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The general notion of complete hydatidiform moles is that most of them consist entirely of paternal DNA; hence, they do not express p57, a paternally imprinted gene. This forms the basis for the diagnosis of hydatidiform moles. There are about 38 paternally imprinted genes. The aim of this study is to determine whether other paternally imprinted genes could also assist in the diagnostic approach of hydatidiform moles. This study comprised of 29 complete moles, 15 partial moles and 17 non-molar abortuses. Immunohistochemical study using the antibodies of paternal-imprinted (RB1, TSSC3 and DOG1) and maternal-imprinted (DNMT1 and GATA3) genes were performed. The antibodies’ immunoreactivity was evaluated on various placental cell types, namely cytotrophoblasts, syncytiotrophoblasts, villous stromal cells, extravillous intermediate trophoblasts and decidual cells. TSSC3 and RB1 expression were observed in all cases of partial moles and non-molar abortuses. In contrast, their expression in complete moles was identified in 31% (TSSC3) and 10.3% (RB1), respectively (p < 0.0001). DOG1 was consistently negative in all cell types in all cases. The expressions of maternally imprinted genes were seen in all cases, except for one case of complete mole where GATA3 was negative. Both TSSC3 and RB1 could serve as a useful adjunct to p57 for the discrimination of complete moles from partial moles and non-molar abortuses, especially in laboratories that lack comprehensive molecular service and in cases where p57 staining is equivocal.

Benzene is a known hematotoxic and leukemogenic agent with hematopoietic stem cells (HSCs) niche being the potential target. Occupational and environmental exposure to benzene has been linked to the incidences of hematological disorders and malignancies. Previous studies have shown that benzene may act via multiple modes of action targeting HSCs niche, which include induction of chromosomal and micro RNA aberrations, leading to genetic and epigenetic modification of stem cells and probable carcinogenesis. However, understanding the mechanism linking benzene to the HSCs niche dysregulation is challenging due to complexity of its microenvironment. The niche is known to comprise of cell populations accounted for HSCs and their committed progenitors of lymphoid, erythroid, and myeloid lineages. Thus, it is fundamental to address novel approaches via lineage-directed strategy to elucidate precise mechanism involved in benzene-induced toxicity targeting HSCs and progenitors of different lineages. Here, we review the key genetic and epigenetic factors that mediate hematotoxicological effects by benzene and its metabolites in targeting HSCs niche. Overall, the use of combined genetic, epigenetic, and lineage-directed strategies targeting the HSCs niche is fundamental to uncover the key mechanisms in benzene-induced hematological disorders and malignancies.

Chronic myeloid leukemia (CML) patients who have BCR-ABL T315I mutation, usually present in the advance phase of the disease with overall survival (OS) shorter than those without the mutation. This study aimed to determine the prevalence of T315I mutation amongst imatinib mesylate (IM) resistant CML patients and to compare the OS between T315I-mutated and non-T315I-mutated patients. Sixty consecutive CML patients who were treated with IM for at least 18 months and their treatment responses, were recorded. The mutation analysis was done using allele-specific oligonucleotide reverse transcriptase-polymerase chain reaction (RT-PCR) assay followed by direct sequencing technique. Forty-two patients (70%) were found to have IM-resistance. Five out of 42 patients had detectable T315I mutation. Median OS of IM-resistant T315I-mutated patients was 96 months (95% CI:54-138) compared to 84 months (95% CI:48-120) in non T315I-mutated patients, although this was found to be statistically insignificant (p = 0.43). The present study showed a higher prevalence of T315I mutation as compared to a few local studies. Median OS of T315I-mutated patients were observed to be longer than non-T315-mutated patients. Further studies encompassing larger cohort of patients are required to confirm this finding.

Previous reports on hematotoxicity and leukemogenicity related to benzene exposure highlighted its adverse effects on hematopoiesis. Despite the reported findings, studies concerning the mechanism of benzene affecting chromosomal integrity in lineage-committed hematopoietic stem/progenitor cells (HSPCs) remain unclear. Here, we studied the clastogenicity and aneugenicity of benzene in lineage-committed HSPCs via karyotyping. Isolated mouse bone marrow cells (MBMCs) were exposed to the benzene metabolite 1,4-benzoquinone (1,4-BQ) at 1.25, 2.5, 5, 7, and 12 μM for 24 h, followed by karyotyping. Then, the chromosomal aberration (CA) in 1,4-BQ-exposed hematopoietic progenitor cells (HPCs) comprising myeloid, Pre-B lymphoid, and erythroid lineages were evaluated following colony-forming cell (CFC) assay. Percentage of CA, predominantly via Robertsonian translocation (Rb), was increased significantly (p &lt, 0.05) in MBMCs and all progenitors at all concentrations. As a comparison, Pre-B lymphoid progenitor demonstrated a significantly higher percentage of CA (p &lt, 0.05) than erythroid progenitor at 1.25, 2.5, and 7 μM as well as a significantly higher percentage (p &lt, 0.05) than myeloid progenitor at 7 μM of 1,4-BQ. In conclusion, 1,4-BQ induced CA, particularly via Rb in both MBMCs and HPCs, notably via a lineage-dependent response. The role of lineage specificity in governing the clastogenicity and aneugenicity of 1,4-BQ deserves further investigation.

