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Purpose: Both vitamin C and D deficiencies are extremely common in clinical practice, especially in elderly population. Unfortunately, the role of vitamin C deficiency in osteoporosis related consequences is often neglected. The aim of the present study is to analyse if combined vitamin C and D deficiency would have an association with bone mineral density (BMD) and osteoporotic vertebral fracture (OVF). Methods: Ninety-nine post-menopausal female patients admitted in the department of spine surgery of third affiliated hospital of Sun Yat-sen University were enrolled in the study. The participants were divided into four groups; vitamin D deficiency alone (comparator group), vitamin C deficiency alone and combined vitamin C and D deficiency as experimental group. The levels of vitamin C, vitamin D, calcium, phosphorous, BMD and condition of OVF were analysed. Results: There were statistically significant differences between the groups in terms of vitamin C and D levels. In terms of lumbar BMD, significant differences were observed between vitamin D deficiency alone and combined vitamin C and D deficiency. Only the combined vitamin C and D deficiency had a significant negative association with lumbar BMD and T-score. Similarly, combined vitamin C and D deficiency had a significant positive association with lumbar osteoporosis. None of the groups had any significant association with OVF. Combined vitamin C and D deficiency was found to be significantly associated with lower lumbar BMD and osteoporosis. Conclusion: Combined vitamin C and D deficiency results in lower bone mineral density and higher risk of osteoporosis. We believe that existence of deficiencies of both vitamins could have a synergistic effect. Therefore, we recommend that vitamin C and D should be routinely measured in clinical practice. [ABSTRACT FROM AUTHOR]

Background: This study employs systematic review and meta-analysis to explore the incidence and characteristics of spinal cord injury (SCI) between 2000 and 2021, aiming to provide the most recent and comprehensive data support for the prevention, diagnosis, treatment, and care of SCI. Methods: Systematic searches were conducted on epidemiological studies of SCI published between January 1, 2000, and March 29, 2024. Meta-analysis, subgroup analysis, meta-regression, publication bias detection, and literature quality assessment were extensively utilized. Results: The pooled results from 229 studies indicated that the overall incidence rate of SCI was 23.77 (95% CI, 21.50–26.15) per million people, with traumatic spinal cord injuries (TSCI) at a rate of 26.48 (95% CI, 24.15–28.93) per million people, and non-traumatic spinal cord injuries (NTSCI) at a rate of 17.93 (95% CI, 13.30-23.26) per million people. The incidence of TSCI exhibited a marked age-related increase and was significantly higher in community settings compared to hospital and database sources. Males experienced TSCI at a rate 3.2 times higher than females. Between 2000 and 2021, the incidence of TSCI remained consistently high, between 20 and 45 per million people, whereas NTSCI incidence has seen a steady rise since 2007, stabilizing at a high rate of 25–35 per million people. Additionally, the incidence of TSCI in developing countries was notably higher than that in developed countries. There were significant differences in the causes of injury, severity, injury segments, gender, and age distribution among the TSCI and NTSCI populations, but the proportion of male patients was much higher than that of female patients. Moreover, study quality, country type, and SCI type contributed to the heterogeneity in the meta-analysis. Conclusions: The incidence rates of different types of SCI remain high, and the demographic distribution of SCI patients is changing, indicating a serious disease burden on healthcare systems and affected populations. These findings underscore the necessity of adopting targeted preventive, therapeutic, and rehabilitative measures based on the incidence and characteristics of SCI. [ABSTRACT FROM AUTHOR]

Demethylcantharidin (DEM) is a widely used antitumor drug; however, its poor tumor targeting and serious organotoxicity limit its application. The aim of this study was to develop a new drug delivery system for efficient delivery of DEM. Nanoemulsion based lipid nanoparticles containing demethylcantharidin (DNLNs) were prepared by loading nanoemulsions into lipid nanoparticles. The cells proliferation, apoptosis, cycle, and uptake were investigated by Cell counting kit‐8 (CCK‐8), flow cytometry, and in situ fluorescence assays, respectively. Then, we established the H22 tumor‐bearing mouse model to evaluate the antitumor efficacy of DNLNs and further studied its organ toxicity and distribution. DNLNs significantly inhibited the proliferation and promoted apoptosis of H22 cells, and H22 cells could take up more DNLNs. Compared with DEM, DNLNs had certain tumor‐targeting properties, and the tumor inhibition rate increased by 23.24%. Moreover, DNLNs can increase white blood cell count and reduce organ toxicity. This study paves the way for nanoemulsion‐based lipid nanoparticle (NLNs)‐efficient DEM delivery to treat liver cancer. [ABSTRACT FROM AUTHOR]

Calcium channel blocker (CCB) is known to possess antibacterial effects. We aimed to apply network pharmacology (docking and protein–protein interaction [PPI] analyses) to predict the potential targets and mechanisms of CCB against Pseudomonas aeruginosa (PA) as well as to verify the effect of these drugs. The chemical structures of three CCBs were obtained through the Drug Bank platform. The potential channel proteins, efflux pump proteins and ion channel proteins of CCB against bacteria were derived from the literature. These proteins were collected through the PDB and Uniprot platform. The binding mode of the docking complexes was simulated by the CB‐Dock platform and Discovery Studio 2019 Client software. The PPI network was constructed by the String platform and Cytoscape 3.8.2 platform. GO was explained by the PANTHER platform. The pathway diagram was drawn with the Pathway Builder Tool 2.0 software. The inhibitory effect of CCB on PA was verified through antibacterial experiments. Finally, 76 proteins were obtained: the iron channel protein of PA demonstrated a good docking relationship with all three CCBs, and the optimum binding energy was approximately −9.0 kcal/mol. GO analysis (biological process [BP], cellular component [CC], and molecular function [MF]) of protein genes showed a good docking relationship (optimum binding energy <−8.0 kcal/mol). The MF annotation results indicated that the target of CCB may be present on the PA membrane protein. The ion channel protein PPI enrichment p‐value was 6.65e‐08, and PfeA showed the strongest correlation. The experimental results suggested that CCB could inhibit the growth of PA. CCB might be an effective and interesting antimicrobial treatment strategy as CCB can potentially inhibit the growth of PA. [ABSTRACT FROM AUTHOR]

