Exploring the Dispersion and Electrostatic Components in Arene-Arene Interactions between Ligands and G4 DNA to Develop G4-Ligands.

G-Quadruplex (G4) DNA structures are important regulatory elements in central biological processes. Small molecules that selectively bind and stabilize G4 structures have therapeutic potential, and there are currently >1000 known G4 ligands. Despite this, only two G4 ligands ever made it to clinical trials. In this work, we synthesized several heterocyclic G4 ligands and studied their interactions with G4s (e.g., G4s from the c-MYC, c-KIT, and BCL-2 promoters) using biochemical assays. We further studied the effect of selected compounds on cell viability, the effect on the number of G4s in cells, and their pharmacokinetic properties. This identified potent G4 ligands with suitable properties and further revealed that the dispersion component in arene-arene interactions in combination with electron-deficient electrostatics is central for the ligand to bind with the G4 efficiently. The presented design strategy can be applied in the further development of G4-ligands with suitable properties to explore G4s as therapeutic targets.

Factors influencing outcomes of surgical therapy of peri-implantitis: A secondary analysis of 1-year results from a randomized clinical study.

AIM: To identify predictors of treatment outcomes following surgical therapy of peri-implantitis. MATERIALS AND METHODS: We performed a secondary analysis of data from a randomized controlled trial (RCT) comparing access flap with or without bone replacement graft. Outcomes at 12 months were probing pocket depth (PPD), bleeding on probing (BOP), soft-tissue recession (REC) and marginal bone level (MBL) change. Multilevel regression analyses were used to identify predictors. We also built an explanatory model for residual signs of inflammation. RESULTS: Baseline PPD was the most relevant predictor, showing positive associations with final PPD, REC and MBL gain, and negative association with probability of pocket closure. Smokers presented higher residual PPD. Absence of keratinized mucosa at baseline increased the probability of BOP but was otherwise not indicative of outcomes. Plaque at 6 weeks was detrimental in terms of residual PPD and BOP. Treatment allocation had an effect on REC. Final BOP was explained by residual PPD ≥6 mm and plaque at more than two sites. CONCLUSIONS: Baseline PPD was the most relevant predictor of the outcomes of surgical therapy of peri-implantitis. Pocket closure should be a primary goal of treatment. Bone replacement grafts may be indicated in aesthetically demanding cases to reduce soft-tissue recession. The importance of smoking cessation and patient-performed plaque control is also underlined.

Managing leukemia patients via liquid biopsy and super rolling circle amplification (superRCA).

The rapidly increasing availability of sequence information for tumor patients, combined with expanding treatment options, motivates efforts to monitor the course of disease for individual patients by analyzing patient-specific mutations in liquid biopsies, as highly specific markers of the malignancy. We discuss the suitability of established molecular methods to monitor patients with malignancies, in particular leukemias, comparing these to the recently developed super rolling circle amplification technique for highly sensitive, parallel measurements of mutant sequences using readily available instruments. The very high sensitivity for tumor-specific mutations-in combination with low cost and ready access at clinics-promises to allow routine monitoring of increasing numbers of tumor patients, in order to initiate improved treatments at the earliest timepoint possible, when necessary. A method with high-enough accuracy to enable monitoring in peripheral blood rather than bone marrow samples would present a great practical advantage, not least from the patient perspective. We describe scenarios in which sufficiently sensitive, inexpensive methods for mutational analysis can provide valuable guidance for the clinician in choosing among therapeutic options and adjusting ongoing treatment and help to promptly identify recurrences of disease in treated patients.

Low Circulating Valine Associate With High Risk of Hip Fractures.

CONTEXT: Hip fractures constitute a major health concern. An adequate supply of amino acids is crucial to ensure optimal acquisition and remodeling of bone. Circulating amino acid levels have been proposed as markers of bone mineral density, but data on their ability to predict incident fractures are scarce. OBJECTIVES: To investigate the associations between circulating amino acids and incident fractures. METHODS: We used UK Biobank (n = 111 257; 901 hip fracture cases) as a discovery cohort and the Umeå Fracture and Osteoporosis (UFO) hip fracture study (hip fracture cases n = 2225; controls n = 2225) for replication. Associations with bone microstructure parameters were tested in a subsample of Osteoporotic Fractures in Men Sweden (n = 449). RESULTS: Circulating valine was robustly associated with hip fractures in the UK Biobank (HR per SD increase 0.79, 95% CI 0.73-0.84), and this finding was replicated in the UFO study (combined meta-analysis including 3126 incident hip fracture cases, odds ratio per SD increase 0.84, 95% CI 0.80-0.88). Detailed bone microstructure analyses showed that high circulating valine was associated with high cortical bone area and trabecular thickness. CONCLUSION: Low circulating valine is a robust predictor of incident hip fractures. We propose that circulating valine may add information for hip fracture prediction. Future studies are warranted to determine whether low valine is causally associated with hip fractures.

