Age, Serum Creatinine, and Left Ventricular Ejection Fraction Improved the Performance of the CatLet Angiographic Scoring System in Terms of Outcome Predictions for Patients with Acute Myocardial Infarction: A Median 4.3-Year Follow-Up Study.

BACKGROUND: We recently developed the Coronary Artery Tree description and Lesion EvaluaTion (CatLet) angiographic scoring system. Our preliminary study demonstrated that the CatLet score better predicted clinical outcomes than the SYNTAX score. The current study aimed at assessing whether 3 clinical variables (CVs) - age, serum creatinine, and left ventricular ejection fraction (LVEF) - improved the performance of the CatLet score in outcome predictions in patients with acute myocardial infarction (AMI). METHODS: This study was a post hoc study of the CatLet score validation trial. Primary endpoint was major adverse cardiac or cerebrovascular events (MACCEs), and secondary endpoints were all-cause deaths and cardiac deaths. RESULTS: Over 1,185 person-years (median [interquartile range], 4.3 [3.8-4.9] years), there were 64 MACCEs (20.8%), 56 all-cause deaths (18.2%), and 47 cardiac deaths (15.2%). The addition of the 3 CVs to the stand-alone CatLet score significantly increased the Harrell's C-index by 0.0967 (p = 0.002) in MACCEs, by 0.1354 (p < 0.001) in all-cause deaths, and by 0.1187 (p = 0.001) in cardiac deaths. When compared with the stand-alone CatLet score, improved discrimination and better calibration led to a significantly refined risk stratification, particularly at the intermediate-risk category. CONCLUSIONS: CatLet score had a predicting value for clinical outcome in AMI patients. This predicting value can be improved through a combination with age, serum creatinine, and LVEF (http://www.chictr.org.cn; unique identifier: ChiCTR-POC-17013536).

Interaction between lipoprotein (a) levels and body mass index in first incident acute myocardial infarction.

BACKGROUND: Possible interaction between Lipoprotein (a) (Lp(a)) and body mass index (BMI) was investigated with regard to the risk of first incident acute myocardial infarction (AMI). METHODS: Cross-sectional study of 1522 cases with initial AMI and 1691 controls without coronary artery disease (CAD) were retrospectively analyzed using logistic regression model. Subjects were categorized based on Lp(a) and BMI and compared with regard to occurrence of AMI by calculating odds ratios (ORs) with 95% confidence intervals (CIs). A potential interaction between Lp(a) and BMI was evaluated by the measures of effect modification on both additive (Relative excess risk due to interaction, RERI) and multiplicative scales. RESULTS: Compared with reference group (BMI < 24 kg/m2 and in the first quintile of Lp(a)), multivariable-adjusted analysis revealed that ORs(95%CI) of AMI were 2.27(1.46-3.52) for higher BMI alone; 1.79(1.11-2.90), 1.65(1.05-2.60), 1.96(1.20-3.20) and 2.34(1.47-3.71) for higher Lp(a) alone across its quintiles; and 2.86(1.85-4.40), 3.30(2.14-5.11), 4.43(2.76-7.09) and 5.98(3.72-9.60) for both higher BMI and higher Lp(a), greater than the sum of the both risks each. Prominent interaction was found between Lp(a) and BMI on additive scale (RERI = 2.45 (0.36-4.54) at the fifth quintile of Lp(a)) but not on multiplicative scale. CONCLUSIONS: This study demonstrates that BMI and Lp(a) levels are important factors affecting the risk of AMI. Significant interaction is found between Lp(a) and BMI in initial AMI on additive scale, indicating that Lp(a) confers greater risk for initial AMI when BMI is elevated. For those whose BMIs are inadequately controlled, Lp(a) lowering may be an option. TRIAL REGISTRATION: This clinical study was not registered in a publicly available registry because this study was a retrospective study first started in 2015. Data are available via the correspondent.

Deep Learning for Electromyographic Lower-Limb Motion Signal Classification Using Residual Learning.

Electromyographic (EMG) signals have gained popularity for controlling prostheses and exoskeletons, particularly in the field of upper limbs for stroke patients. However, there is a lack of research in the lower limb area, and standardized open-source datasets of lower limb EMG signals, especially recording data of Asian race features, are scarce. Additionally, deep learning algorithms are rarely used for human motion intention recognition based on EMG, especially in the lower limb area. In response to these gaps, we present an open-source benchmark dataset of lower limb EMG with Asian race characteristics and large data volume, the JJ dataset, which includes approximately 13,350 clean EMG segments of 10 gait phases from 15 people. This is the first dataset of its kind to include the nine main muscles of human gait when walking. We used the processed time-domain signal as input and adjusted ResNet-18 as the classification tool. Our research explores and compares multiple key issues in this area, including the comparison of sliding time window method and other preprocessing methods, comparison of time-domain and frequency-domain signal processing effects, cross-subject motion recognition accuracy, and the possibility of using thigh and calf muscles in amputees. Our experiments demonstrate that the adjusted ResNet can achieve significant classification accuracy, with an average accuracy rate of 95.34% for human gait phases. Our research provides a valuable resource for future studies in this area and demonstrates the potential for ResNet as a robust and effective method for lower limb human motion intention pattern recognition.

