Influence of detection of pretreatment cytogenetic abnormalities on first complete remission and survival in adult acute lymphoblastic leukemia

Objective: Treatment of acute lymphoblastic leukemia (ALL) in adults focuses on the initial assessment of the prognostic relevant cytogenetic features as well as a response-guided therapy based on molecular data. We examined the importance of molecular-cytogenetic abnormalities for complete remission (CR) rates and the overall survival (OS) in adult ALLs.Materials and Methods: Conventional cytogenetics and fluorescence in situ hybridization were performed on bone marrow cells from 33 newly-diagnosed ALL adults. Two karyotype categories [standard- risk group- normal karyotype, hyperdiplody and other structural aberrations, and high-risk group-t(11q23)/MLL, t(9;22)/bcr-abl, t(1;19), t(8;14), C-MYC and complex karyotype] and the biologically and clinically relevant ALL ploidy subgroups were prospectively defined.Results: Chromosomal abnormalities were found in 52% of the cases with a high rate of poor-risk translocations - t(9;22), t(8q24), t(11q23), t(1;19). The total CR rate was 67% and the median time for achievement 2.33 months. Male sex, an age below 35 years and the absence of high risk translocations might have contributed to the high CR rates. Female patients, hyperdiplody, low white blood cells (WBC), and random cytogenetic aberrations had the longest OS. OS, 3- and 5-years survival periods were significantly shorter for poor-risk than standard risk group (p=.015, p=.001 and p=.005, respectively).Conclusion: This study emphasizes the lack of influence of cytogenetic aberrations on the CR and the time to achieve CR. However, our observations show that these aberrations are an independent prognostic factor in adult ALL - they allow predicting therapy resistance and the OS time after intensetreatment

Splenectomy through the laparoscopic approach and how I do it

Scopul lucrării. Studierea cazurilor de splenectomie prin abord laparoscopic și clasic în vederea stabilirii cauzalității tip procedurăincidente perioperatorii și demonstrării superiorității abordului laparoscopic. Materiale și metode. Au fost selectate cazurile de splenectomie efectuate prin abord clasic și laparoscopic în Clinica de Chirurgie Colțea, perioada 01.01.2019-31.12.2022. Am revăzut filmările intraoperatorii, am evaluat factorii generali și locali asociați abordului chirurgical preferat. Rezultate. Au fost selectate 29 de cazuri, vârsta medie 54.8 ani, 72.4% femei, 27.6% barbati, 55.2% (16) cu multiple comorbidități: antecedente chirurgicale majore, insuficiența cardiacă, asmul bronșic sever etc. Cazurile au fost împărțite în 2 grupe: Gr. I- cu abord laparoscopic 34.5% (10), Gr. II- cu abord clasic 65.5% (19). Incidența comorbidităților a fost de 10% (1) în Gr.I, cu dimensiunea medie a splinei de 13.2 cm (min 8.5 cm, max 21 cm) și 84.2 % (16) în Gr.II cu dimensiunea medie a splinei de 20.4 cm (min 10 cm, max 34 cm). Doar în Gr.II au fost înregistrate sângerări intraoperatorii în 78.9% (15), iar in 15.8% (3) au fost complicații postoperatorii. Pacienții din Gr.I au avut o perioadă de spitalizare postoperatorie medie de 4 zile, iar cei din Gr. II de 7 zile și au fost externați cu o evoluție postoperatorie favorabilă. Concluzie. Abordul laparoscopic are aceleași indicații ca abordul clasic conform EAES, cu avantajul complicațiilor perioperatorii mult reduse și o spitalizare postoperatorie mai mică comparativ cu abordul clasic, iar în cazul echipelor experimentate este posibil abordul laparoscopic inclusiv la pacienții cu splenomegalii masive (>20cm), care poate fi asistat manual.Aim of study. Study of cases of splenectomy by laparoscopic and classic approach in order to establish causality type procedureperioperative incidents and demonstrate the superiority of the laparoscopic approach. Materials and methods. The cases of splenectomy performed by classical and laparoscopic approach in the Colțea Surgery Clinic, period 01.01.2019-31.12.2022, were selected. We reviewed intraoperative films, assessed general and local factors associated with the preferred surgical approach. Results. 29 cases were selected, average age 54.8 years, 72.4% women, 27.6% men, 55.2% (16) with multiple comorbidities: major surgical antecedents, heart failure, severe bronchial asthma, etc. The cases were divided into 2 groups: Gr. I- with laparoscopic approach 34.5% (10), Gr. II- with classic approach 65.5% (19). The incidence of comorbidities was 10% (1) in Gr.I, with mean spleen size of 13.2 cm (min 8.5 cm, max 21 cm) and 84.2% (16) in Gr.II with mean spleen size of 20.4 cm (min 10 cm, max 34 cm). Only in Gr.II, intraoperative bleeding was recorded in 78.9% (15), and in 15.8% (3) there were postoperative complications. The patients in Gr. I had an average postoperative hospitalization period of 4 days, and those in Gr. II of 7 days, and were discharged with a favorable postoperative evolution. Conclusions. The laparoscopic approach has the same indications as the classic one according to EAES, with the advantage of reduced perioperative complications and a shorter postoperative hospitalization, and in the case of experienced teams, the laparoscopic approach is possible, including patients with massive splenomegaly (>20cm), being manually assisted

