Indian monsoon and the elevated-heat-pump mechanism in a coupled aerosol-climate model

A coupled aerosol-atmosphere-ocean-sea ice climate model is used to explore the interaction between aerosols and the Indian summer monsoon precipitation on seasonal-to-interannual time scales. Results show that when increased aerosol loading is found on the Himalayas slopes in the premonsoon period (April-May), intensification of early monsoon rainfall over India and increased low-level westerly flow follow, in agreement with the elevated-heat-pump mechanism. The increase in rainfall during the early monsoon season has a cooling effect on the land surface. In the same period, enhanced surface cooling may also be amplified through solar dimming by more cloudiness and aerosol loading, via increased dust transported by low-level westerly flow. The surface cooling causes subsequent reduction in monsoon rainfall in July-August over India. The time-lagged nature of the reasonably realistic response of the model to aerosol forcing suggests that absorbing aerosols, besides their potential key roles in impacting monsoon water cycle and climate, may influence the seasonal variability of the Indian summer monsoon

Combined Use of Growth Factors to Stimulate the Proliferation of Hematopoietic Progenitor Cells after Autologous Bone Marrow Transplantation for Lymphoma Patients

We studied the kinetic response and concentration of bone marrow (BM) progenitor cells of patients with lymphoid malignancies submitted to autologous bone marrow transplantation (ABMT), treated with a granulocyte-colony-stimulating factor (G-CSF)/interleukin-3 (IL-3) combination. The results were compared with those of lymphoma patients receiving the same pretransplant conditioning regimen followed by G-CSF alone. Recombinant human (rh)G-CSF was administered as a single subcutaneous (s.c.) injection at the dose of 5 μg/kg/day from day +1 after reinfusion of autologous stem cells, while rhIL-3 was added from day +6 at the dose of lOμg/kg/day s.c. (overlapping schedule). In both groups (i.e. G-CSF-and G-CSF/ IL-3-treated patients), cytokine administration was discontinued when the absolute neutrophil count was < 0.5× 109/l of peripheral blood for 3 consecutive days. Following treatment with the CSF combination, the percentage of marrow CFU-GM and erythroid progenitors (BFU-E) in the S phase of the cell cycle increased from 9.3 ± 2 to 33.3 ± 12% and from 14.6 ± 3 to 35 ± 6%, respectively (p < 0.05). The number of actively cycling megakaryocyte progenitors (CFU-MK and BFU-MK) also increased. Conversely, G-CSF augmented the proliferative rate of CFU-GM (22.6 ± 6% compared to a baseline value of 11.5 ± 3%; p < 0.05) but not of BFU-E, CFU-MK or BFU-MK, and the increase in S-phase CFU-GM was significantly lower than that observed in the posttreatment samples of patients receiving IL-3 in addition to G-CSF. The absolute number of both CFU-GM and BFU-E/ml of BM was significantly augmented after treatment with G-CSF/IL-3 but not G-CSF alone. Similarly, administration of the cytokine combination resulted in a higher number of CD34+ cells and their concentration was significantly greater than that observed in the posttreatment samples of G-CSF patients. We also investigated the responsiveness to CSFs, in vitro, of highly enriched CD34+ cells, collected after priming with G-CSF in vivo (i.e. after 5 days of G-CSF administration). Our results demonstrated that pretreatment with G-CSF modified the response of BM cells to subsequent stimulation with additional CSFs. When the hematological reconstitution of patients treated with G-CSF/IL-3 was compared to that of individuals receiving G-CSF alone, the addition of IL-3 resulted in a significant improvement in granulocyte and platelet recovery, a lower transfusion requirement and shorted hospitalization. In conclusion, our results indicate that in vivo administration of two cytokines increases the proliferative rate and concentration of BM progenitor cells better than G-CSF alone and support a role for growth factor combinations for accelerating hematopoietic recovery after high-dose chemotherapy. © 1996 S. Karger AG, Basel

