c-Src drives intestinal regeneration and transformation

The non‐receptor tyrosine kinase c‐Src, hereafter referred to as Src, is overexpressed or activated in multiple human malignancies. There has been much speculation about the functional role of Src in colorectal cancer (CRC), with Src amplification and potential activating mutations in up to 20% of the human tumours, although this has never been addressed due to multiple redundant family members. Here, we have used the adult <i>Drosophila</i> and mouse intestinal epithelium as paradigms to define a role for Src during tissue homeostasis, damage‐induced regeneration and hyperplasia. Through genetic gain and loss of function experiments, we demonstrate that Src is necessary and sufficient to drive intestinal stem cell (ISC) proliferation during tissue self‐renewal, regeneration and tumourigenesis. Surprisingly, Src plays a non‐redundant role in the mouse intestine, which cannot be substituted by the other family kinases Fyn and Yes. Mechanistically, we show that Src drives ISC proliferation through upregulation of EGFR and activation of Ras/MAPK and Stat3 signalling. Therefore, we demonstrate a novel essential role for Src in intestinal stem/progenitor cell proliferation and tumourigenesis initiation <i>in vivo.</i&gt

The Vehicle, 1967, Vol. 9 no. 1

Vol. 9, No. 1 Table of Contents Commentarypage 3 PoofMolly J. Evanspage 4 PreludeMike Baldwinpage 5 UntitledMike Baldwinpage 5 Where is Tomorrow?Paula Bresnanpage 6 Could It Be Or NotMary Hoeggerpage 7 PsalmAnthony Griggspage 7 Where Am I Going?William A. Framepage 8 Out of DarknessMarilyn Henry Hoodpage 9 She CriedMolly J. Evanspage 12 When I MoveAnthony Griggspage 13 Hi Ya, MorningWilliam A. Framepage 13 Summer Twilight ThoughtsSteve Allenpage 14 Too MuchBill Moserpage 16 Ink SketchWilliam A. Framepage 17 No. 1Molly J. Evanspage 18 Youth, So Hated and DamnedJeff Hendrickspage 18 GoneJackie Jaquespage 19 The JesterWilliam A. Framepage 20 ReflectionMike Baldwinpage 20 No. 3Molly J. Evanspage 21 EpitaphBill Moserpage 22 I Take A Long-Out-of-Use BookAnthony Griggspage 23https://thekeep.eiu.edu/vehicle/1016/thumbnail.jp

The Vehicle, 1967, Vol. 9 no. 1

Vol. 9, No. 1 Table of Contents Commentarypage 3 PoofMolly J. Evanspage 4 PreludeMike Baldwinpage 5 UntitledMike Baldwinpage 5 Where is Tomorrow?Paula Bresnanpage 6 Could It Be Or NotMary Hoeggerpage 7 PsalmAnthony Griggspage 7 Where Am I Going?William A. Framepage 8 Out of DarknessMarilyn Henry Hoodpage 9 She CriedMolly J. Evanspage 12 When I MoveAnthony Griggspage 13 Hi Ya, MorningWilliam A. Framepage 13 Summer Twilight ThoughtsSteve Allenpage 14 Too MuchBill Moserpage 16 Ink SketchWilliam A. Framepage 17 No. 1Molly J. Evanspage 18 Youth, So Hated and DamnedJeff Hendrickspage 18 GoneJackie Jaquespage 19 The JesterWilliam A. Framepage 20 ReflectionMike Baldwinpage 20 No. 3Molly J. Evanspage 21 EpitaphBill Moserpage 22 I Take A Long-Out-of-Use BookAnthony Griggspage 23https://thekeep.eiu.edu/vehicle/1016/thumbnail.jp

The Vehicle, 1966, Vol. 8

Vol. 8 Table of Contents CommentaryBill Moser & Avis Eaglestonpage 3 The Vengeance of the DeadStephen W. Gibbspage 5 Ode To A MeadowKathleen McCormackpage 12 Row OnDavid Helmpage 13 Sonnet 63R.L. Hudsonpage 14 UntitledKathleen McCormackpage 14 The Pure GoldDavid Helmpage 15 CommunionDavid Helmpage 15 PreludeMichael Baldwinpage 15 The AlbatrossKaren Cooleypage 16 The Albatross (photo)DeWittpage 17 Ruff and the VaseDavid Helmpage 18 LaBelleKathleen McCormackpage 19 Not Quite SoR.L. Hudsonpage 20 Feeling (no number)David Reifpage 21 Song at DuskDavid Helmpage 21 Arcadia RuminationsR.L. Hudsonpage 22 The BarWayne Johnsonpage 25 HelloWilliam Framepage 26 The ProcessJerry DeWittpage 27 The KillingAdrian Beardpage 30 The Amusement Park GameStephen W. Gibbspage 38 DamnMel Tylerpage 40 PainWilliam Framepage 40 UntitledSusan Champlinpage 41 Portrait of A Scholar As A Young ManStephen W. Gibbspage 42 The TimesW.D.Mpage 46 ParadoxW.D.M.page 46 MankindDavid Helmpage 47https://thekeep.eiu.edu/vehicle/1014/thumbnail.jp

