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At least 289 records · Page 16Linked to original sources
PubMed2003

Immuno-gene therapy of established prostate tumors using chimeric receptor-redirected human lymphocytes.

Targeted adoptive immunotherapy is an attractive option for prostate cancer given its accessible primary location, the presence of specific tissue and tumor antigens, and the acceptability of collateral destruction of healthy prostrate tissue. The "T-body" approach, which uses genetically programmed, patient-derived lymphocytes transfected with chimeric receptor genes, combines the effector functions of T lymphocytes and natural killer cells with the ability of antibodies to recognize predefined surface antigens with high specificity and in a non-MHC restricted manner. We evaluated the therapeutic efficacy of anti-erbB2 chimeric receptor-bearing human lymphocytes on human prostate cancer xenografts in a SCID mouse model. Local delivery of erbB2-specific T bodies to well-established s.c. and orthotopic tumors, together with systemic administration of interleukin-2, resulted in retardation of both tumor growth and prostate-specific antigen secretion, prolongation of survival, and complete tumor elimination in a significant number of mice. These preclinical studies demonstrate the therapeutic potential of the T-body approach for locally advanced or recurrent prostate cancer as an adjunct to, or after, conventional therapy.

Adenocarcinoma↗
PubMed2002

Activation of APCs through CD40 or Toll-like receptor 9 overcomes tolerance and precipitates autoimmune disease.

Some autoreactive T cells normally escape thymic selection and persist in the periphery. This is true of myelin-reactive CD4(+) T cells, the effectors of experimental autoimmune encephalomyelitis (EAE) in laboratory animals and the presumed mediators of multiple sclerosis in humans. Nonetheless, most individuals do not succumb to autoimmune disease. There is growing evidence that while peripheral APCs stimulate immune responses against foreign Ags in the setting of tissue destruction and "danger," they actually maintain tolerance against self Ags under steady state conditions. We hypothesized that tolerance against candidate autoantigens could be reversed by activation of APCs via CD40 or Toll-like receptor 9 signaling. Adult SJL mice injected i.p. with a peptide fragment of proteolipid protein (a candidate autoantigen in multiple sclerosis) emulsified in IFA fail to mount lymphoproliferative or cytokine responses and are protected from EAE upon subsequent challenge with the Ag combined with adjuvants. Here we report that tolerized proteolipid protein-specific lymph node cells regain the ability to divide, differentiate along a Th1 lineage, and transfer EAE when reactivated in the presence of agonistic Abs against CD40 or CpG oligonucleotides. The effects of both anti-CD40 and CpG oligonucleotides are dependent upon induction of IL-12. Our findings suggest two mechanisms to explain the well-documented association between infectious illnesses and flare-ups of multiple sclerosis. Microbial pathogens could 1) release molecules that bind Toll-like receptors, and/or 2) stimulate microbe-specific T cells to express CD40 ligand, thereby licensing APCs that bear both microbial and autoantigens to break tolerance.

Abatacept↗
PubMed1991

Transcription factor AP2 and its role in epidermal-specific gene expression.

The epidermis is a stratified squamous epithelium whose major differentiation-specific products are keratins. To elucidate factors controlling keratinocyte-specific gene expression, we previously identified proximal and distal regulatory elements that act synergistically to drive keratinocyte-specific expression of the gene encoding human epidermal keratin K14. Control by the proximal element is mediated by a transcription factor, KER1, which is more abundant in nuclear extracts of keratinocytes than in extracts of other cell types, including fibroblasts, lymphocytes, and simple epithelial cells. In this report, we identify this factor as transcription factor AP2, shown to be transcribed in cells of epidermal and neural crest lineages. Furthermore, we demonstrate functional AP2 binding sites upstream from three additional epidermal genes, suggesting that AP2 may be generally involved in epidermal gene regulation. Finally, although AP2 is necessary, it is not sufficient for epidermal gene expression: a distal element contributes to tissue-specific expression of the human keratin K14 gene as judged by its ability to enhance expression of a heterologous promoter in keratinocytes but not in hepatoma cells. These results imply that a combination of factors is likely to contribute to epidermal-specific expression of the human keratin K14 gene.

Base Sequence↗
PubMed1993

Analysis of production, purification, and cytolytic potential of bi-specific antibodies reactive with ovarian-carcinoma-associated antigens and the T-cell antigen CD3.

