There is, I think, something ethereal about i —the square root of minus one. I remember first hearing about it at school. It seemed an odd beast at that time—an intruder hovering on the edge of reality.

Usually familiarity dulls this sense of the bizarre, but in the case of i it was the reverse: over the years the sense of its surreal nature intensified. It seemed that it was impossible to write mathematics that described the real world in …

I and i

Retrospective study: The diagnostic accuracy of conventional forceps biopsy of gastric epithelial compared to endoscopic submucosal dissection (STROBE compliant).

AACR Centennial Conference: Translational Cancer Medicine-- Nov 4-8, 2007; Singapore

PL02-05 

All cancers are due to abnormalities in DNA. The availability of the human genome sequence has led to the proposal that resequencing of cancer genomes will reveal the full complement of somatic mutations and hence all the cancer genes. To explore the nature of the information that will be derived from cancer genome sequencing we have sequenced the coding exons of the family of 518 protein kinases, ~1.3Mb DNA per cancer sample, in 210 cancers of diverse histological types. Despite the screen being directed toward the coding regions of a gene family that has previously been strongly implicated in oncogenesis, the results indicate that the majority of somatic mutations detected are “passengers”. There is considerable variation in the number and pattern of these mutations between individual cancers, indicating substantial diversity of processes of molecular evolution between cancers. The imprints of exogenous mutagenic exposures, mutagenic treatment regimes and DNA repair defects can all be seen in the distinctive mutational signatures of individual cancers. This systematic mutation screen and others have previously yielded a number of cancer genes that are frequently mutated in one or more cancer types and which are now anticancer drug targets (for example BRAF , PIK3CA , and EGFR ). However, detailed analyses of the data from our screen additionally suggest that there exist a large number of additional “driver” mutations which are distributed across a substantial number of genes. It therefore appears that cells may be able to utilise mutations in a large repertoire of potential cancer genes to acquire the neoplastic phenotype. However, many of these genes are employed only infrequently. These findings may have implications for future anticancer drug development.

Patterns of Somatic Mutation in Human Cancer Genomes

The hepatic stellate cell has surprised and engaged physiologists, pathologists, and hepatologists for over 130 years, yet clear evidence of its role in hepatic injury and fibrosis only emerged following the refinement of methods for its isolation and characterization. The paradigm in liver injury of activation of quiescent vitamin A-rich stellate cells into proliferative, contractile, and fibrogenic myofibroblasts has launched an era of astonishing progress in understanding the mechanistic basis of hepatic fibrosis progression and regression. But this simple paradigm has now yielded to a remarkably broad appreciation of the cell's functions not only in liver injury, but also in hepatic development, regeneration, xenobiotic responses, intermediary metabolism, and immunoregulation. Among the most exciting prospects is that stellate cells are essential for hepatic progenitor cell amplification and differentiation. Equally intriguing is the remarkable plasticity of stellate cells, not only in their variable intermediate filament phenotype, but also in their functions. Stellate cells can be viewed as the nexus in a complex sinusoidal milieu that requires tightly regulated autocrine and paracrine cross-talk, rapid responses to evolving extracellular matrix content, and exquisite responsiveness to the metabolic needs imposed by liver growth and repair. Moreover, roles vital to systemic homeostasis include their storage and mobilization of retinoids, their emerging capacity for antigen presentation and induction of tolerance, as well as their emerging relationship to bone marrow-derived cells. As interest in this cell type intensifies, more surprises and mysteries are sure to unfold that will ultimately benefit our understanding of liver physiology and the diagnosis and treatment of liver disease.

/pdf/hepatic-stellate-cells-protean-multifunctional-and-enigmatic-1ctrvjmfhn.pdf

Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver

Rapid improvements in sequencing and array-based platforms are resulting in a flood of diverse genome-wide data, including data from exome and whole-genome sequencing, epigenetic surveys, expression profiling of coding and noncoding RNAs, single nucleotide polymorphism (SNP) and copy number profiling, and functional assays. Analysis of these large, diverse data sets holds the promise of a more comprehensive understanding of the genome and its relation to human disease. Experienced and knowledgeable human review is an essential component of this process, complementing computational approaches. This calls for efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data. However, the sheer volume and scope of data pose a significant challenge to the development of such tools.

