Imaging Therapeutic PARP Inhibition In Vivo through Bioorthogonally Developed Companion Imaging Agents

A number of small-molecule poly (ADP-ribose) polymerase (PARP) inhibitors are currently undergoing advanced clinical trials. Determining the distribution and target inhibitory activity of these drugs in individual subjects, however, has proven problematic. Here, we used a PARP agent for positron emission tomography-computed tomography (PET-CT) imaging (¹⁸F-BO), which we developed based on the Olaparib scaffold using rapid bioorthogonal conjugation chemistries. We show that the bioorthogonal ¹⁸F modification of the parent molecule is simple, highly efficient, and well tolerated, resulting in a half maximal inhibitory concentration (IC₅₀) of 17.9 ± 1.1 nM. Intravital imaging showed ubiquitous distribution of the drug and uptake into cancer cells, with ultimate localization within the nucleus, all of which were inhibitable. Whole-body PET-CT imaging showed tumoral uptake of the drug, which decreased significantly, after a daily dose of Olaparib. Standard ¹⁸F-fludeoxyglucose imaging, however, failed to detect such therapy-induced changes. This research represents a step toward developing a more generic approach for the rapid codevelopment of companion imaging agents based on small-molecule therapeutic inhibitors.     

Role of angiogenic growth factors in transplant coronary artery disease

Transplant coronary artery disease (TxCAD) as a manifestation of chronic rejection is a major limitation to long‐term survival of heart transplant recipients. Although the exact molecular and cellular mechanisms contributing to neointimal formation are unknown, it has been generally believed that smooth muscle cells (SMC) of donor origin migrate from the media into the subendothelial layer of the vascular wall, where SMC proliferate and synthesize extracellular matrix resulting in intimal thickening. However, recent observations indicate that hematopoietic and vascular progenitor cells derived from recipient bone marrow may contribute to the arteriosclerotic lesion formation in the coronary arteries of the transplant. On the other hand, studies on postnatal hematopoiesis indicate that angiogenic growth factors such as vascular endothelial growth factor (VEGF) and angiopoietin‐1 (Ang1) may regulate the recruitment of these cells into distant organs. Furthermore, embryonic VEGFR‐2 ⁺ /CD34 ⁺ stem cells may serve as vascular progenitor cells and their differentiation into endothelial cells and SMC may be regulated by VEGF and platelet‐derived growth factor (PDGF), respectively. In this review, we discuss the role of angiogenic growth factors such as VEGF, Ang, and PDGF in the recruitment of hematopoietic and vascular progenitor cells in TxCAD and suggest novel therapies targeted at homing, differentiation and proliferation of these cells in the allograft.     

彩色多普勒超声在下肢深静脉血栓形成诊断中的价值

目的 探讨彩色多普勒血流显像（ＣＤＦＩ）在下肢深静脉血栓形成（ＤＶＴ）诊断中的价值。方法 对８９例拟诊下肢ＤＶＴ患者在７１２条下肢静脉进行ＣＤＦＩ和静脉造影检查。结果 ＣＤＦＩ检出并经静脉造影证实的ＣＶＴ静脉共６４３例。ＣＤＦＩ的主要优点是：①节约时间,易于快速找至静脉;②对鉴别完全或不完全阻塞性血栓有一定帮助;③便于检查髂静脉血栓,尤其血栓髂总静脉蔓延时。ＣＤＦＩ和静脉造影在判断有无ＤＶＴ方面,     

High-dose immunosuppressive therapy and autologous peripheral blood stem cell transplantation for severe multiple sclerosis

There were 26 patients enrolled in a pilot study of high-dose immunosuppressive therapy (HDIT) for severe multiple sclerosis (MS). Median baseline expanded disability status scale (EDSS) was 7.0 (range, 5.0-8.0). HDIT consisted of total body irradiation, cyclophosphamide, and antithymocyte globulin (ATG) and was followed by transplantation of autologous, granulocyte colony-stimulating factor (G-CSF)-mobilized CD34-selected stem cells. Regimen-related toxicities were mild. Because of bladder dysfunction, there were 8 infectious events of the lower urinary tract. One patient died from Epstein-Barr virus (EBV)-related posttransplantation lymphoproliferative disorder (PTLD) associated with a change from horse-derived to rabbit-derived ATG in the HDIT regimen. An engraftment syndrome characterized by noninfectious fever with or without rash developed in 13 of the first 18 patients and was associated in some cases with transient worsening of neurologic symptoms. There were 2 significant adverse neurologic events that occurred, including a flare of MS during mobilization and an episode of irreversible neurologic deterioration after HDIT associated with fever. With a median follow-up of 24 (range, 3-36) months, the Kaplan-Meier estimate of progression (>/= 1.0 point EDSS) at 3 years was 27%. Of 12 patients who had oligoclonal bands in the cerebrospinal fluid at baseline, 9 had persistence after HDIT. After HDIT, 4 patients developed new enhancing lesions on magnetic resonance imaging of the brain. The estimate of survival at 3 years was 91%. Important clinical issues in the use of HDIT and stem cell transplantation for MS were identified; however, modifications of the initial approaches appear to reduce treatment risks. This was a heterogeneous high-risk group, and a phase 3 study is planned to fully assess efficacy.     