Students' understanding of the concepts involved in one-sample hypothesis testing

Hypothesis testing is a prevalent method of inference used to test a claim about a population parameter based on sample data, and it is a central concept in many introductory statistics courses. At the same time, the use of hypothesis testing to interpret experimental data has raised concerns due to common misunderstandings by both scientists and students. With statistics education reform on the rise, as well as an increasing number of students enrolling in introductory statistics courses each year, there is a need for research to investigate students' understanding of hypothesis testing. In this study we used APOS Theory to investigate twelve introductory statistics students' reasoning about one-sample population hypothesis testing while working two real-world problems. Data were analyzed and compared against a preliminary genetic decomposition, which is a conjecture for how an individual might construct an understanding of a concept. This report presents examples of Actions, Processes, and Objects in the context of one-sample hypothesis testing as exhibited through students' reasoning. Our results suggest that the concepts involved in hypothesis testing are related through the construction of higher-order, coordinated Processes operating on Objects. As a result of our data analysis, we propose re�finements to our genetic decomposition and o�ffer suggestions for instruction of one-sample population hypothesis testing. We conclude with appendices containing a comprehensive revised genetic decomposition along with a set of guided questions that are designed to help students make the constructions called for by the genetic decomposition.</p

Maternal complications following open and fetoscopic fetal surgery: A systematic review and meta-analysis

OBJECTIVE: To establish maternal complication rates for fetoscopic or open fetal surgery. METHODS: We conducted a systematic literature review for studies of fetoscopic or open fetal surgery performed since 1990, recording maternal complications during fetal surgery, the remainder of pregnancy, delivery and after the index pregnancy. RESULTS: One hundred and sixty-six studies were included, reporting outcomes for open fetal (n=1193 patients) and fetoscopic surgery (n=9403 patients). No maternal deaths were reported. The risk of any maternal complication in the index pregnancy was 20.9% (95%CI 15.22-27.13) for open fetal and 6.2% (95%CI 4.93-7.49) for fetoscopic surgery. For severe maternal complications (Grade III to V Clavien-Dindo classification of surgical complications) the risk was 4.5% (95%CI 3.24-5.98) for open fetal and 1.7% (95%CI 1.19-2.20) for fetoscopic surgery. In subsequent pregnancies, open fetal surgery increased the risk of preterm birth but not uterine dehiscence or rupture. Nearly one quarter of reviewed studies (n=175, 23.3%) were excluded for failing to report the presence or absence of maternal complications. CONCLUSIONS: Maternal complications occur in 6.2% fetoscopic and 20.9% open fetal surgeries, with serious maternal complications in 1.7% fetoscopic and 4.5% open procedures. Reporting of maternal complications is variable. To properly quantify maternal risks, outcomes should be reported consistently across all fetal surgery studies

Genome-Wide Association Meta-Analysis of Single-Nucleotide Polymorphisms and Symptomatic Venous Thromboembolism during Therapy for Acute Lymphoblastic Leukemia and Lymphoma in Caucasian Children