OV-TL3 and MOv 18 MAbs, due to their restricted specificity, have been successfully used to visualize ovarian cancer in patients and might therefore be used to develop therapies for ovarian cancer. The bi-specific MAbs alpha T3/OC2 and alpha OC/TR (both being combinations of MOv18 and alpha CD3) have been shown to lyse ovarian tumor cells in vitro. To evaluate the relative merits of MOv18/CD3 and OV-TL 3/CD3, the present study was undertaken in which the bi-specific MAbs alpha T3/OC2 and alpha OC/TR, and a newly developed bi-specific MAb, OV-TL 3/CD3, were highly purified and compared for specificity, stability, purification and cytolytic potential. The dual specificity of the hybrid-hybridoma supernatants was analyzed by immunohistochemistry, and by testing bi-specific MAb-mediated cytotoxicity against relevant target cells in the presence of effector cells. Stability testing of bi-specific MAb-producing hybridomas showed that, after sub-cloning, clones stably produced up to 40% bi-specific MAb even after prolonged in vitro culture. The purification of the bi-specific fractions was performed with protein A and by ion-exchange high-pressure liquid chromatography, depending on the sub-class combination of the bi-specific MAb. The purified bi-specific MAbs were tested for their ability to mediate target-cell lysis with the use of cytotoxic T-cell clones and activated peripheral-blood lymphocytes. The purified alpha T3/OC2, alpha OC/TR, and OV-TL3/CD3 were all able to mediate highly specific lysis of various ovarian-carcinoma cell lines. No correlation was found between the level of antigen expression and bi-specific MAb-mediated cytolysis.

Antibodies, Monoclonal↗
PubMed2006

Successful tumor eradication was achieved by collaboration of augmented cytotoxic activity and anti-angiogenic effects following therapeutic vaccines containing helper-activating analog-loaded dendritic cells and tumor antigen DNA.

We reported previously that pigeon cytochrome c-derived peptides (Pan-IA), which bind broad ranges of MHC class II molecules efficiently, activate T helper (Th) function in mice. In an experimental model, Pan-IA DNA vaccines augmented antitumor immunity in tumor antigen-immunized mice. To elicit more potent antitumor immunity and to eradicate tumors in a therapeutic setting, Pan-IA-loaded dendritic cells (DCs) were inoculated in combination with vaccines including ovalbumin (OVA) antigen DNA in tumor-bearing mice. Seventy percent of the immunized mice survived tumor-free for at least 4 months after treatment. In contrast, mice vaccinated with OVA DNA, either with or without naïve DCs, did not eliminate the tumors and died within 5 weeks. Only in mice vaccinated with OVA DNA and Pan-IA-loaded DCs were both cytotoxic and helper responses specific for OVA induced at the spleen and tumor sites as well as at the vaccination sites. Furthermore, accumulation of OVA-specific CD4(+) and CD8(+) T lymphocytes and interferon-gamma-mediated anti-angiogenesis were observed in the tumors of these mice. Thus, the combined vaccination primed both tumor-specific cytotoxicity and helper immunity resulting in augmented tumor lysis ability and anti-angiogenic effects. This is the first report to show that most established tumors were successfully eradicated by collaboration of potent antitumor immunity and anti-angiogenic effects by vaccination with tumor antigens and helper-activating analogs. This novel vaccination strategy is broadly applicable, regardless of identifying helper epitopes in target molecules, and contributes to the development of therapeutic cancer vaccines.

Animals↗
PubMed1999

Surgical options for open adrenalectomy.

We are fortunate that our ability to diagnose the specific adrenal entities that mandate a surgical approach is extremely accurate. The combination of analytical methodology to measure the appropriate adrenocortical and medullary hormone production and the radiology techniques for localization are superb. The management of these adrenal disorders with precise surgical precision following localization is highly successful, resulting in a reversal of both metabolic abnormalities and the hypertension that often accompanies these diseases. Indeed, this has become a true success story with the evolution of these different techniques over the past 50 years.

Adrenal Gland Diseases↗
PubMed1995

Control of mating and development in Ustilago maydis.

