bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Pre-Induced Mesenchymal Stem Cell-Coated Cellulose/Collagen Nanofibrous Nerve Conduit on Regeneration of Transected Facial Nerve
Authors: Cho GwangWon , Moon Changjong , Maharajan Nagarajan , Ang Mary Jasmin , Kim Minseong , Jang Chul Ho
Published: July 2022

(1) Objective: In order to evaluate the effect of a pre-induced mesenchymal stem cell (MSC)-coated cellulose/collagen nanofibrous nerve conduit on facial nerve regeneration in a rat model both in vitro and in vivo. (2) Methods: After fabrication of the cellulose/collagen nanofibrous conduit, its lumen was coated with either MSCs or pre-induced MSCs. The nerve conduit was then applied to the defective main trunk of the facial nerve. Rats were randomly divided into three treatment groups (n = 10 in each): cellulose/collagen nanofiber (control group), cellulose/collagen nanofiber/MSCs (group I), and cellulose/collagen nanofiber/pre-induced MSCs (group II). (3) Results Fibrillation of the vibrissae of each group was observed, and action potential threshold was compared 8 weeks post-surgery. Histopathological changes were also observed. Groups I and II showed better recovery of vibrissa fibrillation than the control group. (4) Conclusions: Group II, treated with the pre-induced MSC-coated cellulose/collagen nanofibrous nerve conduit, showed the highest degree of recovery based on functional and histological evaluations.
Quantitative Trait Locus Mapping of Marsh Spot Disease Resistance in Cranberry Common Bean (Phaseolus vulgaris L.)
Authors: Jia Bosen , Conner Robert L. , Penner Waldo C. , Zheng Chunfang , Cloutier Sylvie , Hou Anfu , Xia Xuhua , You Frank M.
Published: July 2022

Common bean (Phaseolus vulgaris L.) is a food crop that is an important source of dietary proteins and carbohydrates. Marsh spot is a physiological disorder that diminishes seed quality in beans. Prior research suggested that this disease is likely caused by manganese (Mn) deficiency during seed development and that marsh spot resistance is controlled by at least four genes. In this study, genetic mapping was performed to identify quantitative trait loci (QTL) and the potential candidate genes associated with marsh spot resistance. All 138 recombinant inbred lines (RILs) from a bi-parental population were evaluated for marsh spot resistance during five years from 2015 to 2019 in sandy and heavy clay soils in Morden, Manitoba, Canada. The RILs were sequenced using a genotyping by sequencing approach. A total of 52,676 single nucleotide polymorphisms (SNPs) were identified and filtered to generate a high-quality set of 2066 SNPs for QTL mapping. A genetic map based on 1273 SNP markers distributed on 11 chromosomes and covering 1599 cm was constructed. A total of 12 stable and 4 environment-specific QTL were identified using additive effect models, and an additional two epistatic QTL interacting with two of the 16 QTL were identified using an epistasis model. Genome-wide scans of the candidate genes identified 13 metal transport-related candidate genes co-locating within six QTL regions. In particular, two QTL (QTL.3.1 and QTL.3.2) with the highest R2 values (21.8% and 24.5%, respectively) harbored several metal transport genes Phvul.003G086300, Phvul.003G092500, Phvul.003G104900, Phvul.003G099700, and Phvul.003G108900 in a large genomic region of 16.8–27.5 Mb on chromosome 3. These results advance the current understanding of the genetic mechanisms of marsh spot resistance in cranberry common bean and provide new genomic resources for use in genomics-assisted breeding and for candidate gene isolation and functional characterization.
Factors Associated with White Fat Browning: New Regulators of Lipid Metabolism
Authors: Zhang Peiwen , He Yuxu , Wu Shuang , Li Xinrong , Lin Xutao , Gan Mailin , Chen Lei , Zhao Ye , Niu Lili , Zhang Shunhua , Li Xuewei , Zhu Li , Shen Linyuan
Published: July 2022

Mammalian adipose tissue can be divided into white and brown adipose tissue based on its colour, location, and cellular structure. Certain conditions, such as sympathetic nerve excitement, can induce the white adipose adipocytes into a new type of adipocytes, known as beige adipocytes. The process, leading to the conversion of white adipocytes into beige adipocytes, is called white fat browning. The dynamic balance between white and beige adipocytes is closely related to the body’s metabolic homeostasis. Studying the signal transduction pathways of the white fat browning might provide novel ideas for the treatment of obesity and alleviation of obesity-related glucose and lipid metabolism disorders. This article aimed to provide an overview of recent advances in understanding white fat browning and the role of BAT in lipid metabolism.
Mitogen-Activated Protein Kinase Is Involved in Salt Stress Response in Tomato (Solanum lycopersicum) Seedlings
Authors: Wei Lijuan , Feng Li , Liu Yayu , Liao Weibiao
Published: July 2022

Salt stress impairs plant growth and development, thereby causing low yield and inferior quality of crops. In this study, tomato (Solanum lycopersicum L. ‘Micro-Tom’) seedlings treated with different concentrations of sodium chloride (NaCl) were investigated in terms of decreased plant height, stem diameter, dry weight, fresh weight, leaves relative water content and root activity. To reveal the response mechanism of tomato seedlings to salt stress, the transcriptome of tomato leaves was conducted. A total of 6589 differentially expressed genes (DEGs) were identified and classified into different metabolic pathways, especially photosynthesis, carbon metabolism, biosynthesis of amino acids and mitogen-activated protein kinase (MAPK) signaling pathway. Of these, approximately 42 DEGs were enriched in the MAPK signaling pathway, most of which mainly included plant hormone, hydrogen peroxide (H2O2), wounding and pathogen infection signaling pathways. To further explore the roles of MAPK under salt stress, MAPK phosphorylation inhibitor SB203580 (SB) was applied. We found that SB further decreased endogenous jasmonic acid, abscisic acid and ethylene levels under salt stress condition. Additionally, in comparison with NaCl treatment alone, SB + NaCl treatment reduced the content of O2− and H2O2 and the activities of antioxidant enzyme and downregulated the expression levels of genes related to pathogen infection. Together, the results revealed that MAPK might be involved in the salinity response of tomato seedlings by regulating hormone balance, ROS metabolism, antioxidant capacity and plant immunity.
Computer-Aided Design and Synthesis of (Functionalized quinazoline)–(α-substituted coumarin)–arylsulfonate Conjugates against Chikungunya Virus
Authors: Hwu Jih Ru , Roy Animesh , Tsay Shwu-Chen , Huang Wen-Chieh , Lin Chun-Cheng , Hwang Kuo Chu , Hu Yu-Chen , Shieh Fa-Kuen , Leyssen Pieter , Neyts Johan
Published: July 2022

