Site-Selective Lysine Acetylation of Human Immunoglobulin G for Immunoliposomes and Bispecific Antibody Complexes.

Site-selective acetylation of a single lysine residue in a protein that reaches a lysine acetyltransferase's accuracy, precision, and reliability is challenging. Here, we report a peptide-guided, proximity-driven group transfer reaction that acetylates a single lysine residue, Lys 248, of the fragment crystallizable region (Fc region) in the heavy chain of the human Immunoglobulin G (IgG). An Fc-interacting peptide bound with the Fc domain and positioned a phenolic ester close to Lys 248, which induced a nucleophilic reaction and resulted in the transfer of an acetyl group to Lys 248. The acetylation reaction proceeded to a decent yield under the physiological condition without the need for deglycosylation, unnatural amino acids, or catalysts. Along with acetylation, functional moieties such as azide, alkyne, fluorescent molecules, or biotin could also be site-selectively installed on Lys 248, allowing IgG's further derivatization. We then synthesized an antibody-lipid conjugate and constructed antibody-conjugated liposomes (immunoliposomes), targeting HER2-positive (HER2+) cancer cells. We also built a bispecific antibody complex (bsAbC) covalently linking an anti-HER2 antibody and an anti-CD3 antibody. The bsAbC showed in vitro effector-cell-mediated cytotoxicity at nanomolar concentrations. Compared with bispecific antibodies (bsAbs), bsAbCs are constructed based on native IgGs and contain two antigen-binding sites to each antigen, twice that of bsAbs. Altogether, this work reports a method of site-selective acetylation of native antibodies, highlights a facile way of site-selective IgG functionalization, and underscores the potential of bsAbCs in cancer immunotherapy.

An in situ inferior vena cava ligation-stenosis model to study thrombin generation rates with flow.

BACKGROUND: Blood flow-induced shear stress affects platelet participation in coagulation and thrombin generation. We aimed to develop an in vivo model to characterize thrombin generation rates under flow. METHODS: An in situ inferior vena cava (IVC) ligation-stenosis model was established using C57BL/6 mice. Wild type C57BL/6 mice were fed normal chow diet for two weeks before experiments. On the day of experiments, mice were anesthetized, followed by an incision through the abdominal skin to expose the IVC, which was then ligated (followed by reperfusion through a stenosis for up to 2 h). IVC blood flow rate was monitored using a Transonic ultrasound flow meter. In sham animals, the IVC was exposed following the same procedure, but no ligation was applied. Thrombin generation following IVC ligation was estimated by measuring mouse plasma prothrombin fragment 1-2 concentration. Mouse plasma factor Va concentration was measured using phospholipids and a modified prothrombinase assay. Blood vessel histomorphology, vascular wall ICAM-1, von Willebrand Factor, tissue factor, and PECAM-1 expression were measured using immunofluorescence microscopy. RESULTS: IVC blood flow rate increased immediately following ligation and stenosis formation. Sizable clots formed in mouse IVC following ligation and stenosis formation. Both plasma factor Va and prothrombin fragment 1-2 concentration reduced significantly following IVC ligation/stenosis, while no changes were observed with ICAM-1, von Willebrand Factor, tissue factor and PECAM-1 expression. CONCLUSION: Clot formation was successful. However, the prothrombin-thrombin conversion rate constant in vivo cannot be determined as local thrombin and FVa concentration (at the injury site) cannot be accurately measured. Modification to the animal model is needed to further the investigation.

A novel low-molecular-weight chitosan/gamma-polyglutamic acid polyplexes for nucleic acid delivery into zebrafish larvae.

