bluuebunny/crossref_metadata_2025 huggingface dataset:
The Influence of Skin Thickness on Flash Glucose Monitoring System Accuracy in Dogs with Diabetes Mellitus
Authors: Del Baldo Francesca , Diana Alessia , Canton Claudia , Linta Nikolina , Chiocchetti Roberto , Fracassi Federico
Published: February 2021

A flash glucose monitoring system (FGMS) has been validated for use in diabetic dogs. However, it is unknown whether skin thickness affects FGMS measurements. The aim of this study was to evaluate whether FGMS accuracy is affected by skin thickness. Fourteen client-owned diabetic dogs on insulin treatment were prospectively enrolled in the study. The dogs were divided into two groups according to their ultrasound-measured skin thickness: dogs with skin thickness < 5 mm (Group 1) and dogs with skin thickness > 5 mm (Group 2). On days 1, 7 and 14, glucose curves were obtained simultaneously using the FGMS and a validated portable blood glucose meter. Paired measurements were used to calculate the mean bias and to determine accuracy according to ISO 15197:2013 criteria. The mean bias was significantly inversely correlated (p = 0.02; r = −0.6) with the mean skin thickness. Clinical accuracy was observed only in Group 2, with 99% of the results in zone A + B of the Parkes consensus error grid analysis. In conclusion, skin thickness seems to affect FGMS measurements, and the device is accurate in dogs with thicker skin (>5 mm); in dogs with thin skin (<5 mm), the clinical accuracy is low, and the results should be interpreted with caution.
Selection Criteria for Improving Fertility in Spanish Goat Breeds: Estimation of Genetic Parameters and Designing Selection Indices for Optimal Genetic Responses
Authors: Ziadi Chiraz , Muñoz-Mejías Eva , Sánchez Manuel , López María Dolores , González-Casquet Olga , Molina Antonio
Published: February 2021

The aim of this study was to estimate genetic parameters for several female fertility criteria and to choose the most suitable selection index in Spanish Florida and Payoya goat breeds. In this study, we analyzed as fertility traits, the age at first kidding (AgFiKid), and the interval between the first and second kiddings (Int12Kid), between the second, third, and remaining kiddings (Int3toKid), and between all kiddings (IntAllKid) in 51,123 and 22,049 Florida and Payoya females, respectively. Genetic parameters were estimated by fitting animal models using restricted maximum likelihood (REML) methodology. We proposed six selection indices to compare the genetic responses for all traits included, based on a new selection index theory. The heritability and repeatability estimates of the traits were low, as expected. The genetic correlations among fertility traits covered a wide range of values from 0.07 (AgFiKid-Int12Kid) to 0.71 (Int3toKid-IntAllKid) in Florida and from −0.02 (AgFiKid-Int12Kid) to 0.82 (Int3toKid-IntAllKid) in Payoya. Overall, the results of this study indicate that IntAllKid gives the highest genetic responses in both breeds but is expressed late in a female’s life. However, AgFiKid and Int12Kid could be recommended as early selection criteria for female fertility in both breeds.
Trastuzumab Blocks the Receiver Function of HER2 Leading to the Population Shifts of HER2-Containing Homodimers and Heterodimers
Authors: Zhao Jun , Mohan Nishant , Nussinov Ruth , Ma Buyong , Wu Wen Jin
Published: February 2021

HER2, a member of the Erythroblastosis Protein B/Human Epidermal Growth Factor Receptor (ErbB/HER) family of receptor tyrosine kinase, is overexpressed in 20~30% of human breast cancers. Trastuzumab, a HER2-targeted therapeutic monoclonal antibody, was developed to interfere with the homodimerization of HER2 in HER2-overexpressing breast cancer cells, which attenuates HER2-mediated signaling. Trastuzumab binds to the domain IV of the HER2 extracellular domain and does not directly block the dimerization interface of HER2-HER2 molecules. The three-dimensional structures of the tyrosine kinase domains of ErbB/HER family receptors show asymmetrical packing of the two monomers with distinct conformations. One monomer functions as an activator, whereas the other acts as a receiver. Once activated, the receiver monomer phosphorylates the activator or other proteins. Interestingly, in our previous work, we found that the binding of trastuzumab induced phosphorylation of HER2 with the phosphorylation pattern of HER2 that is different from that mediated by epidermal growth factor (EGF) in human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Binding of trastuzumab to HER2 promoted an allosteric effect of HER2, in both tyrosine kinase domain and ectodomain of HER2 although details of allosteric regulation were missing. In this study, we utilized molecular dynamics (MD) simulations to model the allosteric consequences of trastuzumab binding to HER2 homodimers and heterodimers, along with the apo forms as controls. We focused on the conformational changes of HER2 in its monomeric and dimeric forms. The data indicated the apparent dual role of trastuzumab as an antagonist and an agonist. The molecular details of the simulation provide an atomic level description and molecular insight into the action of HER2-targeted antibody therapeutics.
Synergistic Activity of Equol and Meropenem against Carbapenem-Resistant Escherichia coli
Authors: Kim Hye-Rim , Eom Yong-Bin
Published: February 2021

