No potential conflict of interest relevant to this letter was reported. The authors reply: Campochiaro and Caruso are correct that mention of cardiovascular associations with ankylosing spondylitis and axial spondyloarthritis, including specific conductionsystem lesions and aortic-root lesions, was largely absent from our review of spondyloarthritis. These specific lesions are uncommon and tend to occur late in the disease course, as does the other more common but less specific cardiovascular illness mentioned in their letter. The focus of our article was on early diagnosis and clinical management of the axial disease, and this priority, along with space and citation limitations, precluded our describing specific cardiovascular manifestations. Rudwaleit M, van derRudwaleit and colleagues make the important point that diagnosis in clinical practice cannot be based solely on fulfillment of classification criteria. We tried to make this point in the article, but perhaps our wording conveyed some unintended ambiguity. In order to introduce the new concept of axial spondyloarthritis, we described the classification criteria for this entity proposed by the ASAS in 2009. In discussing this concept, including the critical role of MRI, we referred to this entity as a diagnosis, in the sense of its being a defined medical condition. We did not intend by this to imply that one can rely strictly on these criteria to establish a diagnosis in clinical practice. In fact, we stated explicitly, "These classification criteria have limited use outside the arena of clinical research," to introduce the algorithm (in Fig. 2 of our article) for use in clinical practice.The algorithm itself is a modification of one published by the correspondents and their colleagues, 1 but it was modified specifically to further emphasize the importance of weighing clinical data and post-test probabilities 2 and of applying clinical judgment to the diagnostic process. Moreover, the discussion of MRI findings includes mention of lesions that are not part of the classification criteria but that can be helpful in supporting a diagnosis in clinical practice. Finally, the Summary section in our article reemphasizes the potential difficulty in accurately establishing or ruling out a diagnosis of axial spondyloarthritis, with no mention of criteria. Viral Load Kinetics of MERS Coronavirus InfectionTo the Editor: The outbreak of Middle East respiratory syndrome coronavirus (MERS-CoV) infection in South Korea involved 186 patients and resulted in 38 deaths, with four large hospital outbreaks accounting for 82% of the total cases. 1,2 Here, we report changes in viral load over time in patients with MERS.We included all patients who were admitted to three Seoul National University-affiliated hospitals; the institutional review boards of these hospitals approved this study and waived the need for written informed consent on public health grounds. The patients were categorized into a group with severe disease (severe group) or a group with mild disease (mild grou...

The results suggest that readings from the rebound tonometer significantly overestimated those from the applanation tonometer and that the rebound tonometer was tolerated well because of the rapid and minimal stress-inducing method of tonometry in the Eurasian Eagle owls, even without topical anesthesia. Further studies comparing TonoVet with manometric measurements may be necessary to employ rebound tonometer for routine clinical use in Eurasian Eagle owls.

Soft tissue reconstruction often requires multiple surgical procedures that can result in scars and disfiguration. Facial soft tissue reconstruction represents a clinical challenge because even subtle deformities can severely affect an individual’s social and psychological function. We therefore developed a biosynthetic soft tissue replacement composed of poly(ethylene glycol) (PEG) and hyaluronic acid (HA) that can be injected and photocrosslinked in situ with transdermal light exposure. Modulating the ratio of synthetic to biological polymer allowed us to tune implant elasticity and volume persistence. In a small-animal model, implanted photocrosslinked PEG-HA showed a dose-dependent relationship between increasing PEG concentration and enhanced implant volume persistence. In direct comparison with commercial HA injections, the PEG-HA implants maintained significantly greater average volumes and heights. Reversibility of the implant volume was achieved with hyaluronidase injection. Pilot clinical testing in human patients confirmed the feasibility of the transdermal photocrosslinking approach for implantation in abdomen soft tissue, although an inflammatory response was observed surrounding some of the materials.

Our deep resequencing of 131 CD associated genes confirmed 3 reported risk loci and identified 8 novel risk loci for CD in Koreans, providing new insights into the genetic architecture of CD.

