Prenatal diagnosis of fetuses with absent/hypoplastic nasal bone in second-trimester using chromosomal microarray analysis.

BACKGROUND: Pathogenic copy number variants (pCNVs) are associated with fetal ultrasound anomalies, which can be efficiently identified through chromosomal microarray analysis (CMA). The primary objective of the present study was to enhance understanding of the genotype-phenotype correlation in fetuses exhibiting absent or hypoplastic nasal bones using CMA. METHODS: Enrolled in the present study were 94 cases of fetuses with absent/hypoplastic nasal bone, which were divided into an isolated absent/hypoplastic nasal bone group (n = 49) and a non-isolated group (n = 45). All pregnant women enrolled in the study underwent karyotype analysis and CMA to assess chromosomal abnormalities in the fetuses. RESULTS: Karyotype analysis and CMA detection were successfully performed in all cases. The results of karyotype and CMA indicate the presence of 11 cases of chromosome aneuploidy, with trisomy 21 being the most prevalent among them. A small supernumerary marker chromosome (sSMC) detected by karyotype analysis was further interpreted as a pCNV by CMA. Additionally, CMA detection elicited three cases of pCNVs, despite normal findings in their karyotype analysis results. Among them, one case of Roche translocation was identified to be a UPD in chromosome 15 with a low proportion of trisomy 15. Further, a significant difference in the detection rate of pCNVs was observed between non-isolated and isolated absent/hypoplastic nasal bone (24.44% vs. 8.16%, p < .05). CONCLUSION: The present study enhances the utility of CMA in diagnosing the etiology of absent or hypoplastic nasal bone in fetuses. Further, isolated cases of absent or hypoplastic nasal bone strongly suggest the presence of chromosomal abnormalities, necessitating genetic evaluation through CMA.

Chromosomal damage, gene expression and alternative transcription in human lymphocytes exposed to mixed ionizing radiation as encountered in space.

Astronauts travelling in space will be exposed to mixed beams of particle radiation and photons. Exposure limits that correspond to defined cancer risk are calculated by multiplying absorbed doses by a radiation-type specific quality factor that reflects the biological effectiveness of the particle without considering possible interaction with photons. We have shown previously that alpha radiation and X-rays may interact resulting in synergistic DNA damage responses in human peripheral blood lymphocytes but the level of intra-individual variability was high. In order to assess the variability and validate the synergism, blood from two male donors was drawn at 9 time points during 3 seasons of the year and exposed to 0-2 Gy of X-rays, alpha particles or 1:1 mixture of both (half the dose each). DNA damage response was quantified by chromosomal aberrations and by mRNA levels of 3 radiation-responsive genes FDXR, CDKN1A and MDM2 measured 24 h post exposure. The quality of response in terms of differential expression of alternative transcripts was assessed by using two primer pairs per gene. A consistently higher than expected effect of mixed beams was found in both donors for chromosomal aberrations and gene expression with some seasonal variability for the latter. No synergy was detected for alternative transcription.

Chromosome analysis of 303 pregnancy losses in Mexico.

BACKGROUND: Chromosomal abnormalities are present in 50 to 60% of miscarriages and in 6 to 19% of stillbirths. Although microarrays are preferred for studying chromosomal abnormalities, many hospitals cannot offer this methodology. OBJECTIVE: To present the results of the cytogenetic analysis of 303 products of conception (POC), which included 184 miscarriages, 49 stillbirths and 17 cases of undefined age. MATERIAL AND METHODS: Karyotyping, fluorescence in situ hybridization, short tandem repeats and microarrays were used, depending on the type of loss and available sample. RESULTS: In 29 POCs we found maternal tissue and were eliminated from the analyses. Informative results were obtained in 250 (91.2 %)/274 cases; the karyotyping success rate was 80.7%; that of single nucleotide polymorphism microarrays, 94.5%; and that of fluorescence in situ hybridization and short tandem repeat, 100%. Cytogenetic abnormalities were observed in 57.6% of miscarriages and in 24.5% of stillbirths; 94% of total anomalies were numerical and 6% were submicroscopic. CONCLUSIONS: Karyotyping with simultaneous short tandem repeat study to rule out contamination of maternal cells is effective for studying miscarriages; in stillbirths, microarrays are recommended.