Many challenges, such as virus infection, extreme weather and long cultivation periods, during the development of fish larvae have been observed, especially in aquaculture. Gene delivery is a useful method to express functional genes to defend against these challengers. However, the methods for fish larvae are insufficient. In our earlier report, low-molecular-weight chitosan (LMWCS) showed a strong positive charge and may be useful for polyplex formulation. Herein, we present a simple self-assembly of LMWCS polyplexes (LMWCSrNPs) for gene delivery into zebrafish larvae. Different weight ratios of LMWCS/gamma-polyglutamic acid (γ-PGA)/plasmid DNA were analyzed by gel mobility assay. Delivery efficiency determined by green fluorescent protein (GFP) expression in zebrafish liver (ZFL) cells showed that delivery efficiency at a weight ratio of 20:8:1 was higher than others. Zeta potential and transmission electron microscopy (TEM) analysis showed that the round shape of the particle size varied. In our earlier reports, IRF9S2C could induce interferon-stimulated gene (ISG) expression to induce innate immunity in zebrafish and pufferfish. Further delivery of pcDNA3-IRF9S2C-HA plasmid DNA into ZFL cells and zebrafish larvae by LMWCSrNP successfully induced ISG expression. Collectively, LMWCSrNP could be a novel gene delivery system for zebrafish larvae and might be used to improve applications in aquaculture.

Effects of somatic treatments on suicidal ideation and completed suicides.

OBJECTIVE: This work was undertaken to define and characterize the role of currently available somatic treatments in psychiatry in either increasing or reducing the risk for suicide. METHODS: Members of the Suicide Prevention Task Group of the National Network of Depression Centers performed a literature review of somatic treatments known to increase or reduce the risk for suicide. The reviews ventured to include all relevant information about the risk for both suicide ideation and completed suicides. RESULTS: Lithium and clozapine are the only two somatic treatments that have high-quality data documenting their antisuicide effects in mood disorders and schizophrenia, respectively. Lithium discontinuation is also associated with increased suicide risk. Ketamine and esketamine may have a small, but immediate, antisuicide effect. Despite the recent Food and Drug Administration approval of esketamine use in depressed suicidal patients, the small disproportional overrepresentation of suicide in subjects who had received esketamine versus placebo (3 vs. 0 among > 3500 subjects) requires ongoing evaluation. The purported antisuicide effect of electroconvulsive therapy is based on low-quality data. The effect of antidepressants is not at all clear. There appears to be direct evidence for antidepressants increasing suicidal ideation and the risk for suicide over the short-term in young people, but indirect (low quality) evidence that antidepressants reduce suicide risk over the long term. CONCLUSIONS: Clinicians have an expanding pharmacopeia to address suicide potential in their patients. Some of the agents with documented antisuicide effects may also increase suicidality under specific circumstances.

Structural basis of substrate recognition and thermal protection by a small heat shock protein.

Small heat shock proteins (sHsps) bind unfolding proteins, thereby playing a pivotal role in the maintenance of proteostasis in virtually all living organisms. Structural elucidation of sHsp-substrate complexes has been hampered by the transient and heterogeneous nature of their interactions, and the precise mechanisms underlying substrate recognition, promiscuity, and chaperone activity of sHsps remain unclear. Here we show the formation of a stable complex between Arabidopsis thaliana plastid sHsp, Hsp21, and its natural substrate 1-deoxy-D-xylulose 5-phosphate synthase (DXPS) under heat stress, and report cryo-electron microscopy structures of Hsp21, DXPS and Hsp21-DXPS complex at near-atomic resolution. Monomeric Hsp21 binds across the dimer interface of DXPS and engages in multivalent interactions by recognizing highly dynamic structural elements in DXPS. Hsp21 partly unfolds its central α-crystallin domain to facilitate binding of DXPS, which preserves a native-like structure. This mode of interaction suggests a mechanism of sHsps anti-aggregation activity towards a broad range of substrates.

X-ray-Activated Simultaneous Near-Infrared and Short-Wave Infrared Persistent Luminescence Imaging for Long-Term Tracking of Drug Delivery.

Both short-wave infrared (SWIR: 900-1700 nm) and near-infrared (NIR: 650-900 nm) luminescence possess lower optical scattering and higher signal-to-noise in deep tissues than conventional luminescence, gaining increasing attention in biomedicine. Herein, we designed mesoporous silica-coated Yb-doped magnesium germanate nanoparticles (mMGOs) with excellent two-in-one NIR and SWIR persistent luminescence after X-ray irradiation by simply regulating the valence of rare-earth ions, which also possess high cargo loading and a controlled release profile in the tumor region. The investigations in vitro and in vivo showed that mMGOs were repeatedly activated to realize rechargeable persistent luminescence imaging for tracking cargo delivery in mice. Moreover, the stimulative drug-release profile inhibited tumor growth effectively. Both of the X-ray excited two-in-one NIR and SWIR persistent luminescence imaging not only allowed for rechargeable imaging of deep tumors but also achieved long-term tracking with a remarkable tumor inhibition effect.

