bluuebunny/crossref_metadata_2025 huggingface dataset:
Pan-Cancer Analysis Reveals Common and Specific Relationships between Intragenic miRNAs and Their Host Genes
Authors: Liu Baohong , Shyr Yu , Liu Qi
Published: September 2021

MicroRNAs (miRNAs) are small endogenous non-coding RNAs that play important roles in regulating gene expression. Most miRNAs are located within or close to genes (host). miRNAs and their host genes have either coordinated or independent transcription. We performed a comprehensive investigation on co-transcriptional patterns of miRNAs and host genes based on 4707 patients across 21 cancer types. We found that only 11.6% of miRNA-host pairs were co-transcribed consistently and strongly across cancer types. Most miRNA-host pairs showed a strong coexpression only in some specific cancer types, demonstrating a high heterogenous pattern. For two particular types of intergenic miRNAs, readthrough and divergent miRNAs, readthrough miRNAs showed higher coexpression with their host genes than divergent ones. miRNAs located within non-coding genes had tighter co-transcription with their hosts than those located within protein-coding genes, especially exonic and junction miRNAs. A few precursor miRNAs changed their dominate form between 5′ and 3′ strands in different cancer types, including miR-486, miR-99b, let-7e, miR-125a, let-7g, miR-339, miR-26a, miR-16, and miR-218, whereas only two miRNAs with multiple host genes switched their co-transcriptional partner in different cancer types (miR-219a-1 with SLC39A7/HSD17B8 and miR-3615 with RAB37/SLC9A3R1). miRNAs generated from distinct precursors (such as miR-125b from miR-125b-1 or miR-125b-2) were more likely to have cancer-dependent main contributors. miRNAs and hosts were less co-expressed in KIRC than other cancer types, possibly due to its frequent VHL mutations. Our findings shed new light on miRNA biogenesis and cancer diagnosis and treatments.
Splice and Dice: Intronic microRNAs, Splicing and Cancer
Authors: Wong Alex C. H. , Rasko John E. J.
Published: September 2021

Introns span only a quarter of the human genome, yet they host around 60% of all known microRNAs. Emerging evidence indicates the adaptive advantage of microRNAs residing within introns is attributed to their complex co-regulation with transcription and alternative splicing of their host genes. Intronic microRNAs are often co-expressed with their host genes, thereby providing functional synergism or antagonism that is exploited or decoupled in cancer. Additionally, intronic microRNA biogenesis and the alternative splicing of host transcript are co-regulated and intertwined. The importance of intronic microRNAs is under-recognized in relation to the pathogenesis of cancer.
Involvement of Angiogenesis in the Pathogenesis of Coronary Aneurysms
Authors: Iwańczyk Sylwia , Lehmann Tomasz , Cieślewicz Artur , Radziemski Artur , Malesza Katarzyna , Wrotyński Michał , Jagodziński Paweł Piotr , Grygier Marek , Lesiak Maciej , Araszkiewicz Aleksander
Published: September 2021

The present study aimed to evaluate the plasma concentration of pro and antiangiogenic factors and their role in the pathogenesis of coronary artery abnormal dilation (CAAD). We measured the plasma concentration of matrix metalloproteinase-8 (MMP-8), transforming growth factor beta 1 (TGF-β1), Angiopoietin-2, vascular endothelial growth factor (VEGF), and fibroblast growth factor (FGF) using a sandwich ELISA technique in the plasma of patients with coronary artery abnormal dilation (CAAD, Group 1), coronary artery disease (CAD, Group 2), and normal coronary arteries (NCA, Group 3). Patients suffering from CAAD showed significantly higher plasma concentrations of VEGF (p = 0.002) than those from the control group. Both pathological angiogenesis and inflammation appear to be crucial in the pathogenesis of aneurysmal dilatation of the coronary arteries.
Engineering a 3D Vascularized Adipose Tissue Construct Using a Decellularized Lung Matrix
Authors: DeBari Megan , Ng Wai , Griffin Mallory , Kokai Lauren , Marra Kacey , Rubin J. , Ren Xi , Abbott Rosalyn
Published: September 2021

Critically sized defects in subcutaneous white adipose tissue result in extensive disfigurement and dysfunction and remain a reconstructive challenge for surgeons; as larger defect sizes are correlated with higher rates of complications and failure due to insufficient vascularization following implantation. Our study demonstrates, for the first time, a method to engineer perfusable, pre-vascularized, high-density adipose grafts that combine patient-derived adipose cells with a decellularized lung matrix (DLM). The lung is one of the most vascularized organs with high flow, low resistance, and a large blood–alveolar interface separated by a thin basement membrane. For our work, the large volume capacity within the alveolar compartment was repurposed for high-density adipose cell filling, while the acellular vascular bed provided efficient graft perfusion throughout. Both adipocytes and hASCs were successfully delivered and remained in the alveolar space even after weeks of culture. While adipose-derived cells maintained their morphology and functionality in both static and perfusion DLM cultures, perfusion culture offered enhanced outcomes over static culture. Furthermore, we demonstrate that endothelial cells seamlessly integrate into the acellular vascular tree of the DLM with adipocytes. These results support that the DLM is a unique platform for creating vascularized adipose tissue grafts for large defect filling.
Secondary Impacts of COVID-19 Pandemic in Fatigue, Self-Compassion, Physical and Mental Health of People with Multiple Sclerosis and Caregivers: The Teruel Study
Authors: Giménez-Llort Lydia , Martín-González Juan José , Maurel Sara
Published: September 2021

