Tuina Inhibits Chondrocyte Apoptosis by Regulating the FAK/PI3K/Akt Pathway in Rabbits with IVDD.

BACKGROUND: Intervertebral disc degeneration (IVDD), a key contributor to degenerative spinal diseases such as cervical spondylosis, significantly influences the quality of life of patients. Tuina, historically employed in the clinical management of cervical spondylosis, has demonstrated positive therapeutic outcomes; however, the mechanism of Tuina remains unclear. OBJECTIVE: This study examined the efficacy of Tuina in correcting the imbalanced structure of the cervical spine and its impact on apoptotic chondrocytes within the cervical disc. The underlying mechanisms were explored using a rabbit model of IVDD induced by dynamic and static imbalances. METHODS: The IVDD rabbit model was established by restraining the head in a downward position for 12 weeks (Model group). In the Tuina1 group, treatment was performed on the posterior cervical trapezius muscle daily for 2 weeks, whereas in the Tuina2 group, treatment was performed on both the posterior cervical trapezius and anterior sternocleidomastoid muscles daily for 2 weeks. After treatment, X-ray, micro-computed tomography (CT), histological staining, qRT-PCR, and western blotting were used to evaluate the mechanism by which Tuina inhibits chondrocyte apoptosis. RESULTS: The results demonstrated that Tuina treatment inhibited chondrocyte apoptosis in cervical discs by adjusting the neck structure balance, and a more significant therapeutic effect was observed in the Tuina2 group. Lateral cervical spine X-ray and CT scans in rabbits revealed notable improvements in cervical spine curvature and vertebral structure in the treatment groups compared with those in the Model group. Hematoxylin and eosin staining and TUNEL staining further confirmed the positive impact of Tuina treatment on intervertebral disc tissue morphology and chondrocyte apoptosis. Additionally, western blotting and immunohistochemical analysis showed that Tuina treatment suppressed chondrocyte apoptosis by downregulating Bax and caspase-3 while upregulating Bcl-2. Western blotting results further indicated that Tuina could activate the FAK/PI3K/Akt signaling pathway by mediating integrin-ß1. CONCLUSION: Tuina treatment inhibited chondrocyte apoptosis in cervical discs by activating the FAK/PI3K/Akt signaling pathway, providing convincing evidence to support Tuina treatment as a promising method for IVDD.

Hypothermia promotes tunneling nanotube formation and the transfer of astrocytic mitochondria into oxygen-glucose deprivation/reoxygenation-injured neurons.

Mitochondrial transfer occurs between cells, and it is important for damaged cells to receive healthy mitochondria to maintain their normal function and protect against cell death. Accumulating evidence suggests that the functional mitochondria of astrocytes are released and transferred to oxygen-glucose deprivation/reoxygenation (OGD/R)-injured neurons. Mild hypothermia (33 °C) is capable of promoting this process, which partially restores the function of damaged neurons. However, the pathways and mechanisms by which mild hypothermia facilitates mitochondrial transfer remain unclear. We are committed to studying the role of mild hypothermia in neuroprotection to provide reliable evidences and insights for the clinical application of mild hypothermia in brain protection. Tunneling nanotubes (TNTs) are considered to be one of the routes through which mitochondria are transferred between cells. In this study, an OGD/R-injured neuronal model was successfully established, and TNTs, mitochondria, neurons and astrocytes were double labeled using immunofluorescent probes. Our results showed that TNTs were present and involved in the transfer of mitochondria between cells in the mixed-culture system of neurons and astrocytes. When neurons were subjected to OGD/R exposure, TNT formation and mitochondrial transportation from astrocytes to injured neurons were facilitated. Further analysis revealed that mild hypothermia increased the quantity of astrocytic mitochondria transferred into damaged neurons through TNTs, raised the mitochondrial membrane potential (MMP), and decreased the neuronal damage and death during OGD/R. Altogether, our data indicate that TNTs play an important role in the endogenous neuroprotection of astrocytic mitochondrial transfer. Furthermore, mild hypothermia enhances astrocytic mitochondrial transfer into OGD/R-injured neurons via TNTs, thereby promoting neuroprotection and neuronal recovery.

Recent Advances in Cell Sheet-Based Tissue Engineering for Bone Regeneration.

