CD4+CD25+ regulatory T cells ex vivo generated from autologous naïve CD4+ T cells suppress EAE progression.

CD4+CD25+ regulatory T cells (Tregs) play an important role in maintaining immune homeostasis in multiple sclerosis (MS). Hence, we aimed to explore the therapeutic efficacy and safety of adoptive cell therapy (ACT) utilizing induced antigen-specific Tregs in an animal model of MS, that is, in an experimental autoimmune encephalomyelitis (EAE) model. B cells from EAE model that were activated with soluble CD40L were used as antigen-presenting cells (APCs) to induce the differentiation of antigen-specific Tregs from naïve CD4 precursors, and then, a stepwise isolation of CD4+CD25highCD127low Tregs was performed using a flow sorter. All EAE mice were divided into Treg-treated group (2 × 104 cells in 0.2 mL per mouse, n = 14) and sham-treated group (0.2 mL normal saline (NS), n = 20), which were observed daily for clinical assessment, and for abnormal appearance for 6 weeks. Afterward, histological analysis, immunofluorescence and real-time PCR were performed. Compared to sham-treated mice, Treg-treated mice exhibited a significant decrease in disease severity scores and reduced inflammatory infiltration and demyelination in the spinal cord. Additionally, Tregs-treated mice demonstrated higher CCN3 protein and mRNA levels than sham-treated mice. The results of this preclinical study further support the therapeutic potential of this ACT approach in the treatment of MS.

A Pilot Study on Tocilizumab in Very-Late-Onset Myasthenia Gravis.

Objective: This study aimed to initially investigate the efficacy and safety of low-dose tocilizumab combined with glucocorticoid for the treatment of very-late-onset myasthenia gravis (VLOMG). Methods: We conducted a retrospective study in VLOMG patients who were administered intravenous methylprednisolone therapy and subsequently received low-dose oral corticosteroid, in combination with intravenous injection of tocilizumab given once every month for three months. Results: Five patients (mean age 75.0 ± 4.5 years) were included, and all of them were new-onset, and anti-acetylcholine receptor (AChR) antibody-positive generalized MG. The Quantitative Myasthenia Gravis Scale (QMGS) and Myasthenia Gravis Activities of Daily Living (MG-ADL) scores before treatment were 15.4 ± 4.3 and 9.6 ± 2.3, respectively, and they exhibited a continuously decreasing trend after the first, second, and third injection of tocilizumab until 6 months after treatment. At 6 months post-treatment, the QMGS and MG-ADL scores were 5.0 ± 2.9 and 2.0 ± 1.2, respectively, and the difference between scores at baseline and 6-month follow-up was significant (P = 0.005 and P < 0.0001, respectively). No serious adverse drug reactions were reported in any patient during the study period. Discussions and Conclusion: The therapeutic efficacy of tocilizumab in VLOMG remains uncertain. The results from our study support the efficacy and safety of this combination treatment option for VLOMG, and strongly suggests the therapeutic potential of tocilizumab in VLOMG. However, considering the limitation of retrospective nature and small sample size in this study, prospective randomized controlled studies including a larger sample size of selected patients are needed to validate our results.

Ginkgolide attenuates memory impairment and neuroinflammation by suppressing the NLRP3/caspase-1 pathway in Alzheimer's disease.

The NLRP3 inflammasome is involved in the neuroinflammatory pathway of Alzheimer's disease (AD). The aim of this study is to explore the roles and underlying mechanisms of ginkgolide (Baiyu®) on amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mice and a murine microglial cell line, BV-2. In the present study, the APP/PS1 mice were administered with ginkgolide, followed by a Morris water maze test. The mice were then euthanized to obtain brain tissue for histological and Aß analysis. Additionally, BV-2 cells were pretreated with ginkgolide and then incubated with Aß1-42 peptide. NLRP3, ASC, and caspase-1 mRNA and protein expression in brain tissue of mice and BV-2 cells were quantified by real-time PCR and western blotting, as well as reactive oxygen species (ROS) production, interleukin (IL)-1ß and IL-18 levels by lucigenin technique and ELISA. Compared with the APP/PS1 mice, ginkgolide-treated mice demonstrated the shortened escape latency, reduced plaques, less inflammatory cell infiltration and neuron loss in the hippocampi of APP/PS1 mice. The levels of NLRP3, ASC, caspase-1, ROS, IL-1ß, and IL-18 were also decreased in the brain tissue of APP/PS1 mice or Aß1-42-treated BV-2 cells following ginkgolide treatment. Ginkgolide exerted protective effects on AD, at least partly by inactivating the NLRP3/caspase-1 pathway.

