Cerebellar Brain Inhibition Is Associated With the Severity of Cervical Dystonia.

PURPOSE: Cerebellar connectivity is thought to be abnormal in cervical dystonia (CD) and other dystonia subtypes, based on evidence from imaging studies and animal work. The authors investigated whether transcranial magnetic stimulation-induced cerebellar brain inhibition (CBI), a measure of cerebellar efficiency at inhibiting motor outflow, is abnormal in patients with CD and/or is associated with clinical features of CD. Because of methodological heterogeneity in CBI reporting, the authors deployed additional controls to reduce potential sources of variability in this study. METHODS: Cerebellar brain inhibition was applied in 20 CD patients and 14 healthy control subjects. Cerebellar brain inhibition consisted of a cerebellar conditioning stimulus delivered at four different interstimulus intervals (ISIs) before a test stimulus delivered to hand muscle representation in the motor cortex. The average ratio of conditioned to unconditioned motor evoked potential was computed for each ISI. Cervical dystonia clinical severity was measured using the Toronto Western Spasmodic Torticollis Rating Scale. Control experiments involved neuronavigated transcranial magnetic stimulation, neck postural control in patients, and careful screening for noncerebellar pathway inhibition via cervicomedullary evoked potentials. RESULTS: There was no difference between CBI measured in healthy control subjects and CD patients at any of the four ISIs; however, CBI efficiency was significantly correlated with worsening CD clinical severity at the 5 ms ISI. CONCLUSIONS: Cerebellar brain inhibition is a variable measure in both healthy control subjects and CD patients; much of this variability may be attributed to experimental methodology. Yet, CD severity is significantly associated with reduced CBI at the 5 ms ISI, suggestive of cerebello-thalamo-cortical tract dysfunction in this disorder.

Robotic mapping of motor cortex in children with perinatal stroke and hemiparesis.

Brain stimulation combined with intensive therapy may improve hand function in children with perinatal stroke-induced unilateral cerebral palsy (UCP). However, response to therapy varies and underlying neuroplasticity mechanisms remain unclear. Here, we aimed to characterize robotic motor mapping outcomes in children with UCP. Twenty-nine children with perinatal stroke and UCP (median age 11 ± 2 years) were compared to 24 typically developing controls (TDC). Robotic, neuronavigated transcranial magnetic stimulation was employed to define bilateral motor maps including area, volume, and peak motor evoked potential (MEP). Map outcomes were compared to the primary clinical outcome of the Jebsen-Taylor Test of Hand Function (JTT). Maps were reliably obtained in the contralesional motor cortex (24/29) but challenging in the lesioned hemisphere (5/29). Within the contralesional M1 of participants with UCP, area and peak MEP amplitude of the unaffected map were larger than the affected map. When comparing bilateral maps within the contralesional M1 in children with UCP to that of TDC, only peak MEP amplitudes were different, being smaller for the affected hand as compared to TDC. We observed correlations between the unaffected map when stimulating the contralesional M1 and function of the unaffected hand. Robotic motor mapping can characterize motor cortex neurophysiology in children with perinatal stroke. Map area and peak MEP amplitude may represent discrete biomarkers of developmental plasticity in the contralesional M1. Correlations between map metrics and hand function suggest clinical relevance and utility in studies of interventional plasticity.

Influence of perioperative probiotics supplement on short-term clinical outcomes in gastric cancer patients receiving neoadjuvant chemotherapy combined with radical gastrectomy: a prospective study / 中华消化外科杂志

