Arsenic trioxide (ATO) is presently the most active single agent in the treatment of acute promyelocytic leukemia (APL). This review provides insights into the mode of action and the pharmacological ...properties of ATO, and summarizes the most relevant results of more than 20 treatment studies in relapsed or newly diagnosed APL published between 1997 and 2011. ATO acts by targeting multiple pathways in APL leading to apoptosis and myeloid differentiation. It induces complete remission without myelosuppression and causes only few adverse effects. In relapsed APL, ATO-based salvage therapy has been able to induce long-lasting remissions and possible cure in 50-81% of patients. In newly diagnosed APL, two main strategies are currently pursued. ATO is either included into induction therapy with the aim to minimize or eliminate chemotherapy, or it is incorporated as an additive into established first-line concepts with all-trans-retinoic acid and chemotherapy to reinforce their anti-leukemic efficacy. Recent results suggest a high efficacy of ATO in both concepts. In conclusion, experimental research and clinical studies have made contributions toward a better understanding of the molecular mechanisms induced by ATO in APL cells and have established this historic substance as an important candidate for the further improvement of APL therapy.
Teraelectronvolt Astronomy Hinton, J.A.; Hofmann, W.
Annual review of astronomy and astrophysics,
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Ground-based γ-ray astronomy, which provides access to the TeV energy range, is a young and rapidly developing discipline. Recent discoveries in this waveband have important consequences for a wide ...range of topics in astrophysics and astroparticle physics. This article is an attempt to review the experimental status of this field and to provide the basic formulae and concepts required to begin the interpretation of TeV observations.
Invasive pulmonary aspergillosis (IPA) is an emerging and life-threatening infectious disease in patients admitted to the intensive care unit (ICU). Most diagnostic studies are conducted in ...hematological patients and results cannot readily be transferred to ICU patients lacking classical host factors.
In a multicenter, prospective clinical trial including 44 ICU patients, hematological (n = 14) and non-hematological patients (n = 30), concurrent serum and bronchoalveolar lavage (BAL) samples were analyzed by conventional culture, galactomannan (GM), 1-3-beta-D-glucan (BDG) as well as an Aspergillus specific nested polymerase chain reaction (PCR). Nine patients (20%) had putative IPA according to AspICU classification.
GM and PCR showed superior performance in BAL with sensitivity/specificity of 56%/94% and 44%/94% compared to 33%/97% and 11%/94% in serum. Despite better sensitivity of 89%, BDG showed poor specificity of only 31% (BAL) and 26% (serum). Combination of GM and PCR (BAL) with BDG (serum) resulted in 100% sensitivity, but also reduced specificity to 23%. Whereas mean GM levels were significantly higher in hematological patients BDG and PCR did not differ between hematological and non-hematological patients.
Under present clinical conditions test combinations integrating both BAL and blood samples are advantageous. BDG might best serve as possible indicator for ruling out IPA.
ClinicalTrials.gov Identifier: NCT01695499. First posted: September 28, 2012, last update posted: May 8, 2017.
•Combination of galactomannan (GM), beta-d-glucan (BDG) and Aspergillus PCR•Test combinations showed superior compared to single tests•Combining bronchoalveolar lavage and serum samples is beneficial•Low specificity of BDG limits its diagnostic value in intensive care patients•GM levels were significantly higher in hematological patients
MYC is a highly pleiotropic transcription factor whose deregulation promotes cancer. In contrast, we find that Myc haploinsufficient (Myc+/–) mice exhibit increased lifespan. They show resistance to ...several age-associated pathologies, including osteoporosis, cardiac fibrosis, and immunosenescence. They also appear to be more active, with a higher metabolic rate and healthier lipid metabolism. Transcriptomic analysis reveals a gene expression signature enriched for metabolic and immune processes. The ancestral role of MYC as a regulator of ribosome biogenesis is reflected in reduced protein translation, which is inversely correlated with longevity. We also observe changes in nutrient and energy sensing pathways, including reduced serum IGF-1, increased AMPK activity, and decreased AKT, TOR, and S6K activities. In contrast to observations in other longevity models, Myc+/– mice do not show improvements in stress management pathways. Our findings indicate that MYC activity has a significant impact on longevity and multiple aspects of mammalian healthspan.
