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To systematically review the effects of leg-driven treadmill-based exoskeleton robot training on balance and walking ability in post-stroke patients.The PubMed, Cochrane Library, Embase, Web of Science, Medline, CNKI, VIP, and Wanfang databases were searched from inception to August 2021. The literature quality was evaluated using Cochrane Handbook. Primary outcomes include the functional ambulation category scale (FAC) and Berg Balance Scale (BBS), and secondary outcomes include the 10-m time walking test (10TWT), 6-m walking test (6MWT), and gait assessment cadence were analyzed.Seventeen randomized controlled trials were included in the systematic review, 15 studies in meta-analysis. Primary outcomes showed no significant difference in the FAC score; subgroup with the exoskeleton robot + conventional therapy of the BBS score was significantly increased; secondary outcomes showed no significance in 6MWT or 10TWT. The cadence score increased for the subgroup with an onset of6 months in the treatment group. The control group performed better than the subgroup with an onset of6 months.Leg-driven treadmill-based exoskeleton robot training can improve balance function in poststroke patients and is beneficial for patients with an onset of6 months. However, there is no evidence to support the efficacy of walking ability.

Paclitaxel displays clinical activity against a wide variety of solid tumors. However, resistance to paclitaxel significantly attenuates the response to chemotherapy. The ABC transporter subfamily C member 10 (ABCC10), also known as multidrug resistance protein 7 (MRP7) efflux transporter, is a major mediator of paclitaxel resistance. In this study, we show that masitinib, a small molecule stem-cell growth factor receptor (c-Kit) tyrosine kinase inhibitor, at nontoxic concentrations, significantly attenuates paclitaxel resistance in HEK293 cells transfected with ABCC10. Our in vitro studies indicated that masitinib (2.5 μmol/L) enhanced the intracellular accumulation and decreased the efflux of paclitaxel by inhibiting the ABCC10 transport activity without altering the expression level of ABCC10 protein. Furthermore, masitinib, in combination with paclitaxel, significantly inhibited the growth of ABCC10-expressing tumors in nude athymic mice in vivo. Masitinib administration also resulted in a significant increase in the levels of paclitaxel in the plasma, tumors, and lungs compared with paclitaxel alone. In conclusion, the combination of paclitaxel and masitinib could serve as a novel and useful therapeutic strategy to reverse paclitaxel resistance mediated by ABCC10. Mol Cancer Ther; 13(3); 714–23. ©2014 AACR.

PDF file - 255K, Supplemental Figure 1. The expression of c-Kit and p-c-Kit protein in HEK293/pcDNA3.1 and HEK293/ABCC10 cell lines, respectively. Supplemental Figure 2. The effect of masitinib administration on HEK293/pcDNA3.1 tumor growth in vivo. Supplemental Figure 3. Model of masitinib-mediated sensitization of paclitaxel in tumor cells. Supplemental Table 1. Masitinib significantly sensitizes HEK293/ABCC10 cells to vinblastine and vincristine with no or minimal effect on HEK293/pcDNA3.1 cells. Supplemental Table 2. The effect of reversal drugs on the cytotoxicity of paclitaxel to HEK293/pcDNA3.1 and HEK293/ABCB1 cells. Supplemental Table 3. The effect of reversal drugs on the cytotoxicity of vincristine to HEK293/pcDNA3.1 and HEK293/ABCC1 cells.

Purpose: Although clinical studies have shown promise for targeting programmed cell death protein-1 (PD-1) and ligand (PD-L1) signaling in non–small cell lung cancer (NSCLC), the factors that predict which subtype patients will be responsive to checkpoint blockade are not fully understood.Experimental Design: We performed an integrated analysis on the multiple-dimensional data types including genomic, transcriptomic, proteomic, and clinical data from cohorts of lung adenocarcinoma public (discovery set) and internal (validation set) database and immunotherapeutic patients. Gene set enrichment analysis (GSEA) was used to determine potentially relevant gene expression signatures between specific subgroups.Results: We observed that TP53 mutation significantly increased expression of immune checkpoints and activated T-effector and interferon-γ signature. More importantly, the TP53/KRAS comutated subgroup manifested exclusive increased expression of PD-L1 and a highest proportion of PD-L1+/CD8A+. Meanwhile, TP53- or KRAS-mutated tumors showed prominently increased mutation burden and specifically enriched in the transversion-high (TH) cohort. Further analysis focused on the potential molecular mechanism revealed that TP53 or KRAS mutation altered a group of genes involved in cell-cycle regulating, DNA replication and damage repair. Finally, immunotherapeutic analysis from public clinical trial and prospective observation in our center were further confirmed that TP53 or KRAS mutation patients, especially those with co-occurring TP53/KRAS mutations, showed remarkable clinical benefit to PD-1 inhibitors.Conclusions: This work provides evidence that TP53 and KRAS mutation in lung adenocarcinoma may be served as a pair of potential predictive factors in guiding anti–PD-1/PD-L1 immunotherapy. Clin Cancer Res; 23(12); 3012–24. ©2016 AACR.

Analysis of GC>TA transversion in four groups compared common mutations (TP53/KRAS/EGFR/STK11) with corresponding wild type.

Demographics and clinical characteristics of 93 ADC patients according to PD-L1 expression.

Supplementary Figure legends

The nutritional level of vitamin D may affect musculoskeletal health. We have reported that vitamin D is a pivotal protector against tissue injuries by suppressing local renin-angiotensin system (RAS). This study aimed to explore the role of the vitamin D receptor (VDR) in the protection against muscle atrophy and the underlying mechanism. A cross-sectional study on participants (n = 1034) in Shanghai (China) was performed to analyze the association between vitamin D level and the risk of low muscle strength as well as to detect the circulating level of angiotensin II (Ang II). In animal studies, dexamethasone (Dex) was applied to induce muscle atrophy in wild-type (WT) and VDR-null mice, and the mice with the induction of muscle atrophy were treated with calcitriol for 10 days. The skeletal muscle cell line C2C12 and the muscle satellite cells were applied in in vitro studies. The increased risk of low muscle strength was correlated to a lower level of vitamin D (adjusted odds ratio [OR] 0.58) accompanied by an elevation in serum Ang II level. Ang II impaired the myogenic differentiation of C2C12 myoblasts as illustrated by the decrease in the area of myotubes and the downregulation of myogenic factors (myosin heavy chain [MHC] and myogenic differentiation factor D [MyoD]). The phenotype of muscle atrophy induced by Dex and Ang II was aggravated by VDR ablation in mice and in muscle satellite cells, respectively, and mediated by RAS and its downstream phosphatidylinositol 3-kinase/protein kinase B/forkhead box O1 (PI3K/Akt/FOXO1) signaling. Calcitriol treatment exhibited beneficial effects on muscle function as demonstrated by the increased weight-loaded swimming time, grip strength, and fiber area, and improved fiber type composition via regulating ubiquitin ligases and their substrates MHC and MyoD through suppressing renin/Ang II axis. Taken together, VDR protects against skeletal muscle atrophy by suppressing RAS. Vitamin D could be a potential agent for the prevention and treatment of skeletal muscle atrophy. © 2021 American Society for Bone and Mineral Research (ASBMR).

