Failure of human rhombic lip differentiation underlies medulloblastoma formation.

Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain1-4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage5-8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES+KI67+ unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB.

Flow cytometric Immunophenotyping and Hematological Findings at Diagnosis and Relapse of Pediatric Acute Lymphoblastic Leukemia Patients.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is a common pediatric leukemia caused by lymphoid precursor proliferation. We analyzed immunophenotyping and hematological findings, as the risk of relapse, of pediatric ALL patients at diagnosis and relapse. METHODS: Peripheral blood and bone marrow samples of 30 pediatric ALL patients were collected at diagnosis and at relapse. The latter was evaluated for immunophenotyping and cytochemical staining (Periodic Acid Schiff stain (PAS)), while hematological findings were assessed in the former one. RESULTS: The percentage of PAS-positive patients, TdT, and CD4 expression were significantly higher at diagnosis than relapse (p = 0.027, 0.004, and 0.043, respectively), whereas the platelet/lymphocyte ratio (PLR) and neutrophil/lymphocyte ratio were significantly lower at diagnosis (p = 0.004 and 0.032, respectively). There were correla-tions between immunophenotyping and hematology data, including: a) a negative correlation between CD4 expression with blast percentage (r = -0.927, p = 0.003) and hemoglobin level (r = -0.991, p < 0.001) at diagnosis and TdT expression with platelet count (r = -0.441, p = 0.017) at relapse, and b) a positive correlation between CD3 expression with PLR (r = 0.367, p = 0.046) at relapse. CONCLUSIONS: Results suggest that changes in immunophenotyping and hematology findings could be applied as relapse prognostic factors in ALL.

Prognostic role and therapeutic susceptibility of cathepsin in various types of solid tumor and leukemia: A systematic review.

Cathepsins (CTSs) are multifunctional proteins that can play prominent roles in cancer progression and metastasis. In this systematic review, we compared the prognosis of CTS subtypes overexpression in leukemia and solid tumors, and investigated the effect of different factors on CTS prognosis. We systematically searched published articles indexed in PubMed, Scopus, Cochrane library, ISI Web of Science, and EmBase databases from February 2000 until January 2020. Among the selected leukemia and solid tumors studies, overexpression of CTS subtypes in newly diagnosed and treated patients were with poor prognosis in 43 studies (79.6%) and with good prognosis in 9 studies (16.6%). However, there were 2 studies (3.8%) with either good or poor prognosis, depending on conditions and caner stage and host cell. The relation between CTS and human leukocyte antigen (HLA) in leukemia and solid tumors was mentioned in 7 studies (13%). Overexpression of CTS subtypes in all new case patients had contributed to the induction of poor prognosis. It seems that CTS subtypes, based on the type of cancer and its stage, the type of host cells, and the probable relation with HLA, breed good or poor prognosis in patients with cancer. Therefore, monitoring the overexpression of CTS subtypes and determining the effect of each of these factors on CTS prognosis could be helpful in predicting cancer prognosis both in newly diagnosed or under treatment patients. They could also be useful in finding ways for improving the efficiency of contemporary therapeutic strategies in various types of leukemia and solid tumors.

Altering chromatin methylation patterns and the transcriptional network involved in regulation of hematopoietic stem cell fate.

Hematopoietic stem cells (HSCs) are quiescent cells with self-renewal capacity and potential multilineage development. Various molecular regulatory mechanisms such as epigenetic modifications and transcription factor (TF) networks play crucial roles in establishing a balance between self-renewal and differentiation of HSCs. Histone/DNA methylations are important epigenetic modifications involved in transcriptional regulation of specific lineage HSCs via controlling chromatin structure and accessibility of DNA. Also, TFs contribute to either facilitation or inhibition of gene expression through binding to enhancer or promoter regions of DNA. As a result, epigenetic factors and TFs regulate the activation or repression of HSCs genes, playing a central role in normal hematopoiesis. Given the importance of histone/DNA methylation and TFs in gene expression regulation, their aberrations, including changes in HSCs-related methylation of histone/DNA and TFs (e.g., CCAAT-enhancer-binding protein α, phosphatase and tensin homolog deleted on the chromosome 10, Runt-related transcription factor 1, signal transducers and activators of transcription, and RAS family proteins) could disrupt HSCs fate. Herewith, we summarize how dysregulations in the expression of genes related to self-renewal, proliferation, and differentiation of HSCs caused by changes in epigenetic modifications and transcriptional networks lead to clonal expansion and leukemic transformation.

