Exploiting Necroptosis for Therapy of Acute Lymphoblastic Leukemia

Escape from chemotherapy-induced apoptosis is a hallmark of drug resistance in cancer. The recent identification of alternative programmed cell death pathways opens up for possibilities to circumvent the apoptotic blockade in drug resistant cancer and eliminate malignant cells. Indeed, we have recently shown that programmed necrosis, termed necroptosis, could be triggered to induce cell death in a subgroup of primary acute lymphoblastic leukemia (ALL) including highly refractory relapsed cases. In this review we focus on molecular mechanisms that drive drug resistance in ALL of childhood and discuss the potential of necroptosis activation to eradicate resistant disease

organizational solutions to improve timeliness and effectiveness of the stroke care

Saving time means saving neurons in stroke care process. Managerial and organizational solutions that lean the processes should be considered in order to overcome the effects of stroke, which is the second worldwide cause of death. The purpose of the paper is to understand how Health Lean Management (HLM) can be adopted to achieve a more efficient stroke care process. In this peculiar context, efficiency enhancement leads to safety and effectiveness results. For this reason, the investigated projects have been recognized as Lean & Safety (L&S) projects, being HLM projects reporting patient safety improvements. Due to the peculiarity of the project to investigate, a holistic case study has been conducted in a university hospital of Tuscany region. Thanks to the research framework developed in the literature for L&S projects, data regarding motivations, objectives, organizational and managerial aspects, outcomes, enablers and obstacles of the project have been collected and analysed. A multidisciplinary team, already trained on HLM and supported by the top management, was created and the step-by-step Six Sigma approach was adopted. After a mapping phase, a value stream map was created, Key Performance Indicators were defined and, finally, the Door To Needle (DTN) times and the modified Rankin Scales (mRS) were measured. Thanks to root cause analysis, the identified wastes were analyzed and intervention actions were defined and implemented. They regarded mainly different organizational interventions and they led to a decrease of both DTN times and mRS. The analysed project has demonstrated how it is possible to obtain relevant operational and clinical outcomes through organizational solutions. The analysis of this project, in which pursuing efficiency has led to safety and effectiveness results, has demonstrated how these different performances are linked each other in some peculiar care processes, in which shorter time means more effective and safer care, as in the stroke case. The implementation of L&S projects can improve care processes, providing a contribution to realize a more efficient, effective and safer healthcare system

SETBP1 induces transcription of a network of development genes by acting as an epigenetic hub

SETBP1 variants occur as somatic mutations in several hematological malignancies such as atypical chronic myeloid leukemia and as de novo germline mutations in the Schinzel-Giedion syndrome. Here we show that SETBP1 binds to gDNA in AT-rich promoter regions, causing activation of gene expression through recruitment of a HCF1/KMT2A/PHF8 epigenetic complex. Deletion of two AT-hooks abrogates the binding of SETBP1 to gDNA and impairs target gene upregulation. Genes controlled by SETBP1 such as MECOM are significantly upregulated in leukemias containing SETBP1 mutations. Gene ontology analysis of deregulated SETBP1 target genes indicates that they are also key controllers of visceral organ development and brain morphogenesis. In line with these findings, in utero brain electroporation of mutated SETBP1 causes impairment of mouse neurogenesis with a profound delay in neuronal migration. In summary, this work unveils a SETBP1 function that directly affects gene transcription and clarifies the mechanism operating in myeloid malignancies and in the Schinzel- Giedion syndrome caused by SETBP1 mutations.Peer reviewe

De novo UBE2A mutations are recurrently acquired during chronic myeloid leukemia progression and interfere with myeloid differentiation pathways