In the fungus Ustilago maydis, the ability to distinguish between partners that are of the same or of different mating type is controlled by two mating-type loci. One locus allows extracellular recognition though a pheromone-based system. After cell fusion, the other mating-type locus, which exists in multiple alleles, determines intracellular recognition. Each allele encodes a pair of homeodomain proteins that are active only in pairwise combinations in which the two partners originate from different alleles of the locus. Recent discoveries suggest that the underlying molecular recognition mechanism is the ability to form heterodimers. Whereas the proteins in all different allelic combinations interact, it is a specific feature of proteins from the same allele not to interact. This suggests the existence of a code for protein-protein recognition.

Alleles↗
PubMed2006

The limb-girdle muscular dystrophies--diagnostic strategies.

The limb-girdle muscular dystrophies are a group of disorders where our understanding of their underlying molecular basis has made huge strides over the past years, revealing great heterogeneity at the clinical and molecular level. The availability of direct protein and/ or gene based approaches to diagnosis means that these disorders can now be precisely defined, and such definition of a precise diagnosis is increasingly allowing directed management for these diseases by the ability to predict specific complications such as those of the cardiac or respiratory systems. An algorithm combining clinical, biochemical and molecular testing is described which will aid precision of diagnosis and direct specific testing towards the cases most likely to benefit. This brings advantages for the patients of today in recognising the specific risks of their disorders, and in the future will be the starting point for specific gene and protein based therapies.

Animals↗
PubMed2005

Towards more virulent and antibiotic-resistant Salmonella?

Salmonella are well-known pathogens. Virulence determinants can be present on the chromosome, usually encoded on pathogenicity islands, or on plasmids and bacteriophages. Antibiotic resistance determinants usually are encoded on plasmids, but can also be present on the multidrug resistance region of Salmonella Genomic Island 1 (SGI1). Virulence plasmids show a remarkable diversity in the combination of virulence factors they encode, which appears to adapt them to specific hosts and the ability to cause gastroenteritidis or systemic disease. The appearance of plasmids with two replicons may help to extend the host range of these plasmids and thereby increase the virulence of previously non- or low pathogenic serovars. Antibiotic resistance among Salmonella is also increasing. This increase is not only in the percentage isolates resistant to a particular antibiotic, but also the development of resistance against newer antibiotics. The increased occurrence of integrons is particularly worrying. Integrons can harbour a varying set of antibiotic resistance encoding gene cassettes. Gene cassettes can be exchanged between integrons. Although the gene cassettes currently present in Salmonella integrons encode for older antibiotics (however, some still frequently used) gene cassettes encoding resistance against the newest antibiotics has been documented in Enterobacteriaceae. Furthermore, beta-lactamases with activity against broad-spectrum cephalosporins, which are often used in empiric therapy, have been found associated with integrons. So, empiric treatment of Salmonella infections becomes increasingly more difficult. The most worrisome finding is that virulence and resistance plasmids form cointegrates. These newly formed plasmids can be selected by antibiotic pressure and thereby for virulence factors. Taken together these trends may lead to more virulent and antibiotic-resistant Salmonella.

Drug Resistance, Bacterial↗
PubMed2004

Diseases of the adrenal gland.

It is fortunate that the ability to diagnose the specific adrenal entities that mandate a surgical approach is extremely accurate. The combination of analytic methodology to measure the appropriate adrenocortical and medullary hormonal production and the radiologic techniques for localization are superb. The management of these adrenal disorders usually using a laparoscopic approach following localization is highly successful, resulting in a reversal of both metabolic abnormalities and the hypertension that often accompanies these diseases. Indeed, this is a true success story with the evolution of these different techniques over the past 50 years.

Adrenal Gland Diseases↗
PubMed1987

Mycobacterium marinum infections of the hand.

Fifteen patients had culture proven Mycobacterium marinum infections of the hand; 11 had injured their hands while fishing in water around Long Island. No patient had type I lesions (verrucal), six patients had type II lesions (subcutaneous granulomas), and nine patients had type III lesions (deep). Histologic examination showed noncaseating granulomas in all cases. A specific defect in the patients' lymphocytes ability to respond to M. marinum antigens was identified. A combination of surgery and tetracycline provided effective treatment. Follow-up averaged 2 1/2 years.

