Chlorophyll and pheophytin protonated and deprotonated ions: Observation and theory.

Pheophytin a and chlorophyll a have been investigated by electrospray mass spectrometry in the positive and negative modes, in view of the importance of the knowledge of their properties in photosynthesis. Pheophytin and chlorophyll are both observed intensely in the protonated mode, and their main fragmentation route is the loss of their phytyl chain. Pheophytin is observed intact in the negative mode, while under collisions, it is primarily cleaved beyond the phytyl chain and loses the attaching propionate group. Chlorophyll is not detected in normal conditions in the negative mode, but addition of methanol solvent molecule is detected. Fragmentation of this adduct primarily forms a product (-30 amu) that dissociates into dephytyllated deprotonated chlorophyll. Semi-empirical molecular dynamics calculations show that the phytyl chain is unfolded from the chlorin cycle in pheophytin a and folded in chlorophyll a. Density functional theory calculations have been conducted to locate the charges on protonated and deprotonated pheophytin a and chlorophyll a and have found the major location sites that are notably more stable in energy by more than 0.5 eV than the others. The deprotonation site is found identical for pheophytin a and the chlorophyll a-methanol adduct. This is in line with experiment and calculation locating the addition of methanol on a double bond of deprotonated chlorophyll a.

FANCA deficiency promotes leukaemic progression by allowing the emergence of cells carrying oncogenic driver mutations.

Leukaemia is caused by the clonal evolution of a cell that accumulates mutations/genomic rearrangements, allowing unrestrained cell growth. However, recent identification of leukaemic mutations in the blood cells of healthy individuals revealed that additional events are required to expand the mutated clones for overt leukaemia. Here, we assessed the functional consequences of deleting the Fanconi anaemia A (Fanca) gene, which encodes a DNA damage response protein, in Spi1 transgenic mice that develop preleukaemic syndrome. FANCA loss increases SPI1-associated disease penetrance and leukaemic progression without increasing the global mutation load of leukaemic clones. However, a high frequency of leukaemic FANCA-depleted cells display heterozygous activating mutations in known oncogenes, such as Kit or Nras, also identified but at low frequency in FANCA-WT mice with preleukaemic syndrome, indicating that FANCA counteracts the emergence of oncogene mutated leukaemic cells. A unique transcriptional signature is associated with the leukaemic status of FANCA-depleted cells, leading to activation of MDM4, NOTCH and Wnt/ß-catenin pathways. We show that NOTCH signalling improves the proliferation capacity of FANCA-deficient leukaemic cells. Collectively, our observations indicate that loss of the FANC pathway, known to control genetic instability, fosters the expansion of leukaemic cells carrying oncogenic mutations rather than mutation formation. FANCA loss may contribute to this leukaemogenic progression by reprogramming transcriptomic landscape of the cells.

Sunitinib Treatment of VHL C162F Cells Slows Down Proliferation and Healing Ability via Downregulation of ZHX2 and Confers a Mesenchymal Phenotype.

von Hippel-Lindau (VHL) disease, due to mutations of the tumor suppressor VHL gene, is a rare hereditary syndrome with a high risk of developing clear cell renal cell carcinoma (ccRCC). We asked whether the VHL-C162F mutation interferes with proliferation, migration, healing and forming colony ability by using wild-type VHL (WT VHL) and VHL-C162F reconstituted cells. We then analyzed the in vitro impact of the sunitinib treatment on VHL-C162F cells. We showed that VHL-C162F mutations have no impact on cell morphology, colony formation and migration ability but confer a significant higher healing ability than in WT VHL cells. RNA sequencing analysis revealed that VHL-C162F mutation upregulates genes involved in hypoxia and epithelial mesenchymal transition (EMT) pathways by comparison with VHL WT cells. We next showed a decrease in healing ability in VHL-C162F cells depleting on ZHX2, an oncogenic driver of ccRCC, highlighting the potential involvement of ZHX2 in aggressiveness of the VHL-C162F cells. Moreover, we found that sunitinib treatment inhibits ZHX2 expression and induces a reduced proliferation correlating with downregulation of P-ERK. Sunitinib treatment also conferred a more mesenchymal profile to VHL-C162F cells with significant downregulation of E-cadherin and upregulation of N-cadherin, Slug and AXL. Sunitinib therapy may therefore promote disease progression in VHL-C162F patients.

