Fever is associated with increased survival during acute infection, although its mechanism of action is largely unknown. This study found evidence of an unexpectedly integrated mechanism by which fever-range temperatures stimulate lymphocyte homing to secondary lymphoid tissues by increasing L-selectin and ␣4␤7 integrin-dependent adhesive interactions between circulating lymphocytes and specialized high endothelial venules (HEV). Exposure of splenic lymphocytes in vivo to fever-like whole-body hyperthermia (WBH; 39.8 ؎ 0.2°C for 6 hours) stimulated both L-selectin and IntroductionSystemic fever and local increases in temperature at sites of inflammation are cardinal features of host responses to pathogenic stimuli. Although the highly conserved fever response is linked to increased survival, 1,2 the mechanisms underlying the protective action of fever have not been fully elucidated. A central locus of control of the host immune response to foreign pathogens resides at the leukocyte-endothelial interface. To fight infections in peripheral tissues, blood-borne lymphocytes gain entry across specialized high endothelial venules (HEV) in secondary lymphoid organs (ie, lymph nodes [LN] and Peyer patches [PP]) and at extralymphoid sites of infection. Lymphocyte adhesion to HEV is initiated by the L-selectin and ␣4␤7 integrin adhesion molecules on the microvillous processes of lymphocytes. 3,4 These molecules mediate the initial attachment and slow rolling of lymphocytes on HEV counterreceptors under hemodynamic shear conditions. Subsequent G-protein-dependent chemokine activation of a ␤2-integrin, lymphocyte function-associated antigen 1 (LFA-1), results in firm adhesion of lymphocytes to HEV and transendothelial migration. Lymphocyte-HEV interactions in LN are initiated exclusively by L-selectin recognition of sialomucin-like receptors termed peripheral lymph node addressins (PNAd), which are identified by the MECA-79 monoclonal antibody (mAb). [3][4][5][6] In PP, L-selectin and ␣4␤7 integrins initiate lymphocyte tethering on HEV through interactions with distinct domains of MECA-367 mAb-reactive mucosal addressin cell adhesion molecule-1 (MAdCAM-1). 3,7 Mammals respond to natural infection or inflammatory stimuli (eg, pyrogenic cytokines, bacterial lipopolysaccharide, and turpentine) with a mild to moderate fever (1-4°C above normal body temperature). 1,2,8 Fever-range temperatures are associated with enhancement of the innate and adaptive arms of the immune response through augmentation of T-cell proliferation and cytotoxicity, bioactivity of inflammatory cytokines (eg, interferon (IFN)-␣), and neutrophil motility and chemotaxis. 1,2 Recent studies suggest that the highly efficient adhesion mechanism for lymphocyte recirculation can also be amplified by fever-range hyperthermia. In this regard, direct exposure of human and murine lymphocytes to long-duration, fever-range temperatures in vitro markedly stimulates both L-selectin and ␣4␤7 integrin-dependent adhesion to HEV in frozen-section assays. [9][10][11][12] I...

Purpose-Radiation therapy for head and neck cancer causes adverse secondary side effects in the salivary glands and results in diminished quality of life for the patient. A previous in vivo study in parotid salivary glands demonstrated that targeted head and neck irradiation resulted in marked increases in phosphorylated p53 (serine 18 ) and apoptosis, which was suppressed in transgenic mice expressing a constitutively active mutant of Akt1 (myr-Akt1).Methods and Materials-Transgenic and knockout mouse models were exposed to irradiation and p53-mediated transcription, apoptosis, and salivary gland dysfunction were analyzed.Results-We report that the pro-apoptotic p53 target genes PUMA and Bax are induced in parotid salivary glands of mice at early time points following therapeutic radiation. This dose-dependent induction requires expression of p53 as no radiation-induced expression of PUMA and Bax is observed in p53−/− mice. Radiation also induces apoptosis in the parotid gland in a dose dependent manner, which is p53-dependent. Furthermore, expression of p53 is required for the acute and chronic loss of salivary function following irradiation. In contrast, p53−/− mice do not induce apoptosis and preserve salivary function after radiation exposure.Conclusion-These results indicate that apoptosis in the salivary glands following therapeutic head and neck irradiation is mediated by p53 and corresponds to salivary gland dysfunction in vivo.

