Digital Phenotyping of Mental Health using multimodal sensing of multiple situations of interest: A Systematic Literature Review.

Many studies have used Digital Phenotyping of Mental Health (DPMH) to complement classic methods of mental health assessment and monitoring. This research area proposes innovative methods that perform multimodal sensing of multiple situations of interest (e.g., sleep, physical activity, mobility) to health professionals. In this paper, we present a Systematic Literature Review (SLR) to recognize, characterize and analyze the state of the art on DPMH using multimodal sensing of multiple situations of interest to professionals. We searched for studies in six digital libraries, which resulted in 1865 retrieved published papers. Next, we performed a systematic process of selecting studies based on inclusion and exclusion criteria, which selected 59 studies for the data extraction phase. First, based on the analysis of the extracted data, we describe an overview of this field, then presenting characteristics of the selected studies, the main mental health topics targeted, the physical and virtual sensors used, and the identified situations of interest. Next, we outline answers to research questions, describing the context data sources used to detect situations, the DPMH workflow used for multimodal sensing of situations, and the application of DPMH solutions in the mental health assessment and monitoring process. In addition, we recognize trends presented by DPMH studies, such as the design of solutions for high-level information recognition, association of features with mental states/disorders, classification of mental states/disorders, and prediction of mental states/disorders. We also recognize the main open issues in this research area. Based on the results of this SLR, we conclude that despite the potential and continuous evolution for using these solutions as medical decision support tools, this research area needs more work to overcome technology and methodological rigor issues to adopt proposed solutions in real clinical settings.

Neuropilin-1 cooperates with PD-1 in CD8+ T cells predicting outcomes in melanoma patients treated with anti-PD1.

Targeting immune checkpoints, such as Programmed cell Death 1 (PD1), has improved survival in cancer patients by restoring antitumor immune responses. Most patients, however, relapse or are refractory to immune checkpoint blocking therapies. Neuropilin-1 (NRP1) is a transmembrane glycoprotein required for nervous system and angiogenesis embryonic development, also expressed in immune cells. We hypothesized that NRP1 could be an immune checkpoint co-receptor modulating CD8+ T cells activity in the context of the antitumor immune response. Here, we show that NRP1 is recruited in the cytolytic synapse of PD1+CD8+ T cells, cooperates and enhances PD-1 activity. In mice, CD8+ T cells specific deletion of Nrp1 improves anti-PD1 antibody antitumor immune responses. Likewise, in human metastatic melanoma, the expression of NRP1 in tumor infiltrating CD8+ T cells predicts poor outcome of patients treated with anti-PD1. NRP1 is a promising target to overcome resistance to anti-PD1 therapies.

Sensing Apps and Public Data Sets for Digital Phenotyping of Mental Health: Systematic Review.

BACKGROUND: Mental disorders are normally diagnosed exclusively on the basis of symptoms, which are identified from patients' interviews and self-reported experiences. To make mental health diagnoses and monitoring more objective, different solutions have been proposed such as digital phenotyping of mental health (DPMH), which can expand the ability to identify and monitor health conditions based on the interactions of people with digital technologies. OBJECTIVE: This article aims to identify and characterize the sensing applications and public data sets for DPMH from a technical perspective. METHODS: We performed a systematic review of scientific literature and data sets. We searched 8 digital libraries and 20 data set repositories to find results that met the selection criteria. We conducted a data extraction process from the selected articles and data sets. For this purpose, a form was designed to extract relevant information, thus enabling us to answer the research questions and identify open issues and research trends. RESULTS: A total of 31 sensing apps and 8 data sets were identified and reviewed. Sensing apps explore different context data sources (eg, positioning, inertial, ambient) to support DPMH studies. These apps are designed to analyze and process collected data to classify (n=11) and predict (n=6) mental states/disorders, and also to investigate existing correlations between context data and mental states/disorders (n=6). Moreover, general-purpose sensing apps are developed to focus only on contextual data collection (n=9). The reviewed data sets contain context data that model different aspects of human behavior, such as sociability, mood, physical activity, sleep, with some also being multimodal. CONCLUSIONS: This systematic review provides in-depth analysis regarding solutions for DPMH. Results show growth in proposals for DPMH sensing apps in recent years, as opposed to a scarcity of public data sets. The review shows that there are features that can be measured on smart devices that can act as proxies for mental status and well-being; however, it should be noted that the combined evidence for high-quality features for mental states remains limited. DPMH presents a great perspective for future research, mainly to reach the needed maturity for applications in clinical settings.

