Baryon Number Violation Involving Higher Generations

Proton stability seems to constrain rather strongly any baryon number violating process. We investigate the possibility of baryon number violating processes involving right-handed dynamics or higher generation quarks. Our results strongly suggest that there will be no possibility to observe baryon number violation in tau or higher generation quark decays, at any future machine.Comment: Improved figures, small changes in the text, added reference. To appear in Phys. Rev.

Complete CKM quark mixing via dimensional deconstruction

It is shown that the deconstruction of $[SU(2)\times U(1)]^N$ into $[SU(2)\times U(1)]$ is capable of providing all necessary ingredients to completely impliment the complex CKM mixing of quark flavors. The hierarchical structure of quark masses originates from the difference in the deconstructed chiral zero-mode distribution in theory space, while the CP-violating phase comes from the genuinely complex vacuum expectation value of link fields. The mixing is constructed in a specific model to satisfy experimental bounds on quarks' masses and CP violation.Comment: RevTex4, 25 pages, typos in section IIC corrected, published versio

Rare K decays in a model of quark and lepton masses

An extension of a model of neutrino masses to the quark sector provides an interesting link between these two sectors. A parameter which is important to describe neutrino oscillations and masses is found to be a crucial one appearing in various ``penguin'' operators, in particular the so-called Z penguin. This parameter is severely constrained by the rare decay process $K_{L} \to \mu^{+} \mu^{-}$. This in turn has interesting implications on the decay rates of other rare processes such as $K_{L} \to \mu e$, etc..., as well as on the masses of the neutrinos and the masses of the vector-like quarks and leptons which appear in our model.Comment: 34 pages, 10 figures, corrected some typos in the introductio

hMENA11a contributes to HER3-mediated resistance to PI3K inhibitors in HER2-overexpressing breast cancer cells.

Human Mena (hMENA), an actin regulatory protein of the ENA/VASP family, cooperates with ErbB receptor family signaling in breast cancer. It is overexpressed in high-risk preneoplastic lesions and in primary breast tumors where it correlates with HER2 overexpression and an activated status of AKT and MAPK. The concomitant overexpression of hMENA and HER2 in breast cancer patients is indicative of a worse prognosis. hMENA is expressed along with alternatively expressed isoforms, hMENA11a and hMENAΔv6 with opposite functions. A novel role for the epithelial-associated hMENA11a isoform in sustaining HER3 activation and pro-survival pathways in HER2-overexpressing breast cancer cells has been identified by reverse phase protein array and validated in vivo in a series of breast cancer tissues. As HER3 activation is crucial in mechanisms of cell resistance to PI3K inhibitors, we explored whether hMENA11a is involved in these resistance mechanisms. The specific hMENA11a depletion switched off the HER3-related pathway activated by PI3K inhibitors and impaired the nuclear accumulation of HER3 transcription factor FOXO3a induced by PI3K inhibitors, whereas PI3K inhibitors activated hMENA11a phosphorylation and affected its localization. At the functional level, we found that hMENA11a sustains cell proliferation and survival in response to PI3K inhibitor treatment, whereas hMENA11a silencing increases molecules involved in cancer cell apoptosis. As shown in three-dimensional cultures, hMENA11a contributes to resistance to PI3K inhibition because its depletion drastically reduced cell viability upon treatment with PI3K inhibitor BEZ235. Altogether, these results indicate that hMENA11a in HER2-overexpressing breast cancer cells sustains HER3/AKT axis activation and contributes to HER3-mediated resistance mechanisms to PI3K inhibitors. Thus, hMENA11a expression can be proposed as a marker of HER3 activation and resistance to PI3K inhibition therapies, to select patients who may benefit from these combined targeted treatments. hMENA11a activity could represent a new target for antiproliferative therapies in breast cancer

Solvent-Free Synthesis of Quaternary Oxazolidine-2-thione β3-Amino Ester Analogs

A solvent-free organocatalyzed intermolecular cyclization reaction starting from β-substituted γ-hydroxy-α,β-unsaturated esters and aryl isothiocyanates proceeds via an aza-Michael addition to provide previously unknown quaternary oxazolidine-2-thione β3 amino ester analogs. A panel of diversely-substituted esters was investigated, including β,γ-disubstituted examples which provided the target molecules with very high cis diastereoselectivity

Apoptosis induced by a HIPK2 full-length-specific siRNA is due to off-target effects rather than prevalence of HIPK2-Δe8 isoform.

Small interfering RNAs (siRNAs) are widely used to study gene function and extensively exploited for their potential therapeutic applications. HIPK2 is an evolutionary conserved kinase that binds and phosphorylates several proteins directly or indirectly related to apoptosis. Recently, an alternatively spliced isoform skipping 81 nucleotides of exon 8 (Hipk2-∆e8) has been described. Selective depletion of Hipk2 full-length (Hipk2-FL) with a speci c siRNA that spares the Hipk2-∆e8 isoform has been shown to strongly induce apoptosis, suggesting an unpredicted dominant- negative effect of Hipk2-FL over the ∆e8 isoform. From this observation, we sought to take advantage and assessed the therapeutic potential of generating Hipk2 isoform unbalance in tumor-initiating cells derived from colorectal cancer patients. Strong reduction of cell viability was induced in vitro and in vivo by the originally described exon 8-speci c siRNA, supporting a potential therapeutic application. However, validation analyses performed with additional exon8-speci c siRNAs with different stabilities showed that all exon8-targeting siRNAs can induce comparable Hipk2 isoform unbalance but only the originally reported e8-siRNA promotes cell death. These data show that loss of viability does not depend on the prevalence of Hipk2- ∆e8 isoform but it is rather due to microRNA-like off-target effects

Phenomenology of a Quark Mass Matrix from Six Dimensions and its implication for the Strong CP problem

A model of quark mass matrices from six dimensions, which is nearly democatic in nature and which is previously constructed by two of us (PQH and MS), is studied in detail in this manuscript. We found that not only it fits all the six quark masses as well as the CKM matrix but also that there exists a region in the allowed parameter space of the model where the constraint on the parameter \bar{\theta} of the Strong CP problem is satisfied. This region itself puts a constraint on the CKM parameters \bar{\rho} and \bar{\eta}. As such, through our analysis, there appears to be a deep connection between Strong and Weak CP in this modelComment: RevTeX, 21 pages and 14 figure