Selection of exoplanets in the habitable zone for atmospheric characterization with the James Webb Space Telescope

openThe James Webb Space Telescope (JWST) is a powerful new tool that can be used for the atmospheric characterization of exoplanets, with unprecedented sensitivity and spectral resolution. To select the best exoplanets for atmospheric characterization with JWST, we want to prioritize those in the habitable zone and for which we can obtain some atmospheric information through transmission or emission spectroscopy. In this thesis, I will present a selection algorithm for choosing exoplanets in the habitable zone that are optimal for atmospheric characterization with JWST, according to specific metrics. I will also apply this algorithm to a catalogue of known exoplanets to identify a list of priority targets for JWST observations.The James Webb Space Telescope (JWST) is a powerful new tool that can be used for the atmospheric characterization of exoplanets, with unprecedented sensitivity and spectral resolution. To select the best exoplanets for atmospheric characterization with JWST, we want to prioritize those in the habitable zone and for which we can obtain some atmospheric information through transmission or emission spectroscopy. In this thesis, I will present a selection algorithm for choosing exoplanets in the habitable zone that are optimal for atmospheric characterization with JWST, according to specific metrics. I will also apply this algorithm to a catalogue of known exoplanets to identify a list of priority targets for JWST observations

Targeting Brutons Tyrosine Kinase in Chronic Lymphocytic Leukemia at the Crossroad between Intrinsic and Extrinsic Pro-survival Signals

Chemo immunotherapies for chronic lymphocytic leukemia (CLL) showed a positive impact on clinical outcome, but many patients relapsed or become refractory to the available treatments. The main goal of the researchers in CLL is the identification of specific targets in order to develop new therapeutic strategies to cure the disease. The B cell receptor-signalling pathway is necessary for survival of malignant B cells and its related molecules recently become new targets for therapy. Moreover, leukemic microenvironment delivers survival signals to neoplastic cells also overcoming the apoptotic effect induced by traditional drugs. In this context, the investigation of Bruton\u2019s tyrosine kinase (Btk) is useful in: i) dissecting CLL pathogenesis; ii) finding new therapeutic approaches striking simultaneously intrinsic as well as extrinsic pro-survival signals in CLL. This paper will review these main topics

Bendamustine plus rituximab is an effective first-line treatment in hairy cell leukemia variant: A report of three cases

Hairy cell leukemia variant (HCLv) is a chronic lymphoproliferative disorder classified as a provisional entity in the 2016 WHO Classification of Lymphoid Tumors. HCLv is characterized by unfavorable prognosis, low complete remission rates and limited disease control following classical hairy cell leukemia-based regimens. In this study, we report 3 cases of elderly patients with treatment-naive, TP53 un-mutated HCLv, who were effectively treated with four cycles of bendamustine plus rituximab. The regimen was completed in all the patients with acceptable toxicity. All patients achieved a complete clinical response with no evidence of residual disease at bone marrow biopsy and flow-cytometry examination. After a median follow-up of 19 months, the 3 subjects are still in complete remission. In this work, bendamustine plus rituximab proved to be an effective and feasible first-line treatment strategy for elderly patients with TP53 un-mutated HCLv

An Integrated Geologic Map of the Rembrandt Basin, on Mercury, as a Starting Point for Stratigraphic Analysis

Planetary geologic maps are usually carried out following a morpho-stratigraphic approach where morphology is the dominant character guiding the remote sensing image interpretation. On the other hand, on Earth a more comprehensive stratigraphic approach is preferred, using lithology, overlapping relationship, genetic source, and ages as the main discriminants among the different geologic units. In this work we produced two different geologic maps of the Rembrandt basin of Mercury, following the morpho-stratigraphic methods and symbology adopted by many authors while mapping quadrangles on Mercury, and an integrated geo-stratigraphic approach, where geologic units were distinguished also on the basis of their false colors (derived by multispectral image data of the NASA MESSENGER mission), subsurface stratigraphic position (inferred by crater excavation) and model ages. We distinguished two different resurfacing events within the Rembrandt basin, after the impact event, and four other smooth plains units outside the basin itself. This provided the basis to estimate thicknesses, volumes, and ages of the smooth plains inside the basin. Results from thickness estimates obtained using different methodologies confirm the presence of two distinct volcanic events inside the Rembrandt basin, with a total thickness ranging between 1−1.5 km. Furthermore, model ages suggest that the volcanic infilling of the Rembrandt basin is among the ones that extended well into the mid-Calorian period, when Mercury’s effusive volcanism was previously thought to be largely over