Erythrocytosis associated with IgA nephropathy.

BACKGROUND: Erythrocytosis is a hematological disorder usually related to hematopoietic stem cell somatic mutations. However, unexplained erythrocytosis remains frequent. In this study, we evaluated the involvement of IgA1, a regulator of erythropoiesis also implicated in IgA nephropathy (IgAN) pathophysiology, in unexplained polycythemia/erythrocytosis (PE) of IgAN patients. METHODS: IgAN-PE patients' serum was collected, analyzed and used to study IgA1 effect on proliferation and differentiation of erythroid progenitors. Hematological parameters of transgenic mice for human alpha1 heavy chain were studied. Multicentric observational cohorts of chronic kidney disease (CKD) patients, including both native kidney diseases and renal transplants, were studied to analyze patient hemoglobin levels. FINDINGS: We retrospectively identified 6 patients with IgAN and unexplained PE. In large CKD cohorts, IgAN was associated with PE in 3.5% of patients (p<0.001 compared to other nephropathies). IgAN was an independent factor associated with higher hemoglobin levels (13.1g/dL vs 12.2 g/dL, p=0.01). During post-transplant anemia, anemia recovery was faster in IgAN patients. Elevated polymeric/monomeric IgA1 ratio as well as high Gd-IgA1 rate were observed in circulating IgA1 of the 6 IgAN-PE patients as compared with control or IgAN patients without PE. IgA1 from these patients increased the sensitivity of erythroid progenitors to Epo. In mice, we also observed an elevation of hematocrit in alpha1 knock-in mice compared to wild type controls. INTERPRETATION: These data identify a new etiology of erythrocytosis and demonstrate the role of pIgA1 in human erythropoiesis. This syndrome of IgA-related erythrocytosis should be investigated in case of unexplained erythrocytosis and renal disease. FUNDING: This work was supported by INSERM (French national institute for health and medical research), Labex GRex and Imagine Institute (Paris, France).

Uma abordagem atual da utilização de antidepressivos no manejo da depressão pós-parto / A current approach to the use of antidepressants in the management of postpartum depression / Enfoque actual de la utilización de antidepresivos en el manejo de la depresión postparto

OBJETIVO: caracterizar a utilização de antidepressivos no manejo da depressão pós-parto. MÉTODO: empregou-se uma revisão integrativa de literatura, das bases de dados PubMed e Biblioteca Virtual em Saúde, com aplicação de descritores, visando responder a pergunta norteadora do trabalho, entre os dias 25 de fevereiro e 10 de março de 2019. Com base nos critérios de inclusão e exclusão, foram selecionados 23 artigos que, posteriormente, foram submetidos à categorização. RESULTADOS: a sertralina deve ser a droga de escolha para o tratamento farmacológico da depressão puerperal. Constatou-se também, que a utilização profilática de antidepressivos em mulheres susceptíveis é contestável e pouco se sabe sobre os possíveis efeitos colaterais. Ademais, foi encontrado que não há consenso sobre a superioridade da terapia farmacológica em detrimento às psicoterapias. CONCLUSÃO: há evidencias que fundamentam o uso de sertralina, paroxetina, duloxetina, nortriptilina e imipramina para tratar mulheres com depressão pós-parto, sendo a amamentação sempre recomendada. Ressalta-se que emerge a necessidade de estudos com amostras representativas para validar ou restringir o uso de psicofármacos na profilaxia da depressão puerperal.

OBJECTIVE: this study aimed to characterize the use of antidepressants in the management of postpartum depression. METHOD: an integrative literature review of the PubMed and Virtual Health Library databases was used, with the application of descriptors, aiming to answer the guiding question of the work, between February 25th and March 10th, 2019. Based on the inclusion and exclusion criteria, 23 articles were selected that were later submitted to categorization. RESULTS: sertraline should be the drug of choice for the pharmacological treatment of puerperal depression. It was also found that the prophylactic use of antidepressants in susceptible women is controversial and little is known about the possible side effects. In addition, it was found that there is no consensus on the superiority of pharmacological therapy to the detriment of psychotherapies. CONCLUSION: there is evidence supporting the use of sertraline, paroxetine, duloxetine, nortriptyline and imipramine to treat women with postpartum depression, and breastfeeding is always recommended. It is worth noting that the need for studies with representative samples to validate or restrict the use of psychotropic drugs in the prophylaxis of puerperal depression emerges.

