bluuebunny/crossref_metadata_2025 huggingface dataset:
Spatial Downscaling of GOES-R Land Surface Temperature over Urban Regions: A Case Study for New York City
Authors: Bah Abdou Rachid , Norouzi Hamidreza , Prakash Satya , Blake Reginald , Khanbilvardi Reza , Rosenzweig Cynthia
Published: February 2022

The surface urban heat island (SUHI) effect is among the major environmental issues encountered in urban regions. To better predict the dynamics of the SUHI and its impacts on extreme heat events, an accurate characterization of the surface energy balance in urban regions is needed. However, the ability to improve understanding of the surface energy balance is limited by the heterogeneity of surfaces in urban areas. This study aims to enhance the understanding of the urban surface energy budget through an innovation in the use of land surface temperature (LST) observations from remote sensing satellites. A LST database with 5–min temporal and 30–m spatial resolution is developed by spatial downscaling of the Geostationary Operational Environmental Satellites—R (GOES–R) series LST product over New York City (NYC). The new downscaling method, known as the Spatial Downscaling Method (SDM), benefits from the fine spatial resolution of Landsat–8 and high temporal resolution of GOES–R, and considers the temporal variation in LST for each land cover type separately. Preliminary results show that the SDM can reproduce the temporal and spatial variability of LST over NYC reasonably well and the downscaled LST has a spatial root mean square error (RMSE) of the order of 2 K as compared to the independent Landsat–8 observations. The SDM shows smaller RMSE of 1.93 K over the tree canopy land cover, whereas RMSE is 2.19 K for built–up areas. The overall results indicate that the SDM has potential to estimate LST at finer spatial and temporal scales over urban regions.
Zinc Oxide Nanoparticles Promote YAP/TAZ Nuclear Localization in Alveolar Epithelial Type II Cells
Authors: Laiman Vincent , Heriyanto Didik Setyo , Lee Yueh-Lun , Lai Ching-Huang , Pan Chih-Hong , Chen Wei-Liang , Wang Chung-Ching , Chuang Kai-Jen , Chang Jer-Hwa , Chuang Hsiao-Chi
Published: February 2022

We investigated roles of Hippo signaling pathway components in alveolar type II cells (AECII) after zinc oxide nanoparticle (ZnONP) exposure. ZnONPs physicochemistry was characterized using field emission-scanning electron microscopy (FE-SEM) and energy-dispersive X-ray (EDX) microanalysis. ZnONP deposition in human respiratory tract was estimated using multiple-path particle dosimetry (MPPD) model. MLE-12 AECII were cultured and exposed to 0, 1, and 5 μg/mL of ZnONPs for 24 h. Western blots were used to investigate signaling pathways associated with Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ), cell adherens junctions, differentiation, and senescence. ZnONPs morphology was irregular, with Zn and O identified. Approximately 72% of inhaled ZnONPs were deposited in lungs, with 26% being deposited in alveolar regions. ZnONP exposure increased nuclear YAP expression and decreased cytoplasmic YAP expression by AECII. Adherens junction proteins, E-cadherin, α-catenin, and β-catenin, on AECII decreased after ZnONP exposure. ZnONP exposure of AECII increased alveolar type I (AECI) transition protein, LGALS3, and the AECI protein, T1α, while decreasing AECII SPC expression. ZnONP exposure induced Sirt1 and p53 senescence proteins by AECII. Our findings showed that inhalable ZnONPs can deposit in alveoli, which promotes YAP nuclear localization in AECII, resulting in decrease tight junctions, cell differentiation, and cell senescence.
On Cohomology of Simple Modules for Modular Classical Lie Algebras
Authors: Ibraev Sherali S. , Kainbaeva Larissa S. , Menlikozhaeva Saulesh K.
Published: February 2022

In this article, we obtain some cohomology of classical Lie algebras over an algebraically closed field of characteristic p>h, where h is a Coxeter number, with coefficients in simple modules. We assume that these classical Lie algebras are Lie algebras of semisimple and simply connected algebraic groups. To describe the cohomology of simple modules, we will use the properties of the connections between ordinary and restricted cohomology of restricted Lie algebras.
Adapt to Persist: Glioblastoma Microenvironment and Epigenetic Regulation on Cell Plasticity
Authors: Uribe Daniel , Niechi Ignacio , Rackov Gorjana , Erices José I. , San Martín Rody , Quezada Claudia
Published: February 2022

Glioblastoma (GBM) is the most frequent and aggressive brain tumor, characterized by great resistance to treatments, as well as inter- and intra-tumoral heterogeneity. GBM exhibits infiltration, vascularization and hypoxia-associated necrosis, characteristics that shape a unique microenvironment in which diverse cell types are integrated. A subpopulation of cells denominated GBM stem-like cells (GSCs) exhibits multipotency and self-renewal capacity. GSCs are considered the conductors of tumor progression due to their high tumorigenic capacity, enhanced proliferation, invasion and therapeutic resistance compared to non-GSCs cells. GSCs have been classified into two molecular subtypes: proneural and mesenchymal, the latter showing a more aggressive phenotype. Tumor microenvironment and therapy can induce a proneural-to-mesenchymal transition, as a mechanism of adaptation and resistance to treatments. In addition, GSCs can transition between quiescent and proliferative substates, allowing them to persist in different niches and adapt to different stages of tumor progression. Three niches have been described for GSCs: hypoxic/necrotic, invasive and perivascular, enhancing metabolic changes and cellular interactions shaping GSCs phenotype through metabolic changes and cellular interactions that favor their stemness. The phenotypic flexibility of GSCs to adapt to each niche is modulated by dynamic epigenetic modifications. Methylases, demethylases and histone deacetylase are deregulated in GSCs, allowing them to unlock transcriptional programs that are necessary for cell survival and plasticity. In this review, we described the effects of GSCs plasticity on GBM progression, discussing the role of GSCs niches on modulating their phenotype. Finally, we described epigenetic alterations in GSCs that are important for stemness, cell fate and therapeutic resistance.
Endogenous Controls for the Evaluation of Osteoarthritis-Related miRNAs in Extracellular Vesicles from Bone-Marrow-Derived Mesenchymal Stromal Cells and the Impact of Osteoarthritis Synovial Fluid
Authors: Ragni Enrico , Perucca Orfei Carlotta , Viganò Marco , Valli Federico , de Girolamo Laura
Published: February 2022