The secondary impacts of the COVID-19 pandemic are distress triggers and risk factors for mental health. Conversely, self-compassion skills and compassionate thoughts/behaviors towards suffering may contribute to their alleviation. Both psychological constructs are interrelated in life-threatening diseases such as multiple sclerosis (MS). The Teruel Study retrospectively evaluated the impact of strict confinement on the 44 people with MS of this Spanish province and 24 caregivers, specifically assessing (1) fears and perceptions; (2) self-compassion (people with MS) and compassion (caregivers); (3) physical and mental health, and fatigue. Despite better housing conditions, people with MS considered confinement very difficult to handle, more than their caregivers, but they were less afraid of COVID-19 and worsening of MS. Still, they recognized worse health than before confinement. Reclusion and lack of walks were the worst of confinement. Caregivers also referred to lack of leisure and uncertainty–fear. All agreed the best was staying with the family, but some found ‘nothing’ positive. Self-compassion remained moderate–high and strongly correlated with their moderate levels of social function, vitality, physical role, and global health. Physical and cognitive fatigue scores were high, and self-compassion negatively correlated with them, explaining a 19% variance in global health. The high compassion of the caregivers did not correlate with any variable.
Processing Aspectual Agreement in an Inflexionless Language: An ERP Study of Mandarin Chinese
Authors: Hao Yuxin , Duan Xun , Zhang Lu
Published: September 2021

This is a study of the collocation of Chinese verbs with different lexical aspects and aspect markers. Using event-related potentials (ERPs), we explored the processing of aspect violation sentences. In the experiment, we combined verbs of various lexical aspect types with the progressive aspect marker zhe, and the combination of the achievement verbs and the progressive aspect marker zhe constituted the sentence’s aspect violation. The participants needed to judge whether a sentence was correct after it was presented. Finally, we observed and analyzed the components of ERPs. The results suggest that when the collocation of aspect markers and lexical aspect is ungrammatical, the N400-like and P600 are elicited on aspect markers, while the late AN is elicited by the word after the aspect marker. P600 and N400-like show that the collocation of Chinese verbs with various lexical aspects and aspect markers involve not only syntactic processing, but also the semantic processing; and the late AN may have been due to the syntax revision and the conclusion at the end of sentences.
Epigenetic Mediation of AKT1 rs1130233’s Effect on Delta-9-Tetrahydrocannabinol-Induced Medial Temporal Function during Fear Processing
Authors: Blest-Hopley Grace , Colizzi Marco , Prata Diana , Giampietro Vincent , Brammer Michael , McGuire Philip , Bhattacharyya Sagnik
Published: September 2021

High doses of delta-9-tetrahydrocannabinol (THC), the main psychoactive component of cannabis, have been shown to have anxiogenic effects. Additionally, THC effects have been shown to be modulated by genotype, including the single nucleotide polymorphism (SNP) rs1130233 at the protein kinase AKT1 gene, a key component of the dopamine signalling cascade. As such, it is likely that epigenetic methylation around this SNP may affect AKT gene expression, which may in turn impact on the acute effects of THC on brain function. We investigated the genetic (AKT1 rs1130233) and epigenetic modulation of brain function during fear processing in a 2-session, double-blind, cross-over, randomized placebo-controlled THC administration, in 36 healthy males. Fear processing was assessed using an emotion (fear processing) paradigm, under functional magnetic resonance imaging (fMRI). Complete genetic and fMRI data were available for 34 participants. THC caused an increase in anxiety and transient psychotomimetic symptoms and para-hippocampal gyrus/amygdala activation. Number of A alleles at the AKT1 rs1130233 SNP, and percentage methylation at the CpG11–12 site, were independently associated with a greater effect of THC on activation in a network of brain regions including left and right parahippocampal gyri, respectively. AKT1 rs1130233 moderation of the THC effect on left parahippocampal activation persisted after covarying for methylation percentage, and was partially mediated in sections of the left parahippocampal gyrus/hippocampus by methylation percentage. These results may offer an example of how genetic and epigenetic variations influence the psychotomimetic and neurofunctional effects of THC.
Measuring the Impact of Museum Architecture, Spaces and Exhibits on Virtual Visitors Using Facial Expression Analysis Software
Authors: Nubani Linda , Öztürk Aslıhan
Published: September 2021

Since the launch of online video portals in 2005, museums have encouraged visitors to upload and share their visits online. Although much has been written about visitors’ experiences in museums, very little exists on the impact virtual visits have on viewers. In this qualitative pilot study, a total of 2035 emotional reactions were recorded and analyzed after visiting 14 online museums using a facial expression recognition software. Following open and axial coding techniques, themes and subcategories emerged. Findings showed that while the background of the participant mediated how one experiences a museum online, certain architectural and exhibit attributes, if present, triggered similar emotions to those experienced in an in-person visit. Findings suggest that experiencing museums through online video portals may be as engaging as visiting museums in person—only if the creator captures a significant proportion of architectural details, transitioning of spaces and exhibits details. Further findings showed that facial expression software reveals what captures virtual visitors’ emotions, and what architectural and exhibit features keep them curious and engaged.
Plug and Play Modular Façade Construction System for Renovation for Residential Buildings
Authors: Torres Jorge , Garay-Martinez Roberto , Oregi Xabat , Torrens-Galdiz J. Ignacio , Uriarte-Arrien Amaia , Pracucci Alessandro , Casadei Oscar , Magnani Sara , Arroyo Noemi , Cea Angel M.
Published: September 2021

