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Background Reaching the therapeutic target of remission or low-disease activity has improved outcomes in patients with rheumatoid arthritis (RA) significantly. The treat-to-target recommendations, formulated in 2010, have provided a basis for implementation of a strategic approach towards this therapeutic goal in routine clinical practice, but these recommendations need to be re-evaluated for appropriateness and practicability in the light of new insights.
Objective To update the 2010 treat-to-target recommendations based on systematic literature reviews (SLR) and expert opinion.
Methods A task force of rheumatologists, patients and a nurse specialist assessed the SLR results and evaluated the individual items of the 2010 recommendations accordingly, reformulating many of the items. These were subsequently discussed, amended and voted upon by >40 experts, including 5 patients, from various regions of the world. Levels of evidence, strengths of recommendations and levels of agreement were derived.
Results The update resulted in 4 overarching principles and 10 recommendations. The previous recommendations were partly adapted and their order changed as deemed appropriate in terms of importance in the view of the experts. The SLR had now provided also data for the effectiveness of targeting low-disease activity or remission in established rather than only early disease. The role of comorbidities, including their potential to preclude treatment intensification, was highlighted more strongly than before. The treatment aim was again defined as remission with low-disease activity being an alternative goal especially in patients with long-standing disease. Regular follow-up (every 1–3 months during active disease) with according therapeutic adaptations to reach the desired state was recommended. Follow-up examinations ought to employ composite measures of disease activity that include joint counts. Additional items provide further details for particular aspects of the disease, especially comorbidity and shared decision-making with the patient. Levels of evidence had increased for many items compared with the 2010 recommendations, and levels of agreement were very high for most of the individual recommendations (≥9/10).
Conclusions The 4 overarching principles and 10 recommendations are based on stronger evidence than before and are supposed to inform patients, rheumatologists and other stakeholders about strategies to reach optimal outcomes of RA.
Spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS) are neurodegenerative disorders, caused or modified by an unstable CAG-repeat expansion in the SCA2 gene, which encodes a polyglutamine (polyQ) domain expansion in ataxin-2 (ATXN2). ATXN2 is an RNA-binding protein and interacts with the poly(A)-binding protein PABPC1, localizing to ribosomes at the rough endoplasmic reticulum. Under cell stress, ATXN2, PABPC1 and small ribosomal subunits are relocated to stress granules, where mRNAs are protected from translation and from degradation. It is unknown whether ATXN2 associates preferentially with specific mRNAs or how it modulates RNA processing. Here, we investigated the RNA profile of the liver and cerebellum from Atxn2 knockout (Atxn2−/−) mice at two adult ages, employing oligonucleotide microarrays. Prominent increases were observed for Lsm12/Paip1 (>2-fold), translation modulators known as protein interactor/competitor of ATXN2 and for Plin3/Mttp (>1.3-fold), known as apolipoprotein modulators in agreement with the hepatosteatosis phenotype of the Atxn2−/− mice. Consistent modest upregulations were also observed for many factors in the ribosome and the translation/secretion apparatus. Quantitative reverse transcriptase PCR in liver tissue validated >1.2-fold upregulations for the ribosomal biogenesis modulator Nop10, the ribosomal components Rps10, Rps18, Rpl14, Rpl18, Gnb2l1, the translation initiation factors Eif2s2, Eif3s6, Eif4b, Pabpc1 and the rER translocase factors Srp14, Ssr1, Sec61b. Quantitative immunoblots substantiated the increased abundance of NOP10, RPS3, RPS6, RPS10, RPS18, GNB2L1 in SDS protein fractions, and of PABPC1. In mouse embryonal fibroblasts, ATXN2 absence also enhanced phosphorylation of the ribosomal protein S6 during growth stimulation, while impairing the rate of overall protein synthesis rates, suggesting a block between the enhanced translation drive and the impaired execution. Thus, the physiological role of ATXN2 subtly modifies the abundance of cellular translation factors as well as global translation.