Chikungunya virus (CHIKV) has repeatedly spread via the bite of an infected mosquito and affected more than 100 countries. The disease poses threats to public health and the economy in the infected locations. Many efforts have been devoted to identifying compounds that could inhibit CHIKV. Unfortunately, successful clinical candidates have not been found yet. Computations through the simulating recognition process were performed on complexation of the nsP3 protein of CHIKV with the structures of triply conjugated drug lead candidates. The outcomes provided the aid on rational design of functionalized quinazoline-(α-substituted coumarin)-arylsulfonate compounds to inhibit CHIKV in Vero cells. The molecular docking studies showed a void space around the β carbon atom of coumarin when a substituent was attached at the α position. The formed vacancy offered a good chance for a Michael addition to take place owing to steric and electronic effects. The best conjugate containing a quinazolinone moiety exhibited potency with EC50 = 6.46 μM, low toxicity with CC50 = 59.7 μM, and the selective index (SI) = 9.24. Furthermore, the corresponding 4-anilinoquinazoline derivative improved the anti-CHIKV potency to EC50 = 3.84 μM, CC50 = 72.3 μM, and SI = 18.8. The conjugate with 4-anilinoquinazoline exhibited stronger binding affinity towards the macro domain than that with quinazolinone via hydrophobic and hydrogen bond interactions.
Ethylene Inhibits Anthocyanin Biosynthesis by Repressing the R2R3-MYB Regulator SlAN2-like in Tomato
Authors: Xu Yulian , Liu Xiaoxi , Huang Yinggemei , Xia Zhilei , Lian Zilin , Qian Lijuan , Yan Shuangshuang , Cao Bihao , Qiu Zhengkun
Published: July 2022

Fruit ripening is usually accompanied by anthocyanin accumulation. Ethylene is key in ripening-induced anthocyanin production in many fruits. However, the effects of fruit ripening and ethylene on anthocyanin biosynthesis in purple tomato fruits are unclear. This study shows that bagged fruits of the purple tomato cultivar ‘Indigo Rose’ failed to produce anthocyanins at the red ripening stage after bag removal. In contrast, the bagged immature fruits accumulated a significant amount of anthocyanins after removing the bags. The transcriptomic analyses between immature and red ripening fruit before and after bag removal revealed that anthocyanin-related genes, including the key positive R2R3-MYB regulator SlAN2-like, were repressed in the red ripening fruit. The 86 identified transcription factors, including 13 AP2/ERF, 7 bZIP, 8 bHLH and 6 MYB, showed significantly different expressions between immature and red ripening fruits. Moreover, subjecting bagged immature fruits to exogenous ethylene treatment significantly inhibited anthocyanin accumulation and the expression of anthocyanin-related genes, including the anthocyanin structure genes and SlAN2-like. Thus, ethylene inhibits anthocyanin biosynthesis by repressing the transcription of SlAN2-like and other anthocyanin-related genes. These findings provide new insights into anthocyanin regulation in purple tomato fruit.
MiTF/TFE Translocation Renal Cell Carcinomas: From Clinical Entities to Molecular Insights
Authors: Simonaggio Audrey , Ambrosetti Damien , Verkarre Virginie , Auvray Marie , Oudard Stéphane , Vano Yann-Alexandre
Published: July 2022

MiTF/TFE translocation renal cell carcinoma (tRCC) is a rare and aggressive subtype of RCC representing the most prevalent RCC in the pediatric population (up to 40%) and making up 4% of all RCCs in adults. It is characterized by translocations involving either TFE3 (TFE3-tRCC), TFEB (TFEB-tRCC) or MITF, all members of the MIT family (microphthalmia-associated transcriptional factor). TFE3-tRCC was first recognized in the World Health Organization (WHO) classification of kidney cancers in 2004. In contrast to TFEB-tRCC, TFE3-tRCC is associated with many partners that can be detected by RNA or exome sequencing. Both diagnoses of TFE3 and TFEB-tRCC are performed on morphological and immunohistochemical features, but, to date, TFE break-apart fluorescent in situ hybridization (FISH) remains the gold standard for diagnosis. The clinical behavior of tRCC is heterogeneous and more aggressive in adults. Management of metastatic tRCC is challenging, especially in the younger population, and data are scarce. Efficacy of the standard of care-targeted therapies and immune checkpoint inhibitors remains low. Recent integrative exome and RNA sequencing analyses have provided a better understanding of the biological heterogeneity, which can contribute to a better therapeutic approach. We describe the clinico-pathological entities, the response to systemic therapy and the molecular features and techniques used to diagnose tRCC.
Dialdehyde Starch Nanocrystals as a Novel Cross-Linker for Biomaterials Able to Interact with Human Serum Proteins
Authors: Wegrzynowska-Drzymalska Katarzyna , Mylkie Kinga , Nowak Pawel , Mlynarczyk Dariusz T. , Chelminiak-Dudkiewicz Dorota , Kaczmarek Halina , Goslinski Tomasz , Ziegler-Borowska Marta
Published: July 2022