The emergence of carbapenem-resistant Enterobacterales (CRE) seriously limits treatment options for bacterial infections. Combined drugs are an effective strategy to treat these resistant strains. This study aimed to evaluate the synergistic effect of equol and meropenem against carbapenem-resistant Escherichia coli. First, this study investigated the antibacterial activity of carbapenems on clinically isolated E. coli strains by analyzing the minimum inhibitory concentrations (MICs). The E. coli strains were all resistant to carbapenem antibiotics. Therefore, we confirmed the cause of carbapenem resistance by detecting blaKPC and blaOXA-48 among the carbapenemase genes using polymerase chain reaction (PCR) analysis. Checkerboard and time-kill analyses confirmed that equol restored the susceptibility of carbapenem-resistant E. coli to meropenem. Also, the transcription levels of specific carbapenemase genes in E. coli were significantly suppressed by equol. The study also evaluated the anti-virulence effects of equol on bacterial biofilm and motility through phenotypic and genotypic analyses. In conclusion, our results revealed that equol had a synergistic effect with meropenem on carbapenem-resistant E. coli. Therefore, this study suggests that equol is a promising antibiotic adjuvant that prevents the expression of carbapenemases and virulence factors in carbapenem-resistant E. coli.
Sulfaguanidine Hybrid with Some New Pyridine-2-One Derivatives: Design, Synthesis, and Antimicrobial Activity against Multidrug-Resistant Bacteria as Dual DNA Gyrase and DHFR Inhibitors
Authors: Ragab Ahmed , Fouad Sawsan A. , Ali Ola A. Abu , Ahmed Entsar M. , Ali Abeer M. , Askar Ahmed A. , Ammar Yousry A.
Published: February 2021

Herein, a series of novel hybrid sulfaguanidine moieties, bearing 2-cyanoacrylamide 2a–d, pyridine-2-one 3–10, and 2-imino-2H-chromene-3-carboxamide 11, 12 derivatives, were synthesized, and their structure confirmed by spectral data and elemental analysis. All the synthesized compounds showed moderate to good antimicrobial activity against eight pathogens. The most promising six derivatives, 2a, 2b, 2d, 3a, 8, and 11, revealed to be best in inhibiting bacterial and fungal growth, thus showing bactericidal and fungicidal activity. These derivatives exhibited moderate to potent inhibition against DNA gyrase and DHFR enzymes, with three derivatives 2d, 3a, and 2a demonstrating inhibition of DNA gyrase, with IC50 values of 18.17–23.87 µM, and of DHFR, with IC50 values of 4.33–5.54 µM; their potency is near to that of the positive controls. Further, the six derivatives exhibited immunomodulatory potential and three derivatives, 2d, 8, and 11, were selected for further study and displayed an increase in spleen and thymus weight and enhanced the activation of CD4+ and CD8+ T lymphocytes. Finally, molecular docking and some AMED studies were performed.
Effects of the Licorice Isoflavans Licoricidin and Glabridin on the Growth, Adherence Properties, and Acid Production of Streptococcus mutans, and Assessment of Their Biocompatibility
Authors: Vaillancourt Katy , LeBel Geneviève , Pellerin Geneviève , Ben Lagha Amel , Grenier Daniel
Published: February 2021

Pharmacological studies have linked a number of human health benefits with licorice due to its anticancer, anti-inflammatory, anti-oxidant, and antimicrobial properties. The aim of this study was to investigate the effects of licoricidin and glabridin, two major licorice isoflavans, on growth and virulence properties (biofilm formation, acid production, dextran production, adherence) of the cariogenic bacterium Streptococcus mutans. Moreover, the biocompatibility of these licorice compounds was assessed in an in vitro model of oral keratinocytes. We used a broth microdilution assay to show that licoricidin and glabridin exhibit a marked antibacterial activity against S. mutans. Glabridin and, to a lesser extent, licoricidin reduced the biofilm viability of S. mutans. In addition, glabridin decreased the production of dextran by S. mutans. The two licorice isoflavans attenuated the adherence of S. mutans to a saliva-coated hydroxylapatite surface, and reduced acid production from glucose. Lastly, depending on the concentrations tested, the two licorice isoflavans showed no or low toxicity toward oral keratinocytes. Within the limitations of this study, our data suggest that licoricidin and glabridin may be promising agents for controlling dental caries.
Olive Fruit and Leaf Wastes as Bioactive Ingredients for Cosmetics—A Preliminary Study
Authors: Cádiz-Gurrea María de la Luz , Pinto Diana , Delerue-Matos Cristina , Rodrigues Francisca
Published: February 2021

Olea europaea cultivar, native in the Mediterranean basin, has expanded worldwide, mainly due to the olive oil industry. This expansion is attributed to the benefits of olive oil consumption, since this product is rich in nutritional and bioactive compounds. However, the olive industry generates high amounts of wastes, which could be related to polluting effects on soil and water. To minimize the environmental impact, different strategies of revalorization have been proposed. In this sense, the aim of this work was to develop high cosmetic value added oleuropein-enriched extracts (O20 and O30), a bioactive compound from olive byproducts, performing a comprehensive characterization using high performance liquid chromatography coupled to mass spectrometry and evaluate their bioactivity by in vitro assays. A total of 49 compounds were detected, with oleuropein and its derivatives widely found in O30 extract, whereas iridoids were mainly detected in O20 extract. Moreover, 10 compounds were detected for the first time in olive leaves. Both extracts demonstrated strong antioxidant and antiradical activities, although O30 showed higher values. In addition, radical oxygen and nitrogen species scavenging and enzyme inhibition values were higher in O30, with the exception of HOCl and hyaluronidase inhibition assays. Regarding cell viability, olive byproduct extracts did not lead to a decrease in keratinocytes viability until 100 µg/mL. All data reported by the present study reflect the potential of industrial byproducts as cosmetic ingredients.
Renoprotective Effects of DPP-4 Inhibitors
Authors: Kawanami Daiji , Takashi Yuichi , Takahashi Hiroyuki , Motonaga Ryoko , Tanabe Makito
Published: February 2021

