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Background Mapping disease rates is an important aspect of epidemiological research because it helps inform public health policy. Disease maps are often drawn according to local administrative areas (LAAs), such as counties, cities, or towns. In LAAs with small populations, disease rates are unstable and are prone to appear extremely high or low. The empirical Bayes methods consider variance differences among different LAAs, thereby stabilizing the disease rates. The methods of kriging break the constraints of geopolitical boundaries and produce a smooth curved surface in the form of contour lines, but the methods lack the stabilizing effect of the empirical Bayes methods. Methods An easy-to-implement stabilized kriging method is proposed to map disease rates, which allows different errors in different LAAs. Results Monte Carlo simulations revealed that the stabilized kriging method had smaller symmetric mean absolute percentage error than three other types of methods (original LAA-based method, empirical Bayes methods, and traditional kriging methods) in nearly all scenarios considered. Real-world data analysis of oral cancer incidence rates in men from Taiwan demonstrated that the age-standardized rates in the central mountainous sparsely-populated region of Taiwan were stabilized using our proposed method, with no more large differences in numerical values, whereas the rates in other populous regions were not over smoothed. Additionally, the stabilized kriging map had improved resolution and helped locate several hot and cold spots in the incidence rates of oral cancer. Conclusions We recommend the use of the stabilized kriging method for mapping disease rates.

Metabolic reprogramming is an important cancer hallmark that plays a key role in cancer malignancies and therapy resistance. Cancer cells reprogram the metabolic pathways to generate not only energy and building blocks but also produce numerous key signaling metabolites to impact signaling and epigenetic/transcriptional regulation for cancer cell proliferation and survival. A deeper understanding of the mechanisms by which metabolic reprogramming is regulated in cancer may provide potential new strategies for cancer targeting. Recent studies suggest that deregulated transcription factors have been observed in various human cancers and significantly impact metabolism and signaling in cancer. In this review, we highlight the key transcription factors that are involved in metabolic control, dissect the crosstalk between signaling and transcription factors in metabolic reprogramming, and offer therapeutic strategies targeting deregulated transcription factors for cancer treatment.

Strictly regulated protein degradation by ubiquitin-proteasome system (UPS) is essential for various cellular processes whose dysregulation is linked to serious diseases including cancer. Skp2, a well characterized component of Skp2-SCF E3 ligase complex, is able to conjugate both K48-linked ubiquitin chains and K63-linked ubiquitin chains on its diverse substrates, inducing proteasome mediated proteolysis or modulating the function of tagged substrates respectively. Overexpression of Skp2 is observed in various human cancers associated with poor survival and adverse therapeutic outcomes, which in turn suggests that Skp2 engages in tumorigenic activity. To that end, the oncogenic properties of Skp2 are demonstrated by various genetic mouse models, highlighting the potential of Skp2 as a target for tackling cancer. In this article, we will describe the downstream substrates of Skp2 as well as upstream regulators for Skp2-SCF complex activity. We will further summarize the comprehensive oncogenic functions of Skp2 while describing diverse strategies and therapeutic platforms currently available for developing Skp2 inhibitors.

Background Glioblastoma is associated with poor prognosis and high mortality. Although the use of first-line temozolomide can reduce tumor growth, therapy-induced stress drives stem cells out of quiescence, leading to chemoresistance and glioblastoma recurrence. The specificity protein 1 (Sp1) transcription factor is known to protect glioblastoma cells against temozolomide; however, how tumor cells hijack this factor to gain resistance to therapy is not known. Methods Sp1 acetylation in temozolomide-resistant cells and stemlike tumorspheres was analyzed by immunoprecipitation and immunoblotting experiments. Effects of the histone deacetylase (HDAC)/Sp1 axis on malignant growth were examined using cell proliferation–related assays and in vivo experiments. Furthermore, integrative analysis of gene expression with chromatin immunoprecipitation sequencing and the recurrent glioblastoma omics data were also used to further determine the target genes of the HDAC/Sp1 axis. Results We identified Sp1 as a novel substrate of HDAC6, and observed that the HDAC1/2/6/Sp1 pathway promotes self-renewal of malignancy by upregulating B cell-specific Mo-MLV integration site 1 (BMI1) and human telomerase reverse transcriptase (hTERT), as well as by regulating G2/M progression and DNA repair via alteration of the transcription of various genes. Importantly, HDAC1/2/6/Sp1 activation is associated with poor clinical outcome in both glioblastoma and low-grade gliomas. However, treatment with azaindolyl sulfonamide, a potent HDAC6 inhibitor with partial efficacy against HDAC1/2, induced G2/M arrest and senescence in both temozolomide-resistant cells and stemlike tumorspheres. Conclusion Our study uncovers a previously unknown regulatory mechanism in which the HDAC6/Sp1 axis induces cell division and maintains the stem cell population to fuel tumor growth and therapeutic resistance.

