bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence and incidence of chronic obstructive pulmonary disease in Latin America and the Caribbean: a systematic review and meta-analysis
Authors: Olortegui-Rodriguez Juan J. , Soriano-Moreno David R. , Benites-Bullón Alejandro , Pelayo-Luis Pilar P. , Huaringa-Marcelo Jorge
Published: July 2022

Background

Chronic Obstructive Pulmonary Disease (COPD) remains one of the leading causes of morbidity and mortality worldwide, and its epidemiology in Latin America and the Caribbean is not well described. The aim of this study was to evaluate the prevalence and incidence of COPD in Latin America and the Caribbean.

Methods

We searched systematically in Web of Science (WoS)/Core Collection, WoS/MEDLINE, WoS/Scielo, Scopus, PubMed, and Embase from 2010 to 2021. Studies assessing the prevalence and incidence of COPD according to the GOLD classification were included. The overall prevalence of COPD was calculated as a function of the general population using a random-effects model.

Results

20 studies (19 cross-sectional and 1 cohort) met the inclusion criteria. The prevalence of COPD in the general population older than 35 years was 8.9%. The prevalence in men was 13.7% and in women 6.7%. The prevalence in smokers and ex-smokers was 24.3%. The incidence in the general population of COPD according to one study was 3.4% at 9 years of follow-up.

Conclusions

COPD is prevalent in Latin America, especially in men and in smokers and ex-smokers. Further prevalence and incidence studies in the general population are needed, as well as health policies and strategies to address the disease.
Musculoskeletal disorders in video gamers – a systematic review
Authors: Tholl Chuck , Bickmann Peter , Wechsler Konstantin , Froböse Ingo , Grieben Christopher
Published: July 2022

Background

Video gaming is a recreational activity with yearly increasing popularity. It is mostly a sedentary behavior combined with repetitive movements of the upper limbs. If performed excessively, these movements may promote strain injuries and a sedentary lifestyle is one of the contributing factors to musculoskeletal disorders. Therefore, a systematic review was conducted to evaluate if video gaming negatively affects the musculoskeletal system of video gamers.

Methods

PubMed, Web of Science and The Cochrane Library were systematically searched in order to identify relevant peer reviewed original articles in English published between 2000 and 2021. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method was used for the analysis. Studies were included when they contained investigations of changes of the musculoskeletal system due to video gaming in healthy individuals. Studies with participants older than 60 years or solely psychological, social or cardiovascular outcomes were excluded. An adapted version of the Newcastle–Ottawa Scale was used for the risk of bias analysis.

Results

Sixteen observational studies involving a total of 62,987 participants met the inclusion criteria. A majority (11) of the studies reported statistical negative musculoskeletal changes due to video game playtime. Four studies did not report changes and one study found no effect of video game playtime on the musculoskeletal system. Out of the eleven studies, which demonstrated a negative impact of video game playtime on the musculoskeletal system, the most reported painful body parts were the neck (n = 4), shoulder (n = 4) and back (n = 3). Ten studies reported odds ratios (OR) for the dependence of the appearance of musculoskeletal disorders on video game playtime. In eight studies OR were significantly increased (1.3—5.2).

Conclusion

Eleven out of twelve studies demonstrated a negative impact of video game playtime on the musculoskeletal system. In particular, excessive video game playtimes (> 3 h/day) seemed to be a predictor for the appearance of musculoskeletal disorders. Due to their great popularity across multiple generations, specific and tailored prevention and health promotion programs for video gamers need to be developed to counteract this important public health issue.
The scissors sign: a provocative test for detecting the leading-edge tear of subscapularis tendon: a diagnostic study
Authors: Rhee Sung-Min , Youn Seung-Min , Park Joon Hong , Chang Geun Wu , Rhee Yong Girl
Published: July 2022

Background

Several physical examination tests and signs have been described to aid in the diagnosis of subscapularis (SSC) tear, but have limitations and variable sensitivity. This study aimed to introduce a novel test for detecting a leading-edge tear of the subscapularis (LETS), the most important tendinous portion of SSC.

Methods

A total of 233 patients who underwent arthroscopic repair for anterior and superior cuff tears between January 2018 to September 2019 were retrospectively reviewed. The provocative test we have coined as the “scissors sign” and the other related clinical tests (i.e., belly press, belly off, Napoleon, lift off, internal rotation lag, bear hug tests) were performed preoperatively. Whether the patient has a LETS or the complete tear of the SSC (CTS) was confirmed by arthroscopic findings. Sensitivity, specificity, and areas under the receiver operating characteristic curve were calculated for each test.

Results

In patients who had LETS with or without supraspinatus tear, the scissors sign showed the highest sensitivity (91.4%) with a specificity of 81.6%, positive predictive value (PPV) of 80.2%, and negative predictive value (NPV) of 92.1%. In patients with isolated LETS, the scissors sign also showed the highest sensitivity (90.3%) with a specificity of 81.6%, PPV of 57.1%, and NPV of 96.8%. The scissors sign for the complete tear of the subscapularis (CTS) with or without supraspinatus tear and the isolated CTS had a sensitivity of 73.1 and 75%, respectively.

Conclusions

The scissors sign is a novel provocative test that can be helpful in the diagnosis of subscapularis tears, especially LETS, with its high sensitivity and diagnostic accuracy. In combination with other tests, the scissors sign will be a good screening tool.
Effects of high-fat diet on thyroid autoimmunity in the female rat
Authors: Liao Zhengzheng , Kong Ying , Zeng Liang , Wan Qing , Hu Jinfang , Cai Yaojun
Published: July 2022

Background

While contributions of dyslipidemia to autoimmune diseases have been described, its impact on thyroid autoimmunity (TA) is less clear. Programmed cell death 1(PD-1)/PD-ligand 1 (PD-L1) immune checkpoint is crucial in preventing autoimmune attack while its blockade exacerbates TA. We thus unveiled the effect of high-fat diet (HFD) on TA, focusing on the contribution of PD-1/PD-L1.

