bluuebunny/crossref_metadata_2025 huggingface dataset:
Decrease in RNase HII and Accumulation of lncRNAs/DNA Hybrids: A Causal Implication in Psoriasis?
Authors: Mehmetbeyoglu Ecmel , Kianmehr Leila , Borlu Murat , Yilmaz Zeynep , Basar Kılıc Seyma , Rajabi-Maham Hassan , Taheri Serpil , Rassoulzadegan Minoo
Published: February 2022

Functional long non-coding RNAs (lncRNAs) have been in the limelight in aging research because short telomeres are associated with higher levels of TERRA (Telomeric Repeat containing RNA). The genomic instability, which leads to short telomeres, is a mechanism observed in cell aging and in a class of cancer cells. Psoriasis, a skin disease, is a disorder of epidermal keratinocytes, with altered telomerase activity. Research on the fraction of nascent RNAs in hybrid with DNA offers avenues for new strategies. Skin and blood samples from patients were fractionated to obtain the RNA associated with DNA as a R-loop structure. The higher amount of TERRA levels attached with each chromosome end was found with psoriasis patients in blood and skin. In addition to telomeric TERRA, we evidenced accumulation of others non-coding RNA, such as non-telomeric TERRA and centromeric transcripts. Increased levels of non-coding RNAs attached to DNA correlates with a decreased in Ribonuclease HII (RNase-HII) transcript which means that overall unresolved DNA–RNA hybrids can ultimately weaken DNA and cause skin lesions. Since the genome is actively transcribed, cellular RNase-HII is essential for removing RNA from the DNA–RNA hybrid in controls of genome stability and epigenome shaping and can be used as a causal prognostic marker in patients with psoriasis.
The Amazing World of IDPs in Human Diseases II
Authors: Monti Simona Maria , De Simone Giuseppina , Langella Emma
Published: February 2022

Intrinsically Disordered Proteins (IDPs) lack stable tertiary and secondary structures and are extensively distributed across eukaryotic cells, playing critical roles in cell signaling and regulation [...]
The Role of Hub and Spoke Regions in Theory of Mind in Early Alzheimer’s Disease and Frontotemporal Dementia
Authors: Orso Beatrice , Lorenzini Luigi , Arnaldi Dario , Girtler Nicola , Brugnolo Andrea , Doglione Elisa , Mattioli Pietro , Biassoni Erica , Massa Federico , Peira Enrico , Bauckneht Matteo , Donegani Maria I. , Morbelli Silvia , Nobili Flavio , Pardini Matteo
Published: February 2022

Theory of mind (ToM, the ability to attribute mental states to others) deficit is a frequent finding in neurodegenerative conditions, mediated by a diffuse brain network confirmed by 18F-FDG-PET and MR imaging, involving frontal, temporal and parietal areas. However, the role of hubs and spokes network regions in ToM performance, and their respective damage, is still unclear. To study this mechanism, we combined ToM testing with brain 18F-FDG-PET imaging in 25 subjects with mild cognitive impairment due to Alzheimer’s disease (MCI–AD), 24 subjects with the behavioral variant of frontotemporal dementia (bvFTD) and 40 controls. Regions included in the ToM network were divided into hubs and spokes based on their structural connectivity and distribution of hypometabolism. The hubs of the ToM network were identified in frontal regions in both bvFTD and MCI–AD patients. A mediation analysis revealed that the impact of spokes damage on ToM performance was mediated by the integrity of hubs (p < 0.001), while the impact of hubs damage on ToM performance was independent from the integrity of spokes (p < 0.001). Our findings support the theory that a key role is played by the hubs in ToM deficits, suggesting that hubs could represent a final common pathway leading from the damage of spoke regions to clinical deficits.
Gut Microbiome in Non-Alcoholic Fatty Liver Disease: From Mechanisms to Therapeutic Role
Authors: Gupta Haripriya , Min Byeong-Hyun , Ganesan Raja , Gebru Yoseph Asmelash , Sharma Satya Priya , Park Eunju , Won Sung-Min , Jeong Jin-Ju , Lee Su-Been , Cha Min-Gi , Kwon Goo-Hyun , Jeong Min-Kyo , Hyun Ji-Ye , Eom Jung-A. , Park Hee-Jin , Yoon Sang-Jun , Choi Mi-Ran , Kim Dong-Joon , Suk Ki-Tae
Published: February 2022

Non-alcoholic fatty liver disease (NAFLD) is considered to be a significant health threat globally, and has attracted growing concern in the research field of liver diseases. NAFLD comprises multifarious fatty degenerative disorders in the liver, including simple steatosis, steatohepatitis and fibrosis. The fundamental pathophysiology of NAFLD is complex and multifactor-driven. In addition to viruses, metabolic syndrome and alcohol, evidence has recently indicated that the microbiome is related to the development and progression of NAFLD. In this review, we summarize the possible microbiota-based therapeutic approaches and highlight the importance of establishing the diagnosis of NAFLD through the different spectra of the disease via the gut–liver axis.
Biomimetics—Prospects and Developments
Authors: Gebeshuber Ille C.
Published: February 2022

Since its inaugural issue published in 2016, the scientific journal Biomimetics (ISSN 2313-7673), published by MDPI, has developed into a robust scientific journal that is appreciated in the field [...]
Depicting People in Visual Cues Affects Alcohol Cue Reactivity in Male Alcohol-Dependent Patients
Authors: Alarefi Abdulqawi , Wang Xunshi , Tao Rui , Rui Qinqin , Gao Guoqing , Wang Ying , Pang Liangjun , Liu Chialun , Zhang Xiaochu
Published: February 2022