To compare the biomechanical properties of the double simple suture (DSS) technique, Krackow suture (KS) technique, and double Krackow suture (DKS) technique in subpectoral biceps tenodesis using a double-loaded suture anchor in a porcine tendon model.A total of 30 artificial composite (polymer and glass fiber) humeri and porcine flexor profundus tendons with diameter of 4.5 mm were used. The sample size was determined based on the results of the pilot study. Metallic suture anchors with double-loaded No. 2 braided sutures were inserted at the subpectoral tenodesis site, 5 cm from the superomedial corner of the greater tuberosity. Three suture techniques were used to fix the tendons: a DSS used as the control, a KS, and a DKS, which is an alternative tendon graft fixation technique. A preload of 5 N was applied for 2 minutes, followed by cyclic loading for 500 cycles ranging from 5 to 70 N; next, a load-to-failure test at 1 mm/s was performed.The KS (283.5 ± 57 N) and DKS (270.4 ± 50 N) groups had significantly greater ultimate failure loads as compared with the DSS group (84.1 ± 6.4 N) (P.001). Meanwhile, the peak displacement at failure loads in the KS group (9.3 ± 2.2 mm) and DKS group (7.8 ± 1.7 mm) were significantly smaller than that of the DSS group (11.3 ± 2.9 mm) (P = .015). Stiffness in the DSS group (36.4 ± 3.0 N/mm), KS group (39.6 ± 2.5 N/mm), and DKS group (36.9 ± 4.6 N/mm) was not significantly different (P = .125). All DSS constructs and 6 KS constructs failed with tendons being cut through by the sutures, whereas the other 4 KS constructs and all DKS constructs failed resulting from suture breakage.In this subpectoral biceps tenodesis model, both the KS technique and the DKS technique had similar time 0 biomechanical properties that were better than those of the double simple suture technique.A sturdy suture-tendon structure could prevent clinical failure of a subpectoral biceps tenodesis using a suture anchor.

Delayed-onset muscle soreness (DOMS) is associated with exercise-induced muscle damage and inflammation, which is mainly caused by prolonged eccentric exercise in humans. Triptolide, an extract from the Chinese herb Tripterygium wilfordii Hook F, has been used for treating autoimmune and inflammatory diseases in clinical practice. However, whether triptolide attenuates acute muscle damage is still unclear. Here, we examined the effect of triptolide on carrageenan-induced DOMS in rats. Rats were injected with 3% of carrageenan into their muscles to induce acute left gastrocnemius muscular damage, and triptolide treatment attenuated carrageenan-induced acute muscular damage without affecting hepatic function. Triptolide can significantly decrease lipid hydroperoxide and nitric oxide (NO) levels, proinflammatory cytokine production, and the activation of nuclear factor (NF)-ĸB, as well as increase a reduced form of glutathione levels in carrageenan-treated rat muscles. At the enzyme levels, triptolide reduced the inducible nitric oxide synthase (iNOS) expression and muscular myeloperoxidase (MPO) activity in carrageenan-treated DOMS rats. In conclusion, we show that triptolide can attenuate muscular damage by inhibiting muscular oxidative stress and inflammation in a carrageenan-induced rat DOMS model.

Mitochondrial dynamics regulated by mitochondrial fusion and fission maintain mitochondrial functions, whose alterations underline various human diseases. Here, we show that inositol is a critical metabolite directly restricting AMPK-dependent mitochondrial fission independently of its classical mode as a precursor for phosphoinositide generation. Inositol decline by IMPA1/2 deficiency elicits AMPK activation and mitochondrial fission without affecting ATP level, whereas inositol accumulation prevents AMPK-dependent mitochondrial fission. Metabolic stress or mitochondrial damage causes inositol decline in cells and mice to elicit AMPK-dependent mitochondrial fission. Inositol directly binds to AMPKγ and competes with AMP for AMPKγ binding, leading to restriction of AMPK activation and mitochondrial fission. Our study suggests that the AMP/inositol ratio is a critical determinant for AMPK activation and establishes a model in which AMPK activation requires inositol decline to release AMPKγ for AMP binding. Hence, AMPK is an inositol sensor, whose inactivation by inositol serves as a mechanism to restrict mitochondrial fission.

