Bone transport induces the release of factors with multi-tissue regenerative potential for diabetic wound healing in rats and patients.

Tibial cortex transverse distraction is a surgical method for treating severe diabetic foot ulcers (DFUs), but the underlying mechanism is unclear. We show that antioxidant proteins and small extracellular vesicles (sEVs) with multiple-tissue regenerative potential are released during bone transport (BT) in humans and rats. These vesicles accumulate in diabetic wounds and are enriched with microRNAs (miRNAs) (e.g., miR-494-3p) that have high regenerative activities that improve the circulation of ischemic lower limbs while also promoting neovascularization, fibroblast migration, and nerve fiber regeneration. Deletion of miR-494-3p in rats reduces the beneficial effects of BT on diabetic wounds, while hydrogels containing miR-494-3p and reduced glutathione (GSH) effectively repair them. Importantly, the ginsenoside Rg1 can upregulate miR-494-3p, and a randomized controlled trial verifies that the regimen of oral Rg1 and GSH accelerates wound healing in refractory DFU patients. These findings identify potential functional factors for tissue regeneration and suggest a potential therapy for DFUs.

Mesoporous silica-coated silver nanoparticles as ciprofloxacin/siRNA carriers for accelerated infected wound healing.

The colonization of bacterial pathogens is a major concern in wound infection and becoming a public health issue. Herein, a core-shell structured Ag@MSN (silver core embedded with mesoporous silica, AM)-based nanoplatform was elaborately fabricated to co-load ciprofloxacin (CFL) and tumor necrosis factor-α (TNF-α) small interfering RNA (siTNF-α) (AMPC@siTNF-α) for treating the bacterial-infected wound. The growth of bacterial pathogens was mostly inhibited by released silver ions (Ag+) and CFL from AMPC@siTNF-α. Meanwhile, the loaded siTNF-α was internalized by macrophage cells, which silenced the expression of TNF-α (a pro-inflammatory cytokine) in macrophage cells and accelerated the wound healing process by reducing inflammation response. In the in vivo wound model, the Escherichia coli (E. coli)-infected wound in mice almost completely disappeared after treatment with AMPC@siTNF-α, and no suppuration symptom was observed during the course of the treatment. Importantly, this nanoplatform had negligible side effects both in vitro and in vivo. Taken together, this study strongly demonstrates the promising potential of AMPC@siTNF-α as a synergistic therapeutic agent for clinical wound infections.

Acute Glycemic Variability and Functional Outcome in Patients with Acute Ischemic Stroke: A Meta-Analysis.

Dysglycemia are involved in the development of functional impairment after acute ischemic stroke (AIS). The aim of the study was to evaluate the association between acute glycemic variability and functional outcome in patients with AIS. Cohort studies were obtained by search Medline, Web of Science, Embase, Wanfang, and China National Knowledge Infrastructure databases from inception to November, 2021. A random-effect model which incorporates the intra-study heterogeneity was chosen to pool the results. Ten cohort studies including 3038 patients were included, and 1319 (43.4%) had poor functional outcome (modified Rankin Scale >2) up to three months after disease onset. Pooled results showed that higher acute GV was associated with an increased risk of poor functional outcome, as evidenced by GV evaluated by the standard deviation of blood glucose (SDBG, OR: 1.91, 95% CI: 1.38 to 2.65, I2=60%, p<0.001), the coefficient of variation of blood glucose (OR: 2.03, 95% CI: 1.15 to 3.58, I2=17%, p=0.02), the range of glucose (OR: 1.43, 95% CI: 1.11 to 1.83, I2=22%, p=0.005), and the mean amplitude of glycemic excursion (OR: 1.59, 95% CI: 1.10 to 2.31, I2=0%, p=0.01). Subgroup analyses did not support that difference in study design, treatments for AIS, mean age of the patients, duration for GV measuring, or study quality would significantly affect the association between SDBG and functional outcome after AIS. In conclusion, higher acute glycemic variability may predict poor functional outcome within 3 months after AIS.

