In Vivo 6-([18F]Fluoroacetamido)-1-hexanoicanilide PET Imaging of Altered Histone Deacetylase Activity in Chemotherapy-Induced Neurotoxicity

Background. Histone deacetylases (HDACs) regulate gene expression by changing histone deacetylation status. Neurotoxicity is one of the major side effects of cisplatin, which reacts with deoxyribonucleic acid (DNA) and has excellent antitumor effects. Suberoylanilide hydroxamic acid (SAHA) is an HDAC inhibitor with neuroprotective effects against cisplatin-induced neurotoxicity. Purpose. We investigated how cisplatin with and without SAHA pretreatment affects HDAC expression/activity in the brain by using 6-([18F]fluoroacetamido)-1-hexanoicanilide ([18F]FAHA) as a positron emission tomography (PET) imaging agent for HDAC IIa. Materials and Methods. [18F]FAHA and [18F]fluoro-2-deoxy-2-D-glucose ([18F]FDG) PET studies were done in 24 mice on 2 consecutive days and again 1 week later. The mice were divided into three groups according to drug administration between the first and second imaging sessions (Group A: cisplatin 2 mg/kg, twice; Group B: cisplatin 4 mg/kg, twice; Group C: cisplatin 4 mg/kg, twice, and SAHA 300 mg/kg pretreatment, 4 times). Results. The value of [18F]FAHA was increased and the percentage of injected dose/tissue g (% ID/g) of [18F]FDG was decreased in the brains of animals in Groups A and B. The value of [18F]FAHA and % ID/g of [18F]FDG were not significantly different in Group C. Conclusions. [18F]FAHA PET clearly showed increased HDAC activity suggestive of cisplatin neurotoxicity in vivo, which was blocked by SAHA pretreatment

In Vivo

Background. Histone deacetylases (HDACs) regulate gene expression by changing histone deacetylation status. Neurotoxicity is one of the major side effects of cisplatin, which reacts with deoxyribonucleic acid (DNA) and has excellent antitumor effects. Suberoylanilide hydroxamic acid (SAHA) is an HDAC inhibitor with neuroprotective effects against cisplatin-induced neurotoxicity. Purpose. We investigated how cisplatin with and without SAHA pretreatment affects HDAC expression/activity in the brain by using 6-([18F]fluoroacetamido)-1-hexanoicanilide ([18F]FAHA) as a positron emission tomography (PET) imaging agent for HDAC IIa. Materials and Methods. [18F]FAHA and [18F]fluoro-2-deoxy-2-D-glucose ([18F]FDG) PET studies were done in 24 mice on 2 consecutive days and again 1 week later. The mice were divided into three groups according to drug administration between the first and second imaging sessions (Group A: cisplatin 2 mg/kg, twice; Group B: cisplatin 4 mg/kg, twice; Group C: cisplatin 4 mg/kg, twice, and SAHA 300 mg/kg pretreatment, 4 times). Results. The Ki value of [18F]FAHA was increased and the percentage of injected dose/tissue g (% ID/g) of [18F]FDG was decreased in the brains of animals in Groups A and B. The Ki value of [18F]FAHA and % ID/g of [18F]FDG were not significantly different in Group C. Conclusions. [18F]FAHA PET clearly showed increased HDAC activity suggestive of cisplatin neurotoxicity in vivo, which was blocked by SAHA pretreatment

Late initiation of renal replacement therapy is associated with worse outcomes in acute kidney injury after major abdominal surgery

