Erosion of the chronic myeloid leukaemia stem cell pool by PPARγ agonists.

Whether cancer is maintained by a small number of stem cells or is composed of proliferating cells with approximate phenotypic equivalency is a central question in cancer biology. In the stem cell hypothesis, relapse after treatment may occur by failure to eradicate cancer stem cells. Chronic myeloid leukaemia (CML) is quintessential to this hypothesis. CML is a myeloproliferative disorder that results from dysregulated tyrosine kinase activity of the fusion oncoprotein BCR-ABL. During the chronic phase, this sole genetic abnormality (chromosomal translocation Ph(+): t(9;22)(q34;q11)) at the stem cell level causes increased proliferation of myeloid cells without loss of their capacity to differentiate. Without treatment, most patients progress to the blast phase when additional oncogenic mutations result in a fatal acute leukaemia made of proliferating immature cells. Imatinib mesylate and other tyrosine kinase inhibitors (TKIs) that target the kinase activity of BCR-ABL have improved patient survival markedly. However, fewer than 10% of patients reach the stage of complete molecular response (CMR), defined as the point when BCR-ABL transcripts become undetectable in blood cells. Failure to reach CMR results from the inability of TKIs to eradicate quiescent CML leukaemia stem cells (LSCs). Here we show that the residual CML LSC pool can be gradually purged by the glitazones, antidiabetic drugs that are agonists of peroxisome proliferator-activated receptor-γ (PPARγ). We found that activation of PPARγ by the glitazones decreases expression of STAT5 and its downstream targets HIF2α and CITED2, which are key guardians of the quiescence and stemness of CML LSCs. When pioglitazone was given temporarily to three CML patients in chronic residual disease in spite of continuous treatment with imatinib, all of them achieved sustained CMR, up to 4.7 years after withdrawal of pioglitazone. This suggests that clinically relevant cancer eradication may become a generally attainable goal by combination therapy that erodes the cancer stem cell pool.

Germ-line JAK2 mutations in the kinase domain are responsible for hereditary thrombocytosis and are resistant to JAK2 and HSP90 inhibitors.

The main molecular basis of essential thrombocythemia and hereditary thrombocytosis is acquired, and germ-line-activating mutations affect the thrombopoietin signaling axis. We have identified 2 families with hereditary thrombocytosis presenting novel heterozygous germ-line mutations of JAK2. One family carries the JAK2 R867Q mutation located in the kinase domain, whereas the other presents 2 JAK2 mutations, S755R/R938Q, located in cis in both the pseudokinase and kinase domains. Expression of Janus kinase 2 (JAK2) R867Q and S755R/R938Q induced spontaneous growth of Ba/F3-thrombopoietin receptor (MPL) but not of Ba/F3-human receptor of erythropoietin cells. Interestingly, both Ba/F3-MPL cells expressing the mutants and platelets from patients displayed thrombopoietin-independent phosphorylation of signal transducer and activator of transcription 1. The JAK2 R867Q and S755R/R938Q proteins had significantly longer half-lives compared with JAK2 V617F. The longer half-lives correlated with increased binding to the heat shock protein 90 (HSP90) chaperone and with higher MPL cell-surface expression. Moreover, these mutants were less sensitive to JAK2 and HSP90 inhibitors than JAK2 V617F. Our results suggest that the mutations in the kinase domain of JAK2 may confer a weak activation of signaling specifically dependent on MPL while inducing a decreased sensitivity to clinically available JAK2 inhibitors.

Leptospirosis: a clinical and diagnostic challenge.

We present the case of a man in his early 50s who presented with a history of fever, malaise and jaundice. Initial investigations showed liver and renal dysfunction with no discernible cause for the septic process. On starting intravenous antibiotics, the patient developed a septic-shock-like reaction requiring transfer to intensive care. A diagnosis of leptospirosis was eventually established through an extensive and thorough history leading to a stepwise approach to investigations. Treatment targeting leptospirosis was delivered with noticeable clinical improvement.

PPARγ agonists promote the resolution of myelofibrosis in preclinical models.

