Mitochondrial DNA drives abscopal responses to radiation that are inhibited by autophagy.

Autophagy supports both cellular and organismal homeostasis. However, whether autophagy should be inhibited or activated for cancer therapy remains unclear. Deletion of essential autophagy genes increased the sensitivity of mouse mammary carcinoma cells to radiation therapy in vitro and in vivo (in immunocompetent syngeneic hosts). Autophagy-deficient cells secreted increased amounts of type I interferon (IFN), which could be limited by CGAS or STING knockdown, mitochondrial DNA depletion or mitochondrial outer membrane permeabilization blockage via BCL2 overexpression or BAX deletion. In vivo, irradiated autophagy-incompetent mammary tumors elicited robust immunity, leading to improved control of distant nonirradiated lesions via systemic type I IFN signaling. Finally, a genetic signature of autophagy had negative prognostic value in patients with breast cancer, inversely correlating with mitochondrial abundance, type I IFN signaling and effector immunity. As clinically useful autophagy inhibitors are elusive, our findings suggest that mitochondrial outer membrane permeabilization may represent a valid target for boosting radiation therapy immunogenicity in patients with breast cancer.

Synthesis of portimines reveals the basis of their anti-cancer activity.

Marine-derived cyclic imine toxins, portimine A and portimine B, have attracted attention because of their chemical structure and notable anti-cancer therapeutic potential1-4. However, access to large quantities of these toxins is currently not feasible, and the molecular mechanism underlying their potent activity remains unknown until now. To address this, a scalable and concise synthesis of portimines is presented, which benefits from the logic used in the two-phase terpenoid synthesis5,6 along with other tactics such as exploiting ring-chain tautomerization and skeletal reorganization to minimize protecting group chemistry through self-protection. Notably, this total synthesis enabled a structural reassignment of portimine B and an in-depth functional evaluation of portimine A, revealing that it induces apoptosis selectively in human cancer cell lines with high potency and is efficacious in vivo in tumour-clearance models. Finally, practical access to the portimines and their analogues simplified the development of photoaffinity analogues, which were used in chemical proteomic experiments to identify a primary target of portimine A as the 60S ribosomal export protein NMD3.

Deconstructing neutrophil to lymphocyte ratio (NLR) in early breast cancer: lack of prognostic utility and biological correlates across tumor subtypes.

PURPOSE: The prognostic utility and biological correlates of neutrophil to lymphocyte ratio (NLR), a potential biomarker of the balance between immune response and the inflammatory status, are still uncertain in breast cancer (BC). METHODS: We analysed a cohort of 959 women with early breast cancer, mostly treated with neoadjuvant or adjuvant chemotherapy. Clinical and pathological data, survival, NLR (continuous and categorical) and stromal tumor infiltrating lymphocytes (sTIL) were evaluated. RESULTS: NLR was only weakly associated with Ki67, while no association was found for grade, histology, immunohistochemical subtype or stage. Lymphocyte infiltration of the tumor did not correlate with NLR (Rho: 0.05, p = 0.30). These results were similar in the whole group and across the different BC subtypes, with no differences in triple negative BC. Relapse free interval (RFI), breast cancer specific survival (BCSS) and overall survival (OS) changed according to pre-treatment NLR neither in the univariate nor in the multivariate Cox models (RFI: HR 0.948, p = 0.61; BCSS: HR 0.920, p = 0.57; OS: HR 0.96, p = 0.59). CONCLUSION: These results question the utility of NLR as a prognostic biomarker in early breast cancer and suggest the lack of correlation of NLR with tumor microenvironment immune response.

A Cell Type Selective YM155 Prodrug Targets Receptor-Interacting Protein Kinase 2 to Induce Brain Cancer Cell Death.

Glioblastoma (GBM) is the most prevalent and aggressive primary central nervous system (CNS) malignancy. YM155 is a highly potent broad-spectrum anti-cancer drug that was derived from a phenotypic screen for functional inhibitors of survivin expression, but for which the relevant biomolecular target remains unknown. Presumably as a result of its lack of cell-type selectivity, YM155 has suffered from tolerability issues in the clinic. Based on its structural similarity to the GBM-selective prodrug RIPGBM, here, we report the design, synthesis, and characterization of a prodrug form of YM155, termed aYM155. aYM155 displays potent cell killing activity against a broad panel of patient-derived GBM cancer stem-like cells (IC50 = 0.7-10 nM), as well as EGFR-amplified and EGFR variant III-expressing (EGFRvIII) cell lines (IC50 = 3.8-36 nM), and becomes activated in a cell-type-dependent manner. Mass spectrometry-based analysis indicates that enhanced cell-type selectivity results from relative rates of prodrug activation in transformed versus non-transformed cell types. The prodrug strategy also facilitates transport into the brain (brain-to-plasma ratio, aYM155 = 0.56; YM155 = BLQ). In addition, we determine that the survivin-suppressing and apoptosis-inducing activities of YM155 involve its interaction with receptor-interacting protein kinase 2 (RIPK2). In an orthotopic intracranial GBM xenograft model, aYM155 prodrug significantly inhibits brain tumor growth in vivo, which correlates with cell-type selective survivin-based pharmacodynamic effects.

Reversible Chromism of Tethered Ruthenium(II) Complexes in the Solid State.

Tethered ruthenium(II) complexes [Ru(η6:κ1-arene:N)Cl2] (where arene:N is 2-aminobiphenyl (1) and 2-benzylpyridine (2)) can convert into their open-tethered chlorido counterparts [Ru(η6-arene:NH)Cl3], 1·HCl and 2·HCl, at room temperature via solid-state reaction in the presence of HCl vapors. The reaction is accompanied by a change in color, is fully reversible, and crystallinity is maintained in both molecular materials. Organoruthenium tethers are presented as nonporous materials capable of capturing and releasing HCl reversibly in the crystalline solid state.

Immunomodulatory Effects in Healthy Individuals Following a 4-Week Taoist Qigong Intervention: A Comparative Study.

BACKGROUND Qigong, an ancient health preservation technique forming part of Traditional Chinese Medicine, combines slow body movements, breathing, and meditation. While this meditative movement system has been reported to offer various physical and psychological benefits, studies on the Taoist school of qigong are sparse. This study, therefore, aimed to investigate the effects of Taoist qigong on white blood cells and other immune parameters in healthy individuals. MATERIAL AND METHODS Thirty-eight participants were recruited for the study, with 21 assigned to the experimental group and 17 to the control group. Participants in the experimental group engaged in a four-week Taoist qigong program. Blood samples for immune parameter quantification, including leukocyte count, neutrophil, eosinophil, basophil, lymphocyte, and large unstained cell (LUC) counts, as well as concentrations of IgG, IgA, IgM, C3, and C4, were collected one day before the experiment started and one day after it ended. RESULTS Post-program, the experimental group exhibited significantly lower total leukocyte counts, and reduced numbers of lymphocytes and LUCs. Additionally, a higher percentage of monocytes was noted in this group. CONCLUSIONS Taoist qigong practice induced a distinct immunomodulatory profile, characterized by decreased counts of several white blood cell parameters and increased percentages of certain agranulocytes. This outcome presents intriguing implications from a psychobiological perspective and highlights the need for further research into the immune effects of Taoist mind-body practice.

Maximizing Antenna Array Aperture Efficiency for Footprint Patterns.

Despite playing a central role in antenna design, aperture efficiency is often disregarded. Consequently, the present study shows that maximizing the aperture efficiency reduces the required number of radiating elements, which leads to cheaper antennas with more directivity. For this, it is considered that the boundary of the antenna aperture has to be inversely proportional to the half-power beamwidth of the desired footprint for each ϕ-cut. As an example of application, it has been considered the rectangular footprint, for which a mathematical expression was deduced to calculate the aperture efficiency in terms of the beamwidth, synthesizing a rectangular footprint of a 2:1 aspect ratio by starting from a pure real flat-topped beam pattern. In addition, a more realistic pattern was studied, the asymmetric coverage defined by the European Telecommunications Satellite Organization, including the numerical computation of the contour of the resulting antenna and its aperture efficiency.

A Review on the Effects of Thermal Inversions and Electromagnetic Fields on Cell Cultures and Wireless Communications.

Thermal inversions, typical in the winter season, consist of cold air at the Earth's surface being trapped under a layer of warmer air. Such an effect keeps normal convective overturning of the atmosphere from penetrating through. This phenomenon highly increases the toxicity of the atmosphere, while modifying its dielectric constant, resulting in major implications in terms of public health and wireless communications. Indeed, air pollution in large cities (related, in most cases, to particulate matter that consists of different chemical components, which can have warming or cooling effects) is primarily caused by chemical and photochemical reactions in the atmosphere. Appropriate usage of array antennas allows the effective tracking of changes in humidity (e.g., coated Yagi-Uda antennas, which do not interfere with 5G) and in the dielectric constant (e.g., optimized quasi-Yagi-Uda antennas, yielding to accurate measurements of sulfides and black carbon concentration). Remarkably, important health effects come from the combined action of electromagnetic fields with fine and coarse black carbon particles. The appearance of ducts, which are caused by thermal inversions, provokes the creation of super-refractive regions in the troposphere as well, which result in the anomalous propagation of wireless communications.

LL-37 Triggers Antimicrobial Activity in Human Platelets.

Platelets play a crucial role in hemostasis and the immune response, mainly by recognizing signals associated with vascular damage. However, it has recently been discovered that the antimicrobial peptide LL-37 activates platelets in functions related to thrombus formation and inflammation. Therefore, this work aims to evaluate the effect of LL-37 on the activation of antimicrobial functions of human platelets. Our results show that platelets treated with LL-37 increase the surface expression of receptors (Toll-like receptors (TLRs) 2 and -4, CD32, CD206, Dectin-1, CD35, LOX-1, CD41, CD62P, and αIIbß3 integrins) for the recognition of microorganisms, and molecules related to antigen presentation to T lymphocytes (CD80, CD86, and HLA-ABC) secrete the antimicrobial molecules: bactericidal/permeability-increasing protein (BPI), azurocidin, human neutrophil peptide (HNP) -1, and myeloperoxidase. They also translate azurocidin, and have enhanced binding to Escherichia coli, Staphylococcus aureus, and Candida albicans. Furthermore, the supernatant of LL-37-treated platelets can inhibit E. coli growth, or platelets can employ their LL-37 to inhibit microbial growth. In conclusion, these findings demonstrate that LL-37 participates in the antimicrobial function of human platelets.

Enhanced Efficiency at Maximum Power in a Fock-Darwin Model Quantum Dot Engine.

We study the performance of an endoreversible magnetic Otto cycle with a working substance composed of a single quantum dot described using the well-known Fock-Darwin model. We find that tuning the intensity of the parabolic trap (geometrical confinement) impacts the proposed cycle's performance, quantified by the power, work, efficiency, and parameter region where the cycle operates as an engine. We demonstrate that a parameter region exists where the efficiency at maximum output power exceeds the Curzon-Ahlborn efficiency, the efficiency at maximum power achieved by a classical working substance.

Mortality in acquired thrombotic thrombocytopenic purpura in the pre-caplacizumab era.

Despite the effectiveness of plasma exchange (PEX) and immunosuppressants in the treatment of acquired thrombotic thrombocytopenic purpura (aTTP), a number of patients still die as a result of the disease. Whether caplacizumab could rescue these patients remains still unsettled. The objective of this study was to characterise mortality patterns and prognostic factors in the first episode of aTTP.We queried the Spanish TTP Registry for patients with a diagnosis of aTTP in their presenting episode who fulfilled complete clinical and follow-up data (n = 102). The patients were diagnosed between 2004 and 2018, and all were treated with daily PEX and corticosteroids. Clinical and laboratory data were analysed at diagnosis and during the treatment course.Eight patients (7.7%) died between 12 h and 36 days after presentation, and could be classified into three patterns: death before treatment, early death driven by acute cardiac or neurologic events, and late death due to unremitted aTTP. Stupor or coma at diagnosis and platelet count < 20 × 109 /L by the 6th treatment day were independently associated with increased risk of death.Stupor or coma at diagnosis and lack of response to PEX by the 6th day in patients experiencing the first episode of aTTP are strong predictors of mortality. These patients could be rescued by novel agents aimed at halting the microvascular thrombosis until adequate immunosuppression is achieved.

Limited Prosocial Emotions in a Clinical Population of Children and Adolescents: Proposal for Core and Ancillary Characteristics.

OBJECTIVE: Limited prosocial emotions (LPE) has been recently incorporated into international classifications as a specifier for conduct disorder in the DSM-5 and for all disruptive behavioural disorders in the ICD-11. The aims of the current work were to determine (a) the accuracy of each of the characteristics used to assess the LPE specifier and (b) whether the manner in which symptoms group together supports the idea of LPE having core characteristics. METHOD: Trained clinicians conducted interviews and determined LPE characteristics using responses from 74 parent/guardian and child/adolescent participants. RESULTS: The distribution of LPE characteristics among those participants with LPE (n = 13) was compared to those with only one LPE characteristic (n = 11). The proposal of callous lack of empathy (CLE) and shallow deficient affect (SDA) as core characteristics was supported by strong associations with the presence of the LPE specifier, larger specificity, and sensitivity indices than those for unconcerned about performance and lack of remorse or guilt, as well as by a robust aggregation in a latent class analysis. CONCLUSIONS: CLE and SDA could be considered as core characteristics of LPE in children and adolescents.

