Cell-mediated immunological responses in cervical and vaginal cancer patients immunized with a lipidated epitope of human papillomavirus type 16 E7

Human papillomavirus (HPV) infection has been causally associated with cervical cancer. We tested the effectiveness of an HLA-A*0201-restricted, HPV-16 E7 lipopeptide vaccine in eliciting cellular immune responses in vivo in women with refractory cervical cancer. In a nonrandomized Phase I clinical trial, 12 women expressing the HLA-A2 allele with refractory cervical or vaginal cancer were vaccinated with four E786-93 lipopeptide inoculations at 3-week intervals. HLA-A2 subtyping was also performed, and HPV typing was assessed on tumor specimens. Induction of epitope-specific CD8+ T-lymphocyte (CTL) responses was analyzed using peripheral blood leukapheresis specimens obtained before and after vaccination. CTL specificity was measured by IFN-gamma release assay using HLA-A*0201 matched target cells. Clinical responses were assessed by physical examination and radiographic images. All HLA-A*0201 patients were able to mount a cellular immune response to a control peptide. E786-93-specific CTLs were elicited in 4 of 10 evaluable HLA-A*0201 subjects before vaccination, 5 of 7 evaluable HLA-A*0201 patients after two vaccinations, and 2 of 3 evaluable HLA-A*0201 cultures after all four inoculations. Two of three evaluable patients' CTLs converted from unreactive to reactive after administration of all four inoculations. There were no clinical responses or treatment toxicities. The ability to generate specific cellular immune responses is retained in patients with advanced cervical cancer. Vaccination with a lipidated HPV peptide epitope appears capable of safely augmenting CTL reactivity. Although enhancements of cellular immune responses are needed to achieve therapeutic utility in advanced cervical cancer, this approach might prove useful in treating preinvasive disease.     

Biological rhythms as organization and information

The purpose of the current study was to describe four models of cognitive deficit and to outline the statistical hypotheses underlying each model. The four models of cognitive deficit were (a) specific deficit; (b) subgroup deficit; (c) a syndrome dissociation model; and (d) a global function dissociation model. Neuropsychological data are analyzed to examine each of these four models in a sample of mild Multiple Sclerosis (MS) patients. The results suggest that for these subjects and tests, the specific deficit model best fits the data. The results are reviewed initially in the context of MS. There follows a consideration of statistical caveats and finally, general applications of the proposed procedures.     

Structure of the repeating unit of acid polysaccharide from Alteromonas sp. 4MS17

An acidic polysaccharide from Alteromonas sp. 4MC17 is built up of trisaccharide repeating units containing D-glucose, D-mannose and D-galacturonic acid residues. On the basis of methylation studies, 1H and 13C NMR-spectroscopy data, including two-dimensional homonuclear correlation spectroscopy and nuclear Overhauser effects, the following structure was suggested for the polysaccharide repeating unit: -->4)-beta-D-Glcp-(1-->4)-beta-D-GalpA-(1-->4)-beta-D-Manp-( 1-->.     

Dual flaA1 flaB1 mutant of Serpulina hyodysenteriae expressing periplasmic flagella is severely attenuated in a murine model of swine dysentery

The motility imparted by the periplasmic flagella (PF) of Serpulina hyodysenteriae is thought to play a pivotal role in the enteropathogenicity of this spirochete. The complex PF are composed of multiple class A and class B polypeptides. Isogenic strains containing specifically disrupted flaAl or flaB1 alleles remain capable of expressing PF, although such mutants display aberrant motility in vitro. To further examine the role that these proteins play in the maintenance of periplasmic flagellar structural integrity, motility, and fitness for intestinal colonization, we constructed a novel strain of S. hyodysenteriae which is deficient in both FlaA1 and FlaB1. To facilitate construction of this strain, a chloramphenicol gene cassette, with general application as a selectable marker in prokaryotes, was developed. The cloned flaAl and flaB1 genes were disrupted by replacement of internal fragments with chloramphenicol and kanamycin gene cassettes, respectively. The inactivated flagellar genes were introduced into S. hyodysenteriae, and allelic exchange at the targeted chromosomal flaA1 and flaB1 loci was verified by PCR analysis. Immunoblots or cell lysates with antiserum raised against purified FlaA or FlaB confirmed the absence of the corresponding sheath and core proteins in this dual flagellar mutant. These mutations selectively abolished the expression of the targeted genes without affecting the synthesis of other immunologically related FlaB proteins. The resulting flaA1 flaB1 mutant exhibited altered motility in vitro. Surprisingly, it was capable of assembling periplasmic flagella that were morphologically normal as evidenced by electron microscopy. The virulence of this strain was assessed in a murine model of swine dysentery by determining the incidence of cecal lesions and the persistence of S. hyodysenteriae in the gut. Mice challenged with the wild-type strain or a passage control strain showed a dose-related response to the challenge organism. The dual flagellar mutant was severely attenuated in murine challenge experiments, suggesting that the FlaA1 and FlaB1 proteins are dispensable for flagellar assembly but critical for normal flagellar function and colonization of mucosal surfaces of the gastrointestinal tract. This strain represents the first spirochete engineered to contain specifically defined mutations in more than one genetic locus.     