The present paper focuses on the architectural and constructional features required to ensure that building envelope renovation are safe, functional, and adaptable to the building stock, with particular focus on “plug and play” modular facade construction systems. It presents the design of one such system and how it addresses these issues. The outcome of early-stage functional test with a full-scale mock-up system, as well as its applicability to a real construction project is presented. It is found crucial to obtain high quality information about the status of the existing façade with the use of modern technologies such as topographic surveys or 3D scans and point cloud. Detailed design processes are required to ensure the compatibility of manufacture and installation tolerances, along with anchor systems that deliver flexibility for adjustment, and construction processes adapting standard installation methods to the architectural particularities of each case that may hinder its use or require some modification in each situation. This prefabricated plug and play modular system has been tested by reproducing the holistic methodology and new technologies in the market by means of real demonstrators. When compared to more conventional construction methods, this system achieves savings in a real case of 50% (time), 30% (materials) and 25% (waste), thus achieving significant economic savings.
High Cell-Free DNA Integrity Is Associated with Poor Breast Cancer Survival
Authors: Lamminaho Maria , Kujala Jouni , Peltonen Hanna , Tengström Maria , Kosma Veli-Matti , Mannermaa Arto
Published: September 2021

Background: A recent point of focus in breast cancer (BC) research has been the utilization of cell-free DNA (cfDNA) and its concentration (cfDConc) and integrity (cfDI) as potential biomarkers. Though the association of cfDConc and poor survival is already recognized, studies on the prognostic value of cfDI have had contradictory results. Here, we provide further evidence to support the use of cfDI as a potential biomarker. Methods: We selected 204 Eastern Finnish BC cases with non-metastatic disease and isolated cfDNA from the serum collected at the time of diagnosis before any treatment was given. The cfDConc and cfDI were measured with a fluorometer and electrophoresis and analyzed with 25 years of survival data. Results: High cfDConc was not an independent prognostic factor in our analyses while high cfDI was found to be an independent prognostic factor for poor OS (p = 0.020, hazard ratio (HR) = 1.57, 95% confidence interval (CI) 1.07–2.29, Cox) and BCSS (p = 0.006, HR = 1.93, 95% CI 1.21–3.08)). Inclusion of cfDI in the multivariate logistic regression model improved the predictive performance. Conclusions: Our results show high cfDI is an independent prognostic factor for poor OS and BCSS and improves the predictive performance of logistic regression models, thus supporting its prognostic potential.
Targeting the p53 Pathway in CLL: State of the Art and Future Perspectives
Authors: Kwok Marwan , Agathanggelou Angelo , Davies Nicholas , Stankovic Tatjana
Published: September 2021

The p53 pathway is a desirable therapeutic target, owing to its critical role in the maintenance of genome integrity. This is exemplified in chronic lymphocytic leukemia (CLL), one of the most common adult hematologic malignancies, in which functional loss of p53 arising from genomic aberrations are frequently associated with clonal evolution, disease progression, and therapeutic resistance, even in the contemporary era of CLL targeted therapy and immunotherapy. Targeting the ‘undruggable’ p53 pathway therefore arguably represents the holy grail of cancer research. In recent years, several strategies have been proposed to exploit p53 pathway defects for cancer treatment. Such strategies include upregulating wild-type p53, restoring tumor suppressive function in mutant p53, inducing synthetic lethality by targeting collateral genome maintenance pathways, and harnessing the immunogenicity of p53 pathway aberrations. In this review, we will examine the biological and clinical implications of p53 pathway defects, as well as our progress towards development of therapeutic approaches targeting the p53 pathway, specifically within the context of CLL. We will appraise the opportunities and pitfalls associated with these therapeutic strategies, and evaluate their place amongst the array of new biological therapies for CLL.
The PD-1/PD-L1 Checkpoint in Normal Germinal Centers and Diffuse Large B-Cell Lymphomas
Authors: Garcia-Lacarte Marcos , Grijalba Sara C. , Melchor Javier , Arnaiz-Leché Adrián , Roa Sergio
Published: September 2021

Besides a recognized role of PD-1/PD-L1 checkpoint in anti-tumour immune evasion, there is accumulating evidence that PD-1/PD-L1 interactions between B and T cells also play an important role in normal germinal center (GC) reactions. Even when smaller in number, T follicular helper cells (TFH) and regulatory T (TFR) or B (Breg) cells are involved in positive selection of GC B cells and may result critical in the lymphoma microenvironment. Here, we discuss a role of PD-1/PD-L1 during tumour evolution in diffuse large B cell lymphoma (DLBCL), a paradigm of GC-derived lymphomagenesis. We depict a progression model, in two phases, where malignant B cells take advantage of positive selection signals derived from correct antigen-presentation and PD-1/PD-L1 inter-cellular crosstalks to survive and initiate tumour expansion. Later, a constant pressure for the accumulation of genetic/epigenetic alterations facilitates that DLBCL cells exhibit higher PD-L1 levels and capacity to secrete IL-10, resembling Breg-like features. As a result, a complex immunosuppressive microenvironment is established where DLBCL cells sustain proliferation and survival by impairing regulatory control of TFR cells and limiting IL-21-mediated anti-tumour functions of TFH cells and maximize the use of PD-1/PD-L1 signaling to escape from CD8+ cytotoxic activity. Integration of these molecular and cellular addictions into a framework may contribute to the better understanding of the lymphoma microenvironment and contribute to the rationale for novel PD-1/PD-L1-based combinational immunotherapies in DLBCL.
The Psychoneuroimmunology of Stress Regulation in Pediatric Cancer Patients
Authors: White Gillian E. , Caterini Jessica E. , McCann Victoria , Rendall Kate , Nathan Paul C. , Rhind Shawn G. , Jones Heather , Wells Greg D.
Published: September 2021