Bone-marrow-derived stromal cells (BMSCs) have emerged as promising therapeutic option for the treatment of osteoarthritis (OA) due to their tissue regenerative and anti-inflammatory features. BMSCs’ clinical potential is mainly ascribed to their released factors and extracellular vesicles (EVs), whose therapeutic portfolio may be modulated by the environment in vivo or specific priming in vitro. Within the array of molecules shaping EVs’ power, miRNAs are considered privileged players. In this frame, a correct EV-miRNA detection and quantification is mandatory to understand and possibly boost BMSCs potential, either when envisioned as cell therapeutics or when proposed as producer of cell-free and clinical grade EVs. The aim of this study is to identify reliable reference genes (RGs) to study miRNAs in BMSC-EVs cultivated under standard or OA synovial fluid (OA-SF). miR-23a-3p and miR-221-3p emerged as the best candidates, respectively. Moreover, when both conditions were analyzed together, miR-24-3p resulted the most stable RGs, allowing for a sharper comparison of EVs content, further validated on the OA-related miRNA-193b-5p. The different RG stability ranking depending on the culturing conditions, as well as its divergence with respect to adipose (ASCs) and amniotic (hAMSCs) MSCs, confirm that miRNA RG selection in EVs is a mandatory step and that the identification of the most reliable candidate is greatly depending on the cell type and culturing/environmental conditions.
Epigenetic Effects of Gender-Affirming Hormone Treatment: A Pilot Study of the ESR2 Promoter’s Methylation in AFAB People
Authors: Pallotti Francesco , Senofonte Giulia , Konstantinidou Fani , Di Chiano Silvia , Faja Fabiana , Rizzo Flavio , Cargnelutti Francesco , Krausz Csilla , Paoli Donatella , Lenzi Andrea , Stuppia Liborio , Gatta Valentina , Lombardo Francesco
Published: February 2022

Virilization of gender-incongruent subjects to whom were assigned the female gender at birth (AFAB) is achieved through testosterone administration. Inter-individual differences in the timing and acquisition of phenotypic characteristics, even if the same hormone preparations and regimens are used, are frequently observed. Polymorphisms of sex hormone receptors and methylation of their gene promoters, as well of several imprinted genes as H19, may underlie the differential response to treatment. Thus, the aim of this study was to examine the possible relationship between the CpG methylation profile of the estrogen receptor 2 gene (ESR2) and H19 promoters and their influence on phenotype modifications in a cohort of AFAB people at baseline (T0) and after 6 mo (T6) and 12 mo (T12) of testosterone therapy (testosterone enanthate, 250 mg i.m. every 28 d). A total of 13 AFAB subjects (mean age 29.3 ± 12.6) were recruited. The percentage of methylation of the ESR2 promoter significantly increased at T6 (adj. p = 0.001) and T12 (adj. p = 0.05), while no difference was detected for H19 (p = 0.237). Methylation levels were not associated with androgen receptor (AR)/estrogen receptor beta (ERβ) polymorphisms nor hormone levels at baseline and after six months of treatment. On the other hand, total testosterone level and patient age resulted in being significantly associated with ESR2 methylation after twelve months of treatment. Finally, the difference in ESR2 promoter methylation between T6 and baseline was significantly associated with the number of CA repeats of the ERβ receptor, adjusted vs. all considered variables (R2 = 0.62, adj. R2 = 0.35). No associations were found with CAG repeats of the AR, age, and estradiol and testosterone levels. Despite the small sample size, we can hypothesize that treatment with exogenous testosterone can modify the ESR2 methylation pattern. Our data also indicated that epigenetic changes may be regulated, suggesting that the modulation of estrogen signaling is relevant shortly after the beginning of the treatment up to T6, with no further significant modification at T12. Furthermore, estrogen receptor methylation appears to be associated with the age of the subjects and exogenous testosterone administration, representing a marker of androgenic treatment. Nonetheless, it will be necessary to increase the number of subjects to evaluate how epigenetic regulation might play a relevant role in the modulation of phenotypical changes after testosterone treatment.
Host Defense Peptides LL-37 and Lactoferrin Trigger ET Release from Blood-Derived Circulating Monocytes
Authors: Schwäbe Frederic V. , Happonen Lotta , Ekestubbe Sofie , Neumann Ariane
Published: February 2022

