bluuebunny/crossref_metadata_2025 huggingface dataset:
Lipopolysaccharides Enhance Epithelial Hyperplasia and Tubular Adenoma in Intestine-Specific Expression of krasV12 in Transgenic Zebrafish
Authors: Lu Jeng-Wei , Sun Yuxi , Fong Pei-Shi Angelina , Lin Liang-In , Liu Dong , Gong Zhiyuan
Published: August 2021

Intestinal carcinogenesis is a multistep process that begins with epithelial hyperplasia, followed by a transition to an adenoma and then to a carcinoma. Many etiological factors, including KRAS mutations and inflammation, have been implicated in oncogenesis. However, the potential synergistic effects between KRAS mutations and inflammation as well as the potential mechanisms by which they promote intestinal carcinogenesis remain unclear. Thus, the objective of this study was to investigate the synergistic effects of krasV12, lipopolysaccharides (LPS), and/or dextran sulfate sodium (DSS) on inflammation, tumor progression, and intestinal disorders using transgenic adults and larvae of zebrafish. Histopathology and pathological staining were used to examine the intestines of krasV12 transgenic zebrafish treated with LPS and/or DSS. LPS and/or DSS treatment enhanced intestinal inflammation in krasV12 transgenic larvae with concomitant increases in the number of neutrophils and macrophages in the intestines. The expression of krasV12, combined with LPS treatment, also enhanced epithelial hyperplasia and tubular adenoma, demonstrated by histopathological examinations and by increases in cell apoptosis, cell proliferation, and downstream signaling of phosphorylated AKT serine/threonine kinase 1 (AKT), extracellular-signal-regulated kinase (ERK), and histone. We also found that krasV12 expression, combined with LPS treatment, significantly enhanced changes in intestinal morphology, specifically (1) decreases in goblet cell number, goblet cell size, villi height, and intervilli space, as well as (2) increases in villi width and smooth muscle thickness. Moreover, krasV12 transgenic larvae cotreated with DSS and LPS exhibited exacerbated intestinal inflammation. Cotreatment with DSS and LPS in krasV12-expressing transgenic adult zebrafish also enhanced epithelial hyperplasia and tubular adenoma, compared with wild-type fish that received the same cotreatment. In conclusion, our data suggest that krasV12 expression, combined with LPS and/or DSS treatment, can enhance intestinal tumor progression by activating the phosphatidylinositol-3-kinase (PI3K)/AKT signaling pathway and may provide a valuable in vivo platform to investigate tumor initiation and antitumor drugs for gastrointestinal cancers.
Metronidazole- and Amoxicillin-Loaded PLGA and PCL Nanofibers as Potential Drug Delivery Systems for the Treatment of Periodontitis: In Vitro and In Vivo Evaluations
Authors: Mirzaeei Shahla , Mansurian Mahla , Asare-Addo Kofi , Nokhodchi Ali
Published: August 2021

The purpose of this study was to prepare poly (D-L) lactide-co-glycolide (PLGA) and poly ε-caprolactone (PCL) nanofibers containing metronidazole and amoxicillin using an electrospinning process as intrapocket sustained-release drug delivery systems for the treatment of periodontal diseases. Scanning electron microscopy showed that the drug containing PLGA and PCL nanofibers produced from the electrospinning process was uniform and bead-free in morphology. The obtained nanofibers had a strong structure and resisted external tension according to the tensiometry results. The cytotoxicity results indicated acceptable cell viability (>80%). Quantification by high-performance liquid chromatography showed almost complete in vitro drug release between 7 and 9 days, whereas 14 days were required for complete drug release in vivo. No significant signs of irritation or inflammatory reaction were detected after three weeks of subcutaneous implantation of nanofibers in the animal models, thus indicating suitable compatibility. The results therefore suggest that the designed nanofibers can be used as potential commercial formulations in the treatment of periodontitis as controlled-release intrapocket drug delivery systems that can increase patient compliance. This is due to their ability to reduce the frequency of administration from three times daily in a systemic manner to once weekly as local delivery.
Cortisol Dose-Dependently Impairs Migration and Tube-like Formation in a Trophoblast Cell Line and Modulates Inflammatory and Angiogenic Genes
Authors: Húngaro Talita Guerreiro Rodrigues , Gregnani Marcos F. , Alves-Silva Thaís , Herse Florian , Alenina Natalia , Bader Michael , Araújo Ronaldo C.
Published: August 2021

Several stimuli can change maternal hormone levels during pregnancy. These changes may affect trophoblastic cells and modulate the development of the embryo and the placental tissue itself. Changes in cortisol levels are associated with impaired trophoblast implantation and function, in addition to other pregnancy complications. This study aims to analyze the effects of low and high doses of cortisol on an extravillous trophoblast cell line, and the effects of various exposures to this hormone. SGHPL-4 cells were treated with cortisol at five doses (0–1000 nM) and two exposures (continuous: 24 h/day; and intermittent: 2 h/day). In intermittent treatment, cortisol acted mainly as an anti-inflammatory hormone, repressing gene expression of kinin B1 receptors, interleukin-6, and interleukin-1β. Continuous treatment modulated inflammatory and angiogenic pathways, significantly repressing angiogenic factors and their receptors. Cortisol affected cell migration and tube-like structures formation. In conclusion, both continuous and intermittent exposure to cortisol repressed the expression of inflammatory genes, while only continuous exposure repressed the expression of angiogenic genes, suggesting that a sustained increase in the levels of this hormone is more harmful than a high short-term increase. Cortisol also impaired tube-like structures formation, and kinin receptors may be involved in this response.
Are There Biomimetic Lessons from Genetic Regulatory Networks for Developing a Lunar Industrial Ecology?
Authors: Ellery Alex
Published: August 2021

