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Background: Modulation and depletion strategies of regulatory T cells (Tregs) constitute valid approaches in antitumor immunotherapy but suffer from severe adverse effects due to their lack of selectivity for the tumor-infiltrating (ti-)Treg population, indicating the need for a ti-Treg specific biomarker., Methods: We employed single-cell RNA-sequencing in a mouse model of non-small cell lung carcinoma (NSCLC) to obtain a comprehensive overview of the tumor-infiltrating T-cell compartment, with a focus on ti-Treg subpopulations. These findings were validated by flow cytometric analysis of both mouse (LLC-OVA, MC38 and B16-OVA) and human (NSCLC and melanoma) tumor samples. We generated two CCR8-specific nanobodies (Nbs) that recognize distinct epitopes on the CCR8 extracellular domain. These Nbs were formulated as tetravalent Nb-Fc fusion proteins for optimal CCR8 binding and blocking, containing either an antibody-dependent cell-mediated cytotoxicity (ADCC)-deficient or an ADCC-prone Fc region. The therapeutic use of these Nb-Fc fusion proteins was evaluated, either as monotherapy or as combination therapy with anti-programmed cell death protein-1 (anti-PD-1), in both the LLC-OVA and MC38 mouse models., Results: We were able to discern two ti-Treg populations, one of which is characterized by the unique expression of Ccr8 in conjunction with Treg activation markers. Ccr8 is also expressed by dysfunctional CD4 + and CD8 + T cells, but the CCR8 protein was only prominent on the highly activated and strongly T-cell suppressive ti-Treg subpopulation of mouse and human tumors, with no major CCR8-positivity found on peripheral Tregs. CCR8 expression resulted from TCR-mediated Treg triggering in an NF-κB-dependent fashion, but was not essential for the recruitment, activation nor suppressive capacity of these cells. While treatment of tumor-bearing mice with a blocking ADCC-deficient Nb-Fc did not influence tumor growth, ADCC-prone Nb-Fc elicited antitumor immunity and reduced tumor growth in synergy with anti-PD-1 therapy. Importantly, ADCC-prone Nb-Fc specifically depleted ti-Tregs in a natural killer (NK) cell-dependent fashion without affecting peripheral Tregs., Conclusions: Collectively, our findings highlight the efficacy and safety of targeting CCR8 for the depletion of tumor-promoting ti-Tregs in combination with anti-PD-1 therapy., Competing Interests: Competing interests: HR and EA are employees of Oncurious NV. PM is a consultant to Oncurious NV., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

This study reports the long-term storage stability of a formulation of the cyanide (CN) antidote dimethyl trisulfide (DMTS). The F3-formulated DMTS was stored in glass ampules at 4, 22, and 37 °C. Over a period of one year, nine ampules ( n = 3 at each temperature) were analyzed by high-performance liquid chromatography (HPLC)-UV/vis at daily time intervals in the first week, weekly time intervals in the first month, and monthly thereafter for a period of one year to determine the DMTS content. No measurable loss of DMTS was found at 4 and 22 °C, and good stability was noted up to five months for samples stored at 37 °C. At 37 °C, a 10% (M/M) decrease of DMTS was discovered at the sixth month and only 30% (M/M) of DMTS remained by the end of the study; discoloration of the formulation and the growth of new peaks in the HPLC chromatogram were also observed. To identify the unknown peaks at 37 °C, controlled oxidation studies were performed on DMTS using two strong oxidizing agents: meta -chloroperoxybenzoic acid ( m CPBA) and hydrogen peroxide (H 2 O 2 ). Dimethyl tetrasulfide and dimethyl pentasulfide were observed as products using both of the oxidizing agents. Dimethyl disulfide was also observed as a product of degradation, which was further oxidized to S -methyl methanethiosulfonate only when m CPBA was used. HPLC-UV/vis and gas chromatography-mass spectrometry/solid phase microextraction analysis revealed good agreement between the degradation products of the stability study at 37 °C and those of disproportionation reactions. Furthermore, at 4 and 22 °C, chromatograms were remarkably stable over the one-year study period, indicating that the F3-formulated DMTS shows excellent long-term storage stability at T ≤ 22 °C., Competing Interests: The authors declare the following competing financial interest(s): Two patents by two coauthors, related to DMTS are: (1) Gary A. Rockwood, Ilona Petrikovics (SHSU) and Steven I. Baskin (USAMRICD): Dimethyl Trisulfide as a Cyanide Antidote. U.S. Patent No. 9,375,407, 2016, (2) Ilona Petrikovics and Kristof Kovacs (SHSU). Formulations of Dimethyl Trisulfide for Use as a Cyanide Antidote. U.S. Patent No. 9,456,996, 2016., (© 2020 American Chemical Society.)

Monocytes influence multiple aspects of tumor progression, including antitumor immunity, angiogenesis, and metastasis, primarily by infiltrating tumors, and differentiating into tumor-associated macrophages. Emerging evidence suggests that the tumor-induced systemic environment influences the development and phenotype of monocytes before their arrival to the tumor site. As a result, circulating monocytes show functional alterations in cancer, such as the acquisition of immunosuppressive activity and reduced responsiveness to inflammatory stimuli. In this review, we summarize available evidence about cancer-induced changes in monopoiesis and its impact on the abundance and function of monocytes in the periphery. In addition, we describe the phenotypical alterations observed in tumor-educated peripheral blood monocytes and highlight crucial gaps in our knowledge about additional cellular functions that may be affected based on transcriptomic studies. We also highlight emerging therapeutic strategies that aim to reverse cancer-induced changes in monopoiesis and peripheral monocytes to inhibit tumor progression and improve therapy responses. Overall, we suggest that an in-depth understanding of systemic monocyte reprogramming will have implications for cancer immunotherapy and the development of clinical biomarkers., (Copyright © 2020 Kiss, Caro, Raes and Laoui.)

Background: For ICD-11, the WHO emphasized the clinical utility of communication and the need to involve service users and carers in the revision process., Aims: The objective was to assess whether medical vocabulary was accessible, which kinds of feelings it activated, whether and how users and carers would like to rephrase terms, and whether they used diagnosis to talk about mental health experiences., Method: An innovative protocol focused on two diagnoses (depressive episode and schizophrenia) was implemented in 15 different countries. The same issues were discussed with users and carers: understanding, feelings, rephrasing, and communication., Results: Most participants reported understanding the diagnoses, but associated them with negative feelings. While the negativity of "depressive episode" mostly came from the concept itself, that of "schizophrenia" was largely based on its social impact and stigmatization associated with "mental illness". When rephrasing "depressive episode", a majority kept the root "depress*", and suppressed the temporal dimension or renamed it. Almost no one suggested a reformulation based on "schizophrenia". Finally, when communicating, no one used the phrase "depressive episode". Some participants used words based on "depress", but no one mentioned "episode". Very few used "schizophrenia"., Conclusion: Data revealed a gap between concepts and emotional and cognitive experiences. Both professional and experiential language and knowledge have to be considered as complementary. Consequently, the ICD should be co-constructed by professionals, service users, and carers. It should take the emotional component of language, and the diversity of linguistic and cultural contexts, into account.

Over the past decade, cancer immunotherapy has been steering immune responses toward cancer cell eradication. However, these immunotherapeutic approaches are hampered by the tumor-promoting nature of myeloid cells, including monocytes, macrophages, and neutrophils. Despite the arsenal of defense strategies against foreign invaders, myeloid cells succumb to the instructions of an established tumor. Interestingly, the most primordial defense responses employed by myeloid cells against pathogens, such as complement activation, antibody-dependent cell cytotoxicity and phagocytosis, actually seem to favor cancer progression. In this review, we discuss how rudimentary defense mechanisms deployed by myeloid cells can promote tumor progression., (Copyright © 2020 Lebegge, Arnouk, Bardet, Kiss, Raes and Van Ginderachter.)