OBJETIVO: el presente estudio tuvo como objetivo caracterizar la utilización de antidepresivos en el manejo de la depresión posparto. MÉTODO: revisión integradora de literatura, de las bases de datos PubMed y Biblioteca Virtual de Salud, con aplicación de descriptores, para responder a la pregunta orientadora del trabajo, entre el 25 de febrero y el 10 de marzo de 2019. Con base en los criterios de inclusión y exclusión, se seleccionaron 23 artículos que posteriormente se sometieron a categorización. RESULTADOS: la sertralina debe ser la droga elegida para el tratamiento farmacológico de la depresión puerperal. Además, se constató que la utilización profiláctica de antidepresivos en mujeres susceptibles es discutible y poco se sabe sobre los posibles efectos colaterales. Asimismo, se encontró que no hay consenso sobre la superioridad de la terapia farmacológica en detrimento de las psicoterapias. CONCLUSIÓN: hay evidencias que fundamentan el uso de sertralina, paroxetina, duloxetina, nortriptilina e imipramina para tratar a mujeres con depresión posparto, siendo la lactancia siempre recomendada. Se destaca que surge la necesidad de realizar estudios con muestras representativas para validar o restringir el uso de psicofármacos en la profilaxis de la depresión puerperal.

Recognizing Context-Aware Human Sociability Patterns Using Pervasive Monitoring for Supporting Mental Health Professionals.

Traditionally, mental health specialists monitor their patients' social behavior by applying subjective self-report questionnaires in face-to-face meetings. Usually, the application of the self-report questionnaire is limited by cognitive biases (e.g., memory bias and social desirability). As an alternative, we present a solution to detect context-aware sociability patterns and behavioral changes based on social situations inferred from ubiquitous device data. This solution does not focus on the diagnosis of mental states, but works on identifying situations of interest to specialized professionals. The proposed solution consists of an algorithm based on frequent pattern mining and complex event processing to detect periods of the day in which the individual usually socializes. Social routine recognition is performed under different context conditions to differentiate abnormal social behaviors from the variation of usual social habits. The proposed solution also can detect abnormal behavior and routine changes. This solution uses fuzzy logic to model the knowledge of the mental health specialist necessary to identify the occurrence of behavioral change. Evaluation results show that the prediction performance of the identified context-aware sociability patterns has strong positive relation (Pearson's correlation coefficient >70%) with individuals' social routine. Finally, the evaluation conducted recognized that the proposed solution leading to the identification of abnormal social behaviors and social routine changes consistently.

XPO1 regulates erythroid differentiation and is a new target for the treatment of ß-thalassemia.

ß-thalassemia major (ß-TM) is an inherited hemoglobinopathy caused by a quantitative defect in the synthesis of ß-globin chains of hemoglobin, leading to the accumulation of free a-globin chains that aggregate and cause ineffective erythropoiesis. We have previously demonstrated that terminal erythroid maturation requires a transient activation of caspase-3 and that the chaperone Heat Shock Protein 70 (HSP70) accumulates in the nucleus to protect GATA-1 transcription factor from caspase-3 cleavage. This nuclear accumulation of HSP70 is inhibited in human ß-TM erythroblasts due to HSP70 sequestration in the cytoplasm by free a-globin chains, resulting in maturation arrest and apoptosis. Likewise, terminal maturation can be restored by transduction of a nuclear-targeted HSP70 mutant. Here we demonstrate that in normal erythroid progenitors, HSP70 localization is regulated by the exportin-1 (XPO1), and that treatment of ß-thalassemic erythroblasts with an XPO1 inhibitor increased the amount of nuclear HSP70, rescued GATA-1 expression and improved terminal differentiation, thus representing a new therapeutic option to ameliorate ineffective erythropoiesis of ß-TM.

