CD19 CAR T-Cell Therapy in Autoimmune Disease - A Case Series with Follow-up.

BACKGROUND: Treatment for autoimmune diseases such as systemic lupus erythematosus (SLE), idiopathic inflammatory myositis, and systemic sclerosis often involves long-term immune suppression. Resetting aberrant autoimmunity in these diseases through deep depletion of B cells is a potential strategy for achieving sustained drug-free remission. METHODS: We evaluated 15 patients with severe SLE (8 patients), idiopathic inflammatory myositis (3 patients), or systemic sclerosis (4 patients) who received a single infusion of CD19 chimeric antigen receptor (CAR) T cells after preconditioning with fludarabine and cyclophosphamide. Efficacy up to 2 years after CAR T-cell infusion was assessed by means of Definition of Remission in SLE (DORIS) remission criteria, American College of Rheumatology-European League against Rheumatism (ACR-EULAR) major clinical response, and the score on the European Scleroderma Trials and Research Group (EUSTAR) activity index (with higher scores indicating greater disease activity), among others. Safety variables, including cytokine release syndrome and infections, were recorded. RESULTS: The median follow-up was 15 months (range, 4 to 29). The mean (±SD) duration of B-cell aplasia was 112±47 days. All the patients with SLE had DORIS remission, all the patients with idiopathic inflammatory myositis had an ACR-EULAR major clinical response, and all the patients with systemic sclerosis had a decrease in the score on the EUSTAR activity index. Immunosuppressive therapy was completely stopped in all the patients. Grade 1 cytokine release syndrome occurred in 10 patients. One patient each had grade 2 cytokine release syndrome, grade 1 immune effector cell-associated neurotoxicity syndrome, and pneumonia that resulted in hospitalization. CONCLUSIONS: In this case series, CD19 CAR T-cell transfer appeared to be feasible, safe, and efficacious in three different autoimmune diseases, providing rationale for further controlled clinical trials. (Funded by Deutsche Forschungsgemeinschaft and others.).

Performance of serum biomarkers reflective of different pathogenic processes in systemic sclerosis-associated interstitial lung disease.

OBJECTIVE: Interstitial lung disease (ILD) is the leading cause of mortality in SSc. Novel biomarkers are crucial to improve outcomes in SSc-ILD. We aimed to compare the performance of potential serum biomarkers of SSc-ILD that reflect different pathogenic processes: KL-6 and SP-D (epithelial injury), CCL18 (type 2 immune response), YKL-40 (endothelial injury and matrix remodelling) and MMP-7 (ECM remodelling). METHODS: Baseline and follow-up serum samples from 225 SSc patients were analysed by ELISA. Progressive ILD was defined according to the 2022-ATS/ERS/JRS/ALAT guidelines. Linear mixed models and random forest models were used for statistical analyses. RESULTS: Serum levels of KL-6 [MD 35.67 (95% CI 22.44-48.89, P < 0.01)], SP-D [81.13 (28.46-133.79, P < 0.01)], CCL18 [17.07 (6.36-27.77, P < 0.01)], YKL-40 [22.81 (7.19-38.44, P < 0.01)] and MMP-7 [2.84 (0.88-4.80, P < 0.01)] were independently associated with the presence of SSc-ILD. A machine-learning model including all candidates classified patients with or without ILD with an accuracy of 85%. The combination of KL-6 and SP-D was associated with the presence [0.77 (0.53-1.00, P' <0.01)] and previous progression of SSc-ILD [OR 1.28 (1.01-1.61, P' =0.047)]. Higher baseline levels of KL-6 [OR 3.70 (1.52-9.03, P < 0.01)] or SP-D [OR 2.00 (1.06-3.78, P = 0.03)] increased the odds of future SSc-ILD progression, independent of other conventional risk factors, and the combination of KL-6 and SP-D [1.109 (0.665-1.554, P < 0.01)] showed improved performance compared with KL-6 and SP-D alone. CONCLUSION: All candidates performed well as diagnostic biomarkers for SSc-ILD. The combination of KL-6 and SP-D might serve as biomarker for the identification of SSc patients at risk of ILD progression.