Cue reactivity is often used to study alcohol cues brain responses. Standardized image sets are used, but the effect of viewing people interacting with the alcohol drink remains unclear, which is associated with the factors of alcohol cues that influence the degree of response to alcohol stimuli. The present study used fMRI to investigate the reactivity of alcohol dependence (AD) inpatients to alcohol cues with or without human drinking behavior. Cues with a human interacting with a drink were hypothesized to increase sensorimotor activation. In total, 30 AD inpatients were asked to view pictures with a factorial design of beverage types (alcoholic vs. non-alcoholic beverages) and cue types (with or without drink action). Whole-brain analyses were performed. A correlation analysis was conducted to confirm whether the whole-brain analysis revealed cue-related brain activations correlated with problem drinking duration. The left lingual gyrus showed significant beverage types through cue type interaction, and the bilateral temporal cortex showed significant activation in response to alcohol cues depicting human drinking behavior. The right and left lingual gyrus regions and left temporal cortex were positively correlated with problem drinking duration. Sensorimotor activations in the temporal cortex may reflect self-referential and memory-based scene processing. Thus, our findings indicate these regions are associated with alcohol use and suggest them for cue exposure treatment of alcohol addiction.
Effects of Phone-Based Psychological Intervention on Caregivers of Patients with Early-Onset Alzheimer’s Disease: A Six-Months Study during the COVID-19 Emergency in Italy
Authors: De Stefano Manuela , Esposito Sabrina , Iavarone Alessandro , Carpinelli Mazzi Michele , Siciliano Mattia , Buonanno Daniela , Atripaldi Danilo , Trojsi Francesca , Tedeschi Gioacchino
Published: February 2022

Caregivers of patients with early-onset Alzheimer’s disease (EOAD) experience higher level of burden, stress, and depression, due to premature role changes and social isolation. Moreover, the SARS-CoV-2 pandemic compelled restrictions regarding social interactions and mobility in Italy from March 2020, prompting telemedicine approaches for supporting patients and their families confined at home. We reported our experience regarding the effects of psychological phone-intervention (phone-I) on EOAD caregivers during pandemic. Twenty caregivers of EOAD patients were randomly assigned to treatment (TG) or control (CG) group. TG weekly underwent a phone-I for one month. All participants were assessed for caregiver burden and needs, anxiety and depression levels, and subjective impact of traumatic events at baseline (T0), at the fifth week (T1) and after 6 months (T2) from phone-I. We observed higher vulnerability to post-traumatic stress in TG compared to CG in all timepoints (p ≤ 0.05). Decreased stress effects and caregiver burden were revealed in TG at T1 compared to T0 (p ≤ 0.05), although showing an increase of these measures at T2 in the treated caregivers. Our findings suggest that although TG showed a peculiar vulnerability to post-traumatic stress, they showed increased wellbeing immediately after phone-I. However, this benefit disappeared six months later, along with the second infection wave, probably due to “exhaustion stage” achievement in “General Adaptation Syndrome”. This trend may suggest a beneficial but not solving role of a prompt phone-I on burden of caregivers of EOAD patients during the SARS-CoV-2 emergency.
Multi-Informant Assessment of Adolescents’ Social–Emotional Skills: Patterns of Agreement and Discrepancy among Teachers, Parents, and Students
Authors: Mudarra María J. , Álvarez-González Beatriz , García-Salguero Berta , Elliott Stephen N.
Published: February 2022

Objectives: This study explores the patterns of agreement and discrepancy among informants (teachers, parents, and students) in the domains of the Social Emotional Skills Scale Assessment System—Social Skills Scales (SESAS-SS), which is a translation of the Social Skills Improvement System—Rating Scales (SSIS-RS) for use in Spain. Methods: The sample is composed of students, 88 teachers, and 98 parents from Spanish secondary schools. Inter-rater agreements have been assessed, calculating the Pearson correlation coefficients among pairs of raters, effect size indices, and intraclass correlation coefficients at the subscale and total scale level. Results: The convergent validity coefficients were stronger than the divergent ones, with the highest level of agreement between teachers and parents in social skills, particularly for total social skills, engagement, empathy, and communication. The patterns of discrepancies confirmed weaker agreements between teachers and parents in self-control and between parents and students in empathy. Significant differences were also found in students’ estimates depending on gender. Conclusions: The SESAS-SS provides support for previous studies on inter-rater agreements for SS, extending the focus on the degree of agreement in the estimate of dyads of raters when considering the students’ gender.
Experimental Study of Infill Walls with Joint Reinforcement Subjected to In-Plane Lateral Load
Authors: Leal-Graciano Jesús Martin , Pérez-Gavilán Juan J. , Reyes-Salazar Alfredo , Valenzuela-Beltrán Federico , Bojórquez Edén , Bojórquez Juan
Published: February 2022

