Molecular design, construction and analgesic mechanism insights into the novel transdermal fusion peptide ANTP-BgNPB.

Toad venom, a traditional Chinese medicine, exhibits remarkable medicinal properties of significant therapeutic value. The peptides present within toad venom possess a wide range of biological functions, yet the neuropeptide B (NPB) and it modification requires further exploration to comprehensively understand its mechanisms of action and potential applications. In this study, a fusion peptide, ANTP-BgNPB, was designed to possess better analgesic properties through the transdermal modification of BgNPB. After optimizing the conditions, the expression of ANTP-BgNPB was successfully induced. The molecular dynamics simulations suggested that the modified protein exhibited improved stability and receptor binding affinity compared to its unmodified form. The analysis of the active site of ANTP-BgNPB and the verification of mutants revealed that GLN3, SER38, and ARG42 were crucial for the protein's recognition and binding with G protein-coupled receptor 7 (GPR7). Moreover, experiments conducted on mice using the hot plate and acetic acid twist body models demonstrated that ANTP-BgNPB was effective in transdermal analgesia. These findings represent significant progress in the development of transdermal delivery medications and could have a significant impact on pain management.

[Analysis of a case of Multiple pterygium syndrome due to a novel variant of CHRNG gene].

OBJECTIVE: To explore the clinical characteristics and genetic etiology of a child with multiple pterygium syndrome (MPS). METHODS: A child with MPS who was treated at the Orthopedics Department of Guangzhou Women and Children's Medical Center Affiliated to Guangzhou Medical University on August 19, 2020 was selected as the study subject. Clinical data of the child was collected. Peripheral blood samples of the child and her parents were also collected. Whole exome sequencing (WES) was carried out for the child. Candidate variant was validated by Sanger sequencing of her parents and bioinformatic analysis. RESULTS: The child, an 11-year-old female, had a complain of "scoliosis found 8 years before and aggravated with unequal shoulder height for 1 year". WES results revealed that she has carried a homozygous c.55+1G>C splice variant of the CHRNG gene, for which both of her parents were heterozygous carriers. By bioinformatic analysis, the c.55+1G>C variant has not been recorded by the CNKI, Wanfang data knowledge service platform and HGMG databases. Analysis with Multain online software suggested that the amino acid encoded by this site is highly conserved among various species. As predicted with the CRYP-SKIP online software, the probability of activation and skipping of the potential splice site in exon 1 caused by this variant is 0.30 and 0.70, respectively. The child was diagnosed with MPS. CONCLUSION: The CHRNG gene c.55+1G>C variant probably underlay the MPS in this patient.

Iron overload facilitates neonatal hypoxic-ischemic brain damage via SLC7A11-mediated ferroptosis.

Oxidative damage and cell death are involved in the pathogenesis of hypoxic-ischemic brain damage (HIBD). Ferroptosis is a newly identified mode of cell death that results from the oxidative damage induced by excessive iron. In HIBD, iron accumulates in brain tissues due to the massive destruction of red blood cells and increased permeability of the blood brain barrier vasculature, which can trigger ferroptosis. Ferroptosis is implicated in various diseases involving neuronal injury; however, the roles of iron and ferroptosis in HIBD have not been identified. In the present study, we investigated the role of iron overload in neuronal ferroptosis both in HIBD rat models and in oxygen- and glucose-deprived (OGD) SH-SY5Y cells. We observed that iron deposition in the cerebral cortex was significantly increased in HIBD rats. Features of ferroptosis such as shrunken mitochondria, increased MDA (malondialdehyde) levels, and reduced solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) expression were observed in the cerebral cortex of HIBD rats. Administration of an iron chelator in HIBD rats upregulated SLC7A11 expression and alleviated neuronal ferroptosis in cerebral cortex tissue. Additionally, overexpression of SLC7A11 in SH-SY5Y cells increased cell viability and attenuated OGD-induced ferroptosis. Our results demonstrate that iron overload induces neuronal ferroptosis by inhibiting SLC7A11 expression in HIBD. Inhibition of neuronal ferroptosis may be a promising strategy to alleviate brain damage in HIBD.