PATLAB: A graphical computational software package for photoacoustic computed tomography research.

Photoacoustic tomography (PAT) provides high resolution optical images of tissue at depths of up to several centimetres. This modality has been of interest to researchers for at least 30 years and is still the subject of intensive research. However, PAT researchers lack access to a comprehensive open-source graphical simulation and reconstruction software package. In this article, we introduce PATLAB, an open-source MATLAB-based graphical software package that can perform both PAT simulation and image reconstruction. PATLAB is simple to use yet is capable of complex PAT data processing tasks and offers advanced users a framework to build and test new methods.

NF-κB signaling controls H3K9me3 levels at intronic LINE-1 and hematopoietic stem cell genes in cis.

Ionizing radiations (IR) alter hematopoietic stem cell (HSC) function on the long term, but the mechanisms underlying these effects are still poorly understood. We recently showed that IR induces the derepression of L1Md, the mouse young subfamilies of LINE-1/L1 retroelements. L1 contributes to gene regulatory networks. However, how L1Md are derepressed and impact HSC gene expression are not known. Here, we show that IR triggers genome-wide H3K9me3 decrease that occurs mainly at L1Md. Loss of H3K9me3 at intronic L1Md harboring NF-κB binding sites motifs but not at promoters is associated with the repression of HSC-specific genes. This is correlated with reduced NFKB1 repressor expression. TNF-α treatment rescued all these effects and prevented IR-induced HSC loss of function in vivo. This TNF-α/NF-κB/H3K9me3/L1Md axis might be important to maintain HSCs while allowing expression of immune genes during myeloid regeneration or damage-induced bone marrow ablation.

HDAC1 and PRC2 mediate combinatorial control in SPI1/PU.1-dependent gene repression in murine erythroleukaemia.

Although originally described as transcriptional activator, SPI1/PU.1, a major player in haematopoiesis whose alterations are associated with haematological malignancies, has the ability to repress transcription. Here, we investigated the mechanisms underlying gene repression in the erythroid lineage, in which SPI1 exerts an oncogenic function by blocking differentiation. We show that SPI1 represses genes by binding active enhancers that are located in intergenic or gene body regions. HDAC1 acts as a cooperative mediator of SPI1-induced transcriptional repression by deacetylating SPI1-bound enhancers in a subset of genes, including those involved in erythroid differentiation. Enhancer deacetylation impacts on promoter acetylation, chromatin accessibility and RNA pol II occupancy. In addition to the activities of HDAC1, polycomb repressive complex 2 (PRC2) reinforces gene repression by depositing H3K27me3 at promoter sequences when SPI1 is located at enhancer sequences. Moreover, our study identified a synergistic relationship between PRC2 and HDAC1 complexes in mediating the transcriptional repression activity of SPI1, ultimately inducing synergistic adverse effects on leukaemic cell survival. Our results highlight the importance of the mechanism underlying transcriptional repression in leukemic cells, involving complex functional connections between SPI1 and the epigenetic regulators PRC2 and HDAC1.

Demographics and outcomes of laboratory-confirmed COVID-19 cases during the first epidemic wave in Senegal.

BACKGROUND: Few studies have focused on the effects of COVID-19 on African populations. During the first epidemic wave in Senegal (May 1 to July 31, 2020), COVID-19 cases were isolated in treatment centers of epidemics (TCEs). We described the demographics and outcomes of COVID-19 cases in TCEs. PATIENTS AND METHODS: All cases with laboratory-confirmed COVID-19 in Thiès medical region of Senegal were included. RESULTS: COVID-19 was confirmed in 600 cases. Median age of cases (men: 357, 59.5%; women: 243, 40.5%) was 34.0years. The incidence was 12 per 100,000 inhabitants per month. Overall, 46 (7.7%) cases had a severe or critical form of the disease, and nine of them died. Of 455 cases quarantined in non-hospital TCEs, 340 (74.7%) had no symptom and 115 (25.3%) had mild or moderate symptoms. CONCLUSION: In this African retrospective cohort, COVID-19 cases were young and mostly asymptomatic with a low case fatality rate.