Background: Neuron-specific gene family member 1 (NSG1) is a 21 kDa endosomal protein that is specifically expressed in neurons. Aims: This study was to explore the expression of NSG1 and possible mechanism in Esophageal Squamous Cell Carcinoma (ESCC). Methods: The Cancer Genome Atlas (TCGA) database was consulted to analyze the expression of NSG1 in ESCC. Immunohistochemistry (IHC) staining was used to evaluate NSG1 expression in ESCC cancerous tissues and matched paracancerous tissues. The CCK-8 assay, wound-healing assay, and transwell assay were used to detect the cell viability, migration, and invasion of ESCC cells. Western blot was used to assay epithelial-mesenchymal transition (EMT)-related proteins and ERK signaling pathway protein expression. Results: The results showed that the expression of NSG1 in ESCC cancerous tissues was higher than noncancerous tissues. Compared with negative control (NC) group, cell viability, migration. and invasion significantly increased, the expression of p-ERK in ERK signaling pathway was significantly upregulated, the expressions of mesenchymal marker Vimentin and EMT-related transcription factors including snail and slug were significantly upregulated, and the expression of epithelial marker E-cadherin was significantly downregulated in KYSE-150 cells with NSG1 overexpression. However, these effects were reversed by the ERK signaling pathway inhibitor U0126. On the other hand, TE-1 cells with NSG1 knockdown had the changes contrary to that in KYSE-150 cells with NSG1 overexpression. Conclusion: NSG1 plays a potential carcinogenic role on the occurrence and progression of ESCC, and aberrant NSG1 expression might promote ESCC cell EMT by the activation of ERK signaling pathway. [ABSTRACT FROM AUTHOR]

Introduction: Cysteine Protease Inhibitor 1 (CST1), a cystatin superfamily protein with the effect on the inhibition of cysteine protease activity, is reported to be involved in the development of many malignancies. MiR-942-5p has been demonstrated its regulatory effects on some malignancies. However, the roles of CST1 and miR-942-5p on esophageal squamous cell carcinoma (ESCC) are still unknown up to now. Methods: The expression of CST1 in ESCC tissues was analyzed by TCGA database, immunohistochemistry, and RT-qPCR, respectively. Matrigel-uncoated or-coated transwell assay was used to determine the effect of CST1 on migration and invasion of ESCC cells. Regulatory effect of miR-942-5p on CST1 was detected by dual luciferase assay. Results: CST1 was ectopically highly expressed in ESCC tissues, and had the effect on promoting the migration and invasion of ESCC cells by upregulating phosphorylated levels of key effectors including MEK1/2, ERK1/2, and CREB in MEK/ERK/CREB pathway. Dual-luciferase assay results showed that miR-942-5p had a regulatory effect on targeting CST1. Conclusions: CST1 plays a carcinogenic role on ESCC, and miR-942-5p can regulate the migration and invasion of ESCC cells by targeting CST1 to downregulate MEK/ERK/CREB signaling pathway, suggesting that miR-942-5p/CST1 axis might be a promising target for diagnosis and treatment of ESCC. [ABSTRACT FROM AUTHOR]

Background: Iruplinalkib (WX-0593) is an anaplastic lymphoma kinase (ALK)/c-ros oncogene 1 (ROS1) tyrosine kinase inhibitor. Here we reported the single-arm, phase II study (INTELLECT) results of the efficacy and safety of iruplinalkib for ALK-positive crizotinib-resistant advanced non-small cell lung cancer (NSCLC) patients. Methods: ALK-positive crizotinib-resistant advanced NSCLC patients aged ≥18 years, with Eastern Cooperative Oncology Group performance status of 0–2 were eligible. Patients received iruplinalkib 180 mg orally once daily for a 21-day cycle with a 7-day lead-in phase at 60 mg orally once daily. The primary endpoint was the independent review committee (IRC)-assessed objective response rate (ORR). Results: From August 7, 2019, to October 30, 2020, 146 patients were included. As of the data cut-off date on November 30, 2021, the median follow-up time was 18.2 months (95% confidence interval [CI] 16.8–18.8). IRC-assessed ORR and disease control rate (DCR) were 69.9% (95% CI 61.7–77.2%) and 96.6% (95% CI 92.2–98.9%), respectively. Investigator-assessed ORR and DCR were 63.0% (95% CI 54.6–70.8%) and 94.5% (95% CI 89.5–97.6%), respectively. Investigator-assessed median duration of response and progression-free survival (the same as median time to progression) were 13.2 months (95% CI 10.4–17.7) and 14.5 months (95% CI 11.7–20.0), respectively. Corresponding IRC-assessed results were 14.4 months (95% CI 13.1–not evaluable [NE]), 19.8 months (95% CI 14.5–NE), and NE (95% CI 14.5–NE), respectively. Investigator-assessed intracranial ORRs were 46% (41/90, 95% CI 35–56%) in patients with central nervous system metastases and 64% (27/42, 95% CI 48–78%) in patients with measurable intracranial lesions. Overall survival data were immature. Treatment-related adverse events (TRAEs) occurred in 136/146 (93.2%) patients. The most common TRAEs were aspartate aminotransferase increased (63 [43.2%]), alanine aminotransferase increased (54 [37.0%]), and blood creatine phosphokinase increased (51 [34.9%]). Dose interruption, reduction, and discontinuation due to TRAEs occurred in 21 (14.4%), 16 (11.0%), and four (2.7%) patients, respectively. Conclusions: In this study, iruplinalkib (WX-0593) demonstrated favorable efficacy and manageable safety profiles in patients with ALK-positive crizotinib-resistant advanced NSCLC. Iruplinalkib could be a new treatment option for this patient population. Trial registration: Center for Drug Evaluation of National Medical Products Administration of China: CTR20190789, registered on April 28, 2019; ClinicalTrials.gov: NCT04641754, registered on November 24, 2020. [ABSTRACT FROM AUTHOR]