Optimizing Radiation Patterns of Thinned Arrays with Deep Nulls Fixed through Their Representation in the Schelkunoff Unit Circle and a Simulated Annealing Algorithm.

The present work develops an innovative methodology for fixing deep nulls in radiation patterns of symmetrical thinned arrays while maintaining a low side lobe level (SLL) and a high directivity, implementing an optimization strategy based on the simulated annealing algorithm (SA). This procedure optimizes a cost function that has a term for each characteristic of the desired radiation pattern and can distinguish between the deep nulls and the filled ones depending on whether they are on the Schelkunoff unit circle or not. Then, a direct extension of the methodology for planar arrays based on the separable distribution procedure is addressed. Consequently, some examples with half-wavelength spacing are presented, where the fixing of one, two, or three deep nulls in arrays of 40, 60, and 80 elements are illustrated as well as an extension to a 40 × 40-element planar array with rectangular grid and rectangular boundary, with two deep nulls fixed on each one of its main axes. Additionally, a comparison of the obtained results with a genetic algorithm (GA) alternative is performed. The main advantage of the proposed method is its ability to fix deep nulls in the radiation patterns, while maintaining an easy feeding network implementation.

Otto Engine for the q-State Clock Model.

This present work explores the performance of a thermal-magnetic engine of Otto type, considering as a working substance an effective interacting spin model corresponding to the q- state clock model. We obtain all the thermodynamic quantities for the q = 2, 4, 6, and 8 cases in a small lattice size (3×3 with free boundary conditions) by using the exact partition function calculated from the energies of all the accessible microstates of the system. The extension to bigger lattices was performed using the mean-field approximation. Our results indicate that the total work extraction of the cycle is highest for the q=4 case, while the performance for the Ising model (q=2) is the lowest of all cases studied. These results are strongly linked with the phase diagram of the working substance and the location of the cycle in the different magnetic phases present, where we find that the transition from a ferromagnetic to a paramagnetic phase extracts more work than one of the Berezinskii-Kosterlitz-Thouless to paramagnetic type. Additionally, as the size of the lattice increases, the extraction work is lower than smaller lattices for all values of q presented in this study.

Diagnostic classification of irritability and oppositionality in youth: a global field study comparing ICD-11 with ICD-10 and DSM-5.

BACKGROUND: Severe irritability has become an important topic in child and adolescent mental health. Based on the available evidence and on public health considerations, WHO classified chronic irritability within oppositional defiant disorder (ODD) in ICD-11, a solution markedly different from DSM-5's (i.e. the new childhood mood diagnosis, disruptive mood dysregulation disorder [DMDD]) and from ICD-10's (i.e. ODD as one of several conduct disorders without attention to irritability). In this study, we tested the accuracy with which a global, multilingual, multidisciplinary sample of clinicians were able to use the ICD-11 classification of chronic irritability and oppositionality as compared to the ICD-10 and DSM-5 approaches. METHODS: Clinicians (N = 196) from 48 countries participated in an Internet-based field study in English, Spanish, or Japanese and were randomized to review and use one of the three diagnostic systems. Through experimental manipulation of validated clinical vignettes, we evaluated how well clinicians in each condition could identify chronic irritability versus nonirritable oppositionality, episodic bipolar disorder, dysthymic depression, and normative irritability. RESULTS: Compared to ICD-10 and DSM-5, ICD-11 led to more accurate identification of severe irritability and better differentiation from boundary presentations. Participants using DSM-5 largely failed to apply the DMDD diagnosis when it was appropriate, and they more often applied psychopathological diagnoses to developmentally normative irritability. CONCLUSIONS: The formulation of irritability and oppositionality put forth in ICD-11 shows evidence of clinical utility, supporting accurate diagnosis. Global mental health clinicians can readily identify ODD both with and without chronic irritability.

Sexual behaviour, human papillomavirus and its vaccine: a qualitative study of adolescents and parents in Andalusia.

