Actinobaculum schaalii: An Emerging Uropathogen?

A. schaalii is a rare uropathogen. We report urosepsis with Actinobaculum schaalii detected serendipitously in blood and urine culture in a 79-year-old with urinary tract obstruction. This paper illuminates the flaws in our current system in detecting A. schaalii and raises awareness among clinicians and laboratory teams

Androgen receptor modulation by non-androgenic factors and the basal transcription factor TAF1

There is considerable evidence to suggest that progression of prostate cancers to castration-resistant is due to inappropriate activation of the androgen receptor (AR) and hence, the AR is a good target for the treatment of this disease. In this study we used two approaches to investigate AR activation and inhibition. First, we developed high-throughput, non-invasive, cell-based screening assays to rapidly and biologically assess factors that modulate prostate cancer growth and affect AR activity. Using these assays, we found that differentiated osteoblast-like condition media enhanced prostate cancer cell growth, but not AR activity. In addition, we applied this system to screen compounds, selected through in silico approaches against a crucial pocket on the AR protein. The application of our in silico tools and our cell based screening assay resulted in identification of 17 compounds out of 4 millions that can inhibit AR activity. Importantly, some of these compounds are more potent than bicalutamide, which is one of the most potent antiandrogen drugs currently used to treat patients with metastatic prostate cancer. In the context of AR transcription target genes, the presence of AR coactivators is essential for AR activity. Using the repressed transactivator yeast two-hybrid system, we found that TATA binding protein-associated factor 1 (TAF1) interacted with the AR. In tissue microarrays, TAF1 was shown to steadily increase with duration of neoadjuvant androgen withdrawal and with progression to castration resistance. GST pull-down assays established TAF1/AR interaction and co-immunoprecipitation and ChIP assays revealed colocalization of TAF1 and AR on the prostate specific antigen (PSA) promoter in prostate cancer cells. With respect to modulation of AR activity, while full-length TAF1 showed enhancement of both AR and some generic gene transcriptional activity, selective AR coactivator activity was demonstrated in transactivation experiments using cloned TAF1 N-terminal kinase and ubiquitin-activating/conjugating (E1/E2) domains. In keeping with AR coactivation by the E1/E2 domain, TAF1 was found to greatly increase the cellular amount of poly-ubiquitinated AR. In conclusion, our results indicate that TAF1 is a coactivator of AR and its overexpression could be part of a compensatory mechanism adapted by cancer cells to overcome reduced levels of circulating androgens.Medicine, Faculty ofPathology and Laboratory Medicine, Department ofGraduat

Comparing diagnostic techniques of magnetic resonance angiography (MRA) and Doppler ultrasonography in determining severity of renal artery stenosis

BACKGROUND: Renal artery stenosis is one of the important causes of hypertension and endstage renal failure. Magnetic resonance angiography (MRA) and Doppler ultrasonography arenon-invasive and safe diagnostic techniques that have also high sensitivity and specificity. Sincethe accuracy and reliability of these techniques depend upon technicians and softwares, wedecided to evaluate and compare the sensitivity and specificity of these techniques in Isfahan.METHODS: Our study included all the patients (37 patients) who underwent renal arteryangiography during 2 years from May 2003 to May 2005 and up to six months after that hadunderwent MRA (21 patients) and Doppler sonography (16 patients) in Isfahan. Renal arteryangiography was considered as the gold standard.RESULTS: Sensitivity, specificity, positive and negative predictive values of 100%, 25%, 25%,and 100% were obtained for MRA respectively. Specificity and positive predictive values (PPV)of Doppler sonography were 67%. Its sensitivity and negative predictive values (NPV) were 57%.CONCLUSION: Although it seems that technician dependency, technical and softwareproblems were the reasons of low specificity of gadolinium-enhanced MRA in our study, furtherstudies with larger sample sizes are recommended.Keywords: MRA, Doppler Ultrasonography, Renal Artery Stenosis

Mitigation of Radiation-Induced Lung Pneumonitis and Fibrosis Using Metformin and Melatonin: A Histopathological Study

Background and objectives: Pneumonitis and fibrosis are the most common consequences of lung exposure to a high dose of ionizing radiation during an accidental radiological or nuclear event, and may lead to death, after some months to years. So far, some anti-inflammatory and antioxidant agents have been used for mitigation of lung injury. In the present study, we aimed to detect possible mitigatory effects of melatonin and metformin on radiation-induced pneumonitis and lung fibrosis. Materials and methods: 40 male mice were divided into 4 groups (10 mice in each). For control group, mice did not receive radiation or drugs. In group 2, mice were irradiated to chest area with 18 Gy gamma rays. In groups 3 and 4, mice were first irradiated similar to group 2. After 24 h, treatment with melatonin as well as metformin began. Mice were sacrificed after 100 days for determination of mitigation of lung pneumonitis and fibrosis by melatonin or metformin. Results: Results showed that both melatonin and metformin are able to mitigate pneumonitis and fibrosis markers such as infiltration of inflammatory cells, edema, vascular and alveolar thickening, as well as collagen deposition. Conclusion: Melatonin and metformin may have some interesting properties for mitigation of radiation pneumonitis and fibrosis after an accidental radiation event

The cancer precision medicine knowledge base for structured clinical-grade mutations and interpretations.

Objective This paper describes the Precision Medicine Knowledge Base (PMKB; https://pmkb.weill.cornell.edu ), an interactive online application for collaborative editing, maintenance, and sharing of structured clinical-grade cancer mutation interpretations. Materials and Methods PMKB was built using the Ruby on Rails Web application framework. Leveraging existing standards such as the Human Genome Variation Society variant description format, we implemented a data model that links variants to tumor-specific and tissue-specific interpretations. Key features of PMKB include support for all major variant types, standardized authentication, distinct user roles including high-level approvers, and detailed activity history. A REpresentational State Transfer (REST) application-programming interface (API) was implemented to query the PMKB programmatically. Results At the time of writing, PMKB contains 457 variant descriptions with 281 clinical-grade interpretations. The EGFR, BRAF, KRAS, and KIT genes are associated with the largest numbers of interpretable variants. PMKB's interpretations have been used in over 1500 AmpliSeq tests and 750 whole-exome sequencing tests. The interpretations are accessed either directly via the Web interface or programmatically via the existing API. Discussion An accurate and up-to-date knowledge base of genomic alterations of clinical significance is critical to the success of precision medicine programs. The open-access, programmatically accessible PMKB represents an important attempt at creating such a resource in the field of oncology. Conclusion The PMKB was designed to help collect and maintain clinical-grade mutation interpretations and facilitate reporting for clinical cancer genomic testing. The PMKB was also designed to enable the creation of clinical cancer genomics automated reporting pipelines via an API

Upper tract urothelial carcinoma has a luminal-papillary T-cell depleted contexture and activated FGFR3 signaling.

Upper tract urothelial carcinoma (UTUC) is characterized by a distinctly aggressive clinical phenotype. To define the biological features driving this phenotype, we performed an integrated analysis of whole-exome and RNA sequencing of UTUC. Here we report several key insights from our molecular dissection of this disease: 1) Most UTUCs are luminal-papillary; 2) UTUC has a T-cell depleted immune contexture; 3) High FGFR3 expression is enriched in UTUC and correlates with its T-cell depleted immune microenvironment; 4) Sporadic UTUC is characterized by a lower total mutational burden than urothelial carcinoma of the bladder. Our findings lay the foundation for a deeper understanding of UTUC biology and provide a rationale for the development of UTUC-specific treatment strategies