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An aneuploid-immune paradox encompasses somatic copy-number alterations (SCNAs), unleashing a cytotoxic response in experimental precancer systems, while conversely being associated with immune suppression and cytotoxic-cell depletion in human tumors, especially head and neck cancer (HNSC). We present evidence from patient samples and cell lines that alterations in chromosome dosage contribute to an immune hot-to-cold switch during human papillomavirus-negative (HPV(−)) head and neck tumorigenesis. Overall SCNA (aneuploidy) level was associated with increased CD3(+) and CD8(+) T cell microenvironments in precancer (mostly CD3(+), linked to trisomy and aneuploidy), but with T cell-deficient tumors. Early lesions with 9p21.3 loss were associated with depletion of cytotoxic T cell infiltration in TP53 mutant tumors; and with aneuploidy were associated with increased NK-cell infiltration. The strongest driver of cytotoxic T cell and Immune Score depletion in oral cancer was 9p-arm level loss, promoting profound decreases of pivotal IFN-γ-related chemokines (e.g., CXCL9) and pathway genes. Chromosome 9p21.3 deletion contributed mainly to cell-intrinsic senescence suppression, but deletion of the entire arm was necessary to diminish levels of cytokine, JAK-STAT, and Hallmark NF-κB pathways. Finally, 9p arm-level loss and JAK2-PD-L1 codeletion (at 9p24) were predictive markers of poor survival in recurrent HPV(−) HNSC after anti–PD-1 therapy; likely amplified by independent aneuploidy-induced immune-cold microenvironments observed here. We hypothesize that 9p21.3 arm-loss expansion and epistatic interactions allow oral precancer cells to acquire properties to overcome a proimmunogenic aneuploid checkpoint, transform and invade. These findings enable distinct HNSC interception and precision-therapeutic approaches, concepts that may apply to other CN-driven neoplastic, immune or aneuploid diseases, and immunotherapies.

Limb ischemia reperfusion (LIRI) injury is associated with serious local and systemic effects. Reperfusion may augment tissue injury in excess of that produced by ischemia alone. Calcium overloading and inflammation are considered to be two of the pathological mechanisms of limb ischemia/reperfusion (I/R) injury. Tao-Hong-Si-Wu decoction (THSWD) is a traditional Chinese herbal medicine with a powerful anti-inflammatory properties. We studied the probable restorative effect of THSWD on limb I/R-induced calcium overloading and inflammation in myoblast obtained from gastrocnemius muscle tissues of Sprague-Dawley rats (Frizzled Z5,a wnt5a blocker; KN-93, a calmodulin-dependent protein kinase II (CamkII) blocker; XeC, a IP3R blocker as positive controls). The simulated ischemia and reperfusion(I/R) solutions were used to imitate LIRI environment. The results showed that after I/R treatment, the secretion of proinflammatory factors (TNF-α and IL-1β) and Wnt5a/Ca2+ signal molecules (wnt5a, camkII, and IP3R) upregulated significantly, the Ca2+ concentration enhanced too in myoblast cells. THSWD pretreatment decreased the secretion of TNF-α and IL-1β, Ca2+ concentration; and abated the Wnt5a/Ca2+ signal molecules of wnt5a, camkII and IP3R expression activated by I/R injury; but could not abated the Wnt11 and protein kinase C (PKC) expression significantly, the results was similar with Frizzled Z5 treatment cells. Our research illustrated that THSWD may have a mitigating effect on LIRI targeting Wnt/IP3R/CAMKII but not Wnt/IP3R/PKC signaling pathway for the first time. This study may encourage the use of THSWD in the critical clinical settings with LIRI.

Introduction: There are many injection methods for the treatment of knee osteoarthritis, but there is no comprehensive comparison, based on the fixed effect model. Methods: According to the retrieval strategy, we searched randomized controlled trials (RCTs) randomly from PubMed, the Cochrane Library, Embase, the China National Knowledge Infrastructure (CNKI), Wanfang Database from their inceptions to August 2020, and 2 members of us selected literatures and extracted data independently. Methodological quality was assessed by using the Cochrane bias risk tool, and meta-analysis was performed by using the Stat.14.0. Results: This study will evaluate the effectiveness and safety of different injectable drugs for the treatment of knee osteoarthritis and rank the efficacies of drugs, then to determine the optimal treatment. Conclusion: This study will provide evidence for the choice of injection therapy for knee osteoarthritis. INPLASY registration number: INPLASY202080099.

Introduction: Traditional Chinese medicine has been widely used in the treatment of allergic rhinitis. However, currently randomized controlled trials (RCTs) and meta-analysis only compare 1 or 2 types of traditional Chinese medicine therapies, and the comprehensive ranking of efficacy and safety of multiple traditional Chinese medicine therapies for the treatment of allergic rhinitis has not been completed. Therefore, the purpose of this network meta-analysis is to evaluate the efficacy and safety of different traditional Chinese medicine therapies for the treatment of allergic rhinitis. Methods and analysis: Three English databases of PubMed, Embase, Cochrane Library, and 2 Chinese databases of CNKI and Wanfang were searched from their inceptions to September 1, 2020. At the same time, in order to prevent omissions, we also compared the previous meta-analysis to determine the final included trials. The main evaluation outcome was the total Clinical Score (total nasal symptom score [TNSS]), the secondary evaluation outcome was the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) and adverse events. The Cochrane Collaboration's Tool was used to evaluate the methodological quality of articles, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) instrument was used to evaluate the quality of evidence. Network meta-analysis was completed by using Stata Statistical Software (Version 14.0, Stata Corporation, College Station, TX). Results: This study will compare and rank the different traditional Chinese medicine therapies for allergic rhinitis. Conclusion: This study is the first time to use network meta-analysis (NMA) to compare the efficacy and safety of traditional Chinese medicine for the treatment of allergic rhinitis, which will provide ideas and methods for the clinical treatment for allergic rhinitis. INPLASY registration number: No. INPLASY202080119

