Modulation of the activity of histone lysine methyltransferases and demethylases by curcumin analog in leukaemia cells.

Curcumin is a known epigenetic modifier that demonstrated antitumor effect in different types of cancer. The poor solubility and metabolic stability are major drawbacks that limit its development as an antitumor agent. Dimethoxycurcumin (DMC) is a more soluble and stable curcumin analog. In this study, we compared the effect of both drugs on a variety of histone posttranslational modifications and on the activity of histone lysine methyltransferase (HKMTs) and demethylase (HKDMTs) enzymes that target the H3K4, H3K9 and H3K27 epigenetic marks. Mass spectrometry was used to quantitate the changes in 95 histone posttranslational modifications induced by curcumin or DMC. The effect of both drugs on the enzymatic activity of HKMTs and HKDMs was measured using an antibody-based assay. Mass spectrometry analysis showed that curcumin and DMC modulated several histone modifications. Histone changes were not limited to lysine methylation and acetylation but included arginine and glutamine methylation. Only few histone modifications were similarly changed by both drugs. On the contrary, the effect of both drugs on the activity of HKMTs and HKDMs was very similar. Curcumin and DMC inhibited the HKMTs enzymes that target the H3K4, H3K9 and H3K27 marks and increased the activity of the HKDMs enzymes LSD1, JARID and JMJD2. In conclusion, we identified novel enzymatic targets for both curcumin and DMC that support their use and development as epigenetic modifiers in cancer treatment. The multiple targets modulated by both drugs could provide a therapeutic advantage by overcoming drug resistance development.

Differential Histone Posttranslational Modifications Induced by DNA Hypomethylating Agents.

INTRODUCTION: The prototype DNA hypomethylating agents 5-azacytidine (5AC) and decitabine (DAC) are currently FDA-approved for treatment of blood and bone marrow disorders like myelodysplastic syndrome. 5AC and DAC are considered similar drugs and were shown to induce histone modifications that modulate gene expression. The aim of this study is to compare the effect of both drugs on histone acetylation and methylation at multiple histone amino acids residues. METHODS: Mass spectrometry was used to compare the effect of both drugs on 95 different histone posttranslational modifications (PTMs) in leukemia cells. ChIP-Seq analysis was used to compare the impact of both drugs on the genome-wide acetylation of the H3K9 mark using primary leukemia cells from six de-identified AML patients. RESULTS: Both DAC and 5AC induced histone PTMs in different histone isoforms like H1.4, H2A, H3, H3.1, and H4. Changes in both histone methylation and acetylation were observed with both drugs; however, there were distinct differences in the histone modifications induced by the two drugs. Since both drugs were shown to increase the activity of the HDAC SIRT6 previously, we tested the effect of 5AC on the acetylation of H3K9, the physiological substrate SIRT6, using ChIP-Seq analysis and compared it to the previously published DAC-induced changes. Significant H3K9 acetylation changes (P< .05) were detected at 925 genes after 5AC treatment vs only 182 genes after DAC treatment. Nevertheless, the gene set modified by 5AC was different from that modified by DAC with only ten similar genes modulated by both drugs. CONCLUSION: Despite similarity in chemical structure and DNA hypomethylating activity, 5AC and DAC induced widely different histone PTMs and considering them interchangeable should be carefully evaluated. The mechanism of these histone PTM changes is not clear and may involve modulation of the activity or the expression of the enzymes inducing histone PTMs.

Dynamics of Inelastic and Reactive Collisions of 16O(3P) with 15N18O.

