Infections Are Not Increased in Scleroderma Compared to Non-Inflammatory Musculoskeletal Disorders Prior to Disease Onset

The etiology of scleroderma (SSc) is unknown; immunogenic stimuli such as infections and vaccinations could theoretically be risk factors for scleroderma. Our objective was to assess the relationship between viral and bacterial infec-tions, and vaccinations, prior to diagnosis of SSc compared to non-inflammatory controls. Methods: A questionnaire was sent to individuals with SSc (n =83) and controls (n=351) with non-inflammatory musculoskeletal (MSK) disorders (os-teoarthritis, n = 204; tendonitis, n = 58; fibromyalgia, n= 89) from a rheumatology practice. Questions ascertained past in-fections, exposure to infectious agents and vaccination history. Results: The response rate was 78% (SSc) and 56% (MSK controls). The mean age was 56 ± 1.6 (SSc) and 58 ± 0.9 (MSK); 88% (SSc) and 82% (MSK) were female. No association between prior infections and SSc was observed. In fact, controls were more likely than SSc subjects to report any infec-tion within 1-year prior to disease diagnosis (35% vs. 16%, p<0.006), or to have suffered a trauma to affected joints prior to diagnosis (44% vs. 19%, p<0.0002). Within the 1-year prior to disease diagnosis, controls reported slightly more strep-tococcal infections (p<0.2), infections with diarrhea and vomiting (p<0.3), and antibiotic use (p<0.09), although none of these results were statistically significant. Histories of any hepatitis, rubella, any bacterial infection, and having had a pre-vious positive tuberculosis skin test were not significantly different between groups and were actually more often reported by the control subjects. SSc reported slightly more hepatitis B (p<0.08), more rheumatic fever (p<0.8) in past, and herpes zoster (p<0.4), although no differences reached significance. Conclusion: This study does not support that self-report of symptomatic infections are more likely to occur ever (prior to diagnosis) or within 1-year prior to symptom onset of SSc, or that vaccinations in adulthood trigger SSc

Metabolic imaging across scales reveals distinct prostate cancer phenotypes

Hyperpolarised magnetic resonance imaging (HP-13C-MRI) has shown promise as a clinical tool for detecting and characterising prostate cancer. Here we use a range of spatially resolved histological techniques to identify the biological mechanisms underpinning differential [1-13C]lactate labelling between benign and malignant prostate, as well as in tumours containing cribriform and non-cribriform Gleason pattern 4 disease. Here we show that elevated hyperpolarised [1-13C]lactate signal in prostate cancer compared to the benign prostate is primarily driven by increased tumour epithelial cell density and vascularity, rather than differences in epithelial lactate concentration between tumour and normal. We also demonstrate that some tumours of the cribriform subtype may lack [1-13C]lactate labelling, which is explained by lower epithelial lactate dehydrogenase expression, higher mitochondrial pyruvate carrier density, and increased lipid abundance compared to lactate-rich non-cribriform lesions. These findings highlight the potential of combining spatial metabolic imaging tools across scales to identify clinically significant metabolic phenotypes in prostate cancer

Multimodality imaging to assess immediate response to irreversible electroporation in a rat liver tumor model.

PurposeTo compare changes on ultrasonographic (US), computed tomographic (CT), and magnetic resonance (MR) images after irreversible electroporation (IRE) ablation of liver and tumor tissues in a rodent hepatoma model.Materials and methodsStudies received approval from the institutional animal care and use committee. Forty-eight rats were used, and N1-S1 tumors were implanted in 24. Rats were divided into groups and allocated for studies with each modality. Imaging was performed in normal liver tissues and tumors before and after IRE. MR imaging was performed in one group before and after IRE after hepatic vessel ligation. US images were graded to determine echogenicity changes, CT attenuation was measured (in Hounsfield units), and MR imaging signal-to-noise ratio (SNR) was measured before and after IRE. Student t test was used to compare attenuation and SNR measurements before and after IRE (P &lt; .05 indicated a significant difference).ResultsIRE ablation produced greater alterations to echogenicity in normal tissues than in tumors. Attenuation in ablated liver tissues was reduced compared with that in control tissues (P &lt; .001), while small attenuation differences between ablated (42.11 HU ± 2.11) and control (45.14 HU ± 2.64) tumors trended toward significance (P = .052). SNR in ablated normal tissues was significantly altered after IRE (T1-weighted images: pre-IRE, 145.95 ± 24.32; post-IRE, 97.80 ± 18.03; P = .004; T2-weighted images, pre-IRE, 47.37 ± 18.31; post-IRE, 90.88 ± 37.15; P = .023). In tumors, SNR differences before and after IRE were not significant. No post-IRE signal changes were observed after hepatic vessel ligation.ConclusionIRE induces rapid changes on gray-scale US, unenhanced CT, and MR images. These changes are readily visible and may assist a performing physician to delineate ablation zones from the unablated surrounding parenchyma

Multimodality Imaging to Assess Immediate Response to Irreversible Electroporation in a Rat Liver Tumor Model

