New Insights in Prognosis and Therapy of Chronic Lymphocytic Leukaemia

Chronic lymphocytic leukaemia (CLL) is a heterogeneous disease with a very variable clinical outcome. New biological markers, such as cytogenetic abnormalities or mutation status, have become important prognostic factors. Whole-genome sequencing studies have revealed novel genomic mutations, NOTCH1, SF3B1, BIRC3, TP53 and MYD88 being the most important. All these mutations have also been associated with the disease outcome. The treatment of CLL has evolved favourably in recent years. However, adverse events or chemorefractoriness occurs in some cases. Luckily, an increasing number of compounds are under development with promising results. Some of these new targeted therapies include B-cell receptor inhibitors, new anti-CD20 antibodies, Bcl-2 inhibitors, immunomodulatory drugs or chimeric antigen receptors (CARs). In this chapter, we will conduct a review of the new prognostic markers of CLL, the relationship they have with each other to build prognostic scores, the role they have in guiding treatment decisions and the novel therapies that have emerged recently with immunologic, biochemical and genetic targets

Un ejercicio de acceso a la información sobre la eficiencia en el combate contra la trata de personas en México1

ResumenUn ejercicio de acceso a la información sobre la eficiencia en el combate a la trata de personas en México contiene tres apartados: Metodología, Acceso a la información, Procuración e impartición de justicia en materia de trata de personas, así como sus respectivas conclusiones. La trata de personas, denominada “la esclavitud del siglo xxi”, es el comercio de seres humanos que reviste distintas modalidades, entre ellas, la explotación sexual, la explotación laboral, la mendicidad forzada, la extracción de órganos, el matrimonio forzoso, trabajo o servicios forzados y la experimentación biomédica ilícita.El Observatorio Nacional Ciudadano de Seguridad, Justicia y Legalidad presenta este texto con el objetivo de describir parte de lo que sucede en la cadena de justicia en la materia, por lo que se generaron bases de datos estadísticos de la información oficial disponible sobre el número de víctimas que de 2010 a 2013 han detectado las procuradurías estatales; el número de detenidos y sentenciados por este delito; el perfil de las víctimas, y cómo y dónde se realiza el delito. Los resultados demuestran que hay un 2% de efectividad en relación con el número de víctimas, en contraste con el de sentencias condenatorias; y en contraste con el incumplimiento de las entidades y la federación, quienes no generan información estadística confiable y de fácil acceso, lo cual es su obligación. Lo anterior pone en evidencia la falta de una política pública contundente para combatir este fenómeno, debido a que no se cuenta con un diagnóstico oficial sobre las dimensiones y gravedad de este problema en nuestro país.AbstractAn exercise of access to information on the efficiency in combating trafficking in persons in Mexico, contains three sections: Methodology, Access to Information, Procurement and delivery of justice in human trafficking, and their respective conclusions. Trafficking known as slavery of the XXI century is the trade in human beings that takes different forms, including sexual exploitation, labor exploitation, organ removal, forced marriage, forced labor or services and illicit biomedical experimentation.Observatorio Nacional Ciudadano presents this text with the aim of describing what happens in the chain of justice in the matter, statistical databases of official information were generated to measure, with the available information, the number of victims from 2010 to 2013 the state prosecutors have detected, the number of detainees and convicted of this crime, the victim profile, how and where the offense is committed. The results show that there is a 2% success rate in relation to the number of victims in contrast to that of convictions; entities and federation fail to meet the obligation to generate reliable statistical information and easily accessible. This highlights the lack of a strong public policy to combat this phenomenon, because there is no official diagnosis of the extent and severity of this problem in our country

DNA damage response-related alterations define the genetic background of patients with chronic lymphocytic leukemia and chromosomal gains

[EN]The presence of chromosomal gains other than trisomy 12 suggesting a hyperdiploid karyotype is extremely rare in chronic lymphocytic leukemia (CLL) and is associated with a dismal prognosis. However, the genetic mechanisms and mutational background of these patients have not been fully explored. To improve our understanding of the genetic underpinnings of this subgroup of CLL, seven CLL patients with several chromosomal gains were sequenced using a next-generation sequencing (NGS)-targeted approach. The mutational status of 54 genes was evaluated using a custom-designed gene panel including recurrent mutated genes observed in CLL and widely associated with CLL pathogenesis. A total of 21 mutations were detected; TP53 (42.8%), ATM (28.5%), SF3B1 (28.5%), and BRAF (28.5%) were the most recurrently mutated genes. Of these mutations, 61.9% were detected in genes previously associated with a poor prognosis in CLL. Interestingly, five of the seven patients exhibited alterations in TP53 or ATM (deletion and/or mutation), genes involved in the DNA damage response (DDR), which could be related to a high genetic instability in this subgroup of patients. In conclusion, CLL patients with several chromosomal gains exhibit high genetic instability, with mutations in CLL driver genes and high-risk genetic alterations involving ATM and/or TP53 genes