CatLet score and clinical CatLet score as predictors of long-term outcomes in patients with acute myocardial infarction presenting later than 12 hours from symptom onset.

BACKGROUND: Our recently developed Coronary Artery Tree description and Lesion EvaluaTion (CatLet) angiographic scoring system is unique in its description of the variability in the coronary anatomy, the degree of stenosis of a diseased coronary artery, and its subtended myocardial territory, and can be utilized to predict clinical outcomes for patients with acute myocardial infarction (AMI) presenting ≤12 h after symptom onset. The current study aimed to assess whether the Clinical CatLet score (CCS), as compared with CatLet score (CS), better predicted clinical outcomes for AMI patients presenting >12 h after symptom onset. METHODS: CS was calculated in 1018 consecutive AMI patients enrolled in a retrospective registry. CCS was calculated by multiplying CS by the ACEF I score (age, creatinine, and left ventricular ejection fraction). Primary endpoint was major adverse cardiac events (MACEs) at 4-year-follow-up, a composite of cardiac death, myocardial infarction, and ischemia-driven revascularization. RESULTS: Over a 4-year follow-up period, both scores were independent predictors of clinical outcomes after adjustment for a broad spectrum of risk factors. Areas-under-the-curve (AUCs) for CS and CCS were 0.72(0.68-0.75) and 0.75(0.71-0.78) for MACEs; 0.68(0.63-0.73) and 0.78(0.74-0.83) for all-cause death; 0.73(0.68-0.79) and 0.83(0.79-0.88) for cardiac death; and 0.69(0.64-0.73) and 0.75(0.7-0.79) for myocardial infarction; and 0.66(0.61-0.7) and 0.63(0.58-0.68) for revascularization, respectively. CCS performed better than CS in terms of the above-mentioned outcome predictions, as confirmed by the net reclassification and integrated discrimination indices. CONCLUSIONS: CCS was better than CS to be able to risk-stratify long-term outcomes in AMI patients presenting >12 h after symptom onset. These findings have indicated that both anatomic and clinical variables should be considered in decision-making on management of patients with AMI presenting later.

Dynamic Anti-Counterfeiting Labels with Enhanced Multi-Level Information Encryption.

Information encryption is an important means to improve the security of anti-counterfeiting labels. At present, it is still challenging to realize an anti-counterfeiting label with multi-function, high security factor, low production cost, and easy detection and identification. Herein, using inkjet and screen printing technology, we construct a multi-dimensional and multi-level dynamic optical anti-counterfeiting label based on instantaneously luminescent quantum dots and long afterglow phosphor, whose color and luminous intensity varied in response to time. Self-assembled quantum dot patterns with intrinsic fingerprint information endow the label with physical unclonable functions (PUFs), and the information encryption level of the label is significantly improved in view of the information variation in the temporal dimension. Furthermore, the convolutional residual neural networks are used to decode the massive information of PUFs, enabling fast and accurate identification of the anti-counterfeit labels.

Gamma-secretase represents a therapeutic target for the treatment of invasive glioma mediated by the p75 neurotrophin receptor.

The multifunctional signaling protein p75 neurotrophin receptor (p75(NTR)) is a central regulator and major contributor to the highly invasive nature of malignant gliomas. Here, we show that neurotrophin-dependent regulated intramembrane proteolysis (RIP) of p75(NTR) is required for p75(NTR)-mediated glioma invasion, and identify a previously unnamed process for targeted glioma therapy. Expression of cleavage-resistant chimeras of p75(NTR) or treatment of animals bearing p75(NTR)-positive intracranial tumors with clinically applicable gamma-secretase inhibitors resulted in dramatically decreased glioma invasion and prolonged survival. Importantly, proteolytic processing of p75(NTR) was observed in p75(NTR)-positive patient tumor specimens and brain tumor initiating cells. This work highlights the importance of p75(NTR) as a therapeutic target, suggesting that gamma-secretase inhibitors may have direct clinical application for the treatment of malignant glioma.

Efficacy and safety/toxicity study of recombinant vaccinia virus JX-594 in two immunocompetent animal models of glioma.