Stress is a ubiquitous experience that can be adaptive or maladaptive. Physiological stress regulation, or allostasis, can be disrupted at any point along the regulatory pathway resulting in adverse effects for the individual. Children with cancer exhibit significant changes to these pathways in line with stress dysregulation and long-term effects similar to those observed in other early-life stress populations, which are thought to be, in part, a result of cytotoxic cancer treatments. Children with cancer may have disruption to several steps in the stress-regulatory pathway including cognitive-affective function, neurological disruption to stress regulatory brain regions, altered adrenal and endocrine function, and disrupted tissue integrity, as well as lower engagement in positive coping behaviours such as physical activity and pro-social habits. To date, there has been minimal study of stress reactivity patterns in childhood illness populations. Nor has the role of stress regulation in long-term health and function been elucidated. We conclude that consideration of stress regulation in childhood cancer may be crucial in understanding and treating the disease.
Crosstalk between PRLR and EGFR/HER2 Signaling Pathways in Breast Cancer
Authors: Kavarthapu Raghuveer , Anbazhagan Rajakumar , Dufau Maria L.
Published: September 2021

Prolactin receptor (PRLR) and epidermal growth factor receptor (EGFR/ERBB) signaling pathways activated by prolactin (PRL) and epidermal growth factor (EGF), have a major role in the mammary gland development and in the etiology of breast cancer, respectively. ER+ breast tumors comprise up to 75% of all breast cancers and 10% of these are HER2+. Elevated levels of PRLR in breast tumors, high circulating levels of PRL and increased expression of ERBB1/2 in patients that become resistant to endocrine therapy have shown to be associated with higher risk of cancer progression. In this review, we examine the role of crosstalk between PRLR and ERBB1/2 signaling pathways in the activation of unliganded ERα, cyclin-D1 and other oncogenic factors (MYC, FOS, JUN) in breast cancer. PRL/PRLR and EGF/EGFR induces phosphorylation of ERα through activation of MEK/MAPK and PI3K/AKT signaling pathways. PRL in breast cancer cells via PRLR/JAK2 can also induce phosphorylation of ERBB2/HER2, which in turn activates the downstream RAS/MEK/ERK pathway required for ERα phosphorylation. EGFR, independent of PRL/PRLR, can activate STAT5 indirectly via c-SRC and drive the expression of target genes involved in cell proliferation and survival. The crosstalk between PRLR and HER2, where PRL induces HER2 signaling can be an alternative route for ERα activation to induce transcription of PRLR and other ER target genes. We believe that overexpression of EGFR/HER2 and PRLR in breast tumors could maximize the actions of their ligands, and further induce cell proliferation promoting malignancy. This could also explain the resistance to endocrine therapy resulting in tumor growth.
HMGB1 Protein Interactions in Prostate and Ovary Cancer Models Reveal Links to RNA Processing and Ribosome Biogenesis through NuRD, THOC and Septin Complexes
Authors: Barreiro-Alonso Aida , Lamas-Maceiras Mónica , Lorenzo-Catoira Lidia , Pardo Mercedes , Yu Lu , Choudhary Jyoti S. , Cerdán M. Esperanza
Published: September 2021

This study reports the HMGB1 interactomes in prostate and ovary cancer cells lines. Affinity purification coupled to mass spectrometry confirmed that the HMGB1 nuclear interactome is involved in HMGB1 known functions such as maintenance of chromatin stability and regulation of transcription, and also in not as yet reported processes such as mRNA and rRNA processing. We have identified an interaction between HMGB1 and the NuRD complex and validated this by yeast-two-hybrid, confirming that the RBBP7 subunit directly interacts with HMGB1. In addition, we describe for the first time an interaction between two HMGB1 interacting complexes, the septin and THOC complexes, as well as an interaction of these two complexes with Rab11. Analysis of Pan-Cancer Atlas public data indicated that several genes encoding HMGB1-interacting proteins identified in this study are dysregulated in tumours from patients diagnosed with ovary and prostate carcinomas. In PC-3 cells, silencing of HMGB1 leads to downregulation of the expression of key regulators of ribosome biogenesis and RNA processing, namely BOP1, RSS1, UBF1, KRR1 and LYAR. Upregulation of these genes in prostate adenocarcinomas is correlated with worse prognosis, reinforcing their functional significance in cancer progression.
Bacteria-Derived Extracellular Vesicles in Urine as a Novel Biomarker for Gastric Cancer: Integration of Liquid Biopsy and Metagenome Analysis
Authors: Park Jae-Yong , Kang Chil-Sung , Seo Ho-Chan , Shin Jin-Chul , Kym Sung-Min , Park Young-Soo , Shin Tae-Seop , Kim Jae-Gyu , Kim Yoon-Keun
Published: September 2021