In conventional bone tissue engineering, cells are seeded onto scaffolds to create three-dimensional (3D) tissues, but the cells on the scaffolds are unable to effectively perform their physiological functions due to their low density and viability. Cell sheet (CS) engineering is expected to be free from this limitation. CS engineering uses the principles of self-assembly and self-organization of endothelial and mesenchymal stem cells to prepare CSs as building blocks for engineering bone grafts. This process recapitulates the native tissue development, thus attracting significant attention in the field of bone regeneration. However, the method is still in the prebasic experimental stage in bone defect repair. To make the method clinically applicable and valuable in personalized and precision medicine, current research is focused on the preparation of multifunctionalized building blocks using CS technologies, such as 3D layered CSs containing microvascular structures. Considering the great potential of CS engineering in repairing bone defects, in this review, the types of cell technologies are first outlined. We then summarize the various types of CSs as building blocks for engineering bone grafts. Furthermore, the specific applications of CSs in bone repair are discussed. Finally, we present specific suggestions for accelerating the application of CS engineering in the clinical treatment of bone defects.

Role of Intraoperative Imaging in Improving Closed Reduction of Zygomatic Arch Fractures: A Systematic Review and Meta-analysis.

PURPOSE: The use of intraoperative imaging (IOI) to improve the reduction adequacy of zygomatic arch (ZMA) fractures has been reported, but few systematic reviews have examined this topic. The aim of this review was to investigate and compare the value of IOI with conventional methods without IOI (N-IOI) for the closed reduction of ZMA fractures. METHODS: Electronic retrieval of MEDLINE, Embase, Cochrane Library, Web of Science, Scopus, and citation search until December 2, 2022, was used to identify controlled clinical trials that employed IOI for improving adequacy in closed reduction of ZMA fractures. The predictor variable was the use of IOI-yes/no (IOI vs N-IOI). The covariates included imaging technique (ultrasound, C-arm, and cone beam computed tomography) and ZMA fracture type (M-shape fracture, mechanistic force in 1 direction; variable fracture, mechanistic force in 2 directions). The primary outcome variables were the reduction adequacy of ZMA fractures (the remaining cortical step and dislocation angle) compared with the ideal mirrored position. Weighted or mean differences, risk ratios, and corresponding 95% confidence intervals were calculated, where P >.05 and I2＜50% fixed effect model was adopted, and a vice versa random effect model was adopted. RESULTS: A total of 1250 studies were identified, of which 6 studies with 259 participants were included. The meta-analysis results indicated that compared with N-IOI, IOI yielded fewer cortical steps (-1.76 [-2.42, 1.10], P ＜.00001, fixed model) and dislocation angles (-5.60 [-8.08, 3.12], P＜.00001, fixed model) in patients with variable ZMA fractures, while no significant difference was detected in the M-shape ZMA fracture (-0.72, [-2.93, 1.48], P = .52; -1.48, [-3.51, 0.55], P = .15). Although there was no significant difference in postoperative correction (0.35, [0.06, 2.01] P = .24, fixed model), all secondary revision cases occurred in the N-IOI group. Descriptive analysis showed that IOI yielded better symmetry and appearance satisfaction. CONCLUSION: IOI improved the adequacy of the procedure and led to a better postoperative appearance, especially for patients with variable ZMA fractures. Furthermore, the use of IOI avoided the risk of secondary surgery. In future studies, researchers should standardize the scale and outcomes to facilitate the intuitive evaluation of reduction adequacy.

The Value of Intraoperative Computed Tomography in the Treatment of Zygomatic Complex Fractures.