Assessment of myocardial fibrosis in patients with systemic sclerosis using [68Ga]Ga-FAPI-04-PET-CT.

PURPOSE: Myocardial fibrosis (MF) is a factor of poor prognosis in systemic sclerosis (SSc). Direct in-vivo visualization of fibroblast activation as early readout of MF has not been feasible to date. Here, we characterize 68Gallium-labeled-Fibroblast-Activation-Inhibitor-04 ([68Ga]Ga-FAPI-04)-PET-CT as a diagnostic tool in SSc-related MF. METHODS: In this proof-of-concept trial, six SSc patients with and eight without MF of the EUSTAR cohort Erlangen underwent [68Ga]Ga-FAPI-04-PET-CT and cardiac MRI (cMRI) and clinical and serologic investigations just before baseline and during follow-up between January 2020 and December 2020. Myocardial biopsy was performed as clinically indicated. RESULTS: [68Ga]Ga-FAPI-04 tracer uptake was increased in SSc-related MF with higher uptake in SSc patients with arrhythmias, elevated serum-NT-pro-BNP, and increased late gadolinium enhancement (LGE) in cMRI. Histologically, myocardial biopsies from cMRI- and [68Ga]Ga-FAPI-04-positive regions confirmed the accumulation of FAP+ fibroblasts surrounded by collagen deposits. We observed similar but not equal spatial distributions of [68Ga]Ga-FAPI-04 uptake and quantitative cMRI-based techniques. Using sequential [68Ga]Ga-FAPI-04-PET-CTs, we observed dynamic changes of [68Ga]Ga-FAPI-04 uptake associated with changes in the activity of SSc-related MF, while cMRI parameters remained stable after regression of molecular activity and rather indicated tissue damage. CONCLUSIONS: We present first in-human evidence that [68Ga]Ga-FAPI-04 uptake visualizes fibroblast activation in SSc-related MF and may be a diagnostic option to monitor cardiac fibroblast activity in situ.

Diagnostic delay stages and pre-diagnostic treatment in patients with suspected rheumatic diseases before special care consultation: results of a multicenter-based study.

Early and effective discrimination (triage) of patients with inflammatory rheumatic diseases (IRD) and other diseases (non-IRD) is essential for successful treatment and preventing damage. The aim of this study was to investigate diagnostic delays and pre-diagnosis treatment in patients newly presenting to rheumatology outpatient clinics. A total of 600 patients newly presenting to one university hospital and two non-academic centers were included. Time from onset of symptoms to rheumatology consultation "total delay" as well as medical treatment before consultation were recorded. Median time from symptom onset to rheumatologist appointment (total delay) was 30 weeks. Median time to online search, first physician appointment request and first physician appointment was 2, 4 and 5 weeks, respectively. Total delay was significantly shorter for IRD patients compared to non-IRD patients, 26 vs 35 weeks (p = 0.007). Only 17.7% of all patients and 22.9% of IRD patients had a delay of less than 12 weeks. Total delay was significantly lower in patients seen in non-academic centers compared to the university center, 20 vs 50 weeks (p < 0.0001). 32.2% of IRD patients received medical treatment that eased their symptoms prior to the rheumatology appointment. These findings highlight the persistent diagnostic delays in rheumatology; however, they also suggest that current triage strategies effectively lead to earlier appointments for IRD patients. Improvement of triage methods and pre-diagnosis treatment could decrease overall burden of disease in IRD patients.

Long-Term Follow-Up after Surgery for Chronic Pancreatitis: A Bicentric Retrospective Experience.

