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.

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).

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.

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.

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.

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.

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.

Differences in Levodopa Response for Progressive and Non-Progressive Micrographia in Parkinson's Disease.

Background: Micrographia, one element of the dysgraphia of Parkinson's disease (PD), may be classified according to the presence or absence of a decremental pattern. The decremental form, progressive micrographia, is an expression of the sequence effect seen generally in bradykinesia. Its responsiveness to levodopa has not been evaluated kinematically. Objectives: Aim of this study is to investigate the difference in levodopa response for progressive and non-progressive micrographia. Methods: Twenty-four PD patients and 24 age-matched repeatedly wrote the letter e on a computerized digital tablet. PD patients performed the task two times, in a defined off state and again after levodopa. Scripts were classified as progressive micrographia (PDPM) or non-progressive micrographia (PDNPM) depending on whether a 10% decrement was seen between the first and final characters of a line of lettering. Results: While levodopa produced a similar response on the MDS-UPDRS motor scale for the two groups, the effect on the two types of micrographia was different. While writing speed improved significantly in both groups after levodopa, the responses were over twofold greater for PDNPM. Moreover, the decremental features of PDPM-in size, speed, and pen-pressure-were largely unaltered by a levodopa dose. Conclusions: Progressive micrographia is less responsive to levodopa. Our findings agree with research showing that the sequence effect of bradykinesia is relatively resistant to medication. Yet we did not find a weaker overall levodopa motor benefit. Caution is needed in the interpretation of such micrographia measurements for estimating drug responses.

Author Correction: Activation of SIRT6 by DNA hypomethylating agents and clinical consequences on combination therapy in leukemia.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Activation of SIRT6 by DNA hypomethylating agents and clinical consequences on combination therapy in leukemia.

The FDA-approved DNA hypomethylating agents (DHAs) like 5-azacytidine (5AC) and decitabine (DAC) demonstrate efficacy in the treatment of hematologic malignancies. Despite previous reports that showed histone acetylation changes upon using these agents, the exact mechanism underpinning these changes is unknown. In this study, we investigated the relative potency of the nucleoside analogs and non-nucleoside analogs DHAs on DNA methylation reversal using DNA pyrosequencing. Additionally, we screened their effect on the enzymatic activity of the histone deacetylase sirtuin family (SIRT1, SIRT2, SIRT3, SIRT5 and SIRT6) using both recombinant enzymes and nuclear lysates from leukemia cells. The nucleoside analogs (DAC, 5AC and zebularine) were the most potent DHAs and increased the enzymatic activity of SIRT6 without showing any significant increase in other sirtuin isoforms. ChIP-Seq analysis of bone marrow cells derived from six acute myeloid leukemia (AML) patients and treated with the nucleoside analog DAC induced genome-wide acetylation changes in H3K9, the physiological substrate for SIRT6. Data pooling from the six patients showed significant acetylation changes in 187 gene loci at different chromosomal regions including promoters, coding exons, introns and distal intergenic regions. Signaling pathway analysis showed that H3K9 acetylation changes are linked to AML-relevant signaling pathways like EGF/EGFR and Wnt/Hedgehog/Notch. To our knowledge, this is the first report to identify the nucleoside analogs DHAs as activators of SIRT6. Our findings provide a rationale against the combination of the nucleoside analogs DHAs with SIRT6 inhibitors or chemotherapeutic agents in AML due to the role of SIRT6 in maintaining genome integrity and DNA repair.

Techniques and Outcomes of Salvage Robot-Assisted Radical Prostatectomy (sRARP).

BACKGROUND: Salvage Robot-Assisted Radical Prostatectomy (sRARP) has been described as feasible treatment for the management of localised prostate cancer (PCa) recurrence after primary treatment. However, no large reports have published cancer and quality outcomes. OBJECTIVE: To report perioperative, functional and oncologic outcomes of sRARP in patients with localised PCa recurrence. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively evaluated 106 patients with local recurrence eligible for sRARP. SURGICAL PROCEDURE: Surgery was performed using the DaVinci Si system similar to the standard approach but with adaptation to the primary treatment. MEASUREMENTS: Peri-operative outcomes included 90-day complication rate. Functional outcomes included rates of incontinence and erectile dysfunction. Oncological outcomes included tumour staging, margin rate and recurrence. RESULTS AND LIMITATIONS: Primary treatment was High Intensity Focused Ultrasound (HIFU) in 59 (56%) patients, 27 (25%) radiotherapy, 10 (9%) seed brachytherapy, 8 (8%) solitary androgen deprivation therapy (ADT), one (1%) cryotherapy and one (1%) electroporation / Nanoknife. Median follow-up was 2.1 years. 90-day complication rate was 8%. At two years or more, 50% were fully continent and 33% were socially continent. Continence rates tended to be better after focal compared to whole-gland treatments. Erectile dysfunction was present in 95%. Positive surgical margin rate was 39%. Biochemical recurrence occurred in 13% and local or metastatic recurrence in 11%. CONCLUSIONS: sRARP is technically more challenging but is a feasible option in high-volume centres for treatment of recurrent PCa. Patients should be counselled that functional outcomes are inferior to primary RARP. Adjustment of surgical technique according to the primary treatment is key for good surgical outcomes. PATIENT SUMMARY: We report our experience with sRARP for the management of localised PCa recurrence after primary treatment. This represents a feasible approach with acceptable peri-operative complications and cancer outcomes. Functional outcomes are inferior to RARP in the primary setting.