We demonstrate the design, fabrication, and experimental characterization of near-field binary phase transmission diffractive optical elements (DOEs) in single crystal diamond. Top-hat and arbitrary pattern DOE beam shapers were numerically optimized using an iterative Fourier transform algorithm (IFTA). Commercially available single crystal diamond plates (3 m m ×3 m m ×0.3 m m ) were patterned using hardmask deposition ( α -Si), e-beam lithography, and O 2 plasma-based diamond reactive ion etching. The resulting binary phase relief patterns were characterized using scanning electron microscopy (SEM) and atomic force microscopy (AFM). Experimental characterization of the single crystal diamond DOEs in transmission at λ =532 n m confirms excellent uniformity of the resulting top-hat beam profile as required in copper welding applications.

Background and Purpose: Pre-surgical functional MRI (fMRI) is an important modality of examinations before brain surgery. There are several artefacts (e.g. motion, susceptibility) which may hinder the evaluation of fMRI data. Physiological artefacts (breathing, pulsation) also affect the sensitivity and specificity of anatomical localization. The aim of this study is to demonstrate the efficiency of physiological artefact identification and removal methods for presurgical evaluation., Methods: Siemens Magnetom Verio 3T MRI scanner was used to collect data. The physiological parameters (breathing, pulse) were recorded with the MRI system's built-in devices. Data from fourteen patients - with primary brain tumour - were evaluated with SPM12 utilizing the RETROICOR/RVHR tool to detect and decrease the effect of physiological artefacts. We compared the statistical maps obtained with and without the physiological correction using the Jaccard similarity coefficient, and ROI analyses., Results: Significant differences were found in the mean ROI values (p<0.0016) and the extensions of eloquent activations (p<0.0013), when using the physiological correction (RETORICOR/RVHR) based on convolution method. On the other hand, no significant differences were found between the ROIs' standard deviations (F=0.28). The RETROICOR/ RVHR method helps to define the precise localisation of eloquent areas (p<0.009). The number of irrelevant (non-significant) voxels were increased (p<0.001). ., Conclusion: Minimising of physiological artefacts in fMRI data calculations, the (RETROICOR/RVHR) method based on convolution has been successfully adapted. This algorithm could be helpful before neurosurgical intervention. The activity pattern became more reliable.

Congenital muscular dystrophy (CMD), a subgroup of myopathies is a genetically and clinically heterogeneous group of inherited muscle disorders and is characterized by progressive muscle weakness, fiber size variability, fibrosis, clustered necrotic fibers, and central myonuclei present in regenerating muscle. Type IV collagen ( COL4A1 ) mutations have recently been identified in patients with intracerebral, vascular, renal, ophthalmologic pathologies and congenital muscular dystrophy, consistent with diagnoses of Walker-Warburg Syndrome or Muscle-Eye-Brain disease. Morphological characteristics of muscular dystrophy have also been demonstrated Col4a1 mutant mice. Yet, several aspects of the pathomechanism of COL4A1-associated muscle defects remained largely uncharacterized. Based on the results of genetic, histological, molecular, and biochemical analyses in an allelic series of Drosophila col4a1 mutants, we provide evidence that col4a1 mutations arise by transitions in glycine triplets, associate with severely compromised muscle fibers within the single-layer striated muscle of the common oviduct, characterized by loss of sarcomere structure, disintegration and streaming of Z-discs, indicating an essential role for the COL4A1 protein. Features of altered cytoskeletal phenotype include actin bundles traversing over sarcomere units, amorphous actin aggregates, atrophy, and aberrant fiber size. The mutant COL4A1-associated defects appear to recapitulate integrin-mediated adhesion phenotypes observed in RNA-inhibitory Drosophila . Our results provide insight into the mechanistic details of COL4A1-associated muscle disorders and suggest a role for integrin-collagen interaction in the maintenance of sarcomeres.

We demonstrate a novel method for fabricating single crystal diamond diffraction gratings based on crystallographic etching that yields high-quality diffraction gratings from commercially available <100> diamond plates. Both V-groove and rectangular gratings were fabricated and characterised using scanning electron microscopy and atomic force microscopy, revealing angles of 57° and 87° depending on the crystal orientation, with mean roughness below R a = 5 nm on the sidewalls. The gratings were also optically characterised, showing good agreement with simulated results. The fabrication method demonstrated in this contribution shows the way for manufacturing high-quality diamond diffractive components that surpass existing devices both in quality and manufacturability.

In breast cancer patients, the diversity of the microbiome decreases, coinciding with decreased production of cytostatic bacterial metabolites like lithocholic acid (LCA). We hypothesized that LCA can modulate oxidative stress to exert cytostatic effects in breast cancer cells. Treatment of breast cancer cells with LCA decreased nuclear factor-2 (NRF2) expression and increased Kelch-like ECH associating protein 1 (KEAP1) expression via activation of Takeda G-protein coupled receptor (TGR5) and constitutive androstane receptor (CAR). Altered NRF2 and KEAP1 expression subsequently led to decreased expression of glutathione peroxidase 3 (GPX3), an antioxidant enzyme, and increased expression of inducible nitric oxide synthase (iNOS). The imbalance between the pro- and antioxidant enzymes increased cytostatic effects via increased levels of lipid and protein oxidation. These effects were reversed by the pharmacological induction of NRF2 with RA839, tBHQ, or by thiol antioxidants. The expression of key components of the LCA-elicited cytostatic pathway (iNOS and 4HNE) gradually decreased as the breast cancer stage advanced. The level of lipid peroxidation in tumors negatively correlated with the mitotic index. The overexpression of iNOS, nNOS, CAR, KEAP1, NOX4, and TGR5 or the downregulation of NRF2 correlated with better survival in breast cancer patients, except for triple negative cases. Taken together, LCA, a metabolite of the gut microbiome, elicits oxidative stress that slows down the proliferation of breast cancer cells. The LCA-oxidative stress protective pathway is lost as breast cancer progresses, and the loss correlates with poor prognosis.

Introduction: Alzheimer's disease (AD) is the leading cause of cognitive decline. Epilepsy is a frequent comorbid condition of AD. While previous studies analyzed the risk factors of AD-related epileptic seizures, we still lack biomarkers of epilepsy in mild AD cases. Purpose: The aim of our study was to analyze the correlations between neuropsychology, cortical thickness, and brain volumetric measurements in mild Alzheimer patients with concomitant epileptic seizures. Materials and methods: We selected mild AD patients from our database to examine them with structural magnetic resonance imaging, 24 h electroencephalography, and detailed neuropsychology. We made the diagnosis of epilepsy based on epileptology data including neurophysiology. We retrospectively analyzed the neuropsychology pattern, clinical and epidemiologic features, cortical thickness, and volumetric values of mild AD patients with and without overt clinical seizures using covariance weighted general linear model. Results: We found epileptic seizures in 26% of mild AD patients. Patients with seizures performed worse in visuo-spatial scores than patients without ( p = 0.003). Patients with seizures had smaller parietal thickness ( p = 0.018), being associated to reduced thickness of left ( p = 0.007), and right precunei ( p = 0.005). The visuo-spatial performance positively and strongly correlated with the thickness of the parietal lobe ( r = 0.67; p = 0.002) and with the volume of the precuneus ( r = 0.612; p = 0.005). Conclusion: Epileptic seizures are common even in mild AD. We found that a prominent deficit in visuo-spatial skills is a red flag for epileptic seizures in the initial phase of AD, indicating the early involvement of parietal lobe in the neurodegenerative process. Because our findings suggest that the degeneration of precuneus is a sensitive marker of seizures associated to mild AD, clinicians need to pay special attention to the pattern of atrophy shown by structural MRI. Our results confirm previous data suggesting that epileptic seizures might be associated to a faster progressing type of AD with the early degeneration of posterior cortical areas.