Triptonide inhibits growth and metastasis in HCC by suppressing EGFR/PI3K/AKT signaling.

Liver cancer represents one of the deadliest cancers, with a rising incidence worldwide. Triptonide is found in the traditional Chinese medicinal plant Tripterygium wilfordii Hook. This study aimed to examine the anticancer properties of triptonide in human hepatocellular carcinoma (HCC). HCC cells were administered with triptonide at various levels, and CCK-8 and colony formation assays were carried out for detecting HCC cell proliferation. Then, cell apoptosis and cell cycle distribution were evaluated by flow cytometry. Tumor growth was monitored noninvasively by ultrasound imaging. Cell migration and invasion were quantitated by wound healing and Transwell assays. A metastasis model was established via tail vein injection of HCC cells in nude mice. Immunoblot was performed to quantitate the expression of proteins involved in the EGFR/PI3K/AKT signaling and its downstream effectors. Triptonide repressed cell proliferation and induced cell cycle arrest and apoptosis in cultured HCC cells, and suppressed tumor growth in vivo. In addition, triptonide inhibited EMT, migration and invasion in cultured HCC cells, and lung metastasis in nude mice. Mechanistically, triptonide acted by inhibiting the EGFR/PI3K/AKT signaling and regulated its downstream effectors, e.g., the cell cycle-associated protein cyclin D1, the apoptosis-related protein Bcl-2, the EMT marker E-cadherin, and the invasion-related protein MMP-9. Triptonide suppresses proliferation, EMT, migration and invasion, and promotes apoptosis and cell cycle arrest by repressing the EGFR/PI3K/AKT signaling. Therefore, triptonide might be considered for liver cancer treatment.

Radiographic features of congenital thumb duplication type C2 of Wu et al. classification: new subtypes and surgical strategies.

Objective: This study aimed (i) to evaluate the radiographic characteristics of patients with congenital thumb duplication (CTD) type C2 according to the classification of Wu et al., (ii) to describe the various subtypes of type C2 CTD, and (iii) to propose a classification system that allows the identification of different surgical strategies based on the radiographic anatomy of this specific subtype of duplication. Methods: We retrospectively reviewed 92 patients (92 thumbs) with type C2 CTD according to the Wu et al. classification in our institution between August 2015 and April 2021. All CTDs were classified according to the interphalangeal joint alignment of the main thumb at the posteroanterior radiograph of the thumb before operation: type I (no deviation), type II (ulnar deviation), and type III (radial deviation). Results: All CTDs (n = 92) could be classified according to the proposed classification system: 76 (82.6%) were type I, 10 (10.9%) were type II, and six were type III (6.5%). According to the Kim system of subtype classification, there were 55 (59.8%) type 1, 24 (26.1%) type 2, and 13 (14.1%) type 3 cases. Conclusions: The suggested classification completes the Wu et al. system and has the potential to guide surgical treatment in children with type C2 CTD. Level of evidence: III.

CCL2-targeted ginkgolic acid exerts anti-glioblastoma effects by inhibiting the JAK3-STAT1/PI3K-AKT signaling pathway.

AIMS: Glioblastoma (GBM) with aggressive nature and poor prognosis has become the most common intracranial tumor. Most clinical chemotherapeutic drugs fail to achieve the anticipated therapeutic outcome. This study identified the anti-GBM effects of ginkgolic acids (GAs) and elucidated the potential molecular mechanisms, exploiting the significant antitumor effects of GAs, which are widely present in the outer bark of Ginkgo biloba. MATERIALS AND METHODS: Two GBM cell lines, U251 and T98G, were selected for in vitro experiments to evaluate the antitumor effects of GA. Cell viability and proliferation were examined by MTT and colony formation assay. The effect of GA on apoptosis and the cell cycle was examined by flow cytometry. Scratch and Transwell assays reflected the migration and invasion ability. The molecular mechanisms were explored by using immunoblot analysis, RNA sequencing and bioinformatics. In the nude mouse transplantation tumor model, preclinical treatment effects were assessed by ultrasound and MRI. KEY FINDINGS: The present study showed that GA inhibited the proliferation, migration, invasion, stemness, epithelial-to-mesenchymal transition (EMT) of GBM cells and induced apoptosis by inhibiting CCL2, affecting the JAK-STAT and PI3K-AKT signaling pathways, and inhibiting the EMT regulators Snail and Slug. Finally, GA showed significant control of tumors in a GBM xenograft model. SIGNIFICANCE: GA inhibits the progression of GBM cells by targeting CCL2, affecting the JAK-STAT and PI3K-AKT signaling pathways, and inhibiting the EMT regulators Snail and Slug. The outstanding antitumor properties of GA provide a novel strategy for the GBM therapy.