Neuroprotective Effects of Emodin against Ischemia/Reperfusion Injury through Activating ERK-1/2 Signaling Pathway.

BACKGROUND: Stroke is one of the leading causes of death and disability worldwide and places a heavy burden on the economy in our society. Current treatments, such as the use of thrombolytic agents, are often limited by a narrow therapeutic time window. However, the regeneration of the brain after damage is still active days, even weeks, after stroke occurs, which might provide a second window for treatment. Emodin, a traditional Chinese medicinal herb widely used to treat acute hepatitis, has been reported to possess antioxidative capabilities and protective effects against myocardial ischemia/reperfusion injury. However, the underlying mechanisms and neuroprotective functions of Emodin in a rat middle cerebral artery occlusion (MCAO) model of ischemic stroke remain unknown. This study investigates neuroprotective effects of Emodin in ischemia both in vitro and in vivo. METHODS: PC12 cells were exposed to oxygen-glucose deprivation to simulate hypoxic injury, and the involved signaling pathways and results of Emodin treatment were evaluated. The therapeutic effects of Emodin in ischemia animals were further investigated. RESULTS: Emodin reduced infarct volume and cell death following focal cerebral ischemia injury. Emodin treatment restored PC12 cell viability and reduced reactive oxygen species (ROS) production and glutamate release under conditions of ischemia/hypoxia. Emodin increased Bcl-2 and glutamate transporter-1 (GLT-l) expression but suppressed activated-caspase 3 levels through activating the extracellular signal-regulated kinase (ERK)-1/2 signaling pathway. CONCLUSION: Emodin induced Bcl-2 and GLT-1 expression to inhibit neuronal apoptosis and ROS generation while reducing glutamate toxicity via the ERK-1/2 signaling pathway. Furthermore, Emodin alleviated nerve cell injury following ischemia/reperfusion in a rat MCAO model. Emodin has neuroprotective effects against ischemia/reperfusion injury both in vitro and in vivo, which may be through activating the ERK-1/2 signaling pathway.

An Integrated Bioinformatics Analysis Repurposes an Antihelminthic Drug Niclosamide for Treating HMGA2-Overexpressing Human Colorectal Cancer.

Aberrant overexpression of high mobility group AT-hook 2 (HMGA2) is frequently found in cancers and HMGA2 has been considered an anticancer therapeutic target. In this study, a pan-cancer genomics survey based on Cancer Cell Line Encyclopedia (CCLE) and The Cancer Genome Atlas (TCGA) data indicated that HMGA2 was mainly overexpressed in gastrointestinal cancers including colorectal cancer. Intriguingly, HMGA2 overexpression had no prognostic impacts on cancer patients' overall and disease-free survivals. In addition, HMGA2-overexpressing colorectal cancer cell lines did not display higher susceptibility to a previously identified HMGA2 inhibitor (netroposin). By microarray profiling of HMGA2-driven gene signature and subsequent Connectivity Map (CMap) database mining, we identified that S100 calcium-binding protein A4 (S100A4) may be a druggable vulnerability for HMGA2-overexpressing colorectal cancer. A repurposing S100A4 inhibitor, niclosamide, was found to reverse the HMGA2-driven gene signature both in colorectal cancer cell lines and patients' tissues. In vitro and in vivo experiments validated that HMGA2-overexpressing colorectal cancer cells were more sensitive to niclosamide. However, inhibition of S100A4 by siRNAs and other inhibitors was not sufficient to exert effects like niclosamide. Further RNA sequencing analysis identified that niclosamide inhibited more cell-cycle-related gene expression in HMGA2-overexpressing colorectal cancer cells, which may explain its selective anticancer effect. Together, our study repurposes an anthelminthic drug niclosamide for treating HMGA2-overexpression colorectal cancer.

A decision support model for investment on P2P lending platform.