Methods

Female Sprague Dawley (SD) rats were randomly fed with a regular diet or HFD (60% calories from fat) for 24 weeks. Then, thyroid ultrasonography was performed and samples were collected for lipid and thyroid-related parameter measure.

Results

HFD rats exhibited hyperlipemia and abnormal biosynthesis of the unsaturated fatty acid in serum detected by lipidomics. These rats displayed a relatively lower echogenicity and increased inflammatory infiltration in thyroid accompanied by rising serum thyroid autoantibody levels and hypothyroidism, mimicking human Hashimoto’s thyroiditis. These alterations were concurrent with decreased mRNA and immunostaining of intrathyroidal PD-1 and also serum PD-1 levels but not the PD-L1 expression, suggesting a role of a PD-1 pathway. Meanwhile, the infiltration of B and T cell, a key cellular event inhibited by the PD-1 signals, was enhanced in the thyroid of HFD rats, along with thyroid fibrosis and apoptosis.

Conclusions

Our data suggest that HFD triggers TA through a mechanism possibly involving downregulation of PD-1-related immunosuppression, providing a novel insight into the link between dyslipidemia and autoimmune toxicities.
Dysglycemia screening with oral glucose tolerance test in adolescents with polycystic ovary syndrome and relationship with obesity
Authors: Gupta Jyotsna , Antal Zoltan , Mauer Elizabeth , Gerber Linda M. , An Anjile , Censani Marisa
Published: July 2022

Background

Adolescents with polycystic ovary syndrome (PCOS) are at increased risk of impaired glucose tolerance (IGT) and type 2 diabetes mellitus. The aim of this study is to evaluate dysglycemia and biochemical differences based on BMI status and assess the prognostic ability of elevated hemoglobin A1c (HbA1c) in predicting an abnormal 2 hour oral glucose tolerance test (OGTT).

Methods

Retrospective cohort of female patients aged 11-18 years who underwent 75-g OGTT and were evaluated for PCOS at an urban tertiary care hospital between January 2002 to December 2017.

Results

In 106 adolescents with PCOS who had OGTT results available, IGT was markedly pronounced in the ≥95th percentile BMI group (17 out of 72; 23.6%) compared with <95th percentile BMI group (4 out of 34; 11.7%). One patient with obesity met the criteria for type 2 diabetes. Patients with obesity had significantly higher homeostasis model assessment (HOMA-IR) and lower whole body insulin sensitivity index (WBISI) (p < 0.001) compared to patients without obesity. Free testosterone levels were also higher in patients with obesity (p< 0.03) and were significantly associated with HOMA-IR when controlling for body mass index (BMI). HbA1c did not demonstrate a strong ability to predict abnormal OGTT on receiver operating characteristic (ROC) curve analysis [Area under the curve (AUC) = 0.572, 95% CI: 0.428, 0.939]).

Conclusions

In a study to assess glucose abnormalities in adolescents with PCOS, IGT was found to be markedly increased in patients with obesity, with abnormal glucose metabolism identified in over one-fifth of the patients. HbA1c alone may be a poor test to assess IGT and we recommend that adolescents diagnosed with PCOS and obesity undergo formal oral glucose tolerance testing.
Effect of strontium-doped bioactive glass-ceramic containing toothpaste on prevention of artificial dentine caries formation: an in vitro study
Authors: Dai Lin Lu , Mei May Lei , Chu Chun Hung , Lo Edward Chin Man
Published: July 2022

Backgroud

Root caries in aging population was prevalent worldwide. Due to the absence of enamel and specific structure of dentine, bacteria are able to penetrate further into dentine at an earlier stage of lesion development. The aim of this study was to investigate the effect of adding of a strontium-doped bioactive glass-ceramic (HX-BGC) to a fluoride-free toothpaste on prevention of formation of artificial dentine caries.

Methods

Thirty-six human tooth specimens were allocated to three groups (n = 12 per group). Group 1 treated with slurry containing a fluoride-free toothpaste and 5% HX-BGC, Group 2 was treated with fluoride-free toothpaste slurry, and Group 3 received deionized water as a negative control. The specimens were subjected to four cycles (15 h demineralization and 8 h remineralization for one cycle) of biochemical cycling. A mixed suspension of five bacteria species (Streptococcus mutans, Streptococcus sobrinus, Lactobacillus acidophilus, Lactobacillus rhamnosus, and Actinomyces naeslundii) were prepared in brain heart infusion broth with 5% sucrose and used as acidic challenge in biochemical cycling. Subsequently, surface morphology of the dentine lesion was assessed by scanning electron microscopy, while the lesion depths and mineral loss were assessed by micro-computed tomography.

Results

The mean lesion depths in dentine in Groups 1 to 3 were 87.79 ± 16.99 μm, 101.06 ± 10.04 μm and 113.60 ± 16.36 μm, respectively (p = 0.002). The mean amounts of mineral loss in Groups 1 to 3 were 0.82 ± 0.10 g/cm3, 0.89 ± 0.09 g/cm3 and 0.96 ± 0.11 g/cm3, respectively (p = 0.016). No obvious differences in the surface morphology were seen among the groups.

