bluuebunny/crossref_metadata_2025 huggingface dataset:
Poly(lactic-co-glycolic acid) (PLGA) nanoparticles loaded with tetramethylpyrazine and conjugated with TED-1 polypeptide reduce formation of β-amyloid and alleviate oxidative stress in alzheimer’s disease
Authors: Wang Xiaobing , Wang Danhui , Huang Xianli
Published: January 2023

Controlling β-amyloid and oxidative stress is indicated to improve Alzheimer’s disease (AD). In this study, we loaded Poly Lactic-co-Glycolic Acid (PLGA) nanoparticles with ligustrazine and coupled them with TED-1 polypeptide, to explore an effective drug for the condition.
Tet-1 peptide was coupled to Tetramethylpyrazine (TMP)-PLGA nanoparticles. Glioma cells were then treated with PLGA nanoparticles, TMP, TMP-PLGA nanoparticles, and TMP-PLGA-Tet-1 nanoparticles. Microscope and flow cytometry were then conducted to assess the impact of nanoparticles on cell
morphology and toxicity of the nanoparticles. Oxidative stress of the nanoparticles was detected by 2,2-Diphenyl-1-picrylhydrazyl (DPPH) method. TMP-PLGA-Tet-1 nanoparticles were found to have significant ability to scavenge free radicals, also showing significantly increased anti-β-amyloid
activity. Finally, Alamar Blue method and 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) method proved that, the TMP-PLGA-Tet-1 nanoparticles enhanced the efficiency of drug delivery to neurons without toxicity. Moreover, Tet-1-conjugated TMP-PLGA nanoparticles reduced
amyloid and alleviated oxidative stress, and may hence be a potential option for treatment of AD. Labeling Tet-1 to TMP-PLGA could therefore improve drug delivery.
Mechanism research on Long noncoding RNA (lncRNA) GASL1 carried with lipid nanoparticles in restraining cervical carcinoma transplantable tumor through targeting of miR-21 and induction of STAT3/survivin signal channel
Authors: Liu Jin , Liu Xiaojiao , Huang Jianlei
Published: January 2023

This study assessed the mechanism of lncRNA-GASL1 carried with lipid nanoparticles in restraining cervical carcinoma transplantable tumor through targeting miR-21 and inducing the STAT3/Survivin signal channel. 50 rats were randomly divided into control set, model set, GASL1 set, miR-21mimic
set and agonist set. There were ten rats in every set. Expression of lncRNA-GASL1, anti-tumor rate, thymus index, spleen index, and protein expression of MIF, VEGF-C and p53 were studied, including protein expression of factors related with STAT3/Survivin signal transduction pathway, miR-21
presentation, targeting correlation between lncRNA-GASL1 and miR-21 were all observed. Expressions of lncRNA-GASL1 in the model set and agonist set were lower than in the other sets. The second highest expression was in the miR-21mimic set, where it was increased notably in the GASL1 set.
The expression was highest in the control set. The thymus index and spleen index in the control set was highest. The expressions of miR-21mimic set and GASL1 set were increased notably and anti-tumor rate was reversed. There was no apoptosis in the control set, while there was lower quantity
of apoptotic cells in the model and agonist sets. The inhibitor action of lncRNA-GASL1 on the transplantable tumor in cervical carcinoma was related with STAT3/Survivin signal transduction pathway, while there was lncRNA-GASL1 targeting combined with miR-21. The miR-21 presentation was reduced,
while activity of STAT3 as target gene for miR-21 was reduced. The STAT3 was phosphorylated, while activity of Survivin was reduced. The phosphorylation level of Survivin was reduced, while growth of transplantable tumor in cervical carcinoma was restrained.
Microstructure, interface characterization and tensile shear strength of dissimilar friction stir welded AZ31/LZ91 alloys lap joints
Authors: Liu Gang , Ma Zhenduo , Ren Yilei , Zhang Xi , Xie Fang
Published: January 2023

The microstructure, interface characterization and tensile shear strength of AZ31/LZ91 alloys friction stir lap welding were investigated. The results show that the grain size of the upper AZ31 stirred zone gradually decreases from top to bottom. Compared with the thermo-mechanically
affected zone on the retreating side, the grain size of the thermo-mechanically affected zone on the advancing side is smaller, and the distribution is more uniform. The grain size of the α-Mg phase and the β-Li phase in the thermo-mechanically affected zone on the
advancing side and the retreating side of the lower LZ91 are different. The grain size of the α-Mg phase on the retreating side is smaller, while the grain size of the β-Li phase is larger, compared to the thermo-mechanically affected zone on the advancing side. The
grain size and misorientation angle of the α-Mg phase are different on both sides of the thermo-mechanically affected zone/stirred zone-side interface on the advancing side of the AZ31/LZ91 joint. The average grain size of the α-Mg phase in the thermo-mechanically
affected zone is ∼4.5 μm, while the α-Mg phase at the stirred zone-side is ∼3.3 μm. However, the proportion of the misorientation angle at the stirred zone-side ranging from 10° to 45° reaches the maximum value of 68.8%. The AZ31/LZ91 interface
is well connected, and the line scan from the AZ31 side to the LZ91 side shows that the contents of Mg and Al elements are reduced, and the content of Zn elements is basically unchanged. When the welding speed increases in the range of 30 mm/min–120 mm/min, the tensile shear strength
first increases and then decreases. When the welding speed is 100 mm/min, the tensile shear strength reaches the highest value of 145.3 MPa.
Adriamycin-loaded poly(lactic-co-glycolic acid) microspheres: Treatment activity on breast cancer via limitation of the abnormal increment of cancer cells
Authors: Wang Xuan-Xuan , Fang Liang , Gong Xun , Wu Xiao-Wei
Published: January 2023

