bluuebunny/crossref_metadata_2025 huggingface dataset:
Blocking STAT3/5 through direct or upstream kinase targeting in leukemic cutaneous T‐cell lymphoma
Authors: Sorger Helena , Dey Saptaswa , Vieyra‐Garcia Pablo Augusto , Pölöske Daniel , Teufelberger Andrea R , de Araujo Elvin D , Sedighi Abootaleb , Graf Ricarda , Spiegl Benjamin , Lazzeri Isaac , Braun Till , Garces de los Fayos Alonso Ines , Schlederer Michaela , Timelthaler Gerald , Kodajova Petra , Pirker Christine , Surbek Marta , Machtinger Michael , Graier Thomas , Perchthaler Isabella , Pan Yi , Fink‐Puches Regina , Cerroni Lorenzo , Ober Jennifer , Otte Moritz , Albrecht Jana D , Tin Gary , Abdeldayem Ayah , Manaswiyoungkul Pimyupa , Olaoye Olasunkanmi O , Metzelder Martin L , Orlova Anna , Berger Walter , Wobser Marion , Nicolay Jan P , André Fiona , Nguyen Van Anh , Neubauer Heidi A , Fleck Roman , Merkel Olaf , Herling Marco , Heitzer Ellen , Gunning Patrick T , Kenner Lukas , Moriggl Richard , Wolf Peter
Published: November 2022

Leukemic cutaneous T‐cell lymphomas (L‐CTCL) are lymphoproliferative disorders of skin‐homing mature T‐cells causing severe symptoms and high mortality through chronic inflammation, tissue destruction, and serious infections. Despite numerous genomic sequencing efforts, recurrent driver mutations have not been identified, but chromosomal losses and gains are frequent and dominant. We integrated genomic landscape analyses with innovative pharmacologic interference studies to identify key vulnerable nodes in L‐CTCL. We detected copy number gains of loci containing the STAT3/5 oncogenes in 74% (n = 17/23) of L‐CTCL, which correlated with the increased clonal T‐cell count in the blood. Dual inhibition of STAT3/5 using small‐molecule degraders and multi‐kinase blockers abolished L‐CTCL cell growth in vitro and ex vivo, whereby PAK kinase inhibition was specifically selective for L‐CTCL patient cells carrying STAT3/5 gains. Importantly, the PAK inhibitor FRAx597 demonstrated encouraging anti‐leukemic activity in vivo by inhibiting tumor growth and disease dissemination in intradermally xenografted mice. We conclude that STAT3/5 and PAK kinase interaction represents a new therapeutic node to be further explored in L‐CTCL.
Endoscopic Ultrasound-Based Evaluation of Pancreatic Cysts: New Invasive Modalities
Authors: Koo Chieh Sian , Ho Khek-Yu
Published: November 2022

Pancreatic cysts are a heterogenous group of lesions that can be differentiated into mucinous and non-mucinous cysts based on their malignant potential. Crosssectional imaging alone is inadequate to reliably distinguish between the two groups. Endoscopic ultrasound (EUS) and fine needle aspiration has been used for analysis of the cyst morphology and cyst fluid. Traditional markers such as fluid carcinoembryonic antigen and cytology have been useful particularly for the assessment of indeterminate cysts or those with high-risk features, but the overall diagnostic accuracy is still sub-par. As a result, new techniques have been described to improve the ability of EUS to risk stratify a pancreatic cyst. In this review, we describe some of the novel EUS‑based techniques in the evaluation of pancreatic cysts, namely needle-based confocal laser endomicroscopy, through the needle cystoscopy, and through the needle biopsy techniques.
Mass-Forming Immunoglobulin G4-Related Ampullitis Mimicking a Duodenal Subepithelial Tumor: A Case Report
Authors: Lee Hyun Seok , Lee Eaum Seok
Published: November 2022

Subepithelial tumors (SETs) are often found accidentally during gastroscopy, most commonly in the stomach. If a raised lesion is observed around the major papilla, the relationship with the common bile duct or pancreas should be evaluated, and not only SET but also cancer or autoimmune disease should be considered in the differential diagnosis. Herein, we present a case of prominent major papilla mimicking a SET that was accidentally discovered during endoscopy. The patient was asymptomatic, and the physical and laboratory findings were normal. The biopsy findings were nonspecific and imaging findings suggested possible malignancy; thus, surgical ampullectomy was performed. The histopathological results confirmed IgG4-related ampullitis. This case suggests that immunoglobulin G4 (IgG4)-related disease may manifest with atypical findings, hindering its diagnosis and treatment.
Acute Acalculous Cholecystitis associated with Cystic Duct Cancer Diagnosed after Endoscopic Ultrasonography
Authors: Jun Hogyung , Choi Eun Kwang , Hyun Chang Lim , Lee Sang Hyub
Published: November 2022

We present an interesting case of acute acalculous cholecystitis which was diagnosed as cystic duct cancer after endoscopic ultrasonography (EUS). A 63-year-old man visited to an emergency room (ER) because of right upper quadrant (RUQ) abdominal pain. The patient had fever up to 38.2℃ and tenderness at RUQ abdomen. The Murphy’s sign was positive. Laboratory tests showed elevated white blood cell count and abnormal liver function test. The computed tomography scan revealed a distended gallbladder with inflammation without gallstone. Emergent gallbladder drainage was performed at ER. The cholecystogram via percutaneous tube and EUS revealed hypoechoic intraluminal mass at cystic duct. Laparoscopic cholecystectomy was performed at first, and the frozen pathologic examination revealed adenocarcinoma in the cystic duct. The extended cholecystectomy was performed after a month and there was no residual tumor in the liver bed and lymph nodes. The final staging of GBC was revealed as pT2N0M0.
Redox medicine in viral infections: focus on AIDS and COVID-19
Authors: Mas-Bargues Cristina , Borrás Consuelo , Viña José
Published: November 2022

