Serum profiling and biomarker discovery of rat mammary tumors using mass-coded abundance tags (MCAT)

Advances in Mass-spectrometry techniques allow for the rapid processing and evaluation of complex biological mixtures such as blood/serum. These samples represent a protein rich environment as well as a sentinel monitoring system of the entire organism. The central tenet of these studies is that changes in the microenvironment of a tissue, brought about by a disease process, will lead to sufficient changes in the protein and peptide pattern of the serum, such that the differences can be accurately detected and correctly associated with a particular disease state. Using mass-spectrometry approaches we have developed techniques that allow us to compare samples from tumor-free and tumor present serum samples simultaneously to find biomarkers that indicate the presence of cancer. To examine potentially important but less abundant proteins, ultrafiltration (UF) was used to eliminate the more abundant proteins and combine this with the non-isotopic peptide tags (S-methylthioacetimidate and S-methyl thiopropionimidate) described by Beardsley and Reilley (J. Proteome Res. 2: 15-21, 2003) to differentiate our samples. Use of these mass-coded abundance tags (MCAT) allows for simultaneous evaluation of serum samples from tumor present, and tumor free animals. Using an oa time-of-flight mass-spectrometer (Q-tof) with electrospray ionization we produce high quality spectrums to screen for peptides that have only one tag. Specificity of tagging increases the likelihood that the peptide resulted from a protein unique to either the control or conditioned state. Using the ms/ms function of the Q-tof we sequence the peptide and identify the parent protein. Specifically, our lab is using UF, MCAT and the Q-tof to evaluate rat models of chemically-induced tumors. By using animal models we overcome much of the variability that may exist in human serum samples due to differences in gender, diet and cancer initiation. We have shown that these systems allow for the identification of both small molecules such as Alpha S1 casein precursor (24 kDa) as well as proteins greater than the MCO such as Fibrinogen alpha/alpha E precursor and Coagulation factor 2 (86 and 70 kDa, respectively). With positive sequence identification we can now evaluate the tumors themselves to determine if the proteins are over-expressed in the tumor vs. normal tissues. Using this method of “bottom-up” analysis provides information on the nature and composition of our samples to more rapidly identify those proteins that are unique to the tumor state of the animals

TRISTAN: Electromagnetic, gravimetric and seismic measurements to investigate the Tristan da Cunha hot spot and its role in the opening of the South-Atlantic - Cruise No. MSM20/2, January 17 - February 15, 2012, Walvis Bay (Namibia) – Recife (Brazil)

According to classical plume theory, the Tristan da Cunha hotspot is thought to have played a major role in the rifting of the South Atlantic margins and the creation of the aseismic Walvis Ridge by impinging at the base of the continental lithosphere shortly before or during the breakup of the South Atlantic margins. But Tristan da Cunha is enigmatic, as it cannot be clearly identified as a hot-spot but classifies also highly as a more shallow type of anomaly that may actually have been caused by the opening of the South Atlantic. The equivocal character of Tristan is largely due to lack of geophysical data in this region. To understand the tectonic processes of the opening of the South Atlantic, the formation of the Walvis ridge and to understand whether Tristan da Cunha is the cause or the consequence of rifting, it is of central importance to characterize the region around Tristan da Cunha in a more coherent way. Within this research cruise we deployed 26 ocean bottom electromagnetic stations (OEBM) and 24 ocean bottom seismometer (OBS) for a long term acquisition (1 year) of magnetotelluric and seismological data, acquired bathymetry and gravity data and performed geological sampling on Tristan da Cunha. The data will be interpreted in the context of geochemical data and tectonic models developed within the SPP1375‚ South Atlantic Margin Processes and Links with onshore Evolution (SAMPLE)

Waterparks are high risk for cryptosporidiosis: A case-control study in Victoria, 2015

BACKGROUND: An increase in notifications of cryptosporidiosis was observed in Victoria between March and April 2015. Cases mostly resided in one metropolitan region and hypothesis-generating interviews identified common exposures to aquatic facilities. We conducted a case-control study to determine exposure source(s) and facilitate control measures. METHODS: Laboratory-confirmed cases of cryptosporidiosis from the region of interest notified between 1 March and 23 April 2015 were included. Controls residing in the same region were recruited from participants in a population health survey and frequency matched (2 per case) by age group. Details of exposure to potential risk factors were collected using a standardised telephone questionnaire for the 14-days prior to illness for cases, and an analogous exposure period for controls. Univariable and multivariable logistic regression were used to determine risk factors associated with illness using STATA SE 13.1. RESULTS: Thirty cases and 66 controls were included in the study. Half the cases were less than 12 years of age and 62% were female. Illness was most strongly associated with recreational water exposure at any waterpark (adjusted odds ratio (aOR)=73.5; 95% confidence interval (CI):6.74-802), and specifically at Victorian waterparks (aOR=45.6; 95% CI:5.20-399). Cases were linked with attendance at either a waterpark in the region or an adjacent region. As a result of this investigation, hyperchlorination was completed at identified facilities and swim hygiene information distributed. CONCLUSION: This study reinforces the potential for recreational water facilities, particularly waterparks, to act as a transmission source of Cryptosporidium infections. Continued communication to patrons is required to ensure healthy swimming practice in Victorian aquatic facilities

