Epidemiology of leukemia and multiple myeloma in golestan, Iran

Background: The aim of this paper was to present the incidence rates of leukemia and multiple myeloma (MM) in Golestan province located in northeastern Iran during 2004-2009. Materials and Methods: This was a descriptive cross-sectional study. Data on newly diagnosed (incident) leukemia and MM cases were obtained from collected from Golestan population-based cancer registry. Data was entered into CanReg-4 software. Age standardized incidence rates (ASR) (per 100000 person-years) for leukemia and MM were calculated. Data on Golestan population was obtained from the data of Iranian national census in 2006. Results: Totally, 11036 new cancer cases were registered in GPRC from 2004-2009. Leukemia and MM accounted for 693 and 124 of cases, respectively. The mean age in patients with leukemia and MM was 43.8 and 62.4 years, respectively. The ASRs for leukemia among men and women were 10.4 and 7.8, respectively (p<0.001). The ASRs for MM were 2.1 and 2 in men and women, respectively (p=0.93). The rate of leukemia was significantly higher in rural areas (p=0.02) whereas the incidence of MM was higher in urban areas (p<0.001). Conclusions: Our results showed a high incidence rate of leukemia in Golestan province of Iran. The incidence of leukemia was significantly higher in males and residents of rural areas. High exposure to pesticides and other agricultural related products may be a possible explanation for epidemiological pattern of leukemia in this area. Determining and controlling important risk factors, especially environmental factors, of leukemia may lead to decrease in its burden in Golestan province of Iran

Rapid and label-free identification of single leukemia cells from blood in a high-density microfluidic trapping array by fluorescence lifetime imaging microscopy.

The rapid screening and isolation of single leukemia cells from blood has become critical for early leukemia detection and tumor heterogeneity interrogation. However, due to the size overlap between leukemia cells and the more abundant white blood cells (WBCs), the isolation and identification of leukemia cells individually from peripheral blood is extremely challenging and often requires immunolabeling or cytogenetic assays. Here we present a rapid and label-free single leukemia cell identification platform that combines: (1) high-throughput size-based separation of hemocytes via a single-cell trapping array, and (2) leukemia cell identification through phasor approach and fluorescence lifetime imaging microscopy (phasor-FLIM), to quantify changes between free/bound nicotinamide adenine dinucleotide (NADH) as an indirect measurement of metabolic alteration in living cells. The microfluidic trapping array designed with 1600 highly-packed addressable single-cell traps can simultaneously filter out red blood cells (RBCs) and trap WBCs/leukemia cells, and is compatible with low-magnification imaging and fast-speed fluorescence screening. The trapped single leukemia cells, e.g., THP-1, Jurkat and K562 cells, are distinguished from WBCs in the phasor-FLIM lifetime map, as they exhibit significant shift towards shorter fluorescence lifetime and a higher ratio of free/bound NADH compared to WBCs, because of their glycolysis-dominant metabolism for rapid proliferation. Based on a multiparametric scheme comparing the eight parameter-spectra of the phasor-FLIM signatures, spiked leukemia cells are quantitatively distinguished from normal WBCs with an area-under-the-curve (AUC) value of 1.00. Different leukemia cell lines are also quantitatively distinguished from each other with AUC values higher than 0.95, demonstrating high sensitivity and specificity for single cell analysis. The presented platform is the first to enable high-density size-based single-cell trapping simultaneously with RBC filtering and rapid label-free individual-leukemia-cell screening through non-invasive metabolic imaging. Compared to conventional biomolecular diagnostics techniques, phasor-FLIM based single-cell screening is label-free, cell-friendly, robust, and has the potential to screen blood in clinical volumes through parallelization

Kernel Logistic Regression-linear for Leukemia Classification Using High Dimensional Data

