Publications by authors named "P Hoffmann"

1,331 Publications

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Analysis of deficiency of adenosine deaminase 2 pathogenesis based on single-cell RNA sequencing of monocytes.

J Leukoc Biol 2021 May 14. Epub 2021 May 14.

Hematology Branch, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, Maryland, USA.

Deficiency of adenosine deaminase 2 (DADA2) is a rare autosomal recessive disease caused by loss-of-function variants in the ADA2 gene. DADA2 typically presents in childhood and is characterized by vasculopathy, stroke, inflammation, immunodeficiency, as well as hematologic manifestations. ADA2 protein is predominantly present in stimulated monocytes, dendritic cells, and macrophages. To elucidate molecular mechanisms in DADA2, CD14 monocytes from 14 patients and 6 healthy donors were analyzed using single-cell RNA sequencing (scRNA-seq). Monocytes were purified by positive beads selection based on CD14 expression. Subpopulations were imputed from their transcriptomes. Based on scRNA-seq, monocytes could be classified as classical, intermediate, and nonclassical monocytes. Further, we used gene pathway analytics to interpret patterns of up- and down-regulated gene transcription. In DADA2, the frequency of nonclassical monocytes was higher compared with the healthy donors, and M1 macrophage markers were up-regulated in patients. By comparing gene expression of each monocyte subtype between patients and healthy donors, we identified up-regulation of immune response pathways, including IFNα/β and IFNγ signaling, in all monocyte subtypes. Distinctively, the TNFR 2 noncanonical NF-κB pathway was up-regulated only in nonclassical monocytes. Patients' plasma showed increased IFNγ and TNFα levels. Our results in DADA2 suggest that elevated IFNγ activates cell signaling, leading to differentiation into M1 macrophages from monocytes and release of TNFα. Immune responses and more general response to stimuli pathways were up-regulated in DADA2 monocytes, and protein synthesis pathways were down-regulated, perhaps as stress responses. Our identification of novel aberrant immune pathways has implications for novel therapeutic approaches in DAD2 (registered at clinicaltrials.gov NCT00071045).
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http://dx.doi.org/10.1002/JLB.3HI0220-119RRDOI Listing
May 2021

Quantitative Approach Using Matrix-Assisted Laser Desorption/Ionization Time-of-Flight (MALDI-ToF) Mass Spectrometry.

Methods Mol Biol 2021 ;2228:159-166

Future Industries Institute, University of South Australia, Adelaide, Australia.

Quantitation using mass spectrometry (MS) is a routine approach for multiple analytes, including small molecules and peptides. Electrospray-based MS platforms are typically employed, as they provide highly reproducible outputs for batch processing of multiple samples. Quantitation using matrix-assisted laser desorption/ionization (MALDI) time-of-flight (ToF) mass spectrometry, while less commonly adopted, offers the ability to monitor analytes at significantly higher throughput and lower cost compared with ESI MS. Achieving accurate quantitation using this approach requires the development of appropriate sample preparation, spiking of appropriate internal standards, and acquisition to minimize spot-to-spot variability. Here we describe the preparation of samples for accurate quantitation using MALDI-ToF MS. The methodology presented shows the ability to quantitate perfluorooctanesulfonic acid (PFOS) from contaminated water.
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http://dx.doi.org/10.1007/978-1-0716-1024-4_12DOI Listing
January 2021

The BACE1 inhibitor LY2886721 improves diabetic phenotypes of BACE1 knock-in mice.

Biochim Biophys Acta Mol Basis Dis 2021 Jul 20;1867(7):166149. Epub 2021 Apr 20.

Institute of Medical Sciences, University of Aberdeen, Foresterhill Health Campus, Aberdeen AB25 2ZD, UK. Electronic address:

Aim: The β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) has been identified as the central initiator of amyloid β (Aβ) generation in the brain, the key hallmark of Alzheimer's disease (AD). However, recent studies provided evidence that BACE1 also plays a crucial role in metabolic regulation, and we have shown that neuronal human BACE1 knock-in mice (PLB4) display type 2 diabetes mellitus (T2DM)-like symptoms alongside AD-like impairments. Hence, we here investigated if targeted BACE1 inhibition using LY2886721, an active site BACE1 inhibitor, would improve glucose homeostasis, insulin sensitivity and motor performance in PLB4 mice.

Materials And Methods: LY2886721 was administered as a dietary supplement (0.02% wt/wt) for six consecutive weeks. Physiological, metabolic and motor assessments were performed during the last two weeks of treatment, followed by molecular tissue analyses post-mortem.

