bluuebunny/crossref_metadata_2025 huggingface dataset:
Emotional Imagery Influences the Adaptive Force in Young Women: Unpleasant Imagery Reduces Instantaneously the Muscular Holding Capacity
Authors: Schaefer Laura V. , Dech Silas , Wolff Lara L. , Bittmann Frank N.
Published: September 2022

The link between emotions and motor function has been known for decades but is still not clarified. The Adaptive Force (AF) describes the neuromuscular capability to adapt to increasing forces and was suggested to be especially vulnerable to interfering inputs. This study investigated the influence of pleasant and unpleasant food imagery on the manually assessed AF of elbow and hip flexors objectified by a handheld device in 12 healthy women. The maximal isometric AF was significantly reduced during unpleasant vs. pleasant imagery and baseline (p < 0.001, dz = 0.98–1.61). During unpleasant imagery, muscle lengthening started at 59.00 ± 22.50% of maximal AF, in contrast to baseline and pleasant imagery, during which the isometric position could be maintained mostly during the entire force increase up to ~97.90 ± 5.00% of maximal AF. Healthy participants showed an immediately impaired holding function triggered by unpleasant imagery, presumably related to negative emotions. Hence, AF seems to be suitable to test instantaneously the effect of emotions on motor function. Since musculoskeletal complaints can result from muscular instability, the findings provide insights into the understanding of the causal chain of linked musculoskeletal pain and mental stress. A case example (current stress vs. positive imagery) suggests that the approach presented in this study might have future implications for psychomotor diagnostics and therapeutics.
Familiarity of Background Music Modulates the Cortical Tracking of Target Speech at the “Cocktail Party”
Authors: Brown Jane A. , Bidelman Gavin M.
Published: September 2022

The “cocktail party” problem—how a listener perceives speech in noisy environments—is typically studied using speech (multi-talker babble) or noise maskers. However, realistic cocktail party scenarios often include background music (e.g., coffee shops, concerts). Studies investigating music’s effects on concurrent speech perception have predominantly used highly controlled synthetic music or shaped noise, which do not reflect naturalistic listening environments. Behaviorally, familiar background music and songs with vocals/lyrics inhibit concurrent speech recognition. Here, we investigated the neural bases of these effects. While recording multichannel EEG, participants listened to an audiobook while popular songs (or silence) played in the background at a 0 dB signal-to-noise ratio. Songs were either familiar or unfamiliar to listeners and featured either vocals or isolated instrumentals from the original audio recordings. Comprehension questions probed task engagement. We used temporal response functions (TRFs) to isolate cortical tracking to the target speech envelope and analyzed neural responses around 100 ms (i.e., auditory N1 wave). We found that speech comprehension was, expectedly, impaired during background music compared to silence. Target speech tracking was further hindered by the presence of vocals. When masked by familiar music, response latencies to speech were less susceptible to informational masking, suggesting concurrent neural tracking of speech was easier during music known to the listener. These differential effects of music familiarity were further exacerbated in listeners with less musical ability. Our neuroimaging results and their dependence on listening skills are consistent with early attentional-gain mechanisms where familiar music is easier to tune out (listeners already know the song’s expectancies) and thus can allocate fewer attentional resources to the background music to better monitor concurrent speech material.
Exosomes derived from M2 Macrophages Improve Angiogenesis and Functional Recovery after Spinal Cord Injury through HIF-1α/VEGF Axis
Authors: Huang Jiang-Hu , He Hang , Chen Yong-Neng , Liu Zhen , Romani Manini Daudi , Xu Zhao-Yi , Xu Yang , Lin Fei-Yue
Published: September 2022

Exosomes are nano-sized vesicles that contain a variety of mRNAs, miRNAs, and proteins. They are capable of being released by a variety of cells and are essential for cell–cell communication. The exosomes produced by cells have shown protective benefits against spinal cord damage (SCI). Recently, it was discovered that M2 macrophages aid in the angiogenesis of numerous illnesses. However, the functional role of M2 macrophage-derived exosomes on SCI is unclear. Here, we investigate the pro-angiogenesis of M2 macrophage-derived exosomes on SCI. We founded that M2 macrophage exosomes alleviated tissue damage and enhanced functional recovery post-SCI. We discovered that M2 macrophage exosome administration increased angiogenesis after SCI in vivo using immunohistochemistry, immunofluorescence labeling, and Western blot analysis. Additionally, the expression of the pro-angiogenesis factors, HIF-1α and VEGF, were enhanced with the treatment of the M2 macrophage exosomes. Furthermore, we found that M2 macrophage exosomes enhanced neurogenesis after SCI in vivo. In vitro, we found that M2 macrophage exosomes can be taken up by the brain endothelial cell line (bEnd.3) and that they enhanced the tube formation, migration, and proliferation of bEnd.3 cells. Furthermore, by using special siRNA to inhibit HIF-1α expression, we observed that the expression of VEGF decreased, and the tube formation, migration, and proliferation of bEnd.3 cells were attenuated with the treatment of HIF-1α-siRNA. In conclusion, our findings reveal that M2 macrophage exosomes improve neurological functional recovery and angiogenesis post-SCI, and this process is partially associated with the activation of the HIF-1/VEGF signaling pathway.
Letting Go as an Aspect of Rumination and Its Relationship to Mindfulness, Dysphoria, Anxiety, and Eudemonic Well-Being
Authors: Caswell Jesse R. , Duggirala Aishwarya N. , Verhaeghen Paul
Published: September 2022

Background: We examined how a newly proposed facet of rumination, that is, the (in)ability to let go, might relate to other aspects of rumination and to psychological outcomes. Methods: In two independent samples (n = 423 and 329, resp.) of college students, we measured a broad set of rumination and rumination-related measures, letting go, anxiety and dysphoria; in the second sample, we also collected data on mindfulness, self-compassion and eudemonic well-being. Results: Factor analysis of rumination and rumination-related measures yielded three factors: (a) negative intrusive thought; (b) reflectiveness; and (c) the inability to let go. Repetitive intrusive thought and the ability to let go were significant (and thus partially independent) predictors for the three outcomes of anxiety, dysphoria, and wellbeing. The inability to let go and repetitive intrusive thought significantly mediated between mindfulness and all three outcomes. Conclusions: The findings suggest that letting go is a potentially interesting aspect of rumination not fully captured in the traditional concept of rumination and its standard measures.
Lateral Impact Response of Rubberized-Fibrous Concrete-Filled Steel Tubular Columns: Experiment and Numerical Study
Authors: Merwad Abdullah M. , El-Sisi Alaa A. , Mustafa Suzan A. A. , Sallam Hossam El-Din M.
Published: September 2022

This paper presents an experimental and numerical study on the lateral impact behavior of rubberized-fibrous concrete-filled steel tubular (CFST) columns. Four types of concrete were utilized in the experimental program in the infilled columns: normal concrete (NC), rubberized concrete (RuC), steel fiber concrete (SFC), and hybrid RuC-SFC. Twelve specimens were tested using drop-weight impact with fixed-sliding boundary conditions. Three different transverse impact energies were produced by applying two masses of the hammers dropped from two different heights. A high-speed camera was implemented to measure the mid-span deflection against time. A 3-D finite element model was presented and verified against the tested specimens and some other experimental work from the literature. Load-displacement curves, the impact force time history, impact energy absorption, and failure modes of the CFST columns under the lateral impact were fully analyzed. The present results showed that at, certain impact energies, the steel tubular suffered only from the plastic deformation, beyond which it started cracking depending on the type of filled concrete. The steel tubular filled with hybrid RuC-SFC showed the highest resistance to crack formation, followed by that filled with SFC, while those filled with NC showed the lowest resistance to crack formation. There is an agreement between the numerical and the experimental results.
High Blood Concentration of Leukocyte-Derived Extracellular Vesicles Is Predictive of Favorable Clinical Outcomes in Patients with Pancreatic Cancer: Results from a Multicenter Prospective Study
Authors: Brocco Davide , De Bellis Domenico , Di Marino Pietro , Simeone Pasquale , Grassadonia Antonino , De Tursi Michele , Grottola Tommaso , Di Mola Fabio Francesco , Di Gregorio Patrizia , Zappacosta Barbara , Angelone Antonio , Lellis Laura De , Veschi Serena , Florio Rosalba , De Fabritiis Simone , Verginelli Fabio , Marchisio Marco , Caporale Marta , Luisi Dimitri , Di Sebastiano Pierluigi , Tinari Nicola , Cama Alessandro , Lanuti Paola
Published: September 2022

Pancreatic cancer (PC) is one of the leading causes of cancer-related death worldwide. Identification of novel tumor biomarkers is highly advocated in PC to optimize personalized treatment algorithms. Blood-circulating extracellular vesicles hold promise for liquid biopsy application in cancer. We used an optimized flow cytometry protocol to study leukocyte-derived EVs (CD45+) and PD-L1+ EVs in blood from 56 pancreatic cancer patients and 48 healthy controls (HCs). Our results show that PC patients presented higher blood levels of total EVs (p = 0.0003), leukocyte-derived EVs (LEVs) (p = 0.001) and PD-L1+ EVs (p = 0.01), as compared with HCs. Interestingly, a blood concentration of LEVs at baseline was independently associated with improved overall survival in patients with borderline resectable or primary unresectable PC (HR = 0.17; 95% CI 0.04–0.79; p = 0.02). Additionally, increased blood-based LEVs were independently correlated with prolonged progression-free survival (HR = 0.10; 95% CI 0.01–0.82; p = 0.03) and significantly associated with higher disease control rate (p = 0.02) in patients with advanced PC receiving standard chemotherapy. Notably, a strong correlation between a decrease in blood LEVs concentration during chemotherapy and disease control was observed (p = 0.005). These intriguing findings point to the potential of LEVs as novel blood-based EV biomarkers for improved personalized medicine in patients affected by PC.
Adipose Tissue Wasting as a Determinant of Pancreatic Cancer-Related Cachexia
Authors: Yu Seok-Yeong , Luan Yi , Dong Rosemary , Abazarikia Amirhossein , Kim So-Youn
Published: September 2022

Pancreatic cancer (PC) is the third leading cause of cancer-related death in the US, and its 5-year survival rate is approximately 10%. The low survival rates largely stem from diagnostic delay and the presence of significant adipose tissue and muscle wasting, commonly referred to as cachexia. Cachexia is present in nearly 80% of PC patients and is a key cause of poor response to treatment and about 20% of death in PC patients. However, there are few clinical interventions proven to be effective against PC-related cachexia. Different cancer types feature distinct secretome profiles and functional characteristics which would lead to cachexia development differently. Therefore, here we discuss affected tissues and potential mechanisms leading to cachexia in PC. We postulate that the most affected tissue during the development of PC-related cachexia is adipose tissue, historically and still thought to be just an inert repository for excess energy in relation to cancer-related cachexia. Adipose tissue loss is considerably greater than muscle loss in quantity and shows a correlation with poor survival in PC patients. Moreover, we suggest that PC mediates adipose atrophy by accelerating adipocyte lipid turnover and fibroblast infiltration.
Long Non-Coding RNAs: Tools for Understanding and Targeting Cancer Pathways
Authors: Pandey Gaurav Kumar , Kanduri Chandrasekhar
Published: September 2022

The regulatory nature of long non-coding RNAs (lncRNAs) has been well established in various processes of cellular growth, development, and differentiation. Therefore, it is vital to examine their contribution to cancer development. There are ample examples of lncRNAs whose cellular levels are significantly associated with clinical outcomes. However, whether these non-coding molecules can work as either key drivers or barriers to cancer development remains unknown. The current review aims to discuss some well-characterised lncRNAs in the process of oncogenesis and extrapolate the extent of their decisive contribution to tumour development. We ask if these lncRNAs can independently initiate neoplastic lesions or they always need the modulation of well characterized oncogenes or tumour suppressors to exert their functional properties. Finally, we discuss the emerging genetic approaches and appropriate animal and humanised models that can significantly contribute to the functional dissection of lncRNAs in cancer development and progression.
Phosphoproteomic Analysis Identifies TYRO3 as a Mediator of Sunitinib Resistance in Metastatic Thymomas
Authors: Küffer Stefan , Grabowski Jessica , Okada Satoru , Sojka Nikolai , Welter Stefan , von Hammerstein-Equord Alexander , Hinterthaner Marc , Cordes Lucia , von Hahn Xenia , Müller Denise , Sauer Christian , Bohnenberger Hanibal , Marx Alexander , Ströbel Philipp
Published: September 2022

Background: After initially responding to empiric radio-chemotherapy, most advanced thymomas (TH) and thymic carcinomas (TC) become refractory and require second-line therapy. The multi-target receptor tyrosine kinase (RTK) inhibitor, sunitinib, is one of the few options, especially in patients with thymic carcinomas, and has resulted in partial remissions and prolonged overall survival. However, sunitinib shows variable activity in thymomas, and not all patients benefit equally. A better understanding of its mode of action and the definition of predictive biomarkers would help select patients who profit most. Methods: Six cell lines were treated with sunitinib in vitro. Cell viability was measured by MTS assay and used to define in vitro responders and non-responders. A quantitative real-time assay simultaneously measuring the phosphorylation of 144 tyrosine kinase substrates was used to correlate cell viability with alterations of the phospho-kinome, calculate a sunitinib response index (SRI), and impute upstream tyrosine kinases. Sunitinib was added to protein lysates of 29 malignant TH and TC. Lysates were analyzed with the same phosphorylation assay. The SRI tentatively classified cases into potential clinical responders and non-responders. In addition, the activation patterns of 44 RTKs were studied by phospho-RTK arrays in 37 TH and TC. Results: SRI application separated thymic epithelial tumors (TET) in potential sunitinib responders and resistant cases. Upstream kinase prediction identified multiple RTKs potentially involved in sunitinib response, many of which were subsequently shown to be differentially overexpressed in TH and TC. Among these, TYRO3/Dtk stood out since it was exclusively present in metastatic TH. The function of TYRO3 as a mediator of sunitinib resistance was experimentally validated in vitro. Conclusions: Using indirect and direct phosphoproteomic analyses to predict sunitinib response in malignant TET, we have shown that TH and TC express multiple important sunitinib target RTKs. Among these, TYRO3 was identified as a potent mediator of sunitinib resistance activity, specifically in metastatic TH. TYRO3 may thus be both a novel biomarker of sunitinib resistance and a potential therapeutic target in advanced thymomas and thymic carcinomas.
The Landscape of ALK-Rearranged Non-Small Cell Lung Cancer: A Comprehensive Review of Clinicopathologic, Genomic Characteristics, and Therapeutic Perspectives
Authors: Cognigni Valeria , Pecci Federica , Lupi Alessio , Pinterpe Giada , De Filippis Chiara , Felicetti Cristiano , Cantini Luca , Berardi Rossana
Published: September 2022

During the last decade, the identification of oncogenic driver mutations and the introduction of tyrosine kinase inhibitors (TKIs) in daily clinical practice have substantially revamped the therapeutic approach of oncogene-addicted, non-small cell lung cancer (NSCLC). Rearrangements in the anaplastic lymphoma kinase (ALK) gene are detected in around 3–5% of all NSCLC patients. Following the promising results of Crizotinib, a first-generation ALK inhibitor (ALK-i), other second-generation and more recently third-generation TKIs have been developed and are currently a landmark in NSCLC treatment, leading to a significant improvement in patients prognosis. As clinical trials have already demonstrated high efficacy of each ALK-i, both in terms of systemic and intracranial disease control, comparative studies between second and third generation ALK-i are still lacking, and primary or secondary ALK-i resistance inevitably limit their efficacy. Resistance to ALK-i can be due to ALK-dependent or ALK-independent mechanisms, including the activation of bypass signaling pathways and histological transformation: these findings may play an important role in the future to select patients’ subsequent therapy. This review aims to provide an overview of underlying molecular alterations of ALK-i resistance and point out promising role of liquid biopsy in predicting tumor response and monitoring resistance mutations. The purpose of this review is also to summarize current approval for ALK-rearranged NSCLC patients, to help clinicians in making decisions on therapeutic sequence, and to deepen the role of clinicopathological and genomic characteristics influencing patients’ prognosis during treatment with ALK-i.
Development of a Three-Dimensional Multi-Modal Perfusion-Thermal Electrode System for Complete Tumor Eradication
Authors: Zheng Hui , Li Peicheng , Ma Ruidong , Zhang Feng , Ji Hongxiu , Monsky Wayne L. , Johnson Evan , Yang Weizhu , Ni Caifang , Gao Dayong , Yang Xiaoming
Published: September 2022

Background: Residual viable tumor cells after ablation at the tumor periphery serve as the source for tumor recurrence, leading to treatment failure. Purpose: To develop a novel three-dimensional (3D) multi-modal perfusion-thermal electrode system completely eradicating medium-to-large malignancies. Materials and Methods: This study included five steps: (i) design of the new system; (ii) production of the new system; (iii) ex vivo evaluation of its perfusion-thermal functions; (iv) mathematic modeling and computer simulation to confirm the optimal temperature profiles during the thermal ablation process, and; (v) in vivo technical validation using five living rabbits with orthotopic liver tumors. Results: In ex vivo experiments, gross pathology and optical imaging demonstrated the successful spherical distribution/deposition of motexafin gadolinium administered through the new electrode, with a temperature gradient from the electrode core at 80 °C to its periphery at 42 °C. An excellent repeatable correlation of temperature profiles at varying spots, from the center to periphery of the liver tumor, was found between the mathematic simulation and actual animal tumor models (Pearson coefficient ≥0.977). For in vivo validation, indocyanine green (ICG) was directly delivered into the peritumoral zones during simultaneous generation of central tumoral lethal radiofrequency (RF) heat (>60 °C) and peritumoral sublethal RF hyperthermia (<60 °C). Both optical imaging and fluorescent microscopy confirmed successful peritumoral ICG distribution/deposition with increased heat shock protein 70 expression. Conclusion: This new 3D, perfusion-thermal electrode system provided the evidence on the potential to enable simultaneous delivery of therapeutic agents and RF hyperthermia into the difficult-to-treat peritumoral zones, creating a new strategy to address the critical limitation, i.e., the high incidence of residual and recurrent tumor following thermal ablation of unresectable medium-to-large and irregular tumors.
Oral Contraceptive Use and Breast Cancer Risk for BRCA1 and BRCA2 Mutation Carriers: Systematic Review and Meta-Analysis of Case–Control Studies
Authors: Barańska Agnieszka , Kanadys Wiesław
Published: September 2022

Oral contraceptive use is one of the major modifiable risk factors for breast cancer. To investigate the effect of oral contraceptive taking on breast cancer risk by BRCA 1 and BRCA 2 mutation status, we conducted a systematic review and meta-analysis of case-controlled studies. Therefore, English language articles were retrieved by searching MEDLINE (PubMed), EMBASE and the Cochrane Library up to August 2021. Data were pooled from none case–control studies, comprising a total of 33,162 subjects, including 23,453 who had never used oral contraceptives. Overall meta-analysis indicated a statistically insignificant risk reduction: OR = 0.86, 95% CI: 0.70 to 1.06, p = 0.1594. However, increased breast cancer risk was associated with age at first use of OCs ≥20 years: OR = 1.21, 95% CI:1.07 to 1.36, p = 0.002. Multivariable meta-regression with covariates of age of first OC use (β = 0.21, 95% CI: −0.25 to 0.67, p = 0.3767), duration of OC use (β = −0.08, 95% CI; −0.51 to 0.34, p = 0.7093), and time since last OC use (β = 0.32, 95% CI: −0.22 to 0.85, p = 0.2461) did not have a significant effect on the breast cancer risk. This meta-analysis suggests a diverse effect of oral contraceptive use against breast cancer in BRCA carrier mutation. The association between OC use and breast and ovarian cancers needs more investigation.
The Impact of Meat Intake on Bladder Cancer Incidence: Is It Really a Relevant Risk?
Authors: Aveta Achille , Cacciapuoti Crescenzo , Barone Biagio , Di Zazzo Erika , Del Giudice Francesco , Maggi Martina , Ferro Matteo , Terracciano Daniela , Busetto Gian Maria , Lucarelli Giuseppe , Tataru Octavian Sabin , Montanari Emanuele , Mirto Benito Fabio , Falcone Alfonso , Giampaglia Gaetano , Sicignano Enrico , Capone Federico , Villano Gianluca , Angellotto Pasquale , Manfredi Celeste , Napolitano Luigi , Imbimbo Ciro , Pandolfo Savio Domenico , Crocetto Felice
Published: September 2022

Bladder cancer (BC) represents the second most common genitourinary malignancy. The major risk factors for BC include age, gender, smoking, occupational exposure, and infections. The BC etiology and pathogenesis have not been fully defined yet. Since catabolites are excreted through the urinary tract, the diet may play a pivotal role in bladder carcinogenesis. Meat, conventionally classified as “red”, “white” or “processed”, represents a significant risk factor for chronic diseases like cardiovascular disease, obesity, type 2 diabetes, and cancer. In particular, red and processed meat consumption seems to increase the risk of BC onset. The most accepted mechanism proposed for explaining the correlation between meat intake and BC involves the generation of carcinogens, such as heterocyclic amines and polycyclic aromatic hydrocarbons by high-temperature cooking. This evidence claims the consumption limitation of meat. We reviewed the current literature on potential biological mechanisms underlying the impact of meat (red, white, and processed) intake on the increased risk of BC development and progression. Toward this purpose, we performed an online search on PubMed using the term “bladder cancer” in combination with “meat”, “red meat”, “white meat” or “processed meat”. Although some studies did not report any association between BC and meat intake, several reports highlighted a positive correlation between red or processed meat intake, especially salami, pastrami, corned beef and bacon, and BC risk. We speculate that a reduction or rather a weighting of the consumption of red and processed meat can reduce the risk of developing BC. Obviously, this remark claims future indications regarding food education (type of meat to be preferred, quantity of red meat to be eaten and how to cook it) to reduce the risk of developing BC. Further well-designed prospective studies are needed to corroborate these findings.
Role of the Hedgehog Pathway and CAXII in Controlling Melanoma Cell Migration and Invasion in Hypoxia
Authors: Giuntini Gaia , Coppola Federica , Falsini Alessandro , Filippi Irene , Monaci Sara , Naldini Antonella , Carraro Fabio
Published: September 2022

Background: Malignant melanoma is the leading cause of death among skin cancer patients due to its tendency to metastasize. Alterations at the molecular level are often evident, which is why melanoma biology has garnered increasing interest. The hedgehog (Hh) pathway, which is essential for embryonic development, is aberrantly re-activated in melanoma and may represent a promising therapeutic target. In addition, carbonic anhydrase XII (CAXII) represents a poor prognostic target for hypoxic tumors, such as melanoma, and is involved in cell migration. Thus, we decided to investigate whether and how the Hh pathway and CAXII may control melanoma cell migration and invasiveness. Methods: The migratory and invasive capabilities of SK-MEL-28 and A375 cell lines, either un-transfected or transiently transfected with Smoothened (SMO), GLI1, or CAXII siRNA, were studied under normoxic or hypoxic conditions. Results: For the first time, we showed that SMO and GLI1 silencing resulted in the downregulation of CAXII expression in both moderately and highly invasive melanoma cells under hypoxia. The Hh pathway as well as CAXII inhibition by siRNA resulted in impaired malignant melanoma migration and invasion. Conclusion: Our results suggest that CAXII and the Hh pathway are relevant in melanoma invasion and may be novel and promising therapeutical targets for melanoma clinical management.
Nodal Merkel Cell Carcinoma with Unknown Primary Site and No Distant Metastasis: A Single-Center Series
Authors: Fazio Nicola , Maisonneuve Patrick , Spada Francesca , Gervaso Lorenzo , Cella Chiara Alessandra , Pozzari Marta , Zerini Dario , Pisa Eleonora , Fumagalli Caterina , Barberis Massimo , Laffi Alice , Grana C. Chiara Maria , Orsolini Gianmarco , Prestianni Pierpaolo , Bonomo Guido , Funicelli Luigi , Bertani Emilio , Queirolo Paola , Ravizza Davide , Rubino Manila , Tosti Giulio , Pennacchioli Elisabetta
Published: September 2022

Merkel cell carcinoma (MCC) is a very rare and aggressive neuroendocrine carcinoma originating from Merkel cells, typically with a skin nodule; however, it exceptionally presents with only a basin lymph node localization, with neither a cutaneous primary site nor distant metastases. From 1996 to 2020, among patients with histologically confirmed MCC managed at a neuroendocrine neoplasm-referral center, we selected those with an exclusive nodal basin, no distant metastasis, and an unknown primary site defined by cross-sectional and physical examination. A total of 55 out of 310 patients fulfilled the selection criteria. The median age was 64 years and the majority were males. Inguinal lymph-nodes were the most common anatomic site. With a median follow-up of 4.3 years, the 5-year relapse-free survival (RFS) rate was 56.6 (95% CI 42.0–68.8%) and the 5-year cancer specific survival (CSS) rate was 68.5 (95% CI 52.8–79.9%) for the whole population. The 36 patients (65.5%) undergoing lymphadenectomy (LND) + radiotherapy (RT) ± chemotherapy had a 5-year RFS rate of 87.2% (95% CI 65.5–95.7%) and a 5-year CSS rate of 90.5% (95% CI 67.0–97.5), which were better than those receiving LND alone. In a multivariable analysis, the survival benefit for LND + RT remained significant. Results from one of the largest single-center series of nMCC-UP suggest that a curative approach including RT can be effective, similar to what is observed for stage IIIB MCC. Multicentric studies with homogenous populations should be carried out in this controversial clinical entity, to minimize the risk of biases and provide robust data.
Developing a Predictive Grading Model for Children with Gliomas Based on Diffusion Kurtosis Imaging Metrics: Accuracy and Clinical Correlations with Patient Survival
Authors: Voicu Ioan Paul , Napolitano Antonio , Caulo Massimo , Dotta Francesco , Piccirilli Eleonora , Vinci Maria , Diomedi-Camassei Francesca , Lattavo Lorenzo , Carboni Alessia , Miele Evelina , Cacchione Antonella , Carai Andrea , Tomà Paolo , Mastronuzzi Angela , Colafati Giovanna Stefania
Published: September 2022

Purpose: To develop a predictive grading model based on diffusion kurtosis imaging (DKI) metrics in children affected by gliomas, and to investigate the clinical impact of the predictive model by correlating with overall survival and progression-free survival. Materials and methods: 59 patients with a histological diagnosis of glioma were retrospectively studied (33 M, 26 F, median age 7.2 years). Patients were studied on a 3T scanner with a standardized MR protocol, including conventional and DKI sequences. Mean kurtosis (MK), axial kurtosis (AK), radial kurtosis (RK), fractional anisotropy (FA), and apparent diffusion coefficient (ADC) maps were obtained. Whole tumour volumes (VOIs) were segmented semi-automatically. Mean DKI values were calculated for each metric. The quantitative values from DKI-derived metrics were used to develop a predictive grading model to develop a probability prediction of a high-grade glioma (pHGG). Three models were tested: DTI-based, DKI-based, and combined (DTI and DKI). The grading accuracy of the resulting probabilities was tested with a receiver operating characteristics (ROC) analysis for each model. In order to account for dataset imbalances between pLGG and pHGG, we applied a random synthetic minority oversampling technique (SMOTE) analysis. Lastly, the most accurate model predictions were correlated with progression-free survival (PFS) and overall survival (OS) using the Kaplan–Meier method. Results: The cohort included 46 patients with pLGG and 13 patients with pHGG. The developed model predictions yielded an AUC of 0.859 (95%CI: 0.752–0.966) for the DTI model, of 0.939 (95%CI: 0.879–1) for the DKI model, and of 0.946 (95%CI: 0.890–1) for the combined model, including input from both DTI and DKI metrics, which resulted in the most accurate model. Sample estimation with the random SMOTE analysis yielded an AUC of 0.98 on the testing set. Model predictions from the combined model were significantly correlated with PFS (25.2 months for pHGG vs. 40.0 months for pLGG, p < 0.001) and OS (28.9 months for pHGG vs. 44.9 months for pLGG, p < 0.001). Conclusions: a DKI-based predictive model was highly accurate for pediatric glioma grading. The combined model, derived from both DTI and DKI metrics, proved that DKI-based model predictions of tumour grade were significantly correlated with progression-free survival and overall survival.
Preparation of Cex-Mn0.8Fe0.2O2 Catalysts and Its Anti-Sulfur Denitration Performance
Authors: Zhang Yelin , Zhang Chao , Wang Yusi , Zhang Li , Zeng Jing , He Hanbing
Published: September 2022

In order to meet the industrial denitrification demands, inexpensive ferrous metals Mn and Fe have been chosen as the raw materials for the catalysts of CO-SCR, and the anti-sulfur denitrification performance of ferromanganese catalysts can be greatly enhanced by Ce doping. In this study, Cex-Mn0.8Fe0.2O2 catalysts were prepared by co-precipitation, and the effects of Ce addition on the structure and morphology of prepared catalysts and their anti-sulfur denitration performance were investigated with X-ray diffraction (XRD), scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS). The results showed that the Cex-Mn0.8Fe0.2O2 catalysts consisted of nanoparticles sized 20–100 nm. Specifically, the Ce0.2-Mn0.8Fe0.2O2 catalyst had more active sites and the best anti-sulfur denitration performance, with a denitration rate of 90.36% at 350 °C, while the denitrification performance of the Mn0.8Fe0.2O2 catalyst was only 85%. Furthermore, the denitrification rate of the catalyst was maintained above 80% when the CO:NO:SO2 ratio was 3:1:1 for 4 h at 350 °C.
Influences of Ni Content on the Microstructural and Catalytic Properties of Perovskite LaNixCr1−xO3 for Dry Reforming of Methane
Authors: Zhao Tingting , Yu Haoran , Tao Xuyingnan , Yu Feiyang , Li Ming , Wang Haiqian
Published: September 2022

Perovskite oxides were widely used as precursors for developing metal-support type catalysts. It is attractive to explore the catalytic properties of the oxides themselves for dry reforming of methane (DRM). We synthesized LaNixCr1−xO3 (x = 0.05–0.5) samples in powder form using the sol-gel self-combustion method. Ni atoms are successfully doped into the LaCrO3 perovskite lattice. The perovskite grains are polycrystalline, and the crystallite size decreases with increasing Ni content. We demonstrated that the LaNixCr1−xO3 perovskites show intrinsically catalytic activity for DRM reactions. Reducing the Ni content is helpful to reduce carbon deposition resulting from the metal Ni nanoparticles that usually coexist with the highly active perovskite oxides. The CH4 conversion over the LaNi0.1Cr0.9O3 sample reaches approximately 84% at 750 °C, and the carbon deposition is negligible.
Humanized Dsp ACM Mouse Model Displays Stress-Induced Cardiac Electrical and Structural Phenotypes
Authors: Stevens Tyler L. , Manring Heather R. , Wallace Michael J. , Argall Aaron , Dew Trevor , Papaioannou Peter , Antwi-Boasiako Steve , Xu Xianyao , Campbell Stuart G. , Akar Fadi G. , Borzok Maegen A. , Hund Thomas J. , Mohler Peter J. , Koenig Sara N. , El Refaey Mona
Published: September 2022

Arrhythmogenic cardiomyopathy (ACM) is an inherited disorder characterized by fibro-fatty infiltration with an increased propensity for ventricular arrhythmias and sudden death. Genetic variants in desmosomal genes are associated with ACM. Incomplete penetrance is a common feature in ACM families, complicating the understanding of how external stressors contribute towards disease development. To analyze the dual role of genetics and external stressors on ACM progression, we developed one of the first mouse models of ACM that recapitulates a human variant by introducing the murine equivalent of the human R451G variant into endogenous desmoplakin (DspR451G/+). Mice homozygous for this variant displayed embryonic lethality. While DspR451G/+ mice were viable with reduced expression of DSP, no presentable arrhythmogenic or structural phenotypes were identified at baseline. However, increased afterload resulted in reduced cardiac performance, increased chamber dilation, and accelerated progression to heart failure. In addition, following catecholaminergic challenge, DspR451G/+ mice displayed frequent and prolonged arrhythmic events. Finally, aberrant localization of connexin-43 was noted in the DspR451G/+ mice at baseline, becoming more apparent following cardiac stress via pressure overload. In summary, cardiovascular stress is a key trigger for unmasking both electrical and structural phenotypes in one of the first humanized ACM mouse models.
Determination of Reactive Oxygen or Nitrogen Species and Novel Volatile Organic Compounds in the Defense Responses of Tomato Plants against Botrytis cinerea Induced by Trichoderma virens TRS 106
Authors: Nawrocka Justyna , Szymczak Kamil , Maćkowiak Aleksandra , Skwarek-Fadecka Monika , Małolepsza Urszula
Published: September 2022

In the present study, Trichoderma virens TRS 106 decreased grey mould disease caused by Botrytis cinerea in tomato plants (S. lycopersicum L.) by enhancing their defense responses. Generally, plants belonging to the ‘Remiz’ variety, which were infected more effectively by B. cinerea than ‘Perkoz’ plants, generated more reactive molecules such as superoxide (O2−) and peroxynitrite (ONOO−), and less hydrogen peroxide (H2O2), S-nitrosothiols (SNO), and green leaf volatiles (GLV). Among the new findings, histochemical analyses revealed that B. cinerea infection caused nitric oxide (NO) accumulation in chloroplasts, which was not detected in plants treated with TRS 106, while treatment of plants with TRS 106 caused systemic spreading of H2O2 and NO accumulation in apoplast and nuclei. SPME-GCxGC TOF-MS analysis revealed 24 volatile organic compounds (VOC) released by tomato plants treated with TRS 106. Some of the hexanol derivatives, e.g., 4-ethyl-2-hexynal and 1,5-hexadien-3-ol, and salicylic acid derivatives, e.g., 4-hepten-2-yl and isoamyl salicylates, are considered in the protection of tomato plants against B. cinerea for the first time. The results are valuable for further studies aiming to further determine the location and function of NO in plants treated with Trichoderma and check the contribution of detected VOC in plant protection against B. cinerea.
Photosynthesis in Response to Different Salinities and Immersions of Two Native Rhizophoraceae Mangroves
Authors: Chen Chung-I , Lin Kuan-Hung , Huang Meng-Yuan , Wong Shau-Lian , Liao Tien-Szu , Chen Ming-Nan , Weng Jen-Hsien , Hsueh Mei-Li , Lai Yu-Hsiang , Wang Ching-Wen
Published: September 2022

Mangrove ecosystems are vulnerable to rising sea levels as the plants are exposed to high salinity and tidal submergence. The ways in which these plants respond to varying salinities, immersion depths, and levels of light irradiation are poorly studied. To understand photosynthesis in response to salinity and submergence in mangroves acclimated to different tidal elevations, two-year-old seedlings of two native mangrove species, Kandelia obovata and Rhizophora stylosa, were treated at different salinity concentrations (0, 10, and 30 part per thousand, ppt) with and without immersion conditions under fifteen photosynthetic photon flux densities (PPFD μmol photon·m−2·s−1). The photosynthetic capacity and the chlorophyll fluorescence (ChlF) parameters of both species were measured. We found that under different PPFDs, electron transport rate (ETR) induction was much faster than photosynthetic rate (Pn) induction, and Pn was restricted by stomatal conductance (Gs). The Pn of the immersed K. obovata plants increased, indicating that this species is immersed-tolerant, whereas the Pn level of the R. stylosa plants is salt-tolerant with no immersion. All of the plants treated with 30 ppt salinity exhibited lower Pn but higher non-photochemical quenching (NPQ) and heat quenching (D) values, followed by increases in the excess energy and photoprotective effects. Since NPQ or D can be easily measured in the field, these values provide a useful ecological monitoring index that may provide a reference for mangrove restoration, habitat creation, and ecological monitoring.
Mast Cell Interaction with Foxp3+ Regulatory T Cells Occur in the Dermis after Initiation of IgE-Mediated Cutaneous Anaphylaxis
Authors: Msallam Rasha , Malissen Bernard , Launay Pierre , Blank Ulrich , Gautier Gregory , Davoust Jean
Published: September 2022

Mast cells (MCs) are well-known for their role in IgE-mediated cutaneous anaphylactic responses, but their regulatory functions in the skin are still under intense scrutiny. Using a Red MC and Basophil reporter (RMB) mouse allowing red fluorescent detection and diphtheria toxin mediated depletion of MCs, we investigated the interaction of MCs, Foxp3+ regulatory T lymphocytes (Tregs) and Langerhans cells (LCs) during passive cutaneous anaphylaxis (PCA) responses. Using intravital imaging we show that MCs are sessile at homeostasis and during PCA. Breeding RMB mice with Langerin-eGFP mice revealed that dermal MCs do not interact with epidermal-localized LCs, the latter showing constant sprouting of their dendrites at homeostasis and during PCA. When bred with Foxp3-eGFP mice, we found that, although a few Foxp3+ Tregs are present at homeostasis, many Tregs transiently infiltrated the skin during PCA. While their velocity during PCA was not altered, Tregs increased the duration of their contact time with MCs compared to PCA-control mice. Antibody-mediated depletion of Tregs had no effect on the intensity of PCA. Hence, the observed increase in Treg numbers and contact time with MCs, regardless of an effect on the intensity of PCA responses, suggests an anti-inflammatory role dedicated to prevent further MC activation.
The Role of Endothelial Cells in the Onset, Development and Modulation of Vein Graft Disease
Authors: Ladak Shameem S. , McQueen Liam W. , Layton Georgia R. , Aujla Hardeep , Adebayo Adewale , Zakkar Mustafa
Published: September 2022

Endothelial cells comprise the intimal layer of the vasculature, playing a crucial role in facilitating and regulating aspects such nutrient transport, vascular homeostasis, and inflammatory response. Given the importance of these cells in maintaining a healthy haemodynamic environment, dysfunction of the endothelium is central to a host of vascular diseases and is a key predictor of cardiovascular risk. Of note, endothelial dysfunction is believed to be a key driver for vein graft disease—a pathology in which vein grafts utilised in coronary artery bypass graft surgery develop intimal hyperplasia and accelerated atherosclerosis, resulting in poor long-term patency rates. Activation and denudation of the endothelium following surgical trauma and implantation of the graft encourage a host of immune, inflammatory, and cellular differentiation responses that risk driving the graft to failure. This review aims to provide an overview of the current working knowledge regarding the role of endothelial cells in the onset, development, and modulation of vein graft disease, as well as addressing current surgical and medical management approaches which aim to beneficially modulate endothelial function and improve patient outcomes.
Krüppel-Like Factor 1: A Pivotal Gene Regulator in Erythropoiesis
Authors: Caria Cristian Antonio , Faà Valeria , Ristaldi Maria Serafina
Published: September 2022

Krüppel-like factor 1 (KLF1) plays a crucial role in erythropoiesis. In-depth studies conducted on mice and humans have highlighted its importance in erythroid lineage commitment, terminal erythropoiesis progression and the switching of globin genes from γ to β. The role of KLF1 in haemoglobin switching is exerted by the direct activation of β-globin gene and by the silencing of γ-globin through activation of BCL11A, an important γ-globin gene repressor. The link between KLF1 and γ-globin silencing identifies this transcription factor as a possible therapeutic target for β-hemoglobinopathies. Moreover, several mutations have been identified in the human genes that are responsible for various benign phenotypes and erythroid disorders. The study of the phenotype associated with each mutation has greatly contributed to the current understanding of the complex role of KLF1 in erythropoiesis. This review will focus on some of the principal functions of KLF1 on erythroid cell commitment and differentiation, spanning from primitive to definitive erythropoiesis. The fundamental role of KLF1 in haemoglobin switching will be also highlighted. Finally, an overview of the principal human mutations and relative phenotypes and disorders will be described.
Effects of Endochondral and Intramembranous Ossification Pathways on Bone Tissue Formation and Vascularization in Human Tissue-Engineered Grafts
Authors: Bernhard Jonathan C. , Marolt Presen Darja , Li Ming , Monforte Xavier , Ferguson James , Leinfellner Gabriele , Heimel Patrick , Betti Susanna L. , Shu Sharon , Teuschl-Woller Andreas H. , Tangl Stefan , Redl Heinz , Vunjak-Novakovic Gordana
Published: September 2022

Bone grafts can be engineered by differentiating human mesenchymal stromal cells (MSCs) via the endochondral and intramembranous ossification pathways. We evaluated the effects of each pathway on the properties of engineered bone grafts and their capacity to drive bone regeneration. Bone-marrow-derived MSCs were differentiated on silk scaffolds into either hypertrophic chondrocytes (hyper) or osteoblasts (osteo) over 5 weeks of in vitro cultivation, and were implanted subcutaneously for 12 weeks. The pathways’ constructs were evaluated over time with respect to gene expression, composition, histomorphology, microstructure, vascularization and biomechanics. Hypertrophic chondrocytes expressed higher levels of osteogenic genes and deposited significantly more bone mineral and proteins than the osteoblasts. Before implantation, the mineral in the hyper group was less mature than that in the osteo group. Following 12 weeks of implantation, the hyper group had increased mineral density but a similar overall mineral composition compared with the osteo group. The hyper group also displayed significantly more blood vessel infiltration than the osteo group. Both groups contained M2 macrophages, indicating bone regeneration. These data suggest that, similar to the body’s repair processes, endochondral pathway might be more advantageous when regenerating large defects, whereas intramembranous ossification could be utilized to guide the tissue formation pattern with a scaffold architecture.
Novel GATA1 Variant Causing a Bleeding Phenotype Associated with Combined Platelet α-/δ-Storage Pool Deficiency and Mild Dyserythropoiesis Modified by a SLC4A1 Variant
Authors: Jurk Kerstin , Adenaeuer Anke , Sollfrank Stefanie , Groß Kathrin , Häuser Friederike , Czwalinna Andreas , Erkel Josef , Fritsch Nele , Marandiuc Dana , Schaller Martin , Lackner Karl J. , Rossmann Heidi , Bergmann Frauke
Published: September 2022

Germline defects in the transcription factor GATA1 are known to cause dyserythropoiesis with(out) anemia and variable abnormalities in platelet count and function. However, damaging variants closely located to the C-terminal zinc finger domain of GATA1 are nearly unknown. In this study, a 36-year-old male index patient and his 4-year-old daughter suffered from moderate mucocutaneous bleeding diathesis since birth. Whole exome sequencing detected a novel hemizygous GATA1 missense variant, c.886A>C p.T296P, located between the C-terminal zinc finger and the nuclear localization sequence with non-random X-chromosome inactivation in the heterozygous daughter. Blood smears from both patients demonstrated large platelet fractions and moderate thrombocytopenia in the index. Flow cytometry and electron microscopy analysis supported a combined α-/δ (AN-subtype)-storage pool deficiency as cause for impaired agonist-induced platelet aggregation (light transmission aggregometry) and granule exocytosis (flow cytometry). The absence of BCAM in the index (Lu(a-b-)) and its low expression in the daughter (Lu(a-b+)) confirmed a less obvious effect of defective GATA1 also on erythrocytes. Borderline anemia, elevated HbF levels, and differential transcription of GATA1-regulated genes indicated mild dyserythropoiesis in both patients. Furthermore, a mild SLC4A1 defect associated with a heterozygous SLC4A1 c.2210C>T p.A737V variant maternally transmitted in the daughter may modify the disease to mild spherocytosis and hemolysis.