Mesenchymal stem/stromal cells (MSCs) feature promising potential for cellular therapies, yet significant progress in development of MSC therapeutics and assays is hampered because of remarkable MSC heterogeneity in vivo and in vitro. This heterogeneity poses challenges for standardization of MSC characterization and potency assays as well as for MSC study comparability and manufacturing. This review discusses promising marker combinations for prospective MSC subpopulation enrichment and expansion, and reflects MSC phenotype changes due to environment and age. In order to address animal modelling in MSC biology, comparison of mouse and human MSC markers highlights current common ground of MSCs between species.
Ionizing radiation generates DNA double-strand breaks (DSB) which, unless faithfully repaired, can generate chromosomal rearrangements in hematopoietic stem and/or progenitor cells (HSPC), potentially priming the cells towards a leukemic phenotype. Using an enhanced green fluorescent protein (EGFP)-based reporter system, we recently identified differences in the removal of enzyme-mediated DSB in human HSPC versus mature peripheral blood lymphocytes (PBL), particularly regarding homologous DSB repair (HR). Assessment of chromosomal breaks via premature chromosome condensation or γH2AX foci indicated similar efficiency and kinetics of radiation-induced DSB formation and rejoining in PBL and HSPC. Prolonged persistence of chromosomal breaks was observed for higher LET charged particles which are known to induce more complex DNA damage compared to X-rays. Consistent with HR deficiency in HSPC observed in our previous study, we noticed here pronounced focal accumulation of 53BP1 after X-ray and carbon ion exposure (intermediate LET) in HSPC versus PBL. For higher LET, 53BP1 foci kinetics was similarly delayed in PBL and HSPC suggesting similar failure to repair complex DNA damage. Data obtained with plasmid reporter systems revealed a dose- and LET-dependent HR increase after X-ray, carbon ion and higher LET exposure, particularly in HR-proficient immortalized and primary lymphocytes, confirming preferential use of conservative HR in PBL for intermediate LET damage repair. HR measured adjacent to the leukemia-associated MLL breakpoint cluster sequence in reporter lines revealed dose dependency of potentially leukemogenic rearrangements underscoring the risk of leukemia-induction by radiation treatment.
The inhibitor of the nuclear factor-κB (IκB) kinase (IKK) complex is a key regulator of the canonical NF-κB signalling cascade and is crucial for fundamental cellular functions, including stress and immune responses. The majority of IKK complex functions are attributed to NF-κB activation; however, there is increasing evidence for NF-κB pathway-independent signalling. Here we combine quantitative mass spectrometry with random forest bioinformatics to dissect the TNF-α-IKKβ-induced phosphoproteome in MCF-7 breast cancer cells. In total, we identify over 20,000 phosphorylation sites, of which ∼1% are regulated up on TNF-α stimulation. We identify various potential novel IKKβ substrates including kinases and regulators of cellular trafficking. Moreover, we show that one of the candidates, AEG-1/MTDH/LYRIC, is directly phosphorylated by IKKβ on serine 298. We provide evidence that IKKβ-mediated AEG-1 phosphorylation is essential for IκBα degradation as well as NF-κB-dependent gene expression and cell proliferation, which correlate with cancer patient survival in vivo.
BACKGROUND: Plasminogen deficiency is a rare autosomal recessive disease, which is associated with aggressive periodontitis and gingival enlargement. Previously described treatments of plasminogen deficiency associated periodontitis have shown limited success. This is the first case report indicating a successful therapy approach consisting of a non-surgical supra- and subgingival debridement in combination with an adjunctive systemic antibiotic therapy and a strict supportive periodontal regimen over an observation period of 4 years.
CASE PRESENTATION: The intraoral examination of a 17-year-old Turkish female with severe plasminogen deficiency revealed generalized increased pocket probing depths ranging from 6 to 9 mm, bleeding on probing over 30%, generalized tooth mobility, and gingival hyperplasia. Alveolar bone loss ranged from 30% to 50%. Clinical attachment loss corresponded to pocket probing depths. Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Treponema denticola, Prevotella intermedia, Prevotella nigrescens and Eikenella corrodens have been detected by realtime polymerase chain reaction. Periodontal treatment consisted of full mouth disinfection and adjunctive systemic administration of amoxicillin (500 mg tid) and metronidazole (400 mg tid). A strict supportive periodontal therapy regimen every three month in terms of supra- and subgingival debridement was rendered. The reported therapy has significantly improved periodontal health and arrested disease progression. Intraoral examination at the end of the observation period 3.5 years after non-surgical periodontal therapy showed generalized decreased pocket probing depths ranging from 1 to 6 mm, bleeding on probing lower 30%, and tooth mobility class I and II. Furthermore, microbiological analysis shows the absence of Porphyromonas gingivalis, Prevotella intermedia and Treponema denticola after therapy.
