Primary mediastinal large B-cell lymphoma (PMBL) cells depend on the constitutive activity of NF-κB and STAT transcription factors, which drive expression of multiple molecules essential for their ...survival. In a molecularly related B-cell malignant tumor (classic Hodgkin lymphoma), tumor Reed-Sternberg cells overexpress oncogenic (proviral integration site for Moloney murine leukemia virus (PIM) 1, 2, and 3 kinases in a NF-κB– and STAT-dependent manner and PIMs enhance survival and expression of immunomodulatory molecules. Given the multiple overlapping characteristics of Reed-Sternberg and PMBL cells, we hypothesized that PIM kinases may be overexpressed in PMBL and involved in PMBL pathogenesis. The expression of PIM kinases in PMBL diagnostic biopsy specimens was assessed and their role in survival and immune escape of the tumor cells was determined. PIMs were abundantly expressed in primary tumors and PMBL cell lines. Inhibition of PIM kinases was toxic to PMBL cells, attenuated protein translation, and down-regulated NF-κB– and STAT-dependent transcription of prosurvival factors BCL2A1, BCL2L1, and FCER2. Furthermore, PIM inhibition decreased expression of molecules engaged in shaping the immunosuppressive microenvironment, including programmed death ligand 1/2 and chemokine (C-C motif) ligand 17. Taken together, our data indicate that PIMs support PMBL cell survival and immune escape and identify PIMs as promising therapeutic targets for PMBL.
The family of PIM serine/threonine kinases includes three highly conserved oncogenes,
and
, which regulate multiple prosurvival pathways and cooperate with other oncogenes such as
. Recent genomic ...CRISPR-Cas9 screens further highlighted oncogenic functions of PIMs in diffuse large B-cell lymphoma (DLBCL) cells, justifying the development of small-molecule PIM inhibitors and therapeutic targeting of PIM kinases in lymphomas. However, detailed consequences of PIM inhibition in DLBCL remain undefined. Using chemical and genetic PIM blockade, we comprehensively characterized PIM kinase-associated prosurvival functions in DLBCL and the mechanisms of PIM inhibition-induced toxicity. Treatment of DLBCL cells with SEL24/MEN1703, a pan-PIM inhibitor in clinical development, decreased BAD phosphorylation and cap-dependent protein translation, reduced MCL1 expression, and induced apoptosis. PIM kinases were tightly coexpressed with MYC in diagnostic DLBCL biopsies, and PIM inhibition in cell lines and patient-derived primary lymphoma cells decreased MYC levels as well as expression of multiple MYC-dependent genes, including
. Chemical and genetic PIM inhibition upregulated surface CD20 levels in an MYC-dependent fashion. Consistently, MEN1703 and other clinically available pan-PIM inhibitors synergized with the anti-CD20 monoclonal antibody rituximab
, increasing complement-dependent cytotoxicity and antibody-mediated phagocytosis. Combined treatment with PIM inhibitor and rituximab suppressed tumor growth in lymphoma xenografts more efficiently than either drug alone. Taken together, these results show that targeting PIM in DLBCL exhibits pleiotropic effects that combine direct cytotoxicity with potentiated susceptibility to anti-CD20 antibodies, justifying further clinical development of such combinatorial strategies. SIGNIFICANCE: These findings demonstrate that inhibition of PIM induces DLBCL cell death via MYC-dependent and -independent mechanisms and enhances the therapeutic response to anti-CD20 antibodies by increasing CD20 expression.
The paper presents the activity performed at the University of Brescia by students and researchers, belonging to different Mediterranean cultures and different disciplines, to prepare a documentary ...exhibition on irrigation techniques in water scarcity conditions, on the occasion of the International Year of Soils 2015. Traditional irrigation techniques were identified as a key aspect of soil conservation and agricultural practices, to build living and autopoietic ecosystems, also in adverse climatic conditions, and to adapt to climatic changes. Being a structural source of ecosystem survival, and being based on long-lasting observation of the climate and of the environment, they have deep roots in local cultures and they were identified as a common ground also for multicultural interaction. The core of the exhibition is structured in sections focused on techniques for collecting groundwater, atmospheric humidity and surface water, on water lifting techniques and on water distributive systems. The final section of the exhibition is devoted to the oases which are presented as an equilibrium ecosystem, established upon the alliance between man and nature and founded on the capability of collecting water.
New experimental results of 1D Dam-Break flows with shocks and results found in the literature are compared with those obtained by means of a numerical model based on the well-known McCormack ...shock-capturing scheme. In implementing the numerical scheme care has been taken to treat the source terms of the equations so that they are compatible with the resolution of shocks introducing artificial dissipation terms or Total Variation Diminishing (TVD) corrections. To verify the numerical model under severe test conditions, laboratory experiments have been carried out in which shock formation, reverse flow and wetting and drying conditions in the flow field were induced. The good agreement between experimental and computed results confirms the validity of the numerical model even in limit conditions that could occur in nature, for which the St. Venant hypotheses are not completely verified.
