First-in-man evaluation of 124I-PGN650: A PET tracer for detecting phosphatidylserine as a biomarker of the solid tumor microenvironment

Purpose: PGN650 is a F(ab′) 2 antibody fragment that targets phosphatidylserine (PS), a marker normally absent that becomes exposed on tumor cells and tumor vasculature in response to oxidative stress and increases in response to therapy. PGN650 was labeled with 124 I to create a positron emission tomography (PET) agent as an in vivo biomarker for tumor microenvironment and response to therapy. In this phase 0 study, we evaluated the pharmacokinetics, safety, radiation dosimetry, and tumor targeting of this tracer in a cohort of patients with cancer. Methods: Eleven patients with known solid tumors received approximately 140 MBq (3.8 mCi) 124 I-PGN650 intravenously and underwent positron emission tomography–computed tomography (PET/CT) approximately 1 hour, 3 hours, and either 24 hours or 48 hours later to establish tracer kinetics for the purpose of calculating radiation dosimetry (from integration of the organ time-activity curves and OLINDA/EXM using the adult male and female models). Results: Known tumor foci demonstrated mildly increased uptake, with the highest activity at the latest imaging time. There were no unexpected adverse events. The liver was the organ receiving the highest radiation dose (0.77 mGy/MBq); the effective dose was 0.41 mSv/MBq. Conclusion: Although 124 I-PGN650 is safe for human PET imaging, the tumor targeting with this agent in patients was less than previously observed in animal studies

Arsenic trioxide inhibits transforming growth factor-β1-induced fibroblast to myofibroblast differentiation in vitro and bleomycin induced lung fibrosis in vivo

Abstract Background Idiopathic pulmonary fibrosis (IPF) is a progressive disease of insidious onset, and is responsible for up to 30,000 deaths per year in the U.S. Excessive production of extracellular matrix by myofibroblasts has been shown to be an important pathological feature in IPF. TGF-β1 is expressed in fibrotic lung and promotes fibroblast to myofibroblast differentiation (FMD) as well as matrix deposition. Methods To identify the mechanism of Arsenic trioxide’s (ATO)’s anti-fibrotic effect in vitro, normal human lung fibroblasts (NHLFs) were treated with ATO for 24 hours and were then exposed to TGF-β1 (1 ng/ml) before harvesting at multiple time points. To investigate whether ATO is able to alleviate lung fibrosis in vivo, C57BL/6 mice were administered bleomycin by oropharyngeal aspiration and ATO was injected intraperitoneally daily for 14 days. Quantitative real-time PCR, western blotting, and immunofluorescent staining were used to assess the expression of fibrotic markers such as α-smooth muscle actin (α-SMA) and α-1 type I collagen. Results Treatment of NHLFs with ATO at very low concentrations (10-20nM) inhibits TGF-β1-induced α-smooth muscle actin (α-SMA) and α-1 type I collagen mRNA and protein expression. ATO also diminishes the TGF-β1-mediated contractile response in NHLFs. ATO’s down-regulation of profibrotic molecules is associated with inhibition of Akt, as well as Smad2/Smad3 phosphorylation. TGF-β1-induced H2O2 and NOX-4 mRNA expression are also blocked by ATO. ATO-mediated reduction in Smad3 phosphorylation correlated with a reduction of promyelocytic leukemia (PML) nuclear bodies and PML protein expression. PML-/- mouse embryonic fibroblasts (MEFs) showed decreased fibronectin and PAI-1 expression in response to TGF-β1. Daily intraperitoneal injection of ATO (1 mg/kg) in C57BL/6 mice inhibits bleomycin induced lung α-1 type I collagen mRNA and protein expression. Conclusions In summary, these data indicate that low concentrations of ATO inhibit TGF-β1-induced fibroblast to myofibroblast differentiation and decreases bleomycin induced pulmonary fibrosis.http://deepblue.lib.umich.edu/bitstream/2027.42/109463/1/12931_2013_Article_1494.pd

Arsenic trioxide inhibits transforming growth factor-β1-induced fibroblast to myofibroblast differentiation in vitro and bleomycin induced lung fibrosis in vivo

