bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-Term Follow-Up and Predictors of Functional Outcome after Surgery for Spinal Meningiomas: A Population-Based Cohort Study
Authors: Pettersson-Segerlind Jenny , Fletcher-Sandersjöö Alexander , Tatter Charles , Burström Gustav , Persson Oscar , Förander Petter , Mathiesen Tiit , Bartek Jiri , Edström Erik , Elmi-Terander Adrian
Published: June 2021

Spinal meningiomas are the most common adult primary spinal tumor, constituting 24–45% of spinal intradural tumors and 2% of all meningiomas. The aim of this study was to assess postoperative complications, long-term outcomes, predictors of functional improvement and differences between elderly (≥70 years) and non-elderly (18–69 years) patients surgically treated for spinal meningiomas. Variables were retrospectively collected from patient charts and magnetic resonance images. Baseline comparisons, paired testing and regression analyses were used. In conclusion, 129 patients were included, with a median follow-up time of 8.2 years. Motor deficit was the most common presenting symptom (66%). The median time between diagnosis and surgery was 1.3 months. A postoperative complication occurred in 10 (7.8%) and tumor growth or recurrence in 6 (4.7%) patients. Surgery was associated with significant improvement of motor and sensory deficit, gait disturbance, bladder dysfunction and pain. Time to surgery, tumor area and the degree of spinal cord compression significantly predicted postoperative improvement in a modified McCormick scale (mMCs) in the univariable regression analysis, and spinal cord compression showed independent risk association in multivariable analysis. There was no difference in improvement, complications or tumor control between elderly and non-elderly patients. We concluded that surgery of spinal meningiomas was associated with significant long-term neurological improvement, which could be predicted by time to surgery, tumor size and spinal cord compression.
Integrative cBioPortal Analysis Revealed Molecular Mechanisms That Regulate EGFR-PI3K-AKT-mTOR Pathway in Diffuse Gliomas of the Brain
Authors: Brlek Petar , Kafka Anja , Bukovac Anja , Pećina-Šlaus Nives
Published: June 2021

Diffuse gliomas are a heterogeneous group of tumors with aggressive biological behavior and a lack of effective treatment methods. Despite new molecular findings, the differences between pathohistological types still require better understanding. In this in silico analysis, we investigated AKT1, AKT2, AKT3, CHUK, GSK3β, EGFR, PTEN, and PIK3AP1 as participants of EGFR-PI3K-AKT-mTOR signaling using data from the publicly available cBioPortal platform. Integrative large-scale analyses investigated changes in copy number aberrations (CNA), methylation, mRNA transcription and protein expression within 751 samples of diffuse astrocytomas, anaplastic astrocytomas and glioblastomas. The study showed a significant percentage of CNA in PTEN (76%), PIK3AP1 and CHUK (75% each), EGFR (74%), AKT2 (39%), AKT1 (32%), AKT3 (19%) and GSK3β (18%) in the total sample. Comprehensive statistical analyses show how genomics and epigenomics affect the expression of examined genes differently across various pathohistological types and grades, suggesting that genes AKT3, CHUK and PTEN behave like tumor suppressors, while AKT1, AKT2, EGFR, and PIK3AP1 show oncogenic behavior and are involved in enhanced activity of the EGFR-PI3K-AKT-mTOR signaling pathway. Our findings contribute to the knowledge of the molecular differences between pathohistological types and ultimately offer the possibility of new treatment targets and personalized therapies in patients with diffuse gliomas.
The TGF-β Pathway: A Pharmacological Target in Hepatocellular Carcinoma?
Authors: Gonzalez-Sanchez Ester , Vaquero Javier , Férnandez-Barrena Maite G. , Lasarte Juan José , Avila Matías A. , Sarobe Pablo , Reig María , Calvo Mariona , Fabregat Isabel
Published: June 2021

Transforming Growth Factor-beta (TGF-β) superfamily members are essential for tissue homeostasis and consequently, dysregulation of their signaling pathways contributes to the development of human diseases. In the liver, TGF-β signaling participates in all the stages of disease progression from initial liver injury to hepatocellular carcinoma (HCC). During liver carcinogenesis, TGF-β plays a dual role on the malignant cell, behaving as a suppressor factor at early stages, but contributing to later tumor progression once cells escape from its cytostatic effects. Moreover, TGF-β can modulate the response of the cells forming the tumor microenvironment that may also contribute to HCC progression, and drive immune evasion of cancer cells. Thus, targeting the TGF-β pathway may constitute an effective therapeutic option for HCC treatment. However, it is crucial to identify biomarkers that allow to predict the response of the tumors and appropriately select the patients that could benefit from TGF-β inhibitory therapies. Here we review the functions of TGF-β on HCC malignant and tumor microenvironment cells, and the current strategies targeting TGF-β signaling for cancer therapy. We also summarize the clinical impact of TGF-β inhibitors in HCC patients and provide a perspective on its future use alone or in combinatorial strategies for HCC treatment.
Interrelations between Patients’ Clinicopathological Characteristics and Their Association with Response to Immunotherapy in a Real-World Cohort of NSCLC Patients
Authors: Callejo Ana , Frigola Joan , Iranzo Patricia , Carbonell Caterina , Diaz Nely , Marmolejo David , Assaf Juan David , Cedrés Susana , Martinez-Marti Alex , Navarro Alejandro , Pardo Nuria , Amat Ramon , Felip Enriqueta
Published: June 2021