ANTECEDENTES: Las alteraciones cromosómicas están presentes en 50 a 60 % de los abortos espontáneos y en 6 a 19 % de los mortinatos. Aunque se prefieren los microarreglos para estudiarlos, numerosos hospitales no pueden ofrecerlos. OBJETIVO: Presentar los resultados del estudio citogenético de 303 productos de la concepción (POC), 184 se obtuvieron de abortos espontáneos, 49 fueron mortinatos y en 17 no se identificó la de edad gestacional. MATERIAL Y MÉTODOS: Se empleó cariotipo, hibridación in situ con fluorescencia, secuencias cortas repetidas en tándem y microarreglos, según el tipo de pérdida y la muestra disponible. RESULTADOS: En 29 POC se encontró tejido materno, por lo que fueron eliminados de los análisis. En 250 (91.2 %)/274 casos se obtuvieron resultados informativos; la tasa de éxito del cariotipo fue de 80.7 %; la de los microarreglos de SNP, de 94.5 %; y la de la hibridación fluorescente in situ y la repetición corta en tándem, de 100 %. Se observaron anomalías citogenéticas en 57.6 % de los abortos espontáneos y en 24.5 % de los mortinatos; 94 % de las anomalías fueron numéricas y 6 %, submicroscópicas. CONCLUSIONES: El cariotipo en conjunto con el estudio de secuencias cortas repetidas en tándem para descartar contaminación de células maternas es efectivo para estudiar abortos espontáneos; los microarreglos se recomiendan en los mortinatos.

Determinants of mosaic chromosomal alteration fitness.

Clonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in a hematopoietic stem cell that results in a clonal expansion. These driver mutations can be single nucleotide variants in cancer driver genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors that influence the variations in mCA fitness and ultimately result in different clonal expansion rates are not well understood. We used the Passenger-Approximated Clonal Expansion Rate (PACER) method to estimate clonal expansion rate as PACER scores for 6,381 individuals in the NHLBI TOPMed cohort with gain, loss, and copy-neutral loss of heterozygosity mCAs. Our mCA fitness estimates, derived by aggregating per-individual PACER scores, were correlated (R2 = 0.49) with an alternative approach that estimated fitness of mCAs in the UK Biobank using population-level distributions of clonal fraction. Among individuals with JAK2 V617F clonal hematopoiesis of indeterminate potential or mCAs affecting the JAK2 gene on chromosome 9, PACER score was strongly correlated with erythrocyte count. In a cross-sectional analysis, genome-wide association study of estimates of mCA expansion rate identified a TCL1A locus variant associated with mCA clonal expansion rate, with suggestive variants in NRIP1 and TERT.

Efficacy Analysis of Bortezomib Combined with Lenalidomide in Newly Diagnosed Multiple Myeloma with 1q21 Gain/Amp.

OBJECTIVE: 1q21 gain/Amp is one of the most common cytogenetic abnormalities. There are controversies about its effects on prognosis and may be associated with inferior outcomes in patients with newly diagnosed multiple myeloma (NDMM). To explore the optimal induction treatment, we analyzed and compared the efficacy of combinations of bortezomib-lenalidomide-dexamethasone (VRD) and only bortezomib-based triplet regimens without lenalidomide (only bortezomib-based) as induction therapy in patients with NDMM with 1q21 gain/Amp. METHODS: Seventy-six NDMM patients with 1q21 gain/Amp who were admitted to our center from 2016 to 2022 were retrospectively analyzed in this study. The progression and efficacy of the patients were observed. RESULTS: Within our study group, the overall survival rate stood at 75.0%, and the progression-free survival (PFS) rate reached 40.8% in NDMM patients with 1q21 gain/Amp. The best outcome assessment was that 17.1% achieved complete response (CR) and 44.7% achieved very good partial response (VGPR). Patients in the VRD group had a deeper response (VGPR: 63.6% vs 37.0%, P = 0.034), lower disease progression rate (31.8% vs 70.3%, P = 0.002), longer sustained remission (median 49.7 months vs 18.3 months, P = 0.030), and longer PFS (median 61.9 months vs 22.9 months, P = 0.032) than those treated with only bortezomib-based induction therapy. No significant differences were found among patients with partial response or better (86.4% vs 77.8%, P = 0.532) or CR (27.3% vs 13.0%, P = 0.180). Multivariate analysis showed that only bortezomib-based induction therapy (P = 0.003, HR 0.246, 95% CI 0.097-0.620), International Staging System stage III (P = 0.003, HR 3.844, 95% CI 1.588-9.308) and LMR <3.6 (P = 0.032, HR 0.491, 95% CI 0.257-0.940) were significantly associated with adverse PFS. CONCLUSIONS: When compared with the sequential administration of bortezomib and lenalidomide or only bortezomib-based protocols, NDMM patients with 1q21 gain/Amp may benefit more from VRD as initial treatments.

