Genomic amplification of BCR/ABL1 and a region downstream of ABL1 in chronic myeloid leukaemia: a FISH mapping study of CML patients and cell lines

Chronic myeloid leukaemia (CML) is characterized by the expression of the BCR/ABL1 fusion gene, a constitutively activated tyrosine kinase that commonly results from the formation of the Philadelphia (Ph) chromosome after a t(9;22)(q34;q11) or variant rearrangement. The duplication of the Ph chromosome is a recurring abnormality acquired during disease progression, whereas intrachromosomal amplification of BCR/ABL1 is a rare phenomenon and has been associated with imatinib therapy resistance. Archival bone marrow chromosome suspensions from 19 CML patients known to carry more than 1 copy of BCR/ABL1 and 10 CML cell lines were analyzed by fluorescent in situ hybridization with a panel of probes from 9q34.1-qter to investigate whether they carried two identical copies of the Ph chromosome or, instead, one or both Ph contained cryptic imbalances of some regions

Estudio descriptivo y comparativo entre padres y madres que participan en un programa de prevención sobre consumo de drogas y conductas de riesgo

Objetivos: describir y analizar las competencias o habilidades parentales que tienen los padres y las madres que acuden a un programa de prevención sobre el consumo de drogas y otras conductas de riesgo, comprobar si existen diferencias entre los padres y las madres en referencia al rol parental y, por último, conocer si existen diferencias entre el rol parental y el nivel de escolarización de los hijos. Método: la muestra estuvo formada de 89 participantes (22 padres y 67 madres). El instrumento para la recogida de los datos fue un cuestionario formado por 54 ítems con respuesta tipo Likert dividido en tres escalas para medir aspectos conductuales, actitudinales y sobre recursos que pueden necesitar los padres y madres para prevenir las conductas de riesgo. Resultados: los resultados hallados muestran que los padres y madres adoptan conductas favorecedoras para prevenir conductas de riesgo, tienen creencias que relacionan las conductas de riesgo con sentimientos de malestar y difi cultades de comunicación en la familia y manifi estan la necesidad de tener herramientas para aumentar sus habilidades parentales. Se ha encontrado diferencias signifi cativas entre los padres y las madres cuando se trata de ejercer sus capacidades parentales. Por último, se ha hallado una interacción signifi cativa entre el rol parental y el nivel de escolarización de los hijos. Sin duda, estos resultados tienen implicaciones educativas y formativas con el desarrollo de programas de prevención e intervención centrados en las competencias educativas parentales.Aims: The aim of this study is to describe and analyze the parenting skills of fathers and mothers attending a prevention program on drug use and other risk behaviours, to fi nd out whether there are diff erences between mothers and fathers in relation to the parental role and fi nally, to determine whether there are diff erences between the parental role and the children's level of education. Method: The sample consisted of 89 participants (22 fathers and 67 mothers). The instrument for data collection was a questionnaire of 54 Likert scale items divided into three scales to measure behaviours, attitudes and resources that parents may require to prevent risk behaviours. Results: The results show that fathers and mothers act in such a way as to promote prevention of risk behaviours, hold beliefs that associate risk behaviours with feelings of distress and communication diffi culties in the family and display the need for tools to increase their parenting skills. There are signifi cant diff erences between mothers and fathers when it comes to exercising their parental skills. Finally, a signifi cant interaction has been found between the parental role and the children's level of education. These fi ndings undoubtedly have educational and training implications on the development of prevention and intervention programs that focus on parental educational qualifi cations

Randomized phase II trial of FOLFIRI-panitumumab compared with FOLFIRI alone in patients with RAS wild-type circulating tumor DNA metastatic colorectal cancer beyond progression to first-line FOLFOX-panitumumab: the BEYOND study (GEMCAD 17-01)

