The long non-coding RNA LINC00707 interacts with Smad proteins to regulate TGFß signaling and cancer cell invasion.

BACKGROUND: Long non-coding RNAs (lncRNAs) regulate cellular processes by interacting with RNAs or proteins. Transforming growth factor ß (TGFß) signaling via Smad proteins regulates gene networks that control diverse biological processes, including cancer cell migration. LncRNAs have emerged as TGFß targets, yet, their mechanism of action and biological role in cancer remain poorly understood. METHODS: Whole-genome transcriptomics identified lncRNA genes regulated by TGFß. Protein kinase inhibitors and RNA-silencing, in combination with cDNA cloning, provided loss- and gain-of-function analyses. Cancer cell-based assays coupled to RNA-immunoprecipitation, chromatin isolation by RNA purification and protein screening sought mechanistic evidence. Functional validation of TGFß-regulated lncRNAs was based on new transcriptomics and by combining RNAscope with immunohistochemical analysis in tumor tissue. RESULTS: Transcriptomics of TGFß signaling responses revealed down-regulation of the predominantly cytoplasmic long intergenic non-protein coding RNA 707 (LINC00707). Expression of LINC00707 required Smad and mitogen-activated protein kinase inputs. By limiting the binding of Krüppel-like factor 6 to the LINC00707 promoter, TGFß led to LINC00707 repression. Functionally, LINC00707 suppressed cancer cell invasion, as well as key fibrogenic and pro-mesenchymal responses to TGFß, as also attested by RNA-sequencing analysis. LINC00707 also suppressed Smad-dependent signaling. Mechanistically, LINC00707 interacted with and retained Smad proteins in the cytoplasm. Upon TGFß stimulation, LINC00707 dissociated from the Smad complex, which allowed Smad accumulation in the nucleus. In vivo, LINC00707 expression was negatively correlated with Smad2 activation in tumor tissues. CONCLUSIONS: LINC00707 interacts with Smad proteins and limits the output of TGFß signaling, which decreases LINC00707 expression, thus favoring cancer cell invasion. Video Abstract.

Postcardiotomy Extracorporeal Membrane Oxygenation: Narrative Review Navigating the Ethical Issues.

Postcardiotomy shock (PCS) is an uncommon and life-threatening surgical complication. Extracorporeal membrane oxygenation (ECMO) is the first line of mechanical circulatory support for treating PCS when medical therapies are insufficient. Reaching a "therapeutic ceiling" or a "bridge to nowhere" is a common clinical scenario in which medical avenues for recovery have been exhausted. These situations pose emotional and ethical challenges for patients, their surrogates, and clinicians. To shed light on these ethically challenging situations in PCS and potential approaches, the authors conducted a narrative review of the literature. Publications were utilized to describe current trends in the diagnosis and management of the patient with PCS, with particular emphasis on the therapeutic ceiling for life support. Most of the recommendations came from practice parameters or expert opinions to support specific interventions. The authors proposed a stepwise multidisciplinary approach to reduce PCS-associated ethical and emotional challenges. Their proposed algorithm was based on the likelihood of the need for ECMO support based on the mortality risk stratification of cardiac surgery. They suggested focused discussions around the commencement of ECMO or other life-sustaining therapies-ideally preoperatively at the time of consent-through shared decision-making and, subsequently, proactive multidisciplinary education and updates to the surrogate decision-makers relying on realistic prognosis and consideration of the patient wishes during the ECMO run.

Emergency Department Patient Perspectives on the Risk of Addiction to Prescription Opioids.

