bluuebunny/crossref_metadata_2025 huggingface dataset:
Semi-quantum secret sharing protocol using W-state
Authors: Tsai Chia-Wei , Yang Chun-Wei , Lee Narn-Yih
Published: August 2019

Quantum secret sharing protocol, which lets a master share a secret with his/her agents and the agents can recover the master’s secret when they collaborate, is an important research issue in the quantum information field. In order to make the quantum protocol more practical, the concept of semi-quantum protocol is advanced by Boyer et al. Based on this concept, many semi-quantum secret sharing protocols have been proposed. The various entanglement states (including Bell state, GHZ state and so on) were used to be the quantum resources in these SQSS protocols, except for W-state which is the other multi-qubit entanglement state and different from GHZ states. Therefore, this study wants to use the entanglement property of W-state to propose the first three-party SQSS protocol and analyze the proposed protocol is free from the well-known attacks.
Variation of the fine-structure constant caused by expansion of the Universe
Authors: Cardenas Ivan A. , Lipovka Anton A.
Published: August 2019

In this paper, we evaluate the fine-structure constant variation that should take place as the pseudo-Riemannian Universe expands and its curvature is changed adiabatically. Such variation of the fine-structure constant is attributed to an energy loss by an extended physical system (consisting of baryonic component and electromagnetic (EM) field) due to expansion of our Universe. Obtained ratio [Formula: see text] (per second) is only five times smaller than actually reported experimental limit on this value. For this reason, the obtained variation can probably be measured within a couple of years. To argue the correctness of our approach, we calculate the Planck constant as adiabatic invariant of the EM field propagated on the pseudo-Riemannian manifold characterized by slowly varied geometry. Finally, we discuss the double clock experiment based on Al[Formula: see text] and Hg[Formula: see text] clocks carried out by Rosenband et al. (Science 2008). We show that in this case (when the fine-structure constant is changed adiabatically), the method based on double clock experiment cannot be applied to measure the fine-structure constant variation.
CHANGE-POINT ANALYSIS OF ASSET PRICE BUBBLES WITH POWER-LAW HAZARD FUNCTION
Authors: LYNCH CHRISTOPHER , MESTEL BENJAMIN
Published: August 2019

We present a methodology to identify change-points in financial markets where the governing regime shifts from a constant rate-of-return, i.e. normal growth, to a superexponential growth described by a power-law hazard rate. The latter regime corresponds, in our view, to financial bubbles driven by herding behavior of market participants. Assuming that the time series of log-price returns of a financial index can be modeled by arithmetic Brownian motion, with an additional jump process with power-law hazard function to approximate the superexponential growth, we derive a threshold value of the hazard-function control parameter, allowing us to decide in which regime the market is more likely to be at any given time. An analysis of the Standard & Poors 500 index over the last 60 years provides evidence that the methodology has merit in identifying when a period of herding behavior begins, and, perhaps more importantly, when it ends.
Singlet oxygen generation of subphthalocyanine-fused dimer and trimer
Authors: Fujishiro Rei , Sonoyama Hayato , Ide Yuki , Fujimura Takuya , Sasai Ryo , Kaufman Nichole E. M. , Zhou Zehua , Vicente M. Graça H. , Ikeue Takahisa
Published: August 2019

Subphthalocyanine (SubPc) macrocycles are known as an interesting class of nonplanar aromatic dyes. Despite documented high fluorescence and singlet oxygen quantum yields, the properties of SubPcs in photodynamic therapy (PDT) are underestimated, because their absorption bands do not reach a significant wavelength range. With this in mind, we combined a SubPc ring and a SubPc ring by introducing a common benzene ring and obtained a SubPc dimer (2) and trimer (3) with the Q-band at the near-IR region, owing to the expansion of the [Formula: see text] electron conjugated system. In this study, we reported1O2generation abilities of 2 and 3based on the applied absolute singlet oxygen quantum yields ([Formula: see text]absolute). Subsequent research revealed that 2 and 3 showed the potential to generate1O2to not only in toluene but also in DMSO. Although the photocytotoxicity of 2 and 3 were investigated upon photo-irradiation with a low light dose of approximately 1.5 J/cm2, 2 and 3 showed almost negligible toxic properties toward HEp2 cells.
THE IMPACT OF THE CHINESE TEXTILE IMPORTS ON EMPLOYMENT AND VALUE ADDED IN THE TEXTILE INDUSTRY OF THE SOUTH AFRICAN ECONOMY
Authors: BONGA-BONGA LUMENGO , BIYASE MDUDUZI
Published: August 2019

With the increased trade linkage between China and African economies, this paper endeavours to assess the dynamic impacts of Chinese textile imports on employment and value added in the South African textile industry. This paper makes use of the structural vector autoregressive (SVAR) methodology with sign restriction. Moreover, based on this methodology, this paper conducts a counterfactual analysis to uncover what would have happened to employment and value added trends in the South African textile industry in the absence of trade with China. The results of the empirical analysis show that total employment responds negatively to shocks to import from China. Moreover, the results of the counterfactual analysis show that the South African economy could perform better without textile imports from China.
THE EFFICACY OF GREEK GOVERNMENT ECONOMIC TOOLS: 1995–2016
Authors: MACK MICHAELA , LEIGHTNER JONATHAN E.
Published: August 2019

We use a statistical technique that solves the omitted variables problem of regression analysis to estimate the changes in gross domestic product (GDP), unemployment, and inflation of a one-unit change in government spending, exports, and interest rate for Greece using quarterly data from 1995 to 2016. Our primary findings are (1) driving the Greek economy using domestic demand creates a much more stable economy than trying to drive the Greek economy using exports and (2) cutting government spending and exports damage GDP more than equal increases help GDP. Both of these conclusions imply that IMF austerity and IMF support of exporting over domestic demand are counter-productive. Our results are not opposed to naturally occurring globalization, they are contrary to artificially encouraging trade as coerced by the IMF.
Device-guided slow breathing reduces blood pressure and sympathetic activity in young normotensive individuals of both sexes
Authors: Adler Tessa E. , Coovadia Yasmine , Cirone Domenica , Khemakhem Maha L. , Usselman Charlotte W.
Published: August 2019