Traditional chemotherapy for tumors produces strong side effects because of the lack of drug specificity and abrupt release behavior involved. Therefore, the development of suitable drug carriers for the targeted anchoring of in situ tumor cells and long-term local delivery is
vital to improving the tumor cure rate. Following the emulsification-solvent-volatilization method, adriamycin (DOX)/PLGA microspheres were successfully prepared in this work. The size of the microspheres was concentrated at the 2.5–7.5 μm range, thereby providing the possibility
of anchoring and capturing tumor cells. The PLGA microspheres have a high encapsulation rate in relation to the chemotherapeutic drug DOX and have a good slow-release effect when applied in vivo, rendering the DOX/PLGA system applicable for targeted treatment of in situ tumors.
Furthermore, the novel system was assessed for its therapeutic activity in breast cancer treatment, and the related mechanism of action was also explored.
CYGNSS Storm-Centric Tropical Cyclone Gridded Wind Speed Product
Authors: Mayers David R. , Ruf Christopher S. , Warnock April M.
Published: January 2023

The Cyclone Global Navigation Satellite System (CYGNSS) mission has generated several new ocean surface data products. Because of its high overpass rate and ability to measure surface wind speeds through weather, these data products are typically higher temporal resolution than traditional satellite tropical cyclone (TC) data products. However, the nature of the Global Navigation Satellite Systems reflectometry (GNSS-R) signal, which is essentially a single pixelwide measurement along the CYGNSS specular point (SP) track on the ground, necessitates aggregating the wind speed data over a period of time to accurately characterize TCs in terms of intensity and structure. The standard CYGNSS level 3 (L3) wind products are averaged over 1 h, which typically is not sufficient to produce an accurate characterization. A new L3 storm-centric gridded (SCG) wind speed product is presented here. It has been developed to improve upon the standard L3 algorithm for the purpose of providing better characterization of TC wind fields over their storm life cycle. This paper describes the L3 SCG algorithm, provides examples of L3 SCG wind fields, and discusses the potential uses and limitations of the new data product.
Bonding Through Language Imitation: Influence of Social Ostracism on Structural Priming
Authors: Li Heng
Published: January 2023

This research investigated whether being excluded can increase language imitation and thus lead to a stronger structural priming effect. In Study 1, student participants recalling an experience of social exclusion showed a larger priming effect than those recalling an experience of social inclusion. Employing a larger, more diverse sample, Study 2 set out to conceptually replicate Study 1 by creating a concurrent experience of social exclusion through a computerized ball-toss game. It was found that excluded individuals demonstrated a stronger tendency to mimic the syntactic structure used by their interactional partner than included individuals. Taken together, these findings enrich an emergent stream of research that finds structural priming is not an independent cognitive process, but conditioned by various socio-cognitive factors.
The impact of the wind attack angle on a typical bridge deck’s flutter behavior by the distributed aerodynamic characteristics method
Authors: Li Ke , Yang Qingshan , Wang Xianmeng , Li Shaopeng , Hui Yi , Fang Genshen , Qian Guowei
Published: January 2023

To investigate the influence of the wind attack on a bridge deck’s flutter performance, the concept of “pressure flutter derivatives” was introduced as a part of the “distributed aerodynamic characteristics” method, which can be used to visualize the dominant fluctuations of the pressure field. The distributions of the aerodynamic damping and stiffness under different wind attack angles were visualized, instead of using an overall force perspective. The analysis was carried out through two-dimensional computational fluid dynamics simulations based on a typical box deck section. Necessary data were obtained through the forced vibrations of the deck. The dominant pressure fluctuations were demonstrated, around which the wind attack angles’ impact on the Scanlan flutter derivatives was discussed. For the deck section used in this study, the wind attack angle was found to most affect the windward parts of the deck. When wind attack angle ranged from [Formula: see text] to [Formula: see text], two regions contributed the most: one located behind the windward faring vertex and the other located behind the first vertex of the upper slab. When the wind attack angle decreased to [Formula: see text], a new dominant region appeared behind the first vertex of the lower slab, which caused a sudden reduction of the flutter critical speed.
Review: mountain lakes as freshwater resources at risk from chemical pollution
Authors: Machate Oliver , Schmeller Dirk S. , Schulze Tobias , Brack Werner
Published: January 2023

Background

Chemical pollution forms a severe threat for human and environmental health. While the risks for European lowland water bodies are well known, there is little knowledge on remote aquatic ecosystems and particularly mountain lakes, despite their importance for the provision of freshwater. Here, we critically review the current knowledge on the exposure and risk by chemical pollution for mountain lakes and present a tiered approach on how to advance effectively our understanding in the future.