The intrinsic mechanisms sensing the imbalance of energy in cells are pivotal for cell survival under various environmental insults. AMP-activated protein kinase (AMPK) serves as a central guardian maintaining energy homeostasis by orchestrating diverse cellular processes, such as lipogenesis, glycolysis, TCA cycle, cell cycle progression and mitochondrial dynamics. Given that AMPK plays an essential role in the maintenance of energy balance and metabolism, managing AMPK activation is considered as a promising strategy for the treatment of metabolic disorders such as type 2 diabetes and obesity. Since AMPK has been attributed to aberrant activation of metabolic pathways, mitochondrial dynamics and functions, and epigenetic regulation, which are hallmarks of cancer, targeting AMPK may open up a new avenue for cancer therapies. Although AMPK is previously thought to be involved in tumor suppression, several recent studies have unraveled its tumor promoting activity. The double-edged sword characteristics for AMPK as a tumor suppressor or an oncogene are determined by distinct cellular contexts. In this review, we will summarize recent progress in dissecting the upstream regulators and downstream effectors for AMPK, discuss the distinct roles of AMPK in cancer regulation and finally offer potential strategies with AMPK targeting in cancer therapy.

Cancer stem-like cells (CSLCs) acquire enhanced immune checkpoint responses to evade immune cell killing and promote tumor progression. Here we showed that signal regulatory protein γ (SIRPγ) determined CSLC properties and immune evasiveness in a small population of lung adenocarcinoma (LUAD) cancer cells. A SIRPγhi population displayed CSLC properties and transmitted the immune escape signal through sustaining CD47 expression in both SIRPγhi and SIRPγlo/- tumor cells. SIRPγ bridged MST1 and PP2A to facilitate MST1 dephosphorylation, resulting in Hippo/YAP activation and leading to cytokine release by CSLCs, which stimulated CD47 expression in LUAD cells and consequently inhibited tumor cell phagocytosis. SIRPγ promoted tumor growth and metastasis in vivo through YAP signaling. Notably, SIRPγ targeting with genetic SIRPγ knockdown or a SIRPγ-neutralizing antibody inhibited CSLC phenotypes and elicited phagocytosis that suppressed tumor growth in vivo. SIRPG was upregulated in human LUAD and its overexpression predicted poor survival outcome. Thus, SIRPγhi cells serve as CSLCs and tumor immune checkpoint-initiating cells, propagating the immune escape signal to the entire cancer cell population. Our study identifies Hippo/YAP signaling as the first mechanism by which SIRPγ is engaged and reveals that targeting SIRPγ represents an immune- and CSLC-targeting strategy for lung cancer therapy.

The role of oxidative stress in ligamentum flavum (LF) hypertrophy has not been elucidated. We hypothesize that oxidative stress induces inflammatory responses and the subsequent fibrotic processes in LF, via activation of the Akt and MAPK pathways. Specimens of LFs were collected during surgeries for lumbar disc herniation (LDH) or lumbar spinal stenosis (LSS). Part of the LF specimens underwent analyses for ROS, fibrotic markers, and inflammatory mediators, with the remainder minced for cell cultures. The cell cultures were treated with H2O2, after which the cells were lysed and analyzed via western blotting. The specimens of the LSS patients showed increased infiltration of inflammatory cells and were stained positively for MMP-3, MMP-9, vimentin, and fibronectin. The LF of the LSS patients had increased oxidative stress and inflammation compared to that of the LDH patients. In vitro analyses demonstrated that oxidative stress rapidly activated the Akt and MAPK pathways. Inflammatory mediators, iNOS and NF-κB, and fibrotic markers, including TGF-β, β-catenin, α-SMA and vimentin, were significantly upregulated after induction of oxidative stress. Oxidative stress activated the intrinsic apoptotic pathway. These findings revealed that oxidative stress is one of the etiological factors of LF hypertrophy, which might provide new insights into treatment approaches.

Inflammatory response after peripheral nerve injury is required for clearance of tissue debris and effective regeneration. Studies have revealed that hyaluronic acid (HA) may exert different properties depending on their molecular size. High molecular weight HA (>>1,000 kDa; HMW-HA) displays immunosuppressive properties, whereas low molecular weight HA (

It has been suggested that stress stimuli from the microenvironment maintain a subset of tumor cells with stem-like properties, including drug resistance. Here, we investigate whether Sp1, a stress-responsive factor, regulates stemness gene expression and if its inhibition sensitizes cancer cells to chemotherapy. Hydrogen peroxide- and serum deprivation-induced stresses were performed in glioblastoma (GBM) cells and patient-derived cells, and the effect of the Sp1 inhibitor mithramycin A (MA) on these stress-induced stem cells and temozolomide (TMZ)-resistant cells was evaluated. Sp1 and stemness genes were not commonly overexpressed in clinical GBM samples. However, their expression was highly induced by stress stimuli. Using MA, we demonstrated Sp1 as a critical stemness-related transcriptional factor protecting GBM cells against stress- and TMZ-induced death. Thus, Sp1 inhibition may prevent recurrence of malignant cells persisting after primary therapy.