Slow breathing (SLOWB) is recommended for use as an adjuvant treatment for hypertension. However, the extent to which blood pressure (BP) responses to SLOWB differ between men and women are not well-established. Therefore, we tested the hypothesis that an acute bout of SLOWB would induce larger decreases in BP in males than in females, given that males typically have higher resting BP. We also examined autonomic contributors to reduced BP during SLOWB; that is, muscle sympathetic nerve activity and spontaneous cardiovagal (sequence method) and vascular sympathetic baroreflex sensitivity. We tested normotensive females ( n = 10, age: 22 ± 2 y, body mass index: 22 ± 2 kg/m2) and males ( n = 12, age: 23 ± 3 y, body mass index: 26 ± 4 kg/m2). Subjects were tested at baseline and during the last 5 min of a 15-min RESPeRATE-guided SLOWB session. Overall, SLOWB reduced systolic BP by 3.2 ± 0.8 mmHg (main effect, P < 0.01). Females had lower systolic BP (main effect, P = 0.02); we observed no interaction between sex and SLOWB. SLOWB also reduced muscle sympathetic nerve activity burst incidence by −5.0 ± 1.4 bursts/100 heartbeats (main effect, P < 0.01). Although females tended to have lower burst incidence (main effect, P = 0.1), there was no interaction between sex and SLOWB. Cardiovagal baroreflex sensitivity improved during SLOWB (21.0 vs. 36.0 ms/mmHg, P = 0.03) with no effect of sex. Despite lower overall BP in females, our data support a lack of basement effect on SLOWB-induced reductions in BP, as SLOWB was equally effective in reducing BP in males and females. Our findings support the efficacy of the RESPeRATE device for reducing BP in both sexes, even in young, normotensive individuals.

NEW & NOTEWORTHY We provide support for the effectiveness of device-guided slow breathing for blood pressure reduction in young normotensive women and men. Despite having lower baseline blood pressure and sympathetic nerve activity, women experienced equivalent reductions in both measures in response to RESPeRATE-guided slow breathing as men. Thus, slow breathing appears to be effective in young healthy normotensive individuals of both sexes and may be an ideal preventative therapy against future hypertension.
Contraction intensity-dependent variations in the responses to brain and corticospinal tract stimulation after a single session of resistance training in men
Authors: Colomer-Poveda David , Romero-Arenas Salvador , Lundbye-Jensen Jesper , Hortobágyi Tibor , Márquez Gonzalo
Published: August 2019

The aim of this study was to determine the effects of acute resistance training (RT) intensity on motor-evoked potentials (MEPs) generated by transcranial magnetic brain stimulation and on cervicomedullary motor-evoked potentials (CMEPs) produced by electrical stimulation of the corticospinal tract. In four experimental sessions, 14 healthy young men performed 12 sets of eight isometric contractions of the elbow flexors at 0 (Control session), 25, 50, and 75% of the maximal voluntary contraction (MVC). Before and after each session, MEPs, CMEPs, and the associated twitch forces were recorded at rest. MEPs increased by 39% ( P < 0.05 versus 25% in the control condition, Effect size (ES) = 1.04 and 1.76, respectively) after the 50% session and by 70% ( P < 0.05 vs. all other conditions, ES = 0.91–2.49) after the 75% session. In contrast, CMEPs increased similarly after the 25%, 50%, and 75% sessions with an overall increase of 27% ( P < 0.05 vs. control condition, ES = 1.34). The amplitude of maximal compound muscle action potentials (Mmax) was unchanged during the experiment. The MEP- and CMEP-associated twitch forces also increased after RT, but training intensity affected only the increases in MEP twitch forces. The data tentatively suggest that the intensity of muscle contraction used in acute bouts of RT affects cortical excitability.

NEW & NOTEWORTHY Resistance training (RT) can acutely increase the efficacy of the corticospinal-motoneuronal synapse, motoneuron excitability and motor cortical excitability. We show that motor-evoked potential generated by transcranial magnetic stimulation but not cervicomedullary electrical stimulation increased in proportion to the intensity of training used during a single session of RT. The data suggest that the intensity of muscle contraction used in acute bouts of RT affects cortical excitability.
Pavlovian Conditioning of Immunological and Neuroendocrine Functions
Authors: Hadamitzky Martin , Lückemann Laura , Pacheco-López Gustavo , Schedlowski Manfred
Published: August 2019

The phenomenon of behaviorally conditioned immunological and neuroendocrine functions has been investigated for the past 100 yr. The observation that associative learning processes can modify peripheral immune functions was first reported and investigated by Ivan Petrovic Pavlov and his co-workers. Their work later fell into oblivion, also because so little was known about the immune system’s function and even less about the underlying mechanisms of how learning, a central nervous system activity, could affect peripheral immune responses. With the employment of a taste-avoidance paradigm in rats, this phenomenon was rediscovered 45 yr ago as one of the most fascinating examples of the reciprocal functional interaction between behavior, the brain, and peripheral immune functions, and it established psychoneuroimmunology as a new research field. Relying on growing knowledge about efferent and afferent communication pathways between the brain, neuroendocrine system, primary and secondary immune organs, and immunocompetent cells, experimental animal studies demonstrate that cellular and humoral immune and neuroendocrine functions can be modulated via associative learning protocols. These (from the classical perspective) learned immune responses are clinically relevant, since they affect the development and progression of immune-related diseases and, more importantly, are also inducible in humans. The increased knowledge about the neuropsychological machinery steering learning and memory processes together with recent insight into the mechanisms mediating placebo responses provide fascinating perspectives to exploit these learned immune and neuroendocrine responses as supportive therapies, the aim being to reduce the amount of medication required, diminishing unwanted drug side effects while maximizing the therapeutic effect for the patient’s benefit.
Management of Adult Patients with Primary Immune Thrombocytopenia (ITP) in Clinical Practice: A Consensus Approach of the Spanish ITP Expert Group
Authors: Mingot-Castellano M. Eva , Román M. Teresa Álvarez , Fernández Fuertes Luis Fernando , González-López Tomás José , Guinea de Castro José María , Jarque Isidro , López-Fernández M. Fernanda , Lozano Maria Luisa , Sánchez González Blanca , Ferreiras David Valcárcel , González Porras José Ramón
Published: August 2019