Despite the great progress and advancements in scientific knowledge, technology, and medicine, viral infections continue to put human health in trouble. Both acquired immunodeficiency syndrome (AIDS) and coronavirus disease 2019 (COVID-19), caused by human immunodeficiency virus and severe acute respiratory syndrome coronavirus 2, two RNA viruses responsible for global pandemics, respectively, have poor outcomes associated with increased oxidative stress, systemic inflammation, and immunopathology. Here, we have collected the current knowledge linking both viral infections, focusing on the role of oxidative stress and the redox balance. Furthermore, we provide information on some redox-active compounds, such as vitamins, thiol-based agents, and polyphenols, and their possible beneficial effects on both diseases. Thus, in this review, we aim to highlight the importance and impact of nutritional strategies to strengthen our immune system, especially to increase the effectiveness of pharmacological treatments, or when there are no effective treatments.
Suprachiasmatic nucleus and vagus nerve trigger preovulatory LH and ovulation
Authors: Vieyra Elizabeth , García Julio C , Zarco Hugo A , Linares Rosa , Rosas Gabriela , Ramírez Deyra A , Chaparro Andrea , Espinoza Julieta A , Domínguez Roberto , Morales-Ledesma Leticia
Published: November 2022

In brief

In the proestrus day, the neural and endocrine signals modulate ovarian function. This study shows vagus nerve plays a role in the multisynaptic pathways of communication between the suprachiasmatic nucleus and the ovaries where such neural information determines ovulation.

The suprachiasmatic nucleus (SCN) regulates the activity of several peripheral organs through a parasympathetic–sympathetic pathway. Previously, we demonstrated that atropine (ATR) microinjection in the right SCN of rats during proestrus blocks ovulation. In the present study, we analysed whether the vagus nerve is one of the neural pathways by which the SCN regulates ovulation. For this, CIIZ-V strain cyclic rats on the day of proestrus were microinjected with a saline solution (vehicle) or ATR in the right or left SCN, which was followed by ventral laparotomy or ipsilateral vagotomy to the microinjection side. Some animal groups were sacrificed (i) on the same day of the surgery to measure oestradiol, progesterone and luteinizing hormone (LH) levels or (ii) at 24 h after surgery to evaluate ovulation. The left vagotomy in rats microinjected with ATR in the left SCN did not modify ovulation. In rats with ATR microinjection in the right SCN, the right vagotomy increased the levels of steroids and LH on the proestrus and ovulatory response. The present results suggest that the right vagus nerve plays a role in the multisynaptic pathways of communication between the SCN and the ovaries and indicate that such neural information participates in the regulation of the oestradiol and progesterone surge, which triggers the preovulatory peak of LH and determines ovulation.
Improvement of the properties of sugar factory fusel oil waste and investigation of its effect on the performance and emissions of spark ignition engine
Authors: Simsek Suleyman , Ozdalyan Bulent , Saygın Hasan
Published: November 2022

The effects of using blends of unleaded gasoline and refined fusel oil on engine performance and exhaust emissions were analyzed. Prior to the experiment, the fusel oil, which is the final waste product of the sugar factory, was developed to have the chemical properties that can be used in internal combustion engines by removing water and gum contained therein. A four-stroke, single-cylinder, spark-ignition engine was used for the experiments. The tests were conducted at a fixed speed and under different loads. The test fuels were blended with fusel oil contents of 5%, 15%, and 30%. Under each load, the engine’s performance and emissions were measured. Throughout the experiments, it was observed that engine torque and fuel consumption increased as the amount of fusel oil in the blend increased. Nitrogen oxide (NOx), carbon monoxide (CO), and hydrocarbon (HC) emissions were reduced as the amount of fusel oil in the blends increased.
Effect of surface carbonization on mechanical properties of LVL
Authors: Wang Xuehua , Wu Yan , Chen Hong , Zhou Xiaoyan , Zhang Zhankuan , Xu Wei
Published: November 2022

The wood veneer from Monopetalanthus species was heated under different temperatures (120 °C, 160 °C, 200 °C, and 240 °C) and then laminated as the surface of laminated veneer lumber (LVL). Bending modulus of elasticity (MOE), modulus of rupture (MOR), and impact toughness (IT) of the LVL were tested. The results showed that the failure location became scattered as the surface veneer carbonization temperature was increased and that the failure mode changed from split failure in the control and the 120 °C samples to crack failure in the 160 °C, 200 °C, and 240 °C samples under the bending load. Fiber tearing was visible in all five sample types, where the length of the tearing fibers became shorter with increased surface heating temperature under impact load. The carbonization temperature of surface veneer had a minimal effect on the MOE but a considerable effect on the MOR and IT, and the MOR mainly showed a downtrend. The IT loss decreased as the surface veneer carbonization temperature was increased.
Los bosques estacionalmente secos del Perú
Authors: Linares-Palomino Reynaldo , Huamantupa-Chuquimaco Isau , Padrón Eva , La Torre-Cuadros María de los Ángeles , Roncal-Rabanal Manuel , Choquecota Nikki , Collazos Leonardo , Elejalde Renzo , Vergara Nicole , Marcelo Peña José Luis
Published: November 2022

