Unsuccessful therapy with adefovir and entecavir-tenofovir in a patient with chronic hepatitis B infection with previous resistance to lamivudine: a fourteen-year evolution of hepatitis B virus mutations

<p>Abstract</p> <p>Background</p> <p>Complex mutants can be selected under sequential selective pressure by HBV therapy. To determine hepatitis B virus genomic evolution during antiviral therapy we characterized the HBV quasi-species in a patient who did no respond to therapy following lamivudine breakthrough for a period of 14 years.</p> <p>Case Presentation</p> <p>The polymerase and precore/core genes were amplified and sequenced at determined intervals in a period of 14 years. HBV viral load and HBeAg/Anti-HBe serological profiles as well as amino transferase levels were also measured. A mixture of lamivudine-resistant genotype A2 HBV strains harboring the rtM204V mutation coexisted in the patient following viral breakthrough to lamivudine. The L180M+M204V dominant mutant displayed strong lamivudine-resistance. As therapy was changed to adefovir, then to entecavir, and finally to entecavir-tenofovir the viral load showed fluctuations but lamivudine-resistant strains continued to be selected, with minor contributions to the HBV quasi-species composition of additional resistance-associated mutations. At the end of the 14-year follow up period, high viral loads were predominant, with viral strains harboring the lamivudine-resistance signature rtL180M+M204V. The precore/core frame A1762T and G1764A double mutation was detected before treatment and remaining in this condition during the entire follow-up. Specific entecavir and tenofovir primary resistance-associated mutations were not detected at any time. Plasma concentrations of tenofovir indicated adequate metabolism of the drug.</p> <p>Conclusions</p> <p>We report the selection of HBV mutants carrying well-defined primary resistance mutations that escaped lamivudine in a fourteen-year follow-up period. With the exception of tenofovir resistance mutations, subsequent unselected primary resistance mutations were detected as minor populations into the HBV quasispecies composition during adefovir or entecavir monotherapies. Although tenofovir is considered an appropriate therapeutic alternative for the treatment of entecavir-unresponsive patients, its use was not effective in the case reported here.</p

On the importance of substrate deformations for cell migration

Cell migration is essential for many biological processes such as tissue morphogenesis, wound healing or metastatic invasion in cancer. It is a complex and highly regulated phenomena closely guided and fine-tuned by both chemical and mechanical cues. Whereas chemoattraction has been extensively studied, the mechanical influence remains to be fully elucidated. Although cell sensitivity to the substrate rigidity is known under the term durotaxis [Marzban et al.2018] and substrate anisotropy is known to influence cellular organization [Checa et al. 2015] much less is known about cell sensitivity to environmental stresses and strains. This paper proposes to specifically focus on the cell sensitivity to substrate deformations during migration. Those are assumed to play a role in longrange cell-cell interactions [Han et al. 2018] by which a cell deforms the substrate [Tanimoto et al. 2014] and influences the orientation of migration of other cells in its neighbourhood. This form of mechanotaxis (to which we will refer as strain mechanosensing) could in particular explain how cells migrate towards each other to form vascular loops during angiogenesis whenchemotaxis is ruled out in a chemically saturated tissue

Prevention of postcardiopulmonary bypass pericardial adhesions by a new resorbable collagen membrane

cited By 10International audienceReduction in mediastinal adhesions is an issue in cardiac surgery. To evaluate a porcine-bioengineered collagen membrane (Cova™ CARD) intended to promote tissue regeneration, 18 sheep underwent a sternotomy and a 30 min period of cardiopulmonary bypass. They were divided into three equal groups: pericardium left open, placement of an e-polytetrafluoroethylene membrane (Preclude®) taken as a non-absorbable substitute comparator and placement of the absorbable Cova™ CARD membrane. Four months thereafter, the study animals underwent repeat sternotomy and were macroscopically assessed for the degree of material resorption and the intensity of adhesions. Explanted hearts were evaluated blindly for the magnitude of the inflammatory response, fibrosis and epicardial re-mesothelialization. The bioengineered membrane was absorbed by 4 months and replaced by a loosely adherent tissue leading to the best adhesion score. There was no inflammatory reaction (except for a minimal one in an animal). Fibrosis was minimal (P = 0.041 vs Preclude®). The highest degree of epicardial re-mesothelialization, albeit limited, was achieved by the bioengineered group in which five of six sheep demonstrated a new lining of mesothelial cells in contrast to two animals in each of the other groups. This collagen membrane might thus represent an attractive pericardial substitute for preventing post-operative adhesions. © The Author 2012