Background: Rezivertinib (BPI-7711) is a novel third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). This phase IIa study was part of a phase I/IIa study (NCT03386955), aimed to evaluate the efficacy and safety of rezivertinib as the first-line treatment for patients with locally advanced or metastatic/recurrent EGFR mutated non-small cell lung cancer (NSCLC). Methods: Patients received the first-line treatment of 180 mg rezivertinib orally once daily until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was the objective response rate (ORR) assessed by blinded independent central review (BICR). Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Results: From Jun 12, 2019, to Oct 17, 2019, 43 patients were enrolled. At the data cutoff date on Dec 23, 2021, the ORR by BICR was 83.7% (95% CI: 69.3–93.2%). The median DoR was 19.3 (95% CI: 15.8–25.0) months. The median PFS by BICR was 20.7 (95% CI: 13.8–24.8) months and 22.0 (95% CI: 16.8–26.3) months by investigators. Data on OS was immature. Totally, 40 (93.0%) patients had at least one treatment-related adverse event while 4 (9.3%) of them were grade ≥ 3. Conclusions: Rezivertinib (BPI-7711) showed promising efficacy and a favorable safety profile for the treatment among the locally advanced or metastatic/recurrent NSCLC patients with EGFR mutation in the first-line setting. Trial registration: ClinicalTrials.gov, NCT03386955. [ABSTRACT FROM AUTHOR]

Objective: Umbilical cord mesenchymal stem cells (UCMSCs) have great potential in the treatment of spinal cord injury. However, the specific therapeutic effect and optimal transplantation strategy are still unclear. Therefore, exploring the optimal treatment strategy of UCMSCs in animal studies by systematic review can provide reference for the development of animal studies and clinical research in the future. Methods: Databases of PubMed, Ovid-Embase, Web of Science, CNKI, WanFang, VIP, and CBM were searched for the literature in February 11, 2022. Two independent reviewers performed the literature search, identification, screening, quality assessment, and data extraction. Results and Discussion: A total of 40 animal studies were included for combined analysis. In different subgroups, the results of traditional meta-analysis and network meta-analysis were consistent, that is, the therapeutic effect of high-dose (≥ 1 × 106) transplantation of UCMSCs was significantly better than that of low dose (< 1 × 106), the therapeutic effect of local transplantation of UCMSCs was significantly better than that of intravenous transplantation, and the therapeutic effect of subacute transplantation of UCMSCs was significantly better than that of acute and chronic transplantation. However, in view of the inherent risk of bias and limited internal and external validity of the current animal studies, more high-quality, direct comparison studies are needed to further explore the optimal transplantation strategy for UCMSCs in the future. [ABSTRACT FROM AUTHOR]

Purpose: Our pilot study has shown that cystatin SN (CST1) protein is highly expressed in esophageal squamous cell carcinoma (ESCC) tissues. We intend to develop a chemiluminescent enzyme immunoassay (CLEIA) available for serum CST1 detection and define the diagnostic value of CST1 detection for early ESCC patients, and establish a panel of CST1 with traditional tumor markers to improve the diagnostic sensitivity for early ESCC. Methods: Detection performance of CLEIA for CST1 was evaluated by linearity, detection limit, accuracy, precision, anti-interference and stability. Diagnostic performance of CST1 for early ESCC was evaluated by detecting CST1 of 112 early ESCC, 107 esophageal benign lesions (EBL), and 151 healthy controls (HC). CEA, CYFRA21-1 and SCC-Ag were detected by chemiluminescence immunoassay (CLIA). Results: The linear range and detection limit of CLEIA for CST1 were 6.25– 400 pg/mL and 1.35 pg/mL, respectively; the average recovery rate was 102.65%; CVs of intra-batch precision and inter-batch precision were < 1/4 TEa and < 1/3 TEa, respectively; 8 interferents including 7 common interferents and CST4 had no interference on CST1 detection; stability evaluation showed good sample and reagent stability. The level and positive rate of CST1 in early ESCC group were significantly higher than those in EBL/HC groups (P< 0.05). The diagnostic sensitivity of CST1 for early ESCC was 31.25% (specificity 92.64%, AUC 0.654). The diagnostic sensitivity of traditional tumor markers ranged from 16.07% to 28.57%, at > 93.0% specificity, and SCC-Ag showed the highest AUC (0.709). Combination of CST1 and CEA, SCC-Ag exhibited the highest AUC up to 0.736 (sensitivity 49.11%, specificity 89.53%). Conclusion: CLEIA has excellent detection performance for CST1. CST1 might be a prospective serological biomarker for early diagnosis of ESCC, while combination of CST1 and CEA, SCC-Ag might improve the early diagnostic performance. [ABSTRACT FROM AUTHOR]

Background: Hypertrophy is a critical process for chondrocyte differentiation and maturation during endochondral ossification, which is responsible for the formation of long bone and postnatal longitudinal growth. Increasing evidence suggests that melatonin, an indole hormone, plays a pivotal role in chondrogenesis. However, little is known about the effects of melatonin on the terminal differentiation of chondrocytes. Methods: Mesenchymal stem cell (MSC)-derived chondrocytes generated by a high-density micromass culture system were induced to undergo hypertrophic differentiation. Melatonin-mediated hypertrophic differentiation was examined by reverse transcription polymerase chain reaction analysis (RT-PCR) analysis, histological staining and immunohistochemistry. Activation of the Wnt signaling pathway was evaluated by PCR array, RT-PCR, western blotting and immunofluorescence. XAV-939, a Wnt signaling pathway antagonist, was further used to determine whether the effect of melatonin on chondrocyte hypertrophic differentiation was mediated occurred by activation of Wnt signaling pathway. Results: Histological staining showed melatonin increased chondrocyte cell volume and the expression of type X collagen but decreased the expression of type II collagen compared with the control group. RT-PCR showed that melatonin significantly up-regulated the gene expressions of biomarkers of hypertrophic chondrocytes, including type X collagen, alkaline phosphatase, runt-related transcription factor 2, Indian hedgehog and parathyroid hormone-related protein receptor, and melatonin down-regulated the mRNA expression of hallmarks of chondrocytes, including parathyroid hormone-related protein. PCR array showed that the effect of melatonin on chondrocyte hypertrophic differentiation was accompanied by the up-regulation of multiple target genes of the canonical Wnt signaling pathway, and this effect was blocked by XAV-939. Conclusions: The current findings demonstrate that melatonin enhances the hypertrophic differentiation of MSC-derived chondrocytes through the Wnt signaling pathway. Our findings add evidence to the role of melatonin in promoting bone development and highlight the positive effects of melatonin on terminal differentiation of chondrocytes. [ABSTRACT FROM AUTHOR]