Neutrophils are commonly regarded as the first line of immune response during infection or in tissue injury-induced inflammation. The rapid influx of these cells results in the release of host defense proteins (HDPs) or formation of neutrophil extracellular traps (NETs). As a second wave during inflammation or infection, circulating monocytes arrive at the site. Earlier studies showed that HDPs LL-37 and Lactoferrin (LTF) activate monocytes while neutrophil elastase facilitates the formation of extracellular traps (ETs) in monocytes. However, the knowledge about the impact of HDPs on monocytes remains sparse. In the present study, we investigated the effect of LL-37 and LTF on blood-derived CD14+ monocytes. Both HDPs triggered a significant release of TNFα, nucleosomes, and monocyte ETs. Microscopic analysis indicated that ET formation by LL-37 depends on storage-operated calcium entry (SOCE), mitogen-activated protein kinase (MAPK), and ERK1/2, whereas the LTF-mediated ET release is not affected by any of the here used inhibitors. Quantitative proteomics mass spectrometry analysis of the neutrophil granular content (NGC) revealed a high abundance of Lactoferrin. The stimulation of CD14+ monocytes with NGC resulted in a significant secretion of TNFα and nucleosomes, and the formation of monocyte ETs. The findings of this study provide new insight into the complex interaction of HDPs, neutrophils, and monocytes during inflammation.
Extracorporeal Shock Wave Therapy Combined with Platelet-Rich Plasma during Preventive and Therapeutic Stages of Intrauterine Adhesion in a Rat Model
Authors: Cheng Yin-Hua , Tsai Ni-Chin , Chen Yun-Ju , Weng Pei-Ling , Chang Yun-Chiao , Cheng Jai-Hong , Ko Jih-Yang , Kang Hong-Yo , Lan Kuo-Chung
Published: February 2022

Intrauterine adhesion (IUA) is caused by artificial endometrial damage during intrauterine cavity surgery. The typical phenotype involves loss of spontaneous endometrium recovery and angiogenesis. Undesirable symptoms include abnormal menstruation and infertility; therefore, prevention and early treatment of IUA remain crucial issues. Extracorporeal shockwave therapy (ESWT) major proposed therapeutic mechanisms include neovascularization, tissue regeneration, and fibrosis. We examined the effects of ESWT and/or platelet-rich plasma (PRP) during preventive and therapeutic stages of IUA by inducing intrauterine mechanical injury in rats. PRP alone, or combined with ESWT, were detected an increased number of endometrial glands, elevated vascular endothelial growth factor protein expression (hematoxylin-eosin staining and immunohistochemistry), and reduced fibrosis rate (Masson trichrome staining). mRNA expression levels of nuclear factor-kappa B, tumor necrosis factor-α, transforming growth factor-β, interleukin (IL)-6, collagen type I alpha 1, and fibronectin were reduced during two stages. However, PRP alone, or ESWT combined with PRP transplantation, not only increased the mRNA levels of vascular endothelial growth factor (VEGF) and progesterone receptor (PR) during the preventive stage but also increased PR, insulin-like growth factor 1 (IGF-1), and IL-4 during the therapeutic stage. These findings revealed that these two treatments inhibited endometrial fibrosis and inflammatory markers, thereby inhibiting the occurrence and development of intrauterine adhesions.
Exploring Sensitive Label-Free Multiplex Analysis with Raman-Coded Microbeads and SERS-Coded Reporters
Authors: Azhar Umar , Ahmed Qazi , Ishaq Saira , Alwahabi Zeyad T. , Dai Sheng
Published: February 2022

Suspension microsphere immunoassays are rapidly gaining attention in multiplex bioassays. Accurate detection of multiple analytes from a single measurement is critical in modern bioanalysis, which always requires complex encoding systems. In this study, a novel bioassay with Raman-coded antibody supports (polymer microbeads with different Raman signatures) and surface-enhanced Raman scattering (SERS)-coded nanotags (organic thiols on a gold nanoparticle surface with different SERS signatures) was developed as a model fluorescent, label-free, bead-based multiplex immunoassay system. The developed homogeneous immunoassays included two surface-functionalized monodisperse Raman-coded microbeads of polystyrene and poly(4-tert-butylstyrene) as the immune solid supports, and two epitope modified nanotags (self-assembled 4-mercaptobenzoic acid or 3-mercaptopropionic acid on gold nanoparticles) as the SERS-coded reporters. Such multiplex Raman/SERS-based microsphere immunoassays could selectively identify specific paratope–epitope interactions from one mixture sample solution under a single laser illumination, and thus hold great promise in future suspension multiplex analysis for diverse biomedical applications.
Functional Connectivity Signatures Underlying Simultaneous Language Translation in Interpreters and Non-Interpreters of Mandarin and English: An fNIRS Study
Authors: He Yan , Hu Yinying
Published: February 2022

Recent neuroimaging research has suggested that interpreters and non-interpreters elicit different brain activation patterns during simultaneous language translation. However, whether these two groups have different functional connectivity during such a task, and how the neural coupling is among brain subregions, are still not well understood. In this study, we recruited Mandarin (L1)/English (L2) interpreters and non-interpreter bilinguals, whom we asked to perform simultaneous language translation and reading tasks. Functional near-infrared spectroscopy (fNIRS) was used to collect cortical brain data for participants during each task, using 68 channels that covered the prefrontal cortex and the bilateral perisylvian regions. Our findings revealed both interpreter and non-interpreter groups recruited the right dorsolateral prefrontal hub when completing the simultaneous language translation tasks. We also found different functional connectivity between the groups. The interpreter group was characterized by information exchange between the frontal cortex and Wernicke’s area. In comparison, the non-interpreter group revealed neural coupling between the frontal cortex and Broca’s area. These findings indicate expertise modulates functional connectivity, possibly because of more developed cognitive skills associated with executive functions in interpreters.
The Functional Interactions between Cortical Regions through Theta-Gamma Coupling during Resting-State and a Visual Working Memory Task
Authors: Ahn Ji Seon , Heo Jaeseok , Oh Jooyoung , Lee Deokjong , Jhung Kyungun , Kim Jae-Jin , Park Jin Young
Published: February 2022