Deep vein thrombosis: a less noticed complication in hematologic malignancies and immunologic disorders.

Deep vein thrombosis (DVT) is a common complication in hematologic malignancies and immunologic disorders that coagulation and inflammatory factors play a crucial role in its occurrence. The content used in this article has been obtained by PubMed database and Google Scholar search engine of English-language articles (1980-2019) using the "Deep vein thrombosis," "Hematologic malignancies," "Immunologic disorders" and "Treatment." Increased levels of coagulation factors, the presence of genetic disorders, or the use of thrombotic drugs that stimulate coagulation processes are risk factors for the development of DVT in patients with hematologic malignancies. Inflammatory and auto-anti-inflammatory factors, along with coagulant factors, play an essential role in the formation of venous thrombosis in patients with immunological disorders by increasing the recruitment of inflammatory cells and adhesion molecules. Therefore, anti-coagulants in hematologic malignancies and immunosuppressants in immune disorders can reduce the risk of developing DVT by reducing thrombotic and inflammatory activity. Considering the increased risk of DVT due to impaired coagulation and inflammation processes, analysis of coagulation and inflammatory factors have prognostic values in patients with immunologic deficiencies and hematologic malignancies. Evaluation of these factors as diagnostic and prognostic biomarkers in the prediction of thrombotic events could be beneficial in implementing effective treatment strategies for DVT.

Water quality improvement through bioretention media: nitrogen and phosphorus removal.

High nutrient inputs and eutrophication continue to be one of the highest priority water quality problems. Bioretention is a low-impact development technology that has been advocated for use in urban and other developed areas. This work provides an in-depth analysis on removal of nutrients from a synthetic stormwater runoff by bioretention. Results have indicated good removal of phosphorus (70 to 85%) and total Kjeldahl nitrogen (55 to 65%). Nitrate reduction was poor (< 20%) and, in several cases, nitrate production was noted. Variations in flowrate (intensity) and duration had a moderate affect on nutrient removal. Mass balances demonstrate the importance of water attenuation in the facility in reducing mass nutrient loads. Captured nitrogen can be converted to nitrate between storm events and subsequently washed from the system. Analysis on the fate of nutrients in bioretention suggests that accumulation of phosphorus and nitrogen may be controlled by carefully managing growing and harvesting of vegetation.

Water quality improvement through bioretention: lead, copper, and zinc removal.

Intensive automobile use, weathering of building materials, and atmospheric deposition contribute lead, copper, zinc, and other heavy metals to urban and roadway runoff. Bioretention is a low-impact-development best management practice that has the potential to improve stormwater quality from developed areas. The practice represents a soil, sand, organic matter, and vegetation-based storage and infiltration facility used in parking lots and on individual lots to treat runoff. Investigations using pilot-plant laboratory bioretention systems and two existing bioretention facilities documented their effectiveness at removing low levels of lead, copper, and zinc from synthetic stormwater runoff. Removal rates of these metals (based on concentration and total mass) were excellent, reaching close to 100% for all metals under most conditions, with effluent copper and lead levels mostly less than 5 microg/L and zinc less than 25 microg/L. Somewhat less removal was noted for shallow bioretention depths. Runoff pH, duration, intensity, and pollutant concentrations were varied, and all had minimal effect on removal. The two field investigations generally supported the laboratory studies. Overall, excellent removal of dissolved heavy metals can be expected through bioretention infiltration. Although the accumulation of metals is a concern, buildup problems are not anticipated for more than 15 years because of the low metal concentrations expected in runoff.