Production of Androgens by Microbial Transformation of Progesterone in Vitro: A Model for Androgen Production in Rivers Receiving Paper Mill Effluent

We have previously documented the presence of progesterone and androstenedione in the water column and bottom sediments of the Fenholloway River, Taylor County, Florida. This river receives paper mill effluent and contains masculinized female mosquitofish. We hypothesized that plant sterols (e.g., β-sitosterol) derived from the pulping of pine trees are transformed by bacteria into progesterone and subsequently into 17α-hydroxyprogesterone, androstenedione, and other androgens. In this study, we demonstrate that these same androgens can be produced in vitro from the bacterium Mycobacterium smegmatis. In a second part to this study, we reextracted and reanalyzed the sediment from the Fenholloway River and verified the presence of androstadienedione, a Δ1 steroid with androgen activity

Co-circulation of Multidrug-resistant Shigella Among Men Who Have Sex With Men in Australia.

BACKGROUND: In urban Australia, the burden of shigellosis is either in returning travelers from shigellosis-endemic regions or in men who have sex with men (MSM). Here, we combine genomic data with comprehensive epidemiological data on sexual exposure and travel to describe the spread of multidrug-resistant Shigella lineages. METHODS: A population-level study of all cultured Shigella isolates in the state of Victoria, Australia, was undertaken from 1 January 2016 through 31 March 2018. Antimicrobial susceptibility testing, whole-genome sequencing, and bioinformatic analyses of 545 Shigella isolates were performed at the Microbiological Diagnostic Unit Public Health Laboratory. Risk factor data on travel and sexual exposure were collected through enhanced surveillance forms or by interviews. RESULTS: Rates of antimicrobial resistance were high, with 17.6% (95/541) and 50.6% (274/541) resistance to ciprofloxacin and azithromycin, respectively. There were strong associations between antimicrobial resistance, phylogeny, and epidemiology. Specifically, 2 major MSM-associated lineages were identified: a Shigellasonnei lineage (n = 159) and a Shigella flexneri 2a lineage (n = 105). Of concern, 147/159 (92.4%) of isolates within the S. sonnei MSM-associated lineage harbored mutations associated with reduced susceptibility to recommended oral antimicrobials: namely, azithromycin, trimethoprim-sulfamethoxazole, and ciprofloxacin. Long-read sequencing demonstrated global dissemination of multidrug-resistant plasmids across Shigella species and lineages, but predominantly associated with MSM isolates. CONCLUSIONS: Our contemporary data highlight the ongoing public health threat posed by resistant Shigella, both in Australia and globally. Urgent multidisciplinary public health measures are required to interrupt transmission and prevent infection

Role of Engrailed-2 (EN2) as a prostate cancer detection biomarker in genetically high risk men

Controversy surrounds the use of PSA as a biomarker for prostate cancer detection, leaving an unmet need for a novel biomarker in this setting; urinary EN2 may identify individuals with clinically relevant prostate cancer. Male BRCA1 and BRCA2 mutation carriers are at increased risk of clinically significant prostate cancer and may benefit from screening. Urine samples from 413 BRCA1 and BRCA2 mutation carriers and controls were evaluated. Subjects underwent annual PSA screening with diagnostic biopsy triggered by PSA > 3.0 ng/ml; 21 men were diagnosed with prostate cancer. Urinary EN2 levels were measured by ELISA and had a sensitivity of 66.7% and specificity of 89.3% for cancer detection. There was no statistically significant difference in EN2 levels according to genetic status or Gleason score. Urinary EN2 may be useful as a non-invasive early biomarker for prostate cancer detection in genetically high-risk individuals

Risk of End-Stage Liver Disease in HIV-Viral Hepatitis Coinfected Persons in North America From the Early to Modern Antiretroviral Therapy Eras

Background. Human immunodeficiency virus (HIV)–infected patients coinfected with hepatitis B (HBV) and C (HCV) viruses are at increased risk of end-stage liver disease (ESLD). Whether modern antiretroviral therapy has reduced ESLD risk is unknown

Photoredox Catalysts Based on Earth-abundant Metal Complexes

We would like to thank the Engineering and Physical Sciences Research Council and CRITICAT Centre for Doctoral Training for financial support [Ph.D. studentship to B.H.; Grant code: EP/L016419/1]. C.L thanks the Prof. & Mrs Purdie Bequests Scholarship and AstraZeneca for his PhD Studentship.Over the last decade, visible light photoredox catalysis has exploded into the consciousness of the synthetic chemist. The principal photocatalysts used are based on rare and toxic ruthenium(II) and iridium(III) complexes. This critical review focusses on Earth-abundant metal complexes as potential replacement photocatalysts and summarizes the use of photoactive Cu(I), Zn(II), Ni(0), V(V), Zr(IV), W(0), W(VI), Mo(0), Cr(III) , Co(III) and Fe(II) complexes in photoredox reactions. The optoelectronic properties of these complexes and relevant structurally related analogs, not yet used for photoredox catalysis, are disccussed in combination with the reaction scope reported for each photocatalyst. Prospects for the future of photocatalyst design are considered.PostprintPeer reviewe