The dynamics of O(3P) + NO collisions were investigated at a collision energy of ⟨Ecoll⟩ = 84.0 kcal mol-1 with the use of a crossed molecular beams apparatus employing a rotatable mass spectrometer detector. This experiment was performed with beams of 16O atoms and isotopically labeled 15N18O molecules to enable the products of reactive and inelastic scattering to be distinguished. Three scattering pathways were observed: inelastic scattering (16O + 15N18O), O-atom exchange (18O + 15N16O), and O-atom abstraction (18O16O + 15N). All product channels exhibited a preponderance of forward scattering, but scattering over a broad angular range was also observed for all products. For inelastic scattering, an average of 90% of the collision energy is retained in the translation of 16O and 15N18O. On the other hand, for O-atom exchange (which also leads to O + NO products), the collision energy is partitioned roughly evenly between the translation of 18O + 15N16O and the internal excitation of 15N16O. The available energy for O-atom abstraction is significantly lower than the collision energy because of the endoergicity of this reaction, but the available energy is again roughly evenly partitioned between the translation of 18O16O + 15N and the internal excitation of the molecular (O2) product. The relative yields of the three scattering pathways were determined to be 0.751 for inelastic scattering, 0.220 for O-atom exchange, and 0.029 for O-atom abstraction.

Identification of the inhibitor of growth protein 4 (ING4) as a potential target in prostate cancer therapy.

INhibitor of Growth protein 4 (ING4) is a potential chromatin modifier that has been implicated in several cancer-related processes. However, the role of ING4 in prostate cancer (PC) is largely unknown. This study aimed to assess ING4's role in global transcriptional regulation in PC cells to identify potential cellular processes associated with ING4 loss. RNA-Seq using next-generation sequencing (NGS) was used to identify altered genes in LNCaP PC cells following ING4 depletion. Ingenuity pathways analysis (IPA®) was applied to the data to highlight candidates, ING4-regulated pathways, networks and cellular processes. Selected genes were validated using RT-qPCR. RNA-Seq of LNCaP cells revealed a total of 159 differentially expressed genes (fold change ≥ 1.5 or ≤ - 1.5, FDR ≤ 0.05) following ING4 knockdown. RT-qPCR used to validate the expression level of selected genes was in agreement with RNA-Seq results. Key genes, unique pathways, and biological networks were identified using IPA® analysis. This is the first report of global gene regulation in PC cells by ING4. The resultant differential expression profile revealed the potential role of ING4 in PC pathogenesis possibly through modulation of key genes, pathways and biological networks that are central drivers of the disease. Collectively, these findings shed light on a novel transcriptional regulator of PC that ultimately may influence the disease progression and as a potential target in the disease therapy.

Clinical and laboratory characteristics in juvenile-onset systemic lupus erythematosus across age groups.

BACKGROUND: Systemic lupus erythematous (SLE) is a systemic autoimmune/inflammatory condition. Approximately 15-20% of patients develop symptoms before their 18th birthday and are diagnosed with juvenile-onset SLE (JSLE). Gender distribution, clinical presentation, disease courses and outcomes vary significantly between JSLE patients and individuals with adult-onset SLE. This study aimed to identify age-specific clinical and/or serological patterns in JSLE patients enrolled to the UK JSLE Cohort Study. METHODS: Patient records were accessed and grouped based on age at disease-onset: pre-pubertal (≤7 years), peri-pubertal (8-13 years) and adolescent (14-18 years). The presence of American College of Rheumatology (ACR) classification criteria, laboratory results, disease activity [British Isles Lupus Assessment Group (BILAG) and Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2 K) scores] and damage [Systemic Lupus International Collaborating Clinics (SLICC) damage index] were evaluated at diagnosis and last follow up. RESULTS: A total of 418 JSLE patients were included in this study: 43 (10.3%) with pre-pubertal disease onset; 240 (57.4%) with peri-pubertal onset and 135 (32.3%) were diagnosed during adolescence. At diagnosis, adolescent JSLE patients presented with a higher number of ACR criteria when compared with pre-pubertal and peri-pubertal patients [pBILAG2004 scores: 9(4-20] vs. 7(3-13] vs. 7(3-14], respectively, p = 0.015] with increased activity in the following BILAG domains: mucocutaneous (p = 0.025), musculoskeletal (p = 0.029), renal (p = 0.027) and cardiorespiratory (p = 0.001). Furthermore, adolescent JSLE patients were more frequently ANA-positive (p = 0.034) and exhibited higher anti-dsDNA titres (p = 0.001). Pre-pubertal individuals less frequently presented with leukopenia (p = 0.002), thrombocytopenia (p = 0.004) or low complement (p = 0.002) when compared with other age groups. No differences were identified in disease activity (pBILAG2004 score), damage (SLICC damage index) and the number of ACR criteria fulfilled at last follow up. CONCLUSIONS: Disease presentations and laboratory findings vary significantly between age groups within a national cohort of JSLE patients. Patients diagnosed during adolescence exhibit greater disease activity and "classic" autoantibody, immune cell and complement patterns when compared with younger patients. This supports the hypothesis that pathomechanisms may vary between patient age groups.