Causes infectieuses de décompensation du diabète: « un prédateur infectieux se cache chez tout diabétique en Afrique¼ / Infectious causes of diabetes decompensation: "an infectious predator hides in any diabetic in Africa"

Introduction : Les infections survenant chez les sujets diabétiques ont été longtemps considérées comme une des causes de l'accroissement de la morbidité et de la mortalité. Elles représentent un motif de plus en plus fréquent d'admission dans le service de médecine interne du Centre Hospitalier Régional et Universitaire de Thiès. Les mécanismes sont plus ou moins élucidés par l'influence de l'hyperglycémie sur les fonctions des polynucléaires neutrophiles. Le but de cette étude est de déterminer les particularités épidémiologiques des infections chez les diabétiques. Patients et Méthode : Il s'agissait d'une étude rétrospective avec recueil de données réalisée sur 24 mois (1er janvier 2016 au 31 décembre 2018) au service de Médecine Interne du Centre Hospitalier Régional et Universitaire de Thiès. Cette étude incluait tous les patients diabétiques quel que soit le genre et le type de diabète, âgés de 15 ans et plus, présentant une infection comme facteur principal de décompensation. Résultats : Durant la période d'étude 2350 patients ont été hospitalisés dans le service de médecine interne dont 390 diabétiques. Parmi eux, 138 patients ont répondu à nos critères d'inclusion soit une prévalence de 35,38%. La moyenne d'âge de nos malades était de 53,49 ans ± 15,65 ans avec un sex-ratio H/F était de 0,70 en faveur des femmes (81 femmes contre 57 hommes). Les infections responsables de la décompensation étaient à localisation cutanéo-muqueuse (30,4%), pulmonaire (22,4%), uro-génitale (18,11%), buccodentaire (10,11%), ORL (1,44%), phanérienne (0,72%). Ailleurs, une infection aux pieds était retrouvée chez 43 patients soit 31,15% des cas. Plusieurs infections pouvaient être présentes chez un même malade. Le diabète était déséquilibré dans 86,2 % (n=94) des cas avec une HbA1c moyenne à 10, 5 % à l'admission Nous n'avons pas noté de corrélation entre l'infection et l'ancienneté du diabète (p =0, 60), l'infection et le type de diabète (p = 0,50) et paradoxalement entre l'infection et le déséquilibre du diabète (p=0,70). Conclusion : Le dépistage des infections chez le diabétique en déséquilibre chronique ou diabétique de novo doit être systématique car généralement ces infections peuvent être asymptomatiques.

Introduction: Infections in people with diabetes have long been considered one of the causes of increased morbidity and mortality. They represent an increasingly frequent reason for admission to the Department of Internal Medicine of the Regional and University Hospital of Thies. The mechanisms are more or less elucidated by the influence of hyperglycemia on neutrophil polynuclear functions. The purpose of this study is to determine the epidemiological characteristics of infections in diabetics. Method: This was a retrospective study with data collected over 24 months (1 January 2016 to 31 December 2018) at the Internal Medicine Department of the Regional and University Hospital of Thies. This study included all diabetic patients, regardless of gender and type of diabetes, aged 15 years and older, with an infection as the primary decompensation factor. Result: During the study period 2,350 patients were hospitalized in the Internal Medicine Department, 390 of whom were diabetic. Of these, 138 patients met our inclusion criteria, a prevalence of 35.38%. The average age of our patients was 53.49 years 15.65 years with a sex-ratio H/F was 0.70 in favor of women (81 Women versus 57 Men). The infections responsible for decompensation were dermal localization (30.4%), pulmonary (22.4%), urogenital (18.11%), oral (10.11%), ENT (1.44%), phanerian (0.72%). Elsewhere, a foot infection was found in 43 patients or 31.15% of cases. Several infections could be present in the same patient. Diabetes was unbalanced in 86.2% (n=94) of cases with an average HbA1c of 10.5% at admission We did not find a correlation between the infection and the age of diabetes (p =0, 60), the infection and the type of diabetes (p = 0.50), and paradoxically between the infection and the imbalance of diabetes (p = 0.70). Conclusion: The detection of infections in diabetics in chronic imbalance or de novo diabetics must be systematic because generally these infections can be asymptomatic.