Adolescent↗
PubMed1997

Transcranial Doppler monitoring during carotid endarterectomy: is it appropriate for selecting patients in need of a shunt?

PURPOSE: This report summarizes our experience in evaluating a series of 168 patients who underwent a total of 175 carotid endarterectomy procedures under local anesthesia. Patients were monitored by stump pressure (SP) measurement and transcranial Doppler scanning (TCD). The need for shunting was compared between SP/TCD flow velocity reduction and the awake response (gold standard). METHODS: The study cohort represented 56% of all the carotid patients treated during the study period. Clamping ischemia was defined as the appearance of focal deficit (focal ischemia) or unconsciousness (global deficit) on carotid clamping. In the case of clamping ischemia, a shunt was inserted. To define the optimal value of SP and TCD flow velocity that is able to discriminate patients with clamping ischemia, a receiver operator characteristic (ROC) curve was constructed. Sensitivity and specificity tests, together with negative and positive predictive values (NPV and PPV), were calculated. Cutoff values were defined as the ROC curve values that correlated the highest sensitivity with the highest specificity for both SP and TCD. RESULTS: Clamping ischemia was present in 18 procedures (10%) in which a shunt was used. No perioperative deaths were recorded. Major perioperative morbidity occurred in one patient (0.6%). Two nondisabling strokes were also recorded (1.8% overall rate of neurologic morbidity). Cutoff values for both SP and TCD, using the ROC curve, were < or = 50 mm Hg and > or = 70% flow velocity reduction from baseline, respectively. SP values of < or = 50 mm Hg or less showed a sensitivity of 100%, a specificity of 83%, a PPV of 40%, and an NPV of 100%. TCD flow monitoring (> or = 70% flow reduction) revealed a lower sensitivity (83%) but a greater ability to avoid false positive results (96% specificity), resulting in increased PPV (71%) and NPV (98%). Combining SP and TCD failed to provide better results in terms of specificity (81%) and PPV (38%). CONCLUSIONS: SP measurement using a 50 mm Hg cutoff appears to be a reliable predictor of clamping ischemia but requires the use of a shunt in 17% of the patients who would otherwise not require this procedure. In contrast, TCD has greater specificity but is associated with a lower sensitivity, with 17% false negative results. In our experience, both SP and TCD show limitations, as they overestimate or underestimate carotid endarterectomy procedures in need of a shunt. We believe that sensitivity is more important than specificity in carotid endarterectomy, and thus conclude that TCD flow velocity measurement is not an optimal method for detecting clamping ischemia.

Aged↗
PubMed2000

RNA: versatility in form and function.

RNA performs a remarkable range of functions in all cells. In addition to its central role in information transfer from DNA to protein, it is essential for functions as diverse as RNA processing, chromosome end-maintenance and dosage compensation. The versatility of RNA derives from its unique ability to use direct readout via base-pairing for sequence specific targeting (or templating) in combination with its capacity to form elaborate three dimensional structures. Such structures can perform catalysis or serve as protein recognition surfaces. In this short review, we attempt to give a flavor for the diversity of functional RNAs in the cell and highlight, using selected examples, two quite distinct activities, catalysis and sequence specific targeting. Within each section, we discuss how the lessons we have learned from these systems may apply to other, less well understood, RNAs.

Catalysis↗
PubMed1995

HLA-A2 subtypes are functionally distinct in peptide binding and presentation.

Nearly half of HLA-A2-positive individuals in African populations have a subtype of HLA-A2 other than the A*0201 allele. We have isolated the common African HLA-A2 subtype genes from Epstein-Barr virus-transformed B cell lines and have established stable class I reduced transfectants expressing these alleles. We have studied the peptide binding and presentation properties of A*0201, A*0202, A*0205, A*0214, and A*6901 by a combination of approaches: assaying direct binding of labeled synthetic peptides, studying the ability of antigen-specific cytotoxic T lymphocytes to recognize peptide-pulsed cells, and sequencing peptide pools and individual ligands eluted from cells. We find that A*0201-restricted peptides can also bind to A*0202 but do not bind strongly to the other alleles in this study. We show that some cytotoxic T lymphocytes can recognize all subtypes capable of binding an antigenic peptide, whereas others are subtype specific. Sequencing of eluted peptides reveals that A*0202 has a similar peptide motif to A*0201, but that A*0205, A*0214, and A*6901 have different motifs. These data strongly support a model in which residue 9 (Phe or Tyr) of the A2/A68/A69 molecules is a critical factor in determining the specificity of the B pocket of the major histocompatibility complex and the position 2 anchor residue of associated peptides. We conclude that a single-amino acid difference in the major histocompatibility complex can be sufficient to cause a dramatic change in the nature of bound peptides, implying that individuals with closely related HLA subtypes may present very different repertoires of antigenic peptides to T cells in an immune response. It is likely to be a general phenomenon that very similar class I subtypes will behave as functionally distinct HLA allotypes.