Los bosques estacionalmente secos en el Perú constituyen un conjunto de ecosistemas que incluye tres grandes grupos florísticos: bosques costeros, interandinos y orientales. Con la excepción de los bosques estacionalmente secos de las llanuras costeras del norte del país, hasta hace poco la ausencia de datos hacía difícil describir adecuadamente estos grupos en base a su florística. En los últimos 20 años, en estos bosques se han generado diversos estudios florísticos e inventarios botánicos enfocados en plantas leñosas, que han llenado vacíos de conocimiento en áreas críticas. Con estos estudios hemos generado la base de datos DRYFLOR Perú que a la fecha incluye 526 inventarios cuantitativos (listas de especies en áreas discretas incluyendo registros de sus abundancias) y que nos permiten confirmar la distinción florística de los tres grandes grupos. Adicionalmente logramos reconocer claramente dos subgrupos de bosques estacionalmente secos costeros (de llanura y de montaña), dos subgrupos interandinos (valles del Marañón-Mantaro y del Pampas) y tres subgrupos orientales (valles del Huallaga, Tambo y Urubamba). Todos los subgrupos tienen un ensamblaje de especies de plantas leñosas que los distingue y caracteriza en términos de abundancia, frecuencia, riqueza de especies y niveles de endemismo. Si bien ahora podemos describir mejor la heterogeneidad florística de los bosques estacionalmente secos en el Perú, hemos identificado vacíos de conocimiento importantes que requieren de atención prioritaria: i) requerimos de esfuerzos de inventario adicionales en los bosques orientales, ii) necesitamos resolver las afinidades florísticas de los bosques del valle del Apurímac, iii) nuestros datos coinciden en poco más del 75% con las definiciones y distribución de bosques secos del reciente Mapa Nacional de Ecosistemas del Perú, y será necesario revisar el concepto de bosque estacionalmente seco para lograr capturar adecuadamente su distribución en este instrumento de gestión.
Anidación del chorlo nevado (Charadrius nivosus) en Atotonilco, Jalisco, México
Authors: Quintero-Félix Raúl Said , González-Martín del Campo Filiberto Moisés , Contreras-Terrazas Carlos , Sánchez-Hernández Gibrán
Published: November 2022

El chorlo nevado (Charadrius nivosus) es una de las aves playeras menos abundantes. Es una especie amenazada cuyas poblaciones se encuentran en constante declive. México es importante para las poblaciones de esta especie, pero existe poca información sobre su reproducción y amenazas. Con el objetivo obtener datos sobre su anidación y potenciales amenazas existentes, realizamos un monitoreo de la población del chorlo nevado en la laguna de Atotonilco durante la temporada reproductiva (marzo-julio) del año 2020. Efectuamos conteos de individuos y nidos, tamaño de nidada, fecha aproximada de puesta de los huevos y observaciones sobre las amenazas presentes durante este periodo. Los machos representaron el 85% (n = 140) de la población total y el mes con la mayor cantidad de nidos fue mayo (n = 15). El tamaño promedio de la nidada fue de 2.5 huevos. La superficie de agua fue variable durante los meses de muestreo, pero no se comprobó estadísticamente que a mayor desecación el tamaño de la nidada disminuyera (p = 0.09). Las principales amenazas identificadas fueron los vehículos motorizados y la ganadería. La laguna de Atotonilco es un sitio clave para la reproducción del chorlo nevado y se deben implementar acciones de manejo que permitan ampliar la presencia de agua y regulen las actividades humanas.
School Leaders’ Attitudes, Expectations, and Beliefs Starting a Character Education Training in Latvia
Authors: Fernández González Manuel Joaquín , Surikova Svetlana
Published: November 2022

This article explores school leaders’ expectations and beliefs when starting a professional development course about character education in Latvia. The survey used mixed methods, involved 30 participants, and was conducted in 2020. School leaders expected to enhance their practical know-how in this field, the desired opportunities for personal reflection and sharing with colleagues, and believed that shared values and a friendly atmosphere were the key points. The findings can be useful for future similar initiatives.
LEGAL REGULATION OF SPATIAL DEVELOPMENT AND DEVELOPMENT OF TERRITORIES IN UKRAINE: MODERN CHALLENGES IN THE CONDITIONS OF WAR AND POST-WAR RECONSTRUCTION
Authors:   National University “Odesa Academy of Law”, Odesa, Ukraine, Kvasnitska O.О.
Published: November 2022

The article highlights the main problems of legal regulation of the development of territories, defines the directions of development of urban planning legislation in the light of the concept of recovery of Ukraine from the consequences of the war, the need for integrated planning of the development of territories and implementation of construction information modeling technologies. The article states that the full-scale invasion of the russian federation on the territory of Ukraine has become a difficult test for the state, economic entities, and citizens of Ukraine and requires a change in traditional approaches to the organization and implementation of economic activities in the field of urban planning in favor of digitalization and the abandonment of the Soviet system of planning and development. The author concludes that the issues of modernization of the norms of the Economic Code of Ukraine regarding capital construction, taking into account the digitalization of the construction process, the introduction of a European-oriented system of technical regulation in the construction industry, and the optimization of urban planning documentation with the replacement of more flexible urban planning documents that can be transformed depending from the needs of participants in urban development relations, adopted special urban development programs, but remain static within the framework of sanitary, water protection, and environmental restrictions. The reform of urban planning legislation requires clear terminologies, unified procedures, optimization of urban planning documentation, considering the practices of European countries and the experience of rebuilding post-war states, and most importantly, unified principles of urban planning based on people-centeredness, homogeneity and safety, developed as a result of the collaboration of all participants in urban planning activities.
THE EXPERIENCE OF THE TERRITORY DEVELOPMENT OF CROATIA POST THE ARMED CONFLICT: CONDITIONS, PRIORITIES AND TOOLS
Authors:   Luhansk Branch of State Organization “V. Mamutov Institute of Economic and Legal Research of NAS of Ukraine”, Sievierodonetsk, Ukraine, Zablodska I.V. , Rohozian Yu.S. ,   State Organization “V. Mamutov Institute of Economic and Legal Research of NAS of Ukraine”, Kyiv, Ukraine
Published: November 2022

