bluuebunny/crossref_metadata_2025 huggingface dataset:
Y-Box Binding Protein-1 Promotes Epithelial-Mesenchymal Transition in Sorafenib-Resistant Hepatocellular Carcinoma Cells
Authors: Liao Li-Zhu , Chen Chih-Ta , Li Nien-Chen , Lin Liang-Chun , Huang Bo-Shih , Chang Ya-Hui , Chow Lu-Ping
Published: December 2020

Hepatocellular carcinoma is one of the most common cancer types worldwide. In cases of advanced-stage disease, sorafenib is considered the treatment of choice. However, resistance to sorafenib remains a major obstacle for effective clinical application. Based on integrated phosphoproteomic and The Cancer Genome Atlas (TCGA) data, we identified a transcription factor, Y-box binding protein-1 (YB-1), with elevated phosphorylation of Ser102 in sorafenib-resistant HuH-7R cells. Phosphoinositide-3-kinase (PI3K) and protein kinase B (AKT) were activated by sorafenib, which, in turn, increased the phosphorylation level of YB-1. In functional analyses, knockdown of YB-1 led to decreased cell migration and invasion in vitro. At the molecular level, inhibition of YB-1 induced suppression of zinc-finger protein SNAI1 (Snail), twist-related protein 1 (Twist1), zinc-finger E-box-binding homeobox 1 (Zeb1), matrix metalloproteinase-2 (MMP-2) and vimentin levels, implying a role of YB-1 in the epithelial-mesenchymal transition (EMT) process in HuH-7R cells. Additionally, YB-1 contributes to morphological alterations resulting from F-actin rearrangement through Cdc42 activation. Mutation analyses revealed that phosphorylation at S102 affects the migratory and invasive potential of HuH-7R cells. Our collective findings suggest that sorafenib promotes YB-1 phosphorylation through effect from the EGFR/PI3K/AKT pathway, leading to significant enhancement of hepatocellular carcinoma (HCC) cell metastasis. Elucidation of the specific mechanisms of action of YB-1 may aid in the development of effective strategies to suppress metastasis and overcome resistance.
Characterization of New Proteomic Biomarker Candidates in Mucopolysaccharidosis Type IVA
Authors: Álvarez Víctor J. , Bravo Susana B. , Chantada-Vazquez Maria Pilar , Colón Cristóbal , De Castro María J. , Morales Montserrat , Vitoria Isidro , Tomatsu Shunji , Otero-Espinar Francisco J. , Couce María L.
Published: December 2020

Mucopolysaccharidosis type IVA (MPS IVA) is a lysosomal storage disease caused by mutations in the N-acetylgalactosamine-6-sulfatase (GALNS) gene. Skeletal dysplasia and the related clinical features of MPS IVA are caused by disruption of the cartilage and its extracellular matrix, leading to a growth imbalance. Enzyme replacement therapy (ERT) with recombinant human GALNS has yielded positive results in activity of daily living and endurance tests. However, no data have demonstrated improvements in bone lesions and bone grow thin MPS IVA after ERT, and there is no correlation between therapeutic efficacy and urine levels of keratan sulfate, which accumulates in MPS IVA patients. Using qualitative and quantitative proteomics approaches, we analyzed leukocyte samples from healthy controls (n = 6) and from untreated (n = 5) and ERT-treated (n = 8, sampled before and after treatment) MPS IVA patients to identify potential biomarkers of disease. Out of 690 proteins identified in leukocytes, we selected a group of proteins that were dysregulated in MPS IVA patients with ERT. From these, we identified four potential protein biomarkers, all of which may influence bone and cartilage metabolism: lactotransferrin, coronin 1A, neutral alpha-glucosidase AB, and vitronectin. Further studies of cartilage and bone alterations in MPS IVA will be required to verify the validity of these proteins as potential biomarkers of MPS IVA.
An Insight into the Role of Non-Porphyrinoid Photosensitizers for Skin Wound Healing
Authors: Vallejo Mariana C. S. , Moura Nuno M. M. , Ferreira Faustino Maria Amparo , Almeida Adelaide , Gonçalves Idalina , Serra Vanda V. , Neves Maria Graça P. M. S.
Published: December 2020

The concept behind photodynamic therapy (PDT) is being successfully applied in different biomedical contexts such as cancer diseases, inactivation of microorganisms and, more recently, to improve wound healing and tissue regeneration. The effectiveness of PDT in skin treatments is associated with the role of reactive oxygen species (ROS) produced by a photosensitizer (PS), which acts as a “double agent”. The release of ROS must be high enough to prevent microbial growth and, simultaneously, to accelerate the immune system response by recruiting important regenerative agents to the wound site. The growing interest in this subject is reflected by the increasing number of studies concerning the optimization of relevant experimental parameters for wound healing via PDT, namely, light features, the structure and concentration of the PS, and the wound type and location. Considering the importance of developing PSs with suitable features for this emergent topic concerning skin wound healing, in this review, a special focus on the achievements attained for each PS class, namely, of the non-porphyrinoid type, is given.
Oxygen Transport during Ex Situ Machine Perfusion of Donor Livers Using Red Blood Cells or Artificial Oxygen Carriers
Authors: Bodewes Silke B. , van Leeuwen Otto B. , Thorne Adam M. , Lascaris Bianca , Ubbink Rinse , Lisman Ton , Monbaliu Diethard , De Meijer Vincent E. , Nijsten Maarten W. N. , Porte Robert J.
Published: December 2020