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD) worldwide. Dipeptidyl peptidase (DPP)-4 inhibitors are widely used in the treatment of patients with type 2 diabetes (T2D). DPP-4 inhibitors reduce glucose levels by inhibiting degradation of incretins. DPP-4 is a ubiquitous protein with exopeptidase activity that exists in cell membrane-bound and soluble forms. It has been shown that an increased renal DPP-4 activity is associated with the development of DKD. A series of clinical and experimental studies showed that DPP-4 inhibitors have beneficial effects on DKD, independent of their glucose-lowering abilities, which are mediated by anti-fibrotic, anti-inflammatory, and anti-oxidative stress properties. In this review article, we highlight the current understanding of the clinical efficacy and the mechanisms underlying renoprotection by DPP-4 inhibitors under diabetic conditions.
The XSTAR Atomic Database
Authors: Mendoza Claudio , Bautista Manuel A. , Deprince Jérôme , García Javier A. , Gatuzz Efraín , Gorczyca Thomas W. , Kallman Timothy R. , Palmeri Patrick , Quinet Pascal , Witthoeft Michael C.
Published: February 2021

We describe the atomic database of the xstar spectral modeling code, summarizing the systematic upgrades carried out in the past twenty years to enable the modeling of K-lines from chemical elements with atomic number Z≤30 and recent extensions to handle high-density plasmas. Such plasma environments are found, for instance, in the inner region of accretion disks round compact objects (neutron stars and black holes), which emit rich information about the system’s physical properties. Our intention is to offer a reliable modeling tool to take advantage of the outstanding spectral capabilities of the new generation of X-ray space telescopes (e.g., xrism and athena) to be launched in the coming years. Data curatorial aspects are discussed and an updated list of reference sources is compiled to improve the database provenance metadata. Two xstar spin-offs—the ISMabs absorption model and the uaDB database—are also described.
SARS-CoV-2 and Rohingya Refugee Camp, Bangladesh: Uncertainty and How the Government Took Over the Situation
Authors: Kamrujjaman Md. , Mahmud Md. Shahriar , Ahmed Shakil , Qayum Md. Omar , Alam Mohammad Morshad , Hassan Md Nazmul , Islam Md Rafiul , Nipa Kaniz Fatema , Bulut Ummugul
Published: February 2021

Background: Bangladesh hosts more than 800,000 Rohingya refugees from Myanmar. The low health immunity, lifestyle, access to good healthcare services, and social-security cause this population to be at risk of far more direct effects of COVID-19 than the host population. Therefore, evidence-based forecasting of the COVID-19 burden is vital in this regard. In this study, we aimed to forecast the COVID-19 obligation among the Rohingya refugees of Bangladesh to keep up with the disease outbreak’s pace, health needs, and disaster preparedness. Methodology and Findings: To estimate the possible consequences of COVID-19 in the Rohingya camps of Bangladesh, we used a modified Susceptible-Exposed-Infectious-Recovered (SEIR) transmission model. All of the values of different parameters used in this model were from the Bangladesh Government’s database and the relevant emerging literature. We addressed two different scenarios, i.e., the best-fitting model and the good-fitting model with unique consequences of COVID-19. Our best fitting model suggests that there will be reasonable control over the transmission of the COVID-19 disease. At the end of December 2020, there will be only 169 confirmed COVID-19 cases in the Rohingya refugee camps. The average basic reproduction number (R0) has been estimated to be 0.7563. Conclusions: Our analysis suggests that, due to the extensive precautions from the Bangladesh government and other humanitarian organizations, the coronavirus disease will be under control if the maintenance continues like this. However, detailed and pragmatic preparedness should be adopted for the worst scenario.
Nettle-Leaf Extract Derived ZnO/CuO Nanoparticle-Biopolymer-Based Antioxidant and Antimicrobial Nanocomposite Packaging Films and Their Impact on Extending the Post-Harvest Shelf Life of Guava Fruit
Authors: Kalia Anu , Kaur Manpreet , Shami Ashwag , Jawandha Sukhjit Kaur , Alghuthaymi Mousa A. , Thakur Anirudh , Abd-Elsalam Kamel A.
Published: February 2021

Green synthesized metal oxide nanoparticles (NPs) have prominent applications in antimicrobial packaging systems. Here we have attempted for the fabrication of chitosan-based nanocomposite film containing Urtica dioica leaf extract derived copper oxide (CuO) and zinc oxide (ZnO) NPs for shelf-life extension of the packaged guava fruits. Electron microscopy and spectroscopy analysis of the CuO and ZnO NPs exhibited nano-scale size, spherical morphologies, and negative ζ-potential values. The NPs possessed appreciable antioxidant and antimicrobial activity (AMA) in order of CuO NPs > ZnO NPs > nettle extract. Therefore, this work establishes for the first time the successful synthesis of CuO NPs and compares its antimicrobial and antioxidant properties with ZnO NPs. On incorporation in chitosan, the polymer nanocomposite films were developed by solvent casting technique. The developed films were transparent, had low antioxidant but substantial AMA. The NP supplementation improved the film characteristics as evident from the decrease in moisture content, water holding capacity, and solubility of the films. The nanocomposite films improved the quality attributes and shelf life of guava fruits by one week on packaging and storage compared to unpackaged control fruits. Therefore, this study demonstrates the higher antimicrobial potential of the nettle leaf extract derived CuO/ZnO NPs for development of antimicrobial nanocomposite films as a promising packaging solution for enhancing the shelf life of various perishable fruits.
Is Chronic Exposure to Raw Water a Possible Risk Factor for Amyotrophic Lateral Sclerosis? A Pilot Case-Control Study
Authors: Stipa Giuseppe , Ancidoni Antonio , Mazzola Monica , Testai Emanuela , Funari Enzo , Spera Cristina , Fanelli Cinzia , Mancini Alessia , Vanacore Nicola
Published: February 2021