Characterization of antigen-specific CD8+ memory T cell subsets in peripheral blood of patients with multiple sclerosis.

Background: Increasing evidence indicates the importance of CD8+ T cells in autoimmune attack against CNS myelin and axon in multiple sclerosis (MS). Previous research has also discovered that myelin-reactive T cells have memory phenotype functions in MS patients. However, limited evidence is available regarding the role of CD8+ memory T cell subsets in MS. This study aimed to explore potential antigen-specific memory T cell-related biomarkers and their association with disease activity. Methods: The myelin oligodendrocyte glycoprotein (MOG)-specific CD8+ memory T cell subsets and their related cytokines (perforin, granzyme B, interferon (IFN)-γ) and negative co-stimulatory molecules (programmed cell death protein 1 (PD-1), T- cell Ig and mucin domain 3 (Tim-3)) were analyzed by flow cytometry and real-time PCR in peripheral blood of patients with relapsing-remitting MS. Results: We found that MS patients had elevated frequency of MOG-specific CD8+ T cells, MOG-specific central memory T cells (TCM), MOG-specific CD8+ effector memory T cells (TEM), and MOG-specific CD8+ terminally differentiated cells (TEMRA); elevated granzyme B expression on MOG-specific CD8+ TCM; and, on MOG-specific CD8+ TEM, elevated granzyme B and reduced PD-1 expression. The Expanded Disability Status Scale score (EDSS) in MS patients was correlated with the frequency of MOG-specific CD8+ TCM, granzyme B expression in CD8+ TCM, and granzyme B and perforin expression on CD8+ TEM, but with reduced PD-1 expression on CD8+ TEM. Conclusion: The dysregulation of antigen-specific CD8+ memory T cell subsets, along with the abnormal expression of their related cytokines and negative co-stimulatory molecules, may reflect an excessive or persistent inflammatory response induced during early stages of the illness. Our findings strongly suggest positive regulatory roles for memory T cell populations in MS pathogenesis, probably via molecular mimicry to trigger or promote abnormal peripheral immune responses. Furthermore, downregulated PD-1 expression may stimulate a positive feedback effect, promoting MS-related inflammatory responses via the interaction of PD-1 ligands. Therefore, these parameters are potential serological biomarkers for predicting disease development in MS.

Risk factors assessment and a Bayesian network model for predicting ischemic stroke in patients with cardiac myxoma.

Objective: This study aims to identify relevant risk factors, assess the interactions between variables, and establish a predictive model for ischemic stroke (IS) in patients with cardiac myxoma (CM) using the Bayesian network (BN) approach. Methods: Data of patients with CM were collected from three tertiary comprehensive hospitals in Beijing from January 2002 to January 2022. Age, sex, medical history, and information related to CM were extracted from the electronic medical record system. The BN model was constructed using the tabu search algorithm, and the conditional probability of each node was calculated using the maximum likelihood estimation method. The probability of each node of the network and the interrelationship between IS and its related factors were qualitatively and quantitatively analyzed. A receiver operating characteristic (ROC) curve was also plotted. Sensitivity, specificity, and area under the curve (AUC) values were calculated and compared between the BN and logistic regression models to evaluate the efficiency of the predictive model. Results: A total of 416 patients with CM were enrolled in this study, including 61 with and 355 without IS. The BN model found that cardiac symptoms, systemic embolic symptoms, platelet counts, and tumor with high mobility were directly associated with the occurrence of IS in patients with CM. The BN model for predicting CM-IS achieved higher scores on AUC {0.706 [95% confidence interval (CI), 0.639-0.773]} vs. [0.697 (95% CI, 0.629-0.766)] and sensitivity (99.44% vs. 98.87%), but lower scores on accuracies (85.82% vs. 86.06%) and specificity (6.56% vs. 11.48%) than the logistic regression model. Conclusion: Cardiac symptoms, systemic embolic symptoms, platelet counts, and tumor with high mobility are candidate predictors of IS in patients with CM. The BN model was superior or at least non-inferior to the traditional logistic regression model, and hence is potentially useful for early IS detection, diagnosis, and prevention in clinical practice.