Oxygenated ex situ machine perfusion of donor livers is an alternative for static cold preservation that can be performed at temperatures from 0 °C to 37 °C. Organ metabolism depends on oxygen to produce adenosine triphosphate and temperatures below 37 °C reduce the metabolic rate and oxygen requirements. The transport and delivery of oxygen in machine perfusion are key determinants in preserving organ viability and cellular function. Oxygen delivery is more challenging than carbon dioxide removal, and oxygenation of the perfusion fluid is temperature dependent. The maximal oxygen content of water-based solutions is inversely related to the temperature, while cellular oxygen demand correlates positively with temperature. Machine perfusion above 20 °C will therefore require an oxygen carrier to enable sufficient oxygen delivery to the liver. Human red blood cells are the most physiological oxygen carriers. Alternative artificial oxygen transporters are hemoglobin-based oxygen carriers, perfluorocarbons, and an extracellular oxygen carrier derived from a marine invertebrate. We describe the principles of oxygen transport, delivery, and consumption in machine perfusion for donor livers using different oxygen carrier-based perfusion solutions and we discuss the properties, advantages, and disadvantages of these carriers and their use.
Manipulating the Epigenome in Nuclear Transfer Cloning: Where, When and How
Authors: Simmet Kilian , Wolf Eckhard , Zakhartchenko Valeri
Published: December 2020

The nucleus of a differentiated cell can be reprogrammed to a totipotent state by exposure to the cytoplasm of an enucleated oocyte, and the reconstructed nuclear transfer embryo can give rise to an entire organism. Somatic cell nuclear transfer (SCNT) has important implications in animal biotechnology and provides a unique model for studying epigenetic barriers to successful nuclear reprogramming and for testing novel concepts to overcome them. While initial strategies aimed at modulating the global DNA methylation level and states of various histone protein modifications, recent studies use evidence-based approaches to influence specific epigenetic mechanisms in a targeted manner. In this review, we describe—based on the growing number of reports published during recent decades—in detail where, when, and how manipulations of the epigenome of donor cells and reconstructed SCNT embryos can be performed to optimize the process of molecular reprogramming and the outcome of nuclear transfer cloning.
Sex Differences in Placental Protein Expression and Efficiency in a Rat Model of Fetal Programming Induced by Maternal Undernutrition
Authors: Phuthong Sophida , Reyes-Hernández Cynthia Guadalupe , Rodríguez-Rodríguez Pilar , Ramiro-Cortijo David , Gil-Ortega Marta , González-Blázquez Raquel , González M. Carmen , López de Pablo Angel Luis , Arribas Silvia M.
Published: December 2020

Fetal undernutrition programs cardiometabolic diseases, with higher susceptibility in males. The mechanisms implicated are not fully understood and may be related to sex differences in placental adaptation. To evaluate this hypothesis, we investigated placental oxidative balance, vascularization, glucocorticoid barrier, and fetal growth in rats exposed to 50% global nutrient restriction from gestation day 11 (MUN, n = 8) and controls (n = 8). At gestation day 20 (G20), we analyzed maternal, placental, and fetal weights; oxidative damage, antioxidants, corticosterone, and PlGF (placental growth factor, spectrophotometry); and VEGF (vascular endothelial growth factor), 11β-HSD2, p22phox, XO, SOD1, SOD2, SOD3, catalase, and UCP2 expression (Western blot). Compared with controls, MUN dams exhibited lower weight and plasma proteins and higher corticosterone and catalase without oxidative damage. Control male fetuses were larger than female fetuses. MUN males had higher plasma corticosterone and were smaller than control males, but had similar weight than MUN females. MUN male placenta showed higher XO and lower 11β-HSD2, VEGF, SOD2, catalase, UCP2, and feto-placental ratio than controls. MUN females had similar feto-placental ratio and plasma corticosterone than controls. Female placenta expressed lower XO, 11β-HSD2, and SOD3; similar VEGF, SOD1, SOD2, and UCP2; and higher catalase than controls, being 11β-HSD2 and VEGF higher compared to MUN males. Male placenta has worse adaptation to undernutrition with lower efficiency, associated with oxidative disbalance and reduced vascularization and glucocorticoid barrier. Glucocorticoids and low nutrients may both contribute to programming in MUN males.
New Evidence for P-gp-Mediated Export of Amyloid-β Peptides in Molecular, Blood-Brain Barrier and Neuronal Models
Authors: Chai Amanda B. , Hartz Anika M. S. , Gao Xuexin , Yang Alryel , Callaghan Richard , Gelissen Ingrid C.
Published: December 2020

Defective clearance mechanisms lead to the accumulation of amyloid-beta (Aβ) peptides in the Alzheimer’s brain. Though predominantly generated in neurons, little is known about how these hydrophobic, aggregation-prone, and tightly membrane-associated peptides exit into the extracellular space where they deposit and propagate neurotoxicity. The ability for P-glycoprotein (P-gp), an ATP-binding cassette (ABC) transporter, to export Aβ across the blood-brain barrier (BBB) has previously been reported. However, controversies surrounding the P-gp–Aβ interaction persist. Here, molecular data affirm that both Aβ40 and Aβ42 peptide isoforms directly interact with and are substrates of P-gp. This was reinforced ex vivo by the inhibition of Aβ42 transport in brain capillaries from P-gp-knockout mice. Moreover, we explored whether P-gp could exert the same role in neurons. Comparison between non-neuronal CHO-APP and human neuroblastoma SK-N-SH cells revealed that P-gp is expressed and active in both cell types. Inhibiting P-gp activity using verapamil and nicardipine impaired Aβ40 and Aβ42 secretion from both cell types, as determined by ELISA. Collectively, these findings implicate P-gp in Aβ export from neurons, as well as across the BBB endothelium, and suggest that restoring or enhancing P-gp function could be a viable therapeutic approach for removing excess Aβ out of the brain in Alzheimer’s disease.
Promising Antioxidant Activity of Erythrina Genus: An Alternative Treatment for Inflammatory Pain?
Authors: Jiménez-Cabrera Tania , Bautista Mirandeli , Velázquez-González Claudia , Jaramillo-Morales Osmar Antonio , Guerrero-Solano José Antonio , Urrutia-Hernández Thania Alejandra , De la O-Arciniega Minarda
Published: December 2020