Symptomatic venous thromboembolism (VTE) occurs in five percent of children treated for acute lymphoblastic leukemia (ALL), but whether a genetic predisposition exists across different ALL treatment regimens has not been well studied. Methods: We undertook a genome-wide association study (GWAS) meta-analysis for VTE in consecutively treated children in the Nordic/Baltic acute lymphoblastic leukemia 2008 (ALL2008) cohort and the Australian Evaluation of Risk of ALL Treatment-Related Side-Effects (ERASE) cohort. A total of 92 cases and 1481 controls of European ancestry were included. Results: No SNPs reached genome-wide significance (p <5 x 10(-8)) in either cohort. Among the top 34 single-nucleotide polymorphisms (SNPs) (p <1 x 10(-6)), two loci had concordant effects in both cohorts: ALOX15B (rs1804772) (MAF: 1%; p = 3.95 x 10(-7)) that influences arachidonic acid metabolism and thus platelet aggregation, and KALRN (rs570684) (MAF: 1%; p = 4.34 x 10(-7)) that has been previously associated with risk of ischemic stroke, atherosclerosis, and early-onset coronary artery disease. Conclusion: This represents the largest GWAS meta-analysis conducted to date associating SNPs to VTE in children and adolescents treated on childhood ALL protocols. Validation of these findings is needed and may then lead to patient stratification for VTE preventive interventions. As VTE hemostasis involves multiple pathways, a more powerful GWAS is needed to detect combination of variants associated with VTE.Peer reviewe

Nanoscale control of Ag nanostructures for plasmonic fluorescence enhancement of near-infrared dyes

Potential utilization of proteins for early detection and diagnosis of various diseases has drawn considerable interest in the development of protein-based detection techniques. Metal induced fluorescence enhancement offers the possibility of increasing the sensitivity of protein detection in clinical applications. We report the use of tunable plasmonic silver nanostructures for the fluorescence enhancement of a near-infrared (NIR) dye (Alexa Fluor 790). Extensive fluorescence enhancement of ∼2 orders of magnitude is obtained by the nanoscale control of the Ag nanostructure dimensions and interparticle distance. These Ag nanostructures also enhanced fluorescence from a dye with very high quantum yield (7.8 fold for Alexa Fluor 488, quantum efficiency (Qy) = 0.92). A combination of greatly enhanced excitation and an increased radiative decay rate, leading to an associated enhancement of the quantum efficiency leads to the large enhancement. These results show the potential of Ag nanostructures as metal induced fluorescence enhancement (MIFE) substrates for dyes in the NIR “biological window” as well as the visible region. Ag nanostructured arrays fabricated by colloidal lithography thus show great potential for NIR dye-based biosensing applications

Methotrexate-related central neurotoxicity: clinical characteristics, risk factors and genome-wide association study in children treated for acute lymphoblastic leukemia

Symptomatic methotrexate-related central neurotoxicity (MTX neurotoxicity) is a severe toxicity experienced during acute lymphoblastic leukemia (ALL) therapy with potential long-term neurologic complications. Risk factors and long-term outcomes require further study. We conducted a systematic, retrospective review of 1,251 consecutive Australian children enrolled on Berlin-Frankfurt-Münster or Children's Oncology Group-based protocols between 1998-2013. Clinical risk predictors for MTX neurotoxicity were analyzed using regression. A genome-wide association study (GWAS) was performed on 48 cases and 537 controls. The incidence of MTX neurotoxicity was 7.6% (n=95 of 1,251), at a median of 4 months from ALL diagnosis and 8 days after intravenous or intrathecal MTX. Grade 3 elevation of serum aspartate aminotransferase (P=0.005, odds ratio 2.31 [range, 1.28–4.16]) in induction/consolidation was associated with MTX neurotoxicity, after accounting for the only established risk factor, age ≥10 years. Cumulative incidence of CNS relapse was increased in children where intrathecal MTX was omitted following symptomatic MTX neurotoxicity (n=48) compared to where intrathecal MTX was continued throughout therapy (n=1,174) (P=0.047). Five-year central nervous system relapse-free survival was 89.2 4.6% when intrathecal MTX was ceased compared to 95.4 0.6% when intrathecal MTX was continued. Recurrence of MTX neurotoxicity was low (12.9%) for patients whose intrathecal MTX was continued after their first episode. The GWAS identified single-nucletide polymorphism associated with MTX neurotoxicity near genes regulating neuronal growth, neuronal differentiation and cytoskeletal organization (P<1x10-6). In conclusion, increased serum aspartate aminotransferase and age ≥10 years at diagnosis were independent risk factors for MTX neurotoxicity. Our data do not support cessation of intrathecal MTX after a first MTX neurotoxicity event