Multifunctional Drug-Loaded Phase-Change Nanoparticles Inhibit the Epithelial-Mesenchymal Transition of Hepatocellular Carcinoma by Affecting the Activity of Activated Hepatic Stellate Cells.

Objectives. Preparation of a multifunctional drug-loaded phase-change nanoparticle (NP), pirfenidone perfluoropentane liposome NPs (PPL NPs), and combined with low-intensity focused ultrasound (LIFU) to influence epithelial mesenchymal transition (EMT) for hepatocellular carcinoma (HCC) by inhibiting the activity of activated Hepatic Stellate Cells (a-HSCs). Methods. PPL NPs were prepared by the thin film dispersion method. The appearance, particle size, zeta potential, encapsulation efficiency, drug loading rate, drug release in vitro, and stability of PPL NPs were tested. The role of a-HSCs in HCC metastasis was studied by CCK-8, colony formation assay, apoptosis, cellular uptake assay, wound healing assay, and Transwell assay. Western blot was used to detect the related protein expression levels. In vitro and vivo, the acoustic droplet vaporization (ADV) of PPL NPs was tested at different times and LIFU intensities. Biosafety of the PPL NPs was assessed by measuring nude mouse body weight and hematoxylin and eosin (H&E) staining. Results. The results showed that the PPL NPs had good biosafety, with an average particle size of 346.6 ± 62.21 nm and an average zeta potential of -15.23 mV. When the LIFU power is 2.4 W/cm2, it can improve the permeability of cells, further promote the uptake of drugs by cells, and improve the toxicity of drugs. In vitro experiments showed that PPL NPs could inhibit the proliferation of a-HSCs cells, thereby affecting the metastasis of HCC, and were related to the TGFß-Smad2/3-Snail signaling pathway. Both in vivo and in vitro PPL NPs enhanced ultrasound imaging by LIFU-triggered ADV. Conclusion. The PPL NPs designed and prepared in this study combined with LIFU irradiation could significantly alter the EMT of HCC by inhibiting LX2. Clinically, PPL NPs will also be considered a promising contrast agent due to their ultrasound imaging capabilities.

Epidemiological characteristics and distribution of congenital thumb duplication in south China: An analysis of 2,300 thumbs in 2,108 children.

Objective: The objective of this study was to evaluate epidemiological and anatomical characteristics of children with congenital thumb duplication (CTD). Methods: We retrospectively reviewed 2108 children with CTD. Data regarding sex, age at the surgery, laterality, uni- or bilateral involvement, and dominant side were retrieved from the medical charts. Plain radiographs were used to classify all CTD according to Wassel-Flatt, Rotterdam and Chung classification systems and to evaluate the patho-anatomy of the duplication as well as the presence of associated anomaly. Results: A total of 796 girls and 1,312 boys with CTD (n = 2,300 thumbs) met the inclusion criteria. The male to female and unilateral to bilateral ratio were 1.6:1 and 10:1, respectively. Associated anomaly was found in 238/2108 patients (11.3%), and the middle phalanx deformity of the 5th finger was the most common one. A dominant thumb, larger and more developed, was on the ulnar side in 2270/2,300 cases (98.7%).According to the Wassel-Flatt classification, type IV (40.2%) was the most common deformity and the extra thumb was connected to the main thumb by a joint in most cases (437/780); overall, 15.7% of thumbs (n = 360) did not fit the Wassel-Flatt classification.According to the Rotterdam classification, type IV (51.3%) was the most common form; in most cases (363/1180) the thumb was hypoplastic or floating. Overall, 3/2,300 thumbs (0.1%) could not be classified according to Rotterdam classification.According to the Chung classification, type A was the most common subtype (44.1%); in most cases (716/1015) the duplication was at the level of the metacarpal bone. Overall, 2/2,300 thumbs (0.1%) did not fit the Chung classification. Conclusions: In patients from southern China, CTD shows male and right-sided predominance with ulnar-dominant thumb. Abnormalities of the middle phalanx of the 5th finger are more frequent in patients with associated anomaly. The development of a simple and comprehensive classification system is needed to guide treatment and to adequately assess the epidemiological characteristics of patients with CTD in order to facilitate comparison between different patients' populations. Level of evidence: III.