Theta phase-gamma amplitude coupling (TGC) plays an important role in several different cognitive processes. Although spontaneous brain activity at the resting state is crucial in preparing for cognitive performance, the functional role of resting-state TGC remains unclear. To investigate the role of resting-state TGC, electroencephalogram recordings were obtained for 56 healthy volunteers while they were in the resting state, with their eyes closed, and then when they were engaged in a retention interval period in the visual memory task. The TGCs of the two different conditions were calculated and compared. The results indicated that the modulation index of TGC during the retention interval of the visual working memory (VWM) task was not higher than that during the resting state; however, the topographical distribution of TGC during the resting state was negatively correlated with TGC during VWM task at the local level. The topographical distribution of TGC during the resting state was negatively correlated with TGC coordinates’ engagement of brain areas in local and large-scale networks and during task performance at the local level. These findings support the view that TGC reflects information-processing and signal interaction across distant brain areas. These results demonstrate that TGC could explain the efficiency of competing brain networks.
Dimensions of Tinnitus-Related Distress
Authors: Brueggemann Petra , Mebus Wilhelm , Boecking Benjamin , Amarjargal Nyamaa , Niemann Uli , Spiliopoulou Myra , Dobel Christian , Rose Matthias , Mazurek Birgit
Published: February 2022

Objectives: (1) To determine which psychosocial aspects predict tinnitus-related distress in a large self-reported dataset of patients with chronic tinnitus, and (2) to identify underlying constructs by means of factor analysis. Methods: A cohort of 1958 patients of the Charité Tinnitus Center, Berlin completed a large questionnaire battery that comprised sociodemographic data, tinnitus-related distress, general psychological stress experience, emotional symptoms, and somatic complaints. To identify a construct of “tinnitus-related distress”, significant predictive items were grouped using factor analysis. Results: For the prediction of tinnitus-related distress (linear regression model with R2 = 0.7), depressive fatigue symptoms (concentration, sleep, rumination, joy decreased), the experience of emotional strain, somatization tendencies (pain experience, doctor contacts), and age appeared to play a role. The factor analysis revealed five factors: “stress”, “pain experience”, “fatigue”, “autonomy”, and low “educational level”. Conclusions: Tinnitus-related distress is predicted by psychological and sociodemographic indices. Relevant factors seem to be depressive exhaustion with somatic expressions such as sleep and concentration problems, somatization, general psychological stress, and reduced activity, in addition to higher age.
Differences in Odor Identification in Early-Onset and Late-Onset Depression
Authors: Liu Meiling , Chen Ben , Zhong Xiaomei , Zhang Min , Wang Qiang , Zhou Huarong , Wu Zhangying , Hou Le , Peng Qi , Zhang Si , Yang Minfeng , Lin Gaohong , Ning Yuping
Published: February 2022

(1) Background: Odor identification (OI) dysfunction is a potential predictor of developing dementia in late life depression (LLD). However, it is not clear whether patients with early onset depression (EOD) and late onset depression (LOD) may exhibit different OI dysfunctions. The aim of this study was to compare OI between EOD patients and LOD patients and its relationship with cognitive function. (2) Methods: A total of 179 patients with LLD and 189 normal controls were recruited. Participants underwent clinical assessment, olfactory testing, and comprehensive neuropsychological assessment. The OI scores of EOD patients and LOD patients were compared, and correlation analyses and mediation analyses were used to explore the relationship between OI and cognition. (3) Result: LOD patients exhibited lower OI scores than EOD patients and normal controls (NCs). Additionally, the LOD patients exhibited a higher percentage of OI dysfunction than the EOD patients. Moreover, OI scores were associated with global cognition, memory, language, and visuospatial ability in the EOD group (p < 0.05) but were not associated with any cognitive score in the LOD patients (p > 0.05). Finally, the scores of the Auditory Verbal Learning Test Immediate recall and Boston Naming Test exhibited a partially mediating effect on the difference in OI scores between the EOD and LOD patients. (4) Conclusions: LOD patients exhibited worse OI than EOD patients, and their difference in OI was mediated by their memory and language function.
Trust, Media Credibility, Social Ties, and the Intention to Share towards Information Verification in an Age of Fake News
Authors: Majerczak Przemysław , Strzelecki Artur
Published: February 2022

Social media is now the primary form of communication between internet users and has soared in popularity, which has directly impacted the spread of the phenomenon of fake news. Fake news is not only a widespread phenomenon; it is also problematic and dangerous for society. The aim of this study is to understand the phenomenon of fake news better. The study utilised a structural modelling equation in order to identify how Polish society perceives the problem of fake news and assess the extent to which it trusts content that is published on the internet. The key goal was to determine what factors have the most significant influence on the verification of information being viewed on the internet. By deploying the partial least squares method of validation, SmartPLS3 software was used to process the survey results. The strongest positive effect on information verification behaviour was found to be fake news awareness, which was followed by the intention to share information. The research did not consider any clear connections that may exist between the nature of fake news and its recipient; however, much of the fake news that appears on the internet is political in nature. The study can be used by news reporting companies and provides preliminary information for developers responsible for running social media sites as well as users who want to combat and limit the spread of fake news online. This study expands on the available literature related to fake news by identifying the effects on information verification behaviour of fake news awareness and the intention to share data.
The Benefit of Rail: Estimating the Impact of Station Accessibility on Residential Property Prices
Authors: Tordai Dániel , Munkácsy András
Published: February 2022

