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Il giudice amministrativo mediatore del conflitto tra potere pubblico e diritti della persona
No full textAnother step forward in the 20-year history of IGHV mutations in chronic lymphocytic leukemia
Full text linkChronic lymphocytic leukemia (CLL) derives from the expansion of clonal and antigen-experienced mature B lymphocytes, whose accumulation results from a dynamic imbalance between cell death and proliferation. The former is impaired by the overexpression of the anti-apoptotic protein BCL2 by CLL cells and the latter is mainly driven by the B-cell receptor (BCR), the key molecule to elucidate the pathogenic and evolution mechanisms of the disease.
Chronic lymphocytic leukemia is a highly heterogeneous disease both in terms of biological landscape and clinical course, including the interval from diagnosis to first progression requiring treatment (time-to-first-treatment, TTFT), the degree and duration of response to therapy, overall survival (OS), and risk of transformation into an aggressive lymphoma (Richter’s syndrome). The prognosis of CLL patients can be accurately defined by combining clinical and biological parameters that include BCR features, cytogenetic lesions, immunophenotypic markers, and gene mutations. Some biomarkers are also useful predictors of response to therapy.
Mutations of the genes codifying for the immunoglobulin heavy chain variable region (IGHV) of the BCR represent one of the most robust prognostic biomarkers, and, indeed, was one of the first to be identified. IGHV mutations never change over time, and thus represent the fingerprint of the disease. Back in 1999, it was reported that CLL patients with mutated IGHV genes (M-CLL) (i.e. <98% cut-off of IGHV identity to the germline counterpart) display a longer TTFT and a longer survival than CLL with unmutated IGHV genes (U-CLL) (≥98%).1,2 The subsequent identification in about 30% of CLL of stereotyped BCRs was even more intriguing.3,4 Stereotyped BCRs (namely those with a nearly identical length of the HCDR3 region, shared amino acids in key positions and the non-stochastic pairing of IGHV and light chain genes) identify subgroups defined “subsets”. More frequent in U-CLL (40%) than in M-CLL (10%) in Caucasians, CLL subsets display distinctive clinicobiological associations: subset #4, mostly M-CLL, is associated to a young age at diagnosis and an indolent disease; subset #1, U-CLL, to a very aggressive clinical course; subset #8, U-CLL, to a higher risk of developing Richter’s syndrome; subset #2 to a poor prognosis regardless of the percentage of IGHV mutations.5 Although the IGHV gene usage and the frequency of BCR subsets can vary across populations with a different incidence of CLL (i.e. Caucasian vs. Chinese), it is interesting that these clinicobiological associations hold true across all ethnic groups.6
In 2015, the value of the IGHV status in predicting the outcome after chemoimmunotherapy also emerged, since M-CLL patients have a significantly longer progression-free survival (PFS), particularly when devoid of poor-risk fluorescence in situ hybridization (FISH) lesions.7 In contrast, it became apparent that the IGHV status does not influence the efficacy of the BTK inhibitor ibrutinib.8,9 Thus, it has been suggested that both the IGHV status and TP53 deletions/mutations should be investigated at the time of disease progression in order to guide the first-line therapeutic choice between chemoimmunotherapy and novel agents.10 Given the clinical implications, the European Research Initiative on CLL (ERIC) group has conducted an international harmonization process across labs for the analysis and reporting of IGHV and TP53 genes in CLL, and this has led to the recently up-dated recommendations.11,12
Although the pathogenic mechanisms operational in CLL are far from being fully elucidated, the oncogenic function of the BCR is indirectly demonstrated by the high anti-leukemic efficacy of kinase inhibitors that block BCR signaling (i.e. ibrutinib, idelalisib, acalabrutinib, duvelisib). On the one hand, in CLL, unlike other lymphoproliferative diseases, the BCR is capable of generating a cell-autonomous signaling driven by the interactions between HCDR3 of near BCR (BCR-BCR) on the cell surface.13 On the other hand, the quality of BCR signaling is heterogeneous: U-CLL are more responsive in vitro to IgM ligation in terms of modulation of the gene expression profile, advance in the cell cycle, and increase in proliferation compared to M-CLL.14 As for a commonly accepted model, U-CLL show a weak autonomous BCR-BCR signaling, a low affinity binding to auto-antigens, an increased BCR responsiveness, and an aggressive clinical course, while M-CLL patients show a strong autonomous BCR-BCR signaling that leads to an anergic state, a lower proliferative response after BCR stimulus, and an overall indolent course.15,16 This model conciliates a shared pathogenic mechanism with the biological and clinical heterogeneity of CLL. In addition, BCR stereotyping likely supports the role of an antigenic pressure in the selection of the leukemic clone.3–5 Among the various factors that contribute to modulate the BCR responsiveness, the microenvironment certainly has a relevant role, since the CLL cells within the lymph node show an upregulation of genes involved in BCR signaling and NfKB activation, at variance from the circulating CLL cells from the same individual.17
Although the mechanisms driving the heterogeneity of CLL genetics are currently unknown, since leukemia kinetics and genetic complexity are usually closely related, it would seem that the BCR can play a role in maintaining genetic stability or in acquiring genetic instability in CLL. Indeed, U-CLL and M-CLL display a variable proportion of the different genetic lesions, as well as of the BCR subsets; U-CLL is enriched with biomarkers with an adverse prognostic significance, although not exclusively.