Conclusion

Addition of strontium-doped bioactive glass-ceramic to fluoride-free toothpaste has potential to reduce formation of dentine lesions.
Mechanical force regulates root resorption in rats through RANKL and OPG
Authors: Zhou Jianli , Guo Lijia , Yang Yanji , Liu Yi , Zhang Chen
Published: July 2022

Background

External root resorption is one of common complications of orthodontic treatment, while internal root resorption is rarely observed, and the difference between pulp and periodontal tissues during orthodontic treatment is still unknown. The purpose of this study was to evaluate the effects of orthodontic forces on histological and cellular changes of the dental pulp and periodontal tissues.

Methods

Orthodontic tooth movement model was established in Forty-eight adult male Wistar rats. The distance of orthodontic tooth movement was quantitatively analyzed. The histological changes of pulp and periodontal tissues were performed by hematoxylin–eosin staining, tartrate-resistant acid phosphate staining was used to analyze the changes of osteoclast number, immunohistochemistry analysis and reverse transcription polymerase chain reaction were used to examine the receptor of nuclear factor-κB ligand (RANKL) and osteoprotegerin (OPG) expression. The width of tertiary dentine was quantitatively analyzed. Tartrate-resistant acid phosphate staining and the erosion area of osteo assay surface plate was used to evaluate osteoclast activity.

Results

The orthodontic tooth movement distance increased in a force dependent manner, and reached the peak value when orthodontic force is 60 g. Heavy orthodontic force increased the RANKL expression of periodontal ligament srem cells (PDLSCs) which further activated osteoclasts and resulted in external root resorption, while the RANKL expression of dental pulp stem cells (DPSCs) was relatively low to activate osteoclasts and result in internal root resorption, and the dental pulp tend to form tertiary dentine under orthodontic force stimulation.

Conclusions

Heavy orthodontic forces activated osteoclasts and triggered external root resorption by upregulating RANKL expression in rat periodontal tissues, while there was no significant change of RANKL expression in dental pulp tissue under heavy orthodontic forces, which prevented osteoclast activation and internal root resorption.
N-terminus of flagellin enhances vaccine efficacy against Actinobacillus pleuropneumoniae
Authors: Chuekwon Kamonpun , Chu Chun-Yen , Cheng Li-Ting
Published: July 2022

Background

Flagellin elicits potent immune response and may serve as a vaccine adjuvant. We previously reported that the N-terminus of flagellin (residues 1–99, nFliC) is sufficient for vaccine efficacy enhancement against Pasteurella multocida challenge in chickens. In this study, we futher tested the adjuvancy of nFliC in a subunit vaccine against the pig pathogen Actinobacillus pleuropneumoniae in a mice model. For vaccine formulation, the antigen ApxIIPF (the pore-forming region of the exotoxin ApxII) was combined with nFliC, either through genetic fusion or simple admixture.

Results

Immune analysis showed that nFliC, introduced through genetic fusion or admixture, enhanced both humoral (antibody levels) and cellular (T cell response and cytokine production) immunity. In a challenge test, nFliC increased vaccine protective efficacy to 60–80%, vs. 20% for the antigen-only group. Further analysis showed that, even without a supplemental adjuvant such as mineral salt or oil emulsion, genetically linked nFliC still provided significant immune enhancement.

Conclusions

We conclude that nFliC is a versatile and potent adjuvant for vaccine formulation.
Targeting IL-6 by engineered Lactococcus lactis via surface-displayed affibody
Authors: Zahirović Abida , Berlec Aleš
Published: July 2022

Background

Dysregulated production of interleukin (IL)-6 is implicated in the pathology of inflammatory bowel disease (IBD). Neutralization of IL-6 in the gut by safe probiotic bacteria may help alleviate intestinal inflammation. Here, we developed Lactococcus lactis with potent and selective IL-6 binding activity by displaying IL-6-specific affibody on its surface.

Results

Anti-IL-6 affibody (designated as ZIL) was expressed in fusion with lactococcal secretion peptide Usp45 and anchoring protein AcmA. A high amount of ZIL fusion protein was detected on bacterial surface, and its functionality was validated by confocal microscopy and flow cytometry. Removal of IL-6 from the surrounding medium by the engineered L. lactis was evaluated using enzyme-linked immunosorbent assay. ZIL-displaying L. lactis sequestered recombinant human IL-6 from the solution in a concentration-dependent manner by up to 99% and showed no binding to other pro-inflammatory cytokines, thus proving to be highly specific for IL-6. The removal was equally efficient across different IL-6 concentrations (150–1200 pg/mL) that were found to be clinically relevant in IBD patients. The ability of engineered bacteria to capture IL-6 from cell culture supernatant was assessed using immunostimulated human monocytic cell lines (THP-1 and U-937) differentiated into macrophage-like cells. ZIL-displaying L. lactis reduced the content of IL-6 in the supernatants of both cell lines in a concentration-dependent manner by up to 94%. Dose response analysis showed that bacterial cell concentrations of 107 and 109 CFU/mL (colony forming units per mL) were required for half-maximal removal of recombinant and macrophage-derived IL-6, respectively.

Conclusion

The ability of ZIL-displaying L. lactis to bind pathological concentrations of IL-6 at common bacterial doses suggests physiological significance.
LINE-1 promotes tumorigenicity and exacerbates tumor progression via stimulating metabolism reprogramming in non-small cell lung cancer
Authors: Sun Zeguo , Zhang Rui , Zhang Xiao , Sun Yifei , Liu Pengpeng , Francoeur Nancy , Han Lei , Lam Wan Yee , Yi Zhengzi , Sebra Robert , Walsh Martin , Yu Jinpu , Zhang Weijia
Published: July 2022

Background

Long Interspersed Nuclear Element-1 (LINE-1, L1) is increasingly regarded as a genetic risk for lung cancer. Transcriptionally active LINE-1 forms a L1-gene chimeric transcript (LCTs), through somatic L1 retrotransposition (LRT) or L1 antisense promoter (L1-ASP) activation, to play an oncogenic role in cancer progression.