Colorectal cancer; Metastatic disease; Liquid biopsyCáncer colorrectal; Enfermedad metastásica; Biopsia líquidaCàncer colorectal; Malaltia metastàtica; Biòpsia líquidaPurpose Panitumumab plus FOLFOX (P-FOLFOX) is standard first-line treatment for RAS wild-type (WT) metastatic colorectal cancer. The value of panitumumab rechallenge is currently unknown. We assessed addition of panitumumab to FOLFIRI (P-FOLFIRI) beyond progression to P-FOLFOX in patients with no RAS mutations in liquid biopsy (LB). Methods In this randomized phase II trial, patients were assigned (3:2 ratio) to second-line P-FOLFIRI (arm A) or FOLFIRI alone (arm B). LB for circulating tumor DNA analysis was collected at study entry and at disease progression. Primary endpoint was 6-month progression-free survival. Two-stage Simon design required 85 patients to be included (EudraCT 2017-004519-38). Results Between February 2019 and November 2020, 49 patients were screened (16 RAS mutations in LB detected) and 31 included (18 assigned to arm A and 13 to arm B). The study was prematurely closed due to inadequate recruitment. Serious adverse events were more frequent in arm A (44% vs. 23%). Overall response rate was 33% (arm A) vs. 7.7% (arm B). Six-month progression-free survival rate was 66.7% (arm A) and 38.5% (arm B). Median progression-free survival was 11.0 months (arm A) and 4.0 months (arm B) (hazard ratio, 0.58). At disease progression, RAS or BRAF mutations in LB were found in 4/11 patients (36%) in arm A and 2/10 (20%) in arm B. Conclusions The BEYOND study suggests a meaningful benefit of P-FOLFIRI beyond progression to P-FOLFOX in metastatic colorectal cancer patients with WT RAS status selected by LB. This strategy deserves further investigation.This work was supported by AMGEN S.A

Selective derivatization of N-terminal cysteines using cyclopentenediones

The outcome of the Michael-type reaction between thiols and 2,2-disubstituted cyclopentenediones varies depending on the thiol. Stable compounds with two fused rings were formed upon reaction with 1,2-aminothiols (such as N-terminal cysteines in peptides). Other thiols gave reversibly Michael-type adducts that were in equilibrium with the starting materials. This differential reactivity allows differently placed cysteines to be distinguished and has been exploited to prepare bioconjugates incorporating two or three different moieties

Ultrafast spectroscopy on water-processable PCBM: rod-coil block copolymer nanoparticles.

Using ultrafast spectroscopy, we investigate the photophysics of water-processable nanoparticles composed of a block copolymer electron donor and a fullerene derivative electron acceptor

ABCB1 Genetic Variants as Predictors of Irinotecan-Induced Severe Gastrointestinal Toxicity in Metastatic Colorectal Cancer Patients

Irinotecan is widely used in the treatment of metastatic colorectal cancer (mCRC) despite its severe toxicities. Toxicity is often associated with the UGT1A1*28/*28 genotype. An explanation for idiopathic toxicity beyond the UGT1A1 biomarker, however, remains a major concern for clinicians. One of the main irinotecan transporters is P-glycoprotein (P-gp), which is a hepatic efflux pump encoded by ABCB1. P-gp is involved in the biliary excretion of irinotecan and its active metabolite SN-38. We aimed to assess whether functional variants in ABCB1 also contribute to identifying patients at risk of toxicity. A cohort of 308 mCRC patients treated with irinotecan-based regimens were genotyped for polymorphisms in ABCB1 (rs1128503, rs2032582, and rs1045642). The effect of these variants and their haplotypes on irinotecan-induced severe toxicity (diarrhea, neutropenia, asthenia, nausea, and mucositis) was assessed. After adjusting for the relevant clinical and pathological parameters in the multivariate analysis, we found rs1128503 was significantly associated with severe diarrhea and mucositis (P=0.014 and P=0.002, respectively). Additionally, rs2032582 was associated with severe mucositis (P<0.001). Our results show that rs1128503 genotyping could help to predict severe gastrointestinal toxicity induced by irinotecan

Deletions of Immunoglobulin heavy chain and T cell receptor gene regions are uniquely associated with lymphoid blast transformation of chronic myeloid leukemia

<p>Abstract</p> <p>Background</p> <p>Chronic myelogenous leukemia (CML) results from the neoplastic transformation of a haematopoietic stem cell. The hallmark genetic abnormality of CML is a chimeric <it>BCR/ABL1 </it>fusion gene resulting from the Philadelphia chromosome rearrangement t(9;22)(q34;q11). Clinical and laboratory studies indicate that the <it>BCR/ABL1 </it>fusion protein is essential for initiation, maintenance and progression of CML, yet the event(s) driving the transformation from chronic phase to blast phase are poorly understood.</p> <p>Results</p> <p>Here we report multiple genome aberrations in a collection of 78 CML and 14 control samples by oligonucleotide array comparative genomic hybridization. We found a unique signature of genome deletions within the immunoglobulin heavy chain (<it>IGH</it>) and T cell receptor regions (<it>TCR</it>), frequently accompanied by concomitant loss of sequences within the short arm regions of chromosomes 7 and 9, including <it>IKZF1</it>, <it>HOXA7</it>, <it>CDKN2A/2B</it>, <it>MLLT3</it>, <it>IFNA/B</it>, <it>RNF38</it>, <it>PAX5</it>, <it>JMJD2C </it>and <it>PDCD1LG2 </it>genes.</p> <p>Conclusions</p> <p>None of these genome losses were detected in any of the CML samples with myeloid transformation, chronic phase or controls, indicating that their presence is obligatory for the development of a malignant clone with a lymphoid phenotype. Notably, the coincidental deletions at <it>IGH </it>and <it>TCR </it>regions appear to precede the loss of <it>IKZF1 </it>and/or <it>p16 </it>genes in CML indicating a possible involvement of RAG in these deletions.</p

