ObjectiveThis study aims to investigate the action mechanism by which Xiaozheng Zhitong paste （XZP） alleviates bone cancer pain （BCP） by regulating programmed death protein 1 （PD-1）/programmed death-ligand 1 （PD-L1） pathway-induced osteoclast formation. MethodsThirty female C57BL/6 mice were randomly allocated into the following groups （n=6 per group）： normal control group， model group， low‑dose XZP group （31.5 g·kg^-1）， high‑dose XZP group （63 g·kg^-1）， and PD‑1 inhibitor （Niv） group. A bone cancer pain （BCP） model was established by injecting Lewis lung carcinoma cells. Mice in the normal control and model groups received topical application of a blank paste matrix at the wound site. Mice in the low‑ and high‑dose XZP groups were treated with XZP applied topically twice daily. Mice in the Niv group were topically administered the blank paste matrix and additionally received Niv via tail‑vein injection every two days. All interventions were continued for 21 days. During this period， behavioral tests were performed to assess mechanical， motor， and thermal nociceptive sensitivities. After 21 days， all mice were euthanized， and bone tissue from the operated side was collected for sectioning and preservation. Tartrate‑resistant acid phosphatase （TRAP） staining was used to evaluate osteoclast expression in the lesioned bone tissue. Immunohistochemistry was performed to detect the expression of Runt‑related transcription factor 2 （Runx2） in the lesioned bone tissue. Immunofluorescence was employed to assess the expression of PD‑1 and PD‑L1 in the lesioned bone tissue. ResultsCompared with the normal group， the model group showed significantly decreased limb mechanical withdrawal threshold， spontaneous paw flinching， and thermal withdrawal latency （P<0.01）， increased number of osteoclasts in the lesioned bone tissue （P<0.01）， and reduced expression of Runx2 （P<0.01）. Compared with the model group， the BCP mice in the XZP low-dose group， XZP high-dose group， and Niv group exhibited increased limb mechanical withdrawal threshold， movement scores， and thermal withdrawal latency （P<0.01）. The XZP low-dose group showed no significant changes in osteoclast number or Runx2 expression， while the XZP high-dose group and Niv group demonstrated significantly reduced osteoclast numbers （P<0.01） and significantly increased Runx2 expression （P<0.01）. In the lesioned bone tissue of BCP mice， the XZP low-dose group showed no significant decrease in the percentage of PD-1 expression， but a decrease in the percentage of PD-L1 expression （P<0.05）. In contrast， both the XZP high-dose group and the Niv group exhibited significant reductions in the percentages of PD-1 and PD-L1 expression （P<0.01）. ConclusionXZP alleviates the pain of mice with BCP by blocking the PD-1/PD-L1 pathway to inhibit osteoclastogenesis.

