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2.
J Mycol Med ; 34(1): 101456, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38042013

ABSTRACT

Trichophyton rubrum is a common fungal pathogen that usually causes superficial infection limited to epidermis only, so called dermatophytosis. However in immunocompromised patients, dermatophytosis can be exceptionally more invasive with extensive lesions involving deep tissues and generating sometimes systemic course. We report the case of a 43-year-old heart transplanted man, who presented with multiple deep-seated nodules and papules in the inguinal areas and in the buttocks. Involvement of Trichophyton rubrum was confirmed by culture, DNA sequencing and histological examination that showed granulomatous inflammatory infiltrates with the presence of hyphae in the dermis. Antifungal therapy with oral terbinafine for four weeks was successful; in spite of initial remnant atrophic scars, the lesions were completely cleared after four month evolution. Deep-seated invasive dermatophytosis is rare, but should be considered with immunocompromised conditions, especially when history of previous superficial dermatophytosis is present.


Subject(s)
Arthrodermataceae , Muscular Dystrophy, Duchenne , Tinea , Male , Humans , Adult , Antifungal Agents/therapeutic use , Tinea/complications , Tinea/diagnosis , Tinea/drug therapy , Muscular Dystrophy, Duchenne/drug therapy , Trichophyton/genetics
3.
Curr Oncol Rep ; 25(9): 989-996, 2023 09.
Article in English | MEDLINE | ID: mdl-37266890

ABSTRACT

PURPOSE OF REVIEW: Immune checkpoint inhibitors (ICIs) demonstrated robust antitumor activity and tolerable safety in advanced melanoma. Data on long-term outcome of patients who benefited from this therapy and who are still free of progression despite ICI discontinuation is now available. We review here the characteristics of long-term ICI responders and address the critical question of cure. RECENT FINDINGS: Long-term outcome of patients with metastatic melanoma enrolled in large phase 2 and phase 3 clinical trials evaluating ICI in metastatic melanoma is now available. Durable responses, with more than 6 years of median follow-up, may persist after discontinuation. They occur more frequently in patients who achieved a complete response rather than in patients who had partial response or stable disease. Although long-term clinical benefit is more frequent in patients with high PDL-1 expression and smaller tumor burden, durable response may also be observed regardless of baseline characteristics. In patients with asymptomatic brain metastasis, combined immunotherapy (ipilimumab plus nivolumab) may also lead to long-term remission. Clinical trials confirm the durable antitumor activity of ICI. Although the hope for cure seems reasonable for many patients in this situation, late relapses may occur and no relapse-predictive biomarkers have been identified yet. Long-term responders who relapse can respond to a rechallenge of ICI although data are limited concerning the rate and the duration of this new response.


Subject(s)
Melanoma , Neoplasm Recurrence, Local , Humans , Neoplasm Recurrence, Local/drug therapy , Melanoma/drug therapy , Nivolumab/therapeutic use , Ipilimumab/therapeutic use , Immunotherapy/adverse effects
5.
NPJ Parkinsons Dis ; 9(1): 21, 2023 Feb 07.
Article in English | MEDLINE | ID: mdl-36750568

ABSTRACT

Expression or phosphorylation levels of leucine-rich repeat kinase 2 (LRRK2) and its Rab substrates have strong potential as disease or pharmacodynamic biomarkers. The main objective of this study is therefore to assess the LRRK2-Rab pathway for use as biomarkers in human, non-human primate (NHP) and rat urine. With urine collected from human subjects and animals, we applied an ultracentrifugation based fractionation protocol to isolate small urinary extracellular vesicles (uEVs). We used western blot with antibodies directed against total and phosphorylated LRRK2, Rab8, and Rab10 to measure these LRRK2 and Rab epitopes in uEVs. We confirm the presence of LRRK2 and Rab8/10 in human and NHP uEVs, including total LRRK2 as well as phospho-LRRK2, phospho-Rab8 and phospho-Rab10. We also confirm LRRK2 and Rab expression in rodent uEVs. We quantified LRRK2 and Rab epitopes in human cohorts and found in a first cohort that pS1292-LRRK2 levels were elevated in individuals carrying the LRRK2 G2019S mutation, without significant differences between healthy and PD groups, whether for LRRK2 G2019S carriers or not. In a second cohort, we found that PD was associated to increased Rab8 levels and decreased pS910-LRRK2 and pS935-LRRK2. In animals, acute treatment with LRRK2 kinase inhibitors led to decreased pT73-Rab10. The identification of changes in Rab8 and LRRK2 phosphorylation at S910 and S935 heterologous phosphosites in uEVs of PD patients and pT73-Rab10 in inhibitor-dosed animals further reinforces the potential of the LRRK2-Rab pathway as a source of PD and pharmacodynamic biomarkers in uEVs.