Background and Objective. Diagnosis and management of primary immune thrombocytopenia (ITP) have changed dramatically in the last decade. The aim of the study was to obtain information about the opinion of the Spanish ITP Group (GEPTI) members regarding the best clinical practices for diagnosis and management of adult patients with ITP.Materials and Methods. A two-round Delphi method was carried out by sending to 129 experts a 90-item questionnaire developed by 11 specialists, with a 4-point Likert scale (“never,” “sometimes,” “frequently,” and “always”) for the assessment of responses.Results. Forty out of the 129 experts participated in the survey (participation rate 30.2%) and 39 completed the questionnaire (response rate 97.5%). Salient consensus points included the following: the need to indicate workup studies from a sustained platelet count < 100 x 109/L in the absence of a clear etiology; bone marrow aspiration in elderly patients with suspected ITP; beginning treatment in asymptomatic patients with a platelet count < 20 x 109/L; not exceeding 6-7 weeks of corticosteroid therapy; switching from corticosteroids to one thrombopoietin receptor agonist (TRA); switching to other TRA or other options as combinations of them with immunosuppressive drugs in case of failure; how to reduce tapering TRA; treating patients with symptomatic persistent ITP and platelet count > 20 x 109/L; and considering mucosal or severe bleeding as a basic criterion for hospital admission.Conclusions. The present consensus document provides a reference framework for the management of patients with ITP in clinical practice.
Symmergent Gravity, Seesawic New Physics, and Their Experimental Signatures
Authors: Demir Durmuş
Published: August 2019

The standard model of elementary particles (SM) suffers from various problems, such as power-law ultraviolet (UV) sensitivity, exclusion of general relativity (GR), and absence of a dark matter candidate. The LHC experiments, according to which the TeV domain appears to be empty of new particles, started sidelining TeV-scale SUSY and other known cures of the UV sensitivity. In search for a remedy, in this work, it is revealed that affine curvature can emerge in a way restoring gauge symmetries explicitly broken by the UV cutoff. This emergent curvature cures the UV sensitivity and incorporates GR as symmetry-restoring emergent gravity (symmergent gravity, in brief) if a new physics sector (NP) exists to generate the Planck scale and if SM+NP is Fermi-Bose balanced. This setup, carrying fingerprints of trans-Planckian SUSY, predicts that gravity is Einstein (no higher-curvature terms), cosmic/gamma rays can originate from heavy NP scalars, and the UV cutoff might take right value to suppress the cosmological constant (alleviating fine-tuning with SUSY). The NP does not have to couple to the SM. In fact, NP-SM coupling can take any value from zero to ΛSM2/ΛNP2 if the SM is not to jump from ΛSM≈500  GeV to the NP scale ΛNP. The zero coupling, certifying an undetectable NP, agrees with all the collider and dark matter bounds at present. The seesawic bound ΛSM2/ΛNP2, directly verifiable at colliders, implies that (i) dark matter must have a mass ≲ΛSM, (ii) Higgs-curvature coupling must be ≈1.3%, (iii) the SM RGEs must remain nearly as in the SM, and (iv) right-handed neutrinos must have a mass ≲1000  TeV. These signatures serve as a concise testbed for symmergence.
Treatment of Priapism Secondary to Drugs for Erectile Dysfunction
Authors: Saffon Cuartas José Pablo , Sandoval-Salinas Carolina , Martínez Juan M. , Corredor Héctor A.
Published: August 2019

Priapism may present as a side effect in patients treated with medications for erectile dysfunction, in which it should be controlled in a timely manner to avoid complications. There is little information regarding the use of local measures for the treatment of this condition. This study was done with the objective to describe the management of priapism secondary to erectile dysfunction drugs in a cohort of men. Records of emergencies and adverse events were reviewed by two researchers to identify patients diagnosed with erectile dysfunction who received oral or intracavernosal drugs for their illness and presented priapism. Sociodemographic data, clinical background, and information on the duration, management, and evolution of the priapism were extracted. Priapism incidence, percentage of improvement by type of treatment subgroups, and frequency of complications were estimated. 698 patients were treated with PDE-5 inhibitors and 2,135 with intracavernosal drugs. Thirty-one patients (1.4%) reported at least one priapism event during treatment, all with intracavernosal drugs. Treatment with local measures was effective for 10 (32.2%) patients, 1 (3.2%) required terbutaline, 19 (61.2%) used intracavernosal etilefrine, and 1 (3.2%) required drainage and flushing of cavernous bodies. After the priapism episode, 3 (9.6%) patients required an increased dose of the drug in order to achieve satisfactory erection. The results suggest that in men treated for priapism secondary to the use of sexual impotence drugs, initial treatment with local measures and etilefrine can achieve detumescence, decreasing the need for invasive procedures or surgery as a first-line therapy alternative. It is necessary to carry out research studies to confirm this hypothesis.
Macrophage ABHD5 Suppresses NFκB-Dependent Matrix Metalloproteinase Expression and Cancer Metastasis
Authors: Shang Shenglan , Ji Xinran , Zhang Lili , Chen Jun , Li Chuan , Shi Rongchen , Xiang Wei , Kang Xia , Zhang Dapeng , Yang Fan , Dai Rongyang , Chen Peng , Chen Shan , Chen Yongchuan , Li Yongsheng , Miao Hongming
Published: August 2019

Metabolic reprogramming in tumor-associated macrophages (TAM) is associated with cancer development, however, the role of macrophage triglyceride metabolism in cancer metastasis is unclear. Here, we showed that TAMs exhibited heterogeneous expression of abhydrolase domain containing 5 (ABHD5), an activator of triglyceride hydrolysis, with migratory TAMs expressing lower levels of ABHD5 compared with the nonmigratory TAMs. ABHD5 expression in macrophages inhibited cancer cell migration in vitro in xenograft models and in genetic cancer models. The effects of macrophage ABHD5 on cancer cell migration were dissociated from its metabolic function as neither triglycerides nor ABHD5-regulated metabolites from macrophages affected cancer cell migration. Instead, ABHD5 deficiency in migrating macrophages promoted NFκB p65-dependent production of matrix metalloproteinases (MMP). ABHD5 expression negatively correlated with MMP expression in TAMs and was associated with better survival in patients with colorectal cancer. Taken together, our findings show that macrophage ABHD5 suppresses NFκB-dependent MMP production and cancer metastasis and may serve as a prognostic marker in colorectal cancer.

Significance:

These findings highlight the mechanism by which reduced expression of the metabolic enzyme ABHD5 in macrophages promotes cancer metastasis.
Studying Cancer Evolution and Therapeutic Responses in Different Organs: The Pros and Cons of a Broad Focus
Authors: Pham-Danis Catherine , DeGregori James
Published: August 2019

Cellular adaptation brought upon by insults such as old age and therapeutic exposure is a complex phenomenon in which cells undergo adaptive phenotypic changes. Our lab has focused on understanding the mechanisms underlying adaptation during the evolution of cancer, from the early stages of development to the ability of cancer cells to escape therapeutic challenges. Our studies span hematopoietic and lung systems. Herein, we discuss the advantages and disadvantages involved in studying two vastly different organ systems. Through the use of these organ/cancer model systems, we hope to develop interventions to limit oncogenic adaptation leading to cancer development and to prevent adaptation of cancers following treatment leading to cancer relapse.
Purinostat Mesylate Is a Uniquely Potent and Selective Inhibitor of HDACs for the Treatment of BCR-ABL–Induced B-Cell Acute Lymphoblastic Leukemia
Authors: Yang Linyu , Qiu Qiang , Tang Minghai , Wang Fang , Yi Yuyao , Yi Dongni , Yang Zhuang , Zhu Zejiang , Zheng Shoujun , Yang Jianhong , Pei Heying , Zheng Li , Chen Yong , Gou Liping , Luo Liya , Deng Xing , Ye Haoyu , Hu Yiguo , Niu Ting , Chen Lijuan
Published: August 2019

Purpose:

This study was to perform preclinical evaluation of a novel class I and IIb HDAC-selective inhibitor, purinostat mesylate, for the treatment of Ph+ B-cell acute lymphoblastic leukemia (B-ALL).

Experimental Design:

Biochemical assays were used to test enzymatic activity inhibition of purinostat mesylate. Ph+ leukemic cell lines and patient cells were used to evaluate purinostat mesylate activity in vitro. BL-2 secondary transplantation Ph+ B-ALL mouse model was used to validate its efficacy, mechanism, and pharmacokinetics properties in vivo. BCR-ABL(T315I)–induced primary B-ALL mouse model and PDX mouse model derived from relapsed Ph+ B-ALL patient post TKI treatment were used to determine the antitumor effect of purinostat mesylate for refractory or relapsed Ph+ B-ALL. Long-term toxicity and hERG blockade assays were used to safety evaluation of purinostat mesylate.

Results:

Purinostat mesylate, a class I and IIb HDAC highly selective inhibitor, exhibited robust antitumor activity in hematologic cancers. Purinostat mesylate at low nanomolar concentration induced apoptosis, and downregulated BCR-ABL and c-MYC expression in Ph+ leukemia cell lines and primary Ph+ B-ALL cells from relapsed patients. Purinostat mesylate efficiently attenuated Ph+ B-ALL progression and significantly prolonged the survival both in BL-2 secondary transplantation model with clinical patient symptoms of Ph+ B-ALL, BCR-ABL(T315I)–induced primary B-ALL mouse model, and PDX model derived from patients with relapsed Ph+ B-ALL post TKI treatment. In addition, purinostat mesylate possesses favorable pharmacokinetics and low toxicity properties.

Conclusions:

Purinostat mesylate provides a new therapeutic strategy for patients with Ph+ B-ALL, including those who relapse after TKI treatment.
A Novel Mitochondrial Inhibitor Blocks MAPK Pathway and Overcomes MAPK Inhibitor Resistance in Melanoma
Authors: Vashisht Gopal Y.N. , Gammon Seth , Prasad Rishika , Knighton Barbara , Pisaneschi Federica , Roszik Jason , Feng Ningping , Johnson Sarah , Pramanik Snigdha , Sudderth Jessica , Sui Dawen , Hudgens Courtney , Fischer Grant M. , Deng Wanleng , Reuben Alexandre , Peng Weiyi , Wang Jian , McQuade Jennifer L. , Tetzlaff Michael T. , Di Francesco Maria E. , Marszalek Joe , Piwnica-Worms David , DeBerardinis Ralph J. , Davies Michael A.
Published: August 2019

Purpose:

The purpose of this study is to determine if inhibition of mitochondrial oxidative phosphorylation (OxPhos) is an effective strategy against MAPK pathway inhibitor (MAPKi)–resistant BRAF-mutant melanomas.

Experimental Design: The antimelanoma activity of IACS-010759 (OPi), a novel OxPhos complex I inhibitor, was evaluated in vitro and in vivo. Mechanistic studies and predictors of response were evaluated using molecularly and metabolically stratified melanoma cell lines. 13C-labeling and targeted metabolomics were used to evaluate the effect of OPi on cellular energy utilization. OxPhos inhibition in vivo was evaluated noninvasively by [18F]-fluoroazomycin arabinoside (FAZA) PET imaging.