INTRODUCTION: The impact of surgery on nutritional status, pancreatic function, and symptoms of patients affected by chronic pancreatitis (CP) has not been unequivocally determined. This study aimed to evaluate clinical follow-up after surgery for CP in an Italian-Austrian population. MATERIALS AND METHODS: Patients operated for CP at two high-volume centers between 2000 and 2018 were analyzed. The following parameters were compared between the pre- and postoperative period: nutritional status, endocrine and exocrine pancreatic functions, and chronic pain. RESULTS: Overall, 186 patients underwent surgery for CP. Among these, 68 (40%) answered a specific follow-up questionnaire. The body mass index showed a significant increase between pre- and postoperative assessments (21.1 vs. 22.5 p = 0.003). Furthermore, a 60% decrease in the prevalence of chronic pain (81 vs. 21%, p < 0.001) was observed. On the contrary, both exocrine and endocrine pancreatic functions pointed toward a worsening after surgery, with consistent higher rates of patients presenting with diabetes mellitus, as well as patients requiring insulin therapy and oral intake of pancreatic enzymes. The analysis of body composition performed on 40 (24%) patients with a complete imaging pack revealed no significant change in the nutritional status after surgery. DISCUSSION/CONCLUSION: Despite the good results observed in terms of pain relief, the surgical approach led to a consistent worsening of the global pancreatic function. No significant influence of surgery on the nutritional status of patients was detected.

Ten easy steps to conducting transparent, reproducible meta-analyses for infant researchers.

Meta-analyses provide researchers with an overview of the body of evidence in a topic, with quantified estimates of effect sizes and the role of moderators, and weighting studies according to their precision. We provide a guide for conducting a transparent and reproducible meta-analysis in the field of developmental psychology within the framework of the MetaLab platform, in 10 steps: (1) Choose a topic for your meta-analysis, (2) Formulate your research question and specify inclusion criteria, (3) Preregister and document all stages of your meta-analysis, (4) Conduct the literature search, (5) Collect and screen records, (6) Extract data from eligible studies, (7) Read the data into analysis software and compute effect sizes, (8) Visualize your data, (9) Create meta-analytic models to assess the strength of the effect and investigate possible moderators, (10) Write up and promote your meta-analysis. Meta-analyses can inform future studies, through power calculations, by identifying robust methods and exposing research gaps. By adding a new meta-analysis to MetaLab, datasets across multiple topics of developmental psychology can be synthesized, and the dataset can be maintained as a living, community-augmented meta-analysis to which researchers add new data, allowing for a cumulative approach to evidence synthesis.

Improving the generalizability of infant psychological research: The ManyBabies model.

Yarkoni's analysis clearly articulates a number of concerns limiting the generalizability and explanatory power of psychological findings, many of which are compounded in infancy research. ManyBabies addresses these concerns via a radically collaborative, large-scale and open approach to research that is grounded in theory-building, committed to diversification, and focused on understanding sources of variation.

X-linked inhibitor of apoptosis protein (XIAP) inhibition in systemic sclerosis (SSc).

OBJECTIVE: X-linked inhibitor of apoptosis protein (XIAP) is a multifunctional protein with important functions in apoptosis, cellular differentiation and cytoskeletal organisation and is emerging as potential target for the treatment of various cancers. The aim of the current study was to investigate the role of XIAP in the pathogenesis of systemic sclerosis (SSc). METHODS: The expression of XIAP in human skin samples of patients with SSc and chronic graft versus host disease (cGvHD) and healthy individuals was analysed by quantitative PCR, immunofluorescence (IF) and western blot. XIAP was inactivated by siRNA-mediated knockdown and pharmacological inhibition. The effects of XIAP inactivation were analysed in cultured fibroblasts and in the fibrosis models bleomycin-induced and topoisomerase-I-(topoI)-induced fibrosis and in Wnt10b-transgenic mice. RESULTS: The expression of XIAP, but not of other inhibitor of apoptosis protein family members, was increased in fibroblasts in SSc and sclerodermatous cGvHD. Transforming growth factor beta (TGF-ß) induced the expression of XIAP in a SMAD3-dependent manner. Inactivation of XIAP reduced WNT-induced fibroblast activation and collagen release. Inhibition of XIAP also ameliorated fibrosis induced by bleomycin, topoI and overexpression of Wnt10b in well-tolerated doses. The profibrotic effects of XIAP were mediated via WNT/ß-catenin signalling. Inactivation of XIAP reduces binding of ß-catenin to TCF to in a TLE-dependent manner to block WNT/ß-catenin-dependent transcription. CONCLUSIONS: Our data characterise XIAP as a novel link between two core pathways of fibrosis. XIAP is overexpressed in SSc and cGvHD in a TGF-ß/SMAD3-dependent manner and in turn amplifies the profibrotic effects of WNT/ß-catenin signalling on fibroblasts via transducin-like enhancer of split 3. Targeted inactivation of XIAP inhibits the aberrant activation of fibroblasts in murine models of SSc.

