bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of COVID-Induced Mobility Restrictions and Weather Conditions on Air Quality in Hungary
Authors: Varga-Balogh Adrienn , Leelőssy Ádám , Mészáros Róbert
Published: April 2021

Similarly to other countries, the first wave of the COVID pandemic induced a collapse of mobility in Hungary during the spring of 2020. From the environmental perspective, the obtained road traffic reduction of 20–50% could be regarded as an undesired traffic regulation experiment. Air quality impacts within Hungary were evaluated based on data from 52 monitoring sites measuring concentrations of pollutants NOx, O3, and PM10. Air pollution during the lockdown was compared to the same period (February–June) in the reference years 2014–2019. The large spatial heterogeneity of the air quality response was explored. The emission reduction coincided with the extreme weather of 2020, characterized by unusually warm pre-lockdown February and spring drought. The anomalously low pre-lockdown air pollution was further reduced (NOx) or increased (PM10) during the restrictions. Compared to the previous years, NOx concentrations during the curfew were found to differ between −4.1 and +0.2 standard deviations (median −1.55 SD), or −45% and +3% (median −18%) among different monitoring locations. Ozone concentrations were unusually high due to both weather and chemical reasons (median +11% or +0.8 SD), while the PM10 response was modest and largely weather-driven (median +7% or +0.4 SD).
Physicochemical Analysis of Water Extracts of Particulate Matter from Polluted Air in the Area of Kraków, Poland
Authors: Mikrut Magdalena , Macyk Wojciech , van Eldik Rudi , Stochel Grażyna
Published: April 2021

Solubility of transition metal compounds plays a significant role in adverse health effects because that is one of the most important factors of particulate matter bioavailability in the body. In this study, we focus on the chemical analysis of particulate matter (PM) collected at different locations in the area of Kraków, one of the most polluted cities in Poland, and compare them with Standard Reference Material (SRM) 1648a from NIST. The content of four elements (carbon, hydrogen, nitrogen, and sulfur) was determined by elemental analysis, and the ratio between organic and inorganic carbon in PM extracts was confirmed by Total Organic Carbon analysis. Among the most concentrated elements found there are calcium, magnesium, sulfur, silicon, and zinc, whereas copper, iron, and manganese were present in lower concentrations. SEM-EDS analysis showed a similar morphology of the SRM and PM collected in the urban area of Kraków, while PM collected in the industrial area has smaller particles with a smooth surface. The reported analyses are significant for the APARIC project (“Air Pollution versus Autoimmunity: Role of multiphase aqueous Inorganic Chemistry”), which aims to identify the main inorganic components of PM and to understand how they affect the development of immunological diseases.
Field Study on Nationality Differences in Adaptive Thermal Comfort of University Students in Dormitories during Summer in Japan
Authors: Draganova Vanya Y. , Yokose Hiroki , Tsuzuki Kazuyo , Nabeshima Yuki
Published: April 2021

A summer field study was conducted in two university dormitories in the Tokai region of Central Japan. The study aimed at understanding the correlation between subjective thermal responses as well as whether nationality was affecting the responses. It was observed that nationality significantly affected thermal sensitivity and preference. The occupants’ acceptance for thermal stress was invariably above 90%. Despite the high levels of humidity observed, the multiple regression model showed that only the indoor air temperature was significant for explaining the variability of thermal sensation for both Japanese and non-Japanese students. The highest probability of voting neutral for university students in dormitory buildings in the Tokai region of Japan was estimated within 24~26.5 °C (by probit analysis). Japanese students were more sensitive to their indoor environment as opposed to the international students. The adjusted linear regression coefficient yielded from the room-wise day-wise averages were 0.48/K and 0.35/K for Japanese sensitivity and international sensitivity, respectively. In our study, the Griffiths’ model of estimating comfort temperature (or thermal neutrality) showed weak predictability and notable differences from the actually voted comfort. The neutral and comfort temperature observed and estimated in the study remained invariably below the recommended temperature threshold for Japan in summer leading to believe that that threshold is worth reevaluating.
A Feature Extraction and Classification Method to Forecast the PM2.5 Variation Trend Using Candlestick and Visual Geometry Group Model
Authors: Xu Rui , Liu Xiaoming , Wan Hang , Pan Xipeng , Li Jian
Published: April 2021

Currently, the continuous change prediction of PM2.5 concentration is an air pollution research hotspot. Combining physical methods and deep learning models to divide the pollution process of PM2.5 into effective multiple types is necessary to achieve a reliable prediction of the PM2.5 value. Therefore, a candlestick chart sample generator was designed to generate the candlestick chart from the online PM2.5 continuous monitoring data of the Guilin monitoring station site. After these generated candlestick charts were analyzed through the Gaussian diffusion model, it was found that the characteristics of the physical transmission process of PM2.5 pollutants can be reflected. Based on a set three-day period, using the time linear convolution method, 2188 sets of candlestick chart data were obtained from the 2013–2018 PM2.5 concentration data. There existed 16 categories generated by unsupervised classification that met the established classification judgment standards. After the statistical analysis, it was found that the accuracy rate of the change trend of these classifications reached 99.68% during the next period. Using the candlestick chart data as the training dataset, the Visual Geometry Group (VGG) model, an improved convolutional neural network model, was used for the classification. The experimental results showed that the overall accuracy (OA) value of the candlestick chart combination classification was 96.19%, and the Kappa coefficient was 0.960. IN the VGG model, the overall accuracy was improved by 1.93%, on average, compared with the support vector machines (SVM), LeNet, and AlexNet models. According to the experimental results, using the VGG classification method to classify continuous pollution data in the form of candlestick charts can more comprehensively retain the characteristics of the physical pollution process and provide a classification basis for accurately predicting PM2.5 values. At the same time, the statistical feasibility of this method has been proved.
Fluctuation of Lower Ionosphere Associated with Energetic Electron Precipitations during a Substorm
Authors: Fu Tongxing , Wu Zhixu , Hu Peng , Zhang Xin
Published: April 2021