In the present issue of Haematologica, on behalf of the ERIC group, out of a large cohort of 2366 CLL cases, Baliakas et al.18 focused on 1900 stage A CLLs that were divided into the two main CLL immunogenetic subgroups: U-CLL and M-CLL. Considering each of them separately, they analyzed the relative weight of different prognostic markers in determining the TTFT.18 These prognostic markers included: age, sex, CD38, FISH lesions, TP53, SF3B1, NOTCH1, BIRC3, MYD88 gene mutations, and the major BCR subsets #1, #2 and #4.
This IGHV-based prognostic approach suggests that, among stage A M-CLL, cases with trisomy 12 and stereotyped subset #2 show a short TTFT at five and ten years after diagnosis, similar to those with TP53 abnormalities; within stage A U-CLL, cases with del(11q) and/or SF3B1 mutations experience a TTFT as short as cases with TP53 abnormalities. These markers are almost entirely mutually exclusive. The validity of the model is confirmed also in an external validation cohort of 649 Binet A CLL. Interestingly, male sex comes out as a determinant of disease course within U-CLL, a recurrent observation that has never been truly addressed.19
Overall, considering patients in all stages, within IGHV M-CLL, the lowest risk category (stage A/non-TP53 abnormalities/+12/subset #2), representing 73% of all M-CLL, shows a TTFT of 12% and 25% at five and ten years, respectively; this means that only 1 out of 4 patients has required treatment after ten years from diagnosis. The intermediate-risk category (stage A/TP53 abnormalities/+12/subset #2), representing 14% of all M-CLL, shows a TTFT of 40% and 55% at five and ten years, implying that 1 out of 2 patients still remains untreated after ten years from diagnosis.
On the other hand, within IGHV U-CLL, the very low-risk category (stage A/female/non-SF3B1 mutation/del11q), representing 13% of all U-CLL, shows a TTFT of 45% and 65% at five and ten years, respectively, much shorter (median TTFT 6.1 years) than low-risk M-CLL patients (median TTFT not reached). The U-CLL low-risk (stage A/male/non-SF3B1 mutation/del11q) and intermediate-risk (stage A/SF3B1 mutation/del11q) patients, representing 19% and 24% of all U-CLL, respectively, show a median TTFT of 3.6 and 2.1 years.
Although the retrospective nature of the study and the heterogeneity of the treatments administered prevent the authors from assessing OS in this series, these data identify important differences between the two main CLL immunogenetic subgroups and may help in building a novel CLL patient risk stratification where BCR plays a major role as the core of the prognostic model. For example, trisomy 12, associated to an intermediate prognosis in CLL analyzed as a whole, now has a better definition, having a detrimental prognostic impact on TTFT within M-CLL but not within U-CLL. Moreover, subset #2 should be identified and reported since it has an independent impact on TTFT within M-CLL.
The CLL prognostic algorithms proposed so far have always included IGHV status. However, in six different scoring systems (CLL-IPI, MDACC 2007, MDACC 2011, GCLLSG, Barcelona-Brno, O-CLL1), the outcome prediction fails in a proportion ranging from 22% to 35% of early phase CLL.20 Especially within low-risk CLL, there is still a sizable proportion of patients experiencing “early” progression. A prognostic algorithm built within the U-CLL and M-CLL IGHV categories may overcome this limitation. This has clinical implications for patients’ counseling, follow-up planning, and potential enrollment in trials exploring early treatment approaches for stage A CLL.
It is clear that, in an era of new drugs, the value of all the algorithms proposed so far in terms of prediction of OS will need to be re-evaluated, since the BCR/BCL2 inhibitors have the power to overcome the prognostic impact of the IGHV mutational status. For the time being, besides TP53 deletions/mutations, it is advisable to consider IGHV gene sequencing in all CLL patients requiring first-line treatment as a guide to choose between conventional and innovative approaches. In this respect, the ERIC initiative on the IGHV and TP53 harmonization project and the certification system, with external quality controls for the accreditation of the laboratories performing IGHV/TP53 analysis, is a very timely effort
Does MRD have a role in the management of iNHL ?
