tbuckley/cabot-search huggingface dataset:
Beta-catenin signaling in murine liver zonation and regeneration: A Wnt-Wnt situation!
Authors: Jing Yang, Laura E. Mowry, Kari Nichole Nejak-Bowen, Hirohisa Okabe, Cassandra R. Diegel, Richard A. Lang, Bart O. Williams, Satdarshan P. Monga
Journal: Hepatology (2014)

Liver-specific β-catenin knockout (β- Catenin -LKO) mice have revealed an essential role of β-catenin in metabolic zonation where it regulates pericentral gene expression and in initiating liver regeneration (LR) after partial hepatectomy (PH), by regulating expression of Cyclin-D1. However, what regulates β-catenin activity in these events remains an enigma. Here we investigate to what extent β-catenin activation is Wnt-signaling-dependent and the potential cell source of Wnts. We studied liver-specific Lrp5/6 KO ( Lrp -LKO) mice where Wnt-signaling was abolished in hepatocytes while the β-catenin gene remained intact. Intriguingly, like β- catenin -LKO mice, Lrp -LKO exhibited a defect in metabolic zonation observed as a lack of glutamine synthetase (GS), Cyp1a2, and Cyp2e1. Lrp -LKO also displayed a significant delay in initiation of LR due to the absence of β-catenin-TCF4 association and lack of Cyclin-D1. To address the source of Wnt proteins in liver, we investigated conditional Wntless (Wls) KO mice, which lacked the ability to secrete Wnts from either liver epithelial cells ( Wls -LKO), or macrophages including Kupffer cells ( Wls -MKO), or endothelial cells ( Wls -EKO). While Wls -EKO was embryonic lethal precluding further analysis in adult hepatic homeostasis and growth, Wls -LKO and Wls -MKO were viable but did not show any defect in hepatic zonation. Wls -LKO showed normal initiation of LR; however, Wls -MKO showed a significant but temporal deficit in LR that was associated with decreased β-catenin-TCF4 association and diminished Cyclin-D1 expression. Conclusion : Wnt-signaling is the major upstream effector of β-catenin activity in pericentral hepatocytes and during LR. Hepatocytes, cholangiocytes, or macrophages are not the source of Wnts in regulating hepatic zonation. However, Kupffer cells are a major contributing source of Wnt secretion necessary for β-catenin activation during LR. (Hepatology 2014;60:964–976)
The epidemic that never was
Authors: Janice Hopkins Tanne
Journal: BMJ (2002)

Did activists and the media create a suburban legend?

When is an epidemic not an epidemic? When do activist groups help a sometimes uncritical media to create one?

On 6 August, the New York Times reported that a seven year, $8m study by the United States National Cancer Institute on possible links “between pollution and high rates of breast cancer on Long Island had failed to show any connection between the disease and pesticides that were once widely used on the island.”

This was a blow to 1in9, an activist group on Long Island that for years had called for studies of environmental risks for breast cancer. (1in9 refers to the fact that one American woman in nine will develop breast cancer if she lives to be 85.) Breast cancer rates on Long Island were said to be 30% higher than the national average, a figure often cited by women with breast cancer, by politicians seeking votes and funds, by …
Nucleotide Variability at Its Limit? Insights into the Number and Evolutionary Dynamics of the Sex-Determining Specificities of the Honey Bee Apis mellifera
Authors: Sarah Lechner, Luca Ferretti, Caspar Schöning, Wanja Kinuthia, David Willemsen, Martin Hasselmann
Journal: Molecular Biology and Evolution (2013)

