The use of natural interferon alpha conjugated to a monoclonal antibody anti mammary epithelial mucin (Mc5) for the treatment of human breast cancer xenografts

Summary An immunoconjugate composed of natural interferon (nIFN) bound in a noncleavable fashion to a monoclonal antibody (MoAb) recognizing a breast epithelial membrane mucin (Mc5) was used to treat xenografts of a human mammary carcinoma cell line (MCF-7) growing in nude mice. The immunoconjugate (nIFN/Mc5) was administered as 20 intralesional (i.l.) injections to 1 of 2 xenografts in each animal. It was found that nIFN/Mc5 produced a significant enhancement of the growth inhibitory actions of nIFN on the injected tumors. Further enhancement was obtained when nIFN or nIFN together with Mc5 (at a dose 10 times larger than that present in nIFN/Mc5) were added to the immunoconjugate. Biodistribution experiments showed that the uptake of¹²⁵I-nIFN/Mc5 by the tumors was greater and its elimination slower than for¹²⁵I-nIFN alone or conjugated to irrelevant mouse IgG₁. In addition, the immunoconjugate up-regulated the antigenic expression of a breast epithelial membrane mucin by the carcinoma cells, an up-regulation which was not significantly different from that produced by nIFN alone. The contralateral noninjected tumors exposed to systemic levels of the immunoconjugate showed an enhancement of antitumor effects, but to a lesser extent than the injected tumors. These findings suggest that the enhancement of the growth inhibitory action of the immunoconjugate was related to the specific binding of Mc5 which targeted the IFN to the carcinoma cells and impeded its elimination. It is likely that the targeting was favored by the IFN-mediated up-regulation of antigenic expression by the carcinoma cells, thereby producing a cascade of interrelated effects. The results of this study point out the feasibility and potential usefulness of IFN treatment by means of immunoconjugates as well as the worth of pursuing and improving this form of therapy.     

Parent Expectations of the School Health Program in Nebraska

This article presents findings from the first phase of a comprehensive evaluation plan for the school health program in Nebraska public schools. The evaluation utilized the Targeting Outcomes of Programs (TOP) framework to gather parents' perspectives about the benefits of the school health program, and a ranking of important health activities and role providers. A survey was distributed to 1,200 parents randomly selected from 60 school districts. Of these, 450 (38%) were returned: 96% supported funding of health programs; 88% believed families benefited from school health; 92% viewed the health programs as "essential" to the educational mission; 64% preferred a ratio of 1 nurse/500 students; and 89% believed all students needed access to a professional school nurse. The nurse was the only clearly defined role in the health program and had activities rated as "extremely important." Results were reported to the Nebraska legislature for support of state funding for school health nursing.     

Interrater reliability levels of multiple clinical examiners in the evaluation of a schizophrenic patient: quality of life, level of functioning, and neuropsychological symptomatology

Sir Ronald Fisher used a single-subject design to derive the concepts of appropriate research design, randomization, sensitivity, and tests of statistical significance. The seminal work of Broca demonstrated that valid and generalizable findings can and have emerged from studies of a single patient in neuropsychology. In order to assess the reliability and/or validity of any clinical phenomena that derive from single subject research, it becomes necessary to apply appropriate biostatistical methodology. The authors develop just such an approach and apply it successfully to the evaluation of the functioning, quality of life, and neuropsychological symptomatology of a single schizophrenic patient.     

Prostate Specific Antigen Cleaves Parathyroid Hormone-Related Protein in the PTH-like Domain: Inactivation of PTHrP-Stimulated cAMP Accumulation in Mouse Osteoblasts

Purpose

To determine whether parathyroid hormone-related protein (PTHrP) is a substrate of prostate-specific antigen (PSA) and how the biological activity of PTHrP may be altered by cleavage with PSA.

Materials and Methods

Prostate-specific antigen cleavage of recombinant human PTHrP 1-141 was conducted in vitro at 37C and analyzed by SDS-PAGE. Five rounds of automated amino-terminal amino acid sequence analysis were performed on blotted PSA-cleaved PTHrP peptide fragments to determine the PSA cleavage sites. The mouse osteoblast cell line MC3T3-E1 was used to test whether PSA cleavage of PTHrP 1-141 altered its ability to stimulate cAMP production.