Exploring the perspectives of dermatology undergraduates with an escape room game.

BACKGROUND: A UK dermatology curricula review has suggested that undergraduate delivery relies on lectures and is subject to clinical and staffing pressures. Many UK undergraduate students feel less than adequately prepared to manage dermatological conditions, and misconceptions about dermatology are common. Educators have called for innovative solutions, including small group teaching. Escape rooms are games requiring teams to solve puzzles to escape from a room. AIM: To assess the impact of an escape room game on perceptions of dermatology among undergraduate medical students. METHODS: Students were invited to an escape room to consolidate lessons taught in a previous lecture. Students were first asked to complete a questionnaire about their preferred learning environments, perceptions of dermatology and confidence in content. Following the escape room event, these questions were revisited. Focus groups were then held to explore themes raised. RESULTS: In total, 16 students took part in the escape room sessions and in 3 focus groups. Feedback was strongly positive, with 100% of students expressing 'strongly agree' on whether they enjoyed the session. Qualitative data were coded for themes of accessibility, variety of taught content and awareness. The majority (94%) of students stated the escape room made them want to experience more dermatology. CONCLUSION: Prejudices about dermatology exist among medical students, and may act as a barrier to perceived accessibility to the specialty. Escape rooms can provide a shift to a more learner-centred approach, which may aid in combating these negative perceptions. They may act as an enjoyable means of consolidating lecture-based and clinical teaching, and require minimal resources.

Outcomes following mycophenolate mofetil versus cyclophosphamide induction treatment for proliferative juvenile-onset lupus nephritis.

BACKGROUND: Juvenile-onset systemic lupus erythematosus (JSLE) is more severe than adult-onset disease, including more lupus nephritis (LN). Despite differences in phenotype/pathogenesis, treatment is based upon adult trials. This study aimed to compare treatment response, damage accrual, time to inactive LN and subsequent flare, in JSLE LN patients treated with mycophenolate mofetil (MMF) versus intravenous cyclophosphamide (IVCYC). METHODS: UK JSLE Cohort Study participants, ≤16 years at diagnosis, with ≥4 American College of Rheumatology criteria for SLE, with class III or IV LN, were eligible. Mann-Whitney U tests, Fisher's exact test and Chi-squared tests were utilized for statistical analysis. RESULTS: Of the patients, 34/51 (67%) received MMF, and 17/51 (33%) received IVCYC. No significant differences were identified at 4-8 and 10-14 months post-renal biopsy and last follow-up, in terms of renal British Isles Lupus Assessment Grade scores, urine albumin/creatinine ratio, serum creatinine, ESR, anti-dsDNA antibody, C3 levels and patient/physician global scores. Standardized Damage Index scores did not differ between groups at 13 months or at last follow-up. Inactive LN was attained 262 (141-390) days after MMF treatment, and 151 (117-305) days following IVCYC ( p = 0.17). Time to renal flare was 451 (157-1266) days for MMF, and 343 (198-635) days for IVCYC ( p = 0.47). CONCLUSION: This is the largest study to date investigating induction treatments for proliferative LN in children, demonstrating comparability of MMF and IVCYC.

Guillain-Barré syndrome in a patient with neuropsychiatric systemic lupus erythematosus.

Guillain-Barré syndrome is a rare manifestation of neuropsychiatric systemic lupus erythematosus (SLE). Clinical and electrophysiological features of Guillain-Barré syndrome in patients with SLE are different from those in patients without SLE. There is considerable variation in the management and prognosis. We present a patient with Guillain-Barré syndrome and SLE and review the recent knowledge on the various manifestations of neuropsychiatric SLE.

Renal infarction due to lupus vasculopathy.