We examine the prospect for employing a bio-inspired architecture for a lunar industrial ecology based on genetic regulatory networks. The lunar industrial ecology resembles a metabolic system in that it comprises multiple chemical processes interlinked through waste recycling. Initially, we examine lessons from factory organisation which have evolved into a bio-inspired concept, the reconfigurable holonic architecture. We then examine genetic regulatory networks and their application in the biological cell cycle. There are numerous subtleties that would be challenging to implement in a lunar industrial ecology but much of the essence of biological circuitry (as implemented in synthetic biology, for example) is captured by traditional electrical engineering design with emphasis on feedforward and feedback loops to implement robustness.
Atrial Fibrillation Prediction from Critically Ill Sepsis Patients
Authors: Bashar Syed Khairul , Ding Eric Y. , Walkey Allan J. , McManus David D. , Chon Ki H.
Published: August 2021

Sepsis is defined by life-threatening organ dysfunction during infection and is the leading cause of death in hospitals. During sepsis, there is a high risk that new onset of atrial fibrillation (AF) can occur, which is associated with significant morbidity and mortality. Consequently, early prediction of AF during sepsis would allow testing of interventions in the intensive care unit (ICU) to prevent AF and its severe complications. In this paper, we present a novel automated AF prediction algorithm for critically ill sepsis patients using electrocardiogram (ECG) signals. From the heart rate signal collected from 5-min ECG, feature extraction is performed using the traditional time, frequency, and nonlinear domain methods. Moreover, variable frequency complex demodulation and tunable Q-factor wavelet-transform-based time–frequency methods are applied to extract novel features from the heart rate signal. Using a selected feature subset, several machine learning classifiers, including support vector machine (SVM) and random forest (RF), were trained using only the 2001 Computers in Cardiology data set. For testing the proposed method, 50 critically ill ICU subjects from the Medical Information Mart for Intensive Care (MIMIC) III database were used in this study. Using distinct and independent testing data from MIMIC III, the SVM achieved 80% sensitivity, 100% specificity, 90% accuracy, 100% positive predictive value, and 83.33% negative predictive value for predicting AF immediately prior to the onset of AF, while the RF achieved 88% AF prediction accuracy. When we analyzed how much in advance we can predict AF events in critically ill sepsis patients, the algorithm achieved 80% accuracy for predicting AF events 10 min early. Our algorithm outperformed a state-of-the-art method for predicting AF in ICU patients, further demonstrating the efficacy of our proposed method. The annotations of patients’ AF transition information will be made publicly available for other investigators. Our algorithm to predict AF onset is applicable for any ECG modality including patch electrodes and wearables, including Holter, loop recorder, and implantable devices.
Drug Repurposing to Identify a Synergistic High-Order Drug Combination to Treat Sunitinib-Resistant Renal Cell Carcinoma
Authors: Rausch Magdalena , Rutz Adriano , Allard Pierre-Marie , Delucinge-Vivier Céline , Docquier Mylène , Dormond Olivier , Dyson Paul J. , Wolfender Jean-Luc , Nowak-Sliwinska Patrycja
Published: August 2021

Repurposed drugs have been evaluated for the management of clear cell renal cell carcinoma (ccRCC), but only a few have influenced the overall survival of patients with advanced disease. To combine repurposed non-oncology with oncological drugs, we applied our validated phenotypic method, which consisted of a reduced experimental part and data modeling. A synergistic optimized multidrug combination (ODC) was identified to significantly reduce the energy levels in cancer remaining inactive in non-cancerous cells. The ODC consisted of Rapta-C, erlotinib, metformin and parthenolide and low doses. Molecular and functional analysis of ODC revealed a loss of adhesiveness and induction of apoptosis. Gene-expression network analysis displayed significant alterations in the cellular metabolism, confirmed by LC-MS based metabolomic analysis, highlighting significant changes in the lipid classes. We used heterotypic in vitro 3D co-cultures and ex vivo organoids to validate the activity of the ODC, maintaining an efficacy of over 70%. Our results show that repurposed drugs can be combined to target cancer cells selectively with prominent activity. The strong impact on cell adherence and metabolism indicates a favorable mechanism of action of the ODC to treat ccRCC.
miRNAs as Biomarkers for Diagnosing and Predicting Survival of Head and Neck Squamous Cell Carcinoma Patients
Authors: Piotrowski Igor , Zhu Xiang , Saccon Tatiana Dandolini , Ashiqueali Sarah , Schneider Augusto , de Carvalho Nunes Allancer Divino , Noureddine Sarah , Sobecka Agnieszka , Barczak Wojciech , Szewczyk Mateusz , Golusiński Wojciech , Masternak Michal M. , Golusiński Paweł
Published: August 2021