Methods

Here, we developed Retrotransposon-gene fusion estimation program (ReFuse), to identify and quantify LCTs in RNA sequencing data from TCGA lung cancer cohort (n = 1146) and a single cell RNA sequencing dataset then further validated those LCTs in an independent cohort (n = 134). We next examined the functional roles of a cancer specific LCT (L1-FGGY) in cell proliferation and tumor progression in LUSC cell lines and mice.

Results

The LCT events correspond with specific metabolic processes and mitochondrial functions and was associated with genomic instability, hypomethylation, tumor stage and tumor immune microenvironment (TIME). Functional analysis of a tumor specific and frequent LCT involving FGGY (L1-FGGY) reveal that the arachidonic acid (AA) metabolic pathway was activated by the loss of FGGY through the L1-FGGY chimeric transcript to promote tumor growth, which was effectively targeted by a combined use of an anti-HIV drug (NVR) and a metabolic inhibitor (ML355). Lastly, we identified a set of transcriptomic signatures to stratify the LUSC patients with a higher risk for poor outcomes who may benefit from treatments using NVR alone or combined with an anti-metabolism drug.

Conclusions

This study is the first to characterize the role of L1 in metabolic reprogramming of lung cancer and provide rationale for L1-specifc prognosis and potential for a therapeutic strategy for treating lung cancer.

Trial registration

Study on the mechanisms of the mobile element L1-FGGY promoting the proliferation, invasion and immune escape of lung squamous cell carcinoma through the 12-LOX/Wnt pathway, Ek2020111. Registered 27 March 2020 ‐ Retrospectively registered.
Circulating growth differentiation factor 15 levels and apolipoprotein B to apolipoprotein A1 ratio in coronary artery disease patients with type 2 diabetes mellitus
Authors: Mei Yufeng , Zhao Zhiming , Lyu Yongnan , Li Yan
Published: July 2022

Background

Clinical investigations have found that there was a close association between T2DM and adverse cardiovascular events, with possible mechanisms included inflammation, apoptosis, and lipid metabolism disorders. High serum GDF-15 concentration and the apolipoprotein B/apolipoprotein A1 ratio (ApoB/ApoA1) are involved in the above-mentioned mechanisms and are thought to be related to the occurrence of adverse cardiovascular events. However, it remains unclear whether circulating GDF-15 levels and the ApoB/ApoA1 ratio are related to T2DM patients with CAD.

Methods

T2DM patients with or without CAD were eligible for this study. According to the inclusion and exclusion criteria, 502 T2DM patients were enrolled between January 2021 and December 2021 and were then divided into T2DM group (n = 249) and CAD group (n = 253). The ApoB, ApoA1 and GDF-15 concentrations were measured at hospital admission and the ApoB/ApoA1 ratio was then calculated.

Results

Compared with T2DM group, serum GDF-15 levels and ApoB/ApoA1 ratio increased in CAD group. Furthermore, a positive relationship between the occurrence of CAD in diabetic population and circulating GDF-15 concentrations and ApoB/ApoA1 ratio was observed in logistic regression analysis (p < 0.01). Restrictive cubic spline analysis after adjusted for multiple risky variables showed that serum GDF-15 or ApoB/ApoA1 ratio correlated positively with CAD.

Conclusions

Circulating GDF-15 levels and serum ApoB/ApoA1 ratio vary in CAD group and T2DM group. ApoB/ApoA1 and GDF-15 may be helpful for predicting the occurrence of CAD in patients with T2DM.
The associations between serum high-density lipoprotein cholesterol levels and malignant behavior in pancreatic neuroendocrine neoplasms
Authors: Quan Li , Liu Yongkang , Cui Wenjing , Wang Xinru , Zhang Weixiao , Wang Zhongqiu , Guo Chuangen , Lu Chao , Hu Feixiang , Chen Xiao
Published: July 2022

Background

The role of serum high-density lipoprotein cholesterol (HDL-c) in tumorigenesis are observed in several endocrine-related cancers. However, its role in pancreatic neuroendocrine neoplasms (PNENs) has not been understood. In the current study, the relationship between HDL-c levels and malignant behavior in PNENs was explored.

Methods

One hundred ninety-seven patients with histopathology confirmed PNENs were included. PNENs were divided into three grades (G1, G2 and G3) as 2017 WHO classification based on ki67 index and mitosis count. The demographic data, clinical information, tumor morphological and pathological features (organs invasion, lymph node metastasis, vascular invasion and perineural invasion), and serum tumor biomarkers were collected. The relationships between HDL-c levels and malignant behaviors in PNENs were analyzed using logistic regression analysis. Models were also developed for the identification of high grade PNENs.