Immune checkpoint inhibitors (ICIs) have transformed non-small cell lung cancer (NSCLC) treatment. Unfortunately, only some patients benefit from these therapies. Thus, certain clinicopathological characteristics of the patients have been proposed as biomarkers of ICIs response. We assembled a retrospective cohort of 262 NSCLC patients treated with ICIs, compiled relevant clinicopathological characteristics, and studied their associations with treatment outcome using Cox proportional-hazards survival models. Additionally, we investigated the interrelations between clinicopathological features and devised a method to create a compendium associated with ICIs response by selecting those that provide non-redundant information. In multivariate analyses, ECOG performance status (hazard ratio (HR) 1.37 (95% CI 1.11 to 1.68), p < 0.005), LDH (HR 1.24 (95% CI 1.03 to 1.48), p = 0.02)) and PD-L1 negativity were associated with decreased progression-free survival (PFS) (HR 1.92 (95% CI 1.03 to 3.58), p = 0.04), whereas presentation of immune-related adverse events (irAEs) (HR 0.35 (95% CI 0.22 to 0.55, p < 0.005) or females (HR 0.52 (95% CI 0.33 to 0.80, p < 0.005) had longer PFS. Additionally, numerous clinicopathological indicators were found to be interrelated. Thus, we searched for features that provide non-redundant information, and found the combination of LDH levels, irAEs, and gender to have a better association with ICIs treatment response (cross-validated c-index = 0.66). We concluded that several clinicopathological features showed prognostic value in our real-world cohort. However, some are interrelated, and compendiums of features should therefore consider these interactions. Joint assessment of LDH, irAEs, and gender may be a good prognostic compendium.
Targeting NEDDylation as a Novel Approach to Improve the Treatment of Head and Neck Cancer
Authors: Jones Trace M. , Carew Jennifer S. , Bauman Julie E. , Nawrocki Steffan T.
Published: June 2021

Head and neck cancer is diagnosed in nearly 900,000 new patients worldwide each year. Despite this alarming number, patient outcomes, particularly for those diagnosed with late-stage and human papillomavirus (HPV)-negative disease, have only marginally improved in the last three decades. New therapeutics that target novel pathways are desperately needed. NEDDylation is a key cellular process by which NEDD8 proteins are conjugated to substrate proteins in order to modulate their function. NEDDylation is closely tied to appropriate protein degradation, particularly proteins involved in cell cycle regulation, DNA damage repair, and cellular stress response. Components of the NEDDylation pathway are frequently overexpressed or hyperactivated in many cancer types including head and neck cancer, which contribute to disease progression and drug resistance. Therefore, targeting NEDDylation could have a major impact for malignancies with alterations in the pathway, and this has already been demonstrated in preclinical studies and clinical trials. Here, we will survey the mechanisms by which aberrant NEDDylation contributes to disease pathogenesis and discuss the potential clinical implications of inhibiting NEDDylation as a novel approach for the treatment of head and neck cancer.
RASSF1A Suppression as a Potential Regulator of Mechano-Pathobiology Associated with Mammographic Density in BRCA Mutation Carriers
Authors: Reye Gina , Huang Xuan , Britt Kara L. , Meinert Christoph , Blick Tony , Xu Yannan , Momot Konstantin I. , Lloyd Thomas , Northey Jason J. , Thompson Erik W. , Hugo Honor J.
Published: June 2021

High mammographic density (MD) increases breast cancer (BC) risk and creates a stiff tissue environment. BC risk is also increased in BRCA1/2 gene mutation carriers, which may be in part due to genetic disruption of the tumour suppressor gene Ras association domain family member 1 (RASSF1A), a gene that is also directly regulated by tissue stiffness. High MD combined with BRCA1/2 mutations further increase breast cancer risk, yet BRCA1/2 mutations alone or in combination do not increase MD. The molecular basis for this additive effect therefore remains unclear. We studied the interplay between MD, stiffness, and BRCA1/2 mutation status in human mammary tissue obtained after prophylactic mastectomy from women at risk of developing BC. Our results demonstrate that RASSF1A expression increased in MCF10DCIS.com cell cultures with matrix stiffness up until ranges corresponding with BiRADs 4 stiffnesses (~16 kPa), but decreased in higher stiffnesses approaching malignancy levels (>50 kPa). Similarly, higher RASSF1A protein was seen in these cells when co-cultivated with high MD tissue in murine biochambers. Conversely, local stiffness, as measured by collagen I versus III abundance, repressed RASSF1A protein expression in BRCA1, but not BRCA2 gene mutated tissues; regional density as measured radiographically repressed RASSF1A in both BRCA1/2 mutated tissues. The combinatory effect of high MD and BRCA mutations on breast cancer risk may be due to RASSF1A gene repression in regions of increased tissue stiffness.
Reappraising the Role of Trans-Sphenoidal Surgery in Prolactin-Secreting Pituitary Tumors
Authors: Mattogno Pier Paolo , D’Alessandris Quintino Giorgio , Chiloiro Sabrina , Bianchi Antonio , Giampietro Antonella , Pontecorvi Alfredo , De Marinis Laura , Olivi Alessandro , Anile Carmelo , Lauretti Liverana
Published: June 2021

