LINC00355 regulates p27KIP expression by binding to MENIN to induce proliferation in late-stage relapse breast cancer.

Late-stage relapse (LSR) in patients with breast cancer (BC) occurs more than five years and up to 10 years after initial treatment and has less than 30% 5-year relative survival rate. Long non-coding RNAs (lncRNAs) play important roles in BC yet have not been studied in LSR BC. Here, we identify 1127 lncRNAs differentially expressed in LSR BC via transcriptome sequencing and analysis of 72 early-stage and 24 LSR BC patient tumors. Decreasing expression of the most up-regulated lncRNA, LINC00355, in BC and MCF7 long-term estrogen deprived cell lines decreases cellular invasion and proliferation. Subsequent mechanistic studies show that LINC00355 binds to MENIN and changes occupancy at the CDKN1B promoter to decrease p27Kip. In summary, this is a key study discovering lncRNAs in LSR BC and LINC00355 association with epigenetic regulation and proliferation in BC.

Long non-coding RNA RAMS11 promotes metastatic colorectal cancer progression.

Colorectal cancer (CRC) is the most common gastrointestinal malignancy in the U.S.A. and approximately 50% of patients develop metastatic disease (mCRC). Despite our understanding of long non-coding RNAs (lncRNAs) in primary colon cancer, their role in mCRC and treatment resistance remains poorly characterized. Therefore, through transcriptome sequencing of normal, primary, and distant mCRC tissues we find 148 differentially expressed RNAs Associated with Metastasis (RAMS). We prioritize RAMS11 due to its association with poor disease-free survival and promotion of aggressive phenotypes in vitro and in vivo. A FDA-approved drug high-throughput viability assay shows that elevated RAMS11 expression increases resistance to topoisomerase inhibitors. Subsequent experiments demonstrate RAMS11-dependent recruitment of Chromobox protein 4 (CBX4) transcriptionally activates Topoisomerase II alpha (TOP2α). Overall, recent clinical trials using topoisomerase inhibitors coupled with our findings of RAMS11-dependent regulation of TOP2α supports the potential use of RAMS11 as a biomarker and therapeutic target for mCRC.

Sensory, Affective, and Catastrophizing Reactions to Multiple Stimulus Modalities: Results from the Oklahoma Study of Native American Pain Risk.

Native Americans (NAs) have a higher prevalence of chronic pain than any other U.S. racial/ethnic group; however, little is known about the mechanisms for this pain disparity. This study used quantitative sensory testing to assess pain experience in healthy, pain-free adults (n = 137 NAs (87 female), n = 145 non-Hispanic whites (NHW; 68 female)) after painful electric, heat, cold, ischemic, and pressure stimuli. After each stimulus, ratings of pain intensity, sensory pain, affective pain, pain-related anxiety, and situation-specific pain catastrophizing were assessed. The results suggested that NAs reported greater sensory pain in response to suprathreshold electric and heat stimuli, greater pain-related anxiety to heat and ischemic stimuli, and more catastrophic thoughts in response to electric and heat stimuli. Sex differences were also noted; however, with the exception of catastrophic thoughts to cold, these finding were not moderated by race/ethnicity. Together, findings suggest NAs experience heightened sensory, anxiety, and catastrophizing reactions to painful stimuli. This could place NAs at risk for future chronic pain and could ultimately lead to a vicious cycle that maintains pain (eg, pain → anxiety/catastrophizing → pain). PERSPECTIVE: NAs experienced heightened sensory, anxiety, and catastrophizing reactions in response to multiple pain stimuli. Given the potential for anxiety and catastrophic thoughts to amplify pain, this characteristic may place them at risk for pain disorders and could lead to a vicious cycle that maintains pain.

Pan-cancer transcriptome analysis reveals long noncoding RNAs with conserved function.