The article examines experience of the Republic of Croatia in the development of de-occupied and affected territories post the armed conflict. The authors analyzed economic and legal conditions for the construction of the Croatian territories destroyed after the armed conflict and their financial support by international donors through the creation of local economic development agencies, development and implementation of the local economic development concept in Croatia and adaptation of the legal framework to new economic goals. The priorities and four components of the strategic project of the social and economic recovery of Croatia have been determined. The first component of the project aimed at attracting investment in territorial communities, the second component devoted to the process of demining de-occupied territories, the third is the provision of consulting services to strengthen management potential, and the fourth component of the project aimed at supporting sub-projects in such areas as: social integration, economic revival and infrastructure for small communities in Croatia. The article demonstrates the economic and legal instruments of special state support for the development of the de-occupied territories of Croatia as well as the classification of territories requiring special state support. Emphasis placed on the expediency of state administration decentralization and the use of tax incentives, including real estate transfer tax, income tax received in the territory of special state supervision and corporate tax. In addition, noteworthy is the creation of three types of territories that received special state aid through income tax exemption or tax rate differentiation over time. Special state support was provided by providing housing to the population affected by the “Croatian War”. The conducted research made possible to establish the successes and shortcomings of the Croatian experience for the possible extrapolation of developments to Ukrainian realities.
WHOLESALE TRADE IN UKRAINE: MAIN TRENDS OF DEVELOPMENT AND FEATURES OF MARKETING DECISIONS OF SUBJECTS UNDER THE CONDITIONS OF MARITAL LAW
Authors:   Lviv Polytechnic National University, Lviv, Ukraine, Kuzo N.Je. , Kosar N.S. ,   Lviv Polytechnic National University, Lviv, Ukraine
Published: November 2022

The conducted studies show that during 2016—2021 there was a positive trend in the growth of wholesale turnover in Ukraine. But in 2022, as a result of military operations on the territory of Ukraine, this dynamic may be disrupted. In 2021, in the structure of wholesale trade in Ukraine by type of goods, the share of non-food products exceeded the share of food products by 5.41 times, while imported products prevailed. The use of modern marketing concepts will help domestic wholesale intermediaries to adapt to wartime conditions, provide the population of Ukraine with food and non-food products, and support the country's economy. The article presents the main decisions of the wholesale intermediary on the components of the marketing mіx and identifies the specifics of their implementation in the conditions of martial law. Within the limits of the marketing product policy, it means reducing the number of assortment groups, determining the products that are in the greatest demand; reduction of the share of imported goods; determination of the most valuable services from the point of view of customers; if necessary, search for opportunities for additional purchases of goods through the conclusion of one-time commercial contracts. Within the scope of optimizing the price policy, it is said about conducting negotiations with producers regarding the establishment of preferential prices by an intermediary; reduction of the trade allowance for essential goods; study of the influence of factors of the marketing environment on the level of prices of goods; the possibility of use in the short-term period for the purpose of ensuring survival; conducting poly commodity price policy. The formation of the marketing and sales policy of the wholesale intermediary should involve the search for new customers primarily by interactive channels; association with competitors and other interested entities in the field of goods sales; determination and agreement of the most favorable conditions for trade partners; search for new potential suppliers; optimization of logistics costs; business relocation to the central or western regions of Ukraine. As part of the marketing communication policy, wholesale intermediaries must ensure that it is carried out jointly with manufacturers of goods; actively use sales promotion measures; to help the Armed Forces and volunteer organizations; conduct a search for new customers using mail, telephone, and the Internet, providing for the limited use of personal selling.
A Prospective Study of Brief Resolved Unexplained Events: Risk Factors for Persistent Symptoms
Authors: Duncan Daniel R. , Liu Enju , Growdon Amanda S. , Larson Kara , Rosen Rachel L.
Published: November 2022

OBJECTIVE

The risk of persistent symptoms after a brief resolved unexplained event (BRUE) is not known. Our objective was to determine the frequency and risk factors for persistent symptoms after BRUE hospitalizations.

METHODS

We conducted a prospective longitudinal cohort study of infants hospitalized with an admitting diagnosis of BRUE. Caregiver-reported symptoms, anxiety levels, and management changes were obtained by questionnaires during the 2-month follow-up period. Clinical data including repeat hospitalizations were obtained from a medical record review. Multivariable analyses with generalized estimating equations were conducted to determine the risk of persistent symptoms.

RESULTS

Of 124 subjects enrolled at 51.6 ± 5.9 days of age, 86% reported symptoms on at least 1 questionnaire after discharge; 65% of patients had choking episodes, 12% had BRUE spells, and 15% required a repeat hospital visit. High anxiety levels were reported by 31% of caregivers. Management changes were common during the follow-up period and included 30% receiving acid suppression and 27% receiving thickened feedings. Only 19% of patients had a videofluoroscopic swallow study while admitted, yet 67% of these studies revealed aspiration/penetration.