Myelofibrosis (MF) is a non-BCR-ABL myeloproliferative neoplasm associated with poor outcomes. Current treatment has little effect on the natural history of the disease. MF results from complex interactions between (a) the malignant clone, (b) an inflammatory context, and (c) remodeling of the bone marrow (BM) microenvironment. Each of these points is a potential target of PPARγ activation. Here, we demonstrated the therapeutic potential of PPARγ agonists in resolving MF in 3 mouse models. We showed that PPARγ agonists reduce myeloproliferation, modulate inflammation, and protect the BM stroma in vitro and ex vivo. Activation of PPARγ constitutes a relevant therapeutic target in MF, and our data support the possibility of using PPARγ agonists in clinical practice.

Diffusion Tensor Imaging and Tractography Utilized in the Resection of a Midbrain Cavernous Malformation.

Background: Diffusion tensor imaging (DTI) is a magnetic resonance-based imaging technique that can provide important information about the underlying structure and integrity of the white matter in the brain. Tractography, a DTI postprocessing technique, can provide a detailed model of individual white matter fiber tracts. Knowledge of these tracts may be beneficial in the surgical planning and execution for neurosurgical patients. Case Report: We review the basic principles behind DTI and present an illustrative case in which DTI was used to delineate the relationship of eloquent white matter tracts to a cavernous malformation in a patient undergoing resection. Conclusion: The use of DTI during preoperative planning allows the neurosurgeon to understand if a lesion is disrupting, infiltrating, or altering the course of local white matter tracts. With the combined use of DTI and intraoperative neuronavigation, the neurosurgeon can better identify and avoid white matter tracts, not only in the local area of resection but also during approach to the lesion, thereby reducing the risk of damage to vital cortical pathways and subsequent functional impairment.

TET2 haploinsufficiency alters reprogramming into induced pluripotent stem cells.

The discovery of the Ten-Eleven Translocation (TET) protein family was initiated by the identification of the MLL partner TET1, and of mutations in the TET2 gene in hematological malignancies including myeloproliferative neoplasms (MPN). TET1, 2 and 3 proteins hydroxylate 5-methylcytosine (5-mC) into 5-hydroxymethylcytosine (5-hmC) and further oxidize 5-hmC into 5-formylcytosine (5-fC) and 5-carboxylcytosine (5-caC). Previous studies highlight the involvement of TET proteins in somatic cells reprogramming into induced pluripotent stem cells (iPSC), particularly Tet1 and 2 in mouse and TET1 in human. Here, we asked whether endogenous TET2 knockdown also displays this function. Using different shRNA against TET2, we provide evidence that TET2 strongly decreases the reprogramming of human hematopoietic progenitor cells into iPSC. Importantly, using 2 MPN patients, we observed that TET2 mutations affecting catalytic domain allowed iPSC generation. Instead, using another TET2 and TET3-mutated patient, we could only reprogram IPSC with TET3 mutation alone, suggesting that the type of TET2 mutation and/or the cooperation with TET3 mutations may alter the reprogramming activity. Altogether, this work highlights the importance of endogenous TET in the reprogramming process of human hematopoietic progenitors.

Antenatal psychiatric morbidity in Maltese women.

OBJECTIVE: There has been no empirical research on the occurrence of antenatal psychiatric morbidity in Maltese women. Epidemiological studies have shown that depressive episodes occur in 10-20% of pregnant women. Furthermore, studies have shown that antenatal psychiatric morbidity can adversely affect maternal and foetal well being. METHOD: A random sample of 239 pregnant women were interviewed at booking using a detailed sociodemographic history and the Revised Version of the Clinical Interview Schedule (CIS-R). The CIS-R was again administered at 36 weeks and at 8 weeks postpartum to 95.8% of the women. RESULTS: Among the 229 women interviewed the point prevalence of all psychiatric diagnosis was 19.2% and the point prevalence of antenatal depression and anxiety disorders was 14.8% and 4.4%, respectively, at 18.6 weeks of gestation. At 36 weeks of gestation, the point prevalence of depressive disorder was 10%. Two thirds of the antenatal depression remitted postpartum. CONCLUSION: A significant proportion of Maltese women suffer from psychiatric morbidity during pregnancy. Depressive disorders are the commonest morbidity in this study population. Given the scope of the morbidity and potential impact on obstetric and neonatal outcomes, early detection and treatment are recommended.

