bluuebunny/crossref_metadata_2025 huggingface dataset:
Multiplex immunofluorescence to measure dynamic changes in tumor-infiltrating lymphocytes and PD-L1 in early-stage breast cancer
Authors: Sanchez Katherine , Kim Isaac , Chun Brie , Pucilowska Joanna , Redmond William L. , Urba Walter J. , Martel Maritza , Wu Yaping , Campbell Mary , Sun Zhaoyu , Grunkemeier Gary , Chang Shu Ching , Bernard Brady , Page David B.
Published: January 2021

Background

The H&E stromal tumor-infiltrating lymphocyte (sTIL) score and programmed death ligand 1 (PD-L1) SP142 immunohistochemistry assay are prognostic and predictive in early-stage breast cancer, but are operator-dependent and may have insufficient precision to characterize dynamic changes in sTILs/PD-L1 in the context of clinical research. We illustrate how multiplex immunofluorescence (mIF) combined with statistical modeling can be used to precisely estimate dynamic changes in sTIL score, PD-L1 expression, and other immune variables from a single paraffin-embedded slide, thus enabling comprehensive characterization of activity of novel immunotherapy agents.

Methods

Serial tissue was obtained from a recent clinical trial evaluating loco-regional cytokine delivery as a strategy to promote immune cell infiltration and activation in breast tumors. Pre-treatment biopsies and post-treatment tumor resections were analyzed by mIF (PerkinElmer Vectra) using an antibody panel that characterized tumor cells (cytokeratin-positive), immune cells (CD3, CD8, CD163, FoxP3), and PD-L1 expression. mIF estimates of sTIL score and PD-L1 expression were compared to the H&E/SP142 clinical assays. Hierarchical linear modeling was utilized to compare pre- and post-treatment immune cell expression, account for correlation of time-dependent measurement, variation across high-powered magnification views within each subject, and variation between subjects. Simulation methods (Monte Carlo, bootstrapping) were used to evaluate the impact of model and tissue sample size on statistical power.

Results

mIF estimates of sTIL and PD-L1 expression were strongly correlated with their respective clinical assays (p < .001). Hierarchical linear modeling resulted in more precise estimates of treatment-related increases in sTIL, PD-L1, and other metrics such as CD8+ tumor nest infiltration. Statistical precision was dependent on adequate tissue sampling, with at least 15 high-powered fields recommended per specimen. Compared to conventional t-testing of means, hierarchical linear modeling was associated with substantial reductions in enrollment size required (n = 25➔n = 13) to detect the observed increases in sTIL/PD-L1.

Conclusion

mIF is useful for quantifying treatment-related dynamic changes in sTILs/PD-L1 and is concordant with clinical assays, but with greater precision. Hierarchical linear modeling can mitigate the effects of intratumoral heterogeneity on immune cell count estimations, allowing for more efficient detection of treatment-related pharmocodynamic effects in the context of clinical trials.

Trial registration

NCT02950259.
An integrated multi-omics approach to identify regulatory mechanisms in cancer metastatic processes
Authors: Ghaffari Saba , Hanson Casey , Schmidt Remington E. , Bouchonville Kelly J. , Offer Steven M. , Sinha Saurabh
Published: January 2021

Background

Metastatic progress is the primary cause of death in most cancers, yet the regulatory dynamics driving the cellular changes necessary for metastasis remain poorly understood. Multi-omics approaches hold great promise for addressing this challenge; however, current analysis tools have limited capabilities to systematically integrate transcriptomic, epigenomic, and cistromic information to accurately define the regulatory networks critical for metastasis.

Results

To address this limitation, we use a purposefully generated cellular model of colon cancer invasiveness to generate multi-omics data, including expression, accessibility, and selected histone modification profiles, for increasing levels of invasiveness. We then adopt a rigorous probabilistic framework for joint inference from the resulting heterogeneous data, along with transcription factor binding profiles. Our approach uses probabilistic graphical models to leverage the functional information provided by specific epigenomic changes, models the influence of multiple transcription factors simultaneously, and automatically learns the activating or repressive roles of cis-regulatory events. Global analysis of these relationships reveals key transcription factors driving invasiveness, as well as their likely target genes. Disrupting the expression of one of the highly ranked transcription factors JunD, an AP-1 complex protein, confirms functional relevance to colon cancer cell migration and invasion. Transcriptomic profiling confirms key regulatory targets of JunD, and a gene signature derived from the model demonstrates strong prognostic potential in TCGA colorectal cancer data.

Conclusions

Our work sheds new light into the complex molecular processes driving colon cancer metastasis and presents a statistically sound integrative approach to analyze multi-omics profiles of a dynamic biological process.
Membranes for bioethanol production by pervaporation
Authors: Peng Ping , Lan Yongqiang , Liang Lun , Jia Kemeng
Published: January 2021

Background

Bioethanol as a renewable energy resource plays an important role in alleviating energy crisis and environmental protection. Pervaporation has achieved increasing attention because of its potential to be a useful way to separate ethanol from the biomass fermentation process.

Results

This overview of ethanol separation via pervaporation primarily concentrates on transport mechanisms, fabrication methods, and membrane materials. The research and development of polymeric, inorganic, and mixed matrix membranes are reviewed from the perspective of membrane materials as well as modification methods. The recovery performance of the existing pervaporation membranes for ethanol solutions is compared, and the approaches to further improve the pervaporation performance are also discussed.