Acquisition of temozolomide (TMZ) resistance is a major factor leading to the failure of glioblastoma (GBM) treatment. The exact mechanism by which GBM evades TMZ toxicity is not always related to the expression of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT), and so remains unclear. In this study, TMZ-resistant variants derived from MGMT-negative GBM clinical samples and cell lines were studied, revealing there to be increased specificity protein 1 (Sp1) expression associated with reduced reactive oxygen species (ROS) accumulation following TMZ treatment. Analysis of gene expression databases along with cell studies identified the ROS scavenger superoxide dismutase 2 (SOD2) as being disease-related. SOD2 expression was also increased, and it was found to be co-expressed with Sp1 in TMZ-resistant cells. Investigation of the SOD2 promoter revealed Sp1 as a critical transcriptional activator that enhances SOD2 gene expression. Co-treatment with an Sp1 inhibitor restored the inhibitory effects of TMZ, and decreased SOD2 levels in TMZ-resistant cells. This treatment strategy restored susceptibility to TMZ in xenograft animals, leading to prolonged survival in an orthotopic model. Thus, our results suggest that Sp1 modulates ROS scavengers as a novel mechanism to increase cancer malignancy and resistance to chemotherapy. Inhibition of this pathway may represent a potential therapeutic target for restoring treatment susceptibility in GBM.

Peripheral nervous injury (PNI) is a common form of trauma in modern society, especially in sport players. Despite the advance of therapy for PNI, the recovery of function can never reach the preinjury level after treatments. Recently, inhibiting neural oxidative stress shows a beneficial effect in improving functional recovery after PNI. In addition, sesame oil has been reported to possess the excellent antioxidative properties. However, whether sesame oil can improve the functional recovery after PNI by its antioxidative effect has never been investigated. Thirty mice were randomly divided into five groups of six: group I mice received sham operation; group II mice received sciatic nerve crush; and groups III-V mice daily ingested 0.5, 1 and 2 ml/kg of sesame oil for 6 days, respectively, after sciatic nerve crush. Oxidative stress, GAP43 and nuclear Nrf2 levels as well as spinal somatosensory evoked potentials were assessed on day 6, while paw withdrawal latency and sciatic function index were assessed on days 0, 3, and 6. Sesame oil significantly decreased lipid peroxidation and increased nuclear factor erythroid 2-related factor 2 and GAP43 expression in sciatic nerve. Furthermore, sesame oil improved electrophysiological and functional assessments in mice with sciatic nerve crush. In conclusion, sesame oil may improve nerve functional recovery by attenuating nerve oxidative stress in mouse acute peripheral nerve injury. Further, application of natural product sesame oil may be an alternative approach for improving nerve functional recovery in the clinical setting.

Background The optimal insertion angle for suture anchor insertion has long been of great interest. Although greater tuberosity decortication is commonly performed during rotator cuff repair, the effect of decortication on the suture anchor insertion angle remains unclear. The purpose of this study was to compare the pullout strength of threaded suture anchors inserted at 45° and 90° in decorticated and non-decorticated synthetic bone models. Methods Two kinds of synthetic bones were used to simulate the decorticated and non-decorticated conditions, for which 40 metallic suture anchors were used. Anchors were inserted at 45° and 90° in both decorticated and non-decorticated models and tested under cyclic loading followed by load-to-failure testing. The number of completed cycles, ultimate failure load, and failure modes was recorded. Results In the decorticated model, the ultimate failure load of anchors inserted at 45° (67.5 ± 5.3 N) was significantly lower than that of anchors inserted at 90° (114.1 ± 9.8 N) (p

De Quervain's disease is a stenosing tenosynovitis of the first dorsal compartment of the wrist. Histopathological studies have reported that the thickening of the first dorsal retinaculum is characterized by degeneration rather than inflammation. However, significant infiltration of mast cells and macrophages was noted in a torn tendon study, which suggested that innate immune pathways are part of the mechanism that mediates early tendinopathy. Recently, Interleukin-20 (IL-20) has been reported to provoke potent inflammation and regulate angiogenesis and chemotaxis, which are important for the pathogenesis of inflammatory diseases. The main purpose of our study was to investigate the correlation between IL-20 and tumor necrosis factor (TNF-α) and clarify the potential predictor of tendinopathy progression. Hematoxylin and eosin (H & E) and immunohistochemistry (IHC) staining were used to score and analyze the clinical outcome. TNF-α, IL-20 and related inflammation cytokines were examined. Moreover, the tenocytes were cultured with a stimulator and were used to examine inflammatory cytokine secretions. A real-time polymerase chain reaction (Real-time PCR) was used to detect the gene expression profile. The IHC data showed that TNF-α is up-regulated in grade III de Quervain's. The analysis data showed that IL-20 is positively correlated with TNF-α and disease severity. The real-time PCR showed that the inflammation stimulator enhanced the expression of IL-20 mRNA expression. Inflammation cytokines such as TNF-alpha, transforming growth factor-β (TGF-β) and IL-1 have been used as predictors of de Quervain's; IL-20 is a new predictor based on this study. In the future, IL-20 expression's involvement in the molecular mechanism of the severity of de Quervain's should be further investigated.

