Persistence of hepatic hepatitis B virus after serological clearance of HBsAG with autologous peripheral stem cell transplantation

Delayed clearance of hepatitis B surface antigen was previously reported in a 38 year old woman after high dose chemotherapy with autologous peripheral blood stem cell rescue. Sixteen months later, this patient remained hepatitis B surface antigen negative, hepatitis B surface anti-body positive, and serum hepatitis B DNA negative by polymerase chain reaction. Serial liver biopsies (one at hepatitis B e antigen positive stage, one at hepatitis B e antibody positive stage, and one at hepatitis B surface antigen negative and hepatitis B surface antibody positive stage) showed a gradual resolution of the inflammatory activity with loss of hepatitis B e antigen and then hepatitis B surface antigen in the serum. However, the degree of fibrosis, though mild, remained the same. With the serological clearance of hepatitis B surface antigen, a small amount of hepatitis B virus DNA was still detectable in the nuclei of liver cells.published_or_final_versio

The potential of new tumor endothelium-specific markers for the development of antivascular therapy.

Angiogenesis is a hallmark of solid tumors, and disruption of tumor vasculature is an active anticancer therapy in some cases. Several proteins expressed on the surface of tumor endothelium have been identified during the last decade. However, due to the expression in both physiological and tumor angiogenesis, only a few targets have been developed for clinical therapeutics. By thorough SAGE analysis of mouse endothelial cells isolated from various normal resting tissues, regenerating liver, and liver-metastasized tumor, Seaman and colleagues in this issue of Cancer Cell have demonstrated organ-specific endothelial markers, physiological angiogenesis endothelial markers, and tumor endothelial markers and revealed striking differences between physiological and pathological angiogenesis

Nucleation and grain formation of pure Al under Pulsed Magneto-Oscillation treatment

The grain structure of commercially pure Al can be significantly refined by the Pulsed Magneto-Oscillation (PMO) treatment. When PMO was applied to the melt during solidification, the thermal undercooling increased not only near the mold wall but also in the center of the melt. PMO treatment promoted more vigorous convection of the melt, resulting in a significant decrease in the temperature gradient from the mold wall to the center of the casting compared to the case without PMO treatment. The resulting lower temperature gradient led to a more uniform temperature field in the melt, which in turn favored the survival of the Al grains and allowed them to grow rather than remelt. Consideration of the thermal environment during solidification provides a more complete description of the mechanism of grain refinement of pure metals when PMO is applied

Latexin sensitizes leukemogenic cells to gamma-irradiation-induced cell-cycle arrest and cell death through Rps3 pathway

Leukemia is a leading cause of cancer death. Recently, the latexin (Lxn) gene was identified as a potential tumor suppressor in several types of solid tumors and lymphoma, and Lxn expression was found to be absent or downregulated in leukemic cells. Whether Lxn functions as a tumor suppressor in leukemia and what molecular and cellular mechanisms are involved are unknown. In this study, the myeloid leukemogenic FDC-P1 cell line was used as a model system and Lxn was ectopically expressed in these cells. Using the protein pull-down assay and mass spectrometry, ribosomal protein subunit 3 (Rps3) was identified as a novel Lxn binding protein. Ectopic expression of Lxn inhibited FDC-P1 growth in vitro. More surprisingly, Lxn enhanced gamma irradiation-induced DNA damages and induced cell-cycle arrest and massive necrosis, leading to depletion of FDC-P1 cells. Mechanistically, Lxn inhibited the nuclear translocation of Rps3 upon radiation, resulting in abnormal mitotic spindle formation and chromosome instability. Rps3 knockdown increased the radiation sensitivity of FDC-P1, confirming that the mechanism of action of Lxn is mediated by Rps3 pathway. Moreover, Lxn enhanced the cytotoxicity of chemotherapeutic agent, VP-16, on FDC-P1 cells. Our study suggests that Lxn itself not only suppresses leukemic cell growth but also potentiates the cytotoxic effect of radio- and chemotherapy on cancer cells. Lxn could be a novel molecular target that improves the efficacy of anti-cancer therapy

A Novel Redox Regulator, MnTnBuOE-2-PyP\u3csup\u3e5+\u3c/sup\u3e, Enhances Normal Hematopoietic Stem/Progenitor Cell Function