Head and Neck Squamous Cell Carcinoma (HNSCC) is the sixth most common cancer worldwide. These tumors originate from epithelial cells of the upper aerodigestive tract. HNSCC tumors in different regions can have significantly different molecular characteristics. While many microRNAs (miRNAs) have been found to be involved in the regulation of the carcinogenesis and pathogenesis of HNSCC, new HNSCC related miRNAs are still being discovered. The aim of this study was to explore potential miRNA biomarkers that can be used to diagnose HNSCC and prognose survival of HNSCC patients. For this purpose, we chose a panel of 12 miRNAs: miR-146a-5p, miR-449a, miR-126-5p, miR-34a-5p, miR-34b-5p, miR-34c-5p, miR-217-5p, miR-378c, miR-6510-3p, miR-96-5p, miR-149-5p, and miR-133a-5p. Expression of these miRNAs was measured in tumor tissue and neighboring healthy tissue collected from patients diagnosed with HNSCC (n = 79) in either the oral cavity, oropharynx, or larynx. We observed a pattern of differentially expressed miRNAs at each of these cancer locations. Our study showed that some of these miRNAs, separately or in combination, could serve as biomarkers distinguishing between healthy and tumor tissue, and their expression correlated with patients’ overall survival.
CD73 Promotes Tumor Progression in Patients with Esophageal Squamous Cell Carcinoma
Authors: Chen Yen-Hao , Lu Hung-I , Lo Chien-Ming , Li Shau-Hsuan
Published: August 2021

Cluster of differentiation (CD)-73 plays pivotal roles in the regulation of immune reactions via the production of extracellular adenosine, and the overexpression of CD73 is associated with worse outcomes in several types of cancers. Here, we identified 167 esophageal squamous cell carcinoma (ESCC) patients who underwent esophagectomy, including 64 and 103 patients with high and low expression levels of CD73, respectively. Univariate and multivariate analyses showed high expression of CD73 was an independent prognostic factor for worse disease-free survival and overall survival. In addition, we selected another cohort consisting of 38 ESCC patients receiving nivolumab or pembrolizumab and found that treatment response and survival benefit to immunotherapy were strongly correlated with the expression levels of CD73/programmed death ligand 1. Moreover, the transwell assay revealed knockdown of CD73 in two ESCC cell lines, TE1 and KYSE30, exhibited significantly reduced abilities of cell invasion and migration. CD73 silencing also showed that the protein expression levels of CD73, vimentin, and snail were downregulated, while those of E-cadherin were upregulated in Western blotting. The findings of our study indicate CD73 may be an independent prognostic factor for ESCC patients who underwent esophagectomy. Furthermore, it may be associated with the patient responses to immunotherapy.
Survival and Disease Recurrence in Patients with Duodenal Neuroendocrine Tumours—A Single Centre Cohort
Authors: Folkestad Oddry , Wasmuth Hans H. , Mjønes Patricia , Fougner Reidun , Hauso Øyvind , Fossmark Reidar
Published: August 2021

Background: Duodenal neuroendocrine tumours (D-NETs) are rare but increasingly diagnosed. This study aimed to assess the overall survival and recurrence rate among patients treated for D-NETs. Methods: Patients with D-NETs were retrospectively reviewed with a median follow-up time of 4.8 years (range 0.0–17.2 years). Results: A total of 32 patients with median age 68.0 years were identified. Fifteen patients underwent surgery while ten patients underwent endoscopic treatment. Mean estimated overall survival for the entire population was 12.1 years (95% CI 9.5–14.7 years), while 5-year overall survival was 81.3%. Tumour grade G1 was associated with longer mean estimated survival compared to G2 tumours (13.2 years versus 4.4 years, p = 0.010). None of the 23 patients who underwent presumed radical endoscopic or surgical resection had disease recurrence during follow-up. Tumours <10 mm could be treated endoscopically whereas a high proportion of patients with tumours 10–20 mm should be considered for surgery. Conclusion: Patients with D-NETs had long overall survival, and mortality was more influenced by other diseases. Both endoscopic and surgical resections were effective as no recurrences were diagnosed during follow-up.
Endometrial Cancer Molecular Characterization: The Key to Identifying High-Risk Patients and Defining Guidelines for Clinical Decision-Making?
Authors: Baiden-Amissah Regina Esi Mensimah , Annibali Daniela , Tuyaerts Sandra , Amant Frederic
Published: August 2021

Endometrial carcinomas (EC) are the sixth most common cancer in women worldwide and the most prevalent in the developed world. ECs have been historically sub-classified in two major groups, type I and type II, based primarily on histopathological characteristics. Notwithstanding the usefulness of such classification in the clinics, until now it failed to adequately stratify patients preoperatively into low- or high-risk groups. Pieces of evidence point to the fact that molecular features could also serve as a base for better patients’ risk stratification and treatment decision-making. The Cancer Genome Atlas (TCGA), back in 2013, redefined EC into four main molecular subgroups. Despite the high hopes that welcomed the possibility to incorporate molecular features into practice, currently they have not been systematically applied in the clinics. Here, we outline how the emerging molecular patterns can be used as prognostic factors together with tumor histopathology and grade, and how they can help to identify high-risk EC subpopulations for better risk stratification and treatment strategy improvement. Considering the importance of the use of preclinical models in translational research, we also discuss how the new patient-derived models can help in identifying novel potential targets and help in treatment decisions.
Stereotactic Body Radiation Therapy after Chemotherapy for Unresectable Perihilar Cholangiocarcinoma: The STRONG Trial, a Phase I Safety and Feasibility Study
Authors: Baak Rogier , Willemssen François , van Norden Yvette , Eskens Ferry , Milder Maaike , Heijmen Ben , Koerkamp Bas , Sprengers Dave , van Driel Lydi , Klümpen Heinz-Josef , den Toom Wilhelm , Koedijk Merel , IJzermans Jan , Méndez Romero Alejandra
Published: August 2021