CONCLUSION: Adjunctive antibiotic treatment may alter the oral microbiome and thus, the inflammatory response of periodontal disease associated to plasminogen deficiency and diminishes the risk of pseudomembrane formation and progressive attachment loss. This case report indicates that patients with plasminogen deficiency may benefit from non-surgical periodontal treatment in combination with an adjunctive antibiotic therapy and a strict supportive periodontal therapy regimen.
A hallmark of several major neurological diseases is neuronal cell death. In addition to this primary pathology, secondary injury is seen in connected brain regions in which neurons not directly affected by the disease are denervated. These transneuronal effects on the network contribute considerably to the clinical symptoms. Since denervated neurons are viable, they are attractive targets for intervention. Therefore, we studied the role of Sphingosine-1-phosphate (S1P)-receptor signaling, the target of Fingolimod (FTY720), in denervation-induced dendritic atrophy. The entorhinal denervation in vitro model was used to assess dendritic changes of denervated mouse dentate granule cells. Live-cell microscopy of GFP-expressing granule cells in organotypic entorhino-hippocampal slice cultures was employed to follow individual dendritic segments for up to 6 weeks after deafferentation. A set of slice cultures was treated with FTY720 or the S1P-receptor (S1PR) antagonist VPC23019. Lesion-induced changes in S1P (mass spectrometry) and S1PR-mRNA levels (laser microdissection and qPCR) were determined. Denervation caused profound changes in dendritic stability. Dendritic elongation and retraction events were markedly increased, resulting in a net reduction of total dendritic length (TDL) during the first 2 weeks after denervation, followed by a gradual recovery in TDL. These changes were accompanied by an increase in S1P and S1PR1- and S1PR3-mRNA levels, and were not observed in slice cultures treated with FTY720 or VPC23019. We conclude that inhibition of S1PR signaling prevents dendritic destabilization and denervation-induced dendrite loss. These results suggest a novel neuroprotective effect for pharmaceuticals targeting neural S1PR pathways.
In common with several other autoimmune diseases, autoimmune Addison's disease (AAD) is thought to be caused by a combination of deleterious susceptibility polymorphisms in several genes, together with undefined environmental factors and stochastic events. To date, the strongest genomic association with AAD has been with alleles at the HLA locus, DR3-DQ2 and DR4. The contribution of other genetic variants has been inconsistent. We have studied the association of 16 single-nucleotide polymorphisms (SNPs) within the CD28-CTLA-4-ICOS genomic locus, in a cohort comprising 691 AAD patients of Norwegian and UK origin with matched controls. We have also performed a meta-analysis including 1002 patients from European countries. The G-allele of SNP rs231775 in CTLA-4 is associated with AAD in Norwegian patients (odds ratio (OR)=1.35 (confidence interval (CI) 1.10-1.66), P=0.004), but not in UK patients. The same allele is associated with AAD in the total European population (OR=1.37 (CI 1.13-1.66), P=0.002). A three-marker haplotype, comprising PROMOTER_1661, rs231726 and rs1896286 was found to be associated with AAD in the Norwegian cohort only (OR 2.43 (CI 1.68-3.51), P=0.00013). This study points to the CTLA-4 gene as a susceptibility locus for the development of AAD, and refines its mapping within the wider genomic locus.
A 79 year old female patient was admitted to our emergency department with a fracture of the right medial femoral neck six days after a fall on her right side and a cemented hemiprosthesis was implanted. Five days later, she developed a hemorrhagic shock and was diagnosed with a delayed splenic rupture and the spleen was resected. Histopathological examination showed a delayed rupture of an otherwise normal spleen without signs of an underlying pathology. The outcome was fatal: In the postoperative course she developed pneumonia, three weeks later she succumbed due to multiple organ failure.