Objective:To investigate the influence of perioperative probiotics supplement on short-term clinical outcomes in gastric cancer patients receiving neoadjuvant chemotherapy combined with radical gastrectomy.Methods:The prospective randomized controlled study was conducted. The clinicopathological data of 80 patients who underwent neoadjuvant chemotherapy combined with radical gastrectomy in the Affiliated Hospital of Qingdao University from July 2020 to September 2021 were selected. Based on random number table, patients were allocated into two groups. Patients undergoing perioperative probiotics supplement were allocated into the experiment group, and patients undergoing perioperative conventional treatment were allocated into the control group, respectively. Observation indicators: (1) grouping situations of the enrolled patients; (2) intraoperative situations; (3) follow-up and postoperative situations; (4) inflammation related hematological indexes. Follow-up was conducted using telephone interview and outpatient examina-tion to detect postoperative complications and startup of adjuvant chemotherapy up to October 31,2021. Measurement data with normal distribution were represented as Mean± SD, and comparison between groups was conducted using the independent sample t test. Measurement data with skewed distribution were represented as M(range), and comparison between groups was conducted using the Mann-Whitney U test. Count data were described as absolute numbers, and comparison between groups was performed using the chi-square test or Fisher exact probability. Comparison of ordinal data was analyzed using the Mann-Whitney U test. Repeated measurement data were analyzed by the repeated ANOVA or generalized estimating equation. Results:(1) Grouping situations of the enrolled patients. A total of 80 patients were selected for eligibility. There were 51 males and 29 females, aged 64(42-80)years. Of the 80 patients, there were 40 patients in the experiment group and 40 patients in the control group, respectively. (2) Intraoperative situations. All patients in the experiment group and the control group underwent radical gastrectomy successfully. Cases with yield pathologic TNM (ypTNM) stage 0, stage Ⅰ, stage Ⅱ, stage Ⅲ after neoadjuvant chemotherapy, cases undergoing laparoscopic radical gastrectomy or Da Vinci robotic radical gastrectomy, the operation time, the volume of intraoperative blood loss, cases undergoing digestive tract recons-truction as Billroth Ⅱ anastomosis or Roux-en-Y anastomosis were 2, 7, 15, 13, 19, 21,205(180-240)minutes, 50(30-60)mL, 6, 34 in the experiment group, versus 4, 6, 12, 16, 23, 17, 218(190-251)minutes, 50(43-60)mL, 11, 29 in the control group, showing no significant difference in the above indicators between the two groups ( U=683.00, χ2=0.80, U=668.00, 681.00, χ2=1.87, P>0.05). (3) Follow-up and postoperative situations. All the 80 patients were followed up for 1 month after surgery. Cases with postoperative infectious complications were 6 in the experiment group, versus 15 in the control group, showing a significant difference between the two groups ( χ2=5.23, P<0.05). The application of antimicrobial agent, time to postoperative first flatus, time to postoperative first defecation, time to tolerance of solid food, duration of postoperative hospital stay, time to postopera-tive startup of adjuvant chemotherapy were 3(3-6)doses, 53(49-66)hours, 72(62-82)hours, (72±18)hours, 6.0(5.5-7.0)days, 26.0(25.0-28.0)days in the experiment group, versus 6(3-10)doses, 66(60-88)hours, 94(82-112)hours, (107±23)hours, 7.0(6.4-8.3)days, 30.0(28.0-33.0)days in the control group, showing significant differences in the above indicators between the two groups ( U=471.50, 432.00, 343.50, t=-7.62, U=411.50, 319.50, P<0.05). (4) Inflam-mation related hematological indexes. ① The white blood cell counts before surgery and at postoperative day 1, 3, 5 were (5.6±1.4)×10 9/L, (9.9±3.2)×10 9/L, (7.7±2.6)×10 9/L, (6.8±1.8)×10 9/L in the experiment group, versus (6.1±1.9)×10 9/L, (12.3±2.9)×10 9/L, (9.7±3.6)×10 9/L, (7.8±2.7)×10 9/L in the control group, meeting the mauchly′s test of sphericity ( χ2=4.17, P>0.05). Results of intrasubject effect test showed that there were significant differences in the time effect, intervention effect and interaction effect of white blood cell counts between the two groups ( F=106.61, 10.45, 4.56, P<0.05). ② The neutrophilic granulocyte percentages before surgery and at postoperative day 1, 3, 5 were 55%±10%, 76%±11%, 73%±9%, 69%±9% in the experiment group, versus 56%±9%, 84%±5%, 79%±8%, 74%±9% in the control group, not meeting the mauchly′s test of sphericity ( χ2=16.63, P<0.05). Results of multi-variate test showed that there were significant differences in the time effect, intervention effect and interaction effect of neutrophilic granulocyte percentages between the two groups ( F=92.42, 11.46, 5.55, P<0.05). ③ The levels of C-reactive protein before surgery and at postoperative day 1, 3, 5 were 1.35(1.15-1.97)mg/L, 14.94(8.24-21.22)mg/L, 33.39(13.02-66.02)mg/L, 18.36(8.27-60.43)mg/L in the experiment group, versus 1.62(0.97-2.27)mg/L, 24.03(10.42-36.52)mg/L, 81.66(31.20-116.76)mg/L, 46.84(28.30-80.26)mg/L in the control group, not meeting the normal distribution. Results of generalized estimation equation test showed that there were significant differences in the time effect, intervention effect and interaction effect of levels of C-reactive protein between the two groups ( Waldχ2=145.74, 9.48, 9.90, P<0.05). ④ The levels of procalcitonin before surgery and at postoperative day 1, 3, 5 were 0.02(0.02-0.04)μg/L, 0.08(0.06-0.12)μg/L, 0.12(0.07-0.21)μg/L, 0.09(0.06-0.15)μg/L in the experiment group, versus 0.02(0.02-0.04)μg/L, 0.14(0.07-0.71)μg/L, 0.35(0.14-0.71)μg/L, 0.24(0.10-0.48)μg/L in the control group, not meeting the normal distribution. Results of generalized estimation equation test showed that there were signifi-cant differences in the time effect, intervention effect and interaction effect of levels of procalcitonin between the two groups ( Waldχ2=62.88, 14.71, 18.33, P<0.05). Conclusion:Perioperative supple-ment of probiotics can reduce the incidence of postoperative infectious com-plications and the application of antimicrobial agent, promote recovery of gastrointestinal function, reduce the level of inflammation related indexes, shorten the duration of postoperative hospital stay and the time to postoperative startup of chemotherapy in patients undergoing neoadjuvant chemotherapy combined with radical gastrectomy.