The nucleolus is the cellular site of ribosomal (r)DNA transcription and ribosome biogenesis. The 58-kDa microspherule protein (MSP58) is a nucleolar protein involved in rDNA transcription and cell proliferation. However, regulation of MSP58-mediated rDNA transcription remains unknown. Using a yeast two-hybrid system with MSP58 as bait, we isolated complementary (c)DNA encoding Rad50-interacting protein 1 (RINT-1), as a MSP58-binding protein. RINT-1 was implicated in the cell cycle checkpoint, membrane trafficking, Golgi apparatus and centrosome dynamic integrity, and telomere length control. Both in vitro and in vivo interaction assays showed that MSP58 directly interacts with RINT-1. Interestingly, microscopic studies revealed the co-localization of MSP58, RINT-1, and the upstream binding factor (UBF), a rRNA transcription factor, in the nucleolus. We showed that ectopic expression of MSP58 or RINT-1 resulted in decreased rRNA expression and rDNA promoter activity, whereas knockdown of MSP58 or RINT-1 by siRNA exerted the opposite effect. Coexpression of MSP58 and RINT-1 robustly decreased rRNA synthesis compared to overexpression of either protein alone, whereas depletion of RINT-1 from MSP58-transfected cells enhanced rRNA synthesis. We also found that MSP58, RINT-1, and the UBF were associated with the rDNA promoter using a chromatin immunoprecipitation assay. Because aberrant ribosome biogenesis contributes to neoplastic transformation, our results revealed a novel protein complex involved in the regulation of rRNA gene expression, suggesting a role for MSP58 and RINT-1 in cancer development.

Summary RLR-mediated type I IFN production plays a pivotal role in elevating host immunity for viral clearance and cancer immune surveillance. Here, we report that glycolysis, which is inactivated during RLR activation, serves as a barrier to impede type I IFN production upon RLR activation. RLR-triggered MAVS-RIG-I recognition hijacks hexokinase binding to MAVS, leading to the impairment of hexokinase mitochondria localization and activation. Lactate serves as a key metabolite responsible for glycolysis-mediated RLR signaling inhibition by directly binding to MAVS transmembrane (TM) domain and preventing MAVS aggregation. Notably, lactate restoration reverses increased IFN production caused by lactate deficiency. Using pharmacological and genetic approaches, we show that lactate reduction by lactate dehydrogenase A (LDHA) inactivation heightens type I IFN production to protect mice from viral infection. Our study establishes a critical role of glycolysis-derived lactate in limiting RLR signaling and identifies MAVS as a direct sensor of lactate, which functions to connect energy metabolism and innate immunity.

The serine/threonine kinase Akt plays a central role in cell proliferation, survival and metabolism, and its hyperactivation is linked to cancer progression. Here we report that Akt undergoes K64 methylation by SETDB1, which is crucial for cell membrane recruitment, phosphorylation and activation of Akt following growth factor stimulation. Furthermore, we reveal an adaptor function of histone demethylase JMJD2A, which is important for recognizing Akt K64 methylation and recruits E3 ligase TRAF6 and Skp2-SCF to the Akt complex, independently of its demethylase activity, thereby initiating K63-linked ubiquitination, cell membrane recruitment and activation of Akt. Notably, the cancer-associated Akt mutant E17K displays enhanced K64 methylation, leading to its hyper-phosphorylation and activation. SETDB1-mediated Akt K64 methylation is upregulated and correlated with Akt hyperactivation in non-small-cell lung carcinoma (NSCLC), promotes tumour development and predicts poor outcome. Collectively, these findings reveal complicated layers of Akt activation regulation coordinated by SETDB1-mediated Akt K64 methylation to drive tumorigenesis. Wang et al. show that Akt methylation by SETDB1 is recognized by demethylase JMJD2A, which then recruits E3 ligases to induce K63-linked Akt ubiquitination, leading to Akt activation and tumorigenesis.

