Effect of metal cation crosslinking on the mechanical properties and shrimp freshness monitoring sensitivity of pectin/carboxymethyl cellulose sodium/anthocyanin intelligent films.

Although many preparation methods have been reported so far, it is still a great challenge for intelligent packaging films with both excellent mechanical properties and very high sensitivity. Herein, we report a facile method to prepare performance-enhanced pectin (PC)/carboxymethyl cellulose sodium (CMC)/anthocyanins (ACNs)/metal ion films by crosslinking with metal ions (Zn2+, Mg2+ and Ca2+). Cross-linking reaction between PC/CMC and metal ions significantly improved water resistance and mechanical properties of composite films (P < 0.05). Even at high relative humidity (RH = 84 %), cross-linking of Ca2+, Mg2+, and Zn2+ significantly increased the tensile index of the films by 1.37, 1.41, and 1.52 times (P < 0.05), respectively. Moreover, the complexation of metal ions/polysaccharides with ACNs reduced the decomposition rate of ACNs, improved the storage stability and antioxidant capacity of ACNs, and also increased the sensitivity of the colorimetric response of the indicator films in monitoring shrimp freshness. Thus, with this high sensitivity, the Red, Green and Blue (RGB) values of the films can be determined using a mobile phone application to monitor shrimp safety in real time. These results suggest that ACNs-metal cation-polysaccharide composite films have great potential for smart packaging applications.

Comparison of the activation level in the sensorimotor cortex between motor point and proximal nerve bundle electrical stimulation.

Objective.Neuromuscular electrical stimulation (NMES) is widely used for motor function rehabilitation in stroke survivors. Compared with the conventional motor point (MP) stimulation, the stimulation at the proximal segment of the peripheral nerve (PN) bundles has been demonstrated to have multiple advantages. However, it is not known yet whether the PN stimulation can increase the cortical activation level, which is crucial for motor function rehabilitation.Approach.The current stimuli were delivered transcutaneously at the muscle belly of the finger flexors and the proximal segment of the median and ulnar nerves, respectively for the MP and PN stimulation. The stimulation intensity was determined to elicit the same contraction levels between the two stimulation methods in 18 healthy individuals and a stroke patient. The functional near-infrared spectroscopy and the electromyogram were recorded to compare the activation pattern of the sensorimotor regions and the target muscles.Main Results.For the healthy subjects, the PN stimulation induced significantly increased concentration of the oxygenated hemoglobin in the contralateral sensorimotor areas, and enhanced the functional connectivity between brain regions compared with the MP stimulation. Meanwhile, the compound action potentials had a smaller amplitude and the H-reflex became stronger under the PN stimulation, indicating that more sensory axons were activated in the PN stimulation. For the stroke patient, the PN stimulation can elicit finger forces and induce activation of both the contralateral and ipsilateral motor cortex.Conclusions. Compared with the MP stimulation, the PN stimulation can induce more cortical activation in the contralateral sensorimotor areas possibly via involving more activities in the central pathway.Significance.This study demonstrated the potential of the PN stimulation to facilitate functional recovery via increasing the cortical activation level, which may help to improve the outcome of the NMES-based rehabilitation for motor function recovery after stroke.

Classification of Action Potentials With High Variability Using Convolutional Neural Network for Motor Unit Tracking.

The reliable classification of motor unit action potentials (MUAPs) provides the possibility of tracking motor unit (MU) activities. However, the variation of MUAP profiles caused by multiple factors in realistic conditions challenges the accurate classification of MUAPs. The goal of this study was to propose an effective method based on the convolutional neural network (CNN) to classify MUAPs with high levels of variation for MU tracking. MUAP variation was added artificially in the synthetic electromyogram (EMG) signals and was induced by changing the forearm postures in the experimental study. The proposed overlapped-segment-wise EMG decomposition method and the spike-triggered averaging method were combined to obtain the MUAP waveform samples of individual MUs in the experimental study, and the MUAP profile classification performance was tested. Since the ground-truth of MU discharge activities was known for the synthetic EMG, the MU tracking performance was further verified by mimicking the tracking procedure of MU discharge activities and the spike consistency with the true spike trains was tested in the simulation study. The conventional MUAP similarity index (SI)-based method was also performed as comparison. For both the experimental and the synthetic EMG signals, the CNN-based method significantly improved the MUAP tracking performance compared with the conventional SI-based method manifested as a higher classification accuracy (93.3%±5.4% vs 56.2%±13.9%) in the experimental study or higher spike consistency (71.1%±10.2% vs 29.2%±11.0%) in the simulation study with a smaller variation. These results demonstrated the efficiency and robustness of the proposed method to distinguish MUAPs with large variations accurately. Further development of the proposed method can promote the study on the physiological and pathological changes of the neuromuscular system where tracking MU activities is needed.