Cross-talk between chronic lymphocytic leukemia (CLL) tumor B cells and mesenchymal stromal cells (MSCs): implications for neoplastic cell survival

Leukemic cells from Chronic Lymphocytic Leukemia (CLL) patients interact with stromal cells of the surrounding microenvironment. Mesenchymal Stromal Cells (MSCs) represent the main population in CLL marrow stroma, which may play a key role for disease support and progression. In this study we evaluated whether MSCs influence in vitro CLL cell survival. MSCs were isolated from the bone marrow of 46 CLL patients and were characterized by flow cytometry analysis. Following co-culture of MSCs and leukemic B cells, we demonstrated that MSCs were able to improve leukemic B cell viability, this latter being differently dependent from the signals coming from MSCs. In addition, we found that the co-culture of MSCs with leukemic B cells induced an increased production of IL-8, CCL4, CCL11, and CXCL10 chemokines.As far as drug resistance is concerned, MSCs counteract the cytotoxic effect of Fludarabine/Cyclophosphamide administration in vivo, whereas they do not protect CLL cells from the apoptosis induced by the kinase inhibitors Bafetinib and Ibrutinib. The evidence that leukemic clones are conditioned by environmental stimuli suggest new putative targets for therapy in CLL patients

The isopeptidase inhibitor 2cPE triggers proteotoxic stress and ATM activation in chronic lymphocytic leukemia cells

Relapse after treatment is a common and unresolved problem for patients suffering of the B-cell chronic lymphocytic leukemia (B-CLL). Here we investigated the ability of the isopeptidase inhibitor 2cPE to trigger apoptosis in leukemia cells in comparison with bortezomib, another inhibitor of the ubiquitin-proteasome system (UPS). Both inhibitors trigger apoptosis in CLL B cells and gene expression profiles studies denoted how a substantial part of genes up-regulated by these compounds are elements of adaptive responses, aimed to sustain cell survival. 2cPE treatment elicits the up-regulation of chaperones, proteasomal subunits and elements of the anti-oxidant response. Selective inhibition of these responses augments apoptosis in response to 2cPE treatment. We have also observed that the product of the ataxia telangiectasia mutated gene (ATM) is activated in 2cPE treated cells. Stimulation of ATM signaling is possibly dependent on the alteration of the redox homeostasis. Importantly ATM inhibition, mutations or down-modulation increase cell death in response to 2cPE. Overall this work suggests that 2cPE could offer new opportunities for the treatment of B-CLL

In Chronic Lymphocytic Leukemia the JAK2/STAT3 Pathway Is Constitutively Activated and Its Inhibition Leads to CLL Cell Death Unaffected by the Protective Bone Marrow Microenvironment

The bone marrow microenvironment promotes proliferation and drug resistance in chronic lymphocytic leukemia (CLL). Although ibrutinib is active in CLL, it is rarely able to clear leukemic cells protected by bone marrow mesenchymal stromal cells (BMSCs) within the marrow niche. We investigated the modulation of JAK2/STAT3 pathway in CLL by BMSCs and its targeting with AG490 (JAK2 inhibitor) or Stattic (STAT3 inhibitor). B cells collected from controls and CLL patients, were treated with medium alone, ibrutinib, JAK/Signal Transducer and Activator of Transcription (STAT) inhibitors, or both drugs, in the presence of absence of BMSCs. JAK2/STAT3 axis was evaluated by western blotting, flow cytometry, and confocal microscopy. We demonstrated that STAT3 was phosphorylated in Tyr705 in the majority of CLL patients at basal condition, and increased following co-cultures with BMSCs or IL-6. Treatment with AG490, but not Stattic, caused STAT3 and Lyn dephosphorylation, through re-activation of SHP-1, and triggered CLL apoptosis even when leukemic cells were cultured on BMSC layers. Moreover, while BMSCs hamper ibrutinib activity, the combination of ibrutinib+JAK/STAT inhibitors increase ibrutinib-mediated leukemic cell death, bypassing the pro-survival stimuli derived from BMSCs. We herein provide evidence that JAK2/STAT3 signaling might play a key role in the regulation of CLL-BMSC interactions and its inhibition enhances ibrutinib, counteracting the bone marrow niche

