Cells Of Different Lineages Research Articles

Immunophenotyping of Orthotopic Homograft (Syngeneic) of Murine Primary KPC Pancreatic Ductal Adenocarcinoma by Flow Cytometry.

Homograft (syngeneic) tumors are the workhorse of today's immuno-oncology (I/O) preclinical research. The tumor microenvironment (TME), particularly its immune-components, is vital to the prognosis and prediction of treatment outcomes, especially those of immunotherapy. TME immune-components are composed of different subsets of tumor-infiltrating immune cells assessable by multi-color FACS. Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest malignances lacking good treatment options, thus an urgent and unmet medical need. One important reason for its non-responsiveness to various therapies (chemo-, targeted, I/O) has been its abundant TME, consisting of fibroblasts and leukocytes that protect tumor cells from these therapies. Orthotopically implanted PDAC is believed to more accurately recapture the TME of human pancreatic cancers than conventional subcutaneous (SC) models. Homograft tumors (KPC) are transplants of mouse spontaneous PDAC originating from genetically engineered KPC-mice (KrasG12D/+/P53-/-/Pdx1-Cre) (KPC-GEMM). The primary tumor tissue is cut into small fragments (~2 mm3) and transplanted subcutaneously (SC) to the syngeneic recipients (C57BL/6, 7-9 weeks old). The homografts were then surgically orthotopically transplanted onto the pancreas of new C57BL/6 mice, along with SC-implantation, which reached tumor volumes of 300-1,000 mm3 by 17 days. Only tumors of 400-600 mm3 were harvested per approved autopsy procedure and cleaned to remove the adjacent non-tumor tissues. They were dissociated per protocol using a tissue dissociator into single-cell suspensions, followed by staining with designated panels of fluorescently-labeled antibodies for various markers of different immune cells (lymphoid, myeloid and NK, DCs). The stained samples were analyzed using multi-color FACS to determine numbers of immune cells of different lineages, as well as their relative percentage within tumors. The immune profiles of orthotopic tumors were then compared to those of SC tumors. The preliminary data demonstrated significantly elevated infiltrating TILs/TAMs in tumors over the pancreas, and higher B-cell infiltration into orthotopic rather than SC tumors.

Regulation of Mesenchymal Stem Cell Differentiation by Transforming Growth Factor Beta Superfamily.

The ability to differentiate into cells of different lineage, such as muscle, bone, cartilage and fat, is the chief value of adult mesenchymal stem cells (MSCs) which can be used with the final aim to regenerate damaged tissue. Due to potential use, as well as importance in tissue development, a number of questions have been raised regarding the molecular mechanisms of MSC differentiation. As one of the crucial mediators in organism development, transforming growth factor beta (TGF-β) superfamily directs MSCs commitment in the selection of differentiation pathways. In this review we aim to give an overview of the current knowledge on the mechanisms of MSCs differentiation, on the involvement of TGF-β superfamily in MSCs differentiation with additional insight into the mutual regulation of microRNAs and TGF-β in MSCs differentiation. Particular focus has been given to the signaling and transcriptional networks governing the differentiation processes.

The Case for an Expanded Concept of Trained Immunity.

ABSTRACTTrained immunity was originally proposed as a program of innate immunity memory by innate immunity cells of hematopoietic origin such as the monocytes/macrophages and the NK cells. Here I discuss some old and new data justifying this program and some specific, still unanswered, questions it raises regarding the model fungus Candida albicans and the chronic, inflammatory vulvovaginal disease it causes. Building upon this well-established program, the recent reports that epithelial cells of mammals can also acquire memory from previous stimulations, and the apparent intrinsic ability of many living cells from bacteria to mammals to learn from experience, I suggest an expansion of the concept of trained immunity to include all cells of different lineages with the potential of memorizing previous microbial encounters. This expansion would better fit the complexity of innate immunity and the role it plays in infectious and inflammatory diseases.

Bone Marrow Defects and Platelet Function: A Focus on MDS and CLL.