A growing number of gene-centric studies have highlighted the emerging significance of lncRNAs in cancer. However, these studies primarily focus on a single cancer type. Therefore, we conducted a pan-cancer analysis of lncRNAs comparing tumor and matched normal expression levels using RNA-Seq data from ∼ 3,000 patients in 8 solid tumor types. While the majority of differentially expressed lncRNAs display tissue-specific expression we discovered 229 lncRNAs with outlier or differential expression across multiple cancers, which we refer to as 'onco-lncRNAs'. Due to their consistent altered expression, we hypothesize that these onco-lncRNAs may have conserved oncogenic and tumor suppressive functions across cancers. To address this, we associated the onco-lncRNAs in biological processes based on their co-expressed protein coding genes. To validate our predictions, we experimentally confirmed cell growth dependence of 2 novel oncogenic lncRNAs, onco-lncRNA-3 and onco-lncRNA-12, and a previously identified lncRNA CCAT1. Overall, we discovered lncRNAs that may have broad oncogenic and tumor suppressor roles that could significantly advance our understanding of cancer lncRNA biology.

Transcriptome sequencing reveals altered long intergenic non-coding RNAs in lung cancer.

BACKGROUND: Long intergenic non-coding RNAs (lncRNAs) represent an emerging and under-studied class of transcripts that play a significant role in human cancers. Due to the tissue- and cancer-specific expression patterns observed for many lncRNAs it is believed that they could serve as ideal diagnostic biomarkers. However, until each tumor type is examined more closely, many of these lncRNAs will remain elusive. RESULTS: Here we characterize the lncRNA landscape in lung cancer using publicly available transcriptome sequencing data from a cohort of 567 adenocarcinoma and squamous cell carcinoma tumors. Through this compendium we identify over 3,000 unannotated intergenic transcripts representing novel lncRNAs. Through comparison of both adenocarcinoma and squamous cell carcinomas with matched controls we discover 111 differentially expressed lncRNAs, which we term lung cancer-associated lncRNAs (LCALs). A pan-cancer analysis of 324 additional tumor and adjacent normal pairs enable us to identify a subset of lncRNAs that display enriched expression specific to lung cancer as well as a subset that appear to be broadly deregulated across human cancers. Integration of exome sequencing data reveals that expression levels of many LCALs have significant associations with the mutational status of key oncogenes in lung cancer. Functional validation, using both knockdown and overexpression, shows that the most differentially expressed lncRNA, LCAL1, plays a role in cellular proliferation. CONCLUSIONS: Our systematic characterization of publicly available transcriptome data provides the foundation for future efforts to understand the role of LCALs, develop novel biomarkers, and improve knowledge of lung tumor biology.

Endoscopic therapy of necrotizing pancreatitis and pseudocysts.

Endoscopic therapy has become an essential component in the management of postpancreatitis complications, such as infected and/or symptomatic pancreatic pseudocysts and walled-off necrosis. However, although there have been 2 recent randomized, controlled trials performed, a general lack of comparative effectiveness data regarding the timing, indications, and outcomes of these procedures has been a barrier to the development of practice standards for therapeutic endoscopists managing these issues. This article reviews the available data and expert consensus regarding indications for endoscopic intervention, timing of procedures, endoscopic technique, periprocedural considerations, and complications.

The "golden hours" of management in acute pancreatitis.

In the past decade, a significant amount of active and enthusiastic research has changed the way we treat acute pancreatitis (AP) within the first 24 hours of presentation. We highlight the importance of rapid initiation of treatment to help prevent the considerable morbidity and mortality that can occur when interventions are delayed. We review recent data that validate simple and accurate tools for prognostication of AP to replace the older, more tedious methods that relied on numerous factors and required up to 48 hours to complete. Additionally, we aim to provide evidence-based guidelines and end points for fluid resuscitation. Finally, we hope to bring clarification to two previously controversial topics in AP treatment: the use of prophylactic antibiotics and early endoscopic retrograde cholangiopancreatography.

The impact of time elapsed between endoscopic ultrasound and esophagectomy on concordance of ultrasonographic and pathologic staging of esophageal malignancy.

