Low-energy collisions of negative ions with atomic hydrogen

Total cross sections for charge transfer and electron detachment for collisions of a variety of negative ions with atomic hydrogen have been separately determined for laboratory collision energies ranging from about 5 eV to 500 eV. The experiments are performed with an apparatus that utilizes a crossed-beam configuration with a radio-frequency discharge as the source of atomic hydrogen.;For collisions of H{dollar}\sp-{dollar}(D{dollar}\sp-{dollar}) with H the charge transfer cross sections increase monotonically with decreasing energy and display an isotope effect. at the lowest collision energies, the electron detachment cross sections are about one order of magnitude smaller than those for charge transfer; for the two projectiles the detachment cross sections are identical when compared at the same relative collision energy.;Total electron detachment cross sections have also been measured for collisions of Halogen anions with atomic hydrogen. For F{dollar}\sp-{dollar}, Cl{dollar}\sp-{dollar}, and Br{dollar}\sp-{dollar} projectiles the measured detachment cross sections increase with decreasing collision energy, and no energetic threshold is indicated; no charge transfer is observed. For I{dollar}\sp-{dollar} + H, however, the detachment cross sections are small at low collision energies, and increase rapidly with increasing energy. HI{dollar}\sp-{dollar} is known to form a stable molecular anion, and a small charge transfer cross section is measured to be less than 1 A{dollar}\sp2{dollar} at the highest collision energy.;For collisions of O{dollar}\sp-{dollar} and S{dollar}\sp-{dollar} with atomic hydrogen, electron detachment is also found to be the dominant electron loss mechanism, and the measured total detachment cross sections are found to increase with decreasing collision energy. For both projectiles, charge transfer cross sections are measured to be small and energetic thresholds are indicated.;The experimental results are compared with several calculations and previous measurements that overlap the present results at the highest energies, and are discussed, where possible, in terms of various intermolecular potentials which have been calculated previously

Loss of BCL9/9l suppresses Wnt driven tumourigenesis in models that recapitulate human cancer.

Different thresholds of Wnt signalling are thought to drive stem cell maintenance, regeneration, differentiation and cancer. However, the principle that oncogenic Wnt signalling could be specifically targeted remains controversial. Here we examine the requirement of BCL9/9l, constituents of the Wnt-enhanceosome, for intestinal transformation following loss of the tumour suppressor APC. Although required for Lgr5+ intestinal stem cells and regeneration, Bcl9/9l deletion has no impact upon normal intestinal homeostasis. Loss of BCL9/9l suppressed many features of acute APC loss and subsequent Wnt pathway deregulation in vivo. This resulted in a level of Wnt pathway activation that favoured tumour initiation in the proximal small intestine (SI) and blocked tumour growth in the colon. Furthermore, Bcl9/9l deletion completely abrogated β-catenin driven intestinal and hepatocellular transformation. We speculate these results support the just-right hypothesis of Wnt-driven tumour formation. Importantly, loss of BCL9/9l is particularly effective at blocking colonic tumourigenesis and mutations that most resemble those that occur in human cancer

TGFβ pathway limits dedifferentiation following WNT and MAPK pathway activation to suppress intestinal tumourigenesis

Recent studies have suggested increased plasticity of differentiated cells within the intestine to act both as intestinal stem cells (ISCs) and tumour-initiating cells. However, little is known of the processes that regulate this plasticity. Our previous work has shown that activating mutations of Kras or the NF-κB pathway can drive dedifferentiation of intestinal cells lacking Apc. To investigate this process further, we profiled both cells undergoing dedifferentiation in vitro and tumours generated from these cells in vivo by gene expression analysis. Remarkably, no clear differences were observed in the tumours; however, during dedifferentiation in vitro we found a marked upregulation of TGFβ signalling, a pathway commonly mutated in colorectal cancer (CRC). Genetic inactivation of TGFβ type 1 receptor (Tgfbr1/Alk5) enhanced the ability of KrasG12D/+ mutation to drive dedifferentiation and markedly accelerated tumourigenesis. Mechanistically this is associated with a marked activation of MAPK signalling. Tumourigenesis from differentiated compartments is potently inhibited by MEK inhibition. Taken together, we show that tumours arising in differentiated compartments will be exposed to different suppressive signals, for example, TGFβ and blockade of these makes tumourigenesis more efficient from this compartment

mTORC1-mediated translational elongation limits intestinal tumour initiation and growth.

