TLR4 Deficiency Protects against Hepatic Fibrosis and Diethylnitrosamine-Induced Pre-Carcinogenic Liver Injury in Fibrotic Liver

Background The development of hepatocellular carcinoma (HCC) is a common consequence of advanced liver fibrosis but the interactions between fibrogenesis and carcinogenesis are still poorly understood. Recently it has been shown that HCC promotion depends on Toll-like receptor (TLR) 4. Pre-cancerogenous events can be modelled in mice by the administration of a single dose of diethylnitrosamine (DEN), with HCC formation depending amongst others on interleukin (IL) 6 production. Mice lacking the hepatocanalicular phosphatidylcholine transporter ABCB4 develop liver fibrosis spontaneously, resemble patients with sclerosing cholangitis due to mutations of the orthologous human gene, and represent a valid model to study tumour formation in pre-injured cholestatic liver. The aim of this study was to investigate DEN-induced liver injury in TLR4-deficient mice with biliary fibrosis. Methods ABCB4-deficient mice on the FVB/NJ genetic background were crossed to two distinct genetic backgrounds (TLR4-sufficient C3H/HeN and TLR4-deficient C3H/HeJ) for more than 10 generations. The two congenic knockout and the two corresponding wild-type mouse lines were treated with a single dose of DEN for 48 hours. Phenotypic differences were assessed by measuring hepatic collagen contents, inflammatory markers (ALT, CRP, IL6) as well as hepatic apoptosis (TUNEL) and proliferation (Ki67) rates. Results Hepatic collagen accumulation is significantly reduced in ABCB4-/-:TLR4-/-double-deficient mice. After DEN challenge, apoptosis, proliferation and inflammatory markers are decreased in TLR4-deficient in comparison to TLR4-sufficient mice. When combining ABCB4 and TLR4 deficiency with DEN treatment, hepatic IL6 expression and proliferation rates are lowest in fibrotic livers from the double-deficient line. Consistent with these effects, selective digestive tract decontamination in ABCB4-/- mice also led to reduced tumor size and number after DEN. Conclusion This study demonstrates that liver injury upon DEN challenge depends on pre-existing fibrosis and genetic background. The generation of ABCB4-/: TLR4-/- double-deficient mice illustrates that TLR4-deficiency protects against hepatic injury in a preclinical mouse model of chronic liver disease

The progress of early phase bone healing using porous granules produced from calcium phosphate cement

<p>Abstract</p> <p>Objective</p> <p>Bone grafting is a vital component in many surgical procedures to facilitate the repair of bone defects or fusions. Autologous bone has been the gold standard to date in spite of associated donor-site morbidity and the limited amount of available donor bone. The aim of this study was to investigate the progress of bone regeneration and material degradation of calcium phosphate granules (CPG) produced from a calcium phosphate self-setting cement powder compared to the use of autologous bone grafting in the treatment of "critical size defects" on load-bearing long bones of minipigs.</p> <p>Methods</p> <p>A critical size defect in the tibial metaphysis of 16 mini-pigs was filled either with autologous cancellous graft or with micro- and macroporous carbonated, apatic calcium phosphate granules (CPG) produced from a calcium phosphate self-setting cement powder. After 6 weeks, the specimens were assessed by X-ray and histological evaluation. The amount of new bone formation was analysed histomorphometrically.</p> <p>Results</p> <p>The semi-quantitative analysis of the radiological results showed a complete osseous bridging of the defect in three cases for the autograft group. In the same group five animals showed a beginning, but still incomplete bridging of the defect, whereas in the CPG group just two animals developed this. All other animals of the CPG group showed only a still discontinuous new bone formation. Altogether, radiologically a better osseous bridging was observed in the autograft group compared to the CPG group.</p> <p>Histomorphometrical analysis after six weeks of healing revealed that the area of new bone was significantly greater in the autograft group concerning the central area of the defect zone (p < 0.001) as well as the cortical defect zone (p < 0.002). All defects showed new bone formation, but only in the autograft group defects regenerated entirely</p> <p>Conclusions</p> <p>Within the limits of the present study it could be demonstrated that autologous cancellous grafts lead to a significantly better bone regeneration compared to the application of calcium phosphate granules (CPG) produced from a calcium phosphate self-setting cement powder after 6 weeks. In the early phase of bone-healing, the sole application of CPG appears to be inferior to the autologous cancellous grafts in an <it>in vivo </it>critical size defect on load-bearing long bones of mini-pigs.</p