Early detection is crucial for improving the prognosis of gastric cancer, but there are no non-invasive markers for the early diagnosis of gastric cancer in real clinical settings. Recently, bacteria-derived extracellular vesicles (EVs) emerged as new biomarker resources. We aimed to evaluate the microbial composition in gastric cancer using bacteria-derived EVs and to build a diagnostic prediction model for gastric cancer with the metagenome data. Stool, urine, and serum samples were prospectively collected from 453 subjects (gastric cancer, 181; control, 272). EV portions were extracted from the samples for metagenome analysis. Differences in microbial diversity and composition were analyzed with 16S rRNA gene profiling, using the next-generation sequencing method. Biomarkers were selected using logistic regression models based on relative abundances at the genus level. The microbial composition of healthy groups and gastric cancer patient groups was significantly different in all sample types. The compositional differences of various bacteria, based on relative abundances, were identified at the genus level. Among the diagnostic prediction models for gastric cancer, the urine-based model showed the highest performance when compared to that of stool or serum. We suggest that bacteria-derived EVs in urine can be used as novel metagenomic markers for the non-invasive diagnosis of gastric cancer by integrating the liquid biopsy method and metagenome analysis.
CYP3A Activity in End-of-Life Cancer Patients Measured by 4β-Hydroxycholesterol/cholesterol Ratio, in Men and Women
Authors: Bergström Helena , Helde Frankling Maria , Klasson Caritha , Lövgren Sandblom Anita , Diczfalusy Ulf , Björkhem-Bergman Linda
Published: September 2021

More than 50% of all drugs are metabolized by the cytochrome P450 3A enzyme (CYP3A). The aim of this study was to investigate if the CYP3A activity, measured by the endogenous marker 4β-hydroxycholesterol/cholesterol ratio (4β-OHC/C), is changed during the last weeks and days of life in men and women. To this end, serum samples from 137 deceased patients (median age 70 years) collected at a single time point 1–60 days before death, were analyzed and compared to 280 young (median 27 years), and 30 elderly (median age 70 years) non-cancer controls. There were no significant differences in the 4β-OHC/C ratio between men and women in end-of-life patients (p < 0.25). The median 4β-OHC/C was significantly higher in end-of-life male patients compared to both young (p < 0.0001) and elderly (p < 0.05) male controls. In a similar manner, 4β-OHC/C in end-of-life female patients was significantly higher compared to young and elderly female controls, p < 0.0001 and p < 0.001, respectively. There was no significant correlation between 4β-OHC/C and survival time. The results from this study suggest maintained CYP3A activity to the very last days of life and even a capacity of induction of the enzyme in end-of-life cancer patients.
Acetylated DNMT1 Downregulation and Related Regulatory Factors Influence Metastatic Melanoma Patients Survival
Authors: Zhang Xiaoqing , Bustos Matias A. , Shoji Yoshiaki , Ramos Romela Irene , Iida Yuuki , Gentry Rebecca , Takeshima Teh-Ling , Hoon Dave S. B.
Published: September 2021

The role of post-translational modifications (PTM) of the key epigenetic factor DNMT1 protein has not been well explored in cutaneous metastatic melanoma progression. The acetylated DNMT1 (ac-DNMT1) protein level was assessed using an anti-acetylated lysine antibody in a clinically annotated melanoma patient tumor specimen cohort. In this study, we showed that surgically resected tumors have significantly higher DNMT1 protein expression in metastatic melanoma (stage III metastasis n = 17, p = 0.0009; stage IV metastasis n = 164, p = 0.003) compared to normal organ tissues (n = 19). Additionally, reduced ac-DNMT1 protein levels were associated with melanoma progression. There was a significant inverse correlation between ac-DNMT1 and DNMT1 protein levels in stage IV metastatic melanoma (r = −0.18, p = 0.02, n = 164). Additionally, ac-DNMT1 protein levels were also significantly positively correlated with TIP60 (r = 0.6, p < 0.0001) and USP7 (r = 0.74, p < 0.0001) protein levels in stage IV metastatic melanoma (n = 164). Protein analysis in metastatic melanoma tumor tissues showed that with high ac-DNMT1 (p = 0.006, n = 59), or concurrent high ac-DNMT1 with low DNMT1 (p = 0.05, n = 27), or high TIP60 (p = 0.007, n = 41), or high USP7 (p = 0.01, n = 48) consistently showed better 4-year melanoma-specific survival (MSS). Multivariate Cox proportional hazard analysis showed that ac-DNMT1 level is a significant independent factor associated with MSS (HR, 0.994; 95% confidential interval (CI), 0.990–0.998; p = 0.002). These results demonstrated that low ac-DNMT1 levels may represent an important regulatory factor in controlling metastatic melanoma progression and a promising factor for stratifying aggressive stage IV metastasis.
Facing Thyroid Nodules in Paediatric Patients Previously Treated with Radiotherapy for Non-Thyroidal Cancers: Are Adult Ultrasound Risk Stratification Systems Reliable?
Authors: Piccardo Arnoldo , Fiz Francesco , Bottoni Gianluca , De Luca Camilla , Massollo Michela , Catrambone Ugo , Foppiani Luca , Muraca Monica , Garaventa Alberto , Trimboli Pierpaolo
Published: September 2021