Introduction Abdominal surgery is probably associated with more likelihood to cause acute kidney injury (AKI). The aim of this study was to evaluate whether early or late start of renal replacement therapy (RRT) defined by simplified RIFLE (sRIFLE) classification in AKI patients after major abdominal surgery will affect outcome. Methods A multicenter prospective observational study based on the NSARF ( National Taiwan University Surgical ICU Associated Renal Failure) Study Group database. 98 patients (41 female, mean age 66.4 +/- 13.9 years) who underwent acute RRT according to local indications for post-major abdominal surgery AKI between 1 January, 2002 and 31 December, 2005 were enrolled The demographic data, comorbid diseases, types of surgery and RRT, as well as the indications for RRT were documented. The patients were divided into early dialysis (sRIFLE-0 or Risk) and late dialysis (LD, sRIFLE -Injury or Failure) groups. Then we measured and recorded patients' outcome including in-hospital mortality and RRT wean-off until 30 June, 2006. Results The in-hospital mortality was compared as endpoint. Fifty-seven patients (58.2%) died during hospitalization. LD (hazard ratio (HR) 1.846; P = 0.027), old age (HR 2.090; P = 0.010), cardiac failure (HR 4.620; P < 0.001), pre-RRT SOFA score (HR 1.152; P < 0.001) were independent indicators for in-hospital mortality. Conclusions The findings of this study support earlier initiation of acute RRT, and also underscore the importance of predicting prognoses of major abdominal surgical patients with AKI by using RIFLE classification

Hepatocyte Growth Factor Increases Osteopontin Expression in Human Osteoblasts through PI3K, Akt, c-Src, and AP-1 Signaling Pathway

BACKGROUND: Hepatocyte growth factor (HGF) has been demonstrated to stimulate osteoblast proliferation and participated bone remodeling. Osteopontin (OPN) is a secreted phosphoglycoprotein that belongs to the SIBLING family and is present during bone mineralization. However, the effects of HGF on OPN expression in human osteoblasts are large unknown. METHODOLOGY/PRINCIPAL FINDINGS: Here we found that HGF induced OPN expression in human osteoblasts dose-dependently. HGF-mediated OPN production was attenuated by c-Met inhibitor and siRNA. Pretreatment of osteoblasts with PI3K inhibitor (Ly294002), Akt inhibitor, c-Src inhibitor (PP2), or AP-1 inhibitor (curcumin) blocked the potentiating action of HGF. Stimulation of osteoblasts with HGF enhanced PI3K, Akt, and c-Src activation. In addition, incubation of cells with HGF also increased c-Jun phosphorylation, AP-1-luciferase activity, and c-Jun binding to the AP-1 element on the OPN promoter. HGF-mediated AP-1-luciferase activity and c-Jun binding to the AP-1 element was reduced by c-Met inhibitor, Ly294002, Akt inhibitor, and PP2. CONCLUSIONS/SIGNIFICANCE: Our results suggest that the interaction between HGF and c-Met increases OPN expression in human osteoblasts via the PI3K, Akt, c-Src, c-Jun, and AP-1 signaling pathway

Presentations of patients of poisoning and predictors of poisoning-related fatality: Findings from a hospital-based prospective study

<p>Abstract</p> <p>Background</p> <p>Poisoning is a significant public health problem worldwide and is one of the most common reasons for visiting emergency departments (EDs), but factors that help to predict overall poisoning-related fatality have rarely been elucidated. Using 1512 subjects from a hospital-based study, we sought to describe the demographic and clinical characteristics of poisoning patients and to identify predictors for poisoning-related fatality.</p> <p>Methods</p> <p>Between January 2001 and December 2002 we prospectively recruited poisoning patients through the EDs of two medical centers in southwest Taiwan. Interviews were conducted with patients within 24 hours after admission to collect relevant information. We made comparisons between survival and fatality cases, and used logistic regressions to identify predictors of fatality.</p> <p>Results</p> <p>A total of 1512 poisoning cases were recorded at the EDs during the study period, corresponding to an average of 4.2 poisonings per 1000 ED visits. These cases involved 828 women and 684 men with a mean age of 38.8 years, although most patients were between 19 and 50 years old (66.8%), and 29.4% were 19 to 30 years. Drugs were the dominant poisoning agents involved (49.9%), followed by pesticides (14.5%). Of the 1512 patients, 63 fatalities (4.2%) occurred. Paraquat exposure was associated with an extremely high fatality rate (72.1%). The significant predictors for fatality included age over 61 years, insufficient respiration, shock status, abnormal heart rate, abnormal body temperature, suicidal intent and paraquat exposure.</p> <p>Conclusion</p> <p>In addition to well-recognized risk factors for fatality in clinical settings, such as old age and abnormal vital signs, we found that suicidal intent and ingestion of paraquat were significant predictors of poisoning-related fatality. Identification of these predictors may help risk stratification and the development of preventive interventions.</p