In this paper, using the combined observations of the NOAA 16, LANL-01A, IMAGE satellites, VLF radio wave, and ground-based riometers, we study the fluctuation of lower ionosphere-associated precipitating energetic electrons during a geomagnetic storm on 8 November 2004. Associated with the substorm dispersion injection observed by the LANL-01A satellite, the riometers observed obvious enhancements of ionospheric absorption within the electron isotropic zone, which they attributed to the tail current sheet scattering (TCS) mechanism. Through observations of the NOAA 16 satellite, we found a sharp enhancement of the precipitating electron flux within the anisotropic zone, which entailed an obvious separation of energetic electron precipitation at high latitudes. This energetic electron precipitation within the anisotropic zone leads to the significant enhancement of electron density in the D region, thus resulting in the variations of VLF radio wave amplitudes, which propagate in the middle latitudes. Since the projection of the electron precipitation region within the anisotropic zone is at the inner edge of the plasmapause observed by the IMAGE EUV, the precipitation of energetic electrons should be attributed to the ELF hiss-ring current electron interaction. As a result, the energetic electron precipitations due to the tail current sheet scattering mechanism and wave-particle interaction in the inner magnetosphere were both observed and analyzed as they were associated with a substorm during a geomagnetic storm.
Experimental and Numerical Investigation of the Thermal Performance of a Hybrid Battery Thermal Management System for an Electric Van
Authors: Pra Franck , Al Koussa Jad , Ludwig Sebastian , De Servi Carlo M.
Published: April 2021

The temperature and the temperature gradient within the battery pack of an electric vehicle have a strong effect on the life time of the battery cells. In the case of automotive applications, a battery thermal management (BTM) system is required to maintain the temperature of the cells within a prescribed and safe range, and to prevent excessively high thermal gradients within the battery pack. This work documents the assessment of a thermal management system for a battery pack for an electric van, which adopts a combination of active/passive solutions: the battery cells are arranged in a matrix or composite made of expanded graphite and a phase change material (PCM), which can be actively cooled by forced air convection. The thermal dissipation of the cells was predicted based on an equivalent circuit model of the cells (LG Chem MJ1) that was empirically calibrated in a previous study. It resulted that, in order to keep the temperature of the battery pack at or below 40 °C during certain charge/discharge cycles, a purely passive BTM would require a considerable amount of PCM material that would unacceptably increase the battery pack weight. Therefore, the passive solution was combined with an air cooling system that could be activated when necessary. To assess the resulting hybrid BTM concept, CFD simulations were performed and an experimental test setup was built to validate the simulations. In particular, PCM melting and solidification times, the thermal discrepancy among the cells and the melting/solidification temperatures were examined. The melting time experimentally observed was higher than that predicted by the CFD model, but this discrepancy was not observed during the solidification of the PCM. This deviation between the CFD model results and the experimental data during PCM melting can be attributed to the thermal losses occurring through the mock-up casing as the heating elements are in direct contact with the external walls of the casing. Moreover, the temperature range over which the PCM solidifies was 6 °C lower than that estimated in the numerical simulations. This occurs because the simple thermodynamic model cannot predict the metastable state of the liquid phase which occurs before the onset of PCM solidification. The mockup was also used to emulate the heat dissipation of the cells during a highway driving cycle of the eVan and the thermal management solution as designed. Results showed that for this mission of the vehicle and starting from an initial temperature of the cells of 40 °C, the battery pack temperature could be maintained below 40 °C over the entire mission by a cooling air flow at 2.5 m/s and at a temperature of 30 °C.
Effects of Resistance Circuit-Based Training on Body Composition, Strength and Cardiorespiratory Fitness: A Systematic Review and Meta-Analysis
Authors: Ramos-Campo Domingo Jesús , Andreu Caravaca Luis , Martínez-Rodríguez Alejandro , Rubio-Arias Jacobo Ángel
Published: April 2021