In recent years, new cross-linkers from renewable resources have been sought to replace toxic synthetic compounds of this type. One of the most popular synthetic cross-linking agents used for biomedical applications is glutaraldehyde. However, the unreacted cross-linker can be released from the materials and cause cytotoxic effects. In the present work, dialdehyde starch nanocrystals (NDASs) were obtained from this polysaccharide nanocrystal form as an alternative to commonly used cross-linking agents. Then, 5–15% NDASs were used for chemical cross-linking of native chitosan (CS), gelatin (Gel), and a mixture of these two biopolymers (CS-Gel) via Schiff base reaction. The obtained materials, forming thin films, were characterized by ATR-FTIR, SEM, and XRD analysis. Thermal and mechanical properties were determined by TGA analysis and tensile testing. Moreover, all cross-linked biopolymers were also characterized by hydrophilic character, swelling ability, and protein absorption. The toxicity of obtained materials was tested using the Microtox test. Dialdehyde starch nanocrystals appear as a beneficial plant-derived cross-linking agent that allows obtaining cross-linked biopolymer materials with properties desirable for biomedical applications.
JIB-04, a Pan-Inhibitor of Histone Demethylases, Targets Histone-Lysine-Demethylase-Dependent AKT Pathway, Leading to Cell Cycle Arrest and Inhibition of Cancer Stem-Like Cell Properties in Hepatocellular Carcinoma Cells
Authors: Lee Jina , Kim Ji-Soo , Cho Hye-In , Jo So-Ra , Jang Yeun-Kyu
Published: July 2022

JIB-04, a pan-histone lysine demethylase (KDM) inhibitor, targets drug-resistant cells, along with colorectal cancer stem cells (CSCs), which are crucial for cancer recurrence and metastasis. Despite the advances in CSC biology, the effect of JIB-04 on liver CSCs (LCSCs) and the malignancy of hepatocellular carcinoma (HCC) has not been elucidated yet. Here, we showed that JIB-04 targeted KDMs, leading to the growth inhibition and cell cycle arrest of HCC, and abolished the viability of LCSCs. JIB-04 significantly attenuated CSC tumorsphere formation, growth, relapse, migration, and invasion in vitro. Among KDMs, the deficiency of KDM4B, KDM4D, and KDM6B reduced the viability of the tumorspheres, suggesting their roles in the function of LCSCs. RNA sequencing revealed that JIB-04 affected various cancer-related pathways, especially the PI3K/AKT pathway, which is crucial for HCC malignancy and the maintenance of LCSCs. Our results revealed KDM6B-dependent AKT2 expression and the downregulation of E2F-regulated genes via JIB-04-induced inhibition of the AKT2/FOXO3a/p21/RB axis. A ChIP assay demonstrated JIB-04-induced reduction in H3K27me3 at the AKT2 promoter and the enrichment of KDM6B within this promoter. Overall, our results strongly suggest that the inhibitory effect of JIB-04 on HCC malignancy and the maintenance of LCSCs is mediated via targeting the KDM6B-AKT2 pathway, indicating the therapeutic potential of JIB-04.
Nucleosome Assembly Protein 1, Nap1, Is Required for the Growth, Development, and Pathogenicity of Magnaporthe oryzae
Authors: Wang Qing , Wang Jing , Huang Pengyun , Huang Zhicheng , Li Yan , Liu Xiaohong , Lin Fucheng , Lu Jianping
Published: July 2022

Magnaporthe oryzae is the causal agent of rice blast, leading to significant reductions in rice and wheat productivity. Nap1 is a conserved protein in eukaryotes involved in diverse physiological processes, such as nucleosome assembly, histone shuttling between the nucleus and cytoplasm, transcriptional regulation, and the cell cycle. Here, we identified Nap1 and characterized its roles in fungal development and virulence in M. oryzae. MoNap1 is involved in aerial hyphal and conidiophore differentiation, sporulation, appressorium formation, plant penetration, and virulence. ΔMonap1 generated a small, elongated, and malformed appressorium with an abnormally organized septin ring on hydrophobic surfaces. ΔMonap1 was more sensitive to cell wall integrity stresses but more resistant to microtubule stresses. MoNap1 interacted with histones H2A and H2B and the B-type cyclin (Cyc1). Moreover, a nuclear export signal (NES) domain is necessary for Nap1’s roles in the regulation of the growth and pathogenicity of M. oryzae. In summary, NAP1 is essential for the growth, appressorium formation, and pathogenicity of M. oryzae.
Effect of Polymeric Nanoparticles with Entrapped Fish Oil or Mupirocin on Skin Wound Healing Using a Porcine Model
Authors: Komprda Tomáš , Sládek Zbyšek , Vícenová Monika , Simonová Jana , Franke Gabriela , Lipový Břetislav , Matejovičová Milena , Kacvinská Katarína , Sabliov Cristina , Astete Carlos E. , Levá Lenka , Popelková Vendula , Bátik Andrej , Vojtová Lucy
Published: July 2022