Participating or winning a medal in major track and field (athletics) competitions is the goal of every athlete. However, health problems can impair sports performance and affect this dream. Therefore, we present ten tips to help hurdle the challenges of illness/injury at major athletics championships: (1) Prepare for travel (medical checking, vaccine, time-zone, jet lag, culture, food habits…), (2) Respect athlete characteristics and discipline specificity (sex, endurance/explosive), (3) Educate athletes and their entourages regarding prevention, (4) Vigilance of painful symptoms and subclinical illness markers, (5) Avoid infection risk (washing hands, safe food and drink, avoid contact with sick people…), (6) Train appropriately and optimally (physical conditioning, technical training, load management, and psychological preparation), (7) Health status (history of previous injuries, well-being in the month before championships), (8) Lifestyle (good sleep, regular hydration and nutrition with safe water/food, regular fruits and vegetables, improve recovery strategies…), (9) Environmental considerations (heat, cold, air cleaning, changes or climatic conditions…), (10) Safety (equipment, rules, own-practice in athletics, and extra-sport activities). These ten tips "PREVATHLES" are based on our field experience in addition to existing epidemiological and experimental literature in athletics and other sports. Although there is currently no scientific evidence for their efficacy, sound judgement, and logical practice provide a strong basis, and given the low risk of using them in the benefit/risk balance, we suggest athletes and those around them follow these ten tips to limit the impact of injury/illness on championship performance., (Copyright © 2019 Edouard, Richardson, Murray, Duncan, Glover, Kiss, Depiesse and Branco.)

It is a clinical experience that acute lesions of the cerebellum induce pathological tremor, which tends to improve. However, quantitative characteristics, imaging correlates, and recovery of cerebellar tremor have not been systematically investigated. We studied the prevalence, quantitative parameters measured with biaxial accelerometry, and recovery of pathological tremor in 68 patients with lesions affecting the cerebellum. We also investigated the correlation between the occurrence and characteristics of tremor and lesion localization using 3D T1-weighted MRI images which were normalized and segmented according to a spatially unbiased atlas template for the cerebellum. Visual assessment detected pathological tremor in 19% while accelerometry in 47% of the patients. Tremor was present both in postural and intentional positions, but never at rest. Two types of pathological tremor were distinguished: (1) low-frequency tremor in 36.76% of patients (center frequency 2.66 ± 1.17 Hz) and (2) normal frequency-high-intensity tremor in 10.29% (center frequency 8.79 ± 1.43 Hz). The size of the lesion did not correlate with the presence or severity of tremor. Involvement of the anterior lobe and lobule VI was related to high tremor intensity. In all followed up patients with acute cerebellar ischemia, the tremor completely recovered within 8 weeks. Our results indicate that cerebellar lesions might induce pathological postural and intentional tremor of 2-3 Hz frequency. Due to its low frequency and low amplitude, quantitative tremorometry is neccessary to properly identify it. There is no tight correlation between lesion localization and quantitative characteristics of cerebellar tremor.

Formulation optimization and antidotal combination therapy are the two important tools to enhance the antidotal protection of the cyanide (CN) antidote dimethyl trisulfide (DMTS). The focus of this study is to demonstrate how the formulation with polysorbate 80 (Poly80), an excipient used in pharmaceutical technology, and the combinations with other CN antidotes having different mechanisms of action enhance the antidotal efficacy of the unformulated (neat) DMTS. The LD 50 for CN was determined by the statistical Dixon up-and-down method on mice. Antidotal efficacy was expressed as antidotal potency ratio (APR). CN was injected subcutaneously one minute prior to the antidotes' injection intramuscularly. The APR values of 1.17 (dose: 25 mg/kg bodyweight) and 1.45 (dose: 50 mg/kg bodyweight) of the neat DMTS were significantly enhanced by the Poly80 formulation at both investigated doses to 2.03 and 2.33, respectively. The combination partners for the Poly80 formulated DMTS (DMTS-Poly80; 25 and 50 mg/kg bodyweight) were 4-nitrocobinamide (4NCbi) (20 mg/kg bodyweight) and aquohydroxocobinamide (AHCbi; 50, 100, and 250 mg/kg bodyweight). When DMTS-Poly80 (25 and 50 mg/kg bodyweight; APR = 2.03 and 2.33, respectively) was combined with 4NCbi (20 mg/kg bodyweight; APR = 1.35), significant increase in the APR values were noted at both DMTS doses (APR = 2.38 and 3.12, respectively). AHCbi enhanced the APR of DMTS-Poly80 (100 mg/kg bodyweight; APR = 3.29) significantly only at the dose of 250 mg/kg bodyweight (APR = 5.86). These studies provided evidence for the importance of the formulation with Poly80 and the combinations with cobinamide derivatives with different mechanisms of action for DMTS as a CN antidote candidate.

The aim of this research was to develop a modified version of the Munene model summarizing the factors influencing willingness to pay for functional foods, adjusted to the Hungarian population. The questionnaire survey was conducted in 2014 in Hungary on a sample of 500 individuals, representative for gender, age, settlement type and region. Building blocks of the Munene model were examined and tested with a Latent Variable Path Analysis with the Partial Least Squares (LVPLS) model. According to the results, the strongest relationship in the modified model was identified between attitudes towards, and beliefs about, the attributes of functional foods, i.e. the more consumers believe in the health protecting effect of functional foods, the more positive their attitudes towards those foods, and the more they are willing to pay a premium for them. The highest explanatory power in the model was attributed to the attitudes towards functional foods, followed by beliefs about the attributes of functional foods, and then by consumer demographics. The modification of the original Munene model based on a Hungarian sample contributes to an examination of its usability and provides an example of how it can fit to another culture. Moreover, a comprehensive model including factors influencing WTP has not yet been developed among Hungarian consumers., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

We present a design for an analog phase shifter based on Silicon Photonic MEMS technology. The operation principle is based on a two-step parallel plate electrostatic actuation mechanism to bring a vertically movable suspended tapered waveguide in a first step into proximity of the bus waveguide and to tune the phase of the propagating coupled mode in a second step by actuation of the suspended waveguide to tune the vertical gap. In the coupled state, the effective index of the optical supermode and the total accumulated phase delay can be varied by changing the vertical separation between the adiabatically tapered suspended and the fixed bus waveguides. Simulations predict that π phase shift can be achieved with an actuation voltage of 19 V, corresponding to a displacement of 19 nm. With an adiabatic coupler geometry, the optical signal can be coupled between the moving waveguide and the bus waveguide with low loss in a wide wavelength range from 1.5 μm to 1.6 μm keeping the average insertion loss below 0.3 dB.

Excess salt intake could affect the immune system by shifting the immune cell balance toward a pro-inflammatory state. Since this shift of the immune balance is thought to be beneficial in anti-cancer immunity, we tested the impact of high salt diets on tumor growth in mice. Here we show that high salt significantly inhibited tumor growth in two independent murine tumor transplantation models. Although high salt fed tumor-bearing mice showed alterations in T cell populations, the effect seemed to be largely independent of adaptive immune cells. In contrast, depletion of myeloid-derived suppressor cells (MDSCs) significantly reverted the inhibitory effect on tumor growth. In line with this, high salt conditions almost completely blocked murine MDSC function in vitro . Importantly, similar effects were observed in human MDSCs isolated from cancer patients. Thus, high salt conditions seem to inhibit tumor growth by enabling more pronounced anti-tumor immunity through the functional modulation of MDSCs. Our findings might have critical relevance for cancer immunotherapy.