We assessed the effects of resistance circuit-based training (CT) on strength, cardiorespiratory fitness, and body composition. A systematic review with meta-analysis was conducted in three databases, ending on March, 2020. Meta-analysis and subgroup analysis were used to analyze the effects of pre–post-intervention CT and differences from control groups (CG). Of the 830 studies found, 45 were included in the meta-analysis (58 experimental groups (n = 897) and 34 CG (n = 474)). The CT interventions led to increases in muscle mass (1.9%; p < 0.001) and decreases in fat mass (4.3%; p < 0.001). With regard to cardiorespiratory fitness, CT had a favorable effect on VO2max (6.3%; p < 0.001), maximum aerobic speed or power (0.3%; p = 0.04), and aerobic performance (2.6%; p = 0.006) after training. Concerning strength outcome, the CT increased the strength of the upper and lower extremities. Only the magnitude of strength performance appears to be influenced by the training (number of sessions and frequency) and the training status. Moreover, low and moderate intensities and short rest time between exercise increase the magnitude of change in fat mass loss. Therefore, CT has been shown to be an effective method for improving body composition, cardiorespiratory fitness, and strength of the lower and upper limbs.
Concerted Actions by PIICP, CTXII, and TNF-α in Patients with Juvenile Idiopathic Arthritis
Authors: Winsz-Szczotka Katarzyna , Kuźnik-Trocha Kornelia , Lachór-Motyka Iwona , Lemski Wojciech , Olczyk Krystyna
Published: April 2021

Joint destruction in juvenile idiopathic arthritis (JIA), initiated in the early, preclinical stage of the disease, is diagnosed on the basis of clinical evaluation and radiographic imaging. The determination of circulating cartilage-matrix turnover markers can facilitate the diagnosis and application of better and earlier treatment strategies for JIA. We have shown that 96 JIA patients have elevated levels of procollagen II C-terminal propeptide (PIICP), reflecting the extent of joint cartilage biosynthesis, and C-telopeptide of type II collagen (CTXII), a biomarker of the resorption of this tissue. Patients who did not respond to treatment had particularly high levels of these markers. JIA treatment resulted in the normalization of these markers in remissive patients, but not in those with active JIA. We showed correlations between examined variables and inflammatory process indicators, i.e., C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and tumor necrosis factor-α (TNF-α). The TNF-α of patients responding to treatment correlated with PIICP, especially in the patients before treatment (r = 0.898, p < 0.001). Significant changes in serum PIICP during JIA therapy suggest its potential diagnostic utility in the monitoring of disease activity and the possibility of its use in assessing treatment towards remission. Understanding changes in type II collagen metabolism over the course of the discussed arthritis may allow the implementation of both new diagnostic tools and new therapeutic strategies in children with JIA.
The Role of Alcohol, LPS Toxicity, and ALDH2 in Dental Bony Defects
Authors: Tsai Hsiao-Cheng , Chen Che-Hong , Mochly-Rosen Daria , Li Yi-Chen Ethan , Chen Min-Huey
Published: April 2021

It is estimated that 560 million people carry an East Asian-specific ALDH2*2 dominant-negative mutation which leads to enzyme inactivation. This common ALDH2 polymorphism has a significant association with osteoporosis. We hypothesized that the ALDH2*2 mutation in conjunction with periodontal Porphyromonas gingivalis bacterial infection and alcohol drinking had an inhibitory effect on osteoblasts and bone regeneration. We examined the prospective association of ALDH2 activity with the proliferation and mineralization potential of human osteoblasts in vitro. The ALDH2 knockdown experiments showed that the ALDH2 knockdown osteoblasts lost their proliferation and mineralization capability. To mimic dental bacterial infection, we compared the dental bony defects in wild-type mice and ALDH2*2 knockin mice after injection with purified lipopolysaccharides (LPS), derived from P. gingivalis which is a bacterial species known to cause periodontitis. Micro-computed tomography (micro-CT) scan results indicated that bone regeneration was significantly affected in the ALDH2*2 knockin mice with about 20% more dental bony defects after LPS injection than the wild-type mice. Moreover, the ALDH2*2 knockin mutant mice had decreased osteoblast growth and more dental bone loss in the upper left jaw region after LPS injection. In conclusion, these results indicated that the ALDH2*2 mutation with alcohol drinking and chronic exposure to dental bacterial-derived toxin increased the risk of dental bone loss.
The Real Need for Regenerative Medicine in the Future of Congenital Heart Disease Treatment
Authors: Matsuzaki Yuichi , Wiet Matthew G. , Boe Brian A. , Shinoka Toshiharu
Published: April 2021

Bioabsorbable materials made from polymeric compounds have been used in many fields of regenerative medicine to promote tissue regeneration. These materials replace autologous tissue and, due to their growth potential, make excellent substitutes for cardiovascular applications in the treatment of congenital heart disease. However, there remains a sizable gap between their theoretical advantages and actual clinical application within pediatric cardiovascular surgery. This review will focus on four areas of regenerative medicine in which bioabsorbable materials have the potential to alleviate the burden where current treatment options have been unable to within the field of pediatric cardiovascular surgery. These four areas include tissue-engineered pulmonary valves, tissue-engineered patches, regenerative medicine options for treatment of pulmonary vein stenosis and tissue-engineered vascular grafts. We will discuss the research and development of biocompatible materials reported to date, the evaluation of materials in vitro, and the results of studies that have progressed to clinical trials.
Nerve Biopsy in Peripheral Neuropathies: Not All Water Is under the Bridge
Authors: Luigetti Marco , Di Paolantonio Andrea
Published: April 2021

Sural nerve biopsy has long been a valuable diagnostic tool for the study of peripheral neuropathies, although the recent introduction of non-invasive techniques (e.g., neuroimaging techniques, skin biopsy) and advanced genetic and immunological testing has changed the diagnostic workup of peripheral nervous system diseases. [...]
Everyday Memory in People with Down Syndrome
Authors: Yang Yingying , Himmelberger Zachary M. , Robinson Trent , Davis Megan , Conners Frances , Merrill Edward
Published: April 2021

Although memory functions in people with Down Syndrome (DS) have been studied extensively, how well people with DS remember things about everyday life is not well understood. In the current study, 31 adolescents/young adults with DS and 26 with intellectual disabilities (ID) of mixed etiology (not DS) participated. They completed an everyday memory questionnaire about personal facts and recent events (e.g., school name, breakfast). They also completed a standard laboratory task of verbal long-term memory (LTM) where they recalled a list of unrelated words over trials. Results did not indicate impaired everyday memory, but impaired verbal LTM, in people with DS relative to people with mixed ID. Furthermore, the laboratory verbal LTM task predicted everyday memory for both groups after taking into account mental age equivalent. Our research showed both an independence and a connection between everyday memory and the standard laboratory memory task and has important research and clinical implications.
Effects of Specific Virtual Reality-Based Therapy for the Rehabilitation of the Upper Limb Motor Function Post-Ictus: Randomized Controlled Trial
Authors: Rodríguez-Hernández Marta , Polonio-López Begoña , Corregidor-Sánchez Ana-Isabel , Martín-Conty José L. , Mohedano-Moriano Alicia , Criado-Álvarez Juan-José
Published: April 2021

This research analyzed the combined effect of conventional treatment and virtual reality exposure therapy on the motor function of the upper extremities in people with stroke. We designed a randomized controlled trial set in the rehabilitation and neurology departments of a hospital (Talavera de la Reina, Spain). The subjects included 43 participants, all randomized into experimental (conventional treatment + virtual reality exposure therapy) and control group (conventional treatment).; The main measures were Fugl-Meyer Assessment for upper extremity, Modified Ashworth Scale, and Stroke Impact Scale 3.0. The results included 23 patients in the experimental (62.6 ± 13.5 years) and 20 in the control group (63.6 ± 12.2 years) who completed the study. After the intervention, muscle tone diminished in both groups, more so in the experimental group (mean baseline/post-intervention: from 1.30 to 0.60; η2 = 0.237; p = 0.001). Difficulties in performing functional activities that implicate the upper limb also diminished. Regarding the global recovery from stroke, both groups improved scores, but the experimental group scored significantly higher than the controls (mean baseline/post-intervention: from 28.7 to 86.5; η2 = 0.633; p = 0.000). In conclusion, conventional rehabilitation combined with specific virtual reality seems to be more efficacious than conventional physiotherapy and occupational therapy alone in improving motor function of the upper extremities and the autonomy of survivors of stroke in activities of daily living.
Preoperative Repetitive Navigated TMS and Functional White Matter Tractography in a Bilingual Patient with a Brain Tumor in Wernike Area
Authors: Baro Valentina , Caliri Samuel , Sartori Luca , Facchini Silvia , Guarrera Brando , Zangrossi Pietro , Anglani Mariagiulia , Denaro Luca , d’Avella Domenico , Ferreri Florinda , Landi Andrea
Published: April 2021

Awake surgery and intraoperative neuromonitoring represent the gold standard for surgery of lesion located in language-eloquent areas of the dominant hemisphere, enabling the maximal safe resection while preserving language function. Nevertheless, this functional mapping is invasive; it can be executed only during surgery and in selected patients. Moreover, the number of neuro-oncological bilingual patients is constantly growing, and performing awake surgery in this group of patients can be difficult. In this scenario, the application of accurate, repeatable and non-invasive preoperative mapping procedures is needed, in order to define the anatomical distribution of both languages. Repetitive navigated transcranial magnetic stimulation (rnTMS) associated with functional subcortical fiber tracking (nTMS-based DTI-FT) represents a promising and comprehensive mapping tool to display language pathway and function reorganization in neurosurgical patients. Herein we report a case of a bilingual patient affected by brain tumor in the left temporal lobe, who underwent rnTMS mapping for both languages (Romanian and Italian), disclosing the true eloquence of the anterior part of the lesion in both tests. After surgery, language abilities were intact at follow-up in both languages. This case represents a preliminary application of nTMS-based DTI-FT in neurosurgery for brain tumor in eloquent areas in a bilingual patient.
The Human Basal Ganglia Mediate the Interplay between Reactive and Proactive Control of Response through Both Motor Inhibition and Sensory Modulation
Authors: Criaud Marion , Anton Jean-Luc , Nazarian Bruno , Longcamp Marieke , Metereau Elise , Boulinguez Philippe , Ballanger Bénédicte
Published: April 2021

The basal ganglia (BG) have long been known for contributing to the regulation of motor behaviour by means of a complex interplay between tonic and phasic inhibitory mechanisms. However, after having focused for a long time on phasic reactive mechanisms, it is only recently that psychological research in healthy humans has modelled tonic proactive mechanisms of control. Mutual calibration between anatomo-functional and psychological models is still needed to better understand the unclear role of the BG in the interplay between proactive and reactive mechanisms of control. Here, we implemented an event-related fMRI design allowing proper analysis of both the brain activity preceding the target-stimulus and the brain activity induced by the target-stimulus during a simple go/nogo task, with a particular interest in the ambiguous role of the basal ganglia. Post-stimulus activity was evoked in the left dorsal striatum, the subthalamus nucleus and internal globus pallidus by any stimulus when the situation was unpredictable, pinpointing its involvement in reactive, non-selective inhibitory mechanisms when action restraint is required. Pre-stimulus activity was detected in the ventral, not the dorsal, striatum, when the situation was unpredictable, and was associated with changes in functional connectivity with the early visual, not the motor, cortex. This suggests that the ventral striatum supports modulatory influence over sensory processing during proactive control.
Dynamic Properties of Granulated Rubber Using Different Laboratory Tests
Authors: Moussa Ahmed , El Naggar Hany , Sadrekarimi Abouzar
Published: April 2021

Due to the socio-environmental hazards arising from the stockpiling of disposed scrap tires, the necessity to utilize such material in civil construction and other applications is deemed mandatory. The lightweight of rubber and its high damping capacity are excellent properties of a geomaterial that could be used successfully in seismic isolation and vibration damping applications in civil construction. Scrap tires could be shredded into specific sizes, and their category and application depend on their particle size range. Thus, understanding the dynamic properties and behavior of shredded scrap tires under cyclic loading is of paramount importance. In this study, the dynamic characteristics of granulated rubbers (<12 mm) are investigated using cyclic triaxial and cyclic direct simple shear tests. The effect of using different testing techniques, i.e., cyclic triaxial test (CTT) and cyclic simple shear test (CSST), on the dynamic properties of granulated rubber material is further addressed. Undrained cyclic triaxial and constant-volume direct simple shear tests are conducted on granulated rubber samples under vertical consolidation stresses of 25, 50, 100 and 200 kPa at a frequency of 0.5 Hz. The shear strain amplitude is varied from 0.01% to 10%. Furthermore, the variations of shear modulus and damping ratio with shear strain amplitude are presented. In addition, the obtained dynamic properties from this study are compared with existing experimental data from the literature. It was found that the ranges of shear moduli of granulated rubber from the CTT and CSST are 278 to 2647 kPa and 85 to 2270 kPa, respectively. Moreover, the damping ratios obtained from CTT were higher than those from CSST at shear strains of less than 1%. The damping ratio of granulated rubber was also found to be independent of the vertical consolidation stress.
Transient and Efficient Vascular Permeability Window for Adjuvant Drug Delivery Triggered by Microbeam Radiation
Authors: Sabatasso Sara , Fernandez-Palomo Cristian , Hlushchuk Ruslan , Fazzari Jennifer , Tschanz Stefan , Pellicioli Paolo , Krisch Michael , Laissue Jean , Djonov Valentin
Published: April 2021

Background: Microbeam Radiation Therapy (MRT) induces a transient vascular permeability window, which offers a novel drug-delivery system for the preferential accumulation of therapeutic compounds in tumors. MRT is a preclinical cancer treatment modality that spatially fractionates synchrotron X-rays into micrometer-wide planar microbeams which can induce transient vascular permeability, especially in the immature tumor vessels, without compromising vascular perfusion. Here, we characterized this phenomenon using Chicken Chorioallantoic Membrane (CAM) and demonstrated its therapeutic potential in human glioblastoma xenografts in mice. Methods: the developing CAM was exposed to planar-microbeams of 75 Gy peak dose with Synchrotron X-rays. Similarly, mice harboring human glioblastoma xenografts were exposed to peak microbeam doses of 150 Gy, followed by treatment with Cisplatin. Tumor progression was documented by Magnetic Resonance Imaging (MRI) and caliper measurements. Results: CAM exposed to MRT exhibited vascular permeability, beginning 15 min post-irradiation, reaching its peak from 45 min to 2 h, and ending by 4 h. We have deemed this period the “permeability window”. Morphological analysis showed partially fragmented endothelial walls as the cause of the increased transport of FITC-Dextran into the surrounding tissue and the extravasation of 100 nm microspheres (representing the upper range of nanoparticles). In the human glioblastoma xenografts, MRI measurements showed that the combined treatment dramatically reduced the tumor size by 2.75-fold and 5.25-fold, respectively, compared to MRT or Cisplatin alone. Conclusions: MRT provides a novel mechanism for drug delivery by increasing vascular transpermeability while preserving vessel integrity. This permeability window increases the therapeutic index of currently available chemotherapeutics and could be combined with other therapeutic agents such as Nanoparticles/Antibodies/etc.
Esophageal Cancer in Elderly Patients, Current Treatment Options and Outcomes; A Systematic Review and Pooled Analysis
Authors: Mantziari Styliani , Teixeira Farinha Hugo , Bouygues Vianney , Vignal Jean-Charles , Deswysen Yannick , Demartines Nicolas , Schäfer Markus , Piessen Guillaume
Published: April 2021