PurposeTo better understand the relevance of genomic characteristics of NSCLC for the management of advanced NSCLC in Chinese patients, the phase II CLUSTER umbrella trial simultaneously investigated the efficacy of multiple targeted therapies in Chinese patients with advanced non-small cell lung cancer and pre-specified genetic alterations. MethodsCLUSTER was an open-label, umbrella design study with four treatment arms. Capmatinib (METi), ceritinib (ALKi), binimetinib (MEKi), and alpelisib (PI3Kai) monotherapies were investigated in previously treated patients with advanced NSCLC and matched genetic alterations. The primary endpoint for all treatment arms was overall response rate (ORR) per RECIST v1.1. Although not a predefined endpoint, a post-hoc analysis of the overall anti-tumor activity in all treated patients enrolled in the study was also performed. ResultsCeritinib met the pre‑specified statistical threshold for efficacy with an ORR of 73%, whereas an ORR of 19% and 9% were attained with capmatinib and binimetinib, respectively. The overall anti-tumor activity in all treated patients showed encouraging results. ConclusionDespite the limited number of patients in some of the treatment arms and the stringent criteria for preliminary activity, these findings confirm the feasibility of conducting biomarker-integrated studies in China, and warrant the implementation of further umbrella trials to simultaneously evaluate the efficacy of multiple targeted treatments.Trial registrationClinicalTrials.gov, NCT02276027 Registered 27 October 2014 - Retrospectively registeredhttps://clinicaltrials.gov/ct2/show/NCT02276027

To evaluate the safety and effectiveness of Qishe Pill (芪麝丸) on neck pain in real-world clinical practice. A multi-center, prospective, observational surveillance in 8 hospitals across Shanghai was conducted. During patients receiving 4-week Qishe Pill medication, Visual Analogue Scale (VAS) and Neck Disability Index (NDI) assessments have been used to assess their pain and function, while safety monitoring have been observed after 2 and 4 weeks. Results from 2,023 patients (mean age 54.5 years) suggest that the drug exposure per unit of body mass was estimated at 3.41 ± 0.62 g/kg. About 8.5% (172/2,023) of all participants experienced adverse events (AEs), while 3.8% (78/2,023) of all participants experienced adverse reaction. The most common AEs were gastrointestinal events and respiratory events. The VAS score (pain) and NDI score (function) significantly decreased after 4-week treatment. An effect-quantitative analysis was also conducted to show that the normal clinical dosage may be consider as 3–4 g/kg, at which dosage the satisfactory pain-relief effect may achieve by 40-mm reduction in VAS. These findings showed that patients with cervical radiculopathy who received Qishe Pill experienced significant improvement on pain and function. (Registration No. NCT01875562)

In order to comprehensively stretch human fascia, adjust the biomechanical balance of fascia system and promote the recovery of physiological function of fascia, a new type of fascia stretching cup is designed. This design is composed of two or more silica gel cups and elastic stretching belts between cups. The bottom surface of the silica gel cup has an annular exhaust groove, which can increase the adsorption capacity of the cup to the skin. In the meanwhile, a removable magnet is placed in the groove at the top of each silica gel cup to assist analgesia. This design is suitable for the prevention and treatment of acute and chronic tendon and bone diseases with imbalance of meridians and tendons.为达到整体拉伸人体筋膜、调整筋膜系统生物力学平衡、促进筋膜正常生理功能恢复的目的，设计了一种新型筋膜拉伸罐。其由两个及以上硅胶罐和连接罐之间的弹性拉伸带组成，硅胶罐体底面设有环形排气槽，可增加罐体对皮肤的吸附能力；同时在每个硅胶罐顶端凹槽中安放可取出的磁体，以起到辅助镇痛的作用。此器具适用于经筋失衡的急、慢性筋骨病的防治。.

Cervical spondylotic myelopathy (CSM) is a common cause of disability with few treatments. Aberrant mitochondrial dynamics play a crucial role in the pathogenesis of various neurodegenerative diseases. Thus, regulation of mitochondrial dynamics may offer therapeutic benefit for the treatment of CSM. Muscone, the active ingredient of an odoriferous animal product, exhibits anti-inflammatory and neuroprotective effects for which the underlying mechanisms remain obscure. We hypothesized that muscone might ameliorate inflammatory responses and neuronal damage by regulating mitochondrial dynamics. To this end, the effects of muscone on a rat model of chronic cervical cord compression, as well as activated BV2 cells and injured neurons, were assessed. The results showed that muscone intervention improved motor function compared with vehicle-treated rats. Indeed, muscone attenuated pro-inflammatory cytokine expression, neuronal-apoptosis indicators in the lesion area, and activation of the nod-like receptor family pyrin domain-containing 3 inflammasome, nuclear transcription factor-κB, and dynamin-related protein 1 in Iba1- and βIII-tubulin-labeled cells. Compared with vehicle-treated rats, compression sites of muscone-treated animals exhibited elongated mitochondrial morphologies in individual cell types and reduced reactive oxygen species. In vitro results indicated that muscone suppressed microglial activation and neuronal damage by regulating related-inflammatory or apoptotic molecules. Moreover, muscone inhibited dynamin-related protein 1 activation in activated BV2 cells and injured neurons, whereby it rescued mitochondrial fragmentation and reactive oxygen species production, which regulate a wide range of inflammatory and apoptotic molecules. Our findings reveal that muscone attenuates neuroinflammation and neuronal damage in rats with chronic cervical cord compression by regulating mitochondrial fission events, suggesting its promise for CSM therapy.