ObjectiveTo investigate the effects and underlying mechanisms of Xiaozheng Zhitong Paste （XZP） on bone cancer pain （BCP）. MethodsThirty female BALB/c mice were randomly divided into five groups： a Sham group， a BCP group， a BCP+low-dose XZP group， a BCP+high-dose XZP group， and a BCP+high-dose XZP + protease-activated receptor 2 （PAR2） agonist GB-110 group. BCP mice model was constructed by injecting Lewis lung carcinoma cells into the femoral cavity of the right leg， which was followed by being treated with XZP for 21 d. After 21 d， the mice were sacrificed. Nissl staining was used to evaluate the survival of spinal cord neurons. Immunofluorescence staining was conducted to localize ionized calcium-binding adapter molecule 1 （Iba1） and neuronal nuclear antigen （NeuN） in spinal cord tissue， thereby assessing microglial activation and neuronal survival. Enzyme-linked immunosorbent assay （ELISA） was employed to measure the levels of interleukin-1β （IL-1β）， tumor necrosis factor-α （TNF-α）， interleukin-6 （IL-6）， transforming growth factor-β （TGF-β）， interleukin-4 （IL-4）， and interleukin-10 （IL-10） in spinal cord tissue. Real-time quantitative polymerase chain reaction （Real-time PCR） was used to detect mRNA expression levels associated with M1/M2 polarization of microglia. Western blot analysis was performed to examine the expression of proteins related to microglial polarization as well as those involved in the PAR2/nuclear factor kappa B （NF-κB）/NOD-like receptor protein 3 （NLRP3） signaling pathway in the spinal cord. ResultsCompared with the Sham group， the spinal cord neurons were damaged， the number of Nissl-positive spinal cord neurons in the spinal cord tissue was significantly reduced （P<0.01）， and the rate of NeuN-positive cells was significantly decreased （P<0.01）. The spinal cord microglia were activated， the inflammatory level of the spinal cord tissue was enhanced， and Iba1 staining was significantly enhanced （P<0.01）. The levels of IL-1β， TNF-α， IL-6， TGF-β， IL-4 and IL-10 were significantly increased （P<0.01）. The mRNA expressions of IL-1β， TNF-α and inducible nitric oxide synthase （iNOS） were significantly increased （P<0.01）， and the expression of PAR2， NLRP3， ASC and NF-κB p65 proteins in the spinal cord tissue of the BCP mice was significantly enhanced （P<0.01）. Compared with the BCP group， high-dose XZP treatment significantly increased the number of Nissl-positive spinal cord neurons in the BCP mice （P<0.01）， significantly enhanced the rate of NeuN-positive cells in the spinal cord tissue， and significantly weakened Iba1 staining （P<0.01）. In addition， the levels of IL-1β， TNF-α， and IL-6 were significantly decreased， while the levels of TGF-β， IL-4， and IL-10 were significantly increased （P<0.05， P<0.01）. The mRNA expression levels of IL-1β， TNF-α， and iNOS were decreased， whereas those of cluster of differentiation 206 （CD206）， arginase-1 （Arg-1）， and YM1/2 were significantly increased （P<0.05， P<0.01）. Low-dose and high-dose XZP treatment significantly decreased the expression of PAR2， NLRP3， ASC， and NF-κB p65 proteins in the spinal cord tissue （P<0.05， P<0.01）. These effects could all be significantly eliminated by the PAR2 agonist GB-110. ConclusionXZP can mitigate BCP in mice， which may be achieved through blocking the activated PAR2/NF-κB/NLRP3 pathway.

ObjectiveThe paper aims to investigate the action mechanism by which the Xiaozheng Zhitong paste （XZP） relieves bone cancer pain （BCP）. MethodsA model of mice with BCP was established by using Lewis tumor cells. The therapeutic effects of XZP， the ferroptosis inhibitor Ferrostatin-1 （Fer-1）， and the nuclear factor erythroid 2-related factor 2 （Nrf2） inhibitor Brusatol （Bru） on BCP were examined. Mice were randomly divided into the Sham operation group， BCP group， BCP+XZP-L group， BCP+XZP-H group， BCP+Fer-1 group， and BCP+XZP-H+Bru group， with six mice in each group. Pain behavior tests were conducted on the mice to assess pain levels. Colorimetric assays were employed to measure ferroptosis-related factors in serum and spinal cord tissue including Fe， malondialdehyde （MDA）， reactive oxygen species （ROS）， and superoxide dismutase （SOD）. Immunofluorescence staining was used to assess ROS production in spinal cord tissue. Transmission electron microscopy was used to observe the ultrastructure of mitochondria in lumbar spinal cord tissue. Quantitative real-time polymerase chain reaction （Real-time PCR） was employed to detect mRNA expression of Nrf2， heme oxygenase-1 （HO-1）， glutathione peroxidase 4 （GPX4）， and solute carrier family 7 member 11 （SLC7A11） in spinal cord neuron tissue. The protein expression of Nrf2， HO-1， GPX4， and SLC7A11 in spinal cord neurons was measured by Western blot. ResultsCompared with the Sham group， mice in the BCP group exhibited significantly reduced limb usage scores， mechanical foot withdrawal thresholds， and thermal foot withdrawal thresholds （P<0.01）. Serum and lumbar spinal cord tissue levels of Fe， MDA， and reactive oxygen species （ROS） were significantly elevated （P<0.05）， while superoxide dismutase （SOD） levels were significantly decreased （P<0.05）. Lumbar spinal cord mitochondrial structural damage was observed， and mRNA and protein expression of Nrf2， HO-1， GPX4， and SLC7A11 were significantly downregulated （P<0.01）. Compared with the BCP group， both low- and high-dose XZP groups improved the aforementioned pain behavioral indicators （P<0.05，P<0.01）， reduced ferroptosis-related biomarkers including Fe， MDA， and ROS levels （P<0.05）， increased SOD levels （P<0.05，P<0.01）， alleviated mitochondrial damage， and upregulated Nrf2， HO-1， GPX4， SLC7A11 mRNA and protein expression （P<0.05，P<0.01）. The high-dose XZP group exhibited comparable efficacy to Fer-1 in alleviating pain and inhibiting ferroptosis. Following Bru administration， XZP's effects on pain behavioral indicators， regulation of ferroptosis-related markers， mitochondrial structural protection， and activation of the Nrf2/HO-1/GPX4/SLC7A11 pathway were significantly reversed （P<0.05，P<0.01）. ConclusionExternal application of XZP alleviates pain symptoms in BCP mice by activating the Nrf2/HO-1/GPX4/SLC7A11 pathway， thereby inhibiting ferroptosis and neuronal damage in spinal cord neurons.

