AIM： To evaluate the synergistic targeting and killing of human hepatocellular carcinoma （HCC） cells lacking p53 by the oncolytic autonomous parvovirus （PV） H-1 and chemotherapeutic agents and its ...dependence on functional promyelocytic leukemia protein （PML）. METHODS： The role of p53 and PML in regulating cytotoxicity and gene transfer mediated by wild-type （wt） PV H-1 were explored in two pairs of isogenic human hepatoma cell lines with different p53 status. Furthermore, H-1 PV infection was combined with cytostatic drug treatment. RESULTS： While the HCC cells with different p53 status studied were all susceptible to H-1 PV-induced apoptosis, the cytotoxicity of H-1 PV was morepronounced in p53-negative than in p53-positive cells. Apoptosis rates in p53-negative cell lines treated by genotoxic drugs were further enhanced by a treatment with H-1 PV. In flow cytometric analyses, H-1 PV infection resulted in a reduction of the mitochondrial transmembrane potential. In addition, H-1 PV cells showed a significant increase in PML expression. Knocking down PML expression resulted in a striking reduction of the level of H-1 PV infected tumor cell death. CONCLUSION： H-1 PV is a suitable agent to circumvent the resistance of p53-negative HCC cells to genotoxic agents, and it enhances the apoptotic process which is dependent on functional PML. Thus, H-1 PV and its oncolytic vector derivatives may be considered as therapeutic options for HCC, particularly for p53-negative tumors.
To investigate the association between Big Five personality factors and three dimensions of parenting-warmth, behavioral control, and autonomy support- the authors conducted meta-analyses using 5,853 ...parent-child dyads that were included in 30 studies. Effect sizes were significant and robust across mother and father reports and across assessment methods of parenting (self-report versus observations) but were generally small in magnitude. Higher levels of Extraversion, Agreeableness, Conscientiousness, and Openness and lower levels of Neuroticism were related to more warmth and behavioral control, whereas higher levels of Agreeableness and lower levels of Neuroticism were related to more autonomy support. Several factors moderated the relationship between specific personality dimensions and parenting: child and parental age, reliability of observational assessment of parenting behavior, and study design. Taken together, these results indicate that personality can be seen as an inner resource that affects parenting.
Modern high throughput brain wide profiling techniques for cells and their morphology, connectivity, and other properties, make the use of reference atlases with 3D coordinate frameworks essential. ...However, anatomical location of observations made in microscopic sectional images from rodent brains is typically determined by comparison with 2D anatomical reference atlases. A major challenge in this regard is that microscopic sections often are cut with orientations deviating from the standard planes used in the reference atlases, resulting in inaccuracies and a need for tedious correction steps. Overall, efficient tools for registration of large series of section images to reference atlases are currently not widely available. Here we present QuickNII, a stand-alone software tool for semi-automated affine spatial registration of sectional image data to a 3D reference atlas coordinate framework. A key feature in the tool is the capability to generate user defined cut planes through the reference atlas, matching the orientation of the cut plane of the sectional image data. The reference atlas is transformed to match anatomical landmarks in the corresponding experimental images. In this way, the spatial relationship between experimental image and atlas is defined, without introducing distortions in the original experimental images. Following anchoring of a limited number of sections containing key landmarks, transformations are propagated across the entire series of sectional images to reduce the amount of manual steps required. By having coordinates assigned to the experimental images, further analysis of the distribution of features extracted from the images is greatly facilitated.
