bluuebunny/crossref_metadata_2025 huggingface dataset:
PLGA-CS-PEG Microparticles for Controlled Drug Delivery in the Treatment of Triple Negative Breast Cancer Cells
Authors: Jusu Sandra Musu , Obayemi John David , Salifu Ali Azeko , Nwazojie Chukwudalu Clare , Uzonwanne Vanessa Obiageli , Odusanya Olushola Segun , Soboyejo Winnston Oluwole
Published: August 2021

In this study, we explore the development of controlled PLGA-CS-PEG microspheres, which are used to encapsulate model anticancer drugs (prodigiosin (PGS) or paclitaxel (PTX)) for controlled breast cancer treatment. The PLGA microspheres are blended with hydrophilic polymers (chitosan and polyethylene glycol) in the presence of polyvinyl alcohol (PVA) that were synthesized via a water-oil-water (W/O/W) solvent evaporation technique. Chitosan (CS) and polyethylene glycol (PEG) were used as surface-modifying additives to improve the biocompatibility and reduce the adsorption of plasma proteins onto the microsphere surfaces. These PLGA-CS-PEG microspheres are loaded with varying concentrations (5 and 8 mg/mL) of PGS or PTX, respectively. Scanning electron microscopy (SEM) revealed the morphological properties while Fourier transform infrared spectroscopy (FTIR) was used to elucidate the functional groups of drug-loaded PLGA-CS-PEG microparticles. A thirty-day, in vitro, encapsulated drug (PGS or PTX) release was carried out at 37 °C, which corresponds to human body temperature, and at 41 °C and 44 °C, which correspond to hyperthermic temperatures. The thermodynamics and kinetics of in vitro drug release were also elucidated using a combination of mathematical models and the experimental results. The exponents of the Korsmeyer–Peppas model showed that the kinetics of drug release was well characterized by anomalous non-Fickian drug release. Endothermic and nonspontaneous processes are also associated with the thermodynamics of drug release. Finally, the controlled in vitro release of cancer drugs (PGS and PTX) is shown to decrease the viability of MDA-MB-231 cells. The implications of the results are discussed for the development of drug-encapsulated PLGA-CS-PEG microparticles for the controlled release of cancer drugs in treatment of triple negative breast cancer.
Role of Quercetin in Depressive-Like Behaviors: Findings from Animal Models
Authors: Silvestro Serena , Bramanti Placido , Mazzon Emanuela
Published: August 2021

Depressive-like behavior is a highly prevalent worldwide neuropsychiatric disorder that owns a complex pathophysiologic mechanism. The available pharmacotherapy is ineffective for most patients and shown several adverse effects. Therefore, it is important to find efficacy and safe antidepressive compounds. Some phytochemicals compounds regulate the same genes and pathways targeted by drugs; therefore, diets rich in fruits and vegetables could be considered novel treatment approaches. Currently, the functional properties of quercetin acquired great interest, due to its beneficial effects on health. Quercetin is a flavonoid ubiquitously present in vegetables and fruits, interestingly for its strong antioxidant properties. The purpose of this review is to summarize the preclinical studies present in the literature, in the last ten years, aimed at illustrating the effects of quercetin pre-treatment in depressive-like behaviors. Quercetin resulted in antidepressant-like actions due to its antioxidant, anti-inflammatory, and neuroprotective effects. This pointed out the usefulness of this flavonoid as a nutraceutical compound against the development of psychological stress-induced behavioral perturbation. Therefore, quercetin or a diet containing it may become a prospective supplementation or an efficient adjuvant therapy for preventing stress-mediated depressive-like behavior.
Fibers Effects on Contract Turbulence Using a Coupling Euler Model
Authors: Yang Wei , Hu Pei
Published: August 2021

Fiber additive will induce the rheological behavior of suspension, resulting in variation in velocity profile and fiber orientation especially for the non-dilute case. Based on the fluid-solid coupling dynamics simulation, it shows that the fiber orientation aligns along the streamline more and more quickly in the central turbulent region as the fiber concentration increases, especially contract ratio Cx > 4. However, fibers tend to maintain the original uniform orientation and are rarely affected by the contract ratio in the boundary layer. The fibers orientation in the near semi-dilute phase is lower than that in the dilute phase near the outlet, which may be the result of the hydrodynamic contact lubrication between fibers. The orientation distribution and concentration of the fibers change the viscous flow mechanism of the suspension microscopically, which makes a velocity profile vary with the phase concentration. The velocity profile of the approaching semi-dilute phase sublayer is higher than that of the dilute and semi-dilute phases on the central streamline and in the viscous bottom layer, showing weak drag reduction while the situation is opposite on the logarithmic layer of the boundary layer. The relevant research can provide a process strategy for fiber orientation optimization and rheological control in the industrial applications of suspension.
An Algorithm for Solving Robot Inverse Kinematics Based on FOA Optimized BP Neural Network
Authors: Bai Yonghua , Luo Minzhou , Pang Fenglin
Published: August 2021

The solution of robot inverse kinematics has a direct impact on the control accuracy of the robot. Conventional inverse kinematics solution methods, such as numerical solution, algebraic solution, and geometric solution, have insufficient solution speed and solution accuracy, and the solution process is complicated. Due to the mapping ability of the neural network, the use of neural networks to solve robot inverse kinematics problems has attracted widespread attention. However, it has slow convergence speed and low accuracy. This paper proposes the FOA optimized BP neural network algorithm to solve inverse kinematics. It overcomes the shortcomings of low convergence accuracy, slow convergence speed, and easy to fall into local minima when using BP neural network to solve inverse kinematics. The experimental results show that using the trained FOA optimized BP neural network to solve the inverse kinematics, the maximum error range of the output joint angle is [−0.04686, 0.1271]. The output error of the FOA optimized BP neural network algorithm is smaller than that of the ordinary BP neural network algorithm and the PSO optimized BP neural network algorithm. Using the FOA optimized BP neural network algorithm to solve the robot kinematics can improve the control accuracy of the robot.
A Modular Mobile Robotic Platform to Assist People with Different Degrees of Disability
Authors: Catalan Jose M. , Blanco Andrea , Bertomeu-Motos Arturo , Garcia-Perez Jose V. , Almonacid Miguel , Puerto Rafael , Garcia-Aracil Nicolas
Published: August 2021

Robotics to support elderly people in living independently and to assist disabled people in carrying out the activities of daily living independently have demonstrated good results. Basically, there are two approaches: one of them is based on mobile robot assistants, such as Care-O-bot, PR2, and Tiago, among others; the other one is the use of an external robotic arm or a robotic exoskeleton fixed or mounted on a wheelchair. In this paper, a modular mobile robotic platform to assist moderately and severely impaired people based on an upper limb robotic exoskeleton mounted on a robotized wheel chair is presented. This mobile robotic platform can be customized for each user’s needs by exploiting its modularity. Finally, experimental results in a simulated home environment with a living room and a kitchen area, in order to simulate the interaction of the user with different elements of a home, are presented. In this experiment, a subject suffering from multiple sclerosis performed different activities of daily living (ADLs) using the platform in front of a group of clinicians composed of nurses, doctors, and occupational therapists. After that, the subject and the clinicians replied to a usability questionnaire. The results were quite good, but two key factors arose that need to be improved: the complexity and the cumbersome aspect of the platform.
Geotechnical Design Practices and Soil–Structure Interaction Effects of an Integral Bridge System: A Review
Authors: Sigdel Lila Dhar , Al-Qarawi Ahmed , Leo Chin Jian , Liyanapathirana Samanthika , Hu Pan
Published: August 2021

Integral bridges are a class of bridges with integral or semi-integral abutments, designed without expansion joints in the bridge deck of the superstructure. The significance of an integral bridge design is that it avoids durability and recurring maintenance issues with bridge joints, and maybe bearings, which are prevalent in traditional bridges. Integral bridges are less costly to construct. They require less maintenance and therefore cause less traffic disruptions that incur socio-economic costs. As a consequence, integral bridges are becoming the first choice of bridge design for short-to-medium length bridges in many countries, including the UK, USA, Europe, Australia, New Zealand and many other Asian countries. However, integral bridge designs are not without challenges: issues that concern concrete creep, shrinkage, temperature effects, bridge skew, structural constraints, as well as soil–structure interactions are amplified in integral bridges. The increased cyclic soil–structure interactions between the bridge structure and soil will lead to adverse soil ratcheting and settlement bump at the bridge approach. If movements from bridge superstructures were also transferred to pile-supported substructures, there is a risk that the pile–soil interactions may lead to pile fatigue failure. These issues complicate the geotechnical aspects of integral bridges. The aim of this paper is to present a comprehensive review of current geotechnical design practices and the amelioration of soil–structure interactions of integral bridges.
An Integrated SWOT-PESTLE-AHP Model Assessing Sustainability in Adaptive Reuse Projects
Authors: Vardopoulos Ioannis , Tsilika Evangelia , Sarantakou Efthymia , Zorpas Antonis , Salvati Luca , Tsartas Paris
Published: August 2021

In the recent past, sustainable development has been considered a major issue for urban and regional studies. Adaptive reuse appears to be a practical solution for sustainable urban development. Beyond and in addition to a conceptual base consistent with circular economy and sustainability principles, how do we know if adaptive reuse is actually sustainable, provided that it constitutes a multidisciplinary and multilevel process? The present study aims at evaluating, in as much as feasible quantitative terms, adaptive reuse practices sustainability. This was attained using a set of indicators, developed combining PESTLE (the Political, Economic, Technical, Social, Legal, and Environmental aspects) and SWOT (the Strengths, Weaknesses, Opportunities, and Threats) approaches, of which the results were subjected to evaluation by experts (pairwise comparisons), following the Analytic Hierarchy Process (AHP). The indicators representing strengths and opportunities of the process were calculated to be of higher value (overall level of final cumulative indicators values; 70.4%) compared with indicators representing weaknesses and threats. Enhancing strengths and opportunities and counteracting weaknesses and threats contribute making the potential of adaptive reuse practices in urban sustainability more evident. Among analysis dimensions, political and economic aspects rank first, followed by environmental, socio-cultural, technological-technical, and legal aspect. The empirical results of this paper serve as a useful reference point for decision-making and policy formulation addressing adaptive reuse practices in sustainable development strategies.
Artificial Neural Network-Based Method for Real-Time Estimation of Compaction Quality of Hot Asphalt Mixes
Authors: Xue Zhichao , Cao Weidong , Liu Shutang , Ren Fei , Wu Qilun
Published: August 2021

With the advancement of intelligent compaction technology, real-time quality control has been widely investigated on the subgrade, while it is insufficient on asphalt pavement. This paper aims to estimate the real-time compaction quality of hot mix asphalt (HMA) using an artificial neural network (ANN) classifier. A field experiment of HMA compaction was designed. The vibration patterns of the drum were identified by using the ANN classifier and classified based on the compaction levels. The vibration signals were collected and the degree of compaction was measured in the field experiment. The collected signals were processed and the features of vibration patterns were extracted. The processed signals were tagged with their corresponding compaction level to form the sample dataset to train the ANN models. Four ANN models with different hidden layer setups were considered to investigate the effect of hidden layer structure on performance. To test the performance of the ANN classifier, the predictions made by ANN were compared with the measuring results from a non-nuclear density gauge (NNDG). The testing results show that the ANN classifier has good performance and huge potential for estimating the compaction quality of HMA in real-time.
A Novel Dental Caries Model Replacing, Refining, and Reducing Animal Sacrifice
Authors: Wolfoviz-Zilberman Amit , Houri-Haddad Yael , Beyth Nurit
Published: August 2021

In vitro and in vivo models simulating the dental caries process enable the evaluation of anti-caries modalities for prevention and treatment. Animal experimentation remains important for improving human and animal health. Nonetheless, reducing animal sacrifice for research is desirable. The aim of the study was to establish a new reproducible in vitro caries model system and compare it to an in vivo model using similar conditions. Hemi-mandibles were extracted from previously euthanized healthy 10-week-old BALB/C female mice. Jaws were subjected to saliva, high-sucrose diet, and dental caries bacteria Streptococcus mutans UA159 for 5 days. Similar caries induction protocol was used in vivo in fifteen BALB/c female mice (6–7 weeks old) and compared to the in vitro model. Caries lesions were assessed clinically by photographic analysis and µCT analysis, and bacterial growth was evaluated. Under in vitro experimental conditions, carious lesions evolved within 5 days, prominently in the depth of the occlusal fissures in the control group as depicted by photographic analysis, µCT analysis, and bacterial growth. The developed in vitro caries model presented in this study may be a novel animal sparing model for caries disease studies and can be used widely to evaluate the efficacy of different antibacterial dental materials.
Assessing Climate Change Trends and Their Relationships with Alpine Vegetation and Surface Water Dynamics in the Everest Region, Nepal
Authors: Rai Mana Raj , Chidthaisong Amnat , Ekkawatpanit Chaiwat , Varnakovida Pariwate
Published: August 2021

The Himalayas, especially the Everest region, are highly sensitive to climate change. Although there are research works on this region related to cryospheric work, the ecological understandings of the alpine zone and climate impacts are limited. This study aimed to assess the changes in surface water including glacier lake and streamflow and the spatial and temporal changes in alpine vegetation and examine their relationships with climatic factors (temperature and precipitation) during 1995–2019 in the Everest region and the Dudh Koshi river basin. In this study, Landsat time-series data, European Commission’s Joint Research Center (JRC) surface water data, ECMWF Reanalysis 5th Generation (ERA5) reanalysis temperature data, and meteorological station data were used. It was found that the glacial lake area and volume are expanding at the rates of 0.0676 and 0.0198 km3/year, respectively; the average annual streamflow is decreasing at the rate of 2.73 m3/s/year. Similarly, the alpine vegetation greening as indicated by normalized difference vegetation index (NDVI) is increasing at the rate of 0.00352 units/year. On the other hand, the annual mean temperature shows an increasing trend of 0.0329 °C/year, and the annual precipitation also shows a significant negative monotonic trend. It was also found that annual NDVI is significantly correlated with annual temperature. Likewise, the glacial lake area expansion is strongly correlated with annual minimum temperature and annual precipitation. Overall, we found a significant alteration in the alpine ecosystem of the Everest region that could impact on the water–energy–food nexus of the Dudh Koshi river basin.
Assessing the Contrasting Effects of the Exceptional 2015 Drought on the Carbon Dynamics in Two Norway Spruce Forest Ecosystems
Authors: Mensah Caleb , Šigut Ladislav , Fischer Milan , Foltýnová Lenka , Jocher Georg , Acosta Manuel , Kowalska Natalia , Kokrda Lukáš , Pavelka Marian , Marshall John David , Nyantakyi Emmanuel K. , Marek Michal V.
Published: August 2021

The occurrence of extreme drought poses a severe threat to forest ecosystems and reduces their capability to sequester carbon dioxide. This study analysed the impacts of a central European summer drought in 2015 on gross primary productivity (GPP) at two Norway spruce forest sites representing two contrasting climatic conditions—cold and humid climate at Bílý Kříž (CZ-BK1) vs. moderately warm and dry climate at Rájec (CZ-RAJ). The comparative analyses of GPP was based on a three-year eddy covariance dataset, where 2014 and 2016 represented years with normal conditions, while 2015 was characterized by dry conditions. A significant decline in the forest GPP was found during the dry year of 2015, reaching 14% and 6% at CZ-BK1 and CZ-RAJ, respectively. The reduction in GPP coincided with high ecosystem respiration (Reco) during the dry year period, especially during July and August, when several heat waves hit the region. Additional analyses of GPP decline during the dry year period suggested that a vapour pressure deficit played a more important role than the soil volumetric water content at both investigated sites, highlighting the often neglected importance of considering the species hydraulic strategy (isohydric vs. anisohydric) in drought impact assessments. The study indicates the high vulnerability of the Norway spruce forest to drought stress, especially at sites with precipitation equal or smaller than the atmospheric evaporative demand. Since central Europe is currently experiencing large-scale dieback of Norway spruce forests in lowlands and uplands (such as for CZ-RAJ conditions), the findings of this study may help to quantitatively assess the fate of these widespread cultures under future climate projections, and may help to delimitate the areas of their sustainable production.
A Modeling Study on the Downslope Wind of “Katevatos” in Greece and Implications for the Battle of Arachova in 1826
Authors: Solomos Stavros , Nastos Panagiotis , Emmanouloudis Dimitrios , Koutsouraki Antonia , Zerefos Christos
Published: August 2021

Downslope winds and lee gravity waves are common features of mountainous environments. A similar weather type at Mt. Parnassos in Arachova, Greece is known as “Katevatos” and has devastating results for the population and visitors at the local touristic resorts. In this study, we analyze three incidents of this atmospheric pattern at local scale resolution (1 × 1 km) with WRF model. This is the first study of this local weather hazard, and the following key factors are identified. (I) The main synoptic forcing is the propagation of an upper-level trough from central Europe towards the Balkans. (II) The associated generation of a surface low-pressure system over the Aegean Sea results in a northeast flow in the lower troposphere that is perpendicular to the main topographic ridge of Mt. Parnassos. (III) Generation of gravity waves and downward reflection of wave energy at the critical level between the upper level flow and the undercutting northeast current result in the formation of “Katevatos” downslope wind at the lee side of the mountain. This hurricane-scale wind is accompanied with horizontal transport of frozen rain and snow from the mountain tops towards the village of Arachova. This wind pattern appeared also during the battle of Arachova in November 1826 between the Greek and Ottoman forces resulting in enormous casualties due to the adverse weather conditions.
Some New Fractional Estimates of Inequalities for LR-p-Convex Interval-Valued Functions by Means of Pseudo Order Relation
Authors: Khan Muhammad Bilal , Mohammed Pshtiwan Othman , Noor Muhammad Aslam , Baleanu Dumitru , Guirao Juan Luis García
Published: August 2021

It is a familiar fact that interval analysis provides tools to deal with data uncertainty. In general, interval analysis is typically used to deal with the models whose data are composed of inaccuracies that may occur from certain kinds of measurements. In interval analysis, both the inclusion relation (⊆) and pseudo order relation (≤p) are two different concepts. In this article, by using pseudo order relation, we introduce the new class of nonconvex functions known as LR-p-convex interval-valued functions (LR-p-convex-IVFs). With the help of this relation, we establish a strong relationship between LR-p-convex-IVFs and Hermite-Hadamard type inequalities (HH-type inequalities) via Katugampola fractional integral operator. Moreover, we have shown that our results include a wide class of new and known inequalities for LR-p-convex-IVFs and their variant forms as special cases. Useful examples that demonstrate the applicability of the theory proposed in this study are given. The concepts and techniques of this paper may be a starting point for further research in this area.
Brain Organoids: Filling the Need for a Human Model of Neurological Disorder
Authors: Jalink Philip , Caiazzo Massimiliano
Published: August 2021

Neurological disorders are among the leading causes of death worldwide, accounting for almost all onsets of dementia in the elderly, and are known to negatively affect motor ability, mental and cognitive performance, as well as overall wellbeing and happiness. Currently, most neurological disorders go untreated due to a lack of viable treatment options. The reason for this lack of options is s poor understanding of the disorders, primarily due to research models that do not translate well into the human in vivo system. Current models for researching neurological disorders, neurodevelopment, and drug interactions in the central nervous system include in vitro monolayer cell cultures, and in vivo animal models. These models have shortcomings when it comes to translating research about disorder pathology, development, and treatment to humans. Brain organoids are three-dimensional (3D) cultures of stem cell-derived neural cells that mimic the development of the in vivo human brain with high degrees of accuracy. Researchers have started developing these miniature brains to model neurodevelopment, and neuropathology. Brain organoids have been used to model a wide range of neurological disorders, including the complex and poorly understood neurodevelopmental and neurodegenerative disorders. In this review, we discuss the brain organoid technology, placing special focus on the different brain organoid models that have been developed, discussing their strengths, weaknesses, and uses in neurological disease modeling.
Cranial Suture Mesenchymal Stem Cells: Insights and Advances
Authors: Li Bo , Wang Yigan , Fan Yi , Ouchi Takehito , Zhao Zhihe , Li Longjiang
Published: August 2021

The cranial bones constitute the protective structures of the skull, which surround and protect the brain. Due to the limited repair capacity, the reconstruction and regeneration of skull defects are considered as an unmet clinical need and challenge. Previously, it has been proposed that the periosteum and dura mater provide reparative progenitors for cranial bones homeostasis and injury repair. In addition, it has also been speculated that the cranial mesenchymal stem cells reside in the perivascular niche of the diploe, namely, the soft spongy cancellous bone between the interior and exterior layers of cortical bone of the skull, which resembles the skeletal stem cells’ distribution pattern of the long bone within the bone marrow. Not until recent years have several studies unraveled and validated that the major mesenchymal stem cell population of the cranial region is primarily located within the suture mesenchyme of the skull, and hence, they are termed suture mesenchymal stem cells (SuSCs). Here, we summarized the characteristics of SuSCs, this newly discovered stem cell population of cranial bones, including the temporospatial distribution pattern, self-renewal, and multipotent properties, contribution to injury repair, as well as the signaling pathways and molecular mechanisms associated with the regulation of SuSCs.
Transportation of Single-Domain Antibodies through the Blood–Brain Barrier
Authors: Ruiz-López Eduardo , Schuhmacher Alberto J.
Published: August 2021

Single-domain antibodies derive from the heavy-chain-only antibodies of Camelidae (camel, dromedary, llama, alpaca, vicuñas, and guananos; i.e., nanobodies) and cartilaginous fishes (i.e., VNARs). Their small size, antigen specificity, plasticity, and potential to recognize unique conformational epitopes represent a diagnostic and therapeutic opportunity for many central nervous system (CNS) pathologies. However, the blood–brain barrier (BBB) poses a challenge for their delivery into the brain parenchyma. Nevertheless, numerous neurological diseases and brain pathologies, including cancer, result in BBB leakiness favoring single-domain antibodies uptake into the CNS. Some single-domain antibodies have been reported to naturally cross the BBB. In addition, different strategies and methods to deliver both nanobodies and VNARs into the brain parenchyma can be exploited when the BBB is intact. These include device-based and physicochemical disruption of the BBB, receptor and adsorptive-mediated transcytosis, somatic gene transfer, and the use of carriers/shuttles such as cell-penetrating peptides, liposomes, extracellular vesicles, and nanoparticles. Approaches based on single-domain antibodies are reaching the clinic for other diseases. Several tailoring methods can be followed to favor the transport of nanobodies and VNARs to the CNS, avoiding the limitations imposed by the BBB to fulfill their therapeutic, diagnostic, and theragnostic promises for the benefit of patients suffering from CNS pathologies.
Novel Insights into the Immunotherapy of Soft Tissue Sarcomas: Do We Need a Change of Perspective?
Authors: Ozaniak Andrej , Vachtenheim Jiri , Lischke Robert , Bartunkova Jirina , Strizova Zuzana
Published: August 2021

Soft tissue sarcomas (STSs) are rare mesenchymal tumors. With more than 80 histological subtypes of STSs, data regarding novel biomarkers of strong prognostic and therapeutic value are very limited. To date, the most important prognostic factor is the tumor grade, and approximately 50% of patients that are diagnosed with high-grade STSs die of metastatic disease within five years. Systemic chemotherapy represents the mainstay of metastatic STSs treatment for decades but induces response in only 15–35% of the patients, irrespective of the histological subtype. In the era of immunotherapy, deciphering the immune cell signatures within the STSs tumors may discriminate immunotherapy responders from non-responders and different immunotherapeutic approaches could be combined based on the predominant cell subpopulations infiltrating the STS tumors. Furthermore, understanding the immune diversity of the STS tumor microenvironment (TME) in different histological subtypes may provide a rationale for stratifying patients according to the TME immune parameters. In this review, we introduce the most important immune cell types infiltrating the STSs tumors and discuss different immunotherapies, as well as promising clinical trials, that would target these immune cells to enhance the antitumor immune responses and improve the prognosis of metastatic STSs patients.
Significant Implications of APOA1 Gene Sequence Variations and Its Protein Expression in Bladder Cancer
Authors: Magray Javid A. , Pandith Arshad A. , Qasim Iqbal , Khateeb Muzzain , Hamid Arif , Koul Aabid , Shah Zafar A. , Baba Shahid M. , Mansoor Sheikh , Charifi Wafa , Ahmad Ajaz , Wani Mohammad S.
Published: August 2021

Apolipoprotein A1 (APOA1) is a potential biomarker because of its variable concentration in different types of cancers. The current study is the first of its kind to evaluate the association between the APOA1 genotypes of −75 G/A and +83 C/T in tandem with the APOA1 protein expression in urine samples to find out the risk and potential relationship for differentially expressed urinary proteins and APOA1 genotypes. The study included 108 cases of bladder tumors and 150 healthy controls that were frequency matched to cases with respect to age, sex, and smoking status. Genotyping was performed using PCR-RFLP and the urinary expression of the APOA1 protein was done using ELISA. Bladder tumor cases were significantly associated with the APOA1 −75 AA genotype (p < 0.05), while the APOA1 +83 C/T heterozygotes showed an association with cases (p < 0.05). The overall distribution of the different haplotypes showed a marked difference between the cases and controls in GT when compared with the wild type GC (p < 0.03). Bladder tumor cases that carried the variant genotype APOA1 −75AA were found more (70.0%) with a higher expression (≥20 ng/mL)of the APOA1 urinary protein and differed significantly against wild type GG (p = 0.03). Again, in low grade bladder tumors, urinary APOA1 protein was exhibited significantly more (52.4% vs. 15.4% high grade) with a higher expression (≥20 ng), while high grade tumor cases (84.6% vs. 47.5% low grade) showed a lower APOA1 expression (<20 ng/mL) (O.R = 6.08, p = 0.002). A strong association was observed between APOA1 −75G/A and risk for bladder tumor and its relation to urinary protein expression, which substantiates its possible role as a marker for the risk assessment of the disease and as a promising diagnostic marker for different grades of malignant bladder tumors.
Enhancement of TEX264-Mediated ER-Phagy Contributes to the Therapeutic Effect of Glycycoumarin against APA Hepatotoxicity in Mice
Authors: Yan Mingzhu , Wang Zhi , Xia Tianji , Jin Suwei , Liu Yongguang , Hu Hongbo , Chang Qi
Published: August 2021