The results of an experimental study of four infilled frames with brick masonry walls subject to reversal cyclic lateral load are presented. The variables studied were the height to length aspect ratio of the wall and the use of joint reinforcement. The investigation was motivated by the fact that the Mexican code establishes the same specifications about the use of joint reinforcement for infill walls as for confined walls, because there is not enough experimental evidence on joint reinforced infill walls. To investigate the possible interaction of the study variables in the seismic performance of the walls, two pairs of specimens, scaled 1:2, with different aspect ratios (H/L = 0.75, 0.41) were tested. The specimens in each pair were identical except that one of them included steel bars into the bed-joints as reinforcement leading to amount  phfyh=0.6 MPa. The infill walls with H/L = 0.41 were included from a previous study. The behavior of the specimens was defined in terms of lateral strength, ductility, displacement capacity, deformation of the joint reinforcement and crack pattern. The results indicate that joint reinforcement increases the strength of the system; however, the increase was more pronounced in longer walls. Ductility was reduced with horizontal reinforcement and this behavior was more important for longer walls. As occurred in confined walls, the joint reinforcement generates a more distributed cracking and reduces the width of the cracks. The experiments are described and this and other results are discussed in detail.
Assessing Ozone Distribution Vertically and Horizontally in Urban Street Canyons Based on Field Investigation and ENVI-met Modelling
Authors: Miao Chunping , Chen Wei , Yu Shuai
Published: February 2022

High concentrations of ozone (O3) is a major air problem in urban areas, which creates a serious threat to human health. Urban street canyon morphology plays a key role in air pollutant dispersion and photochemical reaction rate. In this study, a one-year observation at three height levels was performed to investigate the O3 distribution vertically in a street canyon of Shenyang. Then, field investigation and ENVI-met modelling were conducted to quantify the influence of street canyon morphology and microclimatic factors on O3 distribution at the pedestrian level. All O3 concentrations at the three height levels were high from 1:00 p.m. to 4:00 p.m. Both O3 concentrations at pedestrian level and the middle level in the canyon were 40% higher than at roof level. O3 accumulated in the canyons rather than spread out. The in-canyon O3 concentrations had significantly positive correlations with building height, aspect ratio, sky view factor, air temperature, and wind speed. Both field investigation and ENVI-met modelling found high O3 concentrations in medium canyons. Photochemical reaction intensity played a more important role in in-canyon O3 distribution than dispersion. Wide canyons were favorable for removing O3.
A FDEM Parametric Investigation on the Impact Fracture of Monolithic Glass
Authors: Chen Xiangxiang , Chen Xudong , Chan Andrew , Cheng Yingyao , Wang Hongfan
Published: February 2022

Due to the brittleness, monolithic glass may fracture under impact, resulting in catastrophic sequences. The combined finite-discrete element method, i.e., FDEM, is employed to investigate both the oblique and the perpendicular impact failures of monolithic glass parametrically, particularly the soda-lime glass. Using FDEM, glass is discretised into discrete elements where a finite element formulation is incorporated, leading to accurate evaluation of the contact forces and structural deformation. Following the basic theories of the FDEM, a cohesive Mode I fracture model of glass is briefly introduced. Numerical examples are given for the verification of the employed fracture model and the applicability of the FDEM, and comparisons have been made against the computational and experimental results in the literature. The investigated parameters include the impact velocity, the impact angle, the material properties of glass, etc. The obtained results not only revealed the impact fracture mechanism of soda-lime glass but also provided guidance for its design and manufacturing.
A Conceptual Framework for Implementing Lean Construction in Infrastructure Recovery Projects
Authors: Habibi Rad Mahyar , Mojtahedi Mohammad , Ostwald Michael J. , Wilkinson Suzanne
Published: February 2022

Natural hazards can have substantial destructive impacts on the built environment. Providing effective services in disaster areas is heavily reliant on maintaining or replacing infrastructure; thus, post-disaster reconstruction of infrastructure has attracted growing attention. Due to the complex and dynamic nature of infrastructure recovery projects, contractor companies engaged in this work have typically experienced poor performance. Furthermore, from a commercial perspective, the post-disaster reconstruction environment is characterized by fierce competition and market uncertainty, challenging the organizational resilience of companies undertaking this work. One approach for improving contractor performance is the implementation of lean construction, but the literature lacks consensus on its capability to affect organizational resilience. To respond to this problem, a conceptual framework applicable for lean implementation in infrastructure, which explicitly addresses organizational resilience, is required for recovery projects. In parallel, contributing components to effective implementation of lean-recovery and supportive theories for justifying the conceptual framework must be identified. Consequently, this paper proposes a conceptual framework to implement lean practices for the enhancement of organizational resilience. The framework is developed using a systematic research method, wherein 110 research documents were discovered initially, and following processing, 18 relevant documents were identified and analyzed. Through this process, contingency and Transformation-Flow-Value (TFV) theories were identified as an appropriate foundation for a framework to implement lean construction in infrastructure recovery projects.
Present Practice of Radiative Deep Hyperthermia in Combination with Radiotherapy in Switzerland
Authors: Stutz Emanuel , Puric Emsad , Ademaj Adela , Künzi Arnaud , Krcek Reinhardt , Timm Olaf , Marder Dietmar , Notter Markus , Rogers Susanne , Bodis Stephan , Riesterer Oliver
Published: February 2022

Background: Moderate hyperthermia is a potent and evidence-based radiosensitizer. Several indications are reimbursed for the combination of deep hyperthermia with radiotherapy (dHT+RT). We evaluated the current practice of dHT+RT in Switzerland. Methods: All indications presented to the national hyperthermia tumor board for dHT between January 2017 and June 2021 were evaluated and treatment schedules were analyzed using descriptive statistics. Results: Of 183 patients presented at the hyperthermia tumor board, 71.6% were accepted and 54.1% (99/183) finally received dHT. The most commonly reimbursed dHT indications were “local recurrence and compression” (20%), rectal (14.7%) and bladder (13.7%) cancer, respectively. For 25.3% of patients, an individual request for insurance cover was necessary. 47.4% of patients were treated with curative intent; 36.8% were in-house patients and 63.2% were referred from other hospitals. Conclusions: Approximately two thirds of patients were referred for dHT+RT from external hospitals, indicating a general demand for dHT in Switzerland. The patterns of care were diverse with respect to treatment indication. To the best of our knowledge, this study shows for the first time the pattern of care in a national cohort treated with dHT+RT. This insight will serve as the basis for a national strategy to evaluate and expand the evidence for dHT.
Status of the Current Treatment Options and Potential Future Targets in Uterine Leiomyosarcoma: A Review
Authors: Asano Hiroshi , Isoe Toshiyuki , Ito Yoichi M. , Nishimoto Naoki , Watanabe Yudai , Yokoshiki Saki , Watari Hidemichi
Published: February 2022

