"Society of Hematologic Oncology (SOHO) State of the Art Updates and Next Questions"-Treatment of ALL.

The outcome of adult acute lymphoblastic leukemia (ALL) has substantially improved by adopting pediatric-inspired regimens, and approximately half of the patients are nowadays cured. The evaluation of minimal residual disease currently represents the most important prognostic indicator, which drives treatment algorithms, which include allogeneic stem cell transplantation (allo-SCT) allocation. Indeed, for high-risk patients, allo-SCT should be pursued as soon as possible, whereas in standard-risk patients this procedure should be avoided also in light of related toxicity and because there are no significant benefits. Furthermore, better characterization of the molecular genetic events can drive therapeutic decisions: a historical example in this respect is represented by the use of tyrosine kinase inhibitors (TKIs) in Philadelphia chromosome-positive ALL; in the upcoming future, TKIs might be used also in other subgroups, such as breakpoint cluster region/Abelson 1-like cases and others with deregulated tyrosine kinases. Finally, the greatest progress is currently achieved with new immunotherapies targeting frequently expressed surface antigens in ALL. It is also a new chance for elderly ALL patients, so far spared from intensive chemotherapy and allo-SCT. These targeted therapies will substantially change this treatment algorithm and the great challenge is to find optimal sequence of the extended therapy options in an individual patient

Recuperación retrospectiva de un archivo policíaco: el “Casellario Politico Centrale”

The research illustrates utilization strategies of description standards and advanced technologies that are the basis of recovery ("recuperación retrospectiva") methodologies of archival finding aids, experienced in overcoming the problems associated with communicating and sharing resources. Considering interoperability, both technological and semantic, and long-term preservation of information as primary objectives of information systems, it is considered that recovery operations have to always be characterized by the choice of reference to specific standard solutions, technological (XML as data format) and descriptive encoding (Ead and Eac-Cpf in the archival area)

Tailoring CD19xCD3-DART exposure enhances T-cells to eradication of B-cell neoplasms.

Many patients with B-cell malignancies can be successfully treated, although tumor eradication is rarely achieved. T-cell-directed killing of tumor cells using engineered T-cells or bispecific antibodies is a promising approach for the treatment of hematologic malignancies. We investigated the efficacy of CD19xCD3 DART bispecific antibody in a broad panel of human primary B-cell malignancies. The CD19xCD3 DART identified 2 distinct subsets of patients, in which the neoplastic lymphocytes were eliminated with rapid or slow kinetics. Delayed responses were always overcome by a prolonged or repeated DART exposure. Both CD4 and CD8 effector cytotoxic cells were generated, and DART-mediated killing of CD4+ cells into cytotoxic effectors required the presence of CD8+ cells. Serial exposures to DART led to the exponential expansion of CD4 + and CD8 + cells and to the sequential ablation of neoplastic cells in absence of a PD-L1-mediated exhaustion. Lastly, patient-derived neoplastic B-cells (B-Acute Lymphoblast Leukemia and Diffuse Large B Cell Lymphoma) could be proficiently eradicated in a xenograft mouse model by DART-armed cytokine induced killer (CIK) cells. Collectively, patient tailored DART exposures can result in the effective elimination of CD19 positive leukemia and B-cell lymphoma and the association of bispecific antibodies with unmatched CIK cells represents an effective modality for the treatment of CD19 positive leukemia/lymphoma

O e-SCM e a gestão dos estoques: um estudo de múltiplos casos em um segmento de cadeia de lojas de departamento