Subcutaneous infusion ports (SIPs) represent a valid method for long-term chemotherapy. The SIPs have several advantages over other methods of venous access: they are easy to implant under local ...anaesthesia, have less discomfort for the patients, allow low costs, can be implanted in day hospital, and can be managed ambulatorily. However, SIPs have delayed complications, frequently related to clinical conditions of the neoplastic patients, and immediate complications, often due to the placement technique. From March 1992 to March 1997 we placed, under local anaesthesia and under fluoroscopic control, 102 SIPs in 99 general oncology patients for long-term chemotherapy (88% solid, 12% haematological tumours). The percutaneous venous access devices were in the subclavian vein in 96% of the cases and in the internal jugular vein in 4% of them. Immediate complications were: 1 haemopneumothorax, which required thoracic aspirations and two blood transfusions, 1 loop of the tunneled part of the catheter without alterations in SIP function, and 1 left jugular thrombosis in a patient with subclavian veins already thrombosed. The venous access was in the subclavian vein in the first 2 cases, and it was not necessary to suspend the therapeutic program. In the third instance, implanted in jugular vein, it was necessary to remove the SIP. Delayed complications were: 1 necrosis of the skin over the port, 1 infection of subcutaneous pocket, 2 infections of the system, 1 catheter deconnection, and 3 catheter ruptures with embolization of the catheter tip. The SIPs were removed in all cases but 1 in whom infection was successfully treated by appropriate antibiotic therapy. Embolization of the catheter required removal from the pulmonary artery under fluoroscopic guidance in the cardiac catheterization laboratory. In conclusion, infection and thrombosis are the two major complications of SIP in general oncology patients. In these cases it is not necessary to remove systematically the system, but a correct therapy (antibiotic, fibrinolytic agents) can be utilized with good results. The catheter rupture is often due to the wear over the costoclavicular angle. The interventional radiology is the method of choice in the treatment of the catheter embolization by rupture or dislocation. The experience of the surgical and nursing staff is probably the most important factor in decreasing the total rate of complications.
A new high-resolution gridded dataset of 1845–2016
monthly precipitation series for the upper Adda river basin was computed
starting from a network of high-quality and homogenised station records
...covering Adda basin and neighbouring areas and spanning more than two
centuries. The long-term signal was reconstructed by a procedure based on
the anomaly method and consisting in the superimposition of two fields which
were computed independently: 1961–1990 monthly climatologies and gridded
anomalies. Model accuracy was evaluated by means of station series
reconstruction in leave-one-out approach and monthly relative mean absolute
errors were found to range between 14 % in summer and 24 % in winter.
Except for the period before the 1870s when station coverage is rather low,
reconstruction errors are quite stable. The 1845–2016 monthly areal
precipitation series integrated over Adda basin was finally computed. The
robustness of this series was evaluated and it was investigated for
long-term trend. While no significant trend emerged for precipitation, the
analysis performed on 1845–2016 annual runoff values recorded at Lake Como
outlet highlighted a negative trend. Runoff decrease is supposed to be
mostly due to an increasing role of evapotranspiration linked to temperature
increase, which is only partially compensated by the increase in glacier
melting rate. In order to test the applicability of the gridded database for
the reconstruction of extreme past events, the episode with the highest
precipitation in Adda basin series (November 2002) was considered and the
corresponding gridded fields of monthly anomalies and precipitation values
were evaluated both with actual station density and with station densities
corresponding to 1922 and 1882. Even considering 1882 station density, the
main spatial patterns are well depicted proving the suitability of anomaly
method to deal also with sparse station networks.
Summary Background Erlotinib is registered for treatment of all patients with advanced non-small-cell lung cancer (NSCLC). However, its efficacy for treatment of patients whose tumours are EGFR ...wild-type—which includes most patients—is still contentious. We assessed the efficacy of erlotinib compared with a standard second-line chemotherapy in such patients. Methods We did this randomised controlled trial in 52 Italian hospitals. We enrolled patients who had metastatic NSCLC, had had platinum-based chemotherapy, and had wild-type EGFR as assessed by direct sequencing. Patients were randomly assigned centrally (1:1) to receive either erlotinib orally 150 mg/day or docetaxel intravenously 75 mg/m2 every 21 days or 35 mg/m2 on days 1, 8, and 15, every 28 days. Randomisation was stratified by centre, stage, type of first-line chemotherapy, and performance status. Patients and investigators who gave treatments or assessed outcomes were not masked to treatment allocation, investigators who analysed results were. The primary endpoint was overall survival in the intention-to-treat population. The study is registered at ClinicalTrials.gov , number NCT00637910. Findings We screened 702 patients, of whom we genotyped 540. 222 patients were enrolled (110 assigned to docetaxel vs 112 assigned to erlotinib). Median overall survival was 8·2 months (95% CI 5·8–10·9) with docetaxel versus 5·4 months (4·5–6·8) with erlotinib (adjusted hazard ratio HR 0·73, 95% CI 0·53–1·00; p=0·05). Progression-free survival was significantly better with docetaxel than with erlotinib: median progression-free survival was 2·9 months (95% CI 2·4–3·8) with docetaxel versus 2·4 months (2·1–2·6) with erlotinib (adjusted HR 0·71, 95% CI 0·53–0·95; p=0·02). The most common grade 3–4 toxic effects were: low absolute neutrophil count (21 20% of 104 in the docetaxel group vs none of 107 in the erlotinib group), skin toxic effects (none vs 15 14%), and asthenia (ten 10% vs six 6%). Interpretation Our results show that chemotherapy is more effective than erlotinib for second-line treatment for previously treated patients with NSCLC who have wild-type EGFR tumours. Funding Agenzia Italiana del Farmaco.
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