Preoperative Transcranial Direct Current Stimulation in Glioma Patients: A Proof of Concept Pilot Study.

Background: Transcranial direct current stimulation (tDCS) has been used extensively in patient populations to facilitate motor network plasticity. However, it has not been studied in patients with brain tumors. We aimed to determine the feasibility of a preoperative motor training and tDCS intervention in patients with glioma. In an exploratory manner, we assessed changes in motor network connectivity following this intervention and related these changes to predicted electrical field strength from the stimulated motor cortex. Methods: Patients with left-sided glioma (n=8) were recruited in an open label proof of concept pilot trial and participated in four consecutive days of motor training combined with tDCS. The motor training consisted of a 60-min period where the subject learned to play the piano with their right hand. Concurrently, they received 40 min of 2 mA anodal tDCS of the left motor cortex. Patients underwent task and resting state fMRI before and after this intervention. Changes in both the connectivity of primary motor cortex (M1) and general connectivity across the brain were assessed. Patient specific finite element models were created and the predicted electrical field (EF) resulting from stimulation was computed. The magnitude of the EF was extracted from left M1 and correlated to the observed changes in functional connectivity. Results: There were no adverse events and all subjects successfully completed the study protocol. Left M1 increased both local and global connectivity. Voxel-wide measures, not constrained by a specific region, revealed increased global connectivity of the frontal pole and decreased global connectivity of the supplementary motor area. The magnitude of EF applied to the left M1 correlated with changes in global connectivity of the right M1. Conclusion: In this proof of concept pilot study, we demonstrate for the first time that tDCS appears to be feasible in glioma patients. In our exploratory analysis, we show preoperative motor training combined with tDCS may alter sensorimotor network connectivity. Patient specific modeling of EF in the presence of tumor may contribute to understanding the dose-response relationship of this intervention. Overall, this suggests the possibility of modulating neural networks in glioma patients.

Case studies in neuroscience: deep brain stimulation changes upper limb cortical motor maps in dystonia.

Deep brain stimulation of the globus pallidus pars interna (GPi-DBS) is an effective treatment for primary dystonia; however, its therapeutic mechanism is poorly understood. Because improvement is gradual, GPi-DBS treatment likely involves short- and long-term mechanisms. Abnormal plasticity resulting in somatotopic reorganization is involved in the development of dystonia and has been proposed as a possible mechanism for this gradual improvement, yet it has not been directly investigated. We hypothesized that GPi-DBS will lead to progressive changes in the cortical representations (motor maps) of upper limb muscles. Neuronavigated robotic transcranial magnetic stimulation was used to map the cortical representation of five upper limb muscles in six healthy controls and a 45-yr-old female cervical dystonia patient before (Pre) and at four time points (Post5 to Post314), 5 to 314 days after GPi-DBS. Motor map area and volume decreased in all muscles following GPi-DBS, while changes in overlap and center of gravity distance between muscles were variable. Despite these motor map changes, only dystonic tremor improved after a year of DBS; neck position worsened slightly. These preliminary findings suggest that GPi-DBS may reduce the cortical representation and excitability of upper limb muscles in dystonia and that these changes can occur without clinical improvement.NEW & NOTEWORTHY Neuronavigated robotic transcranial magnetic stimulation was used to investigate changes in upper limb muscle representation in a cervical dystonia patient before and at four time points up to 314 days after globus pallidus pars interna deep brain stimulation (GPi-DBS). GPi-DBS altered excitability and motor cortical representation of upper limb muscles; however, these changes were not associated with clinical improvement.