BACKGROUND: Endoscopic ultrasound (EUS) is frequently used for staging of esophageal malignancies prior to esophagectomy. AIMS: The purpose of this study was to evaluate the effect of elapsed time between endoscopic ultrasound (EUS) staging and esophagectomy on the accuracy of EUS T- and N-staging. METHODS: This was a retrospective case series of 45 patients with esophageal malignancy who underwent staging EUS and subsequent esophagectomy at our center without neoadjuvant therapy between 2000 and 2009. The main outcome measurements were accuracy of EUS T- and N-staging when compared with surgical pathology. RESULTS: EUS staging was accurate in 55.6% of patients for tumor stage, and in 75.6% of patients for nodal stage. The median time between EUS and esophagectomy was 26 days (range 3-64). Among patients with surgery performed 3-15, 16-30, and 31-64 days after EUS, EUS tumor staging was accurate in 90.9, 47.4, and 40.0%, respectively (P = 0.02). EUS nodal staging among patients with surgery performed 3-15, 16-30, or 31-64 days after EUS was accurate in 63.6, 84.2, and 73.3% of cases, respectively (P = 0.44). Among the 20 patients for whom T-stage was discordant, 45% were understaged and 55% were overstaged by EUS. There were 11 patients in whom N-stage was discordant; 45.5% were understaged and 54.5% were overstaged. CONCLUSIONS: Pathologic T-staging is concordant with EUS T-staging when esophagectomy is performed within 15 days of endoscopic evaluation. Correlation between EUS and pathologic N-staging is unlikely to be affected by length of time between EUS and esophagectomy.

The impact of prior biliary stenting on the accuracy and complication rate of endoscopic ultrasound fine-needle aspiration for diagnosing pancreatic adenocarcinoma.

OBJECTIVES: Our aim was to determine whether the presence of a biliary stent during endoscopic ultrasound fine-needle aspiration (EUS-FNA) affects diagnosis and complication rates. METHODS: Retrospective analysis was performed of 268 patients with pancreatic head or neck adenocarcinoma who underwent EUS-FNA at our academic medical center between 2000 and 2009. Endoscopic ultrasound fine-needle aspiration and endoscopic retrograde cholangiopancreatography reports, cytology results, and physicians' notes were reviewed. RESULTS: A total of 170 patients without stents, 87 patients with stents placed more than 1 day before EUS, and 11 patients with stents placed less than 1 day before EUS were identified. In patients without stents, the tissue diagnosis rate via EUS-FNA was 92.4% compared with a rate of 88.5% for those with stents placed more than 1 day before EUS-FNA (P=0.36). However, the patients with stents placed immediately before EUS-FNA were more likely to have indeterminate results from the EUS-FNA than the other patients were (P=0.008). Complication rates were the same among the groups. CONCLUSIONS: Pre-EUS stenting of biliary obstruction due to pancreatic adenocarcinoma does not influence the rate of tissue diagnosis if performed more than 1 day before EUS-FNA. Lack of immediate EUS access should not preclude stent placement in appropriate patients with malignant biliary obstruction who will undergo EUS-FNA.

African Americans show alterations in endogenous pain regulatory mechanisms and reduced pain tolerance to experimental pain procedures.

OBJECTIVES: To examine ethnic differences in pain sensitivity and relationship of pain tolerance to blood pressure and neuroendocrine factors. METHODS: Fifty-one African Americans (24 men, 27 women) and 55 people from other ethnic groups (primarily Caucasian; 26 men, 29 women) were tested twice for pain sensitivity to tourniquet ischemia, thermal heat, and cold pressor tests, once following mental stress and once following rest control. Resting and stress-induced blood pressure (BP), plasma norepinephrine (NE), and cortisol were assessed. RESULTS: In response to all three pain tests, African Americans had lower pain tolerance relative to Caucasian/Others after both rest and stress. Only the non-African American group showed the expected inverse relationship between BP and pain sensitivity. African Americans had lower cortisol concentrations at rest and stress and showed blunted NE and systolic BP responses to stress. Only in Caucasians/Others was the relationship seen between higher stress-induced BP, cortisol, and NE levels and greater pain tolerance. CONCLUSIONS: The results suggest that there are alterations in endogenous pain regulatory mechanisms involving BP, cortisol, and NE in African Americans. Such dysregulation may contribute to the greater rate of clinical pain symptoms they experience. It is hypothesized that greater chronic stress in African Americans may be a contributing factor to the alterations in pain regulation.