This article focuses on the relationship between the prices and the distance from a metro or commuter railway station to residential properties. Relevant efforts have already been dedicated to estimating the effect of station accessibility, but one of the key limitations of previous studies was the heterogeneity of real estate. Here, the data on homogeneous real estate type in Budapest, Hungary, namely panel flats (built with uniform technology between the 1960s and 1990s) are analysed by statistical methods. First, it is demonstrated that this real estate type is indeed highly homogenous. Second, linear regression is used to understand the relationship and its magnitude between flat prices and distance of stations. The results show a statistically significant relationship, i.e., that five additional minutes of travel time to the nearest station providing fast access to the city centre makes real estate prices drop by nearly 1%. In light of current policies promoting rail for passenger transportation, the findings may be applied for value capture policies to increase the viability and feasibility of urban railway projects.
Current Limitations and Novel Perspectives in Pancreatic Cancer Treatment
Authors: Robatel Steve , Schenk Mirjam
Published: February 2022

Pancreatic cancer is one of the deadliest cancers worldwide, largely due to its aggressive development. Consequently, treatment options are often palliative, as only one-fifth of patients present with potentially curable tumors. The only available treatment with curative intent is surgery followed by adjuvant chemotherapy. However, even for patients that are eligible for surgery, the 5-year OS remains below 10%. Hence, there is an urgent need to find new therapeutic regimens. In the first part of this review, we discuss the tumor staging method and its impact on the corresponding current standard-of-care treatments for PDAC. We also consider the key clinical trials over the last 20 years that have improved patient survival. In the second part, we provide an overview of the major components and cell types involved in PDAC, as well as their respective roles and interactions with each other. A deeper knowledge of the interactions taking place in the TME may lead to the discovery of potential new therapeutic targets. Finally, we discuss promising treatment strategies targeting specific components of the TME and potential combinations thereof. Overall, this review provides an overview of the current challenges and future perspectives in the treatment of pancreatic cancer.
The Immune Landscape of Human Pancreatic Ductal Carcinoma: Key Players, Clinical Implications, and Challenges
Authors: Muller Marie , Haghnejad Vincent , Schaefer Marion , Gauchotte Guillaume , Caron Bénédicte , Peyrin-Biroulet Laurent , Bronowicki Jean-Pierre , Neuzillet Cindy , Lopez Anthony
Published: February 2022

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and deadliest cancer worldwide with an overall survival rate, all stages combined, of still <10% at 5 years. The poor prognosis is attributed to challenges in early detection, a low opportunity for radical resection, limited response to chemotherapy, radiotherapy, and resistance to immune therapy. Moreover, pancreatic tumoral cells are surrounded by an abundant desmoplastic stroma, which is responsible for creating a mechanical barrier, preventing appropriate vascularization and leading to poor immune cell infiltration. Accumulated evidence suggests that PDAC is impaired with multiple “immune defects”, including a lack of high-quality effector cells (CD4, CD8 T cells, dendritic cells), barriers to effector cell infiltration due to that desmoplastic reaction, and a dominance of immune cells such as regulatory T cells, myeloid-derived suppressor cells, and M2 macrophages, resulting in an immunosuppressive tumor microenvironment (TME). Although recent studies have brought new insights into PDAC immune TME, its understanding remains not fully elucidated. Further studies are required for a better understanding of human PDAC immune TME, which might help to develop potent new therapeutic strategies by correcting these immune defects with the hope to unlock the resistance to (immune) therapy. In this review, we describe the main effector immune cells and immunosuppressive actors involved in human PDAC TME, as well as their implications as potential biomarkers and therapeutic targets.
Treatment of Malignant Adnexal Tumors of the Skin: A 12-Year Perspective
Authors: Kleibert Marcin , Płachta Iga , Czarnecka Anna M. , Spałek Mateusz J. , Szumera-Ciećkiewicz Anna , Rutkowski Piotr
Published: February 2022

Malignant adnexal cancers of the skin—extremely rare neoplasms—are mostly reported as non-symptomatic, slow-growing nodules. These carcinomas occur mainly in the middle-aged (50–60 years of age); they are mostly localized on the upper part of the body and are locally aggressive, infiltrate surrounding tissue, and metastasize to regional lymph nodes. The patients’ outcomes depend on multiple prognostic factors, including the size of the primary tumor and its mitotic count. Surgical resection of the primary tumor with or without regional lymph nodes is the treatment method of choice; however, due to aggressive tumor behavior, perioperative treatment may be considered. The role and efficacy of radiotherapy in the treatment of skin adnexal malignancies are not yet fully defined. Some authors suggest that adjuvant radiotherapy may be considered in locally advanced and regional disease. The aim of this study was to evaluate treatment outcomes and assess the efficacy of combined therapy in patients with adnexal malignancies. Our analysis covered all cases of cutaneous adnexal tumor patients diagnosed and provided with multidisciplinary treatment with surgery and radiotherapy since the beginning of 2009.
Upper Gastrointestinal Cancer Surveillance in Lynch Syndrome
Authors: Kumar Shria , Farha Natalie , Burke Carol A. , Katona Bryson W.
Published: February 2022