Kernel Logistic Regression (KLR) is one of the statistical models that has been proposed for classification in the machine learning and data mining communities, and also one of the effective methodologies in the kernel–machine techniques. Basely, KLR is kernelized version of linear Logistic Regression (LR). Unlike LR, KLR has ability to classify data with non linear boundary and also can accommodate data with very high dimensional and very few instances. In this research, we proposed to study the use of Linear Kernel on KLR in order to increase the accuracy of Leukemia Classification. Leukemia is one of the cancer types that causes mortality in medical diagnosis problem. Improving the accuracy of Leukemia Classification is essential for more effective diagnosis and treatment of Leukemia disease. The Leukemia data sets consists of 7120 (very high dimensional) DNA micro arrays data of 72 (very few instances) patient samples on the state of Leukemia types. In Leukemia classification based upon gene expression, monitoring data using DNA micro array offer hope to achieve an objective and highly accurate classification. It can be demonstrated that the use of Linear Kernel on Kernel Logistic Regression (KLR–Linear) can improve the performance in classifying Leukemia patient samples and also can be shown that KLR–Linear has better accuracy than KLR–Polynomial and Penalized Logistic Regression

The role of dwelling type when estimating the effect of magnetic fields on childhood leukemia in the California Power Line Study (CAPS).

PurposeThe type of dwelling where a child lives is an important factor when considering residential exposure to environmental agents. In this paper, we explore its role when estimating the potential effects of magnetic fields (MF) on leukemia using data from the California Power Line Study (CAPS). In this context, dwelling type could be a risk factor, a proxy for other risk factors, a cause of MF exposure, a confounder, an effect-measure modifier, or some combination.MethodsWe obtained information on type of dwelling at birth on over 2,000 subjects. Using multivariable-adjusted logistic regression, we assessed whether dwelling type was a risk factor for childhood leukemia, which covariates and MF exposures were associated with dwelling type, and whether dwelling type was a potential confounder or an effect-measure modifier in the MF-leukemia relationship under the assumption of no-uncontrolled confounding.ResultsA majority of children lived in single-family homes or duplexes (70%). Dwelling type was associated with race/ethnicity and socioeconomic status but not with childhood leukemia risk, after other adjustments, and did not alter the MF-leukemia relationship upon adjustment as a potential confounder. Stratification revealed potential effect-measure modification by dwelling type on the multiplicative scale.ConclusionDwelling type does not appear to play a significant role in the MF-leukemia relationship in the CAPS dataset as a leukemia risk factor or confounder. Future research should explore the role of dwelling as an effect-measure modifier of the MF-leukemia association

CREB is a critical regulator of normal hematopoiesis and leukemogenesis

The cAMP-responsive element binding protein (CREB) is a 43-kDa nuclear transcription factor that regulates cell growth, memory, and glucose homeostasis. We showed previously that CREB is amplified in myeloid leukemia blasts and expressed at higher levels in leukemia stem cells from patients with myeloid leukemia. CREB transgenic mice develop myeloproliferative disease after 1 year, but not leukemia, suggesting that CREB contributes to but is not sufficient for leukemogenesis. Here, we show that CREB is most highly expressed in lineage negative hematopoietic stem cells (HSCs). To understand the role of CREB in hematopoietic progenitors and leukemia cells, we examined the effects of RNA interference (RNAi) to knock down CREB expression in vitro and in vivo. Transduction of primary HSCs or myeloid leukemia cells with lentiviral CREB shRNAs resulted in decreased proliferation of stem cells, cell- cycle abnormalities, and inhibition of CREB transcription. Mice that received transplants of bone marrow transduced with CREB shRNA had decreased committed progenitors compared with control mice. Mice injected with Ba/F3 cells expressing either Bcr-Abl wild-type or T315I mutation with CREB shRNA had delayed leukemic infiltration by bioluminescence imaging and prolonged median survival. Our results suggest that CREB is critical for normal myelopoiesis and leukemia cell proliferation

Generation of a poor prognostic chronic lymphocytic leukemia-like disease model: PKC subversion induces up-regulation of PKC II expression in B lymphocytes