Chelerythrine inhibits the progression of glioblastoma by suppressing the TGFB1-ERK1/2/Smad2/3-Snail/ZEB1 signaling pathway.

AIMS: Glioblastoma (GBM) is the most common and aggressive intracranial tumor with poor prognosis. A large majority of clinical chemotherapeutic agents cannot achieve the desired therapeutic effect. Chelerythrine (CHE), a natural component with multitudinous pharmacological functions, has been proven to have outstanding antitumor effects in addition to antibacterial, anti-inflammatory, and hypotensive effects. However, the anti-GBM effect of CHE has not been reported to date. The purpose of this paper is to observe the anti-GBM effect of CHE and further explore the related mechanism. MATERIALS AND METHODS: GBM cell lines (U251 and T98G) and BALB/c nude mice were used in the experiments. Methyl thiazolyl tetrazolium (MTT) and clone formation assays were applied to detect the viability, proliferation and stemness of GBM cells. Flow cytometry was utilized to identify the effect of CHE on GBM apoptosis. Scratch and Transwell experiments reflected the migration and invasion of cells. In vivo, xenograft tumors were implanted subcutaneously in nude mice. The progression of tumors was assessed by ultrasound and magnetic resonance imaging. Finally, western blot, bioinformatics, and immunohistochemistry experiments were used to explore the molecular mechanisms in depth. KEY FINDINGS: In vitro tests showed that CHE inhibited the proliferation, stemness, migration, and invasion of GBM cells and induced apoptosis. In vitro, CHE was observed to restrain the progression of xenograft tumors. We eventually proved that the cytotoxicity of CHE was relevant to the TGFB1-ERK1/2/Smad2/3-Snail/ZEB1 signaling pathway. SIGNIFICANCE: CHE inhibited GBM progression by inhibiting the TGFB1-ERK1/2/Smad2/3-Snail/ZEB1 signaling pathway and is a potential chemotherapeutic drug for GBM.

Trimodal prehabilitation for older surgical patients: a systematic review and meta-analysis.

OBJECTIVE: To determine the postoperative effectiveness of trimodal prehabilitation in older surgical patients. METHODS: We searched Medline, PubMed, Embase, the Cochrane Library, Web of Science, and ClinicalTrials.gov for observational cohort studies and randomised controlled trials (RCTs) of older surgical patients who underwent trimodal prehabilitation. We performed a meta-analysis to estimate the pooled risk ratio (RR) for dichotomous data and weighted mean difference (MD) for continuous data. Primary outcomes were postoperative mortality and complications, and the secondary outcomes were the 6-min walk test (6MWT) at 4 and 8 weeks after surgery, readmission, and length of hospital stay (LOS). This systematic review and meta-analysis was registered with PROSPERO (registration number: CRD42020201347). RESULTS: We included 10 studies (four RCTs and six cohort studies) comprising 1553 older surgical patients (trimodal prehabilitation group, n = 581; control group, n = 972). There were no significant differences in postoperative mortality (RR 1.32; 95% confidence interval [CI] 0.52-3.35) and postoperative complications (RR 0.91; 95% CI 0.76-1.09). Prehabilitation did not reduce readmission (RR 0.92; 95% CI 0.61-1.38) and LOS (MD 0.10; 95% CI - 0.34-0.53). In a sub-analysis, trimodal prehabilitation did not significantly improve postoperative mortality, postoperative complications, readmission rates, or LOS when compared with standard care. However, trimodal prehabilitation significantly improved the 6MWT at 4 weeks after surgery (MD 37.49; 95% CI 5.81-69.18). CONCLUSIONS: Our systematic review and meta-analysis demonstrated that trimodal prehabilitation did not reduce postoperative mortality and complications significantly but improved postoperative functional status in older surgical patients. Therefore, more high-quality trials are required.