Background: Anxiety and depression, complications of cancer, are prevalent but often overlooked mental illnesses. Studies have demonstrated that massage therapy is useful in relieving anxiety and depression of cancer survivors. However, the mechanism is still unclear and no systematic review has provided sufficient evidence for the treatment. Therefore, this protocol is carried out to comprehensively evaluate the reliability of cancer patients with anxiety and depression treated by massage. Methods: We will systematically search the relevant literature from PubMed, Cochrane Library, EMBASE, Web of Science, Wanfang, Chongqing VIP, CNKI and Chinese Biomedical Literature Database from the establishment of the databases to June 1, 2020. In addition, we will only include randomized controlled trials about massage for cancer survivors with anxiety and depression, regardless of language and publication status. Two experienced researchers will separately screen the literature, collect data, analyze data and synthesize data using RevMan V.5.3 software. The quality of the included trials in the study will be assessed by the Cochrane bias risk assessment tool. Results: The protocol for the meta-analysis will systematically evaluate the reliability of massage therapy for cancer patients with anxiety and depression. Conclusion: This conclusion will provide an important basis for evaluating whether massage is reliable in treating cancer survivors who feel anxious and depressed. INPLASY registration number: INPLASY202060101

By March 31, 2020, COVID-19 had spread to more than 200 countries. Over 750,000 confirmed cases were reported, leading to more than 36,000 deaths. In this study, we analysed the efficiency of various intervention strategies to prevent infection by the virus, SARS-CoV-2, using an agent-based SEIIR model, in the fully urbanised city of Shenzhen, Guangdong Province, China. Shortening the duration from symptom onset to hospital admission, quarantining recent arrivals from Hubei Province, and letting symptomatic individuals stay at home were found to be the three most important interventions to reduce the risk of infection in Shenzhen. The ideal time window for a mandatory quarantine of arrivals from Hubei Province was between 10 January and January 17, 2020, while the ideal time window for local intervention strategies was between 15 and 22 January. The risk of infection could have been reduced by 50% if all symptomatic individuals had immediately gone to hospital for isolation, and by 35% if a 14-day quarantine for arrivals from Hubei Province had been introduced one week earlier. Intervention strategies implemented in Shenzhen were effective, and the spread of infection would be controlled even if the initial basic reproduction number had doubled. Our results may be useful for other cities when choosing their intervention strategies to prevent outbreaks of COVID-19., Highlights • Shortening the delay to hospital is the most effective intervention in Shenzhen. • 10 to 17 January is the best time for a mandatory quarantine of Hubei's arrivals. • 15 to 22 January is the best time for local intervention strategy in Shenzhen. • Work/school closure and mask wearing are effective interventions in other countries. • Airport screening is not very effective.

The aim of this study was to investigate the effects of Grape Seed Proanthocyanidins (GSP) on Nω-Nitro-L-arginine methyl ester-induced hypertension in pregnant mice. Fifty Kunming mice were randomized into control, control + GSP, model, and model + GSP. Three weeks later, the artery systolic blood pressure was examined and the related pathological changes were detected. Aorta relaxation function was assessed by aorta ring apparatus. Blood urea nitrogen and serum creatinine were measured by an automatic biochemistry analyzer. Colorimetric analysis, enzyme-linked immunosorbent assay, immunofluorescence, and western blot were applied to detect related indicator in serum, cardiac, and kidney tissues. The results showed that GSP treatment for 3 weeks could improve cardiovascular and kidney remodeling indexes and decrease blood urea nitrogen and serum creatinine content in serum, as well as could ameliorate oxidative stress status and endothelial dysfunction. Therefore, it is for the first time found that GSP exerts protective effect against Nω-Nitro-L-arginine methyl ester-induced hypertension in pregnant mice, which provided a theoretical basis for potential application in the clinic.

Background Xin-Ji-Er-Kang (XJEK) is a Chinese herbal formula, which has been reported to exert effective protection on cardiovascular diseases like hypertension and myocarditis. Purpose To elucidate the protective effects of XJEK on heart failure (HF) induced by myocardial infarction (MI) through the amelioration of inflammation, oxidative stress (OS) and endothelial dysfunction(ED). Materials and methods Fifty-seven male KM mice were randomized into the following six groups (n = 9–10 for each): control group, model group, MI+XJEK low dose group(XJEKL) group, MI+XJEK middle dose group(XJEKM), MI+XJEK high dose group(XJEKH), and MI+fosinopril group (positive control group). After treatment for four weeks, electrocardiography (ECG) and haemodynamics were recorded. Serum and tissues were collected for further analysis. Endothelium-dependent relaxation induced by acetylcholine was assessed in isolated thoracic aorta ring experiment. Hematoxylin and eosin (HE) and Van Gieson (VG) staining were used to detect the pathological changes of heart and thoracic aorta. Colorimetric analysis was employed to determine serum nitric oxide level (NO), malondialdehyde (MDA) concentration and superoxide dismutase (SOD) activity. ELISA was used to detect serum B-type natriuretic peptide (BNP) and serum inflammatory cytokines, as well as endothelial NO synthetase (eNOS), angiotensinII (Ang II) and endothelin-1(ET-1) concentration in both serum and cardiac tissues. Immunohistochemistry and Western blotting (WB) were employed to detect eNOS and inflammatory cytokine expressions in cardiac tissues. Results XJEK administration markedly ameliorated cardiac dysfunction and abnormal ECG manifested by decreased weight/body weight (HW/BW) ratio, BNP and remedied hypertrophy of cardiomyocytes and deposition of collagen, which might be in part attributed to the increased SOD and decreased MDA in serum. Furthermore, XJEK administration improved ED with boosted eNOS activities in serum and cardiac tissues, as well as up-regulated NO levels in serum, down-regulated Ang II and ET-1 content in serum and cardiac tissues. Lastly, protein expression of pro-inflammation cytokines significantly decreased, and anti-inflammatory cytokine was significantly enhanced in serum and cardiac tissues compared to model group. Conclusion XJEK may exert beneficial effects on HF induced by MI in mice, and the underlying mechanism may be attributable to the amelioration of ED, anti-OS and anti-inflammation effects.