Kinematic difference and asymmetries during level walking in adolescent patients with different types of mild scoliosis.

BACKGROUND: Adolescent idiopathic scoliosis (AIS), three-dimensional spine deformation, affects body motion. Previous research had indicated pathological gait patterns of AIS. However, the impact of the curve number on the walking mechanism has not been established. Therefore, this study aimed to compare the gait symmetry and kinematics in AIS patients with different curve numbers to healthy control. RESULTS: In the spinal region, double curves AIS patients demonstrated a smaller sagittal symmetry angle (SA) and larger sagittal convex ROM of the trunk and lower spine than the control group. In the lower extremities, the single curve patients showed a significantly reduced SA of the knee joint in the frontal plane, while the double curves patients showed a significantly reduced SA of the hip in the transverse plane. CONCLUSION: The curve number indeed affects gait symmetry and kinematics in AIS patients. The double curves patients seemed to adopt a more "careful walking" strategy to compensate for the effect of spinal deformation on sensory integration deficits. This compensation mainly occurred in the sagittal plane. Compared to double curves patients, single curve patients unitized a similar walking strategy with healthy subjects.

Comparison of plugin and redundant marker sets to analyze gait kinematics between different populations.

BACKGROUND: Gait model consists of a marker set and a segment pose estimation algorithm. Plugin marker set and inverse kinematic algorithm (IK.) are prevalent in gait analysis, especially musculoskeletal motion analysis. Adding extra markers for the plugin marker set could increase the robustness to marker misplacement, motion artifacts, and even markers occlusion. However, how the different marker sets affect the gait analysis's kinematic output is unclear. Therefore, this study aims to investigate the effect of marker sets on the kinematic output during level walking in different populations. RESULTS: In all three planes, there are significant differences (P < 0.05) between marker sets in some kinematic variables at the hip, knee, and ankle. In different populations, the kinematic variables that show significant differences varied. When comparing the kinematic differences between populations using the two marker sets separately, the range of motion (ROM) of hip flexion was only found to be a significant difference using the redundant marker set, while the peak internal rotation at the knee was only found a significant difference using plugin marker set. In addition, the redundant marker set shows less intra-subject variation than the plugin marker set. CONCLUSION: The findings in this study demonstrate the importance of marker set selection since it could change the result when comparing the kinematic differences between populations. Therefore, it is essential to increase the caution in explaining the result when using different marker sets. It is crucial to use the same marker set, and the redundant marker set might be a better choice for gait analysis.

Application of serum peptidomics for Parkinson's disease in SNCA-A30P mice.