Isolation and identification of a new strain of nervous necrosis virus from the big-belly seahorse Hippocampus abdominalis.

BACKGROUND: Betanodaviruses, members of the Nodaviridae family, are the causative agents of viral nervous necrosis in fish, resulting in great economic losses worldwide. METHODS: In this study, we isolated a virus strain named seahorse nervous necrosis virus (SHNNV) from cultured big-belly seahorses Hippocampus abdominalis in Xiamen city, Fujian Province, China. Virus isolation, PCR detection, phylogenetic analysis, qRT-PCR, fluorescence in situ hybridization and histology were used for virus identification and analysis of virus histopathology. Furthermore, an artificial infection experiment was conducted for virulence testing. RESULTS: Brain and eye tissue homogenates of diseased big-belly seahorses were inoculated onto a grouper spleen (GS) cell monolayer at 28 °C. Tissue homogenates induced obvious cytopathic effects in GS cells. PCR and sequencing analyses revealed that the virus belonged to Betanodavirus and shared high sequence identity with red-spotted grouper nervous necrosis virus isolates. qRT-PCR and fluorescence in situ hybridization revealed that SHNNV mainly attacked the brain and eye. Histopathological examination revealed that the virus led to cytoplasmic vacuolation in the brain and retinal tissues. Infection experiments confirmed that SHNNV was highly infectious, causing massive death in big-belly seahorses. CONCLUSION: A novel seahorse betanodavirus from the big-belly seahorse cultured in China was discovered. This finding will contribute to the development of efficient strategies for disease management in aquaculture.

Acute glycemic variability and mortality of patients with acute stroke: a meta-analysis.

BACKGROUND: Increased glucose fluctuation has been related to poor prognosis in patients with critical illnesses, while its prognostic role in patients with acute stroke remains unknown. The meta-analysis aimed to evaluate the association between the acute glycemic variation (GV) and mortality risk in patients with acute stroke. METHODS: Cohort studies were obtained by searching Medline, Web of Science, Embase, Wanfang and CNKI databases. A random-effect model which incorporates the intra-study heterogeneity was chosen to pool the results. RESULTS: Ten cohort studies with 1433 patients were included, and 280 (19.5%) of them died within 90 days of disease onset. Results of the meta-analyses showed that a higher acute GV was associated with an increased risk of early mortality in patients with acute stroke, as indicated by GV measured with the coefficient of variation of blood glucose (CVBG, odds ratio [OR]: 2.24, 95% CI 1.40 to 3.58, p < 0.001, I2 = 73%), the standard deviation of blood glucose (SDBG, OR: 2.31, 95% CI 1.70 to 3.13, p < 0.001, I2 = 50%), and the mean amplitude of glycemic excursion (OR: 3.57, 95% CI 1.44 to 8.85, p = 0.006, I2 = 23%). For acute GV measured with CVBG and SDBG, subgroup analyses showed consistent results in patients with acute ischemic and hemorrhagic stroke, and for studies reporting 28-day and 90-day all-cause mortality (p for subgroup analysis all > 0.05). CONCLUSIONS: Higher acute GV may be an independent risk factor of early mortality in patients with acute stroke.

Genome and gene evolution of seahorse species revealed by the chromosome-level genome of Hippocampus abdominalis.

Seahorses belong to the teleost family Syngnathidae that evolved a distinct body plan and unique male pregnancy compared to other teleosts. As a classic model for studying evolution of viviparity and sexual selection of teleosts, seahorse species still lack a publicly available high-quality reference genome. Here, we generated the genome assembly of the big-belly seahorse, Hippocampus abdominalis with long-read and Hi-C technologies. We managed to place over 99% of the total length of 444.7 Mb of assembled genome into 21 linkage groups with almost no gaps. We reconstructed a phylogenomic tree with the big-belly seahorse genome and other representative Syngnathidae and teleost species. We also reconstructed the historical population dynamics of four representative Syngnathidae species. We found the gene families that underwent expansion or contraction in the Syngnathidae ancestor were enriched for immune-related or ion transporter gene ontology terms. Many of these genes were also reported to show a dynamic expression pattern during the pregnancy stages of H. abdominalis. We also identified putative positively selected genes in the Syngnathidae ancestor or in H. abdominalis, whose mouse mutants are enriched for abnormal craniofacial and limb morphological phenotypes. Overall, our study provides an important genome resource for evolutionary and developmental studies of seahorse species, and candidate genes for future experimental works.

