Molecular targeted therapy for advanced hepatocellular carcinoma

Systemic anticancer therapy for hepatocellular carcinoma (HCC) is limited by intrinsic drug resistance and accompanying liver dysfunction. However, recent advances in molecular targeted therapy (MTT) have shed light on the treatment of advanced HCC. A recent randomized, placebo-controlled trial demonstrated that sorafenib, a multi-target tyrosine kinase inhibitor, prolonged overall survival and time-to-progression in patients with advanced HCC. This breakthrough highlights the potential of MTT targeting hepatocarcinogenic pathways, such as the Raf/MAPK/ERK pathway, angiogenic pathways and the EGFR signaling pathway. This review discusses the current status and the potential of developing novel MTTs for advanced HCC.     

Increased expression of MHC class II antigens in rejecting canine lung allografts

Expression of major histocompatibility complex class II antigens was investigated in the normal lungs and in lung allografts of mongrel dogs after single-lung transplantation. Cryostat sections were stained with an indirect immunoperoxidase technique that used B1F6 and 7.5.10.1 as anti-MHC class II monoclonal antibodies. In the normal lungs and native lungs of the recipient dogs after single-lung transplantation, only some cells of lymphoid tissue and macrophages/dendritic cells were MHC class II-positive. During acute rejection, increased infiltration with MHC class II-positive cells in perivascular, peribronchial, and interstitial areas and intraalveolar spaces was found in lung allografts. In addition, expression of MHC class II antigens was induced on the bronchial epithelium and vascular endothelium. Induced expression of MHC class II antigens on the bronchial epithelium and vascular endothelium in rejecting lung allografts was found as early as two days after single-lung transplantation. The intensity of MHC class II antigen expression on bronchial epithelium and vascular endothelium in graft lungs increased with the progression of rejection response and directly correlated with the bronchoalveolar lavage fluid (BALF) levels of biochemical markers, as tumor necrosis factor alpha, gamma-interferon (IFN-gamma), interleukin 2 (IL-2) and soluble interleukin 2 receptor (SIL-2R). Abnormal expression of MHC class II antigens on bronchial epithelium and vascular endothelium and abnormal elevation of BALF levels of the cytokines in lung allografts could be prevented by cyclosporine (CsA) treatment. Our results suggested that MHC class II antigen expression could be induced on the bronchial epithelium and vascular endothelium of canine lung allografts during acute rejection. This abnormal expression of MHC class II antigens on bronchial epithelium and vascular endothelium of graft lungs may serve as a specific index for diagnosis of lung allograft rejection when infection as an inducing factor can be excluded. Furthermore, bronchial epithelium and vascular endothelium of lung allografts have become MHC class II-positive, and are likely to be the targets for low-grade rejection, resulting in the development of bronchiolitis obliterans and occlusive vascular disease in lung allografts.     

Dose-rate scaling factor estimation of THOR BNCT test beam.

In 1998, an epithermal neutron test beam was designed and constructed at the Tsing Hua Open-Pool Reactor (THOR) for the purpose of preliminary dosimetric experiments in boron neutron capture therapy (BNCT). A new epithermal neutron beam was designed at this facility, and is currently under construction, with clinical trials targeted in late 2004. Depth dose-rate distributions for the THOR BNCT test beam have been measured by means of activation foil and dual ion chamber techniques. Neutron and structure-induced gamma spectra measured at the test beam exit were configured into a source function for the Monte Carlo-based treatment planning code NCTPlan. Dose-rate scaling factors (DRSFs) were determined to normalize computationally derived dose-rate distributions with experimental measurements in corresponding mathematical and physical phantoms, and to thus enable accurate treatment planning using the NCTPlan code. A similar approach will be implemented in characterizing the new THOR epithermal beam in preparation for clinical studies. This paper reports the in-phantom calculated and experimental dosimetry comparisons and derived DRSFs obtained with the THOR test beam.     