6.
Mov Disord ; 37(8): 1761-1767, 2022 08.
Article in English | MEDLINE | ID: mdl-35708213

ABSTRACT

BACKGROUND: Pathogenic variants in the LRRK2 gene are a common monogenic cause of Parkinson's disease. However, only seven variants have been confirmed to be pathogenic. OBJECTIVES: We identified two novel LRRK2 variants (H230R and A1440P) and performed functional testing. METHODS: We transiently expressed wild-type, the two new variants, or two known pathogenic mutants (G2019S and R1441G) in HEK-293 T cells, with or without LRRK2 kinase inhibitor treatment. We characterized the phosphorylation and kinase activity of the mutants by western blotting. Thermal shift assays were performed to determine the folding and stability of the LRRK2 proteins. RESULTS: The two variants were found in two large families and segregate with the disease. They display altered LRRK2 phosphorylation and kinase activity. CONCLUSIONS: We identified two novel LRRK2 variants which segregate with the disease. The results of functional testing lead us to propose these two variants as novel causative mutations for familial Parkinson's disease. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Subject(s)
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 , Parkinson Disease , HEK293 Cells , Humans , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics , Mutation/genetics , Parkinson Disease/genetics , Parkinson Disease/pathology , Protein Serine-Threonine Kinases/genetics
7.
Cells ; 11(6)2022 03 17.
Article in English | MEDLINE | ID: mdl-35326469

ABSTRACT

The Leucine Rich Repeat Kinase 2 (LRRK2) gene is a major genetic determinant of Parkinson's disease (PD), encoding a homonymous multi-domain protein with two catalytic activities, GTPase and Kinase, involved in intracellular signaling and trafficking. LRRK2 is phosphorylated at multiple sites, including a cluster of autophosphorylation sites in the GTPase domain and a cluster of heterologous phosphorylation sites at residues 860 to 976. Phosphorylation at these latter sites is found to be modified in brains of PD patients, as well as for some disease mutant forms of LRRK2. The main aim of this study is to investigate the functional consequences of LRRK2 phosphorylation or dephosphorylation at LRRK2's heterologous phosphorylation sites. To this end, we generated LRRK2 phosphorylation site mutants and studied how these affected LRRK2 catalytic activity, neurite outgrowth and lysosomal physiology in cellular models. We show that phosphorylation of RAB8a and RAB10 substrates are reduced with phosphomimicking forms of LRRK2, while RAB29 induced activation of LRRK2 kinase activity is enhanced for phosphodead forms of LRRK2. Considering the hypothesis that PD pathology is associated to increased LRRK2 kinase activity, our results suggest that for its heterologous phosphorylation sites LRRK2 phosphorylation correlates to healthy phenotypes and LRRK2 dephosphorylation correlates to phenotypes associated to the PD pathological processes.


Subject(s)
Parkinson Disease , Humans , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/metabolism , Lysosomes/metabolism , Parkinson Disease/metabolism , Phosphorylation/physiology , Signal Transduction
8.
Cells ; 10(9)2021 09 17.
Article in English | MEDLINE | ID: mdl-34572099

ABSTRACT

Since the initial identification of alpha-synuclein (α-syn) at the synapse, numerous studies demonstrated that α-syn is a key player in the etiology of Parkinson's disease (PD) and other synucleinopathies. Recent advances underline interactions between α-syn and lipids that also participate in α-syn misfolding and aggregation. In addition, increasing evidence demonstrates that α-syn plays a major role in different steps of synaptic exocytosis. Thus, we reviewed literature showing (1) the interplay among α-syn, lipids, and lipid membranes; (2) advances of α-syn synaptic functions in exocytosis. These data underscore a fundamental role of α-syn/lipid interplay that also contributes to synaptic defects in PD. The importance of lipids in PD is further highlighted by data showing the impact of α-syn on lipid metabolism, modulation of α-syn levels by lipids, as well as the identification of genetic determinants involved in lipid homeostasis associated with α-syn pathologies. While questions still remain, these recent developments open the way to new therapeutic strategies for PD and related disorders including some based on modulating synaptic functions.