Acetaminophen (APA)-induced hepatotoxicity is coupled with the activation of autophagy. We sought to determine whether selective autophagy of the endoplasmic reticulum (ER), termed ER-phagy, is involved in APA hepatotoxicity and to explore its potential as a therapeutic target for APA-induced liver injury (AILI). APA (300 or 600 mg/kg) was administered to male C57BL/6N mice, with and without rapamycin, glycycoumarin (GCM) and N-acetylcysteine (NAC). The results demonstrated that ER-phagy accompanied with ER stress was activated after APA overdose. The dynamic changes of LC3 and TEX264 revealed that ER-phagy was induced as early as 6 h and peaked at 24 h following the APA injection. A delayed treatment with GCM, but not rapamycin, considerably attenuated a liver injury and, consequently, reduced its mortality. This is probably due to the inhibition of ER stress and the acceleration of liver regeneration via enhanced ER-phagy. Unlike the impaired hepatocyte proliferation and more severe liver injury in mice that received prolonged treatment with NAC, liver recovery is facilitated by repeated treatment with GCM. These findings suggest that TEX264-mediated ER-phagy is a compensatory mechanism against ER stress provoked by an APA overdose. A delayed and prolonged treatment with GCM enhances ER-phagy, thus serving as a potential therapeutic approach for patients presenting at the late stage of AILI.
Hyperbaric Oxygen Therapy Alleviates the Autoimmune Encephalomyelitis via the Reduction of IL-17a and GM-Csf Production of Autoreactive T Cells as Well as Boosting the Immunosuppressive IL-10 in the Central Nervous System Tissue Lesions
Authors: Chiou Hsin-Ying Clair , Huang Shu-Hung , Hung Chih-Hsing , Tsai Su-Min , Kuo Hui-Ru , Huang Yu-Rui , Wang Jiunn-Wei , Chen Szu-Chia , Kuo Chao-Hung , Wu Deng-Chyang , Huang Shau-Ku , Hsu Shih-Hsien , Lin Ming-Hong
Published: August 2021

Multiple sclerosis (MS) is a chronic autoimmune disease mainly caused by autoreactive T cells, followed by neuronal demyelination and disabling paralysis. Hyperbaric oxygen therapy (HBOT) is usually an adjunct to therapy for the treatment of neurological disorders. However, it remains still controversial whether HBOT is an effective option for the treatment of MS. Experimental autoimmune encephalomyelitis (EAE) is a well-studied mouse model investigated for the MS pathogenesis and the efficacy of the therapeutic intervention. Both encephalitogenic Th1 and Th17 are pivotal T cell subsets immunopathogenically producing several disease-initiating/modifying cytokines in the central nervous system (CNS) lesions to further exacerbate/ameliorate the progression of EAE or MS. However, it remains unclear whether HBOT modulates the context of T helper cell subsets in CNS lesions. We employed EAE in the presence of HBOT to assess whether disease amelioration is attributed to alterations of CNS-infiltrating T cell subsets. Our results demonstrated that semi-therapeutic HBOT significantly alleviated the progression of EAE, at least, via the suppression of Th17 response, the downregulation of CD4 T helper cells expressing GM-CSF or TNF-α, and the boosting of immunomodulatory IL-4 or IL-10-expressed CD4 T cells in the CNS lesions. Conclusively, HBOT attenuated EAE through the modulation of T cell responses in an earlier stage.
Influence of Intervertebral Fixation and Segmental Thrust Level on Immediate Post-Spinal Manipulation Trunk Muscle Spindle Response in an Animal Model
Authors: Lima Carla R. , Martins Daniel F. , Avatapally Snigdhasree , Cho Minjung , Li Peng , Reed William R.
Published: August 2021

Objective: To characterize the effect of unilateral (single and two-level) lumbar facet/zygapophysial joint fixation on paraspinal muscle spindle activity immediately following L4 or L6 high velocity low amplitude spinal manipulation (HVLA-SM) delivered at various thrust durations. Methods: Secondary analysis of immediate (≤2 s) post-HVLA-SM trunk muscle spindle response from two studies involving anesthetized adult cats (n = 39; 2.3–6.0 kg) with either a unilateral single (L5/6) or two-level (L5/6 and L6/7) facet joint fixation. All facet fixations were contralateral to L6 dorsal root recordings. HVLA-SM was delivered to the spinous process in a posterior-to-anterior direction using a feedback motor with a peak thrust magnitude of 55% of average cat body weight and thrust durations of 75, 100, 150, and 250 ms. Time to 1st action potential and spindle activity during 1 and 2 s post-HVLA-SM comparisons were made between facet joint fixation conditions and HVLA-SM segmental thrust levels. Results: Neither two-level facet joint fixation, nor HVLA-SM segmental level significantly altered immediate post-HVLA-SM spindle discharge at tested thrust durations (FDR > 0.05). Conclusions: Two-level facet joint fixation failed to alter immediate (≤2 s) post-HVLA-SM spindle discharge when compared to single-level facet joint fixation at any thrust duration. Segmental thrust level did not alter immediate post-HVLA-SM spindle response in two-level facet joint fixation preparations.
Non-Lynch Familial and Early-Onset Colorectal Cancer Explained by Accumulation of Low-Risk Genetic Variants
Authors: Mur Pilar , Bonifaci Nuria , Díez-Villanueva Anna , Munté Elisabet , Alonso Maria Henar , Obón-Santacana Mireia , Aiza Gemma , Navarro Matilde , Piñol Virginia , Brunet Joan , Tomlinson Ian , Capellá Gabriel , Moreno Victor , Valle Laura
Published: August 2021