Background Glioma stem-like cells (GSCs) are proposed to be responsible for high resistance in glioblastoma multiforme (GBM) treatment. In order to find new strategies aimed at reducing GSC stemness and improving GBM patient survival, we investigated the effects and mechanism of a histone deacetylases (HDACs) inhibitor, suberoylanilide hydroxamic acid (SAHA), since HDAC activity has been linked to cancer stem-like cell (CSC) abundance and properties. Methods Human GBM cell lines were plated in serum-free suspension cultures allowed for sphere forming and CSC enrichment. Subsequently, upon SAHA treatment, the stemness markers, cell proliferation, and viability of GSCs as well as cellular apoptosis and senescence were examined in order to clarify whether inhibition of GSCs occurs. Results We demonstrated that SAHA attenuated cell proliferation and diminished the expression stemness-related markers (CD133 and Bmi1) in GSCs. Furthermore, at high concentrations (more than 5 μM), SAHA triggered apoptosis of GSCs accompanied by increases in both activation of caspase 8- and caspase 9-mediated pathways. Interestingly, we found that a lower dose of SAHA (1 μM and 2.5 μM) inhibited GSCs via cell cycle arrest and induced premature senescence through p53 up-regulation and p38 activation. Conclusion SAHA induces apoptosis and functions as a potent modulator of senescence via the p38-p53 pathway in GSCs. Our results provide a perspective on targeting GSCs via SAHA treatment, and suggest that SAHA could be used as a potent agent to overcome drug resistance in GBM patients. Electronic supplementary material The online version of this article (doi:10.1186/s12929-016-0296-6) contains supplementary material, which is available to authorized users.

Supplementary information includes Figures S1 to S3 and supplementary methods. (DOCX 654Â kb)

The spine is one of the most important parts of the human body. Spine diseases owning to aging or injuries would be treated by spine surgeries. However, the surgeries are highly dangerous and the surgical training can increase the success rate. In this paper, an interactive surgical simulation system for the training of pedicle screw implantation is introduced. We propose an automatic and efficient method to segment the vertebra from the CT images for building the vertebra model. The mean shift method which can cluster points having similar property into groups is used in data clustering. The clustered groups related to the bone region are chosen as the initial model. And then, we apply the Chan-Vese level set method which refines the vertebra contour by using the concepts of statistics. After segmentation, we then apply the marching cube algorithm to generate the 3D vertebra model, and pass it to a virtual surgical environment. A haptic device is adopted to interact with this model to fulfill the surgical simulation in the virtual environment. The average dice coefficient of the segmentation results is 0.92.

Chronic low back pain (CLBP), one of the most common musculoskeletal conditions in older adults, might affect balance and functional independence. The purpose of this study was to investigate the postural responses to a suddenly released pulling force in older adults with and without CLBP. Thirty community-dwelling older adults with CLBP and 26 voluntary controls without CLBP were enrolled. Participants were required to stand on a force platform while, with one hand, they pulled a string that was fastened at the other end to a 2-kg or to a 4-kg force in the opposite direction at a random order. The number of times the participants lost their balance and motions of center of pressure (COP) when the string was suddenly released were recorded. The results demonstrated that although the loss of balance rates for each pulling force condition did not differ between groups, older adults with CLBP had poorer postural responses: delayed reaction, larger displacement, higher velocity, longer path length, and greater COP sway area compared to the older controls. Furthermore, both groups showed larger postural responses in the 4-kg pulling force condition. Although aging is generally believed to be associated with declining balance and postural control, these findings highlight the effect of CLBP on reactive balance when responding to an externally generated force in an older population. This study also suggests that, for older adults with CLBP, in addition to treating them for pain and disability, reactive balance evaluation and training, such as reaction and movement strategy training should be included in their interventions. Clinicians and older patients with CLBP need to be made aware of the significance of impaired reactive balance and the increased risk of falls when encountering unexpected perturbations.

Background: The nucleolar MSP58 protein is a candidate oncogene implicated in cellular transformation. Results: MSP58 is associated with BRG1 and induces cellular senescence through the p53/p21 pathway. Conclusion: MSP58 has both tumor-suppressing and -promoting functions. Significance: This work reveals a novel role for MSP58 in cellular senescence and suggests that MSP58 may have further prognostic and therapeutic implications., The nucleolar 58-kDa microspherule protein (MSP58) protein is a candidate oncogene implicated in modulating cellular proliferation and malignant transformation. In this study, we show that knocking down MSP58 expression caused aneuploidy and led to apoptosis, whereas ectopic expression of MSP58 regulated cell proliferation in a context-dependent manner. Specifically, ectopic expression of MSP58 in normal human IMR90 and Hs68 diploid fibroblasts, the H184B5F5/M10 mammary epithelial cell line, HT1080 fibrosarcoma cells, primary mouse embryonic fibroblasts, and immortalized NIH3T3 fibroblasts resulted in induction of premature senescence, an enlarged and flattened cellular morphology, and increased senescence-associated β-galactosidase activity. MSP58-driven senescence was strictly dependent on the presence of functional p53 as revealed by the fact that normal cells with p53 knockdown by specific shRNA or cells with a mutated or functionally impaired p53 pathway were effective in bypassing MSP58-induced senescence. At least two senescence mechanisms are induced by MSP58. First, MSP58 activates the DNA damage response and p53/p21 signaling pathways. Second, MSP58, p53, and the SWI/SNF chromatin-remodeling subunit Brahma-related gene 1 (BRG1) form a ternary complex on the p21 promoter and collaborate to activate p21. Additionally, MSP58 protein levels increased in cells undergoing replicative senescence and stress-induced senescence. Notably, the results of analyzing expression levels of MSP58 between tumors and matched normal tissues showed significant changes (both up- and down-regulation) in its expression in various types of tumors. Our findings highlight new aspects of MSP58 in modulating cellular senescence and suggest that MSP58 has both oncogenic and tumor-suppressive properties.

