Crosstalk between tumor and endothelial cells promotes tumor angiogenesis by MAPK activation of Notch signaling.

While significant progress has been made in understanding the induction of tumor vasculature by secreted angiogenic factors, little is known regarding contact-dependent signals that promote tumor angiogenesis. Here, we report that the Notch ligand Jagged1 induced by growth factors via mitogen-activating protein kinase (MAPK) in head and neck squamous cell carcinoma (HNSCC) cells triggered Notch activation in neighboring endothelial cells (ECs) and promoted capillary-like sprout formation. Jagged1-expressing HNSCC cells significantly enhanced neovascularization and tumor growth in vivo. Moreover, the level of Jagged1 was significantly correlated with tumor blood vessel content and associated with HNSCC development. Our results elucidate a novel mechanism by which the direct interplay between tumor cells and ECs promotes angiogenesis through MAPK and Notch signaling pathways.

Well-patterned metal-semiconductor interface improving contact conductance.

In an aluminum/silicon system, contact conductance (Gc) and Al crystallization can improve by using the hole array on Si, which is built by electron-beam lithography, and increase with decreasing hole size; this improves Gc from 0.004 microS to 13.390 microS. TEM results show Al crystals located inside and near the holes. The ratio of the total Al grain area over the pad area, defined in short form as Ac, is improved from 0.007 to 0.359. An experimental model demonstrates that Gc is proportional to Ac, divided by the square of the interfacial oxygen content. The well-known Al/Si system, chosen as a vehicle, verifies this paper's methodology and provides an alternative to a highly doped or annealing process for Gc improvement. Most significantly, it yields a more robust and well-controlled interface and overcomes obstacles in the newly introduced material system. It also addresses devices with the size narrowed into the deep nanoscale domain. The methodology prevents an inherently non-planar Al/Si interface.

Families with high-risk characteristics and diagnoses of attention-deficit/hyperactivity disorder, autism spectrum disorder, intellectual disability, and learning disability in children: A national birth cohort study.

Background: A national birth cohort study was used to investigate whether high-risk family factors at 1.5-year-olds can increase the risk of attention-deficit/hyperactivity disorder (ADHD) diagnosis when children reach 5.5 years. The pathway relationship of high-risk family factors, children's developmental conditions, risk of autism spectrum disorder (ASD), and diagnosis of intellectual disability (ID), learning disability (LD), and ASD was also investigated. Methods: The 1.5-, 3- and 5.5-year-old Taiwan Birth Cohort Study (TBCS) dataset was used (N = 19,185). The high-risk familial factor was measured using five questions assessing whether parents are currently unmarried, unemployed, do not have any social insurance, perceive a "very heavy" economic childcare burden, and at least one of the parents has a disability certification. Developmental conditions were assessed using the Taiwan Birth Cohort Study-Developmental Instrument (TBCS-DI), and ASD risk was measured using the Modified Checklist of Autism in Toddlers. Data on ADHD, ID, LD, and ASD diagnoses were collected at age 5.5. The odds ratio model investigated whether children from families with high-risk factors at 1.5-years were at increased risk of ADHD, ID, LD, or ASD diagnosis at 5.5-years, compared to those children from families without such risks. Structural equation modeling investigated the logistic regression pathway relationship of high-risk familial characteristics, children's developmental conditions, autism screening, and diagnosis. Results: In the national birth cohort dataset of 19,185 children, 2070 (10.8%) met at least one of the high-risk familial factors. Children who met one high-risk familial factor had a 1.21-fold increased risk for ADHD diagnosis, 1.36-fold increased risk for LD diagnosis, and 1.80-fold increased risk for ASD diagnosis, compared to children from families without risks. High-risk familial factors directly increased the risk of ADHD and ID diagnosis, and indirectly increased the risk of ADHD, ID, LD, and ASD diagnosis through the mediating factor of children's development. Conclusions: Children who met more high-risk familial characteristics were at higher risk of ADHD, ID, LD, and ASD diagnosis. Development at three years was predictive of diagnosis at 5.5 years. Thus, developmental screening at age three is vital for interventions. Preventive, family-focused, and/or child-rearing services for at-risk families are important for improving outcomes for these children and their families.

Outcomes of assisted reproductive techniques for HIV-1-discordant couples using thawed washed sperm in Taiwan: comparison with control and testicular sperm extraction/microscopic epididymal sperm aspiration groups.

BACKGROUND/PURPOSE: An increasing number of human immunodeficiency virus-1 (HIV-l)-discordant couples in Taiwan have been seeking fertility help. We conducted the first clinical trial in Taiwan of assisted reproductive technology (ART) using sperm washing and viral load measurement. METHODS: From 2005 to 2009, we performed 22 ART cycles on 14 HIV-1-discordant couples. The sperm washing involved density gradient centrifugation followed by swim-up method. HIV-1 RNA was checked by real-time reverse transcription-polymerase chain reaction with a sensitivity of 40 copies/mL. In addition, we enrolled two other groups of ART recipients using frozen sperm to compare the clinical outcomes. RESULTS: There were five pregnancies in the fresh cycles (23.8%) of HIV-1-discordant couples and the cumulative pregnancy per couple was 42.9% (6/14). The data were comparable with normal controls and testicular sperm extraction/microscopic epididymal sperm aspiration groups. The nine babies and the 14 women in this study showed no seroconversion. CONCLUSION: The preliminary data showed good ART results in HIV-1-discordant couples. Fertility services should not be withheld from individuals with HIV-1, although larger series are needed to reach conclusions about safety.

