Diverse temporal and spatial mechanisms work, partially through Stanniocalcin-1, V-ATPase and senescence, to activate the extracellular ATP-mediated drug resistance in human cancer cells.

Introduction: Resistance to drug therapies is associated with a large majority of cancer-related deaths. ATP-binding cassette (ABC) transporter-mediated drug efflux, epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs), glutathione (GSH), senescence, and vacuole-type ATPase (V-ATPase) all contribute to the resistance. We recently showed that extracellular ATP (eATP) induces and regulates EMT, CSC formation, and ABC transporters in human cancer cells and tumors. eATP also consistently upregulates Stanniocalcin-1 (STC1), a gene that significantly contributes to EMT, CSC formation, and tumor growth. We also found that eATP enhances drug resistance in cancer cells through eATP internalization mediated by macropinocytosis, leading to an elevation of intracellular ATP (iATP) levels, induction of EMT, and CSC formation. However, these factors have never been systematically investigated in the context of eATP-induced drug resistance. Methods: In this study, we hypothesized that eATP increases drug resistance via inducing ABC efflux, EMT, CSCs, STC1, and their accompanied processes such as GSH reducing activity, senescence, and V-ATPase. RNA sequencing, metabolomics, gene knockdown and knockout, and functional assays were performed to investigate these pathways and processes. Results and discussion: Our study results showed that, in multiple human cancer lines, eATP induced genes involved in drug resistance, elevated ABC transporters' efflux activity of anticancer drugs; generated transcriptomic and metabolic profiles representing a drug resistant state; upregulated activities of GSH, senescence, and V-ATPase to promote drug resistance. Collectively, these newly found players shed light on the mechanisms of eATP-induced as well as STC1- and V-ATPase-mediated drug resistance and offer potential novel targets for combating drug resistance in cancers.

Elucidating Potential Profibrotic Mechanisms of Emerging Biomarkers for Early Prognosis of Hepatic Fibrosis.

Hepatic fibrosis has been associated with a series of pathophysiological processes causing excessive accumulation of extracellular matrix proteins. Several cellular processes and molecular mechanisms have been implicated in the diseased liver that augments fibrogenesis, fibrogenic cytokines and associated liver complications. Liver biopsy remains an essential diagnostic tool for histological evaluation of hepatic fibrosis to establish a prognosis. In addition to being invasive, this methodology presents with several limitations including poor cost-effectiveness, prolonged hospitalizations, and risks of peritoneal bleeding, while the clinical use of this method does not reveal underlying pathogenic mechanisms. Several alternate noninvasive diagnostic strategies have been developed, to determine the extent of hepatic fibrosis, including the use of direct and indirect biomarkers. Immediate diagnosis of hepatic fibrosis by noninvasive means would be more palatable than a biopsy and could assist clinicians in taking early interventions timely, avoiding fatal complications, and improving prognosis. Therefore, we sought to review some common biomarkers of liver fibrosis along with some emerging candidates, including the oxidative stress-mediated biomarkers, epigenetic and genetic markers, exosomes, and miRNAs that needs further evaluation and would have better sensitivity and specificity. We also aim to elucidate the potential role of cardiotonic steroids (CTS) and evaluate the pro-inflammatory and profibrotic effects of CTS in exacerbating hepatic fibrosis. By understanding the underlying pathogenic processes, the efficacy of these biomarkers could allow for early diagnosis and treatment of hepatic fibrosis in chronic liver diseases, once validated.

Residency training: a failed lumbar puncture is more about obesity than lack of ability.

OBJECTIVE: To identify factors influencing the success of lumbar puncture (LP) performed by neurology residents in an outpatient clinic. BACKGROUND: There is a need to understand the specific influence of patient or operator characteristics in LP performance in order to identify situations at high risk for failure that could benefit from compensatory interventions. METHODS: We performed a retrospective analysis of all consecutive patients who underwent elective LP in the Neurology Clinic at the University of Iowa between 2009 and 2012. We recorded demographic, anthropometric, and clinical information, and the level of training of the resident performing the procedure. Outcomes measure was unsuccessful LP, defined as no quantifiable CSF. This study was previously approved by the University of Iowa institutional review board. RESULTS: A total of 328 patients (59% women) were included. Men were significantly older than women, and the indication of the procedure differed by sex. Headache or possible multiple sclerosis were more common indications in women than in men. Nineteen percent of the LPs were unsuccessful. We found a strong correlation between patient body mass index (BMI) and unsuccessful outcome (p < 0.0001). Age of the patient and level of training of the operator did not predict unsuccessful LP. CONCLUSIONS: Patient BMI is the key factor that determines an unsuccessful LP by neurology residents in an outpatient setting, an association that might be applicable to different clinical settings. The high failure rate in patients with BMI >35 suggests that implementing compensatory interventions such as the use of imaging guidance might be cost-effective and better tolerated by these patients.

Longitudinal study of facial skeletal growth completion in 3 dimensions.

INTRODUCTION: Previous authors have suggested that transverse facial skeletal growth is completed before either anteroposterior or vertical growth and that anteroposterior growth is completed before vertical growth. Our purpose in this study was to examine this concept. METHODS: Twenty-four subjects (11 male, 13 female) who had annual lateral and posteroanterior cephalograms up to and including age 17 or 18 and again at age 25 or older were identified from the Iowa Facial Growth Study. Transverse, anteroposterior, and vertical facial dimensions were measured longitudinally into adulthood by using key skeletal landmarks. Descriptive statistics were calculated, and nonparametric Wilcoxon signed rank tests were performed separately for the sexes to determine the age at which each anteroposterior, vertical, and transverse growth variable reached adult size. RESULTS: For both sexes, an overlap exists at any age in the amount of growth completed for the various measurements in the transverse, anteroposterior, and vertical dimensions. Although some transverse measures (cranial width and interjugal width) attain adult size before any anteroposterior or vertical ones, there is evidence of continued growth for other transverse parameters (interzygomatic width and intergonial width). A similar overlap is seen in the anteroposterior and vertical dimensions. CONCLUSIONS: A distinct separation, by time and dimension, is not seen in the amount of facial growth completed during development. Instead, a dramatic spread and an overlap of growth curves are observed throughout the developing years.