Peer-to-peer (P2P) lending, as a novel economic lending model, has triggered new challenges on making effective investment decisions. In a P2P lending platform, one lender can invest N loans and a loan may be accepted by M investors, thus forming a bipartite graph. Basing on the bipartite graph model, we built an iteration computation model to evaluate the unknown loans. To validate the proposed model, we perform extensive experiments on real-world data from the largest American P2P lending marketplace-Prosper. By comparing our experimental results with those obtained by Bayes and Logistic Regression, we show that our computation model can help borrowers select good loans and help lenders make good investment decisions. Experimental results also show that the Logistic classification model is a good complement to our iterative computation model, which motivates us to integrate the two classification models. The experimental results of the hybrid classification model demonstrate that the logistic classification model and our iteration computation model are complementary to each other. We conclude that the hybrid model (i.e., the integration of iterative computation model and Logistic classification model) is more efficient and stable than the individual model alone.

Patient- and therapy-related factors associated with the incidence of xerostomia in nasopharyngeal carcinoma patients receiving parotid-sparing helical tomotherapy.

We investigated the incidence of moderate to severe patient-reported xerostomia among nasopharyngeal carcinoma (NPC) patients treated with helical tomotherapy (HT) and identified patient- and therapy-related factors associated with acute and chronic xerostomia toxicity. The least absolute shrinkage and selection operator (LASSO) normal tissue complication probability (NTCP) models were developed using quality-of-life questionnaire datasets from 67 patients with NPC. For acute toxicity, the dosimetric factors of the mean doses to the ipsilateral submandibular gland (Dis) and the contralateral submandibular gland (Dcs) were selected as the first two significant predictors. For chronic toxicity, four predictive factors were selected: age, mean dose to the oral cavity (Doc), education, and T stage. The substantial sparing data can be used to avoid xerostomia toxicity. We suggest that the tolerance values corresponded to a 20% incidence of complications (TD20) for Dis = 39.0 Gy, Dcs = 38.4 Gy, and Doc = 32.5 Gy, respectively, when mean doses to the parotid glands met the QUANTEC 25 Gy sparing guidelines. To avoid patient-reported xerostomia toxicity, the mean doses to the parotid gland, submandibular gland, and oral cavity have to meet the sparing tolerance, although there is also a need to take inherent patient characteristics into consideration.

Using multivariate regression model with least absolute shrinkage and selection operator (LASSO) to predict the incidence of Xerostomia after intensity-modulated radiotherapy for head and neck cancer.

PURPOSE: The aim of this study was to develop a multivariate logistic regression model with least absolute shrinkage and selection operator (LASSO) to make valid predictions about the incidence of moderate-to-severe patient-rated xerostomia among head and neck cancer (HNC) patients treated with IMRT. METHODS AND MATERIALS: Quality of life questionnaire datasets from 206 patients with HNC were analyzed. The European Organization for Research and Treatment of Cancer QLQ-H&N35 and QLQ-C30 questionnaires were used as the endpoint evaluation. The primary endpoint (grade 3(+) xerostomia) was defined as moderate-to-severe xerostomia at 3 (XER3m) and 12 months (XER12m) after the completion of IMRT. Normal tissue complication probability (NTCP) models were developed. The optimal and suboptimal numbers of prognostic factors for a multivariate logistic regression model were determined using the LASSO with bootstrapping technique. Statistical analysis was performed using the scaled Brier score, Nagelkerke R(2), chi-squared test, Omnibus, Hosmer-Lemeshow test, and the AUC. RESULTS: Eight prognostic factors were selected by LASSO for the 3-month time point: Dmean-c, Dmean-i, age, financial status, T stage, AJCC stage, smoking, and education. Nine prognostic factors were selected for the 12-month time point: Dmean-i, education, Dmean-c, smoking, T stage, baseline xerostomia, alcohol abuse, family history, and node classification. In the selection of the suboptimal number of prognostic factors by LASSO, three suboptimal prognostic factors were fine-tuned by Hosmer-Lemeshow test and AUC, i.e., Dmean-c, Dmean-i, and age for the 3-month time point. Five suboptimal prognostic factors were also selected for the 12-month time point, i.e., Dmean-i, education, Dmean-c, smoking, and T stage. The overall performance for both time points of the NTCP model in terms of scaled Brier score, Omnibus, and Nagelkerke R(2) was satisfactory and corresponded well with the expected values. CONCLUSIONS: Multivariate NTCP models with LASSO can be used to predict patient-rated xerostomia after IMRT.