4-Aminopyridine induces the release of neuropeptide Y (NPY) to produce an atropine- and tetrodotoxin-resistant contraction in rabbit isolated jejunum

4-Aminopyridine (4-AP) induced an atropine- and tetrodotoxin (TTX)-insensitive contraction (resistant contraction), in a concentration-dependent manner, in the isolated jejunum of rabbits. The failure of specific antagonists of histamine, serotonin and substance P to affect this resistant contraction ruled out the participation of histamine, serotonin and/or substance P. Antiserum against neuropeptide Y (NPY) reduced this resistant contraction in a concentration-dependent manner and inhibited the action of 4-AP totally at a high concentration (1.25% dilution) whereas normal serum lacked this ability. This suggested that the release of NPY was involved in this 4-AP-induced resistant contraction. Radioimmunoassay of NPY-like immunoreactivity in isolated synaptosomal preparations indicated that 4-AP possessed the ability to induce the release of NPY. However, guanethidine did not affect the actions of 4-AP, indicating that NPY is released mainly from non-adrenergic nerves. Our results indicate that 4-AP induces the release of NPY from non-adrenergic nerves to produce an atropine- and TTX-resistant contraction in the isolated jejunum of rabbits.     

Synergistic effects of Nell-1 and BMP-2 on the osteogenic differentiation of myoblasts.

Osteogenesis is synergistically enhanced by the combined effect of complimentary factors. This study showed that Nell-1 and BMP-2 synergistically enhanced osteogenic differentiation of myoblasts and phosphorylated the JNK MAPK pathway. The findings are important because of the osteochondral specificity of Nell-1 signaling and the potential therapeutic effects of coordinated BMP-2 and Nell-1 delivery. INTRODUCTION: BMPs play an important role in the migration and proliferation of mesenchymal cells and have a unique ability to alter the differentiation of mesenchymal cells toward chondrogenic and osteogenic lineages. Signaling upstream of Cbfa1/Runx2, BMPs effects are not limited to cells of the osteoblast lineage. Thus, additional osteoblast-specific factors that could synergize with BMP-2 would be advantageous for bone regeneration procedures. NELL-1 (NEL-like molecule-1; NEL [a protein strongly expressed in neural tissue encoding epidermal growth factor like domain]) is a novel growth factor believed to preferentially target cells committed to the osteochondral lineage. MATERIALS AND METHODS: C2C12 myoblasts were transduced with AdLacZ, AdNell-1, AdBMP-2, or AdNell-1+AdBMP-2 overexpression viruses. Effects were studied by cell morphology, alkaline phosphatase activity, osteopontin production, and MAPK signaling. Additionally, in a nude mouse model, viruses were injected into leg muscles, and new bone formation was examined after 2 and 8 wk. RESULTS: C2C12 myoblasts co-transduced with AdNell-1+AdBMP-2 showed a synergistic effect on osteogenic differentiation as detected by alkaline phosphatase activity and osteopontin production. Nell-1 stimulation on AdNell-1 + AdBMP-2 preconditioned C2C12 cells revealed significant activation of the non-BMP-2 associated c-Jun N-terminal kinase (JNK) MAPK signaling pathway, but not the p38 or extracellular signal-regulated kinase (ERK1/2) MAPK pathways. Importantly Nell-1 alone did not induce osteogenic differentiation of myoblasts. In a nude mouse model, injection of AdNell-1 alone stimulated no bone formation within muscle; however, injection of AdNell-1+AdBMP-2 stimulated a synergistic increase in bone formation compared with AdBMP-2 alone. CONCLUSIONS: These findings are important because of the confirmed osteochondral specificity of Nell-1 signaling and the potential therapeutic effects of enhanced BMP-2 action with coordinated Nell-1 delivery.     