Results

Generally, pollutant monitoring data are currently incomplete, with many regions and substances having been only poorly investigated. More reliable data exist only for persistent organic pollutants (POPs). However, there is increasing evidence that even remote mountain lakes are exposed to a wide range of organic pollutants. Among them potent pesticides currently used in agricultural and biocidal applications, such as diazinon and permethrin. The exposure of mountain lakes to pollutants follows a complex pattern. Pollutants are introduced into mountain lakes via the atmospheric deposition and run-off from the watershed, but also local sources, like tourism and pastoralism. Our risk assessment and recent biomonitoring studies suggest that there are widespread chronic toxic risks on crustacean in mountain ranges. If mountain ranges are exposed to tourism and pastoralism, even acute toxic effects on crustacean are possible. Thereby, the vulnerability of mountain lakes to toxic effects has to be expected to be particularly high due to the harsh environmental conditions at high altitudes, the organism’s traits, the insular position of mountain lakes and a lower species richness with increasing altitudes. Furthermore, there is little knowledge on the biological processes leading to the degradation of chemical pollutants under the environmental and ecological conditions of mountain ecosystems.

Conclusion

While the exposure and sensitivity of mountain aquatic ecosystems is currently poorly investigated, the existing data suggest that it is very likely that also water bodies as remote as mountain lakes do suffer from pollution-induced toxicity. To verify this suggestion and expand the existing knowledge, it is necessary that future studies combine a more holistic pollution monitoring with exposure modelling and links to biological effects. Only then will it be possible to obtain a more reliable understanding of the impact of chemical pollution on aquatic mountain ecosystems and to protect these fragile ecosystems.
Novel delivery system with a dual–trigger release of savory essential oil by mesoporous silica nanospheres and its possible targets in leukemia cancer cells: in vitro study
Authors: AbouAitah Khaled , Hassan Heba A. , Ammar Naglaa M. , Abou Baker Doha H. , Higazy Imane M. , Shaker Olfat G. , Elsayed Ahmed A. A. , Hassan Abeer M. E.
Published: January 2023

Introduction

Essential oils (EOs) are complex structures and possess several pharmacological effects. Nanomedicine offers a solution for their major limitations, including poor solubility, volatility, and non–controlled release, preventing their clinical use.

Methods

Here, we developed a novel delivery system by nanoformulations that were prepared by impregnating savory essential oil (SA) into mesoporous silica nanoparticles (MSNs). The nanoformulations were characterized and examined for their anticancer activities on cancer cells (HepG2 liver and HL60 leukemia cells) and MRC5 normal cells. We further tested the mechanisms of action and possible molecular targets against HL60 cells.

Results

The results demonstrated that SA was governed by nanoformulations under the dual–trigger release of pH/glutathione, and it typically fit the Korsmeyer–Peppas kinetic model. The nanoformulations enhanced the anticancer effect against HepG2 cells and HL60 cells compared to SA but were less cytotoxic to MRC5 normal cells and regulated various molecular pathways of apoptosis. Most importantly, new results were obtained on the genetic regulation principle through the high inhibition of long noncoding RNAs (HOTAIR, HULC, CCAT1, and H19) and matrix metalloproteinases (MMP–2 and MMP–9), providing a novel leukemia target.

Conclusions

These results suggest potential impacts for nanoformulations composed of SA with a sustained release pattern controlled by dual–trigger release of pH/GSH that enhanced anticancer cells. This approach may offer a new route for using EOs as new targets for cancers and open the door for deep preclinical investigations.
Predicting the impact of genotype-by-genotype interaction on the purebred–crossbred genetic correlation from phenotype and genotype marker data of parental lines
Authors: Duenk Pascal , Wientjes Yvonne C. J. , Bijma Piter , Iversen Maja W. , Lopes Marcos S. , Calus Mario P. L.
Published: January 2023

Background

The genetic correlation between purebred (PB) and crossbred (CB) performances ($${r}_{pc}$$

r

pc

) partially determines the response in CB when selection is on PB performance in the parental lines. An earlier study has derived expressions for an upper and lower bound of $${r}_{pc}$$

r

pc

, using the variance components of the parental purebred lines, including e.g. the additive genetic variance in the sire line for the trait expressed in one of the dam lines. How to estimate these variance components is not obvious, because animals from one parental line do not have phenotypes for the trait expressed in the other line. Thus, the aim of this study was to propose and compare three methods for approximating the required variance components. The first two methods are based on (co)variances of genomic estimated breeding values (GEBV) in the line of interest, either accounting for shrinkage (VCGEBV-S) or not (VCGEBV). The third method uses restricted maximum likelihood (REML) estimates directly from univariate and bivariate analyses (VCREML) by ignoring that the variance components should refer to the line of interest, rather than to the line in which the trait is expressed. We validated these methods by comparing the resulting predicted bounds of $${r}_{pc}$$

r

pc

with the $${r}_{pc}$$

r

pc

estimated from PB and CB data for five traits in a three-way cross in pigs.

Results

With both VCGEBV and VCREML, the estimated $${r}_{pc}$$

r

pc

(plus or minus one standard error) was between the upper and lower bounds in 14 out of 15 cases. However, the range between the bounds was much smaller with VCREML (0.15–0.22) than with VCGEBV (0.44–0.57). With VCGEBV-S, the estimated $${r}_{pc}$$

r

pc

was between the upper and lower bounds in only six out of 15 cases, with the bounds ranging from 0.21 to 0.44.