No full textAmong indolent non- Hodgkin lymphomas (iNHLs), the analy sis of measur able / minimal residual disease (MRD) has been exten sively applied to fol lic u lar lym phoma (FL). Treatment com bi na tions have deeply changed over the years, as well as the tech niques to mea sure MRD, which is cur rently eval u ated only in the set ting of clin i cal tri als. Here, we dis cuss the evidence on the role of molec u lar mon i tor ing in the man age ment of FL. Mature data sup port the quan ti fi ca tion of molec u lar tumor bur den at diag no sis as a tool to strat ify patients in risk categories and of MRD eval u a tion at the end of treat ment to pre dict pro gres sion - free sur vival and over all sur vival. Moreover, MRD deserves fur ther stud ies as a tool to refi ne the clinical/ metabolic response and to modulate treatment intensity / duration. Patients with a higher relapse probability can be identifi ed, but the rele vance of continuous molecular follow - up should be clarifi ed by kinetic models of MRD analy sis. Being the BCL2 / heavy chain immu no glob u lin gene hybrid rearrangement detect able in about 50 % to 60 % of advanced FL and in 30% of positron emission tomography / computed tomography - staged localized FL, technical advancements such as next - gener ation sequencing/ tar get locus amplifi cation may allow broadening the FL population carrying a molecular marker. Droplet dig i tal poly mer ase chain reac tion can bet ter quan tify MRD at low lev els, and novel sources of DNA, such as cell - free DNA, may rep re sent a non in va sive tool to mon i tor MRD. Finally, MRD in other iNHLs, such as lymphoplasmacytic lymphoma/ Waldenstr öm macroglobulinemia and mar ginal zone lymphoma, is beginning to be explored
Del Giudice, I tumulti del 1547 in Napoli pel Tribunale dell' Inquisizione
No full textJordan Edouard. Del Giudice, I tumulti del 1547 in Napoli pel Tribunale dell' Inquisizione. In: Mélanges d'archéologie et d'histoire, tome 14, 1894. pp. 620-622
Conformational stability and ligand binding properties of BldR, a member of the MarR family, from Sulfolobus solfataricus.
No full textThe multiple antibiotic resistance regulators (MarR) constitute a family of ligand-responsive transcriptional regulators ubiquitous among the bacterial and archaeal domains. BldR, an archaeal MarR member characterized from the hyperthermophilic crenarchaeon Sulfolobus solfataricus regulates its own expression and that of an alcohol dehydrogenase gene by binding to sequences in their promoters and responding to benzaldehyde as the effector molecule. In this study we assessed the thermodynamic stability of the protein BldR and its binding with benzaldehyde through biophysical measurements. The temperature- and denaturant-induced unfolding experiments, performed by means of circular dichroism (CD) and differential scanning calorimetry (DSC), showed that BldR has an extremely high thermal stability (Td = 108.9 °C) and a remarkable resistance against GuHCl (Cm = 5.3 M at 25 °C). The unfolding Gibbs energy, ΔdG (H2O), calculated by the linear extrapolation model from GuHCl-induced unfolding equilibrium curve, is 72.2 kJ mol− 1. ITC binding experiments showed that four benzaldehyde molecules bind to one BldR dimer with a binding constant Kb of 7.5·105 M− 1, being the binding entropically driven. ITC, CD and fluorescence results are consistent with a conformational change induced by benzaldehyde binding, further proving that this molecule is a specific effector for BldR modulating its DNA binding activity
CLINICAL IMPLICATIONS OF THE MOLECULAR GENETICS OF CHRONIC LYMPHOCYTIC LEUKEMIA
No full textGenetics and molecular genetics have contributed to clarify the biological bases of the clinical heterogeneity of chronic lymphocytic leukemia. In recent years, our knowledge of the molecular genetics of chronic lymphocytic leukemia has significantly broadened, offering potential new clinical implications. Mutations of TP53 and ATM add prognostic information independently of fluorescence in situ hybridization cytogenetic stratification. In addition, next generation sequencing technologies have allowed previously unknown genomic alterations in chronic lymphocytic leukemia to be identified. Mutations of NOTCH1, SF3B1 and BIRC3 have been associated with short time to progression and survival. Each of these lesions recognizes a different distribution across different clinical phases and biological subgroups of the disease. The clinical implications of these molecular lesions are in some instances well established, such as in the case of patients with TP53 disruption, who should be considered for alternative therapies/allogeneic stem cell transplant upfront, or in patients with ATM disruption, who are candidates to rituximab-based immunochemotherapy. On the contrary, NOTCH1, SF3B1 and BIRC3 mutations appear to have a specific significance, the clinical value of which is currently being validated, i.e. association to Richter syndrome transformation for NOTCH1 mutations, and short progression-free survival after treatment for SF3B1 mutations. Certainly, these new lesions have helped clarify the molecular bases of chronic lymphocytic leukemia aggressiveness beside TP53 disruption. This review covers the recent advancements in our understanding of the molecular genetics of chronic lymphocytic leukemia and discusses how they are going to translate into clinical implications for patient management
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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