A large proportion of familial and/or early-onset cancer patients do not carry pathogenic variants in known cancer predisposing genes. We aimed to assess the contribution of previously validated low-risk colorectal cancer (CRC) alleles to familial/early-onset CRC (fCRC) and to serrated polyposis. We estimated the association of CRC with a 92-variant-based weighted polygenic risk score (wPRS) using 417 fCRC patients, 80 serrated polyposis patients, 1077 hospital-based incident CRC patients, and 1642 controls. The mean wPRS was significantly higher in fCRC than in controls or sporadic CRC patients. fCRC patients in the highest (20th) wPRS quantile were at four-fold greater CRC risk than those in the middle quantile (10th). Compared to low-wPRS fCRC, a higher number of high-wPRS fCRC patients had developed multiple primary CRCs, had CRC family history, and were diagnosed at age ≥50. No association with wPRS was observed for serrated polyposis. In conclusion, a relevant proportion of mismatch repair (MMR)-proficient fCRC cases might be explained by the accumulation of low-risk CRC alleles. Validation in independent cohorts and development of predictive models that include polygenic risk score (PRS) data and other CRC predisposing factors will determine the implementation of PRS into genetic testing and counselling in familial and early-onset CRC.
Cell-Extrinsic Differentiation Block Mediated by EphA3 in Pre-Leukaemic Thymus Contributes to Disease Progression
Authors: Pliego Zamora Adriana C. , Ranasinghe Hansini , Lisle Jessica E. , Ng Chun Ki , Huang Stephen , Wadlow Racheal , Scott Andrew M. , Boyd Andrew W. , Slape Christopher I.
Published: August 2021

We recently characterised the NUP98-HOXD13 (NHD13) mouse as a model of T-cell pre-leukaemia, featuring thymocytes that can engraft in recipient animals and progress to T-cell acute lymphoblastic leukaemia (T-ALL). However, loss of this engraftment ability by deletion of Lyl1 did not result in any loss of leukemogenesis activity. In the present study, we observe that NHD13 thymocytes overexpress EPHA3, and we characterise thymocyte behaviour in NHD13 mice with deletion of EphA3, which show a markedly reduced incidence of T-ALL. Deletion of EphA3 from the NHD13 mice does not prevent the abnormal accumulation or transplantation ability of these thymocytes. However, upon transplantation, these cells are unable to block the normal progression of recipient wild type (WT) progenitor cells through the normal developmental pathway. This is in contrast to the EphA3+/+ NHD13 thymocytes, which block the progression of incoming WT progenitors past the DN1 stage. Therefore, EphA3 is not critical for classical self-renewal, but is essential for mediating an interaction between the abnormally self-renewing cells and healthy progenitors—an interaction that results in a failure of the healthy cells to differentiate normally. We speculate that this may orchestrate a loss of healthy cell competition, which in itself has been demonstrated to be oncogenic, and that this may explain the decrease in T-ALL incidence in the absence of EphA3. We suggest that pre-leukaemic self-renewal in this model is a complex interplay of cell-intrinsic and -extrinsic factors, and that multiple redundant pathways to leukaemogenesis are active.
Association between Androgen Deprivation Therapy and Risk of Dementia in Men with Prostate Cancer
Authors: Liu Jui-Ming , Shen Chin-Yao , Lau Wallis C. Y. , Shao Shih-Chieh , Man Kenneth K. C. , Hsu Ren-Jun , Wu Chun-Te , Lai Edward Chia-Cheng
Published: August 2021

The risk of dementia after androgen deprivation therapy (ADT) in patients with advanced prostate cancer (PCa) remains controversial. This study aimed to evaluate the association between ADT and the incidence of dementia in patients with PCa. We identified patients newly diagnosed with PCa in the National Health Insurance Database of Taiwan from 1 January 2002 to 30 June 2016 and in The Health Improvement Network of the United Kingdom (UK) from 1 January 1998 to 31 March 2018. We classified patients with PCa into ADT and ADT-naïve groups. Propensity score (PS) methods were used to minimize the differences in characteristics between the groups. We performed a Cox proportional hazard model to obtain the adjusted hazard ratio (HR) to compare the incidence of dementia between the groups. Our ADT group comprised 8743 and 73,816 patients in Taiwan and the UK, respectively, which were matched 1:1 to ADT-naïve patients by PS. The incidence rates of dementia in the ADT group were 2.74 versus 3.03 per 1000 person-years in the ADT naïve groups in Taiwan, and 2.81 versus 2.79 per 1000 person-years in the UK. There was no statistical difference between ADT and ADT-naïve groups (adjusted HR: 1.12; 95% confidence interval (CI): 0.87–1.43 in Taiwan and adjusted HR: 1.02; 95% CI: 0.85–1.23 in the UK). We found no association between the incidence of dementia and ADT in patients with advanced PCa in either database. Further studies are warranted to evaluate other possible triggers of incident dementia in patients receiving ADT for advanced PCa.
Aflibercept Plus FOLFIRI as Second-Line Treatment for Metastatic Colorectal Cancer: A Single-Institution Real-Life Experience
Authors: Lavacchi Daniele , Roviello Giandomenico , Giommoni Elisa , Dreoni Lorenzo , Derio Silvia , Brugia Marco , Amedei Amedeo , Pillozzi Serena , Antonuzzo Lorenzo
Published: August 2021