Conclusions

We conclude that using REML estimates of variance components within and between parental lines to predict the bounds of $${r}_{pc}$$

r

pc

resulted in better predictions than methods based on GEBV. Thus, we recommend that the studies that estimate $${r}_{pc}$$

r

pc

with genotype data also report estimated genetic variance components within and between the parental lines.
Reporter gene assays and chromatin-level assays define substantially non-overlapping sets of enhancer sequences
Authors: Lindhorst Daniel , Halfon Marc S.
Published: January 2023

Background

Transcriptional enhancers are essential for gene regulation, but how these regulatory elements are best defined remains a significant unresolved question. Traditional definitions rely on activity-based criteria such as reporter gene assays, while more recently, biochemical assays based on chromatin-level phenomena such as chromatin accessibility, histone modifications, and localized RNA transcription have gained prominence.

Results

We examine here whether these two types of definitions, activity-based and chromatin-based, effectively identify the same sets of sequences. We find that, concerningly, the overlap between the two groups is strikingly limited. Few of the data sets we compared displayed statistically significant overlap, and even for those, the degree of overlap was typically small (below 40% of sequences). Moreover, a substantial batch effect was observed in which experiment set rather than experimental method was a primary driver of whether or not chromatin-defined enhancers showed a strong overlap with reporter gene-defined enhancers.

Conclusions

Our results raise important questions as to the appropriateness of both old and new enhancer definitions, and suggest that new approaches are required to reconcile the poor agreement among existing methods for defining enhancers.
Genome-wide identification and systematic analysis of the HD-Zip gene family and its roles in response to pH in Panax ginseng Meyer
Authors: Li Li , Lv Boxin , Zang Kaiyou , Jiang Yue , Wang Chaofan , Wang Yanfang , Wang Kangyu , Zhao Mingzhu , Chen Ping , Lei Jun , Wang Yi , Zhang Meiping
Published: January 2023

Background

Ginseng, Panax ginseng Meyer, is a traditional herb that is immensely valuable both for human health and medicine and for medicinal plant research. The homeodomain leucine zipper (HD-Zip) gene family is a plant-specific transcription factor gene family indispensable in the regulation of plant growth and development and plant response to environmental stresses.

Results

We identified 117 HD-Zip transcripts from the transcriptome of ginseng cv. Damaya that is widely grown in Jilin, China where approximately 60% of the world’s ginseng is produced. These transcripts were positioned to 64 loci in the ginseng genome and the ginseng HD-Zip genes were designated as PgHDZ genes. Identification of 82 and 83 PgHDZ genes from the ginseng acc. IR826 and cv. ChP genomes, respectively, indicated that the PgHDZ gene family consists of approximately 80 PgHDZ genes. Phylogenetic analysis showed that the gene family originated after Angiosperm split from Gymnosperm and before Dicots split from Monocots. The gene family was classified into four subfamilies and has dramatically diverged not only in gene structure and functionality but also in expression characteristics. Nevertheless, co-expression network analysis showed that the activities of the genes in the family remain significantly correlated, suggesting their functional correlation. Five hub PgHDZ genes were identified that might have central functions in ginseng biological processes and four of them were shown to be actively involved in plant response to environmental pH stress in ginseng.

Conclusions

The PgHDZ gene family was identified from ginseng and analyzed systematically. Five potential hub genes were identified and four of them were shown to be involved in ginseng response to environmental pH stress. The results provide new insights into the characteristics, diversity, evolution, and functionality of the PgHDZ gene family in ginseng and lay a foundation for comprehensive research of the gene family in plants.
Inhibition effect of choline and parecoxib sodium on chronic constriction nerve injury-induced neuropathic pain in rats
Authors: Zhang Na , Li Yang , Feng Zeguo
Published: January 2023

Purpose

The simultaneous use of drugs with different mechanisms of analgesic action is a strategy for achieving effective pain control while minimizing dose-related side effects. Choline was described to potentiate the analgesic action of parecoxib sodium at small doses in several inflammatory pain models. However, these findings are still very limited, and more associated data are required to confirm the effectiveness of the combined choline and parecoxib sodium therapy against inflammatory pain.

Methods

Adult rats were randomly divided into 9 groups (N = 6/group). The sham surgery group received an intraperitoneal (i.p.) injection of saline. Rats with chronic constriction injury (CCI) of the sciatic nerve received saline, choline (cho, 6, 12 and 24 mg/kg), parecoxib sodium (pare, 3, 6, and 12 mg/kg), or a combination of choline 6 mg/kg and parecoxib sodium 3 mg/kg. Mechanical and heat pain thresholds were measured at 30 min after drug treatment at Days 3, 5, 7, 10, and 14 after CCI. Another 30 rats were divided into 5 groups (N = 6/group): the sham, CCI + saline, CCI + cho-6 mg/kg, CCI + pare-3 mg/kg, and CCI + cho-6 mg/kg + pare-3 mg/kg groups. After repeated drug treatment for 7 days, five rats were randomly selected from each group, and the lumbar dorsal root ganglia (DRGs) (L4–6) were harvested for western blot analysis.

Results

Choline significantly attenuated mechanical and heat hypersensitivity in CCI rats at 12 and 24 mg/kg doses (P < 0.05) but was not effective at the 6 mg/kg dose. Parecoxib sodium exerted significant pain inhibitory effects at the 6 and 12 mg/kg doses (P < 0.05) but not at the 3 mg/kg dose. Combining a low dose of choline (6 mg/kg) and parecoxib sodium (3 mg/kg) produced significant pain inhibition in CCI rats and reduced the expression of high mobility group protein 1 (HMGB1) and nuclear factor-kappa Bp65 (NF-κBp65) in L4–6 DRGs.