Development and refinement of diagnostic and therapeutic strategies for managing patients with cardiogenic stroke: An arduous journey.

Cardioembolic stroke, referred to as cardiogenic stroke, is a clinical syndrome in which emboli from the heart pass through the circulatory system and cause cerebral artery embolism and corresponding brain dysfunction. Compared to other subtypes of ischemic stroke, cardiogenic stroke presents with more etiologies, greater severity, worse prognosis, and a higher recurrence rate. In this minireview, we provide new insights into the etiological classification, diagnostic methods, and interventions of cardiogenic stroke.

Clinical features, risk factors and survival in cardiac myxoma-related ischemic stroke: A multicenter case-control study.

BACKGROUND: Cardiac myxoma (CM) is an important etiology of stroke in young adults, but studies on CM-related ischemic stroke (CM-IS) are limited and conflicting. Hence, we investigated clinical characterizations, risk factors of CM-IS, and short-term survival after surgical resection. METHODS: We performed a retrospective analysis of data from all CM patients at three referral management centers and conducted follow-up examination. RESULTS: Among 414 CM patients, 402 were recruited for further analysis, including 54 patients with CM-IS and 348 patients with CM without stroke (Non-stroke). In the acute phase, patients presented with NIHSS 3 (interquartile range: 0-10) and clinical presentation comprising neurological, cardiac and constitutional symptoms. Multivariate analysis showed that the factors associated with an increased risk of CM-IS were tumor width < 30 mm [OR = 2.652, 95% CI: 1.061-6.627, P = 0.037], tumors with high-mobility (OR = 2.700, 95% CI: 1.357-5.371, P = 0.005), thrombus on the tumor surface (OR = 1.856, 95% CI: 1.003-3.434, P = 0.049), and lower B-type natriuretic peptide (BNP) levels (OR = 0.995, 95% CI: 0.989-0.999, P = 0.047). The overall three-year survival rate was 95.7% (95% CI: 94.9-96.5) in CM-IS patients who underwent surgery. CONCLUSIONS: CM-IS patients had mild or moderate neurologic deficits with various presentations at disease onset. Narrower tumor width, tumors with high-mobility, thrombus on the tumor surface, and lower BNP levels are potential predictors of CM-IS development. Surgical removal of CM is safe and efficacious in patients with CM-IS.

Risk factors, clinical features, and outcomes of patients with hypertrophic cardiomyopathy complicated by ischemic stroke: A single-center retrospective study.

Objective: This study aimed to explore risk factors, clinical features, and prognosis of patients with hypertrophic cardiomyopathy (HCM) complicated by ischemic stroke (IS). Methods: We conducted a retrospective analysis of all HCM patient data and a 1-year follow-up study. Results: Totally, 506 patients with HCM, including 71 with IS, were enrolled. Older age (≥63 years) was associated with an increased risk of IS in HCM patients (OR = 1.045, 95% CI: 1.018-1.072, p = 0.001). Among 37 patients complicated by IS, 22 (59.5%, 22/37) manifested as cardioembolism (CE) subtype, and 13 (35.1%, 3/37) small artery occlusion (SAO) subtype, according to TOAST classification. In the acute phase, the IS patients presented with NIHSS 4 (interquartile range: 1, 10). Multi-infarction was more common than single infarction (72.7 vs. 27.3%), while cortical + subcortical infarction (CE group: 50%) or subcortical infarction (SAO group: 53.8%) constituted most IS cases. Additionally, the blood supply areas of anterior circulation (CE group: 45.5%; SAO group: 92.3%) or anterior + posterior circulation (CE group: 50%) were mainly involved. The 1-year survival rate of HCM patients with concomitant IS was 81.8%, and IS was associated with 1-year all-cause death in HCM patients (HR = 5.689, 95% CI: 1.784-18.144, p = 0.003). Conclusion: Older age is a risk factor for IS occurrence in HCM patients. Patients with HCM complicated by IS had mild or moderate neurologic deficits at disease onset. CE and SAO subtypes predominate in patients with concomitant IS, especially the former. Multiple cortical and subcortical infarctions are their neuroimaging characteristics, mainly involving the anterior circulation or anterior + posterior circulation. Is is a risk factor for all-cause death in HCM patients within 1 year.