Deciphering the evolutionary processes driving nucleotide variation in multiallelic genes is limited by the number of genetic systems in which such genes occur. The complementary sex determiner (csd) gene in the honey bee Apis mellifera is an informative example for studying allelic diversity and the underlying evolutionary forces in a well-described model of balancing selection. Acting as the primary signal of sex determination, diploid individuals heterozygous for csd develop into females, whereas csd homozygotes are diploid males that have zero fitness. Examining 77 of the functional heterozygous csd allele pairs, we established a combinatorical criteria that provide insights into the minimum number of amino acid differences among those pairs. Given a data set of 244 csd sequences, we show that the total number of csd alleles found in A. mellifera ranges from 53 (locally) to 87 (worldwide), which is much higher than was previously reported (20). Using a coupon-collector model, we extrapolate the presence of in total 116-145 csd alleles worldwide. The hypervariable region (HVR) is of particular importance in determining csd allele specificity, and we provide for this region evidence of high evolutionary rate for length differences exceeding those of microsatellites. The proportion of amino acids driven by positive selection and the rate of nonsynonymous substitutions in the HVR-flanking regions reach values close to 1 but differ with respect to the HVR length. Using a model of csd coalescence, we identified the high originating rate of csd specificities as a major evolutionary force, leading to an origin of a novel csd allele every 400,000 years. The csd polymorphism frequencies in natural populations indicate an excess of new mutations, whereas signs of ancestral transspecies polymorphism can still be detected. This study provides a comprehensive view of the enormous diversity and the evolutionary forces shaping a multiallelic gene.
The deubiquitinase USP28 controls intestinal homeostasis and promotes colorectal cancer
Authors: Markus E. Diefenbacher, Nikita Popov, Sophia M. Blake, Christina Schülein-Völk, Emma Nye, Bradley Spencer-Dene, Laura A. Jaenicke, Martin Eilers, Axel Behrens
Journal: Journal of Clinical Investigation (2014)

Colorectal cancer is the third most common cancer worldwide. Although the transcription factor c-MYC is misregulated in the majority of colorectal tumors, it is difficult to target directly. The deubiquitinase USP28 stabilizes oncogenic factors, including c-MYC; however, the contribution of USP28 in tumorigenesis, particularly in the intestine, is unknown. Here, using murine genetic models, we determined that USP28 antagonizes the ubiquitin-dependent degradation of c-MYC, a known USP28 substrate, as well as 2 additional oncogenic factors, c-JUN and NOTCH1, in the intestine. Mice lacking Usp28 had no apparent adverse phenotypes, but exhibited reduced intestinal proliferation and impaired differentiation of secretory lineage cells. In a murine model of colorectal cancer, Usp28 deletion resulted in fewer intestinal tumors, and importantly, in established tumors, Usp28 deletion reduced tumor size and dramatically increased lifespan. Moreover, we identified Usp28 as a c-MYC target gene highly expressed in murine and human intestinal cancers, which indicates that USP28 and c-MYC form a positive feedback loop that maintains high c-MYC protein levels in tumors. Usp28 deficiency promoted tumor cell differentiation accompanied by decreased proliferation, which suggests that USP28 acts similarly in intestinal homeostasis and colorectal cancer models. Hence, inhibition of the enzymatic activity of USP28 may be a potential target for cancer therapy.
ANTIBODIES OF THE IgA TYPE IN INTESTINAL PLASMA CELLS OF GERMFREE MICE AFTER ORAL OR PARENTERAL IMMUNIZATION WITH FERRITIN
Authors: P. A. Crabbé, D. R. Nash, H. Bazin, H. Eyssen, J. F. Heremans
Journal: The Journal of Experimental Medicine (1969)

In adult germfree C3H mice immunized with horse spleen ferritin, either subcutaneously or intraperitoneally, plasma cells containing specific antibodies were found in lymph nodes and spleen and, in smaller numbers, also in the lamina propria of the intestine. In extraintestinal sites, these antiferritin-containing plasma cells were mainly of the IgM class after a single stimulation, and of the IgG1 class after repeated stimulation. In the intestine, all the anti-ferritin-containing cells appeared to be of the IgA class. Circulating antibodies, after repeated stimulation, were for the major part IgG1 and IgG2. In germfree mice given ferritin in their drinking water, antiferritin-containing cells were abundant in the intestinal mucosa, much less numerous in the mesenteric lymph nodes, and extremely scarce in other lymphoid tissues. All these cells, whatever their location, appeared to belong exclusively to the IgA class. Similarly, all the circulating antibody in these animals was found to be IgA. These findings illustrate the role of the gut as a site of antibody synthesis, as well as its selective commitment to the production of antibodies of the IgA class.
Depression as a Risk Factor for Cancer: From Pathophysiological Advances to Treatment Implications
Authors: M. Beatriz Currier, Charles B. Nemeroff
Journal: Annual Review of Medicine (2013)