On consensus in the Cucker--Smale type model on isolated time scales

This article addresses a consensus phenomenon in a Cucker-Smale model where the magnitude of the step size is not necessarily a constant but it is a function of time. In the considered model the weights of mutual influences in the group of agents do not change. A sufficient condition under which the proposed model tends to a consensus is obtained. This condition strikingly demonstrates the importance of the graininess function in a consensus phenomenon. The results are illustrated by numerical simulations.publishe

Generalizations of Gronwall-Bihari Inequalities on Time Scales

We establish some nonlinear integral inequalities for functions defined on a time scale. The results extend some previous Gronwall and Bihari type inequalities on time scales. Some examples of time scales for which our results can be applied are provided. An application to the qualitative analysis of a nonlinear dynamic equation is discussed.Comment: This is a preprint of an article accepted (16/May/2008) for publication in the "Journal of Difference Equations and Applications"; J. Difference Equ. Appl. is available online at http://www.informaworld.co

Algebraic construction of the Darboux matrix revisited

We present algebraic construction of Darboux matrices for 1+1-dimensional integrable systems of nonlinear partial differential equations with a special stress on the nonisospectral case. We discuss different approaches to the Darboux-Backlund transformation, based on different lambda-dependencies of the Darboux matrix: polynomial, sum of partial fractions, or the transfer matrix form. We derive symmetric N-soliton formulas in the general case. The matrix spectral parameter and dressing actions in loop groups are also discussed. We describe reductions to twisted loop groups, unitary reductions, the matrix Lax pair for the KdV equation and reductions of chiral models (harmonic maps) to SU(n) and to Grassmann spaces. We show that in the KdV case the nilpotent Darboux matrix generates the binary Darboux transformation. The paper is intended as a review of known results (usually presented in a novel context) but some new results are included as well, e.g., general compact formulas for N-soliton surfaces and linear and bilinear constraints on the nonisospectral Lax pair matrices which are preserved by Darboux transformations.Comment: Review paper (61 pages). To be published in the Special Issue "Nonlinearity and Geometry: Connections with Integrability" of J. Phys. A: Math. Theor. (2009), devoted to the subject of the Second Workshop on Nonlinearity and Geometry ("Darboux Days"), Bedlewo, Poland (April 2008

Tumour-derived PGD2 and NKp30-B7H6 engagement drives an immunosuppressive ILC2-MDSC axis.

Group 2 innate lymphoid cells (ILC2s) are involved in human diseases, such as allergy, atopic dermatitis and nasal polyposis, but their function in human cancer remains unclear. Here we show that, in acute promyelocytic leukaemia (APL), ILC2s are increased and hyper-activated through the interaction of CRTH2 and NKp30 with elevated tumour-derived PGD2 and B7H6, respectively. ILC2s, in turn, activate monocytic myeloid-derived suppressor cells (M-MDSCs) via IL-13 secretion. Upon treating APL with all-trans retinoic acid and achieving complete remission, the levels of PGD2, NKp30, ILC2s, IL-13 and M-MDSCs are restored. Similarly, disruption of this tumour immunosuppressive axis by specifically blocking PGD2, IL-13 and NKp30 partially restores ILC2 and M-MDSC levels and results in increased survival. Thus, using APL as a model, we uncover a tolerogenic pathway that may represent a relevant immunosuppressive, therapeutic targetable, mechanism operating in various human tumour types, as supported by our observations in prostate cancer.Group 2 innate lymphoid cells (ILC2s) modulate inflammatory and allergic responses, but their function in cancer immunity is still unclear. Here the authors show that, in acute promyelocytic leukaemia, tumour-activated ILC2s secrete IL-13 to induce myeloid-derived suppressor cells and support tumour growth

Sturm-Liouville operators with measure-valued coefficients

We give a comprehensive treatment of Sturm-Liouville operators with measure-valued coefficients including, a full discussion of self-adjoint extensions and boundary conditions, resolvents, and Weyl-Titchmarsh theory. We avoid previous technical restrictions and, at the same time, extend all results to a larger class of operators. Our operators include classical Sturm-Liouville operators, Lax operators arising in the treatment of the Camassa-Holm equation, Jacobi operators, and Sturm-Liouville operators on time scales as special cases.Comment: 58 page