Primary amenorrhoea - cytogenetic study in 40 Indian women.

BACKGROUND: Primary amenorrhoea (PA) refers to an ailment when adolescent girls do not attain menarche naturally. It is one of the most common gynaecological disorders specified. Chromosomal abnormalities play a pivotal role in PA. Cytogenetic analysis is an indispensable diagnostic tool to determine the abnormality of the chromosome. In an emerging country like India, cytogenetic analysis is at a nascent stage. There are very few studies on Cytogenetics present in eastern India, including West Bengal. In rural and suburban areas PA sufferers often experience late diagnosis and struggle to access suitable curative management. The aim of the study is to evaluate the various types of chromosomal abnormalities in patients suffering from PA for accurate, better management of the same and further counselling. METHODS: A total of 40 PA cases were referred by obstetricians and gynaecologists to the Department of Genetics of Nirnayan Health Care, Kolkata. To screen the chromosomal abnormalities, human leukocyte culture was accomplished with their peripheral venous blood followed by G-banding and then karyotyping was executed according to ISCN-2020. RESULT: Out of 40 patients, 29 were normal among which 46,XX was found in 70% cases (n = 28) and 46,XX,9qh + in 2.5% (n = 1). The remaining 11 showed different types of abnormalities. 45,X was found in 10% (n = 4), 46,X,i(X)(q10) in 2.5% (n = 1), 46,X,del(X)(p11.2) in 2.5% (n = 1), 46,X,del(X)(p22.1) in 2.5% (n = 1), 46,X,del(X)(q24) in 2.5% (n = 1), 46,XY in 2.5% (n = 1), mos 45,X[22]/46,Xi(X)(q.10)[8] in 2.5% (n = 1) and mos 45,X[16]/46,XY[14] (2.5%) in 2.5% (n = 1). CONCLUSION: This study indicates the importance of chromosomal study which must be included in early diagnosis of PA. Karyotyping at the appropriate phase of life will not only help in the judicial management of this disorder but will also give young girls a better lifestyle.

Primary amenorrhoea is a common gynecological disorder reported in adolescent girls, often linked to chromosomal abnormalities. In Eastern India, including West Bengal, where cytogenetic analysis is still in its nascent stage, late diagnosis and limited access to curative management are prevalent issues. A study conducted from January 2021 to May 2023 at Nirnayan Healthcare, Kolkata aimed to evaluate chromosomal abnormalities in 40 PA cases. Out of these, 28 exhibited normal karyotypes (46,XX); one patient was reported with 46,XX,9qh + which is considered a normal karyotype, while the remaining 11 revealed diverse abnormalities, including 45,X; sex reversal & several structural variations. The study underscores the significance of cytogenetic analysis in the early diagnosis of Primary Amenorrhoea. Early karyotyping not only facilitates judicious management but also ensures a better lifestyle for affected girls.

[Detection of cytogenetic abnormalities in multiple myeloma by using optical genome mapping].