BACKGROUND: Due to the complex anatomical morphology and lack of anatomic markers on the surface of zygomatic complex (ZMC), the treatment results of ZMC fractures are often suboptimal. PURPOSE: The study aimed to evaluate the effectiveness of intraoperative computed tomography (ICT) in the treatment of unilateral ZMC fractures, and further study the feasibility of ICT to replace early postoperative Computed Tomography (CT). STUDY DESIGN, SETTING, AND SAMPLE: The investigators designed a retrospective cohort study. Adult patients who underwent surgery with unilateral ZMC fractures were enrolled. PREDICTOR VARIABLE: According to whether intraoperative CT was used, the subjects were divided into the ICT group and the control group (without ICT). MAIN OUTCOME VARIABLES: Five distances and 3 angles representing bilateral ZMC symmetry were main outcome variables. The differences of outcome variables were compared between the 2 groups and the indices of ICT group were further compared with their postoperative indices. COVARIATES: Demographics (eg age), etiology (eg traffic injury), dysfunction (eg diplopia), and surgical approach (eg vestibular incision) were collected as covariates while we conducted clinical investigation, examination, and implementation. ANALYSES: The data were analyzed using independent-samples t test, paired-samples t test, Mann-Whitney U test, and χ2 test. P value < .05 was considered statistically significant. RESULTS: A total of 60 patients (18 to 59 years) were enrolled in this study. All median values of the measurements in the ICT group were smaller than those in the control group, and the differences of horizontal displacement distance (0.56 vs 1.02 mm), anteroposterior displacement distance (1.69 vs 2.34 mm, 0.90 vs 2.35 mm), horizontal angle of bilateral zygomatic arch (2.31 vs 4.19°), and horizontal angle of bilateral zygomatic process (1.77 vs 2.94°) were significantly different between the 2 groups with P value < .05. Moreover, there was no statistically significant difference in all indices between the intraoperatively and postoperatively injured sides in the ICT group. CONCLUSIONS: ICT can improve the treatment outcomes of ZMC fractures by evaluating the fracture reduction adequacy during surgery. Moreover, ICT can replace early postoperative CT.

The Role of Macrophage Phenotype in the Vascularization of Prevascularized Human Bone Marrow Mesenchymal Stem Cell Sheets.

With the development of tissue engineering and regenerative medicine, prevascularized bone marrow mesenchymal stem cell (BMSC) sheets have been regarded as a promising method for tissue regeneration. Furthermore, the inflammatory response is one of the main regulators of vascularization and the restoration of engineered tissue function; among them, macrophages and cytokines produced by them are considered to be the decisive factors of the downstream outcomes. This study investigated the effect of macrophages on the formation of microvascular-like structures of human umbilical vein endothelial cells (HUVECs) in BMSC sheets. First, a human monocytic leukemia cell line (THP-1 cells) was differentiated into derived macrophages (M0) with phorbol 12-myristate 13-acetate and further activated into proinflammatory macrophages (M1 macrophages) with interferon-γ and lipopolysaccharide or anti-inflammatory macrophages (M2 macrophages) with interleukin-4. Then, HUVECs and prevascularized sheets were treated with conditioned media (CM) from different macrophages, and the impact of macrophage phenotypes on vascularized network formation in prevascularized cell sheets was examined by hematoxylin and eosin staining, CD31 immunofluorescence staining and enzyme-linked immunosorbent assay. Our study showed that macrophages may guide the arrangement of endothelial cells through a paracrine pathway. Cell sheets that were cultured in the CM from M2 macrophages were thinner than those cultured in other media. At various time points, the levels of tumor necrosis factor alpha and vascular endothelial growth factor in prevascularized sheets cultured with CM(M1) was higher than that in sheets cultured with other media; however, the levels of platelet-derived growth factor in prevascularized sheets cultured with CM(M2) was higher than that in sheets cultured with other media. These findings suggest that the paracrine effect of macrophages can influence the formation of microvascular networks in prevascularized sheets by regulating the arrangement of cells, the thickness of the cell sheet and the secretion of cytokines related to angiogenesis. Macrophages with different phenotypes have unique effects on prevascularized sheets.

The Role of Intraoperative Navigation in Surgical Treatment of Unilateral Zygomatic Complex Fractures: A Systematic Review and Meta-Analysis.

PURPOSE: The application of a computer-aided navigation system (CANS) in zygomatic complex (ZMC) fractures has been extensively reported, but individual results are heterogeneous. The purpose of this systematic review was to evaluate the role of CANS in the surgical treatment of unilateral ZMC fractures. METHODS: Electronic retrieval of MEDLINE, Embase, and Cochrane Library (CENTRAL) and manual searching until November 1, 2022 were used to identify cohort studies and randomized controlled trials employing CANS in the surgical treatment of ZMC fractures. The identified reports contained at least 1 of the following outcome variables: accuracy of reduction, total treatment time, amount of bleeding, postoperative complications, satisfaction, and cost. Weighted or mean differences (MD), risk ratios, and corresponding 95% confidence intervals (CI) were calculated, where P＜.05 and I2＞50% random-effect model was adopted, and a vice versa fixed-effect model was adopted. Descriptive analysis was applied to qualitative statistics. The protocol was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and prospectively registered with PROSPERO (CRD42022373135). RESULTS: A total of 562 studies were identified, of which 2 cohort studies and 3 randomized controlled trials with 189 participants were included. Meta-analysis indicated that employing CANS significantly decreased the reduction error (MD = -0.86, 95% CI -1.58 to -0.14; P = .02, random-effect model) compared with conventional surgery without using CANS. The differences in total treatment time (preoperative planning time: MD = 1.44, 95% CI -3.55 to 6.43; P = .57 and operative time: MD = 3.02, 95% CI -9.21 to 15.26; P = .63, fixed-effect model) and amount of bleeding (MD = 14.86, 95% CI -8.86 to 38.58; P = .22, fixed-effect model) were not statistically significant between the two groups. Descriptive analysis suggested that postoperative complications, postoperative satisfaction, and cost were also similar with or without CANS. CONCLUSION: Within the limitations of the present review, the reduction accuracy of unilateral ZMC fractures using CANS is superior to that of conventional surgery. CANS presents limited influence on operation time, amount of bleeding, postoperative complications, postoperative satisfaction, and cost.