CONCLUSIONS

Many infants admitted with BRUE have persistent symptoms and continue to access medical care, suggesting current management strategies insufficiently address persistent symptoms. Future randomized trials will be needed to evaluate the potential efficacy of therapies commonly recommended after BRUE.
Understanding Racial, Ethnic, and Socioeconomic Differences in the Ambulatory Care Experience
Authors: Luff Donna , Buscher Sara W. , Ward Valerie L. , Ballal Sonia A. , Holden Paul , Pierre Rachelle , Won Paul , Yu Eun Jin , Toomey Sara L.
Published: November 2022

BACKGROUND AND OBJECTIVE

Racial and ethnic and socioeconomic differences in patient experience are prevalent and can negatively impact health outcomes. Our objective was to examine differences in family experience of care in the pediatric ambulatory setting.

METHODS

We conducted interviews with parents of patients from different demographic groups who had received care at 1 of 3 clinics at a quaternary children’s hospital. Multidisciplinary team conducted inductive and deductive thematic analysis of transcribed interviews. Sentiments and recurring themes were compared within and between racial and ethnic groups, insurance status, and language.

RESULTS

Eighty parents were interviewed. Three primary themes were identified: (1) mitigation of system issues: parents’ mixed experiences with staff or clinicians mitigating system issues impacted their overall perceptions of care; (2) pivotal role of personal interactions: clinicians’ interactions positively influenced family-clinician relationships and offset negative experiences; (3) effective explanations: clinicians’ clear and thorough explanations were crucial in enhancing parent confidence in care. As an overarching theme, discrimination and disrespect by staff undermined trust in care, affecting all aspects of experience. With the exception of explanations, a higher proportion of publicly-insured parents reported negative experiences across all themes compared to those with private insurance. Asian parents with public insurance had the highest proportion of interviews that were mainly negative in sentiment.

CONCLUSIONS

Our findings offer nuanced insights into differences in the experience of ambulatory care. Insurance status emerged as an important marker of differential perceptions of care. Our study points to areas for improvement and highlights family-clinician interactions as vital to overall positive experience.
Atitudes e tomada de decisão de profissionais na avaliação de situações de abuso sexual
Authors: Torres Marck de Souza , Freitas Clarissa Pinto Pizarro de , Habigzang Luísa Fernanda
Published: November 2022

O objetivo deste trabalho foi caracterizar as atitudes dos profissionais que atuam na rede de proteção em relação à avaliação de casos de abuso sexual (AS) e investigar relações com os níveis de autoeficácia ocupacional, tomada de decisão, características sociodemográficas e laborais. Participaram do estudo 165 trabalhadores, 86% do sexo feminino, com idade média de 37,6 anos (DP = 10,1 anos). A análise de rede apontou que a atitude denominada especificidade regula as atitudes de sensibilidade e ceticismo. A autoeficácia ocupacional não se relacionou com nenhuma variável e a tomada decisão apresentou correlação negativa com a atitude sensibilidade. A idade apresentou correlação negativa com a atitude sensibilidade. Profissionais que atuaram na área jurídica apresentaram maiores níveis de medo de não identificar o abuso em comparação aos profissionais da Saúde. Os resultados indicam a necessidade de investimento em treinamentos efetivos para adoção de práticas baseadas em evidências em para atuação nos diferentes setores da rede de proteção e atendimento, bem como importância de supervisão de casos para adequada identificação, notificação e encaminhamentos.
Analyzing properties of path predicate slicing algorithm
Authors: Vishnyakov Alexey Vadimovich
Published: November 2022

Security development lifecycle (SDL) is applied to improve software reliability and security. It extends program lifecycle with additional testing of security properties. Among other things, fuzz testing is widely used, which allows one to detect crashes and hangs of the analyzed code. The hybrid approach that combines fuzzing and dynamic symbolic execution showed even greater efficiency than classical fuzzing. Moreover, symbolic execution empowers one to add additional runtime checks called security predicates that detect memory errors and undefined behavior. This article explores the properties of the path predicate slicing algorithm that eliminates redundant constraints from a path predicate without accuracy loss. The article proves that the algorithm is finite and does not lose solutions. Moreover, the algorithm asymptotic complexity is estimated.
LC-MS/MS method assay for simultaneous determination of the pretomanid and pyrazinamide in rat plasma by LC-MS/MS: Assessment of pharmacokinetic drug-drug interaction study
Authors: Huang Tao , Wang Li , Wang Fang , Shen Xin , Wang Libin
Published: November 2022

In the present study, an LC-MS/MS method allowing to quantify pretomanid and pyrazinamide simultaneously in rat plasma was developed. Chromatographic separation was achieved on an Agilent Eclipse plus C18 column (100 mm × 2.1 mm, 3.5 μm; Agilent, USA) and maintained at 30 °C. Multiple reaction monitoring (MRM) using positive-ion ESI mode to monitor ion transitions of m/z 360.1 → m/z 175.1 for pretomanid, m/z 124.1 → m/z 81.0 for pyrazinamide, m/z 172.1 → m/z 128.1 for metronidazole (IS). The calibration curves showed good linear relationships over the concentration range of 50–7,500 ng mL−1 for pretomanid and 500–75,000 ng mL−1 for pyrazinamide. The precision and accuracy were below 15% and within ±15% of the nominal concentrations, respectively. The selectivity, recovery and matrix effect of this method were all within acceptable limits of bioanalytics. The method was applied to the analysis of plasma samples from pharmacokinetic studies in rats. The results show that the main pharmacokinetic parameters of pyrazinamide, namely, Tmax, t1/2, and AUC(0–t), decreased in the combined group than in the alone group.
Niewyjaśnione aspekty dogmatu chalcedońskiego i reakcja „umiarkowanego” monofizytyzmu w VI wieku według Aloisa Grillmeiera
Authors: Calore Giacomo
Published: November 2022