Lynch syndrome is a common hereditary cancer predisposition syndrome associated with increased digestive cancer risk including colorectal, gastric, and duodenal cancers. While colorectal cancer surveillance is widely accepted to be an important part of a comprehensive Lynch syndrome risk management plan, the use of upper gastrointestinal cancer surveillance in Lynch syndrome remains more controversial. Currently, upper gastrointestinal cancer surveillance guidelines for Lynch syndrome vary widely, and there is no consensus on who should undergo upper gastrointestinal cancer surveillance, how surveillance should be performed, the age at which to initiate surveillance, or how often individuals with Lynch syndrome should undergo upper gastrointestinal cancer surveillance. Fortunately, research groups around the world have been focusing on upper gastrointestinal cancer surveillance in Lynch syndrome, and recent evidence in this field has demonstrated that upper gastrointestinal cancer surveillance can be performed with identification of precancerous lesions as well as early-stage upper gastrointestinal cancers. In this manuscript, we review the upper gastrointestinal cancer risks in Lynch syndrome, differing guideline recommendations for surveillance, outcomes of upper gastrointestinal cancer surveillance, and controversies in the field, and we provide a framework based on our collective experience with which to incorporate upper gastrointestinal cancer surveillance into a risk management program for individuals with Lynch syndrome.
Supportive Care Needs Assessment for Cancer Survivors at a Comprehensive Cancer Center in the Middle East: Mending the Gap
Authors: Al-Omari Amal , Al-Rawashdeh Nedal , Damsees Rana , Ammar Khawlah , Alananzeh Ibrahim , Inserat Bayan , Al-Rimawi Dalia , Tbayshat Shrouq , Ababneh Hazim , Alishreim Haneen , Abu Serhan Hashem , Al-Noaaimi Faisal , Abdel-Razeq Hikmat
Published: February 2022

Background: Cancer survivors are often underprepared for what to expect post-treatment, and there are knowledge gaps regarding cancer survivors’ supportive care needs in Jordan and neighboring Arab countries. This study aimed to identify gaps in supportive care needs among adult cancer survivors seen at King Hussein Cancer Center in Amman, Jordan, and explore predictors of unmet needs. Methods: This was an observational cross-sectional study using a modified version of the Supportive Care Needs Survey 34 item short form (SCNS-SF34). Results: Two hundred and forty adult cancer survivors completed the study questionnaire. The assessed needs were highest in the financial domain, including covering living expenses, managing cancer treatment adverse effects and co-morbidities. The least prevalent reported needs were in sexuality and reproductive consultations. Late-stage diagnosis was independently associated with higher physical, psychological, health system/information, financial and overall need scores, with p-values of 0.032, 0.027, 0.052, 0.002 and 0.024, respectively. The overall quality of life score was independently and inversely associated with physical, psychological, health system/information, financial and overall need domains, with p-values of 0.015, <0.0001, 0.015, 0.004 and 0.0003, respectively. Conclusions: This needs assessment identified problem areas for targeting interventions across the Jordanian cancer survivor population, and understanding these findings highlights opportunities for intervention to address gaps in care.
PARP Inhibitors in Glioma: A Review of Therapeutic Opportunities
Authors: Sim Hao-Wen , Galanis Evanthia , Khasraw Mustafa
Published: February 2022

Gliomas are the most common malignant primary brain tumor in adults. Despite advances in multimodality therapy, incorporating surgery, radiotherapy, systemic therapy, tumor treating fields and supportive care, patient outcomes remain poor, especially in glioblastoma where median survival has remained static at around 15 months, for decades. Low-grade gliomas typically harbor isocitrate dehydrogenase (IDH) mutations, grow more slowly and confer a better prognosis than glioblastoma. However, nearly all gliomas eventually recur and progress in a way similar to glioblastoma. One of the novel therapies being developed in this area are poly(ADP-Ribose) polymerase (PARP) inhibitors. PARP inhibitors belong to a class of drugs that target DNA damage repair pathways. This leads to synthetic lethality of cancer cells with coexisting homologous recombination deficiency. PARP inhibitors may also potentiate the cytotoxic effects of radiotherapy and chemotherapy, and prime the tumor microenvironment for immunotherapy. In this review, we examine the rationale and clinical evidence for PARP inhibitors in glioma and suggest therapeutic opportunities.
L-Thyroxine Improves Vestibular Compensation in a Rat Model of Acute Peripheral Vestibulopathy: Cellular and Behavioral Aspects
Authors: Rastoldo Guillaume , Marouane Emna , El-Mahmoudi Nada , Péricat David , Watabe Isabelle , Lapotre Agnes , Tonetto Alain , López-Juárez Alejandra , El-Ahmadi Abdessadek , Caron Philippe , Fraysse Marie-José Esteve , Chabbert Christian , Zwergal Andreas , Tighilet Brahim
Published: February 2022

Unilateral vestibular lesions induce a vestibular syndrome, which recovers over time due to vestibular compensation. The therapeutic effect of L-Thyroxine (L-T4) on vestibular compensation was investigated by behavioral testing and immunohistochemical analysis in a rat model of unilateral vestibular neurectomy (UVN). We demonstrated that a short-term L-T4 treatment reduced the vestibular syndrome and significantly promoted vestibular compensation. Thyroid hormone receptors (TRα and TRβ) and type II iodothyronine deiodinase (DIO2) were present in the vestibular nuclei (VN), supporting a local action of L-T4. We confirmed the T4-induced metabolic effects by demonstrating an increase in the number of cytochrome oxidase-labeled neurons in the VN three days after the lesion. L-T4 treatment modulated glial reaction by decreasing both microglia and oligodendrocytes in the deafferented VN three days after UVN and increased cell proliferation. Survival of newly generated cells in the deafferented vestibular nuclei was not affected, but microglial rather than neuronal differentiation was favored by L-T4 treatment.
Radon Improves Clinical Response in an Animal Model of Rheumatoid Arthritis Accompanied by Increased Numbers of Peripheral Blood B Cells and Interleukin-5 Concentration
Authors: Deloch Lisa , Hehlgans Stephanie , Rückert Michael , Maier Andreas , Hinrichs Annika , Flohr Ann-Sophie , Eckert Denise , Weissmann Thomas , Seeling Michaela , Nimmerjahn Falk , Fietkau Rainer , Rödel Franz , Fournier Claudia , Frey Benjamin , Gaipl Udo S.
Published: February 2022