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•Reduction of Myc expression in mice promotes longevity•Lower Myc levels benefit multiple organs and physiological processes•Decreased Myc activity triggers changes in core nutrient and energy-sensing pathways•Lower Myc levels do not cause apparent changes in stress management pathways
Reduced expression of MYC increases lifespan in mice and benefits multiple aspects related to the aging process without apparent developmental trade-offs or changes in stress management pathways.
Invasive pulmonary aspergillosis (IPA) is one of the major complications in immunocompromised patients. The mainstay of diagnostic imaging is non-enhanced chest-computed-tomography (CT), for which ...various non-specific signs for IPA have been described. However, contrast-enhanced CT pulmonary angiography (CTPA) has shown promising results, as the vessel occlusion sign (VOS) seems to be more sensitive and specific for IPA in hematologic patients. The aim of this study was to evaluate the diagnostic accuracy of CTPA in a larger cohort including non-hematologic immunocompromised patients. CTPA studies of 78 consecutive immunocompromised patients with proven/probable IPA were analyzed. 45 immunocompromised patients without IPA served as a control group. Diagnostic performance of CTPA-detected VOS and of radiological signs that do not require contrast-media were analyzed. Of 12 evaluable radiological signs, five were found to be significantly associated with IPA. The VOS showed the highest diagnostic performance with a sensitivity of 0.94, specificity of 0.71 and a diagnostic odds-ratio of 36.8. Regression analysis revealed the two strongest independent radiological predictors for IPA to be the VOS and the halo sign. The VOS is highly suggestive for IPA in immunocompromised patients in general. Thus, contrast-enhanced CTPA superior over non-contrast_enhanced chest-CT in patients with suspected IPA.
To explore the molecular profile and its prognostic implication in systemic mastocytosis (SM), we analyzed the mutation status of granulocyte-macrophage colony-forming progenitor cells (CFU-GM) in ...patients with KIT D816V(+) indolent SM (ISM, n=4), smoldering SM (SSM, n=2), aggressive SM (ASM, n=1), SM with associated clonal hematologic non-mast cell lineage disorder (SM-AHNMD, n=5) and ASM-AHNMD (n=7). All patients with (A)SM-AHNMD (n=12) carried 1-4 (median 3) additional mutations in 11 genes tested, most frequently TET2, SRSF2, ASXL1, CBL and EZH2. In multi-mutated (A)SM-AHNMD, KIT D816V(+) single-cell-derived CFU-GM colonies were identified in 8/12 patients (median 60%, range 0-95). Additional mutations were identified in CFU-GM colonies in all patients, and logical hierarchy analysis indicated that mutations in TET2, SRSF2 and ASXL1 preceded KIT D816V. In ISM/SSM, no additional mutations were detected and CFU-GM colonies were exclusively KIT D816V(-). These data indicate that (a) (A)SM-AHNMD is a multi-mutated neoplasm, (b) mutations in TET2, SRSF2 or ASXL1 precede KIT D816V in ASM-AHNMD,
Studies on modern oceanic lithosphere and ophiolites have revealed high degrees of chemical and isotopic heterogeneity in the mantle, as well as isotopic contrasts between mantle and crust. These ...features cannot be explained just by simple extraction of partial melt, but require considerably more complex petrogenetic processes. Here we present an overview of the present knowledge on isotopic heterogeneities of Sr, Nd, Hf and Os in oceanic peridotites (by reviewing data on modern abyssal peridotites and the Alpine–Apennine ophiolites), and discuss their significance in terms of i) length scale and extent of isotopic heterogeneities in the upper mantle and ii) isotopic mantle–crust relations at oceanic settings. Overall results show that mantle peridotites record significant isotopic heterogeneity, detectable on a wide range of length scales, much larger than observed in associated MORB. In addition, abyssal peridotites are on average more depleted than MORB. The high degree of isotopic heterogeneity is clear evidence for the inefficiency of mantle convection in homogenizing mantle rocks. It may be caused by i) variably old depletion events (unrelated to recent MORB production), ii) pyroxenite components in the mantle source, iii) recent pre- and/or post-melting metasomatism. Some abyssal peridotites have extremely depleted isotopic compositions, not seen in MORBs, and these have been interpreted as the evidence for old (1 to 2Ga) refractory domains in the asthenospheric mantle or, alternatively, as evidence for recent incorporation of (also old) subcontinental lithospheric