OBJECTIVE: To characterize emergency department (ED) patients' knowledge and beliefs about the addictive potential of opioids. DESIGN: Mixed methods analysis of data from a randomized controlled trial. SETTING: Urban academic ED (>88,000 visits). SUBJECTS: One hundred and seventy four discharged ED patients prescribed hydrocodone-acetaminophen for acute pain. METHODS: The study analyzed data collected from a randomized controlled trial investigating patients' knowledge of opioids. ED patients discharged with hydrocodone-acetaminophen completed an audio-recorded phone interview 4­7 days later. This analysis focuses on responses about addiction. Responses were categorized using content analysis; thematic analysis identified broad themes common across different categories. RESULTS: Participants' mean age was 45.5 years (SD, 14.8), 58.6% female, 50.6% white, and the majority had an orthopedic diagnosis (24.1% back pain, 52.3% other injuries). Responses were categorized first based on whether the patient believed that opioids could be addictive (categorized as: yes, 58.7%; no, 19.5%; depends, 17.2%; or do not know, 4.6%), and second based on whether or not the patient discussed his/her own experience with the medication (categorized as: personalized, 35.6%; or not personalized, 64.4%). Cohen's Kappa was 0.84 for all categories. Three themes emerged in the thematic analysis: theme 1) patients expect to "feel" addicted if they are addicted, theme 2) patients fear addiction, and theme 3) side effects affected patient views of addiction. CONCLUSION: In this sample, patients had misconceptions about opioid addiction. Some patients did not know opioids could be addictive, others underestimated their personal risk of addiction, and others overtly feared addiction and, therefore, risked inadequate pain management. Despite limited data, we recommend providers discuss opioid addiction with their patients.

Improving patient knowledge and safe use of opioids: a randomized controlled trial.

OBJECTIVES: The use of opioid analgesics in the United States has significantly increased in recent years. However, there is minimal consensus on what discharge counseling should accompany these high-risk prescriptions and large variations in what is done in practice. The objective of this study was to evaluate the effect of a dual-modality (written and spoken) literacy-appropriate educational strategy on patients' knowledge of and safe use of opioid analgesics. METHODS: This was a prospective, randomized controlled trial. Consecutive discharged patients at an urban academic ED (>88,000 visits) with new prescriptions for hydrocodone-acetaminophen were enrolled. Patients were randomized to receive either usual care or the educational intervention. The educational intervention was a one-page information sheet about hydrocodone-acetaminophen, which was both given to the patients and read aloud by the research assistant (nonblinded). Follow-up phone calls were conducted 4 to 7 days after the visit to assess patient knowledge about the medication and self-report of activities associated with safety of use (e.g., double-dipping with acetaminophen, storage, use with alcohol or while driving). RESULTS: A total of 274 patients were enrolled; 210 completed follow-up (110 usual care and 100 intervention). No significant differences in baseline characteristics emerged between the study arms; 42% were male, and 51% were white, with a median age of 43 years. Half of patients had non-back pain orthopedic injuries (49.5%). On follow-up, overall knowledge was poor, with only 28% able to name both active ingredients in the medication. The intervention group had better knowledge of precautions related to taking additional acetaminophen (usual care 18.2%, 95% confidence interval [CI] = 10.9% to 25.5% vs. intervention 38%, 95% CI = 28.3% to 47.7%; difference = 27.6, 95% CI of difference = 21.5 to 33.7) and knowledge of side effects (usual care median = 1, interquartile range [IQR] 0 to 2 vs. intervention median = 2, IQR = 1 to 2; p < 0.0001). Additionally, those who received the intervention were less likely to have reported driving within 6 hours after taking hydrocodone (usual care 13.6%, 95% CI = 7.2% to 20% vs. intervention 3%, 95% CI = -0.3% to 6.3%; difference = 10.6, 95% CI of difference = 3.4 to 17.9). There was no difference between groups related to knowledge about drinking alcohol while taking hydrocodone (overall 18.1%) or knowledge that the opioid could be addictive (overall 72.4%). CONCLUSIONS: This simple strategy improved several, but not all, aspects of patient knowledge and resulted in fewer patients in the intervention arm driving while taking hydrocodone. Integration of a patient education document into conversations about opioids holds promise for improving patient knowledge about these high-risk medications.