Multiple myeloma (MM) is a plasma cell neoplasm characterized by numerous chromosomal number and structural abnormalities, which are of great significance for risk stratification and response evaluation of MM patients. Optical genome mapping (OGM) is a novel technology that has the potential to resolve many of the issues and limitations associated with traditional cytogenetic methods. To date, the clinical utility of OGM has been validated in the fields of cancer, reproduction, and embryonic dysplasia, et al. In this study, we compared OGM to traditional techniques for the first time in five newly diagnosed MM patients, and evaluated the potential of OGM for detecting cytogenetic aberrations and its clinical application value in MM.

Prenatal diagnosis of chromosomal aberrations by chromosomal microarray analysis and pregnancy outcomes of fetuses with polyhydramnios.

OBJECTIVES: To explore the prenatal clinical utility of chromosome microarray analysis (CMA) for polyhydramnios and evaluate the short and long-term prognosis of fetuses with polyhydramnios. METHODS: A total of 600 singleton pregnancies with persistent polyhydramnios from 2014 to 2020 were retrospectively enrolled in this study. All cases received amniocentesis and were subjected to CMA results. All cases were categorized into two groups: isolated polyhydramnios and non-isolated polyhydramnios [with soft marker(s) or with sonographic structural anomalies]. All fetuses were followed up from 6 months to five years after amniocentesis to acquire short and long-term prognosis. RESULTS: The detection rates of either aneuploidy or pathogenic copy number variants in fetuses with non-isolated polyhydramnios were significantly higher than those with isolated polyhydramnios (5.0 vs. 1.5%, p = 0.0243; 3.6 vs. 0.8%, p = 0.0288). The detection rate of total chromosomal abnormalities in the structural abnormality group was significantly higher than that in the isolated group (10.0 vs. 2.3%, p = 0.0003). In the CMA-negative cases, the incidence of termination of pregnancy, neonatal and childhood death, and non-neurodevelopmental disorders in fetuses combined with structural anomalies was significantly higher than that in fetuses with isolated polyhydramnios (p < 0.05). We did not observe any difference in the prognosis between the isolated group and the combined group of ultrasound soft markers. In addition, the risk of postnatal neurodevelopmental disorders was also consistent among the three groups (1.6 vs. 1.3 vs. 1.8%). CONCLUSION: For low-risk pregnancies, invasive prenatal diagnosis of isolated polyhydramnios might be unnecessary. CMA should be considered for fetuses with structural anomalies. In CMA-negative cases, the prognosis of fetuses with isolated polyhydramnios was good, and polyhydramnios itself did not increase the risk of postnatal neurological development disorders. The worse prognosis mainly depends on the combination of polyhydramnios with structural abnormalities.

A human neural crest model reveals the developmental impact of neuroblastoma-associated chromosomal aberrations.

Early childhood tumours arise from transformed embryonic cells, which often carry large copy number alterations (CNA). However, it remains unclear how CNAs contribute to embryonic tumourigenesis due to a lack of suitable models. Here we employ female human embryonic stem cell (hESC) differentiation and single-cell transcriptome and epigenome analysis to assess the effects of chromosome 17q/1q gains, which are prevalent in the embryonal tumour neuroblastoma (NB). We show that CNAs impair the specification of trunk neural crest (NC) cells and their sympathoadrenal derivatives, the putative cells-of-origin of NB. This effect is exacerbated upon overexpression of MYCN, whose amplification co-occurs with CNAs in NB. Moreover, CNAs potentiate the pro-tumourigenic effects of MYCN and mutant NC cells resemble NB cells in tumours. These changes correlate with a stepwise aberration of developmental transcription factor networks. Together, our results sketch a mechanistic framework for the CNA-driven initiation of embryonal tumours.

Relaxation Along a Fictitious Field, continuous wave T1rho, adiabatic T1rho and adiabatic T2rho imaging of human gliomas at 3T: A feasibility study.