The negative impact that oxidative stress has on health is currently known. The complex mechanism of free radicals initiates a series of chain reactions that contribute to the evolution or development of different degenerative disorders. Likewise, these disorders are usually accompanied by inflammatory processes and, therefore, pain. In this sense, reactive oxygen species (ROS) have been shown to promote the nociceptive process, but effective treatment of pain and inflammation still represents a challenge. Over time, it has been learned that there is no single way to relieve pain, and as long as there are no other alternatives, the trend will continue to apply multidisciplinary management, such as promote the traditional use of the Erythrina genus to manage pain and inflammation. In this sense, the Erythrina genus produces a wide range of secondary metabolites, including flavanones, isoflavones, isoflavones, and pterocarpans; these compounds are characterized by their antioxidant activity. Phenolic compounds have demonstrated their ability to suppress pro-oxidants and inhibit inflammatory signaling pathways such as MAPK, AP1, and NFκB. Although there is preclinical evidence supporting its use, the pharmacological effect mechanisms are not entirely clear. Nowadays, there is a fast advancement in knowledge of the disciplines related to drug discovery, but most of nature’s medicinal potential has not yet been harnessed. This review analyzes the decisive role that the Erythrina genus could play in managing inflammatory pain mediated by its compounds and its uses as an antioxidant.
Programmed Editing of Rice (Oryza sativa L.) OsSPL16 Gene Using CRISPR/Cas9 Improves Grain Yield by Modulating the Expression of Pyruvate Enzymes and Cell Cycle Proteins
Authors: Usman Babar , Nawaz Gul , Zhao Neng , Liao Shanyue , Qin Baoxiang , Liu Fang , Liu Yaoguang , Li Rongbai
Published: December 2020

Rice (Oryza sativa L.) is one of the major crops in the world and significant increase in grain yield is constant demand for breeders to meet the needs of a rapidly growing population. The size of grains is one of major components determining rice yield and a vital trait for domestication and breeding. To increase the grain size in rice, OsSPL16/qGW8 was mutagenized through CRISPR/Cas9, and proteomic analysis was performed to reveal variations triggered by mutations. More specifically, mutants were generated with two separate guide RNAs targeting recognition sites on opposite strands and genomic insertions and deletions were characterized. Mutations followed Mendelian inheritance and homozygous and heterozygous mutants lacking any T-DNA and off-target effects were screened. The mutant lines showed a significant increase in grain yield without any change in other agronomic traits in T0, T1, and T2 generations. Proteomic screening found a total of 44 differentially expressed proteins (DEPs), out of which 33 and 11 were up and downregulated, respectively. Most of the DEPs related to pyruvate kinase, pyruvate dehydrogenase, and cell division and proliferation were upregulated in the mutant plants. Pathway analysis revealed that DEPs were enriched in the biosynthesis of secondary metabolites, pyruvate metabolism, glycolysis/gluconeogenesis, carbon metabolism, ubiquinone and other terpenoid-quinone biosynthesis, and citrate cycle. Gene Ontology (GO) analysis presented that most of the DEPs were involved in the pyruvate metabolic process and pyruvate dehydrogenase complex. Proteins related to pyruvate dehydrogenase E1 component subunit alpha-1 displayed higher interaction in the protein-protein interaction (PPI) network. Thus, the overall results revealed that CRISPR/Cas9-guided OsSPL16 mutations have the potential to boost the grain yield of rice. Additionally, global proteome analysis has broad applications for discovering molecular components and dynamic regulation underlying the targeted gene mutations.
Serotonin/5-HT1A Signaling in the Neurovascular Unit Regulates Endothelial CLDN5 Expression
Authors: Sugimoto Kotaro , Ichikawa-Tomikawa Naoki , Nishiura Keisuke , Kunii Yasuto , Sano Yasuteru , Shimizu Fumitaka , Kakita Akiyoshi , Kanda Takashi , Imura Tetsuya , Chiba Hideki
Published: December 2020

