The PhoP-Dependent ncRNA Mcr7 Modulates the TAT Secretion System in Mycobacterium tuberculosis

The PhoPR two-component system is essential for virulence in Mycobacterium tuberculosis where it controls expression of approximately 2% of the genes, including those for the ESX-1 secretion apparatus, a major virulence determinant. Mutations in phoP lead to compromised production of pathogen-specific cell wall components and attenuation both ex vivo and in vivo. Using antibodies against the native protein in ChIP-seq experiments (chromatin immunoprecipitation followed by high-throughput sequencing) we demonstrated that PhoP binds to at least 35 loci on the M. tuberculosis genome. The PhoP regulon comprises several transcriptional regulators as well as genes for polyketide synthases and PE/PPE proteins. Integration of ChIP-seq results with high-resolution transcriptomic analysis (RNA-seq) revealed that PhoP controls 30 genes directly, whilst regulatory cascades are responsible for signal amplification and downstream effects through proteins like EspR, which controls Esx1 function, via regulation of the espACD operon. The most prominent site of PhoP regulation was located in the intergenic region between rv2395 and PE_PGRS41, where the mcr7 gene codes for a small non-coding RNA (ncRNA). Northern blot experiments confirmed the absence of Mcr7 in an M. tuberculosis phoP mutant as well as low-level expression of the ncRNA in M. tuberculosis complex members other than M. tuberculosis. By means of genetic and proteomic analyses we demonstrated that Mcr7 modulates translation of the tatC mRNA thereby impacting the activity of the Twin Arginine Translocation (Tat) protein secretion apparatus. As a result, secretion of the immunodominant Ag85 complex and the beta-lactamase BlaC is affected, among others. Mcr7, the first ncRNA of M. tuberculosis whose function has been established, therefore represents a missing link between the PhoPR two-component system and the downstream functions necessary for successful infection of the host

The EUTOS long-term survival (ELTS) score is superior to the Sokal score for predicting survival in chronic myeloid leukemia

Prognostic scores support clinicians in selecting risk-adjusted treatments and in comparatively assessing different results. For patients with chronic-phase chronic myeloid leukemia (CML), four baseline prognostic scores are commonly used. Our aim was to compare the prognostic performance of the scores and to arrive at an evidence-based score recommendation. In 2949 patients not involved in any score development, higher hazard ratios and concordance indices in any comparison demonstrated the best discrimination of long-term survival with the ELTS score. In a second step, of 5154 patients analyzed to investigate risk group classification differences, 23% (n = 1197) were allocated to high-risk by the Sokal score. Of the 1197 Sokal high-risk patients, 56% were non-high-risk according to the ELTS score and had a significantly more favorable long-term survival prognosis than the 526 high-risk patients according to both scores. The Sokal score identified too many patients as high-risk and relatively few (40%) as low-risk (versus 60% with the ELTS score). Inappropriate risk classification jeopardizes optimal treatment selection. The ELTS score outperformed the Sokal score, the Euro, and the EUTOS score regarding risk group discrimination. The recent recommendation of the European LeukemiaNet for preferred use of the ELTS score was supported with significant statistical evidence

The EUTOS long-term survival (ELTS) score is superior to the Sokal score for predicting survival in chronic myeloid leukemia

Prognostic scores support clinicians in selecting risk-adjusted treatments and in comparatively assessing different results. For patients with chronic-phase chronic myeloid leukemia (CML), four baseline prognostic scores are commonly used. Our aim was to compare the prognostic performance of the scores and to arrive at an evidence-based score recommendation. In 2949 patients not involved in any score development, higher hazard ratios and concordance indices in any comparison demonstrated the best discrimination of long-term survival with the ELTS score. In a second step, of 5154 patients analyzed to investigate risk group classification differences, 23% (n = 1197) were allocated to high-risk by the Sokal score. Of the 1197 Sokal high-risk patients, 56% were non-high-risk according to the ELTS score and had a significantly more favorable long-term survival prognosis than the 526 high-risk patients according to both scores. The Sokal score identified too many patients as high-risk and relatively few (40%) as low-risk (versus 60% with the ELTS score). Inappropriate risk classification jeopardizes optimal treatment selection. The ELTS score outperformed the Sokal score, the Euro, and the EUTOS score regarding risk group discrimination. The recent recommendation of the European LeukemiaNet for preferred use of the ELTS score was supported with significant statistical evidence.Peer reviewe

High promiscuity among females of the invasive pest species Drosophila suzukii

Drosophila suzukii (Matsumura, 1931), the spotted-wing drosophila, is a highly invasive fruit fly that spread from Southern Asia across most regions of Asia and, in the last 15 years, has invaded Europe and the Americas. It is an economically important pest of small fruits such as berries and stone fruits. Drosophila suzukii speciated by adapt ing to cooler, mountainous, and forest environments. In temperate regions, it evolved seasonal polyphenism traits which enhanced its survival during stressful winter population bottlenecks. Consequently, in these temperate regions, the populations undergo seasonal reproductive dynamics. Despite its economic importance, no data are available on the behavioural reproductive strategies of this fly. The presence of polyandry, for example, has not been determined despite the important role it might play in the reproductive dynamics of populations. We explored the presence of poly andry in an established population in Trentino, a region in northern Italy. In this area, D. suzukii overcomes the winter bottleneck and undergoes a seasonal reproductive fluctuation. We observed a high remating frequency in females during the late spring demographic explosion that led to the abundant summer population. The presence of a high degree of polyandry and shared paternity associated with the post-winter population increase raises the question of the possible evolutionary adaptive role of this reproductive behaviour in D. suzuki

Is there a cloud in the silver lining for imatinib?

