Search

Chronic myelomonocytic leukemia (CMML) is a severe myeloid malignancy with limited therapeutic options. Single-cell analysis of clonal architecture demonstrates early clonal dominance with few residual WT hematopoietic stem cells. Circulating myeloid cells of the leukemic clone and the cytokines they produce generate a deleterious inflammatory climate. Our hypothesis is that therapeutic control of the inflammatory component in CMML could contribute to stepping down disease progression. The present study explored the contribution of immature granulocytes (iGRANs) to CMML progression. iGRANs were detected and quantified in the peripheral blood of patients by spectral and conventional flow cytometry. Their accumulation was a potent and independent poor prognostic factor. These cells belong to the leukemic clone and behaved as myeloid-derived suppressor cells. Bulk and single-cell RNA-Seq revealed a proinflammatory status of iGRAN that secreted multiple cytokines of which CXCL8 was at the highest level. This cytokine inhibited the proliferation of WT but not CMML hematopoietic stem and progenitor cells (HSPCs) in which CXCL8 receptors were downregulated. CXCL8 receptor inhibitors and CXCL8 blockade restored WT HSPC proliferation, suggesting that relieving CXCL8 selective pressure on WT HSPCs is a potential strategy to slow CMML progression and restore some healthy hematopoiesis.

Objective: This study aimed to study the relationship between auto-antibodies against apolipoprotein A1 (anti-apoA1 IgG), human immunodeficiency virus (HIV) infection, anti-retroviral therapy (ART), and the tryptophan pathways in HIV-related cardiovascular disease., Design: This case-control study conducted in South Africa consisted of control volunteers ( n  = 50), people living with HIV (PLWH) on ART ( n  = 50), and untreated PLWH ( n  = 44). Cardiovascular risk scores were determined, vascular measures were performed, and an extensive biochemical characterisation (routine, metabolomic, and inflammatory systemic profiles) was performed., Methods: Anti-apoA1 IgG levels were assessed by an in-house ELISA. Inflammatory biomarkers were measured with the Meso Scale Discovery® platform, and kynurenine pathway metabolites were assessed using targeted metabolomic profiling conducted by liquid chromatography-multiple reaction monitoring/mass spectrometry (LC-MRM/MS)., Results: Cardiovascular risk scores and vascular measures exhibited similarities across the three groups, while important differences were observed in systemic inflammatory and tryptophan pathways. Anti-apoA1 IgG seropositivity rates were 15%, 40%, and 70% in control volunteers, PLWH ART-treated, and PLWH ART-naïve, respectively. Circulating anti-apoA1 IgG levels were significantly negatively associated with CD4+ cell counts and positively associated with viremia and pro-inflammatory biomarkers (IFNγ, TNFα, MIPα, ICAM-1, VCAM-1). While circulating anti-apoA1 IgG levels were associated with increased levels of kynurenine in both control volunteers and PLWH, the kynurenine/tryptophan ratio was significantly increased in PLWH ART-treated., Conclusion: HIV infection increases the humoral response against apoA1, which is associated with established HIV severity criteria and kynurenine pathway activation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Frias, Pagano, Bararpour, Sidibé, Kamau, Fétaud-Lapierre, Hudson, Thomas, Lecour, Strijdom and Vuilleumier.)

Background: There is a common agreement that Alzheimers disease (AD) is inherently complex; otherwise, a general disagreement remains on its etiological underpinning, with numerous alternative hypotheses having been proposed., Objective: To perform a scoping review of original manuscripts describing hypotheses and theories of AD published in the past decades., Results: We reviewed 131 original manuscripts that fulfilled our inclusion criteria out of more than 13,807 references extracted from open databases. Each entry was characterized as having a single or multifactorial focus and assigned to one of 15 theoretical groupings. Impact was tracked using open citation tools., Results: Three stages can be discerned in terms of hypotheses generation, with three quarter of studies proposing a hypothesis characterized as being single-focus. The most important theoretical groupings were the Amyloid group, followed by Metabolism and Mitochondrial dysfunction, then Infections and Cerebrovascular. Lately, evidence towards Genetics and especially Gut/Brain interactions came to the fore., Conclusions: When viewed together, these multi-faceted reports reinforce the notion that AD affects multiple sub-cellular, cellular, anatomical, and physiological systems at the same time but at varying degree between individuals. The challenge of providing a comprehensive view of all systems and their interactions remains, alongside ways to manage this inherent complexity.