The concept of tissue-specific gene expression posits that lineage-determining transcription factors (LDTFs) determine the open chromatin profile of a cell via collaborative binding, providing molecular beacons to signal-dependent transcription factors (SDTFs). However, the guiding principles of LDTF binding, chromatin accessibility and enhancer activity have not yet been systematically evaluated. We sought to study these features of the macrophage genome by the combination of experimental (ChIP-seq, ATAC-seq and GRO-seq) and computational approaches. We show that Random Forest and Support Vector Regression machine learning methods can accurately predict chromatin accessibility using the binding patterns of the LDTF PU.1 and four other key TFs of macrophages (IRF8, JUNB, CEBPA and RUNX1). Any of these TFs alone were not sufficient to predict open chromatin, indicating that TF binding is widespread at closed or weakly opened chromatin regions. Analysis of the PU.1 cistrome revealed that two-thirds of PU.1 binding occurs at low accessible chromatin. We termed these sites labelled regulatory elements (LREs), which may represent a dormant state of a future enhancer and contribute to macrophage cellular plasticity. Collectively, our work demonstrates the existence of LREs occupied by various key TFs, regulating specific gene expression programs triggered by divergent macrophage polarizing stimuli., (© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Therapeutic approaches that engage immune cells to treat cancer are becoming increasingly utilized in the clinics and demonstrated durable clinical benefit in several solid tumor types. Most of the current immunotherapies focus on manipulating T cells, however, the tumor microenvironment (TME) is abundantly infiltrated by a heterogeneous population of tumor-associated myeloid cells, including tumor-associated macrophages (TAMs), tumor-associated dendritic cells (TADCs), tumor-associated neutrophils (TANs), and myeloid-derived suppressor cells (MDSCs). Educated by signals perceived in the TME, these cells often acquire tumor-promoting properties ultimately favoring disease progression. Upon appropriate stimuli, myeloid cells can exhibit cytoxic, phagocytic, and antigen-presenting activities thereby bolstering antitumor immune responses. Thus, depletion, reprogramming or reactivation of myeloid cells to either directly eradicate malignant cells or promote antitumor T-cell responses is an emerging field of interest. In this review, we briefly discuss the tumor-promoting and tumor-suppressive roles of myeloid cells in the TME, and describe potential therapeutic strategies in preclinical and clinical development that aim to target them to further expand the range of current treatment options.

Dimethyl trisulfide (DMTS) is a natural organic trisulfide that has been patented as a promising antidotal candidate against cyanide (CN). The primary mode of action of DMTS is as a sulfur donor that enables the conversion of CN to thiocyanate. Recently, it was discovered that DMTS is capable of oxidizing hemoglobin (Hb) to methemoglobin (MetHb) in vitro. The goal of these experiments was to measure the extent of DMTS-induced MetHb formation in vivo. In these experiments, intramuscular (IM) injections of formulated DMTS were administered to mice. Following the IM injection, blood was drawn and analyzed for MetHb using a rapid spectrophotometric method. Methemoglobin levels peaked in a dose-dependent manner between 20 and 30 min., and then began dropping. The highest MetHb levels measured for the 50, 100, 200 and 250 mg/kg doses of DMTS were respectively 3.28, 6.12, 9.69, and 10.76% MetHb. These experiments provide the first experimental evidence that IM administered DMTS generates MetHb in vivo and provide additional evidence for the presence of a secondary therapeutic pathway for DMTS - CN scavenging by DMTS-generated MetHb.

Tumors of various histological origins show abundant infiltration of myeloid cells from early stages of disease progression. These cells have a profound impact on antitumor immunity and influence fundamental processes that underlie malignancy, including neoangiogenesis, sustained cancer cell proliferation, metastasis and therapy resistance. For these reasons, development of therapeutic approaches to deplete or reprogram myeloid cells in cancer is an emerging field of interest. However, knowledge about the heterogeneity of myeloid cells in tumors and their variability between patients and disease stages is still limited. In this review, we summarize the most recent advances in our understanding about how the phenotype of tumor-associated macrophages, monocytes, neutrophils, myeloid-derived suppressor cells and dendritic cells is dictated by their ontogeny, activation status and localization. We also outline major open questions that will only be resolved by applying high-dimensional single-cell technologies and systems biology approaches in the analysis of the tumor microenvironment., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Individuals involved in the criminal justice system have disproportionately high rates of psychiatric disorders when compared to the general U.S., Population: If left untreated, the likelihood of subsequent arrest increases and risk for adverse health consequences is great, particularly among opioid users., Objectives: To explore the prevalence, characteristics, and treatment of mood disorders among justice involved opioid-dependent populations., Methods: The current study enrolled 258 treatment-seeking opioid-dependent individuals under community-based criminal justice supervision (e.g., probation, parole) screened from the larger parent study, Project STRIDE, a seek/test/treat randomized control trial (RCT) examining HIV and opioid use treatment. During baseline, individuals were screened for depression using the Patient Health Questionnaire-9 (PHQ-9) and screened for bipolar disorder using the Mood Disorder Questionnaire (MDQ) tool., Results: Overall, 78 (30%) participants screened positive for moderate to severe depression and 54 (21%) screened positive for bipolar disorder. Participants self-reported mood disorders at higher rates than they screened positive for these conditions. Participants screening positive for these conditions experienced significantly greater family, legal, and medical problems on the Addiction Severity Index-Lite (ASI-Lite) than those who did not screen positive. Incidence of a lifetime suicide attempt was found to be associated with a positive screen for both mood disorders. Prescribed psychotropic treatment utilization was similar among those who screened positive for depression or bipolar disorder with approximately 38% reporting taking medication., Importance: Findings suggest universal mood disorder screening to improve comprehensive psychiatric care and treatment of opioid-dependent justice-involved individuals.

The outstanding material properties of single crystal diamond have been at the origin of the long-standing interest in its exploitation for engineering of high-performance micro- and nanosystems. In particular, the extreme mechanical hardness, the highest elastic modulus of any bulk material, low density, and the promise for low friction have spurred interest most notably for micro-mechanical and MEMS applications. While reactive ion etching of diamond has been reported previously, precision structuring of freestanding micro-mechanical components in single crystal diamond by deep reactive ion etching has hitherto remained elusive, related to limitations in the etch processes, such as the need of thick hard masks, micromasking effects, and limited etch rates. In this work, we report on an optimized reactive ion etching process of single crystal diamond overcoming several of these shortcomings at the same time, and present a robust and reliable method to produce fully released micro-mechanical components in single crystal diamond. Using an optimized Al/SiO 2 hard mask and a high-intensity oxygen plasma etch process, we obtain etch rates exceeding 30 µm/h and hard mask selectivity better than 1:50. We demonstrate fully freestanding micro-mechanical components for mechanical watches made of pure single crystal diamond. The components with a thickness of 150 µm are defined by lithography and deep reactive ion etching, and exhibit sidewall angles of 82°-93° with surface roughness better than 200 nm rms, demonstrating the potential of this powerful technique for precision microstructuring of single crystal diamond., Competing Interests: P.G. is CEO and co-founder of LakeDiamond SA, a commercial supplier of the single crystal diamond samples used for this work. The remaining authors declare that they have no conflict of interest.

