Reactive oxygen species and p21Waf1/Cip1 are both essential for p53-mediated senescence of head and neck cancer cells.

Treatment of head and neck squamous cell carcinoma, HNSCC, often requires multimodal therapy, including radiation therapy. The efficacy of radiotherapy in controlling locoregional recurrence, the most frequent cause of death from HNSCC, is critically important for patient survival. One potential biomarker to determine radioresistance is TP53 whose alterations are predictive of poor radiation response. DNA-damaging reactive oxygen species (ROS) are a by-product of ionizing radiation that lead to the activation of p53, transcription of p21(cip1/waf1) and, in the case of wild-type TP53 HNSCC cells, cause senescence. The expression of p21 and production of ROS have been associated with the induction of cellular senescence, but the intricate relationship between p21 and ROS and how they work together to induce senescence remains elusive. For the first time, we show that persistent exposure to low levels of the ROS, hydrogen peroxide, leads to the long-term expression of p21 in HNSCC cells with a partially functional TP53, resulting in senescence. We conclude that the level of ROS is crucial in initiating p53's transcription of p21 leading to senescence. It is p21's ability to sustain elevated levels of ROS, in turn, that allows for a long-term oxidative stress, and ensures an active p53-p21-ROS signaling loop. Our data offer a rationale to consider the use of either ROS inducing agents or therapies that increase p21 expression in combination with radiation as approaches in cancer therapy and emphasizes the importance of considering TP53 status when selecting a patient's treatment options.

An epizootic of lymphoplasmacytic gastritis attributed to Helicobacter pylori infection in cynomolgus monkeys (Macaca fascicularis).

An epizootic of subclinical lymphoplasmacytic gastritis occurred in cynomolgus monkeys maintained at our research facility. Gastric pathology data and histologic sections of 63 adolescent monkeys (2.5-3.5 years old) sacrificed during the epizootic were reviewed. Localized to multifocal reddening of the gastric mucosa was noted grossly in 7 of 44 (16%) monkeys harboring Helicobacter pylori, but not in any of 19 monkeys in which these bacteria were not seen. Gastritis, characterized by accentuation of lymphoplasmacytic infiltrates in antral and to a lesser degree cardiac mucosa, occurred in 42 of 63 (67%) monkeys evaluated and in 42 of 44 (93%) monkeys in which H. pylori was observed microscopically. Two monkeys with H. pylori infection had infiltrate scores that overlapped with the upper limit of scores of H. pylori-negative animals. Coincident with accentuated infiltrates were gastric gland epithelial hyperplasia, reduction in mucin content of surface and gland epithelia, and comparatively minor infiltrates of neutrophils in superficial lamina propria and gastric glands. Antral mucosa thickness often exceeded 1.5 to 2 times normal. Antral mucosal erosions occurred in 7 of 44 (16%) monkeys with H. pylori. Argyrophilic bacteria morphologically consistent with H. pylori were present in antral and less commonly cardiac mucosal glands. Intensity of bacterial colonization correlated with lymphoplasmacytic infiltrates (r = 0.754) and hyperplasia (r = 0.700), although responses were quite variable. These bacteria were not detected in fundic mucosa except in instances where parietal cells were substantially depleted in glands coincident with localized increases in lamina propria inflammatory cell infiltrates. Helicobacter heilmannii-like organisms (HHLOs) were present in fundic glands of all 63 monkeys; colonization was often pronounced. Scores for fundic mucosal inflammation did not correlate with presence or intensity of colonization with HHLOs (r = 0.005). Rather, fundic inflammation scores positively correlated with the antral inflammation scores (r = 0.548). Bacteria morphologically, biochemically, and genetically consistent with H. pylori were cultured from gastric mucosal specimens confirming bacterial identification. These findings demonstrate that adolescent cynomolgus monkeys are susceptible to natural infection with H. pylori and develop many morphologic hallmarks of H. pylori-related gastritis in humans.

Pharmacological studies of centrifugation-induced analgesia.

Subjecting rats to a brief period of centrifugal rotation produces a brief analgesia (1-2 min) that is similar to that produced by pretreatment with morphine. The effect of the morphine is blocked by naloxone, while that of the centrifugal rotation is only partially blocked by the same dose of naloxone. Cholinergic blocking agents such as scopolamine are also capable of partially blocking the rotational-induced analgesia. The combination of pretreatment with scopolamine plus naloxone is capable of completely blocking the rotational-induced analgesia, suggesting the involvement of both central cholinergic and endogenous opioid components.

Immune function in pheasants experimentally infected with marble spleen disease virus.

Two experiments were conducted to evaluate the effect of marble spleen disease virus (MSDV) infection on the immune response of pheasants. In the first, 15 ring-necked pheasants were inoculated orally with cell-culture-propagated MSDV and 15 received saline (controls). On days 7, 21, and 35 postinoculation (PI), all birds received sheep erythrocytes intravenously. Hemagglutination titers to sheep erythrocytes were determined for serum samples collected weekly for 6 weeks. The virus-inoculated group had significantly (P less than 0.05) lower hemagglutination titers than the control group. In the second experiment, 30 pheasants were allotted into two groups as above. Whole blood was collected from each bird weekly for 5 weeks. The blood was cultured in microtiter plates with or without optimum concentrations of concanavalin A. Five of 10 MSDV-inoculated pheasants had significantly depressed T lymphocyte transformation on either day 7 or day 14 PI. Overall, the depression of T lymphocyte transformation was transient and mild.