Mutant p53R273H attenuates the expression of phase 2 detoxifying enzymes and promotes the survival of cells with high levels of reactive oxygen species.

Uncontrolled accumulation of reactive oxygen species (ROS) causes oxidative stress and induces harmful effects. Both high ROS levels and p53 mutations are frequent in human cancer. Mutant p53 forms are known to actively promote malignant growth. However, no mechanistic details are known about the contribution of mutant p53 to excessive ROS accumulation in cancer cells. Herein, we examine the effect of p53(R273H), a commonly occurring mutated p53 form, on the expression of phase 2 ROS-detoxifying enzymes and on the ability of cells to readopt a reducing environment after exposure to oxidative stress. Our data suggest that p53(R273H) mutant interferes with the normal response of human cells to oxidative stress. We show here that, upon oxidative stress, mutant p53(R273H) attenuates the activation and function of NF-E2-related factor 2 (NRF2), a transcription factor that induces the antioxidant response. This effect of mutant p53 is manifested by decreased expression of phase 2 detoxifying enzymes NQO1 and HO-1 and high ROS levels. These findings were observed in several human cancer cell lines, highlighting the general nature of this phenomenon. The failure of p53(R273H) mutant-expressing cells to restore a reducing oxidative environment was accompanied by increased survival, a known consequence of mutant p53 expression. These activities are attributable to mutant p53(R273H) gain of function and might underlie its well-documented oncogenic nature in human cancer.

Modulation of the vitamin D3 response by cancer-associated mutant p53.

The p53 gene is mutated in many human tumors. Cells of such tumors often contain abundant mutant p53 (mutp53) protein, which may contribute actively to tumor progression via a gain-of-function mechanism. We applied ChIP-on-chip analysis and identified the vitamin D receptor (VDR) response element as overrepresented in promoter sequences bound by mutp53. We report that mutp53 can interact functionally and physically with VDR. Mutp53 is recruited to VDR-regulated genes and modulates their expression, augmenting the transactivation of some genes and relieving the repression of others. Furthermore, mutp53 increases the nuclear accumulation of VDR. Importantly, mutp53 converts vitamin D into an antiapoptotic agent. Thus, p53 status can determine the biological impact of vitamin D on tumor cells.

Pulmonary sarcoidosis associated with etanercept therapy.

We present a case of probable pulmonary sarcoidosis associated with the use of etanercept for psoriatic arthritis. Other cases of etanercept-induced granulomas and skin sarcoidosis were recently published in the medical literature, but we found only one case that involved lung sarcoidosis during etanercept therapy. We describe a 40-year-old man who was receiving etanercept for severe psoriatic arthritis and was admitted to the hospital with dyspnea and subfebrile illness several months after the start of treatment. His diagnosis was consistent exclusively with sarcoidosis. The patient's symptoms improved when etanercept was discontinued, but they did not resolve completely. Treatment with prednisone 40 mg led to complete improvement of his pulmonary disease. Etanercept therapy can induce or exacerbate sarcoidosis. The disease disappears when etanercept is discontinued, although treatment with corticosteroids is sometimes required, as in our patient. Use of the Naranjo adverse drug reaction probability scale revealed a probable likelihood (score of 6) that the adverse reaction was related to etanercept. The association of etanercept with sarcoidosis is still a rare finding. This case highlights the importance of monitoring and possibly discontinuing the drug when sarcoidosis is suspected. Patients should be monitored during and after etanercept therapy for manifestations suggesting sarcoidosis, and we recommend patients receive baseline chest radiography at the start of therapy with follow-up of respiratory symptoms.

Limited Wegener's granulomatosis--is it limited?

Complete heart block associated with Wegener's granulomatosis (WG) is rare especially in the limited form of the disease. We describe a case of a 43-year-old woman with a limited form of WG who developed a complete heart block. Prompt treatment with steroids and cyclophosphamide led to temporary regression of complete heart block. Further involvement of lung was treated successfully by tumor necrosis factor-alpha inhibitor infliximab. Cardiac rhythm abnormalities should always be kept in mind both in diagnosis and follow-up of WG.

Bacterial meningitis associated with infliximab.

We report an episode of bacterial meningitis in a 45 year-old woman, who was treated with infliximab for Wegener's granulomatosis. This patient presented with the classic clinical presentation of acute meningitis: the triad of fever, neck stiffness, and an altered mental state that appeared 6 months after the infliximab initiation. A computed tomographic (CT) scan of the head showed cerebral edema and Streptococcus pneumoniae was isolated from blood and CSF cultures. Prompt diagnosis and early treatment improved the outcome of this patient.

[Marijuana smoking and paroxysmal atrial fibrillation].

INTRODUCTION: Cannabis is the most widely used illegal drug in Israel, and unlike most of the other illegal drugs, it is common among segments of the population with higher demographic characteristics. CASE REPORT: A healthy 20 year old male patient, with two previous admissions with atrial fibrillation, was admitted to the emergency room with paroxysmal atrial fibrillation. The patient presented evidence of cannabis abuse, and no other pathologic cause for atrial fibrillation. Sinus rhythm was restored and the patient was discharged. DISCUSSION: Cannabis abuse is responsible for a wide range of pathologies, including cognitive impairment, a rise in the prevalence of lung, head and neck tumors, atrial and ventricular arrhythmias, and an increase in the risk of ischemic cardiovascular events. CONCLUSIONS: Cannabis abuse can induce atrial fibrillation in predisposed patients. Good practice may consider the inclusion of cannabis abuse tests in young patients admitted due to atrial fibrillation, and definite medical advice to stop the drug abuse.