Fine-mapping reveals novel alternative splicing of the dopamine transporter

Center for Human Genetic Research, Massachusetts General Hospital and Department of Neurology, Harvard Medical School, Harvard University, Boston, Massachusetts.Graduate Program in Biology and Biomedical Science, Yale University, New Haven, Connecticut.The dopamine transporter gene (, ) has been implicated in the pathogenesis of numerous psychiatric and neurodevelopmental disorders, including schizophrenia (SZ). We previously detected association between SZ and intronic variants that replicated in two independent Caucasian samples, but had no obvious function. In follow-up analyses, we sequenced the coding and intronic regions of to identify complete linkage disequilibrium patterns of common variations. We genotyped 78 polymorphisms, narrowing the potentially causal region to two correlated clusters of associated SNPs localized predominantly to introns 3 and 4. Our computational analysis of these intronic regions predicted a novel cassette exon within intron 3, designated E3b, which is conserved among primates. We confirmed alternative splicing of E3b in post-mortem human substantia nigra (SN). As E3b introduces multiple in-frame stop codons, the open reading frame is truncated and the spliced product may undergo nonsense mediated decay. Thus, factors that increase E3b splicing could reduce the amount of unspliced product available for translation. Observations consistent with this prediction were made using cellular assays and in post-mortem human SN. In mini-gene constructs, the extent of splicing is also influenced by at least two common haplotypes, so the alternative splicing was evaluated in relation to SZ risk. Meta-analyses across genome-wide association studies did not support the initial associations and further post-mortem studies did not suggest case-control differences in splicing. These studies do not provide a compelling link to schizophrenia. However, the impact of the alternative splicing on other neuropsychiatric disorders should be investigated. © 2010 Wiley-Liss, Inc

Age at first birth in women is genetically associated with increased risk of schizophrenia

Prof. Paunio on PGC:n jäsenPrevious studies have shown an increased risk for mental health problems in children born to both younger and older parents compared to children of average-aged parents. We previously used a novel design to reveal a latent mechanism of genetic association between schizophrenia and age at first birth in women (AFB). Here, we use independent data from the UK Biobank (N = 38,892) to replicate the finding of an association between predicted genetic risk of schizophrenia and AFB in women, and to estimate the genetic correlation between schizophrenia and AFB in women stratified into younger and older groups. We find evidence for an association between predicted genetic risk of schizophrenia and AFB in women (P-value = 1.12E-05), and we show genetic heterogeneity between younger and older AFB groups (P-value = 3.45E-03). The genetic correlation between schizophrenia and AFB in the younger AFB group is -0.16 (SE = 0.04) while that between schizophrenia and AFB in the older AFB group is 0.14 (SE = 0.08). Our results suggest that early, and perhaps also late, age at first birth in women is associated with increased genetic risk for schizophrenia in the UK Biobank sample. These findings contribute new insights into factors contributing to the complex bio-social risk architecture underpinning the association between parental age and offspring mental health.Peer reviewe

Gene expression imputation across multiple brain regions provides insights into schizophrenia risk

Transcriptomic imputation approaches combine eQTL reference panels with large-scale genotype data in order to test associations between disease and gene expression. These genic associations could elucidate signals in complex genome-wide association study (GWAS) loci and may disentangle the role of different tissues in disease development. We used the largest eQTL reference panel for the dorso-lateral prefrontal cortex (DLPFC) to create a set of gene expression predictors and demonstrate their utility. We applied DLPFC and 12 GTEx-brain predictors to 40,299 schizophrenia cases and 65,264 matched controls for a large transcriptomic imputation study of schizophrenia. We identified 413 genic associations across 13 brain regions. Stepwise conditioning identified 67 non-MHC genes, of which 14 did not fall within previous GWAS loci. We identified 36 significantly enriched pathways, including hexosaminidase-A deficiency, and multiple porphyric disorder pathways. We investigated developmental expression patterns among the 67 non-MHC genes and identified specific groups of pre- and postnatal expression