Abstract Background Idiopathic pulmonary fibrosis (IPF) is a progressive disease of insidious onset, and is responsible for up to 30,000 deaths per year in the U.S. Excessive production of extracellular matrix by myofibroblasts has been shown to be an important pathological feature in IPF. TGF-β1 is expressed in fibrotic lung and promotes fibroblast to myofibroblast differentiation (FMD) as well as matrix deposition. Methods To identify the mechanism of Arsenic trioxide’s (ATO)’s anti-fibrotic effect in vitro, normal human lung fibroblasts (NHLFs) were treated with ATO for 24 hours and were then exposed to TGF-β1 (1 ng/ml) before harvesting at multiple time points. To investigate whether ATO is able to alleviate lung fibrosis in vivo, C57BL/6 mice were administered bleomycin by oropharyngeal aspiration and ATO was injected intraperitoneally daily for 14 days. Quantitative real-time PCR, western blotting, and immunofluorescent staining were used to assess the expression of fibrotic markers such as α-smooth muscle actin (α-SMA) and α-1 type I collagen. Results Treatment of NHLFs with ATO at very low concentrations (10-20nM) inhibits TGF-β1-induced α-smooth muscle actin (α-SMA) and α-1 type I collagen mRNA and protein expression. ATO also diminishes the TGF-β1-mediated contractile response in NHLFs. ATO’s down-regulation of profibrotic molecules is associated with inhibition of Akt, as well as Smad2/Smad3 phosphorylation. TGF-β1-induced H2O2 and NOX-4 mRNA expression are also blocked by ATO. ATO-mediated reduction in Smad3 phosphorylation correlated with a reduction of promyelocytic leukemia (PML) nuclear bodies and PML protein expression. PML-/- mouse embryonic fibroblasts (MEFs) showed decreased fibronectin and PAI-1 expression in response to TGF-β1. Daily intraperitoneal injection of ATO (1 mg/kg) in C57BL/6 mice inhibits bleomycin induced lung α-1 type I collagen mRNA and protein expression. Conclusions In summary, these data indicate that low concentrations of ATO inhibit TGF-β1-induced fibroblast to myofibroblast differentiation and decreases bleomycin induced pulmonary fibrosis.http://deepblue.lib.umich.edu/bitstream/2027.42/134571/1/12931_2013_Article_1494.pd

Epsilon near zero material for electromagnetic energy transport through sub-wavelength channels.

Abstract Not Provide

Stop and Sbottom Searches in Run II of the Fermilab Tevatron

We estimate the Tevatron Run II potential for top and bottom squark searches. We find an impressive reach in several of the possible discovery channels. We also study some new channels which may arise in non-conventional supersymmetry models. In each case we rely on a detailed Monte Carlo simulation of the collider events and the CDF detector performance in Run I.Comment: 30 pages, LaTeX, 10 figure

Review of factors resulting in systemic biases in the screening, assessment, and treatment of individuals at clinical high-risk for psychosis in the United States

BACKGROUND: Since its inception, research in the clinical high-risk (CHR) phase of psychosis has included identifying and exploring the impact of relevant socio-demographic factors. Employing a narrative review approach and highlighting work from the United States, sociocultural and contextual factors potentially affecting the screening, assessment, and service utilization of youth at CHR were reviewed from the current literature. RESULTS: Existing literature suggests that contextual factors impact the predictive performance of widely used psychosis-risk screening tools and may introduce systemic bias and challenges to differential diagnosis in clinical assessment. Factors reviewed include racialized identity, discrimination, neighborhood context, trauma, immigration status, gender identity, sexual orientation, and age. Furthermore, racialized identity and traumatic experiences appear related to symptom severity and service utilization among this population. CONCLUSIONS: Collectively, a growing body of research from the United States and beyond suggests that considering context in psychosis-risk assessment can provide a more accurate appraisal of the nature of risk for psychosis, render more accurate results improving the field\u27s prediction of conversion to psychosis, and enhance our understanding of psychosis-risk trajectories. More work is needed in the U.S. and across the globe to uncover how structural racism and systemic biases impact screening, assessment, treatment, and clinical and functional outcomes for those at CHR

Thy-1 Attenuates TNF-α-Activated Gene Expression in Mouse Embryonic Fibroblasts via Src Family Kinase