Conclusions

Overall, exploring the possibility and limitation of the separation performance of PV membranes for ethanol extraction is a long-standing topic. Collectively, the quest is to break the trade-off between membrane permeability and selectivity. Based on the facilitated transport mechanism, further exploration of ethanol-selective membranes may focus on constructing a well-designed microstructure, providing active sites for facilitating the fast transport of ethanol molecules, hence achieving both high selectivity and permeability simultaneously. Finally, it is expected that more and more successful research could be realized into commercial products and this separation process will be deployed in industrial practices in the near future.

Graphical abstract
New World screwworm (Cochliomyia hominivorax) myiasis in feral swine of Uruguay: One Health and transboundary disease implications
Authors: Altuna Martín , Hickner Paul V. , Castro Gustavo , Mirazo Santiago , Pérez de León Adalberto A. , Arp Alex P.
Published: January 2021

Background

Feral swine (Sus scrofa) are highly invasive and threaten animal and human health in the Americas. The screwworm (Cochliomyia hominivorax) is listed by the World Organization for Animal Health as a notifiable infestation because myiasis cases affect livestock, wildlife, and humans in endemic areas, and outbreaks can have major socioeconomic consequences in regions where the screwworm has been eradicated. However, a knowledge gap exists on screwworm infestation of feral swine in South America, where the screwworm is endemic. Here, we report screwworm infestation of feral swine harvested in Artigas Department (Uruguay), where the Republic of Uruguay shares borders with Brazil and Argentina.

Methods

Myiasis caused by the larvae of screwworm were identified in feral swine with the support and collaboration of members of a local feral swine hunting club over a 3-year period in the Department of Artigas. Harvested feral swine were examined for the presence of lesions where maggots causing the myiasis could be sampled and processed for taxonomic identification. The sites of myiasis on the body of infested feral swine and geospatial data for each case were recorded. The sex and relative size of each feral swine were also recorded. Temperature and precipitation profiles for the region were obtained from public sources.

Results

Myiases caused by screwworms were recorded in 27 of 618 the feral swine harvested. Cases detected in males weighing > 40 kg were associated with wounds that, due to their location, were likely caused by aggressive dominance behavior between adult males. The overall prevalence of screwworm infestation in the harvested feral swine was associated with ambient temperature, but not precipitation. Case numbers peaked in the warmer spring and summer months.

Conclusions

This is the first report on myiasis in feral swine caused by screwworm in South America. In contrast to myiasis in cattle, which can reach deep into host tissues, screwworms in feral swine tended to cause superficial infestation. The presence of feral swine in screwworm endemic areas represents a challenge to screwworm management in those areas. Screwworm populations maintained by feral swine may contribute to human cases in rural areas of Uruguay, which highlights the importance of the One Health approach to the study of this invasive host species–ectoparasite interaction.

Graphical Abstract
Echinococcus multilocularis and other cestodes in red foxes (Vulpes vulpes) of northeast Italy, 2012–2018
Authors: Citterio Carlo Vittorio , Obber Federica , Trevisiol Karin , Dellamaria Debora , Celva Roberto , Bregoli Marco , Ormelli Silvia , Sgubin Sofia , Bonato Paola , Da Rold Graziana , Danesi Patrizia , Ravagnan Silvia , Vendrami Stefano , Righetti Davide , Agreiter Andreas , Asson Daniele , Cadamuro Andrea , Ianniello Marco , Capelli Gioia
Published: January 2021

Background

Echinococcus multilocularis is a small tapeworm affecting wild and domestic carnivores and voles in a typical prey-predator life cycle. In Italy, there has been a focus of E. multilocularis since 1997 in the northern Italian Alps, later confirmed in red foxes collected from 2001 to 2005. In this study, we report the results of seven years of monitoring on E. multilocularis and other cestodes in foxes and describe the changes that occurred over time and among areas (eco-regions) showing different environmental and ecological features on a large scale.

Methods

Eggs of cestodes were isolated from feces of 2872 foxes with a sedimentation/filtration technique. The cestode species was determined through multiplex PCR, targeting and sequencing ND1 and 12S genes. Analyses were aimed to highlight variations among different eco-regions and trends in prevalence across the study years.

Results

Out of 2872 foxes, 217 (7.55%) samples resulted positive for cestode eggs at coproscopy, with differences of prevalence according to year, sampling area and age class. Eight species of cestodes were identified, with Taenia crassiceps (2.65%), Taenia polyacantha (1.98%) and E. multilocularis (1.04%) as the most represented. The other species, Mesocestoides litteratus, Taenia krabbei, T. serialis, T. taeniaeformis and Dipylidium caninum, accounted for < 1% altogether. Echinococcus multilocularis was identified in foxes from two out of six eco-regions, in 30 fecal samples, accounting for 1.04% within the cestode positives at coproscopy. All E. multilocularis isolates came from Bolzano province. Prevalence of cestodes, both collectively and for each of the three most represented species (T. crassiceps, T. polyacantha and E. multilocularis), varied based on the sampling year, and for E. multilocularis an apparent increasing trend across the last few years was evidenced.

