Cytomegalovirus enteritis in immunocompetent patients: Report of two cases diagnosed using single-balloon enteroscopy

SummaryCytomegalovirus (CMV) infection of the gastrointestinal tract involves mostly the colon and rectum and mainly develops in immunocompromised patients. CMV infection in the small intestines has rarely been reported in immunocompetent patients. We report two cases of CMV enteritis that developed in immunocompetent patients and involved the ileum and jejunum, respectively. Both of them were diagnosed with single-balloon enteroscopy (SBE) and further confirmed with histopathology. The first case is a 71-year-old woman with a presentation of obscure gastrointestinal bleeding and severe anemia. Neither esophagogastroduodenoscopy nor colonoscopy identified any active bleeding. SBE and biopsy disclosed multiple scattered ulcers in the distal ileum and histopathology confirmed CMV ileitis. The hemorrhage subsided after conservative medical treatment. The second case is a 59-year-old woman with a presentation of progressive abdominal pain. SBE showed diffuse irregularly-shaped ulcers located from the upper to middle jejunum, and CMV jejunitis was confirmed with endoscopic biopsy and histopathological examination. Antiviral therapy was prescribed and her abdominal pain improved gradually. We discuss the clinical manifestations and management strategies of CMV infection that develops in the small intestines of immunocompetent patients. In addition, we highlight the endoscopic characteristics of CMV enteritis and the clinical utilities of SBE in the evaluation of patients with suspected CMV infection of the small intestines

Dynamics of multiple resistance mechanisms in plasma DNA during EGFR-targeted therapies in non-small cell lung cancer.

Tumour heterogeneity leads to the development of multiple resistance mechanisms during targeted therapies. Identifying the dominant driver(s) is critical for treatment decision. We studied the relative dynamics of multiple oncogenic drivers in longitudinal plasma of 50 EGFR-mutant non-small-cell lung cancer patients receiving gefitinib and hydroxychloroquine. We performed digital PCR and targeted sequencing on samples from all patients and shallow whole-genome sequencing on samples from three patients who underwent histological transformation to small-cell lung cancer. In 43 patients with known EGFR mutations from tumour, we identified them accurately in plasma of 41 patients (95%, 41/43). We also found additional mutations, including EGFR T790M (31/50, 62%), TP53 (23/50, 46%), PIK3CA (7/50, 14%) and PTEN (4/50, 8%). Patients with both TP53 and EGFR mutations before treatment had worse overall survival than those with only EGFR Patients who progressed without T790M had worse PFS during TKI continuation and developed alternative alterations, including small-cell lung cancer-associated copy number changes and TP53 mutations, that tracked subsequent treatment responses. Longitudinal plasma analysis can help identify dominant resistance mechanisms, including non-druggable genetic information that may guide clinical management.We would like to acknowledge the support of The University of Cambridge, Cancer Research UK (grant numbers A11906, A20240) (to N.R.), the European Research Council under the European Union's Seventh Framework Programme (FP/2007- 2013) / ERC Grant Agreement n. 337905 (to N.R.), and Hutchison Whampoa Limited (to N.R.

Latexin expression is downregulated in human gastric carcinomas and exhibits tumor suppressor potential