Background: The etiopathogenesis of amyotrophic lateral sclerosis (ALS) is still largely unknown. Methods: We performed a case-control study (33 cases and 35 controls) in Umbria, Italy. We investigated associations between common lifestyle, clinical factors, as well as environmental exposures potentially implicated with ALS onset. Face-to-face interviews were carried out. All cases were recruited and diagnosed according to El Escorial criteria. Case-control comparisons were made for educational and residential status, occupational exposures, and clinical and lifestyle factors prior to cases’ dates of diagnosis. Results: Our results showed an increased risk of ALS for subjects chronically exposed to raw water use (odds ratio (OR) = 6.55, 95% confidence interval (CI): 2.24–19.12). Garden activities showed a tight association with ALS as well, very likely as a consequence of chronic raw water exposure. Indeed, we could exclude an impact for pesticides, as no significant differences were observed in pesticide exposure in the two groups interviewed. However, cases were more often exposed to fertilizers. After adjustment for age, sex, and heavy physical activities, exposure to raw water was still associated with increased ALS risk (OR = 4.74, 95% CI: 1.33–16.85). Discussion: These findings suggest an association between ALS and exposure to raw water, which should be further investigated for the presence of chemicals interfering with nervous system functionality.
In Search of a Cure: The Development of Therapeutics to Alter the Progression of Spinal Muscular Atrophy
Authors: Ojala Kristine S. , Reedich Emily J. , DiDonato Christine J. , Meriney Stephen D.
Published: February 2021

Until the recent development of disease-modifying therapeutics, spinal muscular atrophy (SMA) was considered a devastating neuromuscular disease with a poor prognosis for most affected individuals. Symptoms generally present during early childhood and manifest as muscle weakness and progressive paralysis, severely compromising the affected individual’s quality of life, independence, and lifespan. SMA is most commonly caused by the inheritance of homozygously deleted SMN1 alleles with retention of one or more copies of a paralog gene, SMN2, which inversely correlates with disease severity. The recent advent and use of genetically targeted therapies have transformed SMA into a prototype for monogenic disease treatment in the era of genetic medicine. Many SMA-affected individuals receiving these therapies achieve traditionally unobtainable motor milestones and survival rates as medicines drastically alter the natural progression of this disease. This review discusses historical SMA progression and underlying disease mechanisms, highlights advances made in therapeutic research, clinical trials, and FDA-approved medicines, and discusses possible second-generation and complementary medicines as well as optimal temporal intervention windows in order to optimize motor function and improve quality of life for all SMA-affected individuals.
Carbon Nanotubes Transform Soft Gellan Gum Hydrogels into Hybrid Organic–Inorganic Coatings with Excellent Cell Growth Capability
Authors: Abalymov Anatolii , Van der Meeren Louis , Volodkin Dmitry , Parakhonskiy Bogdan , Skirtach Andre G.
Published: February 2021

Carbone nanotubes (CNTs) possess distinct properties, for example, hardness, which is very complementary to biologically relevant soft polymeric and protein materials. Combining CNTs with bio-interfaces leads to obtaining new materials with advanced properties. In this work, we have designed novel organic-inorganic hybrid coatings by combining CNTs with gellan gum (GG) hydrogels. The surface topography of the samples is investigated using scanning electron microscopy and atomic force microscopy. Mechanical properties of synthesized hybrid materials are both assessed at the macro-scale and mapped at the nanoscale. A clear correlation between the CNT concentration and the hardness of the coatings is revealed. Cell culture studies show that effective cell growth is achieved at the CNT concentration of 15 mg/mL. The presented materials can open new perspectives for hybrid bio-interfaces and can serve as a platform for advanced cell culture.
The Immune Microenvironment in Multiple Myeloma: Friend or Foe?
Authors: Lopes Raquel , Caetano Joana , Ferreira Bruna , Barahona Filipa , Carneiro Emilie Arnault , João Cristina
Published: February 2021

Multiple myeloma (MM) is one of the most prevalent hematological cancers worldwide, characterized by the clonal expansion of neoplastic plasma cells in the bone marrow (BM). A combination of factors is implicated in disease progression, including BM immune microenvironment changes. Increasing evidence suggests that the disruption of immunological processes responsible for myeloma control ultimately leads to the escape from immune surveillance and resistance to immune effector function, resulting in an active form of myeloma. In fact, one of the hallmarks of MM is the development of a permissive BM milieu that provides a growth advantage to the malignant cells. Consequently, a better understanding of how myeloma cells interact with the BM niche compartments and disrupt the immune homeostasis is of utmost importance to develop more effective treatments. This review focuses on the most up-to-date knowledge regarding microenvironment-related mechanisms behind MM immune evasion and suppression, as well as promising molecules that are currently under pre-clinical tests targeting immune populations.
Remission-Stage Ovarian Cancer Cell Vaccine with Cowpea Mosaic Virus Adjuvant Prevents Tumor Growth
Authors: Stump Courtney T. , Ho Gregory , Mao Chenkai , Veliz Frank A. , Beiss Veronique , Fields Jennifer , Steinmetz Nicole F. , Fiering Steven
Published: February 2021