Surgery for chronic pancreatitis: the comparison of two high-volume centers reveals lack of a uniform operative management.

PURPOSE: Many aspects of surgical therapy for chronic pancreatitis (CP), including the correct indication and timing, as well as the most appropriate operative techniques, are still a matter of debate in the surgical community and vary widely across different centers. The aim of the present study was to uncover and analyze these differences by comparing the experiences of two specialized surgical units in Italy and Austria. METHODS: All patients operated for CP between 2000 and 2018 at the two centers involved were included in this retrospective analysis. Data regarding the clinical history and the pre- and perioperative surgical course were analyzed and compared between the two institutions. RESULTS: Our analysis showed a progressive decrease in the annual rate of pancreatic surgical procedures performed for CP in Verona (no. = 91) over the last two decades (from 3% to less than 1%); by contrast, this percentage increased from 3 to 9% in Vienna (no. = 77) during the same time frame. Considerable differences were also detected with regard to the timing of surgery from the first diagnosis of CP - 4 years (IQR 5.5) in the Austrian series vs two (IQR 4.0) in the Italian series -, and of indications for surgery, with a 12% higher prevalence of groove pancreatitis among patients in the Verona cohort. CONCLUSION: The comparison of the surgical attitude towards CP between two surgical centers proved that a consistent approach to this pathology still is lacking. The identification of common guidelines and labels of surgical eligibility is advisable in order to avoid interinstitutional treatment disparities.

PGC-1α regulates autophagy to promote fibroblast activation and tissue fibrosis.

OBJECTIVES: Coactivators are a heterogeneous family of transcriptional regulators that are essential for modulation of transcriptional outcomes and fine-tune numerous cellular processes. The aim of the present study was to evaluate the role of the coactivator peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) in the pathogenesis of systemic sclerosis (SSc). METHODS: Expression of PGC-1α was analysed by real-time PCR, western blot and immunofluorescence. Modulation of autophagy was analysed by reporter studies by expression of autophagy-related genes. The effects of PGC-1α knockdown on collagen production and myofibroblast differentiation were analysed in cultured human fibroblasts and in two mouse models with fibroblast-specific knockout of PGC-1α. RESULTS: The expression of PGC-1α was induced in dermal fibroblasts of patients with SSc and experimental murine fibrosis. Transforming growth factor beta (TGFß), hypoxia and epigenetic mechanisms regulate the expression of PGC-1α in fibroblasts. Knockdown of PGC-1α prevented the activation of autophagy by TGFß and this translated into reduced fibroblast-to-myofibroblast differentiation and collagen release. Knockout of PGC-1α in fibroblasts prevented skin fibrosis induced by bleomycin and by overexpression of a constitutively active TGFß receptor type I. Moreover, pharmacological inhibition of PGC-1α by SR18292 induced regression of pre-established, bleomycin-induced skin fibrosis. CONCLUSION: PGC-1α is upregulated in SSc and promotes autophagy to foster TGFß-induced fibroblast activation. Targeting of PGC-1α prevents aberrant autophagy, inhibits fibroblast activation and tissue fibrosis and may over therapeutic potential.

Disentangling inflammatory from fibrotic disease activity by fibroblast activation protein imaging.