We previously reported that site-selective claudin-5 (CLDN5) breakdown and protein kinase A (PKA) activation are observed in brain microvessels of schizophrenia, but the underlying molecular basis remains unknown. The 5-HT1 receptors decline the intracellular cAMP levels and inactivate the major downstream PKA, and the 5-HT1A receptor is a promising target for schizophrenia. Therefore, we elucidated the involvement of serotonin/5-HT1A signaling in the endothelial CLDN5 expression. We demonstrate, by immunohistochemistry using post-mortem human brain tissue, that the 5-HT1A receptor is expressed in brain microvascular endothelial cells (BMVECs) and mural cells of the normal prefrontal cortex (PFC) gray matter. We also show that PKA is aberrantly activated not only in BMVECs but also in mural cells of the schizophrenic PFC. We subsequently revealed that the endothelial cell–pericyte tube-like structure was formed in a novel two-dimensional co-culture of human primary BMVECs and a human brain-derived pericyte cell line, in both of which the 5-HT1A receptor was expressed. Furthermore, we disclose that the serotonin/5-HT1A signaling enhances endothelial CLDN5 expression in BMVECs under two-dimensional co-culture conditions. Our findings provide novel insights into the physiological and pathological significance of serotonin/5-HT1A signaling in the region-specific regulation of the blood-brain barrier.
The Effects of Continuous and Withdrawal Voluntary Wheel Running Exercise on the Expression of Senescence-Related Genes in the Visceral Adipose Tissue of Young Mice
Authors: Kimura Masaki , Suzuki Seiya , Moriya Atsushi , Nogami Kazuki , Uchida Ryoei , Saito Yoshimasa , Saito Hidetsugu
Published: December 2020

Obesity has become a global medical problem. The upregulation of senescence-related markers in adipose tissue may cause impairment of adipose tissue and disorders of systemic metabolism. Weight control through diet has been found to ameliorate senescence in the adipose tissue. Exercise is also important in maintaining a healthy lifestyle, however, very few researchers have examined the relationship between senescence-related markers in adipose tissue. Dietary restriction is also reported to have a legacy effect, wherein the effects are maintained for some periods after the termination of the intervention. However, very few researchers have examined the relationship between exercise and senescence-related markers in adipose tissue. Besides, there is no study on the long-term effects of exercise. Hence, we investigated whether the exercise could change the expression of senescence-related genes in the visceral adipose tissue of young mice and whether there was a legacy effect of exercise for 10 weeks after the termination of exercise. Four-week-old male ICR mice were assigned to one of the three groups: 20 weeks of sedentary condition, 20 weeks of voluntary wheel running exercise, or 10 weeks of exercise followed by 10 weeks of sedentary condition. The mice showed decreased expression in genes related to senescence and senescence-associated secretory phenotype, such as p53, p16, and IL-6, in the visceral adipose tissue in response to exercise. These effects were maintained for 10 weeks after the mice stopped exercising. Our study is the first report that exercise reduces the expression of senescence-related genes in the visceral adipose tissue of young mice, and that exercise causes the legacy effect.
Click Beetle Mitogenomics with the Definition of a New Subfamily Hapatesinae from Australasia (Coleoptera: Elateridae)
Authors: Kusy Dominik , Motyka Michal , Bocak Ladislav
Published: December 2020

Elateridae is a taxon with very unstable classification and a number of conflicting phylogenetic hypotheses have been based on morphology and molecular data. We assembled eight complete mitogenomes for seven elaterid subfamilies and merged these taxa with an additional 22 elaterids and an outgroup. The structure of the newly produced mitogenomes showed a very similar arrangement with regard to all earlier published mitogenomes for the Elateridae. The maximum likelihood and Bayesian analyses indicated that Hapatesus Candèze, 1863, is a sister of Parablacinae and Pityobiinae. Therefore, Hapatesinae, a new subfamily, is proposed for the Australian genera Hapatesus (21 spp.) and Toorongus Neboiss, 1957 (4 spp.). Parablacinae, Pityobiinae, and Hapatesinae have a putative Gondwanan origin as the constituent genera are known from the Australian region (9 genera) and Neotropical region (Tibionema Solier, 1851), and only Pityobius LeConte, 1853, occurs in the Nearctic region. Another putative Gondwanan lineage, the Afrotropical Morostomatinae, forms either a serial paraphylum with the clade of Parablacinae, Pityobiinae, and Hapatesinae or is rooted in a more terminal position, but always as an independent lineage. An Eudicronychinae lineage was either recovered as a sister to Melanotini or as a deep split inside Elaterinae and we herein transfer the group to Elaterinae as Eudicronychini, a new status. The mitochondrial genomes provide a sufficient signal for the placement of most lineages, but the deep bipartitions need to be compared with phylogenomic analyses.
Malignant Arrhythmic Mitral Valve Prolapse: A Continuum of Clinical Challenges from Diagnosis to Risk Stratification and Patient Management
Authors: Yedidya Idit , van Wijngaarden Aniek L. , Ajmone Marsan Nina
Published: December 2020

Mitral valve prolapse (MVP) is a common valvular disease, which may remain a benign condition for a long period of time. However, some patients experience malignant ventricular arrhythmias and sudden cardiac death (SCD). It is still largely unknown how to risk-stratify these patients, and no specific recommendations have been proposed to help the clinical decision-making. We present the case of a young man whose first clinical presentation was an out-of-hospital cardiac arrest and was subsequently diagnosed with MVP. We highlighted the possible risk factors for SCD and the challenges in the clinical management of these patients.
Efficacy of Intra-Uterine Tamponade Balloon in Post-Partum Hemorrhage after Cesarean Delivery: An Impact Study
Authors: Soued Mickaël , Vivanti Alexandre J. , Smiljkovski Daniel , Deffieux Xavier , Benachi Alexandra , Le Gouez Agnès , Mercier Frédéric J.
Published: December 2020