Conclusions

Our study confirms the presence of a focus of E. multilocularis in red foxes of northeast Italy. Although this focus seems still spatially limited, given its persistence and apparent increasing prevalence through the years, we recommend research to be conducted in the future on the ecological factors that, on a smaller scale, allow this zoonotic species to persist. On the same scale, we recommend a health education campaign to inform on the measures to prevent this zoonosis, targeted at people living in the area, especially hunters, dog owners, forestry workers and other potentially exposed categories.
Connective tissue remodelling is differently modulated by tocilizumab versus methotrexate monotherapy in patients with early rheumatoid arthritis: the AMBITION study
Authors: Drobinski Patryk J. , Bay-Jensen Anne C. , Karsdal Morten A. , Sardar Samra , Siebuhr Anne S.
Published: January 2021

Objective

Associations between rheumatoid arthritis (RA) and effect of treatment at the tissue levels are poorly understood. We investigated the scope of released extracellular matrix (ECM) metabolites as a consequence of tissue remodelling in patients treated with methotrexate (MTX) and tocilizumab (TCZ) compared to placebo.

Methods

Tissue metabolites from 387 RA patients treated with either TCZ (8 mg/kg) or MTX monotherapy (7.5–20 mg/kg) were measured at baseline and 8 weeks sera by validated ELISA assays. The levels of collagen biomarkers (C1M, C2M, C3M and C4M) together with C-reactive protein (CRP) and CRP metabolite (CRPM) were investigated. Baseline levels of biomarkers have been compared with 72 age- and gender-matched healthy controls. Comparison between treatment and response groups were done by ANCOVA, Spearman’s correlation and logistic regression adjusted for age, gender, BMI and disease duration.

Results

C1M and C3M were significantly (P < 0.05) inhibited by TCZ and C3M by MTX (P < 0.01) compared to placebo. C1M and C3M inhibition with TCZ was respectively 23% and 16% greater than that of MTX (P < 0.01 and P < 0.0001). C4M was inhibited by TCZ and MTX, but the effect of TCZ was 22% greater than MTX (P < 0.0001). TCZ and MTX had minimal effect on C2M levels. MTX had no effect on CRP and CRPM, whereas TCZ reduced their levels to 69% and 27% from baseline. Investigated biomarkers revealed a significant (P < 0.05) difference in biomarker profiles of MTX ACR50 treatment responders and non-responders. Change to week 8 in levels of C3M, C4M, CRP and CRPM in MTX patients correlated significantly (rho = 0.41 to 0.18, P < 0.0001 to 0.039) with change in disease activity (DAS28) at weeks 8, 16 and 24, whereas only CRP in TCZ patients (rho = 0.32 to 0.21, P < 0.0001 to 0.01).

Conclusion

Patients receiving TCZ treatment for 8 weeks had higher suppression of tissue remodelling and inflammatory biomarkers over patients treated with MTX. Measured biomarkers enabled for a discrimination of biomarker profiles of ACR50 treatment responding patients and identification of those who benefit at the early time point. Week 8 change in levels of C3M, C4M, CRP and CRPM significantly predicted clinical response to treatment and correlated with DAS28 at all time points.

Trial registration

ClinicalTrials.gov, NCT00109408. Date of registration: July 2005. Name of the registry: A Study to Assess the Safety and Efficacy of Tocilizumab in Patients with Active Rheumatoid Arthritis.
Expansion of circulating peripheral TIGIT+CD226+ CD4 T cells with enhanced effector functions in dermatomyositis
Authors: Li Wenli , Deng Chuiwen , Yang Hanbo , Lu Xin , Li Shanshan , Liu Xia , Chen Fang , Chen Lida , Shu Xiaoming , Zhang Lu , Liu Qingyan , Wang Guochun , Peng Qinglin
Published: January 2021

Background

T cell Ig and ITIM domain (TIGIT)/CD226 pathway has a critical role in regulating T cell responses and has come to the forefront in cancer as a promising immunotherapeutic target. However, its role in autoimmune diseases is just beginning to be elucidated. Dermatomyositis (DM) is an autoimmune disease, in which T cell dysregulation plays a pivotal role, and importantly, it is a common immune-related adverse event in response to treatment of cancers with immune checkpoint inhibitors, but no studies have implicated the TIGIT/CD226 axis in DM.

Methods

We recruited 30 treatment-naïve DM patients and 26 healthy controls. Flow cytometry analysis was used to investigate the co-expression of TIGIT and CD226 on T cells in blood samples. Magnetic bead or FACS-based cell isolation, T cell proliferation assay, and intracellular cytokine staining were performed to analyze the functions of different TIGIT/CD226 phenotypes. Recombinant proteins CD155, CD112, and anti-CD226 antibodies were used to suppress the function of TIGIT/CD226-expressing CD4 T cells.

Results

Four distinct subsets of T cells based on TIGIT/CD226 co-expression, TIGIT+CD226−, TIGIT+CD226+, TIGIT−CD226+, and TIGIT−CD226−, were identified and characterized in DM patients. Our data showed that the function of CD4 T cell subset varied by the TIGIT/CD226 phenotype. An elevated TIGIT+CD226+ CD4 subset with enhanced effector function was observed in patients with DM, especially the patients complicated with interstitial lung disease. This subpopulation was closely related to DM activity and decreased significantly in DM remission after treatment. Furthermore, the effector function of TIGIT+CD226+ CD4 subset could be suppressed by blocking CD226.