Transformation of castration-resistant prostate cancer (CRPC) into an aggressive neuroendocrine disease (CRPC-NE) represents a major clinical challenge and experimental models are lacking. A CTC-derived eXplant (CDX) and a CDX-derived cell line are established using circulating tumor cells (CTCs) obtained by diagnostic leukapheresis from a CRPC patient resistant to enzalutamide. The CDX and the derived-cell line conserve 16% of primary tumor (PT) and 56% of CTC mutations, as well as 83% of PT copy-number aberrations including clonal TMPRSS2-ERG fusion and NKX3.1 loss. Both harbor an androgen receptor-null neuroendocrine phenotype, TP53, PTEN and RB1 loss. While PTEN and RB1 loss are acquired in CTCs, evolutionary analysis suggest that a PT subclone harboring TP53 loss is the driver of the metastatic event leading to the CDX. This CDX model provides insights on the sequential acquisition of key drivers of neuroendocrine transdifferentiation and offers a unique tool for effective drug screening in CRPC-NE management.

Allogeneic hematopoietic cell transplantation (AHCT) represents the only curative therapy for many hematological malignancies. The graft versus leukemia effect, driven by donor T cells, plays a major role in its curative potential. This effect is sometimes very evident when patients with acute myeloid leukemia and myelodysplasia relapse after AHCT and are treated with donor lymphocyte infusions (DLIs). We retrospectively reviewed the charts of 64 patients who received DLI between 2012 and 2017 in our center. The mean age of the patients was 59 years (range, 34-79). Fifty percent were male (n = 32). The mean follow-up time after AHCT was 50.17 months (range, 8-174). The indication for DLI were disease progression, mixed chimerism, minimal residual disease, and other etiologies in 43.8%, 40.7%, 14%, and 1.5% of patients, respectively. The most common diagnosis was acute leukemia, followed by multiple myeloma. Of all patients, 59.4% received a transplant from a related donor, 39% received a transplant from an unrelated donor, and 1.6% received a transplant from a haploidentical donor. Reduced-intensity conditioning AHCT was the most frequent regimen used (53%). DLI was given alone in 79.7% of patients. Prophylactic DLI was given at 30 days after transplantation in patients who received human leukocyte antigen (HLA)-matched related human stem cell transplantation (HSCT) or 45 to 60 days post-transplant in patients receiving haploidentical HSCT or HLA-matched unrelated HSCT. Patients were treated without graft versus host disease (GVHD) prophylaxis. The use of DLI after transplantation remains a feasible procedure with rates of response >60%. Moreover, DLIs are well tolerated with a GVHD rate <10% in our series. We can hypothesize that in our experience the efficacy of this strategy does not rely on the induction of GVHD., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Frequently, the number of circulating tumor cells (CTC) isolated in 7.5 mL of blood is too small to reliably determine tumor heterogeneity and to be representative as a "liquid biopsy". In the EU FP7 program CTCTrap, we aimed to validate and optimize the recently introduced Diagnostic LeukApheresis (DLA) to screen liters of blood. Here we present the results obtained from 34 metastatic cancer patients subjected to DLA in the participating institutions. About 7.5 mL blood processed with CellSearch® was used as "gold standard" reference. DLAs were obtained from 22 metastatic prostate and 12 metastatic breast cancer patients at four different institutions without any noticeable side effects. DLA samples were prepared and processed with different analysis techniques. Processing DLA using CellSearch resulted in a 0-32 fold increase in CTC yield compared to processing 7.5 mL blood. Filtration of DLA through 5 μm pores microsieves was accompanied by large CTC losses. Leukocyte depletion of 18 mL followed by CellSearch yielded an increase of the number of CTC but a relative decrease in yield (37%) versus CellSearch DLA. In four out of seven patients with 0 CTC detected in 7.5 mL of blood, CTC were detected in DLA (range 1-4 CTC). The CTC obtained through DLA enables molecular characterization of the tumor. CTC enrichment technologies however still need to be improved to isolate all the CTC present in the DLA., (© 2018 UICC.)