Subject(s)
Lipids/adverse effects , Parkinson Disease/pathology , Synucleinopathies/pathology , alpha-Synuclein/metabolism , Animals , Humans , Lipids/analysis , Lipids/physiology , Parkinson Disease/etiology , Synucleinopathies/etiology
9.
Expert Rev Anticancer Ther ; 20(12): 1093-1106, 2020 12.
Article in English | MEDLINE | ID: mdl-33044876

ABSTRACT

INTRODUCTION: Merkel Cell Carcinoma (MCC) is a rare aggressive skin cancer, mostly affecting elderly patients. Until recently, patients with advanced disease were treated with cytotoxic chemotherapies despite rapid chemoresistance and high toxicity. As with other cancers, immune checkpoint inhibitors (CPI), including pembrolizumab, allow durable responses with a manageable safety profile in these patients. AREAS COVERED: This review describes the rationale for using PD-1/PD-L1 inhibitors in MCC, as well as efficacy and safety results from the three open-label trials investigating pembrolizumab or other PD-1/PD-L1 inhibitors in patients with advanced MCC. Real-life experience and predictive pre-treatment biomarkers are discussed to assess which patients are likely to be candidates for such strategies. Ongoing fields of research include the use of CPI in the adjuvant or neoadjuvant setting and combined strategies in refractory patients. Expert Opinion: CPI have become the standard of care for frontline treatment in patients with advanced MCC. Earlier introduction of CPI in the disease course, including neo-adjuvant and adjuvant settings, is likely to improve the outcomes further. Given the rarity of this cancer, we still need to harmonize efforts in order to conduct large-scale trials and efficiently identify best optimal care.


Subject(s)
Carcinoma, Merkel Cell/drug therapy , Immune Checkpoint Inhibitors/administration & dosage , Skin Neoplasms/drug therapy , Aged , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/pharmacokinetics , B7-H1 Antigen/antagonists & inhibitors , Biomarkers, Tumor/metabolism , Carcinoma, Merkel Cell/pathology , Drug Resistance, Neoplasm , Humans , Immune Checkpoint Inhibitors/adverse effects , Immune Checkpoint Inhibitors/pharmacology , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Skin Neoplasms/pathology
10.
Front Neurosci ; 14: 527, 2020.
Article in English | MEDLINE | ID: mdl-32612495

ABSTRACT

Mutations in the Leucine Rich Repeat Kinase 2 (LRRK2) gene are linked to autosomal dominant Parkinson's disease (PD), and genetic variations at the LRRK2 locus are associated with an increased risk for sporadic PD. This gene encodes a kinase that is physiologically multiphosphorylated, including clusters of both heterologous phosphorylation and autophosphorylation sites. Several pieces of evidence indicate that LRRK2's phosphorylation is important for its pathological and physiological functioning. These include a reduced LRRK2 heterologous phosphorylation in PD brains or after pharmacological inhibition of LRRK2 kinase activity as well as the appearance of subcellular LRRK2 accumulations when this protein is dephosphorylated at heterologous phosphosites. Nevertheless, the regulatory mechanisms governing LRRK2 phosphorylation levels and the cellular consequences of changes in LRRK2 phosphorylation remain incompletely understood. In this review, we present current knowledge on LRRK2 phosphorylation, LRRK2 phosphoregulation, and how LRRK2 phosphorylation changes affect cellular processes that may ultimately be linked to PD mechanisms.