Intraneuronal inclusions of alpha-synuclein (α-synuclein, α-syn) are commonly found in the brain of patients with Parkinson's disease (PD). The pathogenesis of the abundant α-syn protein in the blood has been extensively studied to understand its properties better. In recent years, peptidome analysis has received increasing attention. In this study, we identified and analyzed serum peptides from wild-type (WT) and the (Thy-1)-h[A30P] alpha-synuclein transgenic mice (SNCA-A30P mice) using liquid chromatography-tandem mass spectrometry (LC-MS/MS). One thousand eight hundred fifty-six peptides from 771 proteins were analyzed. Among them, 151 peptides from 107 proteins were significantly differentially expressed. The glycoprotein VI platelet pathway (GP6) was the pathway's most significant differentially expressed signaling pathway. Cleavage sites of the differentially expressed peptides may reflect protease distribution and activity. We selected the most significantly differentially expressed peptide, VGGDPI, and found that it contained cathepsin K (Ctsk) and trypsin-1 cleavage sites, suggesting that Ctsk and trypsin-1 may be key peptidases in PD. α-syn is a protein associated with the pathogenesis of PD. mutations in several genes, including SNCA, which encodes α-syn, are associated with the development of PD. Bioinformatics analysis of the physiological pathways related to SNCA genes and apoptosis genes found the five most markedly up-regulated proteins: formin homology 2 domain-containing 1 (FHOD1), insulin receptor substrate 1(IRS1), TRPM8 channel-associated factor 1 (TCAF1), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and interleukin-16 (IL-16). Therefore, the differentially expressed peptides in the five precursor protein domains may be potential bioactive peptides associated with α-syn and apoptosis. This study provides a validated peptidomics profile of SNCA-A30P mice and identifies potentially bioactive peptides linked to α-syn and apoptosis.

The effects of walking aids on shoulder joint kinematics in older persons: an initial study.

BACKGROUND: Many older persons with degenerative physical functions use walking aids to improve their ambulation ability. The aim of this study was to investigate the effects of walking aids with different configurations on shoulder joint motion in older persons. METHODS: The 3D motion capture system VICON was applied to collect data on gait parameters and shoulder motion characteristics of 6 older persons walking either independently or with the assistance of a footed walking frame and a wheeled walking frame. The different effects of walking aids on gait parameters and the shoulder joint motion of older individuals were quantitatively analyzed. RESULTS: The gait parameters of the older individuals changed significantly when they used walking frames to assist walking. Compared to independent walking, the range of motion of the shoulder joint was reduced by 79.92% in flexion when walking with a wheeled walking frame. Meanwhile, the range of motion in flexion, extension, and external rotation increased by 76.04%, 85.55%, and 110.99%, respectively, when walking with a footed walking frame. CONCLUSION: The motion characteristics of shoulder joints in older persons were significantly affected by using different walking aids. These changes in shoulder joint motion characteristics will lead to potential diseases related to the shoulder musculoskeletal system. These findings are beneficial to determine a walking aid for older people.

Independent prognostic value of the congestion and renal index in patients with acute heart failure.

BACKGROUND: Clinical outcomes are poor if patients with acute heart failure (AHF) are discharged with residual congestion in the presence of renal dysfunction. However, there is no single indication to reflect the combined effects of the two related pathophysiological processes. We, therefore, proposed an indicator, congestion and renal index (CRI), and examined the associations between the CRI and one-year outcomes and the incremental prognostic value of CRI compared with the established scoring systems in a multicenter prospective cohort of AHF. METHODS: We enrolled AHF patients and calculated the ratio of thoracic fluid content index divided by estimated glomerular filtration rate before discharge, as CRI. Then we examined the associations between CRI and one-year outcomes. RESULTS: A total of 944 patients were included in the analysis (mean age 63.3 ± 13.8 years, 39.3% women). Compared with patients with CRI ≤ 0.59 mL/min per kΩ, those with CRI > 0.59 mL/min per kΩ had higher risks of cardiovascular death or HF hospitalization (HR = 1.56 [1.13-2.15]) and all-cause death or all-cause hospitalization (HR = 1.33 [1.01-1.74]). CRI had an incremental prognostic value compared with the established scoring system. CONCLUSIONS: In patients with AHF, CRI is independently associated with the risk of death or hospitalization within one year, and improves the risk stratification of the established risk models.

Exosomal hsa_circ_000200 as a potential biomarker and metastasis enhancer of gastric cancer via miR-4659a/b-3p/HBEGF axis.