Background Xin-Ji-Er-Kang (XJEK) is a Chinese herbal formula, which has been reported to exert effective protection against cardiovascular diseases, including hypertension and myocarditis. Methods Cultured human umbilical vascular endothelial cells (HUVECs) were treated with angiotensin II (Ang II) and different concentrations of aqueous layer extracts (AqE). Subsequently nitric oxide (NO) and endothelial nitric oxide synthase (eNOS) expression levels were detected. In addition, fifty Kunming mice were randomized into control, Nω-nitro-L-arginine methyl ester (L-NAME), L-NAME+AqE, L-NAME+XJEK and L-NAME+fosinopril treatment groups. Following 8 weeks of treatment, the cardiac hemodynamic index was measured, relaxation of the aorta was examined and pathological changes were observed. Colorimetric analysis and enzyme linked immunosorbent assay (ELISA) were applied to determine the relevant indicators in plasma and cardiac tissues. Results The in vitro study results demonstrated that AqE could preserve endothelial function (NO, 21.05 ± 2.03 vs. 8.64 ± 0.59; eNOS, 1.08 ± 0.17 vs.0.73 ± 0.06). In addition, the in vivo results demonstrated that compared with the control group, treatment with AqE could enhance a high hemodynamic state (left ventricular systolic pressure, 116.76 ± 9.96 vs.114.5 ± 15.16), improve endothelial function (NO, 7.98 ± 9.64 vs. 1.66 ± 3.11; eNOS, 19.78 ± 3.18 vs.19.38 ± 3.85), suppress oxidative stress (OS) (superoxide dismutase, 178.17 ± 13.78 vs. 159.38 ± 18.86; malondialdehyde, 0.77 ± 0.13 vs.1.25 ± 0.36) and reverse cardiovascular remodeling. Conclusion Polysaccharide from XJEK exerts protective effects against Ang II-induced injury in HUVECs and L-NAME-induced hypertension in mice and the underlying mechanism may be attributed to improving endothelial dysfunction, OS and the inflammation status in mice.

The present study was designed to elucidate the beneficial effects of XJEK on myocardial infarction (MI) in rats, especially through the amelioration of endothelial dysfunction (ED). 136 Sprague-Dawley rats were randomized into 13 groups: control group for 0wk (n = 8); sham groups for 2, 4, and 6 weeks (wk); MI groups for 2, 4, and 6 wk; MI+XJEK groups for 2, 4, and 6w k; MI+Fosinopril groups for 2, 4, and 6 wk (n = 8~10). In addition, 8 rats were treated for Evans blue staining and Tetrazolium chloride (TTC) staining to determine the infarct size. Cardiac function, ECG, and cardiac morphological changes were examined. Colorimetric analysis was employed to detect nitric oxide (NO), and enzyme-linked immunosorbent assay (ELISA) was applied to determine N-terminal probrain natriuretic peptide (NT-ProBNP), endothelin-1 (ET-1), angiotensin II (Ang II), asymmetric dimethylarginine (ADMA), tetrahydrobiopterin (BH4), and endothelial NO synthase (eNOS) content. The total eNOS and eNOS dimer/(dimer+monomer) ratios in cardiac tissues were detected by Western blot. We found that administration of XJEK markedly ameliorated cardiovascular remodeling (CR), which was manifested by decreased HW/BW ratio, CSA, and less collagen deposition after MI. XJEK administration also improved cardiac function by significant inhibition of the increased hemodynamic parameters in the early stage and by suppression of the decreased hemodynamic parameters later on. XJEK also continuously suppressed the increased NT-ProBNP content in the serum of MI rats. XJEK improved ED with stimulated eNOS activities, as well as upregulated NO levels, BH4 content, and eNOS dimer/(dimer+monomer) ratio in the cardiac tissues. XJEK downregulated ET-1, Ang II, and ADMA content obviously compared to sham group. In conclusion, XJEK may exert the protective effects on MI rats and could continuously ameliorate ED and reverse CR with the progression of MI over time.

Aim Cardiovascular diseases, such as coronary heart disease and myocardial infarction (MI) are currently considered as the leading causes of death and disability. The aim of the present study is to investigate the effects of Xin-Ji-Er-Kang (XJEK) on kidney injury and renal oxidative stress. In addition, the associated mechanism involved in these processes was examined in an MI model, and particularly focused on the nuclear factor erythroid 2‐related factor (NRF2)/heme oxygenase‐1 (HO‐1) pathway. Materials and methods A total of 138 Sprague-Dawley rats were used in the present study. The control group was designated as 0 wk (n = 8). A total of 3 phases (2, 4, 6 wk) of administration were used in the sham-operated groups (sham, n = 10), MI groups (MI, n = 10), MI + XJEK groups (XJEK, n = 10) and MI + fosinopril groups (fosinopril, n = 10). Additional 10 rats were used to evaluate the infarct area. At 2, 4 or 6 wk post-MI, the hemodynamic parameters were monitored, the rats were sacrificed, then blood, heart and renal tissues were collected for furtherly analysis. Results The results indicated that XJEK administration continuously ameliorated renal hypertrophy index, blood urea nitrogen and cystatin C concentrations. XJEK further improved post-MI cardiac function by limiting scar formation and caused a downregulation in the hemodynamic parameters at the end of 2 and 4 wk. The hemodynamic parameters were upregulated after 6 wk treatment with XJEKcompared with those noted in the MI groups. Similarly, XJEK treatment for 2 wk potentiated Nrf2 nuclear translocation and HO-1 expression and inhibited the deficiency of nuclear Nrf2 and HO-1 at 6 wk post-MI compared with that of the MI groups, indicating the attenuation of the renal oxidative stress condition. The levels of malondialdehyde and angiotensin II (Ang II) in plasma and renal tissues, as well as the levels of aldosterone, 8-hydroxydeoxyguanosine, angiotensin II type 1 receptor and NADPH Oxidase-4 in the kidney tissue significantly decreased following XJEK treatment for 6 wk. In addition, the XJEK treatment groups revealed a significant upregulation in the activity of superoxide dismutase and in the total antioxidant capacity activity compared with those noted in the corresponding MI groups. Conclusion These results demonstrated that progressive nephropathy in MI rats was associated with intrarenal activation of the renin-angiotensin-aldosterone system. Concomitantly, this process was associated with oxidative stress and impaired Nrf2 activation. The improvement in the severity of nephropathy by XJEK in this model may be associated with the reversal of these abnormalities.