Invasive therapies (surgery or radiological embolization) are used to control severe post-partum hemorrhage. The intra-uterine tamponade balloon is a potential alternative, well documented after vaginal delivery. However, available data on its use after cesarean delivery remain scarce. This study assessed the efficacy of the intra-uterine tamponade balloon during post-partum hemorrhage in a cesarean delivery setting. Using a retrospective impact design, post-partum hemorrhage-related outcomes before (“pre-balloon” period) versus after implementation of intra-uterine tamponade balloon (“post-balloon” period) were compared. All women with post-partum hemorrhage requiring potent uterotonic treatment with prostaglandins after cesarean delivery over a 9-year period were eligible. The primary outcome was the rate of invasive procedure (conservative surgery, radiological embolization and/or hysterectomy). p < 0.05 was considered statistically significant. A total of 279 patients were included (140 vs. 139). Most baseline characteristics were comparable between the two studied periods. The success rate of the intra-uterine tamponade balloon was 82%, and no related complications occurred. Rates of invasive procedures and transfusion were significantly reduced (28.6% vs. 11.5%, p < 0.001 and 44.3% vs. 28.1%, p = 0.006 respectively) during the “post-balloon” period, and length of hospital stay was shorter (p < 0.001). Implementation of intra-uterine tamponade balloon during post-partum hemorrhage after cesarean delivery appears to be safe and effective, with a decrease in both invasive procedures and transfusion rates.
Long-Term Efficacy of Extracorporeal Shock Wave Therapy on Lower Limb Post-Stroke Spasticity: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Authors: Mihai Emanuela Elena , Dumitru Luminita , Mihai Ilie Valentin , Berteanu Mihai
Published: December 2020

The purpose of this systematic review and meta-analysis is to evaluate the long-term efficacy of Extracorporeal Shock Wave Therapy (ESWT) on reducing lower limb post-stroke spasticity in adults. A systematic electronic search of PubMed/ MEDLINE, Physiotherapy Evidence Database (PEDro), Scopus, Ovid MEDLINE(R), and search engine of Google Scholar was performed. Publications that ranged from January 2010 to August 2020, published in English, French, Spanish, Portuguese, and Italian language and available as full texts were eligible for inclusion and they were searched without any restrictions of country. The study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines and followed the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions. Two authors screened the references, extracted data, and assessed the risk of bias. The primary outcome was spasticity grade mainly assessed by the Modified Ashworth Scale (MAS). Secondary outcomes were passive range of motion (PROM), pain intensity, electrophysiological parameters, gait assessment, and adverse events. A total of seven recent randomized controlled trials (RCTs) were included in the systematic review and meta-analysis, and a beneficial effect on spasticity was found. The high level of evidence presented in this paper showed that ESWT ameliorates spasticity considering the parameters: MAS: standardized mean difference (SMD) = 0.53; 95% confidence interval (95% CI): (0.07–0.99); Modified Tardieu Scale (MTS): SMD = 0.56; 95% CI: (0.01–1.12); Visual Analogue Scale (VAS): SMD = 0.35; 95% CI: (−0.21–0.91); PROM: SMD = 0.69; 95% CI: (0.20–1.19). ESWT presented long-term efficacy on lower limb post-stroke spasticity, reduced pain intensity, and increased range of motion. The effect of this novel and non-invasive therapy was significant and the intervention did not present adverse events, proving a satisfactory safety profile.
Clinical Utility of Plasma KRAS, NRAS and BRAF Mutational Analysis with Real Time PCR in Metastatic Colorectal Cancer Patients—The Importance of Tissue/Plasma Discordant Cases
Authors: Formica Vincenzo , Lucchetti Jessica , Doldo Elena , Riondino Silvia , Morelli Cristina , Argirò Renato , Renzi Nicola , Nitti Daniele , Nardecchia Antonella , Dell’Aquila Emanuela , Ferroni Patrizia , Guadagni Fiorella , Palmieri Giampiero , Orlandi Augusto , Roselli Mario
Published: December 2020

Background: Tumor tissue (T) mutational analysis represents the standard for metastatic colorectal cancer (mCRC); however, circulating tumor DNA (ctDNA) detected by liquid biopsy in plasma (PL) can better represent tumor heterogeneity. Methods: mCRC patients undergoing standard first-line chemotherapy with known T-KRAS/NRAS/BRAF status were enrolled in the present prospective study. PL mutations were assessed within 2 weeks before chemotherapy start with real time PCR and correlated with T status and Progression free survival (PFS). Clinical and biochemical variables including also total number of tumor lesions (TNL) and the sum of maximum diameter (SMD) of all lesions were assessed as potential predictors of T/PL discordance. RESULTS: Among 45 enrolled patients, all BRAF mutations were concordant between T and PL and there were 20% of patients RAS discordant: 9% wild type in T and mutated in PL and 11% mutated in T and wild type in PL. T mutations were significantly associated to median PFS (mPFS of 4.5, 8.3 and 22.9 months for T-BRAF mutated, T-RAS mutated, and T-wild type patients, respectively, p for trend 0.00014). PL mutations further refined prognosis: RAS wild type in T and mutated in PL had significantly shorter PFS than concordant RAS wild type in T and PL: mPFS 9.6 vs. 23.3 months, respectively, p = 0.02. Patients RAS mutated in T and wild type in PL had longer PFS than concordant RAS mutated in T and PL: 24.4 vs. 7.8 months, respectively, p = 0.008. At a multivariate cox regression analysis for PFS, PL mutations were independent prognostic factor superior to T analysis (HR 0.13, p = 0.0008). At multivariate logistic regression analysis TNL and SMD were significant predictors of discordant cases. Conclusions: PL mutational analysis allows a better prognostication than T analysis alone and could help in mCRC treatment management.
Emerging Therapies in Pheochromocytoma and Paraganglioma: Immune Checkpoint Inhibitors in the Starting Blocks
Authors: Fanciulli Giuseppe , Di Molfetta Sergio , Dotto Andrea , Florio Tullio , Feola Tiziana , Rubino Manila , de Cicco Federica , Colao Annamaria , Faggiano Antongiulio ,   NIKE Group
Published: December 2020