Optimal modeling for phase I design of a two drug combination-results of a phase I study of cisplatin with 9-nitrocamptothecin.

Combination of platinum with topoisomerase-I inhibitors are synergistic. The objectives of this study were to determine MTD range and toxicity profile of combinations of oral 9-nitrocamptothecin (9NC) and intravenous cisplatin in patients with refractory solid tumors. Each course was 28 days starting on day 1 with cisplatin, and then 9NC daily for 5 days/week for three weeks. A new two arm crossing design was created: patients in arm 1 were treated with at the single agent recommended dose of cisplatin (50 mg/m(2)), and increasing doses of 9NC and in arm 2 with the single agent recommended dose of 9NC (1.5 mg/day) and increasing dose of cisplatin. Once a dose limiting toxicity was observed, the dose of the escalated drug was decreased by one level, and the fixed-dose drug was then escalated. A 3 + 3 design was used. Eligibility criteria were standard for a phase I trial. Pharmacokinetics was performed. Eighteen patients were treated on Arm 1, 3 at the crossing level, and 33 on Arm 2. Dose limiting toxicities were gastrointestinal at the crossing dose level. After crossing, prolonged grade 3 thrombocytopenia was the DLT in arm 1, and grade 4 neutropenia in Arm 2. Only one patient with ovarian cancer had a partial remission, and 12 patients had disease stabilization (24% of clinical benefit). A Bayesian optimal dose finding was tested post-facto. The recommended doses for phase II studies by the 3 + 3 design are cisplatin 60 mg/m(2) and 9NC 1.25 mg/day and cisplatin 40 mg/m(2) and 9NC 2.0 mg/day. The Bayesian optimal dose finding suggested a different solution, closest to that of the latter dosing which may be less toxic.

[Construction of eukaryotic expression plasmid pSecTag2B-msBlyS expressing mouse soluble B lymphocyte stimulator].

OBJECTIVE: The purpose of this study was to clone the soluble form of the mouse BlyS (msBlyS) and insert it into a eukaryotic expression vector pSecTag2B in order to further elucidat the antitumor activity induced by msBlyS expressed by the recombined plasmid pSecTag2B-msBlyS. METHODS: Full length cDNA of mouse soluble BlyS (msBlyS) was amplified by reverse transcription-PCR from total RNA of mouse spleen. The PCR product was ligated directly with linearized vector pCR2.1 supplied in the TA cloning kit. The recombined plasmid pCR2.1-msBlyS which was selected and identified using blue-white screening method and restriction map analysis and the purified original plasmid pSecTag2B were both cut by HindIII and EcoR I. The digested fragments were extracted and purified from low-melting temperature agarose and ligated by T4DNA ligase. The recombined plasmid pSecTag2B-msBlyS were isolated and identified by restricted endonuclease cutting and Sanger dideoxy DNA sequencing. RESULTS: The sequencing data indicated that inserted msBlyS gene had correct DNA sequence and orientation. CONCLUSION: Eukaryotic expression vector pSecTag2B. Expressing mouse BlyS have successfully been cloned. This will provide us an opportunity to do further research work on BlyS.

Granulocyte colony stimulation factor (G-CSF) suppresses interleukin (IL)-12 and/or IL-2 induced interferon (IFN)-gamma production and cytotoxicity of decidual mononuclear cells.

PROBLEM: The placenta is one of the few non-hematopoietic tissues to express granulocyte colony stimulation factor (G-CSF). Placental G-CSF production is considered to be one of the major causes of granulocytosis during pregnancy although its physiological role in pregnancy has not yet been examined. METHOD OF STUDY: The effects of G-CSF on interleukin (IL)-2 and/or IL-12 induced interferon (IFN)-gamma production of magnetic cell sorting (MACS) sorted decidual lymphocytes was examined by enzyme-linked immunosorbent spot-forming cell assay (ELISPOT). The effect of G-CSF on cytotoxicity of decidual lymphocytes against the choriocarcinoma cell line JEG-3 was examined by lactate dehydrogenase (LDH) release assay. RESULTS: As previously reported by us, IL-2 and/or IL-12 activated decidual mononuclear cells were capable of killing choriocarcinoma cells. We observed that G-CSF abolished IFN-gamma production and cytotoxicity of decidual mononuclear cells and MACS sorted CD56+ cells. CONCLUSIONS: In addition to its well-known trophic effects on hematopoiesis, our results suggest about new roles of G-CSF in reproductive immunology.