A high definition picture of somatic mutations in chronic lymphoproliferative disorder of natural killer cells

The molecular pathogenesis of chronic lymphoproliferative disorder of natural killer (NK) cells (CLPD-NK) is poorly understood. Following the screening of 57 CLPD-NK patients, only five presented STAT3 mutations. WES profiling of 13 cases negative for STAT3/STAT5B mutations uncovered an average of 18 clonal, population rare and deleterious somatic variants per patient. The mutational landscape of CLPD-NK showed that most patients carry a heavy mutational burden, with major and subclonal deleterious mutations co-existing in the leukemic clone. Somatic mutations hit genes wired to cancer proliferation, survival, and migration pathways, in the first place Ras/MAPK, PI3K-AKT, in addition to JAK/STAT (PIK3R1 and PTK2). We confirmed variants with putative driver role of MAP10, MPZL1, RPS6KA1, SETD1B, TAOK2, TMEM127, and TNFRSF1A genes, and of genes linked to viral infections (DDX3X and RSF1) and DNA repair (PAXIP1). A truncating mutation of the epigenetic regulator TET2 and a variant likely abrogating PIK3R1-negative regulatory activity were validated. This study significantly furthered the view of the genes and pathways involved in CLPD-NK, indicated similarities with aggressive diseases of NK cells and detected mutated genes targetable by approved drugs, being a step forward to personalized precision medicine for CLPD-NK patients.Peer reviewe

Targeted activation of the SHP-1/PP2A signaling axis elicits apoptosis of chronic lymphocytic leukemia cells

Lyn, a member of the Src family of kinases, is a key factor in the dys-regulation of survival and apoptotic pathways of malignant B cells in chronic lymphocytic leukemia. One of the effects of Lyn's action is spatial and functional segregation of the tyrosine phosphatase SHP-1 into two pools, one beneath the plasma membrane in an active state promoting pro-survival signals, the other in the cytosol in an inhibited conformation and unable to counter the elevated level of cytosolic tyrosine phosphorylation. We herein show that SHP-1 activity can be elicited directly by nintedanib, an agent also known as a triple angiokinase inhibitor, circumventing the phospho-S591-dependent inhibition of the phosphatase, leading to the dephosphorylation of pro-apoptotic players such as procaspase-8 and serine/threonine phosphatase 2A, eventually triggering apoptosis. Furthermore, the activation of PP2A by using MP07-66, a novel FTY720 analog, stimulated SHP-1 activity via dephosphorylation of phospho-S591, which unveiled the existence of a positive feedback signaling loop involving the two phosphatases. In addition to providing further insights into the molecular basis of this disease, our findings indicate that the PP2A/SHP-1 axis may emerge as an attractive, novel target for the development of alternative strategies in the treatment of chronic lymphocytic leukemia

Lermontov crater on Mercury: Geology, morphology and spectral properties of the coexisting hollows and pyroclastic deposits

Abstract We present a multidisciplinary analysis of Lermontov crater, located at 15.24°N, −48.94°E in the Kuiper quadrangle of Mercury. By means of MESSENGER multiband MDIS-WAC and monochrome MDIS-NAC images, we prepare a high-resolution geological map of the crater and its closest surroundings, highlighting the presence of coexisting hollows and pyroclastic deposits on its floor. On the photometrically corrected MDIS-WAC multiband dataset, we apply an unsupervised clustering technique that spectrally separates the different materials located both inside and outside Lermontov crater. We observe that the pyroclastic deposits located on the crater's floor have a steep, red spectral behaviour dominated by the presence of a mixture of various pyroxenes containing Ti and Ni. On the contrary, the vents' rims are characterised by several hollows whose spectral slope is bluer than that of the pyroclastic deposits. By comparing the vent hollows to the hollows located farther out on the crater floor, we observe a steeper 0.62–0.82 μm spectral trend for those within the vents. The vent hollows' spectrum is more similar to the pyroclastic one in the above mentioned wavelength range. In addition, the vent hollows 0.55 μm absorption band could be related to CaS, while the small differences in slope at 0.48 μm and 0.62 μm could be due to the presence of other volatiles compounds, such as MgS or chlorides. When compared to hollows located in other hermean geological settings, Lermontov hollows are characterised by steeper spectra. This supports the interpretation that when hollows form, their bright deposits do not completely overwrite the spectral signature of the surrounding terrain, and their spectroscopic appearance is mixed with the composition of the terrain where they form