Despite the advent of tyrosine kinase inhibitors, a proportion of chronic myeloid leukemia patients in chronic phase fails to respond to Imatinib or to second generation inhibitors and progress to blast crisis. Limited improvements in the understanding of the molecular mechanisms responsible for chronic myeloid leukemia transformation from chronic phase to the aggressive blast crisis were achieved until now. We present here a massive parallel sequencing analysis of 10 blast crisis samples and of the corresponding autologous chronic phase controls which reveals, for the first time, recurrent mutations affecting the ubiquitin-conjugating enzyme E2A gene (UBE2A, formerly RAD6A). Additional analyses on a cohort of 24 blast crisis, 41 chronic phase as well as 40 acute myeloid leukemia and 38 atypical chronic myeloid leukemia patients at onset confirmed that UBE2A mutations are specifically acquired during chronic myeloid leukemia progression with a frequency of 16.7% in advanced phases. In vitro studies show that the mutations here described cause a decrease in UBE2A activity, leading to an impairment of myeloid differentiation in chronic myeloid leukemia cells

Two cases of monomicrobial intraabdominal abscesses due to KPC - 3 Klebsiella pneumoniae ST258 clone

<p>Abstract</p> <p>Background</p> <p>Knowledge of the etiology of pyogenic liver and pancreatic abscesses is an important factor in determining the success of combined surgical and antibiotic treatment. Literature shows geographical variations in the prevalence and distribution of causative organisms, and the spread of <it>Klebsiella pneumoniae </it>carbapenemase-producing bacteria is an emerging cause of abdominal infections.</p> <p>Case presentation</p> <p>We herein describe two cases of intra-abdominal abscesses due to monomicrobial infection by <it>Klebsiella pneumoniae </it>Sequence Type 258 producing <it>K. pneumoniae </it>carbapenemase 3 (KPC-Kp). In case 1, a 50-year-old HIV-negative Italian woman with chronic pancreatitis showed infection of a pancreatic pseudocystic lesion caused by KPC-Kp. In case 2, a 64-year-old HIV- negative Italian woman with pancreatic neoplasm and liver metastases developed a liver abscess due to KPC after surgery. Both women were admitted to our hospital but to different surgical units. The clonal relationship between the two isolates was investigated by pulsed-field gel electrophoresis (PFGE). In case 2, the patient was already colonized at admission and inter-hospital transmission of the pathogen was presumed. A long-term combination regimen of colistin with tigecycline and percutaneous drainage resulted in full recovery and clearance of the multidrug-resistant (MDR) pathogen.</p> <p>Conclusions</p> <p>Timely microbiological diagnosis, the combined use of new and old antibiotics and radiological intervention appeared to be valuable in managing these serious conditions. The emergence and dissemination of MDR organisms is posing an increasing challenge for physicians to develop new therapeutic strategies and control and prevention frameworks.</p

Management simulations for Lean healthcare: exploiting the potentials of role-playing

Purpose: The purpose of this paper is to investigate the potentials of role-playing (RP) both in training healthcare (HC) professionals to implement tools and improvement actions based on Lean principles, and in supporting group discussion and the sharing of different competencies for the development of Lean HC. Design/methodology/approach: The paper presents the case study of an RP simulation called LEAN HEALTHCARE LAB, which is used to train HC professionals at Siena University Hospital. The paper reports and discusses the results of a specific two-day simulation session and of a questionnaire that was distributed to gather feedback from the participants. Findings: The paper verifies the potentials of RP to be a powerful educational and training tool that is able to stimulate the HC participants to apply Lean thinking principles and share their competencies in collaborative decision-making processes. Research limitations/implications: The study provides data in reference to one single simulation session, although the game has already been applied several times in different HC organizations with very similar outcomes. Moreover, a more in-depth analysis of players’ perceptions and decisions could be performed using different tools in addition to the adopted questionnaire. Practical implications: RP games (RPGs) are effective training and educational tools for HC professionals. They offer benefits and learning conditions which are definitely different if compared with more conventional education programs for HC professionals. Originality/value: While previous studies have extensively discussed the potentialities of RPG and simulations in training programs, only a few articles have discussed the RP adoption for Lean thinking and even less to educate HC professionals on Lean principles and tools

Engaging professionals with serious games: The Lean Healthcare Lab at Siena University Hosp