Apatinib combined with PD-1 antibody for third-line or later treatment of advanced gastric cancer.

Background: Both apatinib and programmed death 1 (PD-1) monoclonal antibody (mAb) monotherapy have been licensed in China for the third-line treatment of advanced gastric cancer (AGC). However, whether the combination could improve the prognosis of patients with AGC after second-line treatment has not been evaluated. Methods: We retrospectively screened 892 patients with AGC who received third-line or later treatment from June 2016 to July 2021 at the Affiliated Cancer Hospital of Zhengzhou University and second People's Hospital of Pingdingshan. 166 patients who received apatinib plus PD-1 mAb, apatinib, or PD-1 mAb were included. Based on medical records and follow-up data, we analyzed the efficacy and safety of these three treatment options. Results: Patients received apatinib plus PD-1 mAb (n=49), apatinib monotherapy (n=63), or PD-1 mAb monotherapy (n=54). Apatinib plus PD-1 mAb showed significantly longer progression-free survival (PFS) and overall surivival (OS) compared with the apatinib monotherapy (PFS: 5.5 months versus 3.0 months; p=0.002; OS: 10 months versus 7.6 months; p=0.011) or PD-1 mAb monotherapy (PFS: 5.5 months versus 2.3 months; p=0.017; OS: 10 months versus 6.5 months; p=0.004). Apatinib plus PD-1 mAb showed higher ORR and DCR than the apatinib and PD-1 mAb monotherapy (ORR: 34.7% versus 6.3% versus 9.3%; p=0.001; DCR: 75.5% versus 44.4% versus 40.7%; p=0.001). Further subgroup analysis for PFS and OS shown consistent efficacy in most subgroups with apatinib plus PD-1 mAb versus apatinib monotherapy or PD-1 mAb monotherapy. Multivariate analyses suggested that apatinib plus PD-1 mAb was significantly associated with better PFS and OS. Most of the treatment-related toxicities were mild and tolerable. Conclusion: Compared with the monotherapy of either apatinib or PD-1 mAb, apatinib plus PD-1 mAb treatment yielded longer PFS and OS, and achieved significant higher ORR and DCR.

Genetic deconvolution of fetal and maternal cell-free DNA in maternal plasma enables next-generation non-invasive prenatal screening.

Current non-invasive prenatal screening (NIPS) analyzes circulating fetal cell-free DNA (cfDNA) in maternal peripheral blood for selected aneuploidies or microdeletion/duplication syndromes. Many genetic disorders are refractory to NIPS largely because the maternal genetic material constitutes most of the total cfDNA present in the maternal plasma, which hinders the detection of fetus-specific genetic variants. Here, we developed an innovative sequencing method, termed coordinative allele-aware target enrichment sequencing (COATE-seq), followed by multidimensional genomic analyses of sequencing read depth, allelic fraction, and linked single nucleotide polymorphisms, to accurately separate the fetal genome from the maternal background. Analytical confounders including multiple gestations, maternal copy number variations, and absence of heterozygosity were successfully recognized and precluded for fetal variant analyses. In addition, fetus-specific genomic characteristics, including the cfDNA fragment length, meiotic error origins, meiotic recombination, and recombination breakpoints were identified which reinforced the fetal variant assessment. In 1129 qualified pregnancies tested, 54 fetal aneuploidies, 8 microdeletions/microduplications, and 8 monogenic variants were detected with 100% sensitivity and 99.3% specificity. Using the comprehensive cfDNA genomic analysis tools developed, we found that 60.3% of aneuploidy samples had aberrant meiotic recombination providing important insights into the mechanism underlying meiotic nondisjunctions. Altogether, we show that the genetic deconvolution of the fetal and maternal cfDNA enables thorough and accurate delineation of fetal genome which paves the way for the next-generation prenatal screening of essentially all types of human genetic disorders.