Pain， as one of the most common symptoms in cancer patients， seriously affects the survival quality of patients. The three-step pain relief program currently used in clinical practice cannot completely relieve pain in cancer patients and is accompanied by many problems. From the perspective of Jueyin syndrome in traditional Chinese medicine （TCM）， this paper believed that the core pathogenesis of cancer pain was declined healthy Qi and cold and heat in complexity， and used Wumeiwan as the main formula with modification according to syndrome for clearing the upper， warming the lower part of the body， and harmonizing the cold and heat. It can regulate the pathological environment of deficiency， cold， stasis， toxicity， and heat， and restore the physiological function of Yang transforming Qi while Yin constituting form， so as to prevent， relieve， and even eliminate cancer pain， having achieved good clinical efficacy. It can not only help cancer patients relieve pain， but also control tumor and eliminate tumor， achieving a dual benefit of pain relief and tumor suppression. It gives full play to the characteristics and advantages of syndrome differentiation and treatment in TCM， and expands the scope of ZHANG Zhongjing's treatment for Jueyin syndrome， which provides ideas for the clinical diagnosis and treatment of cancer pain from the perspective of deficiency-excess in complexity and cold and heat in complexity.

Sigma-1 receptor (σ ₁R) has become a focus point of drug discovery for central nervous system (CNS) diseases. A series of novel 1-phenylethan-1-one O-(2-aminoethyl) oxime derivatives were synthesized. In vitro biological evaluation led to the identification of 1a, 14a, 15d and 16d as the most high-affinity (K _i < 4 nmol/L) and selective σ ₁R agonists. Among these, 15d, the most metabolically stable derivative exhibited high selectivity for σ ₁R in relation to σ ₂R and 52 other human targets. In addition to low CYP450 inhibition and induction, 15d also exhibited high brain permeability and excellent oral bioavailability. Importantly, 15d demonstrated effective antipsychotic potency, particularly for alleviating negative symptoms and improving cognitive impairment in experimental animal models, both of which are major challenges for schizophrenia treatment. Moreover, 15d produced no significant extrapyramidal symptoms, exhibiting superior pharmacological profiles in relation to current antipsychotic drugs. Mechanistically, 15d inhibited GSK3β and enhanced prefrontal BDNF expression and excitatory synaptic transmission in pyramidal neurons. Collectively, these in vivo proof-of-concept findings provide substantial experimental evidence to demonstrate that modulating σ ₁R represents a potential new therapeutic approach for schizophrenia. The novel chemical entity along with its favorable drug-like and pharmacological profile of 15d renders it a promising candidate for treating schizophrenia.

