The role of the MiR-200 family on the tumor suppressor RASSF2 and the effect on MAPK pathway activity in colorectal cancer.

This dissertation investigated the role of the miR-200 family in normal colon epithelial (CCD 841) and Dukes’ C (HT-29) colorectal cancer (CRC) cell lines. Our aim was to characterize expression of the miR-200 family (miR-200a, miR-200b, miR-200c, miR-141, and miR-429) in colorectal cell lines, study their effect on the tumor suppressor Ras Associated Domain-Containing Protein (RASSF) 2 and on subsequent activity within the mitogen-activated protein kinase (MAPK) signaling pathway. We wanted to determine whether regulation of miR-200 family members could change cell behavior towards more “cancer-like” in a normal colon epithelium (CCD 841) cell line, or less “cancer-like” in a Dukes’ C (HT-29) CRC cell line. We found the following: 1. All miR-200 family members were highly expressed in colorectal cancer cell lines compared to a normal colon epithelial cell line. 2. RASSF2 mRNA and protein expression was downregulated in all CRC cell lines compared to the normal colon epithelial (CCD 841) cell line. 3. Overexpression of miR-200 family members in a normal colon epithelial (CCD 841) cell line decreased expression of both RASSF2 mRNA and protein. 4. Inhibition of miR-200 family members in a Dukes’ C (HT-29) CRC cell line increased expression of both RASSF2 mRNA and protein. 5. Total K-Ras expression and phosphorylation of ERK 1/2 increased following overexpression of miR-200 family members in a normal colon epithelial (CCD 841) cell line, indicating increased activity within the MAPK pathway resulting in increased cell proliferation. 6. MAPK pathway activity decreased, as measured by reduced ERK 1/2 phosphorylation and reduced cell proliferation in a Dukes’ C (HT-29) CRC cell line following inhibition of miR-200 family members. These findings demonstrate a novel association of the miR-200 family, the tumor suppressor RASSF2, and the MAPK signaling pathway in CRC. In contrast to the previous understanding that miR-200 family dysregulation is considered to exhibit tumor suppressive behavior by blocking epithelial to mesenchymal transition, we refute this in the case of CRC and propose the miR-200 family contribute to CRC tumorigenesis. This improved understanding of the miR-200 family may have the potential to be developed as a therapeutic intervention in CRC

Blood-based microRNAs as biomarkers for the diagnosis of colorectal cancer: a systematic review and meta-analysis

Background: Colorectal cancer (CRC) is common and associated with significant mortality. Current screening methods for CRC lack patient compliance. microRNAs (miRNAs), identified in body fluids, are negative regulators of gene expression and are dysregulated in many cancers, including CRC. This paper summarises studies identifying blood-based miRNAs dysregulated in CRC compared with healthy controls in an attempt to evaluate their use as a screening tool for the diagnosis of CRC. Methods: A search of electronic databases (PubMed and EMBASE) and grey literature was performed between January 2002 and April 2016. Studies reporting plasma or serum miRNAs in the diagnosis of CRC compared with healthy controls were selected. Patient demographics, type of patient sample (serum or plasma), method of miRNA detection, type of normalisation, and the number of significantly dysregulated miRNAs identified were recorded. Statistical evaluation of dysregulated miRNAs using sensitivity, specificity, and area under the curve (AUC) was performed. Results: Thirty-four studies investigating plasma or serum miRNAs in the diagnosis of CRC were included. A total of 31 miRNAs were found to be either upregulated (n=17) or downregulated (n=14) in CRC cases as compared with controls. Fourteen studies identified panels of ⩾2 dysregulated miRNAs. The highest AUC, 0.943, was identified using a panel of 4 miRNAs with 83.3% sensitivity and 93.1% specificity. Meta-analysis of studies identifying a single dysregulated miRNA in CRC cases compared with controls was performed. Overall sensitivity and specificity of 28 individual miRNAs in the diagnosis of CRC were 76% (95% CI 72%–80%) and 76% (95% CI 72%–80%), respectively, indicating good discriminative ability of miRNAs as biomarkers for CRC. These data did not change with sensitivity analyses. Conclusions: Blood-based miRNAs distinguish patients with CRC from healthy controls with high sensitivity and specificity comparable to other common and invasive currently used screening methods for CRC. In future, miRNAs may be used as a relatively non-invasive blood-based marker for detection of CRC

Academic careers in global pulmonary and critical care medicine

The burden of respiratory and critical illness is high worldwide, yet specialist care is underrepresented in low- and middle-income countries (LMICs) [1]. For many areas of medicine, the past decade has witnessed tremendous growth in global health opportunities for trainees; however, these opportunities tend to be restricted to individual institutions and geographic regions and academic global pulmonary and critical care medicine (PCCM) remains a relatively novel concept [2]. Consequently, PCCM fellows and junior faculty at institutions with limited global health mentorship have little guidance in building successful global health careers

Academic careers in global pulmonary and critical care medicine: perspectives from experts in the field

Academic global pulmonary/critical care medicine (PCCM) remains a relatively novel concept not fully embraced by all training programs, so PCCM early-career professionals may have little guidance in building successful careers in this field. To highlight various approaches used by current PCCM faculty to incorporate global health into their academic careers, speakers from a global health careers mini symposia held at the 2017 and 2018 American Thoracic Society International Conferences were invited to submit perspectives reflecting on academic PCCM and global health. The collection of essays was collated into a single manuscript. Eight current global PCCM faculty from diverse geographic and professional backgrounds provide experiential guidance for early-career professionals interested in global academic PCCM. Trainees and junior faculty interested in academic global PCCM will find innumerable obstacles to developing this non-traditional career pathway, but there exist diverse pathways to success