Conclusion

1. In a rat model of chronic neuropathic pain (CCI), at a certain dose, choline or parecoxib sodium can alleviate mechanical pain and thermal hyperalgesia caused by CCI. 2. The combination of choline and parecoxib sodium in nonanalgesic doses can effectively relieve neuropathic pain, and its mechanism may be related to the inhibition of the high mobility group protein 1 (HMGB1)/Toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) pathway.
Overexpression of TPM4 is associated with worse prognosis and immune infiltration in patients with glioma
Authors: Li Yao , Zhang Yanan , Wu Zeyu , Sun Peng
Published: January 2023

Background

Tropomyosin 4 (TPM4), a member of the tropomyosin family, is aberrantly expressed and plays an important role in a variety of cancers. However, studies on TPM4 in glioma patients are currently lacking.

Objective

Our study aimed to evaluate the diagnostic and prognostic characteristics of TPM4 in glioma and its correlation with immune infiltration.

Methods

Bioinformatic analysis was performed to determine whether TPM4 has diagnostic and prognostic value for glioma. The following databases and analytical tools were used to explore the clinical significance of TPM4 in glioma: TCGA, GTEx, GEO, STRING, and TISIDB.

Results

Our study showed that the mRNA and protein expression levels of TPM4 were significantly higher in glioma than in healthy brain tissue. Kaplan–Meier analysis indicated that high expression of TPM4 in glioma correlated with poor prognosis. Univariate Cox analysis indicated that the high expression level of TPM4 in glioma was an independent prognostic characteristic for low overall survival (OS). The areas under the 1-year survival ROC, 2-year survival ROC, and 3-year survival ROC were all greater than 0.8. GO and KEGG enrichment analysis and GSEA showed that humoral immune response and cytokine receptor interaction were significantly enriched in the TPM4 high expression group, where M phase of the cell cycle, neutrophil degranulation, signaling by interleukins, and signaling by rho GTPases were significantly enriched. Furthermore, according to the analysis of immune cell infiltration, TPM4 was associated with tumor infiltration of a variety of immune cells.

Conclusions

In conclusion, our study suggests that TPM4 may be an effective prognostic biomarker for glioma patients, providing new ideas and research directions for glioma research.
Umbrella review of basket trials testing a drug in tumors with actionable genetic biomarkers
Authors: Haslam Alyson , Olivier Timothée , Tuia Jordan , Prasad Vinay
Published: January 2023

Background

The utilization of basket trials in oncology has gained popularity because of the drive for precision medicine and the increasing ease of genetically profiling tumors. However, it is unknown if this has translated into patient benefit, either through higher response rates because of precision treatment or because of increasing options for less-common tumor types that are less represented in oncology drug trials. We sought to characterize basket studies for oncology drugs targeting a genetic biomarker, determine the responses for various tumor types and genetic biomarkers, and test for correlation between the number of participants in each tumor basket and the incidence of the respective tumor.

Methods

We conducted a retrospective cross-sectional review of oncology basket trials on Embase or clinicaltrials.gov with published data. We included studies that reported on oncology drugs that target a genetic biomarker. We examined the response for basket trial participants, stratified by tumor type and genetic biomarker and the correlation between the number of participants in each tumor basket and the incidence of the respective tumor.

Results

The overall response rate for all 25 included trials was 23%. The response for each genetic biomarker ranged from 0 to 69%, and for half of the genetic biomarkers, the response rate ranged from 0 to 100%, depending on tumor type. There is low correlation between the number of participants in each tumor basket and the incidence of the respective tumor (66.41 + -0.20x, R2 = 0.003, p = 0.75).

Conclusion

While there has been an increase in the number of published basket trials and individuals included in these trials, the response rate is low, but varies widely, depending on tumor type and genetic biomarker.
Evolution of treatment patterns and survival outcomes in patients with advanced non-small cell lung cancer treated at Frankfurt University Hospital in 2012–2018
Authors: Wolf Andrea , Stratmann Jan A. , Shaid Shabnam , Niklas Nicolas , Calleja Alan , Ubhi Harveen , Munro Robin , Waldenberger Daniela , Carroll Robert , Daumont Melinda J. , Penrod John R. , Lacoin Laure , Rohde Gernot
Published: January 2023

Background

Immune checkpoint inhibitors (ICIs) have improved outcomes for patients with advanced non-small cell lung cancer (NSCLC) versus chemotherapy in clinical trials. In Germany, ICIs have been used clinically since 2015 for patients with advanced/metastatic NSCLC without epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) aberrations. As part of I-O Optimise, a multinational research program utilizing real-world data on thoracic malignancies, we describe real-world treatment patterns and survival following reimbursement of ICIs for advanced NSCLC in Germany.

Methods

This retrospective cohort study included patients with locally advanced/metastatic NSCLC without known EGFR/ALK aberrations who received a first line of therapy at Frankfurt University Hospital between January 2012 and December 2018, with follow-up to December 2019 or death, whichever occurred first. Using electronic medical records, treatment patterns and survival outcomes were described by histology (squamous cell [SQ]; non-squamous cell [NSQ]/other) and time period (pre- and post-ICI approval).