Innate immune activation and inflammation have been posited to play a role in the pathophysiology of both depression and neoplastic growth. Cancer patients experience a threefold higher rate of depression than the general population within the first five years of diagnosis. Chronic depression is associated with increased cancer risk and shortened survival. Although the precise cellular and molecular mechanisms of this bidirectional relationship remain unclear, elevated concentrations of circulating plasma proinflammatory cytokines associated with depression may mediate the neuroendocrine, neural, and immune pathways that account for the relationship. Proinflammatory cytokines, in turn, are known to modulate key neurobiological correlates of depression including hypothalamic-pituitary-adrenal (HPA) axis dysregulation, monoamine neurotransmitter metabolism, and limbic system activity. Research is needed to determine whether optimal depression treatment improves cancer survival and to develop antidepressant strategies that target molecular and cellular mechanisms mediating inflammation and the neurobiological pathways influenced by the proinflammatory cytokines.
Disrupting the Networks of Cancer
Authors: Daniel F. Camacho, Kenneth J. Pienta
Journal: Clinical Cancer Research (2012)

Ecosystems are interactive systems involving communities of species and their abiotic environment. Tumors are ecosystems in which cancer cells act as invasive species interacting with native host cell species in an established microenvironment within the larger host biosphere. At its heart, to study ecology is to study interconnectedness. In ecologic science, an ecologic network is a representation of the biotic interactions in an ecosystem in which species (nodes) are connected by pairwise interactions (links). Ecologic networks and signaling network models have been used to describe and compare the structures of ecosystems. It has been shown that disruption of ecologic networks through the loss of species or disruption of interactions between them can lead to the destruction of the ecosystem. Often, the destruction of a single node or link is not enough to disrupt the entire ecosystem. The more complex the network and its interactions, the more difficult it is to cause the extinction of a species, especially without leveraging other aspects of the ecosystem. Similarly, successful treatment of cancer with a single agent is rarely enough to cure a patient without strategically modifying the support systems conducive to survival of cancer. Cancer cells and the ecologic systems they reside in can be viewed as a series of nested networks. The most effective new paradigms for treatment will be developed through application of scaled network disruption.
The requirement for Notch signaling at the β-selection checkpoint in vivo is absolute and independent of the pre–T cell receptor
Authors: Ivan Maillard, LiLi Tu, Arivazhagan Sambandam, Yumi Yashiro-Ohtani, John Millholland, Karen Keeshan, Olga Shestova, Lanwei Xu, Avinash Bhandoola, Warren S. Pear
Journal: The Journal of Experimental Medicine (2006)

Genetic inactivation of Notch signaling in CD4−CD8− double-negative (DN) thymocytes was previously shown to impair T cell receptor (TCR) gene rearrangement and to cause a partial block in CD4+CD8+ double-positive (DP) thymocyte development in mice. In contrast, in vitro cultures suggested that Notch was absolutely required for the generation of DP thymocytes independent of pre-TCR expression and activity. To resolve the respective role of Notch and the pre-TCR, we inhibited Notch-mediated transcriptional activation in vivo with a green fluorescent protein–tagged dominant-negative Mastermind-like 1 (DNMAML) that allowed us to track single cells incapable of Notch signaling. DNMAML expression in DN cells led to decreased production of DP thymocytes but only to a modest decrease in intracellular TCRβ expression. DNMAML attenuated the pre-TCR–associated increase in cell size and CD27 expression. TCRβ or TCRαβ transgenes failed to rescue DNMAML-related defects. Intrathymic injections of DNMAML− or DNMAML+ DN thymocytes revealed a complete DN/DP transition block, with production of DNMAML+ DP thymocytes only from cells undergoing late Notch inactivation. These findings indicate that the Notch requirement during the β-selection checkpoint in vivo is absolute and independent of the pre-TCR, and it depends on transcriptional activation by Notch via the CSL/RBP-J–MAML complex.
Glycolysis and sperm motility: does a spoonful of sugar help the flagellum go round?
Authors: W.C.L. Ford
Journal: Human Reproduction Update (2006)