Quasi-Periodic Flares from Star-Accretion Disc Collisions

We present simulated results of quasi-periodic flares generated by the inelastic collisions of a star bound to a super-massive black hole (SMBH) and its attendant accretion disc. We show that the behavior of the quasi-periodicity is affected by the mass and spin of the black hole and the orbital elements of the stellar orbit. We also evaluate the possibility of extracting useful information on these parameters and verifying the character of the Kerr metric from such quasi-periodic signals. Comparisons are made with the observed optical outbursts of OJ287, infrared flares from the Galactic center and X-ray variability in RE J1034+396.Comment: 16 pages, 11 figures, submitted to MNRAS; corrected typo

The role and function of IκKα/β 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/β, a critical part of the NFκB pathway. Impaired monocytes had decreased IκKα mRNA and protein expression and decreased phosphorylation of the IκKα/β 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/β 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-1β, TNF-β, 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/β activation. Our results emphasize that impaired monocyte function is, at least in part, related to dysregulated IκKα/β activation, and that IκKα/β is likely involved in mounting a sufficient monocyte inflammatory response. Future studies may wish to focus on adjuvant therapies that augment IκKα/β function to restore monocyte function in this clinically important problem

UBVRI Light Curves of 44 Type Ia Supernovae

We present UBVRI photometry of 44 type-Ia supernovae (SN Ia) observed from 1997 to 2001 as part of a continuing monitoring campaign at the Fred Lawrence Whipple Observatory of the Harvard-Smithsonian Center for Astrophysics. The data set comprises 2190 observations and is the largest homogeneously observed and reduced sample of SN Ia to date, nearly doubling the number of well-observed, nearby SN Ia with published multicolor CCD light curves. The large sample of U-band photometry is a unique addition, with important connections to SN Ia observed at high redshift. The decline rate of SN Ia U-band light curves correlates well with the decline rate in other bands, as does the U-B color at maximum light. However, the U-band peak magnitudes show an increased dispersion relative to other bands even after accounting for extinction and decline rate, amounting to an additional ~40% intrinsic scatter compared to B-band.Comment: 84 authors, 71 pages, 51 tables, 10 figures. Accepted for publication in the Astronomical Journal. Version with high-res figures and electronic data at http://astron.berkeley.edu/~saurabh/cfa2snIa

Team-taught versus individually taught undergraduate education: A qualitative study of student experiences and preferences

Team teaching is becoming more common in undergraduate programmes of study although the relative merits to the more traditional individually taught courses have not been determined for best practice. For this study, 15 final year undergraduate students were interviewed to gain insight into their learning experiences. A thematic analysis of the interview data identified the perceived advantages and disadvantages of each mode of teaching. The advantages of individually taught courses included: Consistency of content delivery and advice, Familiarity with the lecturer’s teaching style and better Continuity of the subject content. The disadvantage of individually taught modules included Missing knowledge, compared to a team approach. Advantages of team taught modules included: Greater insight into a topic delivered by multiple team members. Disadvantages included: Content overlap, Conflicting messages relating to assessment, team members not taking Ownership of their roles and responsibilities and a belief that overall Team failure is worse than individual failure to deliver a module well. The results revealed that individually taught modules were generally preferred to team taught modules. A set of best practice recommendations are proposed to address the challenges when delivering team-taught teaching and become more student focused

HCV co-infection in HIV positive population in British Columbia, Canada

<p>Abstract</p> <p>Background</p> <p>As HIV and hepatitis C (HCV) share some modes of transmission co-infection is not uncommon. This study used a population-based sample of HIV and HCV tested individuals to determine the prevalence of HIV/HCV co-infection, the sequence of virus diagnoses, and demographic and associated risk factors.</p> <p>Methods</p> <p>Positive cases of HIV were linked to the combined laboratory database (of negative and positive HCV antibody results) and HCV reported cases in British Columbia (BC).</p> <p>Results</p> <p>Of 4,598 HIV cases with personal identifiers, 3,219 (70%) were linked to the combined HCV database, 1,700 (53%) of these were anti-HCV positive. HCV was diagnosed first in 52% of co-infected cases (median time to HIV identification 3 1/2 years). HIV and HCV was diagnosed within a two week window in 26% of cases. Among individuals who were diagnosed with HIV infection at baseline, subsequent diagnoses of HCV infection was independently associated with: i) intravenous drug use (IDU) in males and females, Hazard Ratio (HR) = 6.64 (95% CI: 4.86-9.07) and 9.76 (95% CI: 5.76-16.54) respectively; ii) reported Aboriginal ethnicity in females HR = 2.09 (95% CI: 1.34-3.27) and iii) males not identified as men-who-have-sex-with-men (MSM), HR = 2.99 (95% CI: 2.09-4.27).</p> <p>Identification of HCV first compared to HIV first was independently associated with IDU in males and females OR = 2.83 (95% CI: 1.84-4.37) and 2.25 (95% CI: 1.15-4.39) respectively, but not Aboriginal ethnicity or MSM. HIV was identified first in 22%, with median time to HCV identification of 15 months;</p> <p>Conclusion</p> <p>The ability to link BC public health and laboratory HIV and HCV information provided a unique opportunity to explore demographic and risk factors associated with HIV/HCV co-infection. Over half of persons with HIV infection who were tested for HCV were anti-HCV positive; half of these had HCV diagnosed first with HIV identification a median 3.5 years later. This highlights the importance of public health follow-up and harm reduction measures for people identified with HCV to prevent subsequent HIV infection.</p

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin