bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of Soot Loading and Filtration Efficiency of a Gasoline Particulate Filter with Photoacoustic Sensor and Particle Number Counting Systems
Authors: Nakamura Kazuki , Sugaya Yuta , Yamaguchi Kyohei , Kusaka Jin , Arndt Michael , Dardiotis Christos
Published: February 2023

An optimum operation of a gasoline particulate filter (GPF) for a gasoline direct injection vehicle in terms of its performance of pressure drop, soot loading, and filtration efficiency becomes inevitable to fulfill upcoming emission regulations. This paper proposes a methodology to characterize the GPF performance for validation of simulation models for more precise operation strategies along with future legislative requirements. The feasibility was examined through experiments of miniature GPF samples using a synthetic particle generator. Firstly, permeability of the GPF walls was estimated to be 6.9 ± 1.5 × 10−13 m2 by a flow resistance descriptor model, which was in good agreement with its pore structure. Secondly, photoacoustic sensor systems indicated soot accumulation inside the GPFs in real time thanks to linear correlations between sensor signals and soot mass concentrations in exhaust. Thirdly, particle number counting systems compliant with respective regulatory technical requirements exhibited time-resolved filtration efficiencies of the GPFs in conjunction with solid particle number emissions whose diameter was larger than 10 nm and 23 nm. The filtration efficiencies at a clean state of the GPF were 0.78 and 0.77, respectively. The slight difference could be explained by Brownian diffusion and interception for particle filtration.
Actin Bundles Dynamics and Architecture
Authors: Rajan Sudeepa , Kudryashov Dmitri S. , Reisler Emil
Published: February 2023

Cells use the actin cytoskeleton for many of their functions, including their division, adhesion, mechanosensing, endo- and phagocytosis, migration, and invasion. Actin bundles are the main constituent of actin-rich structures involved in these processes. An ever-increasing number of proteins that crosslink actin into bundles or regulate their morphology is being identified in cells. With recent advances in high-resolution microscopy and imaging techniques, the complex process of bundles formation and the multiple forms of physiological bundles are beginning to be better understood. Here, we review the physiochemical and biological properties of four families of highly conserved and abundant actin-bundling proteins, namely, α-actinin, fimbrin/plastin, fascin, and espin. We describe the similarities and differences between these proteins, their role in the formation of physiological actin bundles, and their properties—both related and unrelated to their bundling abilities. We also review some aspects of the general mechanism of actin bundles formation, which are known from the available information on the activity of the key actin partners involved in this process.
Doxycycline Prevents Preclinical Atherosclerosis, Pancreatic Islet Loss and Improves Insulin Secretion after Glycemic Stimulation: Preclinical Study in Individuals with a High-Fat Diet
Authors: Rodriguez-Hernandez Alejandrina , Delgado-Machuca Marina , Guardado-Mendoza Rodolfo , Mendoza-Hernandez Martha A. , Melnikov Valery , Delgado-Enciso Osiris G. , Tiburcio-Jimenez Daniel , Ceja-Espiritu Gabriel , Hernandez-Fuentes Gustavo A. , Gamboa-Dominguez Armando , Guzman-Esquivel Jose , Martinez-Fierro Margarita L. , Rodriguez-Sanchez Iram P. , Delgado-Enciso Ivan
Published: February 2023

Doxycycline (Doxy) is an antibiotic, which has exhibited anti-inflammatory activity and glucose metabolism improvement. The present study was proposed to evaluate its effects on glucose metabolism and other associated processes, such as lipemia and adipogenesis, as well as, to evaluate its effects on the liver, pancreas, and aorta in subjects fed with an occidental high-fat diet (HFD). The trial followed three groups of BALB/c mice for 6 months: (1) Standard diet (SD); (2) HFD-placebo (saline solution); and (3) HFD-Doxy (10 mg/kg/day). Intrahepatic fat accumulation (steatohepatosis) and the epididymal fat pad, as well as the hepatic inflammatory infiltrate and ALT serum levels were higher in both groups with the HFD (with/without doxycycline) in comparison with the SD group. The thickness of the aorta (preclinic atherosclerosis) was significantly elevated in the HFD group with respect to the HFD + Doxy and SD group, these two being similar groups to each other. The HFD-Doxy group had pancreatic morphological parameters very similar to those of the SD group; on the contrary, the HFD group reduced the number of pancreatic islets and the number of β cells per mm2, in addition to losing large islets. The index of β cell function (∆Insulin0–30/∆Glucose0–30 ratio) was significantly higher in the HFD + Doxy group, compared to the rest of the groups.
Expression Levels of GHRH-Receptor, pAkt and Hsp90 Predict 10-Year Overall Survival in Patients with Locally Advanced Rectal Cancer
Authors: Fodor Dávid , Pozsgai Éva , Schally Andrew V. , László Zoltán , Gömöri Éva , Szabó Éva , Rumi László , Lőcsei Dorottya , Boronkai Árpád , Bellyei Szabolcs
Published: February 2023

Background: Rectal cancer constitutes nearly one-third of all colorectal cancer diagnoses, and certain clinical and molecular markers have been studied as potential prognosticators of patient survival. The main objective of our study was to investigate the relationship between the expression intensities of certain proteins, including growth-hormone-releasing hormone receptor (GHRH-R), Hsp90, Hsp16.2, p-Akt and SOUL, in specimens of locally advanced rectal cancer patients, as well as the time to metastasis and 10-year overall survival (OS) rates. We also investigated whether these outcome measures were associated with the presence of other clinical parameters. Methods: In total, 109 patients were investigated retrospectively. Samples of pretreatment tumors were stained for the proteins GHRH-R, Hsp90, Hsp16.2, p-Akt and SOUL using immunhistochemistry methods. Kaplan–Meier curves were used to show the relationships between the intensity of expression of biomarkers, clinical parameters, the time to metastasis and the 10-year OS rate. Results: High levels of p-Akt, GHRH-R and Hsp90 were associated with a significantly decreased 10-year OS rate (p = 0.001, p = 0.000, p = 0.004, respectively) and high expression levels of p-Akt and GHRH-R were correlated with a significantly shorter time to metastasis. Tumors localized in the lower third of the rectum were linked to both a significantly longer time to metastasis and an improved 10-year OS rate. Conclusions: Hsp 90, pAkt and GHRH-R as well as the lower-third localization of the tumor were predictive of the 10-year OS rate in locally advanced rectal cancer patients. The GHRH-R and Hsp90 expression levels were independent prognosticators of OS. Our results imply that GHRH-R could play a particularly important role both as a molecular biomarker and as a target for the anticancer treatment of advanced rectal cancer.
The Role of the Ectopeptidase APN/CD13 in Cancer
Authors: Lendeckel Uwe , Karimi Farzaneh , Al Abdulla Ruba , Wolke Carmen
Published: February 2023

APN/CD13 is expressed in a variety of cells/tissues and is therefore associated with diverse physiological functions, including proliferation, differentiation, migration, angiogenesis, invasion, metastasis, vasoconstriction, and the regulation of normal and impaired immune function. Increased expression or activity of APN/CD13 has been described for various tumors, such that APN/CD13 is in most cases associated with reduced disease-free and overall survival. The mechanisms that mediate these cellular effects of APN/CD13 have been largely determined and are described here. APN/CD13-regulated signaling pathways include integrin recycling, the regulation of small GTPase activities, cell–ECM interactions, and Erk1/2, PI3K, and Wnt signaling. APN/CD13 is a neo-angiogenesis marker that is not found on normal endothelia, but it is found on neo-angiogenetically active endothelia. Therefore, APN/CD13 represents a specific receptor for so-called “tumor-homing peptides” (NRG peptides). Peptides containing the NRG motif show high-affinity binding to APN/CD13. APN/CD13 thus represents a versatile target for the inhibition of tumor-induced angiogenesis through the tumor-selective administration of, e.g., cytotoxic substances. Furthermore, it enables the molecular imaging of tumor masses and the assessment of (neo)angiogenesis in animal models and in patients. Pharmacological inhibitors of APN/CD13 have been proven to reduce tumor growth and tumor progression in various APN/CD13-positive tumors.
Potential of Caffeic Acid and 10-Dehydrogingerdione as Lipid Regulators Relevant to Their Inhibitory Effect on miR-122 and ATP Citrate Lyase Activity in Diabetic Hyperlipidemic Rats
Authors: Elseweidy Mohamed M. , Elawady Alaa S. , Sobh Mohammed S. , Alqhtani Abdulmohsen H. , Al-Gabri Naif A. , Elnagar Gehad M.
Published: February 2023

The present study aimed to illustrate the hypolipemic effect of 10-Dehydrogengardione (10-DHG) or caffeic acid (CA) with reference to the role of microRNA-122 (miR-122) and ATP citrate lyase (ACLY) activity. Diabetic hyperlipidemia was induced in rats, and then randomly classified into three groups. The first one received only a CCT-diet for 6 weeks and was referred to as the positive control. The other two groups received 10-DHG (10 mg/kg/day) or CA (50 mg/kg/day), orally for 6 weeks along with a CCT-diet. Another group of normal rats was included, received a normal diet, and was referred to as the negative control. Either 10-DHG or CA significantly decreased MiR-122 expression and appeared more remarkable in the CA group by 15.5%. The 10-DHG greatly enhanced phosphorylated form of AMP activated protein kinase (p-AMPK) activity, more than CA by 1.18-fold, while the latter exerted more inhibitory effect on ACLY, and fatty acid synthase (FAS) activities compared with 10-DHG (p < 0.05). Both drugs significantly decreased hydroxy methyl glutaryl coenzyme A (HMG-COA) reductase activity, which appeared more remarkable in 10-DHG, and significantly decreased triglyceride (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) along with a high density lipoprotein cholesterol (HDL-C) increase. The 10-DHG ameliorated the hepatic tissue lesions greatly, more than CA. The 10-DHG or CA significantly inhibited MiR-122, hepatic FAS, and ACLY levels along with p-AMPK activation. This subsequently led to reduced plasma TG, cholesterol levels, and blood glucose improvement and, indeed, may explain their mechanisms as hypolipemic agents.
Identifying Patients in Whom the Follow-Up Scheme after Robot-Assisted Radical Prostatectomy Could Be Optimized in the First Year after Surgery: Reducing Healthcare Burden
Authors: Veerman Hans , van der Graaf Sophia H. , Meijer Dennie , Hagens Marinus J. , Tillier Corinne N. , van Leeuwen Pim J. , van der Poel Henk G. , Vis André N.
Published: February 2023

Background: The currently advised follow-up scheme of PSA testing after robot-assisted radical prostatectomy (RARP) is strict and might pose a burden to our healthcare system. We aimed to optimize the 1-year follow-up scheme for patients who undergo RARP. Methods: All patients with histologically-proven prostate cancer (PCa) who underwent RARP between 2018 and August 2022 in the Prostate Cancer Network in the Netherlands were retrospectively evaluated. We excluded patients who underwent salvage RARP and patients who had <1 year of PSA follow-up. Postoperative PSA values were collected. Biochemical persistence (BCP) was defined as PSA level >0.10 ng/mL at 0–4 months after RARP, whereas biochemical recurrence (BCR) was defined as PSA level >0.2 ng/mL at any time point after RARP. We aimed to identify a group of patients who had a very low risk of BCR at different time points after surgery. Results: Of all 1155 patients, BCP was observed in 151 (13%), of whom 79 (6.8%) had PSA ≥ 0.2 ng/mL. BCR further developed in 51 (4.7%) and 37 (3.4%) patients at 5–8 and 9–12 months after RARP, respectively. In 12 patients, BCR was found at 5–8 months after RARP in the absence of BCP. These patients represented 1.2% (12/1004) of the entire group. In other words, 98.8% (992/1004) of patients who had an unmeasurable PSA level at 0–4 months after RARP also had an unmeasurable PSA level 5–8 months after surgery. Limitations are the retrospective design and incomplete follow-up. Conclusions: Patients with an unmeasurable PSA level at 3–4 months after RARP may not need to be retested until 12 months of follow-up, as almost 100% of patients will not have the biochemically recurrent disease at 5–8 months of follow-up. This will reduce PSA testing substantially at the cost of hardly any missed patients with recurrent disease.
Muscle and Muscle-like Autoantigen Expression in Myasthenia Gravis Thymus: Possible Molecular Hint for Autosensitization
Authors: Iacomino Nicola , Scandiffio Letizia , Conforti Fabio , Salvi Erika , Tarasco Maria Cristina , Bortone Federica , Marcuzzo Stefania , Simoncini Ornella , Andreetta Francesca , Pistillo Daniela , Voulaz Emanuele , Alloisio Marco , Antozzi Carlo , Mantegazza Renato , De Pas Tommaso Martino , Cavalcante Paola
Published: February 2023

The thymus is widely recognized as an immunological niche where autoimmunity against the acetylcholine receptor (AChR) develops in myasthenia gravis (MG) patients, who mostly present thymic hyperplasia and thymoma. Thymoma-associated MG is frequently characterized by autoantibodies to the muscular ryanodine receptor 1 (RYR1) and titin (TTN), along with anti-AChR antibodies. By real-time PCR, we analyzed muscle—CHRNA1, RYR1, and TTN—and muscle-like—NEFM, RYR3 and HSP60—autoantigen gene expression in MG thymuses with hyperplasia and thymoma, normal thymuses and non-MG thymomas, to check for molecular changes potentially leading to an altered antigen presentation and autoreactivity. We found that CHRNA1 (AChR-α subunit) and AIRE (autoimmune regulator) genes were expressed at lower levels in hyperplastic and thymoma MG compared to the control thymuses, and that the RYR1 and TTN levels were decreased in MG versus the non-MG thymomas. Genes encoding autoantigens that share epitopes with AChR-α (NEFM and HSP60), RYR1 (neuronal RYR3), and TTN (NEFM) were up-regulated in thymomas versus hyperplastic and control thymuses, with distinct molecular patterns across the thymoma histotypes that could be relevant for autoimmunity development. Our findings support the idea that altered muscle autoantigen expression, related with hyperplastic and neoplastic changes, may favor autosensitization in the MG thymus, and that molecular mimicry involving tumor-related muscle-like proteins may be a mechanism that makes thymoma prone to developing MG.
COVID-19 in Older Patients: Assessment of Post-COVID-19 Sarcopenia
Authors: López-Sampalo Almudena , Cobos-Palacios Lidia , Vilches-Pérez Alberto , Sanz-Cánovas Jaime , Vargas-Candela Antonio , Mancebo-Sevilla Juan José , Hernández-Negrín Halbert , Gómez-Huelgas Ricardo , Bernal-López María Rosa
Published: February 2023

(1) Background: Acute COVID-19 infections produce alterations in the skeletal muscle, leading to acute sarcopenia, but the medium- and long-term consequences are still unknown. The aim of this study was to evaluate: (1) body composition; (2) muscle strength and the prevalence of sarcopenia; and (3) the relationship between muscle strength with symptomatic and functional evolution in older patients affected by/recovered from COVID-19; (2) Methods: A prospective, longitudinal study of patients aged ≥65 years who had suffered from COVID-19 infection between 1 March and 31 May 2020, as confirmed by PCR or subsequent seroconversion. Persistent symptoms, as well as anthropometric, clinical, and analytical characteristics, were analyzed at 3 and 12 months after infection. The degree of sarcopenia was determined by dynamometry and with SARC-F; (3) Results: 106 participants, aged 76.8 ± 7 years, were included. At 3 months postinfection, a high percentage of sarcopenic patients was found, especially among women and in those with hospitalization. At 12 months postinfection, this percentage had decreased, coinciding with a functional and symptomatic recovery, and the normalization of inflammatory parameters, especially interleukin-6 (4.7 ± 11.6 pg/mL vs. 1.5 ± 2.4 pg/mL, p < 0.05). The improvement in muscle strength was accompanied by significant weight gain (71.9 ± 12.1 kg vs. 74.7 ± 12.7 kg, p < 0.001), but not by an increase in lean mass (49.6 ± 10 vs. 49.9 ± 10, p 0.29); (4) Conclusions: Older COVID-19 survivors presented a functional, clinical, and muscular recovery 12 months postinfection. Even so, it is necessary to carry out comprehensive follow-ups and assessments that include aspects of nutrition and physical activity.
NEK1-Mediated Phosphorylation of YAP1 Is Key to Prostate Cancer Progression
Authors: Ghosh Ishita , Khalil Md Imtiaz , Mirza Rusella , King Judy , Olatunde Damilola , De Benedetti Arrigo
Published: February 2023

The key to preventing mCRPC progression is understanding how androgen-dependent PCa cells progress to independence and modify their transcriptional repertoire accordingly. We recently identified a novel axis of the Hippo pathway characterized by the sequential kinase cascade induced by androgen deprivation, AR−>TLK1B>NEK1>pYAP1-Y407, leading to CRPC adaptation. Phosphorylation of YAP1-Y407 increases upon ADT or induction of DNA damage, correlated with the known increase in NEK1 expression/activity, and this is suppressed in the Y407F mutant. Dominant expression of YAP1-Y407F in Hek293 cells reprograms the YAP1-mediated transcriptome to reduce TEAD- and p73-regulated gene expression and mediates sensitivity to MMC. NEK1 haploinsufficient TRAMP mice display reduced YAP1 expression and, if castrated, fail to progress to overt prostate carcinomas, even while displaying reduced E-Cadherin (E-Cad) expression in hyperplastic ductules. YAP1 overexpression, but not the Y407F mutant, transforms LNCaP cells to androgen-independent growth with a mesenchymal morphology. Immunohistochemical examination of prostate cancer biopsies revealed that the pYAP1-Y407 nuclear signal is low in samples of low-grade cancer but elevated in high GS specimens. We also found that J54, a pharmacological inhibitor of the TLK1>NEK1>YAP1 nexus leading to degradation of YAP1, can suppress the transcriptional reprogramming of LNCaP cells to androgen-independent growth and EMT progression, even when YAP1-WT is overexpressed.
Long-Term Lower Limb Motor Function Correlates with Middle Cerebellar Peduncle Structural Integrity in Sub-Acute Stroke: A ROI-Based MRI Cohort Study
Authors: Wang Daming , Wang Lingyan , Guo Dazhi , Pan Shuyi , Mao Lin , Zhao Yifan , Zou Liliang , Zhao Ying , Shi Aiqun , Chen Zuobing
Published: February 2023

Crossed cerebellar diaschisis (CCD) has been widely investigated in patients with supratentorial stroke. However, the role of CCD in lower limb recovery after stroke is still unknown. In this study, using a region-of-interest-based analysis of diffusion tensor imaging (DTI), a total of 44 cases of stroke within 3 months onset were enrolled for assessment of the cerebral peduncle (CP) and middle cerebellar peduncles (MCP) in CCD. Compared with the control group, the fractional anisotropy ratio (rFA) and laterality index (LI) of the CP and MCP in the stroke group significantly decreased. The rFA of the MCP (unaffected side/affected side) showed a more significant correlation with 1-year paresis grading (PG), lower extremity PG, upper extremity PG, National Institutes of Health Stroke Scale (NIHSS), and functional independence measure (FIM) motor item score, in comparison to the rFA of the CP (affected side/unaffected side) (r = −0.698 vs. r = −0.541, r = −0.651 vs. r = −0.386, r = −0.642 vs. r = −0.565, r = −0.519 vs. r = −0.403, and r = 0.487 vs. r = 0.435, respectively). Furthermore, the LI of the CP had a more significant association with 1-year Brunel Balance Assessment (BBA), upper extremity PG, and Modified Rankin Scale (mRS) as compared to the LI of the MCP (r = 0.573 vs. r = 0.452; r = −0.554 vs. r = −0.528; and r = −0.494 vs. r = −0.344, respectively). We set the cutoff point for the MCP rFA at 0.925 (sensitivity: 79% and specificity: 100%) for predicting lower extremity motor function prognosis and found the receiver operating characteristic (ROC) curve of MCP rFA was larger than that of CP rFA (0.893 vs. 0.737). These results reveal that the MCP may play a significant role in the recovery of walking ability after stroke.
p16 Immunohistochemical Expression as a Surrogate Assessment of CDKN2A Alteration in Gliomas Leading to Prognostic Significances
Authors: Geyer Lucas , Wolf Thibaut , Chenard Marie-Pierre , Cebula Helene , Schott Roland , Noel Georges , Guerin Eric , Pencreach Erwan , Reita Damien , Entz-Werlé Natacha , Lhermitte Benoît
Published: February 2023

CDKN2A is a tumor suppressor gene encoding the p16 protein, a key regulator of the cell cycle. CDKN2A homozygous deletion is a central prognostic factor for numerous tumors and can be detected by several techniques. This study aims to evaluate the extent to which immunohistochemical levels of p16 expression may provide information about CDKN2A deletion. A retrospective study was conducted in 173 gliomas of all types, using p16 IHC and CDKN2A fluorescent in situ hybridization. Survival analyses were performed to assess the prognostic impact of p16 expression and CDKN2A deletion on patient outcomes. Three patterns of p16 expression were observed: absence of expression, focal expression, and overexpression. Absence of p16 expression was correlated with worse outcomes. p16 overexpression was associated with better prognoses in MAPK-induced tumors, but with worse survival in IDH-wt glioblastomas. CDKN2A homozygous deletion predicted worse outcomes in the overall patient population, particularly in IDH-mutant 1p/19q oligodendrogliomas (grade 3). Finally, we observed a significant correlation between p16 immunohistochemical loss of expression and CDKN2A homozygosity. IHC has strong sensitivity and high negative predictive value, suggesting that p16 IHC might be a pertinent test to detect cases most likely harboring CDKN2A homozygous deletion.
Metabolic Barriers to Glioblastoma Immunotherapy
Authors: Choudhary Nikita , Osorio Robert C. , Oh Jun Y. , Aghi Manish K.
Published: February 2023

Glioblastoma (GBM) is the most common primary brain tumor with a poor prognosis with the current standard of care treatment. To address the need for novel therapeutic options in GBM, immunotherapies which target cancer cells through stimulating an anti-tumoral immune response have been investigated in GBM. However, immunotherapies in GBM have not met with anywhere near the level of success they have encountered in other cancers. The immunosuppressive tumor microenvironment in GBM is thought to contribute significantly to resistance to immunotherapy. Metabolic alterations employed by cancer cells to promote their own growth and proliferation have been shown to impact the distribution and function of immune cells in the tumor microenvironment. More recently, the diminished function of anti-tumoral effector immune cells and promotion of immunosuppressive populations resulting from metabolic alterations have been investigated as contributory to therapeutic resistance. The GBM tumor cell metabolism of four nutrients (glucose, glutamine, tryptophan, and lipids) has recently been described as contributory to an immunosuppressive tumor microenvironment and immunotherapy resistance. Understanding metabolic mechanisms of resistance to immunotherapy in GBM can provide insight into future directions targeting the anti-tumor immune response in combination with tumor metabolism.
Establishment, Maintenance, and Performance of the Cooperative Osteosarcoma Study Group (COSS)
Authors: Bielack Stefan S. , Kager Leo , Kühne Thomas , Langer Thorsten , Reichardt Peter , Blattmann Claudia , Kevric Matthias , Mettmann Vanessa , Sorg Benjamin , Hecker-Nolting Stefanie
Published: February 2023

Introduction: Osteosarcoma treatment has benefitted greatly from collaborative research. This paper describes the history and accomplishments of the Cooperative Osteosarcoma Study Group (COSS), mainly dedicated to clinical questions, as well as remaining challenges. Materials and Methods: Narrative review of over four decades of uninterrupted collaboration within the multi-national German–Austrian–Swiss COSS group. Results: Since its very first prospective osteosarcoma trial starting in 1977, COSS has continuously been able to provide high-level evidence on various tumor- and treatment-related questions. This includes both the cohort of patients enrolled into prospective trials as well as those patients excluded from them for various reasons, followed in a prospective registry. Well over one hundred disease-related publications attest to the group’s impact on the field. Despite these accomplishments, challenging problems remain. Discussion: Collaborative research within a multi-national study group resulted in better definitions of important aspects of the most common bone tumor, osteosarcoma, and its treatments. Important challenges continue to persist.
The Liver Cancer Immune Microenvironment: Emerging Concepts for Myeloid Cell Profiling with Diagnostic and Therapeutic Implications
Authors: Arvanitakis Konstantinos , Mitroulis Ioannis , Chatzigeorgiou Antonios , Elefsiniotis Ioannis , Germanidis Georgios
Published: February 2023

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide [...]
Prognostic Impact of Metastatic Site in Patients Receiving First-Line Sorafenib Therapy for Advanced Hepatocellular Carcinoma
Authors: Ielasi Luca , Tovoli Francesco , Tonnini Matteo , Stefanini Bernardo , Tortora Raffaella , Magini Giulia , Sacco Rodolfo , Pressiani Tiziana , Trevisani Franco , Garajová Ingrid , Piscaglia Fabio , Granito Alessandro
Published: February 2023

Extrahepatic spread is a well-known negative prognostic factor in patients with advanced hepatocellular carcinoma (HCC). The prognostic role of different metastatic sites and their response rate to systemic treatment is still being debated. We considered 237 metastatic HCC patients treated with sorafenib as first-line therapy in five different Italian centers from 2010 to 2020. The most common metastatic sites were lymph nodes, lungs, bone and adrenal glands. In survival analysis, the presence of dissemination to lymph nodes (OS 7.1 vs. 10.2 months; p = 0.007) and lungs (OS 5.9 vs. 10.2 months; p < 0.001) were significantly related to worse survival rates compared with all other sites. In the subgroup analysis of patients with only a single metastatic site, this prognostic effect remained statistically significant. Palliative radiation therapy on bone metastases significantly prolonged survival in this cohort of patients (OS 19.4 vs. 6.5 months; p < 0.001). Furthermore, patients with lymph node and lung metastases had worse disease control rates (39.4% and 30.5%, respectively) and shorter radiological progression-free survival (3.4 and 3.1 months, respectively). In conclusion, some sites of an extrahepatic spread of HCC have a prognostic impact on survival in patients treated with sorafenib; in particular, lymph nodes and lung metastases have worse prognosis and treatment response rate.
Recent Advances on Furan-Based Visible Light Photoinitiators of Polymerization
Authors: Dumur Frédéric
Published: February 2023

Photopolymerization is an active research field enabling to polymerize in greener conditions than that performed with traditional thermal polymerization. At present, a great deal of effort is devoted to developing visible light photoinitiating systems. Indeed, the traditional UV photoinitiating systems are currently the focus of numerous safety concerns so alternatives to UV light are being actively researched. However, visible light photons are less energetic than UV photons so the reactivity of the photoinitiating systems should be improved to address this issue. In this field, furane constitutes an interesting candidate for the design of photocatalysts of polymerization due to its low cost and its easy chemical modification. In this review, an overview concerning the design of furane-based photoinitiators is provided. Comparisons with reference systems are also established to demonstrate evidence of the interest of these photoinitiators in innovative structures.
Elevated Levels of Lamin A Promote HR and NHEJ-Mediated Repair Mechanisms in High-Grade Ovarian Serous Carcinoma Cell Line
Authors: Sengupta Duhita , Mukhopadhyay Asima , Sengupta Kaushik
Published: February 2023

Extensive research for the last two decades has significantly contributed to understanding the roles of lamins in the maintenance of nuclear architecture and genome organization which is drastically modified in neoplasia. It must be emphasized that alteration in lamin A/C expression and distribution is a consistent event during tumorigenesis of almost all tissues of human bodies. One of the important signatures of a cancer cell is its inability to repair DNA damage which befalls several genomic events that transform the cells to be sensitive to chemotherapeutic agents. This genomic and chromosomal instability is the most common feature found in cases of high-grade ovarian serous carcinoma. Here, we report elevated levels of lamins in OVCAR3 cells (high-grade ovarian serous carcinoma cell line) in comparison to IOSE (immortalised ovarian surface epithelial cells) and, consequently, altered damage repair machinery in OVCAR3. We have analysed the changes in global gene expression as a sequel to DNA damage induced by etoposide in ovarian carcinoma where lamin A is particularly elevated in expression and reported some differentially expressed genes associated with pathways conferring cellular proliferation and chemoresistance. We hereby establish the role of elevated lamin A in neoplastic transformation in the context of high-grade ovarian serous cancer through a combination of HR and NHEJ mechanisms.
Age-Dependent Dysregulation of APP in Neuronal and Skin Cells from Fragile X Individuals
Authors: Cencelli Giulia , Pacini Laura , De Luca Anastasia , Messia Ilenia , Gentile Antonietta , Kang Yunhee , Nobile Veronica , Tabolacci Elisabetta , Jin Peng , Farace Maria Giulia , Bagni Claudia
Published: February 2023

Fragile X syndrome (FXS) is the most common form of monogenic intellectual disability and autism, caused by the absence of the functional fragile X messenger ribonucleoprotein 1 (FMRP). FXS features include increased and dysregulated protein synthesis, observed in both murine and human cells. Altered processing of the amyloid precursor protein (APP), consisting of an excess of soluble APPα (sAPPα), may contribute to this molecular phenotype in mice and human fibroblasts. Here we show an age-dependent dysregulation of APP processing in fibroblasts from FXS individuals, human neural precursor cells derived from induced pluripotent stem cells (iPSCs), and forebrain organoids. Moreover, FXS fibroblasts treated with a cell-permeable peptide that decreases the generation of sAPPα show restored levels of protein synthesis. Our findings suggest the possibility of using cell-based permeable peptides as a future therapeutic approach for FXS during a defined developmental window.
3D Spheroid Configurations Are Possible Indictors for Evaluating the Pathophysiology of Melanoma Cell Lines
Authors: Ohguro Hiroshi , Watanabe Megumi , Sato Tatsuya , Hikage Fumihito , Furuhashi Masato , Okura Masae , Hida Tokimasa , Uhara Hisashi
Published: February 2023

To study the molecular mechanisms responsible for inducing the spatial proliferation of malignant melanomas (MM), three-dimension (3D) spheroids were produced from several MM cell lines including SK-mel-24, MM418, A375, WM266-4, and SM2-1, and their 3D architectures and cellular metabolisms were evaluated by phase-contrast microscopy and Seahorse bio-analyzer, respectively. Several transformed horizontal configurations were observed within most of these 3D spheroids, and the degree of their deformity was increased in the order: WM266-4, SM2-1, A375, MM418, and SK-mel-24. An increased maximal respiration and a decreased glycolytic capacity were observed within the lesser deformed two MM cell lines, WM266-4 and SM2-1, as compared with the most deformed ones. Among these MM cell lines, two distinct cell lines, WM266-4 and SK-mel-24, whose 3D appearances were the closest and farthest, respectively, from being horizontally circular-shaped, were subjected to RNA sequence analyses. Bioinformatic analyses of the differentially expressed genes (DEGs) identified KRAS and SOX2 as potential master regulatory genes for inducing these diverse 3D configurations between WM266-4 and SK-mel-24. The knockdown of both factors altered the morphological and functional characteristics of the SK-mel-24 cells, and in fact, their horizontal deformity was significantly reduced. A qPCR analysis indicated that the levels of several oncogenic signaling related factors, including KRAS and SOX2, PCG1α, extracellular matrixes (ECMs), and ZO1 had fluctuated among the five MM cell lines. In addition, and quite interestingly, the dabrafenib and trametinib resistant A375 (A375DT) cells formed globe shaped 3D spheroids and showed different profiles in cellular metabolism while the mRNA expression of these molecules that were tested as above were different compared with A375 cells. These current findings suggest that 3D spheroid configuration has the potential for serving as an indicator of the pathophysiological activities associated with MM.
Human Bone Marrow-Derived Mesenchymal Stromal Cells Reduce the Severity of Experimental Necrotizing Enterocolitis in a Concentration-Dependent Manner
Authors: Provitera Livia , Tomaselli Andrea , Raffaeli Genny , Crippa Stefania , Arribas Cristina , Amodeo Ilaria , Gulden Silvia , Amelio Giacomo Simeone , Cortesi Valeria , Manzoni Francesca , Cervellini Gaia , Cerasani Jacopo , Menis Camilla , Pesenti Nicola , Tripodi Matteo , Santi Ludovica , Maggioni Marco , Lonati Caterina , Oldoni Samanta , Algieri Francesca , Garrido Felipe , Bernardo Maria Ester , Mosca Fabio , Cavallaro Giacomo
Published: February 2023

Necrotizing enterocolitis (NEC) is a devastating gut disease in preterm neonates. In NEC animal models, mesenchymal stromal cells (MSCs) administration has reduced the incidence and severity of NEC. We developed and characterized a novel mouse model of NEC to evaluate the effect of human bone marrow-derived MSCs (hBM-MSCs) in tissue regeneration and epithelial gut repair. NEC was induced in C57BL/6 mouse pups at postnatal days (PND) 3–6 by (A) gavage feeding term infant formula, (B) hypoxia/hypothermia, and (C) lipopolysaccharide. Intraperitoneal injections of PBS or two hBM-MSCs doses (0.5 × 106 or 1 × 106) were given on PND2. At PND 6, we harvested intestine samples from all groups. The NEC group showed an incidence of NEC of 50% compared with controls (p < 0.001). Severity of bowel damage was reduced by hBM-MSCs compared to the PBS-treated NEC group in a concentration-dependent manner, with hBM-MSCs (1 × 106) inducing a NEC incidence reduction of up to 0% (p < 0.001). We showed that hBM-MSCs enhanced intestinal cell survival, preserving intestinal barrier integrity and decreasing mucosal inflammation and apoptosis. In conclusion, we established a novel NEC animal model and demonstrated that hBM-MSCs administration reduced the NEC incidence and severity in a concentration-dependent manner, enhancing intestinal barrier integrity.
Low Gut Microbial Diversity Augments Estrogen-Driven Pulmonary Fibrosis in Female-Predominant Interstitial Lung Disease
Authors: Chioma Ozioma S. , Mallott Elizabeth , Shah-Gandhi Binal , Wiggins ZaDarreyal , Langford Madison , Lancaster Andrew William , Gelbard Alexander , Wu Hongmei , Johnson Joyce E. , Lancaster Lisa , Wilfong Erin M. , Crofford Leslie J. , Montgomery Courtney G. , Van Kaer Luc , Bordenstein Seth , Newcomb Dawn C. , Drake Wonder Puryear
Published: February 2023

Although profibrotic cytokines, such as IL-17A and TGF-β1, have been implicated in the pathogenesis of interstitial lung disease (ILD), the interactions between gut dysbiosis, gonadotrophic hormones and molecular mediators of profibrotic cytokine expression, such as the phosphorylation of STAT3, have not been defined. Here, through chromatin immunoprecipitation sequencing (ChIP-seq) analysis of primary human CD4+ T cells, we show that regions within the STAT3 locus are significantly enriched for binding by the transcription factor estrogen receptor alpha (ERa). Using the murine model of bleomycin-induced pulmonary fibrosis, we found significantly increased regulatory T cells compared to Th17 cells in the female lung. The genetic absence of ESR1 or ovariectomy in mice significantly increased pSTAT3 and IL-17A expression in pulmonary CD4+ T cells, which was reduced after the repletion of female hormones. Remarkably, there was no significant reduction in lung fibrosis under either condition, suggesting that factors outside of ovarian hormones also contribute. An assessment of lung fibrosis among menstruating females in different rearing environments revealed that environments favoring gut dysbiosis augment fibrosis. Furthermore, hormone repletion following ovariectomy further augmented lung fibrosis, suggesting pathologic interactions between gonadal hormones and gut microbiota in relation to lung fibrosis severity. An analysis of female sarcoidosis patients revealed a significant reduction in pSTAT3 and IL-17A levels and a concomitant increase in TGF-β1 levels in CD4+ T cells compared to male sarcoidosis patients. These studies reveal that estrogen is profibrotic in females and that gut dysbiosis in menstruating females augments lung fibrosis severity, supporting a critical interaction between gonadal hormones and gut flora in lung fibrosis pathogenesis.
Lacticaseibacillus paracasei GM-080 Ameliorates Allergic Airway Inflammation in Children with Allergic Rhinitis: From an Animal Model to a Double-Blind, Randomized, Placebo-Controlled Trial
Authors: Lin En-Kwang , Chang Wen-Wei , Jhong Jhih-Hua , Tsai Wan-Hua , Chou Chia-Hsuan , Wang I-Jen
Published: February 2023

Background: Probiotics may facilitate the clinical management of allergic diseases. However, their effects on allergic rhinitis (AR) remain unclear. We examined the efficacy and safety of Lacticaseibacillus paracasei GM-080 in a mouse model of airway hyper-responsiveness (AHR) and in children with perennial AR (PAR) by using a double-blind, prospective, randomized, placebo-controlled design. Methods: The production of interferon (IFN)-γ and interleukin (IL)-12 was measured by using an enzyme-linked immunosorbent assay. GM-080 safety was evaluated via the whole-genome sequencing (WGS) of virulence genes. An ovalbumin (OVA)-induced AHR mouse model was constructed, and lung inflammation was evaluated by measuring the infiltrating leukocyte content of bronchoalveolar lavage fluid. A clinical trial was conducted with 122 children with PAR who were randomized to receive different doses of GM-080 or the placebo for 3 months, and their AHR symptom severity scores, total nasal symptom scores (TNSSs), and Investigator Global Assessment Scale scores were examined. Results: Among the tested L. paracasei strains, GM-080 induced the highest IFN-γ and IL-12 levels in mouse splenocytes. WGS analysis revealed the absence of virulence factors or antibiotic-resistance genes in GM-080. The oral administration of GM-080 at 1 × 107 colony forming units (CFU)/mouse/day for 8 weeks alleviated OVA-induced AHR and reduced airway inflammation in mice. In children with PAR, the oral consumption of GM-080 at 2 × 109 CFU/day for 3 months ameliorated sneezing and improved Investigator Global Assessment Scale scores significantly. GM-080 consumption led to a nonsignificant decrease in TNSS and also nonsignificantly reduced IgE but increased INF-γ levels. Conclusion: GM-080 may be used as a nutrient supplement to alleviate airway allergic inflammation.
A Comparative Study of Metabolic Syndrome Using NCEP—ATP III and IDF Criteria in Children and Its Relationship with Biochemical Indicators in Huatusco, Veracruz, Mexico
Authors: Rivadeneyra-Domínguez Eduardo , Díaz-Vallejo Joel Jahaziel , Prado-Bobadilla Aurora Guadalupe , Rodríguez-Landa Juan Francisco
Published: February 2023

Metabolic syndrome includes a set of metabolic alterations associated with overweight and obesity. The criteria for its diagnosis are heterogeneous, and there have been few studies about prevalence in the pediatric population. The aim of this study was to describe how the estimated prevalence of metabolic syndrome varies by International Diabetes Federation (IDF) vs. National Cholesterol Education Program—Adult Treatment Panel III (NCEP—ATP) criteria. We conducted a cross-sectional study in which anthropometric information, triglyceride, cholesterol, glycemia, and insulin levels, among others, were collected. We compared the group potentially misclassified by IDF with the group classified without metabolic syndrome by NCEP—ATP with respect to weight status and biomarkers. Statistical analysis included linear regression, Mann–Whitney U test, Fisher´s exact test, and odds ratio calculation. The IDF criteria missed the association with obesity, although the undetected group differed significantly from the nonmetabolic syndrome group in terms of IBM and weight. The associated biomarkers were ultrasensitive C-reactive protein (Hs-CRP), alanine aminotransferase (ALT) enzyme, insulin, triglycerides, and high-density lipoprotein (HDL) cholesterol. Waist circumference was the parameter with the strongest association for presenting metabolic syndrome, with an odds ratio of 18.33. The results of this study showed the estimated prevalence of MS varies by criteria, due to cutoff points, and how the high prevalence of MS strongly associated with obesity.
Influence of Thermal Aging on Dielectric Properties of High Voltage Cable Insulation Layer
Authors: Liang Boyuan , Lan Rui , Zang Qian , Liu Zhen , Tian Lin , Wang Zhaochen , Li Guochang
Published: February 2023

Thermal aging is one of the main reasons for the degradation of insulation properties of high voltage cable. Dielectric properties and breakdown strength are important parameters to reflect the insulation performance of the cable insulation materials. In the work, the influence of thermal aging on dielectric and breakdown performance of the cable insulation layer was studied. Firstly, XLPE cable insulation samples were prepared and the thermal aging treatment was carried out. Secondly, the microstructure and molecular structure of XLPE samples under different thermal aging time were analyzed. The dielectric properties and breakdown characteristics of XLPE samples under different thermal aging times were characterized in macro aspect. Finally, the effects of different temperatures on the molecular microstructure of XLPE were studied. The results show that with the extension of thermal aging time, the microstructure of XLPE molecule is destroyed, the macromolecular chain is gradually cleaved, and the carbonyl absorption intensity increases. At power frequency, the breakdown strength decreases from 75.37 kV/mm to 62.18 kV/mm, the relative permittivity increases from 2.44 to 2.51, and the dielectric loss increases from 1.47 × 10−4 to 3.10 × 10−3. The free volume rate of XLPE molecules increases with the increasing temperature, and the mean square displacement gradually increases. The work has good guiding significance for the safe operation and condition assessment of high-voltage cables.
Breaks in the Hall–Petch Relationship after Severe Plastic Deformation of Magnesium, Aluminum, Copper, and Iron
Authors: Dangwal Shivam , Edalati Kaveh , Valiev Ruslan Z. , Langdon Terence G.
Published: February 2023

Strengthening by grain refinement via the Hall–Petch mechanism and softening by nanograin formation via the inverse Hall–Petch mechanism have been the subject of argument for decades, particularly for ultrafine-grained materials. In this study, the Hall–Petch relationship is examined for ultrafine-grained magnesium, aluminum, copper, and iron produced by severe plastic deformation in the literature. Magnesium, aluminum, copper, and their alloys follow the Hall–Petch relationship with a low slope, but an up-break appears when the grain sizes are reduced below 500–1000 nm. This extra strengthening, which is mainly due to the enhanced contribution of dislocations, is followed by a down-break for grain sizes smaller than 70–150 nm due to the diminution of the dislocation contribution and an enhancement of thermally-activated phenomena. For pure iron with a lower dislocation mobility, the Hall–Petch breaks are not evident, but the strength at the nanometer grain size range is lower than the expected Hall–Petch trend in the submicrometer range. The strength of nanograined iron can be increased to the expected trend by stabilizing grain boundaries via impurity atoms. Detailed analyses of the data confirm that grain refinement to the nanometer level is not necessarily a solution to achieve extra strengthening, but other strategies such as microstructural stabilization by segregation or precipitation are required.
Non-Schmid Effect on the Fracture Behavior of Tungsten
Authors: Li Zhijie , Cui Yinan
Published: February 2023

The fracture process of tungsten is dominated by the competition mechanism between the plastic deformation and the crack propagation near the crack tip. The non-Schmid (NS) effect, which considers the contribution of non-planar shear stress on the screw dislocation motion, is known to significantly influence the plastic deformation of tungsten at low and medium temperatures. However, how the NS effect influences the crack-tip plasticity and the fracture behavior of tungsten remains to be answered. In this work, the coupled crystal-plasticity and phase-field model (CP-PFM) was adopted to study the influence of the NS effect on the plastic deformation of un-notched tungsten and the fracture process of pre-notched tungsten at different temperatures. It was found that the lower the temperature, the more significant the NS effect on tungsten plasticity, which manifests in the lower yield stress and more unsymmetrical plastic deformation when the NS effect is considered. In contrast, the NS effect displayed the most obvious effect on the fracture behavior of pre-notched tungsten in the medium temperature regime, which manifested as higher fracture stress, a more significant crack-tip shielding effect, different fracture morphology, and lower crack propagation speed. The brittle fracture response at low temperature was not affected too much by the existence of the NS effect.