BACKGROUND: Exosome, a component of liquid biopsy, loaded protein, DNA, RNA and lipid gradually emerges as biomarker in tumors. However, exosomal circRNAs as biomarker and function mechanism in gastric cancer (GC) are not well understood. METHODS: Differentially expressed circRNAs in GC and healthy people were screened by database. The identification of hsa_circ_000200 was verified by RNase R and sequencing, and the expression of hsa_circ_000200 was evaluated using qRT-PCR. The biological function of hsa_circ_000200 in GC was verified in vitro. Western blot, RIP, RNA fluorescence in situ hybridization, and double luciferase assay were utilized to explore the potential mechanism of hsa_circ_000200. RESULTS: Hsa_circ_000200 up-regulated in GC tissue, serum and serum exosomes. Hsa_circ_000200 in serum exosomes showed better diagnostic ability than that of tissues and serum. Combined with clinicopathological parameters, its level was related to invasion depth, TNM staging, and distal metastasis. Functionally, knockdown of hsa_circ_000200 inhibited GC cells proliferation, migration and invasion in vitro, while its overexpression played the opposite role. Importantly, exosomes with up-regulated hsa_circ_000200 promoted the proliferation and migration of co-cultured GC cells. Mechanistically, hsa_circ_000200 acted as a "ceRNA" for miR-4659a/b-3p to increase HBEGF and TGF-ß/Smad expression, then promoted the development of GC. CONCLUSIONS: Our findings suggest that hsa_circ_000200 promotes the progression of GC through hsa_circ_000200/miR-4659a/b-3p/HBEGF axis and affecting the expression of TGF-ß/Smad. Serum exosomal hsa_circ_000200 may serve as a potential biomarker for GC.

The Effects of Pedestrian Environment on Ambulation with a Walking Frame in Elderly Individuals: A Survey and Experimental Study.

Understanding the effects of sloped roads in the pedestrian environment on the body during ambulation with a walking frame can help design friendlier living environments for elderly individuals. A survey of the characteristics of walking frames used in different pedestrian environments was investigated in five communities, and a controlled study of the effects of a sloped road on a subject with different walking frames was carried out as foundational research in the laboratory. A synchronous acquisition system consisting of a wireless motion capture module and a physiological information recording module was applied to collect data on the motion of the shoulder joint and skin conductance response (SCR) of fingers in one participant. Force data were collected from sensors placed on the four legs of the walking frame. The experimental data obtained during different tasks were quantitatively analyzed. Compared to flat ground, the shoulder joint rotated in the opposite direction in horizontal and internal/external planes when using a wheeled walking frame on an uphill road, and the supportive force decreased on both uphill and downhill roads. The range of motion of the shoulder joint reduced and the direction of the shoulder joint motion changed when using a footed walking frame on both uphill and downhill roads. Additionally, the peak value of the supportive force on the uphill road appeared in the first 50% of the gait cycle, which was earlier than in the other cases. In addition, walking on the uphill road with a walking frame had a maximum SCR value, which means a greater impact of psychological arousal. Biomechanics of the shoulder joint and psychological arousal are closely related to the ease of walking on a sloped road with a walking frame. These findings are beneficial for designing more appropriate environments for elderly individuals who walk with aids.

Incidence, risk factors, and consequences of emergence delirium after elective brain tumor resection.

BACKGROUND: Emergence delirium (ED) is a common phenomenon occurring in the recovery period. The aim of this study was to investigate the incidence, risk factors, and consequences of ED in adults after elective brain tumor resection. METHODS: We retrospectively analyzed the data of a prospective cohort performed in a tertiary university hospital. Adult patients admitted to the intensive care unit (ICU) immediately after elective brain tumor resection were consecutively enrolled. Level of consciousness was assessed using the Richmond Agitation-Sedation Scale and ED was assessed using the Confusion Assessment Method for the ICU. Risk factors for ED were determined by multivariable logistic regression. RESULTS: A total of 659 patients met the inclusion criteria, of which 41 patients with coma were excluded. Among the remaining 618 patients, 131 (21.2%) developed ED. Independent risk factors for ED were: age, education level, use of anticholinergic and mannitol, Glasgow Coma Score and arterial partial pressure of oxygen postoperatively, postoperative pain, malignant tumor, and frontal approach craniotomy. ED was associated with increased postoperative delirium, longer length of hospital stay, and higher hospitalization costs. There was no significant difference in the neurological function deficits (modified Rankin Scale score) between ED and non-ED groups. CONCLUSIONS: ED has a high incidence and is associated with poor outcomes in adults after elective brain tumor resection. Early screening and prevention for ED should be established in perioperative management of this population.

