Keratins are cytoplasmic intermediate filament proteins preferentially expressed by epithelial tissues in a site-specific and differentiation-dependent manner. The complex network of keratin filaments in stratified epithelia is tightly regulated during squamous cell differentiation. Keratin 14 (K14) is expressed in mitotically active basal layer cells, along with its partner keratin 5 (K5), and their expression is down-regulated as cells differentiate. Apart from the cytoprotective functions of K14, very little is known about K14 regulatory functions, since the K14 knockout mice show postnatal lethality. In this study, K14 expression was inhibited using RNA interference in cell lines derived from stratified epithelia to study the K14 functions in epithelial homeostasis. The K14 knockdown clones demonstrated substantial decreases in the levels of the K14 partner K5. These cells showed reduction in cell proliferation and delay in cell cycle progression, along with decreased phosphorylated Akt levels. K14 knockdown cells also exhibited enhanced levels of activated Notch1, involucrin, and K1. In addition, K14 knockdown AW13516 cells showed significant reduction in tumorigenicity. Our results suggest that K5 and K14 may have a role in maintenance of cell proliferation potential in the basal layer of stratified epithelia, modulating phosphatidylinositol 3-kinase/Akt–mediated cell proliferation and/or Notch1-dependent cell differentiation.

We reconsider the Feynman-Kislinger-Ravndal model applied to neutrino-excitation of baryon resonances. The effects of lepton mass are included, using the formalism of Kuzmin, Lyubushkin, and Naumov. In addition we take account of the pion-pole contribution to the hadronic axial vector current. Application of this new formalism to the reaction ${\nu }_{\mu }+p\to {\mu }^{-}+{\Delta }^{++}$ at $E_{\nu }\sim 1\mathrm{GeV}$ gives a suppressed cross section at small angles, in agreement with the screening correction in Adler’s forward-scattering theorem. Application to the process ${\nu }_{\tau }+p\to {\tau }^{-}+{\Delta }^{++}$ at $E_{\nu }\sim 7\mathrm{GeV}$ leads to the prediction of right-handed ${\tau }^{-}$ polarization for forward-going leptons, in line with a calculation based on an isobar model. Our formalism represents an improved version of the Rein-Sehgal model, incorporating lepton mass effects in a manner consistent with partially conserved axial-vector current.

Coherent ${\pi }^{+}$ and $\pi °$ production in low energy neutrino reactions is discussed in the framework of the partially conserved axial vector current theory . The role of lepton mass effects in suppressing the ${\pi }^{+}$ production is emphasized. Instead of using models of pion nucleus scattering, the available data on pion carbon scattering are implemented for an analysis of the partially conserved axial vector current theory prediction. Our results agree well with the published upper limits for ${\pi }^{+}$ production but are much below the recent MiniBooNE result for $\pi °$ production.

The short-distance Hamiltonian describing $\overrightarrow{b}{s\left(d\right)e}^{-}{e}^{+}$ in the standard model is used to obtain the decay spectrum of $\overline{B}\to K^{-}{\pi }^{+}{e}^{-}{e}^{+}$ and $\overline{B}\to {\pi }^{-}{\pi }^{+}{e}^{-}{e}^{+},$ assuming the $K\pi$ and $\pi \pi$ systems to be the decay products of $K^{*}$ and $\rho$ respectively. The specific features calculated are (i) the angular distribution of $K^{-}$ (or ${\pi }^{-})$ in the $K^{-}{\pi }^{+}$ (or ${\pi }^{-}{\pi }^{+})$ center-of-mass (c.m.) frame, (ii) the angular distribution of $e^{-}$ in the $e^{-}{e}^{+}$ c.m. frame, and (iii) the correlation between the meson and lepton planes. We also derive $\mathit{CP}$-violating observables obtained by combining the above decays with the conjugate processes $\overrightarrow{B}{K}^{+}{\pi }^{-}{e}^{-}{e}^{+}$ and $\overrightarrow{B}{\pi }^{-}{\pi }^{+}{e}^{-}{e}^{+}.$

Chronic activation of B-cell receptor (BCR) signaling via Bruton tyrosine kinase (BTK) is largely considered to be one of the primary mechanisms driving disease progression in B–Cell lymphomas. Although the BTK-targeting agent ibrutinib has shown promising clinical responses, the presence of primary or acquired resistance is common and often leads to dismal clinical outcomes. Resistance to ibrutinib therapy can be mediated through genetic mutations, up-regulation of alternative survival pathways, or other unknown factors that are not targeted by ibrutinib therapy. Understanding the key determinants, including tumor heterogeneity and rewiring of the molecular networks during disease progression and therapy, will assist exploration of alternative therapeutic strategies. Towards the goal of overcoming ibrutinib resistance, multiple alternative therapeutic agents, including second- and third-generation BTK inhibitors and immunomodulatory drugs, have been discovered and tested in both pre-clinical and clinical settings. Although these agents have shown high response rates alone or in combination with ibrutinib in ibrutinib-treated relapsed/refractory(R/R) lymphoma patients, overall clinical outcomes have not been satisfactory due to drug-associated toxicities and incomplete remission. In this review, we discuss the mechanisms of ibrutinib resistance development in B-cell lymphoma including complexities associated with genomic alterations, non-genetic acquired resistance, cancer stem cells, and the tumor microenvironment. Furthermore, we focus our discussion on more comprehensive views of recent developments in therapeutic strategies to overcome ibrutinib resistance, including novel BTK inhibitors, clinical therapeutic agents, proteolysis-targeting chimeras and immunotherapy regimens.