Key Targets and Molecular Mechanisms of Active Volatile Components of Rabdosia rubescens in Gastric Cancer Cells.

OBJECTIVE: To examine the effect and mechanism of volatile components of Rabdosia rubescens on gastric cancer. METHODS: Gas chromatography-mass spectrometry was used to detect and identify the volatile components of R. rubescens. The network pharmacology method was used to analyze the targets of volatile components of R. rubescens in gastric cancer and to reveal their molecular mechanisms. The effects of volatile components of R. rubescens on gastric cancer cells were verified by biological experiments. RESULTS: Thirteen volatile components of R. rubescens were selected as pharmacologically active components. The 13 active components had 83 targets in gastric cancer, and a Traditional Chinese Medicine-component-targets gastric cancer network was successfully constructed. Five core targets were obtained: TNF, IL1B, MMP9, PTGS2 and CECL8. The volatile components inhibited the proliferation of gastric cancer cells in a concentration-dependent manner and promoted the apoptosis of gastric cancer cells. The volatile components reduced the levels of TNF, IL1B, MPP9, and PTGS2 in a concentration-dependent manner. CONCLUSION: Our study demonstrates the effects of volatile components in R. rubescens on gastric cancer and provides preliminary findings on their mechanisms of action.

Macrophage Infiltration Initiates RIP3/MLKL-Dependent Necroptosis in Paclitaxel-Induced Neuropathic Pain.

Paclitaxel (PTX) is a commonly used antitumor drug. Approximately 80% of all patients receiving PTX chemotherapy develop chemotherapy-induced peripheral neuropathy (CIPN), limiting the use of PTX. Moreover, CIPN responds poorly to conventional analgesics. Experimental evidence suggests that the neuroinflammatory response plays an essential role in paclitaxel-induced peripheral neuropathy (PIPN). Previous studies have confirmed that dorsal root ganglion (DRG) neuron necroptosis and accompanying inflammation are linked with PIPN; however, the potential upstream regulatory mechanisms remain unclear. Preclinical studies have also established that macrophage infiltration in the DRG is associated with PIPN. TNF-α released by activated macrophages is the primary regulatory signal of necroptosis. In this study, we established a rat model of PIPN via quartic PTX administration (accumulated dose: 8 mg/kg, i.p.). The regulatory effect of macrophage infiltration on necroptosis in PIPN was observed using a macrophage scavenging agent (clodronate disodium). The results showed that PTX increased macrophage infiltration and the levels of TNF-α and IL-1ß in the DRG. PTX also upregulated the levels of necroptosis-related proteins, including receptor-interacting protein kinase (RIP3) and mixed-lineage kinase domain-like protein (MLKL) in DRG neurons and promoted MLKL phosphorylation, resulting in neuronal necrosis and hyperalgesia. In contrast, clodronate disodium effectively removed macrophages, reduced the levels of RIP3, MLKL, and pMLKL, and decreased the number of necrotic cells in the DRG of PIPN rats, alleviating the behavioral pain abnormalities. These results suggest that PTX promotes macrophage infiltration, which results in the release of TNF-α and IL-1ß in the DRG and the initiation of neuronal necroptosis via the RIP3/MLKL pathway, ultimately leading to neuropathic pain.

Anlotinib in recurrent or metastatic endometrial cancer.