BRAFV600E alterations are prevalent across multiple tumors. Here we present final efficacy and safety results of a phase 2 basket trial of dabrafenib (BRAF kinase inhibitor) plus trametinib (MEK ...inhibitor) in eight cohorts of patients with BRAFV600E-mutated advanced rare cancers: anaplastic thyroid carcinoma (n = 36), biliary tract cancer (n = 43), gastrointestinal stromal tumor (n = 1), adenocarcinoma of the small intestine (n = 3), low-grade glioma (n = 13), high-grade glioma (n = 45), hairy cell leukemia (n = 55) and multiple myeloma (n = 19). The primary endpoint of investigator-assessed overall response rate in these cohorts was 56%, 53%, 0%, 67%, 54%, 33%, 89% and 50%, respectively. Secondary endpoints were median duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. Median DoR was 14.4 months, 8.9 months, not reached, 7.7 months, not reached, 31.2 months, not reached and 11.1 months, respectively. Median PFS was 6.7 months, 9.0 months, not reached, not evaluable, 9.5 months, 5.5 months, not evaluable and 6.3 months, respectively. Median OS was 14.5 months, 13.5 months, not reached, 21.8 months, not evaluable, 17.6 months, not evaluable and 33.9 months, respectively. The most frequent (≥20% of patients) treatment-related adverse events were pyrexia (40.8%), fatigue (25.7%), chills (25.7%), nausea (23.8%) and rash (20.4%). The encouraging tumor-agnostic activity of dabrafenib plus trametinib suggests that this could be a promising treatment approach for some patients with BRAFV600E-mutated advanced rare cancers. ClinicalTrials.gov registration: NCT02034110 .
To review the evidence concerning the effects of postoperative exercise interventions on exercise capacity and health-related quality of life following resection for non-small cell lung cancer, and ...to review whether different initiation times of exercise produce different effects on exercise capacity.
Comprehensive literature search of MEDLINE, Embase, CENTRAL, CINAHL and PEDro.
Randomized controlled trials examining the effects of exercise interventions were eligible for inclusion.
Postoperative outcome measurements were extracted and the quality of evidence was graded using Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group.
Four randomized controlled trials were identified involving 262 participants. Short-term follow-up (12-20 weeks) showed significantly higher exercise capacity and physical component of health-related quality of life in the intervention group (standardized mean difference (SMD) 0.48; 95% confidence interval (CI) 0.04-0.93) compared with the control group (SMD 0.50; 95% CI 0.19-0.82). There was no difference between the effect of late- and early-initiated exercise intervention.
Exercise has a small-to-moderate effect at short-term follow-up on exercise capacity and the physical component of health-related quality of life in patients operated for lung cancer. The long-term effects of exercise capacity are unknown. Early-initiated exercise programmes (2 weeks post-operation) did not show an effect on exercise capacity. These findings should be interpreted with caution.
This open-label, phase 1 trial (NCT02316197) aimed to determine the maximum-tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of peposertib (formerly M3814), a DNA-dependent protein kinase ...(DNA-PK) inhibitor in patients with advanced solid tumours. Secondary/exploratory objectives included safety/tolerability, pharmacokinetic/pharmacodynamic profiles and clinical activity.
Adult patients with advanced solid tumours received peposertib 100-200 mg once daily or 150-400 mg twice daily (BID) in 21-day cycles.
Thirty-one patients were included (median age 66 years, 61% male). One dose-limiting toxicity, consisting of mainly gastrointestinal, non-serious adverse events (AEs) and long recovery duration, was reported at 300 mg BID. The most common peposertib-related AEs were nausea, vomiting, fatigue and pyrexia. The most common peposertib-related Grade 3 AEs were maculopapular rash and nausea. Peposertib was quickly absorbed systemically (median T
1.1-2.5 h). The p-DNA-PK/t-DNA-PK ratio decreased consistently in peripheral blood mononuclear cells 3-6 h after doses ≥100 mg. The best overall response was stable disease (12 patients), lasting for ≥12 weeks in seven patients.
Peposertib was well-tolerated and demonstrated modest efficacy in unselected tumours. The MTD was not reached; the RP2D was declared as 400 mg BID. Further studies, mainly with peposertib/chemo-radiation, are ongoing.
NCT02316197.
•Headshake enhances galvanic vestibular stimulation (GVS)-induced nystagmus in healthy participants.•GVS-assisted headshake helps to identify nystagmus response, which can be weak or absent during ...the head-still position.•The procedure reflects the integrity, conductivity, and excitability of vestibular afferents.