The bloodstream typically contains >500 billion anucleate circulating platelets, derived from megakaryocytes in the bone marrow. This review will focus on two interesting aspects of bone marrow dysfunction and how this impacts on the quality of circulating platelets. In this regard, although megakaryocytes are from the myeloid lineage leading to granulocytes (including neutrophils), erythrocytes, and megakaryocytes/platelets, recent evidence has shown that defects in the lymphoid lineage leading to B cells, T cells, and natural killer (NK) cells also result in abnormal circulating platelets. Current evidence is limited regarding whether this latter phenomenon might potentially arise from (a) some form of as-yet-undetected defect common to both lineages; (b) adverse interactions occurring between cells of different lineages within the bone marrow environment; and/or (c) unknown disease-related factor(s) affecting circulating platelet receptor expression/function after their release from megakaryocytes. Understanding the mechanisms underlying how both myeloid and lymphoid lineage bone marrow defects lead to dysfunction of circulating platelets is significant because of the potential diagnostic and predictive value of peripheral platelet analysis for bone marrow disease progression, the additional potential effects of new anti-cancer drugs on platelet function, and the critical role platelets play in regulation of bleeding risk, inflammation, and innate immunity.

Papers of note in Nature 546 (7659)

This week’s articles describe engineered exosomes for treating pancreatic cancer, the role of the endoplasmic reticulum in cancer cell apoptosis, the priming of brown fat for cold-induced thermogenesis, synapse loss in a mouse model of lupus, and communication between cells of different lineages during liver development.

Costorage of Enteroendocrine Hormones Evaluated at the Cell and Subcellular Levels in Male Mice.

Recent studies reveal complex patterns of hormone coexpression within enteroendocrine cells (EECs), contrary to the traditional view that gut hormones are expressed individually in EECs. Moreover, different hormones have been found in separate subcellular vesicles. However, detailed analysis of relative expression of multiple hormones has not been made. Subcellular studies have been confined to peptide hormones, and have not included the indolamine 5-hydroxytryptamine (5-HT) or the neuroendocrine protein chromogranin A (CgA). In the present work, coexpression of 5-HT, CgA, secretin, cholecystokinin (CCK), ghrelin, and glucagonlike peptide (GLP)-1 in mouse duodenum was quantified at a cellular and subcellular level by semiautomated cell counting and quantitative vesicle measurements. We investigated whether relative numbers of cells with colocalized hormones analyzed at a cell level matched the numbers revealed by examination of individual storage vesicles within cells. CgA and 5-HT were frequently expressed in EECs that contained combinations of GLP-1, ghrelin, secretin, and CCK. Separate subcellular stores of 5-HT, CgA, secretin, CCK, ghrelin, and GLP-1 were identified. In some cases, high-resolution analysis revealed small numbers of immunoreactive vesicles in cells dominated by a different hormone. Thus the observed incidence of cells with colocalized hormones is greater when analyzed at a subcellular, compared with a cellular, level. Subcellular analysis also showed that relative numbers of vesicles differ considerably between cells. Thus separate packaging of hormones that are colocalized is a general feature of EECs, and EECs exhibit substantial heterogeneity, including the colocalization of hormones that were formerly thought to be in cells of different lineages.

Distribution and characterisation of CCK containing enteroendocrine cells of the mouse small and large intestine.

There is general consensus that enteroendocrine cells, EEC, containing the enteric hormone cholecystokinin (CCK) are confined to the small intestine and predominate in the duodenum and jejunum. Contrary to this, EEC that express the gene for CCK have been isolated from the large intestine of the mouse and there is evidence for EEC that contain CCK-like immunoreactivity in the mouse colon. However, the human and rat colons do not contain CCK cells. In the current study, we use immunohistochemistry to investigate CCK peptide presence in endocrine cells, PCR to identify cck transcripts and chromatography to identify CCK peptide forms in the mouse small and large intestine. The colocalisation of CCK and 5-HT, hormones that have been hypothesised to derive from cells of different lineages, was also investigated. CCK immunoreactivity was found in EEC throughout the mouse small and large intestine but positive cells were rare in the rectum. Immunoreactive EEC were as common in the caecum and proximal colon as they were in the duodenum and jejunum. CCK gene transcripts were found in the mucosa throughout the intestine but mRNA for gastrin, a hormone that can bind some anti-CCK antibodies, was only found in the stomach and duodenum. Characterisation of CCK peptides of the colon by extraction, chromatographic separation and radioimmunoassay revealed bioactive amidated and sulphated forms, including CCK-8 and CCK-33. Moreover, CCK-containing EEC in the large intestine bound antibodies that target the biologically active sulfated form. Colocalisation of CCK and 5-HT occurred in a proportion of EEC throughout the small intestine and in the caecum but these hormones were not colocalised in the colon, where there was CCK and PYY colocalisation. It is concluded that authentic, biologically active, CCK occurs in EEC of the mouse large intestine.