Uterine leiomyosarcoma (uLMS) is the most common subtype of mesenchymal tumors in the uterus. This review aims to summarize the current standard therapies and the molecular properties of uLMS for novel molecular-targeted therapies. Although 65% of uLMS cases are diagnosed in stage I, the 5-year overall survival rate is less than 60%. The only effective treatment for uLMS is complete and early resection, and chemotherapy is the main treatment for unresectable advanced or recurrent cases. No chemotherapy regimen has surpassed doxorubicin monotherapy as the first-line chemotherapy for unresectable advanced or recurrent cases in terms of overall survival in phase 3 trials. As a second-line treatment, pazopanib, trabectedin, and eribulin are used, but their therapeutic effects are not sufficient, highlighting the urgent need for development of novel treatments. Recent developments in gene analysis have revealed that homologous recombination deficiency (HRD), including breast cancer susceptibility gene 2 (BRCA2) mutations, are frequently observed in uLMS. In preclinical studies and several case series, poly(adenosine diphosphate-ribose)polymerase inhibitors showed antitumor effects on uLMS cell lines with BRCA2 mutations or HRD and in recurrent or persistent cases of uLMS with BRCA2 mutations. Thus, HRD, including BRCA mutations, may be the most promising therapeutic target for uLMS.
Cannabidiol Inhibits Tumorigenesis in Cisplatin-Resistant Non-Small Cell Lung Cancer via TRPV2
Authors: Misri Swati , Kaul Kirti , Mishra Sanjay , Charan Manish , Verma Ajeet Kumar , Barr Martin P. , Ahirwar Dinesh K. , Ganju Ramesh K.
Published: February 2022

Chemotherapy forms the backbone of current treatments for many patients with advanced non-small-cell lung cancer (NSCLC). However, the survival rate is low in these patients due to the development of drug resistance, including cisplatin resistance. In this study, we developed a novel strategy to combat the growth of cisplatin-resistant (CR) NSCLC cells. We have shown that treatment with the plant-derived, non-psychotropic small molecular weight molecule, cannabidiol (CBD), significantly induced apoptosis of CR NSCLC cells. In addition, CBD treatment significantly reduced tumor progression and metastasis in a mouse xenograft model and suppressed cancer stem cell properties. Further mechanistic studies demonstrated the ability of CBD to inhibit the growth of CR cell lines by reducing NRF-2 and enhancing the generation of reactive oxygen species (ROS). Moreover, we show that CBD acts through Transient Receptor Potential Vanilloid-2 (TRPV2) to induce apoptosis, where TRPV2 is expressed on human lung adenocarcinoma tumors. High expression of TRPV2 correlates with better overall survival of lung cancer patients. Our findings identify CBD as a novel therapeutic agent targeting TRPV2 to inhibit the growth and metastasis of this aggressive cisplatin-resistant phenotype in NSCLC.
The Evaluation of the 1318 nm Diode Laser in Open Liver Surgery
Authors: Pfitzmaier Patrick , Schwarzbach Matthias , Ronellenfitsch Ulrich
Published: February 2022

(1) Background: Numerous dissection instruments are available for liver resection. So far, there has been no evidence in favor of a specific dissection device effecting a reduction in postoperative mortality and morbidity or a reduction in intraoperative blood loss. The aim of the study was to evaluate the safety of liver resection with the 1318 nm surgical laser. (2) Methods: 151 consecutive patients who underwent liver resection using the 1318 nm surgical laser (n = 119) or conventional dissection methods (n = 32) were evaluated retrospectively. As primary outcome, postoperative complications were assessed using the Clavien–Dindo classification. Secondary outcomes were postoperative mortality, reoperations and reinterventions, intraoperative blood loss, the need for vascular control using the Pringle maneuver and oncological safety assessed through histopathological evaluation of resection margins. (3) Results: For liver resections using the 1318 nm surgical laser, the postoperative morbidity (41.2% vs. 59.4%, p = 0.066), mortality (1.7% vs. 3.1%, p = 0.513) and the reoperation rate (2.5% vs. 3.1%, p = 1.000) were not significantly different from conventional liver resections. In the laser group, a lower reintervention rate (9.2% vs. 21.9%, p = 0.050) was observed. The oncological safety demonstrated by a tumor-free resection margin was similar after laser and conventional resection (93.2% vs. 89.3%, p = 0.256). The median intraoperative blood loss was significantly lower in the laser group (300 mL vs. 500 mL, p = 0.005) and there was a significantly lower need for a Pringle maneuver (3.4% vs. 15.6%, p = 0.021). (4) Conclusions: Liver resections using the 1318 nm surgical laser can be routinely performed with a favorable risk profile. Compared to alternative resection methods, they are associated with low blood loss, appear adequate from an oncological point of view, and are not associated with increased mortality and morbidity.
Efficacy of Retreatment with Oxaliplatin-Based Regimens in Metastatic Colorectal Cancer Patients: The RETROX-CRC Retrospective Study
Authors: Amatu Alessio , Mauri Gianluca , Tosi Federica , Bencardino Katia , Bonazzina Erica , Gori Viviana , Ruggieri Lorenzo , Arena Sabrina , Bardelli Alberto , Marsoni Silvia , Siena Salvatore , Sartore-Bianchi Andrea
Published: February 2022