Mental health ubiquitous monitoring supported by social situation awareness: A systematic review.

Traditionally, the process of monitoring and evaluating social behavior related to mental health has based on self-reported information, which is limited by the subjective character of responses and various cognitive biases. Today, however, there is a growing amount of studies that have provided methods to objectively monitor social behavior through ubiquitous devices and have used this information to support mental health services. In this paper, we present a Systematic Literature Review (SLR) to identify, analyze and characterize the state of the art about the use of ubiquitous devices to monitor users' social behavior focused on mental health. For this purpose, we performed an exhaustive literature search on the six main digital libraries. A screening process was conducted on 160 peer-reviewed publications by applying suitable selection criteria to define the appropriate studies to the scope of this SLR. Next, 20 selected studies were forwarded to the data extraction phase. From an analysis of the selected studies, we recognized the types of social situations identified, the process of transforming contextual data into social situations, the use of social situation awareness to support mental health monitoring, and the methods used to evaluate proposed solutions. Additionally, we identified the main trends presented by this research area, as well as open questions and perspectives for future research. Results of this SLR showed that social situation-aware ubiquitous systems represent promising assistance tools for patients and mental health professionals. However, studies still present limitations in methodological rigor and restrictions in experiments, and solutions proposed by them have limitations to be overcome.

Vitamin D Receptor Controls Cell Stemness in Acute Myeloid Leukemia and in Normal Bone Marrow.

Vitamin D (VD) is a known differentiating agent, but the role of VD receptor (VDR) is still incompletely described in acute myeloid leukemia (AML), whose treatment is based mostly on antimitotic chemotherapy. Here, we present an unexpected role of VDR in normal hematopoiesis and in leukemogenesis. Limited VDR expression is associated with impaired myeloid progenitor differentiation and is a new prognostic factor in AML. In mice, the lack of Vdr results in increased numbers of hematopoietic and leukemia stem cells and quiescent hematopoietic stem cells. In addition, malignant transformation of Vdr-/- cells results in myeloid differentiation block and increases self-renewal. Vdr promoter is methylated in AML as in CD34+ cells, and demethylating agents induce VDR expression. Association of VDR agonists with hypomethylating agents promotes leukemia stem cell exhaustion and decreases tumor burden in AML mouse models. Thus, Vdr functions as a regulator of stem cell homeostasis and leukemic propagation.

Mast cell chymase protects against acute ischemic kidney injury by limiting neutrophil hyperactivation and recruitment.

Here we investigated the role of murine mast cell protease 4 (MCPT4), the functional counterpart of human mast cell chymase, in an experimental model of renal ischemia reperfusion injury, a major cause of acute kidney injury. MCPT4-deficient mice had worsened kidney function compared to wildtype mice. MCPT4 absence exacerbated pathologic neutrophil infiltration in the kidney and increased kidney myeloperoxidase expression, cell death and necrosis. In kidneys with ischemia reperfusion injury, when compared to wildtype mice, MCPT4-deficient mice showed increased surface expression of adhesion molecules necessary for leukocyte extravasation including neutrophil CD162 and endothelial cell CD54. In vitro, human chymase mediated the cleavage of neutrophil expressed CD162 and also CD54, P- and E-Selectin expressed on human glomerular endothelial cells. MCPT4 also dampened systemic neutrophil activation after renal ischemia reperfusion injury as neutrophils expressed more CD11b integrin and produced more reactive oxygen species in MCPT4-deficient mice. Accordingly, after renal injury, neutrophil migration to an inflammatory site distal from the kidney was increased in MCPT4-deficient versus wildtype mice. Thus, contrary to the described overall aggravating role of mast cells, one granule-released mediator, the MCPT4 chymase, exhibits a potent anti-inflammatory function in renal ischemia reperfusion injury by controlling neutrophil extravasation and activation thereby limiting associated damage.

Schwann cells orchestrate peripheral nerve inflammation through the expression of CSF1, IL-34, and SCF in amyotrophic lateral sclerosis.

