Three differentiation states risk-stratify bladder cancer into distinct subtypes

Current clinical judgment in bladder cancer (BC) relies primarily on pathological stage and grade. We investigated whether a molecular classification of tumor cell differentiation, based on a developmental biology approach, can provide additional prognostic information. Exploiting large preexisting gene-expression databases, we developed a biologically supervised computational model to predict markers that correspond with BC differentiation. To provide mechanistic insight, we assessed relative tumorigenicity and differentiation potential via xenotransplantation. We then correlated the prognostic utility of the identified markers to outcomes within gene expression and formalin-fixed paraffin-embedded (FFPE) tissue datasets. Our data indicate that BC can be subclassified into three subtypes, on the basis of their differentiation states: basal, intermediate, and differentiated, where only the most primitive tumor cell subpopulation within each subtype is capable of generating xenograft tumors and recapitulating downstream populations. We found that keratin 14 (KRT14) marks the most primitive differentiation state that precedes KRT5 and KRT20 expression. Furthermore, KRT14 expression is consistently associated with worse prognosis in both univariate and multivariate analyses. We identify here three distinct BC subtypes on the basis of their differentiation states, each harboring a unique tumor-initiating population.     

Molecular basis of bacterial protein Hen1 activating the ligase activity of bacterial protein Pnkp for RNA repair

Ribotoxins cleave essential RNAs for cell killing in vivo, and the bacterial polynucleotide kinase-phosphatase (Pnkp)/hua enhancer 1 (Hen1) complex has been shown to repair ribotoxin-cleaved RNAs in vitro. Bacterial Pnkp/Hen1 is distinguished from other RNA repair systems by performing 3'-terminal 2'-O-methylation during RNA repair, which prevents the repaired RNA from repeated cleavage at the same site. To ensure the opportunity of 2'-O-methylation by bacterial Hen1 during RNA repair and, therefore, maintain the quality of the repaired RNA, Pnkp/Hen1 has evolved to require the participation of Hen1 in RNA ligation, because Pnkp alone is unable to carry out the reaction despite possessing all signature motifs of an RNA ligase. However, the precise role of Hen1 in RNA ligation is unknown. Here, we present the crystal structure of an active RNA ligase consisting of the C-terminal half of Pnkp (Pnkp-C) and the N-terminal half of Hen1 (Hen1-N) from Clostridium thermocellum. The structure reveals that the N-terminal domain of Clostridium thermocellum (Cth) Hen1, shaped like a left hand, grabs the flexible insertion module of CthPnkp and locks its conformation via further interaction with the C-terminal addition module of CthPnkp. Formation of the CthPnkp-C/Hen1-N heterodimer creates a ligation pocket with a width for two strands of RNA, depth for two nucleotides, and the adenosine monophosphate (AMP)-binding pocket at the bottom. The structure, combined with functional analyses, provides insight into the mechanism of how Hen1 activates the RNA ligase activity of Pnkp for RNA repair.     

Structural insights into the biogenesis and biofilm formation by the Escherichia coli common pilus

Bacteria have evolved a variety of mechanisms for developing community-based biofilms. These bacterial aggregates are of clinical importance, as they are a major source of recurrent disease. Bacterial surface fibers (pili) permit adherence to biotic and abiotic substrates, often in a highly specific manner. The Escherichia coli common pilus (ECP) represents a remarkable family of extracellular fibers that are associated with both disease-causing and commensal strains. ECP plays a dual role in early-stage biofilm development and host cell recognition. Despite being the most common fimbrial structure, relatively little is known regarding its biogenesis, architecture, and function. Here we report atomic-resolution insight into the biogenesis and architecture of ECP. We also derive a structural model for entwined ECP fibers that not only illuminates interbacteria communication during biofilm formation but also provides a useful foundation for the design of novel nanofibers.     

Effectiveness of a culturally tailored diabetes self-management program for chinese americans

Purpose The purpose of the study was to test the feasibility and efficacy of a diabetes self-management and education program for Chinese Americans in a support group format. The rationale for the study was to create culturally appropriate diabetes education and management programs in response to the growing diabetes prevalence among Chinese Americans. The investigators hypothesized that participants will have improved diabetes knowledge and practices, hemoglobin A1C, and social support. The study objectives were at least: 50% will have significant improvements in diabetes knowledge and practice activities, 30% of participants will have significant improvements in A1C, and 50% will report a gain in emotional support. Methods The program consisted of 12 90-minute diabetes education and support group sessions offered in a medical office setting. The sample included 23 Chinese Americans with either type 1 or type 2 diabetes. Using a single-group, pre-post test design, A1C and diabetes knowledge were assessed at baseline and 6 months. Data were collected through clinical assessments and written questionnaires. Results The results indicated high attendance and statistically significant increases in glycemic control and diabetes knowledge. Statistically insignificant differences were shown in diabetes management practices. Secondary outcomes assessed participants' perceived diabetes management and emotional and social support. Conclusions Diabetes Self-Management: A Cultural Approach (DSMCA) support group model demonstrates that a culturally tailored support group utilizing a community-based participatory research approach is an effective format to improve diabetes self-management skills among Chinese Americans. The program can be adapted for other ethnic populations. The efficacy of the intervention can be further tested in larger randomized trials.     

Neurodegeneration of the retina in mouse models of Alzheimer’s disease: what can we learn from the retina?

Alzheimer’s disease (AD) is an age-related progressive neurodegenerative disease commonly found among elderly. In addition to cognitive and behavioral deficits, vision abnormalities are prevalent in AD patients. Recent studies investigating retinal changes in AD double-transgenic mice have shown altered processing of amyloid precursor protein and accumulation of β-amyloid peptides in neurons of retinal ganglion cell layer (RGCL) and inner nuclear layer (INL). Apoptotic cells were also detected in the RGCL. Thus, the pathophysiological changes of retinas in AD patients are possibly resembled by AD transgenic models. The retina is a simple model of the brain in the sense that some pathological changes and therapeutic strategies from the retina may be observed or applicable to the brain. Furthermore, it is also possible to advance our understanding of pathological mechanisms in other retinal degenerative diseases. Therefore, studying AD-related retinal degeneration is a promising way for the investigation on (1) AD pathologies and therapies that would eventually benefit the brain and (2) cellular mechanisms in other retinal degenerations such as glaucoma and age-related macular degeneration. This review will highlight the efforts on retinal degenerative research using AD transgenic mouse models.     

Recent progress in the treatment of proliferative lupus nephritis

The recent decades have witnessed significant progress in the treatment of lupus nephritis. Existing immunosuppressive regimens have been refined to enhance efficacy and reduce adverse effects, resulting in improvements in renal and patient survival and patients' quality of life. This review focuses on the new treatments that have emerged over the past 2 decades. The data and methodology of important clinical trials are discussed to highlight the important findings and their limitations. The role of mycophenolate mofetil as induction or maintenance immunosuppressive treatment is discussed in detail. Racial variations in prognosis and treatment response are evident. With increasing treatment options and better appreciation of patient characteristics that impact on response and tolerance, the management of lupus nephritis has become more individualized. The choice and the dosing regimen of immunosuppressive agents should take into account factors such as race, type of lupus nephritis, disease severity, renal reserve, and prior disease course, to aim for an optimal balance of benefit and risk.