The Vehicle, 1966, Vol. 8

Vol. 8 Table of Contents CommentaryBill Moser & Avis Eaglestonpage 3 The Vengeance of the DeadStephen W. Gibbspage 5 Ode To A MeadowKathleen McCormackpage 12 Row OnDavid Helmpage 13 Sonnet 63R.L. Hudsonpage 14 UntitledKathleen McCormackpage 14 The Pure GoldDavid Helmpage 15 CommunionDavid Helmpage 15 PreludeMichael Baldwinpage 15 The AlbatrossKaren Cooleypage 16 The Albatross (photo)DeWittpage 17 Ruff and the VaseDavid Helmpage 18 LaBelleKathleen McCormackpage 19 Not Quite SoR.L. Hudsonpage 20 Feeling (no number)David Reifpage 21 Song at DuskDavid Helmpage 21 Arcadia RuminationsR.L. Hudsonpage 22 The BarWayne Johnsonpage 25 HelloWilliam Framepage 26 The ProcessJerry DeWittpage 27 The KillingAdrian Beardpage 30 The Amusement Park GameStephen W. Gibbspage 38 DamnMel Tylerpage 40 PainWilliam Framepage 40 UntitledSusan Champlinpage 41 Portrait of A Scholar As A Young ManStephen W. Gibbspage 42 The TimesW.D.Mpage 46 ParadoxW.D.M.page 46 MankindDavid Helmpage 47https://thekeep.eiu.edu/vehicle/1014/thumbnail.jp

Long-term effects of amphetamine neurotoxicity on tyrosine hydroxylase mRNA and protein in aged rats

ABSTRACT Four injections (intraperitoneal) of 3 mg/kg amphetamine (2 hr apart) produced pronounced hyperthermia and sustained decreases in dopamine levels and tyrosine hydroxylase (TH) protein levels in the striatum of 15-month-old male rats. A partial recovery of striatal dopamine levels was observed at 4 months after amphetamine. In contrast, TH mRNA and TH protein levels in the midbrain were unaffected at all time points tested up to 4 months after amphetamine treatment. The number of THimmunopositive cells in the midbrain was also unchanged at 4 months after amphetamine, even though the number of THpositive axons in the striatum remained dramatically decreased at this time point. Interestingly, TH-immunopositive cell bodies were observed 4 months after amphetamine in the lateral caudate/putamen, defined anteriorly by the genu of the corpus collosum and posteriorly by the junction of the anterior commissures; these striatal TH-positive cells were not observed in saline-or amphetamine-treated rats that did not become hyperthermic. In addition, low levels (orders of magnitude lower than that present in the midbrain) of TH mRNA were detected using reverse transcription-polymerase chain reaction in the striatum of these amphetamine-treated rats. Our results suggest that even though there is a partial recovery of striatal dopamine levels, which occurs within 4 months after amphetamine treatment, this recovery is not associated with increased TH gene expression in the midbrain. Furthermore, new THpositive cells are generated in the striatum at this 4-month time point

An Analysis of the Systemic Risks Posed by Fannie Mae and Freddie Mac and an Evaluation of the Policy Options for Reducing those Risks

Fannie Mae and Freddie Mac are government-sponsored enterprises that are central players in U.S. secondary mortgage markets. Over the past decade, these institutions have amassed enormous mortgage- and non-mortgage-oriented investment portfolios that pose significant interest-rate risks to the companies and a systemic risk to the financial system. This paper describes the nature of these risks and systemic concerns and then evaluates several policy options for reducing the institutions’ investment portfolios. We conclude that limits on portfolio size (assets or liabilities) would be the most desirable approach to mitigating the systemic risk posed by Fannie Mae and Freddie Mac

Toll-like receptor orchestrates a tumor suppressor response in non-small cell lung cancer