OBJECTIVES: To date, there is no valuable tool to assess fibrotic disease activity in humans in vivo in a non-invasive way. This study aims to uncouple inflammatory from fibrotic disease activity in fibroinflammatory diseases such as IgG4-related disease. METHODS: In this cross-sectional clinical study, 27 patients with inflammatory, fibrotic and overlapping manifestations of IgG4-related disease underwent positron emission tomography (PET) scanning with tracers specific for fibroblast activation protein (FAP; 68Ga-FAP inhibitor (FAPI)-04), 18F-fluorodeoxyglucose (FDG), MRI and histopathological assessment. In a longitudinal approach, 18F-FDG and 68Ga-FAPI-04 PET/CT data were evaluated before and after immunosuppressive treatment and correlated to clinical and MRI data. RESULTS: Using combination of 68Ga-FAPI-04 and 18F-FDG-PET, we demonstrate that non-invasive functional tracking of IgG4-related disease evolution from inflammatory towards a fibrotic outcome becomes feasible. 18F-FDG-PET positive lesions showed dense lymphoplasmacytic infiltration of IgG4+ cells in histology, while 68Ga-FAPI-04 PET positive lesions showed abundant activated fibroblasts expressing FAP according to results from RNA-sequencing of activated fibroblasts. The responsiveness of fibrotic lesions to anti-inflammatory treatment was far less pronounced than that of inflammatory lesions. CONCLUSION: FAP-specific PET/CT permits the discrimination between inflammatory and fibrotic activity in IgG4-related disease. This finding may profoundly change the management of certain forms of immune-mediated disease, such as IgG4-related disease, as subtypes dominated by fibrosis may require different approaches to control disease progression, for example, specific antifibrotic agents rather than broad spectrum anti-inflammatory treatments such as glucocorticoids.

Preregistration in infant research-A primer.

Preregistration, the act of specifying a research plan in advance, is becoming more common in scientific research. Infant researchers contend with unique problems that might make preregistration particularly challenging. Infants are a hard-to-reach population, usually yielding small sample sizes, they can only complete a limited number of trials, and they can be excluded based on hard-to-predict complications (e.g., parental interference, fussiness). In addition, as effects themselves potentially change with age and population, it is hard to calculate an a priori effect size. At the same time, these very factors make preregistration in infant studies a valuable tool. A priori examination of the planned study, including the hypotheses, sample size, and resulting statistical power, increases the credibility of single studies and adds value to the field. Preregistration might also improve explicit decision making to create better studies. We present an in-depth discussion of the issues uniquely relevant to infant researchers, and ways to contend with them in preregistration and study planning. We provide recommendations to researchers interested in following current best practices.

Improving the robustness of infant lexical processing speed measures.

Visual reaction times to target pictures after naming events are an informative measurement in language acquisition research, because gaze shifts measured in looking-while-listening paradigms are an indicator of infants' lexical speed of processing. This measure is very useful, as it can be applied from a young age onwards and has been linked to later language development. However, to obtain valid reaction times, the infant is required to switch the fixation of their eyes from a distractor to a target object. This means that usually at least half the trials have to be discarded-those where the participant is already fixating the target at the onset of the target word-so that no reaction time can be measured. With few trials, reliability suffers, which is especially problematic when studying individual differences. In order to solve this problem, we developed a gaze-triggered looking-while-listening paradigm. The trials do not differ from the original paradigm apart from the fact that the target object is chosen depending on the infant's eye fixation before naming. The object the infant is looking at becomes the distractor and the other object is used as the target, requiring a fixation switch, and thus providing a reaction time. We tested our paradigm with forty-three 18-month-old infants, comparing the results to those from the original paradigm. The Gaze-triggered paradigm yielded more valid reaction time trials, as anticipated. The results of a ranked correlation between the conditions confirmed that the manipulated paradigm measures the same concept as the original paradigm.

Building a collaborative Psychological Science: Lessons learned from ManyBabies 1.

The field of infancy research faces a difficult challenge: some questions require samples that are simply too large for any one lab to recruit and test. ManyBabies aims to address this problem by forming large-scale collaborations on key theoretical questions in developmental science, while promoting the uptake of Open Science practices. Here, we look back on the first project completed under the ManyBabies umbrella - ManyBabies 1 - which tested the development of infant-directed speech preference. Our goal is to share the lessons learned over the course of the project and to articulate our vision for the role of large-scale collaborations in the field. First, we consider the decisions made in scaling up experimental research for a collaboration involving 100+ researchers and 70+ labs. Next, we discuss successes and challenges over the course of the project, including: protocol design and implementation, data analysis, organizational structures and collaborative workflows, securing funding, and encouraging broad participation in the project. Finally, we discuss the benefits we see both in ongoing ManyBabies projects and in future large-scale collaborations in general, with a particular eye towards developing best practices and increasing growth and diversity in infancy research and psychological science in general. Throughout the paper, we include first-hand narrative experiences, in order to illustrate the perspectives of researchers playing different roles within the project. While this project focused on the unique challenges of infant research, many of the insights we gained can be applied to large-scale collaborations across the broader field of psychology.