Esophageal cancer, despite its tendency to increase among younger patients, remains a disease of the elderly, with the peak incidence between 70–79 years. In spite of that, elderly patients are still excluded from major clinical trials and they are frequently offered suboptimal treatment even for curable stages of the disease. In this review, a clear survival benefit is demonstrated for elderly patients treated with neoadjuvant treatment, surgery, and even definitive chemoradiation compared to palliative or no treatment. Surgery in elderly patients is often associated with higher morbidity and mortality compared to younger patients and may put older frail patients at increased risk of autonomy loss. Definitive chemoradiation is the predominant modality offered to elderly patients, with very promising results especially for squamous cell cancer, although higher rates of acute toxicity might be encountered. Based on the all the above, and although the best available evidence comes from retrospective studies, it is not justified to refrain from curative treatment for elderly patients based on their age alone. Thorough assessment and an adapted treatment plan as well as inclusion of elderly patients in ongoing clinical trials will allow better understanding and management of esophageal cancer in this heterogeneous and often frail population.
CHEK2 Pathogenic Variants in Greek Breast Cancer Patients: Evidence for Strong Associations with Estrogen Receptor Positivity, Overuse of Risk-Reducing Procedures and Population Founder Effects
Authors: Apostolou Paraskevi , Dellatola Vasiliki , Papadimitriou Christos , Kalfakakou Despoina , Fountzilas Elena , Faliakou Eleni , Fountzilas Georgios , Romanidou Ourania , Konstantopoulou Irene , Fostira Florentia
Published: April 2021

CHEK2 germline pathogenic variants predispose to breast cancer and possibly to other malignancies, with their spectrum and frequency being variable among populations. Τhe majority of CHEK2-associated breast tumors are hormone receptor positive; however, relevant clinical outcomes are not well defined. Herein, we illustrate the histopathological characteristics and clinical outcomes of 52 Greek breast cancer patients who are CHEK2 carriers. Genetic analysis was performed by Sanger/massively parallel sequencing, followed by MLPA. Subsequent haplotype analysis investigated possible founder effects. Blood relatives were offered cascade testing. CHEK2 variant spectrum was characterized by variability, while influenced by founder effects. The majority of carriers, i.e., 60.8%, were diagnosed with breast cancer before the age of 45. Notably, 91.5% of breast tumors were hormone receptor positive. Hormone therapy and mastectomy at diagnosis seem to have a positive trend on overall survival, after a median follow-up of 9.5 years. Remarkably, 41.9% of patients underwent risk-reducing surgery, one third of which involved salpingo-oophorectomy. Nearly half of families responded to cascade testing. Our data highlight the need for guideline-adherent choices, based on the evidence that CHEK2 carriers are at moderate risk for breast cancer and no risk for ovarian cancer, while underscore the possible role of chemoprevention with tamoxifen.
MRD-Based Therapeutic Decisions in Genetically Defined Subsets of Adolescents and Young Adult Philadelphia-Negative ALL
Authors: Tosi Manuela , Spinelli Orietta , Leoncin Matteo , Cavagna Roberta , Pavoni Chiara , Lussana Federico , Intermesoli Tamara , Frison Luca , Perali Giulia , Carobolante Francesca , Viero Piera , Skert Cristina , Rambaldi Alessandro , Bassan Renato
Published: April 2021

In many clinical studies published over the past 20 years, adolescents and young adults (AYA) with Philadelphia chromosome negative acute lymphoblastic leukemia (Ph− ALL) were considered as a rather homogeneous clinico-prognostic group of patients suitable to receive intensive pediatric-like regimens with an improved outcome compared with the use of traditional adult ALL protocols. The AYA group was defined in most studies by an age range of 18–40 years, with some exceptions (up to 45 years). The experience collected in pediatric ALL with the study of post-induction minimal residual disease (MRD) was rapidly duplicated in AYA ALL, making MRD a widely accepted key factor for risk stratification and risk-oriented therapy with or without allogeneic stem cell transplantation and experimental new drugs for patients with MRD detectable after highly intensive chemotherapy. This combined strategy has resulted in long-term survival rates of AYA patients of 60–80%. The present review examines the evidence for MRD-guided therapies in AYA’s Ph− ALL, provides a critical appraisal of current treatment pitfalls and illustrates the ways of achieving further therapeutic improvement according to the massive knowledge recently generated in the field of ALL biology and MRD/risk/subset-specific therapy
Chromatin-Directed Proteomics Identifies ZNF84 as a p53-Independent Regulator of p21 in Genotoxic Stress Response
Authors: Strzeszewska-Potyrała Anna , Staniak Karolina , Czarnecka-Herok Joanna , Rafiee Mahmoud-Reza , Herok Marcin , Mosieniak Grażyna , Krijgsveld Jeroen , Sikora Ewa
Published: April 2021

The p21WAF1/Cip1 protein, encoded by CDKN1A, plays a vital role in senescence, and its transcriptional control by the tumour suppressor p53 is well-established. However, p21 can also be regulated in a p53-independent manner, by mechanisms that still remain less understood. We aimed to expand the knowledge about p53-independent senescence by looking for novel players involved in CDKN1A regulation. We used a chromatin-directed proteomic approach and identified ZNF84 as a novel regulator of p21 in various p53-deficient cell lines treated with cytostatic dose of doxorubicin. Knock-down of ZNF84, an as-yet un-characterized protein, inhibited p21 gene and protein expression in response to doxorubicin, it attenuated senescence and was associated with enhanced proliferation, indicating that ZNF84-deficiency can favor senescence bypass. ZNF84 deficiency was also associated with transcriptomic changes in genes governing various cancer-relevant processes e.g., mitosis. In cells with ZNF84 knock-down we discovered significantly lower level of H2AX Ser139 phosphorylation (γH2AX), which is triggered by DNA double strand breaks. Intriguingly, we observed a reverse correlation between the level of ZNF84 expression and survival rate of colon cancer patients. In conclusion, ZNF84, whose function was previously not recognized, was identified here as a critical p53-independent regulator of senescence, opening possibilities for its targeting in novel therapies of p53-null cancers.
Genetic Aspects of Myelodysplastic/Myeloproliferative Neoplasms
Authors: Palomo Laura , Acha Pamela , Solé Francesc
Published: April 2021

Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are myeloid neoplasms characterized by the presentation of overlapping features from both myelodysplastic syndromes and myeloproliferative neoplasms. Although the classification of MDS/MPN relies largely on clinical features and peripheral blood and bone marrow morphology, studies have demonstrated that a large proportion of patients (~90%) with this disease harbor somatic mutations in a group of genes that are common across myeloid neoplasms. These mutations play a role in the clinical heterogeneity of these diseases and their clinical evolution. Nevertheless, none of them is specific to MDS/MPN and current diagnostic criteria do not include molecular data. Even when such alterations can be helpful for differential diagnosis, they should not be used alone as proof of neoplasia because some of these mutations may also occur in healthy older people. Here, we intend to review the main genetic findings across all MDS/MPN overlap syndromes and discuss their relevance in the management of the patients.
Combination of Sorafenib and Transarterial Chemoembolization in Selected Patients with Advanced-Stage Hepatocellular Carcinoma: A Retrospective Cohort Study at Three German Liver Centers
Authors: Koch Christine , Göller Markus , Schott Eckart , Waidmann Oliver , op den Winkel Mark , Paprottka Philipp , Zangos Stephan , Vogl Thomas , Bechstein Wolf Otto , Zeuzem Stefan , Kolligs Frank T. , Trojan Jörg
Published: April 2021

Background and Aims. Systemic treatment with sorafenib has been the standard of care (SOC) in patients with advanced Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma (HCC) for more than a decade. TACE has been reported to allow better local tumor control in selected patients with BCLC stage C HCC. Methods. A retrospective analysis of patients with BCLC stage C HCC that were treated with sorafenib and TACE was conducted; they were compared to BCLC stage C patients treated either with TACE or sorafenib in the same period of time outside a clinical trial. Results. A total of 201 patients with BCLC stage C were identified, who were treated with either sorafenib and TACE (group A; n = 54), sorafenib (group B; n = 82) or TACE (group C; n = 65). No significant difference in baseline characteristics was observed. Time to progression was 7.0 months (95% CI: 4.3–9.7), 4.1 months (95% CI: 3.6–4.7) and 5.0 months (95% CI: 2.9–7.1) in groups A, B and C, respectively, and overall survival was 16.5 months (95% CI: 15.0–18.1), 8.4 months (95% CI: 6.0–10.8) and 10.5 months (95% CI: 7.5–13.6), respectively (group A vs. group B: p < 0.001; group A vs. group C: p = 0.0023). Adverse events of grade 3/4 occurred in 34% of patients in group A. Conclusions. Although sorafenib is a SOC in patients with BCLC stage C HCC, TACE is frequently used as an additional locoregional treatment in selected patients. This combined approach resulted in a significant overall survival benefit in selected patients, although randomized trials have not yet proven this benefit.
The Role of p53 Signaling in Colorectal Cancer
Authors: Liebl Magdalena C. , Hofmann Thomas G.
Published: April 2021

The transcription factor p53 functions as a critical tumor suppressor by orchestrating a plethora of cellular responses such as DNA repair, cell cycle arrest, cellular senescence, cell death, cell differentiation, and metabolism. In unstressed cells, p53 levels are kept low due to its polyubiquitination by the E3 ubiquitin ligase MDM2. In response to various stress signals, including DNA damage and aberrant growth signals, the interaction between p53 and MDM2 is blocked and p53 becomes stabilized, allowing p53 to regulate a diverse set of cellular responses mainly through the transactivation of its target genes. The outcome of p53 activation is controlled by its dynamics, its interactions with other proteins, and post-translational modifications. Due to its involvement in several tumor-suppressing pathways, p53 function is frequently impaired in human cancers. In colorectal cancer (CRC), the TP53 gene is mutated in 43% of tumors, and the remaining tumors often have compromised p53 functioning because of alterations in the genes encoding proteins involved in p53 regulation, such as ATM (13%) or DNA-PKcs (11%). TP53 mutations in CRC are usually missense mutations that impair wild-type p53 function (loss-of-function) and that even might provide neo-morphic (gain-of-function) activities such as promoting cancer cell stemness, cell proliferation, invasion, and metastasis, thereby promoting cancer progression. Although the first compounds targeting p53 are in clinical trials, a better understanding of wild-type and mutant p53 functions will likely pave the way for novel CRC therapies.
Genomic Instability in Multiple Myeloma: A “Non-Coding RNA” Perspective
Authors: Taiana Elisa , Gallo Cantafio Maria Eugenia , Favasuli Vanessa Katia , Bandini Cecilia , Viglietto Giuseppe , Piva Roberto , Neri Antonino , Amodio Nicola
Published: April 2021

