An exploratory study of systemic administration of the toll-like receptor-7 agonist 852A in patients with refractory metastatic melanoma.

PURPOSE: A topical Toll-like receptor 7 (TLR7) agonist induces regression of cutaneous melanocytic neoplasms. We explored antitumor activity of a systemically administered TLR7 agonist, 852A, in patients with metastatic melanoma. EXPERIMENTAL DESIGN: We undertook a phase II, multicenter, open-label study in patients with chemotherapy-refractory metastatic melanoma. Patients received i.v. 852A, starting at 0.6 mg/m(2) and increasing to 0.9 mg/m(2) based on tolerance, thrice per week for 12 weeks. Clinical response was determined by Response Evaluation Criteria in Solid Tumors. Immune effects of 852A were monitored by measuring serum type I IFN and IP-10 together with assessment of immune cell markers in peripheral blood. RESULTS: Twenty-one patients were enrolled. Thirteen patients completed the initial 12-week treatment cycle, with two discontinuing for adverse events considered to be possibly related to study drug. Four (19%) patients had disease stabilization for >100 days. One patient had a partial remission after two treatment cycles, but progressed during the third. Dose-limiting toxicity was observed in two patients. Serum type I IFN and IP-10 increased in most patients on 852A administration. Serum type I IFN increases were greater after dosing with 852A 0.9 mg/m(2) than after 0.6 mg/m(2) (P = 0.009). The maximal increase in IP-10 compared with baseline correlated with the maximal increase in type I IFN (P = 0.003). In the eight patients with immune cell marker data, CD86 expression on monocytes increased significantly post-first dose (P = 0.007). CONCLUSION: Intravenous 852A was well tolerated and induced systemic immune activation that eventually resulted in prolonged disease stabilization in some patients with stage IV metastatic melanoma who had failed chemotherapy.     

Precise intraoperative location of gastrointestinal bleeding with a hand-held counter. Work in progress

The nuclear medicine bleeding scan is frequently insufficient to locate sites of bleeding precisely, in spite of its great sensitivity. A small, hand-held Geiger-Müller counter, placed directly on exposed intestine in the operating room, enables precise location of the probable bleeding site. In three patients, the technique allowed a minimal amount of intestine to be resected, distinguished between large- and small-intestinal hemorrhage, and eliminated other foci as sites of bleeding.     

儿童癌症幸存者成年后的慢性疾病

由于治疗方法的进步,近80%的儿童和青少年癌症患者能够长期生存。在美国,约有270000例儿童癌症的幸存者,即每640名20至39岁成年人中就有一名幸存者。大量的幸存者有利于儿童癌症治疗后长期健康结果的研究。现在可以明确的是,化疗和放疗所致的儿童各器官系统损害在临床上可能潜伏多年。为了全面了解治疗儿童癌症而继发的健康问题,重要的是衡量三项长期结果:健康状况、死亡率和患病率。这三项中,关于前两项已有相当好的研究报道。在一项对20227例癌症5年生存者的回顾性分析中,Mertens等发现以下原因导致的超额死亡率具有统计学意义:继发癌症(…     

Promoting Father Involvement for Child and Family Health

Paternal involvement in children's lives is associated with a variety of child outcomes, including improved cognition, improved mental health, reduced obesity rates, and asthma exacerbation. Given this evidence, the American Academy of Pediatrics has promoted actions by pediatricians to engage fathers in pediatric care. Despite these recommendations, the mother–child dyad, rather than the mother–father–child triad, remains a frequent focus of care. Furthermore, pediatric care is often leveraged to improve maternal health, such as screening for maternal depression, but paternal health is infrequently addressed even as men tend to exhibit riskier behaviors, poorer primary care utilization, and lower life expectancy. Therefore, increasing efforts by pediatric clinicians to engage fathers may affect the health of both father and child. These efforts to engage fathers are informed by currently used definitions and measures of father involvement, which are discussed here. Factors described in the literature that affect father involvement are also summarized, including culture and context; interpersonal factors; logistics; knowledge and self-efficacy; and attitudes, beliefs, and incentives. Innovative ways to reach fathers both in the clinic and in other settings are currently under investigation, including use of behavior change models, motivational interviewing, mobile technologies, peer support groups, and policy advocacy efforts. These modalities show promise in effectively engaging fathers and improving family health.     

A one-day, dispense-only IP-One HTRF assay for high-throughput screening of Galphaq protein-coupled receptors: towards cells as reagents

Abstract: Compared to biochemical high-throughput screening (HTS) assays, cell-based functional assays are generally thought to be more time consuming and complex because of additional efforts for running continuous cell cultures as well as the numerous assay steps when transferring media and compounds. A common strategy to compensate the anticipated reduction in overall throughput is to implement highly automated cell culture and screening systems. However, such systems require substantial investments in sophisticated hardware and highly specialized personnel. In trying to set up alternatives to increasing throughput in functional cell-based screening, we combined several approaches. By using (1) cryopreserved cell aliquots instead of continuous cell culture, (2) cells in suspension instead of adherent cells, and (3) "ready-to-screen" assay plates with nanoliter aliquots of test compounds, an assay procedure was developed that very much resembles a standard biochemical, enzymatic assay comprising only a few dispense steps. Chinese hamster ovary cells stably overexpressing a Galphaq-coupled receptor were used as a model system to measure receptor activation by detection of intracellular D-myo-inositol 1-phosphate with the help of homogeneous time-resolved fluorescence (HTRF, CISbio International, Bagnols-sur-Cèze, France). Initially established in 384-well adherent cell format, the assay was successfully transferred to 1,536-well format. The assay quality was sufficient to run HTS campaigns in both formats with good Z'-factors and excellent reproducibility of antagonists. Subsequently, the assay procedure was optimized for usage of suspension cells. The influences of cell culture media, plate type, cell number, and incubation time were assessed. Finally, the suspension cell assay was applied to pharmacological characterization of a small molecule antagonist by Schild plot analysis. Our data demonstrate not only the application of the IP-One HTRF assay (CISbio International) for HTS in a high-density format, but furthermore the successful use of cryopreserved and suspension cells in a one-day functional cell-based assay.