Background: Prolactinomas represent a unique challenge for endocrinologists and neurosurgeons. Considering recent innovations in surgical practice, the authors aimed to investigate the best management for prolactinomas. Methods: A retrospective, cross-sectional and monocentric study was designed. Consecutive patients affected by prolactinomas were enrolled if treated with a first-line treatment with a dopamine agonist (DA) or trans-sphenoidal surgery (TSS). Patients carried giant prolactinomas, and those with a follow-up <12 months were excluded. Results: Two hundred and fifty-nine patients were enrolled. The first treatment was DA for 140 patients and TS for 119 cases. One hundred and forty-six of 249 patients (58.6%) needed a second therapy. The mean follow-up was 102.2 months (12–438 months). Surgery highly impacted on the cure rate—in particular, in females (p = 0.0021) and in microprolactinomas (p = 0.0020). Considering the multivariate analysis, the female gender and surgical treatment in the course of the clinical history were the only independent positive predictors of a cure at the end of 5 years follow-up (p = 0.0016, p = 0.0005). The evaluation of serum prolactin (24 hours after TSS) revealed that 86.4% of patients with postoperative prolactin (PRL) ≤10 ng/mL were cured at the end of the follow-up (p < 0.0001). Conclusions: According to our experience, surgery allows a high cure rate of prolactinomas, particularly in females with microadenoma, with a good safety profile. TSS for prolactinomas should be considered as a concrete option, during the multidisciplinary evaluation, in centers of reference for pituitary diseases.
New Angiogenic Regulators Produced by TAMs: Perspective for Targeting Tumor Angiogenesis
Authors: Larionova Irina , Kazakova Elena , Gerashchenko Tatiana , Kzhyshkowska Julia
Published: June 2021

Angiogenesis is crucial to the supply of a growing tumor with nutrition and oxygen. Inhibition of angiogenesis is one of the main treatment strategies for colorectal, lung, breast, renal, and other solid cancers. However, currently applied drugs that target VEGF or receptor tyrosine kinases have limited efficiency, which raises a question concerning the mechanism of patient resistance to the already developed drugs. Tumor-associated macrophages (TAMs) were identified in the animal tumor models as a key inducer of the angiogenic switch. TAMs represent a potent source not only for VEGF, but also for a number of other pro-angiogenic factors. Our review provides information about the activity of secreted regulators of angiogenesis produced by TAMs. They include members of SEMA and S100A families, chitinase-like proteins, osteopontin, and SPARC. The COX-2, Tie2, and other factors that control the pro-angiogenic activity of TAMs are also discussed. We highlight how these recent findings explain the limitations in the efficiency of current anti-angiogenic therapy. Additionally, we describe genetic and posttranscriptional mechanisms that control the expression of factors regulating angiogenesis. Finally, we present prospects for the complex targeting of the pro-angiogenic activity of TAMs.
Dying to Survive—The p53 Paradox
Authors: Lees Andrea , Sessler Tamas , McDade Simon
Published: June 2021

The p53 tumour suppressor is best known for its canonical role as “guardian of the genome”, activating cell cycle arrest and DNA repair in response to DNA damage which, if irreparable or sustained, triggers activation of cell death. However, despite an enormous amount of work identifying the breadth of the gene regulatory networks activated directly and indirectly in response to p53 activation, how p53 activation results in different cell fates in response to different stress signals in homeostasis and in response to p53 activating anti-cancer treatments remains relatively poorly understood. This is likely due to the complex interaction between cell death mechanisms in which p53 has been activated, their neighbouring stressed or unstressed cells and the local stromal and immune microenvironment in which they reside. In this review, we evaluate our understanding of the burgeoning number of cell death pathways affected by p53 activation and how these may paradoxically suppress cell death to ensure tissue integrity and organismal survival. We also discuss how these functions may be advantageous to tumours that maintain wild-type p53, the understanding of which may provide novel opportunity to enhance treatment efficacy.
Brain Invasion in Meningioma—A Prognostic Potential Worth Exploring
Authors: Behling Felix , Hempel Johann-Martin , Schittenhelm Jens
Published: June 2021

Most meningiomas are slow growing tumors arising from the arachnoid cap cells and can be cured by surgical resection or radiation therapy in selected cases. However, recurrent and aggressive cases are also quite common and challenging to treat due to no established treatment alternatives. Assessment of the risk of recurrence is therefore of utmost importance and several prognostic clinical and molecular markers have been established. Additionally, the identification of invasive growth of meningioma cells into CNS tissue was demonstrated to lead to a higher risk of recurrence and was therefore integrated into the WHO classification of CNS tumors. However, the evidence for its prognostic impact has been questioned in subsequent studies and its exclusion from the next WHO classification proposed. We were recently able to show the prognostic impact of CNS invasion in a large comprehensive retrospective meningioma cohort including other established prognostic factors. In this review we discuss the growing experiences that have been gained on this matter, with a focus on the currently nonuniform histopathological assessment, imaging characteristics and intraoperative sampling as well as the overall outlook on the future role of this potential prognostic factor.
Is It Time to Call Time on Bone Marrow Biopsy for Staging Ewing Sarcoma (ES)?
Authors: Ingley Katrina M. , Wan Simon , Vöö Stefan , Windsor Rachael , Michelagnoli Maria , Saifuddin Asif , Strauss Sandra J.
Published: June 2021