Background: HLX04 is a proposed biosimilar of bevacizumab. Objective: This phase III study aimed to evaluate the efficacy, safety, and immunogenicity of HLX04 compared with reference bevacizumab in combination with XELOX or mFOLFOX6 as first-line treatment for recurrent/metastatic colorectal cancer (CRC). Methods: In this double-blind, parallel-group study, patients were randomized 1:1 to receive HLX04 or bevacizumab (7.5 mg/kg every 3 weeks when combined with XELOX; 5 mg/kg every 2 weeks when combined with mFOLFOX6). The primary endpoint was progression-free survival rate at week 36 (PFSR36w) per Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Prespecified equivalence margins of PFSR36w were set as − 11 to 15% (rate difference) and 0.8 to 1.25 (rate ratio). Secondary endpoints included efficacy, safety, immunogenicity, and pharmacokinetics. Results: A total of 677 patients were randomized (HLX04 n = 340; bevacizumab n = 337) between April 2018 and April 2020. PFSR36w was 46.4% (95% confidence interval [CI] 41.1–51.8) with HLX04 and 50.7% (95% CI 45.4–56.1) with bevacizumab. The rate difference (− 4.2%; 90% CI − 10.6 to 2.1) and rate ratio (0.92; 90% CI 0.80–1.05) both fell within the prespecified equivalence margins. No notable differences were observed between treatment groups in any efficacy endpoints or their subgroup analyses. Safety, immunogenicity, and pharmacokinetic profiles were comparable between the two treatment groups. Conclusions: HLX04 demonstrated equivalent efficacy with similar safety and immunogenicity profiles to reference bevacizumab among patients with recurrent/metastatic CRC, thus offering an alternative treatment option to patients. Trial registration: Chinadrugtrials.org.cn, CTR20171503 (18 March 2018); ClinicalTrials.gov, NCT03511963 (30 April 2018). Plain Language Summary: Colorectal cancer (CRC) is the third most common cancer worldwide. Approximately 20% of patients with CRC have metastases at their first visit. Bevacizumab is a biologic antibody approved in many countries for the treatment of metastatic CRC. However, high treatment costs significantly limit patient access to bevacizumab. Therefore, HLX04, a potential bevacizumab biosimilar, which is almost identical to bevacizumab but less expensive and more accessible, has been developed. This randomized clinical trial was designed to evaluate the efficacy (ability of a drug to produce the desired treatment effects), safety, and immunogenicity (ability of a drug to induce immune response that would affect its efficacy and safety) of HLX04 compared with the reference bevacizumab in patients with recurrent/metastatic CRC. Efficacy of the tested drug was evaluated by comparing the proportion of patients without disease progression or death at week 36 (PFSR36w). Safety was monitored using adverse events and other clinical evaluations. Immunogenicity was assessed by the incidence of antidrug antibodies. Of the 677 patients enrolled in the study, 340 received HLX04 and 337 received bevacizumab. Statistical analyses showed that HLX04 was equivalent to bevacizumab in efficacy evaluations (the difference in PFSR36w between the two treatment groups fell within the prespecified "equivalence margins"). Moreover, the two treatments were similar with respect to safety and immunogenicity evaluations. In summary, patients responded equally well to HLX04 and bevacizumab, supporting the development of HLX04 as a proposed biosimilar to bevacizumab for patients with recurrent/metastatic CRC. [ABSTRACT FROM AUTHOR]

Background: HLX02 is an approved biosimilar of trastuzumab. Objective: This study aimed to evaluated the efficacy, safety, and immunogenicity of HLX02 compared with reference trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive recurrent or metastatic breast cancer. Patients and Methods: This randomized, double-blind, phase III study was conducted at 89 centers in China, the Philippines, Poland, and Ukraine. Eligible patients were randomized (1:1) to receive HLX02 or European Union (EU)-sourced trastuzumab (initial dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks for up to 12 months) in combination with docetaxel intravenously. The primary endpoint was overall response rate up to week 24 (ORR24). Equivalence was declared if the 95% confidence interval (CI) of difference was within ± 13.5%. Safety and immunogenicity were evaluated in patients who received at least one dose of study medication. Results: Between 11 November 2016 and 10 July 2019, a total of 649 patients were enrolled. The ORR24 was 71.3 and 71.4% in the HLX02 (n = 324) and EU-trastuzumab (n = 325) groups, with a difference of − 0.1% (95% CI − 7 to 6.9), which fell entirely in the predefined equivalence margins. No statistically significant differences were observed in all secondary efficacy analyses. Safety profiles and immunogenicity were comparable in HLX02 and EU-trastuzumab groups. In total, 98.8% of patients in each group experienced at least one treatment-emergent adverse event (TEAE), 23.8 and 24.9% experienced serious TEAEs, and 0.6% in each group had antidrug antibodies. Conclusions: Among patients with HER2-positive recurrent or metastatic breast cancer, HLX02 demonstrated equivalent efficacy and similar safety and immunogenicity to reference trastuzumab. Clinical Trial Registration: Chinadrugtrials.org CTR20160526 (12 September 2016), ClinicalTrials.gov NCT03084237 (20 March 2017), EudraCT 2016-000206-10 (27 April 2017). Plain Language Summary: Trastuzumab is a biologic drug used to treat patients with certain types of breast cancer and stomach cancer. Biosimilars are medications that are almost identical to and indistinguishable from original biologic drugs but usually less expensive and more accessible. The main purpose of this study was to evaluate the efficacy (treatment effects) of HLX02 (trastuzumab biosimilar) compared with reference trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive recurrent or metastatic breast cancer. Other objectives were to evaluate the safety of HLX02 by monitoring adverse events and assessing its potential to induce antibody production (which can prevent a drug from being effective). Patients with HER2-positive recurrent or metastatic breast cancer were randomly allocated to receive HLX02 (n = 324) or European Union (EU)-sourced trastuzumab (n = 325). Study drugs (HLX02 or EU-trastuzumab) were given intravenously, with an initial dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks for up to 12 months. Statistical analyses showed that HLX02 was equivalent to trastuzumab in efficacy evaluations. Adverse events observed in the HLX02 treatment group were consistent with those seen with trastuzumab in the current and previous clinical studies. Additionally, no statistically significant differences were seen in the tendency to stimulate antibody production between the two study drugs. To conclude, HLX02 and reference trastuzumab had similar efficacy and safety profiles. These data support the approval of HLX02 as a trastuzumab biosimilar. [ABSTRACT FROM AUTHOR]