Risk factors and a Bayesian network model to predict ischemic stroke in patients with dilated cardiomyopathy.

Objective: This study aimed to identify risk factors and create a predictive model for ischemic stroke (IS) in patients with dilated cardiomyopathy (DCM) using the Bayesian network (BN) approach. Materials and methods: We collected clinical data of 634 patients with DCM treated at three referral management centers in Beijing between 2016 and 2021, including 127 with and 507 without IS. The patients were randomly divided into training (441 cases) and test (193 cases) sets at a ratio of 7:3. A BN model was established using the Tabu search algorithm with the training set data and verified with the test set data. The BN and logistic regression models were compared using the area under the receiver operating characteristic curve (AUC). Results: Multivariate logistic regression analysis showed that hypertension, hyperlipidemia, atrial fibrillation/flutter, estimated glomerular filtration rate (eGFR), and intracardiac thrombosis were associated with IS. The BN model found that hyperlipidemia, atrial fibrillation (AF) or atrial flutter, eGFR, and intracardiac thrombosis were closely associated with IS. Compared to the logistic regression model, the BN model for IS performed better or equally well in the training and test sets, with respective accuracies of 83.7 and 85.5%, AUC of 0.763 [95% confidence interval (CI), 0.708-0.818] and 0.822 (95% CI, 0.748-0.896), sensitivities of 20.2 and 44.2%, and specificities of 98.3 and 97.3%. Conclusion: Hypertension, hyperlipidemia, AF or atrial flutter, low eGFR, and intracardiac thrombosis were good predictors of IS in patients with DCM. The BN model was superior to the traditional logistic regression model in predicting IS in patients with DCM and is, therefore, more suitable for early IS detection and diagnosis, and could help prevent the occurrence and recurrence of IS in this patient cohort.

Preliminary study on the differentiation of vulnerable carotid plaques via analysis of calcium content and spectral curve slope by using gemstone spectral imaging.

Growing evidence indicates that vulnerable carotid plaque rupture is an important cause of stroke. However, the role of novel gemstone spectral imaging (GSI) in the assessment of vulnerable carotid plaques has remained to be sufficiently explored. Therefore, the aim of the present study was to provide a comprehensive evaluation of carotid atherosclerotic plaques using both GSI imaging biomarkers and serological biomarkers, and further explore their possible roles in the atherogenic process. The present study analyzed GSI data, including calcium content of carotid atherosclerotic plaques and spectral curve slope, as well as serum high-sensitivity C-reactive protein (Hs-CRP) and monocyte chemotactic protein-1 (MCP-1) levels in patients with a carotid atherosclerotic plaque using GSI-computed tomographic angiography and immunoturbidimetry. Patients with unstable plaque exhibited a significantly lower calcium content and higher spectral curve slope than those of the stable plaque group. In addition, patients with unstable plaque exhibited an increase in Hs-CRP and MCP-1 levels compared with those of the stable plaque and normal control groups. The alteration in GSI calcium content and spectral curve slope reflects a close link between calcification and plaque instability, while aberrant Hs-CRP and MCP-1 expression are involved in the formation or development of vulnerable plaques. Taken together, the present results strongly support the feasibility of using these serological and newly identified imaging parameters as multiple potential biomarkers relevant to plaque vulnerability or stroke progression.

Protective Effects of Ginkgolide on a Cellular Model of Alzheimer's Disease via Suppression of the NF-κB Signaling Pathway.

SYNOPSIS: NF-κB signaling has been reported to play a key regulatory role in the pathogenesis of Alzheimer's disease (AD). The purpose of this study is to investigate the effects of ginkgolide on cell viability in an AD cellular model involving an APP/PS1 double gene-transfected HEK293 cell line (APP/PS1-HEK293) and further explore the mechanisms of action related to NF-κB signaling. The optimal time point and concentration of ginkgolide for cell proliferation were screened using a cell counting kit-8 assay. Based on the results, an in vitro study was performed by co-culture of APP/PS1-HEK293 with different dosages of ginkgolide, followed by an enzyme-linked immunosorbent assay to measure the levels of supernatant tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and IL-6, as well as western blotting and real-time polymerase chain reaction to detect intracellular protein and mRNA expression of NF-κB p65, IκBa, Bcl-2, and Bax. APP/PS1-HEK293 cells exhibited the highest cell viability at a concentration of 100 µg/ml after 48 h of treatment with ginkgolide. The supernatant levels of TNF-α, IL-1ß, and IL-6 in the high-dosage ginkgolide-treated groups were lower than those in the control group. Compared with the control group, there were decreased intracellular protein and mRNA expression of NF-κB p65 and Bax, but increased protein and mRNA expression of IκBa in both high-dosage and low-dosage groups. Ginkgolide may enhance cell viability, indicative of its neuroprotective effects on AD, at least partially via suppression of the NF-κB signaling pathway involving anti-apoptosis and anti-inflammation mechanisms. Therefore, ginkgolide might be a promising therapeutic agent against AD.