Alleles↗
PubMed1997

Microheterogeneity of the oligosaccharides carried by the recombinant bovine lactoferrin expressed in Mamestra brassicae cells.

The development of therapeutic glycoprotein production using the baculovirus expression system depends on the ability of insect cell lines to reproduce site specific mammalian-like N-glycans. A combination of 1H-NMR and mass spectrometry techniques (MALD-MS, ES-MS, and CID-MS-MS) allowed us to elucidate the N-linked oligosaccharides microheterogeneity on three different N-glycosylation sites, Asn233, Asn476, and Asn545, of a baculovirus-expressed recombinant bovine lactoferrin produced in Mamestra brassicae. Two families of N-glycan structures have been found: first, oligomannosidic glycans (Man[9-5]GlcNAc2) and secondly, short truncated partially fucosylated glycans (Man(3-2)[Fuc(0-1)]GlcNAc2). These results indicate that Mamestra brassicae cell line is not able to synthesize complex N-glycans, even if an alpha1,6-linked fucose residue is frequently present on the asparagine-bound N-acetylglucosamine residue of short truncated structures. Nevertheless, we have shown that Mamestra brassicae ensures the same N-glycosylation pattern as found on natural bovine lactoferrin showing the same distribution between complex and high-mannose type glycans on the different glycosylation sites. Sites which are naturally occupied by high-mannose glycans (Asn233 and Asn545) are substituted essentially by the same type of N-glycans in the recombinant counterpart, and the site Asn476,which carries sialylated complex type chains in the natural glycoprotein, is substituted by short, truncated, partially fucosylated chains in Mamestra brassicae-expressed bovine lactoferrin. These various results lead us to the conclusion that bovine lactoferrin is an interesting model to determine the potential of glycosylation of the baculovirus/insect cell expression systems.

Amino Acid Sequence↗
PubMed1995

Effect of early dietary deficiency in polyunsaturated fatty acids on two lectin binding sites in the small intestine of postweanling rats.

This study was designed to determine whether dietary lipids influence the development of intestinal cell glycosylation, in relationship to diet-induced changes in phospholipid fatty acid composition. The ability of two different lectins, wheat germ agglutinin (WGA) and Maackia amurensis agglutinin (MAA), to combine specifically with particular carbohydrate residues was used to investigate the surface characteristics of epithelial cells of rats fed different dietary lipids from birth to 6 weeks of age. Diets contained 5% (weight) peanut oil (PO), rich in n-6 fatty acids; salmon oil (SO), rich in n-3 fatty acids; hydrogenated palm oil (HPO), deficient in both n-6 and n-3 fatty acids or a PO and rapeseed oil (RO) mixture (PRO), the control diet. Pieces of jejunal and ileal villi were excised from postweanling rats and prepared for lectin histochemical study. Concurrently, epithelial cells were removed from jejunal and ileal segments for determining their phospholipid fatty acid compositions. Polyunsaturated fatty acid (PUFA) deficiency was evidenced in the HPO group by the appearance of eicosatrienoic acid (20:3n-9) in both jejunal and ileal phospholipids, which paralleled the decrease in arachidonic acid content. Accretion of 18:1n-9 and 20:3n-9 in cell phospholipids of group HPO was not sufficient to match the unsaturation level in rats fed nonhydrogenated vegetable oils (PRO, PO) or fish oil (SO). The lectin histochemical study showed that WGA strongly labelled the brush border membrane microvilli whereas binding of MAA was specific to goblet cells and mucus. Regardless of the type of diet, WGA binding was weaker in the ileum than in the jejunum. In comparison to all other groups, WGA-labelling of villi was less intense in the jejunum and disappeared almost completely in the ileum of HPO-fed rats. Although SO- and PO-fed rats had, respectively, very low and high ratios of n-6 to n-3 in their intestinal phospholipids, binding of WGA in both groups was not markedly different from that in the control (PRO). MAA-labelling was very intense in jejunal and ileal villi of n-3-fed (SO) rats, whereas it was strongly attenuated in the n-3- and n-6 deficient (HPO) group. These results suggest that intestinal glycosyltransferase activities involved in cell differentiation were altered relative to the overall unsaturation index of dietary fatty acids. Alterations of epithelial glycosylation mainly resulted from a drop in total n-6 and n-3 fatty acids, although it may be speculated that there is a specific effect of n-3 fatty acids.