Results

Among eligible patients who started first-line treatment, 136 (pre-ICI) and 126 (post-ICI) had NSQ/other histology, and 32 (pre-ICI) and 38 (post-ICI) had SQ histology. Use of an ICI in the NSQ/other cohort increased from 5.9% (all second- or third-line) in the pre-ICI period to 57.1% (22.2% in first-line, including 13.5% as monotherapy and 8.7% combined with chemotherapy) in the post-ICI period. This was paralleled by a significant (P < 0.0001) prolongation of median (95% CI) OS from 9.4 (7.1–11.1) to 14.8 (12.7–20.5) months between the pre-ICI and post-ICI periods. A similar increase in the uptake of ICI was observed for the SQ cohort (from 3.1% pre-ICI [fourth-line] to 52.6% post-ICI [28.9% as first-line, including 15.8% as monotherapy and 13.2% combined with chemotherapy]); however, analysis of survival outcomes was limited by small group sizes.

Conclusion

These real-world data complement clinical trial evidence on the effectiveness of ICIs in patients with advanced NSCLC and NSQ/other histology in Germany.
Face-to-face and online teaching experience on experimental animals and alternative methods with nursing students: a research study
Authors: Garcia Sierra Juan F. , Fernandez Martinez M. Nélida , Lopez Cadenas Cristina , Diez Laiz Raquel , Rodriguez Lago José M. , Sahagun Prieto Ana M.
Published: January 2023

Background

Animal models are increasingly used in Nursing science to study care approaches. Despite the scientific relevance and the ethical debate surrounding the use of experimental animals, there is a scarcity of scholarly literature exploring this topic in Nursing Schools.

Aim

To evaluate perceptions and attitudes of nursing students enrolled in a Pharmacology course on the use of experimental animals and implementation of alternative methods, by comparing the experience for two academic years. An interdisciplinary collaboration has also been developed.

Methods

A descriptive cross-sectional, quantitative study was developed. Undergraduate nursing students were enrolled in the Pharmacology subject at the University of Leon (Spain). The study was carried out in the Pharmacology facilities. Students followed a two-session practical class regarding experimental animals and alternative methods in the Pharmacology course (Degree in Nursing) in two different academic years (2019–20/2020–21). At the end of the activity, they answered a questionnaire to assess their opinions on the use of experimental animals and alternative methods in Pharmacology and the 3Rs principle.

Results

A comparison of the students’ perception with and without direct participation in the evaluation of promazine effects in mice was made. A total of 190 students participated in the teaching experience, providing high scores in all items (4–5 out of 5 points) regarding the teaching experience. Students became also aware of the advantages and disadvantages on the use of experimental animals, as well as the ethical considerations to bear in mind for their use and the need for alternative methods.

Conclusions

In the students’ opinion, the total replacement of animals by alternative techniques was very difficult, and they preferred to do the practice face-to-face. The alternative method designed was useful for the students to accept the employment of experimental animals in biomedical research and education, and know the legislation applied in the protection of animals.
Inhibition of histone deacetylase 6 destabilizes ERK phosphorylation and suppresses cancer proliferation via modulation of the tubulin acetylation-GRP78 interaction
Authors: Wattanathamsan Onsurang , Chantaravisoot Naphat , Wongkongkathep Piriya , Kungsukool Sakkarin , Chetprayoon Paninee , Chanvorachote Pithi , Vinayanuwattikun Chanida , Pongrakhananon Varisa
Published: January 2023

Background

The leading cause of cancer-related mortality worldwide is lung cancer, and its clinical outcome and prognosis are still unsatisfactory. The understanding of potential molecular targets is necessary for clinical implications in precision diagnostic and/or therapeutic purposes. Histone deacetylase 6 (HDAC6), a major deacetylase enzyme, is a promising target for cancer therapy; however, the molecular mechanism regulating cancer pathogenesis is largely unknown.

Methods

The clinical relevance of HDAC6 expression levels and their correlation with the overall survival rate were analyzed based on the TCGA and GEO databases. HDAC6 expression in clinical samples obtained from lung cancer tissues and patient-derived primary lung cancer cells was evaluated using qRT–PCR and Western blot analysis. The potential regulatory mechanism of HDAC6 was identified by proteomic analysis and validated by immunoblotting, immunofluorescence, microtubule sedimentation, and immunoprecipitation-mass spectrometry (IP-MS) assays using a specific inhibitor of HDAC6, trichostatin A (TSA) and RNA interference to HDAC6 (siHDAC6). Lung cancer cell growth was assessed by an in vitro 2-dimensional (2D) cell proliferation assay and 3D tumor spheroid formation using patient-derived lung cancer cells.

Results

HDAC6 was upregulated in lung cancer specimens and significantly correlated with poor prognosis. Inhibition of HDAC6 by TSA and siHDAC6 caused downregulation of phosphorylated extracellular signal-regulated kinase (p-ERK), which was dependent on the tubulin acetylation status. Tubulin acetylation induced by TSA and siHDAC6 mediated the dissociation of p-ERK on microtubules, causing p-ERK destabilization. The proteomic analysis demonstrated that the molecular chaperone glucose-regulated protein 78 (GRP78) was an important scaffolder required for p-ERK localization on microtubules, and this phenomenon was significantly inhibited by either TSA, siHDAC6, or siGRP78. In addition, suppression of HDAC6 strongly attenuated an in vitro 2D lung cancer cell growth and an in vitro 3D patient derived-lung cancer spheroid growth.

