD are considerably larger than in thermal oxides. [ABSTRACT FROM AUTHOR]

Background: Numerous transgenic models have been generated to study breast cancer. However, despite many advantages, traditional transgenic models for breast cancer are also burdened with difficulties in early detection and longitudinal observation of transgene-induced tumours, which in most cases are randomly located and occur at various time points. Methods such as palpation followed by mechanical measurement of the tumours are of limited value in transgenic models. There is a crucial need for making these previously generated models suitable for modern methods of tumour visualisation and monitoring, e.g. by bioluminescence-based techniques. This approach was successfully used in the current study. Results: A new mouse strain (MMTV-Luc2 mice) expressing Luc2 luciferase primarily in mammary tissue in females, with low-level background expression in internal organs, was generated and bred to homozygosity. After these mice were intercrossed with MMTV-PyVT mice, all double transgenic females developed mammary tumours by the age of 10 weeks, the localisation and progression of which could be effectively monitored using the luminescence-based in vivo imaging. Luminescence-based readout allowed for early visualisation of the locally overgrown mammary tissue and for longitudinal evaluation of local progression of the tumours. When sampled ex vivo at the age of 10 weeks, all tumours derived from MMTV-Luc2PyVT females displayed robust bioluminescent signal. Conclusions: We have created a novel transgenic strain for visualisation and longitudinal monitoring of mammary tumour development in transgenic mice as an addition and/or a new and more advanced alternative to manual methods. Generation of this mouse strain is vital for making many of the existing mammary tumour transgenic models applicable for in vivo imaging techniques. [ABSTRACT FROM AUTHOR]

Background: Sodium (Na) balance is unexplored in dialyzed children. We assessed a simplified sodium balance (sNaB) and its correlates in pediatric patients receiving maintenance dialysis. Methods: Patients < 18 years old on hemodialysis (HD) or peritoneal dialysis (PD) in six European Pediatric Dialysis Working Group centers were recruited. sNaB was calculated from enteral Na, obtained by a 3-day diet diary, Na intake from medications, and 24-h urinary Na (uNa). Primary outcomes were systolic blood pressure and diastolic blood pressure standard deviation scores (SBP and DBP SDS), obtained by 24-h ambulatory blood pressure monitoring or office BP according to age, and interdialytic weight gain (IDWG). Results: Forty-one patients (31 HD), with a median age of 13.3 (IQR 5.2) years, were enrolled. Twelve patients (29.3%) received Na-containing drugs, accounting for 0.6 (0.7) mEq/kg/day. Median total Na intake was 1.5 (1.1) mEq/kg/day, corresponding to 60.6% of the maximum recommended daily intake for healthy children. Median uNa and sNaB were 0.6 (1.8) mEq/kg/day and 0.9 (1.7) mEq/kg/day, respectively. The strongest independent predictor of sNaB in the cohort was urine output. In patients receiving HD, sNaB correlated with IDWG, pre-HD DBP, and first-hour refill index, a volume index based on blood volume monitoring. sNaB was the strongest predictor of IDWG in multiple regression analysis (β = 0.63; p = 0.005). Neither SBP SDS nor DBP SDS correlated with sNaB. Conclusions: Na intake is higher than uNa in children on dialysis, and medications may be an important source of Na. sNaB is best predicted by urine output in the population, and it is a significant independent predictor of IDWG in children on HD. [ABSTRACT FROM AUTHOR]

Focus of Presentation During pandemic the social life has been transformed by new regimes of social distancing, face masks, and altered online education. The aim of this presentation is to review the recent philosophical concepts of biopolitics that bring an additional perspective to the COVID-19 pandemic. Findings The most important critical response was brought from the philosopher and cultural theorist Giorgio Agamben who in the book entitled "Where are we now? Epidemic as politics" evoked again, known from his previous writings, the figure of bare life. The epidemic restrictions have shown, that humanity no longer believes in anything but bare existence, to be preserved as such at any cost. There were no reliable risk-benefit analysis that took into account all other aspects of human condition except statistical data on positive test results or "asymptomatic illness". The concepts of another Italian philosopher Roberto Esposito became more than relevant during pandemic. In his book entitled " Immmunitas: the Protection and Negation of Life" he assumes that the more we feel at risk of being infiltrated and infected by foreign elements, the more the life of the individual and society closes off within its protective boundaries, reminding us of the situations during lockdowns. Conclusions/Implications According to biopolitical interpretation of epidemic, the risk of infection can be considered as a "pretext" for ramping up political control on citizens. Key messages Epidemiologists should be aware what are the consequences of the decisions they recommended for governments when the social relations and the power structure are affected. [ABSTRACT FROM AUTHOR]

Background: The majority of studies show a substantially higher consumption of anxiolytics and antidepressants amongwomen than among men and in the age bracket above 45 years.Aims: To analyse association between the use of hypnotics/anxiolytics, and various characteristics of Polish women,including health-related quality of life.Method: One thousand, five hundred and sixty (1,560) women aged 45–60 years completed a questionnaire dealing withthe use of hypnotics/anxiolytics, demographic characteristics, environmental and work stress exposure, and self-reportedquality of life (SF-36 form).Results: The following variables were revealed as the predictors of hypnotic/anxiolytic use on univariate analysis: age;social pension; stress at work and environmental stress; hormone replacement therapy; headache; palpitations; moodswings or increased muscular tension; anger; duration of symptoms longer than one week; consulting a specialist; andlow physical and mental health-related quality of life. The significant protective factors included: vocational and tertiaryeducation; job satisfaction; and home as place of rest. The independent predictors of anxiolytic/hypnotic use includedconsulting a specialist and symptoms lasting more than one week, while job satisfaction and home as place of rest werethe independent protective factors.Conclusions: The use of hypnotic/anxiolytic medication is strongly associated with environmental and psychosocialcharacteristics of women between 40 and 65 years of age. [ABSTRACT FROM AUTHOR]

The HER2 receptor is currently one of the flagship therapeutic targets in clinical oncology. Trastuzumab, an antibody targeting HER2, has become a foundation of care in women with HER2-positive breast cancer. However, many women with metastatic breast cancer do not respond to trastuzumab-based therapy. One possible source of trastuzumab resistance is the presence of truncated forms of HER2 in the tumor. Numerous studies suggest that detection of truncated HER2 in the tumor should result in modification of the classical therapeutic approach. Recent development of several promising compounds brings hope that a generation of novel therapeutic modalities against HER2-positive cancers will be delivered in the future. [Copyright &y& Elsevier]