Pharmacy Fill Patterns in Young Urban Children with Persistent Asthma

Background. Medication adherence impacts healthcare utilization. Pharmacy records are useful to establish fill patterns. Objective. Use pharmacy records to establish medication patterns fill patterns for comparison to healthcare utilization. Methods. Pharmacy records of 175 children with persistent asthma were collected and compared to healthcare utilization. Results. Majority of subjects had significant healthcare utilization, low numbers of rescue medications, and poor controller medication fill rates. Those with more rescue medications had more healthcare utilization and more controller medications. Conclusions. Pharmacy fill patterns demonstrate few rescue and/or controller medication fills. Those with more rescue medications reported increased healthcare utilization despite controller medications.     

The use of the facial translocation technique in the management of tumors of the paranasal sinuses and skull base.

OBJECTIVE: We sought to assess the efficacy of facial translocation in the management of tumors of the skull base and paranasal sinuses. STUDY DESIGN AND SETTING: From July 1993 to December 1999, 75 patients, aged 3 to 102 years old, underwent facial translocation. Thirty-three (44%) patients also underwent a combined neurosurgical procedure. Nineteen (25%) had previous surgery. These patients were followed up to 6 years. RESULTS: There were 21 benign and 54 malignant tumors. There were no perioperative deaths. The morbidity rate was 31%. Of the 54 patients with malignant tumors, the actuarial 3-year survival rate was 59%, whereas the local control rate was 54%. CONCLUSION: The facial translocation technique offers favorable exposure of the critical zones of the anterior and middle cranial base, thus facilitating extensive resection and reconstruction. SIGNIFICANCE: This study demonstrates that facial translocation is one of the best surgical approaches to the skull base.     

Family Functioning and Social Support in the Adaptation of Caregivers of Children With Sickle Cell Syndromes

Objective: To examine moderating effects of family functioningand social support on the relationship of child-related stressorsto caregivers' psychological adaptation in a sample of caregiversof children with a chronic illness. Method: Participants were 67 caregivers of children and adolescentswith sickle cell syndromes. We conducted MANOVAs and subsequenteffect size calculations to determine if family functioningwould buffer the effects of caring for difficult-to-manage childrenwith this illness. Results: Findings supported a moderator effect of family functioningon the association of children's externalizing behavioral problemsto caregivers symptoms of hostility. Greater levels of cohesiveand adaptive family functioning buffered the potential detrimentaleffects of caring for children perceived as hard to manage.No significant associations were obtained between measures ofcaregivers' psychological adaptation and the severity of theirchildren's disease. Conclusions: We make recommendations for family systems interventions,particularly for caregivers of children with behavior problems.     

The epidemiology and surveillance of blood lead in Taiwan (R.O.C.): A report on the PRESS-BLL project

 To monitor the lead hazards in industries and to investigate the prevalence of elevated blood lead levels (BLLs) in lead-exposed workers, a lead surveillance system (PRESS-BLLs) has been established and operated in Taiwan, Republic of China, since July 1993. A cohort of lead-exposed workers who received a periodic annual health examination at 55 accredited hospital laboratories was constructed. A total of 9807 separate BLL measurements were reported to the system in 1994. The mean BLL was 15.8 μg/dl in male workers and 11.6 μg/dl in female workers. The mean BLL of lead-exposed workers was significantly (P<0.05, z-test) higher than that of the general Taiwanese population (8.6 μg/dl for males and 6.7 μg/dl for females). In addition, the BLLs of 983 (10.0%) workers exceeded the regulatory action level (40 μg/dl for males; 30 μg/dl for females). The workplaces and homes of 57% of the workers with elevated BLLs were thoroughly investigated to determine the sources of lead contamination. These actions identified the causes of elevated BLLs and set up strategies to reduce workers’ lead exposure. The establishment of this occupational lead surveillance system represents a method for monitoring of lead hazards from occupational and environmental settings to prevent lead poisoning. The information acquired from the system can help in the setting up of a priority of prevention and the development of control measures. It is also useful for further monitoring of changes in the BLLs of the lead-exposed-worker cohort. The Health Department of Taiwan can use this information to evaluate the effectiveness of current industrial hygiene practice. Subjects with elevated BLLs have been medically treated and placed on long-term follow-up for sequelae. Received: 2 September 1996/Accepted: 29 November 1996