The signaling of reactive oxygen species (ROS) is essential for the maintenance of normal cellular function. However, whether and how ROS regulate stem cells are unclear. Here, we demonstrate that, in transgenic mice expressing the human manganese superoxide dismutase (MnSOD) gene, a scavenger of ROS in mitochondria, the number and function of mouse hematopoietic stem/progenitor cells (HSPC) under physiological conditions are enhanced. Importantly, giving MnTnBuOE-2-PyP5+(MnP), a redox- active MnSOD mimetic, to mouse primary bone marrow cells or to C57B/L6 mice significantly enhances the number of HSPCs. Mechanistically, MnP reduces superoxide to hydrogen peroxide, which activates intracellular Nrf2 signaling leading to the induction of antioxidant enzymes, including MnSOD and catalase, and mitochondrial uncoupling protein 3. The results reveal a novel role of ROS signaling in regulating stem cell function, and suggest a possible beneficial effect of MnP in treating pathological bone marrow cell loss and in increasing stem cell population for bone marrow transplantation

Insights into biofilm dispersal regulation from the crystal structure of the PAS-GGDEF-EAL region of RbdA from Pseudomonas aeruginosa

© 2018 American Society for Microbiology. RbdA is a positive regulator of biofilm dispersal of Pseudomonas aeruginosa. Its cytoplasmic region (cRbdA) comprises an N-terminal Per-ARNT-Sim (PAS) domain followed by a diguanylate cyclase (GGDEF) domain and an EAL domain, whose phosphodiesterase activity is allosterically stimulated by GTP binding to the GGDEF domain. We report crystal structures of cRbdA and of two binary complexes: one with GTP/Mg 2+ bound to the GGDEF active site and one with the EAL domain bound to the c-di-GMP substrate. These structures unveil a 2-fold symmetric dimer stabilized by a closely packed N-terminal PAS domain and a noncanonical EAL dimer. The autoinhibitory switch is formed by an α-helix (S-helix) immediately N-terminal to the GGDEF domain that interacts with the EAL dimerization helix (α6-E) of the other EAL monomer and maintains the protein in a locked conformation. We propose that local conformational changes in cRbdA upon GTP binding lead to a structure with the PAS domain and S-helix shifted away from the GGDEF-EAL domains, as suggested by small-angle X-ray scattering (SAXS) experiments. Domain reorientation should be facilitated by the presence of an α-helical lever (H-helix) that tethers the GGDEF and EAL regions, allowing the EAL domain to rearrange into an active dimeric conformation

Using biomarkers to predict TB treatment duration (Predict TB): a prospective, randomized, noninferiority, treatment shortening clinical trial

Background : By the early 1980s, tuberculosis treatment was shortened from 24 to 6 months, maintaining relapse rates of 1-2%. Subsequent trials attempting shorter durations have failed, with 4-month arms consistently having relapse rates of 15-20%. One trial shortened treatment only among those without baseline cavity on chest x-ray and whose month 2 sputum culture converted to negative. The 4-month arm relapse rate decreased to 7% but was still significantly worse than the 6-month arm (1.6%, P<0.01).  We hypothesize that PET/CT characteristics at baseline, PET/CT changes at one month, and markers of residual bacterial load will identify patients with tuberculosis who can be cured with 4 months (16 weeks) of standard treatment.Methods: This is a prospective, multicenter, randomized, phase 2b, noninferiority clinical trial of pulmonary tuberculosis participants. Those eligible start standard of care treatment. PET/CT scans are done at weeks 0, 4, and 16 or 24. Participants who do not meet early treatment completion criteria (baseline radiologic severity, radiologic response at one month, and GeneXpert-detectable bacilli at four months) are placed in Arm A (24 weeks of standard therapy). Those who meet the early treatment completion criteria are randomized at week 16 to continue treatment to week 24 (Arm B) or complete treatment at week 16 (Arm C). The primary endpoint compares the treatment success rate at 18 months between Arms B and C.Discussion: Multiple biomarkers have been assessed to predict TB treatment outcomes. This study uses PET/CT scans and GeneXpert (Xpert) cycle threshold to risk stratify participants. PET/CT scans are not applicable to global public health but could be used in clinical trials to stratify participants and possibly become a surrogate endpoint. If the Predict TB trial is successful, other immunological biomarkers or transcriptional signatures that correlate with treatment outcome may be identified. TRIAL REGISTRATION: NCT02821832

Identification of a Novel Cetacean Polyomavirus from a Common Dolphin (Delphinus delphis) with Tracheobronchitis

A female short-beaked common dolphin calf was found stranded in San Diego, California in October 2010, presenting with multifocal ulcerative lesions in the trachea and bronchi. Viral particles suggestive of polyomavirus were detected by EM, and subsequently confirmed by PCR and sequencing. Full genome sequencing (Ion Torrent) revealed a circular dsDNA genome of 5,159 bp that was shown to form a distinct lineage within the genus Polyomavirus based on phylogenetic analysis of the early and late transcriptomes. Viral infection and distribution in laryngeal mucosa was characterised using in-situ hybridisation, and apoptosis observed in the virus-infected region. These results demonstrate that polyomaviruses can be associated with respiratory disease in cetaceans, and expand our knowledge of their diversity and clinical significance in marine mammals