Endocannabinoids are lipid signaling molecules that act via G-coupled receptors, CB1 and CB2. The endocannabinoid system is capable of activation of distinct signaling pathways on demand in response to pathogenic events or stimuli, hereby enhancing cell survival and promoting tissue repair. However, the role of endocannabinoids in hematopoietic stem and progenitor cells (HSPCs) and their interaction with hematopoietic stem cells (HSC) niches is not known. HSPCs are maintained in the quiescent state in bone marrow (BM) niches by intrinsic and extrinsic signaling. We report that HSPCs express the CB1 receptors and that BM stromal cells secrete endocannabinoids, anandamide (AEA) (35 pg/107 cells), and 2-AG (75.2 ng/107 cells). In response to the endotoxin lipopolysaccharide (LPS), elevated levels of AEA (75.6 pg/107 cells) and 2-AG (98.8 ng/107 cells) were secreted from BM stromal cells, resulting in migration and trafficking of HSPCs from the BM niches to the peripheral blood. Furthermore, administration of exogenous cannabinoid CB1 agonists in vivo induced chemotaxis, migration, and mobilization of human and murine HSPCs. Cannabinoid receptor knock-out mice Cnr1-/- showed a decrease in side population (SP) cells, whereas fatty acid amide hydrolase (FAAH)-/mice, which have elevated levels of AEA, yielded increased colony formation as compared with WT mice. In addition, G-CSF-induced mobilization in vivo was modulated by endocannabinoids and was inhibited by specific cannabinoid antagonists as well as impaired in cannabinoid receptor knock-out mice Cnr1-/-, as compared with WT mice. Thus, we propose a novel function of the endocannabinoid system, as a regulator of HSPC interactions with their BM niches, where endocannabinoids are expressed in HSC niches and under stress conditions, endocannabinoid expression levels are enhanced to induce HSPC migration for proper hematopoiesis. [ABSTRACT FROM AUTHOR]

Diborides of Ti, Hf and Zr are thermally, mechanically and chemically stable with good thermal and electrical conductivity. We tested their properties in front-end processes used in Si integrated circuits (IC). Films were deposited by e-beam evaporation either on Si, for the formation of contacts to the source/drain (S/D) regions, or on Si oxides, for the formation of metal gates in p-type metal-oxide-semiconductor (PMOS) transistors. We focused on their crystallization caused by rapid thermal processing (RTP) at temperatures up to 1100 °C. Transmission electron microscopy was used for identification of nanocrystallites of TiB2, ZrB2, and HfB2. The grain growth was correlated with temperature and time of RTP. Of all borides, HfB2 resulted in the most complete crystallization with little amorphous phase left. There was no crystallographic degradation of the interface with Si or dielectrics, except for extreme thermal budgets. Complementary techniques were used for monitoring chemical stability and electrical parameters of test structures to assess the role of recrystallization in device behaviour. [ABSTRACT FROM AUTHOR]

Abstract: Substantial evidence exists supporting the notion that Csk and CHK, two negative regulatory kinases of the Src tyrosine kinase family, play distinct roles during development of the nervous system. One of the differences relies on the effects of both kinases on the MAPK transduction pathway. Specifically, CHK was shown to enhance MAPK signaling, while the role of Csk was unclear. In this work, we compared the effect of CHK versus Csk on MAPK signaling and elucidated the signaling pathway mediated by CHK leading to the activation of Erk1/2. Exogenous expression of wild-type CHK, but not Csk or a dead-kinase mutant of CHK, resulted in enhanced Erk1/2 phosphorylation in PC12 cells. CHK inhibited Src activity following stimulation of the cells with NGF. However, stimulation of Erk1/2 activation by CHK was independent of the NGF stimulation or the inhibition of Src kinase by CHK. CHK induced a complex formation between SHP-2 and Grb2, subsequently leading to the increased activity of Ras as well as Erk1/2 activation via the Raf/MEK1/2 pathway. Down-regulation of the expression of endogenous CHK by RNAi in PC12 cells led to a significant decrease in MAPK activation following NGF stimulation. Stimulation of CHK-overexpressing PC12 cells with EGF induced neurite outgrowth in the majority of cells. Taken together, this study describes for the first time the Src-independent actions of CHK and provides novel insights into CHK function in neural cells. [Copyright &y& Elsevier]

In this study we investigated the efficacy of a combination of IL-12 and 5-FU, a chemotherapeutic exerting several immunomodulatory effects, in murine L1210 leukemia. Mice inoculated with 1 x 10(5) leukemia cells were treated with a single dose of 5-FU (50 mg/kg) and seven daily doses of IL-12 (100 ng/dose), and were observed for survival. Treatment with IL-12 or 5-FU given alone produced moderate anti-leukemic effects. However, combination of both drugs resulted in a significant prolongation of mouse survival time. Importantly, there were 70% of long-term (>60 days) survivors among mice treated with both agents simultaneously. Moreover, we observed 100% of long-term survivors when mice were treated with a minimally increased dose of IL-12 (170 ng) in combination with 5-FU (50 mg/kg). The antileukemic effects were completely abrogated in scid/scid mice and in mice depleted of peritoneal macrophages and significantly decreased after administration of anti-CD3+, anti-CD4+ or anti-CD8+ monoclonal antibodies. Administration of anti-NK1.1 antibodies did not decrease the antileukemic effects indicating that NK cells are not important effectors of this treatment regimen. Collectively, these results indicate that the combination of IL-12 and 5-FU is inducing strong antileukemic responses that are dependent on the presence and activity of macrophages and T lymphocytes and warrant further studies of combined chemo-immunotherapy with IL-12. [ABSTRACT FROM AUTHOR]

Examines the use of electron beam evaporation as a low temperature deposition process of boron and boron/amorphous silicon layers as dopant sources in rapid thermal diffusion. Compatibility of the process with the metal-oxide-semiconductor technology; Use of electronic-beam evaporation; Performance of the diffusion processes.

