Dendritic Cells Transduced to Express Interleukin 4 Reduce Diabetes Onset in Both Normoglycemic and Prediabetic Nonobese Diabetic Mice

Background: We and others have previously demonstrated that treatment with bone marrow derived DC genetically modified to express IL-4 reduce disease pathology in mouse models of collagen-induced arthritis and delayed-type hypersensitivity. Moreover, treatment of normoglycemic NOD mice with bone marrow derived DC, genetically modified to express interleukin 4 (IL-4), reduces the onset of hyperglycemia in a significant number of animals. However, the mechanism(s) through which DC expressing IL-4 function to prevent autoimmune diabetes and whether this treatment can reverse disease in pre-diabetic NOD mice are unknown. Methodology/Principal Findings: DC were generated from the bone marrow of NOD mice and transduced with adenoviral vectors encoding soluble murine IL-4 (DC/sIL-4), a membrane-bound IL-4 construct, or empty vector control. Female NOD mice were segregated into normoglycemic (<150mg/dL) and prediabetic groups (between 150 and 250 mg/dL) on the basis of blood glucose measurements, and randomized for adoptive transfer of 106 DC via a single i.v. injection. A single injection of DC/sIL-4, when administered to normoglycemic 12-week old NOD mice, significantly reduced the number of mice that developed diabetes. Furthermore, DC/sIL-4, but not control DC, decreased the number of mice progressing to diabetes when given to prediabetic NOD mice 12-16 weeks of age. DC/sIL-4 treatment also significantly reduced islet mononuclear infiltration and increased the expression of FoxP3 in the pancreatic lymph nodes of a subset of treated animals. Furthermore, DC/sIL-4 treatment altered the antigen-specific Th2:Th1 cytokine profiles as determined by ELISPOT of splenocytes in treated animals. Conclusions: Adoptive transfer of DC transduced to express IL-4 into both normoglycemic and prediabetic NOD mice is an effective treatment for T1D. © 2010 Ruffner, Robbins

Clinical Significance of PTEN Deletion, Mutation, and Loss of PTEN Expression in De Novo Diffuse Large B-Cell Lymphoma

PTEN loss has been associated with poorer prognosis in many solid tumors. However, such investigation in lymphomas is limited. In this study, PTEN cytoplasmic and nuclear expression, PTEN gene deletion, and PTEN mutations were evaluated in two independent cohorts of diffuse large B-cell lymphoma (DLBCL). Cytoplasmic PTEN expression was found in approximately 67% of total 747 DLBCL cases, more frequently in the activated B-cell-like subtype. Nuclear PTEN expression was less frequent and at lower levels, which significantly correlated with higher PTEN mRNA expression. Remarkably, loss of PTEN protein expression was associated with poorer survival only in DLBCL with AKT hyperactivation. In contrast, high PTEN expression was associated with Myc expression and poorer survival in cases without abnormal AKT activation. Genetic and epigenetic mechanisms for loss of PTEN expression were investigated. PTEN deletions (mostly heterozygous) were detected in 11.3% of DLBCL, and showed opposite prognostic effects in patients with AKT hyperactivation and in MYC rearranged DLBCL patients. PTEN mutations, detected in 10.6% of patients, were associated with upregulation of genes involved in central nervous system function, metabolism, and AKT/mTOR signaling regulation. Loss of PTEN cytoplasmic expression was also associated with TP53 mutations, higher PTEN-targeting microRNA expression, and lower PD-L1 expression. Remarkably, low PTEN mRNA expression was associated with down-regulation of a group of genes involved in immune responses and B-cell development/differentiation, and poorer survival in DLBCL independent of AKT activation. Collectively, multi-levels of PTEN abnormalities and dysregulation may play important roles in PTEN expression and loss, and that loss of PTEN tumor-suppressor function contributes to the poor survival of DLBCL patients with AKT hyperactivation