Primary malignant bone sarcomas are rare and Ewing sarcoma (ES), along with osteosarcoma, predominates in teenagers and young adults. The well-established multimodality treatment incorporates systemic chemotherapy with local control in the form of surgery, with or without radiation. The presence and extent of metastases at diagnosis remains the most important prognostic factor in determining patient outcome; patients with skeletal metastases or bone marrow infiltration having a significantly worse outcome than those with lung metastases alone. There is, however, no accepted staging algorithm for ES. Large cooperative groups and national guidelines continue to advocate bone marrow biopsy (BMB) for staging but functional imaging techniques, such as 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) with computerised tomography (CT) have been increasingly used for staging cancers and whole-body magnetic resonance imaging (WB-MRI) for staging skeletal metastases. This review outlines the current literature, from which we conclude that BMB is no longer required for the staging of ES as it does not influence the standard of care management. BMB may, however, provide prognostic information and insights into the biology of ES in selected patients on prospective clinical trials.
Impact of Race and Socioeconomics Disparities on Survival in Young-Onset Colorectal Adenocarcinoma—A SEER Registry Analysis
Authors: Aloysius Mark M. , Goyal Hemant , Shah Niraj J. , Pallav Kumar , John Nimy , Gajendran Mahesh , Perisetti Abhilash , Tharian Benjamin
Published: June 2021

Introduction: We aimed to assess the impact of socio-economic determinants of health (SEDH) on survival disparities within and between the ethnic groups of young-onset (<50 years age) colorectal adenocarcinoma patients. Patients and Methods: Surveillance, epidemiology, and end results (SEER) registry was used to identify colorectal adenocarcinoma patients aged between 25–49 years from 2012 and 2016. Survival analysis was performed using the Kaplan–Meir method. Cox proportional hazards model was used to determine the hazard effect of SEDH. American community survey (ACS) data 2012–2016 were used to analyze the impact of high school education, immigration status, poverty, household income, employment, marital status, and insurance type. Results: A total of 17,145 young-onset colorectal adenocarcinoma patients were studied. Hispanic (H) = 2874, Non-Hispanic American Indian/Alaskan Native (NHAIAN) = 164, Non-Hispanic Asian Pacific Islander (NHAPI) = 1676, Non-Hispanic black (NHB) = 2305, Non-Hispanic white (NHW) = 10,126. Overall cancer-specific survival was, at 5 years, 69 m. NHB (65.58 m) and NHAIAN (65.67 m) experienced worse survival compared with NHW (70.11 m), NHAPI (68.7), and H (68.31). High school education conferred improved cancer-specific survival significantly with NHAPI, NHB, and NHW but not with H and NHAIAN. Poverty lowered and high school education improved cancer-specific survival (CSS) in NHB, NHW, and NHAPI. Unemployment was associated with lowered CSS in H and NAPI. Lower income below the median negatively impacted survival among H, NHAPI NHB, and NHW. Recent immigration within the last 12 months lowered CSS survival in NHW. Commercial health insurance compared with government insurance conferred improved CSS in all groups. Conclusions: Survival disparities were found among all races with young-onset colorectal adenocarcinoma. The pattern of SEDH influencing survival was unique to each race. Overall higher income levels, high school education, private insurance, and marital status appeared to be independent factors conferring favorable survival found on multivariate analysis.
Melatonin as an Adjuvant to Antiangiogenic Cancer Treatments
Authors: González Alicia , Alonso-González Carolina , González-González Alicia , Menéndez-Menéndez Javier , Cos Samuel , Martínez-Campa Carlos
Published: June 2021

Melatonin is a hormone with different functions, antitumor actions being one of the most studied. Among its antitumor mechanisms is its ability to inhibit angiogenesis. Melatonin shows antiangiogenic effects in several types of tumors. Combination of melatonin and chemotherapeutic agents have a synergistic effect inhibiting angiogenesis. One of the undesirable effects of chemotherapy is the induction of pro-angiogenic factors, whilst the addition of melatonin is able to overcome these undesirable effects. This protective effect of the pineal hormone against angiogenesis might be one of the mechanisms underlying its anticancer effect, explaining, at least in part, why melatonin administration increases the sensitivity of tumors to the inhibitory effects exerted by ordinary chemotherapeutic agents. Melatonin has the ability to turn cancer totally resistant to chemotherapeutic agents into a more sensitive chemotherapy state. Definitely, melatonin regulates the expression and/or activity of many factors involved in angiogenesis which levels are affected (either positively or negatively) by chemotherapeutic agents. In addition, the pineal hormone has been proposed as a radiosensitizer, increasing the oncostatic effects of radiation on tumor cells. This review serves as a synopsis of the interaction between melatonin and angiogenesis, and we will outline some antiangiogenic mechanisms through which melatonin sensitizes cancer cells to treatments, such as radiotherapy or chemotherapy.
Mutual Correlation between Non-Coding RNA and S-Adenosylmethionine in Human Cancer: Roles and Therapeutic Opportunities
Authors: Mosca Laura , Vitiello Francesca , Borzacchiello Luigi , Coppola Alessandra , Tranchese Roberta Veglia , Pagano Martina , Caraglia Michele , Cacciapuoti Giovanna , Porcelli Marina
Published: June 2021