In the ISN/RPS 2003 classification of lupus nephritis (LN) renal vascular lesions are not mentioned. We present a patient with postpartum lupus vasculopathy. The renal biopsy in our patient showed concentric intimal thickening with narrowed lumen. No inflammatory changes were found. It also revealed immunoglobulin and complement deposition on the wall of the arteriole. These changes indicate lupus vasculopathy. The glomeruli revealed diffuse proliferative glomerulonephritis, with wire loops and cellular crescent in one glomerulus. The patient showed improvement with immunosuppression.

Transcriptome Analysis of Invasive Plants in Response to Mineral Toxicity of Reclaimed Coal-Mine Soil in the Appalachian Region.

Efficient postmining reclamation requires successful revegetation. By using RNA sequencing, we evaluated the growth response of two invasive plants, goutweed (Aegopodium podagraria L.) and mugwort (Artemisia vulgaris), grown in two Appalachian acid-mine soils (MS-I and -II, pH ∼ 4.6). Although deficient in macronutrients, both soils contained high levels of plant-available Al, Fe and Mn. Both plant types showed toxicity tolerance, but metal accumulation differed by plant and site. With MS-I, Al accumulation was greater for mugwort than goutweed (385 ± 47 vs 2151 ± 251 µg g-1). Al concentration was similar between mine sites, but its accumulation in mugwort was greater with MS-I than MS-II, with no difference in accumulation by site for goutweed. An in situ approach revealed deregulation of multiple factors such as transporters, transcription factors, and metal chelators for metal uptake or exclusion. The two plant systems showed common gene expression patterns for different pathways. Both plant systems appeared to have few common heavy-metal pathway regulators addressing mineral toxicity/deficiency in both mine sites, which implies adaptability of invasive plants for efficient growth at mine sites with toxic waste. Functional genomics can be used to screen for plant adaptability, especially for reclamation and phytoremediation of contaminated soils and waters.

Complete state-resolved non-adiabatic dynamics of the O((3)P) + D2 → OD(X(2)Π) + D reaction.

The first quantum-state-resolved distributions over the full range of available product levels are reported for any isotopic variant of the elementary reaction of O((3)P) with molecular hydrogen. A laser-detonation source was used to produce a hyperthermal oxygen-atom beam, which allowed for sufficient collision energy to surmount the reaction barrier. This beam was crossed by a supersonic beam of D2. The nascent OD products were detected by laser-induced fluorescence. OD rotational distributions in vibrational states v' = 0, 1, and 2 at a collision energy of 25 kcal mol(-1) are reported, together with distributions for the dominant product vibrational level, v'= 0, at lower collision energies of 20 and 15 kcal mol(-1). The OD product is highly rotationally excited, to a degree that declines as expected for the higher vibrational levels or for reductions in the collision energy. The measured rovibrational distributions at the highest collision energy are in excellent agreement with previous theoretical predictions based on quantum scattering calculations on the triplet potential energy surfaces developed by Rogers et al. (J. Phys. Chem. A 2000, 104, 2308-2325). However, no significant OD spin-orbit preference was observed, in contrast to the predictions of most existing theoretical models of the non-adiabatic dynamics based on the widely used reduced-dimensional four-state model of Hoffmann and Schatz (J. Chem. Phys. 2000, 113, 9456-9465). Furthermore, a clear observed preference for OD Π(A') Λ-doublet levels is not consistent with a simple extrapolation of the calculated relative reaction cross sections on intermediate surfaces of (3)A' and (3)A″ symmetry.

Management of Guillain-Barré syndrome with plasmapheresis or immunoglobulin: our experience from a tertiary care institute in South India.