Objective:To systematically sort out and cluster the existing indicators of key issues in the quality of postgraduate clinical degree education based on the bibliometric study, so as to build a multidimensional quality assessment index system that integrates scientificity, rationality and representativeness, and to provide a scientific measurement tool for assessing clinical professional postgraduate education in China.Methods:By mining the related functions of UCINET6 network analysis integration software and its one-dimensional and two-dimensional data analysis NetDraw program, the social network analysis (SNA) method was used to extract and cluster the education quality problem set of clinical professional degree postgraduates.Results:A three-dimensional evaluation index system was constructed. The first dimension concluded such 8 key issues in the quality of postgraduate education in clinical medicine as ability assessment, teaching system, teaching quality assurance system, professional cognition and career prospects, assessment and evaluation system and organization, and the pulse taking and diagnosis.Conclusion:The clinical graduate education quality evaluation index system is an effective measurement tool for education quality improvement, based on a multidimensional perspective, with key issues as priority areas for intervention, providing an effective evidence-based basis for ensuring the development of professional graduate education efforts from 2020-2025.

Objective:To explore the correlations between circulating tumor cells (CTCs) level in peripheral venous blood and clinicopathological characteristics and biomarkers of lung cancer patients using CI-101 cell search immunomagnetic bead enrichment technology combined with fluorescent cytochemical staining.Methods:Blood samples were collected from 100 patients with first-diagnosed lung cancer treated in Department of Thoracic Surgery and Department of Cardiothoracic Surgery of Yunnan Cancer Hospital from March 2014 to September 2014, 40 patients with lung benign tumor (all confirmed by pathological biopsy) and 30 healthy volunteers from the physical examination center. CTCs in peripheral blood were enriched by CI-101 cell search immunomagnetic bead, the morphology of CTCs was analyzed by immunocytofluorescence technique, and tumor cells were identified using HE cell staining method. The recovery rate, sensitivity and specificity of CI-101 cell search instrument for CTCs were detected. The difference of positive rate of CTCs in peripheral blood among lung cancer patients, lung benign tumor patients and healthy volunteers was compared. The relationship between the positive rate of CTCs and the clinicopathological characteristics of patients with lung cancer was analyzed. The correlations between CTCs and serum tumor markers were analyzed by coefficient of contingency in patients with lung cancer and lung benign tumor.Results:The recovery rate of CTCs by CI-101 cell search instrument was 72.0%-89.0%, and there was a significant linear correlation between the number of recovered cells and the number of incorporated cells. The correlation coefficient r=0.998 ( P<0.001), the linear regression equation was y=0.781 x+ 11.307, the sensitivity was 85.0%, and the specificity was 71.4%. The positive rate of CTCs in lung cancer patients (85.0%, 85/100) was higher than that in lung benign tumor patients (15.0%, 6/40) and healthy volunteers (46.7%, 14/30) ( χ2=62.798, P<0.001). The positive rate of CTCs in lung cancer patients was correlated with TNM stage ( χ2=19.059, P<0.001), tumor size ( χ2=13.830, P<0.001) and distant metastasis ( χ2=6.005, P=0.014). Coefficient of contingency analysis showed that the positive of CTCs was positively correlated with serum tumor markers CEA ( φ=0.217, P=0.011), CA125 ( φ=0.198, P=0.020), CA199 ( φ=0.169, P=0.049), CA742 ( φ=0.186, P=0.037) and cytokeratin 19 fragment ( φ=0.461, P<0.001) in patients with lung cancer and lung benign tumor. Conclusion:The application of CI-101 cell search instrument combined with immunomagnetic bead method can successfully enrich CTCs in peripheral venous blood of lung cancer patients. The positive rate of CTCs in patients with lung cancer has obvious correlation with tumor size, TNM stage, distant metastasis, serum tumor markers. It can be used as an auxiliary indicator for monitoring the condition of lung cancer patients.