Correlation Between Gait and Near-Infrared Brain Functional Connectivity Under Cognitive Tasks in Elderly Subjects With Mild Cognitive Impairment.

Older adults with mild cognitive impairment (MCI) have a high risk of developing Alzheimer's disease. Gait performance is a potential clinical marker for the progression of MCI into dementia. However, the relationship between gait and brain functional connectivity (FC) in older adults with MCI remains unclear. Forty-five subjects [MCI group, n = 23; healthy control (HC) group, n = 22] were recruited. Each subject performed a walking task (Task 01), counting backward-walking task (Task 02), naming animals-walking task (Task 03), and calculating-walking task (Task 04). The gait parameters and cerebral oxygenation signals from the left prefrontal cortex (LPFC), right prefrontal cortex (RPFC), left motor cortex (LMC), right motor cortex (RMC), left occipital leaf cortex (LOL), and right occipital leaf cortex (ROL) were obtained simultaneously. Wavelet phase coherence was calculated in two frequency intervals: low frequency (interval I, 0.052-0.145 Hz) and very low frequency (interval II, 0.021-0.052 Hz). Results showed that the FC of RPFC-RMC is significantly lower in interval I in Task 03 compared with that in Task 02 in the MCI group (p = 0.001). Also, the right relative symmetry index (IDpsR) is significantly lower in Task 03 compared with that in Task 02 (p = 0.000). The IDpsR is positively correlated with the FC of RPFC-RMC in interval I in the MCI group (R = 0.205, p = 0.041). The gait symmetry such as left relative symmetry index (IDpsL) and IDpsR is significantly lower in the dual-task (DT) situation compared with the single task in the two groups (p < 0.05). The results suggested that the IDpsR might reflect abnormal change in FC of RPFC-RMC in interval I in the MCI population during Task 03. The gait symmetry is affected by DTs in both groups. The findings of this study may have a pivotal role in the early monitoring and intervention of brain dysfunction among older adults with MCI.

Association of preoperative frailty with postoperative delirium after elective brain tumor resection: Retrospective analysis of a prospective cohort.

BACKGROUND: Preoperative frailty is associated with poor outcomes in major surgery. Postoperative delirium is common after neurosurgery. To date, the association of preoperative frailty with postoperative delirium after neurosurgery has not been established. We aimed to determine the association between preoperative frailty and postoperative delirium in patients undergoing elective brain tumor resection. METHODS: We retrospectively analyzed the data of a prospective cohort, consecutively enrolling adult patients admitted to the intensive care unit after elective craniotomy for brain tumor resection under general anesthesia in a tertiary hospital in China from March 1, 2017 to February 2, 2018. Preoperative frailty was evaluated using the modified frailty index. The primary outcome was postoperative delirium, assessed using the Confusion Assessment Method for the Intensive Care Unit. Univariate and multivariable regression analyses were performed to examine the association. RESULTS: 659 patients met inclusion criteria for our analysis. There were 398 (60.4%) non-frail (modified frailty index = 0), 237 (36.0%) pre-frail (modified frailty index = 1-2), and 24 (3.6%) frail (modified frailty index ≥ 3) patients. Of these, 124 (18.8%) developed postoperative delirium. In adjusted analyses, frailty was independently associated with postoperative delirium (odds ratio 1.7, 95% confidence interval 1.0-2.7, P = .032). Frail patients had longer length of hospital stay and higher total costs than non-frail patients. CONCLUSION: Preoperative frailty is associated with postoperative delirium, length of hospital stay, and total costs in patients undergoing elective brain tumor resection. Preoperative frailty assessment and appropriate management strategies should be involved in the perioperative management of postoperative delirium.

Investigation of Correction Trajectory Considering Bone End-Plane Orientation and the Shortest Growth Path.