Background: Vitamin D deficiency has long been studied as a risk factor for osteoporosis. However, the association between serum vitamin D status, bone mineral density (BMD) and the incidence of vertebral fractures (OVFs) remain controversial. It is believed that free portion of the circulating vitamin D carries the metabolic activities of vitamin D. Therefore, the aim of the present study is to analyse if free vitamin D correlates with BMD and osteoporotic fragile vertebral fractures in the elderly population.Methods: A total of 90 consecutive patients, including 81 female and 9 male patients, aged > 48 years, were included in this cross sectional study between March and July of 2018. Total vitamin D (total 25(OH)D), free vitamin D (free 25(OH)D), calcium and phosphorus were measured. BMD was measured using dual energy X-ray absorptiometry (DEXA) and osteoporotic vertebral fracture was assessed using plain radiograph. Multiple linear regression was performed to find out the association between total vitamin D, free vitamin D and BMD at various sites. To evaluate the association with osteoporotic vertebral multivariate logistic regression model was used.Results: The mean total vitamin D and free vitamin D were 25.1 ± 10.2 and 6.1 ± 1.7 respectively. Free vitamin D had a linear correlation with total vitamin D (R2 = 0.69). While free vitamin D had a positive correlation with lumbar BMD roles (p < 0.05), total vitamin D didn't have any association with BMD at any site. Of the total patients, 62 patients (68.9%) had thoracolumbar junction OVFs. Free vitamin D level correlated with the prevalence of OVFs as well as lumbar osteoporosis (p < 0.05). However, there was no statistical correlation between serum vitamin D status and the OVFs.Conclusions: Free vitamin D was significantly related to the occurrence of thoracolumbar junction OVFs and lumbar BMD, which assumed to be a positive predictor for fracture and osteoporosis prevention. However, total serum vitamin D levels did not have any association with BMD at different sites as well as fragile vertebral fracture.Trial Registration: The study is registered at clinicaltrials.gov NCT03605173. [ABSTRACT FROM AUTHOR]

Objective: To investigate the main problems in the pharmaceutical care of Klebsiella pneumonia-carhapenemase-producing Klebsiella pneumoniae (KPC-Kp) infection in a patient combined with severe acute pancreatitis and hepatic failure. Methods: The pharmaceutical care of a specific case was introduced from the aspects of the choice of initial anti-infective drugs, the optimization of antiotic regimens for KPC-Kp infection and prevention and control of adverse drug reactions (ADRs). Results: Based on the pathophysiological conditions of the patient, optimal medication strategies were proposed and careful pharmaceutical care was provided by the clinical pharmacists. As a consequence, good therapeutic efficacy was achieved. Conclusion: Pharmaceutical care of the patient included development, adjustment and optimization of anti-infective regimens, as well as prevention and control of ADRs. [ABSTRACT FROM AUTHOR]

Background: Tyrosine kinase inhibitors (TKIs) can significantly prolong overall survival for patients with advanced non‐small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR)‐mutation or anaplastic lymphoma kinase (ALK)‐rearrangement. However, the real‐world evaluation status of ALK/EGFR in China remains unclear. Methods: We conducted a prospective study including 1134 patients with cytologically or histologically confirmed advanced NSCLC (stage IIIb–IV) at 12 Chinese hospitals. Results: The most common evaluation methods were amplification‐refractory mutation system for EGFR status and immunohistochemistry targeting D5F3 for ALK status. Among patients with non‐squamous, the EGFR mutation rate was 44.1% and the ALK rearrangement rate was 10.0%. Among patients with squamous cell carcinoma, the EGFR mutation rate was 8.3% and the ALK rearrangement rate was 3.7%. Among all patients, gender (HR = 1.7, 95%CI = 1.2–2.4, P = 0.006), smoking history (HR = 1.8, 95%CI = 1.3–2.7, P = 0.001), histology (HR = 5.0, 95%CI = 2.4–10.1, P < 0.001), and brain metastases (HR = 1.5, 95%CI = 1.1–2.2, P = 0.017) were independent predictors of EGFR mutation, while age (HR = 2.6, 95%CI = 1.7–4.1, P < 0.001) was an independent predictor of ALK rearrangement. The median time from tumor diagnosis to EGFR or ALK status confirmation was 7 and 5 days, respectively. Targeted therapy rate was 73.8% in EGFR‐positive patients and 51.4% in ALK‐positive patients. There was a negative correlation between the first‐line targeted therapy rate and the EGFR mutation detection period (r = −0.152, P = 0.02), while no significant correlation among patients with ALK rearrangement (r = −0.179, P = 0.076). Conclusion: Squamous NSCLC patients should also be routinely tested to determine their EGFR/ALK statuses. The first‐line targeted therapy rate remains low in Chinese patients with NSCLC. [ABSTRACT FROM AUTHOR]

Background: Carcinoma ex pleomorphic adenoma (CXPA), a very rare malignancy found mostly in the major salivary glands, has no established standardized treatment. Case presentation: This report describes a 67-year-old male with advanced CXPA who was effectively treated by anlotinib. Pleomorphic adenoma of the submandibular gland was first diagnosed in 1976 after a surgical resection of a mass underneath the jaw. The patient underwent re-excision 3 years later due to a recurrent pleomorphic adenoma. CXPA was first diagnosed in 2016 after a surgical removal of the left submandibular mass. A lung nodule was found on a chest CT scan in January 2018. Following a CT-guided lung biopsy that demonstrated findings consistent with pulmonary metastasis, the patient underwent local therapy (microwave ablation and radioactive seed implantation) but suffered a recurrence of disease approximately 6 months later. Anlotinib was administered orally at a dose of 12 mg daily on a 2 weeks on/1 week off schedule. A partial response was observed after two cycles of treatment. The disease remains in continued partial response after completion of his sixth cycle. Conclusion: This is the first report for anlotinib in treating CXPA. Further pre-clinical and clinical studies are needed to validate the efficacy and safety of anlotinib in the treatment of CXPA. [ABSTRACT FROM AUTHOR]