OBJECTIVE: For recurrent or metastatic endometrial cancer after second-line treatment, therapeutic options are limited. Anlotinib is a new multi-targeted tyrosine kinase inhibitor of tumor angiogenesis and growth. The aim of this study was to explore the efficacy and safety of anlotinib in patients with recurrent or metastatic endometrial cancer. METHODS: Patients with recurrent or metastatic endometrial cancer who received anlotinib or anlotinib plus pembrolizumab after second-line treatment between July 2017 and October 2020 were analyzed. Objective response rate, disease control rate, progression-free survival, overall survival, and safety were evaluated. RESULTS: A total of 56 patients were analyzed. The median age was 62 years (range 42-80). The median treatment of anlotinib was 5.9 cycles (range 2-21). The overall objective response rate was 42.9%, and the disease control rate was 75%. 44 (78.6%) patients received anlotinib monotherapy and 12 (21.2%) patients received anlotinib plus pembrolizumab. The objective response rate was 40.9% versus 50% (p=0.52) and the disease control rate was 72.7% versus 83.3% (p=0.59) in the monotherapy group and the combination therapy group, respectively. The median progression-free survival and overall survival from initiation of anlotinib therapy was 6 months (95% CI 4.89 to 7.11) and 13.3 months (95% CI 9.94 to 16.61), respectively. On multivariable Cox analysis, age (>60 vs ≤60 years) was an independent impact factor for both progression-free survival and overall survival, while prior lines of treatment (2 lines vs ≥3 lines) was an independent predictor of progression-free survival. The incidences of grade 3/4 adverse events were hypertension (10.7%), fatigue (7.1%), hand-foot syndrome (7.1%), proteinuria (3.6%), sore throat (3.6%), and hypothyroidism (3.6%). CONCLUSION: Anlotinib is effective and well tolerated in patients with recurrent or metastatic endometrial cancer. It may be considered a choice for patients younger than 60 years and who have had <3 lines of treatment.

Assessment of the efficacy of tuina on treating cervicogenic headache: A protocol for systematic review and meta-analysis.

BACKGROUND: Cervicogenic headache is a secondary headache characterized by unilateral headache, symptoms, and signs of neck involvement. It is often worsened by neck movement, sustained awkward head position, or external pressure over the upper cervical or occipital region on the symptomatic side. In this systematic review, we aimed to evaluate the efficacy and safety of massage therapy for the treatment of cervicogenic headache. METHODS: We searched the China National Knowledge Infrastructure, Chinese Scientific Journal Database, Wanfang Database, China Doctoral Dissertations Full-Text Database, China Master's Theses Full-Text Database, Cochrane Central Register of Controlled Trials, PubMed, and Embase. We will select all eligible studies published on or before April 1, 2021. We will use Review Manager 5.4, provided by the Cochrane Collaborative Network for statistical analysis. We then assessed the quality and risk of the included studies and observed the outcome measures. RESULTS: This meta-analysis further confirmed the benefits of tuina in the treatment of cervicogenic headache. CONCLUSION: The purpose of this meta-analysis was to explore the effect of tuina on patients with cervicogenic headache and to provide more options for clinicians and patients to treat cervicogenic headache. ETHICS AND DISSEMINATION: This systematic review will evaluate the efficacy and safety of tuina in the treatment of cervicogenic headache. Since all the data included were published, the systematic review did not require ethical approval. REGISTRATION NUMBER: INPLASY202150053.

RIP3/MLKL pathway-regulated necroptosis: A new mechanism of paclitaxel-induced peripheral neuropathy.

Paclitaxel (PTX) chemotherapy treatment often leads to neuropathic pain, which is resistant to available analgesic treatments. Death of cells and neuroinflammatory response are associated with PTX-induced peripheral neuropathy (PIPN). Necroptosis is a form of regulated necrotic cell death that accompanies strong inflammatory response. It is mediated by receptor-interacting protein kinase 3 (RIP3) and mixed-lineage kinase domain-like protein (MLKL), which contribute to the pathogenesis of several neurodegenerative diseases. Nevertheless, the role of necroptosis in PIPN remains unexplored. The aim of this study was to investigate the role of necroptosis in PIPN using its antagonists (necrostatin-1 and Nec-1). The quartic PTX administration (accumulated dose: 8 mg/kg, ip) in rats induced robust hyperalgesia and allodynia with significant cell necrosis and an increase in proinflammatory cytokines in the dorsal root ganglion (DRG). PTX application also increased RIP3 and MLKL protein levels in DRG, which were primarily in neurons. Moreover, it also promoted satellite glial cells (SGCs) activation, as assayed by glial fibrillary acidic protein (GFAP) upregulation. All these PTX-induced changes were prevented by the Nec-1 treatment. When taken together, the present study indicated that RIP3/MLKL pathway-regulated neuronal necroptosis, which promoted an inflammatory cascade reaction in DRG, might be a new mechanism of PIPN.

Immunoglobulin (Ig) G4-related sclerosing cholangitis in patients resected for presumed perihilar cholangiocarcinoma: a 10-year experience.