Improving Delivery of a Biomaterial Payload in Myocardial Infarction

Survival after an acute coronary syndrome has greatly improved because of advances in thrombolytic therapy, stabilization of the culprit lesion such as with coronary stents, and the use of pharmacological approaches to prevent recurrent thrombotic and arrhythmic events. Despite these approaches, however, myocardial injury culminating in myocardial infarction (MI) continues to be an all too common sequela. The MI region is a highly heterogeneous structure that contains several cell types, such as residual cardiac myocytes, inflammatory cells of different lineages, proliferating and transdifferentiating fibroblasts, and extracellular matrix proteins and signaling molecules. Although canonical thought was that the MI region was a rather static, fibrotic structure, it is now clear that this is a dynamic and ever-evolving entity with changes in geometry, biophysical properties, and cellular/extracellular composition. The time course and extent of these post-MI processes have been generically termed post-MI remodeling and is recognized as a milestone event for the initiation and progression to left ventricular (LV) dilation and dysfunction. One ubiquitous feature of post-MI remodeling is a progressive thinning and dyskinesia of the MI region, which is because of the summation of several factors: a loss of cardiac myocytes and thus functional myocardium, continuous turnover and instability of the extracellular matrix, and significant shifts in stress–strain patterns within this region throughout the cardiac cycle. Specifically, significant heterogeneity arises in the stress–strain patterns both within and surrounding the MI region and in turn can contribute to a feed-forward process of continuous activation of bioactive molecules and extracellular matrix instability. These biomechanical changes result in continued MI thinning and recruitment of border zone myocardium into the MI region, which is defined as MI expansion. As the MI expansion process continues in an inexorable fashion, the degree of heterogeneity in stress–strain relations are exacerbated, bulging of the MI region becomes evident by …

Vitamin D machinery and metabolism in porcine adipose-derived mesenchymal stem cells.

BackgroundVitamin D, a hormone once thought to have a role limited to calcium homeostasis and bone mineralization, has pleiotropic effects on different types of cells. Vitamin D receptors are reported in vascular smooth muscle cells, endothelial cells, and cardiomyocytes. Adipose-derived MSCs (ADMSCs) are multipotent cells with the capacity to differentiate into cells of different lineages. To our knowledge, the presence of vitamin D machinery on porcine ADMSCs has not yet been examined. In this study, we investigated the presence of vitamin D machinery and metabolism in ADMSCs by analyzing the expression levels of vitamin D receptor (VDR), vitamin D metabolizing enzymes (CYP24A1 and CYP27B1) after in vitro stimulation with active vitamin D, calcitriol.Methods and resultsADMSCs isolated from porcine adipose tissue were characterized by positive staining for ADMSC markers, CD44, CD73, and CD90, and negative staining for macrophage marker CD11b and hematopoietic stem cell markers CD34 and CD45, and trilineage differentiation to osteocytes, chondrocytes, and adipocytes. No cytotoxicity was observed when MSCs were stimulated with 0.1–10 nM calcitriol. The ADMSCs were analyzed for mRNA and protein expression of CYP24A1, CYP27B1, and VDR by immunostaining, qPCR, and ELISA. A significant increase (p <0.01) in the mRNA expression of CYP24A1, CYP27B1, and VDR was observed after stimulation of ADMSCs with calcitriol (10 nM). The in vitro time-dependent effect of calcitriol (10 nM) on the components of vitamin D machinery in cultured MSCs was determined by qPCR. The VDR and CYP27B1 expression peaked at 3 h and CYP24A1 at 24 h, respectively. The in vitro biosynthesis of 1, 25(OH)2D3 by ADMSCs was analyzed by ELISA and Western blot. The levels of the active form of vitamin D were significantly decreased once the CYP enzymes were inhibited (p <0.01), demonstrating the ability of ADMSCs to convert inactive vitamin D into active vitamin D for cellular action.ConclusionsPorcine ADMSCs possess vitamin D hydrolases and VDR to metabolize and respond to vitamin D. Hence, in vivo circulating 25-hydroxy vitamin D levels may have a significant role in regulating the differentiation of ADMSCs into different lineages, which might assist in stem cell-based therapy.