Inventory management through the supply chains is a theme that has always enticed managers throughout the world. Due to the increase in market competitiveness and complexity, the traditional statistical models of forecasting demand, based on time series, no longer met the needs imposed on businesses to maintain adequate levels of their inventory and supply interruptions. With the intent to meet these market demands, ERP systems appeared in the 1990's. Nevertheless, even if allowing for a more adequate level of inventory and supply interruptions achieved mainly by the optimization of internal processes and the reduction in lead time, ERP systems did not contribute to reach the SCM's desired levels of inventory that were aimed at by the more competitive businesses. This is because ERP limits itself to an internal analysis of the business. By contrast, inventory management depends on the consumption information (which is external to the business). Aiming to improve even further the level of services delivered to the end consumer, new solutions have been developed, among them the e-SCM, which, since it makes consumption information available in real time, ends up being more dynamic and efficient than the traditional demand forecasting models, Therefore, the present study aims to analyze how the e-SCM can collaborate in maintaining adequate levels of inventory and interruptions in the supply chains. The hypothesis made is that the traditional statistical forecasting models, based on time series and isolatedly, are no longer adequate to adjust the demand, as the tools based on these models do not update the demand in real time and this is fundamental in the current business dynamics. The research method used was the study of multiple cases in a segment of a chain involving a large retailer, its Distribution Center and a supplier of home appliances. For the analysis of the data, the content analysis technique was used. As main results, it was observed that, after the integration of the chain segment by the e-SCM, there was a reduction in the level of the inventory (36.8% in retail and 18% in the industry) and in inventory turnover (from 18.3 to 5.1 days in retail and from 19.6 to 3.2 days in the Distribution Center), aside from the variation in the interruption (from 17.3% to 2.6% in retail and from 3% to 0.1% in the case of the Distribution Center). Therefore, the study brings forth strong indication that the integration of the chain through the e-SCM, may contribute to the SCM's competitiveness.A gestão dos estoques ao longo da cadeia de suprimentos é um tema que sempre instigou gestores por todo o mundo. Com o aumento da competitividade e da complexidade dos mercados, os tradicionais modelos estatísticos de previsão da demanda, fundamentados em séries temporais, não mais atendiam as necessidades impostas às empresas na adequação de seus níveis de estoques e ruptura. No intuito de atender essas exigências do mercado surgem, nos anos 1990, os sistemas ERP. Entretanto, mesmo possibilitando uma adequação nos estoques e na ruptura, levado principalmente pela otimização dos processos internos e redução do lead time, os ERP não contribuíram para que o SCM atingisse o nível de estoque almejado pelas empresas mais competitivas. Isso porque o ERP limita-se a análise interna da empresa. Já a gestão dos estoques depende de informações de consumo (que são externas a empresa). Buscando-se melhorar ainda mais os níveis de serviços prestados ao consumidor final, novas soluções foram desenvolvidas, dentre elas, o e-SCM que por disponibilizar a informação do consumo em tempo real, acaba sendo mais dinâmico e eficiente que os modelos tradicionais de previsão da demanda. Dessa forma, o presente estudo objetiva analisar como o e-SCM pode colaborar para a adequação dos níveis de estoques e ruptura das cadeias de abastecimento. A hipótese defendida é a de que os modelos estatísticos tradicionais de previsão, baseados em séries temporais, isoladamente não são mais adequados para o ajuste da demanda, tendo em vista que ferramentas baseadas nestes modelos não atualizam a demanda em tempo real e isso é fundamental para a atual dinâmica empresarial. O método de pesquisa utilizado foi o estudo de múltiplos casos em um segmento de cadeia que envolve um grande varejista, seu CD e um fornecedor de linha branca. Para análise dos dados, foi utilizada a técnica de análise de conteúdo. Como principais resultados observou-se que, após a integração do segmento de cadeia pelo e-SCM, houve uma redução no nível dos estoques (36,8% no varejo e 18% na indústria) e no giro (de 18,3 para 5,1 dias no varejo e de 19,6 para 3,2 dias no CD), além da variação da ruptura (de 17,3% para 2,6% no varejo e de 3% para 0,1% no caso do CD). Sendo assim, o estudo traz fortes indícios de que a integração da cadeia, por meio do e-SCM, pode colaborar para o aumento da competitividade da SCM

Analysis of the role of liprins protein in breast cancer cell invasion.