Background: In unresectable pCCA, the standard of care is palliative chemotherapy. We investigated the feasibility and safety of adding stereotactic body radiation therapy (SBRT) after chemotherapy. Methods: Patients with unresectable pCCA, stage T1-T4N0-N1M0, ECOG 0-1, having finished 6–8 cycles of cisplatin and gemcitabine without disease progression were eligible. SBRT was planned in 15 fractions of 3.0–4.5 Gy. The primary endpoints were feasibility (defined as completing SBRT as planned) and toxicity, evaluated within 3 months after SBRT (CTCAE v4.03). A conventional “3 + 3” design was used, corresponding to a sample size of 6 patients. Dose-limiting toxicity (DLT) was defined as grade ≥ 4 hepatobiliary or grade ≥ 3 gastrointestinal toxicity. The secondary endpoints, measured from the start of radiotherapy, were local control, progression-free survival, overall survival, and quality of life (QoL). ClinicalTrials.gov identifier: NCT03307538. Results: Six patients were enrolled between November 2017 and March 2020. SBRT was delivered as planned. All patients were treated with 60Gy (15 × 4.0Gy). No SBRT-related DLT was observed. The most common grade ≥ 3 toxicity was cholangitis (n = 5). The median follow-up was 14 months. The 12-month local control rate was 80%. We observed no substantial changes in QoL. Conclusion: In patients with unresectable pCCA with stable disease after palliative chemotherapy, adding SBRT is feasible and safe. The observed local control merits an additional evaluation of effectiveness.
PPAR-Responsive Elements Enriched with Alu Repeats May Contribute to Distinctive PPARγ–DNMT1 Interactions in the Genome
Authors: Sharma Amit , Tobar-Tosse Fabian , Chand Dakal Tikam , Liu Hongde , Biswas Arijit , Menon Athira , Paruchuri Anoosha , Katsonis Panagiotis , Lichtarge Olivier , Gromiha M. Michael , Ludwig Michael , Schmidt-Wolf Ingo G. H. , Holz Frank G. , Loeffler Karin U. , Herwig-Carl Martina C.
Published: August 2021

Background: PPARγ (peroxisome proliferator-activated receptor gamma) is involved in the pathology of numerous diseases, including UM and other types of cancer. Emerging evidence suggests that an interaction between PPARγ and DNMTs (DNA methyltransferase) plays a role in cancer that is yet to be defined. Methods: The configuration of the repeating elements was performed with CAP3 and MAFFT, and the structural modelling was conducted with HDOCK. An evolutionary action scores algorithm was used to identify oncogenic variants. A systematic bioinformatic appraisal of PPARγ and DNMT1 was performed across 29 tumor types and UM available in The Cancer Genome Atlas (TCGA). Results: PPAR-responsive elements (PPREs) enriched with Alu repeats are associated with different genomic regions, particularly the promotor region of DNMT1. PPARγ–DNMT1 co-expression is significantly associated with several cancers. C-terminals of PPARγ and DNMT1 appear to be the potential protein–protein interaction sites where disease-specific mutations may directly impair the respective protein functions. Furthermore, PPARγ expression could be identified as an additional prognostic marker for UM. Conclusions: We hypothesize that the function of PPARγ requires an additional contribution of Alu repeats which may directly influence the DNMT1 network. Regarding UM, PPARγ appears to be an additional discriminatory prognostic marker, in particular in disomy 3 tumors.
A HER2 Tri-Specific NK Cell Engager Mediates Efficient Targeting of Human Ovarian Cancer
Authors: Vallera Daniel A. , Oh Felix , Kodal Behiye , Hinderlie Peter , Geller Melissa A. , Miller Jeffrey S. , Felices Martin
Published: August 2021

Clinical studies validated antibodies directed against HER2, trastuzumab, and pertuzumab, as useful methodology to target breast cancer cases where HER2 is expressed. The hope was that HER2 targeting using these antibodies in ovarian cancer patients would prove useful as well, but clinical studies have shown lackluster results in this setting, indicating a need for a more comprehensive approach. Immunotherapy approaches stimulating the innate immune system show great promise, although enhancing natural killer (NK) function is not an established mainstream immunotherapy. This study focused on a new nanobody platform technology in which the bispecific antibody was altered to incorporate a cytokine. Herein we describe bioengineered CAM1615HER2 consisting of a camelid VHH antibody fragment recognizing CD16 and a single chain variable fragment (scFv) recognizing HER2 cross-linked by the human interleukin-15 (IL-15) cytokine. This tri-specific killer engager (TriKETM) showed in vitro prowess in its ability to kill ovarian cancer human cell lines. In addition, we demonstrated its efficacy in inducing potent anti-cancer effects in an in vivo xenograft model of human ovarian cancer engrafting both cancer cells and human NK cells. While previous approaches with trastuzumab and pertuzumab faltered in ovarian cancer, the hope is incorporating targeting and cytokine priming within the same molecule will enhance efficacy in this setting.
Surgical Management of Sinonasal Cancers: A Comprehensive Review
Authors: Chatelet Florian , Simon François , Bedarida Vincent , Le Clerc Nicolas , Adle-Biassette Homa , Manivet Philippe , Herman Philippe , Verillaud Benjamin
Published: August 2021

