Serafino Zappacosta: An Enlightened Mentor and Educator.

With this article, the authors aim to honor the memory of Serafino Zappacosta, who had been their mentor during the early years of their career in science. The authors discuss how the combination of Serafino Zappacosta's extraordinary commitment to teaching and passion for science created a fostering educational environment that led to the creation of the "Ruggero Ceppellini Advanced School of Immunology." The review also illustrates how the research on the MHC and the inspirational scientific context in the Zappacosta's laboratory influenced the authors' early scientific interests, and subsequent professional work as immunologists

The genotype of MLH1 identifies a subgroup of follicular lymphoma patients who do not benefit from doxorubicin: FIL-FOLL study

Though most follicular lymphoma biomarkers rely on tumor features, the host genetic background may also be relevant for outcome. Here we aimed at verifying the contribution of candidate polymorphisms of FCγ receptor, DNA repair and detoxification genes to prognostic stratification of follicular lymphoma treated with immunochemotherapy. The study was based on 428 patients enrolled in the FOLL05 prospective trial that compared three standard-of-care regimens (rituximab-cyclophosphamide-vincristine-prednisone versus rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone versus rituximab-fludarabine-mitoxantrone) for the first line therapy of advanced follicular lymphoma. Polymorphisms were genotyped on peripheral blood DNA samples. The primary endpoint was time to treatment failure. Polymorphisms of FCGR2A and FCGR3A, which have been suggested to influence the activity of rituximab as a single agent, did not affect time to treatment failure in the pooled analysis of the three FOLL05 treatment arms that combined rituximab with chemotherapy (P=0.742, P=0.252, respectively). These results were consistent even when the analysis was conducted by intention to treat, indicating that different chemotherapy regimens and loads did not interact differentially with the FCGR2A and FCGR3A genotypes. The genotype of MLH1, which regulates the genotoxic effect of doxorubicin, significantly affected time to treatment failure in patients in the rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone arm (P=0.001; q<0.1), but not in arms in which patients did not receive doxorubicin (i.e., the rituximab-cyclophosphamide-vincristine-prednisone and rituximab-fludarabine-mitoxantrone arms). The impact of MLH1 on time to treatment failure was independent after adjusting for the Follicular Lymphoma International Prognostic Index and other potential confounding variables by multivariate analysis. These data indicate that MLH1 genotype is a predictor of failure to benefit from rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone treatment in advanced follicular lymphoma and confirm that FCGR2A and FCGR3A polymorphisms have no impact when follicular lymphoma is treated with rituximab plus chemotherapy (clinicaltrials.gov identifier: NCT00774826)

Chk1 Inhibition Restores Inotuzumab Ozogamicin Citotoxicity in CD22-Positive Cells Expressing Mutant p53

Inotuzumab ozogamicin (IO) is an anti-CD22 calicheamicin immunoconjugate that has been recently approved for the treatment of relapsed or refractory B-Acute Lymphoblastic Leukemia (r/r B-ALL). We employed both immortalized and primary cells derived from CD22-positive lymphoproliferative disorders to investigate the signaling pathways contributing to IO sensitivity or resistance. We found that the drug reduced the proliferation rate of CD22-positive cell lines expressing wild-type p53, but was remarkably less effective on cells exhibiting mutant p53. In addition, CD22-positive cells surviving IO were mostly blocked in the G2/M phase of the cell cycle because of Chk1 activation that, in the presence of a wild-type p53 background, led to p21 induction. When we combined IO with the Chk1 inhibitor UCN-01, we successfully abrogated IO-induced G2/M arrest regardless of the underlying p53 status, indicating that the DNA damage response triggered by IO is also modulated by p53-independent mechanisms. To establish a predictive value for p53 in determining IO responsiveness, we expressed mutant p53 in cell lines displaying the wild-type gene and observed an increase in IO IC50 values. Likewise, overexpression of an inducible wild-type p53 in cells natively presenting a mutant protein decreased their IC50 for IO. These results were also confirmed in primary CD22-positive cells derived from B-ALL patients at diagnosis and from patients with r/r B-ALL. Furthermore, co-treatment with IO and UCN-01 significantly increased cell death in primary cells expressing mutant p53. In summary, our findings suggest that p53 status may represent a biomarker predictive of IO efficacy in patients diagnosed with CD22-positive malignancies