Epigenetics includes modifications in DNA methylation, histone and chromatin structure, and expression of non-coding RNAs (ncRNAs), especially microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). Knowledge of the relationships between S-adenosylmethionine (AdoMet or SAM), the universal methyl donor for all epigenetic methylation reactions and miRNAs or lncRNAs in human cancer may provide helpful insights for the development of new end more effective anticancer therapeutic approaches. In recent literature, a complex network of mutual interconnections between AdoMet and miRNAs or lncRNAs has been reported and discussed. Indeed, ncRNAs expression may be regulated by epigenetic mechanisms such as DNA and RNA methylation and histone modifications. On the other hand, miRNAs or lncRNAs may influence the epigenetic apparatus by modulating the expression of its enzymatic components at the post-transcriptional level. Understanding epigenetic mechanisms, such as dysregulation of miRNAs/lncRNAs and DNA methylation, has become of central importance in modern research. This review summarizes the recent findings on the mechanisms by which AdoMet and miRNA/lncRNA exert their bioactivity, providing new insights to develop innovative and more efficient anticancer strategies based on the interactions between these epigenetic modulators.
Genetic and Proteinic Linkage of MAO and COMT with Oral Potentially Malignant Disorders and Cancers of the Oral Cavity and Pharynx
Authors: Chen Ping-Ho , Wang Yen-Yun , Lan Ting-Hsun , Chan Leong-Perng , Yuan Shyng-Shiou
Published: June 2021

Betel quid (BQ), a group I human carcinogen, strongly contributes to an increased risk of oral potentially malignant disorders (OPMD) and cancers of the oral cavity and pharynx. This study was conducted to discover whether monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) variants play a potential role in the risk assessment of oral cavity and pharynx cancers and OPMD, particularly among BQ users. We applied a case–control study to confirm the polymorphism of MAO and COMT using single-nucleotide polymorphisms. We used qRT-PCR, Western blotting, and immunohistochemistry (IHC) to determine MAO and COMT expression. Carriers of the MAOA rs6323 G-allele, MAOB rs6324 G-allele, and COMT rs4633 C/C-genotype had a prominently increased risk of oral cavity and pharynx cancers (AOR = 56.99; p < 0.001). Compared to adjacent noncancerous tissues, a significant downregulation of MAO and COMT expression was exhibited in cancerous tissues (p < 0.01). Furthermore, in different cell models, MAO and COMT expression was significantly downregulated with an increased dose of arecoline (p < 0.01). In personalized preventive medicine for oral and pharyngeal cancers, our findings are the first to demonstrate the potential role of lower MAO and COMT expression levels, with the risk polymorphisms utilized as clinical biomarkers.
Enhancing B-Cell Malignancies—On Repurposing Enhancer Activity towards Cancer
Authors: Kasprzyk Marta , Sura Weronika , Dzikiewicz-Krawczyk Agnieszka
Published: June 2021

B-cell lymphomas and leukemias derive from B cells at various stages of maturation and are the 6th most common cancer-related cause of death. While the role of several oncogenes and tumor suppressors in the pathogenesis of B-cell neoplasms was established, recent research indicated the involvement of non-coding, regulatory sequences. Enhancers are DNA elements controlling gene expression in a cell type- and developmental stage-specific manner. They ensure proper differentiation and maturation of B cells, resulting in production of high affinity antibodies. However, the activity of enhancers can be redirected, setting B cells on the path towards cancer. In this review we discuss different mechanisms through which enhancers are exploited in malignant B cells, from the well-studied translocations juxtaposing oncogenes to immunoglobulin loci, through enhancer dysregulation by sequence variants and mutations, to enhancer hijacking by viruses. We also highlight the potential of therapeutic targeting of enhancers as a direction for future investigation.
Gold and Ceria as Catalysts for VOC Abatement: A Review
Authors: Gaálová Jana , Topka Pavel
Published: June 2021

Due to its excellent oxygen storage capacity, ceria is a well-known oxidation catalyst. However, its performance in the oxidation of volatile organic compounds can be improved by the introduction of gold. Depending on the type of VOC to be oxidized, the surface of gold nanoparticles and the gold/ceria interface may contribute to enhanced activity and/or selectivity. Choosing a proper preparation method is crucial to obtain optimal gold particle size. Deposition–precipitation was found to be more suitable than coprecipitation or impregnation. For industrial applications, monolithic catalysts are needed to minimize the pressure drop in the reactor and reduce mass and heat transfer limitations. In addition to the approach used with powder catalysts, the method employed to introduce gold in/on the washcoat has to be considered.
Editorial Catalysts: Special Issue on Recent Advances in TiO2 Photocatalysts
Authors: Malankowska Anna , Borowska Ewa , Martins Rui C. , Gmurek Marta
Published: June 2021

The development of civilization and the massive use of traditional energy sources has led to progressive environmental degradation that requires immediate action [...]
Electrochemical Degradation of Methylene Blue Using a Ni-Co-Oxide Anode
Authors: Nwanebu Emmanuel Onyekachi , Liu Xiaocheng , Pajootan Elmira , Yargeau Viviane , Omanovic Sasha
Published: June 2021

The potential of using thermally prepared Ni0.6Co0.4-oxide for the electrochemical degradation of organic contaminants was investigated using methylene blue (MB) in an aqueous solution, as a model pollutant. The results of UV spectroscopy obtained during galvanostatic electrolyses at the anode indicated the complete removal of the methylene blue dye. The high removal of chemical oxygen demand (COD) and total organic carbon (TOC) suggested a high level of mineralization of its intermediates. It was found that the electrocatalytic performance of the electrode in the anodic degradation of the organic pollutant was significantly enhanced by the presence of chloride ions in the solution. The improvement in the degradation rate of MB was attributed to the in situ electrogeneration of chlorine active species. The results show that Ni0.6Co0.4-oxide anode can be employed as a stable energy-efficient electrocatalyst in the electrochemical purification of wastewater.
Indole-3-Carboxaldehyde Restores Gut Mucosal Integrity and Protects from Liver Fibrosis in Murine Sclerosing Cholangitis
Authors: D’Onofrio Fiorella , Renga Giorgia , Puccetti Matteo , Pariano Marilena , Bellet Marina Maria , Santarelli Ilaria , Stincardini Claudia , Mosci Paolo , Ricci Maurizio , Giovagnoli Stefano , Costantini Claudio , Romani Luigina
Published: June 2021