The combination of carmustine, etoposide, aracytin, and melphalan(BEAM) conditioning regimen in autologous stem-cell transplantation (ASCT) is widely used in patients with relapsed/refractory non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma. It is also an option in patients with very-high risk aggressive NHL in first complete remission (CR). Recently, a phase Ib-II feasibility study using bendamustine replacing carmustine (BCNU) was reported. We report herein a safety and efficacy analysis of bendamustine-EAM (BeEAM) with a control BEAM counterpart paired cohort (1/2). One hundred and two patients were analyzed. Overall survival (OS) and progression-free survival (PFS) were not reached and seemed to be comparable between both groups. However, grade III or greater diarrhea was significantly higher in BeEAM patients (44 vs. 15%, p = .002). The median number of days with fever >38 °C was significantly higher in BeEAM group (5.5 vs. 2, p < .001). This case-control study suggests that BeEAM followed by ASCT using bendamustine at 100 mg/m 2 /d is effective but has a different toxicity profile than the BEAM regimen.

Neutrophils represent the most abundant immune cells recruited to inflamed tissues. A lack of dedicated tools has hampered their detection and study. We show that a synthesized peptide, MUB 40 , binds to lactoferrin, the most abundant protein stored in neutrophil-specific and tertiary granules. Lactoferrin is specifically produced by neutrophils among other leukocytes, making MUB 40 a specific neutrophil marker. Naive mammalian neutrophils (human, guinea pig, mouse, rabbit) were labeled by fluorescent MUB 40 conjugates (-Cy5, Dylight405). A peptidase-resistant retro-inverso MUB 40 (RI-MUB 40 ) was synthesized and its lactoferrin-binding property validated. Neutrophil lactoferrin secretion during in vitro Shigella infection was assessed with RI-MUB 40 -Cy5 using live cell microscopy. Systemically administered RI-MUB 40 -Cy5 accumulated at sites of inflammation in a mouse arthritis inflammation model in vivo and showed usefulness as a potential tool for inflammation detection using non-invasive imaging. Improving neutrophil detection with the universal and specific MUB 40 marker will aid the study of broad ranges of inflammatory diseases., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Thrombocytopenia is a major side effect of a new class of anticancer agents that target histone deacetylase (HDAC). Their mechanism is poorly understood. Here, we show that HDAC6 inhibition and genetic knockdown lead to a strong decrease in human proplatelet formation (PPF). Unexpectedly, HDAC6 inhibition-induced tubulin hyperacetylation has no effect on PPF. The PPF decrease induced by HDAC6 inhibition is related to cortactin (CTTN) hyperacetylation associated with actin disorganization inducing important changes in the distribution of megakaryocyte (MK) organelles. CTTN silencing in human MKs phenocopies HDAC6 inactivation and knockdown leads to a strong PPF defect. This is rescued by forced expression of a deacetylated CTTN mimetic. Unexpectedly, unlike human-derived MKs, HDAC6 and CTTN are shown to be dispensable for mouse PPF in vitro and platelet production in vivo. Our results highlight an unexpected function of HDAC6-CTTN axis as a positive regulator of human but not mouse MK maturation.

Chronic kidney disease (CKD) is a risk factor for fractures. The current evaluation of fracture risk is based upon the combination of various clinical factors and quantitative imaging of bone. X-ray-based tools were developed to evaluate bone status and predict fracture risk. Dual energy X-ray absorptiometry (DXA) is available worldwide. Longitudinal studies showed that low areal Bone Mineral Density (BMD) measured by DXA predicts fractures in the CKD population as it does in non uremic populations, with good specificity and moderate sensitivity. Peripheral quantitative computed tomography (pQCT) and high resolution pQCT are research tools which measure volumetric BMD at the tibia and radius. They are able to discriminate between the cortical and trabecular envelopes which are differentially affected by renal osteodystrophy. In CKD, a rapid thinning and increased porosity at the cortex is observed which is associated with increased the risk for fracture.

Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder that typically associates with mutations in epigenetic, splicing, and signaling genes. Genetically modified mouse models only partially recapitulate the disease phenotype, whereas xenotransplantation of CMML cells in immunocompromised mice has been rarely successful so far. Here, CMML CD34 + cells sorted from patient bone marrow (BM) or peripheral blood (PB) were injected intravenously into NSG (NOD/LtSz-scid IL2rγnull) mice and NSG mice engineered to express human granulo-monocyte colony-stimulating factor, stem cell factor, and interleukin-3 (NSGS mice). Fifteen out of 16 patient samples (94%) successfully engrafted into NSG or NSGS or both mouse strains. The expansion of human cells, predominant in the BM, was also observed in the spleen and the PB and was greatly enhanced in mice producing the 3 human cytokines. Gene mutations identified in engrafted cells were mostly similar to those identified in patient cells before injection. Successful secondary engraftment was obtained in NSGS mice in 3 out of 10 attempts. Thus, primary CMML leukemic cells expand much better in NSGS compared with NSG mice with limited efficacy of secondary transplant., Competing Interests: Conflict-of-interest disclosure: The authors declare no competing financial interests.

Megakaryocyte polyploidy is characterized by cytokinesis failure resulting from defects in contractile forces at the cleavage furrow. Although immature megakaryocytes express 2 nonmuscle myosin II isoforms (MYH9 [NMIIA] and MYH10 [NMIIB]), only NMIIB localizes at the cleavage furrow, and its subsequent absence contributes to polyploidy. In this study, we tried to understand why the abundant NMIIA does not localize at the furrow by focusing on the RhoA/ROCK pathway that has a low activity in polyploid megakaryocytes. We observed that under low RhoA activity, NMII isoforms presented different activity that determined their localization. Inhibition of RhoA/ROCK signaling abolished the localization of NMIIB, whereas constitutively active RhoA induced NMIIA at the cleavage furrow. Thus, although high RhoA activity favored the localization of both the isoforms, only NMIIB could localize at the furrow at low RhoA activity. This was further confirmed in erythroblasts that have a higher basal RhoA activity than megakaryocytes and express both NMIIA and NMIIB at the cleavage furrow. Decreased RhoA activity in erythroblasts abolished localization of NMIIA but not of NMIIB from the furrow. This differential localization was related to differences in actin turnover. Megakaryocytes had a higher actin turnover compared with erythroblasts. Strikingly, inhibition of actin polymerization was found to be sufficient to recapitulate the effects of inhibition of RhoA/ROCK pathway on NMII isoform localization; thus, cytokinesis failure in megakaryocytes is the consequence of both the absence of NMIIB and a low RhoA activity that impairs NMIIA localization at the cleavage furrow through increased actin turnover., (© 2016 by The American Society of Hematology.)

Accurately determining time-of-onset of cerebral infarction is important to clearly identify patients who could benefit from reperfusion therapies. We assessed the kinetics of peroxiredoxin 1 (PRDX1), a protein involved in oxidative stress during the acute phase of ischemia, and its ability to determine stroke onset in a population of patients with known onset of less than 24 hours and in a control group. Median PRDX1 levels were significantly higher in stroke patients compared to controls. PRDX1 levels were also higher from blood samples withdrawn before vs. after 3 hours following stroke onset, and before vs. after 6 hours. ROC analysis with area under the curve (AUC), sensitivity (Se) and specificity (Sp) determined from the Youden index was performed to assess the ability of PRDX1 levels to determine onset. Diagnostic performances of PRDX1 levels were defined by an AUC of 69%, Se of 53% and Sp of 86% for identifying cerebral infarction occurring <3 hours, and an AUC of 68%, Se of 49% and Sp of 88% for cerebral infarction occurring <6 hours. These first results suggest that PRDX1 levels could be the basis of a new method using biomarkers for determining cerebral infarction onset.