Predictors of atrial fibrillation detection in embolic stroke of undetermined source patients with implantable loop recorder

BackgroundCovert atrial fibrillation (AF) is a predominant aetiology of embolic stroke of undetermined source (ESUS). Evidence suggested that AF is more frequently detected by implantable loop recorder (ILR) than by conventional monitoring. However, the predictive factors associated with occult AF detected using ILRs are not well established yet. In this study we aim to investigate the predictors of AF detection in patients with ESUS undergoing an ILR.MethodsThis observational multi-centre study included consecutive ESUS patients who underwent ILR implantation. The infarcts were divided in deep, cortical infarcts or both. The infarction sites were categorized as anterior and middle cerebral artery, posterior cerebral artery with and without brainstem/cerebellum involvement. Multivariable logistic regression analysis was performed to investigate variables associated with AF detection.ResultsOverall, 3,000 patients were initially identified. However, in total, 127 patients who consecutively underwent ILR implantation were included in our analysis. AF was detected in 33 (26%) out of 127 patients. The median follow-up was 411 days. There were no significant differences in clinical characteristics and comorbidities between patients with and without AF detected. AF was detected more often after posterior cerebral artery infarct with brainstem/cerebellum involvement (p &lt; 0.001) whereas less often after infarction in the anterior and middle cerebral artery (p = 0.021). Multivariable regression analysis demonstrated that posterior cerebral artery infarct with brainstem/cerebellum involvement was an independent predictor of AF detection.ConclusionOur study showed that posterior circulation infarcts with brainstem/cerebellum involvement are associated with AF detection in ESUS patients undergoing ILR. Larger prospective studies are needed to validate our findings

Can Clinical and Surgical Parameters Be Combined to Predict How Long It Will Take a Tibia Fracture to Heal? A Prospective Multicentre Observational Study: The FRACTING Study

Background. Healing of tibia fractures occurs over a wide time range of months, with a number of risk factors contributing to prolonged healing. In this prospective, multicentre, observational study, we investigated the capability of FRACTING (tibia FRACTure prediction healING days) score, calculated soon after tibia fracture treatment, to predict healing time. Methods. The study included 363 patients. Information on patient health, fracture morphology, and surgical treatment adopted were combined to calculate the FRACTING score. Fractures were considered healed when the patient was able to fully weight-bear without pain. Results. 319 fractures (88%) healed within 12 months from treatment. Forty-four fractures healed after 12 months or underwent a second surgery. FRACTING score positively correlated with days to healing: r = 0.63 (p &lt; 0.0001). Average score value was 7.3 \ub1 2.5; ROC analysis showed strong reliability of the score in separating patients healing before versus after 6 months: AUC = 0.823. Conclusions. This study shows that the FRACTING score can be employed both to predict months needed for fracture healing and to identify immediately after treatment patients at risk of prolonged healing. In patients with high score values, new pharmacological and nonpharmacological treatments to enhance osteogenesis could be tested selectively, which may finally result in reduced disability time and health cost savings

Energy-Based Assessment of Optimal Operating Parameters for Coupled Biochar and Syngas Production in Stratified Downdraft Gasifiers

Biochar represents a valuable solution for carbon sequestration. Infact, it has aroused the interest of the scientific community due to its resistance to the degradation and its potential of soil improving. Stratified downdraft gasifier reactors are characterized by extreme design simplicity and it was proved that are able to operate with non-homogeneous feedstock. On the other hand, stratified reactors dispose a higher amount of char when compared to other downdraft gasifier. This work is aimed at characterizing the char produced through downdraft stratified reactors. Particular conditions which maximize both the quality and the amount of syngas and biochar was investigated. The whole system was evaluated through a composed coefficient Ip (performance index) which takes into account the energy content in the gas stream and the characteristics of the char produced. A lab-scale reactor, able to operate under different conditions, was designed considering the requirements of this work. It was implemented with a sophisticated heating system which allow us to control the reactor surface temperatures independently zone to zone. Results shown the capability of stratified gasifiers to be used for biochar disposal. Results outlined the Ip trend as function of the SV of the gasifier. and tar production was considered to find the more suitable condition