Abstract P1-06-05: The impact of ethnicity on normal breast biology

Abstract The incidence of/mortality from the most aggressive triple negative breast cancer (TNBC) is higher in African American- (AA) than Caucasian (CA)-women. In contrast, breast cancer in Hispanic-women is generally less aggressive. There is an ongoing debate as to whether AA-women have an increased incidence of TNBCs that have poor outcome or there are unique biological factors in AA-women that promote aggressive biology. Through unique approaches, we provide evidence for distinct biology in the normal breasts of CA-women, AA-women, and Hispanic-women. Using resources from the Komen Normal Tissue Bank and a primary cell culturing system that enabled propagation of normal epithelial cells of different lineages including mature-luminal, luminal-progenitor, and stem cells from different ethnic groups, we have identified a subpopulation of CD44high/CD24- cells that are unique to AA-women (p=0.0001). This AA-women-specific subpopulation expressed higher levels of Collagen 3A1, Collagen 5A2, CTNNB1 (β-Catenin of Wnt), FOXC2, and ZEB1 compared to common CD44+/CD24+ subpopulation in every breast. Gene expression pattern in the AA-specific CD44high/CD24- population showed marked similarity to gene expression pattern in the recently described PROCR+ multi-potent mammary stem cells. Indeed, the breast epithelial cells of AA-women were enriched for PROCR-positive stem cells compared to CA-women or Hispanic-women (p=0.015). In contrast to cells from CA- and AA-women, cells isolated from the healthy breast of Hispanic-women displayed mostly differentiated features as they were enriched for CD49f-/EpCAM+ and CD271-/EpCAM+ mature cells. Cells from CA-women, AA-women and Hispanic-women are currently being immortalized to determine the cell types that are preferentially immortalized in each of these ethnic groups. These results suggest ethnicity-dependent differences in Wnt, extracellular matrix, and epithelial to mesenchymal transition (EMT) signaling in normal breast epithelial cells and differences in the proportion of cells that are susceptible to immortalization/transformation. This work is supported by Susan G. Komen for the Cure to HN (SAC110025). Citation Format: Nakshatri H, Anjanappa M, Bhat-Nakshatri P. The impact of ethnicity on normal breast biology. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-06-05.

The Application of Human iPSCs in Neurological Diseases: From Bench to Bedside.

In principle, induced pluripotent stem cells (iPSCs) are generated from somatic cells by reprogramming and gaining the capacity to self-renew indefinitely as well as the ability to differentiate into cells of different lineages. Human iPSCs have absolute advantages over human embryonic stem cells (ESCs) and animal models in disease modeling, drug screening, and cell replacement therapy. Since Takahashi and Yamanaka first described in 2007 that iPSCs can be generated from human adult somatic cells by retroviral transduction of the four transcription factors, Oct3/4, Sox2, Klf4, and c-Myc, disease specific iPSC lines have sprung up worldwide like bamboo shoots after a spring rain, making iPSC one of the hottest and fastest moving topics in modern science. The craze for iPSCs has spread throughout main branches of clinical medicine, covering neurology, hematology, cardiology, endocrinology, hepatology, ophthalmology, and so on. Here in this paper, we will focus on the clinical application of human iPSCs in disease modeling, drug screening, and cell replacement therapy for neurological diseases.

Japanese encephalitis virus invasion of cell: allies and alleys.

The mosquito-borne flavivirus, Japanese encephalitis virus (JEV), is the leading cause of virus-induced encephalitis globally and a major public health concern of several countries in Southeast Asia, with the potential to become a global pathogen. The virus is neurotropic, and the disease ranges from mild fever to severe hemorrhagic and encephalitic manifestations and death. The early steps of the virus life cycle, binding, and entry into the cell are crucial determinants of infection and are potential targets for the development of antiviral therapies. JEV can infect multiple cell types; however, the key receptor molecule(s) still remains elusive. JEV also has the capacity to utilize multiple endocytic pathways for entry into cells of different lineages. This review not only gives a comprehensive update on what is known about the virus attachment and receptor system (allies) and the endocytic pathways (alleys) exploited by the virus to gain entry into the cell and establish infection but also discusses crucial unresolved issues. We also highlight common themes and key differences between JEV and other flaviviruses in these contexts.