To investigate whether a headshake applied during galvanic vestibular stimulation (GVS) can enhance GVS-induced nystagmus in healthy subjects.
In nineteen healthy participants, we evaluated an average slow-phase velocity (aSPV) of nystagmus in a head-still and after the headshake conditions, with/out the bitemporal 2 mA GVS. The GVS was applied also with polarity congruent (supporting) or incongruent (suppressing) to any preexisting spontaneous nystagmus.
The orientation of GVS-induced nystagmus depended on GVS polarity. In the head-still condition, the GVS-induced nystagmus in 14 subjects (74%) for congruent and in 12 subjects (63%) for incongruent GVS. During headshake, we recorded nystagmus in 16 subjects (84%) for congruent and 15 subjects (79%) for incongruent GVS. The aSPV of congruent GVS-induced nystagmus was higher (p = 0.0003) by 1.33 (SE 0.26) deg/s for headshake compared to head-still condition. The aSPV of incongruent GVS also induced higher nystagmus (p = 0.0014) by 1.24 (SE 0.28) deg/s for the headshake condition.
Our study adds a new principle to the knowledge of the central processing of a GVS response in healthy subjects. The GVS-safety profile of current up to 2 mA was sufficient to elicit a significant GVS nystagmus response in a head-still position in 63% and after a headshake in 79%. Compared to the GVS head-still condition, a headshake enhanced the GVS-induced nystagmus more than twice.
The headshake helps to identify GVS-induced nystagmus, which can be weak or absent during the head-still condition.
The objective was to predict insufficient response to 3 months methotrexate (MTX) in DMARD naïve rheumatoid arthritis patients.
A Multivariable logistic regression model of rheumatoid arthritis ...patients starting MTX was developed in a derivation cohort with 285 patients starting MTX in a clinical multicentre, stratified single-blinded trial, performed in seven secondary care clinics and a tertiary care clinic. The model was validated in a validation cohort with 102 patients starting MTX at a tertiary care clinic. Outcome was insufficient response (disease activity score (DAS)28 >3.2) after 3 months of MTX treatment. Clinical characteristics, lifestyle variables, genetic and metabolic biomarkers were determined at baseline in both cohorts. These variables were dichotomized and used to construct a multivariable prediction model with backward logistic regression analysis.
The prediction model for insufficient response in the derivation cohort, included: DAS28>5.1, Health Assessment Questionnaire>0.6, current smoking, BMI>25 kg/m2, ABCB1 rs1045642 genotype, ABCC3 rs4793665 genotype, and erythrocyte-folate<750 nmol/L. In the derivation cohort, AUC of ROC curve was 0.80 (95%CI: 0.73-0.86), and 0.80 (95%CI: 0.69-0.91) in the validation cohort. Betas of the prediction model were transformed into total risk score (range 0-8). At cutoff of ≥4, probability for insufficient response was 44%. Sensitivity was 71%, specificity 72%, with positive and negative predictive value of 72% and 71%.
A prognostics prediction model for insufficient response to MTX in 2 prospective RA cohorts by combining genetic, metabolic, clinical and lifestyle variables was developed and validated. This model satisfactorily identified RA patients with high risk of insufficient response to MTX.
Perineuronal nets (PNNs) are assemblies of extracellular matrix molecules, which surround the cell body and dendrites of many types of neuron and regulate neural plasticity. PNNs are prominently ...expressed around neurons of the deep cerebellar nuclei (DCN), but their role in adult cerebellar plasticity and behavior is far from clear. Here we show that PNNs in the mouse DCN are diminished during eyeblink conditioning (EBC), a form of associative motor learning that depends on DCN plasticity. When memories are fully acquired, PNNs are restored. Enzymatic digestion of PNNs in the DCN improves EBC learning, but intact PNNs are necessary for memory retention. At the structural level, PNN removal induces significant synaptic rearrangements in vivo, resulting in increased inhibition of DCN baseline activity in awake behaving mice. Together, these results demonstrate that PNNs are critical players in the regulation of cerebellar circuitry and function.
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