What role for FTY720, a novel immunosuppressive agent, in canine nonmyeloablative hematopoietic stem cell transplantation?

BACKGROUND: Stable mixed donor/host hematopoietic chimerism was almost uniformly achieved in dogs given 200 cGy total body irradiation (TBI) before, and a short course of immunosuppression after, transplantation of marrow from dog leukocyte antigen-identical littermates, but was transient when the TBI dose was decreased to 100 cGy. Here, we examined whether stable engraftment could be achieved in five dogs given FTY720 (days -5 and -4), followed by 100 cGy TBI, dog leukocyte antigen-identical marrow grafts, and mycophenolate mofetil/cyclosporine. RESULTS AND CONCLUSIONS: Although all five dogs showed initial engraftment, four dogs rejected their grafts within 11 weeks, whereas one dog was euthanized on day 17 due to enteritis. This was not different from the control dogs not given FTY720 (P=0.32). Thus, FTY720 failed to enhance allogeneic engraftment in this model, perhaps due to in vivo T-cell depletion of the graft resulting from sequestration of donor lymphocytes in host central lymphoid tissues.     

Hepatic reticuloendothelial function during parenteral nutrition including an MCT/LCT or LCT emulsion after liver transplantation – a double-blind study

It has been demonstrated that total parenteral nutrition (TPN) modulates the function of the hepatic reticuloendothelial system (RES). The objective of this study was to evaluate the impact of two different TPN lipid emulsions on the recovery of allograft RES function after orthotopic liver transplantation (OLTx). In a prospective, double-blind study, OLTx patients were randomly assigned to two treatment groups. Group I ( n=13) received a TPN regimen that included long-chain triglycerides (LCT). Group II ( n=9) received a TPN regimen that included a fat emulsion consisting of both medium-chain triglycerides (MCT) and LCT. At baseline, i.e., on days 2 or 3 after OLTx ( t1), before lipids for TPN were started, hepatic RES function was determined using the human serum albumin millimicrosphere technique (K-value, 1/min). A second measurement ( t2) was obtained after 7 days of TPN, including one of the study's two fat emulsions. The mean (+/- SD) K-value (1/min) was 0.48+/-0.16 in the LCT group and 0.55+/-0.28 in the MCT/LCT group at t1, and it improved to 0.62+/-0.21 in the LCT group and to 0.86+/-0.32 in the MCT/LCT group at t2. RES function recovery was significantly better in the MCT/LCT group ( P< or = 0.05). MCT/LCT emulsion appears to be the TPN fat emulsion of choice after OLTx as it seems to have less impact on hepatic RES recovery.     

One hundred six live kidney donors in a single German transplantation center: renal, physical, and psychological follow-up

ObjectiveThe objective of this study was to analyze the psychological and physical status as well as renal outcomes of 106 live kidney donors between 1993 and 2003.MethodsWe performed general and nephrological examinations, including measurements of creatinine clearance (ClCr), proteinuria, and 24-hour blood pressure monitoring. We evaluated the psychological and general health situation using the standardized SF-36 questionnaire.ResultsWe evaluated 69/106 (65%) live kidney donors at 5.3 ± 0.4 years after donation. The reason for the 37 drop-outs were unknown current address (n = 21), refusal of study participation (n = 14), and death due to accident and suicide (n = 2). In the 69 donors renal function was well preserved: serum creatinine 1.3 ± 0.0 mg/dL; ClCr 81 ± 2 mL/min; postdonation to predonation ClCr ratio 0.73 ± 0.02; and proteinuria 104 ± 11 mg/d. None of the donors experienced renal failure, although 36/69 (52%) patients have developed de novo hypertension. Compared with normotensive donors, the hypertensive subgroup was significantly older at the time of donation (50.7 ± 1.4 vs 46.4 ± 1.6 years; P = .010) and had a longer interval since donation (6.4 ± 0.2 vs 3.9 ± 0.1 years; P = .001). SF-36 questionnaire results in live kidney donors showed higher scores regarding physical (54.3 ± 0.8 vs 49.3 ± 0.1; P = .048) and psychological health (53.8 ± 0.6 vs 50.7 ± 0.1; P = .043) compared with the average German population.ConclusionOur cohort of live kidney donors showed good renal outcomes and superior SF-36 scores in both physical and psychological health compared with the German population. The risk of de novo hypertension increased with age and time after donation. Blood pressure screening should be regularly performed especially in the long term after donation.