Purpose: To maintain alertness and to remain motionless during scanning represent a substantial challenge for patients/subjects involved in both clinical and research functional magnetic resonance imaging (fMRI) examinations. Therefore, availability and application of new data acquisition protocols allowing the shortening of scan time without compromising the data quality and statistical power are of major importance., Methods: Higher order category-selective visual cortical areas were identified individually, and rapid event-related fMRI design was used to compare three different sampling rates (TR = 2000, 1000, and 410 ms, using state-of-the-art simultaneous multislice imaging) and four different scanning lengths to match the statistical power of the traditional scanning methods to high sampling-rate design., Results: The results revealed that ~ 4 min of the scan time with 1 Hz (TR = 1000 ms) sampling rate and ~ 2 min scanning at ~ 2.5 Hz (TR = 410 ms) sampling rate provide similar localization sensitivity and selectivity to that obtained with 11-min session at conventional, 0.5 Hz (TR = 2000 ms) sampling rate., Conclusion: Our findings suggest that task-based fMRI examination of clinical population prone to distress such as presurgical mapping experiments might substantially benefit from the reduced (20-40%) scanning time that can be achieved by the application of simultaneous multislice sequences.

Background: Dimethyl trisulfide (DMTS) is a highly lipid-soluble cyanide (CN) antidote candidate molecule. In prior studies with various US FDA-approved co-solvents, surfactants, and their combinations, aqueous solutions containing 15% polysorbate 80 (Poly80) were found to effectively solubilize DMTS in formulations for intramuscular administration. However, DMTS formulated in 15% aqueous Poly80 solutions showed gradual losses over time when stored in vials with septum-based seals., Objective: The present study tested whether storing DMTS formulations in hermetically sealed glass ampules could mitigate storage losses., Methods: Samples consisted of 1-mL aliquots of a 50 mg/ml stock solution of DMTS in 15% aqueous Poly80. The control samples were stored using a vial-within-a-vial system-the inner and outer vials were sealed respectively, with a snap cap, and with a crimped septum. The hermetically sealed test samples were stored in fire-sealed glass ampules. The DMTS content was measured by HPLC-UV analysis at specific time points over a 100-day period., Results: While the control samples exhibited systematic DMTS losses, no DMTS losses were observed from the test samples stored in hermetically sealed glass ampules over the 100-day testing period., Conclusion: DMTS formulated in 15% aqueous Poly80 solution has excellent stability when stored in fire-sealed glass ampules and thus has the potential to be effectively stored as an intramuscular CN countermeasure for mass casualty scenarios.

Residential mobility and type of housing contributes to an individual's likelihood and frequency of drug/alcohol use and committing criminal offenses. Little research has focused simultaneously on the influence of housing status on the use of drugs and criminal behavior. The present study examines how residential mobility (transitions in housing) and recent housing stability (prior 30 days) correlates with self-reported criminal activity and drug/alcohol use among a sample of 504 addicted, treatment-seeking opioid users with a history of criminal justice involvement. Findings suggest that those with a greater number of housing transitions were considerably less likely to self-report criminal activity, and criminal involvement was highest among those who were chronically homeless. Residential mobility was unassociated with days of drug and alcohol use; however, residing in regulated housing (halfway houses and homeless shelters) was associated with a decreased frequency of substance use. The finding that residing at sober-living housing facilities with regulations governing behavior (regulated housing) was associated with a lower likelihood of illicit substance use may suggest that regulated housing settings may influence behavior. Further research in this area should explore how social networks and other related variables moderate the effects of housing type and mobility on crime and substance use.

Tumor-associated macrophages (TAM) are by now established as important regulators of tumor progression by impacting on tumor immunity, angiogenesis, and metastasis. Hence, a multitude of approaches are currently pursued to intervene with TAM's protumor activities, the most advanced of which being a blockade of macrophage-colony stimulating factor (M-CSF)/M-CSF receptor (M-CSFR) signaling. M-CSFR signaling largely impacts on the differentiation of macrophages, including TAM, and hence strongly influences the numbers of these cells in tumors. However, a repolarization of TAM toward a more antitumor phenotype may be more elegant and may yield stronger effects on tumor growth. In this respect, several aspects of TAM behavior could be altered, such as their intratumoral localization, metabolism and regulatory pathways. Intervention strategies could include the use of small molecules but also new generations of biologicals which may complement the current success of immune checkpoint blockers. This review highlights current work on the search for new therapeutic targets in TAM., (© 2017 Federation of European Biochemical Societies.)

The molecular basis of signal-dependent transcriptional activation has been extensively studied in macrophage polarization, but our understanding remains limited regarding the molecular determinants of repression. Here we show that IL-4-activated STAT6 transcription factor is required for the direct transcriptional repression of a large number of genes during in vitro and in vivo alternative macrophage polarization. Repression results in decreased lineage-determining transcription factor, p300, and RNA polymerase II binding followed by reduced enhancer RNA expression, H3K27 acetylation, and chromatin accessibility. The repressor function of STAT6 is HDAC3 dependent on a subset of IL-4-repressed genes. In addition, STAT6-repressed enhancers show extensive overlap with the NF-κB p65 cistrome and exhibit decreased responsiveness to lipopolysaccharide after IL-4 stimulus on a subset of genes. As a consequence, macrophages exhibit diminished inflammasome activation, decreased IL-1β production, and pyroptosis. Thus, the IL-4-STAT6 signaling pathway establishes an alternative polarization-specific epigenenomic signature resulting in dampened macrophage responsiveness to inflammatory stimuli., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

MicroRNAs are important components of the post-transcriptional fine-tuning of macrophage gene expression in physiological and pathological conditions. However, the mechanistic underpinnings and the cis-acting genomic factors of how macrophage polarizing signals induce miRNA expression changes are not well characterized. Therefore, we systematically evaluated the transcriptional basis underlying the inflammation-mediated regulation of macrophage microRNome using the combination of different next generation sequencing datasets. We investigated the LPS-induced expression changes at mature miRNA and pri-miRNA levels in mouse macrophages utilizing a small RNA-seq method and publicly available GRO-seq dataset, respectively. Next, we identified an enhancer set associated with LPS-responsive pri-miRNAs based on publicly available H3K4 mono-methylation-specific ChIP-seq and GRO-seq datasets. This enhancer set was further characterized by the combination of publicly available ChIP and ATAC-seq datasets. Finally, direct interactions between the miR-155-coding genomic region and its distal regulatory elements were identified using a 3C-seq approach. Our analysis revealed 15 robustly LPS-regulated miRNAs at the transcriptional level. In addition, we found that these miRNA genes are associated with an inflammation-responsive enhancer network. Based on NFκB-p65 and JunB transcription factor binding, we showed two distinct enhancer subsets associated with LPS-activated miRNAs that possess distinct epigenetic characteristics and LPS-responsiveness. Finally, our 3C-seq analysis revealed the LPS-induced extensive reorganization of the pri-miR-155-associated functional chromatin domain as well as chromatin loop formation between LPS-responsive enhancers and the promoter region. Our genomic approach successfully combines various genome-wide datasets and allows the identification of the putative regulatory elements controlling miRNA expression in classically activated macrophages., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Aims: We hypothesized that the greater the intra- or interventricular dyssynchrony (intraD, interD), the more effective cardiac resynchronization therapy (CRT) is. We sought to improve patient selection for CRT by using novel ECG dyssynchrony criteria., Methods and Results: Left ventricular (LV) intraD was estimated by the absolute time difference between the intrinsicoid deflections (ID) in leads aVL and aVF divided by the QRS duration (QRSd): [aVLID - aVFID]/QRSd (%). InterD was estimated from the formula: [V5ID - V1ID]/QRSd (%). Their >25% value indicated electrical dyssynchrony present (ED+) and ≤25% value electrical dyssynchrony absent (ED-) diagnoses. Using the intraD + interD criteria (intra + interDC) together, if at least one of them indicated ED+ diagnosis, a final ED+ diagnosis, if both indicated ED- diagnosis, a final ED- diagnosis was made. Two authors, blinded to CRT response, retrospectively analysed pre-CRT ECGs of 124 patients with known CRT outcome. CRT response was defined as improvement of ≥ 1 NYHA class, being alive and having no hospitalizations for heart failure during 6 months of follow-up. 35/124 (28%) patients were non-responders (NRs), using the traditional criteria (TC) correct diagnosis was made in the remaining 89/124 (72%) responder (R) cases. The test accuracy (TA) of intra + interDC + TC [100/124 (81%), P < 0.001] was superior to that of TC [89/124 (72%)] due to its superior TA [36/43 (84%) vs. 29/43 (67%), respectively, P = 0.0156] in the non-specific intra-ventricular conduction disturbance (NICD) subgroup [43/124 (35%)]. In the left bundle branch block subgroup [70/124 (56%)] there was no between-criteria difference in TA., Conclusion: The intra + interDC + TC predicts clinical response after CRT more accurately than TC alone, due to greater TA in the NICD subgroup., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For Permissions, please email: journals.permissions@oup.com.)