mantle, potentially through delamination during continental breakup. The first hypothesis has been corroborated by finding, in a few ridge segments (e.g. Gakkel Ridge) of correlations between chemical fertility indexes and isotopic (Os, Hf) ratios, indicative of recycling of old residual oceanic lithospheric mantle into the MORB source. However, no general consensus exists yet on the two proposed models. The difference in average isotopic depletion between peridotites and basalts has been also ascribed to the presence of pyroxenites, which have “enriched” isotopic signature relative to the peridotite component. The origin and composition of such small-scale lithological heterogeneities remain however still controversial and poorly constrained, due to the difficulty to link petrologic and geochemical studies with direct field observations, and to the scarcity of chemical and isotopic data on pyroxenites in ophiolitic and abyssal peridotites, i.e. the closest available “proxies” of the MORB mantle. Larger isotopic homogeneity observed in MORB relative to peridotites in single ridge segments clearly reflect their origin as aggregated melts which inevitably “smooth” and average mantle source heterogeneities. Overall, the questions about the origin and spatial distribution of chemical and isotopic heterogeneities are not resolved, and this calls for detailed field-based studies in spatially-controlled settings to shed light on the issue of small-scale mantle heterogeneities and the role of enriched (e.g. pyroxenites) and highly depleted domains in MORB melting.
High mortality rates of invasive fungal disease (IFD), especially invasive aspergillosis (IA), in immunocompromised haematological patients and current diagnostic limitations require improvement of ...detection of fungal pathogens by defining the optimal use of biomarkers and clinical samples. Concurrent bronchoalveolar lavage (BAL) and peripheral blood samples of 99 haematological patients with suspected IFD were investigated within a multicentre prospective study. Diagnostic performance of a galactomannan (GM) enzyme immune assay (EIA), a 1,3-β-D-glucan assay (BDG), an Aspergillus PCR, and a multifungal DNA-microarray (Chip) alone or in combination were calculated. IFD were classified as proven (n=3), probable (n=34), possible (n=33), and no IFD (n=29) according to EORTC/MSG criteria. GM, PCR, and Chip showed superior diagnostic performance in BAL than in blood, whereas specificity of BDG in BAL was poor (48% (14/29)). The combination of GM (BAL) with BDG (blood) showed sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and DOR (diagnostic odds ratio) of 92% (34/37), 93% (27/29), 94%, 90%, and 153.0, respectively. Combining GM (BAL) with PCR (BAL) showed convincing diagnostic potential for diagnosing IA with sensitivity, specificity, PPV, NPV, and DOR of 85% (17/20), 97% (28/29), 94%, 90%, and 158.7. Addition of the DNA-microarray resulted in further detection of two mucormycetes infections. In 1 out of 15 Aspergillus DNA-positive samples a triazole resistance-mediating Cyp51A mutation was found. Combination of biomarkers is superior to their sole use in diagnosing IFD, particularly IA. Integrating blood and BAL samples into a diagnostic algorithm is an advantageous approach.
Early assessment of response at 3 months of tyrosine kinase inhibitor treatment has become an important tool to predict favorable outcome. We sought to investigate the impact of relative changes of ...BCR-ABL transcript levels within the initial 3 months of therapy. In order to achieve accurate data for high BCR-ABL levels at diagnosis, beta glucuronidase (GUS) was used as a reference gene. Within the German CML-Study IV, samples of 408 imatinib-treated patients were available in a single laboratory for both times, diagnosis and 3 months on treatment. In total, 301 of these were treatment-naïve at sample collection.
(i) with regard to absolute transcript levels at diagnosis, no predictive cutoff could be identified; (ii) at 3 months, an individual reduction of BCR-ABL transcripts to the 0.35-fold of baseline level (0.46-log reduction, that is, roughly half-log) separated best (high risk: 16% of patients, 5-year overall survival (OS) 83% vs 98%, hazard ratio (HR) 6.3, P=0.001); (iii) at 3 months, a 6% BCR-ABL(IS) cutoff derived from BCR-ABL/GUS yielded a good and sensitive discrimination (high risk: 22% of patients, 5-year OS 85% vs 98%, HR 6.1, P=0.002). Patients at risk of disease progression can be identified precisely by the lack of a half-log reduction of BCR-ABL transcripts at 3 months.
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