Safety profiling of technical lignins originating from various bioresources and conversion processes.

In this work, a set of eight technical lignin samples from various botanical origins and production processes were characterized for their chemical composition, higher heating value, size distribution, dust explosion sensitivity and severity, thermal hazard characteristics and biodegradability, in further support of their sustainable use. More specifically, safety-focused parameters have been assessed in terms of consistency with relating physico-chemical properties determined for the whole set of technical lignins. The results emphasized the heterogeneity and variability of technical lignins and the subsequent need for a comprehensive characterization of new lignin feedstocks arising from novel biorefineries. Indeed, significant differences were revealed between the samples in terms of hazards sensitivity. This first comparative physico-chemical safety profiling of technical lignins could be useful for the hazard analysis and the safe design of the facilities associated with large scale valorisation of biomass residues such as lignins, targeting "zero waste" sustainable conversion of bioresources.

Treatment discontinuation following low-dose TKIs in 248 chronic myeloid leukemia patients: Updated results from a campus CML real-life study.

TKIs long-term treatment in CML may lead to persistent adverse events (AEs) that can promote relevant morbidity and mortality. Consequently, TKIs dose reduction is often used to prevent AEs. However, data on its impact on successful treatment-free remission (TFR) are quite scarce. We conducted a retrospective study on the outcome of CML subjects who discontinued low-dose TKIs from 54 Italian hematology centers participating in the Campus CML network. Overall, 1.785 of 5.108 (35.0%) regularly followed CML patients were treated with low-dose TKIs, more frequently due to relevant comorbidities or AEs (1.288, 72.2%). TFR was attempted in 248 (13.9%) subjects, all but three while in deep molecular response (DMR). After a median follow-up of 24.9 months, 172 (69.4%) patients were still in TFR. TFR outcome was not influenced by gender, Sokal/ELTS risk scores, prior interferon, number and last type of TKI used prior to treatment cessation, DMR degree, reason for dose reduction or median TKIs duration. Conversely, TFR probability was significantly better in the absence of resistance to any prior TKI. In addition, patients with a longer DMR duration before TKI discontinuation (i.e., >6.8 years) and those with an e14a2 BCR::ABL1 transcript type showed a trend towards prolonged TFR. It should also be emphasized that only 30.6% of our cases suffered from molecular relapse, less than reported during full-dose TKI treatment. The use of low-dose TKIs does not appear to affect the likelihood of achieving a DMR and thus trying a treatment withdrawal, but might even promote the TFR rate.

Diagnostic and prognostic value of low percentage of glycosylated ferritin in acquired hemophagocytic lymphohistiocytosis: A single-center study.

INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is an aggressive and life-threatening syndrome characterized by an excessive immune activation. Glycosylated ferritin (GF) level has been proposed as highly specific of HLH. METHODS: We have studied 12 subjects with HLH according to the HLH-04 trial criteria and 11 patients with a clinical and laboratoristic suspicion of HLH. The percentage of GF was measured by an in-house assay. RESULTS: The only biomarkers that were significantly different in the two groups were fraction of GF (P<.001) and the presence of hemophagocytosis in bone marrow (P=.006). Subjects with HLH had significantly lower percentage of GF than patients with other inflammatory conditions mimicking HLH. A fraction of GF ≤20% was strongly consistent with a diagnosis of HLH. CONCLUSIONS: Fraction of GF is useful to identify subjects at high risk for early death and therefore in need of early treatment.

Protein kinase CK2 regulates AKT, NF-κB and STAT3 activation, stem cell viability and proliferation in acute myeloid leukemia.

Protein kinase CK2 sustains acute myeloid leukemia cell growth, but its role in leukemia stem cells is largely unknown. Here, we discovered that the CK2 catalytic α and regulatory ß subunits are consistently expressed in leukemia stem cells isolated from acute myeloid leukemia patients and cell lines. CK2 inactivation with the selective inhibitor CX-4945 or RNA interference induced an accumulation of leukemia stem cells in the late S-G2-M phases of the cell cycle and triggered late-onset apoptosis. As a result, leukemia stem cells displayed an increased sensitivity to the chemotherapeutic agent doxorubicin. From a molecular standpoint, CK2 blockade was associated with a downmodulation of the stem cell-regulating protein BMI-1 and a marked impairment of AKT, nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) activation, whereas FOXO3a nuclear activity was induced. Notably, combined CK2 and either NF-κB or STAT3 inhibition resulted in a superior cytotoxic effect on leukemia stem cells. This study suggests that CK2 blockade could be a rational approach to minimize the persistence of residual leukemia cells.

Apoptotic effect of cyclosporin a and dexamethasone in malignant cells of patients with B-chronic lymphocytic leukemia.