Sobór Chalcedonśki orzekł, że Jezus Chrystus jest jedną Osobą (boską) w dwóch naturach, wprowadzając w ten sposób różnicę między pojęciami osoby i natury (ontologia dwupoziomowa). Odróżnienie to było jednak dosyć nowe w chrystologii. To wzbudziło sprzeciw wobec soboru u „umiarkowanych” monofizytów — zwolenników Cyryla, „mistrza” ortodoksji, którzy odrzucili ontologię dwupoziomową na rzecz kontrowersyjnej formuły chrystologicznej Aleksandryjczyka mía phýsis. W tym artykule, na podstawie głównie dzieła Aloisa Grillmeiera Jesus der Christus, autor omawia luki chalcedońskiego odróżnienia osoby od natury oraz niesatysfakcjonującą alternatywę opracowaną przez czołowego przedstawiciela monofizytów, Sewera z Antiochii. Jego nauczanie pozwoli wykazać, że prawdziwa przyczyna ich upartej obrony mía phýsis tkwi nie tyle w słabości definicji soborowej czy w autorytecie Cyryla, ile raczej leży u samych podstaw chrystologii lógos-sárx.
Comparative analysis of immunogenetic characteristics of potential hematopoietic stem cell donors from the registries of two Russian megapolises
Authors: Bubnova L. N. , Kuzmich E. V. , Pavlova I. E. , Belyaeva E. V. , Terentyeva M. A.
Published: November 2022

Efficacy of search for the unrelated compatible transplant donors depends on a number of factors. Of most importance are the standards of primary HLA typing, and the immunogenetic diversity of the donor pool. Timely donor selection guarantees the optimal timing for stem cell transplantation. This factor exerts positive influence upon the transplantation outcomes. In 2019, The Bone Marrow Donors Registry at the Russian Research Institute of Haematology and Transfusiology has implemented HLA-typing for HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1 genes as a standard for primary immunogenetic examination, in order to reduce the donor search period. The aim of our study was to evaluate the HLA typing results for potential stem cell donors at our Registry as compared with immunogenetic profile of donors at the Registries arranged in two Russian megapolises. All currently known groups of HLA-C, HLA-DRB1, HLA-DQB1 gene alleles, 19 of 21 open groups of HLA-A gene alleles, 34 of 36 known groups of HLA-B gene alleles were screened in the donors from our Registry. The most common HLA alleles groups were as follows: A*02 (0.2957), A*03 (0.1432), A*01 (0.1155), A*24 (0.1128); B*07 (0.1282), B*35 (0.1084), B*44 (0.0921), B*18 (0.0745); C*07 (0.2738), C*04 (0.1361), C*12 (0.1202), C*03 (0.1134), C*06 (0.1127); DRB1*15 (0.1445), DRB1*07 (0.1420), DRB1*13 (0.1271), DRB1*01 (0.1269), DRB1*11 (0.1216); DQB1*03 (0.3517), DQB1*06 (0.2269). A total of 1702 HLA-A*-B*-C*-DRB1*-DQB1*-haplotypes were revealed in our donor pool. The frequency of nine HLA-haplotypes exceeded 0.01: A*01-B*08-C*07-DRB1*03-DQB1*02 (0.0366), A*03-B*07-C*07-DRB1*15-DQB1*06 (0.0269), A*03-B*35-C*04-DRB1*01-DQB1*05 (0.0238), A*02-B*13-C*06-DRB1*07-DQB1*02 (0.0204), A*02-B*07-C*07-DRB1*15-DQB1*06 (0.0184), A*25-B*18-C*12-DRB1*15-DQB1*06 (0.0127), A*02-B*18-C*07-DRB1*11-DQB1*03 (0.0126), A*02-B*15-C*03-DRB1*04-DQB1*03 (0.0123), A*02-B*41-C*17-DRB1*13-DQB1*03 (0.0109). We carried out a comparative analysis of the HLA-haplotypes distribution for the donors of three Russian registers: Russian Research Institute of Haematology and Transfusiology (St. Petersburg); First St. Petersburg State I. Pavlov Medical University (St. Petersburg); National Medical Research Center for Hematology (Moscow). The six most common HLA-haplotypes among the donors from three Russian registers had the same rank positions and frequencies. The differences of some less common HLA-haplotypes distribution were determined. The results of our study indicate the immunogenetic diversity of the donor pool the Registry of Russian Research Institute of Haematology and Transfusiology. This fact, along with usage of international standards for primary immunogenetic examination is a prerequisite for effective donor search for the patients requiring stem cell transplantation.
Cytokine profile in community-acquired pneumonia in children
Authors: Iziurova N. V. , Savochkina A. Yu. , Uzunova A. N. , Nokhrin D. Yu.
Published: November 2022