Surgery plays an important role in the treatment of sinonasal cancer. Many surgical approaches have been described, including open, endoscopic, or combined approaches. The choice is based on several criteria: general criteria related to the oncological results and morbidity of each technique, specific criteria related to the tumor (tumor extensions, tumor pathology), the patient, or the surgeon himself. The aims of this review are (i) to provide a complete overview of the surgical techniques available for the management of sinonasal malignant tumors, with a special focus on recent developments in the field of transnasal endoscopic surgery; (ii) to summarize the criteria that lead to the choice of one technique over another. In particular, the oncological outcomes, the morbidity of the different techniques, and the specificities of each histologic subtype will be discussed based on a comprehensive literature review.
New Approaches in Characterization of Lesions Dissemination in DLBCL Patients on Baseline PET/CT
Authors: Cottereau Anne-Ségolène , Meignan Michel , Nioche Christophe , Clerc Jérôme , Chartier Loic , Vercellino Laetitia , Casasnovas Olivier , Thieblemont Catherine , Buvat Irène
Published: August 2021

Dissemination, expressed recently by the largest Euclidian distance between lymphoma sites (SDmax), appeared a promising risk factor in DLBCL patients. We investigated alternative distance metrics to characterize the robustness of the dissemination information. In 290 patients from the REMARC trial (NCT01122472), the Euclidean (Euc), Manhattan (Man), and Tchebychev (Tch) distances between the furthest lesions, firstly based on the centroid of each lesion and then directly from the two most distant tumor voxels and the Travelling Salesman Problem distance (TSP) were calculated. For PFS, the areas under the ROC curves were between 0.63 and 0.64, and between 0.62 and 0.65 for OS. Patients with high SDmax whatever the method of calculation or high SD_TSP had a significantly poorer outcome than patients with low SDmax or SD_TSP (p < 0.001 for both PFS and OS), with significance maintained in Ann Arbor advanced-stage patients. In multivariate analysis with total metabolic tumor volume and ECOG, each distance feature had an independent prognostic value for PFS. For OS, only SDmax_Tch, SDmax_Euc _Vox, and SDmax_Man _Vox reached significance. The spread of DLBCL lesions measured by the largest distance between lymphoma sites is a strong independent prognostic factor and could be measured directly from tumor voxels, allowing its development in the area of the deep learning segmentation methods.
Gut Microbiota Dynamics during Chemotherapy in Epithelial Ovarian Cancer Patients Are Related to Therapeutic Outcome
Authors: D’Amico Federica , Perrone Anna Myriam , Rampelli Simone , Coluccelli Sara , Barone Monica , Ravegnini Gloria , Fabbrini Marco , Brigidi Patrizia , De Iaco Pierandrea , Turroni Silvia
Published: August 2021

Epithelial ovarian cancer (EOC) is one of the most lethal and silent gynecological tumors. Despite appropriate surgery and chemotherapy, relapse occurs in over half of patients with a poor prognosis. Recently, the gut microbiota (GM) was hypothesized to influence the efficacy of anticancer therapies, but no data are available in EOC. Here, by 16S rRNA gene sequencing and inferred metagenomics, we profiled the GM of EOC patients at diagnosis and reconstructed its trajectory along the course of neoadjuvant or adjuvant chemotherapy up to follow-up. Compared to healthy subjects, the GM of EOC patients appeared unbalanced and severely affected by chemotherapy. Strikingly, discriminating patterns were identified in relation to the therapeutic response. Platinum-resistant patients showed a marked temporal reduction in GM diversity and increased instability with loss of health-associated taxa and increased proportions of Coriobacteriaceae and Bifidobacterium. Notably, most of these microorganisms are lactate producers, suggesting increased lactate production as supported by inferred metagenomics. In contrast, the GM of platinum-sensitive patients appeared overall more diverse and stable and enriched in lactate utilizers from the Veillonellaceae family. In conclusion, we identified potential GM signatures of therapeutic outcome in EOC patients, which could open up new opportunities for cancer prognosis and treatment.
Effect of Pterostilbene, a Natural Derivative of Resveratrol, in the Treatment of Colorectal Cancer through Top1/Tdp1-Mediated DNA Repair Pathway
Authors: Zhang Yutian , Li Ying , Sun Changcheng , Chen Xiang , Han Luyao , Wang Tingqiang , Liu Jinfeng , Chen Xijing , Zhao Di
Published: August 2021

Topoisomerase 1 (Top1) inhibitor is an effective anticancer drug, but several factors limit its clinical application such as drug inactivation, tyrosyl-DNA phosphodiesterase 1 (Tdp1)-mediated tumor drug resistance, and its toxicity. Our previous study identified pterostilbene (PTE) and resveratrol (RE) to suppress these two proteins by binding to their active center. PTE and RE could inhibit the proliferation of various colorectal cancer cells, induce cell apoptosis, and make cell cycle stay in G2/M phase in vitro. PTE and RE could decrease Top1 and Tdp1 contents and mRNA expression in wild-type, constructed Tdp1 overexpressing CL187, Top1- or Tdp1- silenced CL187 cell lines. PTE exhibited excellent antitumor activity in subcutaneous CL187 transplantation model (TGI = 79.14 ± 2.85%, 200 mg/kg, i.p.) and orthotopic transplantation model (TGI = 76.57 ± 6.34%, 100 mg/kg, i.p.; TGI = 72.79 ± 4.06%, 500 mg/kg, i.g.) without significant toxicity. PTE had no significant inhibitory effect on non-tumor cell proliferation in vitro and would not induce damage to liver, kidney, and other major organs. Overall, PTE and RE can inhibit the activity of Top1 enzyme and inhibit the DNA damage repair pathway mediated by Top1/Tdp1, and can effectively inhibit colorectal cancer development with low toxicity, thus they have great potential to be developed into a new generation of anti-tumor drugs.
The Prognostic Value of the Lymph Node in Oesophageal Adenocarcinoma; Incorporating Clinicopathological and Immunological Profiling
Authors: Donlon Noel E. , Davern Maria , Sheppard Andrew , Power Robert , O’Connell Fiona , Heeran Aisling B. , King Ross , Hayes Conall , Bhardwaj Anshul , Phelan James J. , Dunne Margaret R. , Ravi Narayanasamy , Donohoe Claire L. , O’Sullivan Jacintha , Reynolds John V. , Lysaght Joanne
Published: August 2021