Pheochromocytoma and paraganglioma are neuroendocrine neoplasms, originating in the adrenal medulla and in parasympathetic and sympathetic autonomic nervous system ganglia, respectively. They usually present as localized tumours curable with surgery. However, these tumours may exhibit heterogeneous clinical course, ranging from no/minimal progression to aggressive (progressive/metastatic) behavior. For this setting of patients, current therapies are unsatisfactory. Immune checkpoint inhibitors have shown outstanding results for several types of solid cancers. We therefore aimed to summarize and discuss available data on efficacy and safety of current FDA-approved immune checkpoint inhibitors in patients with pheochromocytoma and paraganglioma. After an extensive search, we found 15 useful data sources (four full-published articles, four supplements of scientific journals, seven ongoing registered clinical trials). The data we detected, even with the limit of the small number of patients treated, make a great expectation on the therapeutic use of immune checkpoint inhibitors. Besides, the newly detected predictors of response will (hopefully) be of great helps in selecting the subset of patients that might benefit the most from this class of drugs. Finally, new trials are in the starting blocks, and they are expected to shed in the next future new light on a therapy, which is considered a milestone in oncology.
Specificity Influences in (1→3)-β-d-Glucan-Supported Diagnosis of Invasive Fungal Disease
Authors: Finkelman Malcolm A.
Published: December 2020

(1→3)-β-glucan (BDG) testing as an adjunct in the diagnosis of invasive fungal disease (IFD) has been in use for nearly three decades. While BDG has a very high negative predictive value in this setting, diagnostic false positives may occur, limiting specificity and positive predictive value. Although results may be diagnostically false positive, they are analytically correct, due to the presence of BDG in the circulation. This review surveys the non-IFD causes of elevated circulating BDG. These are in the main, iatrogenic patient contamination through the use of BDG-containing medical devices and parenterally-delivered materials as well as translocation of intestinal luminal BDG due to mucosal barrier injury. Additionally, infection with Nocardia sp. may also contribute to elevated circulating BDG. Knowledge of the factors which may contribute to such non-IFD-related test results can improve the planning and interpretation of BDG assays and permit investigational strategies, such as serial sampling and BDG clearance evaluation, to assess the likelihood of contamination and improve patient care.
Apremilast Pharmacogenomics in Russian Patients with Moderate-to-Severe and Severe Psoriasis
Authors: Verbenko Dmitry A. , Karamova Arfenya E. , Artamonova Olga G. , Deryabin Dmitry G. , Rakitko Alexander , Chernitsov Alexandr , Krasnenko Anna , Elmuratov Artem , Solomka Victoria S. , Kubanov Alexey A.
Published: December 2020

One of the target drugs for plaque psoriasis treatment is apremilast, which is a selective phosphodiesterase 4 (PDE4) inhibitor. In this study, 34 moderate-to-severe and severe plaque psoriasis patients from Russia were treated with apremilast for 26 weeks. This allowed us to observe the effectiveness of splitting patient cohorts based on clinical outcomes, which were assessed using the Psoriasis Area Severity Index (PASI). In total, 14 patients (41%) indicated having an advanced outcome with delta PASI 75 after treatment; 20 patients indicated having moderate or no effects. Genome variability was investigated using the Illumina Infinium Global Screening Array. Genome-wide analysis revealed apremilast therapy clinical outcome associations at three compact genome regions with undefined functions situated on chromosomes 2, 4, and 5, as well as on a single single-nucleotide polymorphism (SNP) on chromosome 23. Pre-selected SNP sets were associated with psoriasis vulgaris analysis, which was used to identify four SNP-associated targeted therapy efficiencies: IL1β (rs1143633), IL4 (IL13) (rs20541), IL23R (rs2201841), and TNFα (rs1800629) genes. Moreover, we showed that the use of the global polygenic risk score allowed for the prediction of onset psoriasis in Russians. Therefore, these results can serve as a starting point for creating a predictive model of apremilast therapy response in the targeted therapy of patients with psoriasis vulgaris.
Evaluation of Male Fertility-Associated Loci in a European Population of Patients with Severe Spermatogenic Impairment
Authors: Cerván-Martín Miriam , Bossini-Castillo Lara , Rivera-Egea Rocío , Garrido Nicolás , Luján Saturnino , Romeu Gema , Santos-Ribeiro Samuel ,   IVIRMA Group,   Lisbon Clinical Group, Castilla José A. , Gonzalvo M. Carmen , Clavero Ana , Vicente F. Javier , Guzmán-Jiménez Andrea , Costa Cláudia , Llinares-Burguet Inés , Khantham Chiranan , Burgos Miguel , Barrionuevo Francisco J. , Jiménez Rafael , Sánchez-Curbelo Josvany , López-Rodrigo Olga , Peraza M. Fernanda , Pereira-Caetano Iris , Marques Patricia I. , Carvalho Filipa , Barros Alberto , Bassas Lluís , Seixas Susana , Gonçalves João , Larriba Sara , Lopes Alexandra M. , Palomino-Morales Rogelio J. , Carmona F. David
Published: December 2020