The purpose of this study was to investigate the oncolytic potential of the recombinant, granulocyte macrophage colony-stimulating factor (GM-CSF)-expressing vaccinia virus (VV) JX-594 in experimental malignant glioma (MGs) in vitro and in immunocompetent rodent models. We have found that JX-594 killed all MG cell lines tested in vitro. Intratumoral (i.t.) administration of JX-594 significantly inhibited tumor growth and prolonged survival in rats-bearing RG2 intracranial (i.c.) tumors and mice-bearing GL261 brain tumors. Combination therapy with JX-594 and rapamycin significantly increased viral replication and further prolonged survival in both immunocompetent i.c. MG models with several animals considered "cured" (three out of seven rats >120 days, terminated experiment). JX-594 infected and killed brain tumor-initiating cells (BTICs) from patient samples grown ex vivo, and did so more efficiently than other oncolytic viruses MYXV, Reovirus type-3, and VSV(ΔM51). Additional safety/toxicity studies in nontumor-bearing rodents treated with a supratherapeutic dose of JX-594 demonstrated GM-CSF-dependent inflammation and necrosis. These results suggest that i.c. administered JX-594 triggers a predictable GM-CSF-mediated inflammation in murine models. Before proceeding to clinical trials, JX-594 should be evaluated in the brains of nonhuman primates and optimized for the viral doses, delivery routes as well as the combination agents (e.g., mTOR inhibitors).

Proliferation of human glioblastoma stem cells occurs independently of exogenous mitogens.

Primary glial tumors of the central nervous system, most commonly glioblastoma multiforme (GBM), are aggressive lesions with a dismal prognosis. Despite identification and isolation of human brain tumor stem cells (BTSCs), characteristics that distinguish BTSCs from neural stem cells remain to be elucidated. We cultured cells isolated from gliomas, using the neurosphere culture system, to understand their growth requirements. Both CD133(+) and CD133(-) adult GBM BTSCs proliferated in the absence of exogenous mitogenic stimulation and gave rise to multipotent GBM spheres that were capable of self-renewal. Epidermal growth factor (EGF) and fibroblast growth factor-2 enhanced GBM BTSC survival, proliferation, and subsequent sphere size. Blockade of EGF receptor (EGFR) signaling reduced exogenous mitogen-independent GBM sphere growth. Implantation of as few as 10 exogenous mitogen-independent GBM BTSCs led to the formation of highly invasive intracranial tumors, which closely resembled human GBMs, in immunocompromised mice. These results demonstrate that exogenous mitogen independence, mediated in part through EGFR signaling, is one characteristic that distinguishes CD133(+) and CD133(-) GBM BTSCs from neural stem cells. This novel experimental system will permit the elucidation of additional constitutively activated mechanisms that promote GBM BTSC survival, self-renewal, and proliferation.

Oncolytic efficacy of recombinant vesicular stomatitis virus and myxoma virus in experimental models of rhabdoid tumors.

PURPOSE: Rhabdoid tumors are highly aggressive pediatric tumors that are usually refractory to available treatments. The purpose of this study was to evaluate the therapeutic potential of two oncolytic viruses, myxoma virus (MV) and an attenuated vesicular stomatitis virus (VSV(DeltaM51)), in experimental models of human rhabdoid tumor. EXPERIMENTAL DESIGN: Four human rhabdoid tumor cell lines were cultured in vitro and treated with live or inactivated control virus. Cytopathic effect, viral gene expression, infectious viral titers, and cell viability were examined at various time points after infection. To study viral oncolysis in vivo, human rhabdoid tumor cells were implanted s.c. in the hind flank or intracranially in CD-1 nude mice and treated with intratumoral (i.t.) or i.v. injections of live or UV-inactivated virus. Viral distribution and effects on tumor size and survival were assessed. RESULTS: All rhabdoid tumor cell lines tested in vitro were susceptible to productive lethal infections by MV and VSV(DeltaM51). I.t. injection of live MV or VSV(DeltaM51) dramatically reduced the size of s.c. rhabdoid tumor xenografts compared with control animals. I.v. administration of VSV(DeltaM51) or i.t. injection of MV prolonged the median survival of mice with brain xenografts compared with controls (VSV(DeltaM51): 25 days versus 21 days, log-rank test, P = 0.0036; MV: median survival not reached versus 21 days, log-rank test, P = 0.0007). Most of the MV-treated animals (4 of 6; 66.7%) were alive and apparently "cured" when the experiment was arbitrarily ended (>180 days). CONCLUSIONS: These results suggest that VSV(DeltaM51) and MV could be novel effective therapies against human rhabdoid tumor.

Targeting human medulloblastoma: oncolytic virotherapy with myxoma virus is enhanced by rapamycin.