Drug information sources in professional work-a questionnaire study on physicians' usage and preferences (the drug information study).

PURPOSE: This study aimed to explore physicians' use of drug information in professional work, with special focus on those working in primary care, and also in relation to personal characteristics of physicians. METHODS: A web-based questionnaire was distributed by e-mail to physicians in five regions in Sweden. The questions concerned drug-related queries at issue when searching for information, sources used, and factors of importance for the choice of source, as well as responder characteristics. RESULTS: A total of 3254 (85%) out of 3814 responding physicians stated that they searched for drug information every week. For physicians working in primary health care, the corresponding number was 585 (96%). The most common drug-related issues searched for by 76% of physicians every week concerned pharmacotherapeutic aspects (e.g., dosing), followed by adverse drug reactions (63%). For 3349 (88%) physicians, credibility was the most important factor for the choice of sources of drug information, followed by easy access online (n = 3127, 82%). Further analyses among physicians in primary care showed that some personal characteristics, like seniority, sex, and country of education, as well as research experience, were associated with usage and preferences of drug information sources. CONCLUSIONS: This study confirms that physicians often use drug information sources in professional work, in particular those who work in primary health care. Credibility and easy access are key factors for usage. Among physicians in primary care, personal factors influenced the choice of drug information sources.

Somatic Exonic Deletions in RUNX1 Constitutes a Novel Recurrent Genomic Abnormality in Acute Myeloid Leukemia.

PURPOSE: In acute myeloid leukemia (AML), somatic mutations (commonly missense, nonsense, and frameshift indels) in RUNX1 are associated with a dismal clinical outcome. Inherited RUNX1 mutations cause familial platelet disorder. As approximately 5%-10% of germline RUNX1 mutations are large exonic deletions, we hypothesized that such exonic RUNX1 aberrations may also be acquired during the development of AML. EXPERIMENTAL DESIGN: Sixty patients with well-characterized AML were analyzed with multiplex ligation-dependent probe amplification (n = 60), microarray (n = 11), and/or whole-genome sequencing (n = 8). RESULTS: In total, 25 (42% of the cohort) RUNX1-aberrant patients (defined by the presence of classical mutations and/or exonic deletions) were identified. Sixteen patients (27%) carried only exonic deletions, 5 (8%) carried classical mutations, and 4 (7%) carried both exonic deletions and mutations. No significant difference was observed between patients with classical RUNX1 mutations and RUNX1 exonic deletions in median overall survival (OS, 53.1 vs. 38.8 months, respectively, P = 0.63). When applying the European Leukemia Net (ELN) classification including the RUNX1-aberrant group, 20% of the patients initially stratified as intermediate-risk (5% of the whole cohort) were reassigned to the high-risk group, which improved the performance of ELN classification regarding OS between intermediate- and high-risk groups (18.9 vs. 9.6 months, P = 0.09). CONCLUSIONS: Somatic RUNX1 exonic deletions constitute a novel recurrent aberration in AML. Our findings have important clinical implications regarding AML classification, risk stratification, and treatment decision. Moreover, they argue in favor of further investigating such genomic aberrations not only in RUNX1 but also in other genes implicated in cancer biology and management. See related commentary by Chakraborty and Stengel, p. 2742.

Interaction alerts: A comparison of classifications and recommendations for clinical management between Janusmed and three other knowledge resources.