Heterogeneous surface expression of Thy-1 in fibroblasts modulates inflammation and may thereby modulate injury and repair. As a paradigm, patients with idiopathic pulmonary fibrosis, a disease with pathologic features of chronic inflammation, demonstrate an absence of Thy-1 immunoreactivity within areas of fibrotic activity (fibroblast foci) in contrast to the predominant Thy-1 expressing fibroblasts in the normal lung. Likewise, Thy-1 deficient mice display more severe lung fibrosis in response to an inflammatory injury than wildtype littermates. We investigated the role of Thy-1 in the response of fibroblasts to the pro-inflammatory cytokine TNF-α. Our study demonstrates distinct profiles of TNF-α-activated gene expression in Thy-1 positive (Thy-1+) and negative (Thy-1−) subsets of mouse embryonic fibroblasts (MEF). TNF-α induced a robust activation of MMP-9, ICAM-1, and the IL-8 promoter driven reporter in Thy-1− MEFs, in contrast to only a modest increase in Thy-1+ counterparts. Consistently, ectopic expression of Thy-1 in Thy-1− MEFs significantly attenuated TNF-α-activated gene expression. Mechanistically, TNF-α activated Src family kinase (SFK) only in Thy-1− MEFs. Blockade of SFK activation abrogated TNF-α-activated gene expression in Thy-1− MEFs, whereas restoration of SFK activation rescued the TNF-α response in Thy-1+ MEFs. Our findings suggest that Thy-1 down-regulates TNF-α-activated gene expression via interfering with SFK- and NF-κB-mediated transactivation. The current study provides a novel mechanistic insight to the distinct roles of fibroblast Thy-1 subsets in inflammation

American Academy of Periodontology best evidence consensus statement on modifying periodontal phenotype in preparation for orthodontic and restorative treatment

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154649/1/jper10498.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154649/2/jper10498_am.pd

Truth-telling to the patient, family, and the sexual partner: a rights approach to the role of healthcare providers in adult HIV disclosure in China.

Patients' rights are central in today's legislation and social policies related to health care, including HIV care, in not only Western countries but around the world. However, given obvious socio-cultural differences it is often asked how or to what extent patients' rights should be respected in non-Western societies such as China. In this paper, it is argued that the patients' rights framework is compatible with Chinese culture, and that from the perspective of contemporary patient rights healthcare providers have a duty to disclose truthfully the diagnosis and prognosis to their patients, that the Chinese cultural practice of involving families in care should - with consent from the patient - be promoted out of respect for patients' rights and well-being, and that healthcare providers should be prepared to address the issue of disclosing a patient's HIV status to sexual partner(s). Legally, the provider should be permitted to disclose without consent from the patient but not obliged to in all cases. The decision to do this should be taken with trained sensitivity to a range of ethically relevant considerations. Post-disclosure counseling or psychological support should be in place to address the concerns of potentially adverse consequences of provider-initiated disclosure and to maximize the psychosocial and medical benefits of the disclosure. There is an urgent need for healthcare providers to receive training in ethics and disclosure skills. This paper concludes also with some suggestions for improving the centerpiece Chinese legislation, State Council's "Regulations on AIDS Prevention and Control" (2006), to further safeguard the rights and well-being of HIV patients

Microbiota that affect risk for shigellosis in children in low-income countries

Pathogens in the gastrointestinal tract exist within a vast population of microbes. We examined associations between pathogens and composition of gut microbiota as they relate to Shigella spp./enteroinvasive Escherichia coli infection. We analyzed 3,035 stool specimens (1,735 nondiarrheal and 1,300 moderate-to-severe diarrheal) from the Global Enteric Multicenter Study for 9 enteropathogens. Diarrheal specimens had a higher number of enteropathogens (diarrheal mean 1.4, nondiarrheal mean 0.95; p<0.0001). Rotavirus showed a negative association with Shigella spp. in cases of diarrhea (odds ratio 0.31, 95% CI 0.17–0.55) and had a large combined effect on moderate-to-severe diarrhea (odds ratio 29, 95% CI 3.8–220). In 4 Lactobacillus taxa identified by 16S rRNA gene sequencing, the association between pathogen and disease was decreased, which is consistent with the possibility that Lactobacillus spp. are protective against Shigella spp.–induced diarrhea. Bacterial diversity of gut microbiota was associated with diarrhea status, not high levels of the Shigella spp. ipaH gene.publishedVersio