Response rates to the current gold standards of care for treating oesophageal adenocarcinoma (OAC) remain modest with 15–25% of patients achieving meaningful pathological responses, highlighting the need for novel therapeutic strategies. This study consists of immune, angiogenic, and inflammatory profiling of the tumour microenvironment (TME) and lymph node microenvironment (LNME) in OAC. The prognostic value of nodal involvement and clinicopathological features was compared using a retrospective cohort of OAC patients (n = 702). The expression of inhibitory immune checkpoints by T cells infiltrating tumour-draining lymph nodes (TDLNs) and tumour tissue post-chemo(radio)therapy at surgical resection was assessed by flow cytometry. Nodal metastases is of equal prognostic importance to clinical tumour stage and tumour regression grade (TRG) in OAC. The TME exhibited a greater immuno-suppressive phenotype than the LNME. Our data suggests that blockade of these checkpoints may have a therapeutic rationale for boosting response rates in OAC.
ChroMo, an Application for Unsupervised Analysis of Chromosome Movements in Meiosis
Authors: León-Periñán Daniel , Fernández-Álvarez Alfonso
Published: August 2021

Nuclear movements during meiotic prophase, driven by cytoskeleton forces, are a broadly conserved mechanism in opisthokonts and plants to promote pairing between homologous chromosomes. These forces are transmitted to the chromosomes by specific associations between telomeres and the nuclear envelope during meiotic prophase. Defective chromosome movements (CMs) harm pairing and recombination dynamics between homologues, thereby affecting faithful gametogenesis. For this reason, modelling the behaviour of CMs and their possible microvariations as a result of mutations or physico-chemical stress is important to understand this crucial stage of meiosis. Current developments in high-throughput imaging and image processing are yielding large CM datasets that are suitable for data mining approaches. To facilitate adoption of data mining pipelines, we present ChroMo, an interactive, unsupervised cloud application specifically designed for exploring CM datasets from live imaging. ChroMo contains a wide selection of algorithms and visualizations for time-series segmentation, motif discovery, and assessment of causality networks. Using ChroMo to analyse meiotic CMs in fission yeast, we found previously undiscovered features of CMs and causality relationships between chromosome morphology and trajectory. ChroMo will be a useful tool for understanding the behaviour of meiotic CMs in yeast and other model organisms.
Challenges and Opportunities of Targeting Astrocytes to Halt Neurodegenerative Disorders
Authors: Valori Chiara F. , Possenti Agostino , Brambilla Liliana , Rossi Daniela
Published: August 2021

Neurodegenerative diseases are a heterogeneous group of disorders whose incidence is likely to duplicate in the next 30 years along with the progressive aging of the western population. Non-cell-specific therapeutics or therapeutics designed to tackle aberrant pathways within neurons failed to slow down or halt neurodegeneration. Yet, in the last few years, our knowledge of the importance of glial cells to maintain the central nervous system homeostasis in health conditions has increased exponentially, along with our awareness of their fundamental and multifaced role in pathological conditions. Among glial cells, astrocytes emerge as promising therapeutic targets in various neurodegenerative disorders. In this review, we present the latest evidence showing the astonishing level of specialization that astrocytes display to fulfill the demands of their neuronal partners as well as their plasticity upon injury. Then, we discuss the controversies that fuel the current debate on these cells. We tackle evidence of a potential beneficial effect of cell therapy, achieved by transplanting astrocytes or their precursors. Afterwards, we introduce the different strategies proposed to modulate astrocyte functions in neurodegeneration, ranging from lifestyle changes to environmental cues. Finally, we discuss the challenges and the recent advancements to develop astrocyte-specific delivery systems.
Effects of Salinity Stress on Chloroplast Structure and Function
Authors: Hameed Abdul , Ahmed Muhammad Zaheer , Hussain Tabassum , Aziz Irfan , Ahmad Niaz , Gul Bilquees , Nielsen Brent L.
Published: August 2021

Salinity is a growing problem affecting soils and agriculture in many parts of the world. The presence of salt in plant cells disrupts many basic metabolic processes, contributing to severe negative effects on plant development and growth. This review focuses on the effects of salinity on chloroplasts, including the structures and function of these organelles. Chloroplasts house various important biochemical reactions, including photosynthesis, most of which are considered essential for plant survival. Salinity can affect these reactions in a number of ways, for example, by changing the chloroplast size, number, lamellar organization, lipid and starch accumulation, and interfering with cross-membrane transportation. Research has shown that maintenance of the normal chloroplast physiology is necessary for the survival of the entire plant. Many plant species have evolved different mechanisms to withstand the harmful effects of salt-induced toxicity on their chloroplasts and its machinery. The differences depend on the plant species and growth stage and can be quite different between salt-sensitive (glycophyte) and salt-tolerant (halophyte) plants. Salt stress tolerance is a complex trait, and many aspects of salt tolerance in plants are not entirely clear yet. In this review, we discuss the different mechanisms of salt stress tolerance in plants with a special focus on chloroplast structure and its functions, including the underlying differences between glycophytes and halophytes.
Transcription Control of Liver Development
Authors: Tachmatzidi Evangelia C. , Galanopoulou Ourania , Talianidis Iannis
Published: August 2021