Even careful reevaluation of the case did not provide any clues to expect an injury of the spleen according to trauma mechanism.
This case shows that delayed splenic rupture of a normal spleen may occur even after a low energy trauma. Injury of the spleen should therefore always be considered, even with an uncharacteristic anamnesis. Physical examination after trauma should therefore always include a careful clinical evaluation. The clinical threshold for a FAST examination should be low.
The coincidence of a femoral neck fracture and a splenic rupture after a low energy trauma has not been reported before.
Background The endogenous amino acid homoarginine predicts mortality in cerebro‐ and cardiovascular disease. The objective was to explore whether homoarginine is associated with atrial fibrillation (AF) and outcome in patients with acute chest pain.
Methods and Results One thousand six hundred forty‐nine patients with acute chest pain were consecutively enrolled in this study, of whom 589 were diagnosed acute coronary syndrome (ACS). On admission, plasma concentrations of homoarginine as well as brain natriuretic peptide (BNP), and high‐sensitivity assayed troponin I (hsTnI) were determined along with electrocardiography (ECG) variables. During a median follow‐up of 183 days, 60 major adverse cardiovascular events (MACEs; 3.8%), including all‐cause death, myocardial infarction, or stroke, were registered in the overall study population and 43 MACEs (7.5%) in the ACS subgroup. Adjusted multivariable Cox regression analyses revealed that an increase of 1 SD of plasma log‐transformed homoarginine (0.37) was associated with a hazard reduction of 26% (hazard ratio [HR], 0.74; 95% CI, 0.57–0.96) for incident MACE and likewise of 35% (HR, 0.65; 95% CI, 0.49–0.88) in ACS patients. In Kaplan–Meier survival curves, homoarginine was predictive for patients with high‐sensitivity assayed troponin I (hsTnI) above 27 ng/L (P<0.05). Last, homoarginine was inversely associated with QTc duration (P<0.001) and prevalent AF (OR, 0.83; 95% CI, 0.71–0.95).
Conclusion Low plasma homoarginine was identified as a risk marker for incident MACEs in patients with acute chest pain, in particular, in those with elevated hsTnI. Impaired homoarginine was associated with prevalent AF. Further studies are needed to investigate the link to AF and evaluate homoarginine as a therapeutic option for these patients.
BACKGROUND: We retrospectively evaluated the efficacy and toxicity of gross tumor volume (GTV) mean-dose-optimized and real-time motion-compensated robotic stereotactic body radiation therapy (SBRT) in the treatment of liver metastases.
METHODS: Between March 2011 and July 2015, 52 patients were treated with SBRT for a total of 91 liver metastases (one to four metastases per patient) with a median GTV volume of 12 cc (min 1 cc, max 372 cc). The optimization of mean GTV dose was prioritized during treatment planning at the potential cost of planning target volume (PTV) coverage reduction while adhering to safe normal tissue constraints. The delivered median GTV biological effective dose (BED10) was 142.1 Gy10 (range, 60.2 Gy10 -165.3 Gy10) and the prescribed PTV BED10 ranged from 40.6 Gy10 to 112.5 Gy10 (median, 86.1 Gy10). We analyzed local control (LC), progression-free interval (PFI), overall survival (OS), and toxicity.
RESULTS: Median follow-up was 17 months (range, 2-49 months). The 2-year actuarial LC, PFI, and OS rates were 82.1, 17.7, and 45.0 %, and the median PFI and OS were 9 and 23 months, respectively. In univariate analysis histology (p < 0.001), PTV prescription BED10 (HR 0.95, CI 0.91-0.98, p = 0.002) and GTV mean BED10 (HR 0.975, CI 0.954-0.996, p = 0.011) were predictive for LC. Multivariate analysis showed that only extrahepatic disease status at time of treatment was a significant factor (p = 0.033 and p = 0.009, respectively) for PFI and OS. Acute nausea or fatigue grade 1 was observed in 24.1 % of the patients and only 1 patient (1.9 %) had a side effect of grade ≥ 2.