Negative Prognostic Relevance of a Specific 3-Gene Cluster in Myelodysplastic Syndromes during Azacitidine and Lenalidomide Therapy

none20siBackground and Rationale. Azacitidine (AZA) is a standard first-line therapy in high-risk MDS. Also its combination with Lenalidomide (LEN) has been tested, but its molecular effect is still under investigation. Here we analyzed the effect of AZA+LEN therapy on gene mutations and microRNA expression in MDS patients. Patients and Methods. This study included 44 high-risk MDS patients treated with AZA (75 mg/m2/day, days 1-5, sc) and LEN (10 mg/day, days 1-21, orally) every 4 weeks. Patients showing complete remission (CR), partial remission (PR) or any hematologic improvement were considered as responders, while patients showing stable disease or disease progression were considered as non responders. Molecular analyses were performed at baseline and during the therapy. Gene mutations were studied by an Illumina Cancer Myeloid Panel and an Ion Torrent specific panel, whereas microRNAs expression was assessed using an Affymetrix miRNA 4.0 array. Results. 34/44 patients were considered evaluable for response, with an overall response rate of 76.25% (26/34 cases). 13 patients showed a positive response within the 4th cycle (T4) and maintained it at T8; 9 patients showed a positive response within T4 and lost response at T8; 4 patients responded after T4 and maintained the response at T8; 8 patients never responded. Molecular analyses were performed on serial samples (baseline, T4 and T8) available for 30 patients. Results from the Illumina analysis on cancer myeloid genes showed that 3/30 cases had no mutations at all, all other cases showed mutations both at baseline and during the therapy. The most frequently mutated genes were ASXL1 (14 cases = 47%), TET2 (11 cases = 37%), RUNX1 (8 cases = 27%) and SRSF2 (5 cases = 17%). All samples with a decreasing variant allele frequency (VAF) had a favourable response at T8 (CR, marrow CR or PR), while none of the non responders showed a decreasing VAF. Ion Torrent analysis of 24 inositide-specific genes showed that all patients had mutations both at baseline and during the therapy. Interestingly, all patients responding at T4 and losing response at T8, as well as cases that did not respond, acquired the same 3 point mutations at T8, affecting respectively PIK3CD (D133E), AKT3 (D280G) and PLCG2 (Q548R) genes. Patients responding at T4 and losing response at T8 showed these mutations even at T4. Kaplan-Meier analyses revealed that the presence of these mutations was significantly associated with a decreased duration of therapy (39.5 vs 8.5 months; p&lt;0.05) and duration of response (36 vs 6 months; p&lt;0.05). As for microRNA profiling, paired analysis between responders and non responders showed specific clusters of up- or down-regulated microRNAs. Interestingly, unpaired analysis on patients responding at T4 and losing response at T8 showed 18 up- and 11 down-regulated microRNAs, like miR-3613-3p and miR-6757-5p, whose predicted targets are our 3 genes among the others. Also in patients never responding to the therapy there was a specific cluster of 3 up- and 12 down-regulated microRNAs and, interestingly, 7 of these microRNAs, like miR-4786-5p or miR-6853-3p, targeting our 3-gene cluster among the others, were altered also in patients losing response. Conclusions. Our results show that the presence of a common cluster of point mutations affecting 3 inositide-specific genes (PI3KCD, AKT3, PLCG2, all regulating cell proliferation), is significantly associated with loss of response to AZA+LEN therapy. Moreover, also a cluster of 7 microRNAs, targeting our 3 genes among the others, is associated with unfavourable outcome. Further studies are warranted to confirm these data, to further analyze the role of this 3-gene cluster and to identify the specific targets for the dysregulated microRNAs identified.noneFollo, Matilde Y; Pellagatti, Andrea; Armstrong, Richard N; Ratti, Stefano; Mongiorgi, Sara; Astolfi, Annalisa; Indio, Valentina; Bochicchio, Maria Teresa; Clissa, Cristina; Russo, Domenico; Gobbi, Marco; Parisi, Sarah; Fogli, Miriam; Martinelli, Giovanni; Pession, Andrea; Cavo, Michele; Manzoli, Lucia; Cocco, Lucio; Boultwood, Jacqueline; Finelli, CarloFollo, Matilde Y; Pellagatti, Andrea; Armstrong, Richard N; Ratti, Stefano; Mongiorgi, Sara; Astolfi, Annalisa; Indio, Valentina; Bochicchio, Maria Teresa; Clissa, Cristina; Russo, Domenico; Gobbi, Marco; Parisi, Sarah; Fogli, Miriam; Martinelli, Giovanni; Pession, Andrea; Cavo, Michele; Manzoli, Lucia; Cocco, Lucio; Boultwood, Jacqueline; Finelli, Carl