It is doubtful that diffusion can deliver sufficient ATP from the mitochondria to sustain activity at the distal end of the sperm flagellum. Glycolytic enzymes bound to the fibrous sheath could provide energy along the flagellum at the point it is required. An obligatory role for glycolysis is supported by the lack of progressive motility in sperm from mice where the gene for sperm-specific glyceraldehyde-3-phosphate dehydrogenase (GAPDHs) had been 'knocked out'. Here, I review some evidence against this idea. First, pure diffusion from the mitochondrion is likely to be adequate in species with smaller sperm, and it is possible that rapid ATP delivery required in larger sperm could be achieved by an adenylate kinase shuttle. Second, experience with α-chlorohydrin demonstrates that sperm can remain motile with normal ATP concentrations despite inhibition of GAPDHs; adverse effects only occur if glucose is added and high levels of glycolytic intermediates accumulate. These observations undermine the GAPDHs knockout mouse as evidence for an essential role of local glycolysis. Third, sperm from many species can remain motile for long periods in sugar-free media and excepting dog sperm, evidence that gluconeogenesis is a possible explanation, is weak. In most species, it is unlikely that local glycolysis is the only way that ATP can be supplied to the distal flagellum.
NPHS2 mutations in late-onset focal segmental glomerulosclerosis: R229Q is a common disease-associated allele
Authors: Hiroyasu Tsukaguchi, Akulapalli Sudhakar, Tu Cam Le, Trang Nguyen, Jun Yao, Joshua A. Schwimmer, Asher D. Schachter, Esteban Poch, Patricia F. Abreu, Gerald B. Appel, Aparecido B. Pereira, Raghu Kalluri, Martin R. Pollak
Journal: Journal of Clinical Investigation (2002)

Mutations in NPHS2, encoding podocin, have been identified in childhood onset focal and segmental glomerulosclerosis (FSGS). The role of NPHS2 in adult disease is less well defined. We studied 30 families with FSGS and apparent autosomal recessive inheritance and 91 individuals with primary FSGS. We screened family members for NPHS2 mutations. NPHS2 mutations appeared to be responsible for disease in nine of these families. In six families, the affected individuals were compound heterozygotes for a nonconservative R229Q amino acid substitution. This R229Q variant has an allele frequency of 3.6% in a control population. In these families, R229Q was the only mutation identified on one of the two disease-associated NPHS2 alleles. We used in vitro–translated podocin and purified nephrin to investigate the effect of R229Q on their interaction and found decreased nephrin binding to the R229Q podocin. These data suggest that this common polymorphism contributes to the development of FSGS. Chromosomes bearing the R229Q mutation share a common haplotype defining an approximately 0.2-Mb region. R229Q appears to enhance susceptibility to FSGS in association with a second mutant NPHS2 allele. Identification of R229Q mutations may be of clinical importance, as NPHS2-associated disease appears to define a subgroup of FSGS patients unresponsive to corticosteroids.
Small-cell lung cancer-associated autoantibodies: potential applications to cancer diagnosis, early detection, and therapy
Authors: Meleeneh Kazarian, Ite A Laird-Offringa
Journal: Molecular Cancer (2011)

Small-cell lung cancer (SCLC) is the most aggressive lung cancer subtype and lacks effective early detection methods and therapies. A number of rare paraneoplastic neurologic autoimmune diseases are strongly associated with SCLC. Most patients with such paraneoplastic syndromes harbor high titers of antibodies against neuronal proteins that are abnormally expressed in SCLC tumors. These autoantibodies may cross-react with the nervous system, possibly contributing to autoimmune disease development. Importantly, similar antibodies are present in many SCLC patients without autoimmune disease, albeit at lower titers. The timing of autoantibody development relative to cancer and the nature of the immune trigger remain to be elucidated. Here we review what is currently known about SCLC-associated autoantibodies, and describe a recently developed mouse model system of SCLC that appears to lend itself well to the study of the SCLC-associated immune response. We also discuss potential clinical applications for these autoantibodies, such as SCLC diagnosis, early detection, and therapy.
In vitro efficacy of combined treatment depends on the underlying mechanism of resistance in imatinib-resistant Bcr-Abl–positive cell lines
Authors: Paul La Rosée, Kara Johnson, Amie S. Corbin, Eric P. Stoffregen, Erika M. Moseson, Stephanie Willis, Michael M. Mauro, Junia V. Melo, Michael W. Deininger, Brian J. Druker
Journal: Blood (2003)
Hot off the breath: the 2009 H1N1 flu pandemic may be gone but should not be forgotten
Authors: D. R. Thickett, M. Griffiths, G. D. Perkins, D. F. McAuley
Journal: Thorax (2010)

