Perceptions diverge on aspects related to substance use disorder: An analysis of individuals in recovery, physicians, nurses, and medical students.

Background: Interactions with healthcare workers can provide effective entrance into treatment, ensuring retention and lifelong recovery for individuals with Substance Use Disorder (SUD). Healthcare providers approach the challenges of patient management with different skills, comfort levels, and viewpoints. Individuals in recovery also provide crucial perspectives relevant to the complex aspects of the drug epidemic. The purpose of this study was to determine if perceptions of SUD diverge among individuals in recovery, physicians, nurses and medical students. Methods: A survey consisting of 29 Likert statements was deployed to physicians, nurses, medical students, and persons with SUD in recovery. Respondents were asked to rate their level of agreement on statements about SUD such as treatment, stigma, medications for opioid use disorder (MOUD), naloxone kits, safe injection sites, and methamphetamine usage. Separate Welch's analysis of variances (ANOVAs) were conducted to determine differences between the respondent groups and each statement. For any statistically significant findings, Games-Howell post-hoc analyses were employed. Results: A total of 523 individuals provided survey responses: individuals in recovery (n = 111), physicians (n = 113), nurses (n = 206), and medical students (n = 93). Survey results revealed the majority of items had statistically significant differences in respondent groups. Perceptions diverged on items related to treatment, stigma, MOUD, take-home naloxone kits, safe injection sites, needle exchange programs, and methamphetamine. Conclusion: As healthcare providers and policymakers develop treatment strategies to engage those with SUD in quality treatment, they will benefit from understanding how different viewpoints on SUD affect treatment for these individuals. These attitudes impact stigma, willingness to prescribe new treatments, and development of clinical relationships. The insight from this study allows for important discussions on the substance use health crisis and further inquiry on why these differences exist and how the diverging viewpoints may impact the lives of persons with SUD.

Circulating plasma microRNAs in colorectal neoplasia: A pilot study in assessing response to therapy.

INTRODUCTION: Current serological surveillance markers to monitor colorectal cancer (CRC) or colorectal advanced adenomas (CAA) are hampered by poor sensitivity and specificity. The aim of this study is to identify and validate a panel of plasma microRNAs which change in expression after resection of such lesions. METHODS: A prospectively maintained colorectal surgery database was queried for patients in whom both pre- and post-procedural serum samples had been obtained. An initial screening analysis of CRC and CAA patients (5 each) was conducted using screening cards for 380 miRNAs. Four identified miRNAs were combined with a previously described panel of 7 miRNAs that were diagnostically predictive of CRC and CAA. Differential miRNA expression was assessed using quantitative real-time polymerase chain reaction(qRT-PCR). RESULTS: Fifty patients were included (n = 27 CRC, n = 23 CAA). There was no difference in age, gender, or race profile of CRC patients compared to CAA patients. Six miRNA were significantly increased after CRC resection (miR-324, let7b, miR-454, miR-374a, miR-122, miR-19b, all p<0.05), while three miRNAs were significantly increased following CAA resection (miR-454, miR-374a, miR-122, all p<0.05). Three miRNA were increased in common for both (miR-454, miR-374a, miR-122). DISCUSSION: The expression of miRNAs associated with neoplasia (either CRC or CAA) was significantly increased following surgical resection or endoscopic removal of CRC or CAA. Future studies should focus on the evaluation of these miRNAs in CRC and CAA prognosis.

Interferon-gamma increases monocyte PD-L1 but does not diminish T-cell activation.

Immune dysfunction can occur during sepsis or following major trauma. Decreased monocyte HLA-DR expression and cytokine responses are associated with mortality. Recent studies have shown that adaptive immune system defects can also occur in such patients, characterised by increased PD-L1 expression and associated T-cell anergy. The aim of this study was to determine the effects of an immune adjuvant, interferon-gamma, on monocyte PD-L1 expression and T-cell activation in an ex-vivo human whole blood model of infection. We found that with interferon-gamma treatment, monocytes had increased HLA-DR expression and augmented TNF-α production in response to LPS stimulation, with a decrease in IL-10 levels. Both LPS and interferon-gamma increased the level of monocyte PD-L1 expression, and that a combination of both agents synergistically stimulated a further increase in PD-L1 levels as measured by flow cytometry. However, despite elevated PD-L1 expression, both CD4 and CD8 T-cell activation was not diminished by the addition of interferon-gamma treatment. These findings suggest that PD-L1 may not be a reliable marker for T-cell anergy, and that interferon-gamma remains an adjuvant of interest that can improve the monocyte inflammatory response while preserving T-cell activation.

Long non-coding RNA (lncRNA) and epithelial-mesenchymal transition (EMT) in colorectal cancer: a systematic review.

BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer-related death. Epithelial-mesenchymal transition (EMT) is a major process in tumor metastasis development. This systematic review aims to describe the role of long non-coding RNA (lncRNA) in EMT in CRC. METHODS: The electronic databases, PubMed, Cochrane, and EMBASE, were searched from January1990 to June 2019 to identify studies examining lncRNA and their role in mediating EMT in CRC. Studies examining clinical specimens and/or in vitro experiments were included. RESULTS: In 61 identified studies, 54 lncRNAs were increased in CRC compared to normal colorectal epithelium. Increased lncRNA expression was frequently associated with worse survival. Many lncRNAs mediate their effect through competitive endogenous RNA or transcription factor regulation. The ZEB1, 2/E-cadherin, Wnt/ß-catenin signaling, and chromatin remodeling pathways are discussed in particular. CONCLUSIONS: lncRNAs are major regulators of EMT and predictor adverse outcome in CRC patients. Future research must focus on delineating lncRNA function prior to potential clinical use.

The role and function of IκKα/ß in monocyte impairment.