Primary sclerosing cholangitis (PSC) is a long-term liver disease characterized by a progressive course of cholestasis with liver inflammation and fibrosis. Intestinal barrier dysfunction has been implicated in the pathogenesis of PSC. According to the “leaky gut” hypothesis, gut inflammation alters the permeability of the intestinal mucosa, with the translocation of gut-derived products that enter the enterohepatic circulation and cause hepatic inflammation. Thus, the administration of molecules that preserve epithelial barrier integrity would represent a promising therapeutic strategy. Indole-3-carboxaldehyde (3-IAld) is a microbial-derived product working at the interface between the host and the microbiota and is able to promote mucosal immune homeostasis in a variety of preclinical settings. Herein, by resorting to a murine model of PSC, we found that 3-IAld formulated for localized delivery in the gut alleviates hepatic inflammation and fibrosis by modulating the intestinal microbiota and activating the aryl hydrocarbon receptor-IL-22 axis to restore mucosal integrity. This study points to the therapeutic potential of 3-IAld in liver pathology.
Identification of Cilia in Different Mouse Tissues
Authors: Li Xinhua , Yang Shuting , Deepak Vishwa , Chinipardaz Zahra , Yang Shuying
Published: June 2021

Cilia are microtubule-based hair-like organelles that extend from the cell surface. However, the existence and distribution of cilia in each organ and tissue at the postnatal stage in vivo remain largely unknown. In this study, we defined cilia distribution and arrangement and measured the ciliary lengths and the percentage of ciliated cells in different organs and tissues in vivo by using cilium dual reporter-expressing transgenic mice. Cilia were identified by the presence of ARL13B with an mCherry+ signal, and the cilium basal body was identified by the presence of Centrin2 with a GFP+ signal. Here, we provide in vivo evidence that chondrocytes and cells throughout bones have cilia. Most importantly, we reveal that: 1. primary cilia are present in hepatocytes; 2. no cilia but many centrioles are distributed on the apical cell surface in the gallbladder, intestine, and thyroid epithelia; 3. cilia on the cerebral cortex are well oriented, pointing to the center of the brain; 4. ARL13B+ inclusion is evident in the thyroid and islets of Langerhans; and 5. approximately 2% of cilia show irregular movement in nucleus pulposus extracellular fluid. This study reveals the existence and distribution of cilia and centrioles in different tissues and organs, and provides new insights for further comprehensive study of ciliary function in these organs and tissues.
Age-Dependent Decline in Neuron Growth Potential and Mitochondria Functions in Cortical Neurons
Authors: Sutherland Theresa C. , Sefiani Arthur , Horvat Darijana , Huntington Taylor E. , Lei Yuanjiu , West A. Phillip , Geoffroy Cédric G.
Published: June 2021

The age of incidence of spinal cord injury (SCI) and the average age of people living with SCI is continuously increasing. However, SCI is extensively modeled in young adult animals, hampering translation of research to clinical applications. While there has been significant progress in manipulating axon growth after injury, the impact of aging is still unknown. Mitochondria are essential to successful neurite and axon growth, while aging is associated with a decline in mitochondrial functions. Using isolation and culture of adult cortical neurons, we analyzed mitochondrial changes in 2-, 6-, 12- and 18-month-old mice. We observed reduced neurite growth in older neurons. Older neurons also showed dysfunctional respiration, reduced membrane potential, and altered mitochondrial membrane transport proteins; however, mitochondrial DNA (mtDNA) abundance and cellular ATP were increased. Taken together, these data suggest that dysfunctional mitochondria in older neurons may be associated with the age-dependent reduction in neurite growth. Both normal aging and traumatic injury are associated with mitochondrial dysfunction, posing a challenge for an aging SCI population as the two elements can combine to worsen injury outcomes. The results of this study highlight this as an area of great interest in CNS trauma.
Interdependent Impact of Lipoprotein Receptors and Lipid-Lowering Drugs on HCV Infectivity
Authors: Zapatero-Belinchón Francisco J. , Ötjengerdes Rina , Sheldon Julie , Schulte Benjamin , Carriquí-Madroñal Belén , Brogden Graham , Arroyo-Fernández Laura M. , Vondran Florian W. R. , Maasoumy Benjamin , von Hahn Thomas , Gerold Gisa
Published: June 2021