In pre-clinical models of brain gliomas, Relaxation Along a Fictitious Field in second rotating frame (TRAFF2), continues wave T1rho (T1ρcw), adiabatic T1rho (T1ρadiab), and adiabatic T2rho (T2ρadiab) relaxation time mappings have demonstrated potential to non-invasively characterize brain gliomas. Our aim was to evaluate the feasibility and potential of 4 different spin lock methods at 3T to characterize primary brain glioma. 22 patients (26-72 years) with suspected primary glioma. T1ρcw was performed using pulse peak amplitude of 500Hz and pulse train durations of 40 and 80 ms while the corresponding values for T1ρadiab, T2ρadiab, TRAFF2 were 500/500/500Hz and 48 and 96, 64 and 112, 45 and 90 ms, respectively. The parametric maps were calculated using a monoexponential model. Molecular profiles were evaluated from tissue specimens obtained during the resection. The lesion regions-of-interest were segmented from high intensity FLAIR using automatic segmentation with manual refinement. Statistical descriptors from the voxel intensity values inside each lesion and radiomic features (Pyrad MRC package) were calculated. From extracted radiomics, mRMRe R package version 2.1.0 was used to select 3 features in each modality for statistical comparisons. Of the 22 patients, 10 were found to have IDH-mutant gliomas and of those 5 patients had 1p/19q codeletion group comparisons. Following correction for effects of age and gender, at least one statistical descriptor was able to differentiate between IDH and 1p/19q codeletion status for all the parametric maps. In the radiomic analysis, corner-edge detector features with Harris-Stephens filtered signal showed significant group differences in IDH and 1p/19q codeletion groups. Spin lock imaging at 3T of human glioma was feasible and various qualitative parameters derived from the parametric maps were found to have potential to differentiate IDH and 1p19q codeletion status. Future larger prospective clinical trials are warranted to evaluate these methods further.

Real-world advantage and challenge of post-autologous stem cell transplantation MRD negativity in high-risk patients with double-hit multiple myeloma.

BACKGROUND: Autologous stem-cell transplantation (ASCT) remains a beneficial approach for patients with newly diagnosed multiple myeloma (NDMM) in the age of novel therapeutic agents. Nevertheless, limited real-world data is available to establish criteria for identifying high-risk ASCT patients. METHODS: We analyzed outcomes for 168 NDMM patients who underwent ASCT at our center from December 2015 to December 2022. We investigated the impact of the number of high-risk cytogenetics (HRCA), defined as t(4;14), t(14;16), 1q21 gain/amplification, and del(17p), as well as the post-ASCT minimal residual disease (MRD) status as prognostic indicators. We assessed progression-free survival (PFS) and overall survival (OS), and focused on identifying risk factors. RESULTS: The cohort included 42% of patients (n = 71) with 0 HRCA, 42% (n = 71) with 1 HRCA, and 16% (n = 26) with ≥ 2 HRCA. After a median follow-up of 31 months, the median PFS was 53 months (95% CI, 37-69), and OS was not reached for the entire cohort. Despite similar rates of MRD-negativity post-ASCT, patients with ≥ 2 HRCA, termed "double hit" (DH), had a significantly higher risk of progression/mortality than those with 0 or 1 HRCA. Multivariate analysis highlighted DH (HR 4.103, 95% CI, 2.046-8.231) and MRD positivity post-ASCT (HR 6.557, 95% CI, 3.217-13.366) as adverse prognostic factors for PFS, with DH also linked to inferior OS. As anticipated, DH patients with post-ASCT MRD positivity displayed the poorest prognosis, with a median PFS of 7 months post-ASCT. Meanwhile, DH patients with MRD negativity post-ASCT showed improved prognosis, akin to MRD-negative non-DH patients. It is noteworthy to exercise caution, as DH patients who initially achieved MRD negativity experienced a 41% cumulative loss of that status within one year. CONCLUSIONS: This study strongly advocates integrating DH genetic assessments for eligible ASCT patients and emphasizes the importance of ongoing MRD monitoring, as well as considering MRD-based treatment adaptation for those patients in real-world settings.

[Prenatal diagnosis of fetal microdeletion and microduplication syndromes among pregnant women with advanced maternal ages].