Introduction: Long-term glucocorticoid therapy is the leading cause of secondary osteoporosis. The management of glucocorticoid-induced osteoporosis (GIOP) seems to be inadequate in many European countries., Objective: To evaluate the rate of screening and treatment of GIOP., Design: Information was collected from a national public health-insurance database in our geographic area of Provence-Alpes-Côte-d'Azur and in Corsica, from September 2009 through August 2011., Patients: We identified participants aged 15 years and over starting glucocorticoid therapy (≥7.5 mg of prednisone equivalent per day during at least 90 days consecutive). This cohort was compared with an age-matched and sex-matched population that did not receive glucocorticoids., Main Outcome Measures: Bone mass, prescription of bone antiresorptive medication and use of calcium and/or vitamin D treatment., Results: We identified 32 812 patients who were prescribed glucocorticoid therapy, yielding 1% prevalence. Incidence of glucocorticoid therapy was 2.8/1000 inhabitants/year. Males represented 44%, the mean age was 58 years. The median prednisone-equivalent dose was 11 mg/day (IQR 9-18 mg/day). 8% underwent bone mass measurement. Calcium and/or vitamin D, and bisphosphonates were prescribed in 18% and 12%, respectively. Results were lower for the control population: 3% underwent bone mass measurement and 3% received bisphosphonate therapy. The rates of osteodensitometry and treatments were higher in women over 55 years of age than in men and women 55 years of age and younger, and also when glucocorticoid therapy was initiated by a rheumatologist versus other physician specialty., Conclusions: The management of GIOP remains very inadequate, despite the availability of a statutory health insurance system. Targeted interventions are needed to improve the management of GIOP.

Purpose: The aim of this study was to describe the extent of methylphenidate (MPH) abuse and characterize its patterns by following several cases involving intravenous administration of crushed MPH tablets., Methods: First, a drug reimbursement database (covering 4 million inhabitants) was explored to assess the magnitude of MPH abuse among the general population, and second, a specific study based on individuals with drug dependence was performed to describe abusers' characteristics (n = 64), patterns of abuse and clinical implications., Results: From 2005 to 2011, the number of patients who were dispensed MPH at least once increased by 166%. The patients with 'deviant' patterns of MPH consumption were mainly male adults with opiate maintenance treatment reimbursements. MPH abusers had precarious living conditions. Half of them consumed MPH daily by intravenous route and reported amphetamine-like effects (cardiovascular events, weight loss, psychiatric adverse events)., Conclusion: Given the increase of MPH use, it is important to warn the scientific community about possible MPH abuse, especially in individuals with drug dependence. This study has facilitated public health intervention and dissemination of information related to MPH abuse among health care professionals at local and national levels., (© 2015 S. Karger AG, Basel.)

Introduction: The objective of this study was to estimate and to characterize the actual patterns of triptan use and overuse in France using a drug reimbursement database., Methods: We included all people covered by the French General Health Insurance System (GHIS) from the Provence-Alpes-Côte-d'Azur (PACA) and Corsica administrative areas who had at least one dispensed dose of triptans between May 2010 and December 2011. All dispensed doses of triptans, migraine prophylactic treatment and psychotropic medications were extracted from the GHIS database. Triptan overuse was defined as triptan use >20 defined daily doses (DDD) per month on a regular basis for more than three consecutive months. Risk of overuse was assessed using logistic regression adjusted for gender and age., Results: We included 99,540 patients who had at least one prescription of a triptan over the 20 months of the study. Among them, 2243 patients (2.3%) were identified as overusers and received 20.2% of the total DDD prescribed. Twelve percent of overusers and 6.9% of non-overusers were aged more than 65 years (OR: 1.81). Overusers did not have a greater number of prescribers and pharmacists than non-overusers. They were more frequently prescribed a prophylactic medication for migraine treatment (56.8% vs 35.9%, OR: 2.36), benzodiazepines (69.9% vs 54.7%, OR: 1.93) and antidepressants (49.4% vs 30.2%, OR: 2.33)., Conclusions: This work suggests that triptan overuse may be due to insufficient prescriber awareness of appropriate prescribing. The off-label prescription of triptans among the elderly necessitates investigating their cardiovascular risk profile in this sub-group., (© International Headache Society 2015.)

