Jaime F. Modiano

Bio: Jaime F. Modiano is an academic researcher from University of Minnesota. The author has contributed to research in topics: Canine Osteosarcoma & Cancer. The author has an hindex of 44, co-authored 181 publications receiving 6198 citations. Previous affiliations of Jaime F. Modiano include Anschutz Medical Campus & University of Colorado Boulder.

Rethinking dog domestication by integrating genetics, archeology, and biogeography

Abstract: The dog was the first domesticated animal but it remains uncertain when the domestication process began and whether it occurred just once or multiple times across the Northern Hemisphere. To ascertain the value of modern genetic data to elucidate the origins of dog domestication, we analyzed 49,024 autosomal SNPs in 1,375 dogs (representing 35 breeds) and 19 wolves. After combining our data with previously published data, we contrasted the genetic signatures of 121 breeds with a worldwide archeological assessment of the earliest dog remains. Correlating the earliest archeological dogs with the geographic locations of 14 so-called "ancient" breeds (defined by their genetic differentiation) resulted in a counterintuitive pattern. First, none of the ancient breeds derive from regions where the oldest archeological remains have been found. Second, three of the ancient breeds (Basenjis, Dingoes, and New Guinea Singing Dogs) come from regions outside the natural range of Canis lupus (the dog's wild ancestor) and where dogs were introduced more than 10,000 y after domestication. These results demonstrate that the unifying characteristic among all genetically distinct so-called ancient breeds is a lack of recent admixture with other breeds likely facilitated by geographic and cultural isolation. Furthermore, these genetically distinct ancient breeds only appear so because of their relative isolation, suggesting that studies of modern breeds have yet to shed light on dog origins. We conclude by assessing the limitations of past studies and how next-generation sequencing of modern and ancient individuals may unravel the history of dog domestication.

The dog as a cancer model.

Abstract: To the editor: Your very sympathetic editorial in the February issue (Nat. Biotechnol. 23, 215, 2006) regarding the demise of the Biomolecular Interaction Network Database (BIND) assigns the blame for this resource’s passing to “...bureaucratic delays [and] government fiscal nitpicking....” and calls on science funding agencies to provide more long-term funding for databases. Worthy as your crusade to better direct my tax dollars may be, I don’t find BIND to be a particularly suitable poster child for the effort. According to your account, BIND, via the Blueprint Initiative, burned through $25 million in about two years. Even in Canadian dollars that burn rate is nothing short of shocking, especially given BIND’s relatively modest scope, and the ease with which its data were to be ‘scraped’ from a relatively small number of scientific publications (I have quite a bit of professional experience in this domain, so I say this with some insight.) Personally, I admire Genome Canada’s decision to stop the bleeding. I’m sure there were, and are, those who have found BIND useful. Whether or not it was another $20.8 million worth of ‘useful’ or a total of $46 million worth of useful, given all the other worthy scientific uses to which that sum could be put, was the question, and Genome Canada decided this in the negative, citing concerns regarding management, budget justification and financial plan— concerns your editorial brushed aside without comment. A happy consequence of Genome Canada’s decision is that BIND is now where many such efforts belong. . . in private hands (albeit under the same management), where the rigors of the marketplace can impose upon its owners some deep regard for efficiency and utility. If BIND is truly valuable, then Christopher Hogue can charge users a modest access fee; perhaps research funding agencies will view their grantees’ carefully justified requests for these small sums with favor. He may then use such hardwon revenues prudently to sustain and improve the product. If, on the other hand, BIND isn’t a particularly important resource, then users won’t be willing to pay, and it will pass on. This is as it should be. Much the same may be said for the Alliance for Cellular Signaling’s Molecule Pages, which never really amounted to much (numerically, at least). Now under Nature Publishing Group’s costand profit-conscious guidance they will, no doubt, either flourish or fold. Rather than arguing for the importance of long-term database funding by granting agencies, BIND’s saga in fact argues for greater caution and more demanding oversight when these agencies elect to fund a database’s initial development. Realistic plans for long-term sustainability must be demanded, as must some basic enterprise management ability on the grant recipient’s part. Such expectations are anything but fiscal nitpicking; they are a fiduciary responsibility. I have no bone to pick with researchers who bemoan the intermingling of capitalism and scientific research (if, in this Bayh-Dole era, there’s anyone left who can still do so with a straight face). But those who feel this way should be prepared to make every precious tax dollar go as far as it possibly can. Those who fail at this should be quicker to blame themselves, and slower to blame ‘bureaucrats’.