Imatinib mesylate (Gleevec® or Glivec®), a small molecule tyrosine kinase inhibitor for the treatment of chronic myeloid leukaemia, has been said to herald the dawn of a new er-a of rationally designed, molecularly targeted oncotherapy. Lurking on the same new horizon, however, is the age-old spectre of drug resistance. This review sets the intoxicating clinical perspective against the more sobering laboratory evidence of such divergent mechanisms of imatinib resistance as gene amplification and stem cell quiescence. Polychemotherapy has already been considered to combat resistance, but a more innovative, as yet unformulated, approach may be advocated

New dosing schedules of dasatinib for CML and adverse event management

Resistance to imatinib in patients with chronic myelogenous leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) has emerged as a significant clinical issue. Dasatinib is a tyrosine kinase inhibitor that has 325-fold greater in vitro activity against native BCR-ABL (breakpoint cluster region-Abelson leukemia virus) compared with imatinib and can overcome primary (intrinsic) and secondary (acquired) imatinib resistance. Here, we review the clinical profile of dasatinib in imatinib-resistant and -intolerant patients and share clinical approaches for managing adverse events (AEs) to ensure maximum patient benefit. References were obtained through literature searches on PubMed as well as from the Proceedings of Annual Meetings of the American Society of Clinical Oncology, the American Society of Hematology, and European Hematology Association. Phase II and III studies of dasatinib in patients with imatinib-resistant or -intolerant CML in any phase or Ph+ ALL were selected for discussion. Dasatinib is currently indicated for the treatment of patients with imatinib-resistant or -intolerant CML or Ph+ ALL. AEs associated with dasatinib are typically mild to moderate, and are usually resolved with temporary treatment interruption and/or dose adjustments. A Phase III dose optimization study showed that in patients with chronic phase (CP) CML, 100 mg once-daily dasatinib improves the safety profile, particularly pleural effusion and thrombocytopenia, while maintaining efficacy compared with the previously recommended dose of 70 mg twice-daily. Dasatinib has a manageable safety profile. For patients with CP CML, a new recommended starting dose of 100 mg once daily has recently been approved. The recommended dose for patients with advanced CML or Ph+ ALL remains 70 mg twice daily

Irreversible Pulmonary Hypertension Associated with the use of Interferon Alpha for Chronic Hepatitis C

The interferons are a complex group of virally induced proteins produced by activated macrophages and lymphocytes, which have become the mainstay of therapy for hepatitis C infection. Sustained viral response (SVR) rates in noncirrhotic patients vary from 40–80% with interferon-based therapy. This, along with transplantation, has drastically changed the course of hepatitis C virus (HCV) infection over the last two decades. Numerous side effects associated with interferon therapy have been reported. These range from transient flu-like symptoms to serious effects such as cardiac arrhythmias, cardiomyopathy, renal and liver failure, polyneuropathy, and myelosuppression. Pulmonary side effects including pneumonitis, pulmonary fibrosis, and reversible pulmonary hypertension have been reported. Herein, we present four cases in which irreversible pulmonary hypertension was diagnosed after prolonged treatment with interferon alpha. In each case, other causes of pulmonary hypertension were systematically eliminated. Pulmonary artery hypertension, which may be irreversible, should be considered in patients being treated with interferon alpha who present with exertional dyspnea and do not have a readily identifiable inflammatory or thromboembolic cause

The occurrence and management of fluid retention associated with TKI therapy in CML, with a focus on dasatinib

Tyrosine kinase inhibitors (TKIs) like dasatinib and nilotinib are indicated as second-line treatment for chronic myeloid leukemia resistant or intolerant to the current first-line TKI imatinib. These are agents are well tolerated, but potent and as such should be monitored for potentially serious side-effects like fluid retention and pleural effusions. Here we present key clinical trial data and safety considerations for all FDA approved TKIs in context for effective management of fluid retention and pleural effusions. Altering the dasatinib regimen from 70 mg twice daily to 100 mg daily reduces the risk of pleural effusion for patients taking dasatinib. Should pleural effusion develop, dasatinib should be interrupted until the condition resolves. Patients with a history of pleural effusion risk factors should be monitored closely while taking dasatinib. Patients receiving imatinib and nilotinib are not without risk of fluid retention. All patients should also be educated to recognize and report key symptoms of fluid retention or pleural effusion. Pleural effusions are generally managed by dose interruption/reduction and other supportive measures in patients with chronic myeloid leukemia receiving dasatinib therapy

Mycobacterium leprae Phenolglycolipid-1 Expressed by Engineered M. bovis BCG Modulates Early Interaction with Human Phagocytes

The species-specific phenolic glycolipid 1 (PGL-1) is suspected to play a critical role in the pathogenesis of leprosy, a chronic disease of the skin and peripheral nerves caused by Mycobacterium leprae. Based on studies using the purified compound, PGL-1 was proposed to mediate the tropism of M. leprae for the nervous system and to modulate host immune responses. However, deciphering the biological function of this glycolipid has been hampered by the inability to grow M. leprae in vitro and to genetically engineer this bacterium. Here, we identified the M. leprae genes required for the biosynthesis of the species-specific saccharidic domain of PGL-1 and reprogrammed seven enzymatic steps in M. bovis BCG to make it synthesize and display PGL-1 in the context of an M. leprae-like cell envelope. This recombinant strain provides us with a unique tool to address the key questions of the contribution of PGL-1 in the infection process and to study the underlying molecular mechanisms. We found that PGL-1 production endowed recombinant BCG with an increased capacity to exploit complement receptor 3 (CR3) for efficient invasion of human macrophages and evasion of inflammatory responses. PGL-1 production also promoted bacterial uptake by human dendritic cells and dampened their infection-induced maturation. Our results therefore suggest that M. leprae produces PGL-1 for immune-silent invasion of host phagocytic cells