Distal axonopathy is a recognized pathological feature of amyotrophic lateral sclerosis (ALS). In the peripheral nerves of ALS patients, motor axon loss elicits a Wallerian-like degeneration characterized by denervated Schwann cells (SCs) together with immune cell infiltration. However, the pathogenic significance of denervated SCs accumulating following impaired axonal growth in ALS remains unclear. Here, we analyze SC phenotypes in sciatic nerves of ALS patients and paralytic SOD1G93A rats, and identify remarkably similar and specific reactive SC phenotypes based on the pattern of S100ß, GFAP, isolectin and/or p75NTR immunoreactivity. Different subsets of reactive SCs expressed colony-stimulating factor-1 (CSF1) and Interleukin-34 (IL-34) and closely interacted with numerous endoneurial CSF-1R-expressing monocyte/macrophages, suggesting a paracrine mechanism of myeloid cell expansion and activation. SCs bearing phagocytic phenotypes as well as endoneurial macrophages expressed stem cell factor (SCF), a trophic factor that attracts and activates mast cells through the c-Kit receptor. Notably, a subpopulation of Ki67+ SCs expressed c-Kit in the sciatic nerves of SOD1G93A rats, suggesting a signaling pathway that fuels SC proliferation in ALS. c-Kit+ mast cells were also abundant in the sciatic nerve from ALS donors but not in controls. Pharmacological inhibition of CSF-1R and c-Kit with masitinib in SOD1G93A rats potently reduced SC reactivity and immune cell infiltration in the sciatic nerve and ventral roots, suggesting a mechanism by which the drug ameliorates peripheral nerve pathology. These findings provide strong evidence for a previously unknown inflammatory mechanism triggered by SCs in ALS peripheral nerves that has broad application in developing novel therapies.

CD34 Identifies a Subset of Proliferating Microglial Cells Associated with Degenerating Motor Neurons in ALS.

Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of upper and lower motor neurons accompanied by proliferation of reactive microglia in affected regions. However, it is unknown whether the hematopoietic marker CD34 can identify a subpopulation of proliferating microglial cells in the ALS degenerating spinal cord. Immunohistochemistry for CD34 and microglia markers was performed in lumbar spinal cords of ALS rats bearing the SOD1G93A mutation and autopsied ALS and control human subjects. Characterization of CD34-positive cells was also performed in primary cell cultures of the rat spinal cords. CD34 was expressed in a large number of cells that closely interacted with degenerating lumbar spinal cord motor neurons in symptomatic SOD1G93A rats, but not in controls. Most CD34+ cells co-expressed the myeloid marker CD11b, while only a subpopulation was stained for Iba1 or CD68. Notably, CD34+ cells actively proliferated and formed clusters adjacent to damaged motor neurons bearing misfolded SOD1. CD34+ cells were identified in the proximity of motor neurons in autopsied spinal cord from sporadic ALS subjects but not in controls. Cell culture of symptomatic SOD1G93A rat spinal cords yielded a large number of CD34+ cells exclusively in the non-adherent phase, which generated microglia after successive passaging. A yet unrecognized CD34+ cells, expressing or not the microglial marker Iba1, proliferate and accumulate adjacent to degenerating spinal motor neurons, representing an intriguing cell target for approaching ALS pathogenesis and therapeutics.

Lessons to Learn From Low-Dose Cyclosporin-A: A New Approach for Unexpected Clinical Applications.

Cyclosporin-A has been known and used for a long time, since its "fast track" approval in the early 80's. This molecule has rapidly demonstrated unexpected immunosuppressive properties, transforming the history of organ transplantation. Cyclosporin's key effect relies on modulation on T-lymphocyte activity, which explains its role in the prevention of graft rejection. However, whether cyclosporin-A exerts other effects on immune system remains to be determined. Until recently, cyclosporin-A was mainly used at a high-dose, but given the drug toxicity and despite the fear of losing its immunosuppressive effects, there is nowadays a tendency to decrease its dose. The literature has been reporting data revealing a paradoxical effect of low dosage of cyclosporin-A. These low-doses appear to have immunomodulatory properties, with different effects from high-doses on CD8+ T lymphocyte activation, auto-immune diseases, graft-vs.-host disease and cancer. The aim of this review is to discuss the role of cyclosporin-A, not only as a consecrated immunosuppressive agent, but also as an immunomodulatory drug when administrated at low-dose. The use of low-dose cyclosporin-A may become a new therapeutic strategy, particularly to treat cancer.