Autophagy is involved in neurofibromatosis type I gene-modulated osteogenic differentiation in human bone mesenchymal stem cells.

Neurofibromatosis type I (NF1) is an autosomal dominant genetic disease that is caused by mutations in the NF1 gene. Various studies have previously demonstrated that the mTOR complex 1 signaling pathway is essential for the NF1-modulated osteogenic differentiation of bone mesenchymal stem cells (BMSCs). Additionally, the mTOR signaling pathway plays a notable role in autophagy. The present study hypothesized that NF1 could modulate the osteogenic differentiation of BMSCs by regulating the autophagic activities of BMSCs. In the present study, human BMSCs were cultured in an osteogenic induction medium. The expression of the NF1 gene was either knocked down or overexpressed by transfection with a specific small interfering RNA (siRNA) targeting NF1 or the pcDNA3.0 NF1-overexpression plasmid, respectively. Autophagic activities of BMSCs (Beclin-1, P62, LC3B I, and LC3B II) were determined using western blotting, electron microscopy, acridine orange (AO) staining and autophagic flux/lysosomal detection by fluorescence microscopy. In addition, the autophagy activator rapamycin (RAPA) and inhibitor 3-methyladenine (3-MA) were used to investigate the effects of autophagy on NF1-modulated osteogenic differentiation in BMSCs. Inhibiting NF1 with siRNA significantly decreased the expression levels of autophagy markers Beclin-1 and LC3B-II, in addition to osteogenic differentiation markers osterix, runt-related transcription factor 2 and alkaline phosphatase. By contrast, overexpressing NF1 with pcDNA3.0 significantly increased their levels. Transmission electron microscopy, AO staining and autophagic flux/lysosomal detection assays revealed that the extent of autophagosome formation was significantly decreased in the NF1-siRNA group but significantly increased in the NF1-pcDNA3.0 group when compared with the NC-siRNA and pcDNA3.0 groups, respectively. In addition, the activity of the PI3K/AKT/mTOR pathway [phosphorylated (p)-PI3K, p-AKT, p-mTOR and p-p70S6 kinase] was significantly upregulated in the NF1-siRNA group compared with the NC-siRNA group, and significantly inhibited in the NF1-pcDNA3.0 group, compared with the pcDNA3.0 group. The knockdown effects of NF1-siRNA on the autophagy and osteogenic differentiation of BMSCs were reversed by the autophagy activator RAPA, while the overexpression effects of NF1-pcDNA3.0 on the autophagy and osteogenic differentiation of BMSCs were reversed by the autophagy inhibitor 3-MA. In conclusion, results from the present study suggest at the involvement of autophagy in the NF1-modulated osteogenic differentiation of BMSCs. Furthermore, NF1 may partially regulate the autophagic activity of BMSCs through the PI3K/AKT/mTOR signaling pathway.

PFP@PLGA/Cu12Sb4S13-mediated PTT ablates hepatocellular carcinoma by inhibiting the RAS/MAPK/MT-CO1 signaling pathway.