The prognosis of glioblastoma (GBM) is usually poor even following treatment with the first-line chemotherapeutic agent temozolomide (TMZ). One most known resistant mechanism is the presence of DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). However, compared with MGMT-mediated innate TMZ resistance, the development of acquired resistance is considered more complex with multi-factorial involvement such as the presence of cancer stem cells (CSCs). In this study, we treated the MGMT-negative GBM cells with TMZ to investigate the acquired resistance, and found that both histone deacetylases (HDACs) and Sp1 are key factors protecting GBM against TMZ. These results include the following: (1) Stemness markers were highly increased in TMZ-resistant GBMs; (2) The activity of HDACs affected the stem-like characteristics and cell survival of GBM stem cells (GSCs); (3) An HDAC1/2/6-selective inhibitor MPT0B291 increased TMZ-sensitivity and induced senescence in TMZ-resistant cells; (4) MPT0B291 suppressed anti-senescence genes (hTERT and BMI1) expression via inhibition Sp1 transactivation; (5) Both HDACs and Sp1 were elevated and interacted with each other in GSCs and resistant GBM cells; (6) TMZ treatment induced Sp1 deacetylation, but MPT0B291 attenuated that. In summary, we verified that HDACs increases Sp1 activation via protein deacetylation and causes Sp1-downstream target upregulation, which may enrich stemness properties and protect GBM against chemotherapeutic drugs. Citation Format: Jian-Ying Chuang, Che-Chia Hsu, Kwang-Yu Chang, Wen-Chang Chang. Sp1 acetylation associates with stemness characteristics in temozolomide-resistant glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5905.

Background De Quervain disease is a stenosing condition of the sheath of the abductor pollicis longus and extensor pollicis brevis tendons at the radial styloid process. Previous studies consistently reported that the pathological change of this condition is thought to be primarily an extensor retinaculum thickened by fibrosis and angiogenesis instead of inflammation. Contradictorily, the conservative treatment for de Quervain disease is anti-inflammatory medication. The inflammatory response may be involved in this disease; however, there is no present study directly evidencing whether the inflammatory responses exist in de Quervain disease or not. The histopathology of de Quervain disease is yet to be elucidated clearly. Purpose To grade all specimens in the different stages and characterize specific inflammatory cell and factors to examine whether inflammatory response is involved in de Quervain disease. Methods Retinaculum samples were collected from 13 patients with de Quervain disease after surgery. The specimens were evaluated histologically by collagen structure grading and immunohistochemically by quantifying the presence of neutrophil elastase, macrophages, cyclooxygenase, and vascular endothelium. Results Neutrophil elastase and cyclooxygenase occur in the de Quervain disease retinaculum and increased with the grade of collagen structure. After angiogenesis, macrophage infiltration occurs in the grade II matrix worse than grade III matrix. Conclusions Inflammation is present in de Quervain disease. This study provides direct evidence for inflammatory cell and infiltration factors and offer valuable clues for specific pharmacological therapies for de Quervain disease.

Pedicle screws for spinal fixation risk neural damage because of the proximity between screw and nerve root. We assessed whether spinal somatosensory evoked potential (SSEP) could selectively detect pedicle-screw-related acute isolated nerve injury. Because pedicle screws are too large for a rat's spine, we inserted a K-wire close to the pedicle in 32 rats, intending not to injure the nerve root in eight (controls), and to injure the L4 or L5 root in 24. We used sciatic-nerve-elicited SSEP pre- and postinsertion. Radiologic, histologic, and postmortem observations confirmed the level and degree of root injury. Sciatic (SFI), tibial (TFI), and peroneal function indices (PFI) were calculated and correlated with changes in potential. Although not specific for injuries to different roots, amplitude reduction immediately postinsertion was significant in the experimental groups. Animals with the offending wire left in place for one hour showed a further non-significant deterioration of amplitude. Electrophysiologic changes correlated with SFI and histologic findings in all groups. SSEP monitoring provided reliable, useful diagnostic and intraoperative information about the functional integrity of single nerve-root injury. These findings are clinically relevant to acute nerve-root injury and pedicle-screw insertion. If a nerve-root irritant remains in place, a considerable neurologic deficit will occur.