The metastatic process requires the ability of cancer cells to break the basement mem¬brane and migrate through a complex three-dimensional environment. The laboratory has recently identified the protein liprin-α1 as an important regulator of integrin me¬diated focal adhesion dynamics and cell motility in non-neuronal cells (Asperti et al., 2009, Asperti et al., 2010). Liprins are a family of cytosolic scaffold proteins including the liprin-α and liprin-β subfamilies based on sequence similarities (Serra Pagés et al., 1998). The human genome encodes four liprin-α (liprin-α1-4) and two liprin-β proteins (liprin-β1 and liprin-β2). Interestingly, the gene PPFIA1 for liprin-α1 is frequently am-plified in tumors. Moreover, the levels of expression of the liprin-α1 protein are often increased in human breast cancers (Astro et al., 2011). Functional analysis has revealed that liprin-α1 is specifically required for migration and invasion in vitro of highly invasi¬ve MDA-MB-231 human breast cancer cells. The analysis of lamellipodia dynamics has revealed a decrease of the stability of these protrusions in cells depleted of endogenous liprin-α1, which are defective in cell motility. Furthermore, liprin-α1 silencing causes a reduction of tumor cell invasion through Matrigel. The examination of the invasive po¬tential has demonstrated that liprin-α1 is important also for the degradation of the extra¬cellular matrix (ECM) (Astro et al., 2011). Starting from these observations, the first aim of my project has been to investigate the function of liprin-α1 in vivo. I have generated MDA-MB-231-derived cell lines with either stable overexpression or stable depletion of liprin-α1, and I have used these cells for injection or transplantation in mice, to determine their invasive potential. The characterization of these cell lines in vitro has confirmed that liprin-α1 overexpression causes an increase of both cell migration on FN and invasion through Matrigel, by promoting the stability of the lamellipodia. On the other hand, li¬prin-α1-depleted cells have reduced ability to both migrate and invade in vitro. However, all the cell lines with altered liprin-α1 levels have shown similar proliferation rates and viability compared to the control MDA-MB-231 cells. To investigate the involvement of liprin-α1 in invasion in vivo, experimental metastasis assays and spontaneous metastasis assays were performed. In both assays, the formation of lung metastases by the modified and control breast cancer cell lines has been evaluated. The results indicated that liprin-α1 overexpression did not affect lung colonization. Considering the high invasive ability of MDA-MB-231 wild type cells, increase in lung colonization by liprin-α1 overexpression may be irrelevant in vivo. On the contrary, injection of liprin-α1-depleted cells resulted in the reduction of the formation of lung metastases compared to control cells. This is the first evidence that liprin-α1 is not involved in primary tumor growth, while it is important for tumor cell invasion. Being a scaffold protein, liprin-α1 is unlikely to act alone as a regulator of tumor cell invasion. Previous studies have described the interaction between liprin-α1 and liprin-β1 (Serra-Pages et al., 1998), and have suggested a possible role of liprin-β2 in migration and invasion (von Thun et al., 2012). However, the available data on the functions of li¬prin-β proteins and their relationship with liprin-α1 are not exhaustive. As the second aim of my PhD, I have addressed the biochemical interaction of liprin-α1 with either liprin-β1 or liprin-β2, and I have tried to elucidate the role of the two proteins in cell motility and invasion. While liprin-α1 interacts with liprin-β1, it does not interact with liprin-β2. This is the first evidence of the different ability of the two liprin-β proteins to interact with liprin−α1. The biochemical analysis has shown that the interaction between liprin-α1 and liprin-β1 occurs via the C-terminus of liprin-α1, and that two of the three SAM domains of liprin-α1 are sufficient to mediate this interaction. The study of the subcellular localization has indicated that liprin-β1 colocalizes with liprin-α1 at the cell edge, whereas liprin-β2 partially colocalizes with cortactin-positive invadopodia. Functional analysis has shown that liprin-β1 silencing did not affect cell invasion through matrigel, whereas liprin-β2 silencing led to an increase of cell invasion, and enhanced ECM degradation, supporting the hypothesis of the different role of this protein in regulating the function of invadopodia with respect to liprin-α1 and liprin-β1. Analysis of the involvement of liprin-β1 and liprin-β2 in cell migration underlined the different effects of the two proteins. As previously observed for liprin-α1 (Astro et al, 2011), silencing of liprin-β1 led to a decrease of the speed of the cells in random migra¬tion assays. On the contrary, liprin-β2 silencing did not significantly affect cell motility. These data support the hypothesis of a cooperation between liprin-α1 and liprin-β1 in regulating cell motility, while they indicate that liprin-β2 does not have a relevant role in this process. Altogether the work presented in my thesis sustains a key role of liprin-α1 as a positive regulator of the invasive apparatus of tumour cells in vivo, and has highlighted for the first time first time distinct roles of liprin-β1 and liprin-β2 in tumor cell motility

Control of hyperglycaemia in paediatric intensive care (CHiP): study protocol.

BACKGROUND: There is increasing evidence that tight blood glucose (BG) control improves outcomes in critically ill adults. Children show similar hyperglycaemic responses to surgery or critical illness. However it is not known whether tight control will benefit children given maturational differences and different disease spectrum. METHODS/DESIGN: The study is an randomised open trial with two parallel groups to assess whether, for children undergoing intensive care in the UK aged <or= 16 years who are ventilated, have an arterial line in-situ and are receiving vasoactive support following injury, major surgery or in association with critical illness in whom it is anticipated such treatment will be required to continue for at least 12 hours, tight control will increase the numbers of days alive and free of mechanical ventilation at 30 days, and lead to improvement in a range of complications associated with intensive care treatment and be cost effective. Children in the tight control group will receive insulin by intravenous infusion titrated to maintain BG between 4 and 7.0 mmol/l. Children in the control group will be treated according to a standard current approach to BG management. Children will be followed up to determine vital status and healthcare resources usage between discharge and 12 months post-randomisation. Information regarding overall health status, global neurological outcome, attention and behavioural status will be sought from a subgroup with traumatic brain injury (TBI). A difference of 2 days in the number of ventilator-free days within the first 30 days post-randomisation is considered clinically important. Conservatively assuming a standard deviation of a week across both trial arms, a type I error of 1% (2-sided test), and allowing for non-compliance, a total sample size of 1000 patients would have 90% power to detect this difference. To detect effect differences between cardiac and non-cardiac patients, a target sample size of 1500 is required. An economic evaluation will assess whether the costs of achieving tight BG control are justified by subsequent reductions in hospitalisation costs. DISCUSSION: The relevance of tight glycaemic control in this population needs to be assessed formally before being accepted into standard practice