Purpose: Using deep learning and image processing technology, a standardized automatic segmentation and quantitation network of lumbar disc degeneration based on T2MRI was proposed to help residents accurately evaluate the intervertebral disc (IVD) degeneration.Materials and Methods: A semantic segmentation network (BianqueNet) consist of self-attention mechanism skip connection module and deep feature extraction module was proposed to achieve high-precision segmentation of IVD related areas. A quantitative method was used to calculate the signal intensity difference (∆SI) in IVD, average disc height (DH), disc height index (DHI), and disc height-to-diameter ratio (DHR). Quantitative ranges for these IVD parameters in a larger population was established among the 1051 MRI images collected from four hospitals around China.Results: The average dice coefficients of BianqueNet for vertebral bodies and intervertebral discs segmentation are 97.04% and 94.76%, respectively. This procedure was suitable for different MRI centers and different resolution of lumbar spine T2MRI (ICC=.874~.958). These geographic parameters of IVD degeneration have a significant negative correlation with the modified Pfirrmann Grade, while signal intensity in IVD degeneration had excellent reliability according to the modified Pfirrmann Grade (macroF1=90.63%~92.02%).Conclusion: we developed a fully automated deep learning-based lumbar spine segmentation network, which demonstrated strong versatility and high reliability to assist residents on IVD degeneration evaluating by means of IVD degeneration quantitation.Implication for Patient Care: Deep learning–based approaches have the potential to maximize diagnostic performance for detecting disc degeneration and assessing risk of disc herniation while reducing subjectivity, variability, and errors due to distraction and fatigue associated with human interpretation.

As a severe progressive degenerative disease, cervical spondylotic myelopathy (CSM) has a poor prognosis and is associated with physical pain, stiffness, motor or sensory dysfunction, and a high risk of spinal cord injury and acroparalysis. Thus, therapeutic strategies that promote efficient spinal cord regeneration in this chronic and progressive disease are urgently needed. Effective and reproducible animal spinal cord compression models are required to understand the complex biological mechanism underlying CSM. Most spinal cord injury models reflect acute and structural destructive conditions, whereas animal models of CSM present a chronic compression in the spinal cord. This paper presents a protocol to generate a rat spinal cord compression model, which was further evaluated by assessing the behavioral score and observing the compressed spinal cord region. The behavioral assessments showed decreased monitor motor disability, including joint movements, stepping ability, coordination, trunk stability, and limb muscle strength. Hematoxylin and eosin (H&E) staining and immunostaining revealed considerable neuronal apoptosis in the compressed region of the spinal cord.

Background Pleural effusion (PE) has been one of the promising sources of liquid biopsy in advanced lung cancer patients. However, its clinical utility is not widely accepted due to the lack of full estimation of its potential versus routine clinical samples. Method A total of 164 advanced lung cancer patients were enrolled with 164 matched tumor tissue and PE-cfDNA, 153 accompanied plasma and 63 1 PE-sDNA. Result PE-cfDNA displayed significantly higher median mutant allele frequency and an overall mutation concordance rate of 65% to tissue, which was higher than PE-sDNA (43%) and plasma-cfDNA (43%). The discrepancies between PE-cfDNA and tumor tissue were high in several genes, including SMARCA4, PIK3CA, ERBB2, KM T2A, ALK and NF1. For clinically actionable mutations, the concordance rate between PE-cfDNA and tumor tissue is 87%. Eleven patients were identified with actionable mutations in PE-cfDNA and four patients benefited from PE-cfDNA-guided targeted. Meanwhile, PE-cfDNA recapitulated mutations of diverse tissue origins and provided more mutational information under the circumstance that tumor tissue or tumor tissue of different origins were unavailable. The combination of tumor tissue and PE-cfDNA profiling increased positive detection rates of patients compared to tumor tissue alone. Our finding highlighted the importance of PE-cfDNA in the optimal selection of patients for targeted therapy. Conclusion The PE-cfDNA-based liquid biopsy displays better performance in the characterization of gene alterations than PE-sDNA and plasma-cfDNA. PE-cfDNA together with tumor tissue profiling optimizes comprehensively genomic profiling of lung cancer patients, which might be important for selecting patients for better treatment management.

Intervertebral disc degeneration (IDD) is a common pathological change leading to low back pain. Appropriate animal models are desired for understanding the pathological processes and evaluating new drugs. Here, we introduced a surgically induced lumbar spine instability (LSI) mouse model that develops IDD starting from 1 week post operation. In detail, the mouse under anesthesia was operated by low back skin incision, L3-L5 spinous processes exposure, detachment of paraspinous muscles, resection of processes and ligaments, and skin closure. L4-L5 IVDs were chosen for the observation. The LSI model develops lumbar IDD by porosity and hypertrophy in endplates at an early stage, decrease in intervertebral disc volume, shrinkage in nucleus pulposus at an intermediate stage, and bone loss in lumbar vertebrae (L5) at a later stage. The LSI mouse model has the advantages of strong operability, no requirement of special equipment, reproducibility, inexpensive, and relatively short period of IDD development. However, LSI operation is still a trauma that causes inflammation within the first week post operation. Thus, this animal model is suitable for study of lumbar IDD.

Background Shenqisherong pill (SQSRP) has been used clinically to treat cervical spondylotic myelopathy (CSM) with satisfactory results; however, its active ingredients and mechanisms are unclear. The present study aimed to explore the active ingredients and molecular mechanisms of SQSRP against CSM using network pharmacology and molecular docking. Methods The compounds in SQSRP were obtained from public databases and related literature, and oral bioavailability (≥30%) and drug-likeness (≥0.18) were screened using absorption, distribution, metabolism, and excretion (ADME) criteria. Compounds-related and CSM-related target genes were identified using public databases, and the overlapping genes between compounds and CSM target genes were identified using a Venn diagram. Cytoscape and STRING were used to construct, visualize, and analyze the interaction network between these overlapping targets. Gene Ontology (GO) and KEGG pathway enrichment analysis of overlapping targets used Omicshare tools and constructed a compound-overlapping targets network, target-pathway network, and compound-target-pathway network using Cytoscape. Finally, molecular docking software was used to verify the targets. Results A total of 447 compounds in SQSRP were identified, and ADME screening identified 96 compounds as potentially active ingredients. A total of 249 compound-related genes and 280 CSMrelated genes were identified using public databases, and 53 overlapping genes were identified. The results of compound targets and protein-protein interaction network analysis showed that the pharmacological effects of SQSRP against CSM involved 56 compounds and 53 genes. The results of GO and KEGG pathway enrichment analysis suggested that the therapeutic effects of SQSRP against CSM were exerted by reducing inflammation, inhibiting apoptosis, and protecting neurons. The molecular mechanisms may be strongly associated with PI3K-Akt, MAPK, IL-17, and TNF, which might be pivotal signaling pathways. Conclusions The active ingredients and mechanisms of SQSRP against CSM were investigated using network pharmacology. The findings proved that the pill could treat CSM through multi-component, multitarget, and multi-pathway synergy and provide a theoretical basis for the subsequent extraction of active ingredients from SQSRP.