OBJECTIVE: To assess the value of combined chromosomal karyotyping and chromosomal microarray analysis (CMA) and/or copy number variation sequencing (CNV-seq) for the prenatal diagnosis for women with advanced maternal ages, and to explore the challenges of prenatal genetic counseling brought by the types of fetal CNVs and uncertainty of related phenotypes. METHODS: A retrospective analysis was carried out on 1 841 women with advanced maternal age who underwent interventional prenatal diagnosis at the Prenatal Diagnosis Center of Xiamen University Affiliated Women and Children's Hospital from January 2017 to December 2020. Routine chromosomal karyotyping analysis and CMA/CNV-seq detection were carried out. RESULTS: CMA/CNV-seq had detected pathogenic variants in 2 cases which had failed karyotyping analysis. Two hundred and twenty one fetal chromosomal abnormalities were detected by karyotyping analysis, among which 187 were detected by CMA/CNV-seq. CMA/CNV-seq analysis of 23 cases with balanced chromosome structural aberrations and 10 cases with low proportion mosaicisms (including a marker chromosome) had yielded a negative result. In addition, 26 cases (26/1 841, 1.4%) with pathogenic CNVs were discovered among those with a normal karyotype, of which 13 (50.0%) were recurrent CNVs associated with neurocognitive impairment, with 22q11.21 microdeletions and microduplications being the most common types (26.92%). CONCLUSION: The combination of karyotyping analysis and CMA/CNV-seq not only increased the rate of prenatal diagnosis, but also complemented with each other, which has facilitated genetic counseling and formulation of prenatal diagnosis strategy for the affected families.

The clinical value of optical genome mapping in the rapid characterization of RB1 duplication and 15q23q24.2 triplication, for more appropriate prenatal genetic counselling.

BACKGROUND: Despite recent advances in prenatal genetic diagnosis, medical geneticists still face considerable difficulty in interpreting the clinical outcome of copy-number-variant duplications and defining the mechanisms underlying the formation of certain chromosomal rearrangements. Optical genome mapping (OGM) is an emerging cytogenomic tool with proved ability to identify the full spectrum of cytogenetic aberrations. METHODS: Here, we report on the use of OGM in a prenatal diagnosis setting. Detailed breakpoint mapping was used to determine the relative orientations of triplicated and duplicated segments in two unrelated foetuses harbouring chromosomal aberrations: a de novo 15q23q24.2 triplication and a paternally inherited 13q14.2 duplication that overlapped partially with the RB1 gene. RESULTS: OGM enabled us to suggest a plausible mechanism for the triplication and confirmed that the RB1 duplication was direct oriented and in tandem. This enabled us to predict the pathogenic consequences, refine the prognosis and adapt the follow-up and familial screening appropriately. CONCLUSION: Along with an increase in diagnostic rates, OGM can rapidly highlight genotype-phenotype correlations, improve genetic counselling and significantly influence prenatal management.

Cytogenetic abnormalities associated with reproductive failure in Pakistani population: Experience of a tertiary care hospital.

Constitutional chromosomal abnormalities play a significant role in causing reproductive anomalies in individuals of reproductive age. With the rapid advancement of genome engineering techniques, it has now become possible to cure different genetic disorders. However, very limited data is available regarding the prevalence of such aberrations in the Pakistani population. Considering this factor, this retrospective analysis was undertaken to elucidate the type and prevalence rate of such abnormalities in our population. A total of 241 individuals, who were referred to the Liaquat National Hospital, from January 2017 to December 2021, with a history of infertility or miscarriages, were evaluated using the standard GTG banding technique. The results revealed a notably high percentage 44(18.2%) of chromosomal abnormalities in our population. Surprisingly, the frequency of these anomalies was observed to be higher in males than in females. However, further research is needed using a larger sample size to confirm the findings of this investigation.

[Application of the Second Revision of the International Staging System (R2-ISS) in the prognostic assessment of newly diagnosed multiple myeloma].