Background: This study will evaluate the clinical effect of vestibular rehabilitation (VR) on benign paroxysmal positional vertigo (BPPV). Methods: In this study, we will identify relevant trials on the topic published in MEDLINE, EBASE, Web of Science, Cochrane Library, Scopus, CINAHL, CBM, and CNKI from inception to the present. We will also search conference proceedings, thesis/dissertation, ongoing trials in clinical trial registry, and reference lists of included studies. Two researchers will independently carry out record selection, data extraction, and study quality assessment, respectively. Any disagreement will be arbitrated and solved with the help of a third researcher. If necessary, we will conduct random-effects meta-analysis to pool the effect estimates of included trials determined to be acceptable heterogeneity. Results: We will summarize the latest evidence to assess the effect of VR for the treatment of patients with BPPV. Conclusion: The findings of this study will help determine whether or not VR is effective in treating BPPV. OSF registration: osf.io/k83y5.

Background: Knee osteoarthritis (KOA), a concerning public health problem, seriously threatens well being of human beings. At present, studies have shown that massage therapy is effective in relieving related symptoms of KOA. However, the evidence of massage for KOA has not been systematically evaluated. Therefore, the study is conducted to systematically assess the reliability of patients with KOA treated by massage. Methods: We will retrieve the relevant literature of massage for KOA from PubMed, Cochrane Library, EMBASE, Web of Science, Wanfang, Chongqing VIP, CNKI, and Chinese Biomedical Literature Database from the establishment of the databases to August 1, 2020. Two researchers will independently perform the screening of literature and extract the basic information of the data. In addition, RevMan V.5.3 software will be used for data analysis. Results: The study will comprehensively assess the effect of massage for KOA. Conclusion: The study will provide comprehensive evidence for evaluating whether massage therapy is useful in treating patients with KOA. INPLASY registration number: INPLASY202080115.

Background: With the rising incidences stroke, the Post-Stroke Urinary Incontinence (PSUI) has become one of the common clinical sequelae. PSUI not only lowers the quality of life of patients, but also impacts tremendously to mental health. As a treasure of Chinese medicine, acupuncture and its related therapies have been widely accepted in clinical treatment of PSUI. Recently, there have been many clinical studies on the treatment of PSUI with acupuncture and related therapies, but the best way to treat PSUI is controversial. Therefore, the purpose of this paper is to provide an optimal ranking regarding acupuncture and its related therapies for PSUI. Methods: The five domestic and foreign databases including PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, Wanfang Database will be systematically searched. The time range of the literature search is from the date of establishment to August 31, 2020. The main evaluation outcome was the number of patients after treatment, and the frequency of urinary incontinence. The secondary evaluation outcome was International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF), Barthel Activities of Daily Living Index (Barthel ADL Index) and the incidence rate of adverse events. The methodological quality of the article will evaluated by Cochrane Collaboration's Tool and the quality of evidence will evaluated through Grading of Recommendations Assessment, Development and Evaluation (GRADE) instrument. The Network Meta-Analysis (NMA) will be completed using Stata statistical software. Results: The final results of this study will be published in a peer-reviewed journal. Conclusion: This network meta-analysis will compare the efficacy and safety of different acupuncture therapies in the treatment of PSUI and summarize the best treatment options, which will help patients and doctors to choose effective acupuncture methods in time.

Background This systematic review is designed to provide an assessment of the effectiveness and safety of moxibustion therapy for cervical vertigo (CV). Methods Relevant randomized controlled trials (RCTs) will be searched from the databases of PubMed, the Cochrane Library, Embase, the China National Knowledge Infrastructure, Wanfang Database, Chinese Science and Technology Periodical Database, and Chinese Biomedical Literature Database from their inception to June 2020. Two authors will independently select studies, collect data, and assess the methodology quality by the Cochrane risk of bias tool. RevMan V.5.3 software will be used for statistical analysis. Results The results of this study will provide an assessment of the current state of moxibustion for CV and aim to prove the effectiveness and safety of moxibustion therapy. Conclusion This systematic review will provide a credible Evidence-based for the treatment of CV with moxibustion. Study registration number INPLASY202060004.

Circulating tumor cells (CTCs) play a key role in cancer metastasis but are very difficult to detect. in vivo monitoring CTCs has been recognized as an important technique for cancer research and clinical diagnosis. Recently, a noninvasive method, in vivo flow cytometry (IVFC) has been developed to enable continuous, real-time, and long-duration detection of CTCs in animal models by detecting CTC fluorescence in blood vessels excited by lasers. In this study, we present a simple optical scheme for direct noninvasive CTC detection using confocal microscopes. We demonstrate that line scanning of confocal microscopy can provide effective and quantitative CTC detection in live mice during cancer development. Rare CTC signals can be acquired at the early stage of the tumor development after implantation of subcutaneous tumor and monitored continuously to the end. Signals from CTC clusters can also be acquired and distinguished from single CTCs. Our results suggest confocal microscopy is a simple and reliable method for biologists and doctors to use for cancer research. © 2018 International Society for Advancement of Cytometry.

Recent progress in anti-tumor therapy has revealed the significance of anti-tumor immune responses in tumor progression and clinical course in several kinds of malignant tumors. The draining lymph node is an important immune system component that contains a number of antigen-presenting cells, which induce rapid immune responses to foreign antigens. Current studies have shown that higher expression of CD169 on lymph node sinus macrophages is associated with the induction of anti-tumor immunity. In the present study, we searched for natural compounds that regulate the CD169-positive phenotype in macrophages to identify potential new anti-cancer agents targeting macrophage activation. Among 50 natural compounds, aculeatiside A, naringin, and onionin A significantly induced the CD169-positive phenotype in human monocyte-derived macrophages. These compounds also induced CD169 overexpression and secretion of inflammatory cytokines, including interleukin (IL)-1β and IL-12, in murine macrophages. Subcutaneous injection of aculeatiside A and naringin enhanced mRNA expression of IL-1β, IL12, and CD169 in regional lymph nodes in mice. These findings suggest aculeatiside A and naringin may enhance anti-tumor immune responses by inducing CD169-positive macrophages in lymph nodes.