Impact of Peritumoral Edema During Tumor Treatment Field Therapy: A Computational Modelling Study.

BACKGROUND: Tumor treatment fields (TTFie-lds) are an approved adjuvant therapy for glioblastoma (GBM). The magnitude of applied electrical field has been shown to be related to the anti-tumoral response. However, peritumoral edema may result in shunting of electrical current around the tumor, thereby reducing the intra-tumoral electric field. In this study, we systematically address this issue with computational simulations. METHODS: Finite element models are created of a human head with varying amounts of peritumoral edema surrounding a virtual tumor. The electric field distribution was simulated using the standard TTFields electrode montage. Electric field magnitude was extracted from the tumor and related to edema thickness. Two patient specific models were created to confirm these results. RESULTS: The inclusion of peritumoral edema decreased the average magnitude of the electric field within the tumor. In the model considering a frontal tumor and an anterior-posterior electrode configuration, ≥6 mm of peritumoral edema decreased the electric field by 52%. In the patient specific models, peritumoral edema decreased the electric field magnitude within the tumor by an average of 26%. The effect of peritumoral edema on the electric field distribution was spatially heterogenous, being most significant at the tissue interface between edema and tumor. CONCLUSIONS: The inclusion of peritumoral edema during TTFields modelling may have a dramatic effect on the predicted electric field magnitude within the tumor. Given the importance of electric field magnitude for the anti-tumoral effects of TTFields, the presence of edema should be considered both in future modelling studies and when planning TTField therapy.

Theta-Burst Stimulation for Cognitive Enhancement in Parkinson's Disease With Mild Cognitive Impairment: A Randomized, Double-Blind, Sham-Controlled Trial.

Background: Mild cognitive impairment is a common non-motor symptom of Parkinson's disease (PD-MCI) and has minimal treatment options. Objective: In this double-blind, randomized, sham-controlled trial, we assessed the effect of repeated sessions of intermittent theta-burst stimulation over the left dorsolateral prefrontal cortex on cognition and brain connectivity in subjects with PD-MCI. Methods: Forty-one subjects were randomized to receive real (n = 21) or sham stimulation (n = 20). All subjects underwent neuropsychological assessments before, 1 day, and 1 month after stimulation. Subjects also underwent resting-state functional magnetic resonance imaging before and 48 h after stimulation. The primary outcome was the change in the cognitive domain (executive function, attention, memory, language, and visuospatial abilities) z-scores across time. Results: There was an insignificant effect on cognitive domain z-scores across time when comparing real with sham stimulation and correcting for multiple comparisons across cognitive domains (p > 0.05 Bonferroni correction). However, the real stimulation group demonstrated a trend toward improved executive functioning scores at the 1-month follow-up compared with sham (p < 0.05 uncorrected). After real stimulation, the connectivity of the stimulation site showed decreased connectivity to the left caudate head. There was no change in connectivity within or between the stimulation network (a network of cortical regions connected to the stimulation site) and the striatal network. However, higher baseline connectivity between the stimulation network and the striatal network was associated with improved executive function scores at 1 month. Conclusions: These results suggest that intermittent theta-burst stimulation over the dorsolateral prefrontal cortex in subjects with PD-MCI has minimal effect on cognition compared with sham, although there were trends toward improved executive function. This intervention may be more effective in subjects with higher baseline connectivity between the stimulation network and the striatal network. This trial supports further investigation focusing on executive function and incorporating connectivity-based targeting. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT03243214.

Treatment of Persistent Post-Traumatic Headache and Post-Concussion Symptoms Using Repetitive Transcranial Magnetic Stimulation: A Pilot, Double-Blind, Randomized Controlled Trial.