Infertility is a growing concern in developed societies. Two extreme phenotypes of male infertility are non-obstructive azoospermia (NOA) and severe oligospermia (SO), which are characterized by severe spermatogenic failure (SpF). We designed a genetic association study comprising 725 Iberian infertile men as a consequence of SpF and 1058 unaffected controls to evaluate whether five single-nucleotide polymorphisms (SNPs), previously associated with reduced fertility in Hutterites, are also involved in the genetic susceptibility to idiopathic SpF and specific clinical entities. A significant difference in the allele frequencies of USP8-rs7174015 was observed under the recessive model between the NOA group and both the control group (p = 0.0226, OR = 1.33) and the SO group (p = 0.0048, OR = 1.78). Other genetic associations for EPSTI1-rs12870438 and PSAT1-rs7867029 with SO and between TUSC1-rs10966811 and testicular sperm extraction (TESE) success in the context of NOA were observed. In silico analysis of functional annotations demonstrated cis-eQTL effects of such SNPs likely due to the modification of binding motif sites for relevant transcription factors of the spermatogenic process. The findings reported here shed light on the molecular mechanisms leading to severe phenotypes of idiopathic male infertility, and may help to better understand the contribution of the common genetic variation to the development of these conditions.
Multi-Layer Wear and Tool Life Calculation for Forging Applications Considering Dynamical Hardness Modeling and Nitrided Layer Degradation
Authors: Behrens Bernd-Arno , Brunotte Kai , Wester Hendrik , Rothgänger Marcel , Müller Felix
Published: December 2020

As one of the oldest shaping manufacturing processes, forging and especially hot forging is characterized by extreme loads on the tool. The thermal load in particular is able to cause constant changes in the hardness of the surface layer, which in turn has a decisive influence on the numerical estimation of wear. Thus, also during numerical wear, modeling hardness changes need to be taken into account. Within the scope of this paper, a new implementation of a numerical wear model is presented, which, in addition to dynamic hardness models for the base material, can also take into account the properties of a nitride wear protection layer as a function of the wear depth. After a functional representation, the new model is applied to the wear calculation of a multi-stage industrial hot forging process. The applicability of the new implementation is validated by the evaluation of the occurring hardness, wear depths and the locally associated removal of the wear protection layer. Consecutively, a tool life calculation module based on the calculated wear depth is implemented and demonstrated. In general, a good agreement of the results is achieved, making the model suitable for detailed 2D as well as large 3D Finite Element calculations.
HTLV/HIV Dual Infection: Modeling and Analysis
Authors: Elaiw Ahmed M. , H. AlShamrani Noura
Published: December 2020

Human T-lymphotropic virus type I (HTLV-I) and human immunodeficiency virus (HIV) are two famous retroviruses that share similarities in their genomic organization, and differ in their life cycle as well. It is known that HTLV-I and HIV have in common a way of transmission via direct contact with certain body fluids related to infected patients. Thus, it is not surprising that a single-infected person with one of these viruses can be dually infected with the other virus. In the literature, many researchers have devoted significant efforts for modeling and analysis of HTLV or HIV single infection. However, the dynamics of HTLV/HIV dual infection has not been formulated. In the present paper, we formulate an HTLV/HIV dual infection model. The model includes the impact of the Cytotoxic T lymphocyte (CTLs) immune response, which is important to control the dual infection. The model describes the interaction between uninfected CD4+T cells, HIV-infected cells, HTLV-infected cells, free HIV particles, HIV-specific CTLs, and HTLV-specific CTLs. We establish that the solutions of the model are non-negative and bounded. We calculate all steady states of the model and deduce the threshold parameters which determine the existence and stability of the steady states. We prove the global asymptotic stability of all steady states by utilizing the Lyapunov function and Lyapunov–LaSalle asymptotic stability theorem. We solve the system numerically to illustrate the our main results. In addition, we compared between the dynamics of single and dual infections.
Variational Nonlinear Optimization in Fluid Dynamics: The Case of a Channel Flow with Superhydrophobic Walls
Authors: Cherubini Stefania , Picella Francesco , Robinet Jean-Christophe
Published: December 2020

Variational optimization has been recently applied to nonlinear systems with many degrees of freedom such as shear flows undergoing transition to turbulence. This technique has unveiled powerful energy growth mechanisms able to produce typical coherent structures currently observed in transition and turbulence. However, it is still not clear the extent to which these nonlinear optimal energy growth mechanisms are robust with respect to external disturbances or wall imperfections. Within this framework, this work aims at investigating how nano-roughnesses such as those of superhydrophobic surfaces affect optimal energy growth mechanisms relying on nonlinearity. Nonlinear optimizations have been carried out in a channel flow with no-slip and slippery boundaries, mimicking the presence of superhydrophobic surfaces. For increasing slip length, the energy threshold for obtaining hairpin-like nonlinear optimal perturbations slightly rises, scaling approximately with Re−2.36 no matter the slip length. The corresponding energy gain increases with Re with a slope that reduces with the slip length, being almost halved for the largest slip and Reynolds number considered. This suggests a strong effect of boundary slip on the energy growth of these perturbations. While energy is considerably decreased, the shape of the optimal perturbation barely changes, indicating the robustness of optimal perturbations with respect to wall slip.
Dye Separation and Antibacterial Activities of Polyaniline Thin Film-Coated Poly(phenyl sulfone) Membranes
Authors: Alam Javed , Shukla Arun , Ansari Mohammad , Ali Fekri , Alhoshan Mansour
Published: December 2020