Inactivation of APC is a strongly predisposing event in the development of colorectal cancer, prompting the search for vulnerabilities specific to cells that have lost APC function. Signalling through the mTOR pathway is known to be required for epithelial cell proliferation and tumour growth, and the current paradigm suggests that a critical function of mTOR activity is to upregulate translational initiation through phosphorylation of 4EBP1 (refs 6, 7). This model predicts that the mTOR inhibitor rapamycin, which does not efficiently inhibit 4EBP1 (ref. 8), would be ineffective in limiting cancer progression in APC-deficient lesions. Here we show in mice that mTOR complex 1 (mTORC1) activity is absolutely required for the proliferation of Apc-deficient (but not wild-type) enterocytes, revealing an unexpected opportunity for therapeutic intervention. Although APC-deficient cells show the expected increases in protein synthesis, our study reveals that it is translation elongation, and not initiation, which is the rate-limiting component. Mechanistically, mTORC1-mediated inhibition of eEF2 kinase is required for the proliferation of APC-deficient cells. Importantly, treatment of established APC-deficient adenomas with rapamycin (which can target eEF2 through the mTORC1-S6K-eEF2K axis) causes tumour cells to undergo growth arrest and differentiation. Taken together, our data suggest that inhibition of translation elongation using existing, clinically approved drugs, such as the rapalogs, would provide clear therapeutic benefit for patients at high risk of developing colorectal cancer

Oncogenic BRAF, unrestrained by TGFβ-receptor signalling, drives right-sided colonic tumorigenesis

Right-sided (proximal) colorectal cancer (CRC) has a poor prognosis and a distinct mutational profile, characterized by oncogenic BRAF mutations and aberrations in mismatch repair and TGFβ signalling. Here, we describe a mouse model of right-sided colon cancer driven by oncogenic BRAF and loss of epithelial TGFβ-receptor signalling. The proximal colonic tumours that develop in this model exhibit a foetal-like progenitor phenotype (Ly6a/Sca1+) and, importantly, lack expression of Lgr5 and its associated intestinal stem cell signature. These features are recapitulated in human BRAF-mutant, right-sided CRCs and represent fundamental differences between left- and right-sided disease. Microbial-driven inflammation supports the initiation and progression of these tumours with foetal-like characteristics, consistent with their predilection for the microbe-rich right colon and their antibiotic sensitivity. While MAPK-pathway activating mutations drive this foetal-like signature via ERK-dependent activation of the transcriptional coactivator YAP, the same foetal-like transcriptional programs are also initiated by inflammation in a MAPK-independent manner. Importantly, in both contexts, epithelial TGFβ-receptor signalling is instrumental in suppressing the tumorigenic potential of these foetal-like progenitor cells

Electron stimulated desorption of H À from thin films of 5-halouracils

We present measurements of low-energy (1-20 eV) electron stimulated desorption (ESD) of H À from thin films of 5-halouracils (5-XU, X ¼ F, Cl, Br and I) condensed on polycrystalline Pt. The onset for H À desorption is $5.0 eV. For all 5-XU a single dissociative electron attachment (DEA) H À peak is observed, which is attributed to at least two dissociation channels at approximately 7.1 and 8.6 eV, resulting from N-H and C-H bond cleavage, respectively. Their relative contribution is parent-molecule dependent. Also, for a given molecule, these dissociation channels are affected differently by the metal, and the DEA maximum shifts by$0.5 eV as the film thickness increases. Above 10 eV, dipolar dissociation (DD) is the dominant H À formation mechanism. The yields of H À vary in the following relative order (T ¼ thymine, U ¼ uracil): T > U > 5-FU > 5-ClU > 5-BrU > 5-IU. A model is developed to explain the film thickness dependence of the desorbed anion signal: above a coverage of $1 monolayer (ML), the film thickness dependence of the H À ESD yield is interpreted in terms of incident electron and desorbing ion transmission within the films. The main difference in the thickness dependence of H À produced via DEA and DD is attributed to the fact that electron transfer to the metal from the transient molecular anion leads to dramatic decrease in the