Quantitative expression of regulatory and differentiation-related genes in the key steps of human hematopoiesis: The LeukoStage Database

Differentiation during hematopoiesis leads to the generation of many cell types with specific functions. At various stages of maturation, the cells may change pathologically, leading to diseases including acute leukemias (ALs). Expression levels of regulatory molecules (such as the IKZF, GATA, HOX, FOX, NOTCH and CEBP families, as well as SPI-1/PU1 and PAX5) and lineage-specific molecules (including CD2, CD14, CD79A, and BLNK) may be compared between pathological and physiological cells. Although the key steps of differentiation are known, the available databases focus mainly on fully differentiated cells as a reference. Precursor cells may be a more appropriate reference point for diseases that evolve at immature stages. Therefore, we developed a quantitative real-time polymerase chain reaction (qPCR) array to investigate 90 genes that are characteristic of the lymphoid or myeloid lineages and/or are thought to be involved in their regulation. Using this array, sorted cells of granulocytic, monocytic, T and B lineages were analyzed. For each of these lineages, 3–5 differentiation stages were selected (17 stages total), and cells were sorted from 3 different donors per stage. The qPCR results were compared to similarly processed AL cells of lymphoblastic (n=18) or myeloid (n=6) origins and biphenotypic AL cells of B cell origin with myeloid involvement (n=5). Molecules characteristic of each lineage were found. In addition, cells of a newly discovered switching lymphoblastic AL (swALL) were sorted at various phases during the supposed transdifferentiation from an immature B cell to a monocytic phenotype. As demonstrated previously, gene expression changed along with the immunophenotype. The qPCR data are publicly available in the LeukoStage Database in which gene expression in malignant and non-malignant cells of different lineages can be explored graphically and differentially expressed genes can be identified. In addition, the LeukoStage Database can aid the functional analyses of next-generation sequencing data.

Lectin-Magnetic Beads for Plasma Membrane Isolation

Plasma membrane proteins mainly function to transmit external signals into the cell. Many plasma membrane receptor tyrosine kinases (e.g., HER2 and EGFR) are known to mediate oncogenic progression, making them prime targets for cancer therapy. Recently, it has become important to identify plasma membrane proteins that are differentially expressed in normal versus cancer cells, in drug-sensitive versus drug-resistant cells, or among tumor cells that metastasize to different organ sites because these differentially expressed membrane proteins may lead to the identification of therapeutic targets or diagnostic markers. In addition, there is an increased interest in identifying cell-surface proteins that could serve as markers for stem cells, progenitor cells, or cells of different lineages. Traditionally, membrane isolation requires multiple centrifugation steps to isolate different organelles based on their density. With the advent of affinity matrix technology, it is possible to separate organelles based on their molecular differences. A defining characteristic of the plasma membrane is that plasma membrane proteins are more extensively glycosylated than are intracellular membrane proteins. As a result, affinity chromatography employing lectin, a carbohydrate-binding protein, is commonly used to isolate plasma membrane proteins. We have extended this concept for plasma membrane isolation by using concanavalin A (ConA), a lectin with mannose specificity. Here we describe a protocol that uses immobilized ConA bound to magnetic beads to isolate plasma membranes from homogenized cell lysates. The captured plasma membrane proteins are then solubilized from the ConA-magnetic beads by detergents in the presence of a competing sugar, methyl α-mannopyranoside.

Epigenetic/Genetic Mismatch: Using Transdifferentiation as a Potential Cancer Therapy to Exploit the Cell Type Specificity of Cancer

Every cell type capable of proliferation can be malignantly transformed. However, there appears to be no naturally occurring universal set of genetic mutations capable of converting every cell type to a malignant state. Any specific cell type is generally resistant to transformation by the cancer mutations accumulated by cells of different lineages, presumably due to epigenetic differences. Evidence for this idea derives from experiments in which the developmental fates of cancer cells are altered to reduce malignancy. Reprogramming cancer cells to more primitive developmental states using pluripotency factors (IPS) or somatic nuclear transfer suppresses the malignant phenotype, as does subsequent directed differentiation to mature cells of lineages distinct from the originating cell. Direct transdifferentiation to an alternative cell fate also reduces tumorigenicity. In contrast, after reprogramming, cells induced to redifferentiate toward the original tumor cell type are tumorigenic. In these types of experiments an epigenetic/genetic mismatch often results in suppression of malignancy or cell death. Elucidating the specific transcription and cell signaling network incompatibilities will identify new targets for cancer therapy. Moreover, novel strategies to induce an incompatible transdifferentiated state, in which expression of thousands of genes are altered, will prove useful in controlling malignancies that otherwise easily evolve resistance to single target-based therapeutics. Engineering small molecules, genetic vectors, cytokines, growth factors, targeted extracellular vesicles, and cell fusion will help realize transdifferentiation-based therapeutics for cancer.

Emerging immune functions of non-hematopoietic stromal cells.

Emerging immune functions of non-hematopoietic stromal cells.

Lineage-specific regulation of epigenetic modifier genes in human liver and brain.