Background. Xin-Ji-Er-Kang (XJEK) shows protective effects on the myocardial ischemic diseases in our previous reports. We hypothesized that XJEK may exert preventing effects on L-NAME induced hypertensive mice by ameliorating oxidative stress (OS) and endothelial dysfunction (ED). Methods. After treatment with XJEK for four weeks, cardiac function and cardiovascular pathology changes were evaluated. Then, endothelial-dependent vascular relaxation and serum NO, eNOS, AMDA, SOD, MDA content, and cardiac tissue eNOS expression were detected. Results. The hypertensive mice displayed distinct cardiovascular remodeling including increased HW/BW index (4.7 ± 0.33 versus 5.2 ± 0.34), cross-section area, and collagen deposition. In addition, ED was found manifested by decreased serum NO (20.54 ± 8.05 versus 6.29 ± 2.33), eNOS (28.34 ± 2.36 versus 20.37 ± 2.30), content, and decreased eNOS expression in cardiac tissue and damaged endothelium-dependent diastolic function. Moreover, OS was detected confirmed by decreased SOD activity and increased MDA content in serum. However, treatment with XJEK for 4 wk could reverse cardiovascular remodeling (HW/BW index normalized from 5.2 ± 0.34 to 4.59 ± 0.25), ameliorate and preserve endothelial function (NO: 16.67 ± 7.24 versus 6.29 ± 2.33; eNOS: 16.67 ± 7.24 versus 6.29 ± 2.33), and suppress OS. Conclusion. XJEK has protective effects against cardiovascular remodeling in L-NAME induced hypertensive mice.

Manganese (Mn) is an essential trace element for physiological functions since it acts as an enzymatic co-factor. Nevertheless, overexposure to Mn has been associated with a pathologic condition called manganism. Furthermore, Mn has been reported to affect lipid metabolism by mechanisms which have yet to be established. Herein, we used the nematode Caenorhabditis elegans to examine Mn’s effects on the dopaminergic (DAergic) system and determine which transcription factors that regulate with lipid metabolism are affected by it. Worms were exposed to Mn for four hours in the presence of bacteria and in a liquid medium (85 mM NaCl). Mn increased fat storage as evidenced both by Oil Red O accumulation and triglyceride levels. In addition, metabolic activity was reduced as a reflection of decreased oxygen consumption caused by Mn. Mn also affected feeding behavior as evidenced by decreased pharyngeal pumping rate. DAergic neurons viability were not altered by Mn, however the dopamine levels were significantly reduced following Mn exposure. Furthermore, the expression of sbp-1 transcription factor and let-363 protein kinase responsible for lipid accumulation control was increased and decreased, respectively, by Mn. Altogether, our data suggest that Mn increases the fat storage in C. elegans, secondary to DAergic system alterations, under the control of SBP-1 and LET-363 proteins.

Guillain-Barré syndrome (GBS) is a post-infectious autoimmune disease. Dendritic cells (DCs) can recognize the pathogen and modulate the host immune response. Exploring the role of DCs in GBS will help our understanding of the disease development. In this study, we aimed to analyze plasmacytoid and conventional DCs in peripheral blood of patients with GBS at different stages of the disease: acute phase as well as early and late recovery phases. There was a significant increase of plasmacytoid DCs in the acute phase (p=0.03 vs healthy donors). There was a positive correlation between percentage of plasmacytoid DCs and the clinical severity of patients with GBS (r=0.61, p0.001). Quantitative polymerase chain reaction and flow cytometry confirmed the aberrant plasmacytoid DCs in GBS. Thus, plasmacytoid DCs may participate in the development of GBS.

Gear transmission is a key component in locomotive where it delivers the traction or braking forces between the motor and the wheelset. Its working performance has a direct effect on the operating reliability and safety. Therefore, investigation on the dynamic characteristics of the gear transmission in locomotives is very meaningful. In this study, a gear transmission-locomotive-track spatial coupled dynamic model is established based on the classical locomotive-track coupled dynamics and the gear dynamics theory. Based on this model, the dynamic responses of the gear transmission can be analysed under excitations from different track geometrical irregularity, and the dynamic performance of the gear transmission can be obtained. This paper also studies the effect law of the track irregularity on the vibration of the gear transmission by using statistical indicators RMS (Root Mean Square) and PtP (Peak-to-Peak). The results indicate that the track geometrical irregularity has an obvious impact to the dynamic performance of gear transmission. The dynamic response of the gear transmission will increase violently when the locomotive runs on the track in a worse condition. The results are expected to be capable of providing some references for fatigue life prediction and reliability analysis of the gear transmissions in locomotive.

Recent findings have shown the significance of CD163-positive macrophages in tumor progression, yet there have been few studies on the function of CD163 in macrophages. Here, we uncover the role of CD163 in macrophage activation using CD163-deficient mice and human samples. We detected CD163 in 62 undifferentiated pleomorphic sarcoma samples, in which a high percentage of CD163-positive macrophages was associated with decreased overall survival and higher histologic grade. We observed macrophage-induced tumor cell proliferation in cocultures of human monocyte-derived macrophages and leiomyosarcoma (TYLMS-1) and myxofibrosarcoma (NMFH-1) cell lines, which was abrogated by silencing of CD163. Tumor development of sarcoma (MCA205 and LM8) cells in CD163-deficient mice was significantly abrogated in comparison with wild-type (WT) mice. Coculture with WT peritoneal macrophages significantly increased proliferation of MCA205 cells but decreased in the presence of CD163-deficient macrophages. Production of IL6 and CXCL2 in CD163-deficient macrophages was suppressed in comparison with WT macrophages, and overexpression of CD163 in CD163-deficient macrophages induced production of IL6 and CXCL2. Silencing of IL6 but not CXCL2 abrogated macrophage-induced proliferation of MCA205 cells. Taken together, our results show that CD163 is involved in protumoral activation of macrophages and subsequent development and progression of tumors in mice and humans. Significance: Macrophage CD163-mediated induction of IL6 promotes tumor development and progression in murine and human malignant tumors. Cancer Res; 78(12); 3255–66. ©2018 AACR.

We explore how to add haptics to walls and other heavy objects in virtual reality. When a user tries to push such an object, our system actuates the user's shoulder, arm, and wrist muscles by means of electrical muscle stimulation, creating a counter force that pulls the user's arm backwards. Our device accomplishes this in a wearable form factor. In our first user study, participants wearing a head-mounted display interacted with objects provided with different types of EMS effects. The repulsion design (visualized as an electrical field) and the soft design (visualized as a magnetic field) received high scores on "prevented me from passing through" as well as "realistic". In a second study, we demonstrate the effectiveness of our approach by letting participants explore a virtual world in which all objects provide haptic EMS effects, including walls, gates, sliders, boxes, and projectiles.