The utilization of poly(lactic-co-glycolic) acid (PLGA) nanoparticles (NPs) with entrapped fish oil (FO) loaded in collagen-based scaffolds for cutaneous wound healing using a porcine model is unique for the present study. Full-depth cutaneous excisions (5 × 5 cm) on the pig dorsa were treated with pure collagen scaffold (control, C), empty PLGA NPs (NP), FO, mupirocin (MUP), PLGA NPs with entrapped FO (NP/FO) and PLGA NPs with entrapped MUP (NP/MUP). The following markers were evaluated on days 0, 3, 7, 14 and 21 post-excision: collagen, hydroxyproline (HP), angiogenesis and expressions of the COX2, EGF, COL1A1, COL1A3, TGFB1, VEGFA, CCL5 and CCR5 genes. The hypothesis that NP/FO treatment is superior to FO alone and that it is comparable to NP/MUP was tested. NP/FO treatment increased HP in comparison with both FO alone and NP/MUP (day 14) but decreased (p < 0.05) angiogenesis in comparison with FO alone (day 3). NP/FO increased (p < 0.05) the expression of the CCR5 gene (day 3) and tended (p > 0.05) to increase the expressions of the EGF (day 7, day 14), TGFB1 (day 21) and CCL5 (day 7, day 21) genes as compared with NP/MUP. NP/FO can be suggested as a suitable alternative to NP/MUP in cutaneous wound treatment.
The Puzzle of Hereditary Spastic Paraplegia: From Epidemiology to Treatment
Authors: Meyyazhagan Arun , Kuchi Bhotla Haripriya , Pappuswamy Manikantan , Orlacchio Antonio
Published: July 2022

Inherited neurodegenerative pathology characterized by lower muscle tone and increasing spasticity in the lower limbs is termed hereditary spastic paraplegia (HSP). HSP is associated with changes in about 80 genes and their products involved in various biochemical pathways, such as lipid droplet formation, endoplasmic reticulum shaping, axon transport, endosome trafficking, and mitochondrial function. With the inheritance patterns of autosomal dominant, autosomal recessive, X-linked recessive, and mitochondrial inheritance, HSP is prevalent around the globe at a rate of 1–5 cases in every 100,000 individuals. Recent technology and medical interventions somewhat aid in recognizing and managing the malaise. However, HSP still lacks an appropriate and adequate therapeutic approach. Current therapies are based on the clinical manifestations observed in the patients, for example, smoothing the relaxant spastic muscle and physiotherapies. The limited clinical trial studies contribute to the absence of specific pharmaceuticals for HSPs. Our current work briefly explains the causative genes, epidemiology, underlying mechanism, and the management approach undertaken to date. We have also mentioned the latest approved drugs to summarise the available knowledge on therapeutic strategies for HSP.
Increased Acetylcholine Levels and Other Brain Effects in 5XFAD Mice after Treatment with 8,14-Dihydroxy Metabolite of Efavirenz
Authors: Mast Natalia , Li Yong , Pikuleva Irina A.
Published: July 2022

Efavirenz (EFV), an FDA-approved anti-HIV drug, has off-target binding to CYP46A1, the CNS enzyme which converts cholesterol to 24-hydroxycholesterol. At small doses, EFV allosterically activates CYP46A1 in mice and humans and mitigates some of the Alzheimer’s disease manifestations in 5XFAD mice, an animal model. Notably, in vitro, all phase 1 EFV hydroxymetabolites activate CYP46A1 as well and bind either to the allosteric site for EFV, neurotransmitters or both. Herein, we treated 5XFAD mice with 8,14-dihydroxyEFV, the binder to the neurotransmitter allosteric site, which elicits the highest CYP46A1 activation in vitro. We found that treated animals of both sexes had activation of CYP46A1 and cholesterol turnover in the brain, decreased content of the amyloid beta 42 peptide, increased levels of acetyl-CoA and acetylcholine, and altered expression of the brain marker proteins. In addition, male mice had improved performance in the Barnes Maze test and increased expression of the acetylcholine-related genes. This work expands our knowledge of the beneficial CYP46A1 activation effects and demonstrates that 8,14-dihydroxyEFV crosses the blood–brain barrier and has therapeutic potential as a CYP46A1 activator.
MIL-100(Fe) Sub-Micrometric Capsules as a Dual Drug Delivery System
Authors: Abuçafy Marina Paiva , Frem Regina Celia Galvao , Polinario Giulia , Pavan Fernando Rogerio , Zhao Heng , Mielcarek Angelika , Boissiere Cedric , Serre Christian , Chiavacci Leila Aparecida
Published: July 2022

Nanoparticles of metal–organic frameworks (MOF NPs) are crystalline hybrid micro- or mesoporous nanomaterials that show great promise in biomedicine due to their significant drug loading ability and controlled release. Herein, we develop porous capsules from aggregate of nanoparticles of the iron carboxylate MIL-100(Fe) through a low-temperature spray-drying route. This enables the concomitant one-pot encapsulation of high loading of an antitumor drug, methotrexate, within the pores of the MOF NPs, and the collagenase enzyme (COL), inside the inter-particular mesoporous cavities, upon the formation of the capsule, enhancing tumor treatment. This association provides better control of the release of the active moieties, MTX and collagenase, in simulated body fluid conditions in comparison with the bare MOF NPs. In addition, the loaded MIL-100 capsules present, against the A-375 cancer cell line, selective toxicity nine times higher than for the normal HaCaT cells, suggesting that MTX@COL@MIL-100 capsules may have potential application in the selective treatment of cancer cells. We highlight that an appropriate level of collagenase activity remained after encapsulation using the spray dryer equipment. Therefore, this work describes a novel application of MOF-based capsules as a dual drug delivery system for cancer treatment.
Levetiracetam Suppresses the Infiltration of Neutrophils and Monocytes and Downregulates Many Inflammatory Cytokines during Epileptogenesis in Pilocarpine-Induced Status Epilepticus Mice
Authors: Matsuo Taira , Komori Rie , Nakatani Minami , Ochi Shiori , Yokota-Nakatsuma Aya , Matsumoto Junichi , Takata Fuyuko , Dohgu Shinya , Ishihara Yasuhiro , Itoh Kouichi
Published: July 2022