Prevalence and genotype distribution of human papillomavirus among 29 263 women from the Longgang community of Shenzhen.

BACKGROUND: Human papillomavirus (HPV) vaccination and screening have been demonstrated to be effective methods for controlling cervical cancer. To provide evidence for effective targeted interventions, we investigated the HPV prevalence and genotypic distribution in women of different age groups in the Longgang community of Shenzhen, China. METHODS: A total of 29 263 women were enrolled in the Longgang District Central Hospital from January 2018 to October 2020. Cervical specimens were collected at enrolment. We used a polymerase chain reaction diagnostic kit to detect the genotypes of HPV. RESULTS: The prevalence of overall, high-risk, probable high-risk (PHR) and low-risk HPV infection was 8.2% (95% confidence interval [CI] 7.9 to 8.5), 6.9% (95% CI 6.6 to 7.2), 0.9% (95% CI 0.8 to 1.1) and 1.6% (95% CI 1.5 to 1.8), respectively. High-risk HPV genotype infections accounted for 84.4% (95% CI 82.8 to 85.8) of the overall HPV infections. The five most predominant genotypes were HPV-52, HPV-16, HPV-58, HPV-53 and HPV-51. CONCLUSION: Our study found that the prevalence of HPV infection increased with age and women 55-59 y of age presented the highest HPV prevalence. As a PHR subtype, HPV-53 has a higher infection rate in women. HPV-52, HPV-16 and HPV-58 are common infection genotypes.

Krüppel-like factor 2 inhibits hepatocarcinogenesis through negative regulation of the Hedgehog pathway.

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. The most important reason for the occurrence of HCC is hepatitis C or B infection. Moreover, genetic factors play an important role in the tumorigenesis of HCC. Here, we demonstrated that Krüppel-like factor 2 (KLF2) expression was downregulated in HCC samples compared with adjacent tissues. Additionally, KLF2 was shown to inhibit the growth, migration and colony-formation ability of liver cancer cells. Further mechanistic studies revealed that KLF2 can compete with Gli1 for interaction with HDAC1 and restrains Hedgehog signal activation. Together, our results suggest that KLF2 has potential as a diagnostic biomarker and therapeutic target for the treatment of HCC.

lncRNA PVT1 identified as an independent biomarker for prognosis surveillance of solid tumors based on transcriptome data and meta-analysis.

PURPOSE: Long noncoding RNA PVT1 is dysregulated in some human tumors and has been found to increase the risk of tumor progression and poor prognosis. This study aimed to reanalyze the effect of PVT1 on tumorous prognosis. MATERIALS AND METHODS: The effect of PVT1 on metastasis and survival were analyzed by univariate logistic regression and Cox proportional hazards model for 32 types of cancer in the Cancer Genome Atlas database (TCGA), and the relationship between PVT1 level and expression of relative genes was assessed by Pearson correlation analysis. RevMan5.3 and STATA14.0 were used to estimate pooled effects of PVT1 on cancer prognosis with data from TCGA and published studies. RESULTS: In TCGA data, high PVT1 expression tended to increase the risk of TNM progression and decreased the overall survival (OS) time in most of cancers. The pooled effect of PVT1 on TNM (pooled-OR=1.46, 95% CI: 1.29-1.65) and OS (pooled HR=1.32, 95% CI: 1.22-1.43), calculated from 37 and 48 cohorts, identified that high PVT1 expression promoted the metastasis and poor prognosis of cancer. Furthermore, the pooled ORs of 2.77 (95% CI: 1.65-4.66), 4.32 (95% CI: 1.99-9.36), 1.35 (95% CI: 1.01-1.80), 1.62 (95% CI: 1.21-2.18) and 1.48 (95% CI: 1.02-2.15) provided evidence that PVT1 played a role in lymph node metastasis, depth of invasion, distant metastasis, differentiation and lymphatic invasion; while the expression of 24 identified target genes was significantly associated with PVT1 level, and high PVT1 expression dependently decreased the OS time under the influence of co-expression genes (OR=1.29, 95% CI: 1.25-1.32) in high-throughput RNA sequencing merging data. In addition, the expression of PVT1 could be upregulated by smoking, with the pooled OR being 1.09 (95% CI 1.01-1.16). CONCLUSION: PVT1 is a dependent biomarker for tumorous prognosis surveillance. However, the reference value of PVT1 needs further study.