Widespread use of pentachlorophenol (PCP) in schistosomiasis endemic areas had led to ubiquitous exposure to PCP and its residues. Numerous studies had revealed that occupational PCP exposure probably increased risk of cancers, but whether long-term community-level exposure to PCP generates the similarly carcinogenic effect, seldom studies focused on it. This study was to explore the cancer risks of long-term community-level PCP exposure from drinking water in a Chinese general population. Incident (2009-2012) cancer records were identified by local government national registry. And PCP concentration of raw drinking water samples in each district was measured by GC-MS/MS analysis for further division of three PCP exposure categories by interquartile range (high vs. medium vs. low). Internal comparisons were performed, and standard rate ratio was calculated to describe the relationship between PCP exposure and cancer risks by using low-exposure group as the reference group. PCP was detected in all 27 raw drinking water samples ranging from 11.21 to 684.00 ng/L. A total of 6,750 cases (4,409 male and 2,341 female cases) were identified, and age-standardized rate (world) was 154.95 per 100,000 person-years. The cancer incidence for the high-exposure group was remarkably high. Internal comparisons indicated that high PCP exposure might be positively associated with high cancer risks in the community population, particularly for leukemia (SRR = 5.93, 95 % CI = 5.24-6.71), maligant lymphoma (SRR = 2.27, 95 % CI = 2.10-2.54), and esophageal cancer (SRR = 2.42, 95 % CI = 2.35-2.50). Long-term community-level exposure to PCP was probably associated with hemolymph neoplasm, neurologic tumors, and digestive system neoplasm.

As an important methyltransferase, DNMT1 plays a key role in DNA methylation that is essential for normal spermatogenesis, which suggests that it may be involved in male infertility with spermatogenesis impairment. To explore the relationship between DNMT1 and spermatogenesis impairment, polymorphic distributions of single-nucleotide polymorphisms (SNP) rs16999593, rs2228612 and rs2228611 in DNMT1 were investigated in 342 infertile patients with idiopathic azoospermia or oligospermia and 232 fertile controls in a Chinese population. As a result, no significant differences in allele and genotype frequencies of the three SNP between total patients and controls were observed. However, after stratifying the patients, significant differences in allele and genotype frequencies were detected between oligospermia subgroup and control group. The frequencies of rs16999593 allele A (83.6% versus 77.6%, P =0.033) and genotype AA (69.2% versus 59.0%, P =0.037) and SNP rs2228611 genotype AA (18.4% versus 9.9%, P =0.016) in patients with oligospermia were significantly higher than those in control group. These findings suggest that the polymorphism in DNMT1 might be associated with oligospermia and could modify the susceptibility of oligospermia. The DNMT1 gene plays a key role in DNA methylation, which is essential for normal spermatogenesis, and it may be involved in male infertility with spermatogenesis impairment. To explore the possible relationship between DNMT1 and spermatogenesis impairment, polymorphic distributions of the single-nucleotide polymorphisms (SNP) rs16999593, rs2228612 and rs2228611 in DNMT1 were investigated in 342 infertile patients with idiopathic azoospermia or oligospermia and 232 fertile controls in a Chinese population. As a result, the frequencies of allele A and genotype AA of SNP rs6999593 and of genotype AA of SNP rs2228611 were significantly higher in patients with oligospermia than in controls. These findings suggest that the polymorphism of DNMT1 might be associated with oligospermia and could modify the susceptibility of oligospermia.

Aim The goal of the present study was to determine the disparities in prevalence and risk factors of loneliness between rural empty nest and non-empty nest older adults in Chizhou, China. Methods A sample of 730 participants (381 empty nest older adults and 349 non-empty nest older adults) were surveyed using the University of California at Los Angeles-Loneliness Scale, the 30-item Geriatric Depression Scale (GDS-30), the Pittsburgh Sleep Quality Index, the Social Support Rate Scale, the Perceived Social Support from Family Scale and the World Health Organization Quality of Life questionnaire abbreviated version. Results The present study showed that the mean level of loneliness did significantly differ between empty nest older adults and non-empty nest older adults (41.52 ± 6.98 vs 39.46 ± 7.38). Empty nesters had significantly higher GDS scores; by contrast, they received lower objective, subjective and family support. Family support, objective support and social interaction were associated significantly with loneliness, which was more pronounced in empty nest older adults, excluding subjective support and psychological domain. The GDS scores (β = 0.237, P

KIT/KITLG signaling system is crucial for spermatogenesis, which suggests that KIT and KITLG genes may be involved in spermatogenesis impairment and male infertility. To explore the possible association of KIT and KITLG genes with male infertility having spermatogenesis impairment, polymorphism distributions of SNP rs3819392 in KIT gene as well as rs995030 and rs4474514 in KITLG gene were investigated in 372 patients with idiopathic azoospermia or oligospermia and 205 fertile controls. As a result, the significant differences in polymorphism distributions of SNP rs3819392 in KIT gene and rs4474514 in KITLG gene were observed between the patients with oligospermia and controls. The frequencies of allele G (94.2% versus 90.0% p = 0.022) and genotype GG (89.2% versus 82.0% p = 0.042) in patients with oligospermia were significantly higher than those in controls at rs3819392 locus in KIT gene. In addition, the genotype CC of rs4474514 in KITLG (8.2% versus 3.4%, p = 0.034) also significantly increased in oligospermic patients in comparison to controls. These findings indicated that SNP rs3819392 in KIT gene and rs4474514 in KITLG gene may be associated with oligospermia, suggesting that polymorphism of KIT and KITLG genes may play a role in oligospermia.

Eur J Clin Invest 2012; 42 (5): 517–525 Abstract Background Hepcidin plays a central role in iron homeostasis, which is regulated by iron stores, the rate of erythropoiesis, inflammation, and hypoxia. Aberrant expression of hepcidin was found in many diseases, however, there is scant information on hepcidin expression in acute leukemia (AL). Materials and methods 32 patients with AL which diagnosis according to FAB criteria were studied. Serum hepcidin levels, erythropoietin (EPO), interleukin-6 (IL-6), hematological parameters, intracellular and extracellular iron store were evaluated. Results Hepcidin was elevated significantly with increased iron storage in patients at onset of AL when erythropoiesis was depressed by blast cells, then decreased significantly with AL remission, while soluble transferrin receptor (sTfR) concentration was elevated. Negative correlations were found between serum hepcidin and erythropoietic markers including RBC, Hb, Ret and sTfR. Positive correlations were shown between hepcidin and ferritin, between hepcidin and ratio of sideroblasts, as well as between hepcidin and IL-6. Conclusions Hepcidin production was regulated by iron stores, inflammation and erythropoietic activity in AL patients. Erythropoietic activity may play the main role among the regulators of hepcidin expresssion.