Phospholipase A2-IVA (PLA2G4A) is the most abundant subtype of cytoplasmic phospholipase A2 (cPLA2) and is an important enzyme in tumor development. Our study aimed to explore the role of PLA2G4A in the regulation of lung cancer. The contents of cell-related cytokines (microsomal prostaglandin E synthase-1 [mPGES], PGE2, and prostacyclin [PGI2]) in A549 cells were analyzed by ELISA kits. Cell counting kit-8 (CCK8) was used to detect the effects of inhibitor of cPLA2 (arachidonyl trifluoromethyl ketone [AACOCF3]) on the proliferation of A549 cells. The migration and invasion of A549 cells were tested by cell scratch wound healing assay and transwell assay, respectively. Real-time quantitative PCR and Western blotting were used to detect the effect of inhibitor AACOCF3 on the expression of related mRNA and protein in A549 cells. ELISA result showed that the levels of mPGES, PGE2, and PGI2 in control group were significantly higher than those in the AACOCF3 group. Cell inhibition rate in the control group was significantly lower than that in the AACOCF3 group. The percentage of wound healing in the control group was significantly higher than that in the AACOCF3 group. Meanwhile, the relative invasive number of cells in the control group was significantly higher than those in the AACOCF3 group. The expression levels of related mRNA of PLA2G4A and cyclooxygenase-2 (COX-2) and the expression levels of mPGES, COX-1, and COX-2 protein in the control group were significantly higher than those in the AACOCF3 group. Our research showed that PLA2G4A was involved in migration and invasion of lung cancer cells. [ABSTRACT FROM AUTHOR]

Purpose: The objective of the study is to explore the etiology, clinical manifestations, imaging features, diagnosis, treatment, and prognosis of cerebral air embolism complicated computed tomography (CT) scan-guided percutaneous liver biopsy.Materials and Methods: A case of air embolism was developed in the brain during a CT-guided percutaneous needle biopsy of the liver. In addition, retrospective analysis was performed on the previously reported typical cases of cerebral air embolism secondary to CT-guided percutaneous lung biopsy.Results: Cerebral air embolism has been recognized as a potentially fatal but extremely rare complication following CT-guided percutaneous liver or lung biopsy. It was usually caused by cough, positive pressure ventilation, incorrect puncture position, repeated punctures, cavity or cyst in the target sites, and vascular inflammatory lesions.Conclusions: Clinicians should focus on timely and correct diagnosis of this complication during their interventional procedures. The current main treatment for this complication has been hyperbaric oxygen therapy. [ABSTRACT FROM AUTHOR]

Abstract: Bone marrow‐derived mesenchymal stem cells (BMSCs), with inherent chondrogenic differentiation potential appear to be ideally suited for therapeutic use in cartilage regeneration. Accumulating evidence has demonstrated that melatonin can promote chondrogenic differentiation in human BMSCs. However, little is known about the mechanism. MicroRNAs (miRNAs) have been shown to regulate the differentiation of BMSCs, but their roles in melatonin‐promoted chondrogenic differentiation have not been characterized. Here, we demonstrate that melatonin promoted chondrogenic differentiation of human BMSCs via upregulation of miR‐526b‐3p and miR‐590‐5p. Mechanistically, the elevated miR‐526b‐3p and miR‐590‐5p enhanced SMAD1 phosphorylation by targeting SMAD7. Additionally, administration of miR‐526b‐3p mimics or miR‐590‐5p mimics successfully promoted the chondrogenic differentiation of human BMSCs. Collectively, our study suggests that modification of BMSCs using melatonin or miRNA transduction could be an effective therapy for cartilage damage and degeneration. [ABSTRACT FROM AUTHOR]

Background: Hidden haemorrhage has been proved to be significant in joint surgery. However, when referring to lumbar interbody fusion, it is often ignored because of its invisibility. This randomized controlled study aimed to calculate and compare hidden haemorrhage following minimally invasive and open transforaminal lumbar interbody fusion (MIS-TLIF and open TLIF). Meanwhile, its clinical significance was also analyzed.Materials and Methods: A total of 41 patients were included in this study, then they were randomized to receive MIS-TLIF or open TLIF, 21 and 20, respectively. For each case, total volume loss of red blood cell (RBC) was calculated by Gross' formula based on perioperative haematocrit change, then perioperative visible volume loss of RBC was calculated through haemorrhage volume and weight. After deducting it from total volume loss of RBC, hidden volume loss of RBC was obtained. Absolute amount of hidden haemorrhage and its ratio upon total haemorrhage, as well as indicators assessing clinical outcomes, including visual analogue scale (VAS) for back and leg, Oswestry disability index (ODI), interbody fusion rate and complication incidence were compared and analyzed.Results: Mean hidden volume loss of RBC in MIS-TLIF was significantly reduced compared with open TLIF (166.7 versus 245.6 ml). Besides, both mean total and visible volume loss of RBC in MIS-TLIF were also statistically less than those in open TLIF (355.3 versus 538.6 ml; 188.6 versus 293.0 ml). While mean ratio of hidden haemorrhage upon total haemorrhage was 46.7% for MIS-TLIF and 44.5% for open TLIF, respectively, showing no statistical significance. At one week postoperatively, more significant improvements of VAS for back and leg, as well as ODI were seen in MIS-TLIF compared with open TLIF. While at final follow-up of at least 2 years, all parameters continued to improve and revealed no statistical difference between both surgeries. Similar interbody fusion rate and complication incidence were observed in both series.Conclusions: Besides reduced visible haemorrhage and improved clinical outcomes, MIS-TLIF also owns the superiority of less hidden haemorrhage, offering another advantage over open TLIF.Level Of Evidence: Level II. [ABSTRACT FROM AUTHOR]