The results of electrochemical and SOD activity measurements of such copper(II) complexes of terminally protected multihistidine peptides that may mimic the active site of CuZnSOD enzyme are submitted and completed with solution equilibrium studies of some copper(II)-ligand systems. The equilibrium data confirm that the thermodynamic stabilities increase with the increasing number of histidyl residues in the amino acid sequence, the stability order, however, can be finely tuned by the number and quality of amino acids between histidine residues. Based on the cyclic voltammetric studies we concluded that the formal reduction potential values of imidazole nitrogen coordinated complexes decrease with the increasing number of imidazole donor atoms in the coordination sphere. However, the redox parameters of [CuH -1 L] + and [CuH -2 L] complexes containing amide nitrogen coordination can be determined as well. All formal potential values of [CuL] 2+ , [CuH -1 L] + and [CuH -2 L] complexes fall in the middle potential range of SOD activity. Finally, after the detailed analysis of species distribution curves based upon the equilibrium data SOD activity of copper(II) containing systems at two pH (pH=6.8 and 7.4) were determined. The imidazole coordinated [CuL] 2+ complexes of the multihistidine peptide containing the HXH sequence exhibit the most significant activity, but the presence of amide nitrogen coordinated species with slightly distorted geometry could considerably contribute to the SOD activity., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Retinoid X receptor (RXR) regulates several key functions in myeloid cells, including inflammatory responses, phagocytosis, chemokine secretion, and proangiogenic activity. Its importance, however, in tumor-associated myeloid cells is unknown. In this study, we demonstrate that deletion of RXR in myeloid cells enhances lung metastasis formation while not affecting primary tumor growth. We show that RXR deficiency leads to transcriptomic changes in the lung myeloid compartment characterized by increased expression of prometastatic genes, including important determinants of premetastatic niche formation. Accordingly, RXR-deficient myeloid cells are more efficient in promoting cancer cell migration and invasion. Our results suggest that the repressive activity of RXR on prometastatic genes is mediated primarily through direct DNA binding of the receptor along with nuclear receptor corepressor (NCoR) and silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) corepressors and is largely unresponsive to ligand activation. In addition, we found that expression and transcriptional activity of RXRα is down-modulated in peripheral blood mononuclear cells of patients with lung cancer, particularly in advanced and metastatic disease. Overall, our results identify RXR as a regulator in the myeloid cell-assisted metastatic process and establish lipid-sensing nuclear receptors in the microenvironmental regulation of tumor progression., Competing Interests: The authors declare no conflict of interest.

Anomalous origin of a left circumflex artery from the right coronary sinus represents a technical challenge in patients who require aortic valve/root procedures. This case report describes a patient who presented with bicuspid aortic valve, anomalous origin of the circumflex artery, severe aortic regurgitation, and aneurysm of the ascending aorta as well as aortic root that was safely managed following the Bentall procedure with the combined button technique.

Mice lacking secreted IgM (sIgM -/- ) antibodies display abnormal splenic B cell development, which results in increased marginal zone and decreased follicular B cell numbers. However, the mechanism by which sIgM exhibit this effect is unknown. Here, we demonstrate that B cells in sIgM -/- mice display increased B cell receptor (BCR) signaling as judged by increased levels of phosphorylated Bruton's tyrosine kinase (pBtk), phosphorylated Spleen tyrosine kinase (pSyk), and nuclear receptor Nur77. Low dosage treatment with the pBtk inhibitor Ibrutinib reversed the altered B cell development in the spleen of sIgM -/- mice, suggesting that sIgM regulate splenic B cell differentiation by decreasing BCR signaling. Mechanistically, we show that B cells, which express BCRs specific to hen egg lysozyme (HEL) display diminished responsiveness to HEL stimulation in presence of soluble anti-HEL IgM antibodies. Our data identify sIgM as negative regulators of BCR signaling and suggest that they can act as decoy receptors for self-antigens that are recognized by membrane bound BCRs.

Background: Auditory verbal hallucinations (AVHs) played an important role in the psychiatric diagnostics, but in the last few decades the diagnostic-free complex phenomenological understanding of the phenomena of voice hearing became the focus of studies., Materials: Six semi-structured interviews with recovering voice hearers were conducted and analysed using interpretative phenomenological analysis (IPA)., Discussion: The self-help group gives significant help in identification and dealing with the voices; therefore, it serves as turning point in the life story of voice hearers., Conclusion: Applying self-help group in clinical context contributes to better outcomes in treatment of voice hearers.

Introduction: CO 2 laser- assisted sclerectomy surgery (CLASS) can be used for the surgical treatment of open-angle glaucoma., Aim: To introduce our results with CLASS., Method: We performed 21 CLASS operations using OT-134-IOPtiMate (IOPtima Ltd, Ramat-Gan, Israel). Patients were examined on the 1st day, and in the 1st, 3rd, 6th, 9th and 12th months postoperatively. We evaluated intraocular pressure (IOP), antiglaucomatous medication-use, visual acuity, complications., Results: Mean age was 65.6 yrs. Complete success (no hypotensive medication required to target IOP) was achieved in 61.1% (18 patients) at 6 months, whereas in 50% (10 patients) at 12 months. Qualified success (hypotensive medication required to target IOP) was achieved in 72.2% and in 70%, preoperative mean IOP was 29.2 ± 9.4 Hgmm, which falled to 17.7 ± 4.9 Hgmm and 17.3 ± 4.3 Hgmm, respectively. Antiglaucomatous medication use falled significantly from 2.90 ± 0.83 to 2.05 ± 1.46. Apart from 1 macroperforation, no serious complication occurred., Conclusions: With CLASS it is possible to effectively lower intraocular pressure in open-angle glaucoma. Orv Hetil. 2017; 158(18): 701-705.

In psoriatic skin, laminin integrity is altered, which could lead to insufficient laminin integrin interactions, leaving the α6-integrin exposed and possibly accessible for autoantibody production. Therefore we investigated the presence of anti-α6-integrin autoantibodies in the serum of patients with psoriasis vulgaris (Ps), psoriatic arthritis (PsA) and rheumatoid arthritis (RA) in comparison with healthy donors. The level of circulating anti-α6-integrin antibodies was determined by enzyme-linked immunoassay using α6-integrin fragments. Antibodies against at least one recombinant fragment were found in approximately 30% of Ps and PsA patients. In contrast, in RA patients, the frequency of antibodies was similar to healthy controls. Our study shows the presence of anti-α6-integrin antibodies in Ps and PsA but not in RA, which could indicate ongoing abnormal processes in the skin. Anti-α6-integrin autoantibodies may contribute to the formation of micro-wounds in the skin and to the characteristic wound-healing phenotype in psoriasis., (© 2016 Japanese Dermatological Association.)