Autologous reference types can confound the detection of somatic mutation in solid cancers.

Vast number of somatic mutations has been proved to be affected by the factors of sequencing methods, analysis pipelines and validation methods. We here showed the effect of autologous reference types on the detection of cancer-associated somatic mutations with the somatic single nucleotide variations (SNVs) and clinical data of solid tumors from the Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC). The distribution of somatic SNVs was significantly different among groups of autologous references in 6 cancers detected by whole genome sequencing (WGS) and 5 cancers detected by the random sequencing of exonic regions selected from the genome (WXS), especially in protein coding region of 5 cancers with age, gender and TNM adjusted. In addition, only 60.24% (95% CI: 49.65%-70.83%) of the somatic SNVs called from normal blood by WXS were found in those called from normal solid tissue tested by WXS / WGS, while 31.78% (95%CI: 4.14%-59.42%) of the somatic SNVs called from normal tissue adjacent to primary by WXS were found in those from normal blood tested by WXS / WGS. These findings suggested that more representative types of normal tissues should be included in detection of cancer-associated somatic mutations.

The effect of circulating miR-223 on surveillance of different cancers: a meta-analysis.

PURPOSE: Abnormal expression of miR-223 in cancerous tissue has confirmed it as an important player in tumorigenesis of cancers, such as hepatocellular carcinoma, colorectal carcinoma, osteosarcoma, gastric cancer, and chronic lymphocytic leukemia. The present meta-analysis aimed to explore the association between circulating miR-223 and prognosis of cancers. METHODS: The studies were accessed by an electronic search of multiple databases. RevMan5.3 and STATA14.0 were used to estimate the heterogeneity among studies, pooled effects, and publication bias. RESULTS: Ten studies with data of 1,002 patients with cancer were included in this meta-analysis. The risk of metastasis from stages 3 to 4 of TNM did not decrease when high versus low circulating expression of miR-223 were compared (pooled odds ratio =0.50, 95% CI: 0.24-1.03). In case of prognosis, the overall survival time was not significantly longer with high circulating miR-223 expression (pooled hazard ratio [HR] =0.64, 95% CI: 0.38-1.11) in all cancer types. However, the overall survival time of chronic lymphocytic leukemia (pooled HR =0.19, 95% CI: 0.07-0.54) increased in subgroup analysis. Moreover, the treatment-free survival of chronic lymphocytic leukemia was significantly increased with high circulating miR-223 expression (pooled HR =0.38, 95% CI: 0.23-0.64). CONCLUSION: Circulating miR-223 was not an effective biomarker in prognosis surveillance in all cancers but in chronic lymphocytic leukemia.

Circulating miR-31 as an effective biomarker for detection and prognosis of human cancer: a meta-analysis.