Aim. To investigate the feasibility and effectiveness of intraoperative myelography in determining adequacy of indirect spinal canal decompression during transpsoas lateral lumbar interbody fusion (LLIF). Methods. Seven patients diagnosed with degenerative lumbar spinal stenosis (DLSS) were prospectively included to this study. All patients underwent LLIF and subsequently received intraoperative myelography to determine the effect of indirect spinal canal decompression, which was visualized in both anterior-posterior and lateral images. Those patients with insufficient indirect canal decompression were further resolved by microendoscopic canal decompression (MECD). Radiological parameters, including stenosis ratio and dural sac area of operated levels, were measured and compared before and after operation. Besides, all patients were followed up for at least one year using visual analogue scale (VAS) for back and leg, Japanese Orthopaedic Association score (JOA), and Oswestry disability index (ODI). Results. Seven patients with 8 operated levels underwent LLIF safely and demonstrated significant symptom relief postoperatively. Five operated levels showed adequate indirect canal decompression intraoperatively, while the remaining three levels did not achieve the adequacy, and their residual stenosis was resolved following MECD. Radiological parameters were improved statistically when compared with preoperation (P<0.05). Furthermore, neurological symptoms of all patients were also improved significantly (P<0.05), shown by improved VAS (back and leg), JOA, and ODI at both two-week and one-year follow-up. Conclusions. Intraoperative myelography during LLIF is able to assess adequacy of indirect canal decompression for DLSS, thus promising favorable clinical outcomes. [ABSTRACT FROM AUTHOR]

Purpose: Using MR imaging, nerve root sedimentation sign (SedSign) was demonstrated to have a high sensitivity and specificity for diagnosis of symptomatic lumbar spinal stenosis (LSS) in selected patients. This study was to evaluate the diagnostic value of SedSign in differential diagnosis of LSS and non-specific low back pain (LBP) in consecutive patients.Methods: A series of consecutive patients with lumbar spinal MRI examination for back/leg pain in orthopeadic clinic were included. These patients were followed up and divided into two groups, symptomatic LSS and non-specific LBP, according to symptoms and radiological findings. Using MR images, SedSign was assessed by two spine surgeons and one radiologist independently. Then sensitivity and specificity of SedSign was calculated.Result: A total of 320 patients (105 LSS and 215 non-specific LBP) were included. The SedSign had a sensitivity of 77.1 % and specificity of 47.0 % in the whole cohort. When these patients were stratified by dural sac cross-sectional areas (CSA), the SedSign had a sensitivity of 95.0 % and specificity of 4.7 % in patients with CSA ≤ 80 mm2 (severe radiologic stenosis), sensitivity of 74.2 % and specificity of 22.6 % in patients with CSA 80-100 mm2 (moderate radiologic stenosis), and sensitivity of 58.8 % and specificity of 61.0 % in patients with CSA 100-120 mm2 (mild radiologic stenosis). In selected cases composed by LSS patients with CSA ≤ 80 mm2 and non-specific LBP patients with CSA > 120 mm2, however, the SedSign had a sensitivity of 95.0 % and specificity of 80.0 %.Conclusion: The present data demonstrated that the SedSign was not able to discriminate symptomatic LSS from non-specific LBP after adjusting by dural sac CSA. The diagnostic value of the SedSign was still uncertain. [ABSTRACT FROM AUTHOR]

Triggering receptor expressed on myeloid cell 2 (TREM2) signaling often drives opposing effects in traumatic versus demyelinating CNS disorders. Here, we identify two distinct phenotypes of microglia and infiltrating myeloid populations dependent on TREM2 expression levels at the acute stage and elucidate how they mediate the opposing effects of TREM2 in spinal cord injury (SCI) versus multiple sclerosis animal models (experimental autoimmune encephalomyelitis [EAE]). High TREM2 levels sustain phagocytic microglia and infiltrating macrophages after SCI. In contrast, moderate TREM2 levels sustain immunomodulatory microglia and infiltrating monocytes in EAE. TREM2-ablated microglia (purine-sensing phenotype in SCI and reduced immunomodulatory phenotype in EAE) drive transient protection at the acute stage of both disorders, whereas reduced phagocytic macrophages and lysosome-activated monocytes lead to contrasting neuroprotective and demyelinating effects in SCI versus EAE, respectively. Our study provides comprehensive insights into the complex roles of TREM2 in myeloid populations across diverse CNS disorders, which has crucial implications in devising TREM2-targeting therapeutics. [Display omitted] • TREM2 ablation in microglia leads to transient protection at the acute stage of SCI and EAE • Different levels of TREM2 characterize distinct macrophage phenotypes in SCI versus EAE • TREM2 ablation reduces macrophage phagocytic phenotype leading to neuroprotection in SCI • TREM2 ablation induces monocyte lysosome-activated phenotype worsening demyelination in EAE Gao et al. identify the existence of two distinct phenotypes of microglia and infiltrating myeloid cells dependent on TREM2 expression levels at the acute stage of spinal cord injury (SCI) and experimental autoimmune encephalomyelitis (EAE), and the authors elucidate how they mediate the opposing effects of TREM2 in the two disorder models. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to determine the diagnostic value of the nerve root sedimentation sign, a relatively new radiological sign using magnetic resonance imaging, for diagnosing lumbar spinal stenosis. Materials and methods: The literature search was based on PUBMED, EMBASE, Cochrane Library, Google Scholar, and the Chinese Biomedical Literature Database up to March 2014. A total of 120 articles were identified. Seven studies involving 1,182 patients were included. Results: The quality of the methodology of the seven studies was good. Overall, the pooled weighted value showed that the sedimentation sign had moderate sensitivity of 0.80 [95 % confidence interval (CI) 0.77-0.83] and high specificity of 0.96 (95 % CI 0.94-0.98). The area under the curve was 0.76. Subgroup analysis showed that the degree of morphological spinal stenosis was responsible for the heterogeneity. In the patients with severe morphological lumbar spinal stenosis, the sedimentation sign had even higher sensitivity and specificity: 0.899 (95 % CI 0.87-0.92) and 0.99 (95 % CI 0.98-1.00), respectively. The area under the curve was 0.96. In the patients with lumbar spinal stenosis without definition of morphological stenosis, there was a notable threshold effect and significant heterogeneity. The area under the curve was 0.63. Conclusion: Current evidence suggests that the sedimentation sign has high sensitivity and specificity for diagnosing severe lumbar spinal stenosis. Its performance in diagnosing moderate and mild spinal stenosis, however, has yet to be corroborated in properly designed studies. [ABSTRACT FROM AUTHOR]