Monoclonal antibodies (mAbs) targeting specific proteins are currently the most popular form of immunotherapy used in the treatment of cancer and other non-malignant diseases. Since the first approval of anti-CD20 mAb rituximab in 1997 for the treatment of B-cell malignancies, the market is continuously booming and the clinically used mAbs have undergone a remarkable evolution. Novel molecular targets are constantly emerging and the development of genetic engineering have facilitated the introduction of modified mAbs with improved safety and increased capabilities to activate the effector mechanisms of the immune system. Next to their remarkable success in hematooncology, mAbs have also an already established role in the treatment of solid malignancies. The recent development of mAbs targeting the immune checkpoints has opened new avenues for the use of this form of immunotherapy, also in the immune-rich milieu of the skin. In this review we aim at presenting a comprehensive view of mAbs' application in the modern treatment of skin cancer. We present the characteristics and efficacy of mAbs currently used in dermatooncology and summarize the recent clinical trials in the field. We discuss the side effects and strategies for their managing. [ABSTRACT FROM AUTHOR]

Recently, a breakthrough immunotherapeutic strategy of chimeric antigen receptor (CAR) T-cells has been introduced to hematooncology. However, to apply this novel treatment in solid cancers, one must identify suitable molecular targets in the tumors of choice. CEACAM family proteins are involved in the progression of a range of malignancies, including pancreatic and breast cancers, and pose attractive targets for anticancer therapies. In this work, we used a new CEACAM-targeted 2A3 single-domain antibody-based chimeric antigen receptor T-cells to evaluate their antitumor properties in vitro and in animal models. Originally, 2A3 antibody was reported to target CEACAM6 molecule; however, our in vitro co-incubation experiments showed activation and high cytotoxicity of 2A3-CAR T-cells against CEACAM5 and/or CEACAM6 high human cell lines, suggesting cross-reactivity of this antibody. Moreover, 2A3-CAR T-cells tested in vivo in the BxPC-3 xenograft model demonstrated high efficacy against pancreatic cancer xenografts in both early and late intervention treatment regimens. Our results for the first time show an enhanced targeting toward CEACAM5 and CEACAM6 molecules by the new 2A3 sdAb-based CAR T-cells. The results strongly support the further development of 2A3-CAR T-cells as a potential treatment strategy against CEACAM5/6-overexpressing cancers. [ABSTRACT FROM AUTHOR]

The flow cytometry method could support physicians' decisions in the diagnosis and treatment monitoring of immunodeficient patients. Most clinical recommendations are focused on the search for alterations in T- and B-lymphocyte subsets, less commonly natural killer (NK) cells and granulocytes. While reference values for clinically meaningful lymphocyte subsets have been published ubiquitously among numerous countries, we have not found significant data for a population of adult Polish habitats; thus we determined reference values for T, B, and NK subsets according to sex and age. The female group showed a higher percentage of lymphocytes (CD45++), T helper lymphocytes with a higher absolute count, as well as CD4/CD8 ratio, marginal zone-like B cells, class-switched B cells, and CD21low B cells than the male group. The male group was found to have elevated percentages of naïve B lymphocytes, transitional B cells, and plasmablasts. A weak positive correlation with age was found among double positive T lymphocytes, natural killer T cells (NKT) lymphocytes, and CD21low B cells. A negative correlation with age for double negative T lymphocytes, marginal zone-like B cells, and plasmablasts was noted. The results indicated the importance of creating distinct reference ranges regarding sex and age concerning immunophenotype. [ABSTRACT FROM AUTHOR]

Introduction The potential role of antipsychotic treatment in increasing cardiovascular risk and in explaining the increased mortality due to somatic disorders is still debated. The aim of this study was to assess the sequences of atypical and atypical neuroleptic prescriptions in relation to cardiovascular medication and death occurrence. Methods We conducted a retrospective longitudinal analysis involving 84,881 patients who had drug insurance benefits in Pomeranian voivodship and who were receiving a typical or atypical antipsychotic medication between 2008 and 2012. Data on deaths have been collected from National Death Registry. The sequence creation was performed according to algorithm that iterates over neuroleptic prescriptions in chronological order and appends them to the end of patient's prescriptions sequence. Patients were also assigned to cardiovascular groups depending on the use of cardiovascular or diabetic medications before, simultaneously or after the treatment with neuroleptics. Results There were 1,095,518 neuroleptic prescriptions and 16,010 deaths among antipsychotic users in analyzed period. The most prevalent sequence was consisting of typical neuroleptics. Less frequent were sequenced with use of both typical and atypical drugs or only atypical medications. The least frequent were sequenced with clozapine or clozapine with other neuroleptics. The highest occurrence of death and occurrence of cardiovascular drug after introducing antipsychotic treatment was observed for clozapine. There was lower occurrence of death in atypical neuroleptic sequence compared to typical drug sequence but similar prevalence of cardiovascular drugs. Conclusion These results suggest that conventional antipsychotic medications are associated with increased risk of death compared to atypical drugs. [ABSTRACT FROM AUTHOR]

Background: Impaired neutrophil activity is an important issue in chronic lymphocytic leukemia (CLL), as it contributes to a dysfunctional immune response leading to life-threatening infections in patients. Some features typical of CLL neutrophils, e.g., the B-cell-supportive secretion profile, have already been described. However, most of these studies were performed on cells isolated from peripheral blood. It is still unclear which molecular factors and cell types are involved in shaping neutrophil function and phenotype in the CLL microenvironment. Since regulatory T cells (Treg) play an important role in CLL progression and influence the activity of neutrophils, we investigated the crosstalk between Treg and neutrophils in the spleen using a murine model of CLL. Methods: In this work, we used an Eµ-TCL1 mouse model of human CLL. For our in vivo and ex vivo experiments, we inoculated wild-type mice with TCL1 leukemic cells isolated from Eµ-TCL1 transgenic mice and then monitored disease progression by detecting leukemic cells in peripheral blood. We analyzed both the phenotype and activity of neutrophils isolated from the spleens of TCL1 leukemia-bearing mice. To investigate the interrelation between Treg and neutrophils in the leukemia microenvironment, we performed experiments using TCL1-injected DEREG mice with Treg depletion or RAG2KO mice with adoptively transferred TCL1 cells alone or together with Treg. Results: The obtained results underline the plasticity of the neutrophil phenotype, observed under the influence of leukemic cells alone and depending on the presence of Treg. In particular, Treg affect the expression of CD62L and IL-4 receptor in neutrophils, both of which are crucial for the function of these cells. Additionally, we show that Treg depletion and IL-10 neutralization induce changes in the leukemia microenvironment, partially restoring the "healthy" phenotype of neutrophils. Conclusions: Altogether, the results indicate that the crosstalk between Treg and neutrophils in CLL may play an important role in CLL progression by interfering with the immune response. [ABSTRACT FROM AUTHOR]