PURPOSE: Circulating miR-31 was found to be associated with cancers detection and prognosis. The present meta-analysis aimed to explore the effect of circulating miR-31 on cancer detection and prognosis. METHOD: The studies were accessed using multiple databases. RevMan5.3, Meta-DiSc 1.4, and STATA14.0 were used to estimate the pooled effects, heterogeneity among studies, and publication bias. RESULTS: A total of 14 studies with 1397 cancer patients and 1039 controls were included. For the 12 prognostic tests, the adjusted pooled-AUC was 0.79 (95% CI: 0.73-0.86) as the pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odd ratio (DOR) from 10 tests was 0.79 (95% CI: 0.76-0.82), 0.79 (95% CI: 0.76-0.82), 3.81 (95% CI: 2.90-5.01), 0.26 (95% CI: 0.20-0.35), and 16.81 (95% CI: 9.67-29.25), respectively. For the 5 prognosis analyses, the pooled HR (hazard ratio) of overall survival (OS) was 1.55 (95% CI 1.30-1.86) for high versus low circulating miR-31 expression. However, high expression of circulating miR-31 did not significantly increase the risk of poor differentiation (pooled OR=1.39, 95% CI: 0.56-3.47) and LNM (pooled OR=3.46, 95% CI: 0.96-12.42) in lung cancer. CONCLUSION: Circulating miR-31 is an effective biomarker and could be used as a component of miRs signature for cancer detection and prognosis surveillance.

Validation of the chinese version of the EORTC QLQ-CR29 in patients with colorectal cancer.

AIM: To assess the validity and reliability of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Colorectal Cancer 29 (EORTC QLQ-CR29) in Chinese patients with colorectal cancer (CRC). METHODS: From March 2014 to January 2015, 356 patients with CRC from four different hospitals in China were enrolled in the study, and all patients self-administered the EORTC QLQ-CR29 and the quality of life core questionnaire (EORTC QLQ-C30). Evaluation of the scores was based on the Karnofsky Performance Scale (KPS). The reliability and validity of the questionnaires were assessed by Cronbach's α coefficient, the Spearman correlation test and Wilcoxon rank sum test. RESULTS: The EORTC QLQ-CR29 showed satisfactory reliability (α > 0.7), although the urinary frequency and blood and mucus in stool dimensions had only moderate reliability (α = 0.608). The multitrait scaling analyses showed good convergent (r > 0.4) and discriminant validity. Significant differences were obtained for each item in the different KPS subgroups (KPS ≤ 80; KPS > 80). Body image and most single-item dimensions showed statistically significant differences in patients with a stoma compared with the rest of the patients. CONCLUSION: The EORTC QLQ-CR29 exhibits high validity and reliability in Chinese patients with CRC, and can therefore be recommended as a valuable tool for the assessment of quality of life in these patients.

AlncRNA HULC as an effective biomarker for surveillance of the outcome of cancer: A meta-analysis.

PURPOSE: High expression of highly upregulated in iver cancer (HULC) has been found associated with increased metastasis and poor prognosis with cancer. This meta-analysis aimed to determine the pooled effect of HULC on metastasis and prognosis of cancers. METHOD: The studies were accessed using multiple databases. RevMan5.3 and STATA14.0 were used to estimate pooled effects, the heterogeneity among studies, and publication bias for the association of HULC and overall survival (OS). RESULTS: A total of 9 studies of 966 cancer patients were included. Risk of lymph node metastasis was increased with high versus low HULC expression (pooled odds ratio [OR] = 4.83, 95% confidence interval [CI] 1.59-14.63) as was distant metastasis (pooled OR = 5.44, 95% CI 2.33-12.74). Furthermore, OS time was shortened with high HULC expression (pooled hazard ratio [HR] = 1.48, 95% CI 1.03-2.12), especially in Chinese patients (pooled HR = 2.04, 95% CI 1.55-2.68), and risk of recurrence was increased (pooled OR = 6.68, 95% CI 2.77-16.13). CONCLUSION: HULC might be a potential biomarker for therapy and prognosis surveillance in cancers.

Dietary intake and urinary level of cadmium and breast cancer risk: A meta-analysis.