Targeting early-stage lung cancer is vital to improve survival. However, the mechanisms and components of the early tumor suppressor response in lung cancer are not well understood. In this report, we study the role of Toll-like receptor 2 (TLR2), a regulator of oncogene-induced senescence, which is a key tumor suppressor response in premalignancy. Using human lung cancer samples and genetically engineered mouse models, we show that TLR2 is active early in lung tumorigenesis, where it correlates with improved survival and clinical regression. Mechanistically, TLR2 impairs early lung cancer progression via activation of cell intrinsic cell cycle arrest pathways and the proinflammatory senescence-associated secretory phenotype (SASP). The SASP regulates non-cell autonomous anti-tumor responses, such as immune surveillance of premalignant cells, and we observe impaired myeloid cell recruitment to lung tumors after Tlr2 loss. Last, we show that administration of a TLR2 agonist reduces lung tumor growth, highlighting TLR2 as a possible therapeutic target.F.R.M. is funded by a Wellcome Trust clinical research fellowship through the Edinburgh Clinical Academic Track (ECAT) program (203913/Z/16/Z), a Wellcome Trust-ISSF3 award (IS3-R1.07 20/21), and a Wellcome Trust iTPA award (209710/Z/17/Z). J.C.A. core lab funding was received from Cancer Research UK (C47559/A16243, Training and Career Development Board – Career Development Fellowship), the University of Edinburgh (Chancellor’s Fellowship), and the Ministry of Science and Innovation of the Government of Spain (Proyecto PID2020-117860GB-100 financiado por MCIN/AEI/10.13039/501100011033). S.W. is supported by a Cancer Research UK senior fellowship (A29576). J.C. is supported by a Wellcome Trust clinical lectureship through the ECAT program (203913/Z/16/Z). M.M. is supported by a CRUK Edinburgh Centre Award (C157/A25140). S.V. and J.F.P. are funded by National Institute on Aging (NIA) grants (R01AG 68048-1 and UG3CA 268103-1)

Versican G3 Promotes Mouse Mammary Tumor Cell Growth, Migration, and Metastasis by Influencing EGF Receptor Signaling

Increased versican expression in breast tumors is predictive of relapse and has negative impact on survival rates. The C-terminal G3 domain of versican influences local and systemic tumor invasiveness in pre-clinical murine models. However, the mechanism(s) by which G3 influences breast tumor growth and metastasis is not well characterized. Here we evaluated the expression of versican in mouse mammary tumor cell lines observing that 4T1 cells expressed highest levels while 66c14 cells expressed low levels. We exogenously expressed a G3 construct in 66c14 cells and analyzed its effects on cell proliferation, migration, cell cycle progression, and EGFR signaling. Experiments in a syngeneic orthotopic animal model demonstrated that G3 promoted tumor growth and systemic metastasis in vivo. Activation of pERK correlated with high levels of G3 expression. In vitro, G3 enhanced breast cancer cell proliferation and migration by up-regulating EGFR signaling, and enhanced cell motility through chemotactic mechanisms to bone stromal cells, which was prevented by inhibitor AG 1478. G3 expressing cells demonstrated increased CDK2 and GSK-3β (S9P) expression, which were related to cell growth. The activity of G3 on mouse mammary tumor cell growth, migration and its effect on spontaneous metastasis to bone in an orthotopic model was modulated by up-regulating the EGFR-mediated signaling pathway. Taken together, EGFR-signaling appears to be an important pathway in versican G3-mediated breast cancer tumor invasiveness and metastasis

Causes of genome instability: the effect of low dose chemical exposures in modern society.

Genome instability is a prerequisite for the development of cancer. It occurs when genome maintenance systems fail to safeguard the genome's integrity, whether as a consequence of inherited defects or induced via exposure to environmental agents (chemicals, biological agents and radiation). Thus, genome instability can be defined as an enhanced tendency for the genome to acquire mutations; ranging from changes to the nucleotide sequence to chromosomal gain, rearrangements or loss. This review raises the hypothesis that in addition to known human carcinogens, exposure to low dose of other chemicals present in our modern society could contribute to carcinogenesis by indirectly affecting genome stability. The selected chemicals with their mechanisms of action proposed to indirectly contribute to genome instability are: heavy metals (DNA repair, epigenetic modification, DNA damage signaling, telomere length), acrylamide (DNA repair, chromosome segregation), bisphenol A (epigenetic modification, DNA damage signaling, mitochondrial function, chromosome segregation), benomyl (chromosome segregation), quinones (epigenetic modification) and nano-sized particles (epigenetic pathways, mitochondrial function, chromosome segregation, telomere length). The purpose of this review is to describe the crucial aspects of genome instability, to outline the ways in which environmental chemicals can affect this cancer hallmark and to identify candidate chemicals for further study. The overall aim is to make scientists aware of the increasing need to unravel the underlying mechanisms via which chemicals at low doses can induce genome instability and thus promote carcinogenesis