CONCLUSIONS: Robotic real-time motion-compensated SBRT is a safe and effective treatment for one to four liver metastases. Reducing the PTV prescription dose and keeping a high mean GTV dose allowed the reduction of toxicity while maintaining a high local control probability for the treated lesions.
Cortical development extensively depends on sensory experience. Effects of congenital monaural and binaural deafness on cortical aural dominance and representation of binaural cues were investigated in the present study. We used an animal model that precisely mimics the clinical scenario of unilateral cochlear implantation in an individual with single-sided congenital deafness. Multiunit responses in cortical field A1 to cochlear implant stimulation were studied in normal-hearing cats, bilaterally congenitally deaf cats (CDCs), and unilaterally deaf cats (uCDCs). Binaural deafness reduced cortical responsiveness and decreased response thresholds and dynamic range. In contrast to CDCs, in uCDCs, cortical responsiveness was not reduced, but hemispheric-specific reorganization of aural dominance and binaural interactions were observed. Deafness led to a substantial drop in binaural facilitation in CDCs and uCDCs, demonstrating the inevitable role of experience for a binaural benefit. Sensitivity to interaural time differences was more reduced in uCDCs than in CDCs, particularly at the hemisphere ipsilateral to the hearing ear. Compared with binaural deafness, unilateral hearing prevented nonspecific reduction in cortical responsiveness, but extensively reorganized aural dominance and binaural responses. The deaf ear remained coupled with the cortex in uCDCs, demonstrating a significant difference to deprivation amblyopia in the visual system.
Novel insights into the regulation of cyclooxygenase-2 expression by platelet-cancer cell cross-talk
(2015)
Platelets are activated by the interaction with cancer cells and release enhanced levels of lipid mediators [such as thromboxane (TX)A2 and prostaglandin (PG)E2, generated from arachidonic acid (AA) by the activity of cyclooxygenase (COX)-1], granule content, including ADP and growth factors, chemokines, proteases and Wnt proteins. Moreover, activated platelets shed different vesicles, such as microparticles (MPs) and exosomes (rich in genetic material such as mRNAs and miRNAs). These platelet-derived products induce several phenotypic changes in cancer cells which confer high metastatic capacity. A central event involves an aberrant expression of COX-2 which influences cell-cycle progression and contribute to the acquisition of a cell migratory phenotype through the induction of epithelial mesenchymal transition genes and down-regulation of E-cadherin expression. The identification of novel molecular determinants involved in the cross-talk between platelets and cancer cells has led to identify novel targets for anti-cancer drug development.
The wide range of immunosuppressive therapies and protocols permits tailored planning of the initial regimen according to the immunological risk status of individual patients. Pre-transplant risk assessment can include many factors, but there is no clear consensus on which parameters to take into account, and their relative importance. In general younger patients are known to be at higher risk for acute rejection, compounded by higher rates of non-adherence in adolescents. Donor age and recipient gender do not appear to exert a meaningful effect on risk of rejection per se, but black recipient ethnicity remains a well-established risk factor even under modern immunosuppression regimens. Little difference in risk is now observed between deceased- and living-donor recipients. Immunological risk assessment has developed substantially in recent years. Cross-match testing with cytotoxic analysis has long been supplemented by flow cytometry, but development of solid-phase single-bead antigen testing of solubilized human leukocyte antigens (HLA) to detect donor-specific antibodies (DSA) permits a far more nuanced stratification of immunological risk status, including the different classes and intensities of HLA antibodies Class I and/or II, including HLA-DSA. Immunologic risk evaluation is now often based on a combination of these tests, but other assessments are becoming more widely introduced, such as measurement of non-HLA antibodies against angiotensin type 1 (AT1) receptors or T-cell ELISPOT assay of alloantigen-specific donor. Targeted densensitization protocols can improve immunological risk, notably for DSA-positive patients with negative cytotoxicity and flow cross-match. HLA mismatch remains an important and undisputed risk factor for rejection. Delayed graft function also increases the risk of subsequent acute rejection, and the early regimen can be modified in such cases. Overall, there is a shift towards planning the immunosuppressive regimen based on pre-transplant immunology testing although certain conventional risk factors retain their importance.