Introduction The potential role of antipsychotic treatment in affecting suicide rates and in explaining the increased mortality due to somatic disorders is still debated. The aim of this study was to assess mortality in individuals who were prescribed typical and atypical neuroleptics in one voivodship in Poland. Methods We conducted a retrospective cohort study involving 84881 patients who had drug insurance benefits in Pomeranian voivodship and who began receiving a conventional or atypical antipsychotic medication between 2008 and 2012. Data on deaths in this population have been collected from National Death Registry. Age-standardized death rates were calculated in the adult population exposed population to any dose of atypical antipsychotic medication, in popualtion of users of atypical antipsychotics only, in population of users of conventional antipsychotic drugs only and in population of clozapine users. Results In individuals who were prescribed conventional antipsychotic medication age-standardized death rate was significantly higher than in ever users of atypical medicatioons and people using only atypical drugs: 69.6 per 1000, 95% confidence interval (95% CI) 67.64–71.56 compared with 53.24 per 1000, 95% CI 50.8–55.69 and 48,38 per 1000, 95% CI 44.78–51.98. Mortality rate in clozapine users was also higher than in users oaf atypical medications (65,11 per 1000, 95% CI 50.8–55.69). Conclusion These results suggest that conventional antipsychotic medications are associated with increased risk of death compared to atypical drugs. Analysis based on administrative record linkage is the major limitation of this study. No adjustment has been made for confounding factors that may modify mortality risk. [ABSTRACT FROM AUTHOR]

Background: Our previous work has shown peroxiredoxin-1 (PRDX1), one of major antioxidant enzymes, to be a biomarker in human breast cancer. Hereby, we further investigate the role of PRDX1, compared to its close homolog PRDX2, in mammary malignant cells.Methods: CRISPR/Cas9- or RNAi-based methods were used for genetic targeting PRDX1/2. Cell growth was assessed by crystal violet, EdU incorporation or colony formation assays. In vivo growth was assessed by a xenotransplantation model. Adenanthin was used to inhibit the thioredoxin-dependent antioxidant defense system. The prooxidant agents used were hydrogen peroxide, glucose oxidase and sodium L-ascorbate. A PY1 probe or HyPer-3 biosensor were used to detect hydrogen peroxide content in samples.Results: PRDX1 downregulation significantly impaired the growth rate of MCF-7 and ZR-75-1 breast cancer cells. Likewise, xenotransplanted PRDX1-deficient MCF-7 cells presented a retarded tumour growth. Furthermore, genetic targeting of PRDX1 or adenanthin, but not PRDX2, potently sensitised all six cancer cell lines studied, but not the non-cancerous cells, to glucose oxidase and ascorbate.Conclusions: Our study pinpoints the dominant role for PRDX1 in management of exogeneous oxidative stress by breast cancer cells and substantiates further exploration of PRDX1 as a target in this disease, especially when combined with prooxidant agents. [ABSTRACT FROM AUTHOR]

Introduction: Despite spectacular progress in cellular transplantology, there are still many concerns about the fate of transplanted cells. More preclinical studies are needed, especially on large animal models, to bridge the translational gap between basic research and the clinic. Herein, we propose a novel approach in analysis of cell transplantation effects in large animals explants using in vivo imaging system (IVIS®) or similar equipment. Material and methods: In the in vitro experiment cells labeled with fluorescent membrane dyes: DID (far red) or PKH26 (orange) were visualized with IVIS®. The correlation between the fluorescence signal and cell number with or without addition of minced muscle tissue was calculated. In the ex vivo study urethras obtained from goats after intraurethral cells (n = 9) or PBS (n = 4) injections were divided into 0.5 cm cross-slices and analyzed by using IVIS®. Automatic algorithm followed or not by manual setup was used to separate specific dye signal from tissue autofluorescence. The results were verified by systematic microscopic analysis of standard 10 μm specimens prepared from slices before and after immunohistochemical staining. Comparison of obtained data was performed using diagnostic test function. Results: Fluorescence signal strength in IVIS® was directly proportional to the number of cells regardless of the dye used and detectable for minimum 0.25x106 of cells. DID-derived signal was much less affected by the background signal in comparison to PKH26 in in vitro test. Using the IVIS® to scan explants in defined arrangement resulted in precise localization of DID but not PKH26 positive spots. Microscopic analysis of histological specimens confirmed the specificity (89%) and sensitivity (80%) of IVIS® assessment relative to DID dye. The procedure enabled successful immunohistochemical staining of specimens derived from analyzed slices. Conclusions: The IVIS® system under appropriate conditions of visualization and analysis can be used as a method for ex vivo evaluation of cell transplantation effects. Presented protocol allows for evaluation of cell delivery precision rate, enables semi-quantitative assessment of signal, preselects material for further analysis without interfering with the tissue properties. Far red dyes are appropriate fluorophores to cell labeling for this application. [ABSTRACT FROM AUTHOR]

Chitotriosidase (CHIT1) is an enzyme produced by macrophages that regulates their differentiation and polarization. Lung macrophages have been implicated in asthma development; therefore, we asked whether pharmacological inhibition of macrophage-specific CHIT1 would have beneficial effects in asthma, as it has been shown previously in other lung disorders. CHIT1 expression was evaluated in the lung tissues of deceased individuals with severe, uncontrolled, steroid-naïve asthma. OATD-01, a chitinase inhibitor, was tested in a 7-week-long house dust mite (HDM) murine model of chronic asthma characterized by accumulation of CHIT1-expressing macrophages. CHIT1 is a dominant chitinase activated in fibrotic areas of the lungs of individuals with fatal asthma. OATD-01 given in a therapeutic treatment regimen inhibited both inflammatory and airway remodeling features of asthma in the HDM model. These changes were accompanied by a significant and dose-dependent decrease in chitinolytic activity in BAL fluid and plasma, confirming in vivo target engagement. Both IL-13 expression and TGFβ1 levels in BAL fluid were decreased and a significant reduction in subepithelial airway fibrosis and airway wall thickness was observed. These results suggest that pharmacological chitinase inhibition offers protection against the development of fibrotic airway remodeling in severe asthma. [ABSTRACT FROM AUTHOR]

We designed planar electrodes, for dielectrophoretic manipulation of single-walled carbon nanotubes (SWNTs), built as metal-oxide-semiconductor nanogap capacitors with common substrate and oxide thicknesses of 17 and 150 nm. Such design generates high electric fields (109 V m[?]1) and also the fringing field is curved due to the conducting substrate, unlike fields generated by conventionally used planar electrodes. Scanning electron microscopy images showed SWNTs aligned parallel and perpendicular to the electrodes. Raman spectroscopic mapping was used to produce separate images of the metallic (m-SWNT) and semiconducting (s-SWNT) nanotube density distributions. As expected, parallel alignment of the m-SWNTs with the E-field was found; however, also a perpendicular alignment of s-SWNTs was observed. Such orthogonal alignment of s-SWNTs is a rare observation and has not been experimentally reported before in detail with Raman images. Due to the unique electrode design, we were able to obtain substantial separation of m-SWNTs and s-SWNTs. Numerical modeling of the electric field factor of the dielectrophoresis force was done, and it matched perfectly with the experimental results. The orthogonal alignment of s-SWNTs results from comparable values of parallel and perpendicular polarizability to the nanotube axis. [ABSTRACT FROM AUTHOR]

An abstract of the study "The Value of Heart Rate Turbulence (HRT) in Patients With Dilated Cardiomyopathy (DCM) and Ventricular Tachyarrhythmias (VT)," by L. Lepska and colleagues is presented.