Animals↗
PubMed2006

Induction of melanocytes from embryonic stem cells and their therapeutic potential.

Embryonic stem (ES) cells from many organisms have the capacity to generate in vitro a wide variety of cell types depending on their environment. Understanding precisely how such toti- or pluripotent cells may be driven towards a specific lineage represents a major challenge if our ambition of using ES cells to generate a ready supply of healthy cells for cell-based therapies for a range of diseases is to be realized. Recent advances have demonstrated that melanocytes and retinal pigmented epithelial (RPE) cells exhibiting the characteristics of their natural counterparts can be induced from undifferentiated ES cells grown on monolayers of specific stromal cell lines or by using a combination of Wnt3a, Endothelin-3 and SCF. The ability to induce pigment cells from ES cells promises to facilitate our understanding of the precise molecular mechanisms underlying this process and moreover enable us to distinguish the program of gene expression that underpins the choice made between generating a nerual crest-type melanocyte versus an RPE cell. Moreover, once the combination of signals required to induce a particular type of pigment cell are characterized, the way may be open for future cell-based therapy for various diseases caused by defective pigment cells.

Animals↗
PubMed1996

Clinically significant pharmacokinetic drug interactions with carbamazepine. An update.

Carbamazepine is one of the most commonly prescribed antiepileptic drugs and is also used in the treatment of trigeminal neuralgia and psychiatric disorders, particularly bipolar depression. Because of its widespread and long term use, carbamazepine is frequently prescribed in combination with other drugs, leading to the possibility of drug interactions. The most important interactions affecting carbamazepine pharmacokinetics are those resulting in induction or inhibition of its metabolism. Phenytoin, phenobarbital (phenobarbitone) and primidone accelerate the elimination of carbamazepine, probably by stimulating cytochrome P450 (CYP) 3A4, and reduce plasma carbamazepine concentrations to a clinically important extent. Inhibition of carbamazepine metabolism and elevation of plasma carbamazepine to potentially toxic concentrations can be caused by stiripentol, remacemide, acetazolamide, macrolide antibiotics, isoniazid, metronidazole, certain antidepressants, verapamil, diltiazem, cimetidine, danazol and (dextropropoxyphene) propoxyphene. In other cases, toxic symptoms may result from elevated plasma concentrations of the active metabolite carbamazepine-10,11-epoxide, due to the inhibition of epoxide hydrolase by valproic acid (sodium valproate), valpromide, valnoctamide and progabide. Carbamazepine is a potent inducer of CYP3A4 and other oxidative enzyme system in the liver, and it may also increase glucuronyltransferase activity. This results in the acceleration of the metabolism of concurrently prescribed anticonvulsants, particularly valproic acid, clonazepam, ethosuximide, lamotrigine, topiramate, tiagabine and remacemide. The metabolism of many other drugs such as tricyclic antidepressants, antipsychotics, steroid oral contraceptives, glucocorticoids, oral anticoagulants, cyclosporin, theophylline, chemotherapeutic agents and cardiovascular drugs can also be induced, leading to a number of clinically relevant drug interactions. Interactions with carbamazepine can usually be predicted on the basis of the pharmacological properties of the combined drug, particularly with respect to its therapeutic index, site of metabolism and ability to affect specific drug metabolising isoenzymes. Avoidance of unnecessary polypharmacy, selection of alternative agents with lower interaction potential, and careful dosage adjustments based on serum drug concentration monitoring and clinical observation represent the mainstays for the minimisation of risks associated with these interactions.

Analgesics, Non-Narcotic↗