Background: It is occasionally difficult to distinguish the stellate reticulum-like region of ameloblastoma from the fibrous connective tissue stroma. This difficulty is further pronounced in the plexiform variant of ameloblastoma that has very sparse fibrous connective tissue.
Aim: To test the utility of Azan trichrome stain in marking tumour regions and the peri-tumour environment of ameloblastoma.
Materials and Methods: Sections were prepared for 18 formalin fixed paraffin-embedded blocks of ameloblastoma cases and stained with Azan trichrome stain according to the manufacturer's specification.
Results and Conclusions: The tumour areas were stained mostly brown, with the ameloblasts mainly marked as deep brown while the stellate reticulum-like region was light brown. The structures in the peri-tumour region were marked with different shades of blue. Azan trichrome staining was able to distinguish between the fibrous connective tissue and the stellate reticulum-like areas in 100% of the cases.
Introduction: ameloblastoma is a slow growing, painless odontogenic swelling which can attain sizes that result in severe deformities of the craniofacial complex. It is the most commonly encountered odontogenic tumor in Nigeria. Surgical intervention is currently the method of treatment; however identification of altered molecular pathways may inform chemotherapeutic potential. The Protein Patched homolog 1 (PTCH-1) is overexpressed in ameloblastoma. Also, mutation in the MDM2 gene can reduce the tumor suppressor function of p53 and promote ameloblastoma growth. No study however has characterized the molecular profile of African cases of ameloblastoma with a view to developing chemotherapeutic alternatives. The objective was to characterize the PTCH-1 genetic profile of Ameloblastoma in Nigerian patients as a first step in investigating its potential for chemotherapeutic intervention.
Methods: twenty-eight FFPE blocks of ameloblastoma cases from Nigerian patients were prepared for antibody processing to PTCH-1 (Polyclonal Anti-PTCH antibody ab39266) and MDM2 (Monoclonal Anti-MDM2 antibody (2A10) ab16895). Cytoplasmic brown staining was considered as positive for PTCH while nuclear staining was positive for MDM2.
Results: moderate and strong expressions for PTCH in ameloblast and stellate reticulum were 78.6% and 60.7% respectively. Only 3 (10.7%) cases expressed MDM2.
Conclusion: the importance of our study is that it supports, in theory, anti-PTCH/SHH chemotherapeutics for Nigerian ameloblastoma cases and also infers the possible additional use of anti-p53 agents.
Protein turnover and quality control by the proteasome is of paramount importance for cell homeostasis. Dysfunction of the proteasome is associated with aging processes and human diseases such as neurodegeneration, cardiomyopathy, and cancer. The regulation, i.e. activation and inhibition of this fundamentally important protein degradation system, is still widely unexplored. We demonstrate here that the evolutionarily highly conserved type II triple-A ATPase VCP and the proteasome inhibitor PSMF1/PI31 interact directly, and antagonistically regulate proteasomal activity. Our data provide novel insights into the regulation of proteasomal activity.
Polo-like kinase 1 regulates the stability of the mitotic centromere-associated kinesin in mitosis
(2014)
Proper bi-orientation of chromosomes is critical for the accurate segregation of chromosomes in mitosis. A key regulator of this process is MCAK, the mitotic centromere-associated kinesin. During mitosis the activity and localization of MCAK are regulated by mitotic key kinases including Plk1 and Aurora B. We show here that S621 in the MCAK’s C-terminal domain is the major phosphorylation site for Plk1. This phosphorylation regulates MCAK’s stability and facilitates its recognition by the ubiquitin/proteasome dependent APC/CCdc20 pathway leading to its D-box dependent degradation in mitosis. While phosphorylation of S621 does not directly affect its microtubule depolymerising activity, loss of Plk1 phosphorylation on S621 indirectly enhances its depolymerization activity in vivo by stabilizing MCAK, leading to an increased level of protein. Interfering with phosphorylation at S621 causes spindle formation defects and chromosome misalignments. Therefore, this study suggests a new mechanism by which Plk1 regulates MCAK: by regulating its degradation and hence controlling its turnover in mitosis.