Results:

OPi potently inhibited OxPhos and the in vivo growth of multiple MAPKi-resistant BRAF-mutant melanoma models with high OxPhos at well-tolerated doses. In vivo tumor regression with single-agent OPi treatment correlated with inhibition of both MAPK and mTOR complex I activity. Unexpectedly, antitumor activity was not improved by combined treatment with MAPKi in vitro or in vivo. Signaling and growth-inhibitory effects were mediated by LKB1–AMPK axis, and proportional to AMPK activation. OPi increased glucose incorporation into glycolysis, inhibited glucose and glutamine incorporation into the mitochondrial tricarboxylic acid cycle, and decreased cellular nucleotide and amino acid pools. Early changes in [18F]-FAZA PET uptake in vivo, and the degree of mTORC1 pathway inhibition in vitro, correlated with efficacy.

Conclusions:

Targeting OxPhos with OPi has significant antitumor activity in MAPKi-resistant, BRAF-mutant melanomas, and merits further clinical investigation as a potential new strategy to overcome intrinsic and acquired resistance to MAPKi in patients.
A Phase II Trial of Vandetanib in Children and Adults with Succinate Dehydrogenase–Deficient Gastrointestinal Stromal Tumor
Authors: Glod John , Arnaldez Fernanda I. , Wiener Lori , Spencer Melissa , Killian J. Keith , Meltzer Paul , Dombi Eva , Derse-Anthony Claudia , Derdak Joanne , Srinivasan Ramaprasad , Linehan W. Marston , Miettinen Markku , Steinberg Seth M. , Helman Lee , Widemann Brigitte C.
Published: August 2019

Purpose:

Gastrointestinal stromal tumors (GIST) are resistant to cytotoxic chemotherapy and radiotherapy. Most GIST in children are wild-type for KIT and PDGFRA (WT GIST) and deficient in expression of succinate dehydrogenase (dSDH GIST). We tested the activity of vandetanib, an oral small-molecule inhibitor of VEGFR2, EGFR, and RET, in patients with dSDH GIST.

Patients and Methods:

Phase II study of vandetanib (300 mg orally once daily to patients ≥18 years, and 100 mg/m2/dose to patients < 18 years) on a continuous dosing schedule (1 cycle = 28 days) to assess the clinical activity (partial and complete response rate RECIST v1.1) in patients with dSDH GIST. A Simon optimal two-stage design (target response rate 25%, rule out 5%) was used: If ≥1 of 9 patients in stage 1 responded, enrollment would be expanded to 24 patients, and if ≥3 of 24 responded, vandetanib would be considered active.

Results:

Nine patients (7 female and 2 male; median age, 24 years; range, 11–52) with metastatic disease were enrolled. Three of the initial 5 adult patients developed treatment-modifying toxicities. After a protocol amendment, two adults received vandetanib at 200 mg/dose with improved tolerability. The two children (<18 years old) enrolled did not experience treatment-modifying toxicities. No partial or complete responses were observed (median number of cycles, 4; range, 2–18).

Conclusions:

Vandetanib at a dose of 300 mg daily was not well tolerated by adults with dSDH GIST. Two of 9 patients had prolonged stable disease, but no partial or complete responses were observed, and vandetanib is thus not considered active in dSDH GIST.
Mediators of Inflammation-Driven Expansion, Trafficking, and Function of Tumor-Infiltrating MDSCs
Authors: Tannenbaum Charles S. , Rayman Patricia A. , Pavicic Paul G. , Kim Jin Sub , Wei Wei , Polefko Alexandra , Wallace Wesley , Rini Brian I. , Morris-Stiff Gareth , Allende Daniela S. , Hamilton Thomas , Finke James H. , Diaz-Montero C. Marcela
Published: August 2019

Myeloid-derived suppressor cells (MDSC) are induced by and accumulate within many histologically distinct solid tumors, where they promote disease by secreting angiogenic and immunosuppressive molecules. Although IL1β can drive the generation, accumulation, and functional capacity of MDSCs, the specific IL1β-induced inflammatory mediators contributing to these activities remain incompletely defined. Here, we identified IL1β-induced molecules that expand, mobilize, and modulate the accumulation and angiogenic and immunosuppressive potencies of polymorphonuclear (PMN)-MDSCs. Unlike parental CT26 tumors, which recruited primarily monocytic (M)-MDSCs by constitutively expressing GM-CSF– and CCR2-directed chemokines, IL1β-transfected CT26 produced higher G-CSF, multiple CXC chemokines, and vascular adhesion molecules required for mediating infiltration of PMN-MDSCs with increased angiogenic and immunosuppressive properties. Conversely, CT26 tumors transfected with IL1β-inducible molecules could mobilize PMN-MDSCs, but because they lacked the ability to upregulate IL1β-inducible CXCR2-directed chemokines or vascular adhesion molecules, additional PMN-MDSCs could not infiltrate tumors. IL1β-expressing CT26 increased angiogenic and immunosuppressive factors of tumor-infiltrating MDSCs, as did CT26 tumors individually transfected with G-CSF, Bv8, CXCL1, or CXCL5, demonstrating that mediators downstream of IL1β could also modulate MDSC functional activity. Translational relevance was indicated by the finding that the same growth factors, cytokines, chemokines, and adhesion molecules responsible for the mobilization and recruitment of PMN-MDSCs into inflammatory CT26 murine tumors were also coordinately upregulated with increasing IL1β expression in human renal cell carcinoma tumors. These studies demonstrated that IL1β stimulated the components of a multifaceted inflammatory program that produces, mobilizes, chemoattracts, activates, and mediates the infiltration of PMN-MDSCs into inflammatory tumors to promote tumor progression.
Possible Involvement of Nitric Oxide in the Antipruritic Effect of Metformin on Chloroquine-Induced Scratching in Mice
Authors: Haddadi Nazgol-Sadat , Shakiba Saeed , Afshari Khashayar , Haj-Mirzaian Arvin , Vesaghati Sara , Gharagozlou Saber , Foroumadi Roham , Shafaroodi Hamed , Ostadhadi Sattar , Dehpour Ahmad Reza
Published: August 2019

