The anti-tumoral effects of the oxygen carrier YQ23 in a triple-negative breast cancer syngeneic model.

BACKGROUND: Triple-negative breast cancer (TNBC), an aggressive breast cancer subtype, is associated with poor prognosis and high mortality rate. In the search for effective therapeutic options, preclinical studies have suggested using systemic oxygenation to inhibit tumor growth and metastasis in various cancer models, including TNBC, by weakening the hypoxia-A2A adenosine receptors (A2AR)-driven immunosuppression in the tumor microenvironment (TME). In our present study, a hemoglobin-based oxygen carrier (HBOC) "YQ23" was tested for its role in modulating the TME and tumor inhibition. METHODS: A syngeneic TNBC mouse model was established by inoculating 4T1 cells subcutaneously in BALB/c mice. Tumor (~100 mm3) bearing mice were treated either with saline or YQ23 (400 mg/kg) i.v. once weekly. To prove the immune-regulatory role of YQ23, CD4+ and CD8+ cells were depleted from a group of mice prior to treatment. Tumor growth was monitored for four weeks while xenografts were isolated at the end of the treatment for ex vivo immunohistological examination. RESULTS: YQ23 significantly inhibited the tumor growth, and this suppressive effect was abolished by depleting the host immune cells. Immunohistochemical staining of xenograft sections showed YQ23 reduced the level of hypoxia and adenosine producing ecto-enzyme CD73. Although there was no significant difference in the make up of the intra-tumoral immune populations, we observed a down-regulation of the immune checkpoint PD-1. In concordance with the weakened immunosuppression, the inflammatory cytokine interferon γ and cytolytic granzyme B were upregulated. CONCLUSIONS: YQ23 treatment may be a potential therapeutic strategy to modulate the TME in TNBC.

The Role of Social Problem Solving, Criminal Attitude, and ADHD in Aggression Among Incarcerated Youth in Hong Kong.

It is not atypical for young offenders to use aggression to handle problems. This exploratory study examined the contribution of social problem-solving deficit, criminal attitude, and attention-deficit/hyperactivity disorder (ADHD) symptoms to aggression among incarcerated young offenders in Hong Kong. Correlational and regression analyses were conducted to identify factors that help to predict aggression. To control for the influence of ADHD symptoms, hierarchical regression analysis was conducted to reexamine the contribution of the identified factors. The results showed that negative problem orientation (NPO) and contemptuous attitudes toward the law, court, and police (LCP) helped to predict aggression at the current moment and 3 months later. After controlling for ADHD symptoms, only LCP but not NPO remained a significant predictor of both current and near-future aggression. This finding suggests that the contribution of criminal attitude to aggression tends to be independent of the effects of ADHD and social problem-solving deficit. We conclude by discussing the theoretical and practical implications of conceptualizing aggression and improving psychological services for young offenders.

Asymmetry of the "strongest" OHO hydrogen bond, in the monoanion of (+/-)-alpha,alpha'-di-tert-butylsuccinate.

The large pK(a) difference between first and second deprotonations of (+/-)-alpha,alpha'-di-tert-butylsuccinic acid has been interpreted as evidence for a short, strong intramolecular hydrogen bond in the monoanion. Incorporation of (18)O into one carboxyl group allows investigation of the symmetry of the H-bond in solution by the method of isotopic perturbation. Relative to the intrinsic (18)O-induced isotope shift at the carboxyl carbon, as measured in the diacid, an additional isotope shift of 8 ppb in methanol, 14 ppb in acetone, and 5 ppb in THF is observed for potassium hydrogen (+/-)-alpha,alpha'-di-tert-butylsuccinate-(18)O. This increase indicates that the ion exists as an equilibrating pair of interconverting tautomers and not as a single symmetric resonance hybrid. The X-ray crystal structures of the tetrapropylammonium, tetrabutylammonium, tetrabutylphosphonium, magnesium, and calcium hydrogen (+/-)-alpha,alpha'-di-tert-butylsuccinate salts show a remarkably short O-O distance of 2.41 A, consistent with a strong hydrogen bond. However, the dicesium salt of the (+/-)-alpha,alpha'-di-tert-butylsuccinate dianion also shows the short O-O distance of 2.41 A, so this cannot be taken as evidence for a strong hydrogen bond in the monoanion. Moreover, the two O-H distances in the monoanions are unequal, and the hydrogen bond is asymmetric in these crystals. It is concluded that there is no evidence for any special stabilization associated with symmetric H-bonds. The large Delta pK(a) difference is therefore not due to any feature of the H-bond itself but is attributed to the electrostatic repulsion between the carboxylates in the dianion, which is relieved in the monoanion by inserting a proton between the carboxylates.

HIV-1 Tat dysregulation of lipopolysaccharide-induced cytokine responses: microbial interactions in HIV infection.

OBJECTIVE: To examine whether the HIV-1 Tat protein impairs the lipopolysaccharide (LPS)-induced cytokine responses. DESIGN: Concurrent infections with pathogens including bacteria and viruses are common in AIDS patients. However, cytokine and interferon responses during infection with or translocation from the gut of these pathogens in HIV-infected patients are not well studied. As HIV-1 Tat contributes partly to the HIV-induced immune dysregulation, we investigated whether the protein may play a role in perturbing the LPS-induced cytokine responses. METHODS: Expression levels of cytokines in human primary blood monocytes/macrophages were determined by quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. Expression level of the cell surface Toll-like receptor 4 was examined by flow cytometry. Activations of signaling molecules were assayed by western blot and immunofluorescence. RESULTS: We demonstrated that HIV-1 Tat downregulated the LPS-induction of IFN-beta and concomitantly upregulated IL-6 expression in primary blood monocytes/macrophages, whereas the viral protein had no significant effects on TNF-alpha expression. To delineate the underlying mechanism, we showed that Tat inhibited the LPS-activation of ERK1/2 but not the p38 mitogen-activated protein kinases. The viral protein suppressed the LPS-induced activation of NFkappaB p65 via its induction of IkappaBalpha expression, which resulted in retention of NFkappaB p65 in the cytosol. CONCLUSION: These findings suggest that Tat may play a role in modulating the immune responses triggered by other coinfecting pathogens and thus providing a permissive environment for both HIV and other opportunistic microbes.

Hydrogen-bond symmetry in zwitterionic phthalate anions: symmetry breaking by solvation.

The cationic nitrogen of zwitterion 1 is located symmetrically with respect to its intramolecular OHO hydrogen bond. Incorporation of one (18)O allows investigation of the H-bond symmetry by the NMR method of isotopic perturbation. In both CD(3)OD and CD(2)Cl(2) equilibrium isotope shifts are detected at the carboxyl and ipso carbons. Therefore, 1 exists as a pair of interconverting tautomers, not as a single symmetric structure with its hydrogen centered between the two oxygens. The H-bond is instantaneously asymmetric, and there is an equilibrium between solvatomers (isomers or stereoisomers that differ in solvation). The broader implications of this result regarding the role of the local environment ("solvation") in breaking symmetry are discussed.