In contrast to classic Turner syndrome, Turner patients with ring X chromosome are associated with distinct dysmorphism and are likely to be mentally impaired. Four Turner patients with ring X chromosome were examined for phenotypic features of Turner syndrome and additional dysmorphism. Both patients 1 and 2 are twins with normal intelligence whereas patients 3 and 4 have mental impairment. With the exception of patient 4, the other three patients only have few Turner characteristics. None of the patients have the distinctive dysmorphism previously reported in Turner syndrome with ring X chromosome. Both twins developed spontaneous puberty. Patients 3 and 4 however had no spontaneous puberty. We postulate that this variation may be related to the ring size, the proportion of 45,X and ring X chromosome in cell lines of various body tissues as well as the ability of these rings to be inactivated as a result of lyonisation.

Bronchopulmonary dysplasia (BPD) is a devastating lung disorder of preterm infants as a result of an aberrant reparative response following exposures to various antenatal and postnatal insults. Despite sophisticated medical treatment in this modern era, the incidence of BPD remains unabated. The current strategies to prevent and treat BPD have met with limited success. The emergence of stem cell therapy may be a potential breakthrough in mitigating this complex chronic lung disorder. Over the last two decades, the human placenta and umbilical cord have gained increasing attention as a highly potential source of stem cells. Placenta-derived stem cells (PDSCs) and umbilical cord-derived stem cells (UCDSCs) display several advantages such as immune tolerance and are generally devoid of ethical constraints, in addition to their stemness qualities. They possess the characteristics of both embryonic and mesenchymal stromal/stem cells. Recently, there are many preclinical studies investigating the use of these cells as therapeutic agents in neonatal disease models for clinical applications. In this review, we describe the preclinical and clinical studies using PDSCs and UCDSCs as treatment in animal models of BPD. The source of these stem cells, routes of administration, and effects on immunomodulation, inflammation and regeneration in the injured lung are also discussed. Lastly, a brief description summarized the completed and ongoing clinical trials using PDSCs and UCDSCs as therapeutic agents in preventing or treating BPD. Due to the complexity of BPD, the development of a safe and efficient therapeutic agent remains a major challenge to both clinicians and researchers.

Hematopoietic stem/progenitor cells (HSPCs) are susceptible to benzene-induced genotoxicity. However, little is known about the mechanism of DNA damage response affecting lineage-committed progenitors for myeloid, erythroid, and lymphoid. Here, we investigated the genotoxicity of a benzene metabolite, 1,4-benzoquinone (1,4-BQ), in HSPCs using oxidative stress and lineage-directed approaches. Mouse bone marrow cells (BMCs) were exposed to 1,4-BQ (1.25&ndash, 12 &mu, M) for 24 h, followed by oxidative stress and genotoxicity assessments. Then, the genotoxicity of 1,4-BQ in lineage-committed progenitors was evaluated using colony forming cell assay following 7&ndash, 14 days of culture. 1,4-BQ exposure causes significant decreases (p &lt, 0.05) in glutathione level and superoxide dismutase activity, along with significant increases (p &lt, 0.05) in levels of malondialdehyde and protein carbonyls. 1,4-BQ exposure induces DNA damage in BMCs by significantly (p &lt, 0.05) increased percentages of DNA in tail at 7 and 12 &mu, M and tail moment at 12 &mu, M. We found crucial differences in genotoxic susceptibility based on percentages of DNA in tail between lineage-committed progenitors. Myeloid and pre-B lymphoid progenitors appeared to acquire significant DNA damage as compared with the control starting from a low concentration of 1,4-BQ exposure (2.5 &micro, M). In contrast, the erythroid progenitor showed significant damage as compared with the control starting at 5 &micro, M 1,4-BQ. Meanwhile, a significant (p &lt, 0.05) increase in tail moment was only notable at 7 &micro, M and 12 &micro, M 1,4-BQ exposure for all progenitors. Benzene could mediate hematological disorders by promoting bone marrow oxidative stress and lineage-specific genotoxicity targeting HSPCs.