Guillain-Barré syndrome (GBS), an acute inflammatory demyelinating polyneuropathy is the most common generalized paralytic disorder. The objective was to study the outcome of disability grade in two groups of GBS treated with plasmapheresis alone and treated with IVIg alone. A retrospective analysis of all consecutive patients with GBS, admitted in our intensive care unit during the period of 3 years, 2009-2012 were included in the study. All patients of GBS who were to be treated with plasmapheresis or IVIg, the modality of management were always decided at their preference and consent after explaining the modalities to patient/family. The plasma exchange done was ∼200-250 mL of plasma per kilogram weight in five sessions (40-50 mL/kg per session) within 7-14 days. The replacement fluid contained 100 mL of 20% albumin diluted in 1000 mL of normal saline and 1000 mL of fresh frozen plasma. IVIg was administered as 0.4 g/kg body weight daily for 5 days. Our observations brought out the following, both the plasmapheresis and IVIg treatments were effective in reducing the disability grade amongst all time points, i.e., at presentation, immediate post-therapy and after 4 weeks. There was a marginal superiority in plasmapheresis over IVIg effect. However, whether the delay in presentation as noted in our study probably would have contributed to this effect was conjectural.

Silver nanoparticles enhanced enzyme-linked immunosorbent assay (ELISA) detection of cancer testis antigens (CTAs).

OBJECTIVE: The Enzyme-Linked Immunosorbent Assay (ELISA) has been a cornerstone technique in laboratory medicine for over 55 years, relying on the specific binding of antibodies to antigens. ELISA's widespread use stems from its ability to detect low concentrations, its specificity, reproducibility, and potential for high-throughput screening. However, its sensitivity has limitations, prompting the exploration of innovative methods to improve the limit of detection (LOD). Nanoparticles provide a promising platform for enhancing ELISA sensitivity. Due to their high surface-to-volume ratio, they offer increased binding sites for capture elements and reporting tags, leading to amplified analytical signals. Recent studies have demonstrated improved sensitivity in ELISA through nanoparticle application, yielding faster detection times and enhanced sensitivities. This study investigates the potential of 50 nm citrate-capped silver nanoparticles to enhance ELISA's performance in quantifying cancer testis antigens (CTAs). PATIENTS AND METHODS: In our study, we used the Human NY-ESO-1 ELISA kit (for research purposes) to determine the concentration of CTAs in randomly selected samples from healthy (n=89) and oncological (n=80) subjects, aged 18-75. We employed 50 nm citrate-capped silver nanoparticles (AGCB50-1M, BioPure Silver Nanoparticles - bare citrate, nano-Composix, San Diego, CA, USA). ELISA reactions followed the manufacturer's instructions, and data processing aligned with the same guidelines. Absorbance (OD) measurements occurred at 450 nm, influencing nanoparticle selection. Each ELISA well contained 5 ml of nanoparticles' stock solution with specified concentrations. CTAs concentrations were derived from the standard curve through CurveExpert Basic software. Statistical analysis was performed using SPSS v. 27 software, with p-values indicating significance if <0.03. The study adhered to Helsinki Declaration principles and received ethical approval. Participants provided informed written consent. RESULTS: The increased concentration values of CTAs for healthy individuals and cancer patients were determined in the case of the application of silver nanoparticles. CONCLUSIONS: The usage of nanoparticles can enhance the sensitivity of the ELISA method and positively influence its specific detection limit.

fmo-4 promotes longevity and stress resistance via ER to mitochondria calcium regulation in C. elegans.

Flavin-containing monooxygenases (FMOs) are a conserved family of xenobiotic enzymes upregulated in multiple longevity interventions, including nematode and mouse models. Previous work supports that C. elegans fmo-2 promotes longevity, stress resistance, and healthspan by rewiring endogenous metabolism. However, there are five C. elegans FMOs and five mammalian FMOs, and it is not known whether promoting longevity and health benefits is a conserved role of this gene family. Here, we report that expression of C. elegans fmo-4 promotes lifespan extension and paraquat stress resistance downstream of both dietary restriction and inhibition of mTOR. We find that overexpression of fmo-4 in just the hypodermis is sufficient for these benefits, and that this expression significantly modifies the transcriptome. By analyzing changes in gene expression, we find that genes related to calcium signaling are significantly altered downstream of fmo-4 expression. Highlighting the importance of calcium homeostasis in this pathway, fmo-4 overexpressing animals are sensitive to thapsigargin, an ER stressor that inhibits calcium flux from the cytosol to the ER lumen. This calcium/ fmo-4 interaction is solidified by data showing that modulating intracellular calcium with either small molecules or genetics can change expression of fmo-4 and/or interact with fmo-4 to affect lifespan and stress resistance. Further analysis supports a pathway where fmo-4 modulates calcium homeostasis downstream of activating transcription factor-6 ( atf-6 ), whose knockdown induces and requires fmo-4 expression. Together, our data identify fmo-4 as a longevity- promoting gene whose actions interact with known longevity pathways and calcium homeostasis.