The Most Common VHL Point Mutation R167Q in Hereditary VHL Disease Interferes with Cell Plasticity Regulation.

Von Hippel-Lindau disease (VHL) is a rare hereditary syndrome due to mutations of the VHL tumor suppressor gene. Patients harboring the R167Q mutation of the VHL gene have a high risk of developing ccRCCs. We asked whether the R167Q mutation with critical aspects of pseudo-hypoxia interferes with tumor plasticity. For this purpose, we used wild-type VHL (WT-VHL) and VHL-R167Q reconstituted cells. We showed that WT-VHL and VHL-R167Q expression had a similar effect on cell morphology and colony formation. However, cells transfected with VHL-R167Q display an intermediate, HIF2-dependent, epithelial-mesenchymal phenotype. Using RNA sequencing, we showed that this mutation upregulates the expression of genes involved in the hypoxia pathway, indicating that such mutation is conferring an enhanced pseudo-hypoxic state. Importantly, this hypoxic state correlates with the induction of genes belonging to epithelial-mesenchymal transition (EMT) and stemness pathways, as revealed by GSEA TCGA analysis. Moreover, among these deregulated genes, we identified nine genes specifically associated with a poor patient survival in the TCGA KIRC dataset. Together, these observations support the hypothesis that a discrete VHL point mutation interferes with tumor plasticity and may impact cell behavior by exacerbating phenotypic switching. A better understanding of the role of this mutation might guide the search for more effective treatments to combat ccRCCs.

In silico characterisation of putative Plasmodium falciparum vaccine candidates in African malaria populations.

Genetic diversity of surface exposed and stage specific Plasmodium falciparum immunogenic proteins pose a major roadblock to developing an effective malaria vaccine with broad and long-lasting immunity. We conducted a prospective genetic analysis of candidate antigens (msp1, ama1, rh5, eba175, glurp, celtos, csp, lsa3, Pfsea, trap, conserved chrom3, hyp9, hyp10, phistb, surfin8.2, and surfin14.1) for malaria vaccine development on 2375 P. falciparum sequences from 16 African countries. We described signatures of balancing selection inferred from positive values of Tajima's D for all antigens across all populations except for glurp. This could be as a result of immune selection on these antigens as positive Tajima's D values mapped to regions with putative immune epitopes. A less diverse phistb antigen was characterised with a transmembrane domain, glycophosphatidyl anchors between the N and C- terminals, and surface epitopes that could be targets of immune recognition. This study demonstrates the value of population genetic and immunoinformatic analysis for identifying and characterising new putative vaccine candidates towards improving strain transcending immunity, and vaccine efficacy across all endemic populations.

Serial transplantation unmasks galectin-9 contribution to tumor immune escape in the MB49 murine model.

Mechanisms of tumor immune escape are quite diverse and require specific approaches for their exploration in syngeneic tumor models. In several human malignancies, galectin-9 (gal-9) is suspected to contribute to the immune escape. However, in contrast with what has been done for the infiltrating cells, the contribution of gal-9 produced by malignant cells has never been demonstrated in an animal model. Therefore, we derived isogenic clones-either positive or negative for gal-9-from the MB49 murine bladder carcinoma cell line. A progressive and consistent reduction of tumor growth was observed when gal-9-KO cells were subjected to serial transplantations into syngeneic mice. In contrast, tumor growth was unaffected during parallel serial transplantations into nude mice, thus linking tumor inhibition to the enhancement of the immune response against gal-9-KO tumors. This stronger immune response was at least in part explained by changing patterns of response to interferon-γ. One consistent change was a more abundant production of CXCL10, a major inflammatory factor whose production is often induced by interferon-γ. Overall, these observations demonstrate for the first time that serial transplantation into syngeneic mice can be a valuable experimental approach for the exploration of novel mechanisms of tumor immune escape.