Community-acquired pneumonia (CAP) is one of the most common acute infectious diseases. To date, the incidence of CAP among children was decreased significantly worldwide, mainly due to increasing use of effective preventive measures. Nevertheless, CAP remains a common cause of childhood morbidity and mortality. Pneumonia may develop at any age, but most often it occurs in young children, who are more likely to have a more severe course of pneumonia. Currently, early diagnosis and prognosis of the disease severity in children is an urgent issue. It was found that, in most cases, a panel of conventional biomarkers, including the number of leukocytes, procalcitonin, CRP is not sufficient for the diagnosis of pediatric CAP. There is a demand for new biological markers which, along with clinical evaluation, may significantly improve diagnostics and management of CAP in children, thus reducing the risk of adverse outcomes associated with this disease. Such markers could be found among the cytokines, which are active participants in the CAP pathogenesis. The aim of this study was to determine the level of several cytokines in blood serum of children with CAP and to assess changes in the cytokine profile depending on the patient’s age and severity of the disease. The study included 117 children aged 1 to 18 years with a diagnosis of CAP confirmed by X-ray examination. The comparison group included 28 healthy children who did not have CAP or other signs of acute respiratory viral infection at the time of examination, being free of any chronic pathology requiring outpatient observation. A number of cytokines were determined quantitatively in blood serum, i.e., IL-1β, IFNγ, IL-2, IL-4, IL-6, IL-10, TNFα, IFNλ2 (IL-28A), IFNλ3 (IL-28B), IL-8, MCP-1, IL-17AF, GM-CSF using test systems based on the “sandwich” method of solid-phase ELISA using peroxidase labeling. As a result, it was found that the content of IL-6, IL-17AF, IL-1β, IFNγ, MCP-1, IFNλ2 (IL-28A), IFNλ3 (IL-28B), GM-CSF was significantly higher in the group of children with severe community-acquired pneumonia. The levels of certain cytokines, e.g., IL-6, IFNλ2 (IL-28A), IFNλ3 (IL-28B), GM-CSF varied depending on the age of patients, thus, probably, reflecting the degree of immune system activation in the children of different age groups.
M-CSF and GM-CSF determinate fibromodulatory activity of polarized human macrophages
Authors: Maksimova A. A. , Shevela E. Ya. , Sakhno L. V. , Tikhonova M. A. , Ostanin A. A. , Chernykh E. R.
Published: November 2022

GM-CSF and M-CSF, the hematopoietic colony-stimulating factors, induce various phenotypic changes in macrophage lineage populations and promote cell differentiation, respectively, into M1- and M2-like macrophages. The pro- and anti-inflammatory properties of macrophages generated by these colony-stimulating factors are well described, but the contribution of differentiation and polarization signals to the fibromodulatory activity of macrophages remains unexplored. To clarify the differences in the fibrogenesis regulation mechanisms inherent in differently activated macrophages, we studied the effects of macrophage-conditioned media on proliferation and differentiation of dermal fibroblasts. In this study, the human macrophages generated from peripheral blood monocytes were investigated. They were induced for differentiation by M-CSF or GM-CSF, being further polarized in the M1 direction with lipopolysaccharide and, in the M2 direction, with IL-4 or dexamethasone. Proliferative response of the fibroblasts was determined radiometrically by [3H]-thymidine incorporation. Differentiation into myofibroblasts was determined with flow cytometry technique, as expression of a specific marker α-smooth muscle actin (α-SMA). The level of macrophage TGF-β1 production was assessed using an appropriate ELISA kit. The data obtained indicate that the macrophages differentiated under the influence of “homeostatic” M-CSF are characterized by a moderate stimulating effect upon fibroblast proliferation, and the effects of M2 (IL-4) and M2 (Dex) macrophages exceed that of M1 (LPS), but do not differ significantly from each other. The M-CSF-induced M1 (LPS) and M2 (IL-4) macrophages, but not M2 (Dex), enhance the fibroblast differentiation and show similar level of stimulation. In contrast to M-CSF, the macrophages induced by “pro-inflammatory” GM-CSF exhibit a pronounced stimulatory effect on fibroblast proliferation, and the effects of M2 macrophages exceed those of M1 cells, being most pronounced for M2 (Dex). At the same time, only GM-CSF-induced M2 (IL-4) macrophages enhance fibroblast differentiation. Dexamethasone-polarized macrophages do not significantly affect fibroblast differentiation regardless of the CSF used (M-CSF or GM-CSF). The content of TGF-β1 in the supernatants of differently activated macrophages does not correlate with the level of stimulating effect of macrophage-conditioned media upon fibroblast differentiation. In general, the data obtained suggest the involvement of differentiation and polarization signals into modulation of pro- and anti-fibrogenic properties of macrophages.
Osteoimmunology: an interdisciplinary approach to studying the relationships between immune and bone cells
Authors: Shirinsky V. S. , Shirinsky I. V.
Published: November 2022

In this review, we discuss molecular and cellular mechanisms underlying cross-talk between immune cells and bone cells, both in healthy conditions and in some diseases. We provide short description of the main cell populations of bone tissue, i.e., osteoblasts, osteoclasts, osteocytes, bone marrow macrophages, OsteoMacs, and their effects on immune cells during bone modeling and remodeling. The data are presented on regulatory molecular pathways of bone marrow cell activity, T and B cells, macrophages, and formation of “endosteal niche” by the bone cells. We describe the key system of bone tissue homeostasis: RANK/RANKL/ OPG, which regulates differentiation of osteoclasts and bone destruction. In addition, RANK/RANKL/ OPG system modulates maturation and activity of various T and B cell subsets. We present the data on pleiotropic effects of T cells, B cells, dendritic cells, macrophage subpopulations, Tregs, NK cells, neutrophils upon differentiation and function of osteoblasts and osteoclasts. These effects promote accumulation and maintenance of the bone mass. We describe mechanisms of these effects based on direct cell-to-cell contacts and various soluble mediators and intracellular signaling pathways. A brief characteristic of some diseases is provided with concomitant dysfunction of immune cells and bone cells which play a decisive pathogenetic role (fractures, rheumatoid arthritis, periodontitis, postmenopausal osteoporosis, multiple myeloma). It was shown that the destructive bone inflammation, both in RA and periodontitis, leads to loss of bone mass, being featured by similar pathophysiological mechanisms involving immune and bone cell populations. Therapy of these diseases requires newer treatment strategies aimed not only at pro-inflammatory cytokines, but for increased bone resorption. We describe involvement of activated T cells, their cytokines into the pathogenesis of postmenopausal osteoporosis, thus providing a rationale for the novel term of “immunoporosis”, coined in 2018. The relationships between multiple myeloma cells and bone marrow microenvironment are provided. This cross-talk is based on contact cell-cell interactions, as well as due to effects of soluble mediators upon osteoclasts, stromal cells, and osteoblasts. These effects result in osteolysis, loss of bone mass, and myeloma progression. In conclusion, the relationships between the immune and bone cell populations suggest that they function as an entire regulatory system. This consideration provides a framework for the development of new therapeutic targets for the treatment of bone and immune system disorders.
Role of cytokines in hepatocellular carcinoma
Authors: Aghayev T. , Titerina E. K. , Khoreva M. V. , Gankovskaya L. V.
Published: November 2022