Despite an abundance of studies on chromatin states and dynamics, there is an astonishing dearth of information on the expression of genes responsible for regulating histone and DNA modifications. We used here a set of 156 defined epigenetic modifier genes (EMG) and profiled their expression pattern in cells of different lineages. As reference value, expression data from human embryonic stem cells (hESC) were used. Hepatocyte-like cells were generated from hESC, and their EMG expression was compared to primary human liver cells. In parallel, we generated postmitotic human neurons (Lu d6), and compared their relative EMG expression to human cortex (Ctx). Clustering analysis of all cell types showed that neuronal lineage samples grouped together (94 similarly regulated EMG), as did liver cells (61 similarly-regulated), while the two lineages were clearly distinct. The general classification was followed by detailed comparison of the major EMG groups; genes that were higher expressed in differentiated cells than in hESC included the acetyltransferase KAT2B and the methyltransferase SETD7. Neuro-specific EMGs were the histone deacetylases HDAC5 and HDAC7, and the arginine-methyltransferase PRMT8. Comparison of young (Lu d6) and more aged (Ctx) neuronal samples suggested a maturation-dependent switch in the expression of functionally homologous proteins. For instance, the ratio of the histone H3 K27 methyltransfereases, EZH1 to EZH2, was high in Ctx and low in Lu d6. The same was observed for the polycomb repressive complex 1 (PRC1) subunits CBX7 and CBX8. A large proportion of EMGs in differentiated cells was very differently expressed than in hESC, and absolute levels were significantly higher in neuronal samples than in hepatic cells. Thus, there seem to be distinct qualitative and quantitative differences in EMG expression between cell lineages.

The cellular form of the prion protein guides the differentiation of human embryonic stem cells into neuron-, oligodendrocyte-, and astrocyte-committed lineages

Prion protein, PrPC, is a glycoprotein that is expressed on the cell surface beginning with the early stages of embryonic stem cell differentiation. Previously, we showed that ectopic expression of PrPC in human embryonic stem cells (hESCs) triggered differentiation toward endodermal, mesodermal, and ectodermal lineages, whereas silencing of PrPC suppressed differentiation toward ectodermal but not endodermal or mesodermal lineages. Considering that PrPC might be involved in controlling the balance between cells of different lineages, the current study was designed to test whether PrPC controls differentiation of hESCs into cells of neuron-, oligodendrocyte-, and astrocyte-committed lineages. PrPC was silenced in hESCs cultured under three sets of conditions that were previously shown to induce hESCs differentiation into predominantly neuron-, oligodendrocyte-, and astrocyte-committed lineages. We found that silencing of PrPC suppressed differentiation toward all three lineages. Similar results were observed in all three protocols, arguing that the effect of PrPC was independent of differentiation conditions employed. Moreover, switching PrPC expression during a differentiation time course revealed that silencing PrPC expression during the very initial stage that corresponds to embryonic bodies has a more significant impact than silencing at later stages of differentiation. The current work illustrates that PrPC controls differentiation of hESCs toward neuron-, oligodendrocyte-, and astrocyte-committed lineages and is likely involved at the stage of uncommitted neural progenitor cells rather than lineage-committed neural progenitors.

Will Detection of MicroRNA Biomarkers in Blood Improve the Diagnosis and Survival of Patients With Pancreatic Cancer?

Will Detection of MicroRNA Biomarkers in Blood Improve the Diagnosis and Survival of Patients With Pancreatic Cancer?

Bruton's tyrosine kinase: potential target in human multiple myeloma

Bruton's tyrosine kinase (BTK), a Tec family non-receptor tyrosine kinase that is required for B cell development, is critical for the initiation and maintenance of human B-cell malignancies. However, the expression of BTK and the role that BTK plays in the pathogenesis of multiple myeloma (MM) remain seldom reported. In this study we examined the expression and screened for gene mutations of BTK in MM cells. We showed that BTK was elevated and activated in a dexamethasone-resistant cell line and in two out of nine (22.2%) patients’ cells. Interestingly, patients with higher BTK expression had a poorer prognosis. In addition, a single nucleotide polymorphism (SNP) at cDNA position 2062 (T2062C) in the BTK gene was recorded in six out of eight (75%) patients and in U266 cells. This SNP in MM cells was not detected in other malignant hematopoietic cells of different lineages. These results suggest that the function of BTK warrants further investigation, and BTK expression might be used as a prognostic indicator for patients with MM.