Persistent post-traumatic headache (PTH) after mild traumatic brain injury is one of the most prominent and highly reported persistent post-concussion symptoms (PPCS). Non-pharmacological treatments, including non-invasive neurostimulation technologies, have been proposed for use. Our objective was to evaluate headache characteristics at 1 month after repetitive transcranial magnetic stimulation (rTMS) treatment in participants with PTH and PPCS. A double-blind, randomized, sham-controlled, pilot clinical trial was performed on 20 participants (18-65 years) with persistent PTH (International Classification of Headache Disorders, 3rd edition) and PPCS (International Classification of Diseases, Tenth Revision). Ten sessions of rTMS therapy (10 Hz, 600 pulses, 70% resting motor threshold amplitude) were delivered to the left dorsolateral pre-frontal cortex. The primary outcome was a change in headache frequency or severity at 1 month post-rTMS. Two-week-long daily headache diaries and clinical questionnaires assessing function, PPCS, cognition, quality of life, and mood were completed at baseline, post-treatment, and at 1, 3, and 6 months post-rTMS. A two-way (treatment × time) mixed analyisis of variance indicated a significant overall time effect for average headache severity (F(3,54) = 3.214; p = 0.03) and a reduction in headache frequency at 1 month post-treatment (#/2 weeks, REAL -5.2 [standard deviation {SD} = 5.8]; SHAM, -3.3 [SD = 7.7]). Secondary outcomes revealed an overall time interaction for headache impact, depression, post-concussion symptoms, and quality of life. There was a significant reduction in depression rating in the REAL group between baseline and 1 month post-treatment, with no change in the SHAM group (Personal Health Questionnaire-9; REAL, -4.3 [SD = 3.7[ p = 0.020]; SHAM, -0.7 [SD = 4.7; p = 1.0]; Bonferroni corrected). In the REAL group, 60% returned to work whereas only 10% returned in the SHAM group (p = 0.027). This pilot study demonstrates an overall time effect on headache severity, functional impact, depression, PPCS, and quality of life after rTMS treatment in participants with persistent PTH; however, findings were below clinical significance thresholds. There was a 100% response rate, no dropouts, and minimal adverse effects, warranting a larger phase II study. Clinicaltrials.gov: NCT03691272.

METTL1 overexpression is correlated with poor prognosis and promotes hepatocellular carcinoma via PTEN.

RNA methylation is emerging as an important regulator of gene expression. Dysregulation of methyltransferase that is essential for RNA modification contributes to the development and progression of human cancers. Here we show that methyltransferase-like 1 (METTL1) is upregulated in hepatocellular carcinoma (HCC) and exhibits oncogenic activities via PTEN/AKT signaling pathway. High expression of METTL1 is correlated with larger tumor size, higher serum AFP level, tumor vascular invasion, and poor prognosis in two independent cohorts containing 892 patients with HCC. Multivariate analyses suggest METTL1 as an independent factor for unfavorable overall survival. In vitro studies demonstrate that METTL1 overexpression promotes cell proliferation and migration, whereas its knockdown results in opposite phenotypes. Gene set enrichment analysis (GSEA) indicates PTEN pathway is activated in patients with low METTL1 expression. Ectopic expression of PTEN or inhibition of AKT activity significantly attenuates the METTL1-mediated malignant phenotypes. In clinical samples, METTL1 expression is reversely associated with PTEN expression. Combination of low METTL1 expression and high PTEN expression is significantly correlated with overall survival, more so than either METTL1 or PTEN expression alone. Collectively, our data suggest that METTL1 serves as a promising prognostic biomarker and that targeting METTL1/PTEN axis may provide therapeutic potential in HCC intervention. KEY MESSAGES: METTL1 is upregulated in HCC and correlated with poor outcomes. METTL1 promotes cell proliferation and migration in HCC. METTL1 exerts oncogenic activities via suppression of PTEN signaling.

Theta band high definition transcranial alternating current stimulation, but not transcranial direct current stimulation, improves associative memory performance.

Associative memory (AM) deficits are common in neurodegenerative disease and novel therapies aimed at improving these faculties are needed. Theta band oscillations within AM networks have been shown to be important for successful memory encoding and modulating these rhythms represents a promising strategy for cognitive enhancement. Transcranial alternating current stimulation (TACS) has been hypothesized to entrain and increase power of endogenous brain rhythms. For this reason, we hypothesized that focal delivery of theta band electrical current, using high-definition TACS, would result in improved AM performance compared to sham stimulation or transcranial direct current stimulation (TDCS). In this pilot study, 60 healthy subjects were randomized to receive high definition TACS, high definition TDCS, or sham stimulation delivered to the right fusiform cortex during encoding of visual associations. Consistent with our hypothesis, improved AM performance was observed in the TACS group, while TDCS had no effect. However, TACS also resulted in improved correct rejection of never seen items, reduced false memory, and reduced forgetting, suggesting the effect may not be specific for AM processes. Overall, this work informs strategies for improving associative memory and suggests alternating current is more effective than direct current stimulation in some contexts.