Conclusion

Our data revealed that the TIGIT and CD226 expression profiles could be used to identify functionally distinct subsets of CD4 T cells and TIGIT+CD226+ CD4 T cells is a significant subset in DM with enhanced frequency and effector function. This abnormal subset could be suppressed by blocking CD226, providing insight into the therapeutic target of the TIGIT/CD226 axis.
Resveratrol induces H3 and H4K16 deacetylation and H2A.X phosphorylation in Toxoplasma gondii
Authors: Contreras Susana M. , Ganuza Agustina , Corvi María M. , Angel Sergio O.
Published: January 2021

Objective

Resveratrol (RSV) is a multitarget drug that has demonstrated activity against Toxoplasma gondii in macrophage and human foreskin fibroblast (HFF) cell line infection models. However, the mechanism of action of RSV has not yet been determined. Thus, with the aim of identifying a possible mechanism of the anti-T. gondii activity of this compound, we analyzed the effects of RSV on histones H3 and H4 lysine 16 acetylation (H4K16). We also analyzed RSV-induced DNA damage to intracellular tachyzoites by using the DNA damage marker phosphorylated histone H2A.X (γH2AX).

Results

RSV inhibited intracellular T. gondii tachyzoite growth at concentrations below the toxic threshold for host cells. The IC50 value after 24 h of treatment was 53 μM. RSV induced a reduction in H4K16 acetylation (H4K16ac), a marker associated with transcription, DNA replication and homologous recombination repair. A similar deacetylation effect was observed on histone H3. RSV also increased T. gondii H2A.X phosphorylation at the SQE motif (termed γH2A.X), which is a DNA damage-associated posttranslational modification. Our findings suggest a possible link between RSV and DNA damage or repair processes that is possibly associated with DNA replication stress.
Collagen type 1A1, type 3A1, and LOXL1/4 polymorphisms as risk factors of pelvic organ prolapse
Authors: Ashikari Asuka , Suda Tetsuji , Miyazato Minoru
Published: January 2021

Objective

Collagen and elastin are the main components of the female pelvic tissue. We investigated whether single nucleotide polymorphisms (SNPs) of collagen type 1 alpha 1 (COL1A1), collagen type 3 alpha 1 (COL3A1), and lysyl oxidase-like (LOXL) 1 and 4 were associated with the onset of pelvic organ prolapse (POP) in Japanese women. Fifty-two women with POP and 28 women without POP were included. SNPs were identified using the TaqMan® SNP genotyping assay.

Results

Age, parity, and lower urinary tract symptoms were significantly higher in the POP group than in the control group. The prevalence of genotypes with rs2862296 polymorphism of LOXL4, an enzyme essential for extracellular matrix remodeling, was different between the POP (26.9% for GG, 51.9% for AG) and control groups (14.8% for GG, 33.3% for AG). However, polymorphisms of COL1A1, COL3A1, and LOXL1 were not related to the onset of POP. In the multivariate logistic regression analysis, age was significantly associated with the occurrence of POP. In the univariate analysis, LOXL4 polymorphism was associated with the onset of POP in Japanese women. The knowledge of acquired risk factors and polymorphisms in the genomic background of patients with POP may help prevent POP via early conservative interventions.
Insights into how development and life-history dynamics shape the evolution of venom
Authors: Surm Joachim M. , Moran Yehu
Published: January 2021

Venomous animals are a striking example of the convergent evolution of a complex trait. These animals have independently evolved an apparatus that synthesizes, stores, and secretes a mixture of toxic compounds to the target animal through the infliction of a wound. Among these distantly related animals, some can modulate and compartmentalize functionally distinct venoms related to predation and defense. A process to separate distinct venoms can occur within and across complex life cycles as well as more streamlined ontogenies, depending on their life-history requirements. Moreover, the morphological and cellular complexity of the venom apparatus likely facilitates the functional diversity of venom deployed within a given life stage. Intersexual variation of venoms has also evolved further contributing to the massive diversity of toxic compounds characterized in these animals. These changes in the biochemical phenotype of venom can directly affect the fitness of these animals, having important implications in their diet, behavior, and mating biology. In this review, we explore the current literature that is unraveling the temporal dynamics of the venom system that are required by these animals to meet their ecological functions. These recent findings have important consequences in understanding the evolution and development of a convergent complex trait and its organismal and ecological implications.
ESR EuroSafe Imaging and its role in promoting radiation protection – 6 years of success
Authors:   the European Society of Radiology, Frija Guy , Hoeschen Christoph , Granata Claudio , Vano Eliseo , Paulo Graciano , Damilakis John , Donoso Lluis , Bonomo Lorenzo , Loose Reinhard , Ebdon-Jackson Steve
Published: January 2021

This article introduces the European Society of Radiology’s EuroSafe Imaging initiative in the year of its 6th anniversary. The European and global radiation protection frameworks are outlined and the role of the EuroSafe Imaging initiative’s Call for Action in successfully achieving international radiation protection goals as set out by those frameworks is detailed.
Radial extracorporeal shockwave promotes subchondral bone stem/progenitor cell self-renewal by activating YAP/TAZ and facilitates cartilage repair in vivo
Authors: Zhao Zhidong , Wang Yuxing , Wang Qian , Liang Jiawu , Hu Wei , Zhao Sen , Li Peilin , Zhu Heng , Li Zhongli
Published: January 2021

Background

Radial extracorporeal shockwave (r-ESW), an innovative and noninvasive technique, is gaining increasing attention in regenerative medicine due to its mechanobiological effects. Subchondral bone stem/progenitor cells (SCB-SPCs), originating from the pivotal zone of the osteochondral unit, have been shown to have multipotency and self-renewal properties. However, thus far, little information is available regarding the influences of r-ESW on the biological properties of SCB-SPCs and their therapeutic effects in tissue regeneration.