Results

The levels of serum HDL-c in G2/G3 tumor were significantly lower than that in G1 tumor (P = 0.031). However, no such difference was found between G3 and G1/G2. The proportions of low HDL-c (≤ 0.9 mmol/L) were higher in high-grade PNENs (G2/G3 or G3) than those in low-grade (G1 or G1/G2) (29.0 vs 15.2%, P = 0.032; 37.0 vs 20.5%, P = 0.023). The risk of G2/G3 tumors in patients with high serum HDL-c levels was decreased (odds ratio (OR) = 0.35, 95% confidence interval (CI): 0.12–0.99). Similarly, the risk of G3 PNENs increased in patients with low HDL-c levels (OR = 2.51, 95%CI:1.12–5.60). HDL-c level was also associated with a high ki67 index (> 55%) (OR = 0.10, 95%CI: 0.02–0.51) and neuroendocrine carcinoma G3 (OR = 0.21, 95%CI: 0.06–0.80). The area under the curve (AUC) of HDL-c + tumor size + age was 0.85 (95% CI: 0.79–0.91) in identifying G2/G3 PNENs, and HDL-c (> 0.9 mmol/L) + tumor size + age had an AUC of 0.77 (95% CI: 0.70–0.84) in identifying G3 PNENs. HDL-c level was associated with lymph node metastasis (OR = 0.24, 95%CI:0.08–0.99).

Conclusion

Serum HDL-c levels were significantly associated with malignant behaviors in PNENs, in particular to tumor grade and lymph node metastasis.
Rod-like hybrid nanomaterial with tumor targeting and pH-responsive for cancer chemo/photothermal synergistic therapy
Authors: Wang Shaochen , Zhou Qiaoqiao , Yu Shuling , Zhao Shuang , Shi Jiahua , Yuan Jintao
Published: July 2022

The development of chemo/photothermal nanotherapeutic systems with excellent photothermal performance, stable drug loading, tumor targeting and strong membrane penetration still remains a challenge. To address this problem, herein a rod-like nanocomposite system (AuNR@FA-PR/PEG) forming from folic acid (FA) terminated carboxylated cyclodextrin (CD) pseudopolyrotaxane (FA-PR) and polyethylene glycol (PEG) modifying gold nanorods (AuNR) was reported. Cisplatin (CDDP) was loaded in AuNR@FA-PR/PEG via coordination bonds to prepare a rod-like pH-responsive nanosystem (AuNR@FA-PR/PEG/CDDP) with chemotherapy/photothermal therapy. The rod-like morphology of AuNR@FA-PR/PEG was characterized by transmission electron microscope. In vitro drug release experiments showed the pH-responsive of AuNR@FA-PR/PEG/CDDP. In vivo real-time imaging assays proved AuNR@FA-PR/PEG/CDDP could rapidly enrich in the tumor area and stay for a long time because of folate targeting and their rod-like morphology. In vivo photothermal imaging assays showed AuNR@FA-PR/PEG/CDDP excellent photothermal performance, the average temperature of tumor region could reach 63.5 °C after 10 min irradiation. In vitro and in vivo experiments also demonstrated that the combined therapy of chemotherapy and photothermal therapy had an outstandingly synergistic effect and improved the therapeutic efficacy comparing with chemotherapy and photothermal therapy alone. Therefore, the prepared rod-like AuNR@FA-PR/PEG/CDDP will provide a new strategy for the effective treatment of cancer.
pH-sensitive packaging of cationic particles by an anionic block copolymer shell
Authors: Solomun Jana I. , Martin Liam , Mapfumo Prosper , Moek Elisabeth , Amro Elias , Becker Friedrich , Tuempel Stefan , Hoeppener Stephanie , Rudolph K. Lenhard , Traeger Anja
Published: July 2022

Cationic non-viral vectors show great potential to introduce genetic material into cells, due to their ability to transport large amounts of genetic material and their high synthetic versatility. However, designing materials that are effective without showing toxic effects or undergoing non-specific interactions when applied systemically remains a challenge. The introduction of shielding polymers such as polyethylene glycol (PEG) can enhance biocompatibility and circulation time, however, often impairs transfection efficiency. Herein, a multicomponent polymer system is introduced, based on cationic and hydrophobic particles (P(nBMA46-co-MMA47-co-DMAEMA90), (PBMD)) with high delivery performance and a pH-responsive block copolymer (poly((N-acryloylmorpholine)-b-(2-(carboxy)ethyl acrylamide)) (P(NAM72-b-CEAm74), PNC)) as shielding system, with PNAM as alternative to PEG. The pH-sensitive polymer design promotes biocompatibility and excellent stability at extracellular conditions (pH 7.4) and also allows endosomal escape and thus high transfection efficiency under acidic conditions. PNC shielded particles are below 200 nm in diameter and showed stable pDNA complexation. Further, interaction with human erythrocytes at extracellular conditions (pH 7.4) was prevented, while acidic conditions (pH 6) enabled membrane leakage. The particles demonstrate transfection in adherent (HEK293T) as well as difficult-to-transfect suspension cells (K-562), with comparable or superior efficiency compared to commercial linear poly(ethylenimine) (LPEI). Besides, the toxicity of PNC-shielded particles was significantly minimized, in particular in K-562 cells and erythrocytes. In addition, a pilot in vivo experiment on bone marrow blood cells of mice that were injected with PNC-shielded particles, revealed slightly enhanced cell transfection in comparison to naked pDNA. This study demonstrates the applicability of cationic hydrophobic polymers for transfection of adherent and suspension cells in culture as well as in vivo by co-formulation with pH-responsive shielding polymers, without substantially compromising transfection performance.