Overwhelming evidence identifies the microenvironment as a critical factor in the development and progression of chronic lymphocytic leukemia, underlining the importance of developing suitable translational models to study the pathogenesis of the disease. We previously established that stable expression of kinase dead protein kinase C alpha in hematopoietic progenitor cells resulted in the development of a chronic lymphocytic leukemia-like disease in mice. Here we demonstrate that this chronic lymphocytic leukemia model resembles the more aggressive subset of chronic lymphocytic leukemia, expressing predominantly unmutated immunoglobulin heavy chain genes, with upregulated tyrosine kinase ZAP-70 expression and elevated ERK-MAPK-mTor signaling, resulting in enhanced proliferation and increased tumor load in lymphoid organs. Reduced function of PKCα leads to an up-regulation of PKCβII expression, which is also associated with a poor prognostic subset of human chronic lymphocytic leukemia samples. Treatment of chronic lymphocytic leukemia-like cells with the selective PKCβ inhibitor enzastaurin caused cell cycle arrest and apoptosis both in vitro and in vivo, and a reduction in the leukemic burden in vivo. These results demonstrate the importance of PKCβII in chronic lymphocytic leukemia-like disease progression and suggest a role for PKCα subversion in creating permissive conditions for leukemogenesis

miR-196b target screen reveals mechanisms maintaining leukemia stemness with therapeutic potential.

We have shown that antagomiR inhibition of miRNA miR-21 and miR-196b activity is sufficient to ablate MLL-AF9 leukemia stem cells (LSC) in vivo. Here, we used an shRNA screening approach to mimic miRNA activity on experimentally verified miR-196b targets to identify functionally important and therapeutically relevant pathways downstream of oncogenic miRNA in MLL-r AML. We found Cdkn1b (p27Kip1) is a direct miR-196b target whose repression enhanced an embryonic stem cell–like signature associated with decreased leukemia latency and increased numbers of leukemia stem cells in vivo. Conversely, elevation of p27Kip1 significantly reduced MLL-r leukemia self-renewal, promoted monocytic differentiation of leukemic blasts, and induced cell death. Antagonism of miR-196b activity or pharmacologic inhibition of the Cks1-Skp2–containing SCF E3-ubiquitin ligase complex increased p27Kip1 and inhibited human AML growth. This work illustrates that understanding oncogenic miRNA target pathways can identify actionable targets in leukemia

Patient Attitudes Toward Genetic Testing for Inherited Predispositions to Hematologic Malignancies

Although inherited predispositions to hematologic malignancies have previously been considered extremely rare, approximately 12 causative genes have been implicated in the last decade. Since individuals diagnosed with leukemia have not historically been considered for evaluation of inherited predispositions, genetic testing is underperformed in this population. This study used focus group discussions to explore the attitudes, motivations, and barriers to genetic testing for 23 patients with leukemia. Participants generally exhibited a positive regard for the utility of genetic testing, and were primarily motivated by concern for their family and a sense of altruism toward all leukemia patients. While drawbacks and barriers were difficult for participants to identify, a few individuals cited concerns about confidentiality of genetic information and possible discrimination based on test results. Participants unanimously agreed that the skin punch biopsy required for genetic testing in leukemia patients would not deter their decision to be tested. The findings from this study are valuable for guiding genetic counseling that best meets the specific needs of leukemia patients, and future studies will analyze how these issues are perceived by a larger and more diverse population of individuals with leukemia

In vivo imaging enables high resolution preclinical trials on patients' leukemia cells growing in mice.

Xenograft mouse models represent helpful tools for preclinical studies on human tumors. For modeling the complexity of the human disease, primary tumor cells are by far superior to established cell lines. As qualified exemplary model, patients' acute lymphoblastic leukemia cells reliably engraft in mice inducing orthotopic disseminated leukemia closely resembling the disease in men. Unfortunately, disease monitoring of acute lymphoblastic leukemia in mice is hampered by lack of a suitable readout parameter