Methods

SCB-SPCs were isolated from human knee plateau osteochondral specimens and treated with gradient doses of r-ESW in a suspension stimulation system. The optimized parameters for SCB-SPC self-renewal were screened out by colony-forming unit fibroblast assay (CFU-F). Then, the effects of r-ESW on the proliferation, apoptosis, and multipotency of SCB-SPCs were evaluated. Moreover, the repair efficiency of radial shockwave-preconditioned SCB-SPCs was evaluated in vivo via an osteochondral defect model. Potential mechanisms were explored by western blotting, confocal laser scanning, and high-throughput sequencing.

Results

The CFU-F data indicate that r-ESW could augment the self-renewal of SCB-SPCs in a dose-dependent manner. The CCK-8 and flow cytometry results showed that the optimized shockwave markedly promoted SCB-SPC proliferation but had no significant influence on cell apoptosis. Radial shockwave exerted no significant influence on osteogenic capacity but strongly suppressed adipogenic ability in the current study. For chondrogenic potentiality, the treated SCB-SPCs were mildly enhanced, while the change was not significant. Importantly, the macroscopic scores and further histological analysis strongly demonstrated that the in vivo therapeutic effects of SCB-SPCs were markedly improved post r-ESW treatment. Further analysis showed that the cartilage-related markers collagen II and proteoglycan were expressed at higher levels compared to their counterpart group. Mechanistic studies suggested that r-ESW treatment strongly increased the expression of YAP and promoted YAP nuclear translocation in SCB-SPCs. More importantly, self-renewal was partially blocked by the YAP-specific inhibitor verteporfin. Moreover, the high-throughput sequencing data indicated that other self-renewal-associated pathways may also be involved in this process.

Conclusion

We found that r-ESW is capable of promoting the self-renewal of SCB-SPCs in vitro by targeting YAP activity and strengthening its repair efficiency in vivo, indicating promising application prospects.
Preclinical efficacy of stem cell therapy for skin flap: a systematic review and meta-analysis
Authors: Li Yuan , Jiang Qi-lin , Van der Merwe Leanne , Lou Dong-hao , Lin Cai
Published: January 2021

Background

A skin flap is one of the most critical surgical techniques for the restoration of cutaneous defects. However, the distal necrosis of the skin flap severely restricts the clinical application of flap surgery. As there is no consensus on the treatment methods to prevent distal necrosis of skin flaps, more effective and feasible interventions to prevent skin flaps from necrosis are urgently needed. Stem therapy as a potential method to improve the survival rate of skin flaps is receiving increasing attention.

Methods

This review followed the recommendations from the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statements. Twenty studies with 500 animals were included by searching Web of Science, EMBASE, PubMed, and Cochrane Library databases, up until October 8, 2020. Moreover, the references of the included articles were searched manually to obtain other studies. All analyses were conducted using Review Manager V.5.3 software.

Results

Meta-analysis of all 20 studies demonstrated stem cell treatment has significant effects on reducing necrosis of skin flap compared with the control group (SMD: 3.20, 95% CI 2.47 to 3.93). Besides, subgroup analysis showed differences in the efficacy of stem cells in improving the survival rate of skin flaps in areas of skin flap, cell type, transplant types, and method of administration of stem cells. The meta-analysis also showed that stem cell treatment had a significant effect on increasing blood vessel density (SMD: 2.96, 95% CI 2.21 to 3.72) and increasing the expression of vascular endothelial growth factor (VEGF, SMD: 4.34, 95% CI 2.48 to 6.1).

Conclusions

The preclinical evidence of our systematic review indicate that stem cell-based therapy is effective for promoting early angiogenesis by up regulating VEGF and ultimately improving the survival rate of skin flap. In summary, small area skin flap, the administration method of intra-arterial injection, ASCs and MSCs, and xenogenic stem cells from humans showed more effective for the survival of animal skin flaps. In general, stem cell-based therapy may be a promising method to prevent skin flap necrosis.
Human amnion-derived mesenchymal stem cells promote osteogenic differentiation of lipopolysaccharide-induced human bone marrow mesenchymal stem cells via ANRIL/miR-125a/APC axis
Authors: Wang Yuli , Lv Fengyi , Huang Lintong , Zhang Hengwei , Li Bing , Zhou Weina , Li Xuan , Du Yifei , Pan Yongchu , Wang Ruixia
Published: January 2021

Background and aim

Periodontitis is a chronic inflammatory disease inducing the absorption of alveolar bone and leading to tooth loss. Human amnion-derived mesenchymal stem cells (HAMSCs) have been used for studying inflammatory processes. This study aimed to explore the role of long noncoding RNA (lncRNA) antisense noncoding RNA in the INK4 locus (ANRIL) in HAMSC-driven osteogenesis in lipopolysaccharide (LPS)-induced human bone marrow mesenchymal stem cells (HBMSCs).

Methods

The cells were incubated with a co-culture system. Reactive oxygen species (ROS) level and superoxide dismutase (SOD) activity were used to detect the oxidative stress level. Flow cytometry was performed to determine cell proliferation. The alkaline phosphatase (ALP) activity, Alizarin red assay, cell transfection, and rat mandibular defect model were used to evaluate the osteogenic differentiation. Quantitative real-time reverse transcription–polymerase chain reaction (RT-PCR), Western blot analysis, dual-luciferase reporter assay, and immunofluorescence staining were used to evaluate the molecular mechanisms.