Radon treatment is used as an established therapy option in chronic painful inflammatory diseases. While analgesic effects are well described, little is known about the underlying molecular effects. Among the suspected mechanisms are modulations of the anti-oxidative and the immune system. Therefore, we aimed for the first time to examine the beneficial effects of radon exposure on clinical outcome as well as the underlying mechanisms by utilizing a holistic approach in a controlled environment of a radon chamber with an animal model: K/BxN serum-induced arthritic mice as well as isolated cells were exposed to sham or radon irradiation. The effects on the anti-oxidative and the immune system were analyzed by flow-cytometry, qPCR or ELISA. We found a significantly improved clinical disease progression score in the mice, alongside significant increase of peripheral blood B cells and IL-5. No significant alterations were visible in the anti-oxidative system or regarding cell death. We conclude that neither cell death nor anti-oxidative systems are responsible for the beneficial effects of radon exposure in our preclinical model. Rather, radon slightly affects the immune system. However, more research is still needed in order to fully understand radon-mediated effects and to carry out reasonable risk-benefit considerations.
Intratumor Microbiome in Neuroendocrine Neoplasms: A New Partner of Tumor Microenvironment? A Pilot Study
Authors: Massironi Sara , Facciotti Federica , Cavalcoli Federica , Amoroso Chiara , Rausa Emanuele , Centonze Giovanni , Cribiù Fulvia Milena , Invernizzi Pietro , Milione Massimo
Published: February 2022

Neuroendocrine neoplasms (NENs) are rare neoplasms with heterogeneous clinical behavior. Alteration in human microbiota was reported in association with carcinogenesis in different solid tumors. However, few studies addressed the role of microbiota in NEN. We here aimed at evaluating the presence of bacterial infiltration in neuroendocrine tumoral tissue. To assess the presence of bacteria, 20 specimens from pancreatic NEN (pan-NEN) and 20 from intestinal NEN (I-NEN) were evaluated through Fluorescent In situ Hybridization and confocal microscopy. Demographic data, pre-operative investigations, operative findings, pathological diagnosis, follow-up, and survival data were evaluated. Among I-NEN, bacteria were detected in 15/20 (75%) specimens, with high variability in microbial distribution. In eight patients, a high infiltration of microorganisms was observed. Among pan-NEN, 18/20 (90%) showed microorganisms’ infiltration, with a homogeneous microbial distribution. Bacterial localization in pan-NEN was observed in the proximity of blood vessels. A higher bacterial infiltration in the tumoral specimen as compared with non-tumoral tissue was reported in 10/20 pan-NEN (50%). No significant differences were observed in mean bacterial count according to age, sex, ki67%, site, tumor stage. Mean bacterial count did not result to be a predictor of disease-specific survival. This preliminary study demonstrates the presence of a significant microbiota in the NEN microenvironment. Further research is needed to investigate the potential etiological or clinical role of microbiota in NEN.
Impaired Function of PLEKHG2, a Rho-Guanine Nucleotide-Exchange Factor, Disrupts Corticogenesis in Neurodevelopmental Phenotypes
Authors: Nishikawa Masashi , Ito Hidenori , Tabata Hidenori , Ueda Hiroshi , Nagata Koh-ichi
Published: February 2022

Homozygosity of the p.Arg204Trp variation in the Pleckstrin homology and RhoGEF domain containing G2 (PLEKHG2) gene, which encodes a Rho family-specific guanine nucleotide-exchange factor, is responsible for microcephaly with intellectual disability. However, the role of PLEKHG2 during neurodevelopment remains unknown. In this study, we analyzed mouse Plekhg2 function during cortical development, both in vitro and in vivo. The p.Arg200Trp variant in mouse (Plekhg2-RW), which corresponds to the p.Arg204Trp variant in humans, showed decreased guanine nucleotide-exchange activity for Rac1, Rac3, and Cdc42. Acute knockdown of Plekhg2 using in utero electroporation-mediated gene transfer did not affect the migration of excitatory neurons during corticogenesis. On the other hand, silencing Plekhg2 expression delayed dendritic arbor formation at postnatal day 7 (P7), perhaps because of impaired Rac/Cdc42 and p21-activated kinase 1 signaling pathways. This phenotype was rescued by expressing an RNAi-resistant version of wildtype Plekhg2, but not of Plekhg2-RW. Axon pathfinding was also impaired in vitro and in vivo in Plekhg2-deficient cortical neurons. At P14, knockdown of Plekhg2 was observed to cause defects in dendritic spine morphology formation. Collectively, these results strongly suggest that PLEKHG2 has essential roles in the maturation of axon, dendrites, and spines. Moreover, impairment of PLEKHG2 function is most likely to cause defects in neuronal functions that lead to neurodevelopmental disorders.
Going Micro in Leptospirosis Kidney Disease
Authors: Chancharoenthana Wiwat , Leelahavanichkul Asada , Schultz Marcus J. , Dondorp Arjen M.
Published: February 2022