<p>Abstract</p> <p>Background</p> <p>Latexin, also known as endogenous carboxypeptidase inhibitor (CPI), has been found to inhibit mouse stem cell populations and lymphoma cell proliferation, demonstrating its potential role as a tumor suppressor. Our previous study also suggested a correlation between latexin expression and malignant transformation of immortalized human gastric epithelial cells. Here, we examined latexin expression in human gastric carcinomas and investigated the effect of differential latexin expression on proliferation of gastric cancer cells <it>in vitro </it>and <it>in vivo</it>.</p> <p>Methods</p> <p>Monoclonal antibody against human latexin was prepared and immunohistochemical analysis was performed to detect latexin expression in 41 paired gastric carcinomas and adjacent normal control tissues. Human gastric cancer cells MGC803 (latexin negative) stably transfected with LXN gene and BGC823 cells (latexin positive) stably transfected with antisense LXN gene were established for anchorage-dependent colony formation assay and tumorigenesis assay in nude mice. Differentially expressed genes in response to exogeneous latexin expression were screened using microarray analysis and identified by RT-PCR. Bisulfite sequencing was performed to analyze the correlation of the methylation status of LXN promoter with latexin expression in cell lines.</p> <p>Results</p> <p>Immunohistochemical analysis showed significantly reduced latexin expression in gastric carcinomas (6/41, 14.6%) compared to control tissues (31/41, 75.6%) (<it>P </it>< 0.05). Overexpression of LXN gene in MGC803 cells inhibited colony formation and tumor growth in nude mice. Conversely, BGC823 cells transfected with antisense LXN gene exhibited enhanced tumor growth and colony formation. Additionally, several tumor related genes, including Maspin, WFDC1, SLPI, S100P, and PDGFRB, were shown to be differentially expressed in MGC803 cells in response to latexin expression. Differential expression of Maspin and S100P was also identified in BGC823 cells while latexin expression was downregulated. Further bisulfite sequencing of the LXN gene promoter indicated CpG hypermethylation was correlated with silencing of latexin expression in human cells.</p> <p>Conclusions</p> <p>Latexin expression was reduced in human gastric cancers compared with their normal control tissues. The cellular and molecular evidences demonstrated the inhibitory effect of latexin in human gastric cancer cell growth and tumorigenicity. These results strongly suggest the possible involvement of latexin expression in tumor suppression.</p

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Papillary Squamous Intraepithelial Lesions of the Uterine Cervix: Human Papillomavirus-Dependent Changes in Cell Cycle Expression and Cytologic Features

Most human papillomavirus associated squamous intraepithelial lesions of the uterine cervix are flat; some have papillary architecture that shows a spectrum of differentiation from low-grade squamous intraepithelial lesions to high-grade squamous intraepithelial lesions. For this subset of lesions, there are few data relating human papillomavirus type to cytology and cell cycle activity. Here, we collected 24 cases of papillary squamous intraepithelial lesions with either low-risk (15 cases) or high- risk (9 cases) human papillomavirus infection. We described their morphology and performed immunohistochemical staining with cell cycle related markers Ki-67, p53, pRb, and P16INK4a. The Ki-67 labeling index was significantly lower in the low-risk group than in the high-risk group (P < .001). A cut point of less than 50% labeling index detected all but one low-risk group case. Degradation of p53 and pRb was less evident in the low-risk group than in the high- risk group (p53, P < .001; pRb, P = . 006). P16INK4a produced an unexpectedly high positive rate of staining in the low- risk group (60%). However, a specific top-heavy distribution pattern was noted, with evident nuclear but faint cytoplasmic staining, whereas the high-risk group showed strong full-thickness nuclear and cytoplasmic staining. The detection of these lesions by smear examination was not reliable, given the wide expression pattern. Papillary structure was evident in none. We conclude that cell cycle related markers are helpful in distinguishing low- and high- risk lesions. The strong p16INK4a staining in the low-risk group may imply that more cell cycle controlling pressure is elicited in papillary lesions than in flat lesions. The distribution pattern of p16INK4a staining is important when making a diagnosis; cytology is not effective. Human papillomavirus type, histology , and cell cycle markers could clearly separate these lesions into either a low-risk or a high-risk group, properly designated low-grade squamous intraepithelial lesions or high-grade squamous intraepithelial lesions in current management algorithms. Thus, the previously used terms papillary immature metaplasia and immature condyloma, although descriptive for low- risk group lesions, are confusing and should be discarded

Perivascular epithelioid cell tumor of the gastrointestinal tract

Perivascular epithelioid cell tumor (PEComa) is a rare subtype of soft tissue sarcoma that coexpresses melanocytic and smooth muscle markers. We report a case of malignant PEComa arising from the gastrointestinal tract. Definitive diagnosis of malignant PEComa is based on pathological examination and the standard treatment is complete surgical resection. Cytotoxic chemotherapy has limited efficacy in recurrent or metastatic malignant PEComa. Overactivation of the mammalian target of rapamycin (mTOR) pathway is observed in PEComa, and mTOR inhibitors have been recommended as an effective systemic treatment