A Low Frequency of Losses in 11q Chromosome Is Associated with Better Outcome and Lower Rate of Genomic Mutations in Patients with Chronic Lymphocytic Leukemia

[EN] To analyze the impact of the 11q deleted (11q-) cells in CLL patients on the time to first therapy (TFT) and overall survival (OS), 2,493 patients with CLL were studied. 242 patients (9.7%) had 11q-. Fluorescence in situ hybridization (FISH) studies showed a threshold of 40% of deleted cells to be optimal for showing that clinical differences in terms of TFT and OS within 11q-CLLs. In patients with >= 40% of losses in 11q (11q-H) (74%), the median TFT was 19 months compared with 44 months in CLL patients with <40% del(11q) (11q-L) (P<0.0001). In the multivariate analysis, only the presence of 11q-L, mutated IGHV status, early Binet stage and absence of extended lymphadenopathy were associated with longer TFT. Patients with 11q-H had an OS of 90 months, while in the 11q-L group the OS was not reached (P = 0.008). The absence of splenomegaly (P = 0.02), low LDH (P = 0.018) or beta 2M (P = 0.006), and the presence of 11q-L (P = 0.003) were associated with a longer OS. In addition, to detect the presence of mutations in the ATM, TP53, NOTCH1, SF3B1, MYD88, FBXW7, XPO1 and BIRC3 genes, a select cohort of CLL patients with losses in 11q was sequenced by next-generation sequencing of amplicons. Eighty % of CLLs with 11q-showed mutations and fewer patients with low frequencies of 11q-had mutations among genes examined (50% vs 94.1%, P = 0.023). In summary, CLL patients with <40% of 11q-had a long TFT and OS that could be associated with the presence of fewer mutated genes.European Commision (EC). Funding FP7/SP1/HEALTH. Project Code: 30624

Novel swirl flow-focusing microfluidic device for the production of monodisperse microbubbles

A novel swirl flow-focusing microfluidic axisymmetric device for the generation of monodisperse microbubbles at high production rates to be used as in-line contrast agents for medical applications is presented. The swirl effect is induced upstream of the discharge orifice by a circular array of microblades which form a given angle with the radial direction. The induced vortical component on the focusing liquid stabilizes the gas meniscus by the vorticity amplification due to vortex stretching as the liquid is forced through the discharge orifice. The stabilized meniscus tapers into a steady gas ligament that breaks into monodisperse microbubbles. A reduction up to 57% in the microbubble diameter is accomplished when compared to conventional axisymmetric flow-focusing microdevices. An exhaustive experimental study is performed for various blade angles and numerous gas to liquid flow rate ratios, validating previous VoF numerical simulations. The microbubbles issued from the stabilized menisci verify prior scaling law of flow-focusing

Resultados y alcances del proyecto de instalación de 32 plantas solares-fotovoltaicas en zonas marginadas del Estado de Zacatecas

Resumen— En este documento se presentan la revisión de los resultados y alcances que trajo consigo la instalación de 32 paquetes tecnológicos que proporcionan energía eléctrica en viviendas clasificadas como de muy alta marginación, luego de cumplir cinco años de su instalación. La investigación fue llevada a cabo principalmente mediante entrevistas y cuestionarios realizados a las familias beneficiadas. Los resultados arrojaron un cambio favorable a partir de un grupo de indicadores: sociales (avance educativo, acceso a los medios de telecomunicación y mejoras en la salud) económicos (mejora del ingreso o gasto de consumo), y medioambientales (una reducción considerable en el uso de leña, carbón y gasolina como su principal fuente de combustible), sin embargo, también se menciona el fracaso del proyecto, principalmente por la falta de seguimiento en los hogares. Finalmente, se establecen propuestas para futuros proyectos donde se busca garantizar la continuidad de éstos

Biological significance of monoallelic and biallelic BIRC3 loss in del(11q) chronic lymphocytic leukemia progression

© The Author(s) 2021.BIRC3 is monoallelically deleted in up to 80% of chronic lymphocytic leukemia (CLL) cases harboring del(11q). In addition, truncating mutations in the remaining allele of this gene can lead to BIRC3 biallelic inactivation, which has been shown to be a marker for reduced survival in CLL. Nevertheless, the biological mechanisms by which these lesions could contribute to del(11q) CLL pathogenesis and progression are partially unexplored. We implemented the CRISPR/Cas9-editing system to generate isogenic CLL cell lines harboring del(11q) and/or BIRC3 mutations, modeling monoallelic and biallelic BIRC3 loss. Our results reveal that monoallelic BIRC3 deletion in del(11q) cells promotes non-canonical NF-κB signaling activation via RelB-p52 nuclear translocation, being these effects allelic dose-dependent and therefore further enhanced in del(11q) cells with biallelic BIRC3 loss. Moreover, we demonstrate ex vivo in primary cells that del(11q) cases including BIRC3 within their deleted region show evidence of non-canonical NF-κB activation which correlates with high BCL2 levels and enhanced sensitivity to venetoclax. Furthermore, our results show that BIRC3 mutations in del(11q) cells promote clonal advantage in vitro and accelerate leukemic progression in an in vivo xenograft model. Altogether, this work highlights the biological bases underlying disease progression of del(11q) CLL patients harboring BIRC3 deletion and mutation.This work was supported by grants from the Spanish Fondo de Investigaciones Sanitarias PI15/01471, PI18/01500, Instituto de Salud Carlos III (ISCIII), European Regional Development Fund (ERDF) “Una manera de hacer Europa”, “Consejería de Educación, Junta de Castilla y León” (SA271P18), “Proyectos de Investigación del SACYL”, Spain GRS 2062/A/19, GRS 1847/A/18, GRS1653/A17,“Fundación Memoria Don Samuel Solórzano Barruso” (FS/23-2018), by grants (RD12/0036/0069) from Red Temática de Investigación Cooperativa en Cáncer (RTICC), Universidad de Salamanca (Programa XIII), Centro de Investigación Biomédica en Red de Cáncer (CIBERONC CB16/12/00233) and SYNtherapy “Synthetic Lethality for Personalized Therapy-based Stratification In Acute Leukemia” (ERAPERMED2018-275); ISCIII (AC18/00093), co-funded by ERDF/ESF, “Investing in your future”. M.Q.Á. and A.E.R.V. are supported with a research grant by FEHH (“Fundación Española de Hematología y Hemoterapia”); M.H.S. holds a Sara Borrell postdoctoral contract (CD19/00222) from the Instituto de Salud Carlos III (ISCIII). C.P.C. was supported by an “Ayuda predoctoral en Oncología” (AECC) and is a recipient of a PFIS grant (FI19/00191) from Instituto de Salud Carlos III; PFIS grant and Sara Borrell postdoctoral contrat are co-founded by Fondo Social Europeo (FSE) “El Fondo Social Europeo invierte en tu futuro”; J.L.O. and R.B.S. are supported by a grant from the University of Salamanca (“Contrato postdoctoral programa II”)

From Biomarkers to Models in the Changing Landscape of Chronic Lymphocytic Leukemia: Evolve or Become Extinct

hronic lymphocytic leukemia (CLL) is an extremely heterogeneous disease. With the advent of oral targeted agents (Tas) the treatment of CLL has undergone a revolution, which has been accompanied by an improvement in patient’s survival and quality of life. This paradigm shift also affects the value of prognostic and predictive biomarkers and prognostic models, most of them inherited from the chemoimmunotherapy era but with a different behavior with Tas. This review discusses: (i) the role of the most relevant prognostic and predictive biomarkers in the setting of Tas; and (ii) the validity of classic and new scoring systems in the context of Tas. In addition, a critical point of view about predictive biomarkers with special emphasis on 11q deletion, novel resistance mutations, TP53 abnormalities, IGHV mutational status, complex karyotype and NOTCH1 mutations is stated. We also go over prognostic models in early stage CLL such as IPS-E. Finally, we provide an overview of the applicability of the CLL-IPI for patients treated with Tas, as well as the emergence of new models, generated with data from patients treated with Tas

TRAF3 alterations are frequent in del-3′IGH chronic lymphocytic leukemia patients and define a specific subgroup with adverse clinical features

Interstitial 14q32 deletions involving IGH gene are infrequent events in chronic lymphocytic leukemia (CLL), affecting less than 5% of patients. To date, little is known about their clinical impact and molecular underpinnings, and its mutational landscape is currently unknown. In this work, a total of 871 CLLs were tested for the IGH break-apart probe, and 54 (6.2%) had a 300 kb deletion of 3′IGH (del-3′IGH CLLs), which contributed to a shorter time to first treatment (TFT). The mutational analysis by next-generation sequencing of 317 untreated CLLs (54 del-3′IGH and 263 as the control group) showed high mutational frequencies of NOTCH1 (30%), ATM (20%), genes involved in the RAS signaling pathway (BRAF, KRAS, NRAS, and MAP2K1) (15%), and TRAF3 (13%) within del-3′IGH CLLs. Notably, the incidence of TRAF3 mutations was significantly higher in del-3′IGH CLLs than in the control group (p < .001). Copy number analysis also revealed that TRAF3 loss was highly enriched in CLLs with 14q deletion (p < .001), indicating a complete biallelic inactivation of this gene through deletion and mutation. Interestingly, the presence of mutations in the aforementioned genes negatively refined the prognosis of del-3′IGH CLLs in terms of overall survival (NOTCH1, ATM, and RAS signaling pathway genes) and TFT (TRAF3). Furthermore, TRAF3 biallelic inactivation constituted an independent risk factor for TFT in the entire CLL cohort. Altogether, our work demonstrates the distinct genetic landscape of del-3′IGH CLL with multiple molecular pathways affected, characterized by a TRAF3 biallelic inactivation that contributes to a marked poor outcome in this subgroup of patients.Funding information: Universidad de Salamanca; Fundación Española de Hematología y Hemoterapia (FEHH); Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Grant/Award Number: CB16/12/00233; Red Temática de Investigación Cooperativa en Cáncer (RTICC); “Fundación Memoria Don Samuel Solórzano Barruso”: FS/33–2020, Grant/Award Number: RD12/0036/0069; “Gerencia Regional de Salud, SACYL”:, Grant/Award Numbers: GRS2385/A/21, GRS2140/A/20; Consejería de Educación, Junta de Castilla y León, Grant/Award Number: SA118P20; European Regional Development Fund and Instituto de Salud Carlos III, Grant/Award Numbers: CD19/00222, FI19/00191; Spanish Fondo de Investigaciones Sanitarias, Grant/Award Numbers: PI21/00983, PI18/0150

Dissecting the role of TP53 alterations in del(11q) chronic lymphocytic leukemia

© 2021 The Authors.[Background]: Several genetic alterations have been identified as driver events in chronic lymphocytic leukemia (CLL) pathogenesis and oncogenic evolution. Concurrent driver alterations usually coexist within the same tumoral clone, but how the cooperation of multiple genomic abnormalities contributes to disease progression remains poorly understood. Specifically, the biological and clinical consequences of concurrent high-risk alterations such as del(11q)/ATM-mutations and del(17p)/TP53-mutations have not been established.[Methods]: We integrated next-generation sequencing (NGS) and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 techniques to characterize the in vitro and in vivo effects of concurrent monoallelic or biallelic ATM and/or TP53 alterations in CLL prognosis, clonal evolution, and therapy response.[Results]: Targeted sequencing analysis of the co-occurrence of high-risk alterations in 271 CLLs revealed that biallelic inactivation of both ATM and TP53 was mutually exclusive, whereas monoallelic del(11q) and TP53 alterations significantly co-occurred in a subset of CLL patients with a highly adverse clinical outcome. We determined the biological effects of combined del(11q), ATM and/or TP53 mutations in CRISPR/Cas9-edited CLL cell lines. Our results showed that the combination of monoallelic del(11q) and TP53 mutations in CLL cells led to a clonal advantage in vitro and in in vivo clonal competition experiments, whereas CLL cells harboring biallelic ATM and TP53 loss failed to compete in in vivo xenotransplants. Furthermore, we demonstrated that CLL cell lines harboring del(11q) and TP53 mutations show only partial responses to B cell receptor signaling inhibitors, but may potentially benefit from ATR inhibition.[Conclusions]: Our work highlights that combined monoallelic del(11q) and TP53 alterations coordinately contribute to clonal advantage and shorter overall survival in CLL.Spanish Fondo de Investigaciones Sanitarias, Grant/Award Numbers: PI15/01471, PI18/01500); Fundación Memoria Don Samuel Solórzano Barruso, Grant/Award Number: RD12/0036/006