Classifications of drug interaction alerts differ between knowledge resources, but agreement regarding recommendations for clinical management is less explored. Starting from the medication lists of 274 older patients with ≥2 drugs, all unique drug pairs that triggered a clinically significant interaction alert in Janusmed were included: 100 Category C (manageable by, e.g. dose adjustment) and nine Category D interactions (should be avoided). Out of 109 C/D alerts in Janusmed, 89 (82%), 75 (69%) and 45 (41%) drug pairs triggered an alert of similar clinical significance in Lexicomp, Micromedex® and Stockley's Drug Interactions/Checker (Stockley), respectively. Eight (7%), 20 (18%) and 10 (9%) drug pairs did not trigger any alert in these resources. For 81 (74%), 81 (74%) and 94 (86%) drug pairs, Lexicomp, Micromedex and Stockley provided at least one recommendation for clinical management similar to those provided by Janusmed. For 16 (15%), 9 (8%) and 21 (19%) drug pairs, these resources provided recommendation(s) entirely in agreement with Janusmed. Although many drug pairs elicit alerts of similar significance, and partly concordant recommendations, a non-negligible proportion do not. The findings encourage medical/pharmaceutical reflection by prescribing clinicians and dispensing pharmacists; recommendations provided by knowledge resources vary considerably and cannot be considered definite.

Onset of periodontitis - a registry-based cohort study.

OBJECTIVES: The present retrospective registry-based cohort study aimed to identify parameters associated with the onset of periodontitis in young adults. MATERIAL AND METHODS: A total of 345 Swedish subjects were clinically examined at age 19 years (as part of an epidemiological survey) and then followed up to 31 years through the Swedish Quality Registry for Caries and Periodontal diseases (SKaPa). The registry data including periodontal parameters were obtained for the period 2010-2018 (23-31 years). Logistic regression and survival models were used to identify risk factors for periodontitis (PPD ≥6 mm at ≥2 teeth). RESULTS: The incidence of periodontitis during the 12-year observation period was 9.8%. Cigarette smoking (modified pack-years; HR 2.35, 95%CI 1.34-4.13) and increased probing pocket depth (number of sites with PPD 4-5 mm; HR 1.04, 95%CI 1.01-1.07) at 19 years were risk factors for periodontitis in subsequent young adulthood. No statistically significant association was identified for gender, snuff use, plaque and marginal bleeding scores. CONCLUSION: Cigarette smoking and increased probing pocket depth (≥4 mm) in late adolescence (19 years) were relevant risk factors for periodontitis in young adulthood. CLINICAL RELEVANCE: Our study identified cigarette smoking and increased probing depth in late adolescence as relevant risk factors of periodontitis in young adulthood. Preventive programs should therefore consider both cigarette smoking and probing pocket depths in their risk assessment.

Modified free gingival graft technique for treatment of gingival recession defects at mandibular incisors: A randomized clinical trial.

BACKGROUND: The aim of this study was to evaluate clinical and patient-reported outcomes following surgical root coverage at RT1 gingival recession defects at mandibular incisors, using either a conventional free gingival graft (FGG) or a modified FGG (ModFGG). METHODS: Total of 30 patients with RT1 gingival recessions at mandibular incisors were enrolled and randomly allocated to either a control (FGG) or test group (ModFGG). Evaluations of clinical changes (recession depth, height of keratinized tissue) and patient satisfaction were performed over a follow-up period of 12 months. Post-surgical changes of keratinized tissue height (shrinkage) were assessed from 1 month and onward. RESULTS: ModFGG resulted in more pronounced root coverage at 1 year compared to FGG (91.8% vs. 60.7%, p < 0.001). Height of keratinized tissue was improved by 4.2 and 2.2 mm (p < 0.001), respectively, with significantly less shrinkage in ModFGG. Post-surgical morbidity was significantly lower for ModFGG at 2 weeks and patient satisfaction was significantly higher 12 months after treatment (9.1 vs. 5.4; p < 0.001). CONCLUSIONS: ModFGG represents a valid approach for the management of RT1 recession defects at mandibular incisors. The technique is superior to traditional FGG in terms of root coverage, the gain of keratinized tissue height, and patient satisfaction.

Androgen deprivation therapy in men with prostate cancer is not associated with COVID-2019 infection.