Benefits and biosafety of use of buckypaper for surgical applications. A pilot study in a rabbit clinical trial model

Background: One of the main problems related to prosthetic abdominal surgery is mesh fixation. Suture line tension, mesh separation, displacement, or improper application of stitches are the leading causes of complications, including seroma, postoperative pain, and recurrence. A surface able to adhere firmly to living tissue represents an effective alternative to conventional perforating fixations. As a bio-adhesive tape, we report experimental evidence on the potential applicability of the BuckyPaper (BP), a felt composed of entangled multi-walled carbon nanotubes. Matherial and methods: BP is implanted to assess its biosafety and effectiveness as an adhesive prosthetic device. Results: During 35 days we observed no rabbit behavioral alteration, BP stability in the implantation site, good adhesion, and integration of the device with the surrounding tissue, and no adverse reactions. Conclusions: BP could be used as an adhesive to secure the prostheses to tissues in abdominal wall prosthetic surgery, but large-size animal studies are needed

Comparison of Centella with flavonoids for treatment of symptoms in hemorrhoidal disease and after surgical intervention: A randomized clinical trial

Gli effetti dei flebotonici sono stati valutati per il tempo di arresto del sanguinamento e il tempo di scomparsa dell'irritazione anale in 130 pazienti affetti da malattia emorroidaria, tempo di arresto del sanguinamento e tempo di scomparsa del dolore dopo intervento [emorroidectomia (in 31 pazienti) oppure incisione e drenaggio di trombosi emorroidaria (in 34 pazienti)]. Queste valutazioni sono state fatte nel breve periodo di tempo 0-42 gg. Sessanta pazienti randomizzati hanno ricevuto la procedura di routine (sia conservativa che chirurgica) (gruppo di controllo C). Il gruppo dei pazienti che hanno ricevuto il trattamento con flebotonici (sia conservativo che chirurgico) è stato suddiviso in due sottogruppi: quello trattato con flavonoidi (Gruppo A, n = 73) e quello trattato con Centella (Gruppo B, n = 66). Il tempo di scomparsa del sanguinamento è stato verificato dal Giorno 0 fino al Giorno 42. La guarigione è stata stimata con il metodo Kaplan-Meier, il test Kruskal-Wallis è stato utilizzato per valutare le variazioni del punteggio VAS per studiare il dolore (dopo intervento per emorroidectomia oppure incisione e drenaggio di trombosi emorroidaria), oppure irritazione anale nei pazienti trattati conservativamente. Il tempo medio di emorragia è stato di 2 settimane per i gruppi A e B; 3 settimane per il gruppo C. Il confronto dei punteggi VAS tra i gruppi (irritazione): A vs C, p = 0,007; B vs C, p = 0,041; e A vs B, rispettivamente p = 0,782. Per quanto riguarda gli operati con emorroidectomia, il tempo di arresto del sanguinamento è stato rispettivamente di 3 e 4 settimane nei gruppi A e B, 5 settimane nel gruppo C. L'istopatologia ha mostrato un'associazione tra flavonoidi e fibrosi emorroidaria (p = 0,008). I flebotonici hanno mostrato significativi effetti benefici sia negli operati che nei pazienti trattati conservativamente. Tra i flebotonici, i flavonoidi sono stati più efficaci contro il sanguinamento e l'irritazione anale.Phlebotonics' effects were evaluated to reduce time-to-stop bleeding and anal irritation in 130 patients who complained of hemorrhoidal disease (HD); bleeding and pain after hemorrhoidectomy (31 patients) and hemorrhoidal thrombosis (34 patients) in the short time. Sixty patients were randomized to receive the routine treatment (both conservative and surgical) (control Group C). The treated group (both conservative and surgical) was divided into two subgroups: one treated with flavonoids (Group A, n = 73), the other with Centella (Group B, n = 66). Time-to-stop bleeding was checked at baseline and checkups (0 up to day 42). Healing was estimated with Kaplan-Meier method, the Kruskal-Wallis test estimated changes in the VAS scores. The HD median time-to-stop bleeding was 2 weeks for Groups A and B; 3 weeks for Group C. VAS scores comparison among Groups (irritation): A vs C, p = 0.007; B vs C, p = 0.041; and A vs B, p = 0.782 resulted respectively. As for operated hemorrhoids, the time-to-stop bleeding was 3 and 4 weeks in Groups A and B and 5 in Group C. Histopathology showed an association between flavonoids and piles' fibrosis (p = 0.008). Phlebotonics in HD, as well as after surgery, showed significant beneficial effects. Flavonoids are the most effective phlebotonics against bleeding and anal irritation