Chitinases and chitinase-like proteins are thought to play a role in innate inflammatory responses. Our study aimed to assess whether chitinase concentration and activity in induced sputum (IS) of patients exposed to tobacco smoke are related to the level of airway inflammation including the level and activity of chitinases and chitinase-like proteins. The study included 22 patients with chronic obstructive pulmonary disease (COPD), 12 non-COPD smokers, and nine nonsmoking subjects. Sputum CHIT1 and YKL-40 levels and chitinolytic activity were compared with sputum IL-6, IL-8, IL-18, and MMP-9 levels. A hierarchical cluster analysis was also performed. Sputum YKL-40 was higher in COPD patients than in the control groups. Sputum CHIT1 and YKL-40 levels correlated with IS inflammatory cell count as well as with MMP-9 and IL-8 levels. Two main clusters were revealed: Cluster 1 had lower chitinase levels and activity, lower IS macrophage and neutrophil count, and lower IS IL-8, IL-18, and MMP-9 than Cluster 2. Comparison of COPD patients from both clusters revealed significant differences in the IS inflammatory profile despite comparable clinical and functional data. Our findings seem to confirm the involvement of chitinases in smoking-associated chronic airway inflammation and show that airway chitinases may be a potential novel marker in COPD phenotyping. [ABSTRACT FROM AUTHOR]

We report on investigations of nonlinear radiofrequency responses of electrolytes with Na+ and Cl- ions placed within gold electrodes of a capacitor. The sample was part of a frequency-adjustable inductance-capacitance-resistance (LCR) parallel resonant circuit, and measurements were carried out using the two frequencies intermodulation distortion technique. We employed double layer model to analyze the observed nonlinearities and their dependence on ionic concentration. Electrode-electrolyte interface polarization was found to be a predominant cause of this intrinsic nonlinearity and to be dependent on electrolytic ion concentration. We also measured and calculated coefficients of resistive and capacitive components of the observed nonlinearity. [ABSTRACT FROM AUTHOR]

Photofrin®-based photodynamic therapy (PDT) has recently been approved for palliative and curative purposes in cancer patients. It has been demonstrated that neutrophils are indispensable for its anti-tumour effectiveness. We decided to evaluate the extent of the anti-tumour effectiveness of PDT combined with administration of granulocyte colony-stimulating factor (G-CSF) as well as the influence of Photofrin® and G-CSF on the myelopoiesis and functional activity of neutrophils in mice. An intensive treatment with G-CSF significantly potentiated anti-tumour effectiveness of Photofrin®-based PDT resulting in a reduction of tumour growth and prolongation of the survival time of mice bearing two different tumours: colon-26 and Lewis lung carcinoma. Moreover, 33% of C-26-bearing mice were completely cured of their tumours after combined therapy and developed a specific and long-lasting immunity. The tumours treated with both agents contained more infiltrating neutrophils and apoptotic cells then tumours treated with either G-CSF or PDT only. Importantly, simultaneous administration of Photofrin® and G-CSF stimulated bone marrow and spleen myelopoiesis that resulted in an increased number of neutrophils demonstrating functional characteristics of activation. Potentiated anti-tumour effects of Photofrin®-based PDT combined with G-CSF observed in two murine tumour models suggest that clinical trials using this tumour therapy protocol would be worth pursuing. [ABSTRACT FROM AUTHOR]

Background/aim: Children on dialysis are under increased risk of influenza and invasive pneumococcal disease. Although vaccination against these microorganisms are recommended in dialysis patients and despite the fact that these vaccines can reduce disease burden and rates of hospitalization due to infection, vaccination rates are below expected and desired. We aimed to evaluate influenza and pneumococcal vaccination and infection rates in European pediatric dialysis centers. Materials and methods: In 16 centers from 11 countries, 357 pediatric dialysis patients were evaluated retrospectively during 1 year of observation period between 01.01.2014 and 01.01.2015. Results: In all centers, vaccination policy included immunization of dialysis patients with inactive influenza vaccine and pneumococcal conjugate vaccine (PCV). Fifty percent of the centers recommended pneumococcal polysaccharide vaccine following routine PCV series. A significantly higher pneumococcal vaccination rate (43.9%) was seen in peritoneal dialysis (PD) patients compared to those on hemodialysis (HD) (32.9%) (p = 0.035), while the rates for influenza were similar (42.4% and 46.1% respectively, p = 0.496). Among all dialysis patients, 2.2% (n = 8) developed pneumonia and 6.4% (n = 23) was infected by Influenza. Pneumococcic pneumonia rate was 5% for 140 patients who received antipneumococcal vaccine, while only one pneumonia episode was recorded out of 217 unvaccinated patients (p = 0.007). The influenza virus infection rates were similar for patients vaccinated and nonvaccinated (7 % and 6 %, respectively). Conclusions: Although influenza and pneumococcal vaccines are highly recommended in pediatric dialysis patients, vaccination rates were lower than expected. Pneumococcal vaccination rates were higher in PD compared to the patients on HD. The rate of children with influenza infection was higher than pneumonia. The efficacy of influenza and pneumococcal vaccines was highlighted by the low infection rates. Higher pneumonia rates in patients vaccinated against pneumococcus compared to unvaccinated ones might be due to coexisting risk factors. [ABSTRACT FROM AUTHOR]