Conclusions

HDAC6 inhibition led to upregulate tubulin acetylation, causing GRP78-p-ERK dissociation from microtubules. As a result, p-ERK levels were decreased, and lung cancer cell growth was subsequently suppressed. This study reveals the intriguing role and molecular mechanism of HDAC6 as a tumor promoter, and its inhibition represents a promising approach for anticancer therapy.
Community acceptability, participation, and adherence to mass drug administration with primaquine for Plasmodium vivax elimination in Southern Thailand: a mixed methods approach
Authors: Saita Sayambhu , Roobsoong Wanlapa , Khammaneechan Patthanasak , Sukchan Phnom , Lawpoolsri Saranath , Sattabongkot Jetsumon , Cui Liwang , Okanurak Kamolnetr , Phuanukoonnon Suparat , Parker Daniel M.
Published: January 2023

Background

Mass drug administration (MDA) with primaquine (PQ) is being considered for accelerating Plasmodium vivax elimination in remaining active foci. This study aimed to determine the acceptability of MDA with PQ in malaria endemic villages in a malarious setting in the South of Thailand undergoing MDA with PQ.

Methods

A cross-sectional mixed-methods approach was conducted in seven malaria endemic villages where MDA with PQ was implemented. The data were collected from community villagers and health workers using structured questionnaires, in-depth interviews, and focus group discussions. Descriptive statistics and logistic regression models were used for quantitative data analysis. Thematic analysis was applied for qualitative data.

Results

Among a total of 469 participants from the MDA villages, 293 participants were eligible for MDA with PQ and 79.86% (234) completed 14-days of PQ. The logistic regressions indicated that males (adjusted odds ratio: 2.52 [95% confidence interval: 1.33–4.81]) and those who are farmers (2.57 [1.12–5.90]) were most likely to participate in the MDA. Among 293 participants in the post-MDA study, 74.06% had originally agreed to participate in the MDA with PQ while 25.94% had originally reported not wanting to participate in the MDA. Of those who originally reported being willing to participate in the MDA, 71.23% followed through with participation in the first or second round. Conversely, 93.24% of those who originally reported not being willing to participate in the MDA did in fact participate in the MDA. Factors contributing to higher odds of agreeing to participate and following through with participation included being male (1.98 [1.06–3.69]) and correctly responding that malaria is preventable (2.32 [1.01–5.35]) with some differences by village. Five key themes emerged from the qualitative analyses: concern about side effects from taking PQ; disbelief that malaria could be eliminated in this setting; low overall concern about malaria infections; misunderstandings about malaria; and a general need to tailor public health efforts for this unique context.

Conclusion

While the reported likelihood of participating in MDA was high in this setting, actual follow-through was relatively moderate, partially because of eligibility (roughly 71% of those in the follow-up survey who originally agreed to participate actually followed through with participation). One of the largest concerns among study participants was PQ-related side effects—and these concerns likely heavily influenced participant adherence to the MDA. The results of this study can be used to tailor future MDAs, or other public health interventions, in this and potentially other similar settings.
Peptide-anchored neutrophil membrane-coated biomimetic nanodrug for targeted treatment of rheumatoid arthritis
Authors: Yang Ni , Li Miaomiao , Wu Ling , Song Yinhong , Yu Shi , Wan Yingying , Cheng Wenjing , Yang Baoye , Mou Xiaoqin , Yu Hong , Zheng Jing , Li Xinzhi , Yu Xiang
Published: January 2023

Macrophage polarization determines the production of cytokines that fuel the initiation and evolution of rheumatoid arthritis (RA). Thus, modulation of macrophage polarization might represent a potential therapeutic strategy for RA. However, coordinated modulation of macrophages in the synovium and synovial fluid has not been achieved thus far. Herein, we develop a biomimetic ApoA-I mimetic peptide-modified neutrophil membrane-wrapped F127 polymer (R4F-NM@F127) for targeted drug delivery during RA treatment. Due to the high expression of adhesion molecules and chemokine receptors on neutrophils, the neutrophil membrane coating can endow the nanocarrier with synovitis-targeting ability, with subsequent recruitment to the synovial fluid under the chemotactic effects of IL-8. Moreover, R4F peptide modification further endows the nanocarrier with the ability to target the SR-B1 receptor, which is highly expressed on macrophages in the synovium and synovial fluid. Long-term in vivo imaging shows that R4F-NM@F127 preferentially accumulates in inflamed joints and is engulfed by macrophages. After loading of the anti-inflammatory drug celastrol (Cel), R4F-NM@F127-Cel shows a significant reduction in hepatotoxicity, and effectively inhibits synovial inflammation and alleviates joint damage by reprogramming macrophage polarization. Thus, our results highlight the potential of the coordinated targeted modulation of macrophages as a promising therapeutic option for the treatment of RA.
Implementing electronic patient reported outcomes in inflammatory bowel disease: patient participation, score reliability and validity
Authors: Deutscher Daniel , Weil Clara , Chodick Gabriel , Tsukinovsky Sveta , Bodger Keith , Waterman Matti , Kariv Revital
Published: January 2023

Background

Patient-reported outcome measures (PROMs) are recommended for assessing patient-centered outcomes in inflammatory bowel disease (IBD). The main aims were to assess the level of participation in an electronic PROM (ePROM) data collection system among patients with IBD, and evaluate reliability and validity of the resulting scores.