Thyroid nodule ultrasound-based risk stratification systems (US-RSSs) have been successfully used in adults to predict the likelihood of malignancies. However, their applicability to the paediatric population is unclear, especially in children with a history of radiation exposure, who are at a higher cancer risk. We tested the efficacy of three US-RSSs in this setting by retrospectively applying three classification systems (ACR-TIRADS, ATA and EU-TIRADS) to all paediatric patients referred for thyroid nodules and with a radiation exposure history. We compared the results with a reference standard (pathology or 36-month follow-up); sensitivity, specificity, positive and negative predictive values (PPV and NPV) and accuracy were calculated. A total of 52 patients were included; fourteen of them (27%) had papillary thyroid cancer (PTC) at the final histology. No significant differences across the US-RSSs were detected; specificity (range 95–97%) and NPV (range 88–93%) were particularly elevated. However, ACR-TIRADS, ATA and EU-TIRADS did not indicate the need for a biopsy in six (42.8%), seven (50%) and eight (57%) cases of PTC; in five cases, this lack of indication was due to a small (<1 cm) nodule size. In conclusion, US-RSSs show a high NPV and specificity in paediatric patients, whereas the cytology indication could be improved by reconsidering the dimensional criterion.
STARD3: A Prospective Target for Cancer Therapy
Authors: Asif Kanwal , Memeo Lorenzo , Palazzolo Stefano , Frión-Herrera Yahima , Parisi Salvatore , Caligiuri Isabella , Canzonieri Vincenzo , Granchi Carlotta , Tuccinardi Tiziano , Rizzolio Flavio
Published: September 2021

Cancer is one of the major causes of death in developed countries and current therapies are based on surgery, chemotherapeutic agents, and radiation. To overcome side effects induced by chemo- and radiotherapy, in recent decades, targeted therapies have been proposed in second and even first lines. Targeted drugs act on the essential pathways involved in tumor induction, progression, and metastasis, basically all the hallmark of cancers. Among emerging pathways, the cholesterol metabolic pathway is a strong candidate for this purpose. Cancer cells have an accelerated metabolic rate and require a continuous supply of cholesterol for cell division and membrane renewal. Steroidogenic acute regulatory related lipid transfer (START) proteins are a family of proteins involved in the transfer of lipids and some of them are important in non-vesicular cholesterol transportation within the cell. The alteration of their expression levels is implicated in several diseases, including cancers. In this review, we report the latest discoveries on StAR-related lipid transfer protein domain 3 (STARD3), a member of the START family, which has a potential role in cancer, focusing on the structural and biochemical characteristics and mechanisms that regulate its activity. The role of the STARD3 protein as a molecular target for the development of cancer therapies is also discussed. As STARD3 is a key protein in the cholesterol movement in cancer cells, it is of interest to identify inhibitors able to block its activity.
Cathepsin S Evokes PAR2-Dependent Pain in Oral Squamous Cell Carcinoma Patients and Preclinical Mouse Models
Authors: Tu Nguyen Huu , Inoue Kenji , Chen Elyssa , Anderson Bethany M. , Sawicki Caroline M. , Scheff Nicole N. , Tran Hung D. , Kim Dong H. , Alemu Robel G. , Yang Lei , Dolan John C. , Liu Cheng Z. , Janal Malvin N. , Latorre Rocco , Jensen Dane D. , Bunnett Nigel W. , Edgington-Mitchell Laura E. , Schmidt Brian L.
Published: September 2021

Oral squamous cell carcinoma (SCC) pain is more prevalent and severe than pain generated by any other form of cancer. We previously showed that protease-activated receptor-2 (PAR2) contributes to oral SCC pain. Cathepsin S is a lysosomal cysteine protease released during injury and disease that can activate PAR2. We report here a role for cathepsin S in PAR2-dependent cancer pain. We report that cathepsin S was more active in human oral SCC than matched normal tissue, and in an orthotopic xenograft tongue cancer model than normal tongue. The multiplex immunolocalization of cathepsin S in human oral cancers suggests that carcinoma and macrophages generate cathepsin S in the oral cancer microenvironment. After cheek or paw injection, cathepsin S evoked nociception in wild-type mice but not in mice lacking PAR2 in Nav1.8-positive neurons (Par2Nav1.8), nor in mice treated with LY3000328 or an endogenous cathepsin S inhibitor (cystatin C). The human oral SCC cell line (HSC-3) with homozygous deletion of the gene for cathepsin S (CTSS) with CRISPR/Cas9 provoked significantly less mechanical allodynia and thermal hyperalgesia, as did those treated with LY3000328, compared to the control cancer mice. Our results indicate that cathepsin S is activated in oral SCC, and that cathepsin S contributes to cancer pain through PAR2 on neurons.
Targeted Therapies and Druggable Genetic Anomalies in Acute Myeloid Leukemia: From Diagnostic Tools to Therapeutic Interventions
Authors: Lanza Francesco , Bazarbachi Ali
Published: September 2021

Acute myeloid leukemia (AML) is a clonal disorder resulting from acquired somatic mutations in hematopoietic progenitor cells that lead to the dysregulation of differentiation and the proliferation of hematopoietic cells [...]
Metabolic Flexibility Is a Determinant of Breast Cancer Heterogeneity and Progression
Authors: Fukano Marina , Park Morag , Deblois Geneviève
Published: September 2021

Breast cancer progression is characterized by changes in cellular metabolism that contribute to enhanced tumour growth and adaptation to microenvironmental stresses. Metabolic changes within breast tumours are still poorly understood and are not as yet exploited for therapeutic intervention, in part due to a high level of metabolic heterogeneity within tumours. The metabolic profiles of breast cancer cells are flexible, providing dynamic switches in metabolic states to accommodate nutrient and energy demands and further aggravating the challenges of targeting metabolic dependencies in cancer. In this review, we discuss the intrinsic and extrinsic factors that contribute to metabolic heterogeneity of breast tumours. Next, we examine how metabolic flexibility, which contributes to the metabolic heterogeneity of breast tumours, can alter epigenetic landscapes and increase a variety of pro-tumorigenic functions. Finally, we highlight the difficulties in pharmacologically targeting the metabolic adaptations of breast tumours and provide an overview of possible strategies to sensitize heterogeneous breast tumours to the targeting of metabolic vulnerabilities.
Vorinostat (SAHA) and Breast Cancer: An Overview
Authors: Wawruszak Anna , Borkiewicz Lidia , Okon Estera , Kukula-Koch Wirginia , Afshan Syeda , Halasa Marta
Published: September 2021