Treatment of nasopharyngeal carcinoma by tomotherapy: five-year experience.

PURPOSE: To analyze of survival curve and toxicity outcomes for patients treated for nasopharyngeal carcinoma (NPC) by intensity-modulated radiotherapy (IMRT) delivered by helical TomoTherapy (HT). MATERIALS AND METHODS: Since May 2006, 72 patients with primary NPC were treated. In 67 cases PET-CT was used to help delineate the gross tumor volume (GTV); in 4 of these cases distant metastases in bone, mediastinal lymph nodes and unexpected small neck nodes were detected by high SUV uptake. 3, 22, 19, and 27 patients, respectively, had AJCC stage I to IV disease. Patients received a median total dose of 72 Gy to the GTV, 64.8 Gy to the elective PTV, and 54 Gy to the clinically negative neck region. RESULTS: At a median follow-up of 41 months (range 0.2 to 67 months), no patient has recurred locally. Two patients with stage IIb disease, both of whom received chemotherapy, recurred regionally. Ten patients developed distant metastases. One died from progressive disease with initial proved bony metastasis. Two patients with stage IIb disease, both of whom received chemotherapy, experienced neck node recurrence. 5-year locoregional control rate was 97%; freedom from distant metastases was 84.6% at 5 years. No evidence of disease was detected in 13 early stage (I/IIa/IIb) patients who did not receive chemotherapy. Acute grade 3 toxicity occurred in four patients and grade 4 in two patients. Late toxicities were low, with no grade 3+ xerostomia, grade 2 xerostomia in two patients (3%), and grade 3 hearing loss in two patients (3%). CONCLUSIONS: HT resulted in excellent long-term disease control and survival in heterogeneous NPC patients. Generally mild acute and late toxicity, with low rates of xerostomia, were obtained. Image-guided HT offers the ability to deliver conformal, OAR-sparing dose distributions to a wide variety of NPC patients with good long-term clinical outcomes.

Health-related quality of life in 640 head and neck cancer survivors after radiotherapy using EORTC QLQ-C30 and QLQ-H&N35 questionnaires.

BACKGROUND: With the advances in modern radiotherapy (RT), many patients with head and neck cancer (HNC) can be effectively cured, and their health-related quality of life (HR-QoL) has become an important issue. In this study, we evaluated the prognosticators of HR-QoL in a large cohort of HNC patients, with a focus on the result from technological advances in RT. METHODS: A cross-sectional investigation was conducted to assess the HR-QoL of 640 HNC patients with cancer-free survival of more than 2 years. Among them, 371 patients were treated by two-dimensional RT (2DRT), 127 by three-dimensional conformal RT (3DCRT), and 142 by intensity-modulated RT (IMRT). The EORTC QLQ-C30 questionnaire and QLQ-H&N35 module were used. A general linear model multivariate analysis of variance was used to analyze the prognosticators of HR-QoL. RESULTS: By multivariate analysis, the variables of gender, annual family income, tumor site, AJCC stage, treatment methods, and RT technique were prognosticators for QLQ-C30 results, so were tumor site and RT technique for H&N35. Significant difference (p < 0.05) of HR-QoL outcome by different RT techniques was observed at 2 of the 15 scales in QLQ-C30 and 10 of the 13 scales in H&N35. Compared with 2DRT, IMRT had significant better outcome in the scales of global QoL, physical functioning, swallowing, senses (taste/smell), speech, social eating, social contact, teeth, opening mouth, dry mouth, sticky saliva, and feeling ill. CONCLUSIONS: The technological advance of RT substantially improves the head-and-neck related symptoms and broad aspects of HR-QoL for HNC survivors.

Six-year clinical follow-up after treatment of diffuse in-stent restenosis with cutting balloon angioplasty followed by intracoronary brachytherapy with liquid rhenium-188-filled balloon via transradial approach.