Background: Metformin ameliorates non-histamine-mediated itch. We have recently reported that the nitric oxide (NO) pathway is involved in chloroquine (CQ)-induced scratching behavior. Here we investigated the involvement of the NO pathway in the antipruritic effect of metformin on CQ-induced itch. Methods: Metformin (5–200 mg/kg, given intraperitoneally [i.p.]) was injected 4 h before CQ (400 µg/site, given intradermally [i.d.]) or compound 48/80 (100 µg/site, i.d.). A nonspecific nitric oxide synthase (NOS) inhibitor, NG-nitro-L-arginine methyl ester (L-NAME; 1 and 10 mg/kg, i.p.), or an NO precursor, L-arginine (10 and 100 mg/kg, i.p.) was administered 30 min before injection of CQ. A neural NOS (nNOS) inhibitor, 7-nitroindazole (7-NI; 1 and 10 nmol/site, i.d.) was concurrently administered with CQ. The scratching behavior was recorded for 30 min following the injection of CQ. We studied the changes in skin and spinal nitrite levels after treatments. Results: Our results showed that metformin (100 and 200 mg/kg) significantly reduced the CQ-induced scratching behavior but not the compound 48/80-induced scratching behavior. L-Arginine inhibited the antipruritic effect of metformin, while L-NAME and 7-NI significantly potentiated the inhibitory effects of a subeffective dose of metformin on the CQ-induced scratching behavior. The skin but not the spinal nitrite level was significantly increased after CQ administration. The elevated cutaneous nitrite level was reversed by effective doses of either metformin or 7-NI, but not by the subeffective doses of metformin + 7-NI. Conclusion: Acute injection of metformin significantly inhibits CQ-induced scratching behavior. This effect is mediated through inhibition of the NO pathway, especially by inhibiting the dermal nNOS enzyme.
Early Predictors for INtubation-SURfactant-Extubation Failure in Preterm Infants with Neonatal Respiratory Distress Syndrome: A Systematic Review
Authors: De Bisschop Barbara , Derriks Frank , Cools Filip
Published: August 2019

The INtubation-SURfactant-Extubation (INSURE) procedure is a widely-used surfactant administration method to treat preterm infants with respiratory distress syndrome (RDS) but is not always successful. We conducted a systematic review to identify early predictive factors for failure of this procedure. A systematic literature search was performed until July 2018 in MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials. Original studies comparing INSURE success with INSURE failure in preterm infants with RDS were included. A predefined data extraction form was used to retrieve data from articles, and methodological quality was assessed using the SIGN checklists. Fifteen studies out of 690 identified records met inclusion criteria. Methodological quality varied, only 8 studies performed multivariate analysis. We identified 20 different risk factors in total. Evidence for birth weight (BW) as a predictor for INSURE failure was inconsistent, but there was a significant association between decreasing gestational age (GA) and failure risk. RDS severity was assessed in multiple ways, using arterial blood gas values, imaging, and scoring systems. In conclusion, extremely low BW, low GA, and severe RDS appear to be risk factors for INSURE failure. However, evidence is inconsistent due to important methodological heterogeneity. Therefore, clinical applicability of these results is limited and implies the need for future large cohort studies on this subject.
Male Breast Cancer Patients’ Perspectives on Their Health Care Situation: A Mixed-Methods Study
Authors: Halbach Sarah Maria , Midding Evamarie , Ernstmann Nicole , Würstlein Rachel , Weber Rainer  , Christmann Sherin , Kowalski Christoph
Published: August 2019

Background: Male breast cancer is rare. No information was available on how male breast cancer patients (MBCPs) experience the health care they receive in Germany in a setting that is tailored to women. The aim of this study was to explore the health care situation of MBCPs from their perspectives. Methods: The study follows a mixed-methods design, combining quantitative data from a standardized written questionnaire with qualitative data from personal interviews. Descriptive statistics (quantitative data) and qualitative content analysis (qualitative data) were used for data analysis. Results: Questionnaires completed by 100 and personal interviews of 27 MBCPs were analyzed. Several men reported mainly positive experiences while others experienced shortcomings. These included delays in diagnosis, health care provider uncertainty about treatment (tamoxifen, radiation therapy), experiences of stigmatization, and issues of continuity of care including unclear responsibilities for aftercare and access challenges to breast-cancer-specific care in gynecology settings. Conclusions: The awareness of male breast cancer needs to be increased among the public, health care providers and researchers in order to avoid delays in diagnosis and reduce stigmatization and uncertainty about treatment. Health care structures ensuring access to gynecology care and clear responsibilities for aftercare need to be established.
Diuretic Resistance in Cardio-Nephrology: Role of Pharmacokinetics, Hypochloremia, and Kidney Remodeling
Authors: Masella Cristina , Viggiano Davide , Molfino Ida , Zacchia Miriam , Capolongo Giovanna , Anastasio Pietro , Simeoni Mariadelina
Published: August 2019