Acute brain inflammation after status epilepticus (SE) is involved in blood–brain barrier (BBB) dysfunction and brain edema, which cause the development of post-SE symptomatic epilepsy. Using pilocarpine-induced SE mice, we previously reported that treatment with levetiracetam (LEV) after SE suppresses increased expression levels of proinflammatory mediators during epileptogenesis and prevents the development of spontaneous recurrent seizures. However, it remains unclear how LEV suppresses neuroinflammation after SE. In this study, we demonstrated that LEV suppressed the infiltration of CD11b+CD45high cells into the brain after SE. CD11b+CD45high cells appeared in the hippocampus between 1 and 4 days after SE and contained Ly6G+Ly6C+ and Ly6G−Ly6C+ cells. Ly6G+Ly6C+ cells expressed higher levels of proinflammatory cytokines such as IL-1β and TNFα suggesting that these cells were inflammatory neutrophils. Depletion of peripheral Ly6G+Ly6C+ cells prior to SE by anti-Ly6G antibody (NIMP-R14) treatment completely suppressed the infiltration of Ly6G+Ly6C+ cells into the brain. Proteome analysis revealed the downregulation of a variety of inflammatory cytokines, which exhibited increased expression in the post-SE hippocampus. These results suggest that Ly6G+Ly6C+ neutrophils are involved in the induction of acute brain inflammation after SE. The proteome expression profile of the hippocampus treated with LEV after SE was similar to that after NIMP-R14 treatment. Therefore, LEV may prevent acute brain inflammation after SE by suppressing inflammatory neutrophil infiltration.
Microscale Thermophoresis as a Tool to Study Protein Interactions and Their Implication in Human Diseases
Authors: Magnez Romain , Bailly Christian , Thuru Xavier
Published: July 2022

The review highlights how protein–protein interactions (PPIs) have determining roles in most life processes and how interactions between protein partners are involved in various human diseases. The study of PPIs and binding interactions as well as their understanding, quantification and pharmacological regulation are crucial for therapeutic purposes. Diverse computational and analytical methods, combined with high-throughput screening (HTS), have been extensively used to characterize multiple types of PPIs, but these procedures are generally laborious, long and expensive. Rapid, robust and efficient alternative methods are proposed, including the use of Microscale Thermophoresis (MST), which has emerged as the technology of choice in drug discovery programs in recent years. This review summarizes selected case studies pertaining to the use of MST to detect therapeutically pertinent proteins and highlights the biological importance of binding interactions, implicated in various human diseases. The benefits and limitations of MST to study PPIs and to identify regulators are discussed.
S-Adenosylmethionine Inhibits Colorectal Cancer Cell Migration through Mirna-Mediated Targeting of Notch Signaling Pathway
Authors: Borzacchiello Luigi , Veglia Tranchese Roberta , Grillo Roberta , Arpino Roberta , Mosca Laura , Cacciapuoti Giovanna , Porcelli Marina
Published: July 2022

Metastasis is a leading cause of mortality and poor prognosis in colorectal cancer (CRC). Thus, the identification of new compounds targeting cell migration represents a major clinical challenge. Recent findings evidenced a central role for dysregulated Notch in CRC and a correlation between Notch overexpression and tumor metastasis. MicroRNAs (miRNAs) have been reported to cross-talk with Notch for its regulation. Therefore, restoring underexpressed miRNAs targeting Notch could represent an encouraging therapeutic approach against CRC. In this context, S-adenosyl-L-methionine (AdoMet), the universal biological methyl donor, being able to modulate the expression of oncogenic miRNAs could act as a potential antimetastatic agent. Here, we showed that AdoMet upregulated the onco-suppressor miRNAs-34a/-34c/-449a and inhibited HCT-116 and Caco-2 CRC cell migration. This effect was associated with reduced expression of migration-/EMT-related protein markers. We also found that, in colorectal and triple-negative breast cancer cells, AdoMet inhibited the expression of Notch gene, which, by luciferase assay, resulted the direct target of miRNAs-34a/-34c/-449a. Gain- and loss-of-function experiments with miRNAs mimics and inhibitors demonstrated that AdoMet exerted its inhibitory effects by upregulating miRNAs-34a/-34c/-449a. Overall, these data highlighted AdoMet as a novel Notch inhibitor and suggested that the antimetastatic effects of AdoMet involve the miRNA-mediated targeting of Notch signaling pathway.
Characterization of Adrenal miRNA-Based Dysregulations in Cushing’s Syndrome
Authors: Vetrivel Sharmilee , Zhang Ru , Engel Mareen , Oßwald Andrea , Watts Deepika , Chen Alon , Wielockx Ben , Sbiera Silviu , Reincke Martin , Riester Anna
Published: July 2022

MiRNAs are important epigenetic players with tissue- and disease-specific effects. In this study, our aim was to investigate the putative differential expression of miRNAs in adrenal tissues from different forms of Cushing’s syndrome (CS). For this, miRNA-based next-generation sequencing was performed in adrenal tissues taken from patients with ACTH-independent cortisol-producing adrenocortical adenomas (CPA), from patients with ACTH-dependent pituitary Cushing’s disease (CD) after bilateral adrenalectomy, and from control subjects. A confirmatory QPCR was also performed in adrenals from patients with other CS subtypes, such as primary bilateral macronodular hyperplasia and ectopic CS. Sequencing revealed significant differences in the miRNA profiles of CD and CPA. QPCR revealed the upregulated expression of miR-1247-5p in CPA and PBMAH (log2 fold change > 2.5, p < 0.05). MiR-379-5p was found to be upregulated in PBMAH and CD (log2 fold change > 1.8, p < 0.05). Analyses of miR-1247-5p and miR-379-5p expression in the adrenals of mice which had been exposed to short-term ACTH stimulation showed no influence on the adrenal miRNA expression profiles. For miRNA-specific target prediction, RNA-seq data from the adrenals of CPA, PBMAH, and control samples were analyzed with different bioinformatic platforms. The analyses revealed that both miR-1247-5p and miR-379-5p target specific genes in the WNT signaling pathway. In conclusion, this study identified distinct adrenal miRNAs as being associated with CS subtypes.
Psychometric Properties of the Spanish Version of the Fatigue Assessment Scale in Caregivers of Palliative Care Patients
Authors: Esteban-Burgos Ana A. , Fernández-Alcántara Manuel , Escribano Silvia , Perpiñá-Galvañ Juana , Campos-Calderón Concepción Petra , Cabañero-Martínez María José
Published: July 2022