Ovarian cancer is the deadliest gynecological malignancy. Though most patients enter remission following initial interventions, relapse is common and often fatal. Accordingly, there is a substantial need for ovarian cancer therapies that prevent relapse. Following remission generated by surgical debulking and chemotherapy, but prior to relapse, resected and inactivated tumor tissue could be used as a personalized vaccine antigen source. The patient’s own tumor contains relevant antigens and, when combined with the appropriate adjuvant, could generate systemic antitumor immunity to prevent relapse. Here, we model this process in mice to investigate the optimal tumor preparation and vaccine adjuvant. Cowpea mosaic virus (CPMV) has shown remarkable efficacy as an immunostimulatory cancer therapy in ovarian cancer mouse models, so we use CPMV as an adjuvant in a prophylactic vaccine against a murine ovarian cancer model. Compared to its codelivery with tumor antigens prepared in three other ways, we show that CPMV co-delivered with irradiated ovarian cancer cells constitutes an effective prophylactic vaccine against a syngeneic model of ovarian cancer in C57BL/6J mice. Following two vaccinations, 72% of vaccinated mice reject tumor challenges, and all those mice survived subsequent rechallenges, demonstrating immunologic memory formation. This study supports remission-stage vaccines using irradiated patient tumor tissue as a promising option for treating ovarian cancer, and validates CPMV as an antitumor vaccine adjuvant for that purpose.
MicroRNA Profile for Diagnostic and Prognostic Biomarkers in Thyroid Cancer
Authors: Park Jong-Lyul , Kim Seon-Kyu , Jeon Sora , Jung Chan-Kwon , Kim Yong-Sung
Published: February 2021

The challenge in managing thyroid nodules is to accurately diagnose the minority of those with malignancy. We aimed to identify diagnostic and prognostic miRNA markers for thyroid nodules. In a discovery cohort, we identified 20 candidate miRNAs to differentiate between noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) and papillary thyroid carcinomas (PTC) by using the high-throughput small RNA sequencing method. We then selected three miRNAs (miR-136, miR-21, and miR-127) that were differentially expressed between the PTC follicular variant and other variants in The Cancer Genome Atlas data. High expression of three miRNAs differentiated thyroid cancer from nonmalignant tumors, with an area under curve (AUC) of 0.76–0.81 in an independent cohort. In patients with differentiated thyroid cancer, the high-level expression of the three miRNAs was an independent indicator for both distant metastases and recurrent or persistent disease. In patients with PTC, a high expression of miRNAs was associated with an aggressive histologic variant, extrathyroidal extension, distant metastasis, or recurrent or persistent disease. Three miRNAs may be used as diagnostic markers for differentiating thyroid cancers from benign tumors and tumors with extremely low malignant potential (NIFTP), as well as prognostic markers for predicting the risk of recurrent/persistent disease for differentiated thyroid cancer.
Anticancer Therapy with HDAC Inhibitors: Mechanism-Based Combination Strategies and Future Perspectives
Authors: Jenke Robert , Reßing Nina , Hansen Finn K. , Aigner Achim , Büch Thomas
Published: February 2021

The increasing knowledge of molecular drivers of tumorigenesis has fueled targeted cancer therapies based on specific inhibitors. Beyond “classic” oncogene inhibitors, epigenetic therapy is an emerging field. Epigenetic alterations can occur at any time during cancer progression, altering the structure of the chromatin, the accessibility for transcription factors and thus the transcription of genes. They rely on post-translational histone modifications, particularly the acetylation of histone lysine residues, and are determined by the inverse action of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Importantly, HDACs are often aberrantly overexpressed, predominantly leading to the transcriptional repression of tumor suppressor genes. Thus, histone deacetylase inhibitors (HDACis) are powerful drugs, with some already approved for certain hematological cancers. Albeit HDACis show activity in solid tumors as well, further refinement and the development of novel drugs are needed. This review describes the capability of HDACis to influence various pathways and, based on this knowledge, gives a comprehensive overview of various preclinical and clinical studies on solid tumors. A particular focus is placed on strategies for achieving higher efficacy by combination therapies, including phosphoinositide 3-kinase (PI3K)-EGFR inhibitors and hormone- or immunotherapy. This also includes new bifunctional inhibitors as well as novel approaches for HDAC degradation via PROteolysis-TArgeting Chimeras (PROTACs).
Shorter Survival after Liver Pedicle Clamping in Patients Undergoing Liver Resection for Hepatocellular Carcinoma Revealed by a Systematic Review and Meta-Analysis
Authors: Wassmer Charles-Henri , Moeckli Beat , Berney Thierry , Toso Christian , Orci Lorenzo A.
Published: February 2021