Tumor-infiltrating immune cells are capable of effective cancer surveillance, and their abundance is linked to better prognosis in numerous tumor types. However, in uveal melanoma (UM), extensive immune infiltrate is associated with poor survival. This study aims to decipher the role of different tumor-infiltrating cell subsets in UM in order to identify potential targets for future immunotherapeutic treatment. We have chosen the TCGA-UVM cohort as a training dataset and GSE22138 as a testing dataset by mining publicly available databases. The abundance of 22 immune cell types was estimated using CIBERSORTx. Then, to determine the significance of tumor-infiltrating cell subsets in UM, we built a multicell type prognostic signature, which was validated in the testing cohort. The created signature was built upon the negative prognostic role of CD8+ T cells and M0 macrophages and the positive role of neutrophils. Based on the created signature score, we divided the patients into low- and high-risk groups. Kaplan-Meier, Cox, and ROC analyses demonstrated superior performance of our risk score compared to either clinical or pathologic characteristics of both cohorts. Further, we found the molecular pathways associated with cancer immunoevasion and metastasis to be enriched in the high-risk group, explaining both the lack of adequate immune surveillance despite increased infiltration of CD8+ T cells as well as the higher metastatic potential. Genes associated with tryptophan metabolism (IDO1 and KYNU) and metalloproteinases were among the most differentially expressed between the high- and low-risk groups. Our correlation analyses interpreted in context of published in vitro data strongly suggest the central role of CD8+ T cells in shifting the UM tumor microenvironment towards suppressive and metastasis-promoting. Therefore, we propose further investigations of IDO1 and metalloproteinases as novel targets for immunotherapy in lymphocyte-rich metastatic UM patients. [ABSTRACT FROM AUTHOR]

A film residue obtained by evaporating surfactant-stabilized single-walled carbon nanotube (SWNT) suspension was characterized at 12 GHz using a scanning-sample dielectric resonator technique. Resonant frequency and quality factor changes were measured and cavity perturbation method was used to calculate the SWNT complex permittivity. The effective permittivity of the SWNT was determined as (3516-j316.5), which provided an average dielectric constant and conductivity for a single SWNT to be 8.1×105 and 8.4×106 S/m, respectively. Microwave induced losses originated only from the electric field, not from the magnetic field, thus indicating an absence of direct electrical contact between nanotubes and a below percolation-limit configuration. [ABSTRACT FROM AUTHOR]

Deregulated metabolism of oxygen with increased generation of reactive oxygen species (ROS) is characteristic for a majority of cancers. The elevated ROS levels are in part responsible for further progression of cancer, but when produced in large excess, they endanger the viability of the cancer cells. To protect themselves from ROS-mediated toxicity, many types of cancers enhance the intrinsic antioxidant defenses, which make them dependent on the efficacy of a given ROS-detoxifying system. This poses an attractive target for anticancer therapy by two main approaches: the use of ROS-generating agents (i.e., prooxidants) or by inhibition of a chosen antioxidant system. However, the clinical efficacy of either of these approaches used alone is modest at best. The solution may rely on combining these strategies into an advanced prooxidant therapy (APoT) in order to produce a synergistic and cancer-specific effect. Indeed, such strategies have proven efficient in preclinical models, e.g., in B cell malignancies and breast cancer. Following promising experimental reports on APoT, this approach needs to be further extensively tested in order to become a potential alternative or an enhancement for classical chemotherapy. [ABSTRACT FROM AUTHOR]

The aim of our study was to determine whether sildenafil citrate influences the production of Th1- (TNF-α, INF-γ) or Th2-type (TGF-β, IL-10) cytokines by lymphocytes of healthy men. Sildenafil citrate (SC) is a selective blocker of phosphodiesterase 5, by competing for the binding site with cGMP. It was reported that a higher risk of sexually transmitted diseases (STD) could be correlated with a recreational use of sildenafil, especially when combined with another drug. While behavioral causes of these findings are understood, it is worth considering other causes of that phenomenon that might rely on the influence of sildenafil on the immune system. Material and Methods. Peripheral blood mononuclear cells (PBMCs) were isolated from 27 healthy men donors and cultured in the presence of SC at a concentration of 400 ng/ml. The first set of research was performed on cells stimulated, for at least 4 hours, by incubation with phorbol myristate acetate (PMA), ionomycin, and Golgi-Stop. Subsequently, we determined cytokine production in cells stimulated with phytohemagglutinin (PHA) for 12 hours in the presence of Golgi-Stop. Flow cytometry immunophenotyping of PBMC was performed towards the surface marker of T cells: CD3 and intracellular cytokine expression: TNF-α, IFN-γ, TGF-β, and IL-10. Our findings show that SC significantly decreased the percentage of T cells producing TNF-α and displayed tendency to decrease IFN-γ, when stimulated with PMA. Frequent usage of SC might strengthen this effect. That could partially explain the impaired immune response to the pathogens of men using the drug. [ABSTRACT FROM AUTHOR]

Background: Lapatinib has clinical efficacy in the treatment of trastuzumab-refractory HER2-positive breast cancer. However, a significant proportion of patients develop progressive disease due to acquired resistance to the drug. Induction of apoptotic cell death is a key mechanism of action of lapatinib in HER2-positive breast cancer cells.Methods: We examined alterations in regulation of the intrinsic and extrinsic apoptosis pathways in cell line models of acquired lapatinib resistance both in vitro and in patient samples from the NCT01485926 clinical trial, and investigated potential strategies to exploit alterations in apoptosis signalling to overcome lapatinib resistance in HER2-positive breast cancer.Results: In this study, we examined two cell lines models of acquired lapatinib resistance (SKBR3-L and HCC1954-L) and showed that lapatinib does not induce apoptosis in these cells. We identified alterations in members of the BCL-2 family of proteins, in particular MCL-1 and BAX, which may play a role in resistance to lapatinib. We tested the therapeutic inhibitor obatoclax, which targets MCL-1. Both SKBR3-L and HCC1954-L cells showed greater sensitivity to obatoclax-induced apoptosis than parental cells. Interestingly, we also found that the development of acquired resistance to lapatinib resulted in acquired sensitivity to TRAIL in SKBR3-L cells. Sensitivity to TRAIL in the SKBR3-L cells was associated with reduced phosphorylation of AKT, increased expression of FOXO3a and decreased expression of c-FLIP. In SKBR3-L cells, TRAIL treatment caused activation of caspase 8, caspase 9 and caspase 3/7. In a second resistant model, HCC1954-L cells, p-AKT levels were not decreased and these cells did not show enhanced sensitivity to TRAIL. Furthermore, combining obatoclax with TRAIL improved response in SKBR3-L cells but not in HCC1954-L cells.Conclusions: Our findings highlight the possibility of targeting altered apoptotic signalling to overcome acquired lapatinib resistance, and identify potential novel treatment strategies, with potential biomarkers, for HER2-positive breast cancer that is resistant to HER2 targeted therapies. [ABSTRACT FROM AUTHOR]