Graphical Abstract
Protective role of small extracellular vesicles derived from HUVECs treated with AGEs in diabetic vascular calcification
Authors: Guo Bei , Shan Su-Kang , Xu Feng , Lin Xiao , Li Fu-Xing-zi , Wang Yi , Xu Qiu-Shuang , Zheng Ming-Hui , Lei Li-Min , Li Chang-Chun , Zhou Zhi-Ang , Ullah Muhammad Hasnain Ehsan , Wu Feng , Liao Xiao-Bo , Yuan Ling-Qing
Published: July 2022

The pathogenesis of vascular calcification in diabetic patients remains elusive. As an effective information transmitter, small extracellular vesicles (sEVs) carry abundant microRNAs (miRNAs) that regulate the physiological and pathological states of recipient cells. In the present study, significant up-regulation of miR-126-5p was observed in sEVs isolated from human umbilical vein endothelial cells (HUVECs) stimulated with advanced glycation end-products (A-EC/sEVs). Intriguingly, these sEVs suppressed the osteogenic differentiation of vascular smooth muscle cells (VSMCs) by targeting BMPR1B, which encodes the receptor for BMP, thereby blocking the smad1/5/9 signalling pathway. In addition, knocking down miR-126-5p in HUVECs significantly diminished the anti-calcification effect of A-EC/sEVs in a mouse model of type 2 diabetes. Overall, miR-126-5p is highly enriched in sEVs derived from AGEs stimulated HUVECs and can target BMPR1B to negatively regulate the trans-differentiation of VSMCs both in vitro and in vivo.

Graphical Abstract
Light triggered release of a triple action porphyrin-cisplatin conjugate evokes stronger immunogenic cell death for chemotherapy, photodynamic therapy and cancer immunotherapy
Authors: Song Haiqin , Cai Zhenghao , Li Juyi , Xiao Haihua , Qi Ruogu , Zheng Minhua
Published: July 2022

Photodynamic therapy (PDT) has emerged as an attractive therapeutic approach which can elicit immunogenic cell death (ICD). However, current ICD inducers are still very limited as the representative ICD induces of photosensitizers can only evoke insufficient ICD to achieve unsatisfactory cancer immunotherapy. Herein, we demonstrated the use of a triple action cationic porphyrin-cisplatin conjugate (Pt-1) for drug delivery by a reactive oxygen species (ROS) sensitive polymer as nanoparticles (NP@Pt-1) for combined chemotherapy, PDT and immunotherapy. This unique triple action Pt-1 contains both chemotherapeutic Pt drugs and Porphyrin as a photosensitizer to generate ROS for PDT. Moreover, the ROS generated by Pt-1 can on the one hand degrade polymer carriers to release Pt-1 for chemotherapy and PDT. On the other hand, the ROS generated by Pt-1 subsequently triggered the ICD cascade for immunotherapy. Taken together, we demonstrated that NP@Pt-1 were the most effective and worked in a triple way. This study could provide us with new insight into the development of nanomedicine for chemotherapy, PDT as well as cancer immunotherapy.
PLA-lignin nanofibers as antioxidant biomaterials for cartilage regeneration and osteoarthritis treatment
Authors: Liang Ruiming , Yang Xingchen , Yew Pek Yin Michelle , Sugiarto Sigit , Zhu Qiang , Zhao Jinmin , Loh Xian Jun , Zheng Li , Kai Dan
Published: July 2022

Background

Osteoarthritis (OA) is common musculoskeletal disorders associated with overgeneration of free radicals, and it causes joint pain, inflammation, and cartilage degradation. Lignin as a natural antioxidant biopolymer has shown its great potential for biomedical applications. In this work, we developed a series of lignin-based nanofibers as antioxidative scaffolds for cartilage tissue engineering.

Results

The nanofibers were engineered by grafting poly(lactic acid) (PLA) into lignin via ring-opening polymerization and followed by electrospinning. Varying the lignin content in the system was able to adjust the physiochemical properties of the resulting nanofibers, including fiber diameters, mechanical and viscoelastic properties, and antioxidant activity. In vitro study demonstrated that the PLA-lignin nanofibers could protect bone marrow-derived mesenchymal stem/stromal cells (BMSCs) from oxidative stress and promote the chondrogenic differentiation. Moreover, the animal study showed that the lignin nanofibers could promote cartilage regeneration and repair cartilage defects within 6 weeks of implantation.

Conclusion

Our study indicated that lignin-based nanofibers could serve as an antioxidant tissue engineering scaffold and facilitate the cartilage regrowth for OA treatment.

Graphical Abstract
Radiodynamic therapy with CsI(na)@MgO nanoparticles and 5-aminolevulinic acid
Authors: Jiang Fangchao , Lee Chaebin , Zhang Weizhong , Jiang Wen , Cao Zhengwei , Chong Harrison Byron , Yang Wei , Zhan Shuyue , Li Jianwen , Teng Yong , Li Zibo , Xie Jin
Published: July 2022

Background

Radiodynamic therapy (RDT) holds the potential to overcome the shallow tissue penetration issue associated with conventional photodynamic therapy (PDT). To this end, complex and sometimes toxic scintillator–photosensitizer nanoconjugates are often used, posing barriers for large-scale manufacturing and regulatory approval.

Methods

Herein, we report a streamlined RDT strategy based on CsI(Na)@MgO nanoparticles and 5-aminolevulinic acid (5-ALA). 5-ALA is a clinically approved photosensitizer, converted to protoporphyrin IX (PpIX) in cancer cells’ mitochondria. CsI(Na)@MgO nanoparticles produce strong ~ 410 nm X-ray luminescence, which matches the Soret band of PpIX. We hypothesize that the CsI(Na)@MgO-and-5-ALA combination can mediate RDT wherein mitochondria-targeted PDT synergizes with DNA-targeted irradiation for efficient cancer cell killing. Because scintillator nanoparticles and photosensitizer are administered separately, the approach forgoes issues such as self-quenching or uncontrolled release of photosensitizers.