Apo AIV and citrulline plasma concentrations in Short Bowel Syndrome patients: the influence of Short Bowel Anatomy

Introduction Parenteral nutrition (PN) dependence in short bowel syndrome (SBS) patients is linked to the functionality of the remnant small bowel (RSB). Patients may wean off PN following a period of intestinal adaptation that restores this functionality. Currently, plasma citrulline is the standard biomarker for monitoring intestinal functionality and adaptation. However, available studies reveal that the relationship the biomarker with the length and function of the RSB is arguable. Thus, having additional biomarkers would improve pointing out PN weaning. Aim By measuring concomitant changes in citrulline and the novel biomarker apolipoprotein AIV (Apo AIV), as well as taking into account the anatomy of the RSB, this exploratory study aims to a better understanding of the intestinal adaptation process and characterization of the SBS patients under PN. Methods Thirty four adult SBS patients were selected and assigned to adapted (aSBS) and non-adapted (nSBS) groups after reconstructive surgeries. Remaining jejunum and ileum lengths were recorded. The aSBS patients were either on an oral diet (ORAL group), those with intestinal insufficiency, or on oral and home parenteral nutrition (HPN group), those with chronic intestinal failure. Apo AIV and citrulline were analyzed in plasma samples after overnight fasting. An exploratory ROC analysis using citrulline as gold standard was performed. Results Biomarkers, Apo AIV and citrulline showed a significant correlation with RSBL in aSBS patients. In jejuno-ileocolic patients, only Apo AIV correlated with RSBL (rb = 0.54) and with ileum length (rb = 0.84). In patients without ileum neither biomarker showed any correlation with RSBL. ROC analysis indicated the Apo AIV cut-off value to be 4.6 mg /100 mL for differentiating between the aSBS HPN and ORAL groups. Conclusions Therefore, in addition to citrulline, Apo AIV can be set as a biomarker to monitor intestinal adaptation in SBS patients. As short bowel anatomy is shown to influence citrulline and Apo AIV plasma values, both biomarkers complement each other furnishing a new insight to manage PN dependence

Pharmacogenetic clinical randomised phase II trial to evaluate the efficacy and safety of FOLFIRI with high-dose irinotecan (HD-FOLFIRI) in metastatic colorectal cancer patients according to their UGT1A 1 genotype

Patients harbouring the UGT1A1 *28/*28 genotype are at risk of severe toxicity with the standard irinotecan dose. However, this dose is considerably lower than the dose that can be tolerated by UGT1A1 *1/*1 and *1/*28 patients. This randomised phase II trial evaluated the efficacy and safety of the FOLFIRI regimen with high-dose irinotecan (HD-FOLFIRI) in metastatic colorectal cancer patients. Eighty-two patients with the UGT1A1 *1/*1 or the *1/*28 genotype were randomised to receive HD-FOLFIRI versus FOLFIRI. Patients with the UGT1A1 *28/*28 genotype were excluded. In the experimental group, the irinotecan dose was 300 mg/m 2 for UGT1A1 *1/*1 and 260 mg/m 2 for *1/*28 patients. In the control group, the dose was 180 mg/m 2. We analysed the overall response rate (ORR), toxicity, and survival. The ORR was significantly higher in the HD-FOLFIRI group (67.5 versus 43.6%; p = 0.001 OR: 1.73 [95% CI:1.03-2.93]). Neutropenia (17.7%), diarrhoea (5.1%), and asthenia (5.1%) were the most common grade 3-4 toxicity. No differences were observed in severe toxicity (22.5% versus 20.5%), dose reduction (22.5% versus 28.2%), or prophylactic G-CSF (17.5% versus 12.8%). No difference in survival was found. Patients with the UGT1A1 *1/*1 and *1/*28 genotypes can receive high doses of irinotecan to achieve a more favourable ORR without significant adverse events