Background Treatment of antibody-mediated rejection (AMR) is one of the main problems after kidney transplantation (KTx). The results of intensive AMR treatment with plasmapheresis (PF) and repeated infusions of intravenous immunoglobulin (IVIg) are presented. Methods Diagnosis of AMR was based on graft biopsy and the presence of donor-specific antibodies (DSAs). AMR therapy consisted of 5 PF and IVIg infusions given after the last PF. Subsequent IVIg doses were given every 4 weeks for 6 months. Graft biopsy and DSA assessment were repeated at the end of the treatment (ET). Results Four women and 10 men were included in our study; mean time from KTx to AMR was 79 (range, 3–193) months. During the treatment, 4 patients had graft failure. Graft function at baseline was significantly worse ( P = .02) in this group compared with patients who completed the therapy. At baseline, mean flourescence intensity (MFI) was 6574 (range, 852–15,917) in the whole group, 7088 (range, 1054–15,917) in patients who completed treatment, and 4828 (range, 852–11,797) in patients who restarted hemodialysis. At ET, DSA MFI decreased in 8 of 10 patients (80%) who completed the therapy. The MFI decrease was 3946 (range, 959–11,203). Control graft biopsies revealed decreased intensity of C4d deposits in peritubular capillaries in 7 patients (78%) and decreased peritubular capillaritis in 2 patients (22%). Conclusion Intensive, prolonged AMR therapy with PF and IVIg resulted in a decrease in DSA titer and intensity of C4d deposits, but was not associated with reduction of microcirculation inflammation. Treatment was ineffective in patients with baseline advanced graft insufficiency. [ABSTRACT FROM AUTHOR]

This article highlights our work toward the identification of a potent, selective, and efficacious acidic mammalian chitinase (AMCase) inhibitor. Rational design, guided by X-ray analysis of several inhibitors bound to human chitotriosidase (hCHIT1), led to the identification of compound 7f as a highly potent AMCase inhibitor (IC50 values of 14 and 19 nM against human and mouse enzyme, respectively) and selective (>150x against mCHIT1) with very good PK properties. This compound dosed once daily at 30 mg/kg po showed significant anti-inflammatory efficacy in HDM-induced allergic airway inflammation in mice, reducing inflammatory cell influx in the BALF and total IgE concentration in plasma, which correlated with decrease of chitinolytic activity. Therapeutic efficacy of compound 7f in the clinically relevant aeroallergen-induced acute asthma model in mice provides a rationale for developing AMCase inhibitor for the treatment of asthma. [ABSTRACT FROM AUTHOR]

This article describes our work towards the identification of a potent and selective inhibitor of mouse chitotriosidase (mCHIT1). A series of small molecule inhibitors of mCHIT1 and mAMCase have been developed from early lead compound 1 . Examination of synthetized analogues led to discovery of several novel highly potent compounds. Among them compound 9 ( OAT-2068 ) displays a remarkable 143-fold mCHIT1 vs . mAMCase selectivity. To explain the observed SAR molecular docking experiments were performed, which were in line with the experimental data from the enzymatic assays. Inhibitor 9 ( OAT-2068 ) was found to have an excellent pharmacokinetic profile. This, together with high activity and selectivity, makes the compound an ideal and unique tool for studying the role of CHIT1 in biological models. [ABSTRACT FROM AUTHOR]

E-type cyclins (cyclins E1 and E2) are components of the core cell cycle machinery and are overexpressed in many human tumor types. E cyclins are thought to drive tumor cell proliferation by activating the cyclin-dependent kinase 2 (CDK2). The cyclin E1 gene represents the site of recurrent integration of the hepatitis B virus in the pathogenesis of hepatocellular carcinoma, and this event is associated with strong up-regulation of cyclin E1 expression. Regardless of the underlying mechanism of tumorigenesis, the majority of liver cancers overexpress E-type cyclins. Here we used conditional cyclin E knockout mice and a liver cancer model to test the requirement for the function of E cyclins in liver tumorigenesis. We show that a ubiquitous, global shutdown of E cyclins did not visibly affect postnatal development or physiology of adult mice. However, an acute ablation of E cyclins halted liver cancer progression. We demonstrated that also human liver cancer cells critically depend on E cyclins for proliferation. In contrast, we found that the function of the cyclin E catalytic partner, CDK2, is dispensable in liver cancer cells. We observed that E cyclins drive proliferation of tumor cells in a CDK2- and kinase-independent mechanism. Our study suggests that compounds which degrade or inhibit cyclin Emight represent a highly selective therapeutic strategy for patients with liver cancer, as these compounds would selectively cripple proliferation of tumor cells, while sparing normal tissues. [ABSTRACT FROM AUTHOR]

Downregulation of CD20, a molecular target for monoclonal antibodies (mAbs), is a clinical problem leading to decreased efficacy of anti-CD20-based therapeutic regimens. The epigenetic modulation of CD20 coding gene (MS4A1) has been proposed as a mechanism for the reduced therapeutic efficacy of anti-CD20 antibodies and confirmed with nonselective histone deacetylase inhibitors (HDACis). Because the use of pan- HDACis is associated with substantial adverse effects, the identification of particular HDAC isoforms involved in CD20 regulation seems to be of paramount importance. In this study, we demonstrate for the first time the role of HDAC6 in the regulation of CD20 levels. We show that inhibition of HDAC6 activity significantly increases CD20 levels in established B-cell tumor cell lines and primary malignant cells. Using pharmacologic and genetic approaches, we confirm that HDAC6 inhibition augments in vitro efficacy of anti- CD20 mAbs and improves survival of mice treated with rituximab. Mechanistically, we demonstrate that HDAC6 influences synthesis of CD20 protein independently of the regulation of MS4A1 transcription. We further demonstrate that translation of CD20 mRNA is significantly enhanced after HDAC6 inhibition, as shown by the increase of CD20 mRNA within the polysomal fraction, indicating a new role of HDAC6 in the posttranscriptional mechanism of CD20 regulation. Collectively, our findings suggest HDAC6 inhibition is a rational therapeutic strategy to be implemented in combination therapies with anti-CD20 monoclonal antibodies and open up novel avenues for the clinical use of HDAC6 inhibitors. [ABSTRACT FROM AUTHOR]

Gene transfer into normal quiescent human B cells is a challenging procedure. The present study aimed to investigate whether it is possible to increase the levels of transgene expression by using various types of promoters to drive the expression of selected genes‑of‑interest. To produce lentiviral particles, the present study used the 2nd generation psPAX2 packaging vector and the vesicular stomatitis virus ‑expressing envelope vector pMD2.G. Subsequently, lentiviral vectors were generated containing various promoters, including cytomegalovirus (CMV), elongation factor‑1 alpha (EF1α) and spleen focus‑forming virus (SFFV). The present study was unable to induce satisfactory transduction efficiency in quiescent normal B cells; however, infection of normal B cells with Epstein‑Barr virus resulted in increased susceptibility to lentiviral transduction. In addition, the SFFV promoter resulted in a higher level of transgene expression compared with CMV or EF1α promoters. As a proof‑of concept that this approach allows for stable gene expression in normal B cells, the present study used bicistronic lentiviral vectors with genes encoding fluorescent reporter proteins, as well as X‑box binding protein‑1 and binding immunoglobulin protein. [ABSTRACT FROM AUTHOR]