Objective: To investigate the prognostic value of the Second Revision of the International Staging System (R2-ISS) in patients with newly diagnosed multiple myeloma (NDMM) . Methods: The retrospective study was performed in 326 NDMM patients with immunomodulatory drugs and/or proteasome inhibitors as the first-line treatment attending the Department of Hematology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China, from December 2012 to March 2022. The Kaplan-Meier method was used for the survival analysis, with the Log-rank test comparing the between-group differences and Cox proportional risk regression modeling A multifactorial analysis was performed. Results: ①326 patients were included in the study, 190 of whom were males. The median age was 63 years, and the median followup time was 37 months. R2-ISS can effectively predict prognosis, particularly for R-ISS Ⅱ patients. The median progression-free survival (PFS) time of R2-ISS Ⅰ, R2-ISS Ⅱ, R2-ISS Ⅲ, and R2-ISS Ⅳ was 52, 29, 20, and 15 months (P<0.001), while the median overall survival (OS) time was 91, 60, 44, and 36 months (P<0.001). Multifactor analysis revealed that ISS Ⅱ, ISS Ⅲ, del (17p), t (4;14), 1q+, LDH increased, and age >65 years old were independent negative prognostic factors for OS. ISS Ⅱ, ISS Ⅲ, del (17p), t (4;14), 1q+, and LDH were independent negative prognostic factors for PFS. ②The C-index score of R2-ISS was 0.724, higher than that of R-ISS (0.678), indicating high prediction efficiency. ③The median PFS for 1q+-related double-hit in R2-ISS Ⅲ and Ⅳ were 20, 15 months (P=0.084) and the median OS were 35, 36 months (P=0.786), respectively. In R2-ISS Ⅲ, there were twenty-seven cases of 1q+-related double-hit, sixty-one cases of 1q+ single abnormality, and sixty-eight cases with no 1q+. The median PFS for the three groups were 20, 18, and 21 months (P=0.974), while the median OS was 35, 47, and 56 months (P=0.042), respectively. Adjusting the assignment of 1q+ to 1, the median PFS and OS of different R2-ISS stages differed significantly after regrouping (P<0.001) . Conclusions: The prognostic stratification value of R2-ISS is higher than R-ISS, particularly in the highly heterogeneous R-ISS Ⅱ population. Adjusting the assignment of the 1q+-related double-hit can improve R2-ISS, which should be validated in future studies with multi-center and expanded cases.

Investigation of multidirectional toxicity induced by high-dose molybdenum exposure with Allium test.

In this study, the multifaceted toxicity induced by high doses of the essential trace element molybdenum in Allium cepa L. was investigated. Germination, root elongation, weight gain, mitotic index (MI), micronucleus (MN), chromosomal abnormalities (CAs), Comet assay, malondialdehyde (MDA), proline, superoxide dismutase (SOD), catalase (CAT) and anatomical parameters were used as biomarkers of toxicity. In addition, detailed correlation and PCA analyzes were performed for all parameters discussed. On the other hand, this study focused on the development of a two hidden layer deep neural network (DNN) using Matlab. Four experimental groups were designed: control group bulbs were germinated in tap water and application group bulbs were germinated with 1000, 2000 and 4000 mg/L doses of molybdenum for 72 h. After germination, root tips were collected and prepared for analysis. As a result, molybdenum exposure caused a dose-dependent decrease (p < 0.05) in the investigated physiological parameter values, and an increase (p < 0.05) in the cytogenetic (except MI) and biochemical parameter values. Molybdenum exposure induced different types of CAs and various anatomical damages in root meristem cells. Comet assay results showed that the severity of DNA damage increased depending on the increasing molybdenum dose. Detailed correlation and PCA analysis results determined significant positive and negative interactions between the investigated parameters and confirmed the relationships of these parameters with molybdenum doses. It has been found that the DNN model is in close agreement with the actual data showing the accuracy of the predictions. MAE, MAPE, RMSE and R2 were used to evaluate the effectiveness of the DNN model. Collective analysis of these metrics showed that the DNN model performed well. As a result, it has been determined once again that high doses of molybdenum cause multiple toxicity in A. cepa and the Allium test is a reliable universal test for determining this toxicity. Therefore, periodic measurement of molybdenum levels in agricultural soils should be the first priority in preventing molybdenum toxicity.

Measuring cancer driving force of chromosomal aberrations through multi-layer Boolean implication networks.