Human CD4- invariant NKT lymphocytes regulate graft versus host disease.

Despite increasing evidence for a protective role of invariant (i) NKT cells in the control of graft-versus-host disease (GVHD), the mechanisms underpinning regulation of the allogeneic immune response in humans are not known. In this study, we evaluated the distinct effects of human in vitro expanded and flow-sorted human CD4+ and CD4- iNKT subsets on human T cell activation in a pre-clinical humanized NSG mouse model of xenogeneic GVHD. We demonstrate that human CD4- but not CD4+ iNKT cells could control xenogeneic GVHD, allowing significantly prolonged overall survival and reduced pathological GVHD scores without impairing human T cell engraftment. Human CD4- iNKT cells reduced the activation of human T cells and their Th1 and Th17 differentiation in vivo. CD4- and CD4+ iNKT cells had distinct effects upon DC maturation and survival. Compared to their CD4+ counterparts, in co-culture experiments in vitro, human CD4- iNKT cells had a higher ability to make contacts and degranulate in the presence of mouse bone marrow-derived DCs, inducing their apoptosis. In vivo we observed that infusion of PBMC and CD4- iNKT cells was associated with decreased numbers of splenic mouse CD11c+ DCs. Similar differential effects of the iNKT cell subsets were observed on the maturation and in the induction of apoptosis of human monocyte-derived dendritic cells in vitro. These results highlight the increased immunosuppressive functions of CD4-versus CD4+ human iNKT cells in the context of alloreactivity, and provide a rationale for CD4- iNKT selective expansion or transfer to prevent GVHD in clinical trials.

Mast cells and neutrophils mediate peripheral motor pathway degeneration in ALS.

Neuroinflammation is a recognized pathogenic mechanism underlying motor neuron degeneration in amyotrophic lateral sclerosis (ALS), but the inflammatory mechanisms influencing peripheral motor axon degeneration remain largely unknown. A recent report showed a pathogenic role for c-Kit-expressing mast cells mediating inflammation and neuromuscular junction denervation in muscles from SOD1G93A rats. Here, we have explored whether mast cells infiltrate skeletal muscles in autopsied muscles from ALS patients. We report that degranulating mast cells were abundant in the quadriceps muscles from ALS subjects but not in controls. Mast cells were associated with myofibers and motor endplates and, remarkably, interacted with neutrophils forming large extracellular traps. Mast cells and neutrophils were also abundant around motor axons in the extensor digitorum longus muscle, sciatic nerve, and ventral roots of symptomatic SOD1G93A rats, indicating that immune cell infiltration extends along the entire peripheral motor pathway. Postparalysis treatment of SOD1G93A rats with the tyrosine kinase inhibitor drug masitinib prevented mast cell and neutrophil infiltration, axonal pathology, secondary demyelination, and the loss of type 2B myofibers, compared with vehicle-treated rats. These findings provide further evidence for a yet unrecognized contribution of immune cells in peripheral motor pathway degeneration that can be therapeutically targeted by tyrosine kinase inhibitors.

The lack of PI3Kγ favors M1 macrophage polarization and does not prevent kidney diseases progression.

Acute kidney injury (AKI) and chronic kidney disease (CKD) are major concerns in worldwide public health, and their pathophysiology involves immune cells activation, being macrophages one of the main players of both processes. It is suggested that metabolic pathways could contribute to macrophage modulation and phosphatidylinositol­3 kinase (PI3K) pathway was shown to be activated in kidneys subjected to ischemia and reperfusion as well as unilateral ureteral obstruction (UUO). Although PI3K inhibition is mostly associated with anti-inflammatory response, its use in kidney injuries has been shown controversial results, which indicates the need for further studies. Our aim was to unveil the role of PI3Kγ in macrophage polarization and in kidney diseases development. We analyzed bone-marrow macrophages polarization from wild-type (WT) and PI3Kγ knockout (PI3K KO) animals. We observed increased expression of M1 (CD86, CCR7, iNOS, TNF, CXCL9, CXCL10, IL-12 and IL-23) and decreased of M2 (CD206, Arg-1, FIZZ1 and YM1) markers in the lack of PI3Kγ. And this modulation was accompanied by higher levels of inflammatory cytokines in PI3K KO M1 cells. PI3K KO mice had increased M1 in steady state kidneys, and no protection was observed in these mice after acute and chronic kidney insults. On the contrary, they presented higher levels of protein-to-creatinine ratio and Kim-1 expression and increased tubular injury. In conclusion, our findings demonstrated that the lack of PI3Kγ favors M1 macrophages polarization providing an inflammatory-prone environment, which does not prevent kidney diseases progression.