PURPOSE: To compare changes on ultrasonographic (US), computed tomographic (CT), and magnetic resonance (MR) images after irreversible electroporation (IRE) ablation of liver and tumor tissues in a rodent hepatoma model. MATERIALS AND METHODS: Studies received approval from the institutional animal care and use committee. Forty-eight rats were used, and N1-S1 tumors were implanted in 24. Rats were divided into groups and allocated for studies with each modality. Imaging was performed in normal liver tissues and tumors before and after IRE. MR imaging was performed in one group before and after IRE after hepatic vessel ligation. US images were graded to determine echogenicity changes, CT attenuation was measured (in Hounsfield units), and MR imaging signal-to-noise ratio (SNR) was measured before and after IRE. Student t test was used to compare attenuation and SNR measurements before and after IRE (P < .05 indicated a significant difference). RESULTS: IRE ablation produced greater alterations to echogenicity in normal tissues than in tumors. Attenuation in ablated liver tissues was reduced compared with that in control tissues (P < .001), while small attenuation differences between ablated (42.11 HU ± 2.11) and control (45.14 HU ± 2.64) tumors trended toward significance (P = .052). SNR in ablated normal tissues was significantly altered after IRE (T1-weighted images: pre-IRE, 145.95 ± 24.32; post-IRE, 97.80 ± 18.03; P = .004; T2-weighted images, pre-IRE, 47.37 ± 18.31; post-IRE, 90.88 ± 37.15; P = .023). In tumors, SNR differences before and after IRE were not significant. No post-IRE signal changes were observed after hepatic vessel ligation. CONCLUSION: IRE induces rapid changes on gray-scale US, unenhanced CT, and MR images. These changes are readily visible and may assist a performing physician to delineate ablation zones from the unablated surrounding parenchyma. © RSNA, 2014 Online supplemental material is available for this article

Metabolic imaging across scales reveals distinct prostate cancer phenotypes

Acknowledgements: This study was supported by Prostate Cancer UK (PCUK; Grant PA14-012), Cancer Research UK (CRUK; Grant C19212/A27150), AstraZeneca, and the National Institute for Health and Care Research (NIHR) Cambridge Biomedical Research Centre (BRC; Grant NIHR203312). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. N.S. was supported by the Gates Cambridge Trust and is now a Research Fellow of Emmanuel College, Cambridge. A.Y.W. is supported by the Urological Malignancies Programme of the Cancer Research UK Cambridge Centre (C9685/A25177) and NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). V.J.G. acknowledges infrastructure support from the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). Additional support provided from the Cancer Research UK Cambridge Centre, the Cambridge Experimental Cancer Medicine Centre, a Wellcome Trust Strategic Award, Addenbrooke’s Charitable Trust, the Canadian Institute For Advanced Research, and Cambridge University Hospitals National Health Service Foundation Trust. The authors thank Dr Julia Jones of the Cancer Research UK Cambridge Institute for her help with the RNAscope component of the study.AbstractHyperpolarised magnetic resonance imaging (HP-13C-MRI) has shown promise as a clinical tool for detecting and characterising prostate cancer. Here we use a range of spatially resolved histological techniques to identify the biological mechanisms underpinning differential [1-13C]lactate labelling between benign and malignant prostate, as well as in tumours containing cribriform and non-cribriform Gleason pattern 4 disease. Here we show that elevated hyperpolarised [1-13C]lactate signal in prostate cancer compared to the benign prostate is primarily driven by increased tumour epithelial cell density and vascularity, rather than differences in epithelial lactate concentration between tumour and normal. We also demonstrate that some tumours of the cribriform subtype may lack [1-13C]lactate labelling, which is explained by lower epithelial lactate dehydrogenase expression, higher mitochondrial pyruvate carrier density, and increased lipid abundance compared to lactate-rich non-cribriform lesions. These findings highlight the potential of combining spatial metabolic imaging tools across scales to identify clinically significant metabolic phenotypes in prostate cancer.</jats:p

Metabolic imaging across scales reveals distinct prostate cancer phenotypes.

Hyperpolarised magnetic resonance imaging (HP-13C-MRI) has shown promise as a clinical tool for detecting and characterising prostate cancer. Here we use a range of spatially resolved histological techniques to identify the biological mechanisms underpinning differential [1-13C]lactate labelling between benign and malignant prostate, as well as in tumours containing cribriform and non-cribriform Gleason pattern 4 disease. Here we show that elevated hyperpolarised [1-13C]lactate signal in prostate cancer compared to the benign prostate is primarily driven by increased tumour epithelial cell density and vascularity, rather than differences in epithelial lactate concentration between tumour and normal. We also demonstrate that some tumours of the cribriform subtype may lack [1-13C]lactate labelling, which is explained by lower epithelial lactate dehydrogenase expression, higher mitochondrial pyruvate carrier density, and increased lipid abundance compared to lactate-rich non-cribriform lesions. These findings highlight the potential of combining spatial metabolic imaging tools across scales to identify clinically significant metabolic phenotypes in prostate cancer

Design of Potent mRNA Decapping Scavenger Enzyme (DcpS) Inhibitors with Improved Physicochemical Properties To Investigate the Mechanism of Therapeutic Benefit in Spinal Muscular Atrophy (SMA)

The C-5 substituted 2,4-diaminoquinazoline RG3039 (compound <b>1</b>), a member of a chemical series that was identified and optimized using an SMN2 promoter screen, prolongs survival and improves motor function in a mouse model of spinal muscular atrophy (SMA). It is a potent inhibitor of the mRNA decapping scavenger enzyme (DcpS), but the mechanism whereby DcpS inhibition leads to therapeutic benefit is unclear. Compound <b>1</b> is a dibasic lipophilic molecule that is predicted to accumulate in lysosomes. To understand if the <i>in vivo</i> efficacy is due to DcpS inhibition or other effects resulting from the physicochemical properties of the chemotype, we undertook structure based molecular design to identify DcpS inhibitors with improved physicochemical properties. Herein we describe the design, synthesis, and <i>in vitro</i> pharmacological characterization of these DcpS inhibitors along with the <i>in vivo</i> mouse CNS PK profile of PF-DcpSi (compound <b>24</b>), one of the analogs found to be efficacious in SMA mouse model