Hepatocellular carcinoma (HCC) is one of the most malignant tumors in the world, and patients with HCC face a poor prognosis. The conventional therapeutic strategies for HCC have undergone a challenge-riddled evolution owing to side effects and unsatisfactory efficacy. Here, aiming to provide a new method of HCC elimination, we formulated a novel multifunctional nanocapsule (PFP@PLGA/Cu12Sb4S13, PPCu) with applications in contrast-enhanced ultrasound imaging (CEUS) and photothermal therapy (PTT). These PPCu were successfully constructed with an average diameter of 346 nm (polydispersity index, PDI = 0.276). The reinforced contrast ratio of these PPCu was determined by CEUS, revealing their promising applications in image-guided monitoring of HCC treatment. Furthermore, the excellent photoabsorption and biocompatibility indicated by organ H&E staining indicated that PPCu meet quality expectations for use as photothermal transduction agent (PTA). PPCu treatment at 50 °C and higher temperatures efficiently repressed the proliferation, induced the apoptosis and decreased the motility of HCC cells. These effects might have been results of RAS/MAPK/MT-CO1 signaling pathway inhibition. In summary, PPCu were constructed to integrate CEUS and PTT successfully into therapy, which can lead to HCC elimination through RAS/MAPK/MT-CO1 signaling pathway repression.

Does the vascular development of the femoral head correlate with the incidence of avascular necrosis of the proximal femoral epiphysis in children with developmental dysplasia of the hip treated by closed reduction?

PURPOSE: The purpose of this study was to identify the correlation between the vascular development of the femoral head and avascular necrosis (AVN) in patients with developmental dysplasia of the hip (DDH) treated by closed reduction (CR). METHODS: We retrospectively reviewed 78 patients with DDH treated by CR (83 hips). The vascular maturity, number of vessels and perfusion changes of the femoral head were assessed on perfusion MRI (pMRI) before and after CR. RESULTS: The number of vessels (mean 4.2 sd 1.4) of the femoral head and the ratio (36.1%) of mature vessels (type III) on the dislocated side were significantly less than those at contralateral side (mean 6.0 sd 1.2; 82.2%) (p < 0.001). Of the included 83 hips, 39 hips (61.5%) showed decreased perfusion of the femoral head, including partial decreased (Class B, 47.0%) and global decreased (Class C, 14.5%), at the dislocated side, which was significantly more than those at contralateral side (0.0%) (p < 0.001). In total, 32 out of 83 hips (38.5%) developed AVN. The rate of AVN with Class A (18.8%) which perfusion of the femoral head was normal (unchanged or enhanced) was significantly less than those with Class C (66.7%) (p = 0.006). CONCLUSION: The vascular development and perfusion changes of the femoral head on the dislocated side are significantly worse than those at contralateral side. Immature vascularity of the femoral head before CR and poor perfusion of the femoral head after CR may be risk factors for AVN in patients with DDH. LEVEL OF EVIDENCE: III.

A novel mutation in ext2 caused hereditary multiple exostoses through reducing the synthesis of heparan sulfate.

Hereditary multiple exostoses (HME) is a rare skeletal disorder characterized by the formation of multiple benign cartilage-capped tumors, usually in the metaphyseal region of the long bones. Over 70% of HME cases arise from monoallelic mutations in either of the two genes encoding the heparan sulfate (HS) synthesis enzymes, ext1 and ext2. To identify more HME-associated mutations, genomic DNA from members of five independent consanguineous families with HME was sequenced with whole exome sequencing (WES). A novel heterozygous splice site mutation (c.1173+2T>A) in ext2 was detected in all three affected members of family V. Further study showed that the novel mutation caused exon 7 of ext2 mRNA to be skipped during splicing and caused a frameshift after the codon for Arg360, which results in the appearance of new 43 codons, followed by a termination codon. Although the resulting truncated protein was still localized to the Golgi, similar to the full-length EXT2, its HS synthesis activity decreased by 40%. In this study, a novel splice site mutation in ext2 was identified and suggested to be a pathogenic mutation of HME, which may expand the genetic etiology spectrum of HME and may be helpful for clinical genetic counseling and prenatal diagnosis.

Homoharringtonine inhibits the progression of hepatocellular carcinoma by suppressing the PI3K/AKT/GSK3ß/Slug signaling pathway.