Results

Prostate-specific antigen was found to specifically cleave PTHrP 1-141 in a time- and dose-dependent manner. Cleavage of PTHrP 1-141 by PSA generated fragments on Coomassiestained acrylamide gels that migrated with mobilities that corresponded to 19.5, 17, 15 and less than 7 kd. The preferred PSA cleavage site of PTHrP 1-141 was determined to be at the carboxyl-terminus of phenylalanine 23, consistent with chymotryptic-like enzymatic activity of PSA. Cleavage of PTHrP by PSA completely abolished the ability of PTHrP to stimulate cAMP production.

Conclusions

Cleavage of PTHrP 1-141 by PSA carboxyl-terminal to phenylalanine 23 represents a unique pattern of PTHrP processing that may be specific to the prostate. Prostate-specific antigen inactivation of the cAMP-inducing activity of PTHrP 1-141 demonstrates that PSA cleavage regulates the biological activity of PTHrP. These results have implications for the role of PTHrP in prostate cancer metastasis to bone and its subsequent regulation of bone remodeling Study of the biological activities of the PSA-generated PTHrP peptides identified in this study merits further investigation.     

Huntington's Disease — Imbalance of free amino acids in the cerebrospinal fluid of patients and offspring at-risk

Summary A total of 27 different amino acids were determined in the fasting, morning lumbar CSF of 12 patients with Huntington's Disease (HD), 8 at-risk offspring and 16 non-choreic control patients. A significant (P<0.001) decrease was observed for asparagine, isoleucine, leucine, phenylalanine, histidine, arginine, -aminoadipic acid and homocarnosine in patients with HD compared to the non-choreic controls. Only tyrosine was increased in HD. These alterations were to an extent more pronounced in 5 neurophysiologically conspicuous offspring. The alterations suggest that amino acid imbalance is an early metabolic disturbance in HD.

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Zusammenfassung Bei 12 Patienten mit manifester Huntingtonscher Krankheit (HD), 8 nicht erkrankten Nachkommen und 16 nicht choreatischen Kontrollpatienten wurden 27 verschiedene Aminosäuren im Liquor cerebrospinalis (nüchterner Lumballiquor) untersucht. Asparagin, Isoleucin, Leucin, Phenylalanin, Histidin, Arginin, -Aminoadipinsäure und Homocarnosin waren signifikant (P<0.001) erniedrigt bei Patienten gegenüber den Kontrollen. Diese Veränderungen waren bei 5 neurophysiologisch auffälligen Nachkommen teilweise ausgeprägter, was für eine frühzeitige metabolische Störung spricht. Tyrosin war als einzige Aminosäure erhöht. Die Veränderungen sprechen für eine Aminosäurenimbalanz bei Huntingtonscher Krankheit, deren Bedeutung besprochen wird.

     

Haptoglobin-alpha subunit as potential serum biomarker in ovarian cancer: identification and characterization using proteomic profiling and mass spectrometry.

PURPOSE: The objective of this study was to identify and characterize new serum biomarkers in ovarian cancer patients using mass spectrometric protein profiling and specific immunological assays. Experimental Design: Serum samples from 80 cancer patients and 91 healthy women were analyzed by surface enhanced laser desorption and ionization-mass spectrometry (MS) profiling. A candidate biomarker was purified by affinity chromatography, and its sequence was determined by liquid chromatography-tandem MS. An antibody was generated from the synthesized peptide for quantitative validation in the cases and controls. CA125 was determined and compared with the same set of specimens. RESULTS: Using surface enhanced laser desorption and ionization, we found a serum biomarker at approximately 11700 Da, which had peak intensity significantly higher in cases (1.366) compared with controls (0.208, P = 0.002), and subsequently identified this as the alpha chain of haptoglobin. ELISA indicated that Hp-alpha was 相似文献   

Hypertension secondary to progressive vascular neurofibromatosis

A 4 year old girl with neurofibromatosis type 1 (NF1) was referred for hypertension. An aortogram showed narrowing of the left main renal artery. An angiogram three and a half years later showed coarctation of the abdominal aorta. She underwent aortoplasty but the stenosis recurred. Vascular involvement in NF1 may be progressive and requires long term follow up.