Diagnosis of Canine Lymphoid Neoplasia Using Clonal Rearrangements of Antigen Receptor Genes

Abstract: Although the diagnosis of canine leukemia and lymphoma in advanced stages is usually uncomplicated, some presentations of the disease can be a diagnostic challenge. In certain situations, lymphoma and leukemia can be difficult to distinguish from a benign reactive proliferation of lymphocytes. Because clonality is the hallmark of malignancy, we have developed an assay that uses the polymerase chain reaction to amplify the variable regions of immunoglobulin genes and T-cell receptor genes to detect the presence of a clonal lymphocyte population. The assay detected clonally rearranged antigen receptor genes in 91% of the 77 dogs with lymphoid malignancy. Of the 24 dogs tested, that were either healthy or had clearly defined conditions not related to lymphoid malignancy, a clonally rearranged antigen receptor gene was found in one (a dog with Ehrlichia canis infection). Gene rearrangement was appropriate for the immunophenotype (immunoglobulin gene rearrangement in B-cell leukemias and T-cell receptor gene rearrangement in T-cell leukemias). Dilution analysis showed that the clonal rearrangement could be detected when 0.1-10% of the DNA was derived from neoplastic cells, depending on the source tissue. Potential applications of this assay include the diagnosis of lymphoma or leukemia in biopsy samples, cavity fluids, fine needle aspirates, bone marrow and peripheral blood; the determination of lineage (B or T cell); staging of lymphoma; and detection of residual disease after chemotherapy.

A Sleeping Beauty forward genetic screen identifies new genes and pathways driving osteosarcoma development and metastasis

Abstract: Branden Moriarity, David Largaespada and colleagues report a Sleeping Beauty forward genetic screen in mice that identifies candidate genes and pathways for osteosarcoma tumor development and progression. They identify sites specifically associated with tumorigenesis and metastasis and find that several candidate oncogenes are involved in axon guidance.

Evolutionarily conserved cytogenetic changes in hematological malignancies of dogs and humans – man and his best friend share more than companionship

Abstract: The pathophysiological similarities shared by many forms of human and canine disease, combined with the sophisticated genomic resources now available for the dog, have placed 'man's best friend' in a position of high visibility as a model system for a variety of biomedical concerns, including cancer. The importance of nonrandom cytogenetic abnormalities in human leukemia and lymphoma was recognized over 40 years ago, but the mechanisms of genome reorganization remain incompletely understood. The development of molecular cytogenetics, using fluorescence in situ hybridization (FISH) technology, has played a significant role in our understanding of cancer biology by providing a means for 'interrogating' tumor cells for a variety of gross genetic changes in the form of either numerical or structural chromosome aberrations. Here, we have identified cytogenetic abnormalities in naturally occurring canine hematopoietic tumors that are evolutionarily conserved compared with those that are considered characteristic of the corresponding human condition. These data suggest that humans and dogs share an ancestrally retained pathogenetic basis for cancer and that cytogenetic evaluation of canine tumors may provide greater insight into the biology of tumorigenesis.

Stem Cells,Cancer and Cancer Stem Cells

Abstract: Stem cells are defined as cells able to both extensively self-renew and differentiate into progenitors. Research data show that more resistant stem cells than common cancer cells exist in cancer patients.To identify unrecognized differences between cancer stem cells and cancer cells might be able to develope effective classification,diagnose and treat ment for cancer.