Background & Aims: In advanced cirrhosis new hepatocytic nodules are generated by budding of ductules in areas of parenchymal extinction. However, the vascular alterations in the areas of parenchymal extinction, the blood supply and the structure of the new hepatocytic nodules have not been analyzed in detail., Methods: Explanted human cirrhotic livers of three different etiologies and two experimental rat models of cirrhosis were thoroughly examined. 3D reconstruction of the immunohistochemically stained serial sections and casting of human and experimental cirrhotic livers have been used to reveal the structural organization of the regenerative buds., Results: In areas of parenchymal extinction the skeleton of the liver, the portal tree is preserved. The developing regenerative nodules are positioned along the portal tree and are directly supplied by terminal portal venules. The expanding nodules grow along the trunks of the portal vein. Casting of human and experimental cirrhotic livers by colored resin confirms that nodules are supplied by portal blood. The two other members of the portal triads become separated from the portal veins., Conclusions: As the structure of the hepatocyte nodules (centrally located portal vein branches, bile ducts at the periphery, hepatic veins and arteries in the connective tissue) impedes the restoration of normal liver structure, the basic architecture of hepatic tissue suffers permanent damage. We suggest that "budding" may initiate the second, irreversible stage of cirrhosis., Lay Summary: Cirrhosis is the final common outcome of long lasting hepatic injury defined as the destruction of the normal liver architecture by scar tissue. In the late phase of cirrhosis stem cells-derived hepatocyte nodules appear along the branches of the portal vein suggesting an important role of this specially composed blood vessels (containing digestive end-products from the stomach and intestines) in liver regeneration. Our results contribute to a better understanding of this serious liver disease., (Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Ocular anterior segment dysgenesis (ASD) describes a spectrum of clinically and genetically heterogeneous congenital disorders affecting anterior structures that often lead to impaired vision. More importantly, 50-75% of patients with ASD develop early onset and aggressive glaucoma. Although several genes have been implicated in the etiology of ASD, the underlying mechanisms remain elusive. Type IV collagen alpha 1 (COL4A1) is an extracellular matrix protein and a critical component of nearly all basement membranes. COL4A1 mutations cause multi-system disorders in patients, including ASD (congenital cataracts, Axenfeld-Rieger's anomaly, Peter's anomaly and microphthalmia) and congenital or juvenile glaucoma. Here, we use a conditional Col4a1 mutation in mice to determine the location and timing of pathogenic events underlying COL4A1-related ocular dysgenesis. Our results suggest that selective expression of the Col4a1 mutation in neural crest cells and their derivatives is not sufficient to cause ocular dysgenesis and that selective expression of the Col4a1 mutation in vascular endothelial cells can lead to mild ASD and optic nerve hypoplasia but only on a sensitized background. In contrast, lens-specific expression of the conditional Col4a1 mutant allele led to cataracts, mild ASD and optic nerve hypoplasia, and age-related intraocular pressure dysregulation and optic nerve damage. Finally, ubiquitous expression of the conditional Col4a1 mutation at distinct developmental stages suggests that pathogenesis takes place before E12.5. Our results show that the lens and possibly vasculature play important roles in Col4a1 -related ASD and that the pathogenic events occur at mid-embryogenesis in mice, during early stages of ocular development., (© 2017. Published by The Company of Biologists Ltd.)

Previous published results have revealed that Rhinolight ® intranasal phototherapy is safe and effective in intermittent allergic rhinitis. The present objective was to assess whether phototherapy is also safe and effective in persistent allergic rhinitis. Thirty-four patients with persistent allergic rhinitis were randomized into two groups; twenty-five subjects completed the study. The Rhinolight ® group was treated with a combination of UV-B, UV-A, and high-intensity visible light, while the placebo group received low-intensity visible white light intranasal phototherapy on a total of 13 occasions in 6 weeks. The assessment was based on the diary of symptoms, nasal inspiratory peak flow, quantitative smell threshold, mucociliary transport function, and ICAM-1 expression of the epithelial cells. All nasal symptom scores and nasal inspiratory peak flow measurements improved significantly in the Rhinolight ® group relative to the placebo group and this finding persisted after 4 weeks of follow-up. The smell and mucociliary functions did not change significantly in either group. The number of ICAM-1 positive cells decreased non-significantly in the Rhinolight ® group. No severe side-effects were reported during the treatment period. These results suggest that Rhinolight ® treatment is safe and effective in persistent allergic rhinitis.

Various steady state and inflamed tissues have been shown to contain a heterogeneous DC population consisting of developmentally distinct subsets, including cDC1s, cDC2s and monocyte-derived DCs, displaying differential functional specializations. The identification of functionally distinct tumour-associated DC (TADC) subpopulations could prove essential for the understanding of basic TADC biology and for envisaging targeted immunotherapies. We demonstrate that multiple mouse tumours as well as human tumours harbour ontogenically discrete TADC subsets. Monocyte-derived TADCs are prominent in tumour antigen uptake, but lack strong T-cell stimulatory capacity due to NO-mediated immunosuppression. Pre-cDC-derived TADCs have lymph node migratory potential, whereby cDC1s efficiently activate CD8 + T cells and cDC2s induce Th17 cells. Mice vaccinated with cDC2s displayed a reduced tumour growth accompanied by a reprogramming of pro-tumoural TAMs and a reduction of MDSCs, while cDC1 vaccination strongly induces anti-tumour CTLs. Our data might prove important for therapeutic interventions targeted at specific TADC subsets or their precursors.

Introduction: The prevalence of morbid obesity and its co-morbidities - first of all diabetes type 2 - increased dramatically in the last decades. As the conservative ways of treatment (diet, training, etc.) in most cases does not lead to effective and long term weight loss, there is an increasing need for the metabolic surgical interventions., Method: During the last 6 and half years 514 laparoscopic RouxY gastric bypass (LRYGB) and 54 laparoscopic gastric sleeve resection (LGSR) were performed in our department. The data of random selected 40 patients after primary LRYGB and 15 patients after sleeve resection were collected. The applied criteria of the indication for surgery, the routine examinations and treatments before and after the intervention, the results and the type and the rate of the complications will be presented., Results: According to our experience both procedures are long term effective for weight loss and for the resolution of co-morbidities, and can be performed with low risk of complications. After LRYGB more effective weight loss (extra weight loss 88% vs. 68%) and higher rate of resolution of diabetes type 2, hypertension and gastro-esophageal reflux were found compared to sleeve resection., Conclusion: Based on our results we prefer LRYGB. Gastric sleeve resection is indicated by us, when there is no way - or only with high risk - to perform gastric bypass, taking into consideration of course the individual requirements of the patients.