Dendritic cell-derived exosomes (Dex) are small extracellular vesicles secreted by viable dendritic cells. In the two phase-I trials that we conducted using the first generation of Dex (IFN-γ-free) in end-stage cancer, we reported that Dex exerted natural killer (NK) cell effector functions in patients. A second generation of Dex (IFN-γ-Dex) was manufactured with the aim of boosting NK and T cell immune responses. We carried out a phase II clinical trial testing the clinical benefit of IFN-γ-Dex loaded with MHC class I- and class II-restricted cancer antigens as maintenance immunotherapy after induction chemotherapy in patients bearing inoperable non-small cell lung cancer (NSCLC) without tumor progression. The primary endpoint was to observe at least 50% of patients with progression-free survival (PFS) at 4 mo after chemotherapy cessation. Twenty-two patients received IFN-γ-Dex. One patient exhibited a grade three hepatotoxicity. The median time to progression was 2.2 mo and median overall survival (OS) was 15 mo. Seven patients (32%) experienced stabilization of >4 mo. The primary endpoint was not reached. An increase in NKp30-dependent NK cell functions were evidenced in a fraction of these NSCLC patients presenting with defective NKp30 expression. Importantly, MHC class II expression levels of the final IFN-γ-Dex product correlated with expression levels of the NKp30 ligand BAG6 on Dex, and with NKp30-dependent NK functions, the latter being associated with longer progression-free survival. This phase II trial confirmed the capacity of Dex to boost the NK cell arm of antitumor immunity in patients with advanced NSCLC.

The immunosurveillance mechanisms governing high-risk neuroblastoma (HR-NB), a major pediatric malignancy, have been elusive. We identify a potential role for natural killer (NK) cells, in particular the interaction between the NK receptor NKp30 and its ligand, B7-H6, in the metastatic progression and survival of HR-NB after myeloablative multimodal chemotherapy and stem cell transplantation. NB cells expressing the NKp30 ligand B7-H6 stimulated NK cells in an NKp30-dependent manner. Serum concentration of soluble B7-H6 correlated with the down-regulation of NKp30, bone marrow metastases, and chemoresistance, and soluble B7-H6 contained in the serum of HR-NB patients inhibited NK cell functions in vitro. The expression of distinct NKp30 isoforms affecting the polarization of NK cell functions correlated with 10-year event-free survival in three independent cohorts of HR-NB in remission from metastases after induction chemotherapy (n = 196, P < 0.001), adding prognostic value to known risk factors such as N-Myc amplification and age >18 months. We conclude that the interaction between NKp30 and B7-H6 may contribute to the fate of NB patients and that both the expression of NKp30 isoforms on circulating NK cells and the concentration of soluble B7-H6 in the serum may be clinically useful as biomarkers for risk stratification., (Copyright © 2015, American Association for the Advancement of Science.)

Introduction: Although several theories and treatment plans use unusual sexual fantasies (SF) as a way to identify deviancy, they seldom describe how the fantasies referred to were determined to be unusual., Aim: The main goal of this study was to determine which SF are rare, unusual, common, or typical from a statistical point of view among a relatively large sample of adults recruited from the general population. A secondary goal was to provide a statistical comparison of the nature and intensity of sexual fantasies for men and women. This study also aims at demonstrating with both quantitative and qualitative analyses that certain fantasies often considered to be unusual are common., Methods: An Internet survey was conducted with 1,516 adults (799 ♀; 717 ♂) who ranked 55 different SF and wrote their own favorite SF. Each SF was rated as statistically rare (2.3% or less), unusual (15.9% or less), common (more than 50%), or typical (more than 84.1% of the sample)., Main Outcome Measures: An extended version of the Wilson's Sex Fantasy Questionnaire with an open question., Results: Only two sexual fantasies were found to be rare for women or men, while nine others were unusual. Thirty sexual fantasies were common for one or both genders, and only five were typical. These results were confirmed with qualitative analyses. Submission and domination themes were not only common for both men and women, but they were also significantly related to each other. Moreover, the presence of a single submissive fantasy was a significant predictor of overall scores for all SF in both genders., Conclusion: Care should be taken before labeling an SF as unusual, let alone deviant. It suggested that the focus should be on the effect of a sexual fantasy rather than its content., (© 2014 International Society for Sexual Medicine.)