The 2009 influenza pandemic was caused by the emergence of a new influenza virus, pandemic H1N1 2009 influenza A (pH1N1), to which many people had no pre-existing immunity. It caused unusual and extensive outbreaks of disease in the summer months in many countries and very high levels of disease in the winter months. The pandemic virus had almost complete dominance over other seasonal influenza viruses and was unusual in its clinical presentation because the most severe cases occurred more often in younger age groups. The WHO and the world's healthcare systems mobilised a massive healthcare resource effort to prepare for the potentially devastating effects of an influenza pandemic. In the UK there have been 474 deaths reported associated with confirmed cases of pH1N1 since the beginning of the pandemic. While this is almost certainly a sizeable underestimate, fortunately it is a figure much lower than some initial predictions.1

As of 10 August 2010, the WHO announced that the pandemic was over. In the southern hemisphere pH1N1 rates remain well below those observed during the same period in 2009 during the first pandemic wave. No large and unusual summer outbreaks have occurred in either northern or southern hemispheres. Indeed, the seasonal influenza A (H3N2) and influenza B viruses are currently being reported in …
Dissection of the proliferative and differentiative signals controlling murine cytotoxic T lymphocyte responses.
Authors: H Wagner, C Hardt, B T Rouse, M Röllinghoff, P Scheurich, K Pfizenmaier
Journal: The Journal of Experimental Medicine (1982)

Evidence is presented that interleukin 2 (IL-2) is not sufficient to cause the differentiation of primary cytotoxic T lymphocytes (CTL). Sources of IL-2 were compared for their ability to cause proliferation as well as differentiation into CTL. Whereas all factors caused proliferation, only the crude Con A supernatant had cytotoxic T cell differentiation factor (CTDF) activity. Furthermore, factors absorbed with an IL-2-dependent cell line to remove IL-2 still retained CTDF activity. Thus, IL-2 functions to cause clonal expansion of CTL precursors preactivated by antigen or mitogen, but for their differentiation into CTL, an additional factor is required, here called CTDF.
Activation of CCR9/CCL25 in Cutaneous Melanoma Mediates Preferential Metastasis to the Small Intestine
Authors: Farin F. Amersi, Alicia M. Terando, Yasufumi Goto, Richard A. Scolyer, John F. Thompson, Andy N. Tran, Mark B. Faries, Donald L. Morton, Dave S.B. Hoon
Journal: Clinical Cancer Research (2008)

Specific chemokines and their respective receptors have been implicated in distant tumor cell metastasis. Cutaneous melanoma has a distinct pattern of metastasis, preferentially targeting the submucosa of the small intestine. However, the underlying pathogenic mechanism remains unknown. Migration of CCR9(+) lymphocytes to the small intestine is known to occur in response to the chemoattractant effects of CCL25 (thymus-expressed chemokine). The integrin heterodimers alphabeta are also known to be important mediators of cellular adhesion. We hypothesize that the mechanism of small intestinal metastasis by melanoma is via the CCR9-CCL25 axis and specific integrins.Quantitative reverse transcription-PCR, flow cytometry, and immunohistochemistry were used to assess melanoma tumors for CCR9 and CCL25. Integrin expression was assessed using flow cytometry. CCR9 expression by quantitative reverse transcription-PCR was assessed in primary (n = 23) and metastatic (n = 198) melanomas, and melanoma lines derived from small intestinal metastases (n = 23).We showed CCR9 expression in 88 of 102 paraffin-embedded metastatic melanomas from the small intestine, 8 of 8 melanoma lines derived from metastases in the small intestine, and 0 of 96 metastatic melanomas from other sites. In vitro migration and invasion studies done on CCR9(+) melanoma lines showed migration in response to CCL25 that was inhibited by anti-CCR9 antibody or by short interfering RNA CCR9. Flow cytometric analysis confirmed CCR9 expression by melanomas to the small intestine and showed concomitant alpha(4)beta(1) integrin expression.Our findings show that functionally active CCR9 on melanoma cells facilitates metastasis to the small intestine. The CCR9-CCL25 axis may explain the high incidence of melanoma metastasis to this specific location.