During liver organogenesis, cellular transcriptional profiles are constantly reshaped by the action of hepatic transcriptional regulators, including FoxA1-3, GATA4/6, HNF1α/β, HNF4α, HNF6, OC-2, C/EBPα/β, Hex, and Prox1. These factors are crucial for the activation of hepatic genes that, in the context of compact chromatin, cannot access their targets. The initial opening of highly condensed chromatin is executed by a special class of transcription factors known as pioneer factors. They bind and destabilize highly condensed chromatin and facilitate access to other “non-pioneer” factors. The association of target genes with pioneer and non-pioneer transcription factors takes place long before gene activation. In this way, the underlying gene regulatory regions are marked for future activation. The process is called “bookmarking”, which confers transcriptional competence on target genes. Developmental bookmarking is accompanied by a dynamic maturation process, which prepares the genomic loci for stable and efficient transcription. Stable hepatic expression profiles are maintained during development and adulthood by the constant availability of the main regulators. This is achieved by a self-sustaining regulatory network that is established by complex cross-regulatory interactions between the major regulators. This network gradually grows during liver development and provides an epigenetic memory mechanism for safeguarding the optimal expression of the regulators.
Physcion Induces Potential Anticancer Effects in Cervical Cancer Cells
Authors: Trybus Wojciech , Król Teodora , Trybus Ewa , Stachurska Anna
Published: August 2021

Background: The extent of morphological and ultrastructural changes in HeLa cells was assessed by optical, fluorescence and electron microscopy after exposure to various concentrations of physcion, taking into account the biological properties of the test compound. Methods: Cell viability was assessed by MTT assay, while the cell cycle, LC3 expression, apoptosis, change of mitochondrial potential, Bcl-2 protein expression level and the level of reactive oxygen species were analyzed by flow cytometry. Results: As a result of physcion encumbrance, concentration-dependent inhibition of HeLa cell viability and the G0/G1 phase of the cell cycle was observed. Activation of the lysosomal system was also revealed, which was expressed by an increased number of lysosomes, autophage vacuoles and increased expression of the LC3 protein, a marker of the autophagy process. Transmission electron microscopy and fluorescence microscopy showed that physcion induced clear changes in cervical cancer cells, especially in the structure of the nucleus and mitochondria, which correlated with the production of reactive oxygen species by the test compound and indicated the induction of the oxidative process. At the same time, the pro-apoptotic effect of physcion was demonstrated, and this mechanism was dependent on the activation of caspases 3/7 and the reduction in Bcl-2 protein expression. Conclusion: The obtained results indicate an antitumor mechanism of action of physcion, based on the induction of oxidative stress, autophagy and apoptosis.
NAFLD-Related Hepatocarcinoma: The Malignant Side of Metabolic Syndrome
Authors: Michelotti Anna , de Scordilli Marco , Palmero Lorenza , Guardascione Michela , Masala Mario , Roncato Rossana , Foltran Luisa , Ongaro Elena , Puglisi Fabio
Published: August 2021

Hepatocellular carcinoma (HCC) is the seventh most common cancer worldwide and the second leading cause of cancer-related mortality. HCC typically arises within a cirrhotic liver, but in about 20% of cases occurs in absence of cirrhosis. Among non-cirrhotic risk factors, non-alcoholic fatty liver disease (NAFLD) currently represents the most important emerging cause of HCC in developed countries. It has been estimated that annual incidence of HCC among patients with non-cirrhotic NAFLD is approximately 0.1–1.3 per 1000 patients/year and ranges from 0.5% to 2.6% among patients with non-alcoholic steatohepatitis (NASH) cirrhosis. However, only a few clinical trials enrolling HCC patients actually distinguished NAFLD/NASH-related cases from other non-cirrhotic causes and therefore evidence is still lacking in this subset of patients. This review aims to describe the biology underpinning NAFLD development, to investigate the main molecular pathways involved in its progression to NASH and HCC and to describe how different pathogenetic mechanisms underlying the onset of HCC can have an impact in clinical practice. We hereby also provide an overview of current HCC treatment options, with a particular focus on the available data on NAFLD-related cases in practice-changing clinical trials.
Severe Hepatic Insulin Resistance Induces Vascular Dysfunction: Improvement by Liver-Specific Insulin Receptor Isoform A Gene Therapy in a Murine Diabetic Model
Authors: Gómez-Hernández Almudena , de las Heras Natalia , López-Pastor Andrea R. , García-Gómez Gema , Infante-Menéndez Jorge , González-López Paula , González-Illanes Tamara , Lahera Vicente , Benito Manuel , Escribano Óscar
Published: August 2021

