Induction of B-cell lymphoma by UVB Radiation in p53 Haploinsufficient Mice

<p>Abstract</p> <p>Background</p> <p>The incidence of non-Hodgkin's lymphoma has increased over recent years. The exact etiology of lymphoma remains unknown. Ultraviolet light exposure has been associated with the development of internal lymphoid malignancies and some reports suggest that it may play a role in the development of lymphoma in humans. Here we describe the characterization and progression of lymphoma in p53 heterozygous mice exposed to UVB irradiation.</p> <p>Methods</p> <p>UVB-irradiated p53^+/-mice developed enlargement of the spleen. Isolated spleen cells were transplanted into Rag deficient hosts. The UV-induced tumor cells were analyzed by flow cytometry. The tumor cells were tagged with GFP to study their metastatic potential. SKY and karyotypic analysis were carried out for the detection of chromosomal abnormalities. Functional assays included in vitro class switch recombination assay, immunoglobulin rearrangement assay, as well as cytokine profiling.</p> <p>Results</p> <p>UVB-exposed mice showed enlargement of the spleen and lymph nodes. Cells transplanted into Rag deficient mice developed aggressive tumors that infiltrated the lymph nodes, the spleen and the bone marrow. The tumor cells did not grow in immune competent syngeneic C57Bl/6 mice yet showed a modest growth in UV-irradiated B6 mice. Phenotypic analysis of these tumor cells revealed these cells are positive for B cell markers CD19⁺, CD5⁺, B220⁺, IgM⁺and negative for T cell, NK or dendritic cell markers. The UV-induced tumor cells underwent robust in vitro immunoglobulin class switch recombination in response to lipopolysaccharide. Cytogenetic analysis revealed a t(14;19) translocation and trisomy of chromosome 6. These tumor cells secret IL-10, which can promote tumor growth and cause systemic immunosuppression.</p> <p>Conclusion</p> <p>UV-irradiated p53^+/-mice developed lymphoid tumors that corresponded to a mature B cell lymphoma. Our results suggest that an indirect mechanism is involved in the development of internal tumors after chronic exposure to UV light. The induction of B cell lymphoma in UV-irradiated p53 heterozygous mice may provide a useful model for lymphoma development in humans.</p

Asynchronous combinatorial action of four regulatory factors activates Bcl11b for T cell commitment

During T cell development, multipotent progenitors relinquish competence for other fates and commit to the T cell lineage by turning on Bcl11b, which encodes a transcription factor. To clarify lineage commitment mechanisms, we followed developing T cells at the single-cell level using Bcl11b knock-in fluorescent reporter mice. Notch signaling and Notch-activated transcription factors collaborate to activate Bcl11b expression irrespectively of Notch-dependent proliferation. These inputs work via three distinct, asynchronous mechanisms: an early locus 'poising' function dependent on TCF-1 and GATA-3, a stochastic-permissivity function dependent on Notch signaling, and a separate amplitude-control function dependent on Runx1, a factor already present in multipotent progenitors. Despite their necessity for Bcl11b expression, these inputs act in a stage-specific manner, providing a multitiered mechanism for developmental gene regulation

Oblivious Pseudorandom Functions from Isogenies

An oblivious PRF, or OPRF, is a protocol between a client and a server, where the server has a key $k$ for a secure pseudorandom function $F$, and the client has an input $x$ for the function. At the end of the protocol the client learns $F(k,x)$, and nothing else, and the server learns nothing. An OPRF is verifiable if the client is convinced that the server has evaluated the PRF correctly with respect to a prior commitment to $k$. OPRFs and verifiable OPRFs have numerous applications, such as private-set-intersection protocols, password-based key-exchange protocols, and defense against denial-of-service attacks. Existing OPRF constructions use RSA-, Diffie-Hellman-, and lattice-type assumptions. The first two are not post-quantum secure. In this paper we construct OPRFs and verifiable OPRFs from isogenies. Our main construction uses isogenies of supersingular elliptic curves over $\mathbb{F}_{p^{2}}$ and tries to adapt the Diffie-Hellman OPRF to that setting. However, a recent attack on supersingular-isogeny systems due to Galbraith et al. [ASIACRYPT 2016] makes this approach difficult to secure. To overcome this attack, and to validate the server\u27s response, we develop two new zero-knowledge protocols that convince each party that its peer has sent valid messages. With these protocols in place, we obtain an OPRF in the SIDH setting and prove its security in the UC framework. Our second construction is an adaptation of the Naor-Reingold PRF to commutative group actions. Combining it with recent constructions of oblivious transfer from isogenies, we obtain an OPRF in the CSIDH setting

