Autologous olfactory mucosa mesenchymal stem cells treatment improves the neural network in chronic refractory epilepsy.

BACKGROUND AND AIMS: Refractory epilepsy is also known as drug-resistant epilepsy with limited clinical treatment. Benefitting from its safety and easy availability, olfactory mucosa mesenchymal stem cells (OM-MSCs) are considered a preferable MSC source for clinical application. This study aims to investigate whether OM-MSCs are a promising alternative source for treating refractory epilepsy clinically and uncover the mechanism by OM-MSCs administration on an epileptic mouse model. METHODS: OM-MSCs were isolated from turbinal and characterized by flow cytometry. Autologous human OM-MSCs treatment on a patient was carried out using intrathecal administration. Epileptic mouse model was established by 1 mg/kg scopolamine and 300 mg/kg pilocarpine treatment (intraperitoneal). Stereotaxic microinjection was employed to deliver the mouse OM-MSCs. Mouse electroencephalograph recording was used to investigate the seizures. Brain structure was evaluated by magnetic resonance imaging (MRI). Immunohistochemical and immunofluorescent staining of GFAP, IBA1, MAP2, TUBB3, OLIG2, CD4, CD25, and FOXP3 was carried out to investigate the neural cells and Treg cells. QRT-PCR and ELISA were performed to determine the cytokines (Il1b, Il6, Tnf, Il10) on mRNA and protein level. Y-maze, the object location test, and novel object recognition test were performed to measure the cognitive function. Footprint test, rotarod test, balance beam test, and grip strength test were conducted to evaluate the locomotive function. Von Frey testing was carried out to assess the mechanical allodynia. RESULTS: Many beneficial effects of the OM-MSC treatment on disease status, including seizure type, frequency, severity, duration, and cognitive function, and no apparent adverse effects were observed at the 8-year follow-up case. Brain MRI indicated that autologous OM-MSC treatment alleviated brain atrophy in epilepsy patients. A study in an epileptic mouse model revealed that OM-MSC treatment recruited Treg cells to the brain, inhibited inflammation, rebuilt the neural network, and improved the cognitive, locomotive, and perceptive functions of epileptic mice. CONCLUSIONS: Autologous OM-MSC treatment is efficacious for improving chronic refractory epilepsy, suggesting a future therapeutic candidate for epilepsy. TRIAL REGISTRATION: The study was registered with Chinese Clinical Trial Registry (ChiCTR2200055357).

Clinical recommendations for perioperative immunotherapy-induced adverse events in patients with non-small cell lung cancer.

Perioperative adjuvant treatment has become an increasingly important aspect of the management of patients with non-small cell lung cancer (NSCLC). In particular, the success of immune checkpoint inhibitors, such as antibodies against PD-1 and PD-L1, in patients with lung cancer has increased our expectations for the success of these therapeutics as neoadjuvant immunotherapy. Neoadjuvant therapy is widely used in patients with resectable stage IIIA NSCLC and can reduce primary tumor and lymph node stage, improve the complete resection rate, and eliminate microsatellite foci; however, complete pathological response is rare. Moreover, because the clinical benefit of neoadjuvant therapy is not obvious and may complicate surgery, it has not yet entered the mainstream of clinical treatment. Small-scale clinical studies performed in recent years have shown improvements in the major pathological remission rate after neoadjuvant therapy, suggesting that it will soon become an important part of NSCLC treatment. Nevertheless, neoadjuvant immunotherapy may be accompanied by serious adverse reactions that lead to delay or cancellation of surgery, additional illness, and even death, and have therefore attracted much attention. In this article, we draw on several sources of information, including (i) guidelines on adverse reactions related to immune checkpoint inhibitors, (ii) published data from large-scale clinical studies in thoracic surgery, and (iii) practical experience and published cases, to provide clinical recommendations on adverse events in NSCLC patients induced by perioperative immunotherapy.

The important effect of 5-HTTLPR polymorphism on the risk of depression in patients with coronary heart disease: a meta-analysis.