An unusual histopathologic feature of angiomatoid fibrous histiocytoma – A case report and molecular study

Angiomatoid fibrous histiocytoma (AFH) is a rare soft tissue tumor with intermediate malignant potential. It predominantly affects children and young adults and is most often located in the extremities. The atypical pattern of AFH may create significant diagnostic difficulty. We present a case of AFH diagnosed via molecular confirmation by fluorescence in situ hybridization (FISH) and also review cases of AFH with atypical histologic presentations in Taiwan. We present this case to remind clinicians that identification of gene fusions by molecular testing is a valuable diagnostic tool for AFHs, especially in cases with atypical histopathological presentations. Keywords: Angiomatoid fibrous histiocytoma (AFH), Fluorescence in situ hybridization (FISH), Molecular testin

Fever, eosinophilia, and abnormal liver function are early signs suggestive of DRESS: A comparative study between DRESS and MPE

Background/Objective: There is a rising awareness of drug reaction with eosinophilia and systemic symptoms (DRESS) due to its possible morbidity and mortality. Early diagnosis of DRESS is crucial for administering timely treatment; however, prompt diagnosis based on its early presentation can be quite problematic due to its clinical resemblance to common maculopapular eruptions (MPE). Methods: A retrospective cohort study of patient data from September 2010 to June 2016 was conducted to compare the clinical presentations of DRESS and MPE validated by the RegiSCAR scoring system. The demographic data, clinical presentations, and histopathological patterns were reviewed. Results: Fifty-eight patients with DRESS and 29 patients with MPE were included. The mean age at diagnosis of DRESS was 47 years (range: 2–82 years), and female patients predominated by a ratio of 2.2:1. The three most common culprit medications for DRESS were allopurinol, sulfasalazine, and trimethoprim/sulfamethoxazole. The most significant differences between the DRESS and MPE groups were the presence of fever, peripheral blood eosinophilia and atypical lymphocytosis, characteristic skin lesions, abnormal liver functions, and prolonged resolution of skin lesions for more than 15 days in the DRESS patients. The most common histologic features in the DRESS patients were coexistent eczematous, interface dermatitis, and vascular damage patterns, or interface dermatitis alone. The concurrence of fever, peripheral blood eosinophilia, and abnormal liver function within three days of visiting a medical facility were more common in cases of DRESS than of MPE (24.1% vs. 0%, P = 0.004). Conclusion: Although DRESS and MPE look similar, especially in the early stage of DRESS, the concurrence of fever, peripheral blood eosinophilia, and abnormal liver functions within three days of visiting a medical facility might aid in the early diagnosis of DRESS

Anti-Allergic and Anti-Inflammatory Effects of Neferine on RBL-2H3 Cells

Mast cells play a very important role in skin allergy and inflammation, including atopic dermatitis and psoriasis. In the past, it was found that neferine has anti-inflammatory and anti-aging effects on the skin, but its effect on mast cells has not yet been studied in detail. In this study, we used mast cells (RBL-2H3 cells) and mouse models to study the anti-allergic and inflammatory effects of neferine. First, we found that neferine inhibits the degranulation of mast cells and the expression of cytokines. In addition, we observed that when mast cells were stimulated by A23187/phorbol 12-myristate-13-acetate (PMA), the elevation of intracellular calcium was inhibited by neferine. The phosphorylation of the MAPK/NF-κB pathway is also reduced by pretreatment of neferine. The results of in vivo studies show that neferine can improve the appearance of dermatitis and mast cell infiltration caused by dinitrochlorobenzene (DNCB). Moreover, the expressions of barrier proteins in the skin are also restored. Finally, it was found that neferine can reduce the scratching behavior caused by compound 48/80. Taken together, our results indicate that neferine is a very good anti-allergic and anti-inflammatory natural product. Its effect on mast cells contributes to its pharmacological mechanism