Transcriptional regulation by calcium, calcineurin, and NFAT

Abstract: The NFAT family of transcription factors encompasses five proteins evolutionarily related to the Rel/NF B family (Chytil and Verdine 1996; Graef et al. 2001b). The primordial family member is NFAT5, the only NFATrelated protein represented in the Drosophila genome. NFAT5 is identical to TonEBP (tonicity element binding protein), a transcription factor crucial for cellular responses to hypertonic stress (Lopez-Rodriguez et al. 1999; Miyakawa et al. 1999). We focus here on the remaining four NFAT proteins (NFAT1–NFAT4, also known as NFATc1–c4; see Table 1), referring to them collectively as NFAT. The distinguishing feature of NFAT is its regulation by Ca and the Ca/calmodulin-dependent serine phosphatase calcineurin. NFAT proteins are phosphorylated and reside in the cytoplasm in resting cells; upon stimulation, they are dephosphorylated by calcineurin, translocate to the nucleus, and become transcriptionally active, thus providing a direct link between intracellular Ca signaling and gene expression. NFAT activity is further modulated by additional inputs from diverse signaling pathways, which affect NFAT kinases and nuclear partner proteins. In the first part of this review, we describe the influence of these multiple inputs on the nuclear–cytoplasmic distribution and transcriptional function of NFAT. Recent structural data emphasize the remarkable versatility of NFAT binding to DNA. At composite NFAT:AP-1 elements found in the regulatory regions of many target genes, NFAT proteins bind cooperatively with an unrelated transcription factor, AP-1 (Fos–Jun; Chen et al. 1998). At DNA elements that resemble NF B sites, NFAT proteins bind DNA as dimers (Giffin et al. 2003; Jin et al. 2003). In the second section of this review, we describe these two modes of DNA binding by NFAT. NFAT also acts synergistically with transcription factors other than Fos and Jun, but the structural basis for synergy remains unknown. Drawing on published structures, we discuss the potential cooperation of NFAT with other classes of DNA-binding proteins. It is clear that NFAT activates transcription of a large number of genes during an effective immune response (Rao et al. 1997; Kiani et al. 2000; Serfling et al. 2000; Macian et al. 2001). In the third part of this review, we present information obtained from these studies, highlighting experimental and bioinformatics approaches to identifying NFAT target genes. We discuss the finding that NFAT and NFAT–Fos–Jun complexes activate distinct subsets of target genes in lymphocytes (Macian et al. 2002). We also describe a novel aspect of gene regulation by NFAT, in which this transcription factor participates in an early phase of chromatin remodeling that occurs at specific genetic loci in differentiating T cells (Avni et al. 2002). There is evidence that NFAT regulates cell differentiation programs in cell types other than immune cells (Crabtree and Olson 2002; Horsley and Pavlath 2002; Graef et al. 2003; Hill-Eubanks et al. 2003). In the last section of this review, we select three differentiation programs—fiber-type specification in differentiated skeletal muscle, cardiac valve development, and osteoclast differentiation—for detailed consideration. We evaluate the evidence for NFAT involvement, point out novel cellular and molecular mechanisms that might regulate this familiar transcription factor, and discuss how NFAT exerts its biological effects. Because the phenotypes of NFAT knockout mice have been reviewed elsewhere (Crabtree and Olson 2002; Horsley and Pavlath 2002), we refer to them only as necessary to illustrate specific points.

NFAT proteins: key regulators of T-cell development and function

Abstract: Since the discovery of the first nuclear factor of activated T cells (NFAT) protein more than a decade ago, the NFAT family of transcription factors has grown to include five members. It has also become clear that NFAT proteins have crucial roles in the development and function of the immune system. In T cells, NFAT proteins not only regulate activation but also are involved in the control of thymocyte development, T-cell differentiation and self-tolerance. The functional versatility of NFAT proteins can be explained by their complex mechanism of regulation and their ability to integrate calcium signalling with other signalling pathways. This Review focuses on the recent advances in our understanding of the regulation, mechanism of action and functions of NFAT proteins in T cells.

The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy

Abstract: Activation of the B-cell antigen receptor (BCR) signaling pathway contributes to the initiation and maintenance of B-cell malignancies and autoimmune diseases. The Bruton tyrosine kinase (Btk) is specifically required for BCR signaling as demonstrated by human and mouse mutations that disrupt Btk function and prevent B-cell maturation at steps that require a functional BCR pathway. Herein we describe a selective and irreversible Btk inhibitor, PCI-32765, that is currently under clinical development in patients with B-cell non-Hodgkin lymphoma. We have used this inhibitor to investigate the biologic effects of Btk inhibition on mature B-cell function and the progression of B cell-associated diseases in vivo. PCI-32765 blocked BCR signaling in human peripheral B cells at concentrations that did not affect T cell receptor signaling. In mice with collagen-induced arthritis, orally administered PCI-32765 reduced the level of circulating autoantibodies and completely suppressed disease. PCI-32765 also inhibited autoantibody production and the development of kidney disease in the MRL-Fas(lpr) lupus model. Occupancy of the Btk active site by PCI-32765 was monitored in vitro and in vivo using a fluorescent affinity probe for Btk. Active site occupancy of Btk was tightly correlated with the blockade of BCR signaling and in vivo efficacy. Finally, PCI-32765 induced objective clinical responses in dogs with spontaneous B-cell non-Hodgkin lymphoma. These findings support Btk inhibition as a therapeutic approach for the treatment of human diseases associated with activation of the BCR pathway.