[Ensuring continuity of care at the time of COVID-19: challenges for the Dakar Integrated Support Center for Addictions]. / Assurer la continuité des soins au temps de la COVID-19 : défis pour le centre de traitement des addictions à Dakar.

The COVID-19 pandemic has an impact on health systems, whose modes of adaptation and response on the ground are still poorly documented and are evolving. The Dakar Integrated Support Center for Addictions (CEPIAD) has been implementing risk reduction since 2014, particularly with drug users. The COVID-19 pandemic and related public health measures were an obstacle to its attendance by patients, in particular due to movement restriction. In addition to the implementation of individual and collective preventive measures in the center, CEPIAD has experimented "take-home" for methadon that is generally provided daily through directly observed treatment. The center has also taken care of amnestied incarcerated cannabis users. Several aspects of this experience, perceived positively, could be relevant outside the pandemic context.

Mise en place d'un centre de traitement des épidémies (CTE) pour COVID-19 dans un service de Médecine Interne; les leçons apprises / Establishment of an Outbreak Center for Covid-19 (OCC), in an Internal Medicine department

Introduction: La fulgurante progression de la pandémie à covid -19 a imposé au Sénégal l'adoption de stratégies de riposte parmi lesquelles la mise en place de centres de traitement des épidémies (CTE) au sein des hôpitaux . Nous nous proposons d'évaluer les activités d'un CTE Covid-19 implanté dans un service de médecine interne et les leçons tirées de ce vécu. Méthodologie : Le CTE Covid -19 a été installé dans le service de médecine interne de l'Hôpital Régional de Thiès (HRT), mais avec conservation de lits dédiés aux patients non atteints de Covid-19. Les étudiants en année de doctorat affectés dans le service de médecine interne étaient responsables de la gestion quotidienne du CTE sous la supervision des spécialistes en médecine interne Ce service était subdivisé en deux parties: le CTE qui prenait en charge les cas de Covid -19 et le reste du service qui devait continuer à accueillir les patients atteints d'autres affections ou qui y étaient régulièrement suivies. Résultats : Du 1er mai au 30 octobre 2020, 237 patients ont été admis dans le CTE. Ils étaient âgés de 7 à 88 ans avec une moyenne d'âge de 53,41 ans et un sexe ratio de 1,60. Les motifs d'admission étaient une désaturation en oxygène inférieure à 90%, la présence d'au moins une comorbidité (autres infections, diabète , hypertension artérielle , obésité, maladies auto-immunes, cancers…). L'âge avancé mais aussi les patients ne pouvant être à domicile faisaient également partie des critères d'admission . Trois (3) cas de co-infection Covid-19 et tuberculose pulmonaire ont été relevés et trois (3) patients avaient un portage chronique du virus de l'hépatite B. Dans le cadre des hospitalisations non Covid -19, les affections suivantes ont été retrouvées : 8 cas de diabète déséquilibrés et autant d'hépatopathie (6,10%); l'accès palustre dans 3, 05% (n=3) ; la tuberculose pulmonaire (3,81%, n=3) ; 3 cas (2,29 %) d'anémie de type biermerien et de lupus érythémateux systémique. De même, 1 cas (0,76%) d 'empyème cérébral ; une polyarthrite rhumatoïde (0,76 %), une (01) maladie rénale chronique , 1 cas de défaillance cardiaque ont également été enregistrées. Cinq (5) cas (3,81 %) non affectés par l'infection à Covid -19 , à leur admission l'ont été au cours de leur hospitalisation et donc transférés au niveau de la zone rouge du CTE. Conclusion: La mise en place du CTE au niveau du service de Médecine interne , a permis une adaptation efficiente dans la prise en charge des patients concernés mais aussi de ceux qui étaient suivis pour des pathologies chroniques comme les urgences médicales reçues durant la période. La continuité des soins a été assurée et les liens avec les autres secteurs de la pyramide sanitaire du Sénégal ont été raffermis.