BACKGROUND: Human papillomavirus (HPV) is one of the most common sexually transmitted infections and can be prevented by vaccination. The purpose of this study is to gain a better understanding, by analysing interview responses of adolescents and parents, of how adolescent sexual behaviour is approached in families, how widespread knowledge about HPV is in Andalusia, the autonomous region with the lowest vaccination rate in Spain, as well as to learn more about the interviewees' position regarding vaccination. METHODS: A qualitative study by means of 15 focus groups of adolescents (N = 137, aged 14-17 years) and five focus groups of parents with children of those ages (N = 37) was conducted in the provinces of Granada, Seville and Jaén (Andalusia, Spain). The audio data were transcribed verbatim, coded and analysed thematically using NVIVO-10 software. RESULTS: There were three major results: (1) There is a lack of communication between adolescents and parents regarding sexual behaviour; (2) In both groups, scarce knowledge about HPV and vaccination was found; (3) Parents mistrust vaccination due to a lack of qualified and verified information about its benefits. CONCLUSIONS: Healthy adolescent sexual behaviour is aided by communication within the family. Families need more information based on the evidence about HPV and vaccination. Health professionals are a key element in this process.

An Improved Pattern Synthesis Iterative Method in Planar Arrays for Obtaining Efficient Footprints with Arbitrary Boundaries.

In the present paper, an iterative technique devoted to reproducing efficient footprints with arbitrary boundaries for planar arrays is addressed. The methodology here depicted is based on exploiting the nature of the continuous aperture distribution by expressing it as a Fourier series of moderately high orders. In this manner, the resulting illumination boundary is defined by a target three-dimensional flat-topped pattern composed of stretching and shrinking modified circular Taylor patterns and the maximum order of the series to obtain a good reconstruction is determined by means of the iterative process. Examples and comparisons with the previous literature were conducted by analyzing square and rectangular contoured beams as test cases. Additionally, interesting potentials regarding space applications from a geostationary satellite are outlined by means of the EuTELSAT (European Telecommunications Satellite Organization) European coverage case study. In such a way, its numerical approach was analyzed by including subarray architectures and discussing improvements about dynamic range ratio of the excitations without critical power losses within the illumination region.

Using Antenna Arrays with Only One Active Element for Beam Reconfiguration and Sensitive Study in Dielectric Media.

Antenna array pattern reconfiguration is usually achieved by changing the relative amplitudes and/or phases of the excitation distribution present in the array, at the cost of complex feeding networks. In this work, the mechanical displacement of a parasitic array perpendicular to another array with a single driven element is proposed. Additionally, the antenna is optimized addressing the variation of its response led by changes of the environmental dielectric constant of a surrounding gaseous medium. In such a way, a novel multipurpose antenna of utmost simplicity is obtained. From the computation of the self and mutual impedances, a control of the antenna radiation pattern by means of the induced currents in the parasitic elements is modelled. To illustrate the procedure, the technique will be applied to the variation of the side lobe level of a pencil beam and to obtain a flat-topped broadside beam from the same pencil beam, something with high interest for satellite applications. The proposed methodology represents an advance on the development of multipurpose antennas which resounds in simplicity not only in the reconfiguration of antenna beams, but in applications for the detection of particulate matter and/or measurements of the atmospheric dielectric constant.

Exposure to 2.45 GHz Radiation Triggers Changes in HSP-70, Glucocorticoid Receptors and GFAP Biomarkers in Rat Brain.

Brain tissue may be especially sensitive to electromagnetic phenomena provoking signs of neural stress in cerebral activity. Fifty-four adult female Sprague-Dawley rats underwent ELISA and immunohistochemistry testing of four relevant anatomical areas of the cerebrum to measure biomarkers indicating induction of heat shock protein 70 (HSP-70), glucocorticoid receptors (GCR) or glial fibrillary acidic protein (GFAP) after single or repeated exposure to 2.45 GHz radiation in the experimental set-up. Neither radiation regime caused tissue heating, so thermal effects can be ruled out. A progressive decrease in GCR and HSP-70 was observed after acute or repeated irradiation in the somatosensory cortex, hypothalamus and hippocampus. In the limbic cortex; however, values for both biomarkers were significantly higher after repeated exposure to irradiation when compared to control animals. GFAP values in brain tissue after irradiation were not significantly different or were even lower than those of nonirradiated animals in all brain regions studied. Our results suggest that repeated exposure to 2.45 GHz elicited GCR/HSP-70 dysregulation in the brain, triggering a state of stress that could decrease tissue anti-inflammatory action without favoring glial proliferation and make the nervous system more vulnerable.