Symptoms of fatigue and lack of energy are very common in caregivers of palliative care (PC) patients, traditionally associated with variables such as burden or depression. There are no Spanish-language instruments validated for assessing fatigue levels in this population. The Fatigue Assessment Scale (FAS) is a useful and simple instrument for assessing fatigue in this group. The aim of this study was to examine its psychometric properties (factor structure, reliability and validity) in a sample of caregivers of PC patients. Instrumental design for instrument validation was performed. One hundred and eight caregivers of PC patients participated and completed measures of fatigue, family functioning, life satisfaction, caregiver burden, anxiety, depression, resilience and quality of life. A confirmatory factor analysis was performed; non-linear reliability coefficient and Pearson correlations and t-tests were conducted to assess evidence of reliability and validity. The Spanish version of the FAS was found to have a one-dimensional structure. Reliability was 0.88. Validity evidence showed that FAS scores were positively associated with levels of burden, anxiety and depression. They were negatively associated with family functioning, life satisfaction, resilience and quality of life. The Spanish version of the FAS in caregivers of PC patients shows adequate psychometric properties.
Advances in Percutaneous Patent Foramen Ovale Closure: From the Procedure to the Echocardiographic Guidance
Authors: Sperlongano Simona , Giordano Mario , Ciccarelli Giovanni , Bassi Giuseppe , Malvezzi Caracciolo D’Aquino Marco , Del Giudice Carmen , Gaio Gianpiero , D’Andrea Antonello , Postolache Adriana , Cappelli Bigazzi Maurizio , Scognamiglio Giancarlo , Sarubbi Berardo , Russo Maria , Golino Paolo , Lancellotti Patrizio
Published: July 2022

Percutaneous patent foramen ovale (PFO) closure by traditional, double disc occluder devices was shown to be safe for patients with PFO, and more effective than prolonged medical therapy in preventing recurrent thromboembolic events. The novel suture-mediated “deviceless” PFO closure system overcomes most of the risks and limitations associated with the traditional PFO occluders, appearing to be feasible in most interatrial septum anatomies, even if data about its long-term effectiveness and safety are still lacking. The aim of the present review was to provide to the reader the state of the art about the traditional and newer techniques of PFO closure, focusing both on the procedural aspects and on the pivotal role of transesophageal echocardiography (TEE) in patient’s selection, peri-procedural guidance, and post-interventional follow-up.
Impact of KRAS Mutation Subtypes and Co-Occurring Mutations on Response and Outcome in Advanced NSCLC Patients following First-Line Treatment
Authors: Sun Yingjia , Li Ziming , Jian Hong , Xia Liliang , Lu Shun
Published: July 2022

(1) Background: The purpose was to systematically assess the impact of KRAS subtypes and co-mutations on responses of first-line treatment and outcomes by genetic classification in advanced KRAS mutant NSCLC. (2) Methods: Molecular pathology was confirmed with NGS; Kaplan–Meier analysis and Cox multivariate model were used to analyze the efficacy of first-line treatment and prognosis in KRAS subgroups. (3) Results: Advanced KRAS mutant NSCLC was confirmed among 183 patients, who received first-line therapy. The most common KRAS subtype and co-mutation were G12C (29.5%) and TP53 (59.6%). ICIs/CHE group prolonged PFS to 16.9 m, vs. (CHE)4.6 m vs. (CHE/BEV)7.0 m (p < 0.0001); mOS (ICIs/CHE)37.1 m vs. (CHE)19.8 m vs. [CHE/BEV] 20.7 m (p = 0.024). PFS benefited to different degrees after first-line ICI-based treatment in each genetic classification. KRAS G12D even benefited from OS (p = 0.045). CHE/BEV prolonged mPFS of KRAS/STK11 co-mutation (p = 0.043), but decreased mPFS in G12A subtype (p = 0.026). Multivariate analysis indicated that heavy smoking history (≥20 pack-years) (HR = 0.45, p = 0.039) predicts optimistic prognosis; PS score 1 (HR = 3.604, p = 0.002) and KRAS/SMAD4 co-mutation (HR = 4.293, p = 0.027) remained as independent predictors of shorter OS. (4) Conclusions: First-line treatment with ICI benefited KRAS-mutant-NSCLC patients and resulted in non-negative predictive value for any genetic classification. Bevacizumab should be cautiously chosen for patients with KRAS G12A subtype but is recommended for KRAS/STK11 patients. KRAS/SMAD4 is a new co-mutation genotype that displayed independent risk prognostic factors in patients with advanced KRAS-mutant NSCLC.
Predicting the Severity of Neurological Impairment Caused by Ischemic Stroke Using Deep Learning Based on Diffusion-Weighted Images
Authors: Zeng Ying , Long Chen , Zhao Wei , Liu Jun
Published: July 2022