BACKGROUND: Depression has been recognized as an independent risk factor of coronary heart disease (CHD). Moreover, there is interrelationship of both depression and CHD. However, the potential pathophysiological mechanisms remain unknown. It might be influenced by genetic and environmental factors. According to recent researches, there is potential association between serotonin transporter gene-linked polymorphic region (5-HTTLPR) polymorphism and risk of depression in CHD patients, but the results are still inconclusive. Therefore, we performed this meta-analysis based on unadjusted and adjusted data to ascertain a more precise conclusion. METHODS: We searched relevant articles through PubMed, Embase, Web of Science, Chinese BioMedical Literature (CBM) and Chinese National Knowledge Infrastructure (CNKI) databases up to August 26, 2019. Study selection and data extraction were accomplished by two authors independently. The strength of the correlation was assessed via odds ratios (ORs) with their 95% confidence intervals (95%CIs). RESULTS: This meta-analysis enrolled six observational studies. Based on unadjusted data, there was significant relationship between 5-HTTLPR polymorphism and depression risk in CHD patients under all genetic models (S vs. L: OR = 1.31, 95%CI = 1.07-1.60; SS vs. LL: OR = 1.73, 95%CI = 1.12-2.67; LS vs. LL: OR = 1.47, 95%CI = 1.13-1.92; LS + SS vs. LL: OR = 1.62, 95%CI = 1.25-2.09; SS vs. LL + LS: OR = 1.33, 95%CI = 1.02-1.74). The results of adjusted data further strengthened this relationship (SS vs. LL: OR = 1.89, 95%CI = 1.28-2.80; LS vs. LL: OR = 1.69, 95%CI = 1.14-2.51; LS + SS vs. LL: OR = 1.80, 95%CI = 1.25-2.59). Subgroup analyses based on ethnicity and major depressive disorder revealed similar results to that of the overall analysis. No evidence of publication bias was observed. CONCLUSIONS: Our results suggest that 5-HTTLPR polymorphism may have an important effect on the risk of depression among patients with CHD, and carriers of the S allele of 5-HTTLPR are more vulnerable to depression.

Potential predictors for mental stress-induced myocardial ischemia in patients with coronary artery disease.

BACKGROUND: Mental stress-induced myocardial ischemia (MSIMI) is closely associated with adverse cardiac events in patients with coronary artery disease (CAD) and we aimed to determine whether biomarkers and blood pressure could be potential predictors of MSIMI. METHODS: This study enrolled 82 patients with documented CAD between June 1, 2017 and November 9, 2017. Patient blood samples were obtained at resting period and at the end of mental arithmetic. Then, patients were assigned to MSIMI positive group and MSIMI negative group. The main statistical methods included linear regression, receiver operating characteristic (ROC) curves, and logistic regression. RESULTS: Patients with CAD with MSIMI had significantly greater median resting N-terminal pro-brain natriuretic peptide (NT-proBNP, 141.02 [45.85-202.76] pg/mL vs. 57.95 [27.06-117.64] pg/mL; Z = -2.23, P = 0.03) and mean systolic blood pressure (SBP) (145.56 ±â€Š16.87 mmHg vs. 134.92 ±â€Š18.16 mmHg, Z = -2.13, P = 0.04) when compared with those without MSIMI. After 5-min mental stress task, those who developed MSIMI presented higher elevation of median post-stressor high sensitivity cardiac troponin I (hs-cTnI, 0.020 [0.009-0.100] ng/mL vs. 0.009 [0.009-0.010] ng/mL; Z = -2.45, P = 0.01), post-stressor NT-proBNP (138.96 [39.93-201.56] pg/mL vs. 61.55 [25.66-86.50] pg/mL; Z = -2.15, P = 0.03) compared with those without MSIMI. Using the ROC curves, and after the adjustment for basic characteristics, the multiple logistic regression analysis showed that patients presenting a post-stressor hs-cTnI ≥ 0.015 ng/mL had seven-fold increase in the risk of developing MSIMI (odds ratio [OR]: 7.09; 95% confidence interval [CI]: 1.65-30.48; P = 0.009), a rest NT-proBNP ≥ 80.51 pg/mL had nearly eight-fold increase (OR: 7.85; 95% CI: 1.51-40.82; P = 0.014), a post-stressor NT-proBNP ≥ 98.80 pg/mL had 35-fold increase (OR: 34.96; 95% CI: 3.72-328.50; P = 0.002), a rest SBP ≥ 129.50 mmHg had 11-fold increase (OR: 11.42; 95% CI: 1.21-108.17; P = 0.034). CONCLUSIONS: The present study shows that CAD patients with higher hs-cTnI level, and/or greater NT-proBNP and/or SBP are at higher risk of suffering from MSIMI when compared with those without MSIMI, indicating that hs-cTnI, NT-proBNP, SBP might be potential predictors of MSIMI.