Germline duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies.

No major predisposition gene for familial myeloproliferative neoplasms (MPN) has been identified. Here we demonstrate that the autosomal dominant transmission of a 700-kb duplication in four genetically related families predisposes to myeloid malignancies, including MPN, frequently progressing to leukemia. Using induced pluripotent stem cells and primary cells, we demonstrate that overexpression of ATG2B and GSKIP enhances hematopoietic progenitor differentiation, including of megakaryocytes, by increasing progenitor sensitivity to thrombopoietin (TPO). ATG2B and GSKIP cooperate with acquired JAK2, MPL and CALR mutations during MPN development. Thus, the germline duplication may change the fitness of cells harboring signaling pathway mutations and increases the probability of disease development.

Prevalence rates and psychosocial characteristics associated with depression in pregnancy and postpartum in Maltese women.

BACKGROUND: Investigators have commented on the apparent high prevalence of psychiatric symptoms in pregnancy. In Malta there is lack of epidemiological data and therefore, the prevalence of depression during pregnancy and at 8 weeks postpartum among a community sample of Maltese women was carried out. METHOD: A random sample of 239 pregnant women were interviewed at booking using a detailed sociodemographic history, the revised version of the clinical interview schedule (CIS-R) and Maltese translation of the Edinburgh postnatal depression scale (EPDS). The CIS-R was again administered over the phone at 36 weeks and the EPDS sent by post. At 8 weeks postpartum, the CIS-R, modified version of the social maladjustment schedule and the EPDS were again administered to 95.8% of women. RESULTS: The point prevalence of depression meeting ICD-10 research criteria was 15.5% at booking, 11.1% in the third trimester and 8.7% postpartum of which only 3.9% had an onset since delivery. CONCLUSIONS: The low rate of new onset postpartum depression compared with other studies in our sample may be attributable to the social support available to women living in a cohesive Catholic island community. LIMITATION: The follow-up was limited to 8 weeks postpartum. No control group was used to compare the prevalence of depression in women who did not recently have a baby.

Heterozygous and homozygous JAK2(V617F) states modeled by induced pluripotent stem cells from myeloproliferative neoplasm patients.

JAK2(V617F) is the predominant mutation in myeloproliferative neoplasms (MPN). Modeling MPN in a human context might be helpful for the screening of molecules targeting JAK2 and its intracellular signaling. We describe here the derivation of induced pluripotent stem (iPS) cell lines from 2 polycythemia vera patients carrying a heterozygous and a homozygous mutated JAK2(V617F), respectively. In the patient with homozygous JAK2(V617F), additional ASXL1 mutation and chromosome 20 allowed partial delineation of the clonal architecture and assignation of the cellular origin of the derived iPS cell lines. The marked difference in the response to erythropoietin (EPO) between homozygous and heterozygous cell lines correlated with the constitutive activation level of signaling pathways. Strikingly, heterozygous iPS cells showed thrombopoietin (TPO)-independent formation of megakaryocytic colonies, but not EPO-independent erythroid colony formation. JAK2, PI3K and HSP90 inhibitors were able to block spontaneous and EPO-induced growth of erythroid colonies from GPA(+)CD41(+) cells derived from iPS cells. Altogether, this study brings the proof of concept that iPS can be used for studying MPN pathogenesis, clonal architecture, and drug efficacy.

The Section and Board of Psychiatry of the Union of European Medical Specialists (UEMS): achievements and perspectives.

The enlargement of the European Union (EU) creates new inspiration and challenges for the Section and Board of Psychiatry of the Union of European Medical Specialists (UEMS). The Section and Board, which have an active history dating back to the early 1990s, aim to promote and harmonise psychiatry throughout Europe, mainly by working to produce standards for training, including conditions for training and continuous professional development (CPD). However, European society is complex and in transition. The move towards a more unified European professional identity first requires the identification and acknowledgement of differences.