Objective To explore the effects of Res on the proliferation and apoptosis of human cervical cancer cell lines C33A, SiHa and HeLa. Methods Inhibition rates by different concentrations of Res were calculated using MTT method. Apoptosis rates and cell cycles were measured and examined by flow cytometry (FCM). Morphological configuration of apoptotic cells were observed under the fluorescence microscope. Results The growth of cancer cells was inhibited by Res of varied concentrations in a time- and dose-dependent manner (P Conclusion Res inhibits the growth of cervical cell lines C33A, SiHa and HeLa by inducing cell apoptosis in a time- and dose-dependent manner.

The immunosuppressive effect and low immunogenicity of mesenchymal stem cells (MSCs) make them ideal candidates for immunosuppressive strategies. Adult MSCs have been applied widely in organ transplantation. However, their limited accessibility limits their application in the clinic. Furthermore, successive passages slow the proliferation rate, reduce the multipotency and lower the immunosuppressive activity of adult MSCs in culture. Induced pluripotent stem cells-derived MSCs (iPSC-MSCs) may provide an alternative source of MSCs. iPSC-MSCs have the same characteristics as adult MSCs and exhibit great immunomodulatory properties. For example, iPSC-MSCs displayed significant inhibition of NK cell proliferation and cytolytic function [1]. iPSC-MSCs modulated T-cell phenotypes towards Th2 suppression and induced T regulatory cell (Treg) expansion in the peripheral blood from allergic rhinitis patients [2]. And the similar therapeutic effects on Th2 cytokines were observed in a mouse model of ovalbumin-induced allergic inflammation [3]. Given the great immunomodulatory properties of the iPSC-MSCs, we speculated that iPSC-MSCs could be a promising strategy for preventing transplant rejection. Indeed, we found that iPSC-MSCs combined with low-dose rapamycin (Rapa, 0.1 mg/kg/d, i.p., from day 0 to day 9) significantly prolonged islet allograft survival in the diabetic mice, and even induced immune tolerance in 50% recipients, though iPSC-MSCs alone was inefficient in preventing rejection [4]. We also found that production of interleukin-2 and interferon-γ was reduced, which indicated iPSC-MSCs + Rapa treatment reduces Th1 inflammatory cytokines and may modulate T-cell phenotypes towards Th1 suppression. However, the iPSC-MSCs modulated T-cell phenotypes towards Th2 suppression in allergic rhinitis patients and animal models [2, 3]. These results indicate that iPSC-MSCs maybe exerts different effects and activities in different pathological conditions. It allows the iPSC-MSCs to rectify the imbalance of the immune responses in different environments. Previous studies have verified that adult MSCs alone, or combined with immunosuppressive drugs, induce allograft immune tolerance through Treg induction in vivo. Berman et al. first reported that infusions of donor or third-party MSCs prolonged islet function, which was associated with increased numbers of Tregs in peripheral blood [5]. We speculated that iPSC-MSCs exert the therapeutic effect possibly through the induction of Tregs, acting like adult MSCs. Since TGF-β is the perpetrator of immune suppression via regulatory T cells [6], we examined TGF-β expression in the islet grafts and sera of the recipient mice. The results showed that iPSC-MSCs + Rapa treatment increased sera TGF-β concentrations, and graft TGF-β mRNA levels, compared with Rapa treatment. Flow cytometry results also showed that the number of T regulatory cells was increased in spleen and lymph nodes in the iPSC-MSCs+ Rapa group compared with Rapa group. These results support our hypothesis. In addition to 2,3-dioxygenase, prostaglandin-E2, nitric oxide, TGF-β, and hepatocyte growth factor, IL-10 has been reported to induce MSC-mediated immunosuppressive effects. IL-10 induced by CD11b(+) cells and IL-10-activated regulatory T cells played important roles in immune modulation of mesenchymal stem cells in rat islet allografts [7]. In our research, iPSC-MSCs alone or in the combination with Rapa increased IL-10 secretion in sera, and IL-10 mRNA levels in the graft, whereas Rapa alone did not. Further research is still required to determine whether IL-10 mediates the immunosuppressive effect of iPSC-MSCs + Rapa on T cells. In addition, transwell separation significantly weakened the immunosuppressive effects of iPSC-MSCs on the proliferation of Con A-treated splenic T cells, which revealed that the combined treatment exerts its immunosuppressive effects though cell-cell contact and the regulation of cytokines production. Anti-aging and anti-cancer benefits of low-dose rapamycin were recently discussed [8]. The synergistic immunomodulatory effects of iPSC-MSCs and lowdose Rapa in islet transplantation suggest a promising strategy for inducing immune tolerance, not only in allogeneic islets transplantation, but also in other solid organ transplantation. There may be differences in immunosuppressive effects and mechanisms between iPSC-MSCs and MSCs from other sources. And the origin of the cell sources and the long-term effects of iPSC-MSCs also need to be investigated.

We investigated the acceptability of early anti-retroviral therapy (ART) among HIV-infected people in Anhui Province, China. A cross-sectional study was conducted in 11 convenience selected cities of Anhui Province from September 2012 to December 2013. Study participants were convenience recruited from local Centers for Disease Control and Prevention when they attended for CD4(+) cell counts testing and HIV counselling. Answers to questionnaires were obtained through face-to-face structured interviews. Factors influencing the acceptability of early ART were identified by multiple logistic regression analysis. A total of 287 HIV-infected people met the criteria and completed the survey. The acceptability of early ART was 65.2%. The results of multiple logistic regression analysis indicated that the acceptability of early ART was associated with the following factors: CD4(+) T cell count (above 750 cells/µL vs. 350 cells/µL to 550 cells/µL: OR = 0.144, P0.001), years of HIV diagnosis confirmation (1 year to 5 years vs.1 year: OR = 0.418, P = 0.005; above 5 years vs.1 year: OR = 0.160, P0.001), whether had sexual behaviour after HIV diagnosis confirmation (yes vs. no: OR = 2.342, P = 0.005) and the awareness of two early ART-related questions (OR = 4.101, P = 0.015; OR = 3.294, P0.001). In summary, the present study showed that most HIV-infected people can accept early ART. Early ART interest in Anhui HIV-infected population was high. The awareness of early ART-related knowledge in HIV-infected population was low and should be improved to achieve higher acceptability and keep adherence to early ART for HIV prevention.