Application and Progress of Combined Mesenchymal Stem Cell Transplantation in the Treatment of Ischemic Cardiomyopathy.

Treatment of ischemic cardiomyopathy caused by myocardial infarction (MI) using mesenchymal stem cell (MSC) transplantation is a widely researched field, with promising clinical application. However, the low survival rate of transplanted cells has a severe impact on treatment outcome. Currently, research is focused on investigating the strategy of combining genetic engineering, tissue engineering materials, and drug/hypoxia preconditioning to improve ischemic cardiomyopathy treatment outcome using MSC transplantation treatment (MSCTT). This review discusses the application and progress of these techniques.

Voxel-based analysis of fractional anisotropy in post-stroke apathy.

OBJECTIVE: To explore the structural basis of post-stroke apathy by using voxel-based analysis (VBA) of fractional anisotropy (FA) maps. METHODS: We enrolled 54 consecutive patients with ischemic stroke during convalescence, and divided them into apathy (n = 31) and non-apathy (n = 23) groups. We obtained magnetic resonance images of their brains, including T1, T2 and DTI sequences. Age, sex, education level, Hamilton Depression Scale (HAMD) scores, Mini-Mental State Examination (MMSE) scores, National Institutes of Health Stroke Scale (NIHSS) scores, and infarct locations for the two groups were compared. Finally, to investigate the structural basis of post-stroke apathy, VBA of FA maps was performed in which we included the variables that a univariate analysis determined had P-values less than 0.20 as covariates. RESULTS: HAMD (P = 0.01) and MMSE (P<0.01) scores differed significantly between the apathy and non-apathy groups. After controlling for age, education level, HAMD scores, and MMSE scores, significant FA reduction was detected in four clusters with peak voxels at the genu of the corpus callosum (X = -16, Y = 30, Z = 8), left anterior corona radiata (-22, 30, 10), splenium of the corpus callosum (-24, -56, 18), and right inferior frontal gyrus white matter (52, 24, 18), after family-wise error correction for multiple comparisons. CONCLUSIONS: Post-stroke apathy is related to depression and cognitive decline. Damage to the genu of the corpus callosum, left anterior corona radiata, splenium of the corpus callosum, and white matter in the right inferior frontal gyrus may lead to apathy after ischemic stroke.

In vivo magnetic resonance imaging tracking of transplanted superparamagnetic iron oxide-labeled bone marrow mesenchymal stem cells in rats with myocardial infarction.

Superparamagnetic iron oxide (SPIO) nanoparticles generate superparamagnetism, thereby resulting in an inhomogeneous local magnetic field, which shortens the T2 value on magnetic resonance imaging (MRI). The purpose of the present study was to use MRI to track bone marrow mesenchymal stem cells (BMSCs) labeled with SPIO in a rat model of myocardial infarction. The BMSCs were isolated from rats and labeled with SPIO. The anterior descending branch of the coronary artery was ligated under anesthesia. Two weeks later, the rats received, at random, 5 x 10(7) SPIO-labeled BMSCs, 5 x 10(7) unlabeled BMSCs or a vehicle (100 µl phosphate-buffered saline) via direct injection into the ischemic area (20 animals/group). MRI was used to track the SPIO­labeled BMSCs and the rats were then sacrificed to verify the presence of BMSCs using immunohistochemistry with an anti-CD90 antibody. The procedure labeled 99% of the BMSCs with SPIO, which exhibited low-intensity signals on T2 and T2* MRI imaging. At 24 h post-BMSC transplantation, low-intensity MRI signals were detected on the T2 and T2* sequences at the infarction margins. After 3 weeks following transplantation, low-intensity signals started to appear within the infarcted area; however, the signal intensity subsequently decreased and became indistinct. Immunohistochemistry revealed that the SPIO-labeled BMSCs migrated from the margin into the infarcted region. In conclusion, the BMSCs were readily labeled with SPIO and in vivo and MRI tracking demonstrated that the SPIO-labeled BMSCs established and grew in the infarcted myocardium.