PYY (3-36) protects against high fat feeding induced changes of pancreatic islet and intestinal hormone content and morphometry.

BACKGROUND: Prolonged high fat feeding negatively impacts pancreatic and intestinal morphology. In this regard, direct effects of PYY(3-36) on intestinal cell and pancreatic islet morphometry are yet to be fully explored in the setting of obesity. METHODS: We examined the influence of 21-days twice daily treatment with PYY(3-36) on these parameters in mice fed a high fat diet (HFD). RESULTS: PYY(3-36) treatment decreased food intake, body weight and circulating glucose in HFD mice. In terms of intestinal morphology, crypt depth was restored to control levels by PYY(3-36), with an additional enlargement of villi length. PYY(3-36) also reversed HFD-induced decreases of ileal PYY, and especially GLP-1, content. HFD increased numbers of PYY and GIP positive ileal cells, with PYY(3-36) fully reversing the effect on PYY cell detection. There were no obvious differences in the overall number of GLP-1 positive ileal cells in all mice, barring PYY(3-36) marginally decreasing GLP-1 villi cell immunoreactivity. Within pancreatic islets, PYY(3-36) significantly decreased alpha-cell area, whilst islet, beta-, PYY- and delta-cell areas remained unchanged. However, PYY(3-36) increased the percentage of beta-cells while also reducing percentage alpha-cell area. This was related to PYY(3-36)-induced reductions of beta-cell proliferation and apoptosis frequencies. Co-localisation of islet PYY with glucagon or somatostatin was elevated by PYY(3-36), with GLP-1/glucagon co-visualisation increased when compared to lean controls. CONCLUSION: PYY(3-36) exerts protective effects on pancreatic and intestinal morphology in HFD mice linked to elevated ileal GLP-1 content. GENERAL SIGNIFICANCE: These observations highlight mechanisms linked to the metabolic and weight reducing benefits of PYY(3-36).

Multimodal wavelet embedding representation for data combination (MaWERiC): integrating magnetic resonance imaging and spectroscopy for prostate cancer detection.

Recently, both Magnetic Resonance (MR) Imaging (MRI) and Spectroscopy (MRS) have emerged as promising tools for detection of prostate cancer (CaP). However, due to the inherent dimensionality differences in MR imaging and spectral information, quantitative integration of T(2) weighted MRI (T(2)w MRI) and MRS for improved CaP detection has been a major challenge. In this paper, we present a novel computerized decision support system called multimodal wavelet embedding representation for data combination (MaWERiC) that employs, (i) wavelet theory to extract 171 Haar wavelet features from MRS and 54 Gabor features from T(2)w MRI, (ii) dimensionality reduction to individually project wavelet features from MRS and T(2)w MRI into a common reduced Eigen vector space, and (iii), a random forest classifier for automated prostate cancer detection on a per voxel basis from combined 1.5 T in vivo MRI and MRS. A total of 36 1.5 T endorectal in vivo T(2)w MRI and MRS patient studies were evaluated per voxel by MaWERiC using a three-fold cross validation approach over 25 iterations. Ground truth for evaluation of results was obtained by an expert radiologist annotations of prostate cancer on a per voxel basis who compared each MRI section with corresponding ex vivo wholemount histology sections with the disease extent mapped out on histology. Results suggest that MaWERiC based MRS T(2)w meta-classifier (mean AUC, µ = 0.89 ± 0.02) significantly outperformed (i) a T(2)w MRI (using wavelet texture features) classifier (µ = 0.55 ± 0.02), (ii) a MRS (using metabolite ratios) classifier (µ = 0.77 ± 0.03), (iii) a decision fusion classifier obtained by combining individual T(2)w MRI and MRS classifier outputs (µ = 0.85 ± 0.03), and (iv) a data combination method involving a combination of metabolic MRS and MR signal intensity features (µ = 0.66 ± 0.02).