External fixators are widely used in orthopedics for the purposes of fracture reduction and bone deformity correction. Since there is nonlinear mapping between the joint and operation spaces of the external fixator, bone correction trajectories achieved by equally adjusting the length of the struts in the joint space are usually not the trajectories that clinicians expect. Based on two different adjustment strategies, a new strategy considering bone end-plane orientation and the shortest growth path is proposed to plan the position and orientation of the distal bone end, which is named joint adjustment for equal bone distraction. By proposing the inverse and forward kinematic solutions of an Ortho-SUV external fixator, correction trajectories with three different adjustment strategies are generated and compared, and the bone shapes for each strategy are modeled. The results obtained by comparative analysis indicate that a smooth and uniformly spaced linear trajectory can be acquired using the new adjustment strategy, which can avoid bone end interference and maintain an optimal distraction rate of 1.03 mm/day, with only a 3% error compared with 1 mm/day. The new strategy can perform multiplane corrections simultaneously and is beneficial for stimulating the growth of new bone tissue.

Configuration design and correction ability evaluation of a novel external fixator for foot and ankle deformity treated by U osteotomy.

As a basic osteotomy technique, U osteotomy can be applied for certain complex foot and ankle deformities. Gradual correction cases using Ilizarov apparatus and Taylor Spatial Frame have been reported. This paper proposes a novel parallel distraction apparatus for U osteotomy (PDA-Uos) to supplement the correction equipment for surgeon. Designed with an adjustable structure, the PDA-Uos can adopt different assembly shapes (joint connection points). However, the influence of the change in assembly shape on interference-free workspace and self-structural performance of the external fixator have received little attention. To address this issue and enhance the selection of the most suitable assembly shape for patient, an algorithm to obtain the interference-free workspace of different assembly shapes is proposed based on the inverse position solution of the PDA-Uos. Additionally, correction ability indices are defined according to the requirements of accurately controlled motion and high structural stiffness of the external fixator along the correction path. The results of simulation cases indicate that the interference-free workspace and the correction ability vary according to the assembly shape and thus the proposed method can be used to select an assembly shape with sufficient workspace and the best correction ability before performing correction for a given patient. Graphical abstract.

The effect of prosthetic alignment on hip and knee joint kinetics in individuals with transfemoral amputation.

BACKGROUND: Prosthetic alignment directly affects the biomechanical loading in individuals with lower-limb amputation, and improper alignment may be contribute to the high incidence of hip and knee osteoarthritis (OA). The biomechanical changes caused by different alignments should be considered in prosthetic fitting. However, the quantitative effect of alignment on the kinetic features of individuals with transfemoral amputation remains unclear. RESEARCH QUESTION: As important kinetics indexes, how are the hip and knee joint moments affected by prosthetic alignment in individuals with transfemoral amputation? METHODS: Gait tests of ten individuals with transfemoral amputation and fifteen individuals without amputation (control group) were performed. Several prosthetic alignment conditions were used, including the so-called "initial" alignment and eight malalignments. The hip and knee joint moments of the individuals with amputation under various alignments were analysed and compared with those of the control group. Statistical analyses were performed by one-way ANOVA, repeated measure multivariate ANOVA, and paired t tests. RESULTS: The peaks and impulses of the hip abductor and external rotator moments on the residual side were significantly smaller than those of the control group (P < 0.0056). The peaks of the hip extensor, adductor and external rotator moments on the intact side were significantly larger than those on the residual side (P < 0.05). Alignment significantly affected the intact hip and knee joint moments for each individual with amputation (P < 0.00625), but there was no consistent effect among individuals. SIGNIFICANCE: The significantly larger hip joint moment on the intact side of individuals with transfemoral amputation may be associated with the higher incidence of hip OA on the intact side. Alignment significantly affects the hip and knee joint moments of each individual with transfemoral amputation, but the individual responses to alignment changes are different. This situation may imply that the method for optimizing alignment should be personalized.

[Dynamic simulation and experimental verification of human body turning over in supine position].