Background: Diuretic resistance is among the most challenging problems that the cardio-nephrologist must address in daily clinical practice, with a considerable burden on hospital admissions and health care costs. Indeed, loop diuretics are the first-line therapy to overcome fluid overload in heart failure patients. The pathophysiological mechanisms of fluid and sodium retention are complex and depend on several neuro-hormonal signals mainly acting on sodium reabsorption along the renal tubule. Consequently, doses and administration modalities of diuretics must be carefully tailored to patients in order to overcome under- or overtreatment. The frequent and tricky development of diuretic resistance depends in part on post-diuretic sodium retention, reduced tubular secretion of the drug, and reduced sodium/chloride sensing. Sodium and chloride depletions have been recently shown to be major factors mediating these processes. Aquaretics and high-saline infusions have been recently suggested in cases of hyponatremic conditions. This review discusses the limitations and strengths of these approaches. Summary: Long-term diuretic use may lead to diuretic resistance in cardio-renal syndromes. To overcome this complication intravenous administration of loop diuretics and a combination of different diuretic classes have been proposed. In the presence of hyponatremia, high-saline solutions in addition to loop diuretics might be beneficial, whereas aquaretics require caution to avoid overcorrection. Key Messages: Diuretic resistance is a central theme for cardio-renal syndromes. Hyponatremia and hypochloremia may be part of the mechanisms for diuretic resistance. Aquaretics and high-saline solutions have been proposed as possible new therapeutic solutions.
ЗАСТОСУВАННЯ КІБЕРФІЗИЧНИХ БІОСЕНСОРНИХ ТА ІМУНОСЕНСОРНИХ СИСТЕМ
Authors: Martsenyuk V. P. , Sverstiuk A. S. , Bihunyak T. V. , Pavlyshyn A. V. , Mochulska O. M.
Published: August 2019

У роботі проведено огляд кіберфізичних біосенсорних та імуносенсорних систем, що є новим поколінням інформаційно-вимірювальних систем із використанням у конструкції біологічних матеріалів, які забезпечують їх високу селективність. Проведена класифікація досліджуваних систем відносно чутливих елементів і можливості використанням різних режимів фізико-хімічного перетворення вимірювальної величини. Розглянуто такі види кіберфізичних біосенсорних та імуносенсорних систем: електрохімічні; оптичні; на основі оксиду кремнію, кварцу та скла; на основі наноматеріалів; генетично кодовані або синтетичні флуоресцентні; мікробні, розроблені за допомогою синтетичної біології та генетичної інженерії. Досліджувані системи порівняно за технологією, специфічністю, порогом виявлення, тривалістю аналізу, вартістю та портативністю.

Розглянуто методи виготовлення електрохімічних кіберфізичних біосенсорних та імуносенсорних систем. Окремо представлено методи виготовлення, шляхом модифікування поверхні металевих і вуглецевих електродів із використанням біоматеріалів, таких як ферменти, антитіла або ДНК. Представлено оптичні досліджувані системи, що реалізуть свою дію за допомогою іммобілайзерів і можуть виготовлятися із золота, матеріалів на основі вуглецю, кварцу або скла. Описано найбільш важливі напрями використання кіберфізичних біосенсорних та імуносенсорних систем у лікувальних і діагностичних закладах, зокрема для моніторингу рівня глюкози в крові пацієнтів із цукровим діабетом, а також для розроблення нових лікарських засобів, біозондування та біомедицини. Зроблено висновок, що досліджувані системи з наноматеріалів на основі оксиду кремнію володіють найбільш високим потенціалом щодо застосування для біовізуалізаціі, біосенсорного аналізу та лікування онкологічнх захворювань.

Розглянуто мічені кіберфізичні біосенсорні та імуносенсорні системи з використанням генетичного кодування або синтетичної флуоресценції, що дало змогу вивчати біологічні процеси, в тому числі, різні молекулярні перетворення всередині клітин. Наведено переваги візуалізації in vivo за допомогою досліджуваних систем малих молекул з метою кращого розуміння клітинної активності та механізму дії ДНК, РНК та мікро-РНК. Описано клітинні біосенсорні та імуносенсорні системи, що можна застосовувати для моніторингу біохімічної потреби в кисні, токсичності в навколишньому середовищі, для виявлення пестицидів і важких металів, спостереженні за екологічною ефективністю при виробництві електроенергії. Зроблено висновок, що для створення високочутливих мініатюрних пристроїв потрібне розроблення різних мікро- і нано-кіберфізичних біосенсорних та імуносенсорних платформ із залученням інтегрованих технологій, які використовують електрохімічний або оптичний біоелектронні принципи з комбінацією біомолекул або біологічних матеріалів, полімерів і наноматеріалів.
ФІЗІОЛОГІЧНІ ЕФЕКТИ СВІТЛА З ПЕРЕТВОРЕНОЮ ФУЛЛЕРЕНОМ ПРОСТОРОВОЮ СТРУКТУРОЮ
Authors: Gulyar S. O. , Tamarova Z. A. , Kyrylenko E. K. , Filimonova N. B. , Makarchuk N. Yu. , Kryvdiuk Yu. N.
Published: August 2019

Експериментально показано, що перетворене фуллереном поляризоване (апарат Біоптрон) або розсіяне (окуляри Tesla HyperLight Eyewear) світло викликають достовірні фізіологічні зміни, виявлені в антиноцицептивній сфері, ЦНС і ВНД. Виявлено достовірне ослаблення больової реакції (анальгетичну дію) і збільшення тривалості сну (заспокійливу дію). Багатомісячне перебування тварин під фуллереновим освітленням виявило уповільнення розвитку деяких ознак старіння. Мозаїка ЕЕГ-активності свідчила про розвиток більш споглядального ставлення до інтроспективного емоційних переживань минулих подій при активному залученні їх в образне моделювання гіпотетичного майбутнього. Встановлено, що в природних умовах перетворене фулереном світло полегшує виконання зорово-моторних тестів. При тривалому коректурному навантаженні фуллеренове світло, сприяло збільшенню швидкості перероблення інформації в зоровому аналізаторі, підвищувало уважність і послаблювало стомлюваність. Якість виконання інтенсивного розумового навантаження зростала. Моделювання «засліплення» водія за даними сенсо-моторних реакцій на тлі ЕЕГ мозку людини виявило збільшення швидкості міжпівкульних інформаційних процесів і підвищення якості та ефективності прийнятих рішень.
СИСТЕМНА БІОЛОГІЯ СТАРІННЯ: МОДЕЛЮВАННЯ МОЛЕКУЛЯРНИХ МЕХАНІЗМІВ РОЗВИТКУ ВІКОВИХ ЗАХВОРЮВАНЬ. КОНЦЕПТУАЛЬНИЙ АНАЛІТИЧНИЙ ОГЛЯД
Authors: Mintser O.P. , Zaliskyi V.Z.
Published: August 2019