We fabricated a nanofiltration membrane consisting of a polyaniline (PANI) film on a polyphenylsulfone (PPSU) substrate membrane. The PANI film acted as a potent separation enhancer and antimicrobial coating. The membrane was analyzed via scanning electron microscopy and atomic force microscopy to examine its morphology, topography, contact angle, and zeta potential. We aimed to investigate the impact of the PANI film on the surface properties of the membrane. Membrane performance was then evaluated in terms of water permeation and rejection of methylene blue (MB), an organic dye. Coating the PPSU membrane with a PANI film imparted significant advantages, including finely tuned nanometer-scale membrane pores and tailored surface properties, including increased hydrophilicity and zeta potential. The PANI film also significantly enhanced separation of the MB dye. The PANI-coated membrane rejected over 90% of MB with little compromise in membrane permeability. The PANI film also enhanced the antimicrobial activity of the membrane. The bacteriostasis (BR) values of PANI-coated PPSU membranes after six and sixteen hours of incubation with Escherichia coli were 63.5% and 95.2%, respectively. The BR values of PANI-coated PPSU membranes after six and sixteen hours of incubation with Staphylococcus aureus were 70.6% and 88.0%, respectively.
Microstructure and Mechanical Properties of Nickel-Based Coatings Fabricated through Laser Additive Manufacturing
Authors: Qian Shaoxiang , Zhang Yongkang , Dai Yibo , Guo Yuhang
Published: December 2020

In this study, single-layer and three-layer nickel-based coatings were fabricated on 316L SS by laser additive manufacturing. The phase characterization, microstructure observation, and microhardness analysis of the coatings were carried out by X-ray diffraction (XRD), scanning electron microscope (SEM), and microhardness tester. And the wear resistance of the coatings was analyzed through dry sliding friction and wear test. The results show that the cross-section microstructure of the three-layer nickel-based coating is different from that of the single-layer one under the influence of heat accumulation; the dendrite structure in the central region of the former is equiaxial dendrite, while that of the latter still remains large columnar dendrites. The existence of solid solution phase γ-(Fe, Ni) and hard phases of Ni17Si3, Cr5B3, Ni3B in the coating significantly improve the wear resistance of the coating, and the microhardness is nearly 2.5 times higher than that of the substrate. However, the average microhardness of multilayer cladding coating is about 48 HV0.2 higher than that of the single-layer cladding coating. In addition, the fine surface structure of the three-layer nickel-based coating improves the wear resistance of the coating, making this coating with the best wear resistance.
SeMPI 2.0—A Web Server for PKS and NRPS Predictions Combined with Metabolite Screening in Natural Product Databases
Authors: Zierep Paul F. , Ceci Adriana T. , Dobrusin Ilia , Rockwell-Kollmann Sinclair C. , Günther Stefan
Published: December 2020

Microorganisms produce secondary metabolites with a remarkable range of bioactive properties. The constantly increasing amount of published genomic data provides the opportunity for efficient identification of biosynthetic gene clusters by genome mining. On the other hand, for many natural products with resolved structures, the encoding biosynthetic gene clusters have not been identified yet. Of those secondary metabolites, the scaffolds of nonribosomal peptides and polyketides (type I modular) can be predicted due to their building block-like assembly. SeMPI v2 provides a comprehensive prediction pipeline, which includes the screening of the scaffold in publicly available natural compound databases. The screening algorithm was designed to detect homologous structures even for partial, incomplete clusters. The pipeline allows linking of gene clusters to known natural products and therefore also provides a metric to estimate the novelty of the cluster if a matching scaffold cannot be found. Whereas currently available tools attempt to provide comprehensive information about a wide range of gene clusters, SeMPI v2 aims to focus on precise predictions. Therefore, the cluster detection algorithm, including building block generation and domain substrate prediction, was thoroughly refined and benchmarked, to provide high-quality scaffold predictions. In a benchmark based on 559 gene clusters, SeMPI v2 achieved comparable or better results than antiSMASH v5. Additionally, the SeMPI v2 web server provides features that can help to further investigate a submitted gene cluster, such as the incorporation of a genome browser, and the possibility to modify a predicted scaffold in a workbench before the database screening.
Holistic Metabolomic Laboratory-Developed Test (LDT): Development and Use for the Diagnosis of Early-Stage Parkinson’s Disease
Authors: Lokhov Petr G. , Maslov Dmitry L. , Lichtenberg Steven , Trifonova Oxana P. , Balashova Elena E.
Published: December 2020

A laboratory-developed test (LDT) is a type of in vitro diagnostic test that is developed and used within a single laboratory. The holistic metabolomic LDT integrating the currently available data on human metabolic pathways, changes in the concentrations of low-molecular-weight compounds in the human blood during diseases and other conditions, and their prevalent location in the body was developed. That is, the LDT uses all of the accumulated metabolic data relevant for disease diagnosis and high-resolution mass spectrometry with data processing by in-house software. In this study, the LDT was applied to diagnose early-stage Parkinson’s disease (PD), which currently lacks available laboratory tests. The use of the LDT for blood plasma samples confirmed its ability for such diagnostics with 73% accuracy. The diagnosis was based on relevant data, such as the detection of overrepresented metabolite sets associated with PD and other neurodegenerative diseases. Additionally, the ability of the LDT to detect normal composition of low-molecular-weight compounds in blood was demonstrated, thus providing a definition of healthy at the molecular level. This LDT approach as a screening tool can be used for the further widespread testing for other diseases, since ‘omics’ tests, to which the metabolomic LDT belongs, cover a variety of them.