Cervical spondylotic myelopathy (CSM) is a clinically symptomatic entity arising from the spinal cord compression by degenerative diseases. Although endoplasmic reticulum (ER) stress has been commonly observed in several neurodegenerative diseases, the relationship between ER stress and CSM remains unknown. Shikonin is known to protect PC12 by inhibiting apoptosis in vitro. This study hypothesised that ER stress was vital in neuronal apoptosis in CSM. Shikonin might inhibit such responses by regulating ER stress through the protein kinase-like ER kinase-eukaryotic translation initiation factor 2 α-subunit-C/EBP homologous protein (PERK-eIF2α-CHOP) signalling pathway. Thus, the aim of this study was evaluating the neuroprotective effect of shikonin in rats with double-level chronic cervical cord compression, as well as primary rat cortical neurons with glutamate-induced neurotoxicity. The result showed that ER stress-related upregulation of PERK-eIF2α-CHOP resulted in rat neuronal apoptosis after chronic cervical cord compression; then, shikonin promoted motor recovery and inhibited neuronal apoptosis by attenuating PERK-eIF2α-CHOP and prevented Bax translocation from cytoplasm to mitochondrion induced by CHOP of neurons in rats with chronic compression. Also, it was found that shikonin could protect rat primary cortical neuron against glutamate toxicity by regulating ER stress through the PERK-eIF2α-CHOP pathway in vitro. In conclusion, shikonin might inhibit neuronal apoptosis by regulating ER stress through attenuating the activation of PERK-eIF2α-CHOP.

2591 Background: Immune checkpoint inhibitors (ICIs) have suboptimal efficacy in non-small cell lung cancer (NSCLC) patients with ERBB2 mutations, including ERBB2 exon 20 insertions. This study aims to investigate the efficacy of ICIs and immune characteristics in NSCLC patients harboring ERBB2 ex20ins and non-ex20ins mutations. Methods: Advanced NSCLC patients harboring ERBB2 mutations were recruited from January 2016 to December 2020. Pre-ICI tumor tissue samples were collected and performed with targeted next-generation sequencing. Patients received ICIs were followed up every 3 months until November 2021. Genomic features were compared between patients with ERBB2 ex20ins and non-ex20ins mutations. Progression-free survival (PFS), overall survival (OS), and tumor immune microenvironment (TIME) features characterized by multiplex immunohistochemistry (IHC) were further analyzed in patients receiving ICIs. Two-sample T-tests were performed to compare means; Cox models were fitted to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Two external datasets of ERBB2-mutant NSCLC patients, including TCGA (n = 23) and META (n = 33), were used for validation. Results: A total of 117 eligible patients were enrolled (median age: 59 [range: 24-82], males 57.3%, stage IV 68.4%, adenocarcinoma 93.2%), of whom 37 received subsequent ICI treatment. similar PD-L1 tumor proportion score (mean: 8.1% vs. 13.2%, p = 0.25) and significantly lower mutation number (mean: 3.0 vs. 6.2 muts/person, p < 0.01) were detected in patients with ERBB2 ex20ins, compared to patients with ERBB2 mutations other than ex20ins. Similarly, in the TCGA cohort, tumor mutation burden was significantly lower in ERBB2 ex20ins patients (mean: 2.2 vs. 10.3 muts/Mb, p = 0.02). Of 37 patients receiving ICIs, ERBB2 non-ex20ins patients displayed superior PFS (mPFS: 13.5 vs. 4.4 months, HR: 0.31, 95% CI: 0.14-0.71), relatively long OS (mOS: 27.5 vs. 8.1 months, HR: 0.47, 95% CI: 0.20-1.14), and a relatively high rate of durable clinical benefit (64.3% vs. 34.8%, p = 0.10) than ex20ins patients, consistent with what was observed in the META cohort (PFS, mPFS: 13.2 vs. 2.5 months, HR: 0.20, 95% CI: 0.06-0.68; OS, mOS: 23.3 vs. 8.0 months, HR: 0.32, 95% CI: 0.11-0.90). Moreover, the CD4+ T cell density appeared to be lower in the tumor stroma of ERBB2 ex20ins patients than that of non-ex20ins patients (300.5 vs. 1288.0 /mm2, p = 0.08), even though the general TIME features of ex20ins patients were similar to those of non-ex20ins patients. Conclusions: NSCLC patients carrying ERBB2 ex20ins demonstrated worse clinical outcome under ICI treatment, similar PD-L1 expression and lower mutation number when compared to those with non-ex20ins mutations. Genomic and TIME characteristics should be further investigated to elucidate the efficacy of ICIs in lung cancer patients carrying ERBB2 mutations.

To evaluate the safety and effectiveness of Qishe Pill () on neck pain in real-world clinical practice.A multi-center, prospective, observational surveillance in 8 hospitals across Shanghai was conducted. During patients receiving 4-week Qishe Pill medication, Visual Analogue Scale (VAS) and Neck Disability Index (NDI) assessments have been used to assess their pain and function, while safety monitoring have been observed after 2 and 4 weeks.Results from 2,023 patients (mean age 54.5 years) suggest that the drug exposure per unit of body mass was estimated at 3.41 ± 0.62 g/kg. About 8.5% (172/2,023) of all participants experienced adverse events (AEs), while 3.8% (78/2,023) of all participants experienced adverse reaction. The most common AEs were gastrointestinal events and respiratory events. The VAS score (pain) and NDI score (function) significantly decreased after 4-week treatment. An effect-quantitative analysis was also conducted to show that the normal clinical dosage may be consider as 3-4 g/kg, at which dosage the satisfactory pain-relief effect may achieve by 40-mm reduction in VAS.These findings showed that patients with cervical radiculopathy who received Qishe Pill experienced significant improvement on pain and function. (Registration No. NCT01875562).