The addition of aflibercept to FOLFIRI has been demonstrated to improve survival in patients with metastatic colorectal cancer (mCRC) who progressed after receiving a standard oxaliplatin-based regimen. In this retrospective, single-institution, observational study we collected clinical data from mCRC patients who received aflibercept in combination with FOLFIRI in routine clinical practice from October 2012 to March 2021 to describe feasibility and efficacy of this regimen in a real-world population. Forty-nine patients receiving aflibercept-FOLFIRI as second-line treatment were identified, 40.8% of whom were aged over 65 years. The majority of patients had multi-organ metastases (73.5%), and had previously received bevacizumab in combination with chemotherapy (CT) as first-line treatment (79.6%). Median overall survival (OS) and progression-free survival (PFS) were 13 and 6 months, respectively; overall response rate (ORR) and disease control rate (DCR) were 12.3% and 49.1%, respectively. Several factors were associated with survival in univariate analysis, including PFS in first-line therapy, number of metastatic sites, bone metastases and others. However, in multivariate analysis, only PFS in first-line CT over 12 months was significantly associated with better OS (HR 0.32; 95% CI 0.13–0.79; p = 0.01). Hypertension was the most commonly reported grade (G) 3–4 adverse event (AE), affecting 18.4% of the overall population. Thromboembolic events were observed in 16.3% of patients, hemorrhagic events in 10.2%, and proteinuria in 8.2%. Neutropenia was the most frequently observed hematological G3–4 AE with an incidence of 10.2%. Aflibercept-FOLFIRI has been confirmed as a feasible second-line treatment for mCRC in a re-al-life setting, and PFS in first-line therapy >12 months resulted as the only predictive marker of better survival.
Diffuse PRAME Expression Is Highly Specific for Thin Melanomas in the Distinction from Severely Dysplastic Nevi but Does Not Distinguish Metastasizing from Non-Metastasizing Thin Melanomas
Authors: Gassenmaier Maximilian , Hahn Matthias , Metzler Gisela , Bauer Jürgen , Yazdi Amir Sadegh , Keim Ulrike , Garbe Claus , Wagner Nikolaus Benjamin , Forchhammer Stephan
Published: August 2021

Background: PReferentially expressed Antigen in MElanoma (PRAME) immunohistochemistry is increasingly used as diagnostic adjunct in the evaluation of melanocytic tumors. The expression and prognostic significance of PRAME in melanomas ≤1.0 mm and its diagnostic utility in the distinction from severely dysplastic compound nevi (SDN) have not been studied. Methods: We investigated and compared the immunohistochemical PRAME expression in 70 matched thin metastasizing and non-metastasizing melanomas and 45 nevi from patients with long-term follow-up (35 SDN and 10 unequivocally benign compound nevi). Results: Diffuse PRAME staining in >75% of lesional epidermal and dermal melanocytes identified 58.6% of thin melanomas but did not distinguish metastasizing from non-metastasizing melanomas (p = 0.81). A superficial atypical melanocytic proliferation of uncertain significance, in which the final diagnostic interpretation favored a SDN was the only nevus with diffuse PRAME expression (1/45). Melanomas and SDN with PRAME immunoreactivity exhibited different staining patterns. Most melanomas (67.6%) showed uniform PRAME expression in the in situ and invasive component, whereas most SDN (81.0%) showed a decreasing gradient with depth. Conclusion: Diffuse intraepidermal and dermal PRAME staining is highly specific for melanomas in the distinction from SDN. PRAME expression is not a prognostic biomarker in melanomas ≤1.0 mm.
Review of the Molecular Genetics of Basal Cell Carcinoma; Inherited Susceptibility, Somatic Mutations, and Targeted Therapeutics
Authors: Kilgour James M. , Jia Justin L. , Sarin Kavita Y.
Published: August 2021

Basal cell carcinoma (BCC) is a significant public health concern, with more than 3 million cases occurring each year in the United States, and with an increasing incidence. The molecular basis of BCC is complex, involving an interplay of inherited genetic susceptibility, including single nucleotide polymorphisms and genetic syndromes, and sporadic somatic mutations, often induced by carcinogenic exposure to UV radiation. This review outlines the currently known germline and somatic mutations implicated in the pathogenesis of BCC, including the key molecular pathways affected by these mutations, which drive oncogenesis. With advances in next generation sequencing and our understanding of the molecular genetics of BCC, established and emerging targeted therapeutics are offering new avenues for the non-surgical treatment of BCC. These agents, including Hedgehog pathway inhibitors, immune modulators, and histone deacetylase inhibitors, will also be discussed.
The Role of Chemotherapy in Management of Inoperable, Metastatic and/or Recurrent Melanotic Neuroectodermal Tumor of Infancy—Own Experience and Systematic Review
Authors: Styczewska Małgorzata , Krawczyk Małgorzata A. , Brecht Ines B. , Haug Konrad , Iżycka-Świeszewska Ewa , Godziński Jan , Raciborska Anna , Ussowicz Marek , Kukwa Wojciech , Cwalina Natalia , Lundstrom Emil , Bień Ewa
Published: August 2021

Melanotic Neuroectodermal Tumor of Infancy (MNTI) is a very rare pediatric neoplasm of neural crest origin. In most cases, it develops in infants as a localized tumor of the maxilla, and surgery is usually curative. In less than 10% of patients with inoperable, metastatic or persistently recurring MNTI, chemotherapy (CHT) may be considered; however, its role is still unclear. The aim of our study was to assess the efficacy of CHT in children with large, inoperable, metastatic and/or recurrent MNTI. Four such infants, treated with CHT in Polish and German centers of pediatric oncology, were presented. Additionally, a systematic literature search of the PubMed/MEDLINE, Scopus and Web of Science databases was performed, yielding 38 similar cases within the last 42 years. Neoadjuvant CHT, based mainly on the protocols for neuroblastoma, was often effective, allowing for complete delayed surgery in most cases. However, the role of adjuvant CHT in preventing recurrences after incomplete resection of MNTI remains unclear. Disseminated inoperable MNTI was almost universally associated with poor response to CHT and unfavorable outcome. Further investigations to elaborate standards of management in patients with inoperable, metastatic or persistently recurring MNTIs are necessary to improve outcomes.