Liver cancer ranks No. 5 in the world among all types of cancer and takes 3rd position among cancer-related deaths. Hepatocellular carcinoma (HCC) is a primary malignancy which does not include liver metastases from other sites. It is the most common form of liver cancers, and one of the leading causes of cancer-related deaths worldwide. HCC includes genetically and morphologically heterogeneous group of malignant tumors. HCC is characterized by a gender predisposition, namely, it occurs in men 1.5-fold more often, than in women. Viral infections such as hepatitis B and C are major risk factors for HCC. Moreover, non-alcoholic steatohepatitis (NASH) associated with metabolic syndrome and type 2 diabetes also becomes an increasingly common risk factor in developed countries. The mechanisms underlying the development of HCC are based on genetic changes in tumor cells and their microenvironment. Recently, the role of changes in the tumor microenvironment has drawn more attention, thus becoming the key characteristic in the HCC pathogenesis at all stages of the malignant process. Hepatocytes have a close relationship with immune cells, since in the liver, in addition to hepatocytes, there are Kupffer cells, myeloid cells (dendritic cells, monocytes and neutrophils) and other types of immune cells (T and B lymphocytes, NK and NKT, etc.). Cytokines released by various immune cells in the liver may influence liver processes, e.g., inflammation and carcinogenesis. Chronic inflammation results from persistent stimulation, or deficiencies of anti-inflammatory mechanisms. Its key features include immune cell infiltration, presence of inflammatory mediators, and imbalance of pro- and antiinflammatory cytokines leading to aggressive angiogenesis and tissue remodeling which, in turn, promotes the malignant process. Currently, there are several approaches to the HCC treatment which depend on the stage of the disease. Immunotherapy and its combinations have shown positive advances, and further research in this area will provide therapeutic options at the terminal stages of HCC. A variety of cytokines and their functions in HCC development are discussed in the present review article.
Uso da Escala de Avaliação do Desenvolvimento Infantil Bayley III em Crianças Brasileiras: Revisão Sistemática
Authors: Cruz Edson Júnior Silva da , Lima Samyra Said de , Cavalcante Lília Ieda Chaves , Pedroso Janari da Silva
Published: November 2022

Resumo O objetivo deste estudo foi realizar uma revisão sistemática de pesquisas com a Escala Bayley-III em crianças brasileiras. Foram seguidas as recomendações PRISMA, com buscas nas bases MEDLINE, LILACS, SCIELO, Scopus, PUBMED e Web of Science. A revisão incluiu artigos publicados nos idiomas português e inglês entre 2006 e 2018. Foram encontrados 856 estudos e, após análise do título e resumo, selecionaram-se 24. Os estudos avaliaram o desenvolvimento de crianças prematuras, típicas, frequentadoras de creche, e atípicas,sendo a maioria residente na região Sudeste e com até 12 meses de idade. A literatura apontou a prevalência de fatores de risco e altos percentuais de suspeitas e atrasos do desenvolvimento neuropsicomotor entre as crianças brasileiras avaliadas.
Permanence Policy in the Brazilian University: Psychology and Social Insertion through Education
Authors: Gomes Lucélia Maria Lima da Silva , Oliveira Adélia Augusta Souto de
Published: November 2022

Abstract Social access and permanence policies changed the profile of Brazilian graduate students, and new demands have required physical and human investments from the federal government. This study aims to discuss the implications of the permanence policy for the practice in psychology in federal higher education institutions, specifically in the context of student assistance in the Northeast of Brazil, using 88 documents from the websites of nine of the 63 federal universities. The interpretative results indicated four Meaning Nuclei: the presence of psychology in student healthcare; the development of teamwork; staff who contribute to the loss of students; and focus on the actions on the student body. These provide topics for further reflection by managers and student assistance professionals, in social insertion actions through education.
Política de Permanência na Universidade Brasileira: Psicologia e Inserção Social pela Educação
Authors: Gomes Lucélia Maria Lima da Silva , Oliveira Adélia Augusta Souto de
Published: November 2022

Resumo Políticas sociais de acesso e permanência modificaram o perfil do estudante brasileiro de graduação e novas demandas exigiram investimentos físicos e humanos do Governo Federal. Objetiva-se discutir as implicações da Política de Permanência para a prática em Psicologia no ensino superior federal, especificamente no contexto da assistência estudantil no Nordeste brasileiro. Utilizam-se 88 documentos online, nos sites de 9 das 63 universidades federais. Os resultados interpretativos indicaram quatro Núcleos de Significação, os quais evidenciaram a presença da Psicologia na atenção à saúde do estudante, o desenvolvimento do trabalho em equipe, um quadro de psicólogos/as deficitário e foco das ações no corpo discente. Esses apontam reflexões para gestores e profissionais da assistência estudantil, em ações de inserção social através da educação.