Introduction : The fast progression of covid -19 throughout the world has forced Senegal to adopt response strategies including the establishment of Outbreak Center for Covid- 19 (OCC ) within hospitals . We propose to evaluate the activi ties of an OCC implemented in an internal medicine department and the lessons learned from this experience. Methodology: The center for care of Covid-19 has been installed in the Internal Medicine department of the Thies Regional Hospital (HRT ), but with dedicated beds for patients non affected by the pandemic . Fifteen doctoral students were assigned, by local medical school , to the Department of Internal Medicine in order to be responsible for the day-to-day management of the OCC. They were supervised by internal medicine specialists . This service was divided into two parts: the OCC that handled Covid -19 cases and the rest of the service , which was to continue to take care of patients with other conditions or who were regularly monitored. Results: From May 1 to October 30, 2020, 237 patients were admitted to the CTE They ranged from 7 to 88 years old with an average age of 53.41 and a sex ratio of 1.60 .The reasons for admission were an oxygen desaturation of less than 90%, the presence of at least one comorbidity (other infections, diabetes, arterial hypertension, obesity, autoimmune diseases, cancers, etc .). Advanced age but also patients who could not be at home were also part of the admission criteria. Three (3) cases of Covid -19 co -infection and pulmonary tuberculosis were identified and three (3) patients had a chronic carriage of the hepatitis B virus. In the context of non -Covid -19 hospitalizations, the following conditions have been found: 8 cases of unbalanced diabetes and as many hepatopathy (6.10%); malaria access in 3.05% (n = 3); pulmonary tuberculosis (3.81%, n = 3); 3 cases (2.29%) of biermeric type anemia and systemic lupus erythematosus. Similarly, 1 case (0.76 %) of cerebral empyema; rheumatoid arthritis (0.76%), one (01) chronic kidney disease, 1 case of heart failure were also recorded Five (5) cases (3.81%) not affected by Covid-19 infection, on admission, were during their hospitalization and therefore transferred to the red zone of the CTE. Conclusion : The establishment of the OCC in the internal medicine service allowed an efficient adaptation in the care of the patients affected by covid disease but also of those who were followed for chronic pathologies or admitted for other medical emergencies This strategy has improved and strengthened the links with other sectors of Senegal 's health pyramid.

Constitutive Activation of RAS/MAPK Pathway Cooperates with Trisomy 21 and Is Therapeutically Exploitable in Down Syndrome B-cell Leukemia.

PURPOSE: Children with Down syndrome (constitutive trisomy 21) that develop acute lymphoblastic leukemia (DS-ALL) have a 3-fold increased likelihood of treatment-related mortality coupled with a higher cumulative incidence of relapse, compared with other children with B-cell acute lymphoblastic leukemia (B-ALL). This highlights the lack of suitable treatment for Down syndrome children with B-ALL. EXPERIMENTAL DESIGN: To facilitate the translation of new therapeutic agents into clinical trials, we built the first preclinical cohort of patient-derived xenograft (PDX) models of DS-ALL, comprehensively characterized at the genetic and transcriptomic levels, and have proven its suitability for preclinical studies by assessing the efficacy of drug combination between the MEK inhibitor trametinib and conventional chemotherapy agents. RESULTS: Whole-exome and RNA-sequencing experiments revealed a high incidence of somatic alterations leading to RAS/MAPK pathway activation in our cohort of DS-ALL, as well as in other pediatric B-ALL presenting somatic gain of the chromosome 21 (B-ALL+21). In murine and human B-cell precursors, activated KRASG12D functionally cooperates with trisomy 21 to deregulate transcriptional networks that promote increased proliferation and self renewal, as well as B-cell differentiation blockade. Moreover, we revealed that inhibition of RAS/MAPK pathway activation using the MEK1/2 inhibitor trametinib decreased leukemia burden in several PDX models of B-ALL+21, and enhanced survival of DS-ALL PDX in combination with conventional chemotherapy agents such as vincristine. CONCLUSIONS: Altogether, using novel and suitable PDX models, this study indicates that RAS/MAPK pathway inhibition represents a promising strategy to improve the outcome of Down syndrome children with B-cell precursor leukemia.