Depression is partially caused by inflammation in the central nervous system. Early study demonstrated that musk, glandular secretion from male musk deer, exerted an antidepressant-like effect. The aim of this study was to investigate if muscone, a bioactive ingredient in musk, could ameliorate neuroinflammation and depressive-like behaviors as well as explore the potential action mechanism. Mice were intraperitoneally (i.p.) injected with muscone for 2 weeks prior to administration of lipopolysaccharides (LPS, 1[Formula: see text]mg/kg, i.p.). Pre-treatment with muscone reversed the LPS-induced decrease in body weight within 24[Formula: see text]h and ameliorated depressive-like behaviors shown by sucrose preference, tail suspension test, and forced swimming test. LPS-induced activation of microglial cells and elevation in expression of inflammatory cytokines including IL-1[Formula: see text], RANTES, and MCP-1 in the prefrontal cortex of mice were effectively abrogated by muscone, which significantly down-regulated expression of TLR4, MyD88, Caspase-1, NLRP3, renin, and Ang II. In addition, treatment of BV2 microglia cells with muscone markedly attenuated the LPS-induced rise in protein expression of TLR4, Ang II, and IL-1[Formula: see text]. This study revealed that muscone could ameliorate LPS-induced depressive-like behaviors by repressing neuroinflammation in the prefrontal cortex of mice caused by its suppression on microglia activation and production of inflammatory cytokines via acting on TLR4 pathway and RAS cascade.

Background Shoulder pain is a common musculoskeletal disorder in Chinese population, which affects more than 1,3 billion individuals. To the best of our knowledge, there has been no available Chinese-language version of measurements of shoulder pain and disability so far. Moreover, the Constant-Murley score (CMS) questionnaire is a universally recognized patient-reported questionnaire for clinical practice and research. The present study was designed to evaluate a Chinese translational version of CMS and subsequently assess its reliability and validity. Methods The Chinese translational version of CMS was formulated by means of forward-backward translation. Meanwhile, a final review was carried out by an expert committee, followed by conducting a test of the pre-final version. Therefore, the reliability and validity of the Chinese translational version of CMS could be assessed using the internal consistency, construct validity, factor analysis, reliability and floor and ceiling effects. Specifically, the reliability was assessed by testing the internal consistency (Cronbach’s α) and test-retest reliability (intraclass coefficient correlation [ICC]), while the construct validity was evaluated via comparison between the Chinese translational version of CMS with visual analog scale (VAS) score and the 36-Item Short Form Health Survey (SF-36, Spearman correlation). Results The questionnaire was verified to be acceptable after distribution among 120 subjects with unilateral shoulder pain. Factor analysis had revealed a two-factor and 10-item solution. Moreover, the assessment results indicated that the Chinese translational version of CMS questionnaire harbored good internal consistency (Cronbach’s α = 0.739) and test-retest reliability (ICC = 0.827). In addition, the Chinese translational version of CMS was moderately correlated with VAS score (r = 0.497) and SF-36 (r = 0.135). No obvious floor and ceiling effects were observed in the Chinese translational version of CMS questionnaire. Conclusion Chinese translational version of CMS exhibited good reliability, which is relatively acceptable and is likely to be widely used in this population.

Purpose: Although clinical studies have shown promise for targeting programmed cell death protein-1 (PD-1) and ligand (PD-L1) signaling in non–small cell lung cancer (NSCLC), the factors that predict which subtype patients will be responsive to checkpoint blockade are not fully understood. Experimental Design: We performed an integrated analysis on the multiple-dimensional data types including genomic, transcriptomic, proteomic, and clinical data from cohorts of lung adenocarcinoma public (discovery set) and internal (validation set) database and immunotherapeutic patients. Gene set enrichment analysis (GSEA) was used to determine potentially relevant gene expression signatures between specific subgroups. Results: We observed that TP53 mutation significantly increased expression of immune checkpoints and activated T-effector and interferon-γ signature. More importantly, the TP53/KRAS comutated subgroup manifested exclusive increased expression of PD-L1 and a highest proportion of PD-L1+/CD8A+. Meanwhile, TP53- or KRAS-mutated tumors showed prominently increased mutation burden and specifically enriched in the transversion-high (TH) cohort. Further analysis focused on the potential molecular mechanism revealed that TP53 or KRAS mutation altered a group of genes involved in cell-cycle regulating, DNA replication and damage repair. Finally, immunotherapeutic analysis from public clinical trial and prospective observation in our center were further confirmed that TP53 or KRAS mutation patients, especially those with co-occurring TP53/KRAS mutations, showed remarkable clinical benefit to PD-1 inhibitors. Conclusions: This work provides evidence that TP53 and KRAS mutation in lung adenocarcinoma may be served as a pair of potential predictive factors in guiding anti–PD-1/PD-L1 immunotherapy. Clin Cancer Res; 23(12); 3012–24. ©2016 AACR.

Objectives: Large sample and high-quality evidence to evaluate the preliminary safety of the mobilizations and massage for cervical vertigo are not yet available. Thus, the present study aimed to i...