Background: oxaliplatin with fluoropyrimidine is a “mainstay” regarding the upfront treatment of metastatic colorectal cancer (mCRC). In contrast, the efficacy and safety of oxaliplatin-based regimens in late-care settings have been poorly reported. Methods: we identified a real-world mCRC patient cohort who were re-treated with oxaliplatin, and in which clinicopathological features were retrospectively analyzed to identify efficacy–predictive determinants (RETROX-CRC study). Results: of 2606 patients, 119 fulfilled the eligibility criteria. Oxaliplatin retreatment response rate (RR) and disease control rate (DCR) were 21.6% (CI 14.4–31.0%), and 57.8% (CI 47.7–67.4). A trend towards better RR and DCR was observed among patients who had first oxaliplatin in an adjuvant setting; a poorer outcome was observed if two or more intervening treatments were delivered. Median progression-free survival (PFS) was 5.1 months (95%CI 4.3–6.1), reducing to 4.0 months (95%CI 3.07–5.13) if oxaliplatin was readministered beyond third-line (HR 2.02; 1.25–3.25; p = 0.004). Safety data were retrieved in 65 patients (54.6%); 18.5% (12/65) and 7.7% (5/65) had G3–4 toxicities. Toxicities led to discontinuation in 34/119 (28.6%). Conclusions: oxaliplatin retreatment produced further RR in around one-fifth of patients and DCR 57.8%. Efficacy decreased in more pre-treated patients and around one-third of patients discontinued treatment due to adverse events. Translational studies improving patient selection are warranted.
Loxl3 Promotes Melanoma Progression and Dissemination Influencing Cell Plasticity and Survival
Authors: Vázquez-Naharro Alberto , Bustos-Tauler José , Floristán Alfredo , Yuste Lourdes , Oltra Sara S. , Vinyals Antònia , Moreno-Bueno Gema , Fabra Àngels , Portillo Francisco , Cano Amparo , Santamaría Patricia G.
Published: February 2022

Malignant melanoma is a highly aggressive tumor causing most skin cancer-related deaths. Understanding the fundamental mechanisms responsible for melanoma progression and therapeutic evasion is still an unmet need for melanoma patients. Progression of skin melanoma and its dissemination to local or distant organs relies on phenotypic plasticity of melanoma cells, orchestrated by EMT-TFs and microphthalmia-associated TF (MITF). Recently, melanoma phenotypic switching has been proposed to uphold context-dependent intermediate cell states benefitting malignancy. LOXL3 (lysyl oxidase-like 3) promotes EMT and has a key role in human melanoma cell survival and maintenance of genomic integrity. To further understand the role of Loxl3 in melanoma, we generated a conditional Loxl3-knockout (KO) melanoma mouse model in the context of BrafV600E-activating mutation and Pten loss. Melanocyte-Loxl3 deletion increased melanoma latency, decreased tumor growth, and reduced lymph node metastatic dissemination. Complementary in vitro and in vivo studies in mouse melanoma cells confirmed Loxl3’s contribution to melanoma progression and metastasis, in part by modulating phenotypic switching through Snail1 and Prrx1 EMT-TFs. Importantly, a novel LOXL3-SNAIL1-PRRX1 axis was identified in human melanoma, plausibly relevant to melanoma cellular plasticity. These data reinforced the value of LOXL3 as a therapeutic target in melanoma.
Targeting Angiogenesis in Squamous Cell Carcinoma of the Head and Neck: Opportunities in the Immunotherapy Era
Authors: Saba Nabil F. , Vijayvargiya Pooja , Vermorken Jan B. , Rodrigo Juan P. , Willems Stefan M. , Zidar Nina , de Bree Remco , Mäkitie Antti , Wolf Greg T. , Argiris Athanassios , Teng Yong , Ferlito Alfio
Published: February 2022

Despite the lack of approved anti-angiogenic therapies in squamous cell carcinoma of the head and neck (SCCHN), preclinical and more recent clinical evidence support the role of targeting the vascular endothelial growth factor (VEGF) in this disease. Targeting VEGF has gained even greater interest following the recent evidence supporting the role of immunotherapy in the management of advanced SCCHN. Preclinical evidence strongly suggests that VEGF plays a role in promoting the growth and progression of SCCHN, and clinical evidence exists as to the value of combining this strategy with immunotherapeutic agents. Close to 90% of SCCHNs express VEGF, which has been correlated with a worse clinical prognosis and an increased resistance to chemotherapeutic agents. As immunotherapy is currently at the forefront of the management of advanced SCCHN, revisiting the rationale for targeting angiogenesis in this disease has become an even more attractive proposition.
Broad Transcriptomic Impact of Sorafenib and Its Relation to the Antitumoral Properties in Liver Cancer Cells
Authors: Contreras Laura , Rodríguez-Gil Alfonso , Muntané Jordi , de la Cruz Jesús
Published: February 2022