Acyltransferase skinny hedgehog regulates TGFß-dependent fibroblast activation in SSc.

OBJECTIVES: Systemic sclerosis (SSc) is characterised by aberrant hedgehog signalling in fibrotic tissues. The hedgehog acyltransferase (HHAT) skinny hedgehog catalyses the attachment of palmitate onto sonic hedgehog (SHH). Palmitoylation of SHH is required for multimerisation of SHH proteins, which is thought to promote long-range, endocrine hedgehog signalling. The aim of this study was to evaluate the role of HHAT in the pathogenesis of SSc. METHODS: Expression of HHAT was analysed by real-time polymerase chain reaction(RT-PCR), immunofluorescence and histomorphometry. The effects of HHAT knockdown were analysed by reporter assays, target gene studies and quantification of collagen release and myofibroblast differentiation in cultured human fibroblasts and in two mouse models. RESULTS: The expression of HHAT was upregulated in dermal fibroblasts of patients with SSc in a transforming growth factor-ß (TGFß)/SMAD-dependent manner. Knockdown of HHAT reduced TGFß-induced hedgehog signalling as well as myofibroblast differentiation and collagen release in human dermal fibroblasts. Knockdown of HHAT in the skin of mice ameliorated bleomycin-induced and topoisomerase-induced skin fibrosis. CONCLUSION: HHAT is regulated in SSc in a TGFß-dependent manner and in turn stimulates TGFß-induced long-range hedgehog signalling to promote fibroblast activation and tissue fibrosis. Targeting of HHAT might be a novel approach to more selectively interfere with the profibrotic effects of long-range hedgehog signalling.

Protein kinases G are essential downstream mediators of the antifibrotic effects of sGC stimulators.

OBJECTIVES: Stimulators of soluble guanylate cyclase (sGC) are currently investigated in clinical trials for the treatment of fibrosis in systemic sclerosis (SSc). In this study, we aim to investigate the role of protein kinases G (PKG) as downstream mediators of sGC-cyclic guanosine monophosphate (cGMP) in SSc. METHODS: Mice with combined knockout of PKG1 and 2 were challenged with bleomycin and treated with the sGC stimulator BAY 41-2272. Fibroblasts were treated with BAY 41-2272 and with the PKG inhibitor KT 5823. RESULTS: PKG1 and 2 are upregulated in SSc in a transforming growth factor-ß1 (TGFß1)-dependent manner, as an attempt to compensate for the decreased signalling through the sGC-cGMP-PKG pathway. Inhibition or knockout of PKG1 and 2 abrogates the inhibitory effects of sGC stimulation on fibroblast activation in a SMAD-independent, but extracellular signal-regulated kinase (ERK)-dependent manner. In vivo, sGC stimulation fails to prevent bleomycin-induced fibrosis in PKG1 and 2 knockout mice. CONCLUSIONS: Our data provide evidence that PKGs are essential mediators of the antifibrotic effects of sGC stimulators through interfering with non-canonical TGFß signalling. TGFß1 promotes its profibrotic effects through inhibition of sGC-cGMP-PKG signalling, sGC stimulation exerts its antifibrotic effects by inhibition of TGFß1-induced ERK phosphorylation.

The histone demethylase Jumonji domain-containing protein 3 (JMJD3) regulates fibroblast activation in systemic sclerosis.