11.
Ann Intensive Care ; 6(1): 88, 2016 Dec.
Article in English | MEDLINE | ID: mdl-27620878

ABSTRACT

BACKGROUND: Computed tomography angiography (CTA) is largely performed in European countries as an ancillary test for diagnosing brain death. However, CTA suffers from a lack of sensitivity, especially in patients who have previously undergone decompressive craniectomy. The aim of this study was to assess the performance of a revised four-point venous CTA score, including non-opacification of the infratentorial venous circulation, for diagnosing brain death. METHODS: A preliminary study of 43 control patients with normal CTAs confirmed that the infratentorial superior petrosal vein (SPV) was consistently visible. Therefore, 76 patients (including ten with decompressive craniectomy) who were investigated with 83 CTAs to confirm clinical brain death were consecutively enrolled between July 2011 and July 2013 at a university centre. The image analysis consisted of recording non-opacification of the cortical segment of the middle cerebral artery and internal cerebral vein (ICV), which were used as the reference CTA score, as well as non-opacification of the SPV. The diagnostic performance of the revised four-point venous CTA score based on the non-opacification of both the ICV and SPV was assessed and compared with that of the reference CTA score. RESULTS: The revised four-point venous CTA score showed a sensitivity of 95 % for confirming clinical brain death versus a sensitivity of 88 % with the reference CTA score. Non-opacification of the SPV was observed in 95 % of the patients. In the decompressive craniectomy group, the revised four-point CTA score showed a sensitivity of 100 % compared with a sensitivity of 80 % using the reference CTA score. CONCLUSION: Compared with the reference CTA score, the revised four-point venous CTA score based on ICV and SPV non-opacification showed superior diagnostic performance for confirming brain death, including for patients with decompressive craniectomy.

12.
Eur Radiol ; 23(6): 1711-9, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23242003

ABSTRACT

OBJECTIVES: To investigate the contribution of whole-body post-mortem computed tomography (PMCT) in sudden unexpected death in infants and children. METHODS: Forty-seven cases of sudden unexpected death in children investigated with radiographic skeletal survey, whole-body PMCT and autopsy were enrolled. For imaging interpretation, non-specific post-mortem modifications and abnormal findings related to the presumed cause of death were considered separately. All findings were correlated with autopsy findings. RESULTS: There were 31 boys and 16 girls. Of these, 44 children (93.6 %) were younger than 2 years. The cause of death was found at autopsy in 18 cases (38.3 %), with 4 confirmed as child abuse, 12 as infectious diseases, 1 as metabolic disease and 1 as bowel volvulus. PMCT results were in accordance with autopsy in all but three of these 18 cases. Death remains unexplained in 29 cases (61.7 %) and was correlated with no abnormal findings on PMCT in 27 cases. Major discrepancies between PMCT and autopsy findings concerned pulmonary analysis. CONCLUSIONS: Whole-body PMCT may detect relevant findings that can help to explain sudden unexpected death and is essential for detecting non-accidental injuries. We found broad concordance between autopsy and PMCT, except in a few cases of pneumonia. It is a non-invasive technique acceptable to relatives. KEY POINTS: • Whole-body post-mortem computed tomography (PMCT) is an effective non-invasive method. • Whole-body PMCT is essential for detecting child abuse in unexpected death. • There is concordance on cause of death between PMCT and autopsy. • Whole-body PMCT could improve autopsy through dissection and sampling guidance. • PMCT shows findings that may be relevant when parents reject autopsy.


Subject(s)
Death, Sudden/etiology , Tomography, X-Ray Computed/methods , Autopsy , Cause of Death , Child , Child Abuse , Child, Preschool , Female , Head/pathology , Humans , Infant , Male , Radiographic Image Interpretation, Computer-Assisted , Time Factors , Whole Body Imaging/methods
13.
AJR Am J Roentgenol ; 199(1): 142-50, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22733905

ABSTRACT

OBJECTIVE: The purpose of this article is to illustrate the causes of snapping knee. The value of imaging techniques is discussed with an emphasis on dynamic sonography in light of the available surgical and radiologic literature. CONCLUSION: Because of its dynamic capabilities, dynamic sonography provides real-time visualization of snapping knee syndrome and may be used as a first-line modality.


Subject(s)
Joint Diseases/diagnostic imaging , Knee Joint/diagnostic imaging , Knee Prosthesis , Menisci, Tibial/diagnostic imaging , Bone Neoplasms/diagnostic imaging , Diagnosis, Differential , Equipment Failure Analysis , Humans , Joint Instability/diagnostic imaging , Joint Loose Bodies/diagnostic imaging , Knee/diagnostic imaging , Syndrome , Synovitis/diagnostic imaging , Tendon Entrapment/diagnostic imaging , Ultrasonography
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