Hepatocellular carcinoma (HCC) is one of the most frequent and essentially incurable cancers in its advanced stages. The tyrosine kinase inhibitor Sorafenib (Sfb) remains the globally accepted treatment for advanced HCC. However, the extent of its therapeutic benefit is limited. Sfb exerts antitumor activity through its cytotoxic, anti-proliferative and pro-apoptotic roles in HCC cells. To better understand the molecular mechanisms underlying these effects, we used RNA sequencing to generate comprehensive transcriptome profiles of HepG2 and SNU423, hepatoblastoma- (HB) and HCC-derived cell lines, respectively, following a Sfb treatment at a pharmacological dose. This resulted in similar alterations of gene expression in both cell lines. Genes functionally related to membrane trafficking, stress-responsible and unfolded protein responses, circadian clock and activation of apoptosis were predominantly upregulated, while genes involved in cell growth and cycle, DNA replication and repair, ribosome biogenesis, translation initiation and proteostasis were downregulated. Our results suggest that Sfb causes primary effects on cellular stress that lead to upregulation of selective responses to compensate for its negative effect and restore homeostasis. No significant differences were found specifically affecting each cell line, indicating the robustness of the Sfb mechanism of action despite the heterogeneity of liver cancer. We discuss our results on terms of providing rationalization for possible strategies to improve Sfb clinical outcomes.
Impact of Exogenous Treatment with Histidine on Hepatocellular Carcinoma Cells
Authors: Park Yusun , Han Yeonju , Kim Dongwoo , Cho Sua , Kim WonJin , Hwang Hyemin , Lee Hye Won , Han Dai Hoon , Kim Kyung Sik , Yun Mijin , Lee Misu
Published: February 2022

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Sorafenib, a multi-kinase inhibitor, is the first-line therapy for advanced HCC. However, long-term exposure to sorafenib often results in reduced sensitivity and the development of resistance. Although various amino acids have been shown to contribute to cancer initiation and progression, little is known about the effects of histidine, a dietary essential amino acid that is partially taken up via histidine/large neutral amino acid transporter (LAT1), on cancer cells. In this study, we evaluated the effects of histidine on HCC cells and sensitivity to sorafenib. Remarkably, we found that exogenous histidine treatment induced a reduction in the expression of tumor markers related to glycolysis (GLUT1 and HK2), inflammation (STAT3), angiogenesis (VEGFB and VEGFC), and stem cells (CD133). In addition, LAT1 expression was downregulated in HCC tumor regions with high expression of GLUT1, CD133, and pSTAT3, which are known to induce sorafenib resistance. Finally, we demonstrated that combined treatment with sorafenib and histidine could be a novel therapeutic strategy to enhance the sensitivity to sorafenib, thereby improving long-term survival in HCC.
A Swedish Genome-Wide Haplotype Association Analysis Identifies a Novel Breast Cancer Susceptibility Locus in 8p21.2 and Characterizes Three Loci on Chromosomes 10, 11 and 16
Authors: Barnekow Elin , Liu Wen , Helgadottir Hafdis T. , Michailidou Kyriaki , Dennis Joe , Bryant Patrick , Thutkawkorapin Jessada , Wendt Camilla , Czene Kamila , Hall Per , Margolin Sara , Lindblom Annika
Published: February 2022

(1) Background: The heritability of breast cancer is partly explained but much of the genetic contribution remains to be identified. Haplotypes are often used as markers of ethnicity as they are preserved through generations. We have previously demonstrated that haplotype analysis, in addition to standard SNP association studies, could give novel and more detailed information on genetic cancer susceptibility. (2) Methods: In order to examine the association of a SNP or a haplotype to breast cancer risk, we performed a genome wide haplotype association study, using sliding window analysis of window sizes 1–25 and 50 SNPs, in 3200 Swedish breast cancer cases and 5021 controls. (3) Results: We identified a novel breast cancer susceptibility locus in 8p21.1 (OR 2.08; p 3.92 × 10−8), confirmed three known loci in 10q26.13, 11q13.3, 16q12.1-2 and further identified novel subloci within these three loci. Altogether 76 risk SNPs, 3302 risk haplotypes of window size 2–25 and 113 risk haplotypes of window size 50 at p < 5 × 10−8 on chromosomes 8, 10, 11 and 16 were identified. In the known loci haplotype analysis reached an OR of 1.48 in overall breast cancer and in familial cases OR 1.68. (4) Conclusions: Analyzing haplotypes, rather than single variants, could detect novel susceptibility loci even in small study populations but the method requires a fairly homogenous study population.
Role of Polo-like Kinases Plk1 and Plk4 in the Initiation of Centriole Duplication—Impact on Cancer
Authors: Hoffmann Ingrid
Published: February 2022

Centrosomes nucleate and anchor microtubules and therefore play major roles in spindle formation and chromosome segregation during mitosis. Duplication of the centrosome occurs, similar to DNA, only once during the cell cycle. Aberration of the centrosome number is common in human tumors. At the core of centriole duplication is the conserved polo-like kinase 4, Plk4, and two structural proteins, STIL and Sas-6. In this review, I summarize and discuss developments in our understanding of the first steps of centriole duplication and their regulation.
T Lymphocyte and CAR-T Cell-Derived Extracellular Vesicles and Their Applications in Cancer Therapy
Authors: Calvo Victor , Izquierdo Manuel
Published: February 2022