Liver pedicle clamping minimizes surgical bleeding during hepatectomy. However, by inducing ischemia-reperfusion injury to the remnant liver, pedicle clamping may be associated with tumor recurrence in the regenerating liver. Hepatocellular carcinoma (HCC) having a high rate of recurrence, evidences demonstrating an eventual association with pedicle clamping is strongly needed. We did a systematic review of the literature until April 2020, looking at studies reporting the impact of liver pedicle clamping on long-term outcomes in patients undergoing liver resection for HCC. Primary and secondary outcomes were overall survival (OS) and disease-free survival, respectively. Results were obtained by random-effect meta-analysis and expressed as standardized mean difference (SMD). Eleven studies were included, accounting for 8087 patients. Results of seven studies were pooled in a meta-analysis. Findings indicated that, as compared to control patients who did not receive liver pedicle clamping, those who did had a significantly shorter OS (SMD = −0.172, 95%CI: −0.298 to −0.047, p = 0.007, I2 = 76.8%) and higher tumor recurrence rates (odds ratio 1.36 1.01 to 1.83. p = 0.044, I2 = 50.7%). This meta-analysis suggests that liver pedicle clamping may have a deleterious impact on long-term outcomes. An individual patient-data meta-analysis of randomized trials evaluating liver pedicle clamping is urgently needed.
Follicular Lymphoma Microenvironment: An Intricate Network Ready for Therapeutic Intervention
Authors: Dobaño-López Cèlia , Araujo-Ayala Ferran , Serrat Neus , Valero Juan G. , Pérez-Galán Patricia
Published: February 2021

Follicular Lymphoma (FL), the most common indolent non-Hodgkin’s B cell lymphoma, is a paradigm of the immune microenvironment’s contribution to disease onset, progression, and heterogeneity. Over the last few years, state-of-the-art technologies, including whole-exome sequencing, single-cell RNA sequencing, and mass cytometry, have precisely dissected the specific cellular phenotypes present in the FL microenvironment network and their role in the disease. In this already complex picture, the presence of recurring mutations, including KMT2D, CREBBP, EZH2, and TNFRSF14, have a prominent contributory role, with some of them finely tuning this exquisite dependence of FL on its microenvironment. This precise characterization of the enemy (FL) and its allies (microenvironment) has paved the way for the development of novel therapies aimed at dismantling this contact network, weakening tumor cell support, and reactivating the host’s immune response against the tumor. In this review, we will describe the main microenvironment actors, together with the current and future therapeutic approaches targeting them.
Biomarkers of Response to Etoposide-Platinum Chemotherapy in Patients with Grade 3 Neuroendocrine Neoplasms
Authors: Lacombe Caroline , De Rycke Ophélie , Couvelard Anne , Turpin Anthony , Cazes Aurélie , Hentic Olivia , Gounant Valérie , Zalcman Gérard , Ruszniewski Philippe , Cros Jérôme , de Mestier Louis
Published: February 2021

Etoposide-platinum (EP) chemotherapy has long been the reference treatment for grade 3 neuroendocrine neoplasms (G3 NEN). However, G3 NEN are heterogeneous, including well-differentiated tumors (NET) and poorly differentiated large (LCNEC) or small (SCNEC) cell carcinomas, whose response to EP chemotherapy varies considerably. Our aim was to evaluate predictive biomarkers for the response to EP chemotherapy in G3 NEN. We retrospectively studied 89 patients with lung (42%) and digestive (58%) G3 NEN treated by EP chemotherapy between 2006 and 2020. All cases were centrally reviewed for cytomorphology/Ki-67 and immunohistochemistry of retinoblastoma protein (Rb)/p53/p16, analyzed using a semi-quantitative score. The absence of Rb staining (Rbinap) or the absence of very intense p53 staining (p53inap) were considered inappropriate. Rb staining was also studied as a quantitative marker, the best threshold being determined by ROC curve. Intense p16 staining (p16high) also suggested cell cycle dysregulation. Our primary endpoint was the objective response rate (ORR). We included 10 G3 NET, 31 LCNEC and 48 SCNEC, which showed ORR of 20%, 32% and 75%, respectively (NET vs. NEC, p = 0.040; LCNEC vs. SCNEC, p < 0.001). The ORR was significantly higher in NEN presenting with Rbinap (63% vs. 42%, p = 0.025) and p16high (66% vs. 35%, p = 0.006). Rb < 150 optimally identified responders (AUC = 0.657, p < 0.001). The ORR was 67% in Rb < 150 (vs. 25%, p = 0.005). On multivariate analysis, only Rb < 150 was independently associated with ORR (OR 4.16, 95% CI 1.11–15.53, p = 0.034). We confirm the heterogeneity of the response to EP treatment in G3 NEN. Rb < 150 was the best predictive biomarker for the response to EP, and p53 immunostaining had no additional value.
Genetic Perturbation of Pyruvate Dehydrogenase Kinase 1 Modulates Growth, Angiogenesis and Metabolic Pathways in Ovarian Cancer Xenografts
Authors: Venturoli Carolina , Piga Ilaria , Curtarello Matteo , Verza Martina , Esposito Giovanni , Venuto Santina , Navaglia Filippo , Grassi Angela , Indraccolo Stefano
Published: February 2021

Pyruvate dehydrogenase kinase 1 (PDK1) blockade triggers are well characterized in vitro metabolic alterations in cancer cells, including reduced glycolysis and increased glucose oxidation. Here, by gene expression profiling and digital pathology-mediated quantification of in situ markers in tumors, we investigated effects of PDK1 silencing on growth, angiogenesis and metabolic features of tumor xenografts formed by highly glycolytic OC316 and OVCAR3 ovarian cancer cells. Notably, at variance with the moderate antiproliferative effects observed in vitro, we found a dramatic negative impact of PDK1 silencing on tumor growth. These findings were associated with reduced angiogenesis and increased necrosis in the OC316 and OVCAR3 tumor models, respectively. Analysis of viable tumor areas uncovered increased proliferation as well as increased apoptosis in PDK1-silenced OVCAR3 tumors. Moreover, RNA profiling disclosed increased glucose catabolic pathways—comprising both oxidative phosphorylation and glycolysis—in PDK1-silenced OVCAR3 tumors, in line with the high mitotic activity detected in the viable rim of these tumors. Altogether, our findings add new evidence in support of a link between tumor metabolism and angiogenesis and remark on the importance of investigating net effects of modulations of metabolic pathways in the context of the tumor microenvironment.
Selective Targeting of Cancer-Associated Fibroblasts by Engineered H-Ferritin Nanocages Loaded with Navitoclax
Authors: Sitia Leopoldo , Bonizzi Arianna , Mazzucchelli Serena , Negri Sara , Sottani Cristina , Grignani Elena , Rizzuto Maria Antonietta , Prosperi Davide , Sorrentino Luca , Morasso Carlo , Allevi Raffaele , Sevieri Marta , Silva Filippo , Truffi Marta , Corsi Fabio
Published: February 2021