Rapid assembly of customized TALENs into multiple

Transcriptional activator-like effector nucleases (TALENs) have become a powerful tool for genome editing. Here we present an efficient TALEN assembly approach in which TALENs are assembled by direct Golden Gate ligation into Gateway® Entry vectors from a repeat variable di-residue (RVD) plasmid array. We constructed TALEN pairs targeted to mouse Ddx3 subfamily genes, and demonstrated that our modified TALEN assembly approach efficiently generates accurate TALEN moieties that effectively introduce mutations into target genes. We generated "user friendly" TALEN Entry vectors containing TALEN expression cassettes with fluorescent reporter genes that can be efficiently transferred via Gateway (LR) recombination into different delivery systems. We demonstrated that the TALEN Entry vectors can be easily transferred to an adenoviral delivery system to expand application to cells that are difficult to transfect. Since TALENs work in pairs, we also generated a TALEN Entry vector set that combines a TALEN pair into one PiggyBac transposon-based destination vector. The approach described here can also be modified for construction of TALE transcriptional activators, repressors or other functional domains. © 2013 Zhang et al

p63 expression confers significantly better survival outcomes in high-risk diffuse large B-cell lymphoma and demonstrates p53-like and p53-independent tumor suppressor function

The role of p53 family member, p63 in oncogenesis is the subject of controversy. Limited research has been done on the clinical implications of p63 expression in diffuse large B-cell lymphoma (DLBCL). In this study, we assessed p63 expression in de novo DLBCL samples (n=795) by immunohistochemistry with a pan-p63-monoclonal antibody and correlated it with other clinicopathologic factors and clinical outcomes. p63 expression was observed in 42.5% of DLBCL, did not correlate with p53 levels, but correlated with p21, MDM2, p16INK4A, Ki-67, Bcl-6, IRF4/MUM-1 and CD30 expression, REL gains, and BCL6 translocation. p63 was an independent favorable prognostic factor in DLBCL, which was most significant in patients with International Prognostic Index (IPI) >2, and in activated-B-cell–like DLBCL patients with wide-type TP53. The prognostic impact in germinal-center-B-cell–like DLBCL was not apparent, which was likely due to the association of p63 expression with high-risk IPI, and potential presence of ∆Np63 isoform in TP63 rearranged patients (a mere speculation). Gene expression profiling suggested that p63 has both overlapping and distinct functions compared with p53, and that p63 and mutated p53 antagonize each other. In summary, p63 has p53-like and p53-independent functions and favorable prognostic impact, however this protective effect can be abolished by TP53 mutations

Measurements of the electric and magnetic form factors of the neutron for time-like momentum transfer

We present the first measurements of the electric and magnetic form factors of the neutron in the time-like (positive $q^2$) region as function of four-momentum transfer. We explored the differential cross sections of the reaction $e^+e^- \rightarrow \bar{n}n$ with data collected with the BESIII detector at the BEPCII accelerator, corresponding to an integrated luminosity of 354.6 pb$^{-1}$ in total at twelve center-of-mass energies between $\sqrt{s} = 2.0 - 2.95$ GeV. A relative uncertainty of 18% and 12% for the electric and magnetic form factors, respectively, is achieved at $\sqrt{s} = 2.3935$ GeV. Our results are comparable in accuracy to those from electron scattering in the comparable space-like (negative $q^2$) region of four-momentum transfer. The electromagnetic form factor ratio $R_{\rm em}\equiv |G_E|/|G_M|$ is within the uncertainties close to unity. We compare our result on $|G_E|$ and $|G_M|$ to recent model predictions, and the measurements in the space-like region to test the analyticity of electromagnetic form factors.Comment: main paper: 9 pages, 6 figures, 3 tables; supplement: 9 pages, 28 table

Search for an axion-like particle in J/ψJ/\psi radiative decays

We search for an axion-like particle (ALP) $a$ through the process $\psi(3686)\rightarrow\pi^+\pi^-J/\psi$, $J/\psi\rightarrow\gamma a$, $a\rightarrow\gamma\gamma$ in a data sample with $(2708.1\pm14.5)\times10^6$ $\psi(3686)$ events collected by the BESIII detector. No significant ALP signal is observed over the expected background, and the upper limits on the branching fraction of the decay $J/\psi\rightarrow\gamma a$ and the ALP-photon coupling constant $g_{a\gamma\gamma}$ are set at the 95\% confidence level in the mass range of 0.165\leq m_a\leq2.84\,\mbox{GeV}/c^2. The limits on $\mathcal{B}(J/\psi\rightarrow\gamma a)$ range from $8.3\times10^{-8}$ to $1.8\times10^{-6}$ over the search region, and the constraints on the ALP-photon coupling are the most stringent to date for 0.165\leq m_a\leq1.468\,\mbox{GeV}/c^2.Comment: 10 pages, 5 figure