Results

When tested in vitro with 4T1 cells, the CsI(Na)@MgO and 5-ALA combination elevated radiation-induced reactive oxygen species (ROS), enhancing damages to mitochondria, DNA, and lipids, eventually reducing cell proliferation and clonogenicity. When tested in vivo in 4T1 models, RDT with the CsI(Na)@MgO and 5-ALA combination significantly improved tumor suppression and animal survival relative to radiation therapy (RT) alone. After treatment, the scintillator nanoparticles, made of low-toxic alkali and halide elements, were efficiently excreted, causing no detectable harm to the hosts.

Conclusions

Our studies show that separately administering CsI(Na)@MgO nanoparticles and 5-ALA represents a safe and streamlined RDT approach with potential in clinical translation.

Graphical Abstract
Antibacterial metal nanoclusters
Authors: Zheng Youkun , Wei Min , Wu Haibin , Li Fangyuan , Ling Daishun
Published: July 2022

Combating bacterial infections is one of the most important applications of nanomedicine. In the past two decades, significant efforts have been committed to tune physicochemical properties of nanomaterials for the development of various novel nanoantibiotics. Among which, metal nanoclusters (NCs) with well-defined ultrasmall size and adjustable surface chemistry are emerging as the next-generation high performance nanoantibiotics. Metal NCs can penetrate bacterial cell envelope more easily than conventional nanomaterials due to their ultrasmall size. Meanwhile, the abundant active sites of the metal NCs help to catalyze the bacterial intracellular biochemical processes, resulting in enhanced antibacterial properties. In this review, we discuss the recent developments in metal NCs as a new generation of antimicrobial agents. Based on a brief introduction to the characteristics of metal NCs, we highlight the general working mechanisms by which metal NCs combating the bacterial infections. We also emphasize central roles of core size, element composition, oxidation state, and surface chemistry of metal NCs in their antimicrobial efficacy. Finally, we present a perspective on the remaining challenges and future developments of metal NCs for antibacterial therapeutics.

Graphical Abstract
Malting barley carbon dots-mediated oxidative stress promotes insulin resistance in mice via NF-κB pathway and MAPK cascade
Authors: Zhang Boya , Yu Lidong , Zhu Ruijiao , Wei Xiangjuan , Fan Xingpei , Hu Hailong , Yang Daqian , Du Haining , Zhao Meimei , Li Li , Oh Yuri , Feng Yujie , Gu Ning
Published: July 2022

Background

Food-borne carbon dots (CDs) are widely generated during food processing and are inevitably ingested by humans causing toxicity. However, the toxic effects of food-borne CDs on the blood glucose metabolism are unknown.

Results

In this study, we brewed beer via a representative strategy and extracted the melting-barley CDs (MBCDs) to explore the toxic effects on blood glucose in mice. We found the accumulation of fluorescent labeled MBCDs in various organs and oral administration of MBCDs can cause visceral toxicity, manifested as liver damage. Mice were orally administered MBCDs (5 and 25 mg/kg) for 16 weeks, and increased levels of fasting blood glucose were observed in both MBCDs-treated groups. Transcriptomic analyses revealed that MBCDs activate oxidative stress, inflammatory responses, the MAPK cascade, and PI3K/Akt signaling in mice livers. Mechanistically, MBCDs exposure-induced reactive oxygen species (ROS) overproduction activates the nuclear factor-κB (NF-κB) signaling pathway and MAPK cascade, thereby promoting phosphorylated insulin receptor substrate (IRS)-1 at Ser307 and inducing insulin resistance (IR). Meanwhile, the IR promoted gluconeogenesis, which enhanced MBCDs-induced hyperglycemia of mice. Importantly, inhibition of the ROS significantly attenuated the MBCDs-induced inflammatory response and MAPK cascade, thereby alleviating IR and hyperglycemia in mice.

Conclusion

In summary, this study revealed that MBCDs promote ROS overproduction and thus induced IR, resulting in imbalance of glucose homeostasis in mice. More importantly, this study was further assessed to reveal an imperative emphasis on the reevaluation of dietary and environmental CDs exposure, and has important implications for T2DM prevention research.

Graphical Abstract
Modularity of RBC hitchhiking with polymeric nanoparticles: testing the limits of non-covalent adsorption
Authors: Lenders Vincent , Escudero Remei , Koutsoumpou Xanthippi , Armengol Álvarez Laura , Rozenski Jef , Soenen Stefaan J. , Zhao Zongmin , Mitragotri Samir , Baatsen Pieter , Allegaert Karel , Toelen Jaan , Manshian Bella B.
Published: July 2022

Red blood cell (RBC) hitchhiking has great potential in enhancing drug therapy, by improving targeting and reducing rapid clearance of nanoparticles (NPs). However, to improve the potential for clinical translation of RBC hitchhiking, a more thorough understanding of the RBC-NP interface is needed. Here, we evaluate the effects of NP surface parameters on the success and biocompatibility of NP adsorption to extracted RBCs from various species. Major differences in RBC characteristics between rabbit, mouse and human were proven to significantly impact NP adsorption outcomes. Additionally, the effects of NP design parameters, including NP hydrophobicity, zeta potential, surfactant concentration and drug encapsulation, on RBC hitchhiking are investigated. Our studies demonstrate the importance of electrostatic interactions in balancing NP adsorption success and biocompatibility. We further investigated the effect of varying the anti-coagulant used for blood storage. The results presented here offer new insights into the parameters that impact NP adsorption on RBCs that will assist researchers in experimental design choices for using RBC hitchhiking as drug delivery strategy.
Artificial stem cells mediated inflammation-tropic delivery of antiviral drugs for pneumonia treatment
Authors: Qin Aiping , Chen Sheng , Li Songpei , Li Qizhen , Huang Xiaotao , Xia Luoxing , Lin Yinshan , Shen Ao , Xiang Andy Peng , Zhang Lingmin
Published: July 2022

Background

Cytomegalovirus (CMV) pneumonia is a major cause of morbidity and mortality in immunodeficiency individuals, including transplant recipients and Acquired Immune Deficiency Syndrome patients. Antiviral drugs ganciclovir (GCV) and phosphonoformate (PFA) are first-line agents for pneumonia caused by herpesvirus infection. However, the therapy suffers from various limitations such as low efficiency, drug resistance, toxicity, and lack of specificity.