We have shown previously the oncolytic potential of myxoma virus in a murine xenograft model of human glioma. Here, we show that myxoma virus used alone or in combination with rapamycin is effective and safe when used in experimental models of medulloblastoma in vitro and in vivo. Nine of 10 medulloblastoma cell lines tested were susceptible to lethal myxoma virus infection, and pretreatment of cells with rapamycin increased the extent of in vitro oncolysis. Intratumoral injection of live myxoma virus when compared with control inactivated virus prolonged survival in D341 and Daoy orthotopic human medulloblastoma xenograft mouse models [D341 median survival: 21 versus 12.5 days; P = 0.0008; Daoy median survival: not reached (three of five mice apparently "cured" after 223 days) versus 75 days; P = 0.0021]. Rapamycin increased the extent of viral oncolysis, "curing" most Daoy tumor-bearing mice and reducing or eliminating spinal cord and ventricle metastases. Rapamycin enhanced tumor-specific myxoma virus replication in vivo and prolonged survival of D341 tumor-bearing mice (median survival of mice treated with live virus (LV) and rapamycin, versus LV alone, versus rapamycin alone, versus inactivated virus: 25 days versus 19, 13, and 11 days, respectively; P < 0.0001). Rapamycin increased the levels of constitutively activated Akt in Daoy and D341 cells, which may explain its ability to enhance myxoma virus oncolysis. These observations suggest that myxoma virus may be an effective oncolytic agent against medulloblastoma and that combination therapy with signaling inhibitors that modulate activity of the phosphatidylinositol 3-kinase/Akt pathway will further enhance the oncolytic potential of myxoma virus.

Modulation of glucocorticoid-induced GAD expression in pancreatic beta-cells by transcriptional activation of the GAD67 promoter and its possible effect on the development of diabetes.

GAD is a pancreatic beta-cell autoantigen in humans and nonobese diabetic (NOD) mice. Modulation of GAD expression in pancreatic beta-cells has been suggested to be associated with the development of autoimmune diabetes. Hormonal changes through environmental stimuli are considered to influence the expression of the disease. We determined whether steroid hormones would modulate the expression of GAD in pancreatic beta-cells. We treated NOD mouse beta-cells (MIN6N8a cells) with various steroids, including testosterone, estradiol, progesterone, and cortisol, and examined the expression of GAD67 mRNA. We found that only cortisol enhanced the expression of GAD67, whereas the other steroid hormones had no effect. When we treated MIN6N8a cells with a synthetic glucocorticoid, dexamethasone, we found that GAD67 mRNA expression was stimulated in a dose- and time-dependent manner. Cells treated with 100 nmol/l dexamethasone for 6 h showed a 10-fold increase in the expression of GAD67 mRNA and an increase in GAD67 protein. The upregulation of GAD67 expression in beta-cells by dexamethasone was found to be due to the transcriptional activation of the GAD67 promoter. We then examined whether dexamethasone would influence the development of diabetes in NOD mice. Injection of dexamethasone into neonatal NOD mice resulted in a significant increase in the expression of GAD67 mRNA in pancreatic beta-cells and the development of insulitis and diabetes. We conclude that glucocorticoid hormones can modulate GAD expression by the transcriptional activation of the GAD promoter and may influence the development of autoimmune diabetes in NOD mice.

Treating brain tumor-initiating cells using a combination of myxoma virus and rapamycin.

BACKGROUND: Intratumoral heterogeneity in glioblastoma multiforme (GBM) poses a significant barrier to therapy in certain subpopulation such as the tumor-initiating cell population, being shown to be refractory to conventional therapies. Oncolytic virotherapy has the potential to target multiple compartments within the tumor and thus circumvent some of the barriers facing conventional therapies. In this study, we investigate the oncolytic potential of myxoma virus (MYXV) alone and in combination with rapamycin in vitro and in vivo using human brain tumor-initiating cells (BTICs). METHODS: We cultured fresh GBM specimens as neurospheres and assayed their growth characteristics in vivo. We then tested the susceptibility of BTICs to MYXV infection with or without rapamycin in vitro and assessed viral biodistribution/survival in vivo in orthotopic xenografts. RESULTS: The cultured neurospheres were found to retain stem cell markers in vivo, and they closely resembled human infiltrative GBM. In this study we determined that (i) all patient-derived BTICs tested, including those resistant to temozolomide, were susceptible to MYXV replication and killing in vitro; (ii) MYXV replicated within BTICs in vivo, and intratumoral administration of MYXV significantly prolonged survival of BTIC-bearing mice; (iii) combination therapy with MYXV and rapamycin improved antitumor activity, even in mice bearing "advanced" BTIC tumors; (iv) MYXV treatment decreased expression of stem cell markers in vitro and in vivo. CONCLUSIONS: Our study suggests that MYXV in combination with rapamycin infects and kills both the BTICs and the differentiated compartments of GBM and may be an effective treatment even in TMZ-resistant patients.