Cancer-associated fibroblasts (CAFs) are key actors in regulating cancer progression. They promote tumor growth, metastasis formation, and induce drug resistance. For these reasons, they are emerging as potential therapeutic targets. Here, with the aim of developing CAF-targeted drug delivery agents, we functionalized H-ferritin (HFn) nanocages with fibroblast activation protein (FAP) antibody fragments. Functionalized nanocages (HFn-FAP) have significantly higher binding with FAP+ CAFs than with FAP− cancer cells. We loaded HFn-FAP with navitoclax (Nav), an experimental Bcl-2 inhibitor pro-apoptotic drug, whose clinical development is limited by its strong hydrophobicity and toxicity. We showed that Nav is efficiently loaded into HFn (HNav), maintaining its mechanism of action. Incubating Nav-loaded functionalized nanocages (HNav-FAP) with FAP+ cells, we found significantly higher cytotoxicity as compared to non-functionalized HNav. This was correlated with a significantly higher drug release only in FAP+ cells, confirming the specific targeting ability of functionalized HFn. Finally, we showed that HFn-FAP is able to reach the tumor and to target CAFs in a mouse syngeneic model of triple negative breast cancer after intravenous administration. Our data show that HNav-FAP could be a promising tool to enhance specific drug delivery into CAFs, thus opening new therapeutic possibilities focused on tumor microenvironment.
The microRNA let-7b-5p Is Negatively Associated with Inflammation and Disease Severity in Multiple Sclerosis
Authors: Mandolesi Georgia , Rizzo Francesca Romana , Balletta Sara , Stampanoni Bassi Mario , Gilio Luana , Guadalupi Livia , Nencini Monica , Moscatelli Alessandro , Ryan Colleen Patricia , Licursi Valerio , Dolcetti Ettore , Musella Alessandra , Gentile Antonietta , Fresegna Diego , Bullitta Silvia , Caioli Silvia , Vanni Valentina , Sanna Krizia , Bruno Antonio , Buttari Fabio , Castelli Chiara , Presutti Carlo , De Santa Francesca , Finardi Annamaria , Furlan Roberto , Centonze Diego , De Vito Francesca
Published: February 2021

The identification of microRNAs in biological fluids for diagnosis and prognosis is receiving great attention in the field of multiple sclerosis (MS) research but it is still in its infancy. In the present study, we observed in a large sample of MS patients that let-7b-5p levels in the cerebrospinal fluid (CSF) were highly correlated with a number of microRNAs implicated in MS, as well as with a variety of inflammation-related protein factors, showing specific expression patterns coherent with let-7b-5p-mediated regulation. Additionally, we found that the CSF let-7b-5p levels were significantly reduced in patients with the progressive MS compared to patients with relapsing-remitting MS and were negatively correlated with characteristic hallmark processes of the two phases of the disease. Indeed, in the non-progressive phase, let-7b-5p inversely associated with both central and peripheral inflammation; whereas, in progressive MS, the CSF levels of let-7b-5p negatively correlated with clinical disability at disease onset and after a follow-up period. Overall, our results uncovered, by the means of a multidisciplinary approach and multiple statistical analyses, a new possible pleiotropic action of let-7b-5p in MS, with potential utility as a biomarker of MS course.
Brassinin Inhibits Proliferation in Human Liver Cancer Cells via Mitochondrial Dysfunction
Authors: Hong Taeyeon , Ham Jiyeon , Song Jisoo , Song Gwonhwa , Lim Whasun
Published: February 2021

Brassinin is a phytochemical derived from Chinese cabbage, a cruciferous vegetable. Brassinin has shown anticancer effects on prostate and colon cancer cells, among others. However, its mechanisms and effects on hepatocellular carcinoma (HCC) have not been elucidated yet. Our results confirmed that brassinin exerted antiproliferative effects by reducing proliferating cell nuclear antigen (PCNA) activity, a proliferation indicator and inducing cell cycle arrest in human HCC (Huh7 and Hep3B) cells. Brassinin also increased mitochondrial Ca2+ levels and depolarized the mitochondrial membrane in both Huh7 and Hep3B cells. Moreover, brassinin generated high amounts of reactive oxygen species (ROS) in both cell lines. The ROS scavenger N-acetyl-L-cysteine (NAC) inhibited this brassinin-induced ROS production. Brassinin also regulated the AKT and mitogen-activated protein kinases (MAPK) signaling pathways in Huh7 and Hep3B cells. Furthermore, co-administering brassinin and pharmacological inhibitors for JNK, ERK1/2 and P38 decreased cell proliferation in both HCC cell lines more than the pharmacological inhibitors alone. Collectively, our results demonstrated that brassinin exerts antiproliferative effects via mitochondrial dysfunction and MAPK pathway regulation on HCC cells.
TFEB Biology and Agonists at a Glance
Authors: Chen Mingyue , Dai Yashuang , Liu Siyu , Fan Yuxin , Ding Zongxian , Li Dan
Published: February 2021