BACKGROUND: Androgens may play a role in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and host responses as the virus is dependent on the androgen-regulated protein transmembrane serine protease 2 for cell entry. Studies have indicated that prostate cancer patients receiving androgen deprivation therapy (ADT) are at reduced risk of SARS-CoV-2 infection and serious complications compared with patients without ADT, but data are inconsistent. METHODS: A total of 655 prostate cancer patients who were under surveillance at two urology departments in Sweden on April 1, 2020 were included in the study as well as 240 patients with benign prostatic hyperplasia (BPH). At follow-up early in 2021, the participants completed a questionnaire containing information about symptoms compatible with coronavirus disease 2019 (COVID-19). Blood samples were also collected for the assessment of SARS-CoV-2 IgG antibodies (SARS-CoV-2 Total; Siemens). We used multivariable logistic regression models to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between ADT and the risk of SARS-CoV-2 infection. RESULTS: The cumulative incidence of SARS-CoV-2 seropositivity was 13.4% among patients receiving ADT and 10.4% among patients without ADT. After adjusting for potential confounders, we observed no differences in symptoms or risk of SARS-CoV-2 infection between patients with and without ADT (OR: 0.98; 95% CI: 0.52-1.85). Higher body mass index, Type 1 diabetes, and prostate cancer severity, defined by high Gleason score (8-10; OR: 2.06; 95% CI: 1.04-4.09) or elevated levels of prostate-specific antigen (>20 µg/l; OR: 2.15; 95% CI: 1.13-4.07) were associated with increased risk of SARS-CoV-2 infection. Overall, the risk of SARS-CoV-2 infection was not higher among men with prostate cancer than among men with BPH. CONCLUSIONS: Our results do not support the hypothesis that ADT use in prostate cancer patients reduces the risk or symptom severity of SARS-CoV-2 infection or that prostate cancer patients are at increased risk of COVID-19 compared with men without prostate cancer.

Furcation involvement and tooth loss: A registry-based retrospective cohort study.

AIM: This registry-based retrospective cohort study aimed to evaluate the impact of furcation status on the risk for molar loss. MATERIALS AND METHODS: Subjects with and without furcation involvement (FI) in 2010/2011 were identified in a nationwide registry in Sweden (age- and gender-matched sample: 381,450 subjects; 2,374,883 molars). Data on dental and periodontal status were extracted for the subsequent 10-year period. Impact of FI (at baseline or detected during follow-up) on molar loss (i.e., tooth extraction) was evaluated through multilevel logistic regression and survival analyses. RESULTS: FI had a significant impact on molar loss. FI degrees 2 and 3 resulted in adjusted risk ratios of 1.67 (95% confidence interval [CI] 1.63-1.71) and 3.30 (95% CI 3.18-3.43), respectively. Following the first detection of deep FI (degrees 2-3), estimated survival decreased by 4% at 5 years and 8% at 10 years. In addition to FI, endodontic status and probing depth were relevant risk factors for molar loss. CONCLUSIONS: Furcation status had a clinically relevant impact on the risk for molar loss. Following first detection of deep FI, however, the decline in molar survival was minor.

SARS-CoV-2 vaccines are not associated with hypercoagulability in apparently healthy people.

Background: SARS-CoV-2 adenoviral vector DNA vaccines have been linked to the rare but serious thrombotic postvaccine complication vaccine-induced immune thrombotic thrombocytopenia. This has raised concerns regarding the possibility of increased thrombotic risk after any SARS-CoV-2 vaccines. Objectives: To investigate whether SARS-CoV-2 vaccines cause coagulation activation leading to a hypercoagulable state. Methods: This observational study included 567 health care personnel; 521 were recruited after the first dose of adenoviral vector ChAdOx1-S (Vaxzevria, AstraZeneca) vaccine and 46 were recruited prospectively before vaccination with a messenger RNA (mRNA) vaccine, either Spikevax (Moderna, n = 38) or Comirnaty (Pfizer-BioNTech, n = 8). In the mRNA group, samples were acquired before and 1 to 2 weeks after vaccination. In addition to the prevaccination samples, 56 unvaccinated blood donors were recruited as controls (total n = 102). Thrombin generation, D-dimer levels, and free tissue factor pathway inhibitor (TFPI) levels were analyzed. Results: No participant experienced thrombosis, vaccine-induced immune thrombotic thrombocytopenia, or thrombocytopenia (platelet count <100 × 109/L) 1 week to 1 month postvaccination. There was no increase in thrombin generation, D-dimer level, or TFPI level in the ChAdOx1-S vaccine group compared with controls or after the mRNA vaccines compared with baseline values. Eleven of 513 (2.1%) participants vaccinated with ChAdOx1-S had anti-PF4/polyanion antibodies without a concomitant increase in thrombin generation. Conclusion: In this study, SARS-CoV-2 vaccines were not associated with thrombosis, thrombocytopenia, increased thrombin generation, D-dimer levels, or TFPI levels compared with baseline or unvaccinated controls. These findings argue against the subclinical activation of coagulation post-COVID-19 vaccination.

