Citations

Alterations in nuclear morphology are common in cancer progression. However, the degree to which gross morphological abnormalities translate into compromised higher‐order chromatin organization is poorly understood. To explore the functional links between gene expression and chromatin structure in breast cancer, we performed RNA‐seq gene expression analysis on the basal breast cancer progression model based on human MCF10A cells. Positional gene enrichment identified the major histone gene cluster at chromosome 6p22 as one of the most significantly upregulated (and not amplified) clusters of genes from the normal‐like MCF10A to premalignant MCF10AT1 and metastatic MCF10CA1a cells. This cluster is subdivided into three sub‐clusters of histone genes that are organized into hierarchical topologically associating domains (TADs). Interestingly, the sub‐clusters of histone genes are located at TAD boundaries and interact more frequently with each other than the regions in‐between them, suggesting that the histone sub‐clusters form an active chromatin hub. The anchor sites of loops within this hub are occupied by CTCF, a known chromatin organizer. These histone genes are transcribed and processed at a specific sub‐nuclear microenvironment termed the major histone locus body (HLB). While the overall chromatin structure of the major HLB is maintained across breast cancer progression, we detected alterations in its structure that may relate to gene expression. Importantly, breast tumor specimens also exhibit a coordinate pattern of upregulation across the major histone gene cluster. Our results provide a novel insight into the connection between the higher‐order chromatin organization of the major HLB and its regulation during breast cancer progression.

Abstract Introduction Multiple intravenous doses of ponezumab, an anti‐amyloid antibody, were evaluated in subjects with mild‐to‐moderate Alzheimer's disease (AD). Methods In part A, 77 subjects were randomized to ponezumab 0.1, 0.5, or 1 mg/kg (75 treated) and 26 to placebo (24 treated). In part B, 63 subjects were randomized and treated with ponezumab 3 or 8.5 mg/kg and 32 with placebo. Subjects received 10 infusions over 18 months and were followed for 6 months thereafter. Results Ponezumab was generally safe and well tolerated. Most common adverse events were fall (16.7% ponezumab, 21.4% placebo), headache (13.8%, 21.4%), and cerebral microhemorrhage (13.8%, 19.6%). Plasma ponezumab increased dose‐dependently with limited accumulation. Cerebrospinal fluid penetration was low. Plasma Aβ 1–x and Aβ 1–40 showed robust increases, but cerebrospinal fluid biomarkers showed no dose response. Ponezumab had no effects on cognitive/functional outcomes or brain volume. Conclusions Multiple‐dose ponezumab was generally safe, but not efficacious, in mild‐to‐moderate AD.

AbstractRecent research has identified important barriers that potential living organ donors face in utilizing travel reimbursement funds from the National Living Donor Assistance Center (NLDAC). In this article, we provide clarification and comment on these potential barriers from the NLDAC program perspective. The goal of financial neutrality for living donors requires further action. We discuss recent developments and further steps that may help achieve this goal and ultimately affect the shortage of donor organs.

We established and validated diagnostic criteria for pityriasis rosea and Gianotti-Crosti syndrome. In this paper, we compare and contrast both diagnostic criteria to formulate a protocol in establishing diagnostic criteria for other dermatological diseases. The diagnostic criteria are similar in employing clear dividing lines and conjunctions (‘and/or') to assure high reliability. Both sets of criteria should be applicable for all ethnic groups. Spontaneous remission is not included, so diagnosis is not delayed while waiting for disease remission. Laboratory investigations are not enlisted, so that the criteria can be used in medical care systems in different parts of the world. The diagnostic criteria are different in that pathognomonic clinical manifestations exist for pityriasis rosea, such as the herald patch and the orientation of lesions along the lines of skin cleavages. These features, however, score low for sensitivity. These specific manifestations are not seen in Gianotti-Crosti syndrome. Such differences led to different categorisation of clinical features. Atypical variants are more common for pityriasis rosea. The diagnostic criteria for pityriasis rosea therefore do not include a list of differential diagnoses, while diagnostic criteria for Gianotti-Crosti syndrome do. Using this comparison, we constructed a protocol to establish diagnostic criteria for other skin diseases. We advocate the need to justify the establishment of diagnostic criteria, that multiple diagnostic criteria for the same disease should be avoided, that diagnostic criteria should be compatible with the disease classification if applicable, and that the scope should be well-delineated with regard to clinical variants. We outline the need for validation studies to assess the criteria-related validity, test-retest intra-clinician reliability, and inter-clinician reliability. We emphasise that the establishment of diagnostic criteria should not be a generic process. We also highlight limitations of diagnostic criteria, and emphasise that no diagnostic criteria can replace the bedside experience of clinicians.

AbstractBackgroundAn international group of experts evaluated and revised recommendations for ambulatory reflux monitoring for the diagnosis of gastro‐esophageal reflux disease (GERD).MethodsLiterature search was focused on indications and technical recommendations for GERD testing and phenotypes definitions. Statements were proposed and discussed during several structured meetings.Key ResultsReflux testing should be performed after cessation of acid suppressive medication in patients with a low likelihood of GERD. In this setting, testing can be either catheter‐based or wireless pH‐monitoring or pH‐impedance monitoring. In patients with a high probability of GERD (esophagitis grade C and D, histology proven Barrett's mucosa >1 cm, peptic stricture, previous positive pH monitoring) and persistent symptoms, pH‐impedance monitoring should be performed on treatment. Recommendations are provided for data acquisition and analysis. Esophageal acid exposure is considered as pathological if acid exposure time (AET) is greater than 6% on pH testing. Number of reflux episodes and baseline impedance are exploratory metrics that may complement AET. Positive symptom reflux association is defined as symptom index (SI) >50% or symptom association probability (SAP) >95%. A positive symptom‐reflux association in the absence of pathological AET defines hypersensitivity to reflux.Conclusions and InferencesThe consensus group determined that grade C or D esophagitis, peptic stricture, histology proven Barrett's mucosa >1 cm, and esophageal acid exposure greater >6% are sufficient to define pathological GERD. Further testing should be considered when none of these criteria are fulfilled.