BACKGROUND: Long-term follow-up studies revealed a significant decline in the benefits of intracoronary radiation for in-stent restenosis. METHODS AND RESULTS: A total of 25 study and 25 contemporaneous control patients with diffuse in-stent restenosis who underwent cutting balloon angioplasty (CBA) transradially, followed by subsequent intracoronary irradiation with a liquid ß-emitter Rhenium-188 (¹88Re)-filled balloon were enrolled in the study. The mean clinical follow-up durations were 64.9 ± 13.0 and 66.3 ± 13.8 months for the irradiated and control patients, respectively. Six-month angiographic restenosis was observed in 16% (4 of 25) of the patients in the irradiated group and 48% (12 of 25) of the patients in the control groups (P = 0.03). The 6-month major adverse cardiac events (MACE) rate was 12% and 44%, respectively (P = 0.025). The 3-year follow-up angiography was performed in 16 of 21 (76%) irradiated patients and in 4 of 13 (31%) control patients who had no significant restenosis at the 6-month angiographic follow-up. Restenosis occurred in 1 of 16 (7%) irradiated patients and 2 of 4 (50%) control patients. Late target lesion revascularization was performed in 1 irradiated and 2 control patients. The MACE rate within 6 years was significantly reduced in the irradiated group (20% vs. 56%, P = 0.019). CONCLUSIONS: Brachytherapy using ¹88Re-filled balloon following CBA for diffuse in-stent restenotic native coronary arteries is effective in reducing target lesion restenosis and improving long-term outcomes.

Helical tomotherapy for single and multiple liver tumours.

PURPOSE: Dosimetric evaluations of single and multiple liver tumours performed using intensity-modulated helical tomotherapy (HT) were quantitatively investigated. Step-and-shoot intensity-modulated radiotherapy (SaS-IMRT) was used as a benchmark. METHODS: Sixteen patients separated into two groups with primary hepatocellular carcinomas or metastatic liver tumours previously treated using SaS-IMRT were examined and re-planned by HT. The dosimetric indices used included the conformity index (CI) and homogeneity index (HI) for the planned target volume (PTV), max/mean dose, quality index (QI), normal tissue complication probability (NTCP), V(30 Gy), and V(50%) for the specified organs at risk (OARs). The monitor units per fraction (MU/fr) and delivery time were also analysed. RESULTS: For the single tumour group, both planning systems satisfied the required PTV prescription, but no statistical significance was shown by the indexes checking. A shorter delivery time and lower MU/fr value were achieved by the SaS-IMRT. For the group of multiple tumours, the average improvement in CI and HI was 14% and 4% for HT versus SaS-IMRT, respectively. Lower V(50%), V(30 Gy) and QI values were found, indicating a significant dosimetric gain in HT. The NTCP value of the normal liver was 20.27 +/- 13.29% for SaS-IMRT and 2.38 +/- 2.25% for HT, indicating fewer tissue complications following HT. The latter also required a shorter delivery time. CONCLUSIONS: Our study suggests dosimetric benefits of HT over SaS-IMRT plans in the case of multiple liver tumours, especially with regards sparing of OARs. No significant dosimetric difference was revealed in the case of single liver tumour, but SaS-IMRT showed better efficiency in terms of MU/fr and delivery time.

Dosimetric comparisons of helical tomotherapy and step-and-shoot intensity-modulated radiotherapy in nasopharyngeal carcinoma.