Multi-layer Complex networks are commonly used for modeling and analysing biological entities. This paper presents the advantage of using COMBO (Combining Multi Bio Omics) to suggest a new role of the chromosomal aberration as a cancer driver factor. Exploiting the heterogeneous multi-layer networks, COMBO integrates gene expression and DNA-methylation data in order to identify complex bilateral relationships between transcriptome and epigenome. We evaluated the multi-layer networks generated by COMBO on different TCGA cancer datasets (COAD, BLCA, BRCA, CESC, STAD) focusing on the effect of a specific chromosomal numerical aberration, broad gain in chromosome 20, on different cancer histotypes. In addition, the effect of chromosome 8q amplification was tested in the same TCGA cancer dataset. The results demonstrate the ability of COMBO to identify the chromosome 20 amplification cancer driver force in the different TCGA Pan Cancer project datasets.

Assessment of genotoxicity biomarkers in gasoline station attendants due to occupational exposure.

Gasoline station attendants are exposed to numerous chemicals that might have genotoxic and carcinogenic potential, such as benzene in fuel vapor and particulate matter and polycyclic aromatic hydrocarbons in vehicle exhaust emission. According to IARC, benzene and diesel particulates are Group 1 human carcinogens, and gasoline has been classified as Group 2A "possibly carcinogenic to humans." At gas stations, self-service is not implemented in Turkey; fuel-filling service is provided entirely by employees, and therefore they are exposed to those chemicals in the workplace during all working hours. Genetic monitoring of workers with occupational exposure to possible genotoxic agents allows early detection of cancer. We aimed to investigate the genotoxic damage due to exposures in gasoline station attendants in Turkey. Genotoxicity was evaluated by the Comet, chromosomal aberration, and cytokinesis-block micronucleus assays in peripheral blood lymphocytes. Gasoline station attendants (n = 53) had higher tail length, tail intensity, and tail moment values than controls (n = 61). In gasoline station attendants (n = 46), the frequencies of chromatid gaps, chromosome gaps, and total aberrations were higher compared with controls (n = 59). Increased frequencies of micronuclei and nucleoplasmic bridges were determined in gasoline station attendants (n = 47) compared with controls (n = 40). Factors such as age, duration of working, and smoking did not have any significant impact on genotoxic endpoints. Only exposure increased genotoxic damage in gasoline station attendants independently from demographic and clinical characteristics. Occupational exposure-related genotoxicity risk may increase in gasoline station attendants who are chronically exposed to gasoline and various chemicals in vehicle exhaust emissions.

Pan-neuronal expression of human mutant SOD1 in Drosophila impairs survival and motor performance, induces early neuroinflammation and chromosome aberrations.

Several mutations in the SOD1 gene encoding for the antioxidant enzyme Superoxide Dismutase 1, are associated with amyotrophic lateral sclerosis, a rare and devastating disease characterized by motor neuron degeneration and patients' death within 2-5 years from diagnosis. Motor neuron loss and related symptomatology manifest mostly in adult life and, to date, there is still a gap of knowledge on the precise cellular and molecular events preceding neurodegeneration. To deepen our awareness of the early phases of the disease, we leveraged two Drosophila melanogaster models pan-neuronally expressing either the mutation A4V or G85R of the human gene SOD1 (hSOD1A4V or hSOD1G85R). We demonstrate that pan-neuronal expression of the hSOD1A4V or hSOD1G85R pathogenic construct impairs survival and motor performance in transgenic flies. Moreover, protein and transcript analysis on fly heads indicates that mutant hSOD1 induction stimulates the glial marker Repo, up-regulates the IMD/Toll immune pathways through antimicrobial peptides and interferes with oxidative metabolism. Finally, cytological analysis of larval brains demonstrates hSOD1-induced chromosome aberrations. Of note, these parameters are found modulated in a timeframe when neurodegeneration is not detected. The novelty of our work is twofold: we have expressed for the first time hSOD1 mutations in all neurons of Drosophila and confirmed some ALS-related pathological phenotypes in these flies, confirming the power of SOD1 mutations in generating ALS-like phenotypes. Moreover, we have related SOD1 pathogenesis to chromosome aberrations and antimicrobial peptides up-regulation. These findings were unexplored in the SOD1-ALS field.