Results

This study showed that HAMSCs promoted the osteogenesis of LPS-induced HBMSCs, while the ANRIL level in HBMSCs decreased during co-culture. ANRIL had no significant influence on the proliferation of LPS-induced HBMSCs. However, its overexpression inhibited the HAMSC-driven osteogenesis in vivo and in vitro, whereas its knockdown reversed these effects. Mechanistically, this study found that downregulating ANRIL led to the overexpression of microRNA-125a (miR-125a), and further contributed to the competitive binding of miR-125a and adenomatous polyposis coli (APC), thus significantly activating the Wnt/β-catenin pathway.

Conclusion

The study indicated that HAMSCs promoted the osteogenic differentiation of LPS-induced HBMSCs via the ANRIL/miR-125a/APC axis, and offered a novel approach for periodontitis therapy.
Sarcoglycan A mutation in miniature dachshund dogs causes limb-girdle muscular dystrophy 2D
Authors: Mickelson James R. , Minor Katie M. , Guo Ling T. , Friedenberg Steven G. , Cullen Jonah N. , Ciavarella Amanda , Hambrook Lydia E. , Brenner Karen M. , Helmond Sarah E. , Marks Stanley L. , Shelton G. Diane
Published: January 2021

Background

A cohort of related miniature dachshund dogs with exercise intolerance, stiff gait, dysphagia, myoglobinuria, and markedly elevated serum creatine kinase activities were identified.

Methods

Muscle biopsy histopathology, immunofluorescence microscopy, and western blotting were combined to identify the specific pathologic phenotype of the myopathy, and whole genome SNP array genotype data and whole genome sequencing were combined to determine its genetic basis.

Results

Muscle biopsies were dystrophic. Sarcoglycanopathy, a form of limb-girdle muscular dystrophy, was suspected based on immunostaining and western blotting, where α, β, and γ-sarcoglycan were all absent or reduced. Genetic mapping and whole genome sequencing identified a premature stop codon mutation in the sarcoglycan A subunit gene (SGCA). Affected dachshunds were confirmed on several continents.

Conclusions

This first SGCA mutation found in dogs adds to the literature of genetic bases of canine muscular dystrophies and their usefulness as comparative models of human disease.
Muscle spindle function in healthy and diseased muscle
Authors: Kröger Stephan , Watkins Bridgette
Published: January 2021

Almost every muscle contains muscle spindles. These delicate sensory receptors inform the central nervous system (CNS) about changes in the length of individual muscles and the speed of stretching. With this information, the CNS computes the position and movement of our extremities in space, which is a requirement for motor control, for maintaining posture and for a stable gait. Many neuromuscular diseases affect muscle spindle function contributing, among others, to an unstable gait, frequent falls and ataxic behavior in the affected patients. Nevertheless, muscle spindles are usually ignored during examination and analysis of muscle function and when designing therapeutic strategies for neuromuscular diseases. This review summarizes the development and function of muscle spindles and the changes observed under pathological conditions, in particular in the various forms of muscular dystrophies.
Practices of decision making in priority setting and resource allocation: a scoping review and narrative synthesis of existing frameworks
Authors: Seixas Brayan V. , Dionne François , Mitton Craig
Published: January 2021

Background

Due to growing expenditures, health systems have been pushed to improve decision-making practices on resource allocation. This study aimed to identify which practices of priority setting and resource allocation (PSRA) have been used in healthcare systems of high-income countries.

Methods

A scoping literature review (2007–2019) was conducted to map empirical PSRA activities. A two-stage screening process was utilized to identify existing approaches and cluster similar frameworks. That was complemented with a gray literature and horizontal scanning. A narrative synthesis was carried out to make sense of the existing literature and current state of PSRA practices in healthcare.

Results

One thousand five hundred eighty five references were found in the peer-reviewed literature and 25 papers were selected for full-review. We identified three major types of decision-making framework in PSRA: 1) Program Budgeting and Marginal Analysis (PBMA); 2) Health Technology Assessment (HTA); and 3) Multiple-criteria value assessment. Our narrative synthesis indicates these formal frameworks of priority setting and resource allocation have been mostly implemented in episodic exercises with poor follow-up and evaluation. There seems to be growing interest for explicit robust rationales and ample stakeholder involvement, but that has not been the norm in the process of allocating resources within healthcare systems of high-income countries.

Conclusions

No single dominate framework for PSRA appeared as the preferred approach across jurisdictions, but common elements exist both in terms of process and structure. Decision-makers worldwide can draw on our work in designing and implementing PSRA processes in their contexts.
Mesenchymal stem cells desensitize castration-resistant prostate cancer to docetaxel chemotherapy via inducing TGF-β1-mediated cell autophagy
Authors: Yu Yang , Yang Fu-han , Zhang Wen-tao , Guo Ya-dong , Ye Lin , Yao Xu-dong
Published: January 2021

Background

Mesenchymal stem cells (MSCs) have been proved to drive castration resistant prostate cancer (CRPC). In this study, we aim to investigate the contribution of MSCs to the development of docetaxel resistance in CRPC cells and its potential mechanisms.

Methods

The effect of MSCs on CRPC cells resistance to docetaxel was determined using in vivo and in vitro approaches. CCK8 and PI/Annexin V-FITC assay were used to examined the cell viability and apoptosis. The concentration of transforming growth factor-β1 was measured by enzyme-linked immunosorbent assay and small interfering RNA was used for functional analyses.

Results

MSCs significantly reduced the sensitivity of CRPC cells to docetaxel-induced proliferation inhibition and apoptosis promotion in vivo and in vitro. CRPC cells cocultured with MSCs under docetaxel administration have an increased autophagy activation, while autophagy inhibitor could effectively reversed MSCs-induced resistance to docetaxel. Additionally, MSCs-induced CRPC cell autophagy increase under docetaxel administration depends on MSCs secreting TGF-β1 and inhibition of TGF-β1 secretion in MSCs could consequently increase the sensitivity of CRPC cells to docetaxel.