The tilted supine position has been evaluated to be one of the significantly effective approaches to prevent bedsore of the patients in the bedridden state. Thus, it has deeply positive influences that in view of dynamics this study explores how the position works. Based on the anatomical theories, this study formulates the human dynamic model. Furthermore, the dynamic simulation of three usual postures in tilted supine position including lying on back, lying with one knee bent and lying with the upper and lower limb on one side lifted is carried out. Therefore, the changes of the three driving forces named as chest force, waist force and thigh force in the tilted supine position can be observed. In order to verify the validity of this simulation, this study obtains the electromyogram measurements of ectopectoralis, external obliques and thigh muscles which are respectively close to the chest, waist and thigh by conducting the human force measurements experiment. The result revealed that in terms of range and trend, the experimental data and simulation's data were consistent. In conclusion, the changes of these muscles in the supine position movements are researched efficiently by both this experiment and the dynamic simulation. Besides, the result is crucially key to find the mechanism of human's tilted supine position movements.

MicroRNA-335/ID4 dysregulation predicts clinical outcome and facilitates leukemogenesis by activating PI3K/Akt signaling pathway in acute myeloid leukemia.

MircoRNA-335 (miR-335) has been reported as a significant cancer-associated microRNA, which was often epigenetically silenced and acted as a tumor suppressor gene in diverse human solid tumors. Conversely, recent studies show that miR-335 overexpression was identified in both adult and pediatric acute myeloid leukemia (AML), suggesting that it might play an oncogenic role of miR-335 in AML. However, the role of miR-335 during leukemogenesis remains to be elucidated. MiR-335/ID4 expression was detected by real-time quantitative PCR and/or western blot. Survival analysis was performed to explore the association between miR-335/ID4 expression and the prognosis, and further validated by public databases. Gain-of-function experiments determined by cell proliferation, apoptosis, and differentiation were conducted to investigate the biological functions of miR-335/ID4. Herein, we found that miR-335 expression, independent of its methylation, was significantly increased and negatively correlated with reduced ID4 expression in AML. Moreover, aberrant miR-335/ID4 expression independently affected chemotherapy response and leukemia-free/overall survival in patients with AML. Gain-of-function experiments in vitro showed the oncogenic role of miR-335 by affecting cell apoptosis and proliferation in AML, and could be rescued by ID4 restoration. Mechanistically, we identified and verified that miR-335/ID4 contributed to leukemogenesis through activating PI3K/Akt signaling pathway. Collectively, aberrant miR-335/ID4 expression was an independent prognostic biomarker in AML. MiR-335/ID4 dysregulation facilitated leukemogenesis through the activation of PI3K/Akt signaling pathway.

Reduced protocadherin17 expression in leukemia stem cells: the clinical and biological effect in acute myeloid leukemia.

BACKGROUND: Leukemia stem cell (LSC)-enriched genes have been shown to be highly prognostic in acute myeloid leukemia (AML). However, the prognostic value of tumor suppressor genes (TSGs) that are repressed early in LSC remains largely unknown. METHODS: We compared the public available expression/methylation profiling data of LSCs with that of hematopoietic stem cells (HSCs), in order to identify potential tumor suppressor genes in LSC. The prognostic relevance of PCDH17 was analyzed on a cohort of 173 AML patients from The Cancer Genome Atlas (TCGA), and further validated in three independent cohorts (n = 339). RESULTS: We identified protocadherin17 (PCDH17) and demonstrated that it was significantly down-regulated and hypermethylated in LSCs compared with HSCs. Our analyses of primary AML patient samples also confirmed these deregulations. Clinically, low PCDH17 expression was associated with female sex (P = 0.01), higher WBC (P < 0.0001), higher percentages of blasts in bone marrow (BM) and peripheral blood (PB) (P = 0.04 and < 0.001, respectively), presence of FLT3-internal tandem duplications (P = 0.002), mutated NPM1 (P = 0.02), and wild-type TP53 (P = 0.005). Moreover, low PCDH17 expression predicted worse overall survival (OS) in four independent cohorts as well as in the molecularly defined subgroups of AML patients. In multivariable analyses, low PCDH17 expression retained independent prognostic value for OS. Biologically, PCDH17 expression-associated gene signatures were characterized by deregulations of EMT- and Wnt pathway-related genes. CONCLUSIONS: PCDH17 gene was silenced by DNA methylation in AML. Low PCDH17 expression is associated with distinct clinical and biological features and improves risk stratification in patients with AML.