Cell transplantation into ischemic myocardium using mesenchymal stem cells transfected by vascular endothelial growth factor.

AIMS: To investigate the effects of mesenchymal stem cells (MSCs) transplantation combining with vascular endothelial growth factor (VEGF) gene therapy on myocardium rebuilding, angiogenesis, and heart function improvement in rats with myocardial infarction. METHODS: SD rat MSCs were isolated, cultured in vitro, labeled with BrdU and transfected by Ad.VEGF gene. Four weeks after left anterior descending artery was ligated to create rat myocardial infarction, cardiac function was examined with echocardiography. Rats were randomly divided into four groups (n = 10 in each group): Group I: MSCs/Ad.VEGF implantation; Group II: MSCs implantation; Group III: Ad.VEGF injection; Group IV: Control. MSCs differentiation was observed 4 weeks after transplantation. Immunohistochemistry and angiogenesis were observed. Echocardiography was performed to detect the effects on heart function. RESULTS: MSCs labeled with BrdU could be identified in host hearts in group I and II, most of them positively stained with cTnT antibody. Echocardiography indicated that the improvement of the LVEF value in group I was more significant than that in the other three groups (P < 0.01, respectively). Some cells were incorporated into the coronary capillaries in the infarcted region. The capillary density in group I was higher than that in the other three groups (P < 0.01, respectively). CONCLUSION: MSCs implantation combining with VEGF gene therapy can obviously repair damaged myocardium and enhance the angiogenesis in ischemic heart tissue.

[Comparision of high dose impulsion and low dose density chemotherapeutic regimens with paclitaxel plus cisplatin in advanced NSCLC].

OBJECTIVE: To explore high effective and low toxic chemotherapeutic regimens in the treatment of non-small-cell lung cancer (NSCLC). METHODS: A total of 126 patients with advanced NSCLC (Stage III, IV) were randomly divided into two groups: high dose impulsion chemotherapy group (HDIC group) and low dose density chemotherapy group (LDDC group) with 54 patients in HDIC group who received paclitaxel 135-175 mg/m2 on day 1, DDP 80-100 mg/m2 on day 1 and BCNU 125 mg given for brain metastasis on days 1-3 in a 4-6 weeks cycle. Seventy-two patients in LDDC group were given paclitaxel 60-80 mg/m2 on day 1, DDP 40-80 mg/m2 on day 1 repeated weekly and BCNU 125 mg given for brain metastasis with an interval of 2 weeks, in a 4-6 weeks cycle. Antiemetic agent and fluid were administered routinely in HDIC group whereas LDDC group was given antiemetic agent only. RESULTS: Of 157 courses in HDIC group, an average of 2.9 courses per patient, CR 3, PR 23, SD 17 and PD 11 were observed. The effective remission rate was 48.1%, the median effective remission period was 4.5 months and the 1-year survival rate was 46.3%. Of 184 courses in LDDC group, an average of 2.6 courses per patient, CR 9, PR 30, SD 24 and PD 9 were observed. The effective remission rate was 54.2%, the median effective remission period was 6 months and the 1-year survival rate was 56.9%. The effective remission rate and the 1-year survival rate were higher in HDIC group than those in LDDC group, but there was no statistical difference between the two groups (P > 0.05). Severe toxicity was higher in HDIC group than in LDDC group. Two patients in HDIC group died of treatment-related complications (3.7%). Quality of life was better in LDDC group (70.8%) than in HDIC group (51.9%). CONCLUSION: When comparing with high dose impulsion, low dose density regimen of paclitaxel plus cisplatin is more effective and better tolerated with improvement of quality of patients' life in the treatment of NSCLC due to its low dose and short interval duration.