Motion platforms are used to increase the realism of virtual interaction. Unfortunately, their size and weight is proportional to the size of what they actuate. We present haptic turk, a different approach to motion platforms that is light and mobile. The key idea is to replace motors and mechanical components with humans. All haptic turk setups consist of a player who is supported by one or more turkers. The player enjoys an interactive experience, such as a flight simulation. The motion in the player's experience is generated by the turkers who manually lift, tilt, and push the player's limbs or torso. To get the timing and force right, timed motion instructions in a format familiar from rhythm games are displayed on turkers' mobile devices, which they attach to the player's body. We demonstrate a range of installations based on mobile phones, projectors, and head-mounted displays. In our user study, participants rated not only the experience as player as enjoyable (6.1/7), but also the experience as a turker (4.4/7). The approach of leveraging humans allows us to deploy our approach anytime anywhere, as we demonstrate by experimentally deploying at an art festival in the Nevada desert.

The association between glutathione-S-transferase polymorphisms (GSTM1, GSTT1 and GSTP1) and risk of acute leukemia in Asians remains controversial. This study was therefore designed to evaluate the precise association in 23 studies identified by a search of PubMed and several other databases, up to December 2013. Using random or fixed effects models odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were calculated. Heterogeneity across studies was assessed, and funnel plots were constructed to test for publication bias. The meta-analysis showed positive associations between GST polymorphisms (GSTM1 and GSTT1 but not GSTP1) and acute leukemia risk [(OR=1.47, 95% CI 1.18-1.83); (OR=1.32, 95% CI 1.07-1.62); (OR=1.01, 95% CI 0.84-1.23), respectively] and heterogeneity between the studies. The results suggested that the GSTM1 null genotype and GSTT1null genotype, but not the GSTP1 polymorphism, might be a potential risk factors for acute leukemia. Further well-designed studies are needed to confirm our findings.

Motion platforms are used to increase the realism of virtual interaction. Unfortunately, their size and weight is proportional to what they actuate. We present haptic turk, a different approach to motion platforms that is light and mobile. The key idea is to replace motors and mechanical components with humans. All haptic turk setups consist of a player who is supported by one or more “turkers”. The player enjoys an interactive expe-rience, such as a flight simulation. The motion in the player's experience is generated by the turkers who manually lift, tilt, and push the player's limbs or torso. To get the timing and force right, timed motion instructions in a format familiar from rhythm games are dis-played on turkers' mobile devices, which they attach to the player's body. We also present an immersive set-up based on a head-mounted display.

MicroRNA-183 (miR-183) family is proposed as promising biomarkers for early cancer detection and accurate prognosis as well as targets for more efficient treatment. The results of their expression feature in cancer tissues are inconsistent and controversy still exists in identifying them as new biomarkers of cancers. Therefore, to systemically evaluate the most frequently reported cancers in which miR-183 family members were up- or down-regulated is critical for further investigation on physiological impact of its aberrant regulation in specific cancers. The published studies that compared the level of miR-183 family expression in cancer tissues with those in noncancerous tissues were reviewed by the meta-analysis with a vote-counting strategy. Among the 49 included studies, a total of 18 cancers were reported, with 11 cancers reported in at least two studies. In the panel of miR-183 family members' expression analysis, colorectal cancer and prostate cancer ranked at the top among consistently reported cancer types with up-regulated feature. Bladder cancer, lung cancer and hepatocellular carcinoma were the third most frequently reported cancer types with significant over-expression of miR-96, miR-182 and miR-183 respectively. Breast cancer and gastric cancer were presented with inconsistent regulations and the members of this family had their own distinct regulated features in other different cancers. MiR-183 family, either individually or as a cluster, may be useful prognostic markers and/or therapeutic targets in several cancers. Further studies and repeat efforts are still required to determine the role of miR-183 family in various cancer progressions.

Hepcidin is a key hormone governing mammalian iron homeostasis and may be directly or indirectly involved in the development of most iron deficiency/overload and inflammation-induced anemia. The objective of this study was to investigate the expression of hepcidin in anemia of chronic disease. To characterize serum hepcidin, iron and inflammatory indicators associated with anemia of chronic disease (ACD), we studied ACD, ACD concomitant iron-deficiency anemia (ACD/IDA), pure IDA and acute inflammation (AcI) patients and analyzed the associations between hepcidin levels and inflammation parameters in various types of anemia. Serum hepcidin levels in patient groups were statistically different, from high to low: ACD, AcI > ACD/IDA > the control > IDA. Serum ferritin levels were significantly increased in ACD and AcI patients but were decreased significantly in ACD/IDA and IDA. Elevated serum EPO concentrations were found in ACD, ACD/IDA and IDA patients but not in AcI patients and the controls. A positive correlation between hepcidin and IL-6 levels only existed in ACD/IDA, AcI and the control groups. A positive correlation between hepcidin and ferritin was marked in the control group, while a negative correlation between hepcidin and ferritin was noted in IDA. The significant negative correlation between hepcidin expression and reticulocyte count was marked in both ACD/IDA and IDA groups. All of these data demonstrated that hepcidin might play role in pathogenesis of ACD, ACD/IDA and IDA, and it could be a potential marker for detection and differentiation of these anemias.

To further enhance anticancer effect of Shepherdin and overcome limitation of peptide therapy, recombinant adeno-associated virus (rAAV) was constructed with following strategies: therapeutic peptide secretory expression and adeno-associated virus gene transfer system. MTT assay and flow cytometric analysis revealed that rAAV harboring fusion gene NT4-Ant-Shepherdin significantly suppressed A549 cell growth in a time-dependent manner and induced apoptosis. In the infected A549 cells, survivin expression level decreased strongly while Caspase-3/7 activities increased significantly. These results indicated that rAAV harboring fusion gene NT4-Ant-Shepherdin may be a novel strategy in lung cancer peptide therapy.