Efficacy of access flap and pocket elimination procedures in the management of peri-implantitis: A systematic review and meta-analysis.

AIM: To evaluate the efficacy of access flap and pocket elimination procedures in the surgical treatment of peri-implantitis. MATERIALS AND METHODS: Systematic electronic searches (Central/MEDLINE/EMBASE) up to March 2022 were conducted to identify prospective clinical studies evaluating surgical therapy (access flap or pocket elimination procedures) of peri-implantitis. Primary outcome measures were reduction of probing depth (PD) and bleeding on probing (BOP). Risk of bias was evaluated according to study design. Meta-analysis and meta-regression were performed. Results were expressed as standardized mean effect with 95% confidence interval (CI). RESULTS: Evidence from studies directly comparing surgical with non-surgical therapy is lacking. Based on pre-post data originating from 13 prospective patient cohorts, pronounced reductions of PD (standardized mean effect: 2.2 mm; 95% CI 1.8-2.7) and BOP% (27.0; 95% CI 19.8-34.2) as well as marginal bone level gain (0.2 mm; 95% CI -0.0 to 0.5) were observed at evaluation time points ranging from 1 to 5 years. Wide prediction intervals suggested a high degree of heterogeneity. Reduction of mean PD increased by 0.7 mm (95% CI 0.5-0.9) for every millimetre in increase of mean PD at baseline. During the follow-up period ranging from 1 to 5 years, disease recurrence occurred frequently and implant loss was not uncommon. CONCLUSIONS: Access flap and pocket elimination surgery are effective procedures in the management of peri-implantitis, although rates of disease recurrence during 5 years were high. Treatment outcomes were affected by baseline conditions.

Proteogenomic analysis of acute myeloid leukemia associates relapsed disease with reprogrammed energy metabolism both in adults and children.

Despite improvement of current treatment strategies and novel targeted drugs, relapse and treatment resistance largely determine the outcome for acute myeloid leukemia (AML) patients. To identify the underlying molecular characteristics, numerous studies have been aimed to decipher the genomic- and transcriptomic landscape of AML. Nevertheless, further molecular changes allowing malignant cells to escape treatment remain to be elucidated. Mass spectrometry is a powerful tool enabling detailed insights into proteomic changes that could explain AML relapse and resistance. Here, we investigated AML samples from 47 adult and 22 pediatric patients at serial time-points during disease progression using mass spectrometry-based in-depth proteomics. We show that the proteomic profile at relapse is enriched for mitochondrial ribosomal proteins and subunits of the respiratory chain complex, indicative of reprogrammed energy metabolism from diagnosis to relapse. Further, higher levels of granzymes and lower levels of the anti-inflammatory protein CR1/CD35 suggest an inflammatory signature promoting disease progression. Finally, through a proteogenomic approach, we detected novel peptides, which present a promising repertoire in the search for biomarkers and tumor-specific druggable targets. Altogether, this study highlights the importance of proteomic studies in holistic approaches to improve treatment and survival of AML patients.

Characterization of therapy-related acute myeloid leukemia: increasing incidence and prognostic implications.

Studies of therapy-related AML (t-AML) are usually performed in selected cohorts and reliable incidence rates are lacking. In this study, we characterized, defined the incidence over time and studied prognostic implications in all t-AML patients diagnosed in Sweden between 1997 and 2015. Data were retrieved from nationwide population-based registries. In total, 6,779 AML patients were included in the study, of whom 686 (10%) had t-AML. The median age for t-AML was 71 years and 392 (57%) patients were females. During the study period, the incidence of t-AML almost doubled with a yearly increase in t-AML of 4.5% (95% confidence interval: 2.8%-6.2%), which contributed significantly to the general increase in AML incidence over the study period. t-AML solidly constituted over 10% of all AML cases during the later period of the study. Primary diagnoses with the largest increase in incidence and decrease in mortality rate during the study period (i.e., breast and prostate cancer) contributed significantly to the increased incidence of t-AML. In multivariable analysis, t-AML was associated with poorer outcome in cytogenetically intermediate- and adverse-risk cases but t-AML had no significant impact on outcome in favorable-risk AML, including core binding leukemias, acute promyelocytic leukemia and AML with mutated NPM1 without FLT3-ITD. We conclude that there is a strong increase in incidence in t-AML over time and that t-AML constitutes a successively larger proportion of the AML cases. Furthermore, we conclude that t-AML confers a poor prognosis in cytogenetically intermediate- and adverse-risk, but not in favorable-risk AML.

Prevention and management of peri-implant mucositis and peri-implantitis: A systematic review of outcome measures used in clinical studies in the last 10 years.

OBJECTIVES: To evaluate outcome measures, methods of assessment, and analysis in clinical studies on the prevention and management of peri-implant mucositis and peri-implantitis. METHODS: Systematic electronic searches (CENTRAL/MEDLINE/SCOPUS) up to April 2021 were conducted to identify longitudinal clinical studies with ≥10 patients on either the prevention or management of peri-implant diseases. Outcome measures of this analysis were the choice of outcome measures, methods of assessment, and analytical methods. Risk of bias was evaluated according to study design. Data were extracted into evidence tables and outcomes were analysed in a descriptive manner. RESULTS: The analysis of the 159 selected studies revealed that probing pocket depth (PPD) and bleeding/suppuration on probing (BOP) were reported in 89% and 87% of all studies, respectively. Additional outcome measures included plaque scores (reported in 64% of studies), radiographic outcomes (49%), soft tissue dimensions (34%), and composite outcomes (26%). Adverse events (8%) and patient-reported outcomes (6%) were only rarely mentioned. A primary outcome measure was clearly defined only in 36% of studies. Data on PPD, radiographic outcomes, and soft tissue dimensions were primarily reported as mean values and rarely as frequency distributions. For radiographic outcomes and soft tissue dimensions, it was frequently unclear how clustered data were handled. CONCLUSIONS: PPD and BOP were routinely reported in studies on the prevention and management of peri-implant mucositis and peri-implantitis, while composite outcomes, adverse events, and patient-reported outcomes were only infrequently described.

Prevention and management of peri-implant mucositis and peri-implantitis: A systematic review of outcome measures used in clinical studies in the last 10 years.

OBJECTIVES: To evaluate outcome measures, methods of assessment, and analysis in clinical studies on the prevention and management of peri-implant mucositis and peri-implantitis. METHODS: Systematic electronic searches (CENTRAL/MEDLINE/SCOPUS) up to April 2021 were conducted to identify longitudinal clinical studies with ≥10 patients on either the prevention or management of peri-implant diseases. Outcome measures of this analysis were the choice of outcome measures, methods of assessment, and analytical methods. Risk of bias was evaluated according to study design. Data were extracted into evidence tables and outcomes were analysed in a descriptive manner. RESULTS: The analysis of the 159 selected studies revealed that probing pocket depth (PPD) and bleeding/suppuration on probing (BOP) were reported in 89% and 87% of all studies, respectively. Additional outcome measures included plaque scores (reported in 64% of studies), radiographic outcomes (49%), soft tissue dimensions (34%), and composite outcomes (26%). Adverse events (8%) and patient-reported outcomes (6%) were only rarely mentioned. A primary outcome measure was clearly defined only in 36% of studies. Data on PPD, radiographic outcomes, and soft tissue dimensions were primarily reported as mean values and rarely as frequency distributions. For radiographic outcomes and soft tissue dimensions, it was frequently unclear how clustered data were handled. CONCLUSIONS: PPD and BOP were routinely reported in studies on the prevention and management of peri-implant mucositis and peri-implantitis, while composite outcomes, adverse events, and patient-reported outcomes were only infrequently described.

Scientific rationale for study: In 2012, recommendations on study design, key outcome measures, and reporting in clinical studies on the prevention and management of peri-implant diseases were presented. We aimed to evaluate how these recommendations were adapted and utilized in relevant studies published during the last decade. Principal findings: Recommendations on outcome measures and reporting in clinical studies on the prevention and management of peri-implant mucositis and peri-implantitis were only partially followed. Practical implications: When evaluating the evidence on the prevention and management of peri-implant diseases, the clinician should be aware of the limitations in terms of choice of outcome measures and data reporting.

Enhanced cytotoxicity of a novel family of ATPase inhibitors in colorectal cancer cells with high NAT2 activity.

Loss of heterozygosity (LOH) is a hallmark feature of cancer genomes that reduces allelic variation, thereby creating tumor specific vulnerabilities which could be exploited for therapeutic purposes. We previously reported that loss of drug metabolic arylamine N-acetyltransferase 2 (NAT2) activity following LOH at 8p22 could be targeted for collateral lethality anticancer therapy in colorectal cancer (CRC). Here, we report a novel compound CBK034026C that exhibits specific toxicity towards CRC cells with high NAT2 activity. Connectivity Map analysis revealed that CBK034026C elicited a response pattern related to ATPase inhibitors. Similar to ouabain, a potent inhibitor of the Na+/K+-ATPase, CBK034026C activated the Nf-kB pathway. Further metabolomic profiling revealed downregulation of pathways associated with antioxidant defense and mitochondrial metabolism in CRC cells with high NAT2 activity, thereby weakening the protective response to oxidative stress induced by CBK034026C. The identification of a small molecule targeting metabolic vulnerabilities caused by NAT2 activity provides novel avenues for development of anticancer agents.

Plasma protein biomarker profiling reveals major differences between acute leukaemia, lymphoma patients and controls.

Aiming to accommodate the unmet need for easily accessible biomarkers with a focus on biological differences between haematological diseases, the diagnostic value of plasma proteins in acute leukaemias and lymphomas was investigated. A multiplex proximity extension assay (PEA) was used to analyze 183 proteins in diagnostic plasma samples from 251 acute leukaemia and lymphoma patients and compared with samples from 60 healthy controls. Multivariate modelling using partial least square discriminant analysis revealed highly significant differences between distinct disease subgroups and controls. The model allowed explicit distinction between leukaemia and lymphoma, with few patients misclassified. Acute leukaemia samples had higher levels of proteins associated with haemostasis, inflammation, cell differentiation and cell-matrix integration, whereas lymphoma samples demonstrated higher levels of proteins known to be associated with tumour microenvironment and lymphoma dissemination. PEA technology can be used to screen for large number of plasma protein biomarkers in low µL sample volumes, enabling the distinction between controls, acute leukaemias and lymphomas. Plasma protein profiling could help gain insights into the pathophysiology of acute leukaemia and lymphoma and the technique may be a valuable tool in the diagnosis of these diseases.

Quantitative proteomics reveals protein dysregulation during T cell activation in multiple sclerosis patients compared to healthy controls.

BACKGROUND: Multiple sclerosis (MS) is an autoimmune, neurodegenerative disorder with a strong genetic component that acts in a complex interaction with environmental factors for disease development. CD4+ T cells are pivotal players in MS pathogenesis, where peripherally activated T cells migrate to the central nervous system leading to demyelination and axonal degeneration. Through a proteomic approach, we aim at identifying dysregulated pathways in activated T cells from MS patients as compared to healthy controls. METHODS: CD4+ T cells were purified from peripheral blood from MS patients and healthy controls by magnetic separation. Cells were left unstimulated or stimulated in vitro through the TCR and costimulatory CD28 receptor for 24 h prior to sampling. Electrospray liquid chromatography-tandem mass spectrometry was used to measure protein abundances. RESULTS: Upon T cell activation the abundance of 1801 proteins was changed. Among these proteins, we observed an enrichment of proteins expressed by MS-susceptibility genes. When comparing protein abundances in T cell samples from healthy controls and MS patients, 18 and 33 proteins were differentially expressed in unstimulated and stimulated CD4+ T cells, respectively. Moreover, 353 and 304 proteins were identified as proteins exclusively induced upon T cell activation in healthy controls and MS patients, respectively and dysregulation of the Nur77 pathway was observed only in samples from MS patients. CONCLUSIONS: Our study highlights the importance of CD4+ T cell activation for MS, as proteins that change in abundance upon T cell activation are enriched for proteins encoded by MS susceptibility genes. The results provide evidence for proteomic disturbances in T cell activation in MS, and pinpoint to dysregulation of the Nur77 pathway, a biological pathway known to limit aberrant effector T cell responses.