Immune checkpoint inhibition-related colitis: symptoms, endoscopic features, histology and response to management

Background: Immune checkpoint inhibitors are successfully introduced as anticancer treatment. However, they may induce severe immune-related adverse events (irAEs). One of the most frequent irAEs is diarrhoea. The main objective of this study was to analyse symptoms (ie, grade of diarrhoea), endoscopic and histological features and response to management in immune checkpoint inhibition-related colitis (IRC). Patients and methods: We retrospectively analysed patients who developed diarrhoea on checkpoint inhibition and therefore underwent an endoscopy and/or were treated with corticosteroids. Patients were treated between August 2010 and March 2016 for metastatic melanoma or non-small cell lung cancer. Severity of IRC was scored using the endoscopic Mayo score and the van der Heide score. Results: Out of a cohort of 781 patients, 92 patients were identified who developed diarrhoea and therefore underwent an endoscopy and/or were treated with corticosteroids. Patients were treated with monotherapy anticytotoxic T-lymphocyte antigen-4, antiprogrammed death receptor-1 or a combination of both. All patients had symptoms of diarrhoea (grade 1: 16%; grade 2: 39% and grade 3: 44%). A complete colonoscopy was performed in 62 (67%) patients, of whom 42 (68%) had a pancolitis (>/=3 affected segments). Ulcers were seen in 32% of endoscopies. There was no significant correlation between the grade of diarrhoea at presentation and endoscopic severity scores, the presence of ulcers or histological features. In 54 episodes of diarrhoea (56%), patients received one or more cycles infliximab for steroid-refractory colitis. Patients with higher endoscopic severity scores, ulcers and/or a pancolitis needed infliximab more often. Conclusions: The correlation between grade of diarrhoea and endoscopic or histological features for severity of colitis is poor. Patients with higher endoscopic severity scores, ulcers or a pancolitis needed the addition of infliximab more often. Therefore, endoscopy may have value in the evaluation of the severity of IRC and may help in decision making for optimal management

Sarcocystis cafferi n. sp. (Protozoa : Apicomplexa) from the African Buffalo (Syncerus caffer)

Sarcocystis infections have been reported from the African buffalo (Syncerus caffer), but the species have not been named. Here we propose a new name Sarcocystis cafferi from the African buffalo. Histological examination of heart (92), skeletal muscle (36), and tongue (2) sections from 94 buffalos from the Greater Kruger National Park, South Africa, and a review of the literature revealed only 1 species of Sarcocystis in the African buffalo. Macrocysts were up to 12 mm long and 6 mm wide and were located in the neck muscles and overlying connective tissue. They were pale yellow; shaped like a lychee fruit stone or cashew nut; turgid or flaccid and oval to round (not fusiform). By light microscopy (LM) the sarcocyst wall was relatively thin. By scanning electron microscopy (SEM), the sarcocyst wall had a mesh-like structure with irregularly shaped villar protrusions (vp) that were of different sizes and folded over the sarcocyst wall. The entire surfaces of vp were covered with papillomatous structures. By transmission electron microscopy (TEM), the sarcocyst wall was up to 3.6 lm thick and had highly branched villar protrusions that were up to 3 lm long. The villar projections contained filamentous tubular structures, most of which were parallel to the long axis of the projections, but some tubules criss-crossed, especially at the base. Granules were absent from these tubules. Longitudinally cut bradyzoites were 12.132.7 lm in size, had a long convoluted mitochondrion, and only 2 rhoptries. Phylogenetic analysis of 18S rRNA and cytochrome C oxidase subunit 1 (cox1) gene sequences indicated that this Sarcocystis species is very closely related to, but distinct from, Sarcocystis fusiformis and Sarcocystis hirsuta. Thus, morphological findings by LM, SEM, and TEM together with molecular phylogenetic data (from 18S rRNA and cox1) confirm that the Sarcocystis species in the African buffalo is distinct from S. fusiformis and has therefore been named Sarcocystis cafferi.http://digitalcommons.unl.edu/jrnlparasitology/hb201

The Princeton Protein Orthology Database (P-POD): A Comparative Genomics Analysis Tool for Biologists

Many biological databases that provide comparative genomics information and tools are now available on the internet. While certainly quite useful, to our knowledge none of the existing databases combine results from multiple comparative genomics methods with manually curated information from the literature. Here we describe the Princeton Protein Orthology Database (P-POD, http://ortholog.princeton.edu), a user-friendly database system that allows users to find and visualize the phylogenetic relationships among predicted orthologs (based on the OrthoMCL method) to a query gene from any of eight eukaryotic organisms, and to see the orthologs in a wider evolutionary context (based on the Jaccard clustering method). In addition to the phylogenetic information, the database contains experimental results manually collected from the literature that can be compared to the computational analyses, as well as links to relevant human disease and gene information via the OMIM, model organism, and sequence databases. Our aim is for the P-POD resource to be extremely useful to typical experimental biologists wanting to learn more about the evolutionary context of their favorite genes. P-POD is based on the commonly used Generic Model Organism Database (GMOD) schema and can be downloaded in its entirety for installation on one's own system. Thus, bioinformaticians and software developers may also find P-POD useful because they can use the P-POD database infrastructure when developing their own comparative genomics resources and database tools

Detection and localization of early- and late-stage cancers using platelet RNA

Cancer patients benefit from early tumor detection since treatment outcomes are more favorable for less advanced cancers. Platelets are involved in cancer progression and are considered a promising biosource for cancer detection, as they alter their RNA content upon local and systemic cues. We show that tumor-educated platelet (TEP) RNA-based blood tests enable the detection of 18 cancer types. With 99% specificity in asymptomatic controls, thromboSeq correctly detected the presence of cancer in two-thirds of 1,096 blood samples from stage I–IV cancer patients and in half of 352 stage I–III tumors. Symptomatic controls, including inflammatory and cardiovascular diseases, and benign tumors had increased false-positive test results with an average specificity of 78%. Moreover, thromboSeq determined the tumor site of origin in five different tumor types correctly in over 80% of the cancer patients. These results highlight the potential properties of TEP-derived RNA panels to supplement current approaches for blood-based cancer screening

Role of Binding of Plectin to the Integrin β4 Subunit in the Assembly of Hemidesmosomes

We have previously shown that plectin is recruited into hemidesmosomes through association of its actin-binding domain (ABD) with the first pair of fibronectin type III (FNIII) repeats and a small part of the connecting segment (residues 1328–1355) of the integrin β4 subunit. Here, we show that two proline residues (P1330 and P1333) in this region of the connecting segment are critical for supporting β4-mediated recruitment of plectin. Additional binding sites for the plakin domain of plectin on β4 were identified in biochemical and yeast two-hybrid assays. These sites are located at the end of the connecting segment (residues 1383–1436) and in the region containing the fourth FNIII repeat and the C-tail (residues 1570–1752). However, in cells, these additional binding sites cannot induce the assembly of hemidesmosomes without the interaction of the plectin-ABD with β4. Because the additional plectin binding sites overlap with sequences that mediate an intramolecular association of the β4 cytoplasmic domain, we propose that they are not accessible for binding and need to become exposed as the result of the binding of the plectin-ABD to β4. Furthermore, these additional binding sites might be necessary to position the β4 cytoplasmic domain for an optimal interaction with other hemidesmosomal components, thereby increasing the efficiency of hemidesmosome assembly