Homoharringtonine (HHT), was first isolated from the bark of Cephalotaxus harringtonia (Knight ex J. Forbes) K. Koch and Cephalotaxus fortunei Hook trees. The bark extract is used to treat leukemia and in recent years has also been used in traditional Chinese medicine (TCM) to treat solid tumors. However, the inhibitory mechanism of HHT in the progression of hepatocellular carcinoma (HCC) is rarely studied. We aimed to evaluate the antitumor efficacy of HHT on HCC in vitro and in vivo and elucidate the underlying molecular mechanism(s). HCC cell lines, including HCCLM3, HepG2, and Huh7, were used to evaluate the antitumor efficacy of HHT in vitro. Cytotoxicity and proliferative ability were evaluated by MTT and colony formation assays. Cell cycle progression and apoptosis in HHT-treated HCC cells were evaluated by flow cytometry. To determine the migration and invasion abilities of HCC cells, wound-healing and Transwell assays were used. Finally, western blot analysis was used to reveal the proteins involved. We also established a xenograft nude mouse model for in vivo assessments of the preclinical efficacy of HHT, mainly using hematoxylin and eosin staining, immunohistochemistry, ultrasound imaging (USI), and magnetic resonance imaging (MRI). HHT suppressed the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of HCC cells, and induced cell cycle arrest at the G2 phase and apoptosis. In the HCC xenograft model, HHT showed an obvious tumor-suppressive effect. Surprisingly, Slug expression was also decreased by HHT via the PI3K/AKT/GSK3ß signaling pathway at least partially suppressed the growth of HCC via the PI3K/AKT/GSK3ß/Slug signaling pathway.

Influence of Malnutrition According to the GLIM Criteria on the Clinical Outcomes of Hospitalized Patients With Cancer.

Background: Malnutrition is prevalent among patients with cancer. The Global Leadership Initiative on Malnutrition (GLIM) released new universal criteria for diagnosing malnutrition in 2019. The objectives of this study were to assess the prevalence of malnutrition in patients with cancer using the GLIM criteria, explore the correlation between the GLIM criteria, and clinical outcomes, and compare the GLIM criteria with subjective global assessment (SGA). Methods: This retrospective analysis was conducted on 2,388 patients with cancer enrolled in a multicenter study. Nutritional risk was screened using the Nutritional Risk Screening-2002, and the nutritional status was assessed using SGA and GLIM criteria. Chi-square analysis and Wilcoxon rank sum test, stratified by age 65 years, were used to evaluate the effect of GLIM-defined malnutrition on clinical outcomes. Logistic regression analysis was used to analyze the nutritional status and complications, and the interrater reliability was measured using a kappa test. Results: The prevalence of malnutrition defined by the GLIM criteria was 38.9% (929/2,388). GLIM-defined malnutrition was significantly associated with in-hospital mortality (P = 0.001) and length of hospital stays (P = 0.001). Multivariate logistic regression analysis showed GLIM-defined malnutrition significantly increased complications (odds ratio [OR] 1.716, 95% CI 1.227-2.400, P = 0.002). The GLIM criteria had a "moderate agreement" (kappa = 0.426) compared with the SGA. Conclusions: The prevalence of malnutrition in hospitalized patients with cancer is high, and malnourishment in patients with cancer is associated with poorer clinical outcomes. The use of the GLIM criteria in assessing the nutritional status of inpatients with cancer is recommended and can be used as the basis for nutritional interventions.

Polydatin executes anticancer effects against glioblastoma multiforme by inhibiting the EGFR-AKT/ERK1/2/STAT3-SOX2/Snail signaling pathway.