Background: We explored the variation in country mortality rates in the paediatric population receiving renal replacement therapy across Europe, and estimated how much of this variation could be explained by patient-level and country-level factors.Methods: In this registry analysis, we extracted patient data from the European Society for Paediatric Nephrology/European Renal Association-European Dialysis and Transplant Association (ESPN/ERA-EDTA) Registry for 32 European countries. We included incident patients younger than 19 years receiving renal replacement therapy. Adjusted hazard ratios (aHR) and the explained variation were modelled for patient-level and country-level factors with multilevel Cox regression. The primary outcome studied was all-cause mortality while on renal replacement therapy.Findings: Between Jan 1, 2000, and Dec 31, 2013, the overall 5 year renal replacement therapy mortality rate was 15·8 deaths per 1000 patient-years (IQR 6·4-16·4). France had a mortality rate (9·2) of more than 3 SDs better, and Russia (35·2), Poland (39·9), Romania (47·4), and Bulgaria (68·6) had mortality rates more than 3 SDs worse than the European average. Public health expenditure was inversely associated with mortality risk (per SD increase, aHR 0·69, 95% CI 0·52-0·91) and explained 67% of the variation in renal replacement therapy mortality rates between countries. Child mortality rates showed a significant association with renal replacement therapy mortality, albeit mediated by macroeconomics (eg, neonatal mortality reduced from 1·31 [95% CI 1·13-1·53], p=0·0005, to 1·21 [0·97-1·51], p=0·10). After accounting for country distributions of patient age, the variation in renal replacement therapy mortality rates between countries increased by 21%.Interpretation: Substantial international variation exists in paediatric renal replacement therapy mortality rates across Europe, most of which was explained by disparities in public health expenditure, which seems to limit the availability and quality of paediatric renal care. Differences between countries in their ability to accept and treat the youngest patients, who are the most complex and costly to treat, form an important source of disparity within this population. Our findings can be used by policy makers and health-care providers to explore potential strategies to help reduce these health disparities.Funding: ERA-EDTA and ESPN. [ABSTRACT FROM AUTHOR]

A custom-designed semifluorinated phosphonic acid, (9,9,10,10,11,11,12,12,13,13,14,14,15,15,16,16,16-heptadecafluorohexadecyl)phosphonic acid (F8H8PA), and a normal hexadecylphosphonic acid (H16PA) were synthesized and used to generate self-assembled monolayers (SAMs) on commercially available yttrium barium copper oxide (YBCO) tapes. In this study, we wished to evaluate the effectiveness of these monolayer films as coatings for selectively etching YBCO. Initial films formed by solution deposition and manual stamping using a non-patterned polydimethylsiloxane stamp allowed for a comparison of the film-formation characteristics. The resulting monolayers were characterized by X-ray photoelectron spectroscopy (XPS), contact angle goniometry, and polarization modulation infrared reflection absorption spectroscopy (PM-IRRAS). To prepare line-patterned (filamentized) YBCO tapes, standard microcontact printing (μ-CP) procedures were used. The stamped patterns on the YBCO tapes were characterized by scanning electron microscopy (SEM) before and after etching to confirm the effectiveness of the patterning process on the YBCO surface and energy-dispersive X-ray spectroscopy (EDX) to obtain the atomic composition of the exposed interface. [ABSTRACT FROM AUTHOR]

Natural killer ( NK) cells are considered critical components of the innate and adaptive immune responses. Deficiencies in NK cell activity are common, such as those that occur in cancer patients, and they can be responsible for dysfunctional immune surveillance. Persistent oxidative stress is intrinsic to many malignant tumours, and numerous studies have focused on the effects of reactive oxygen species on the anti-tumour activity of NK cells. Indeed, investigations in animal models have suggested that one of the most important thiol-dependent antioxidant enzymes, peroxiredoxin 1 ( PRDX1), is essential for NK cell function. In this work, our analysis of the transcriptomic expression pattern of antioxidant enzymes in human NK cells has identified PRDX1 as the most prominently induced transcript out of the 18 transcripts evaluated in activated NK cells. The change in PRDX1 expression was followed by increased expression of two other enzymes from the PRDX-related antioxidant chain: thioredoxin and thioredoxin reductase. To study the role of thiol-dependent antioxidants in more detail, we applied a novel compound, adenanthin, to induce an abrupt dysfunction of the PRDX-related antioxidant chain in NK cells. In human primary NK cells, we observed profound alterations in spontaneous and antibody-dependent NK cell cytotoxicity against cancer cells, impaired degranulation, and a decreased expression of activation markers under these conditions. Collectively, our study pinpoints the unique role for the antioxidant activity of the PRDX-related enzymatic chain in human NK cell functions. Further understanding this phenomenon will prospectively lead to fine-tuning of the novel NK-targeted therapeutic approaches to human disease. [ABSTRACT FROM AUTHOR]

Background:Glioblastoma (GBM), being a highly vascularised and locally invasive tumour, is an attractive target for anti-angiogenic and anti-invasive therapies. The GBM/endothelial cell response to gossypol/temozolomide (TMZ) treatment was investigated with a particular aim to assess treatment effects on cancer hallmarks.Methods:Cell viability, endothelial tube formation and GBM tumour cell invasion were variously assessed following combined treatment in vitro. The U87MG-luc2 subcutaneous xenograft model was used to investigate therapeutic response in vivo. Viable tumour response to treatment was interrogated using immunohistochemistry. Combined treatment protocols were also tested in primary GBM patient-derived cultures.Results:An endothelial/GBM cell viability inhibitory effect, as well as an anti-angiogenic and anti-invasive response, to combined treatment have been demonstrated in vitro. A significantly greater anti-proliferative (P=0.020, P=0.030), anti-angiogenic (P=0.040, P<0.0001) and pro-apoptotic (P=0.0083, P=0.0149) response was observed when combined treatment was compared with single gossypol/TMZ treatment response, respectively. GBM cell line and patient-specific response to gossypol/TMZ treatment was observed.Conclusions:Our results indicate that response to a combined gossypol/TMZ treatment is related to inhibition of tumour-associated angiogenesis, invasion and proliferation and warrants further investigation as a novel targeted GBM treatment strategy. [ABSTRACT FROM AUTHOR]