Comparative Effectiveness Analyses of Salvage Prostatectomy and Salvage Radiotherapy Outcomes Following Focal or Whole-Gland Ablative Therapy (High-Intensity Focused Ultrasound, Cryotherapy or Electroporation) for Localised Prostate Cancer.

AIMS: Ablative therapy, such as focal therapy, cryotherapy or electroporation, aims to treat clinically significant prostate cancer with reduced treatment-related toxicity. Up to a third of patients may require further local salvage treatment after ablative therapy failure. Limited descriptive, but no comparative, evidence exists between different salvage treatment outcomes. The aim of this study was to compare oncological and functional outcomes after salvage robot-assisted radical prostatectomy (SRARP) and salvage radiotherapy (SRT). MATERIALS AND METHODS: Data were collected prospectively and retrospectively on 100 consecutive SRARP cases and 100 consecutive SRT cases after ablative therapy failure in a high-volume tertiary centre. RESULTS: High-risk patients were over-represented in the SRARP group (66.0%) compared with the SRT group (48.0%) (P = 0.013). The median (interquartile range) follow-up after SRARP was 16.5 (10.0-30.0) months and 37.0 (18.5-64.0) months after SRT. SRT appeared to confer greater biochemical recurrence-free survival at 1, 2 and 3 years compared with SRARP in high-risk patients (year 3: 86.3% versus 66.0%), but biochemical recurrence-free survival was similar for intermediate-risk patients (year 3: 90.0% versus 75.6%). There was no statistical difference in pad-free continence at 12 and 24 months between SRARP (77.2 and 84.7%) and SRT (75.0 and 74.0%) (P = 0.724, 0.114). Erectile function was more likely to be preserved in men who underwent SRT. After SRT, cumulative bowel and urinary Radiation Therapy Oncology Group toxicity grade I were 25.0 and 45.0%, grade II were 11.0 and 11.0% and grade III or IV complications were 4.0 and 5.0%, respectively. CONCLUSION: We report the first comparative analyses of salvage prostatectomy and radiotherapy following ablative therapy. Men with high-risk disease appear to have superior oncological outcomes after SRT; however, treatment allocation does not appear to influence oncological outcomes for men with intermediate-risk disease. Treatment allocation was associated with a different spectrum of toxicity profile. Our data may inform shared decision-making when considering salvage treatment following focal or whole-gland ablative therapy.

fMRI BOLD and MEG theta power reflect complementary aspects of activity during lexicosemantic decision in adolescents with ASD.

Neuroimaging studies of autism spectrum disorder (ASD) have been predominantly unimodal. While many fMRI studies have reported atypical activity patterns for diverse tasks, the MEG literature in ASD remains comparatively small. Our group recently reported atypically increased event-related theta power in individuals with ASD during lexicosemantic processing. The current multimodal study examined the relationship between fMRI BOLD signal and anatomically-constrained MEG (aMEG) theta power. Thirty-three adolescents with ASD and 23 typically developing (TD) peers took part in both fMRI and MEG scans, during which they distinguished between standard words (SW), animal words (AW), and pseudowords (PW). Regions-of-interest (ROIs) were derived based on task effects detected in BOLD signal and aMEG theta power. BOLD signal and theta power were extracted for each ROI and word condition. Compared to TD participants, increased theta power in the ASD group was found across several time windows and regions including left fusiform and inferior frontal, as well as right angular and anterior cingulate gyri, whereas BOLD signal was significantly increased in the ASD group only in right anterior cingulate gyrus. No significant correlations were observed between BOLD signal and theta power. Findings suggest that the common interpretation of increases in BOLD signal and theta power as 'activation' require careful differentiation, as these reflect largely distinct aspects of regional brain activity. Some group differences in dynamic neural processing detected with aMEG that are likely relevant for lexical processing may be obscured by the hemodynamic signal source and low temporal resolution of fMRI.