AIMS: Glioblastoma multiforme (GBM) is characterized by aggressive infiltration and terrible lethality. The overwhelming majority of chemotherapeutic drugs fail to exhibit the desired treatment effects. Polydatin (PD), which was initially extracted from Polygonum cuspidatum, is distinguished for its outstanding cardioprotective, hepatoprotective, and renal protective effects, as well as significant anticancer activities. However, the anti-GBM effect of PD is unclear. MATERIALS AND METHODS: Cell proliferation and apoptosis after PD intervention were estimated using MTT, colony formation and flow cytometry assays in vitro, while wound-healing and Transwell assays were applied to assess cell migration and invasion. In addition, the anti-GBM effects of PD in vivo were detected in the subcutaneous tumor model of nude mice. Moreover, Western blot, immunofluorescence and immunohistochemical staining assays were employed to elaborate the relevant molecular mechanisms. KEY FINDINGS: The present study demonstrated that PD repressed cell proliferation, migration, invasion and stemness and promoted apoptosis in GBM cells. Moreover, by correlating the molecular characteristics of cancer cells with different sensitivities to PD and employing diverse analytical methods, we ultimately verified that the cytotoxicity of PD was related to EGFR-AKT/ERK1/2/STAT3-SOX2/Snail signaling pathway inhibition, in which multiple components were vital therapeutic targets of GBM. SIGNIFICANCE: This work demonstrated that PD could inhibit proliferation, migration, invasion and stemness and induce apoptosis by restraining multiple components of the EGFR-AKT/ERK1/2/STAT3-SOX2/Snail signaling pathway in GBM cells.

Whole­exome sequencing identifies a novel mutation of SLC20A2 (c.C1849T) as a possible cause of hereditary multiple exostoses in a Chinese family.

Although the main causative genes for hereditary multiple exostoses (HME) are exostosin (EXT)­1 and EXT­2, there are numerous patients with HME without EXT­1 and EXT­2 mutations. The present study aimed to identify novel candidate genes for the development of HME in patients without EXT­1 and EXT­2 mutations. Whole­exome sequencing was performed in a Chinese family with HME and without EXT­1 and EXT­2 mutations, followed by a combined bioinformatics pipeline including annotation and filtering processes to identify candidate variants. Candidate variants were then validated using Sanger sequencing. A total of 1,830 original variants were revealed to be heterozygous mutations in three patients with HME which were not present in healthy controls. Two mutations [c.C1849T in solute carrier family 20 member 2 (SLC20A2) and c.G506A in leucine zipper and EF­hand containing transmembrane protein 1 (LETM1)] were identified as possible causative variants for HME through a bioinformatics filtering procedure and harmful prediction. Sanger sequencing results confirmed these two mutations in all patients with HME. A mutation in SLC20A2 (c.C1849T) led to a change in an amino acid (p.R617C), which may be involved in the development of HME by inducing metabolic disorders of phosphate and abnormal proliferation and differentiation in chondrocytes. In conclusion, the present study revealed two mutations [SLC20A2 (c.C1849T) and LETM1 (c.G506A) in a Chinese family with HME. The mutation in SLC20A2 (c.C1849T)] was more likely to be involved in the development of HME.

Does the size of the femoral head correlate with the incidence of avascular necrosis of the proximal femoral epiphysis in children with developmental dysplasia of the hip treated by closed reduction?

PURPOSE: The purpose of this study was to identify if any correlation between size of the proximal femoral epiphysis and avascular necrosis (AVN) exists. METHODS: We retrospectively reviewed 111 patients with developmental dysplasia of the hip treated by closed reduction (124 hips). The diameter and height of both femoral head and ossific nucleus were assessed on preoperative MRI. RESULTS: The diameter and the height of the femoral head as well as of the ossific nucleus of the contralateral side were significantly greater than the dislocated side. AVN occurred in 21 (16.9%) out of 124 hips. The rate of AVN gradually decreased with age: 30.0% at six to 12 months, 18.2% at 12 to 18 months and 3.7% at 18 to 24 months. Spearman correlation analysis showed that age is negatively correlated with the incidence of AVN (r = -0.274; p = 0.002) and the diameter of the femoral head has a significantly negative association with the incidence of AVN (r = -0.287; p = 0.001). No significant association was observed between the incidence of AVN and height of the femoral head or size of the ossific nucleus. Hips with AVN were significantly smaller than hips without AVN. CONCLUSIONS: The size of both the femoral head and the ossific nucleus increase with age although the dislocated femoral head is smaller compared with the contralateral side. The diameter of the femoral head and not the size of the ossific nucleus negatively correlate with the risk of AVN, with a bigger femoral head showing lower risk of AVN. LEVEL OF EVIDENCE: III.