Evidence for mast cells contributing to neuromuscular pathology in an inherited model of ALS.

Evidence indicates that neuroinflammation contributes to motor neuron degeneration in amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease leading to progressive muscular paralysis. However, it remains elusive whether inflammatory cells can interact with degenerating distal motor axons, influencing the progressive denervation of neuromuscular junctions (NMJs). By analyzing the muscle extensor digitorum longus (EDL) following paralysis onset in the SOD1G93A rat model, we have observed a massive infiltration and degranulation of mast cells, starting after paralysis onset and correlating with progressive NMJ denervation. Remarkably, mast cells accumulated around degenerating motor axons and NMJs, and were also associated with macrophages. Mast cell accumulation and degranulation in paralytic EDL muscle was prevented by systemic treatment over 15 days with masitinib, a tyrosine kinase inhibitor currently in clinical trials for ALS exhibiting pharmacological activity affecting mast cells and microglia. Masitinib-induced mast cell reduction resulted in a 35% decrease in NMJ denervation and reduced motor deficits as compared with vehicle-treated rats. Masitinib also normalized macrophage infiltration, as well as regressive changes in Schwann cells and capillary networks observed in advanced paralysis. These findings provide evidence for mast cell contribution to distal axonopathy and paralysis progression in ALS, a mechanism that can be therapeutically targeted by masitinib.

Serum Iron Protects from Renal Postischemic Injury.

Renal transplants remain a medical challenge, because the parameters governing allograft outcome are incompletely identified. Here, we investigated the role of serum iron in the sterile inflammation that follows kidney ischemia-reperfusion injury. In a retrospective cohort study of renal allograft recipients (n=169), increased baseline levels of serum ferritin reliably predicted a positive outcome for allografts, particularly in elderly patients. In mice, systemic iron overload protected against renal ischemia-reperfusion injury-associated sterile inflammation. Furthermore, chronic iron injection in mice prevented macrophage recruitment after inflammatory stimuli. Macrophages cultured in high-iron conditions had reduced responses to Toll-like receptor-2, -3, and -4 agonists, which associated with decreased reactive oxygen species production, increased nuclear localization of the NRF2 transcription factor, increased expression of the NRF2-related antioxidant response genes, and limited NF-κB and proinflammatory signaling. In macrophage-depleted animals, the infusion of macrophages cultured in high-iron conditions did not reconstitute AKI after ischemia-reperfusion, whereas macrophages cultured in physiologic iron conditions did. These findings identify serum iron as a critical protective factor in renal allograft outcome. Increasing serum iron levels in patients may thus improve prognosis of renal transplants.

FLT3 inhibitors: clinical potential in acute myeloid leukemia.

Acute myeloid leukemia (AML) is an aggressive hematopoietic malignancy that is cured in as few as 15%-40% of cases. Tremendous improvements in AML prognostication arose from a comprehensive analysis of leukemia cell genomes. Among normal karyotype AML cases, mutations in the FLT3 gene are the ones most commonly detected as having a deleterious prognostic impact. FLT3 is a transmembrane tyrosine kinase receptor, and alterations of the FLT3 gene such as internal tandem duplications (FLT3-ITD) deregulate FLT3 downstream signaling pathways in favor of increased cell proliferation and survival. FLT3 tyrosine kinase inhibitors (TKI) emerged as a new therapeutic option in FLT3-ITD AML, and clinical trials are ongoing with a variety of TKI either alone, combined with chemotherapy, or even as maintenance after allogenic stem cell transplantation. However, a wide range of molecular resistance mechanisms are activated upon TKI therapy, thus limiting their clinical impact. Massive research efforts are now ongoing to develop more efficient FLT3 TKI and/or new therapies targeting these resistance mechanisms to improve the prognosis of FLT3-ITD AML patients in the future.