Integrative Genomics Viewer

Treatment with immune checkpoint inhibitors (ICIs) has recently achieved unprecedented clinical benefits, becoming a critical treatment for patients with cancer. However, a set of patients are resistant to immune checkpoint inhibitor therapy, likely due to the limited presence or lack of tumor-infiltrating lymphocytes in their tumors. Increasing data indicate that antiangiogenic therapy substantially reduces cancer-induced immunosuppression and is an effective way to enhance the efficacy of cancer immunotherapies by combination with ICIs. Endostatin, an angiogenesis inhibitor, has been widely used as an antiangiogenic therapy for cancer. We showed that combined therapy with an adenovirus encoding human endostatin, named Ad-E, and programmed cell death-1 (PD-1) blockade dramatically abrogated tumor growth, inhibited microvessel density, and promoted tumor apoptosis, compared to treatment with the single agents. Further investigation using flow cytometry showed that combined therapy significantly increased CD8+ T-cell infiltration into tumors and promoted the level of CD8+ IFN-γ+ T cells. Moreover, combined therapy effectively reduced the frequencies of CD11b+ F4/80+ tumor-associated macrophages (TAMs) and slightly increased M1/M2 ratio in the tumors. RNA-seq analysis of tumor tissue following combined therapy also demonstrated upregulated expression of genes associated with the antitumor immune response. These data support the rationale for combining antiangiogenic and ICIs for cancer therapy. 

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/mog2.21

Combining an adenovirus encoding human endostatin and PD‐1 blockade enhanced antitumor immune activity

In the title compound, C21H16FN3OS, the thieno[2,3-b]pyridine system forms dihedral angles of 10.57 (12) and 83.87 (5)° with the fluoro­phenyl ring at the 6-position and the phenyl ring of the benzyl group, respectively. In the crystal, mol­ecules are linked by weak N—H⋯N anf N—H⋯O hydrogen bonds and π–π stacking inter­actions involving fluoro­phenyl rings of adjacent mol­ecules, with a centroid–centroid distance of 3.648 (10) A. In addition, intra­molecular N—H⋯S and N—H⋯O hydrogen bonds contribute to the stability of the mol­ecular conformation.

https://journals.iucr.org/e/issues/2012/06/00/ds2191/ds2191.pdf

3-Amino-N-benzyl-6-(4-fluoro-phen-yl)thieno[2,3-b]pyridine-2-carboxamide.

Gastroenterol Hepatol 2016; 28:628–632. 2 Zanetti AR, Mariano A, Romanò L, D’Amelio R, Chironna M, Coppola RC, et al. Long-term immunogenicity of hepatitis B vaccination and policy for booster: an Italian multicentre study. Lancet 2005; 366:1379–1384. 3 Rahier JF, Magro F, Abreu C, Armuzzi A, Ben-Horin S, Chowers Y, et al. Second European evidence-based consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease. J Crohns Colitis 2014; 8:443–468. 4 Belle A, Baumann C, Bigard MA, Zallot C, Gizard E, Guéant JL, et al. Impact of immunosuppressive therapy on hepatitis B vaccination in inflammatory bowel diseases. Eur J Gastroenterol Hepatol 2015; 27:877–881. 5 Cekic C, Aslan F, Krc A, Gümüs ZZ, Arabul M, Yüksel ES, et al. Evaluation of factors associated with response to hepatitis B vaccination in patients with inflammatory bowel disease. Medicine (Baltimore) 2015; 94:e940.

Infections in hospitalized patients with decompensated cirrhosis should be used in determining prognosis: a validation on a large Chinese cohort.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that causes endless pain and poor quality of life in patients. Usage of a lubricant combined with anti-inflammatory therapy is considered a reasonable and effective approach for the treatment of RA. Herein, inspired by glycopeptides, a peptide-decorated hyaluronic acid was synthesized, and the grafted Fmoc-phenylalanine-phenylalanine-COOH (FmocFF) peptide self-assembled with β-sheet conformations could induce the folding of polymer molecular chains to form a vesicle structure in aqueous solution. The hydrophobic anti-inflammatory drug curcumin (Cur) could be embedded in the vesicle walls through π-π interactions with the FmocFF peptide. Furthermore, the inflammation suppression function of the Cur-loaded vesicles both in vitro and in vivo was demonstrated to be an effective treatment for RA therapy. This work proposes new insights into the folding and hierarchical assembly of glycopeptide mimics, providing an efficient approach for constructing intelligent platforms for drug delivery, disease therapy, and diagnostic applications.

Li Yang

Papers

Combining an adenovirus encoding human endostatin and PD‐1 blockade enhanced antitumor immune activity

3-Amino-N-benzyl-6-(4-fluoro-phen-yl)thieno[2,3-b]pyridine-2-carboxamide.

Infections in hospitalized patients with decompensated cirrhosis should be used in determining prognosis: a validation on a large Chinese cohort.

Drug-Embedded Nanovesicles Assembled from Peptide-Decorated Hyaluronic Acid for Rheumatoid Arthritis Synergistic Therapy.

A composite hydrogel improves the survival and differentiation of human iPSC-derived neural stem cells after ischemic stroke