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Several recurrent mutations and epigenetic changes have been identified in advanced gastric cancer, but the genetic alterations associated with early gastric carcinogenesis and malignant transformation remain unclear. We investigated the genomic and transcriptomic landscape of adenomas with low-grade dysplasia (LGD) and high-grade dysplasia (HGD), and intestinal-type early gastric cancer (EGC). The results were validated in an independent cohort that included EGCs directly adjacent to adenoma (EGC-adenomas) that were in the process of malignant transformation, and de novo EGCs that do not seem to have been derived from adenoma. The expression patterns clearly divided into normal, LGD, and EGC, whereas those of HGD overlapped with LGD or EGC. These results suggest that HGD is the critical stage determining malignant transformation. We found that genes related to focal adhesion and extracellular matrix receptor interaction pathways were upregulated as LGD progressed to EGC, whereas canonical Wnt signalling and peroxisome proliferator-activated receptor (PPAR) signalling pathway genes were downregulated in EGC. Genomic alterations such as somatic mutation, gene fusion and copy number variation increased gradually from LGD to EGC. APC mutations were present in 67% of LGDs, 58% of HGDs, and 18% of EGCs. RNF43 mutations were present only in HGD and EGC, and TP53 mutations were present only in EGC. In a validation cohort, RNF43 mutations were present in 35.2% of EGC-adenomas, but in only 8.6% of de novo EGCs. This is the first study to investigate the genomic and transcriptomic landscape of multistep gastric carcinogenesis. We investigated important alterations and their related pathways in each step as tumours progressed from LGD to HGD and eventually to EGC. We suggest that mutations and downregulation of RNF43 may play a critical role in the transition from adenoma to carcinoma. Given these findings and Wnt dependency in tumours with RNF43 mutation, intestinal-type gastric cancer or adenoma with RNF43 mutation might represent a promising indication for Wnt-targeted agents. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide. Recent high-throughput analyses of genomic alterations revealed several driver genes and altered pathways in GC. However, therapeutic applications from genomic data are limited, largely as a result of the lack of druggable molecular targets and preclinical models for drug selection. To identify new therapeutic targets for GC, we performed array comparative genomic hybridization (aCGH) of DNA from 103 patients with GC for copy number alteration (CNA) analysis, and whole-exome sequencing from 55 GCs from the same patients for mutation profiling. Pathway analysis showed recurrent alterations in the Wnt signaling [APC, CTNNB1, and DLC1 (deleted in liver cancer 1)], ErbB signaling (ERBB2, PIK3CA, and KRAS), and p53 signaling/apoptosis [TP53 and BCL2L1 (BCL2-like 1)] pathways. In 18.4% of GC cases (19/103), amplification of the antiapoptotic gene BCL2L1 was observed, and subsequently a BCL2L1 inhibitor was shown to markedly decrease cell viability in BCL2L1-amplified cell lines and in similarly altered patient-derived GC xenografts, especially when combined with other chemotherapeutic agents. In 10.9% of cases (6/55), mutations in DLC1 were found and were also shown to confer a growth advantage for these cells via activation of Rho-ROCK signaling, rendering these cells more susceptible to a ROCK inhibitor. Taken together, our study implicates BCL2L1 and DLC1 as potential druggable targets for specific subsets of GC cases.gastric cancer | copy number alteration | whole-exome sequencing | patient-derived xenograft | druggable target G astric cancer (GC) is a highly prevalent malignancy and is the third leading cause of cancer-related deaths in the world (1). In unresectable and metastatic cases, the clinical outcome for this disease remains poor (median survival is 10-14 mo) (2), and other treatment options are often limited because of the lack of effective therapeutic approaches and molecular prognostic markers (2, 3). To date, with the exception of the application of trastuzumab [ERBB2 (ErbB2 receptor tyrosine kinase 2) antagonist] or ramucirumab [VEGFR2 (Vascular endothelial growth factor receptor 2) antagonist] for advanced GC cases (4, 5), drugs that target GC on a molecular level are limited.Recent genomic studies have demonstrated the heterogeneous genomic characteristics of GC (6-10). In addition, previous studies of patients with GC by whole-genome and whole-exome sequencing (WES) have identified frequent somatic mutations in tumor suppressors such as TP53, ARID1A, APC, and FAT4, and oncogenes including PI3KCA, KRAS, and RHOA (6-10). However, these findings, although academically meaningful, are far from ready for clinical applications, largely because of the lack of identified druggable molecular targets and the availability of reliable preclinical models for validation of potential target inhibitors.To identify novel therapeutic targets for GC, we explored genomic alterations in GC through an integrated genomic data set from WE...

Collagen-rich tissues in the cornea exhibit unique and highly organized extracellular matrix ultrastructures, which contribute to its high load-bearing capacity and light transmittance. Corneal collagen fibrils are controlled during development by small leucine-rich proteoglycans (SLRPs) that regulate the fibril diameter and spacing in order to achieve the unique optical transparency. Cyclodextrins (CDs) of varying size and chemical functionality for their ability to regulate collagen assembly during vitrification process are screened in order to create biosynthetic materials that mimic the native cornea structure. Addition of βCD to collagen vitrigels produces materials with aligned fibers and lamellae similar to native cornea, resulting in mechanically robust and transparent materials. Biochemistry analysis revealed that CD interacts with hydrophobic amino acids in collagen to influence assembly and fibril organization. To translate the self-assembled collagen materials for cornea reconstruction, custom molds for gelation and vitrification are engineered to create βCD/Col implants with curvature matching that of the cornea. Acellular βCD/Col materials are implanted in a rabbit partial keratoplasty model with interrupted sutures. The implants demonstrate tissue integration and support re-epithelialization. Therefore, the addition of CD molecules regulates collagen self-assembly and provides a simple process to engineer corneal mimetic substitutes with advanced structural and functional properties.