Following major trauma, sepsis or surgery, some patients exhibit an impaired monocyte inflammatory response that is characterized by a decreased response to a subsequent bacterial challenge. To investigate this poorly understood phenomenon, we adopted an in-vitro model of endotoxin tolerance utilising primary human CD14 + monocytes to focus on the effect of impairment on IκKα/ß, a critical part of the NFκB pathway. Impaired monocytes had decreased IκKα mRNA and protein expression and decreased phosphorylation of the IκKα/ß complex. The impaired monocyte secretome demonstrated a distinct cytokine/chemokine footprint from the naïve monocyte, and that TNF-α was the most sensitive cytokine or chemokine in this setting of impairment. Inhibition of IκKα/ß with a novel selective inhibitor reproduced the impaired monocyte phenotype with decreased production of TNF-α, IL-6, IL-12p70, IL-10, GM-CSF, VEGF, MIP-1ß, TNF-ß, IFN-α2 and IL-7 in response to an LPS challenge. Surgical patients with infection also exhibited an impaired monocyte phenotype and had decreased SITPEC, TAK1 and MEKK gene expression, which are important for IκKα/ß activation. Our results emphasize that impaired monocyte function is, at least in part, related to dysregulated IκKα/ß activation, and that IκKα/ß is likely involved in mounting a sufficient monocyte inflammatory response. Future studies may wish to focus on adjuvant therapies that augment IκKα/ß function to restore monocyte function in this clinically important problem.

The microRNA-200 family acts as an oncogene in colorectal cancer by inhibiting the tumor suppressor RASSF2.

This study aimed to determine whether manipulation of the microRNA-200 (miR-200) family could influence colon adenocarcinoma cell behavior. The miR-200 family has a significant role in tumor suppression and functions as an oncogene. In vitro studies on gain and loss of function with small interfering RNA demonstrated that the miR-200 family could regulate RASSF2 expression. Knockdown of the miR-200 family in the HT-29 colon cancer cell line increased KRAS expression but decreased signaling in the MAPK/ERK signaling pathway through reduced ERK phosphorylation. Increased expression of the miR-200 family in the CCD-841 colon epithelium cell line increased KRAS expression and led to increased signaling in the MAPK/ERK signaling pathway but increased ERK phosphorylation. Functionally, knockdown of the miR-200 family led to decreased cell proliferation in the HT-29 cells; therefore, increased miR-200 family expression could increase cell proliferation in the CCD-841 cell line. The present study included a large paired miR array dataset (n=632), in which the miR-200 family was significantly found to be increased in colon cancer when compared with normal adjacent colon epithelium. In a miR-seq dataset (n=199), the study found that miR-200 family expression was increased in localized colon cancer compared with metastatic disease. Decreased expression was associated with poorer overall survival. The miR-200 family directly targeted RASSF2 and was inversely correlated with RASSF2 expression (n=199, all P<0.001). Despite the well-defined role of the miR-200 family in tumor suppression, the present findings demonstrated a novel function of the miR-200 family in tumor proliferation.

The effect of IκK-16 on lipopolysaccharide-induced impaired monocytes.

This study focuses on impaired monocyte function, which occurs in some patients after trauma, major elective surgery, or sepsis. This monocyte impairment increases the risk of secondary infection and death. We aimed to determine the influence IκK-16 had on monocytes using an ex-vivo model of human monocyte impairment. We included the effects of the well-studied comparators interferon-gamma (IFN-γ) and granulocyte-macrophage colony-stimulating factor (GM-CSF) on impaired monocytes. Primary human monocytes were stimulated with 10ng/mL of lipopolysaccharide (LPS) for 16h and then challenged with 100ng/mL LPS to assess the monocyte inflammatory response. Treatment regimens, consisting of either IκK-16, IFN-γ, or GM-CSF, were administered to impaired monocytes near the time of initial LPS stimulation. Stimulation with 10ng/mL LPS initially promoted a pro-inflammatory response but subsequently impaired production of both tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10) and decreased HLA-DR expression. IκK-16 treatment attenuated TNF-α production and programmed death-ligand 1 (PD-L1) expression and increased IL-10 and CD14 expression. IFN-γ treatment increased TNF-α production as well as PD-L1 and HLA-DR expression. In conclusion, limiting early inflammation with IκK-16 suppresses TNF-α production and PD-L1 expression but enhances IL-10 production and preserves CD14 expression for potential future exposure to infective stimuli.

IκK-16 decreases miRNA-155 expression and attenuates the human monocyte inflammatory response.

Excessive inflammatory responses in the surgical patient may result in cellular hypo-responsiveness, which is associated with an increased risk of secondary infection and death. microRNAs (miRNAs), such as miR-155, are powerful regulators of inflammatory signalling pathways including nuclear factor κB (NFκB). Our objective was to determine the effect of IκK-16, a selective blocker of inhibitor of kappa-B kinase (IκK), on miRNA expression and the monocyte inflammatory response. In a model of endotoxin tolerance using primary human monocytes, impaired monocytes had decreased p65 expression with suppressed TNF-α and IL-10 production (P < 0.05). miR-155 and miR-138 levels were significantly upregulated at 17 h in the impaired monocyte (P < 0.05). Notably, IκK-16 decreased miR-155 expression with a corresponding dose-dependent decrease in TNF-α and IL-10 production (P < 0.05), and impaired monocyte function was associated with increased miR-155 and miR-138 expression. In the context of IκK-16 inhibition, miR-155 mimics increased TNF-α production, while miR-155 antagomirs decreased both TNF-α and IL-10 production. These data demonstrate that IκK-16 treatment attenuates the monocyte inflammatory response, which may occur through a miR-155-mediated mechanism, and that IκK-16 is a promising approach to limit the magnitude of an excessive innate inflammatory response to LPS.