Genome-Wide Association Study of Young-Onset Hypertension in the Han Chinese Population of Taiwan

Young-onset hypertension has a stronger genetic component than late-onset counterpart; thus, the identification of genes related to its susceptibility is a critical issue for the prevention and management of this disease. We carried out a two-stage association scan to map young-onset hypertension susceptibility genes. The first-stage analysis, a genome-wide association study, analyzed 175 matched case-control pairs; the second-stage analysis, a confirmatory association study, verified the results at the first stage based on a total of 1,008 patients and 1,008 controls. Single-locus association tests, multilocus association tests and pair-wise gene-gene interaction tests were performed to identify young-onset hypertension susceptibility genes. After considering stringent adjustments of multiple testing, gene annotation and single-nucleotide polymorphism (SNP) quality, four SNPs from two SNP triplets with strong association signals (−log10(p)>7) and 13 SNPs from 8 interactive SNP pairs with strong interactive signals (−log10(p)>8) were carefully re-examined. The confirmatory study verified the association for a SNP quartet 219 kb and 495 kb downstream of LOC344371 (a hypothetical gene) and RASGRP3 on chromosome 2p22.3, respectively. The latter has been implicated in the abnormal vascular responsiveness to endothelin-1 and angiotensin II in diabetic-hypertensive rats. Intrinsic synergy involving IMPG1 on chromosome 6q14.2-q15 was also verified. IMPG1 encodes interphotoreceptor matrix proteoglycan 1 which has cation binding capacity. The genes are novel hypertension targets identified in this first genome-wide hypertension association study of the Han Chinese population

Oncologic impact of delay between diagnosis and radical nephroureterectomy

PurposeThis study aimed to evaluate the oncological outcome of delayed surgical wait time from the diagnosis of upper tract urothelial carcinoma (UTUC) to radical nephroureterectomy (RNU).MethodsIn this multicenter retrospective study, medical records were collected between 1988 and 2021 from 18 participating Taiwanese hospitals under the Taiwan UTUC Collaboration Group. Patients were dichotomized into the early (≤90 days) and late (&gt;90 days) surgical wait-time groups. Overall survival, disease-free survival, and bladder recurrence-free survival were calculated using the Kaplan–Meier method and multivariate Cox regression analysis. Multivariate analysis was performed using stepwise linear regression.ResultsOf the 1251 patients, 1181 (94.4%) were classifed into the early surgical wait-time group and 70 (5.6%) into the late surgical wait-time group. The median surgical wait time was 21 days, and the median follow-up was 59.5 months. Our study showed delay-time more than 90 days appeared to be associated with worse overall survival (hazard ratio [HR] 1.974, 95% confidence interval [CI] 1.166−3.343, p = 0.011), and disease-free survival (HR 1.997, 95% CI 1.137−3.507, p = 0.016). This remained as an independent prognostic factor after other confounding factors were adjusted. Age, ECOG performance status, Charlson Comorbidity Index (CCI), surgical margin, tumor location and adjuvant systemic therapy were independent prognostic factors for overall survival. Tumor location and adjuvant systemic therapy were also independent prognostic factors for disease-free survival.ConclusionsFor patients with UTUC undergoing RNU, the surgical wait time should be minimized to less than 90 days. Prolonged delay times may be associated with poor overall and disease-free survival