Multiple myeloma (MM) is a complex hematological malignancy characterized by abnormal proliferation of malignant plasma cells (PCs) within a permissive bone marrow microenvironment. The pathogenesis of MM is unequivocally linked to the acquisition of genomic instability (GI), which indicates the tendency of tumor cells to accumulate a wide repertoire of genetic alterations. Such alterations can even be detected at the premalignant stages of monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) and, overall, contribute to the acquisition of the malignant traits underlying disease progression. The molecular basis of GI remains unclear, with replication stress and deregulation of DNA damage repair pathways representing the most documented mechanisms. The discovery that non-coding RNA molecules are deeply dysregulated in MM and can target pivotal components of GI pathways has introduced a further layer of complexity to the GI scenario in this disease. In this review, we will summarize available information on the molecular determinants of GI in MM, focusing on the role of non-coding RNAs as novel means to tackle GI for therapeutic intervention.
Prediction of Incident Cancers in the Lifelines Population-Based Cohort
Authors: Cortés-Ibañez Francisco O. , Nagaraj Sunil Belur , Cornelissen Ludo , Navis Gerjan J. , van der Vegt Bert , Sidorenkov Grigory , de Bock Geertruida H.
Published: April 2021

Cancer incidence is rising, and accurate prediction of incident cancers could be relevant to understanding and reducing cancer incidence. The aim of this study was to develop machine learning (ML) models that could predict an incident diagnosis of cancer. Participants without any history of cancer within the Lifelines population-based cohort were followed for a median of 7 years. Data were available for 116,188 cancer-free participants and 4232 incident cancer cases. At baseline, socioeconomic, lifestyle, and clinical variables were assessed. The main outcome was an incident cancer during follow-up (excluding skin cancer), based on linkage with the national pathology registry. The performance of three ML algorithms was evaluated using supervised binary classification to identify incident cancers among participants. Elastic net regularization and Gini index were used for variables selection. An overall area under the receiver operator curve (AUC) <0.75 was obtained, the highest AUC value was for prostate cancer (random forest AUC = 0.82 (95% CI 0.77–0.87), logistic regression AUC = 0.81 (95% CI 0.76–0.86), and support vector machines AUC = 0.83 (95% CI 0.78–0.88), respectively); age was the most important predictor in these models. Linear and non-linear ML algorithms including socioeconomic, lifestyle, and clinical variables produced a moderate predictive performance of incident cancers in the Lifelines cohort.
Immobilization of the Peroxygenase from Agrocybe aegerita. The Effect of the Immobilization pH on the Features of an Ionically Exchanged Dimeric Peroxygenase
Authors: Carballares Diego , Morellon-Sterling Roberto , Xu Xiaomin , Hollmann Frank , Fernandez-Lafuente Roberto
Published: April 2021

This paper outlines the immobilization of the recombinant dimeric unspecific peroxygenase from Agrocybe aegerita (rAaeUPO). The enzyme was quite stable (remaining unaltered its activity after 35 h at 47 °C and pH 7.0). Phosphate destabilized the enzyme, while glycerol stabilized it. The enzyme was not immobilized on glyoxyl-agarose supports, while it was immobilized albeit in inactive form on vinyl-sulfone-activated supports. rAaeUPO immobilization on glutaraldehyde pre-activated supports gave almost quantitative immobilization yield and retained some activity, but the biocatalyst was very unstable. Its immobilization via anion exchange on PEI supports also produced good immobilization yields, but the rAaeUPO stability dropped. However, using aminated agarose, the enzyme retained stability and activity. The stability of the immobilized enzyme strongly depended on the immobilization pH, being much less stable when rAaeUPO was adsorbed at pH 9.0 than when it was immobilized at pH 7.0 or pH 5.0 (residual activity was almost 0 for the former and 80% for the other preparations), presenting stability very similar to that of the free enzyme. This is a very clear example of how the immobilization pH greatly affects the final biocatalyst performance.
Complexity and Specificity of Sec61-Channelopathies: Human Diseases Affecting Gating of the Sec61 Complex
Authors: Sicking Mark , Lang Sven , Bochen Florian , Roos Andreas , Drenth Joost P. H. , Zakaria Muhammad , Zimmermann Richard , Linxweiler Maximilian
Published: April 2021

The rough endoplasmic reticulum (ER) of nucleated human cells has crucial functions in protein biogenesis, calcium (Ca2+) homeostasis, and signal transduction. Among the roughly one hundred components, which are involved in protein import and protein folding or assembly, two components stand out: The Sec61 complex and BiP. The Sec61 complex in the ER membrane represents the major entry point for precursor polypeptides into the membrane or lumen of the ER and provides a conduit for Ca2+ ions from the ER lumen to the cytosol. The second component, the Hsp70-type molecular chaperone immunoglobulin heavy chain binding protein, short BiP, plays central roles in protein folding and assembly (hence its name), protein import, cellular Ca2+ homeostasis, and various intracellular signal transduction pathways. For the purpose of this review, we focus on these two components, their relevant allosteric effectors and on the question of how their respective functional cycles are linked in order to reconcile the apparently contradictory features of the ER membrane, selective permeability for precursor polypeptides, and impermeability for Ca2+. The key issues are that the Sec61 complex exists in two conformations: An open and a closed state that are in a dynamic equilibrium with each other, and that BiP contributes to its gating in both directions in cooperation with different co-chaperones. While the open Sec61 complex forms an aqueous polypeptide-conducting- and transiently Ca2+-permeable channel, the closed complex is impermeable even to Ca2+. Therefore, we discuss the human hereditary and tumor diseases that are linked to Sec61 channel gating, termed Sec61-channelopathies, as disturbances of selective polypeptide-impermeability and/or aberrant Ca2+-permeability.