Purpose: To develop a preliminary deep learning model that uses diffusion-weighted imaging (DWI) images to classify the severity of neurological impairment caused by ischemic stroke. Materials and Methods: This retrospective study included 851 ischemic stroke patients (711 patients in the training set and 140 patients in the test set). The patients’ NIHSS scores, which reflect the severity of neurological impairment, were reviewed upon admission and on Day 7 of hospitalization and were classified into two stages (stage 1 for NIHSS < 5 and stage 2 for NIHSS ≥ 5). A 3D-CNN was trained to predict the stage of NIHSS based on different preprocessed DWI images. The performance in predicting the severity of anterior and posterior circulation stroke was also investigated. The AUC, specificity, and sensitivity were calculated to evaluate the performance of the model. Results: Our proposed model obtained better performance in predicting the NIHSS stage on Day 7 of hospitalization than that at admission (best AUC 0.895 vs. 0.846). Model D trained with DWI images (normalized with z-score and resized to 256 × 256 × 64 voxels) achieved the best AUC of 0.846 in predicting the NIHSS stage at admission. Model E rained with DWI images (normalized with maximum–minimum and resized to 128 × 128 × 32 voxels) achieved the best AUC of 0.895 in predicting the NIHSS stage on Day 7 of hospitalization. Our model also showed promising performance in predicting the NIHSS stage on Day 7 of hospitalization for anterior and posterior circulation stroke, with the best AUCs of 0.905 and 0.903, respectively. Conclusions: Our proposed 3D-CNN model can effectively predict the neurological severity of IS using DWI images and performs better in predicting the NIHSS stage on Day 7 of hospitalization. The model also obtained promising performance in subgroup analysis, which can potentially help clinical decision making.
Comparison of the Differences in State-Trait Anxiety Inventory Scores and Insomnia Histories between Monozygotic and Dizygotic Twins: A Cross-Sectional Study Using KoGES HTS Data
Authors: Kim So Young , Yoo Dae Myoung , Kwon Mi Jung , Kim Ji Hee , Kim Joo-Hee , Bang Woo Jin , Choi Hyo Geun
Published: July 2022

The heritability of anxiety and its association with insomnia have been suggested. This study investigated the coincidence of anxiety and insomnia in monozygotic twins compared to dizygotic twins. The Korean Genome and Epidemiology Study 2005–2014 was used. The ≥20-year-old cohort population was composed of 1300 twin participants. A total of 980 monozygotic twins and 232 dizygotic twins were compared for the concordance for the history of insomnia in both twin pairs (coincidence of insomnia) and the difference in state of anxiety and trait of anxiety scores. The odds ratios (ORs) for the coincidence of insomnia in monozygotic twins compared to dizygotic twins were analyzed using multiple logistic regression analysis. The estimated values (EV) of the difference of state and trait of anxiety scores were analyzed using a linear regression model. The coincidence of insomnia was not high in monozygotic twins compared to dizygotic twins. The difference in the state of anxiety score was comparable between monozygotic twins and dizygotic twins. However, the difference in anxiety scores was higher in dizygotic twins than in monozygotic twins. The monozygotic twin group did not demonstrate higher coincidence of insomnia or the state of anxiety than the dizygotic twin group. However, the monozygotic twin group indicated higher coincidence of the trait of anxiety than the dizygotic twins. The current results implied the potential contribution of heritable factors for the trait of anxiety.
Doripenem in the Treatment of Patients with Nosocomial Pneumonia: A Meta-Analysis
Authors: Huang Chienhsiu , Chen Ihung , Yang Yalun
Published: July 2022

Introduction: Clinically, doripenem therapy for nosocomial pneumonia remains a serious concern. The purpose of this meta-analysis was to explore the efficacy and the safety of doripenem therapy for nosocomial pneumonia in comparison with other antimicrobial agents. Methods: Studies were eligible for inclusion only if they directly compared the clinical effectiveness of doripenem and other antimicrobial agent therapies for nosocomial pneumonia in adult patients between 1 January 2000 and 30 April 2022. All studies were included if they reported one or more of the following outcomes: clinical cure rate, microbiological cure rate, all-cause mortality, and adverse events. Results: Six randomized controlled trials and three retrospective studies were included in the meta-analysis. There were 952 patients in the doripenem group and 1183 patients in the comparator group. The comparator antimicrobial agents included imipenem/cilastatin, meropenem, and piperacillin/tazobactam. Seven studies had a high risk of bias. Doripenem therapy for nosocomial pneumonia had a microbiological cure rate, a clinical cure rate, an all-cause mortality, and adverse events similar to those of comparators. Conclusions: The efficacy and the safety of doripenem therapy for nosocomial pneumonia were comparable with those of comparators. Randomized controlled trials are needed to confirm the role of doripenem in nosocomial pneumonia therapy.
Vestibular Disability/Handicap in Fibromyalgia: A Questionnaire Study
Authors: Mucci Viviana , Demori Ilaria , Rapallo Fabio , Molinari Elena , Losacco Serena , Marinelli Lucio , Browne Cherylea J. , Burlando Bruno
Published: July 2022

Fibromyalgia (FM) is a poorly understood, central pain processing disorder characterized by a broad range of symptoms, such as chronic pain, sleep disruption, chronic fatigue, and psychosomatic symptoms. In addition, recent studies have shown that FM patients also experience dizziness. We aimed to establish a prevalence rate of vestibular symptoms in a population of FM patients through a battery of questionnaires investigating socio-demographic, clinical and psychological characteristics, combined with the Dizziness Handicap Inventory (DHI) and the Situational Vertigo Questionnaire (SVQ). A total of 277 respondents, officially diagnosed with FM, completed the full study, while 80 controls were also included for DHI and SVQ questionnaires. We found that FM participants were significantly affected by vestibular symptoms, which correlated with FM-associated pain and non-pain symptoms. The dizziness reported by FM participants showed peculiar features suggesting an FM-intrinsic mechanism of vestibular dysfunction, possibly linked to migraine and dysautonomia conditions. Correlations between dizziness and depressive mood (or neuroticism), revealed an impact of dizziness on psychological status, leading to depressive reactions and interpersonal difficulties, and possibly involving a noxious, self-sustained stress condition. In conclusion, data showed a manifesting dizziness condition in FM patients that warrants careful clinical attention due to its possible inherent role in the syndrome.
Our Clinical Experience in the Treatment of Myasthenia Gravis Acute Exacerbations with a Novel Nanomembrane-Based Therapeutic Plasma Exchange Technology
Authors: Tonev Dimitar , Georgieva Radostina , Vavrek Evgeniy
Published: July 2022