Network basis of the dysexecutive and posterior cortical cognitive profiles in Parkinson's disease.

BACKGROUND: The dual syndrome hypothesis of cognitive impairment in PD suggests that two cognitive profiles exist with distinct pathological mechanisms and a differential risk for further cognitive decline. How these profiles relate to network dysfunction has never been explicitly characterized. OBJECTIVE: First, to assess intranetwork functional connectivity while considering global connectivity, and second, to relate network connectivity with measures of the dysexecutive and posterior cortical profiles. METHODS: Eighty-two subjects with idiopathic PD and 37 age-matched controls underwent resting-state functional MRI and comprehensive neuropsychological assessment. Intranetwork and global connectivity was compared between groups. Measures of the dysexecutive and posterior cortical profiles were related to network connectivity while considering demographic and disease-related covariates. RESULTS: PD subjects show decreased connectivity within several cortical networks. However, only the sensorimotor network displayed a loss of connectivity independent of the observed decreased global connectivity. The dysexecutive factor was independently related to increased motor severity, less education, and decreased connectivity in the sensorimotor network. The posterior cortical factor was related to increased age, less education, decreased connectivity in the central executive network, as well as increased connectivity in the temporal network. CONCLUSIONS: Our results provide evidence supporting a network-specific process of degeneration in the sensorimotor network which contributes to the dysexecutive cognitive profile. In contrast, connectivity of the temporal and central executive network is related to the posterior cortical profile, representing a distinct network signature of this syndrome. © 2019 International Parkinson and Movement Disorder Society.

Both 50 and 30 Hz continuous theta burst transcranial magnetic stimulation depresses the cerebellum.

The cerebellum is implicated in the pathophysiology of numerous movement disorders, which makes it an attractive target for noninvasive neurostimulation. Continuous theta burst stimulation (cTBS) can induce long lasting plastic changes in human brain; however, the efficacy of different simulation protocols has not been investigated at the cerebellum. Here, we compare a traditional 50-Hz and a modified 30-Hz cTBS protocols at modulating cerebellar activity in healthy subjects. Seventeen healthy adults participated in two testing sessions where they received either 50-Hz (cTBS50) or 30-Hz (cTBS30) cerebellar cTBS. Cerebellar brain inhibition (CBI), a measure of cerebello-thalamocortical pathway strength, and motor evoked potentials (MEP) were measured in the dominant first dorsal interosseous muscle before and after (up to ~ 40 min) cerebellar cTBS. Both cTBS protocols induced cerebellar depression, indicated by significant reductions in CBI (P < 0.001). No differences were found between protocols (cTBS50 and cTBS30) at any time point (P = 0.983). MEP amplitudes were not significantly different following either cTBS protocol (P = 0.130). The findings show cerebellar excitability to be equally depressed by 50-Hz and 30-Hz cTBS in heathy adults and support future work to explore the efficacy of different cerebellar cTBS protocols in movement disorder patients where cerebellar depression could provide therapeutic benefits.

Salinomycin induces apoptosis and differentiation in human acute promyelocytic leukemia cells.

At present, acute promyelocytic leukemia (APL) is the most curable form of acute myeloid leukemia and can be treated using all-trans retinoic acid and arsenic trioxide. However, the current treatment of APL is associated with some issues such as drug toxicity, resistance and relapse. Therefore, other strategies are necessary for APL treatment. In the present study, we investigated the effects of salinomycin (SAL) on APL cell lines NB4 and HL-60 and determined its possible mechanisms. We observed that SAL inhibited cell proliferation, as determined by performing Cell Counting Kit-8 (CCK-8) assay, promoted cell apoptosis, as determined based on morphological changes, and increased Annexin V/propidium iodide (PI)-positive apoptotic cell percentage. Treatment with SAL increased Bax/Bcl-2 and cytochrome c expression and activated caspase-3 and -9, thus leading to poly(ADP-ribose) polymerase (PARP) cleavage and resulting in cell apoptosis. These results revealed that SAL induced cell apoptosis through activation of the intrinsic apoptosis pathway. The present study is the first to show that SAL induced the differentiation of APL cells, as determined based on mature morphological changes, increased NBT-positive cell and CD11b-positive cell percentages and increased CD11b and C/EBPß levels. Furthermore, SAL decreased the expression of ß-catenin and its targets cyclin D1 and C-myc. Results of immunofluorescence analysis revealed that SAL markedly decreased the ß-catenin level in both the nucleus and cytoplasm. Combination treatment with SAL and IWR-1, an inhibitor of Wnt signaling, synergistically triggered SAL-induced differentiation of APL cells. These findings demonstrated that SAL effectively inhibited cell proliferation accompanied by induction of apoptosis and promotion of cell differentiation by inhibiting Wnt/ß-catenin signaling. Collectively, these data revealed that SAL is a potential drug for treatment of APL.