Extracellular vesicles (EV) are a very diverse group of cell-derived vesicles released by almost all kind of living cells. EV are involved in intercellular exchange, both nearby and systemically, since they induce signals and transmit their cargo (proteins, lipids, miRNAs) to other cells, which subsequently trigger a wide variety of biological responses in the target cells. However, cell surface receptor-induced EV release is limited to cells from the immune system, including T lymphocytes. T cell receptor activation of T lymphocytes induces secretion of EV containing T cell receptors for antigen and several bioactive molecules, including proapoptotic proteins. These EV are specific for antigen-bearing cells, which make them ideal candidates for a cell-free, EV-dependent cancer therapy. In this review we examine the generation of EV by T lymphocytes and CAR-T cells and some potential therapeutic approaches of these EV.
Cardiac Tissue-like 3D Microenvironment Enhances Route towards Human Fibroblast Direct Reprogramming into Induced Cardiomyocytes by microRNAs
Authors: Paoletti Camilla , Marcello Elena , Melis Maria Luna , Divieto Carla , Nurzynska Daria , Chiono Valeria
Published: February 2022

The restoration of cardiac functionality after myocardial infarction represents a major clinical challenge. Recently, we found that transient transfection with microRNA combination (miRcombo: miR-1, miR-133, miR-208 and 499) is able to trigger direct reprogramming of adult human cardiac fibroblasts (AHCFs) into induced cardiomyocytes (iCMs) in vitro. However, achieving efficient direct reprogramming still remains a challenge. The aim of this study was to investigate the influence of cardiac tissue-like biochemical and biophysical stimuli on direct reprogramming efficiency. Biomatrix (BM), a cardiac-like extracellular matrix (ECM), was produced by in vitro culture of AHCFs for 21 days, followed by decellularization. In a set of experiments, AHCFs were transfected with miRcombo and then cultured for 2 weeks on the surface of uncoated and BM-coated polystyrene (PS) dishes and fibrin hydrogels (2D hydrogel) or embedded into 3D fibrin hydrogels (3D hydrogel). Cell culturing on BM-coated PS dishes and in 3D hydrogels significantly improved direct reprogramming outcomes. Biochemical and biophysical cues were then combined in 3D fibrin hydrogels containing BM (3D BM hydrogel), resulting in a synergistic effect, triggering increased CM gene and cardiac troponin T expression in miRcombo-transfected AHCFs. Hence, biomimetic 3D culture environments may improve direct reprogramming of miRcombo-transfected AHCFs into iCMs, deserving further study.
Antibody-Drug Conjugates in Urothelial Carcinoma: A New Therapeutic Opportunity Moves from Bench to Bedside
Authors: Ungaro Antonio , Tucci Marcello , Audisio Alessandro , Di Prima Lavinia , Pisano Chiara , Turco Fabio , Delcuratolo Marco Donatello , Di Maio Massimo , Scagliotti Giorgio Vittorio , Buttigliero Consuelo
Published: February 2022

Significant progress has been achieved over the last decades in understanding the biology and mechanisms of tumor progression in urothelial carcinoma (UC). Although the therapeutic landscape has dramatically changed in recent years with the introduction of immune checkpoint inhibitors, advanced UC is still associated with rapidly progressing disease and poor survival. The increasing knowledge of the pathogenesis and molecular pathways underlying cancer development and progression is leading the introduction of target therapies, such as the recently approved FGFR inhibitor Erdafitinib, or the anti-nectin 4 antibody drug-conjugate Enfortumab vedotin. Antibody drug conjugates represent an innovative therapeutic approach that allows the combination of a tar get-specific monoclonal antibody covalently conjugated via a linker to a cytotoxic agent (payload). UC is a perfect candidate for this therapeutic approach since it is particularly enriched in antigen expression on its surface and each specific antigen can represent a potential therapeutic target. In this review we summarize the mechanism of action of ADCs, their applications in localized and metastatic UC, the main mechanisms of resistance, and future perspectives for their use in clinical practice.
Chromatin Remodeler Smarca5 Is Required for Cancer-Related Processes of Primary Cell Fitness and Immortalization
Authors: Thakur Shefali , Cahais Vincent , Turkova Tereza , Zikmund Tomas , Renard Claire , Stopka Tomáš , Korenjak Michael , Zavadil Jiri
Published: February 2022

Smarca5, an ATPase of the ISWI class of chromatin remodelers, is a key regulator of chromatin structure, cell cycle and DNA repair. Smarca5 is deregulated in leukemia and breast, lung and gastric cancers. However, its role in oncogenesis is not well understood. Chromatin remodelers often play dosage-dependent roles in cancer. We therefore investigated the epigenomic and phenotypic impact of controlled stepwise attenuation of Smarca5 function in the context of primary cell transformation, a process relevant to tumor formation. Upon conditional single- or double-allele Smarca5 deletion, the cells underwent both accelerated growth arrest and senescence entry and displayed gradually increased sensitivity to genotoxic insults. These phenotypic characteristics were explained by specific remodeling of the chromatin structure and the transcriptome in primary cells prior to the immortalization onset. These molecular programs implicated Smarca5 requirement in DNA damage repair, telomere maintenance, cell cycle progression and in restricting apoptosis and cellular senescence. Consistent with the molecular programs, we demonstrate for the first time that Smarca5-deficient primary cells exhibit dramatically decreased capacity to bypass senescence and immortalize, an indispensable step during cell transformation and cancer development. Thus, Smarca5 plays a crucial role in key homeostatic processes and sustains cancer-promoting molecular programs and cellular phenotypes.
Activation of Subcutaneous Mast Cells in Acupuncture Points Triggers Analgesia
Authors: Wang Li-Na , Wang Xue-Zhi , Li Yu-Jia , Li Bing-Rong , Huang Meng , Wang Xiao-Yu , Grygorczyk Ryszard , Ding Guang-Hong , Schwarz Wolfgang
Published: February 2022