The HCV replication cycle is tightly associated with host lipid metabolism: Lipoprotein receptors SR-B1 and LDLr promote entry of HCV, replication is associated with the formation of lipid-rich membranous organelles and infectious particle assembly highjacks the very-low-density lipoprotein (VLDL) secretory pathway. Hence, medications that interfere with the lipid metabolism of the cell, such as statins, may affect HCV infection. Here, we study the interplay between lipoprotein receptors, lipid homeostasis, and HCV infection by genetic and pharmacological interventions. We found that individual ablation of the lipoprotein receptors SR-B1 and LDLr did not drastically affect HCV entry, replication, or infection, but double lipoprotein receptor knock-outs significantly reduced HCV infection. Furthermore, we could show that this effect was neither due to altered expression of additional HCV entry factors nor caused by changes in cellular cholesterol content. Strikingly, whereas lipid-lowering drugs such as simvastatin or fenofibrate did not affect HCV entry or infection of immortalized hepatoma cells expressing SR-B1 and/or LDLr or primary human hepatocytes, ablation of these receptors rendered cells more susceptible to these drugs. Finally, we observed no significant differences between statin users and control groups with regards to HCV viral load in a cohort of HCV infected patients before and during HCV antiviral treatment. Interestingly, statin treatment, which blocks the mevalonate pathway leading to decreased cholesterol levels, was associated with mild but appreciable lower levels of liver damage markers before HCV therapy. Overall, our findings confirm the role of lipid homeostasis in HCV infection and highlight the importance of the mevalonate pathway in the HCV replication cycle.
Improving the Utility of Polygenic Risk Scores as a Biomarker for Alzheimer’s Disease
Authors: Vlachakis Dimitrios , Papakonstantinou Eleni , Sagar Ram , Bacopoulou Flora , Exarchos Themis , Kourouthanassis Panos , Karyotis Vasileios , Vlamos Panayiotis , Lyketsos Constantine , Avramopoulos Dimitrios , Mahairaki Vasiliki
Published: June 2021

The treatment of complex and multifactorial diseases constitutes a big challenge in day-to-day clinical practice. As many parameters influence clinical phenotypes, accurate diagnosis and prompt therapeutic management is often difficult. Significant research and investment focuses on state-of-the-art genomic and metagenomic analyses in the burgeoning field of Precision (or Personalized) Medicine with genome-wide-association-studies (GWAS) helping in this direction by linking patient genotypes at specific polymorphic sites (single-nucleotide polymorphisms, SNPs) to the specific phenotype. The generation of polygenic risk scores (PRSs) is a relatively novel statistical method that associates the collective genotypes at many of a person’s SNPs to a trait or disease. As GWAS sample sizes increase, PRSs may become a powerful tool for prevention, early diagnosis and treatment. However, the complexity and multidimensionality of genetic and environmental contributions to phenotypes continue to pose significant challenges for the clinical, broad-scale use of PRSs. To improve the value of PRS measures, we propose a novel pipeline which might better utilize GWAS results and improve the utility of PRS when applied to Alzheimer’s Disease (AD), as a paradigm of multifactorial disease with existing large GWAS datasets that have not yet achieved significant clinical impact. We propose a refined approach for the construction of AD PRS improved by (1), taking into consideration the genetic loci where the SNPs are located, (2) evaluating the post-translational impact of SNPs on coding and non-coding regions by focusing on overlap with open chromatin data and SNPs that are expression quantitative trait loci (QTLs), and (3) scoring and annotating the severity of the associated clinical phenotype into the PRS. Open chromatin and eQTL data need to be carefully selected based on tissue/cell type of origin (e.g., brain, excitatory neurons). Applying such filters to traditional PRS on GWAS studies of complex diseases like AD, can produce a set of SNPs weighted according to our algorithm and a more useful PRS. Our proposed methodology may pave the way for new applications of genomic machine and deep learning pipelines to GWAS datasets in an effort to identify novel clinically useful genetic biomarkers for complex diseases like AD.
Lysophosphatidic Acid Receptor Antagonists and Cancer: The Current Trends, Clinical Implications, and Trials
Authors: Lin Yu-Hsuan , Lin Yueh-Chien , Chen Chien-Chin
Published: June 2021

Lysophosphatidic acid (LPA) is a bioactive lipid mediator primarily derived from membrane phospholipids. LPA initiates cellular effects upon binding to a family of G protein-coupled receptors, termed LPA receptors (LPAR1 to LPAR6). LPA signaling drives cell migration and proliferation, cytokine production, thrombosis, fibrosis, angiogenesis, and lymphangiogenesis. Since the expression and function of LPA receptors are critical for cellular effects, selective antagonists may represent a potential treatment for a broad range of illnesses, such as cardiovascular diseases, idiopathic pulmonary fibrosis, voiding dysfunctions, and various types of cancers. More new LPA receptor antagonists have shown their therapeutic potentials, although most are still in the preclinical trial stage. This review provided integrative information and summarized preclinical findings and recent clinical trials of different LPA receptor antagonists in cancer progression and resistance. Targeting LPA receptors can have potential applications in clinical patients with various diseases, including cancer.
What Do the Animal Studies of Stress Resilience Teach Us?
Authors: Dziedzicka-Wasylewska Marta , Solich Joanna , Korlatowicz Agata , Faron-Górecka Agata
Published: June 2021

Long-lasting stress factors, both biological and psychological, are commonly accepted as the main cause of depressive disorders. Several animal models, using various stressful stimuli, have been used to find biochemical and molecular alterations that could help us understand the etiopathogenesis of depression. However, recent sophisticated studies indicate that the most frequently used animal models of stress only capture a portion of the molecular features associated with complex human disorders. On the other hand, some of these models generate groups of animals resilient to stress. Studies of the mechanisms of stress resilience bring us closer to understanding the process of adapting to aversive stimuli and the differences between stress-susceptible vs. resilient phenotypes. Especially interesting in this context is the chronic mild stress (CMS) experimental paradigm, most often using rats. Studies using this animal model have revealed that biochemical (e.g., the dopamine D2 receptor) and molecular (e.g., microRNA) alterations are dynamic (i.e., depend on stress duration, 2 vs. 7 weeks) and much more pronounced in stress-resilient than stress-susceptible groups of animals. We strongly suggest that studies aimed at understanding the molecular and biochemical mechanisms of depression must consider these dynamics. A good candidate to serve as a biomarker in such studies might be serum microRNA, since it can be obtained relatively easily from living individuals at various time points.
Synergistic Effects of Melatonin and Gamma-Aminobutyric Acid on Protection of Photosynthesis System in Response to Multiple Abiotic Stressors
Authors: Shomali Aida , Aliniaeifard Sasan , Didaran Fardad , Lotfi Mahmoud , Mohammadian Mohammad , Seif Mehdi , Strobel Wacław Roman , Sierka Edyta , Kalaji Hazem M.
Published: June 2021

GABA (gamma-aminobutyric acid) and melatonin are endogenous compounds that enhance plant responses to abiotic stresses. The response of Vicia faba to different stressors (salinity (NaCl), poly ethylene glycol (PEG), and sulfur dioxide (SO2)) was studied after priming with sole application of GABA and melatonin or their co-application (GABA + melatonin). Both melatonin and GABA and their co-application increased leaf area, number of flowers, shoot dry and fresh weight, and total biomass. Plants treated with GABA, melatonin, and GABA + melatonin developed larger stomata with wider aperture compared to the stomata of control plants. The functionality of the photosynthetic system was improved in primed plants. To investigate the photosynthetic functionality in details, the leaf samples of primed plants were exposed to different stressors, including SO2, PEG, and NaCl. The maximum quantum yield of photosystem II (PS II) was higher in the leaf samples of primed plants, while the non-photochemical quenching (NPQ) of primed plants was decreased when leaf samples were exposed to the stressors. Correlation analysis showed the association of initial PIabs with post-stress FV/FM and NPQ. Stressors attenuated the association of initial PIabs with both FV/FM and NPQ, while priming plants with GABA, melatonin, or GABA + melatonin minimized the effect of stressors by attenuating these correlations. In conclusion, priming plants with both GABA and melatonin improved growth and photosynthetic performance of Vicia faba and mitigated the effects of abiotic stressors on the photosynthetic performance.
NR4A1 Regulates Tamoxifen Resistance by Suppressing ERK Signaling in ER-Positive Breast Cancer
Authors: Kim Yu Cheon , Kim Clara Yuri , Oh Ji Hoon , Kim Myoung Hee
Published: June 2021

Endocrine therapy is used to treat estrogen receptor (ER)-positive breast cancer. Tamoxifen is effective against this cancer subtype. Nonetheless, approximately 30% of patients treated with tamoxifen acquire resistance, resulting in therapeutic challenges. NR4A1 plays key roles in processes associated with carcinogenesis, apoptosis, DNA repair, proliferation, and inflammation. However, the role of NR4A1 in tamoxifen-resistant ER-positive breast cancer has not yet been elucidated. Here, we propose that NR4A1 is a promising target to overcome tamoxifen resistance. NR4A1 gene expression was downregulated in tamoxifen-resistant MCF7 (TamR) cells compared to that in MCF7 cells. Kaplan-Meier plots were used to identify high NR4A1 expression correlated with increased survival rates in patients with ER-positive breast cancer following tamoxifen treatment. Gain and loss of function experiments showed that NR4A1 restores sensitivity to tamoxifen by regulating cell proliferation, migration, invasion, and apoptosis. NR4A1 localized to the cytoplasm enhanced the expression of apoptotic factors. In silico and in vitro analyses revealed that NR4A1 enhanced responsiveness to tamoxifen by suppressing ERK signaling in ER-positive breast cancer, suggesting that the NR4A1/ERK signaling axis modulates tamoxifen resistance. These results indicate that NR4A1 could be a potential therapeutic target to overcome tamoxifen resistance in ER-positive breast cancer.
Label-Free and Quantitative Dry Mass Monitoring for Single Cells during In Situ Culture
Authors: Su Ya , Fu Rongxin , Du Wenli , Yang Han , Ma Li , Luo Xianbo , Wang Ruliang , Lin Xue , Jin Xiangyu , Shan Xiaohui , Lv Wenqi , Huang Guoliang
Published: June 2021

Quantitative measurement of single cells can provide in-depth information about cell morphology and metabolism. However, current live-cell imaging techniques have a lack of quantitative detection ability. Herein, we proposed a label-free and quantitative multichannel wide-field interferometric imaging (MWII) technique with femtogram dry mass sensitivity to monitor single-cell metabolism long-term in situ culture. We demonstrated that MWII could reveal the intrinsic status of cells despite fluctuating culture conditions with 3.48 nm optical path difference sensitivity, 0.97 fg dry mass sensitivity and 2.4% average maximum relative change (maximum change/average) in dry mass. Utilizing the MWII system, different intrinsic cell growth characteristics of dry mass between HeLa cells and Human Cervical Epithelial Cells (HCerEpiC) were studied. The dry mass of HeLa cells consistently increased before the M phase, whereas that of HCerEpiC increased and then decreased. The maximum growth rate of HeLa cells was 11.7% higher than that of HCerEpiC. Furthermore, HeLa cells were treated with Gemcitabine to reveal the relationship between single-cell heterogeneity and chemotherapeutic efficacy. The results show that cells with higher nuclear dry mass and nuclear density standard deviations were more likely to survive the chemotherapy. In conclusion, MWII was presented as a technique for single-cell dry mass quantitative measurement, which had significant potential applications for cell growth dynamics research, cell subtype analysis, cell health characterization, medication guidance and adjuvant drug development.