Quercetin is a unique dietary polyphenol because it can exert biphasic dose-responses on cells depending on its concentration. Cancer preventative effects of quercetin are observed at concentrations of approximately 1-40 microM and are likely mediated by quercetin's antioxidant properties. Pro-oxidant effects are present at cellular concentrations of 40-100 microM. However, at higher concentrations, many novel pathways in addition to ROS contribute to its effects. The potent bioactivity of quercetin has led to vigorous study of this compound and revealed numerous pathways that could interact synergistically to prevent or treat cancer. The effect of intake and concentration on emerging pathways and how they may interact are discussed in this review.

BackgroundRadiotherapy for head and neck cancer results in severe and chronic salivary gland dysfunction in most individuals. This results in significant side effects including xerostomia, dysphagia, and malnutrition which are linked to significant reductions in patients' quality of life. Currently there are few xerostomia treatment approaches that provide long-term results without significant side effects. To address this problem we investigated the potential for post-therapeutic IGF-1 to reverse radiation-induced salivary gland dysfunction.MethodsFVB mice were treated with targeted head and neck radiation and significant reductions in salivary function were confirmed 3 days after treatment. On days 4-8 after radiation, one group of mice was injected intravenously with IGF-1 while a second group served as a vehicle control. Stimulated salivary flow rates were evaluated on days 30, 60, and 90 and histological analysis was performed on days 9, 30, 60, and 90.ResultsIrradiated animals receiving vehicle injections have 40-50% reductions in stimulated salivary flow rates throughout the entire time course. Mice receiving injections of IGF-1 have improved stimulated salivary flow rates 30 days after treatment. By days 60-90, IGF-1 injected mice have restored salivary flow rates to unirradiated control mice levels. Parotid tissue sections were stained for amylase as an indicator of functioning acinar cells and significant reductions in total amylase area are detected in irradiated animals compared to unirradiated groups on all days. Post-therapeutic injections of IGF-1 results in increased amylase-positive acinar cell area and improved amylase secretion. Irradiated mice receiving IGF-1 show similar proliferation indices as untreated mice suggesting a return to tissue homeostasis.ConclusionsPost-therapeutic IGF-1 treatment restores salivary gland function potentially through normalization of cell proliferation and improved expression of amylase. These findings could aid in the rational design of therapy protocols or drugs for the treatment of radiation-induced salivary gland dysfunction in patients who have completed their anti-cancer therapies.

A major mammalian heat shock protein of 110 kDa (hsp110) has long been observed, but has not been cloned. We have cloned the hamster cDNA for hsp110 and show that it hybridizes on a Northern blot to a 3.5-kilobase heat-inducible message in hamster and mouse. The hsp110 sequence was found to share an approximately 30-33% amino acid identity with members of the hsp70 family, most of which occurs in the conserved ATP-binding domain of these molecules. In addition, five sequences were found to be highly similar to hsp110. These are the sea urchin egg receptor for sperm (Foltz, K.R., Partin, J. S., and Lennarz, W.J. (1993) Science 259, 1421-1425) and additional sequences from human and Caenorhaditis elegans and two from yeast. The carboxyl-terminal two-thirds of hsp110 and these five related proteins contain a pattern of highly conserved regions of sequence unique to this group. A probe containing these conserved sequences was found to strongly cross-react on a Southern blot with genomic sequences from yeast to man. A Western blot analysis of several murine tissues indicates that hsp110 is constitutively expressed in all mouse tissues and is highly expressed in brain. Therefore, hsp110 belongs to a new category of large and structurally unique stress proteins that are the most distantly related known members of the hsp70 family.