Production of doubly-charged Δ\Delta baryon in e+e−e^{+}e^{-} annihilation at energies from 2.3094 to 2.6464 GeV

The processes $e^{+}e^{-} \to \Delta^{++}\bar{\Delta}^{--}$ and $e^{+}e^{-}\to \Delta^{++} \bar{p} \pi^{-} + c.c.$ are studied for the first time with $179~{\rm pb}^{-1}$ of $e^{+}e^{-}$ annihilation data collected with the BESIII detector at center-of-mass energies from $2.3094$ GeV to $2.6464$ GeV. No significant signal for the $e^{+}e^{-}\to \Delta^{++}\bar{\Delta}^{--}$ process is observed and the upper limit of the Born cross section is estimated at each energy point. For the process $e^{+}e^{-} \to \Delta^{++} \bar{p} \pi^{-} + c.c.$, a significant signal is observed at center-of-mass energies near 2.6454 GeV and the corresponding Born cross section is reported.Comment: 10 pages, 4 figure

First Observation of a Three-Resonance Structure in e+e−→e^+e^-\rightarrow{non-open} Charm Hadrons

We report the measurement of the cross sections for $e^+e^-$$\rightarrow${nOCH} (nOCH stands for non-open charm hadrons) with improved precision at center-of-mass energies from 3.645 to 3.871 GeV. We observe for the first time a three-resonance structure in the energy-dependent lineshape of the cross sections, which are $\mathcal R(3760)$, $\mathcal R(3780)$ and $\mathcal R(3810)$ with significances of $9.4\sigma$, $15.7\sigma$, and $9.8\sigma$, respectively. The $\mathcal R(3810)$ is observed for the first time. We found two solutions in analysis of the cross sections. For solution I [solution II], we measure the mass, the total width and the product of electronic width and nOCH decay branching fraction to be $(3805.8 \pm 1.1 \pm 2.7)$ [$(3805.8 \pm 1.1 \pm 2.7)$] MeV/$c^2$, $(11.6 \pm 2.6 \pm 1.9)$ [$(11.5 \pm 2.5 \pm 1.8)$] MeV, and $(10.8\pm 3.2\pm 2.3)$ [$(11.0\pm 2.9\pm 2.4)$] eV for the $\mathcal R(3810)$, respectively. In addition, we measure the branching fractions ${\mathcal B}({\mathcal R}(3760)$$\rightarrow${nOCH}$)=(24.5 \pm 13.4 \pm 27.4)\% [(6.8 \pm 5.4 \pm 7.6)\%]$ for the first time, and ${\mathcal B}(\mathcal R(3780)$$\rightarrow${nOCH}$)=(11.6 \pm 5.8 \pm 7.8)\% [(10.3 \pm 4.5 \pm 6.9)\%]$. Moreover, we determine the open-charm (OC) branching fraction ${\mathcal B}({\mathcal R}$$(3760)\rightarrow${OC}$)=(75.5 \pm 13.4 \pm 27.4)\% [(93.2 \pm 5.4 \pm 7.6)\%]$, which supports the interpretation of $\mathcal R(3760)$ as an OC pair molecular state, but contained a simple four-quark state component. The first uncertainties are from fits to the cross sections, and the second are systematic

Measurements of the branching fractions of the inclusive decays D0(D+)→π+π+π−X

Using eþe− annihilation data corresponding to an integrated luminosity of 2.93 fb−1 taken at a center-of mass energy of 3.773 GeV with the BESIII detector, we report the first measurements of the branching fractions of the inclusive decays D0 → πþπþπ−X and Dþ → πþπþπ−X, where pions from K0 S decays have been excluded from the πþπþπ− system and X denotes any possible particle combination. The branching fractions of D0ðDþÞ → πþπþπ−X are determined to be BðD0 → πþπþπ−XÞ¼ð17.60 0.11 0.22Þ% and BðDþ → πþπþπ−XÞ¼ð15.25 0.09 0.18Þ%, where the first uncertainties are statistical and the second systematic