Intramembranous ossification and endochondral ossification are two ways through which bone formation and fracture healing occur. Accumulating amounts of evidence suggests that melatonin affects osteoblast differentiation, but little is known about the effects of melatonin on the process of chondrogenic differentiation. In this study, the effects of melatonin on human mesenchymal stem cells ( MSCs) undergoing chondrogenic differentiation were investigated. Cells were induced along chondrogenic differentiation via high-density micromass culture in chondrogenic medium containing vehicle or 50 n m melatonin. Histological study and quantitative analysis of glycosaminoglycan ( GAG) showed induced cartilage tissues to be larger and richer in GAG, collagen type II and collagen type X in the melatonin group than in the untreated controls. Real-time RT- PCR analysis demonstrated that melatonin treatment significantly up-regulated the expression of the genes involved in chondrogenic differentiation, including aggrecan ( ACAN), collagen type II ( COL2A1), collagen type X ( COL10A1), SRY (sex-determining region Y)-box 9 ( SOX9), runt-related transcription factor 2 ( RUNX2) and the potent inducer of chondrogenic differentiation, bone morphogenetic protein 2 ( BMP2). And the expression of melatonin membrane receptors ( MT) MT1 and MT2 were detected in the chondrogenic-induced- MSCs by immunofluorescence staining. Luzindole, a melatonin receptor antagonist, was found to partially block the ability of melatonin to increase the size and GAG synthesis of the induced cartilage tissues, as well as to completely reverse the effect of melatonin on the gene expression of ACAN, COL2A1, COL10A1, SOX9 and BMP2 after 7 days of differentiation. These findings demonstrate that melatonin enhances chondrogenic differentiation of human MSCs at least partially through melatonin receptors. [ABSTRACT FROM AUTHOR]

Melatonin promotes bone formation and prevents bone degradation via receptor-dependent or receptor-independent actions. The aim of this study is to encapsulate melatonin into poly (lactic-co-glycolic acid) (PLGA) microspheres (PLGA-MEL-MS) and create a melatonin sustained release system, then to evaluate its effect on the osteogenesis of human mesenchymal stem cells (hMSCs) in vitro. PLGA-MEL-MS were prepared by single emulsion solvent evaporation technique. Scanning electron microscopy demonstrated the incorporation of melatonin did not disturb the conventional generation of PLGA microspheres in size and morphology. In vitro drug release assay showed that PLGA-MEL-MS exhibited a biphasic drug release pattern: a low initial burst release effect with approximately 40% drug release at the first 3 days and a relatively retarded and continuous release with about 85% drug release over the 25 days. Cell proliferation assay demonstrated that PLGA-MEL-MS had no apparent effect on proliferation of human MSCs. In an osteogenesis assay, PLGAMEL- MS obviously enhanced alkaline phosphatase (ALP) mRNA expression and increased ALP activity compared to that in the control group. Meanwhile, several markers of osteoblast differentiation were also significantly upregulated, including runx2, osteopontin, and osteocalcin. Furthermore, quantificational alizarin red-based assay demonstrated that PLGA-MEL-MS significantly enhanced calcium deposit of hMSCs compared to the controls. Therefore, this simple melatonin sustained release system can control released melatonin to generate a microenvironment with a relatively stable concentration of melatonin for a period of time to support osteogenic differentiation of hMSCs in vitro. This suggests that this system may be used as bone growth stimulator in bone healing in vivo. [ABSTRACT FROM AUTHOR]

new type II collagenopathy, caused by the p.Gly1170Ser mutation of COL2A1, which presents as premature hip osteoarthritis (OA), avascular necrosis of the femoral head (ANFH) or Legg-Calvé-Perthes (LCP) disease, was recently found in several families with an inherited disease of the hip joint. In this study, femoral head cartilage was harvested for histological and ultrastructural examination to determine the pre-existing generalised abnormalities of the mutant cartilage. The histological results showed that the hierarchical structure of the mutant cartilage and the embedded chondrocytes were markedly abnormal. The expression and distribution of type II collagen was non-uniform in sections of the mutant cartilage. Ultrastructural examination showed obvious abnormal chondrocytes and disarrangement of collagen fibres in the mutant cartilage. Furthermore, the predicted stability of type II collagen dramatically decreased with the substitution of serine for glycine. Our study demonstrated that the p.Gly1170Ser mutation of COL2A1 caused significant structural alterations in articular cartilage, which are responsible for the new type II collagenopathy. [ABSTRACT FROM AUTHOR]

To report results of radiation therapy treatment of 30 B-cell lymphoma patients with an initial cutaneous presentation according to the new classification by the WHO/EORTC. Thirty patients with cutaneous B-cell lymphoma (CBCL) were treated by cutaneous irradiation based on the number and location of the lesions and the stage of their tumor. Treatment was conducted using a Saturne Clinac. A complete response (CR) from the treatment for our series was 86%. The length of complete remission ranged from 4 to 301 months. Three patients (11%) developed a partial response (PR). One patient was progressive. Disease-free survival(DFS) at 10 years was 87%. Three patiens died [One PCMZL two PCLBCL leg type (29%)]. Radiotherapy was generally well tolerated. According to the WHO/EORTC classification, the survivor results were good for PCMZL and PCFCL. The PCLBCL leg type had a poor prognosis. Localized field irradiation is an effective treatment for some localized forms of primary cutaneous B-cell lymphoma, and this mode of therapy can produce prolonged remissions. The patients with wide-spread skin involvement are usually candidates for extended field irradiation and/or chemotherapy. For advanced stages of cutaneous B-cell lymphoma, where chemotherapy is the treatment of choice, a degree of palliation can be achieved using local field irradation. [ABSTRACT FROM AUTHOR]

Induced pluripotent stem cells (iPSCs) are of great clinical interest for they are derived from one's own somatic cells and have the potential of committed differentiation without immunological rejection after autografting. However, the use of viral and other modified vectors may still cause tumorigenesis due to chromosome insertion mutation, leading to limited practical use. iPSCs generated by reprogramming proteins overcome the potential safety risk and complicated manipulation procedures, thus they own better application prospective, yet some technical difficulties need to be studied and resolved, for instance, low reprogramming efficiency, unclear transduction, and reprogramming mechanism. In this paper, we summarize the current progress of proteins reprogramming technology for generation of iPSCs and discuss the promising efficiency-improved reprogramming methods by proteins plus other kinds of chemical compounds. [ABSTRACT FROM AUTHOR]