RNA delivery by extracellular vesicles in mammalian cells and its applications.

The term 'extracellular vesicles' refers to a heterogeneous population of vesicular bodies of cellular origin that derive either from the endosomal compartment (exosomes) or as a result of shedding from the plasma membrane (microvesicles, oncosomes and apoptotic bodies). Extracellular vesicles carry a variety of cargo, including RNAs, proteins, lipids and DNA, which can be taken up by other cells, both in the direct vicinity of the source cell and at distant sites in the body via biofluids, and elicit a variety of phenotypic responses. Owing to their unique biology and roles in cell-cell communication, extracellular vesicles have attracted strong interest, which is further enhanced by their potential clinical utility. Because extracellular vesicles derive their cargo from the contents of the cells that produce them, they are attractive sources of biomarkers for a variety of diseases. Furthermore, studies demonstrating phenotypic effects of specific extracellular vesicle-associated cargo on target cells have stoked interest in extracellular vesicles as therapeutic vehicles. There is particularly strong evidence that the RNA cargo of extracellular vesicles can alter recipient cell gene expression and function. During the past decade, extracellular vesicles and their RNA cargo have become better defined, but many aspects of extracellular vesicle biology remain to be elucidated. These include selective cargo loading resulting in substantial differences between the composition of extracellular vesicles and source cells; heterogeneity in extracellular vesicle size and composition; and undefined mechanisms for the uptake of extracellular vesicles into recipient cells and the fates of their cargo. Further progress in unravelling the basic mechanisms of extracellular vesicle biogenesis, transport, and cargo delivery and function is needed for successful clinical implementation. This Review focuses on the current state of knowledge pertaining to packaging, transport and function of RNAs in extracellular vesicles and outlines the progress made thus far towards their clinical applications

DVT in degenerative cervical spine disease

Study design: A prospective observational study. Objectives: To determine the incidence of deep venous thrombosis (DVT) and to evaluate the risk factors for DVT development associated with degenerative cervical spine disease. Setting: Hokkaido Spinal Cord Injury Center, Japan. Methods: Between April 2008 and March 2015, patients with degenerative cervical spine disease, such as compressive myelopathy or radiculopathy, who underwent surgical treatment were prospectively assessed. Leg vein ultrasonography and D-dimer tests were performed preoperatively and at 4 days after surgery. All patients received treatment with intermittent pneumatic compression and elastic stockings for primary DVT prophylaxis. No anticoagulation medications were used for DVT prophylaxis. Results: A total of 289 patients (203 males, 86 females; median age: 67 years (interquartile range, 58-76)) were included. Nine patients (3.1%) exhibited DVT during the perioperative period. All 9 cases were women who had distal DVT. The incidences of preoperative and postoperative DVT were 1.1% and 2.1%, respectively. The univariate analysis showed that statistically significant risk factors for perioperative DVT included female gender (P < 0.01), advanced age (P = 0.04), a low Japanese Orthopaedic Association score (P = 0.03), rapidly progressive myelopathy (P < 0.01), and inability to walk (P = 0.01). The multivariate analysis showed that rapidly progressive myelopathy (P = 0.04) was the most important risk factor. Conclusion: Female gender and rapidly progressive myelopathy are high-risk factors that predict the development of DVT during the perioperative period of cervical spine surgery. This result indicates that screening and treatment for DVT are needed in such high-risk patients