Феномен старіння включає групу взаємопов'язаних процесів, що відбуваються на організмовому, тканинному, клітинному та молекулярно-генетичному рівнях. Давно висловлювалося припущення, що старіння тісно пов'язано зі складною динамікою фізіологічних систем, які підтримують гомеостаз і, зокрема з дерегуляцією регуляторних молекулярних мереж. У роботі представлено докази важливості динаміки таких складних систем при старінні й того, що фізіологічна дерегуляція (поступове руйнування здатності складних регуляторних мереж підтримувати гомеостаз) є емерджентною властивістю цих мереж, що грає важливу роль у старінні. Завданням цього огляду є узагальнення наявних концепцій про основні детермінанти старіння та довголіття, а також розгляд тенденцій розвитку математичних моделей процесів старіння. Показано, що відсутність інтегрованих трансляційних досліджень на шляху розвитку системної медицини та системної біології є одним із основних факторів, що обмежують надання сучасних засобів у вирішенні проблеми боротьби зі старінням. Серед основних факторів старіння звернуто увагу на те, що вплив на мітохондрії представляється привабливою перспективою для досягнення покращання здоров'я та тривалості життя, оскільки омолодження старих мітохондрій може виявитися важливою терапевтичною стратегією для покращання здоров'я літніх людей. Постулюється також, що швидкість і простота інтеграції сучасних програмних комплексів для моделювання біологічних систем дозволяють дослідникам вивчати великі моделі, включаючи їх взаємодію в багатовимірних форматах із ансамблями невеликих моделей.
АВТОМАТИЗОВАНА ЕКСПЕРТНА СИСТЕМА ОЦІНЮВАННЯ РЕЗУЛЬТАТІВ ОБСТЕЖЕННЯ МОЛОЧНИХ ЗАЛОЗ ДЛЯ КОНТАКТНОЇ ЦИФРОВОЇ ТЕРМОГРАФІЇ
Authors: Biloshenko V. O. , Gurianov V.Z. , Liakh Yu. Ye. , Pryhodchenko V. V.
Published: August 2019

Проблеми ранньої діагностики раку молочної залози пов'язані з якістю та тривалістю життя жінок. Одним із шляхів вирішення цієї проблеми є проведення скринінгу — профілактичного обстеження жінок, починаючи з 35-річного віку. Контактна цифрова термографія молочних залоз відповідає вимогам для первинного обстеження молочних залоз, проте оцінювання результатів термографії потребує підготовки кваліфікованих спеціалістів. Вирішення проблеми спрощення та прискорення оцінювання результатів термографії може бути здійснено за рахунок розроблення програмного комплексу для автоматизованого оцінювання термограм. Проведено аналіз 685 записів термограм жінок, віком від 18 до 86 років, яким за результатом комплексного обстеження був виставлений кінцевий діагноз. Для оцінювання розподілу поля температур молочних залоз використано алгоритм оцінювання показника Херста для фракталів високої розмірності. При проведенні статистичного аналізу виявлено інформативні показники, що описують поле температур молочних залоз, які дозволяють провести дискримінацію норми та патології. На виділених ознаках побудована математична модель прогнозування ризику патології молочних залоз. Автоматизована система аналізу реалізована в нелінійних нейромережевих моделях, що дозволило з 90,2 % чутливістю та 85,1 % специфічністю прогнозувати ризик патології. Отже, розроблено автоматизовану систему, що дозволяє з використанням методу термографії виявляти патологію молочних залоз при проведенні скринінгових досліджень підготовленим медичним працівником із сестринською або фельдшерською освітою, сімейним лікарем.
ЛОГІКА ПІДГОТОВКИ ЗДОБУВАЧІВ ВИЩОЇ ОСВІТИ СТУПЕНЯ ДОКТОРА ФІЛОСОФІЇ ЗІ СПЕЦІАЛІЗАЦІЇ «МЕДИЧНА ТА БІОЛОГІЧНА ІНФОРМАТИКА І КІБЕРНЕТИКА»
Authors: Mintser O.P. , Babintseva L. Yu.
Published: August 2019

Представлено освітню програму та навчальний план підготовки здобувачів вищої освіти ступеня доктора філософії на третьому (освітньо-науковому) рівні за всіма формами навчання для спеціалізації «Медична та біологічна інформатика і кібернетика». Навчання в аспірантурі та поза нею відбувається відповідно до Закону України «Про вищу освіту», постанов Кабінету Міністрів України від 23.03.2016 № 261 «Про затвердження Порядку підготовки здобувачів вищої освіти ступеня доктора філософії та доктора наук у вищих навчальних закладах (наукових установах)» та від 30.12.2015 № 1187 «Про затвердження Ліцензійних умов провадження освітньої діяльності закладів освіти».

Кінцеві цілі з навчальної дисципліни «Медична та біологічна інформатика і кібернетика» спрямовані на здобуття глибинних знань зі спеціальності, за якою здобувач проводить дослідження, зокрема засвоєння основних концепцій, розуміння теоретичних і практичних проблем, оволодіння термінологією з досліджуваного наукового напряму тощо.

Відомо, що навчальний план відповідно до наказу МОН України є нормативним документом (стандартом) закладу вищої освіти. Проте освітня програма та навчальний план складено на кафедрі медичної інформатики, що є опорною в системі післядипломної медичної освіти, тому запропоновані документи можуть розглядатись як уніфікована освітня програма та навчальний план.