A preliminary study of association of cigarette smoking with risk of neuromyelitis optica spectrum disorder.

ABSTRACT: Various studies have revealed an association between cigarette smoking and increased risk for multiple sclerosis (MS). However, its role in neuromyelitis optica spectrum disorder (NMOSD) remains elusive. Therefore, in the present case-control study, we aimed to assess the association of active and passive cigarette smoking with the risk of MS and NMOSD.Thirty-six patients with NMOSD, 46 patients with MS, and 122 healthy individuals were included in this study. Standardized questionnaires and telephone interviews were used to collect information regarding the active and passive cigarette smoking behaviors of the patients and normal controls.The risk of MS was significantly higher among smokers than among nonsmokers (odds ratio = 2.166, 95% confidence interval: 1.109-4.170; P = .027). Further analysis of the risk between active and passive smokers, male smokers and nonsmokers showed no statistical difference. However, neither smokers nor active smokers had a greater or lower risk of NMOSD than their nonsmoking counterparts.Our preliminary study showed no significant association between cigarette smoking and the risk of NMOSD, strongly suggesting that, unlike MS, cigarette smoking might not confer NMOSD susceptibility, at least in the Northern Han Chinese population.

[Nucleic acid aptamer-based traditional Chinese medicine application:therapy,targeting and diagnosis].

Nucleic acid aptamers, broad-spectrum target-specific single-stranded oligonucleotides, serve as molecules in targeted therapy, targeted delivery and disease diagnosis for the treatment of tumor or microbial infection and clinical detection. Due to the existence of components in the use of traditional Chinese medicine(TCM), the target is difficult to concentrate and the specificity of treatment is poor. The effective components of TCM are toxic components, so a highly sensitive detection method is urgently needed to reduce the toxicity problem at the same time. The combined application of TCM and modern medical treatment strategy are difficult and cannot improve the therapeutic effect. Aptamers, advantageous in biosensors, aptamer-nanoparticles for targeted drug delivery, and aptamer-siRNA chimeras, are expected to connect Chinese medicinals with nanotechnology, diagnostic technology and combined therapies. We summarized the preparation, screening, and modification techniques of nucleic acid aptamers and the biomedical applications and advantages in therapy, targeting, and diagnosis, aiming at providing a reference for the in-depth research and development in TCM.

SENEBLOC, a long non-coding RNA suppresses senescence via p53-dependent and independent mechanisms.

Long non-coding RNAs (lncRNAs) have emerged as important biological tuners. Here, we reveal the role of an uncharacterized lncRNA we call SENEBLOC that is expressed by both normal and transformed cells under homeostatic conditions. SENEBLOC was shown to block the induction of cellular senescence through dual mechanisms that converge to repress the expression of p21. SENEBLOC facilitates the association of p53 with MDM2 by acting as a scaffold to promote p53 turnover and decrease p21 transactivation. Alternatively, SENEBLOC was shown to affect epigenetic silencing of the p21 gene promoter through regulation of HDAC5. Thus SENEBLOC drives both p53-dependent and p53-independent mechanisms that contribute to p21 repression. Moreover, SENEBLOC was shown to be involved in both oncogenic and replicative senescence, and from the perspective of senolytic agents we show that the antagonistic actions of rapamycin on senescence are dependent on SENEBLOC expression.

LncRNA REG1CP promotes tumorigenesis through an enhancer complex to recruit FANCJ helicase for REG3A transcription.