According to the American Academy of Neurology 2011 guidelines, there is insufficient evidence to support or refute the use of therapeutic plasma exchange (TPE) for myasthenia gravis (MG). The goal of this study was to determine whether a novel nanomembrane-based TPE could be useful in the treatment of MG. Thirty-six adult patients, MGFA 4/4B and 5, with acute MG episodes were enrolled into a single-center retrospective before-and-after study to compare a conventional treatment group (n = 24) with a nanomembrane-based TPE group (n = 12). TPE or intravenous immunoglobulins (IVIG) infusions were used in impending/manifested myasthenic crises, especially in patients at high-risk for prolonged invasive ventilation (IMV) and in those tolerating non-invasive ventilation (NIV). The clinical improvement was assessed using the Myasthenia Muscle Score (0–100), with ≥20 increase for responders. The primary outcome measures included the rates of implemented TPE, IVIG, and corticosteroids immunotherapies, NIV/IMV, early tracheotomy, MMS scores, extubation time, neuro-ICU/hospital LOS, complications, and mortality rates. The univariate analysis found that IMV was lower in the nanomembrane-based group (42%) compared to the conventional treatment group (83%) (p = 0.02). The multivariate analysis using binary logistic regression revealed TPE and NIV as independent predictors for short-term (≤7 days) respiratory support (p = 0.014 for TPE; p = 0.002 for NIV). The novel TPE technology moved our clinical practice towards proactive rather than protective treatment in reducing prolonged IMV during MG acute exacerbations.
Prolonged Sitting Causes Leg Discomfort in Middle Aged Adults: Evaluation of Shear Wave Velocity, Calf Circumference, and Discomfort Questionaries
Authors: Okino Kumiko , Aoki Mitsuhiro , Yamane Masahiro , Kataoka Yoshiaki , Nitta Asami , Kohmura Chikashi
Published: July 2022

Introduction: Prolonged sitting causes leg discomfort. We evaluated shear wave velocity (SWV) of leg muscles, leg circumference, and leg discomfort associated with 2 h sitting. Methods: Twenty-one middle-aged men and 19 middle-aged women participated in the study. SWV and leg circumference was measured just after sitting, 60 min, 120 min, and after 3 min of leg raising. Leg discomfort was assessed before sitting and 120 min. Results: SWV was significantly greater in men than women and increased over time, and decreased with leg raising. The percentage increase in lower leg circumference was significantly greater in women than in men, and it increased over time. Leg discomfort significantly increased after 120 min in both men and women. Discussions: Because SWV is proportional to an increase in intramuscular compartment pressure in the lower leg, intramuscular compartment pressure increased over time with sitting and decreased with leg raising. Considering the changes in SWV and leg circumference, it was inferred that prolonged sitting causes an increase in intramuscular compartment pressure and intravascular blood volume, as well as an increase in water content in the leg subcutaneous tissue. Leg discomfort was estimated to be due to increased intra-leg fluid. Brief leg raising may resolve leg edema and discomfort.
Dynamic Label Assignment for Object Detection by Combining Predicted IoUs and Anchor IoUs
Authors: Zhang Tianxiao , Luo Bo , Sharda Ajay , Wang Guanghui
Published: July 2022

Label assignment plays a significant role in modern object detection models. Detection models may yield totally different performances with different label assignment strategies. For anchor-based detection models, the IoU (Intersection over Union) threshold between the anchors and their corresponding ground truth bounding boxes is the key element since the positive samples and negative samples are divided by the IoU threshold. Early object detectors simply utilize the fixed threshold for all training samples, while recent detection algorithms focus on adaptive thresholds based on the distribution of the IoUs to the ground truth boxes. In this paper, we introduce a simple while effective approach to perform label assignment dynamically based on the training status with predictions. By introducing the predictions in label assignment, more high-quality samples with higher IoUs to the ground truth objects are selected as the positive samples, which could reduce the discrepancy between the classification scores and the IoU scores, and generate more high-quality boundary boxes. Our approach shows improvements in the performance of the detection models with the adaptive label assignment algorithm and lower bounding box losses for those positive samples, indicating more samples with higher-quality predicted boxes are selected as positives.
Lipids and Fatty Acids in Some Mesopelagic Fish Species: General Characteristics and Peculiarities of Adaptive Response to Deep-Water Habitat
Authors: Voronin Viktor P. , Artemenkov Dmitrii V. , Orlov Alexei M. , Murzina Svetlana A.
Published: July 2022

The lipid and fatty acid composition of muscles of mesopelagic fish species Lampanyctus macdonaldi, Bathylagus euryops, Serrivomer beanii, Scopelogadus beanii in the Irminger Sea at deep range were studied. The contents of the total lipids (TLs), total phospholipids (PLs), monoacylglycerols (MAGs), diacylglycerols (DAGs), triacylglycerols (TAGs), cholesterol (Chol), Chol esters, non-esterified fatty acids (NEFAs), and wax esters were determined by HPTLC; the PL classes were determined by HPLC; and fatty acids (FAs) were determined using GC. It was found significant differences in lipid profile of the studied fishes: Chol esters and waxes were dominant in L. macdonaldii and S. beanii, fish species with diel vertical migrations (DVM), while TAGs were prevalent in B. euryops and Sc. Beanii—non-migratory species. It was revealed the species-specific differences in FAs profiles of the studied fish. Along with this, it was detected the similarity of FAs in fish, which is associated with food sources. A comparative analysis of lipids and FAs among L. macdonaldi and S. beanii collected in the Irminger Sea and L. alatus and S. beanii collected in the Tropic Seamount revealed similar biochemical strategies for the accumulation of certain lipids characterized the mesopelagic inhabit despite latitude differences of the area of study.