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.

Management of intractable bladder neck strictures following radical prostatectomy using the Memokath®045 stent.

The incidence of vesicourethral anastomotic stenosis (VUAS) post radical prostatectomy varies from 1 to 26%. Current treatment can be challenging and includes a variety of different procedures. These range from endoscopic dilations to bladder neck reconstruction to urinary diversion. We investigated a 2-stage endoscopic treatment, using the thermo-expandable Memokath®045 bladder neck stent to manage patients with VUAS post radical prostatectomy. We retrospectively reviewed 30 patients, between 2013 and 2017, who underwent a Memokath®045 stent insertion following failed primary treatment (dilation and clean intermittent catheterisation) for VUAS. The mean interval time between prostatectomy and Memokath®045 stent insertion was 13 months. The mean follow-up time was 3.6 years with all patients having a minimum of 12-month follow-up. All patients had two previous attempts at endoscopic dilatation with or without incision and a trial of clean intermittent catheterisation. During stage 1, the anastomotic stricture is dilated/incised to diameter of 30 Fr, the stricture length is measured, and a catheter is left in situ. One to 2 weeks later, post haemostasis and healing, an appropriately sized Memokath®045 stent is inserted. The stent is then removed 1-year post-op. Our series of patients had a median age of 62 (54-72). Most patients (26) had a robot-assisted radical prostatectomy (RARP) or salvage procedure. Results showed improvement in IPSS scores, IPSS quality of life scores, Qmax and PVR after the Memokath®045 stent was removed compared to pre-operation. With a minimum of 12 months post stent removal, 93% of patients were fully continent, whilst 7% of patients were socially continent. 2 (7%) patients had their stents removed and not replaced due to re-stricturing and stone formation. However, no urinary tract infections, stricture recurrence or urinary retention was observed in the rest of the cohort (93%). Overall, the Memokath®045 stent was successful in treating 93% of our patients with VUAS. Our series had minimal complications that were managed with conservative measures and in three patients' re-operation was needed. In conclusion, the Memokath®045 stent is a minimally invasive technique with faster recovery time compared to other techniques such as bladder neck reconstruction or urinary diversion. Additionally, it provides superior patency results compared to other techniques such as bladder neck incision and injection of Mitomycin C. Therefore, this management option should be considered in the management of VUAS.

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.

Serotonergic system, cognition, and BPSD in Alzheimer's disease.

Behavioral and Psychological Symptoms of Dementia (BPSD), present in almost 90% of patients with Alzheimer's Disease (AD), cause extensive impairment leading to reduced independence and inability to complete activities of daily living. Though BPSD includes a wide range of symptoms, such as agitation, aggression, disinhibition, anxiety, depression, apathy, delusions, and hallucinations. Certain BPSD in AD co-present and can be clustered into distinct domains based on their frequency of co-occurrence. As these BPSD are so pervasive in any stages of AD, the disease may be better characterized as a disorder of heterogeneous degenerative symptoms across a number of symptom domains, with the most prominent domain comprising memory and cognitive deficits. Importantly, there are no FDA-approved drugs to treat these BPSD, and new approaches must be considered to develop effective treatments for AD patients. The biogenic monoamine 5-hydroxytryptamine (5-HT), or serotonin, works as both a neurotransmitter and neuromodulator, which has been tied to cognitive decline and multiple BPSD domains. This review summarizes the evidence for specific serotonergic system alterations across some of the well-studied cognitive, behavioral, and psychiatric domains. Though differences in overall serotonergic transmission occur in AD, circuit-specific alterations in individual 5-HT receptors (5-HTRs) are likely linked to the heterogeneous presentation of BPSD in AD.

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.

Evaluation and Classification of Physical and Psychological Stress in Firefighters using Heart Rate Variability.

Stress detection has a huge potential for disease prevention and management, and to improve the quality of life of people. Also, work safety can be improved if stress is timely and reliably detected. The availability of low-cost consumer wearable devices that monitor vital-signs, gives access to stress detection schemes. Heart rate variability (HRV), a stress-related vital-sign, was derived from wearable device data to reliably determine stress-levels. In order to build and train a deployable stress-detector, we collected labeled HRV data in controlled environments, where subjects were exposed to physical, psychological and combined stress. We then applied machine learning to separate and identify the different stress types and understand the relationship with HRV data. The resulting C5 decision tree model is capable of identifying the stress type with 88% accuracy, in a 1-minute time window. For the first time physical and psychological stress can be distinguished with a 1-minute time resolution from smoke-divers, firefighters, who enter high-risk environments to rescue people, and experience intense physical and psychological stress. To improve our model, we created an integrated system to acquire expert labels in real-time from firefighters during their training in a Rescue Maze. A next goal is to transfer the algorithms into generic systems for monitoring and coaching high-risk professionals to improve their stress resilience during training and reduce their risk in the field.