[Neuro-Behçet in a Sub-Saharan Africa Country: a Series of Sixteen Patients in Fann Teaching Hospital, Dakar, Senegal]. / Neuro-Behçet dans un pays d'Afrique subsaharienne : une série de 16 patients au centre hospitalier national universitaire de Fann de Dakar, Sénégal.

Neuro-Behçet (NB) African studies are mainly North African, but Sub-Saharan Africa is not to be outdone. Our aim was to describe diagnostic and therapeutic features of NB in a Senegalese series collected in Dakar. This was a descriptive and retrospective study conducted at the Neurology department of Fann Teaching Hospital in Dakar, Senegal. All patients who met the NB's diagnostic criteria were included. Sixteen patients were collected, 14 males and 2 females with an average age of 40 years [18-71]. The main neurological signs were motor deficit (13 cases), headache (10 cases), and language disorders (4 cases). Extra-neurological signs were dermatological (14 cases), ocular (2 cases), and articular (2 cases) with aseptic unilateral gonarthritis. Fever was present in 9 patients. Neurological involvement was mostly isolated parenchymal (8 cases) or mixed (6 cases). The main clinical forms of NB were rhombencephalitis (8 cases) and retrobulbar optic neuritis (4 cases). Seven patients had a cerebral angio-Behçet with cerebral venous thrombosis (3 cases), ischemic stroke (2 cases), and intracerebral hematoma (2 cases). Under prednisone (16 cases) and azathioprine (3 cases), the short-term clinical outcome was mostly favorable (14 cases) with a modified Rankin scale at 2. NB is an under-diagnosed adult male disease in Sub-Saharan Africa and further studies are needed.

Les études africaines sur le neuro-Behçet (NB) sont majoritairement maghrébines, mais l'Afrique noire n'est pas en reste. L'objectif de l'étude était de décrire les particularités diagnostiques et thérapeutiques du NB dans une série sénégalaise colligée à Dakar. Il s'agit d'une étude rétrospective à visée descriptive menée à la clinique de neurologie du centre hospitalier universitaire de Fann de Dakar, au Sénégal. Tous les patients répondant aux critères diagnostiques de NB ont été inclus. Seize patients ont été colligés, 14 hommes et deux femmes avec un âge moyen de 40 ans [18­71]. Les principaux signes neurologiques étaient un déficit moteur (13 cas), des céphalées (10 cas) et un trouble du langage (4 cas). Les signes extraneurologiques étaient dermatologiques (14 cas), oculaires (2 cas) et articulaires (2 cas) à type de gonarthrite unilatérale aseptique. Une fièvre était présente chez neuf patients. L'atteinte neurologique était majoritairement parenchymateuse isolée (8 cas) ou mixte (6 cas). Les principales formes cliniques de NB étaient la rhombencéphalite (8 cas) et la névrite optique rétrobulbaire (4 cas). Sept patients avaient un angio-Behçet cérébral à type de thromboses veineuses cérébrales (3 cas), d'infarctus cérébraux (2 cas) et d'hématomes intracérébraux (2 cas). Sous prednisone (16 cas) et azathioprine (3 cas), l'évolution clinique à court terme était majoritairement favorable (14 cas) avec un score de Rankin modifié de 2 au moment de l'exeat. Le NB est une maladie de l'homme adulte sous-diagnostiquée en Afrique noire. Des études ultérieures multicentriques nationales et sous-régionales sont souhaitables.

Ontogenic Changes in Hematopoietic Hierarchy Determine Pediatric Specificity and Disease Phenotype in Fusion Oncogene-Driven Myeloid Leukemia.