Methods

Patients included in the IBD registry of Maccabi Healthcare Services, a state-mandated healthcare provider for over 2.6 million people in Israel, were invited to complete the IBD-Control measure and a general health item, with follow-up ePROMs at 3 and 6 months including a global rating of change item. Descriptive statistics were used to compare patient characteristics by participation rate, and assess survey completion time. Initial scores were assessed for internal consistency reliability using Cronbach's alpha. Test–retest reliability was assessed using the intraclass correlation coefficient from paired scores of patients identified as unchanged between the initial and first follow-up. Construct validity was assessed by the ability of IBD-control scores to discriminate between patient sub-groups in expected ways. Empirical validity was assessed using ePROM score correlations with laboratory markers of disease activity. Score coverage was also assessed.

Results

A total of 13,588 patients were invited to participate [Mean age = 49 years (SD = 17); females = 51%]. Participation rate was 31.5%. Participants compared to non-participants were slightly older, were more likely to be female, to have a history of biologic treatment, to have higher socio-economic status, and to be more experienced in the usage of the digital patient portal. Median survey completion time was approximately 1:30 min. Internal consistency and test–retest reliability were 0.86 and 0.98, respectively. Scores discriminated between patient sub-groups in clinically expected ways, with expected correlations to laboratory markers of disease activity. A notable ceiling effect was observed (> 15%) for IBD-Control scores.

Conclusions

Feasibility, reliability, and validity of the ePROM system was supported for measuring the level of perceived disease control in patients diagnosed with IBD in Israel. Additional research is needed to identify ways to increase patient participation, assess clinical implications of the identified measurement ceiling of the IBD-control, and evaluate the added value of the derived scores in support of clinical decision making.
Therapeutic benefits of lower limb prostheses: a systematic review
Authors: Lathouwers Elke , Díaz María Alejandra , Maricot Alexandre , Tassignon Bruno , Cherelle Claire , Cherelle Pierre , Meeusen Romain , De Pauw Kevin
Published: January 2023

Background

Enhancing the quality of life of people with a lower limb amputation is critical in prosthetic development and rehabilitation. Yet, no overview is available concerning the impact of passive, quasi-passive and active ankle–foot prostheses on quality of life.

Objective

To systematically review the therapeutic benefits of performing daily activities with passive, quasi-passive and active ankle–foot prostheses in people with a lower limb amputation.

Methods

We searched the Pubmed, Web of Science, Scopus and Pedro databases, and backward citations until November 3, 2021. Only English-written randomised controlled trials, cross-sectional, cross-over and cohort studies were included when the population comprised individuals with a unilateral transfemoral or transtibial amputation, wearing passive, quasi-passive or active ankle–foot prostheses. The intervention and outcome measures had to include any aspect of quality of life assessed while performing daily activities. We synthesised the participants’ characteristics, type of prosthesis, intervention, outcome and main results, and conducted risk of bias assessment using the Cochrane risk of bias tool. This study is registered on PROSPERO, number CRD42021290189.

Results

We identified 4281 records and included 34 studies in total. Results indicate that quasi-passive and active prostheses are favoured over passive prostheses based on biomechanical, physiological, performance and subjective measures in the short-term. All studies had a moderate or high risk of bias.

Conclusion

Compared to passive ankle–foot prostheses, quasi-passive and active prostheses significantly enhance the quality of life. Future research should investigate the long-term therapeutic benefits of prosthetics devices.
Recurrent endobronchial occlusion and aorto-bronchial fistula formation in Behcet’s disease
Authors: Rahman Niloy , Senanayake Eshan , Mascaro Jorge , Situnayake Deva , Bishay Ehab S. , Patel Akshay J.
Published: January 2023

Background

Behcet’s disease is a multi-system inflammatory disorder. A small subset of patients with Behcet’s develop relapsing polychondritis which is classified as a separate disease known as Mouth and Genital ulcers with inflamed cartilage (MAGIC syndrome). It has previously been observed that this condition can also affect the cartilaginous tissue in the tracheobronchial tree.

Case presentation

We present the case of a 44-year-old lady with Behcet’s Disease, Mouth and Genital ulcers with inflamed cartilage (MAGIC) syndrome and an aortic Frozen Elephant Trunk (FET) who presented to hospital with recurrent episodes of left lobar collapse of the lung. During bronchoscopy, we found the presence of multiple inflammatory endobronchial webs occluding segments of the left bronchial tree. Repeated examinations showed evidence that these inflammatory webs were progressing in size, density and location. Furthermore, we noticed herniation of her descending aortic FET into her left bronchial tree forming an aorto-bronchial fistula which was complicated by a graft infection. Her descending aortic FET section was surgically replaced with an open procedure and bronchoscopic interventions attempted to remove the occlusions in her bronchial tree. Despite optimisation of medical management and surgical correction, this patient continued to develop progressive occlusion of her left bronchial tree, resulting in a chronically collapsed left lung.

Conclusions

A multi-disciplinary team approach is of paramount importance in order to optimally manage patients with Behcet’s disease, balancing immunosuppressive regimens that need close monitoring and titration in the context of potential surgical intervention and the risk for intercurrent infection.