Cadmium, a human carcinogenic heavy metal, has been reported to be associated with breast cancer risk; however, the results from the epidemiological studies are not always consistent. The objective of this study was to quantitatively summarize the current evidence for the relationship between cadmium exposure and breast cancer risk using meta-analysis methods. Six studies determining the dietary cadmium intake level and five studies evaluating the urinary cadmium level were identified in a systematic search of MEDLINE and PubMed databases, and the associations between these levels and breast cancer risk were analysed. The pooled estimates under the random-effects model suggested that higher urinary cadmium levels were associated with an increased risk for breast cancer (highest versus lowest quantile, pooled odds ratio [OR]=2.24, 95% confidence interval [95%CI]=1.49-3.35) and a 1µg/g creatinine increase in urinary cadmium led to a 1.02-fold increment of breast cancer (pooled OR=2.02, 95%CI=1.34-3.03); however, pooled estimates for dietary cadmium intake found no significant association between cadmium exposure and breast cancer risk (highest versus lowest quantile, pooled relative risk [RR]=1.01, 95%CI=0.89-1.15). These results suggest that cadmium exposure may lead to an increased risk of breast cancer, and urinary cadmium levels can serve as a reliable biomarker for long-term cadmium exposure and may predict the breast cancer risk.

PDGFR-ß-activated ACK1-AKT signaling promotes glioma tumorigenesis.

Aberrant PDGF-PDGFR signaling and its effects on downstream effectors have been implicated in glioma development. A crucial AKT regulator, ACK1 (TNK2) has been shown to be a downstream mediator of PDGF signaling; however, the exact underlying mechanisms in gliomas remain elusive. Here, we report that in glioma cells, PDGFR-ß activation enhanced the interaction between ACK1 and AKT, resulting in AKT activation. PDGF treatment consistently promoted the formation of complexes containing PDGFR-ß and ACK1. Mutational analysis suggested that Y635 of ACK1 is a PDGFR-ß phosphorylation site and that the ACK1 Y635F mutant abrogated the sequential activation of AKT. Moreover, PDK1 interacted with ACK1 during PDGF stimulation, which is required for the binding of ACK1 to PDGFR-ß. Further mutational analysis showed that T325 of ACK1 was crucial for the ACK1 and PDK1 interaction. ACK1 Y635F or T325A mutants abolished PDGFR-ß-induced AKT activation, the subsequent nuclear translocation of ß-catenin and the expression of cyclin D1. Glioma cell cycle progression, proliferation and tumorigenesis were accordingly blocked by ACK1 Y635F or T325A. In glioblastoma multiforme samples from 51 patients, increased ACK1 tyrosine phosphorylation correlated with upregulated PDGFR-ß activity and AKT activation. Taken together, our data demonstrate that ACK1 plays a pivotal role in PDGF-PDGFR-induced AKT signaling in glioma tumorigenesis. This knowledge contributes to our understanding of glioma progression and may facilitate the identification of novel therapeutic targets for future glioma treatment.

Asparagus polysaccharide and gum with hepatic artery embolization induces tumor growth and inhibits angiogenesis in an orthotopic hepatocellular carcinoma model.

Liver cancer is one of leading digestive malignancies with high morbidity and mortality. There is an urgent need for the development of novel therapies for this deadly disease. It has been proven that asparagus polysaccharide, one of the most active derivates from the traditional medicine asparagus, possesses notable antitumor properties. However, little is known about the efficacy of asparagus polysaccharide as an adjuvant for liver cancer chemotherapy. Herein, we reported that asparagus polysaccharide and its embolic agent form, asparagus gum, significantly inhibited liver tumor growth with transcatheter arterial chemoembolization (TACE) therapy in an orthotopic hepatocellular carcinoma (HCC) tumor model, while significantly inhibiting angiogenesis and promoting tumor cell apoptosis. Moreover, asparagine gelatinous possessed immunomodulatory functions and showed little toxicity to the host. These results highlight the chemotherapeutic potential of asparagus polysaccharide and warrant a future focus on development as novel chemotherapeutic agent for liver cancer TACE therapy.