Cervical spondylotic myelopathy (CSM) is a leading cause of spinal cord dysfunction with few treatment options. Although mitochondrial dynamics are linked to a wide range of pathological changes in neurodegenerative diseases, a connection between aberrant mitochondrial dynamics and CSM remains to be illuminated. In addition, mechanisms underlying the emerging anti-inflammatory and neuroprotective effects of echinacoside (ECH), the main active ingredient of Cistanche salsa, are poorly understood. We hypothesized that excessive mitochondrial fission plays a critical role in regulating inflammatory responses in CSM, and ECH might alleviate such responses by regulating mitochondrial dynamics. To this end, we assessed the effects of ECH and Mdivi-1, a selective inhibitor of dynamin-related protein (Drp1), in a rat model of chronic cervical cord compression and activated BV2 cells. Our results showed that rats with Mdivi-1 intervention had improved motor function compared with vehicle-treated rats. Indeed, Mdivi-1 treatment attenuated pro-inflammatory cytokine expression, as well as activation of the nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, nuclear transcription factor-κB (NF-κB), and Drp1 in lesions. Compared with vehicle-treated rats, compression sites of Mdivi-1-treated animals exhibited elongated mitochondrial morphologies and reduced reactive oxygen species (ROS). Similarly, ECH-treated rats exhibited neurological recovery and suppression of inflammatory response or related signals in the lesion area after treatment. Interestingly, ECH treatment partly reversed aberrant mitochondrial fragmentation and oxidative stress within the lesion area. In vitro data suggested that ECH suppressed activated microglia by modulating activation of the NLRP3 inflammasome and NF-κB signaling. Furthermore, we observed that ECH markedly inhibited Drp1 translocation onto mitochondria, whereby it regulated mitochondrial dynamics and ROS production, which act as regulators of NLRP3 inflammasome activation and NF-κB signaling. Thus, our findings reveal that mitochondrial dynamics modulate inflammatory responses during CSM. Moreover, ECH may attenuate neuroinflammation in rats subjected to chronic cervical cord compression by regulating Drp1-dependent mitochondrial fission and activation of downstream signaling.

Background: Bcl-2 family members play an important role in the development of malignant lymphoma and can induce drug resistance in anticancer treatment. The development of small molecules targeting Bcl-2 family protein can be new strategy for malignant lymphoma treatment. In this study, we investigate the antitumor effect and the cellular mechanism of a novel Bcl-2/Bcl-xL dual inhibitor BM-1197 in DCBCL and Burkitt lymphoma cells. Methods: CCK-8 assay was used to detect cell viability. Apoptosis was determined by Hoechst 33258 staining and flow cytometry. The activity of caspase-3/caspase-9 was determined using the caspase-3/ caspase-9 activity kit. Western blotting analysis was performed to evaluate the change of protein expression. The functional analysis was evalueated via immunoprecipitation and siRNA interference. Human malignant lymphoma xenograft models in nude mice were established for in vivo efficacy detection. Results: We find that BM-1197 exerts potent growth-inhibitory activity against lymphoma cells which harbor Bcl-2 and Bcl-xL high expression in vitro and has synergistic effect with chemotherapeutic drugs. Mechanistically, we see that the intrinsic apoptosis pathway is activated upon BM-1197 treatment. BM-1197 affects the protein interaction of Bak/Bcl-xl, Bim/Bcl-2, Bim/Bcl-xl, PUMA/Bcl-2 and induced conformational change in the Bax protein.which results in activation of Bax and release cytochrome c, and activated caspase -9, -3, -7 and finally induce cell apoptosis. Furthermore, our data demonstrates that BM-1197 exhibits strong anti-tumor effects against established human malignant lymphoma xenograft models. Conclusions: Our study demonstrated BM-1197 exerts potent antitumor effects both in vitro and in vivo, and provides promising preclinical data for further development of BM-1197 in malignant lymphoma. Funding Statement: This work is supported by National Natural Scientific Research Fund of China (Project Number: 81301904), Medical Scientific Technology and Research Fund of Guangdong (Project Number: A2016023), Special Project by Guangdong Science and Technology Department (2018YJ021), and National Natural Scientific Research Fund of China (Project Number: 81101671) Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: All animal experiments were performed under the guidance of Sun Yat-Sen University Committee for Use and Care of Laboratory Animals and approved by the animal experimentation ethics committee.

Study design Systematic review of cross-cultural adaptation of the Oswestry Disability Index (ODI). Objective The aim of this study was to evaluate the translation procedures for and measurement properties of cross-cultural adaptations of the ODI. Summary of background data The ODI is the most commonly used questionnaire to determine the outcome of low back pain, and has been translated into many other languages, such as Danish, Greek, and Korean, and adapted for use in different countries. Methods PubMed, the Cochrane Library, Medline, and EMBASE were searched from the time they were established to January 2015. Studies related to cross-cultural adaptation of the ODI in a specific language/culture were included. Guidelines for the Process of Cross-Cultural Adaptation of Self-Report Measures and Quality Criteria for Psychometric Properties of Health Status Questionnaire were used for assessment. Results This study included 27 versions of ODI adaptations in 24 different languages/cultures. Only the Danish-Danish adaptation employed all six of the cross-cultural adaptation processes. Expert committee review (three of 27), back translation (eight of 27), and pretesting (nine of 27) were conducted in very few studies. The Polish-Polish (two) adaptation reported all (nine of nine) the measurement properties, whereas the Traditional Chinese-Taiwan and Hungarian-Hungarian adaptations reported six of them. Content validity (16/27), construct validity (17/27), and reliability (22/27) were determined in a relatively high number of studies, whereas agreement (three of 27), responsiveness (12/27), floor and ceiling effects (six of 27), and interpretability (one of 27) were only determined in some studies. Conclusion We recommend the Traditional Chinese-Taiwan, Simplified Chinese-Mandarin Chinese, Danish-Danish, German-Swiss, Hungarian-Hungarian, Italian-Italian, and Polish-Polish (two) versions for application, but Traditional Chinese-Hong Kong, French-Swiss, Japanese-Japanese (two), Polish-Polish (two), Tamil-Indian, and Thai-Thai versions may need more research. Furthermore, supplementary tests for the adaptations are necessary, especially for assessing agreement, responsiveness, and interpretability. Level of evidence 1.