Tris(pyrazolyl)hydroborate ligands have been utilized in the fields of inorganic and coordination chemistry due to the ease of introduction of steric and electronic substitutions at the pyrazole rings. The development and use of the tris(pyrazolyl)hydroborate ligand, called a `scorpionate', were pioneered by the late Professor Swiatoslaw Trofimenko. He developed a second generation for his ligand system by the introduction of 3-tert-butyl and 3-phenyl substituents and this new ligand system accounted for many remarkable developments in inorganic and coordination chemistry in stabilizing monomeric species while maintaining an open coordination site. Bismuth is remarkably harmless among the toxic heavy metal p-block elements and is now becoming popular as a replacement for highly toxic metal elements, such as lead. Two bismuth(III) complexes of the anionic sulfur-containing tripod tris(3-tert-butyl-2-sulfanylidene-1H-imidazol-1-yl)hydroborate ligand were prepared. By recrystallization from MeOH/CH 2 Cl 2 , orange crystals of dichlorido(methanol-κO)[tris(3-tert-butyl-2-sulfanylidene-1H-imidazol-1-yl-κS)hydroborato]bismuth(III), [Bi(C 21 H 34 BN 6 S 3 )Cl 2 (CH 4 O)], (I), were obtained, manifesting a mononuclear structure. By using a noncoordinating solvent, red crystals of the binuclear structure with bridging Cl atoms were obtained, namely di-μ-chlorido-bis{chlorido[tris(3-tert-butyl-2-sulfanylidene-1H-imidazol-1-yl-κS)hydroborato]bismuth(III)}, [Bi 2 (C 21 H 34 BN 6 S 3 ) 2 Cl 4 ], (II). These complexes show {Bi III S 3 Cl 2 O} and {Bi III S 3 Cl 3 } coordination geometries with average Bi III -S bond lengths of 2.73 and 2.78 Å in (I) and (II), respectively. The overall Bi III coordination geometry is distorted octahedral due to stereochemically active lone pairs. The three Bi III -S bond lengths are almost equal in (I) but show considerable differences in (II), with one long and two shorter distances that also correlate with changes in the UV-Vis and 1 H NMR spectra. For direct measurements of the Bi-S/Cl coordination, ligand K-edge X-ray absorption measurements were carried out in combination with ground and excited-state electronic structure analyses. For p-block elements, these sulfur-containing ligands are useful for preparing the appropriate complexes due to their flexible coordination geometry.

The linear nickel-nitrosyl complex [Ni(NO)(L3)] supported by a highly hindered tridentate nitrogen-based ligand, hydrotris(3-tertiary butyl-5-isopropyl-1-pyrazolyl)borate (denoted as L3), was prepared by the reaction of the potassium salt of the ligand with the nickel-nitrosyl precursor [Ni(NO)(Br)(PPh 3 ) 2 ]. The obtained nitrosyl complexes as well as the corresponding chlorido complexes [Ni(NO)(Cl)(PPh 3 ) 2 ] and [Ni(Cl)(L3)] were characterized by X-ray crystallography and different spectroscopic methods including IR/far-IR, UV-Vis, NMR, and multi-edge X-ray absorption spectroscopy at the Ni K-, Ni L-, Cl K-, and P K-edges. For comparative electronic structure analysis we also performed DFT calculations to further elucidate the electronic structure of [Ni(NO)(L3)]. These results provide the nickel oxidation state and the character of the Ni-NO bond. The complex [Ni(NO)(L3)] is best described as [Ni (II) (NO (-) )(L3)], and the spectroscopic results indicate that the phosphane complexes have a similar [Ni (II) (NO (-) )(X)(PPh 3 ) 2 ] ground state.

Antidrug antibodies have been shown to be associated with a loss of response during biologic therapy. Despite the potential association, there has been no report on the simultaneous monitoring of the following parameters in psoriasis: presence of neutralizing antibodies, plasma tumor necrosis factor (TNF)-α concentration, TNFi concentration and disease activity. Plasma concentrations of adalimumab, infliximab, etanercept and their respective antidrug antibodies, as well as plasma concentrations of TNF-α were measured in 77 psoriasis patients receiving biologic therapy, and the values were correlated with the clinical activity of the skin disease. Antidrug antibodies were identified in the plasma of 25% of infliximab-treated patients and 29.6% of adalimumab-treated patients, but not in the etanercept group. Clinical severity scores were significantly higher in the antibody-positive patients. In patients receiving infliximab or adalimumab therapy, the presence of antidrug antibodies was directly associated with reduced plasma TNF-inhibitor concentration and elevated plasma TNF-α level., (© 2016 Japanese Dermatological Association.)

Both up- and down-regulation of the Toll-like receptors (TLRs) and antimicrobial peptides (AMPs) of the sinonasal mucosa have already been associated with the pathogenesis of chronic rhinosinusitis with (CRSwNP) or without (CRSsNP) nasal polyps. The objective of this study was to determine the expression of all known TLR and several AMP genes and some selected proteins in association with allergy, asthma and aspirin intolerance (ASA) in CRS subgroups. RT-PCR was applied to measure the mRNA expressions of 10 TLRs, four defensins, lysozyme, cathelicidin and lactoferrin (LTF) in sinonasal samples from patients with CRSsNP (n = 19), CRSwNP [ASA(-): 17; ASA(+): 7] and in control subjects (n = 12). Protein expressions were detected with immunohistochemistry (n = 10). Statistical analysis was done with the Kruskal-Wallis ANOVA, Mann-Whitney U, and Student t test. TLR2, TLR5, TLR6, TLR7, TLR8, TLR9, β-defensins 1 and 4, cathelicidin and LTF mRNA expressions were significantly (p < 0.05) increased in CRSwNP, whereas only TLR2 and LTF were up-regulated in CRSsNP compared to controls. There was no statistical difference in respect of allergy, aspirin intolerance and smoking between CRSsNP, ASA(-) and ASA(+) CRSwNP patients. TLR2, TLR3, TLR4, LTF, β defensin 2 and lysozyme protein expressions were found to be elevated in macrophages of CRSwNP samples (p < 0.05). Gene expression analysis showed markedly different expressions in CRSwNP (6 out of 10 TLR and 4 out of 7 AMP genes were up-regulated) compared to CRSsNP (1/10, 1/7). The distinct activation of the innate immunity may support the concept that CRSsNP and CRSwNP are different subtypes of CRS. These findings were found to be independent from allergy, asthma, smoking, aspirin intolerance and systemic steroid application.

Background: IL-4-driven alternative macrophage activation and proliferation are characteristic features of both antihelminthic immune responses and wound healing in contrast to classical macrophage activation, which primarily occurs during inflammatory responses. The signaling pathways defining the genome-wide microRNA expression profile as well as the cellular functions controlled by microRNAs during alternative macrophage activation are largely unknown. Hence, in the current work we examined the regulation and function of IL-4-regulated microRNAs in human and mouse alternative macrophage activation., Methods: We utilized microarray-based microRNA profiling to detect the dynamic expression changes during human monocyte-macrophage differentiation and IL-4-mediated alternative macrophage activation. The expression changes and upstream regulatory pathways of selected microRNAs were further investigated in human and mouse in vitro and in vivo models of alternative macrophage activation by integrating small RNA-seq, ChIP-seq, ChIP-quantitative PCR, and gene expression data. MicroRNA-controlled gene networks and corresponding functions were identified using a combination of transcriptomic, bioinformatic, and functional approaches., Results: The IL-4-controlled microRNA expression pattern was identified in models of human and mouse alternative macrophage activation. IL-4-dependent induction of miR-342-3p and repression of miR-99b along with miR-125a-5p occurred in both human and murine macrophages in vitro. In addition, a similar expression pattern was observed in peritoneal macrophages of Brugia malayi nematode-implanted mice in vivo. By using IL4Rα- and STAT6-deficient macrophages, we were able to show that IL-4-dependent regulation of miR-342-3p, miR-99b, and miR-125a-5p is mediated by the IL-4Rα-STAT6 signaling pathway. The combination of gene expression studies and chromatin immunoprecipitation experiments demonstrated that both miR-342-3p and its host gene, EVL, are coregulated directly by STAT6. Finally, we found that miR-342-3p is capable of controlling macrophage survival through targeting an anti-apoptotic gene network including Bcl2l1., Conclusions: Our findings identify a conserved IL-4/STAT6-regulated microRNA signature in alternatively activated human and mouse macrophages. Moreover, our study indicates that miR-342-3p likely plays a pro-apoptotic role in such cells, thereby providing a negative feedback arm to IL-4-dependent macrophage proliferation.