This review summarizes experimental evidence indicating that subcutaneous mast cells are involved in the trigger mechanism of analgesia induced by acupuncture, a traditional oriental therapy, which has gradually become accepted worldwide. The results are essentially based on work from our laboratories. Skin mast cells are present at a high density in acupuncture points where fine needles are inserted and manipulated during acupuncture intervention. Mast cells are sensitive to mechanical stimulation because they express multiple types of mechanosensitive channels, including TRPV1, TRPV2, TRPV4, receptors and chloride channels. Acupuncture manipulation generates force and torque that indirectly activate the mast cells via the collagen network. Subsequently, various mediators, for example, histamine, serotonin, adenosine triphosphate and adenosine, are released from activated mast cells to the interstitial space; they or their downstream products activate the corresponding receptors situated at local nerve terminals of sensory neurons in peripheral ganglia. The analgesic effects are thought to be generated via the reduced electrical activities of the primary sensory neurons. Alternatively, these neurons project such signals to pain-relevant regions in spinal cord and/or higher centers of the brain.
Transience of the Retinal Output Is Determined by a Great Variety of Circuit Elements
Authors: Ganczer Alma , Szarka Gergely , Balogh Márton , Hoffmann Gyula , Tengölics Ádám Jonatán , Kenyon Garrett , Kovács-Öller Tamás , Völgyi Béla
Published: February 2022

Retinal ganglion cells (RGCs) encrypt stimulus features of the visual scene in action potentials and convey them toward higher visual centers in the brain. Although there are many visual features to encode, our recent understanding is that the ~46 different functional subtypes of RGCs in the retina share this task. In this scheme, each RGC subtype establishes a separate, parallel signaling route for a specific visual feature (e.g., contrast, the direction of motion, luminosity), through which information is conveyed. The efficiency of encoding depends on several factors, including signal strength, adaptational levels, and the actual efficacy of the underlying retinal microcircuits. Upon collecting inputs across their respective receptive field, RGCs perform further analysis (e.g., summation, subtraction, weighting) before they generate the final output spike train, which itself is characterized by multiple different features, such as the number of spikes, the inter-spike intervals, response delay, and the rundown time (transience) of the response. These specific kinetic features are essential for target postsynaptic neurons in the brain in order to effectively decode and interpret signals, thereby forming visual perception. We review recent knowledge regarding circuit elements of the mammalian retina that participate in shaping RGC response transience for optimal visual signaling.
Dupilumab Improves Pruritus in Netherton Syndrome: A Case Study
Authors: Inaba Yutaka , Kanazawa Nobuo , Muraoka Kyoko , Yariyama Azusa , Kawaguchi Ami , Kunimoto Kayo , Kaminaka Chikako , Yamamoto Yuki , Tsujioka Kaoru , Yoshida Akira , Yanagi Teruki , Jinnin Masatoshi
Published: February 2022

The patient was a 26-year-old male. He had red and scaling skin of the entire body since birth, as well as an elevated level of serum IgE. Genetic testing revealed a mutation in the SPINK5 gene, which had confirmed the diagnosis with Netherton syndrome. He has had significant pruritis since birth, and subsequently had symptoms of sleeping disorders and concentration difficulty throughout the day. Since treatment with various antihistamines were not effective, we administered dupilumab and found that it was effective in immediate elimination of pruritus and gradual reduction of the rash. Dupilumab has been administered for one year without any adverse events or recurrence of symptoms. Although studies have previously described cases who used dupilumab for Netherton syndrome, reported effects have been limited or transient. Additional studies are needed to confirm the effect of dupilumab for Netherton syndrome, which currently lack any effective treatment strategies.
Epidemiology of Child Maltreatment during the COVID-19 Pandemic in Saudi Arabia
Authors: Alenezi Shuliweeh , Alnamnakani Mahdi A. , Temsah Mohamad-Hani , Murshid Rozan , Alfahad Fahad , Alqurashi Haitham , Alonazy Hana , Alothman Mohamad , Aleissa Majid
Published: February 2022

Child maltreatment, especially during health crises, is a major public health issue transcending cultural, social, and racial contexts. We assessed the sociodemographic and related risk factors associated with the types and rates of child maltreatment. We also assessed the economic, social, and environmental characteristics of child maltreatment victims and their perpetrators, as they were reported to the Saudi National Family Safety Program (NFSP), with consideration of the COVID-19 pandemic’s impact. A secondary data analysis of a retrospective review was conducted to compare types and rates before and during the COVID-19 outbreak, utilizing descriptive and multivariate analyses on anonymized data from the NFSP. According to a predetermined list of relevant risk factors for child maltreatment outlined by the NFSP, these anonymized data were obtained and analyzed with no exclusion criteria (n = 1304). The findings showed that a child’s age correlated significantly and positively with their odds of being physically maltreated; as a child’s age increased by one year, on average, their corresponding predicted odds of being physically maltreatment tended to rise by a factor equal to 7.6% (p < 0.001). Neglected children, compared to those who had not been previously neglected, were predicted to be almost twice (2.23 times more) as likely to be victims of physical maltreatment on average (p < 0.001). Children were notably more likely to experience sexual abuse during the COVID-19 pandemic than those exposed to abuse during the period before (1.69 times). The COVID-19 pandemic was associated with significantly lower odds of physical child maltreatment (47.7% less). This study found no statistically significant effect of the COVID-19 pandemic on children’s odds of being emotionally maltreated (p = 0.169). These findings support the existence of specific risk factors for child maltreatment for both child victims and perpetrators. They also attest to the significant differences between different types of maltreatment. A systematic, proactive system is needed to screen and document child maltreatment with a higher degree of integration with community reporting systems.