58-kDa microspherule protein (MSP58) plays an important role in a variety of cellular processes including transcriptional regulation, cell proliferation and oncogenic transformation. Currently, the mechanisms underlying the oncogenic effect of MSP58 are not fully understood. The human telomerase reverse transcriptase ( hTERT ) gene, which encodes an essential component for telomerase activity that is involved in cellular immortalization and transformation, is strictly regulated at the gene transcription level. Our previous study revealed a novel function of MSP58 in cellular senescence. Here we identify telomerase transcriptional element-interacting factor (TEIF) as a novel MSP58-interacting protein and determine the effect of MSP58 on hTERT transcription. This study thus provides evidence showing MSP58 to be a negative regulator of hTERT expression and telomerase activity. Luciferase reporter assays indicated that MSP58 could suppress the transcription of hTERT promoter. Additionally, stable overexpression of MSP58 protein in HT1080 and 293T cells decreased both endogenous hTERT expression and telomerase activity. Conversely, their upregulation was induced by MSP58 silencing. Chromatin immunoprecipitation assays showed that MSP58 binds to the hTERT proximal promoter. Furthermore, overexpression of MSP58 inhibited TEIF-mediated hTERT transactivation, telomerase activation, and cell proliferation promotion. The inhibitory effect of MSP58 occurred through inhibition of TEIF binding to DNA. Ultimately, the HT1080-implanted xenograft mouse model confirmed these cellular effects. Together, our findings provide new insights into both the biological function of MSP58 and the regulation of telomerase/hTERT expression.

This study presents a robust bounded control that prevents wheel skidding for an autonomous 4WS4WD vehicle under uncertain tire/road condition and aerodynamic drag. Constraint on combined wheel slip is incorporated as a priori in design to prevent the skidding. A robust low-and-high gain technique is used to suppress the path-tracking error and to enhance the utilization of the limited wheel slip. Simulation shows that, under the uncertain tire/road condition and aerodynamic drag, the proposed control scheme can effectively limit the combined wheel slip and achieve the goal of path tracking. Moreover, the control inputs of wheel torque and wheel steering are coordinated well during the path tracking.

Telomerase expression is essential for cell proliferation and survival, which also plays a role in development, senescence and cancer. In our previous studies, we demonstrated that ectopic expression MSP58 regulates cell proliferation in context-dependent manner and induces premature senescence in HT1080 cells and normal human diploid fibroblasts through p53/p21 senescence pathway. In addition, we also demonstrated that MSP58 overexpression significantly suppressed telomerase activity in HT1080 cells. Currently, we identified a novel MSP58 interacting protein, TEIF (Telomerase transcription element-interacting factor) by yeast-two hybrid screening. TEIF has been reported to up-regulate the hTERT gene expression and telomerase activity. Interestingly, we found that MSP58 represses the TEIF-mediated activation of telomerase. Furthermore, overexpression of MSP58 represses TEIF promoted anchorage-independent growth in HT1080 cells. In contrast, knockdown MSP58 expression increases TEIF promoted anchorage -independent growth in HT1080 cells. These results suggest that MSP58 regulates telomerase activity via interaction with TEIF and contributes to control cell proliferation. Citation Format: Che-Chia Hsu. MSP58 regulates telomerase activity and cell proliferation via interaction with TEIF. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5182. doi:10.1158/1538-7445.AM2013-5182

The nucleolar protein 58-kDa microspherule protein (MSP58) is a candidate oncogene implicated in modulating cellular proliferation. In our studies, acute depletion of MSP58 expression using short hairpin (sh)RNA synthesis led to aneuploidy and apoptosis, whereas ectopic expression of MSP58 regulated cell proliferation in a context-dependent manner. Remarkably, ectopic expression of MSP58 in HT1080, NIH3T3, normal human fibroblasts, and mammary epithelial cell lines resulted in induction of premature senescence, caused large and flattened cell morphology, and increased senescence-associated β-galactosidase activity. This phenotype was accompanied by hypophosphorylated Rb, elevation of p53 and p21 protein expressions, activation of p53-mediated transcription, accumulation of phosphorylated forms of ATM/ATR and Chk1/Chk2 kinases, and formation of γH2AX and RPA70 foci, indicating that MSP58 activates the DNA damage response (DDR) and p53/p21 signaling pathways. Furthermore, we identified the SWI/SNF chromatin remodeling subunit, BRG1, as a critical mediator of MSP58-induced senescence. MSP58, BRG1, and p53 form a ternary complex on the p21 promoter, and collaborate to activate p21. This study revealed novel links among MSP58, p53, and cellular senescence in human tumors and normal cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3955. doi:1538-7445.AM2012-3955