Vorinostat (SAHA), an inhibitor of class I and II of histone deacetylases, is the first histone deacetylase inhibitor (HDI) approved for the treatment of cutaneous T-cell lymphoma in 2006. HDIs are promising anticancer agents that inhibit the proliferation of many types of cancer cells including breast carcinoma (BC). BC is a heterogeneous disease with variable biological behavior, morphological features, and response to therapy. Although significant progress in the treatment of BC has been made, high toxicity to normal cells, serious side effects, and the occurrence of multi-drug resistance limit the effective therapy of BC patients. Therefore, new active agents which improve the effectiveness of currently used regimens are highly needed. This manuscript analyzes preclinical and clinical trials data of SAHA, applied individually or in combination with other anticancer agents, considering different histological subtypes of BC.
The Agony of Choice—Where to Place the Wave of BCMA-Targeted Therapies in the Multiple Myeloma Treatment Puzzle in 2022 and Beyond
Authors: Strassl Irene , Schreder Martin , Steiner Normann , Rudzki Jakob , Agis Hermine , Künz Tina , Müser Nino , Willenbacher Wolfgang , Petzer Andreas , Neumeister Peter , Krauth Maria Theresa
Published: September 2021

Since the introduction of first-generation proteasome inhibitors and immunomodulatory agents, the multiple myeloma (MM) treatment landscape has undergone a remarkable development. Most recently, immunotherapeutic strategies targeting the B cell maturation antigen (BCMA) entered the clinical stage providing access to highly anticipated novel treatment strategies. At present, numerous different approaches investigate BCMA as an effective multi-modal target. Currently, BCMA-directed antibody–drug conjugates, bispecific and trispecific antibodies, autologous and allogeneic CAR-T cell as well as CAR-NK cell constructs are either approved or in different stages of clinical and preclinical development for the treatment of MM. This armamentarium of treatment choices raises several challenges for clinical decision making, particularly in the absence of head-to-head comparisons. In this review, we provide a comprehensive overview of BCMA-targeting therapeutics, deliver latest updates on clinical trial data, and focus on potential patient selection criteria for different BCMA-targeting immunotherapeutic strategies.
LSD1 Facilitates Pro-Inflammatory Polarization of Macrophages by Repressing Catalase
Authors: Sobczak Maciej , Strachowska Magdalena , Gronkowska Karolina , Karwaciak Iwona , Pułaski Łukasz , Robaszkiewicz Agnieszka
Published: September 2021

The increased level of hydrogen peroxide accompanies some modes of macrophage specification and is linked to ROS-based antimicrobial activity of these phagocytes. In this study, we show that activation of toll-like receptors with bacterial components such as LPS is accompanied by the decline in transcription of hydrogen peroxide decomposing enzyme-catalase, suppression of which facilitates the polarization of human macrophages towards the pro-inflammatory phenotype. The chromatin remodeling at the CAT promoter involves LSD1 and HDAC1, but activity of the first enzyme defines abundance of the two proteins on chromatin, histone acetylation status and the CAT transcription. LSD1 inhibition prior to macrophage activation with LPS prevents CAT repression by enhancing the LSD1 and interfering with the HDAC1 recruitment to the gene promoter. The maintenance of catalase level with LSD1 inhibitors during M1 polarization considerably limits LPS-triggered expression of some pro-inflammatory cytokines and markers such as IL1β, TNFα, COX2, CD14, TLR2, and IFNAR, but the effect of LSD1 inhibitors is lost upon catalase deficiency. Summarizing, activity of LSD1 allows for the CAT repression in LPS stimulated macrophages, which negatively controls expression of some key pro-inflammatory markers. LSD1 inhibitors can be considered as possible immunosuppressive drugs capable of limiting macrophage M1 specialization.
The Tissue Architecture of Oral Squamous Cell Carcinoma Visualized by Staining Patterns of Wheat Germ Agglutinin and Structural Proteins Using Confocal Microscopy
Authors: Silveyra Estefania , Bologna-Molina Ronell , Gónzalez-Gónzalez Rogelio , Arocena Miguel
Published: September 2021

Objectives: Tissue architecture and cell morphology suffer profound alterations during oral cancer and are important markers for its progression and outcome. For precise visualization of tissue architecture in oral cancer, we used confocal microscopy to examine the staining pattern of wheat germ agglutinin, a lectin that binds membrane glycoproteins, and the staining patterns of structural proteins. Materials and Methods: Paraffin sections of oral squamous cell carcinoma were stained with fluorescently labeled wheat germ agglutinin and with antibodies against structural proteins, which were revealed by immunohistochemistry with tyramide signal amplification. Results: Membrane localization of wheat germ agglutinin was markedly decreased in the basal layers and in regions of tumor invasion, accompanied by cytoplasmic redistribution of E-cadherin, β-actin and syndecan-1. Wheat germ agglutinin staining clearly identified tumor clusters within the surrounding stroma, and tumor cells with elongated morphology. Conclusions: Our results suggest that the wheat germ agglutinin staining pattern is indicative of the degree of cell cohesion in oral squamous cell carcinoma, which decreases in basal layers and invasive tumor clusters with more migratory morphologies. Wheat germ agglutinin staining in combination with confocal microscopy could constitute, therefore, a valuable tool for the study of tissue architecture in oral cancer.
An Autophagy Modulator Peptide Prevents Lung Function Decrease and Corrects Established Inflammation in Murine Models of Airway Allergy
Authors: Daubeuf François , Schall Nicolas , Petit-Demoulière Nathalie , Frossard Nelly , Muller Sylviane
Published: September 2021

The involvement of autophagy and its dysfunction in asthma is still poorly documented. By using a murine model of chronic house dust mite (HDM)-induced airway inflammation, we tested the expression of several autophagy markers in the lung and spleen of asthma-like animals. Compared to control mice, in HDM-sensitized and challenged mice, the expression of sequestosome-1/p62, a multifunctional adaptor protein that plays an important role in the autophagy machinery, was raised in the splenocytes. In contrast, its expression was decreased in the neutrophils recovered from the bronchoalveolar fluid, indicating that autophagy was independently regulated in these two compartments. In a strategy of drug repositioning, we treated allergen-sensitized mice with the therapeutic peptide P140 known to target chaperone-mediated autophagy. A single intravenous administration of P140 in these mice resulted in a significant reduction in airway resistance and elastance, and a reduction in the number of neutrophils and eosinophils present in the bronchoalveolar fluid. It corrected the autophagic alteration without showing any suppressive effect in the production of IgG1 and IgE. Collectively, these findings show that autophagy processes are altered in allergic airway inflammation. This cellular pathway may represent a potential therapeutic target for treating selected patients with asthma.
A Comparative Study of the Effect of Anatomical Site on Multiple Differentiation of Adipose-Derived Stem Cells in Rats
Authors: Hendawy Hanan , Kaneda Masahiro , Metwally Elsayed , Shimada Kazumi , Tanaka Takashi , Tanaka Ryou
Published: September 2021

Mesenchymal stem cells (MSCs) derived from adipose tissue are evolved into various cell-based regenerative approaches. Adipose-derived stem cells (ASCs) isolated from rats are commonly used in tissue engineering studies. Still, there is a gap in knowledge about how the harvest locations influence and guide cell differentiation. This study aims to investigate how the harvesting site affects stem-cell-specific surface markers expression, pluripotency, and differentiation potential of ASCs in female Sprague Dawley rats. ASCs were extracted from the adipose tissue of the peri-ovarian, peri-renal, and mesenteric depots and were compared in terms of cell morphology. MSCs phenotype was validated by cell surfaces markers using flow cytometry. Moreover, pluripotent gene expression of Oct4, Nanog, Sox2, Rex-1, and Tert was evaluated by reverse transcriptase-polymerase chain reaction (RT-PCR). ASCs multipotency was evaluated by specific histological stains, and the results were confirmed by quantitative polymerase chain reaction (RT-qPCR) expression analysis of specific genes. There was a non-significant difference detected in the cell morphology and immunophenotype between different harvesting sites. ASCs from multiple locations were significantly varied in their capacity to differentiate into adipocytes, osteoblastic cells, and chondrocytes. To conclude, depot selection is a critical element that should be considered when using ASCs in tissue-specific cell-based regenerative therapies research.
The Mitochondrial Biomarkers FGF-21 and GDF-15 in Patients with Episodic and Chronic Migraine
Authors: Burow Philipp , Haselier Marc , Naegel Steffen , Scholle Leila Motlagh , Gaul Charly , Kraya Torsten
Published: September 2021

Mitochondrial processes may play a role in the pathophysiology of migraine. Serum levels of two biomarkers, Fibroblast-growth-factor 21 (FGF-21) and Growth-differentiation-factor 15 (GDF-15), are typically elevated in patients with mitochondrial disorders. The study investigated whether the presence of migraine may influence FGF-21 and GDF-15 serum levels considering vascular and metabolic disorders as possible confounders. A cross-sectional study in two headache centers was conducted analyzing GDF-15 and FGF-21 serum concentration in 230 patients with episodic and chronic migraine compared to a control group. Key clinical features of headache were evaluated, as well as health-related life quality, anxiety and depression using SF-12 and HADS-questionnaires. Elevated GDF-15 values were detected in the migraine group compared to the control group (506.65 ± 275.87 pg/mL vs. 403.34 ± 173.29 pg/mL, p < 0.001, Mann–Whitney U test). A strong correlation between increasing age and higher GDF-15 levels was identified (p < 0.001, 95%-CI elevation of GDF-15 per year 5.246–10.850 pg/mL, multiple linear regression). Mean age was different between the groups, and this represents a confounding factor of the measurements. FGF-21 levels did not differ between migraine patients and controls (p = 0.635, Mann–Whitney U test) but were significantly influenced by increasing BMI (p = 0.030, multiple linear regression). Neither biomarker showed correlation with headache frequency. Higher FGF-21 levels were associated with a higher mean intensity of headache attacks, reduced health-related life quality and anxiety. When confounding factors were considered, increased serum levels of FGF-21 and GDF-15 were not detected in migraine patients. However, the results show an age-dependence of GDF-15 in migraine patients, and this should be considered in future studies. Similar findings apply to the relationship between FGF-21 and BMI. Previous studies that did not adjust for these factors should be interpreted with caution.