Effects of Transcranial Direct-Current Stimulation on Neurosurgical Skill Acquisition: A Randomized Controlled Trial.

BACKGROUND: Recent changes in surgical training environments may have limited opportunities for trainees to gain proficiency in skill. Complex skills such as neurosurgery require extended periods of training. Methods to enhance surgical training are required to overcome duty-hour restrictions, to ensure the acquisition of skill proficiency. Transcranial direct-current stimulation (tDCS) can enhance motor skill learning, but is untested in surgical procedural training. We aimed to determine the effects of tDCS on simulation-based neurosurgical skill acquisition. METHODS: Medical students were trained to acquire tumor resection skills using a virtual reality neurosurgical simulator. The primary outcome of change in tumor resection was scored at baseline, over 8 repetitions, post-training, and again at 6 weeks. Participants received anodal tDCS or sham over the primary motor cortex. Secondary outcomes included changes in brain resected, resection effectiveness, duration of excessive forces (EF) applied, and resection efficiency. Additional outcomes included tDCS tolerability. RESULTS: Twenty-two students consented to participate, with no dropouts over the course of the trial. Participants receiving tDCS intervention increased the amount of tumor resected, increased the effectiveness of resection, reduced the duration of EF applied, and improved resection efficiency. Little or no decay was observed at 6 weeks in both groups. No adverse events were documented, and sensation severity did not differ between stimulation groups. CONCLUSIONS: The addition of tDCS to neurosurgical training may enhance skill acquisition in a simulation-based environment. Trials of additional skills in high-skill residents, and translation to nonsimulated performance are needed to determine the potential utility of tDCS in surgical training.

Verteporfin Inhibits Cell Proliferation and Induces Apoptosis in Human Leukemia NB4 Cells without Light Activation.

Background and Aims: Verteporfin (VP), clinically used in photodynamic therapy for neovascular macular degeneration, has recently been proven a suppressor of yes-associated protein (YAP) and has shown potential in anticancer treatment. However, its anti-human leukemia effects in NB4 cells remain unclear. In this study, we investigated the effects of VP on proliferation and apoptosis in human leukemia NB4 cells. Methods: NB4 cells were treated with VP for 24 h. The effects of VP on cell proliferation were determined using a Cell-Counting Kit-8 assay (CCK-8) assay and colony forming assay. Apoptosis and cell cycle were evaluated by flow cytometry (FCM). The protein levels were detected by western blot. Results: We found that VP inhibited the proliferation of NB4 cells in a concentration and time-dependent manner. FCM analysis showed that VP induced apoptosis in a concentration dependent manner and that VP treatment led to cell cycle arrest at G0/G1 phase. Moreover, VP significantly decreased the protein expression of YAP, p-YAP, Survivin, c-Myc, cyclinD1, p-ERK, and p-AKT. In addition, VP increased the protein expression of cleaved caspase3, cleaved PARP, Bax, and p-p38 MAPK. Conclusions: VP inhibited the proliferation and induced apoptosis in NB4 cells.

Effect of YAP Inhibition on Human Leukemia HL-60 Cells.

Background: Yes-associated protein (YAP), the nuclear effector of the Hippo pathway, is a candidate oncoprotein and participates in the progression of various malignancies. However, few reports have examined the effect of YAP inhibition in human leukemia HL-60 cells. Methods: We examined the effects of YAP knockdown or inhibition using short hairpin RNA (shRNA) or verteporfin (VP), respectively. Western blot assays were used to determine the expression levels of YAP, Survivin, cyclinD1, PARP, Bcl-2, and Bax. Cell proliferation was assessed using the cell counting kit (CCK-8) assay. Cell cycle progression and apoptosis were evaluated by flow cytometry, and apoptotic cell morphology was observed by Hoechst 33342 staining. Results: Knockdown or inhibition of YAP led to cell cycle arrest at the G0/G1 phase and increased apoptosis, inhibited cell proliferation, increased levels of Bax and cleaved PARP, and decreased levels of PARP, Bcl-2, Survivin, and cyclinD1. Moreover, Hoechst 33342 staining revealed increased cell nuclear fragmentation. Conclusion: Collectively, these results show that inhibition of YAP inhibits proliferation and induces apoptosis in HL-60 cells. Therefore, a novel treatment regime involving genetic or pharmacological inhibition of YAP could be established for acute promyelocytic leukemia.