PURPOSE: The study evaluates and quantifies the potential dosimetric gains of helical tomotherapy (HT) versus step-and-shoot intensity-modulated radiotherapy (SaS-IMRT) for nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: Twenty consecutive NPC patients curatively treated by HT were examined. Each case was planned by HT and SaS-IMRT (ADAC Pinnacle(3)) planning system, respectively. Dose plans were compared using dose volume histograms (DVH), conformity index (CI), homogeneity index (HI), and minimal dose to 1cc (D(min_1cc)) of the planned target volume (PTV) and a comprehensive quality index (CQI) of ten organs at risk (OARs). The prescribed dose/fractionation was 72Gy to the PTV, 64.8Gy to the elective PTV, and 54Gy to the clinically negative neck region. The plan of 54Gy to the PTV (PTV(54)) was used to evaluate the CI and HI in the target. The cumulative doses of the three PTV plans to the OARs were calculated. RESULTS: We observed the HT plans significantly improved the CI (improvement ratio: 11.9+/-5.5%) and HI (improvement ratio: 8.8+/-1.5%) of the PTV(54) compared with SaS-IMRT plans. In addition, the mean/maximal dose of most of the OARs except chiasm was significantly reduced in HT plans, with the CQI of 0.92+/-0.08. A negative result of HT in chiasm was observed but only significantly revealed in cases without skull base infiltration. CONCLUSIONS: A dosimetric gain in CI and HI of PTV and sparing of OARs was significantly obtained in HT versus SaS-IMRT plans in NPC patients. Whether such dosimetric superiority in HT could transfer into clinical advantages needs further investigation.

Increased expression of nuclear NF-kappaB after coronary artery balloon injury can be inhibited by intracoronary beta-irradiation.

PURPOSE: Molecular mechanisms by which balloon angioplasty injury-induced neointimal hyperplasia can be reduced by intravascular brachytherapy are unclear. We investigated the role of nuclear factor-kappaB (NF-kappaB) in neointimal hyperplasia following intracoronary irradiation. MATERIALS AND METHODS: Fifty-four coronary arteries from 30 pigs were divided into 6 groups: sham control, balloon angioplasty injury alone, beta-irradiation at doses of 14 or 20 Gy, and 14 or 20 Gy beta-irradiation immediately followed by balloon injury. Coronary arteries were injured by overstretch balloon angioplasty and then the arteries were irradiated using a Rhenium-188 ((188)Re) beta-emitting solution-filled balloon. Pigs were scarified one day or one week after coronary interventions for molecular detection and six weeks after the procedures for histological examination. RESULTS: Six weeks after coronary interventions, the histological results show that balloon angioplasty injury had induced intimal hyperplasia in coronary artery but the response was significantly reduced by 28% and 60% when the injury was immediately treated by 14 and 20 Gy (188)Re beta-irradiation, respectively. The expression of arterial NF-kappaB p65, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) were detected at one day and one week after the procedures. The treatment of balloon injury could significantly induce the NF-kappaB p65 expression in both gene and protein levels, and such induction could be significantly reduced by (188)Re beta-irradiation at dose of 20 Gy. However, the similar result on the regulation of gene expression affected by the beta-irradiation could not be observed in ICAM-1 and VCAM-1. CONCLUSION: The inhibitory effect of intracoronary brachytherapy on neointimal formation following overstretch balloon angioplasty could involve inhibition of NF-kappaB p65.

Incidence of needle tract seeding and responses of soft tissue metastasis by hepatocellular carcinoma postradiotherapy.

AIM: To determine the incidence of needle tract seeding after fine needle aspiration (FNA) or percutaneous ethanol injection (PEI) and compare iatrogenic or spontaneous soft tissue metastasis (STM) by hepatocellular carcinoma (HCC) postradiotherapy (RT) in responses. METHODS: From November 1997 to January 2006, those who presented with STM by HCC after our invasive procedures or developed spontaneously were enrolled into this retrospective study. Metastatic lesions could be divided into procedure related (PR), which were located at the liver span and were related to invasive procedures, and non-procedure related (NPR), which were in extrahepatic areas. STM was treated with an electron or photon beam. RESULTS: A total of 39 HCC cases with developed STM were referred for RT, including 17 in the PR group and 22 in the NPR group. During the same period, a total of 18,227 person-times of FNA or PEI were performed on these HCC patients. The overall incidence of HCC with STM that was caused by invasive procedures was estimated at 0.13%. According to the Cox' regression model, the initial treatment modality influences the time duration after the initial diagnosis of HCC when STM has not occurred. None of these patients' soft tissue tumor increased in size during RT. The PR group had lower rates of bone metastasis (P=0.003) and coexisting extrahepatic metastasis (P=0.011) and a longer survival rate (P=0.003) than the NPR group. The estimated rates of 18-gauge and 22-gauge needle-induced HCC-related STM were 0.60% and 0.11%, respectively (P=0.064). CONCLUSION: The PR group bears a better prognosis than the NPR group post-RT.