We present a case of a 61-year-old woman with relapse/refractory multiple myeloma post-autologous peripheral blood stem cell transplantation who presented with recurrent febrile episodes and infection. Worsening thrombocytopenia during lenalidomide-based therapy for early biochemical relapse warranted further investigations. Even though it was initially attributed to lenalidomide and relapse/refractory multiple myeloma, there was not much improvement in her counts despite adjustment of her medications. Subsequent serial bone marrow results and cytogenetic evolution eventually revealed therapy-related myelodysplastic syndrome progressing to therapy-related acute myeloid leukemia. In view of her age and comorbidities, she was treated with subcutaneous azacytidine with palliative intent which resulted in transient disappearance of blasts in the peripheral blood. She subsequently succumbed to progressive therapy-related acute myeloid leukemia and relapse/refractory multiple myeloma. This case highlights the complexity in diagnosing therapy-related myelodysplastic syndrome earlier as prompt diagnosis is crucial in delaying its progression to therapy-related acute myeloid leukemia. Managing therapy-related acute myeloid leukemia in the setting of relapse/refractory multiple myeloma post-autologous peripheral blood stem cell transplantation is challenging in terms of balancing the treatment toxicity and providing the best possible quality of life.

Benzene exposure has been associated with hematotoxicity and leukemogenicity. However, the impact of benzene exposure on complex microenvironment of Hematopoetic Stem Cells (HSCs) niche, comprising of HSCs and lineage-specific progenitors remains elusive. Thus, a study on benzene-targeting HSCs niche could uncover mechanism linking benzene to HSCs niche alteration. This study evaluates the lineage-specific responses following exposure to a benzene metabolite, namely hydroquinone (HQ) in targeting HSCs and myeloid-committed progenitors. Freshly isolated murine bone marrow cells (BMCs) were exposed to HQ at series of concentrations (0 – 50 µM) for 24 hours; followed by cell viability analysis using MTT assay. Chromosomal aberration (CA) status was determined using karyotyping analysis. Expression of surface antigen for HSCs (Sca-1) was confirmed by flow cytometer. Lineage-specific myelotoxicity was studied using the colony-forming unit (CFU) assay for the following myeloid progenitors: CFU granulocyte /erythrocyte /macrophage /megakaryocyte (CFU-GEMM), CFU-granulocyte/macrophage (CFU-GM), CFU-granulocyte (CFU-G), CFU-macrophage (CFU-M), CFU-erythroid (CFU-E) and Burst-forming unit erythroid (BFU-E). HQ reduced (p

Background The World Health Organization (WHO) classification system defines recurrent chromosomal translocations as the sole diagnostic and prognostic criteria for acute leukemia (AL). These fusion transcripts are pivotal in the pathogenesis of AL. Clinical laboratories universally employ conventional karyotype/FISH to detect these chromosomal translocations, which is complex, labour intensive and lacks multiplexing capacity. Hence, it is imperative to explore and evaluate some newer automated, cost-efficient multiplexed technologies to accommodate the expanding genetic landscape in AL. Methods “nCounter® Leukemia fusion gene expression assay” by NanoString was employed to detect various fusion transcripts in a large set samples (n = 94) utilizing RNA from formalin fixed paraffin embedded (FFPE) diagnostic bone marrow biopsy specimens. This series included AL patients with various recurrent translocations (n = 49), normal karyotype (n = 19), or complex karyotype (n = 21), as well as normal bone marrow samples (n = 5). Fusion gene expression data were compared with results obtained by conventional karyotype and FISH technology to determine sensitivity/specificity, as well as positive /negative predictive values. Results Junction probes for PML/RARA; RUNX1-RUNX1T1; BCR/ABL1 showed 100 % sensitivity/specificity. A high degree of correlation was noted for MLL/AF4 (85 sensitivity/100 specificity) and TCF3-PBX1 (75 % sensitivity/100 % specificity) probes. CBFB-MYH11 fusion probes showed moderate sensitivity (57 %) but high specificity (100 %). ETV6/RUNX1 displayed discordance between fusion transcript assay and FISH results as well as rare non-specific binding in AL samples with normal or complex cytogenetics. Conclusions Our study presents preliminary data with high correlation between fusion transcript detection by a throughput automated multiplexed platform, compared to conventional karyotype/FISH technique for detection of chromosomal translocations in AL patients. Our preliminary observations, mandates further vast validation studies to explore automated molecular platforms in diagnostic pathology. Electronic supplementary material The online version of this article (doi:10.1186/s13000-016-0541-z) contains supplementary material, which is available to authorized users.