Fusion oncogenes are prevalent in several pediatric cancers, yet little is known about the specific associations between age and phenotype. We observed that fusion oncogenes, such as ETO2-GLIS2, are associated with acute megakaryoblastic or other myeloid leukemia subtypes in an age-dependent manner. Analysis of a novel inducible transgenic mouse model showed that ETO2-GLIS2 expression in fetal hematopoietic stem cells induced rapid megakaryoblastic leukemia whereas expression in adult bone marrow hematopoietic stem cells resulted in a shift toward myeloid transformation with a strikingly delayed in vivo leukemogenic potential. Chromatin accessibility and single-cell transcriptome analyses indicate ontogeny-dependent intrinsic and ETO2-GLIS2-induced differences in the activities of key transcription factors, including ERG, SPI1, GATA1, and CEBPA. Importantly, switching off the fusion oncogene restored terminal differentiation of the leukemic blasts. Together, these data show that aggressiveness and phenotypes in pediatric acute myeloid leukemia result from an ontogeny-related differential susceptibility to transformation by fusion oncogenes. SIGNIFICANCE: This work demonstrates that the clinical phenotype of pediatric acute myeloid leukemia is determined by ontogeny-dependent susceptibility for transformation by oncogenic fusion genes. The phenotype is maintained by potentially reversible alteration of key transcription factors, indicating that targeting of the fusions may overcome the differentiation blockage and revert the leukemic state.See related commentary by Cruz Hernandez and Vyas, p. 1653.This article is highlighted in the In This Issue feature, p. 1631.

Genetic characterization of B-cell prolymphocytic leukemia: a prognostic model involving MYC and TP53.

B-cell prolymphocytic leukemia (B-PLL) is a rare hematological disorder whose underlying oncogenic mechanisms are poorly understood. Our cytogenetic and molecular assessments of 34 patients with B-PLL revealed several disease-specific features and potential therapeutic targets. The karyotype was complex (≥3 abnormalities) in 73% of the patients and highly complex (≥5 abnormalities) in 45%. The most frequent chromosomal aberrations were translocations involving MYC [t(MYC)] (62%), deletion (del)17p (38%), trisomy (tri)18 (30%), del13q (29%), tri3 (24%), tri12 (24%), and del8p (23%). Twenty-six (76%) of the 34 patients exhibited an MYC aberration, resulting from mutually exclusive translocations or gains. Whole-exome sequencing revealed frequent mutations in TP53, MYD88, BCOR, MYC, SF3B1, SETD2, CHD2, CXCR4, and BCLAF1. The majority of B-PLL used the IGHV3 or IGHV4 subgroups (89%) and displayed significantly mutated IGHV genes (79%). We identified 3 distinct cytogenetic risk groups: low risk (no MYC aberration), intermediate risk (MYC aberration but no del17p), and high risk (MYC aberration and del17p) (P = .0006). In vitro drug response profiling revealed that the combination of a B-cell receptor or BCL2 inhibitor with OTX015 (a bromodomain and extra-terminal motif inhibitor targeting MYC) was associated with significantly lower viability of B-PLL cells harboring a t(MYC). We concluded that cytogenetic analysis is a useful diagnostic and prognostic tool in B-PLL. Targeting MYC may be a useful treatment option in this disease.

Dynamic gene regulation by nuclear colony-stimulating factor 1 receptor in human monocytes and macrophages.

Despite their location at the cell surface, several receptor tyrosine kinases (RTK) are also found in the nucleus, as either intracellular domains or full length proteins. However, their potential nuclear functions remain poorly understood. Here we find that a fraction of full length Colony Stimulating Factor-1 Receptor (CSF-1R), an RTK involved in monocyte/macrophage generation, migrates to the nucleus upon CSF-1 stimulation in human primary monocytes. Chromatin-immunoprecipitation identifies the preferential recruitment of CSF-1R to intergenic regions, where it co-localizes with H3K4me1 and interacts with the transcription factor EGR1. When monocytes are differentiated into macrophages with CSF-1, CSF-1R is redirected to transcription starting sites, colocalizes with H3K4me3, and interacts with ELK and YY1 transcription factors. CSF-1R expression and chromatin recruitment is modulated by small molecule CSF-1R inhibitors and altered in monocytes from chronic myelomonocytic leukemia patients. Unraveling this dynamic non-canonical CSF-1R function suggests new avenues to explore the poorly understood functions of this receptor and its ligands.