Protein products of the regenerating islet-derived (REG) gene family are important regulators of many cellular processes. Here we functionally characterise a non-protein coding product of the family, the long noncoding RNA (lncRNA) REG1CP that is transcribed from a DNA fragment at the family locus previously thought to be a pseudogene. REG1CP forms an RNA-DNA triplex with a homopurine stretch at the distal promoter of the REG3A gene, through which the DNA helicase FANCJ is tethered to the core promoter of REG3A where it unwinds double stranded DNA and facilitates a permissive state for glucocorticoid receptor α (GRα)-mediated REG3A transcription. As such, REG1CP promotes cancer cell proliferation and tumorigenicity and its upregulation is associated with poor outcome of patients. REG1CP is also transcriptionally inducible by GRα, indicative of feedforward regulation. These results reveal the function and regulation of REG1CP and suggest that REG1CP may constitute a target for cancer treatment.

Enantioselective photooxygenation of ß-dicarbonyl compounds in batch and flow photomicroreactors.

A series of C-2' modified cinchonine-derived phase-transfer catalysts were synthesized and used in the enantioselective photo-organocatalytic aerobic oxidation of ß-dicarbonyl compounds with excellent yields (up to 97%) and high enantioselectivities (up to 90% ee). Furthermore, the reaction was carried out in a flow photomicroreactor, in which the heterogeneous gas-liquid-liquid asymmetric photocatalytic oxidation reaction was performed affording good yields (up to 97%) and enantioselectivities (up to 86% ee) within 0.89 min.

Increased Peripheral CD137 Expression in a Mouse Model of Permanent Focal Cerebral Ischemia.

Various studies demonstrate that CD137 (TNFRSF9, 4-1BB) promotes atherosclerosis and vascular inflammation in experimental models via interactions with the CD137 ligand (CD137L). However, the exact role of CD137 in ischemic stroke remains unclear. In this study, we analyzed dynamic changes of peripheral CD137 expression on T cells in a mouse model of cerebral ischemia-middle cerebral artery occlusion (MCAO), as well as alternation of neurological function, infarct size and cerebral inflammatory status after inhibition of the CD137/CD137L pathway using an anti-CD137L monoclonal antibody. MCAO mice showed elevated surface expression of CD137 on T cells in both peripheral blood and lymphoid tissues during early cerebral ischemia. Remarkably, blockade of the CD137/CD137L pathway reduced the post-ischemic brain damage. Our findings indicate that enhanced CD137 costimulation occurs in early cerebral ischemia and promotes T cell activation, which in turn upregulates inflammatory immune response and possibly exerting deleterious effects on cerebral ischemia.

Dual functions for OVAAL in initiation of RAF/MEK/ERK prosurvival signals and evasion of p27-mediated cellular senescence.

Long noncoding RNAs (lncRNAs) function through a diverse array of mechanisms that are not presently fully understood. Here, we sought to find lncRNAs differentially regulated in cancer cells resistant to either TNF-related apoptosis-inducing ligand (TRAIL) or the Mcl-1 inhibitor UMI-77, agents that act through the extrinsic and intrinsic apoptotic pathways, respectively. This work identified a commonly up-regulated lncRNA, ovarian adenocarcinoma-amplified lncRNA (OVAAL), that conferred apoptotic resistance in multiple cancer types. Analysis of clinical samples revealed OVAAL expression was significantly increased in colorectal cancers and melanoma in comparison to the corresponding normal tissues. Functional investigations showed that OVAAL depletion significantly inhibited cancer cell proliferation and retarded tumor xenograft growth. Mechanically, OVAAL physically interacted with serine/threonine-protein kinase 3 (STK3), which, in turn, enhanced the binding between STK3 and Raf-1. The ternary complex OVAAL/STK3/Raf-1 enhanced the activation of the RAF protooncogene serine/threonine-protein kinase (RAF)/mitogen-activated protein kinase kinase 1 (MEK)/ERK signaling cascade, thus promoting c-Myc-mediated cell proliferation and Mcl-1-mediated cell survival. On the other hand, depletion of OVAAL triggered cellular senescence through polypyrimidine tract-binding protein 1 (PTBP1)-mediated p27 expression, which was regulated by competitive binding between OVAAL and p27 mRNA to PTBP1. Additionally, c-Myc was demonstrated to drive OVAAL transcription, indicating a positive feedback loop between c-Myc and OVAAL in controlling tumor growth. Taken together, these results reveal that OVAAL contributes to the survival of cancer cells through dual mechanisms controlling RAF/MEK/ERK signaling and p27-mediated cell senescence.