• Purpose: This article aims to stimulate interest in the potentials of serious games within organizations. Through the examination of a case study, emphasis is given to serious games designed for healthcare organizations that are adopting Lean Thinking principles and tools. • Design/methodology/approach: The article discusses how serious games can be designed and implemented in practice by describing a case study based on a healthcare organization. The program, now in its second year, has been used extensively to train healthcare professionals. • Findings: The article is based on the authors’ firsthand experience with serious games and the outcome of several projects carried out in the healthcare setting under analysis. Serious games were found to be powerful training and management development tools as well as engaging environments for professionals. Specifically, the Lean Healthcare Lab supported professionals in their use and implementation of several Lean principles and techniques. • Research implications: The article suggests the opportunity to evaluate the effectiveness of serious games also to improve team performance and develop leadership skills. • Practical implications: Serious games have an enormous potential in sustaining processes of both individual and organizational learning, as well as facilitating improved teamwork. Moreover, serious games are very effective educational tools when compared to more conventional programs. • Originality/value: The approach described in this study can be used to design and implement serious games in any type of organization, in particular, those employing highly skilled professionals. Additionally, this article highlights how serious games can provide learners with a simulated close-to-reality environment where they are challenged to develop policies and use a variety of Lean and management tools

Applicazione della metodologia SMED per il miglioramento delle operations nelle sale operatorie. Il caso Azienda Ospedaliera Universitaria Senese

In molte strutture sanitarie, la riduzione dei tempi di cambio paziente in sala operatoria è un tema molto importante. Questa innovativa ricerca, fra le prime nel sue genere, condotta tramite la metodologia dell’action research, vuole analizzare come i tempi di changeover possano essere migliorati tramite l’utilizzo dello SMED (Single Minute Exchange of Die), un metodo per ridurre gli sprechi nei processi di set-up. La ricerca è stata sviluppata nell’ambito di una sala operatoria della Azienda Ospedaliera Universitaria Senese. La metodologia deriva dal lean thinking giapponese ed è particolarmente utilizzata nel mondo manifatturiero; l’obiettivo è quello di ridurre il più possibile i tempi per passare da un intervento chirurgico al successivo (tempo di set-up). I risultati dimostrano che il tempo di cambio è stato ridotto significativamente, così come la variabilità tra un paziente e il successivo, seguendo alcuni principi base: l’identificazione delle attività esterne e di quelle interne, l’analisi di ciascuna attività, ricerca di soluzioni a basso costo di realizzo e riduzione del tempo di cambio. Il progetto, dal punto di vista delle performance, ha portato a un abbattimento dei tempi di cambio paziente nonché a una riduzione degli interventi rinviati e di quelli conclusi oltre l’orario di chiusura previsto. Ma l’aspetto più importante è forse quello del miglioramento organizzativo apportato

TNFR2 is required for RIP1-dependent cell death in human leukemia

Despite major advances in the treatment of patients with acute lymphoblastic leukemia in the last decades, refractory and/or relapsed disease remains a clinical challenge, and relapsed leukemia patients have an exceedingly dismal prognosis. Dysregulation of apoptotic cell death pathways is a leading cause of drug resistance; thus, alternative cell death mechanisms, such as necroptosis, represent an appealing target for the treatment of high-risk malignancies. We and other investigators have shown that activation of receptor interacting protein kinase 1 (RIP1)-dependent apoptosis and necroptosis by second mitochondria derived activator of caspase mimetics (SMs) is an attractive antileukemic strategy not currently exploited by standard chemotherapy. However, the underlying molecular mechanisms that determine sensitivity to SMs have remained elusive. We show that tumor necrosis factor receptor 2 (TNFR2) messenger RNA expression correlates with sensitivity to SMs in primary human leukemia. Functional genetic experiments using clustered regularly interspaced short palindromic repeats/Cas9 demonstrate that TNFR2 and TNFR1, but not the ligand TNF-α, are essential for the response to SMs, revealing a ligand-independent interplay between TNFR1 and TNFR2 in the induction of RIP1-dependent cell death. Further potential TNFR ligands, such as lymphotoxins, were not required for SM sensitivity. Instead, TNFR2 promotes the formation of a RIP1/TNFR1-containing death signaling complex that induces RIP1 phosphorylation and RIP1-dependent apoptosis and necroptosis. Our data reveal an alternative paradigm for TNFR2 function in cell death signaling and provide a rationale to develop strategies for the identification of leukemias with vulnerability to RIP1-dependent cell death for tailored therapeutic interventions