Introduction Patients with non-small cell lung cancer (NSCLC) harboring uncommon epidermal growth factor receptor (EGFR) mutations are a heterogeneous group exhibiting differential responses to EGFR inhibitors. This retrospective study reviews the prevalence of uncommon EGFR mutations in a Chinese NSCLC cohort and the clinical characteristics and efficacy of EGFR tyrosine kinase inhibitors (TKIs) associated with these patients. Materials andmethods A total of 5363 lung cancer patients were screened and underwent EGFR genotyping at the Guangdong Lung Cancer Institute. Of those with uncommon EGFR mutations, the clinical characteristics and responses to EGFR-TKIs were reviewed retrospectively. Results Uncommon EGFR mutations were observed in 218 patients, comprising 11.9% of all patients with documented EGFR mutations. More smokers (30.7% vs. 24.3%, P=0.039) and males (54.1% vs. 44.4%, P=0.007) were among the patients with uncommon mutations compared with common mutations. The most frequent uncommon mutations were exon 20 insertions (30.7%, n=67), followed by G719X mutations (21.1%, n=46) and compound L858R mutations (17.0%, n=37). Favorable efficacy was observed in patients harboring compound L858R or G719X mutations, with a median progression-free survival (PFS) of 15.2 (95% CI: 8.7-21.7) or 11.6 (95% CI: 3.6-19.6) months, respectively. The median PFS of those with the T790M mutation or an exon 20 insertion was 1.0 (95% CI: 0.0-2.2) and 3.0 (95% CI: 1.3-4.7) months, respectively. Conclusion This study reviewed the prevalence of uncommon EGFR mutations and their sensitivity to EGFR-TKIs. Favorable responses were observed in patients with G719X and compound L858R mutations, indicating that they may benefit from EGFR-TKIs as a first-line therapy.

Introduction Subtype classification of lung adenocarcinoma (LUAD) divides different survivals and therapeutic vulnerabilities; however, little is known about the disease's underlying molecular mechanism. This study sought to determine the genetic and immune profiles of histologic subtypes and identify the evidence for adjuvant immunotherapy. Methods We performed an integrated analysis of multidimensional data from a discovery set consisting of cohorts of The Cancer Genome Atlas and the Broad Institute data set from the LUAD public database and a validation set from the Guangdong Lung Cancer Institute. Immunohistochemical staining was carried out to determine the expression of the proteins programmed cell death 1 ligand (PD-L1) and CD8. Results Patients with solid predominant LUAD showed poor disease-free survival and a high frequency of relapse/metastasis compared with those with the nonsolid subtype of LUAD. The solid subtype tended to occur more frequently in those with a history of smoking. Solid predominant LUAD exclusively showed increased expression of PD-L1 and a high proportion of dual positive PD-L1– and tumor-infiltrating lymphocytes. Meanwhile, a notable increase in the tumor mutation burden and higher frequency of GC>TA transversions were specifically identified in tumors of the solid subtype. Furthermore, the solid subtype of tumor displayed an active cytotoxic immune signature and increased incidence of genetic mutations related to immunogenicity. Conclusion Solid predominant LUAD was identified as a subtype with adaptive immune resistance, higher cytotoxic activity, and enhanced immunogenicity. These findings suggest that patients with solid predominant LUAD may represent a potential selective group that will benefit from adjuvant programmed cell death 1 blockade immunotherapy.

Traditional herbal medicine, an alternative medicine in the clinical setting, has received increased attention in recent years. Before delivery to the body, an additional extraction procedure is commonly required to release the active constituents from raw herbs. Water decoction is a classical extraction procedure that is still broadly used in the clinical settings. Here, we propose a detailed protocol for er-xian decoction (EXD) in order to apply herbal decoctions to experimental studies. The calculation of an animal-appropriate dose is described, as well as the four main steps of EXD: soaking, water decoction, filtration, and concentration. In addition, serum-containing EXD is introduced to rats as a means of in vitro validation. Here, rats were orally administered EXD for three days. Blood samples were then collected, inactivated, centrifuged, and filtered. The serum, diluted with the culture medium, can be utilized to treat cells or tissues in vitro. For example, EXD was applied to both in vivo and in vitro studies and demonstrated that EXD enhances osteogenesis. This protocol can be used as a reference for the preparation and application of herbal medicines.

Paclitaxel displays clinical activity against a wide variety of solid tumors. However, resistance to paclitaxel significantly attenuates the response to chemotherapy. The ABC transporter subfamily C member 10 (ABCC10), also known as multidrug resistance protein 7 (MRP7) efflux transporter, is a major mediator of paclitaxel resistance. In this study, we show that masitinib, a small molecule stem-cell growth factor receptor (c-Kit) tyrosine kinase inhibitor, at nontoxic concentrations, significantly attenuates paclitaxel resistance in HEK293 cells transfected with ABCC10. Our in vitro studies indicated that masitinib (2.5 μmol/L) enhanced the intracellular accumulation and decreased the efflux of paclitaxel by inhibiting the ABCC10 transport activity without altering the expression level of ABCC10 protein. Furthermore, masitinib, in combination with paclitaxel, significantly inhibited the growth of ABCC10-expressing tumors in nude athymic mice in vivo. Masitinib administration also resulted in a significant increase in the levels of paclitaxel in the plasma, tumors, and lungs compared with paclitaxel alone. In conclusion, the combination of paclitaxel and masitinib could serve as a novel and useful therapeutic strategy to reverse paclitaxel resistance mediated by ABCC10. Mol Cancer Ther; 13(3); 714–23. ©2014 AACR.

The presence of acquired multidrug resistance (MDR) is one of the primary impediments to the success of chemotherapy. MDR is often a result of overexpression of ATP-binding cassette (ABC) transporters, which are involved in the extrusion of therapeutic drugs. Recently, it was shown that several ABC transporters could be modulated by specific tyrosine-kinase inhibitors (TKIs). Ponatinib, a multi-targeted TKI, inhibits the activity of BCR-ABL with very high potency and broad specificity, including the T315I mutation which confers resistance to other TKIs. It was reported that ponatinib was capable of reversing breast cancer resistance protein (BCRP)- and P-glycoprotein (P-gp)-mediated MDR. In the present study, we report for the first time that ponatinib also potentiates the cytotoxicity of widely used therapeutic substrates of MRP7, such as paclitaxel, docetaxel, vincristine and vinblastine. Ponatinib signi ficantly enhances the accumula - tion of ( 3 H)-paclitaxel in cells expressing MRP7. Furthermore, accumulation of ( 3 H)-paclitaxel was achieved by inhibition of MRP7-mediated transport. Ponatinb limited drug export via MRP7 by multiple mechanisms. In addition to inhibition of pump function, ponatinib also downregulated MRP7 protein expression in a time- and concentration-dependent manner. Thus, ponatinib may represent a potential reversal agent for the treatment of MDR and may be useful for combination therapy in MDR cancer patients in clinical practice.