Results: LY2886721 treatment improved glucose homeostasis and hepatic gluconeogenesis in diabetic PLB4 mice, as determined by improvements in basal glucose and glucose/pyruvate tolerance tests. Furthermore, LY2886721 improved hepatic insulin sensitivity, as indicated by enhanced basal hyperphosphorylation of insulin receptors. In PLB4 brains, we detected altered basal conditions of APP expression and processing, with beneficial effects on APP processing achieved by LY2886721 treatment. No improvements in motor coordination were found.

Conclusions: Our data provide support for a role of BACE1 as a regulator of systemic glucose homeostasis and suggest BACE1 inhibitors for the treatment of T2DM-associated pathologies, especially in cases where diabetes is comorbid to AD.
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http://dx.doi.org/10.1016/j.bbadis.2021.166149DOI Listing
July 2021

Scavenging of soluble and immobilized CCL21 by ACKR4 regulates peripheral dendritic cell emigration.

Proc Natl Acad Sci U S A 2021 Apr;118(17)

Chemokine Biology Laboratory, Department of Molecular and Biomedical Science, School of Biological Science, The University of Adelaide, Adelaide, SA 5005, Australia;

Leukocyte homing driven by the chemokine CCL21 is pivotal for adaptive immunity because it controls dendritic cell (DC) and T cell migration through CCR7. ACKR4 scavenges CCL21 and has been shown to play an essential role in DC trafficking at the steady state and during immune responses to tumors and cutaneous inflammation. However, the mechanism by which ACKR4 regulates peripheral DC migration is unknown, and the extent to which it regulates CCL21 in steady-state skin and lymph nodes (LNs) is contested. Specifically, our previous findings that CCL21 levels are increased in LNs of ACKR4-deficient mice [I. Comerford et al., 116, 4130-4140 (2010)] were refuted [M. H. Ulvmar et al., 15, 623-630 (2014)], and no differences in CCL21 levels in steady-state skin of ACKR4-deficient mice were reported despite compromised CCR7-dependent DC egress in these animals [S. A. Bryce et al., 196, 3341-3353 (2016)]. Here, we resolve these issues and reveal that two forms of CCL21, full-length immobilized and cleaved soluble CCL21, exist in steady-state barrier tissues, and both are regulated by ACKR4. Without ACKR4, extracellular CCL21 gradients in barrier sites are saturated and nonfunctional, DCs cannot home directly to lymphatic vessels, and excess soluble CCL21 from peripheral tissues pollutes downstream LNs. The results identify the mechanism by which ACKR4 controls DC migration in barrier tissues and reveal a complex mode of CCL21 regulation in vivo, which enhances understanding of functional chemokine gradient formation.
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http://dx.doi.org/10.1073/pnas.2025763118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092586PMC
April 2021

Surgical management of diaphragmatic and thoracic endometriosis': A French multicentric descriptive study.

J Gynecol Obstet Hum Reprod 2021 Apr 20;50(8):102147. Epub 2021 Apr 20.

Department of gynecology, Croix Rousse University Hospital, Hospices civils de Lyon (HCL), 103 Grande Rue de la Croix-Rousse, 69004 Lyon, France. Electronic address:

Introduction: Surgical management of Diaphragmatic and thoracic endometriosis (DTE) is still controversial, a thoracic or an abdominal approach can be proposed.

Methods: We conducted a multicentric retrospective study in 8 thoracic, gynecology or digestive surgery units in 5 French university hospitals. The main objective was to review the current management of DTE.

Results: 50 patients operated for DTE from 2010 to 2017 were included: 26 with a thoracic approach and 24 with an abdominal approach. Preoperative pelvic endometriosis (PE) concerned 25 patients. In 38 patients, DTE diagnosis was made on clinical symptoms (pneumothorax (n = 19), chronic or catamenial chest pain (n = 18) or hemopneumothorax (n = 1)). Median time from onset of symptoms to diagnosis was 47 months (0-212). PE surgery concurrently occurred in 22 patients. We report diaphragmatic nodules, pleuropulmonary nodules and diaphragmatic perforations in 42, 5 and 22 women respectively. Lesions were right-sided in 45 patients. Nodules were destructed in 12 cases and resected in 38 cases. When a diaphragmatic reconstruction was needed (n = 31), a simple suture was performed in 26 patients, while 5 patients needed a mesh repair. Pleural symphysis was performed for all patients who received a thoracic approach. DTE resection was considered complete in 46 patients. Three patients had severe 30-days complications of DTE surgery. Median follow-up was 20 months (range 1-69). Recurrence occurred in 10 patients.

Conclusion: The results emphasize the importance of systematically looking for chest pain in patients suffering from PE and underline the lack of a standardized procedure and treatment in DTE.
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http://dx.doi.org/10.1016/j.jogoh.2021.102147DOI Listing
April 2021