Computer tomography-assisted three-dimensional technique to assess rectal and bladder wall dose in intracavitary brachytherapy for uterine cervical cancer.

We used a computer tomography (CT)-assisted three-dimensional (3D) technique to assess dose to the rectum and bladder in intracavitary brachytherapy (ICBT) for patients with cervical cancer, and compared this technique with the conventional method. The results revealed that the difference in dose to the rectal and bladder wall between these two methods were significant. The CT-assisted technique is a feasible method, and it gives different results than the conventional method.

Clinical comparison of two linear-quadratic model-based isoeffect fractionation schemes of high-dose-rate intracavitary brachytherapy for cervical cancer.

PURPOSE: Two linear-quadratic model-based isoeffect fractionation schemes of high-dose-rate intracavitary brachytherapy (HDR-IC) were used to treat cervical cancer in two consecutive periods. Patient outcomes and complications were analyzed and compared. METHODS AND MATERIALS: Between November 1987 and December 1996, a total of 541 women diagnosed with cervical cancer were treated with curative-intent radiotherapy. Patients were categorized into two groups according to the two isoeffect schemes used. Group 1 consisted of 254 patients treated with external beam radiotherapy (EBRT) plus 7.2 Gy HDR-IC to Point A for three fractions in the first period. Group 2 consisted of 284 patients treated with EBRT plus 4.8 Gy HDR-IC for five fractions in the second period. The goal of the new scheme for the latter group was to deliver an isoeffect dose that maintained similar tumor control but reduced normal tissue complications. The calculated biologically effective dose (BED(10), assuming an alpha/beta ratio = 10) of EBRT plus HDR-IC for tumor and acute responding tissue in Groups 1 and 2 was 90 Gy(10) (52.8 + 37.2 Gy) and 88.6 Gy(10) (53.1 + 35.5 Gy), respectively. The corresponding BED(3) for late responding tissue (assuming an alpha/beta ratio = 3) in Groups 1 and 2 was 146.7 Gy(3) (73.3 + 73.4 Gy) and 134.4 Gy(3) (72 + 62.4 Gy), respectively. Patients were followed for 6.1-15.2 years (median, 9.8 years). RESULTS: Overall, 66 patients (12.2%) developed pelvic recurrence. Of these, 53 patients had central recurrence. Of the 53 patients with central recurrence, 24 (9.4%) were in Group 1 and 29 (10.1%) in Group 2 (p = 0.722). The actuarial pelvic control rate for Groups 1 and 2 was 88.2% and 86.3% at 5 years and 87.3% and 85.5% at 10 years, respectively (p = 0.504). The actuarial overall survival rate for Groups 1 and 2 was 63.5% and 56.1% at 5 years and 47.8% and 49.3% at 10 years, respectively (p = 0.734). The actuarial proctitis rate for Groups 1 and 2 was 49.7% and 32.7% at 5 years and 50.5% and 32.7% at 10 years, respectively (p <0.001). Most of the decrease in the rate of proctitis was a result of a decrease in the incidence of low-grade proctitis (38% vs. 22%). The incidence of high-grade complications remained unchanged, 8% vs. 7%. The actuarial cystitis rate for Groups 1 and 2 was 14.3% vs. 11.4% at 5 years and 24.1% vs. 15% at 10 years, respectively (p = 0.134). Multivariate analysis revealed that the fractionation scheme (three fractions vs. five fractions) was a significant factor influencing the proctitis rate (p = 0.004, hazard ratio = 0.807; 95% confidence interval, 0.697-0.934), but not the local pelvic control rate, overall survival rate, or cystitis rate. CONCLUSION: The treatment results of the two groups maintained similar outcomes, while the complications decreased. The linear-quadratic model correctly predicted this outcome. Biologically, the manipulation of the fraction size in our study suggested that the sensitivity of the late responding tissue to the fractional change from 7.2 Gy to 4.8 Gy in HDR-IC is high and detectable clinically. The success, however, had its limitations, and the improvement was confined to low-grade complications.