Background: Cardiovascular dysfunction is linked to insulin-resistant states. In this paper, we analyzed whether the severe hepatic insulin resistance of an inducible liver-specific insulin receptor knockout (iLIRKO) might generate vascular insulin resistance and dysfunction, and whether insulin receptor (IR) isoforms gene therapy might revert it. Methods: We studied in vivo insulin signaling in aorta artery and heart from iLIRKO. Vascular reactivity and the mRNA levels of genes involved in vascular dysfunction were analyzed in thoracic aorta rings by qRT-PCR. Finally, iLIRKO mice were treated with hepatic-specific gene therapy to analyze vascular dysfunction improvement. Results: Our results suggest that severe hepatic insulin resistance was expanded to cardiovascular tissues. This vascular insulin resistance observed in aorta artery from iLIRKO mice correlated with a reduction in both PI3K/AKT/eNOS and p42/44 MAPK pathways, and it might be implicated in their vascular alterations characterized by endothelial dysfunction, hypercontractility and eNOS/iNOS levels’ imbalance. Finally, regarding long-term hepatic expression of IR isoforms, IRA was more efficient than IRB in the improvement of vascular dysfunction observed in iLIRKO mice. Conclusion: Severe hepatic insulin resistance is sufficient to produce cardiovascular insulin resistance and dysfunction. Long-term hepatic expression of IRA restored the vascular damage observed in iLIRKO mice.
Evaluating the Effect of a Brewery By-Product as Feed Supplementation on the Quality of Eggs by Means of a Human Panel and E-Tongue and E-Nose Analysis
Authors: Aguinaga Bósquez Juan Pablo , Kovacs Zoltan , Gillay Zoltán , Bázár György , Palkó Csaba , Hingyi Hajnalka , Csavajda Éva , Üveges Márta , Jókainé Szatura Zsuzsanna , Barbulescu Iuliana Diana , Begea Mihaela , Tóth Tamás
Published: August 2021

The objective of our research was to evaluate the possible alteration of the organoleptic properties of eggs produced by hens (Lohmann Brown-Classic) fed with diets containing different doses of an industrial by-product enriched with organic zinc (Zincoppyeast, ZP): Control 0%, ZP 2.5%, and ZP 5.0%. Eggs were collected after 30 days (batch 1) and 60 days (batch 2) of feeding with the experimental diets and subjected to chemical, microbiological, human sensory, e-nose, and e-tongue analyses. There was no significant difference among the microbiological status of eggs of the three groups, but there were significant differences (p < 0.05) in the fat (9.5% vs. 9.3%) and protein contents (12.7% vs. 13.4%) of the Control and ZP 5.0% groups, respectively. Human sensory analysis showed no clear change in the organoleptic characteristics of the eggs. Using linear discriminant analysis (LDA), the e-tongue could recognize the three groups of eggs in batch 1 and batch 2 with 95.9% and 100% accuracy and had a prediction accuracy of 64.8% and 56.2%, respectively. When the eggs were incubating at 50 °C or 80 °C before the e-nose analysis, the groups of eggs could be recognized with 98.0% and 82.7% accuracy, and predicted with 68.5% and 62.2% accuracy, respectively, using principal component analysis-based discriminant analysis (PCA–DA). The aroma compounds and respective sensory descriptors showing changes among the different groups of eggs (batch, storage, and feeding) were identified based on the e-nose analysis. The supplementation of laying hens’ feed with the investigated industrial by-product can be applied without any substantial effect on egg quality, which can, however, be detected with advanced analytical methods.
Perovskite@Graphene Nanohybrids for Breath Analysis: A Proof-of-Concept
Authors: Casanova-Chafer Juan , Garcia-Aboal Rocio , Atienzar Pedro , Bittencourt Carla , Llobet Eduard
Published: August 2021

Nanohybrids comprising graphene loaded with perovskite nanocrystals have been demonstrated as a potential option for sensing applications. Specifically, their combination presents an interesting synergistic effect owing to greater sensitivity when bare graphene is decorated with perovskites. In addition, since the main drawback of perovskites is their instability towards ambient moisture, the hydrophobic properties of graphene can protect them, enabling their use for ambient monitoring, as previously reported. However not limited to this, the present work provides a proof-of-concept to likewise employ them in a potential application as breath analysis for the detection of health-related biomarkers. There is a growing demand for sensitive, non-invasive, miniaturized, and inexpensive devices able to detect specific gas molecules in human breath. Sensors gathering these requirements may be employed as a screening tool for reliable and fast detection of potential health issues. Moreover, perovskite@graphene nanohybrids present additional properties highly desirable as the capability to be operated at room temperature (i.e., reduced power consumption), reversible interaction with gases (i.e., reusability), and long-term stability. Within this perspective, the combination of both nanomaterials, perovskite nanocrystals and graphene, possibly includes the main requirements needed, being a promising option to be employed in the next generation of sensing devices.
Shining a Light on the Challenging Behaviors of Adolescents with Comorbid Diagnoses: Use of Pictorial Concurrent Operant Preference Assessment
Authors: Zhou Zhichun , McAdam David Burrell , Napolitano Deborah Ann , Douthit Kathryn
Published: August 2021

Currently, there are no published studies that have used the concurrent operant preference assessment procedure to identify functions of challenging behaviors displayed by individuals with comorbid diagnoses. Four participants (aged 11–16 years) with comorbid diagnoses who displayed multiple challenging behaviors were referred to this study. We modified the standard concurrent operant preference assessment and used the new modified version, the pictorial concurrent operant preference assessment, to identify the functions of the challenging behaviors. Utilizing the triangulation mixed-methods design, we compared the indirect functional behavioral assessment (FBA) and the direct FBA with the pictorial concurrent operant preference assessment. The results obtained successfully demonstrated the concordance among these assessments in identifying the behavioral function for each participant. The results further showed that (1) the preferences served the same functional effects on both the challenging behaviors and the adaptive behaviors and (2) the pictorial concurrent operant preference assessment can be used independently to identify potential behavioral function and to specify the reinforcing potency of each behavioral function. The significance of the study results, limitations of this study, and directions for future research and clinical practice are discussed.