Conclusions

These results suggest that docetaxel administrated CRPC cells may elicit MSCs secreting TGF-β1 increase, which desensitizes CRPC to docetaxel chemotherapy accelerating chemoresistance occurrence via inducing cell autophagy.
BIRC3 and BIRC5: multi‐faceted inhibitors in cancer
Authors: Frazzi Raffaele
Published: January 2021

Background

The evasion from apoptosis is a common strategy adopted by most tumors, and inhibitors of apoptosis proteins (IAPs) are among the most studied molecular and therapeutic targets. BIRC3 (cellular IAP2) and BIRC5 (survivin) are two of the eight members of the human IAPs family. This family is characterized by the presence of the baculoviral IAP repeat (BIR) domains, involved in protein-protein interactions. In addition to the BIR domains, IAPs also contain other important domains like the C-terminal ubiquitin-conjugating (UBC) domain, the caspase recruitment (CARD) domain and the C-terminal Ring zinc-finger (RING) domain.

Main body

BIRC3 and BIRC5 have been characterized in some solid and hematological tumors and are therapeutic targets for the family of drugs called “Smac mimetics”. Many evidences point to the pro-survival and antiapoptotic role of BIRC3 in cancer cells, however, not all the data are consistent and the resulting picture is heterogeneous. For instance, BIRC3 genetic inactivation due to deletions or point mutations is consistently associated to shorter progression free survival and poor prognosis in chronic lymphocytic leukemia patients. BIRC3 inactivation has also been associated to chemoimmunotherapy resistance. On the contrary, the progression from low grade gliomas to high grade gliomas is accompanied by BIRC3 expression increase, which bears relevant prognostic consequences. Due to the relationship between BIRC3, MAP3K14 and the non-canonical NF-kB pathway, BIRC3 inactivation bears consequences also on the tumor cells relying on NF-kB pathway to survive. BIRC5, on the contrary, is commonly considered an anti-apoptotic molecule, promoting cell division and tumor progression and it is widely regarded as potential therapeutic target.

Conclusions

The present manuscript collects and reviews the most recent literature concerning the role played by BIRC3 and BIRC5 in cancer cells, providing useful information for the choice of the best therapeutic targets.
The hybrid Cramér-Rao lower bound for simultaneous self-localization and room geometry estimation
Authors: Veisman Maya , Noam Yair , Gannot Sharon
Published: January 2021

This paper addresses the problem of tracking a moving source, e.g., a robot, equipped with both receivers and a source, that is tracking its own location and simultaneously estimating the locations of multiple plane reflectors. We assume a noisy knowledge of the robot’s movement. We formulate this problem, which is also known as simultaneous localization and mapping (SLAM), as a hybrid estimation problem. We derive the extended Kalman filter (EKF) for both tracking the robot’s own location and estimating the room geometry. Since the EKF employs linearization at every step, we incorporate a regulated kinematic model, which facilitates a successful tracking. In addition, we consider the echo-labeling problem as solved and beyond the scope of this paper. We then develop the hybrid Cramér-Rao lower bound on the estimation accuracy of both the localization and mapping parameters. The algorithm is evaluated with respect to the bound via simulations, which shows that the EKF approaches the hybrid Cramér-Rao bound (CRB) (HCRB) as the number of observation increases. This result implies that for the examples tested in simulation, the HCRB is an asymptotically tight bound and that the EKF is an optimal estimator. Whether this property is true in general remains an open question.
Hyers–Ulam stability of second-order differential equations using Mahgoub transform
Authors: Raj Aruldass Antony , Pachaiyappan Divyakumari , Park Choonkil
Published: January 2021

The aim of this research is investigating the Hyers–Ulam stability of second-order differential equations. We introduce a new method of investigation for the stability of differential equations by using the Mahgoub transform. This is the first attempt of the investigation of Hyers–Ulam stability by using Mahgoub transform. We deal with both homogeneous and nonhomogeneous second-order differential equations.
Existence and uniqueness of solutions for a class of fractional nonlinear boundary value problems under mild assumptions
Authors: Bachar Imed , Mâagli Habib , Eltayeb Hassan
Published: January 2021

We deal with the following Riemann–Liouville fractional nonlinear boundary value problem: $$ \textstyle\begin{cases} \mathcal{D}^{\alpha }v(x)+f(x,v(x))=0, & 2< \alpha \leq 3, x\in (0,1), \\ v(0)=v^{\prime }(0)=v(1)=0. \end{cases} $$

{

D
α

v
(
x
)
+
f
(
x
,
v
(
x
)
)
=
0
,

2
<
α
≤
3
,
x
∈
(
0
,
1
)
,

v
(
0
)
=

v
′

(
0
)
=
v
(
1
)
=
0
.