Quenching of chlorophyll fluorescence by quinones

Obese (Lepr(fa)/Lepr(fa)) Zucker rats have a missense mutation in the leptin receptor gene. One amino acid substitution in the extracellular domain common to all known leptin receptor proteins results from this mutation. Obese Zucker rats are unable to respond behaviorally to leptin which is peripherally administered. However, conflicting reports exist on whether obese Zucker rats can respond to centrally administered leptin. The purpose of this study was to determine whether obese Zucker rats responded behaviorally and metabolically to intracerebroventricularly (i.c.v.) administered leptin and to compare the responses of lean and obese Zucker rats. We found that both lean and obese Zucker rats had similar body weight and food intake responses when administered a single i.c.v. leptin injection in a range of doses (1.25, 2.5, 5, and 10 microg), as well as daily i.c.v. administered leptin for five consecutive days. Both single and daily leptin administration also decreased respiratory quotient (RQ) similarly in lean and obese Zucker rats, indicating mobilization of fat as an energy source for leptin-treated rats. After withdrawal of daily leptin treatment, lean and obese Zucker rats exhibited different recovery responses. It is concluded that obese Zucker rats can respond to exogenous leptin when leptin is delivered into the brain ventricles.     

Cognitive shifting as a predictor of progress in social understanding in high-functioning adolescents with autism: a prospective study

The pyrolytic behavior of inulin, a (2-->1)-linked fructofuranan, is described. Parallel investigations of the pyrolysis of glucose and of fructose were conducted to supplement the inulin results and to aid comparison with previous results from glucans. Effects of neutral and basic additives are emphasized. As with glucans, the addition of such additives (especially basic) increases the yields of the one-, two-, and three-carbon products (as well as of hexosaccharinolactones), while generally decreasing the yields of anhydro sugar and furan derivatives. The former products include glycolaldehyde, acetol, dihydroxy-acetone, acetic acid, formic acid, and lactic acid. Mechanistic speculations are made regarding the origins of these compounds, as well as of furan derivatives and saccharinic acid lactones. Parallels with alkaline degradation are considered.     

Endothelin receptors mediating vasoconstriction in rat pressurized small arteries

The effects of endothelin-1 (ET-1), a nonselective ETA and ETB receptor agonist, and sarafotoxin S6c, a selective ETB agonist, were investigated in the presence and absence of BQ123 and BQ788, ETA- and ETB-selective antagonists, respectively, in rat mesenteric small arteries, using a perfusion pressurized arteriograph in which segments of vessels were cannulated and exposed to constant pressure and flow. ET-1 (10(-13)-10(-7) M) induced vasoconstriction in both intact and endothelium-denuded arteries in a concentration-dependent manner. BQ123 (10(-7) and 10(-6) M) inhibited the effect of ET-1, displacing the concentration-response curve to the right in a concentration-dependent manner. The effect of ET-1 was not significantly affected by BQ788 (10(-7) and 10(-6) M), a selective antagonist of ETB receptors. Sarafotoxin S6c (10(-11)-10(-7) M) also induced a slight concentration-dependent vasoconstriction. The effect of sarafotoxin S6c (10(-8) M) was inhibited by the ETB-selective antagonist BQ788 (10(-7) M), but was not significantly changed by BQ123 (10(-7) M). Vasoconstriction induced by sarafotoxin S6c (10(-8) M) in a single bolus concentration was significantly greater than the contraction induced by the same concentration as part of a cumulative concentration-response curve, indicating desensitization or downregulation of ETB receptors during the latter. Repeated application of single concentrations of sarafotoxin S6c (10(-8) M) caused progressively smaller contraction of arteries. These results show the existence of both ETA and ETB vasoconstrictor receptors located on smooth muscle of small arteries. They also show that ETB receptors induce a smaller constrictor effect, and rapidly undergo desensitization after sustained or repeated activation.