High intrinsic or acquired expression of membrane spanning, adenosine triphosphate binding cassette (ABC) transporter proteins, such as P-glycoprotein (P-gp), in cancers represents a major impediment to chemotherapy, with accelerated drug efflux leading to multi-drug resistance (MDR). Although ABC transporter inhibitors offer the prospect of reversing the MDR phenotype, no inhibitors have advanced to the clinic. We employed a range of intracellular fluorescence and radio-ligand accumulation and efflux assays, together with cytotoxicity and MDR reversal assays, as well as flow cytometry, fluorescence microscopy and radioimmunoprecipitation, to discover and evaluate new P-gp inhibitors from a unique library of southern Australian and Antarctic marine natural products. This study successfully characterized two rare bromoditerpenes, parguerenes I and II, sourced from a southern Australian collection of the red alga Laurencia filiformis, as P-gp inhibitors. We determined that the parguerenes were non-cytotoxic, dose-dependent inhibitors of P-gp mediated drug efflux, that modify the extracellular antibody binding epitope of P-gp in a manner that differs markedly from that of the known inhibitors verapamil and cyclosporine A. We confirmed that parguerenes were capable of reversing P-gp mediated vinblastine, doxorubicin and paclitaxel MDR, that inhibitory properties span both P-gp and multidrug resistant protein 1 (MRP1), but do not extend to breast cancer resistance protein (BCRP), and that parguerene II is superior (more potent) to verapamil. Our investigations validate the proposition that marine natural products can deliver new ABC transporter inhibitor scaffolds, with structure characteristics fundamentally different from existing inhibitor classes.

The aim of this study is to translate and cross-culturally adapt the Shoulder Pain and Disability Index (SPADI) for the Chinese language, and to evaluate its psychometric properties. The SPADI was translated and cross-culturally adapted for the Chinese language according to established guidelines. Participants completed the SPADI questionnaire, a visual analogue scale (VAS), and the 36-item short form health survey (SF-36), and were assessed using the Constant–Murley shoulder outcome score. Exploratory factor analysis was used to examine the latent dimensions, and Cronbach’s α to measure internal consistency. The construct validity was tested by Pearson correlations with the Constant–Murley score, VAS, and SF-36, while intraclass correlation coefficient (ICC) was calculated to assess the test–retest reliability of the Chinese SPADI. The floor and ceiling effects were calculated by the proportion of participants who obtained the highest (100) and lowest (0) possible score on the baseline questionnaires. We tested its psychometric properties with 120 participants (55 men and 65 women, age: 55.64 ± 9.49 years, duration: 62.75 ± 15.96 weeks) with shoulder pain. And 58 participants completed the SPADI again within 7 days of the first completion to test the test–retest reliability. The Chinese version of the SPADI displayed high internal consistency (Cronbach’s α = 0.91). Test–retest reliability was high with an intraclass correlation coefficient of 0.87. A very good correlation was observed between the SPADI and the Constant–Murley score (r = 0.69), a good correlation between the SPADI and the VAS (r = 0.40), and a fair correlation between the SPADI and the SF-36 (r = 0.36). There were no significant floor and ceiling effects in the total Chinese SPADI. The Chinese version of the SPADI is a valid and reliable tool that could be used to measure the degree of pain and disability in Chinese-speaking patients with shoulder pain.

Phosphodiesterase type 5 (PDE5) inhibitors are widely used in the treatment of male erectile dysfunction and pulmonary hypertension. Recently, several groups have evaluated the ability of PDE5 inhibitors for their anticancer activities. Previously, we had shown that sildenafil, vardenafil and tadalafil could reverse P‐glycoprotein (ATP‐binding cassette B1)‐mediated MDR. In the present study, we determined whether these PDE5 inhibitors have the potential to reverse multidrug resistance protein 7 (MRP7; ATP‐binding cassette C10)‐mediated MDR. We found that sildenafil and vardenafil dose‐dependently enhanced the sensitivity of MRP7‐transfected HEK293 cells to paclitaxel, docetaxel and vinblastine, while tadalafil had only a minimal effect. Accumulation and efflux experiments demonstrated that sildenafil and vardenafil increased the intracellular accumulation of [3H]‐paclitaxel by inhibiting the efflux of [3H]‐paclitaxel in HEK/MRP7 cells. In addition, immunoblot and immunofluorescence analyses indicated that no significant alterations of MRP7 protein expression and localization in plasma membranes were found after treatment with sildenafil, vardenafil or tadalafil. These results demonstrate that sildenafil and vardenafil reverse MRP7‐mediated a MDR through inhibition of the drug efflux function of MRP7. Our findings indicate a potentially novel use of PDE5 inhibitors as an adjuvant chemotherapeutic agent in clinical practice. (Cancer Sci, doi: 10.1111/j.1349‐7006.2012.02328.x, 2012)

The overexpression of ATP binding cassette (ABC) transporters often leads to the development of multidrug resistance (MDR) and results in a suboptimal response to chemotherapy. Previously, we reported that lapatinib (GW572016), a human epidermal growth factor receptor (EGFR) and HER-2 tyrosine kinase inhibitor (TKI), significantly reverses MDR in cancer cells by blocking the efflux function of ABC subfamily B member 1 (ABCB1)- and ABC subfamily G member 2 (ABCG2)-mediated MDR. In the present study, we conducted in vitro experiments to evaluate if GW583340 and GW2974, structural analogues of lapatinib, could reverse ABCB1-and ABCG2-mediated MDR. Our results showed that GW583340 and GW2974 significantly sensitized ABCB1 and ABCG2 overexpressing MDR cells to their anticancer substrates. GW583340 and GW2974 significantly increased the intracellular accumulation of [3H]-paclitaxel in ABCB1 overexpressing cells and [3H]-mitoxantrone in ABCG2 overexpressing cells respectively. In addition, GW583340 and GW2974 significantly inhibited ABCG2-mediated transport of methotrexate in ABCG2 overexpressing membrane vesicles. There was no significant change in the expression levels of ABCB1 and ABCG2 in the cell lines exposed to 5 μM of either GW583340 or GW2974 for 3 days. In addition, a docking model predicted the binding conformation of GW583340 and GW2974 to be within the transmembrane region of homology modeled human ABCB1 and ABCG2. We conclude that GW583340 and GW2974, at clinically achievable plasma concentrations, reverse ABCB1- and ABCG2-mediated MDR by blocking the drug efflux function of these transporters. These findings may be useful in developing combination therapy for cancer treatment with EGFR TKIs.