BACKGROUND: This study aimed to investigate the incidence of immunoglobulin (Ig) G4-related sclerosing cholangitis (IgG4-SC) in patients resected for perihilar cholangiocarcinoma (PHC) in a designated hospital from 2010 to 2019. We also aimed to evaluate the diagnostic dilemma of IgG4-SC clinically. METHODS: Between January 2010 and December 2019, all patients who underwent radical resection due to presumed PHC were included. Independent pathologists scored bile duct samples based on the International Consensus Pathology Criteria for IgG4-related Disease (ICPD). RESULTS: Of the 289 patients who underwent radical resection of primary liver cancer, 26 (9%) were diagnosed as benign, without histological evidence of malignancy, among them, 23 had sclerosing inflammation, 1 had cystadenoma, and 2 had xanthogranulomatous cholangitis. Additionally, 18 had a definitive diagnosis of IgG4-SC. The misdiagnosis rate was 19% (54/289), of which, 26 patients had benign disease, and 28 patients had malignancies. CONCLUSIONS: It is difficult to distinguish IgG-SC from PHC. The misdiagnosis has resulted in a large number of ineffective hepatectomies. Improving the detection rate of serum IgG4 (sIgG4) may therefore avoid misdiagnosis, surgery, and life-threatening complications.

Novel core-shell CHX/ACP nanoparticles effectively improve the mechanical, antibacterial and remineralized properties of the dental resin composite.

OBJECTIVE: The core-shell chlorhexidine/amorphous calcium phosphate (CHX/ACP) nanoparticles were synthesized and used to modify the dental resin composite, aiming to improve its remineralized and antibacterial properties. METHODS: The core-shell CHX/ACP nanoparticles were synthesized by vesicle-templating technology and characterized, and their sustained release and antibacterial properties were also evaluated. Subsequently, the synthesized nanoparticles were incorporated into the dental resin composite at 1 wt.%, 5 wt.% or 10 wt.% to obtain different experimental groups. The physical properties, including curing depth, double bond conversion rate, water absorption and solubility, the sustained-release effects, and mechanical properties of the modified resin composite were evaluated. The remineralization ability was also measured by SEM. The antibacterial experiment of the modified resin composite with fresh preparation or aging in water for 28 days was carried out by a plate count method. RESULTS: The physical and chemical characterizations showed that the synthesized nanoparticles presented a core-shell structure, and their diameter was about 98.5 nm. The shell was composed of ACP with the core full of CHX. These nanoparticles had a release effect on calcium, phosphate ions, and CHX. The nanoparticles could effectively inhibit the growth of S. mutan at a lower concentration (≥50 µg/mL). The curing depth, the double bond conversion, the water absorption, the solubility, the flexural strength, the flexural modulus, and the compressive strength of the modified resin composite were 3.86-4.88 mm, 62.32-73.61%, 1.47-2.84%, 0.21-0.48%, 45.83-109.46 MPa, 2.57-4.91 GPa, and 66.43-160.38 MPa, respectively. The modified resin composite containing 5 wt.% and above CHX/ACP nanoparticles could effectively inhibit the growth of S. mutans regardless of aging in water, with immediate and aging antibacterial rate of more than 92%. In addition, the modified resin composite had a certain remineralization property in the SBF solution verified by SEM. SIGNIFICANCE: The core-shell CHX/ACP nanoparticles were successfully prepared and used to modify the resin composite. The modified dental resin composite with 5 wt.% CHX/ACP nanoparticles had excellent mechanical, antibacterial, and remineralization properties. It is expected to be an ideal restorative filling material for clinical application.

A Retrospective Observational Study of Anlotinib in Patients with Platinum-Resistant or Platinum-Refractory Epithelial Ovarian Cancer.