Leptospirosis is a zoonotic and waterborne disease worldwide. It is a neglected infectious disease caused by Leptospira spp., as well as a reemerging disease and global public health problem with respect to morbidity and mortality both in humans and animals. Leptospirosis emerges as a leading cause of acute febrile illness along with hepatorenal injury in many countries, including Thailand. While most affected persons are symptomatic in acute disease, which is always difficult to differentiate from other tropical diseases, there is growing evidence of subtle manifestations that cause unrecognized chronic symptoms. The kidney is one of the common organs affected by Leptospires. Although acute kidney injury in the spectrum of interstitial nephritis is a well-described characteristic in severe leptospirosis, chronic kidney disease from leptospirosis is widely discussed. Early recognition of severe leptospirosis leads to reduce morbidity and mortality. Thus, in this review, we highlight the spectrum of characteristics involved in leptospirosis kidney disease and the use of serologic and molecular methods, as well as the treatments of severe leptospirosis.
Quantitative CT Correlates with Local Inflammation in Lung of Patients with Subtypes of Chronic Lung Allograft Dysfunction
Authors: Ram Sundaresh , Verleden Stijn E. , Bell Alexander J. , Hoff Benjamin A. , Labaki Wassim W. , Murray Susan , Vanaudenaerde Bart M. , Vos Robin , Verleden Geert M. , Kazerooni Ella A. , Galbán Stefanie , Hatt Charles R. , Han Meilan K. , Lama Vibha N. , Galbán Craig J.
Published: February 2022

Chronic rejection of lung allografts has two major subtypes, bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS), which present radiologically either as air trapping with small airways disease or with persistent pleuroparenchymal opacities. Parametric response mapping (PRM), a computed tomography (CT) methodology, has been demonstrated as an objective readout of BOS and RAS and bears prognostic importance, but has yet to be correlated to biological measures. Using a topological technique, we evaluate the distribution and arrangement of PRM-derived classifications of pulmonary abnormalities from lung transplant recipients undergoing redo-transplantation for end-stage BOS (N = 6) or RAS (N = 6). Topological metrics were determined from each PRM classification and compared to structural and biological markers determined from microCT and histopathology of lung core samples. Whole-lung measurements of PRM-defined functional small airways disease (fSAD), which serves as a readout of BOS, were significantly elevated in BOS versus RAS patients (p = 0.01). At the core-level, PRM-defined parenchymal disease, a potential readout of RAS, was found to correlate to neutrophil and collagen I levels (p < 0.05). We demonstrate the relationship of structural and biological markers to the CT-based distribution and arrangement of PRM-derived readouts of BOS and RAS.
ACAGT-007a, an ERK MAPK Signaling Modulator, in Combination with AKT Signaling Inhibition Induces Apoptosis in KRAS Mutant Pancreatic Cancer T3M4 and MIA-Pa-Ca-2 Cells
Authors: Khandakar Golam Iftakhar , Satoh Ryosuke , Takasaki Teruaki , Fujitani Kana , Tanabe Genzoh , Sakai Kazuko , Nishio Kazuto , Sugiura Reiko
Published: February 2022

The mitogen-activated protein kinase (MAPK)/ERK and phosphatidylinositol-3 kinase (PI3K)/AKT pathways are dysregulated in various human cancers, including pancreatic ductal adenocarcinoma (PDAC), which has a very poor prognosis due to its lack of efficient therapies. We have previously identified ACAGT-007a (GT-7), an anti-cancer compound that kills ERK-active melanoma cells by inducing ERK-dependent apoptosis. Here, we investigated the apoptosis-inducing effect of GT-7 on three PDAC cell lines and its relevance with the MAPK/ERK and PI3K/AKT signaling pathways. GT-7 induced apoptosis in PDAC cells with different KRAS mutations (MIA-Pa-Ca-2 (KRAS G12C), T3M4 (KRAS Q61H), and PANC-1 (KRAS G12D)), being T3M4 most susceptible, followed by MIA-Pa-Ca-2, and PANC-1 was most resistant to apoptosis induction by GT-7. GT-7 stimulated ERK phosphorylation in the three PDAC cells, but only T3M4 displayed ERK-activation-dependent apoptosis. Furthermore, GT-7 induced a marked down-regulation of AKT phosphorylation after a transient peak in T3M4, whereas PANC-1 displayed the strongest and most sustained AKT activation, followed by MIA-Pa-Ca-2, suggesting that sustained AKT phosphorylation as a determinant for the resistance to GT-7-mediated apoptosis. Consistently, a PI3K inhibitor, Wortmannin, abolished AKT phosphorylation and enhanced GT-7-mediated apoptosis in T3M4 and MIA-Pa-Ca-2, but not in PANC-1, which showed residual AKT phosphorylation. This is the first report that ERK stimulation alone or in combination with AKT signaling inhibition can effectively induce apoptosis in PDAC and provides a rationale for a novel concurrent targeting of the PI3K/AKT and ERK pathways.
Electrocatalysts for the Oxygen Reduction Reaction: From Bimetallic Platinum Alloys to Complex Solid Solutions
Authors: Martínez-Hincapié Ricardo , Čolić Viktor
Published: February 2022

The oxygen reduction reaction has been the object of intensive research in an attempt to improve the sluggish kinetics that limit the performance of renewable energy storage and utilization systems. Platinum or platinum bimetallic alloys are common choices as the electrode material, but prohibitive costs hamper their use. Complex alloy materials, such as high-entropy alloys (HEAs), or more generally, multiple principal component alloys (MPCAs), have emerged as a material capable of overcoming the limitations of platinum and platinum-based materials. Theoretically, due to the large variety of active sites, this new kind of material offers the opportunity to identify experimentally the optimal binding site on the catalyst surface. This review discusses recent advances in the application of such alloys for the oxygen reduction reaction and existing experimental challenges in the benchmarking of the electrocatalytic properties of these materials.