Objective? To explore the effect of hierarchical management mode in family rehabilitation in out-of-hospital nursing of elderly patients with chronic obstructive pulmonary disease (COPD). Methods? The elderly patients with COPD at stable stage in two communities were divided into the observation group (n=33) and the control group (n=31) based on the unit of community. The observation group was managed by family oxygen therapy and rehabilitation training guided by hierarchical management mode, while the control group received routine community care for chronic diseases. Exercise of Self-Care Agency Scale(ESCA) and Health Promoting Lifestyle Profile(HPLP) were used to compare the intervention effect of the two groups and count the acute episodes of COPD during the intervention period of the two groups. Results? Before intervention, there were no statistical differences in both of the dimensional scores of ESCA and HPLP scales between the two groups (P＞0.05). After 12 months of intervention, the dimensional scores of "health knowledge" (41.76±6.20), "self-responsibility"(22.94±8.22), and "self-nursing skills" (25.85±6.46) in ESCA of the observation group were higher than those of the control group with statistical significance(t=2.894, 4.138, 6.096;P＜ 0.05); in the observation group, the dimensional score of "health responsibility" was(23.79±7.44),"mental growth" was (16.70±3.73), "stress management" was (17.09±5.44), "interpersonal relationship" was (17.97±4.54), "sports activity" was (15.70±4.57), "nutrition" was (16.70±4.10), all higher than the control group with statistical significance (t=3.184,3.365,3.212,5.277,5.131,4.589;P＜ 0.05). Within the 12 months of intervention, there were 11 cases in the observation group and 4 cases in the control group without acute episodes of COPD, and the difference was statistically significan(t Z=2.166,P＜ 0.05). Conclusions? Hierarchical management mode infamily rehabilitation can effectively improve the elderly COPD patients' compliance of family oxygen therapy and rehabilitation training,hence improve their prognosis.

Objective To detect mutations of the ABCA12 gene in 2 Chinese families with autosomal recessive congenital ichthyosis (ARCI).Methods According to the typical clinical manifestations,two probands were diagnosed with ARCI.DNA was extracted from the peripheral blood samples collected from the patients and their parents.High-throughput sequencing was conducted by using multi-gene array for genetic skin disorders to determine mutation sites in the probands,and then DNA isolated from the probands and their parents were bidirectionally verified by Sanger sequencing.Results Two compound heterozygous mutations (c.2759A＞G and c.7004A＞G) in the ABCA12 gene were found in the proband 1,and another two compound heterozygous mutations (c.6163_6164insT and c.7406G＞A) were identified in the proband 2.The parents of the two probands were heterozygous carriers of one of the two mutations in the ABCA12 gene.Function prediction for the 4 mutations showed that all of the 3 missense mutations (c.2759A＞G,c.7004A＞G and c.7406G＞A) may exert pathogenic effect,and fragnin encoded by the frameshift mutation c.6163_6164insT may also affect protein function,c.2759A＞G and c.6163_6164insT were newly identified mutation sites.Conclusion The compound heterozygous mutations in the ABCA 12 gene are the causative mutations responsible for ARCI in the two probands of the two pedigrees.

Objective To report a case of X-linked ichthyosis complicated by Mal de Meleda,and to identify the gene mutations.Methods Clinical data were collected from the patient,and peripheral blood samples were obtained from the patient,his parents and 100 unrelated healthy people who served as controls.Genomic DNA was extracted from these blood samples,and PCR was performed to amplify all the exons and their flanking sequences of the SLURP-1 and STS genes.All the amplification products were analyzed by agarose gel electrophoresis,and amplification products of the SLURP-1 gene were analyzed by DNA sequencing.Results The patient presented with regularly-arranged polygonal brown or black scales all over the trunk and limbs,erythematous hyperkeratotic lesions on the palms and soles,elbows and knees,inguinal and perianal regions,which extended to the dorsa of the hands and feet.Then,the patient was diagnosed with X-linked ichthyosis complicated by Mal de Meleda.Genetic testing showed complete deletion of the STS gene,and a homozygous mutation (c.286C ＞ T) at position 286 in exon 3 of the SLURP-1 gene,which led to the formation of a premature termination codon at amino acid position 96 (p.R96*).His parents were heterozygous carriers of the mutation (c.286C ＞ T).No mutation was found in the unrelated healthy controls.Conclusion The complete deletion of the STS gene and the homozygous nonsense mutation in the SLURP-1 gene may be the reason for X-linked ichthyosis complicated by Mal de Meleda in the patient.