OBJECTIVE: Anlotinib, an oral small-molecular tyrosine kinase inhibitor (TKI) on tumor angiogenesis and growth, has a wide spectrum of inhibitory effects on targets such as vascular endothelial growth factor receptors 2/3 (VEGFR2/3), etc. The efficacy and safety of anlotinib in the treatment of platinum-resistant or platinum-refractory ovarian cancer were evaluated. PATIENTS AND METHODS: Patients with platinum-resistant or platinum-refractory ovarian cancer that treated with anlotinib in the Affiliated Cancer Hospital of Zhengzhou University from May 2018 to March 2020 were included. Medical records were reviewed in terms of objective response, survival outcomes, and safety. RESULTS: A total of 38 patients were analyzed. The median progression-free survival and the median overall survival were 7.7 months (95% CI: 6.7-8.7) and 16.5 months (95% CI: 13.3-19.7), respectively. About 17 patients received anlotinib monotherapy, and the median progression-free survival was 7.7 months (95% CI: 6.3-9.1). A total of 19 cases received anlotinib plus chemotherapy with a median progression-free survival of 8.0 months (95% CI: 4.8-11.2). A total of 2 cases received anlotinib plus anti-PD-1 antibody pembrolizumab, and 1 case had partial response, the other progressive disease. The objective response rate was 42.1% while the disease control rate was 86.8%. A total of 5 patients experienced dose reduction from 12 mg to 10 mg because of adverse effects. The most common adverse effects were hypertension (31.6%), fatigue (28.9%), anorexia (26.3%) and hand-foot syndrome (23.7%). No treatment-related deaths were recorded. CONCLUSION: Anlotinib produced moderate improvements in progression-free survival and overall survival in patients with platinum-resistant or platinum-refractory ovarian cancer. It indicates that anlotinib maybe a new treatment option for patients with platinum-resistant or platinum-refractory ovarian cancer.

Mild hypothermia protects rat cortical neurons against oxygen-glucose deprivation/reoxygenation injury via the PI3K/Akt pathway.

Ischemic stroke is the most frequent cause of long-term morbidity and mortality in the elderly worldwide. Mild hypothermia (32-35°C) has been found to have a neuroprotective effect against ischemic stroke. However, the protective mechanisms remain unclear. In the present study, we explore the neuroprotective effect of mild hypothermia in neuron-astrocyte cocultures by oxygen-glucose deprivation/reoxygenation (OGD/R) as well as the underlying mechanisms. Thionin staining was performed and cell viability, extracellular glutamate concentration and the phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) pathway-related proteins were detected after OGD/R. The results indicated that mild hypothermia significantly alleviated damage to Nissl bodies and increased the viability of neurons, which alleviated OGD/R-triggered neuronal injury. Furthermore, mild hypothermia significantly enhanced the phosphorylation of Akt (pAkt) and glutamate transporter-1 (GLT-1) and reduced extracellular glutamate concentration after OGD/R. When the PI3K inhibitor LY294002 was added, neuronal viability and the expression of pAkt and GLT-1 decreased, and extracellular glutamate concentration increased. The protective effect of mild hypothermia was counteracted by LY294002. There was no significant change in neuronal viability or the expression of pAkt and GLT-1 in the group treated with dihydrokainate, an inhibitor of GLT-1-function, compared with the mild hypothermia + OGD/R (HOGD) group, but extracellular glutamate concentration was increased. Consequently, mild hypothermia promoted glutamate clearance by regulating GLT-1 expression via the PI3K/Akt pathway, providing a neuroprotective effect against OGD/R injury.

Acupuncture combine with Tuina for diabetic peripheral neuropathy: A protocol for a systematic review and meta-analysis.

BACKGROUND: Diabetic peripheral neuropathy (DPN) is one of the most common microvascular complications of diabetes mellitus, with an incidence ranging from 60% to 90%. With the change in modern dietary structure, the incidence of diabetes is increasing year by year, and DPN is also on the rise. Acupuncture and Tuina treatments are often combined to treat DPN; however, there has been no meta-analysis on their synergistic effect; therefore, we aimed to perform a systematic review and meta-analysis to estimate the effectiveness of acupuncture combined with Tuina in DPN treatment. METHODS: Nine electronic databases were retrieved for this study. The English databases mainly retrieved PubMed, Web of Science, Embase, AMED, and the Cochrane Library, while the CNKI, VIP, CBM, and Wanfang databases were used to retrieve the Chinese literature; there was no definite time limit for the retrieval literature, and the languages were limited to Chinese and English. We will consider articles published between database initiation and November 2021. We used Review Manager 5.4 software provided by the Cochrane Collaborative Network for statistical analysis. We then assessed the quality and risk of the included studies and observed the outcome measures. RESULTS: This study provides a high-quality synthesis to assess the effectiveness and safety of acupuncture combined with Tuina for treating DPN. CONCLUSION: This systematic review provided evidence to determine whether acupuncture combined with Tuina is an effective and safe intervention for patients with DPN. ETHICS AND DISSEMINATION: The protocol for this systematic review does not require ethical approval because it does not involve humans. This article will be published in peer-reviewed journals and presented at relevant conferences. SYSTEMATIC REVIEW REGISTRATION: INPLASY2021110017.