Methods

The antiviral drugs GCV and PFA were loaded into the pH-responsive nanoparticles fabricated by poly(lactic-co-glycolic acid) (PLGA) and 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), and further coated with cell membranes derived from bone marrow mesenchymal stem cells to form artificial stem cells, namely MPDGP. We evaluated the viral suppression effects of MPDGP in vitro and in vivo.

Results

MPDGP showed significant inflammation tropism and efficient suppression of viral replication and virus infection-associated inflammation in the CMV-induced pneumonia model. The synergistic effects of the combination of viral DNA elongation inhibitor GCV and viral DNA polymerase inhibitor PFA on suppressing the inflammation efficiently.

Conclusion

The present study develops a novel therapeutic intervention using artificial stem cells to deliver antiviral drugs at inflammatory sites, which shows great potential for the targeted treatment of pneumonia. To our best knowledge, we are the first to fabricate this kind of artificial stem cell to deliver antiviral drugs for pneumonia treatment.

Graphical Abstract
Heparanase is a prognostic biomarker independent of tumor purity and hypoxia based on bioinformatics and immunohistochemistry analysis of esophageal squamous cell carcinoma
Authors: Wang Yu , Song Tongjun , Li Kai , Liu Hao , Han Yan , Xu Tao , Cao Fengjun , Li Yong , Yu Yuandong
Published: July 2022

Background

Esophageal squamous cell carcinoma (ESCC) is a common malignant tumor of the digestive tract with a poor prognosis. The tumor microenvironment (TME) is mainly composed of tumor cells, stromal cells, and immune cells and plays an important role in ESCC development. There are substantial differences in tumor purity among different parts of ESCC tissues, consisting of distinct immune and stromal cells and variations in the status of hypoxia. Thus, prognostic models of ESCC based on bioinformatic analysis of tumor tissues are unreliable.

Method

Differentially expressed genes (DEGs) independent of tumor purity and hypoxia were screened by Spearman correlation analysis of public ESCC cohorts. Subsequently, the DEGs were subjected to Cox regression analysis. Then, we constructed a protein–protein interaction (PPI) network of the DEGs using Cytoscape. Intersection analysis of the univariate Cox and PPI results indicated that heparanase (HPSE), an endo-β-D-glucuronidase capable of cleaving heparan sulfate side chains, was a predictive factor. Gene set enrichment analysis (GSEA) was used to reveal the potential function of HPSE, and single-cell sequencing data were analyzed to evaluate the distribution of HPSE in immune cells. Furthermore, a human ESCC tissue microarray was used to validate the expression and prognostic value of HPSE.

Result

We found that HPSE was downregulated in ESCC tissues and was not correlated with tumor purity or hypoxia status. HPSE is involved in multiple biological processes. ESCC patients with low HPSE expression in cancerous tissues exhibited poor prognosis.

Conclusions

These results indicate that low HPSE expression in cancerous tissues correlates with poor prognosis in patients with ESCC. HPSE is a novel prognostic biomarker independent of tumor purity and hypoxia status in ESCC.
Systematic review and critical methodological appraisal of community-based falls prevention economic models
Authors: Kwon Joseph , Squires Hazel , Franklin Matthew , Young Tracey
Published: July 2022

Background

Falls impose significant health and economic burdens on community-dwelling older persons. Decision modelling can inform commissioning of alternative falls prevention strategies. Several methodological challenges arise when modelling public health interventions including community-based falls prevention. This study aims to conduct a systematic review (SR) to: systematically identify community-based falls prevention economic models; synthesise and critically appraise how the models handled key methodological challenges associated with public health modelling; and suggest areas for further methodological research.

Methods

The SR followed the 2021 PRISMA reporting guideline and covered the period 2003–2020 and 12 academic databases and grey literature. The extracted methodological features of included models were synthesised by their relevance to the following challenges: (1) capturing non-health outcomes and societal intervention costs; (2) considering heterogeneity and dynamic complexity; (3) considering theories of human behaviour and implementation; and (4) considering equity issues. The critical appraisal assessed the prevalence of each feature across models, then appraised the methods used to incorporate the feature. The methodological strengths and limitations stated by the modellers were used as indicators of desirable modelling practice and scope for improvement, respectively. The methods were also compared against those suggested in the broader empirical and methodological literature. Areas of further methodological research were suggested based on appraisal results.

Results

46 models were identified. Comprehensive incorporation of non-health outcomes and societal intervention costs was infrequent. The assessments of heterogeneity and dynamic complexity were limited; subgroup delineation was confined primarily to demographics and binary disease/physical status. Few models incorporated heterogeneity in intervention implementation level, efficacy and cost. Few dynamic variables other than age and falls history were incorporated to characterise the trajectories of falls risk and general health/frailty. Intervention sustainability was frequently based on assumptions; few models estimated the economic/health returns from improved implementation. Seven models incorporated ethnicity- and severity-based subgroups but did not estimate the equity-efficiency trade-offs. Sixteen methodological research suggestions were made.

Conclusion

Existing community-based falls prevention models contain methodological limitations spanning four challenge areas relevant for public health modelling. There is scope for further methodological research to inform the development of falls prevention and other public health models.