Shikonin suppresses proliferation and induces apoptosis in human leukemia NB4 cells through modulation of MAPKs and c­Myc.

Acute promyelocytic leukemia (APL) is a special subtype of acute myeloid leukemia that responds to treatment with all­trans retinoic acid and arsenic trioxide. However, severe side effects and drug resistance limit the effectiveness of these treatments. Hence, new drugs for APL are required urgently. Shikonin, an active naphthoquinone derived from the Chinese medical herb Zi Cao exerts antitumor activity in several cancers. In the present study, the effects of shikonin on proliferation and apoptosis in NB4 cells, as well as related mechanisms were assessed. Treatment of NB4 cells with shikonin inhibited proliferation in a concentration­ and time­dependent manner. The cell cycle was arrested in the G1 phase. NB4 cells treated with shikonin exhibited more apoptosis and higher levels of cleaved caspase­3 and poly ADP­ribose polymerase than control cells. Western blotting results demonstrated that the expression of p­p38 mitogen­activated protein kinase (p­p38MAPK) and p­c­Jun N­terminal kinase (p­JNK) was increased significantly by shikonin treatment, while the expression of p­ERK and c­Myc was decreased. In summary, these findings indicated that shikonin inhibited cell proliferation and induced apoptosis partly through modulation of the MAPKs and downregulation of c­Myc.

Tool-Tissue Interaction Forces in Brain Arteriovenous Malformation Surgery.

OBJECTIVE: Surgical resection of a brain arteriovenous malformation (AVM) poses a technical challenge because of the fragility and number of small feeding and draining vessels around the nidus. Acquiring knowledge of the optimal force applied to such tissue is important in surgical performance and education. METHODS: A force-sensing bipolar forceps was developed through installation of strain gauge sensors, and force profiles were obtained from 2 AVM surgeries. The force data associated with vessel injury, unsuccessful trial, was compared with that from successful trials. Receiver operating curve analysis was used for determining optimal force threshold and evaluating the discriminative accuracy of measurement. RESULTS: Force data from 519 trials was collected, of which 16 (3.1%) were unsuccessful. The mean and maximum forces in successful trials were 0.23 ± 0.06 N and 0.35 ± 0.11 N compared with unsuccessful trials of 0.33 ± 0.05 N and 0.53 ± 0.11 N, respectively (P < 0.001). There was a strong association of mean and maximum force peaks with unsuccessful trials as reflected by the area under the curve of 0.91 and 0.87, respectively. Threshold analysis showed that the rate of unsuccessful trials and error forces tended to increase with surgical time. CONCLUSIONS: Excessive force at the tool tip may result in injury to fragile vessels during AVM surgery. A quantifiable metric through force sensing instruments can detect and predict the occurrence of such injury. Such an instrument may be ideal for resident training and evaluation.

Effects of LG268 on Cell Proliferation and Apoptosis of NB4 Cells.

AIMS: To investigate the effect of LG100268 (LG268) on cell proliferation and apoptosis in NB4 cells. METHODS: NB4 cells were treated with LG268 for 24 h or 48 h. The effect of LG268 on cell proliferation was assessed by the CCK-8 assay and colony-forming assay. Apoptosis and cell cycle were evaluated by flow cytometry. The protein expression levels of Survivin, PARP, c-Myc, cyclin D1, ERK, p-ERK, p38 MAPK, and p- p38 MAPK were detected by western blot. RESULTS: We found that LG268 inhibited the proliferation of NB4 cells in a dose-dependent manner. Flow cytometry analysis showed that LG268 accelerated apoptosis in NB4 cells in a time- dependent manner and that LG268 treatment led to cell cycle arrest at G0/G1 phase. Moreover, LG268 significantly decreased the protein levels of Survivin, c-Myc, and cyclinD1. Cleaved PARP was observed in the LG268 treatment group but not in the control group. In addition, LG268 increased the phosphorylation level of p38 MAPK and decreased the phosphorylation level of ERK. CONCLUSIONS: LG268 inhibited cell proliferation and promoted cell apoptosis in NB4 cells.