Under mild assumptions, we prove the existence of a unique continuous solution v to this problem satisfying $$ \bigl\vert v(x) \bigr\vert \leq cx^{\alpha -1}(1-x)\quad\text{for all }x \in [ 0,1]\text{ and some }c>0. $$
|
v
(
x
)
|
≤
c

x

α
−
1

(
1
−
x
)

for all 
x
∈
[
0
,
1
]
 and some 
c
>
0
.
Our results improve those obtained by Zou and He (Appl. Math. Lett. 74:68–73, 2017).
Construction of a new family of Fubini-type polynomials and its applications
Authors: Srivastava H. M. , Srivastava Rekha , Muhyi Abdulghani , Yasmin Ghazala , Islahi Hibah , Araci Serkan
Published: January 2021

This paper gives an overview of systematic and analytic approach of operational technique involves to study multi-variable special functions significant in both mathematical and applied framework and to introduce new families of special polynomials. Motivation of this paper is to construct a new class of generalized Fubini-type polynomials of the parametric kind via operational view point. The generating functions, differential equations, and other properties for these polynomials are established within the context of the monomiality principle. Using the generating functions, various interesting identities and relations related to the generalized Fubini-type polynomials are derived. Further, we obtain certain partial derivative formulas including the generalized Fubini-type polynomials. In addition, certain members belonging to the aforementioned general class of polynomials are considered. The numerical results to calculate the zeros and approximate solutions of these polynomials are given and their graphical representation are shown.
Double-stranded RNA confers resistance to pepper mottle virus in Nicotiana benthamiana
Authors: Yoon Jeongyeon , Fang Miao , Lee Dowhan , Park Minsu , Kim Kook-Hyung , Shin Chanseok
Published: January 2021

RNA interference (RNAi) is a regulatory mechanism of gene expression mediated by small RNAs. By using the RNAi technique, exogenous double-stranded RNA (dsRNA) designed to target mRNA, suppresses target gene expression levels in plants. In this study, we adopted the RNAi mechanism as a tool to protect plants from viruses. We designed and synthesized several dsRNAs targeting the pepper mottle virus (PepMoV) genes HC-Pro and NIb. When used on Nicotiana benthamiana plants, these dsRNAs protected the plant against viral infection over a specific period. By optimizing dsRNA and virus injection time, the protection efficiency of dsRNA by targeting virus genes could be maximized. It seems that exogenous dsRNA-derived RNA-induced silencing complex was able to defend the host against viral infection instantly. Furthermore, each dsRNA designed to target different regions within a transcript had varying levels of effects on virus survival in the host plants. When targeting the middle part of both the NIb and HC-Pro genes using the dsRNAs, the highest viral growth inhibitory effect was observed. An RLM-5′ RACE was performed using plant leaves infected with PepMoV after dsRNA treatment and it was observed that most of the mRNA cleavages occurred close to the 3′ part within the dsRNA target position on the mRNA. These results suggest that the dsRNA tool can be used as a plant vaccine platform for crop protection.
Accessing the syndemic of COVID-19 and malaria intervention in Africa
Authors: Shi Benyun , Zheng Jinxin , Xia Shang , Lin Shan , Wang Xinyi , Liu Yang , Zhou Xiao-Nong , Liu Jiming
Published: January 2021

Background

The pandemic of the coronavirus disease 2019 (COVID-19) has caused substantial disruptions to health services in the low and middle-income countries with a high burden of other diseases, such as malaria in sub-Saharan Africa. The aim of this study is to assess the impact of COVID-19 pandemic on malaria transmission potential in malaria-endemic countries in Africa.

Methods

We present a data-driven method to quantify the extent to which the COVID-19 pandemic, as well as various non-pharmaceutical interventions (NPIs), could lead to the change of malaria transmission potential in 2020. First, we adopt a particle Markov Chain Monte Carlo method to estimate epidemiological parameters in each country by fitting the time series of the cumulative number of reported COVID-19 cases. Then, we simulate the epidemic dynamics of COVID-19 under two groups of NPIs: (1) contact restriction and social distancing, and (2) early identification and isolation of cases. Based on the simulated epidemic curves, we quantify the impact of COVID-19 epidemic and NPIs on the distribution of insecticide-treated nets (ITNs). Finally, by treating the total number of ITNs available in each country in 2020, we evaluate the negative effects of COVID-19 pandemic on malaria transmission potential based on the notion of vectorial capacity.

Results

We conduct case studies in four malaria-endemic countries, Ethiopia, Nigeria, Tanzania, and Zambia, in Africa. The epidemiological parameters (i.e., the basic reproduction number $$R_0$$

R
0

and the duration of infection $$D_I$$

D
I

) of COVID-19 in each country are estimated as follows: Ethiopia ($$R_0=1.57$$

R
0

=
1.57

, $$D_I=5.32$$

D
I

=
5.32

), Nigeria ($$R_0=2.18$$

R
0

=
2.18

, $$D_I=6.58$$

D
I

=
6.58

), Tanzania ($$R_0=2.47$$

R
0

=
2.47

, $$D_I=6.01$$

D
I

=
6.01

), and Zambia ($$R_0=2.12$$

R
0

=
2.12

, $$D_I=6.96$$

D
I

=
6.96

). Based on the estimated epidemiological parameters, the epidemic curves simulated under various NPIs indicated that the earlier the interventions are implemented, the better the epidemic is controlled. Moreover, the effect of combined NPIs is better than contact restriction and social distancing only. By treating the total number of ITNs available in each country in 2020 as a baseline, our results show that even with stringent NPIs, malaria transmission potential will remain higher than expected in the second half of 2020.

Conclusions

By quantifying the impact of various NPI response to the COVID-19 pandemic on malaria transmission potential, this study provides a way to jointly address the syndemic between COVID-19 and malaria in malaria-endemic countries in Africa. The results suggest that the early intervention of COVID-19 can effectively reduce the scale of the epidemic and mitigate its impact on malaria transmission potential.