B-chronic lymphocytic leukemia (B-CLL) is a malignant disorder characterized by the accumulation of the leukemic cells in the G0-G1 phase of the cell cycle and expressing high levels of the anti-apoptotic protein Bcl-2. Since we observed that the treatment of autoimmune complications with Cyclosporine A (CsA) determined in some CLL patients an improvement not only of the autoimmune phenomena, but also of the leukemic process, we evaluated the in vitro cytotoxicity of CsA as compared to Dexamethasone (Dex) on leukemic cells. Leukemic cells obtained from 32 B-CLL patients showed a heterogeneous pattern of spontaneous apoptosis at 24 h interval and this pattern permitted to identify: Group 1 (14/32) with high (>20%) apoptotic rate and Group 2 (18/32) with low cell death. CsA and Dex increased cell death in both groups with a different timing by an apoptotic mechanism that does not involve Bcl-2. Furthermore, in Group 2, CsA-induced apoptosis was significant higher than that observed with Dex both at 4 and 24 h. We suggest that, in B-CLL, CsA has a significant pro-apoptotic activity manifested also in patients with low spontaneous apoptosis. Our observations might be taken into account to consider new therapeutic strategies in B-CLL.

Ifosfamide and cyclophosphamide: effects on immunosurveillance.

Ifosfamide (IF) and cyclophosphamide (CTX) are chemotherapeutic agents frequently used in the treatment of human malignancies. These drugs can exhibit a bimodal mechanism of antitumor action with cytotoxic and immunomodulatory effects when associated with adoptive immunotherapy. In human peripheral blood lymphocytes, IF irreversibly inhibits the proliferative response to interleukin-2 in a dose-dependent manner and may also induce the phosphorylation of HSP27 by depleting glutathione. CTX promotes discrete cytokine profiles upregulating the expansion of Th1 cells, and this may be important to increase cellular immune response. The data presented in this report indicate that treatment regimens of CTX and IF may be used according to the tumor immunogenicity.

Cxcr3 and its ligand CXCL10 are expressed by inflammatory cells infiltrating lung allografts and mediate chemotaxis of T cells at sites of rejection.

The attraction of T lymphocytes into the pulmonary parenchyma represents an essential step in mechanisms ultimately leading to lung allograft rejection. In this study we evaluated whether IP-10 (CXCL10), a chemokine that is induced by interferon-gamma and stimulates the directional migration of activated T cells, plays a role in regulating the trafficking of effector T cells during lung allograft rejection episodes. Immunohistochemical examination showed that areas characterized by acute cellular rejection (grades 1 to 4) and active obliterative bronchiolitis (chronic rejection, Ca) were infiltrated by T cells expressing CXCR3, i.e., the specific receptor for CXCL10. In parallel, T cells accumulating in the bronchoalveolar lavage of lung transplant recipients with rejection episodes were CXCR3+ and exhibited a strong in vitro migratory capability in response to CXCL10. In lung biopsies, CXCL10 was abundantly expressed by graft-infiltrating macrophages and occasionally by epithelial cells. Alveolar macrophages expressed and secreted definite levels of CXCL10 capable of inducing chemotaxis of the CXCR3+ T-cell line 300-19; the secretory capability of alveolar macrophages was up-regulated by preincubation with interferon-gamma. Interestingly, striking levels of CXCR3 ligands could be demonstrated in the fluid component of the bronchoalveolar lavage in individuals with rejection episodes. These data indicate the role of the CXCR3/CXCL10 interactions in the recruitment of lymphocytes at sites of lung rejection and provide a rationale for the use of agents that block the CXCR3/CXCL10 axis in the treatment of lung allograft rejection.

Antiapoptotic effects of IL-15 on pulmonary Tc1 cells of patients with human immunodeficiency virus infection.

In the early phases of human immunodeficiency virus (HIV) disease a T-cell alveolitis sustained by cytotoxic T lymphocytes (CTL) with anti-HIV activity occurs in the lung. With the progression of HIV disease, pulmonary CTL become infected and their cytotoxic activity declines. To investigate the potential causes leading to this phenomenon, we evaluated T cells obtained from the bronchoalveolar lavage (BAL) of 18 HIV-infected patients with T-cell alveolitis. BAL T cells were CD45R0+/CD8+ defined as Tc1 cells because they expressed cytoplasmic interferon gamma (IFN-gamma) and were CXCR3+/IL-12Rbeta2+. Furthermore, they bore the interleukin (IL)- 15 receptor, Fas antigen, and tumor necrosis factor receptor (TNFR) type II. When cultured for 24 h highly purified BAL T cells showed an excessive spontaneous apoptosis; after activation with anti-CD3 or ionomycin, the proportion of T cells undergoing cell death increased. Interestingly, we found a direct relationship between the predisposition to undergo spontaneous apoptosis and the levels of Fas expression by BAL T cells. Alveolar macrophages (AMs) expressed high levels of IL-15 which paralleled the intensity of T-cell infiltration in most patients. The predisposition of CD8 T cells to undergo cell death was downregulated by the incubation with IL-15; the protective effect of the cytokine was dose-dependent. Nonetheless, AMs also expressed proapoptotic molecules, including membrane TNF-alpha (mTNF-alpha). Based on these observations it may be suggested that an excessive, spontaneous, and activation-induced apoptosis of pulmonary lymphocytes may be observed in HIV lung and that AMs are major regulators of T-cell homeostasis.