OBJECTIVES: Systemic sclerosis (SSc) fibroblasts remain activated even in the absence of exogenous stimuli. Epigenetic alterations are thought to play a role for this endogenous activation. Trimethylation of histone H3 on lysine 27 (H3K27me3) is regulated by Jumonji domain-containing protein 3 (JMJD3) and ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX) in a therapeutically targetable manner. The aim of this study was to explore H3K27me3 demethylases as potential targets for the treatment of fibrosis. METHODS: JMJD3 was inactivated by small interfering RNA-mediated knockdown and by pharmacological inhibition with GSKJ4. The effects of targeted inactivation of JMJD3 were analysed in cultured fibroblasts and in the murine models of bleomycin-induced and topoisomerase-I (topoI)-induced fibrosis. H3K27me3 at the FRA2 promoter was analysed by ChIP. RESULTS: The expression of JMJD3, but not of UTX, was increased in fibroblasts in SSc skin and in experimental fibrosis in a transforming growth factor beta (TGFß)-dependent manner. Inactivation of JMJD3 reversed the activated fibroblast phenotype in SSc fibroblasts and prevented the activation of healthy dermal fibroblasts by TGFß. Pharmacological inhibition of JMJD3 ameliorated bleomycin-induced and topoI-induced fibrosis in well-tolerated doses. JMJD3 regulated fibroblast activation in a FRA2-dependent manner: Inactivation of JMJD3 reduced the expression of FRA2 by inducing accumulation of H3K27me3 at the FRA2 promoter. Moreover, the antifibrotic effects of JMJD3 inhibition were reduced on knockdown of FRA2. CONCLUSION: We present first evidence for a deregulation of JMJD3 in SSc. JMJD3 modulates fibroblast activation by regulating the levels of H3K27me3 at the promoter of FRA2. Targeted inhibition of JMJD3 limits the aberrant activation of SSc fibroblasts and exerts antifibrotic effects in two murine models.

Promoting Replicability in Developmental Research Through Meta-analyses: Insights From Language Acquisition Research.

Previous work suggests that key factors for replicability, a necessary feature for theory building, include statistical power and appropriate research planning. These factors are examined by analyzing a collection of 12 standardized meta-analyses on language development between birth and 5 years. With a median effect size of Cohen's d = .45 and typical sample size of 18 participants, most research is underpowered (range = 6%-99%; median = 44%); and calculating power based on seminal publications is not a suitable strategy. Method choice can be improved, as shown in analyses on exclusion rates and effect size as a function of method. The article ends with a discussion on how to increase replicability in both language acquisition studies specifically and developmental research more generally.

Inhibition of phosphodiesterase 4 (PDE4) reduces dermal fibrosis by interfering with the release of interleukin-6 from M2 macrophages.

OBJECTIVES: To investigate the disease-modifying effects of phosphodiesterase 4 (PDE4) inhibition in preclinical models of systemic sclerosis (SSc). METHODS: We studied the effects of PDE4 inhibition in a prevention and a treatment model of bleomycin-induced skin fibrosis, in the topoisomerase mouse model as well as in a model of sclerodermatous chronic graft-versus-host disease. To better understand the mode of action of PDE4 blockade in preclinical models of SSc, we investigated fibrosis-relevant mediators in fibroblasts and macrophages from healthy individuals and patients suffering from diffuse-cutaneous SSc on blockade of PDE4. RESULTS: Specific inhibition of PDE4 by rolipram and apremilast had potent antifibrotic effects in bleomycin-induced skin fibrosis models, in the topoisomerase I mouse model and in murine sclerodermatous chronic graft-versus-host disease. Fibroblasts were not the direct targets of the antifibrotic effects of PDE4 blockade. Reduced leucocyte infiltration in lesional skin on PDE4 blockade suggested an immune-mediated mechanism. Further analysis revealed that PDE4 inhibition decreased the differentiation of M2 macrophages and the release of several profibrotic cytokines, resulting in reduced fibroblast activation and collagen release. Within these profibrotic mediators, interleukin-6 appeared to play a central role. CONCLUSIONS: PDE4 inhibition reduces inflammatory cell activity and the release of profibrotic cytokines from M2 macrophages, leading to decreased fibroblast activation and collagen release. Importantly, apremilast is already approved for the treatment of psoriasis and psoriatic arthritis. Therefore, PDE4 inhibitors might be further developed as potential antifibrotic therapies for patients with SSc. Our findings suggest that particularly patients with inflammation-driven fibrosis might benefit from PDE4 blockade.