Autophagy is a critical regulator of cellular survival, differentiation, development, and homeostasis, dysregulation of which is associated with diverse diseases including cancer and neurodegenerative diseases. Transcription factor EB (TFEB), a master transcriptional regulator of autophagy and lysosome, can enhance autophagic and lysosomal biogenesis and function. TFEB has attracted a lot of attention owing to its ability to induce the intracellular clearance of pathogenic factors in a variety of disease models, suggesting that novel therapeutic strategies could be based on the modulation of TFEB activity. Therefore, TFEB agonists are a promising strategy to ameliorate diseases implicated with autophagy dysfunction. Recently, several TFEB agonists have been identified and preclinical or clinical trials are applied. In this review, we present an overview of the latest research on TFEB biology and TFEB agonists.
A Trans-Omics Comparison Reveals Common Gene Expression Strategies in Four Model Organisms and Exposes Similarities and Differences between Them
Authors: Forés-Martos Jaume , Forte Anabel , García-Martínez José , Pérez-Ortín José E.
Published: February 2021

The ultimate goal of gene expression regulation is on the protein level. However, because the amounts of mRNAs and proteins are controlled by their synthesis and degradation rates, the cellular amount of a given protein can be attained by following different strategies. By studying omics data for six expression variables (mRNA and protein amounts, plus their synthesis and decay rates), we previously demonstrated the existence of common expression strategies (CESs) for functionally related genes in the yeast Saccharomyces cerevisiae. Here we extend that study to two other eukaryotes: the yeast Schizosaccharomyces pombe and cultured human HeLa cells. We also use genomic data from the model prokaryote Escherichia coli as an external reference. We show that six-variable profiles (6VPs) can be constructed for every gene and that these 6VPs are similar for genes with similar functions in all the studied organisms. The differences in 6VPs between organisms can be used to establish their phylogenetic relationships. The analysis of the correlations among the six variables supports the hypothesis that most gene expression control occurs in actively growing organisms at the transcription rate level, and that translation plays a minor role. We propose that living organisms use CESs for the genes acting on the same physiological pathways, especially for those belonging to stable macromolecular complexes, but CESs have been modeled by evolution to adapt to the specific life circumstances of each organism.
Tumor Evolution and Therapeutic Choice Seen through a Prism of Circulating Tumor Cell Genomic Instability
Authors: Tayoun Tala , Oulhen Marianne , Aberlenc Agathe , Farace Françoise , Pawlikowska Patrycja
Published: February 2021

Circulating tumor cells (CTCs) provide an accessible tool for investigating tumor heterogeneity and cell populations with metastatic potential. Although an in-depth molecular investigation is limited by the extremely low CTC count in circulation, significant progress has been made recently in single-cell analytical processes. Indeed, CTC monitoring through molecular and functional characterization may provide an understanding of genomic instability (GI) molecular mechanisms, which contribute to tumor evolution and emergence of resistant clones. In this review, we discuss the sources and consequences of GI seen through single-cell analysis of CTCs in different types of tumors. We present a detailed overview of chromosomal instability (CIN) in CTCs assessed by fluorescence in situ hybridization (FISH), and we reveal utility of CTC single-cell sequencing in identifying copy number alterations (CNA) oncogenic drivers. We highlight the role of CIN in CTC-driven metastatic progression and acquired resistance, and we comment on the technical obstacles and challenges encountered during single CTC analysis. We focus on the DNA damage response and depict DNA-repair-related dynamic biomarkers reported to date in CTCs and their role in predicting response to genotoxic treatment. In summary, the suggested relationship between genomic aberrations in CTCs and prognosis strongly supports the potential utility of GI monitoring in CTCs in clinical risk assessment and therapeutic choice.
Hemolytic Uremic Syndrome Due to Methylmalonic Acidemia and Homocystinuria in an Infant: A Case Report and Literature Review
Authors: Karava Vasiliki , Kondou Antonia , Dotis John , Sotiriou Georgia , Gerou Spyridon , Michelakakis Helen , Vargiami Euthymia , Economou Marina , Zafeiriou Dimitrios , Printza Nikoleta
Published: February 2021

Methylmalonic acidemia and homocystinuria cobalamin C (cblC) type is the most common inborn error of the intracellular cobalamin metabolism, associated with multisystem involvement and high mortality rates, especially in the early-onset form of the disease. Hemolytic uremic syndrome (HUS) is a rare manifestation and needs to be distinguished from other causes of renal thrombotic microangiopathy. We describe a case of a 3-month-old infant, with failure to thrive, hypotonia and pallor, who developed HUS in the setting of cblC deficit, along with dilated cardiomyopathy, and presented delayed response to optic stimulation in visual evoked potentials, as well as enlarged bilateral subarachnoid spaces and delayed myelination in brain magnetic resonance imaging. Renal damage was reversed, while neurodevelopmental profile and eye contact improved after supplementation with parenteral hydroxycobalamin, oral folic acid, betaine and levocarnitine. Homozygous mutation of c.271dupA in the MMACHC gene was ultimately detected. In this report, we highlight the diagnostic challenges as well as the significance of early recognition and multidisciplinary management of this unusual condition. A brief review of published case reports of early-onset cblC deficit and related HUS is depicted, pointing out the initial clinical presentation, signs of renal damage and outcome, MMACHC gene type of mutations and accompanying extra-renal manifestations.