Acacetin inhibits the proliferation of Hep G2 by blocking cell cycle progression and inducing apoptosis

Flavonoids are a broadly distributed class of plant pigments, universally present in vascular plants and responsible for much of the coloring in nature. They are strong antioxidants that occur naturally in foods and can inhibit carcinogenesis in rodents. In this study, we examined acacetin (5,7-dihydroxy-4'-methoxyflavone), a flavonoid compound, for its effect on proliferation in a human liver cancer cell line, Hep G2. The results showed that acacetin inhibited the proliferation of Hep G2 by inducing apoptosis and blocking cell cycle progression in the G1 phase. Enzyme-linked immunosorbent assay showed that acacetin significantly increased the expression of p53 and p21/WAF1 protein, contributing to cell cycle arrest. An enhancement in Fas/APO-1 and its two form ligands, membrane-bound Fas ligand and soluble Fas ligand, as well as Bax protein, was responsible for the apoptotic effect induced by acacetin. Taken together, our study suggests that the induction of p53 and activity of the Fas/Fas ligand apoptotic system may participate in the antiproliferative activity of acacetin in Hep G2 cells.     

Therapeutic potential of cannabinoids in trigeminal neuralgia

Trigeminal neuralgia is a disorder of paroxysmal and severely disabling facial pain and continues to be a real therapeutic challenge to the clinicians. While the exact cause and pathology of this disorder is uncertain, it is thought that trigeminal neuralgia caused by irritation of the trigeminal nerve. This irritation results from damage due to the change in the blood vessels, the presence of a tumor or other lesions that cause the compression of the trigeminal root. The pain of trigeminal neuralgia is characterized by unilateral pain attacks that start abruptly and last for varying periods of time from minutes to hours. The quality of pain is usually sharp, stabbing, lancinating, and burning. The attacks are initiated by mild stimuli such as light touch of the skin, eating, chewing, washing the face, brushing the teeth, and exposure to wind. Although antiepileptic drug therapy may be beneficial in the treatment of trigeminal neuralgia, up to one-half of the patients become refractory or intolerant to these medications. At present there are few other effective drugs. In cases of lacking effect after pharmacotherapy, surgical options may be considered. Currently there is growing amount of evidence to suggest that the psychoactive ingredient in cannabis and individual cannabinoids may be effective in alleviating neuropathic pain and hyperalgesia. Evidence suggests that cannabinoids may prove useful in pain modulation by inhibiting neuronal transmission in pain pathways. Considering the pronounced antinociceptive effects produced by cannabinoids, they may be a promising therapeutic approach for the clinical management of trigeminal neuralgia.     

Mutant, wild type, or overall p53 expression: freedom from clinical progression in tumours of astrocytic lineage

Abnormalities of the p53 tumor-suppressor gene are found in a significant proportion of astrocytic brain tumours. We studied tumour specimens from 74 patients evaluated over 20 years at the Massachusetts General Hospital, where clinical outcome could be determined and sufficient pathologic material was available for immunostaining. p53 expression studies employed an affinity-purified p53 monoclonal antibody, whose specificity was verified in absorption studies and, in a minority of cases, a second antibody recognising a different epitope of p53. Significant overexpression of p53 protein was found in 48% of the 74 tumours included in this series and high levels of expression were associated with higher mortality from astrocytic tumours (P<0.001, log rank). Multivariate analyses revealed that immunohistochemically detected p53 was an independent marker of shortened progression-free and overall actuarial survival in patients with astrocytic tumours, suggesting that increased expression of p53 plays an important role in the pathobiology of these tumours. In a subset of 36 cases, coding regions of the p53 gene were completely sequenced via SSCP and direct DNA sequencing, revealing that overexpression of p53 protein is not always associated with point mutations in conserved exons of the p53 gene. Finally, we confirmed p53 protein expression in early-passage human glioma cell lines of known p53 mutational status and immunostaining scores. Although grade continues to be the strongest prognostic variable, the use of p53 staining as a prognostic indicator, in contrast to mutational DNA analyses, may be a useful adjunct in identifying patients at higher risk of treatment failure.     

Induction of unresponsiveness limits tumor protection by adoptively transferred MDM2-specific cytotoxic T lymphocytes

There is evidence showing that high avidity CTLs can be more effective than low avidity CTLs for adoptive tumor immunotherapy. Because many T cell-recognized tumor antigens are nonmutated self-proteins, tolerance mechanisms are likely to render high avidity T cells unresponsive or cause T cell elimination by clonal deletion. We recently used the allo-restricted strategy to circumvent immunologic tolerance to a ubiquitously expressed tumor-associated protein, MDM2, and raised high avidity CTLs in humans and in mice. In this study, we investigated whether high avidity MDM2-specific CTLs can mediate tumor protection without causing damage to normal tissues in mice. Although the CTLs prolonged survival of tumor-bearing mice without causing damage to normal tissues, tumor protection was incomplete. We show that tumor growth occurred despite the continued presence of MDM2-specific CTLs and the continued susceptibility of tumor cells to CTL killing. However, analysis of the CTLs revealed that they had been rendered unresponsive in vivo because they did not produce interferon gamma in response to antigen-specific stimulation. These experiments suggest that induction of unresponsiveness may be an important mechanism limiting the efficacy of adoptive CTL therapy.     

Array comparative genomic hybridization analysis of genomic alterations in breast cancer subtypes

In this study, we performed high-resolution array comparative genomic hybridization with an array of 4153 bacterial artificial chromosome clones to assess copy number changes in 44 archival breast cancers. The tumors were flow sorted to exclude non-tumor DNA and increase our ability to detect gene copy number changes. In these tumors, losses were more frequent than gains, and gains in 1q and loss in 16q were the most frequent alterations. We compared gene copy number changes in the tumors based on histologic subtype and estrogen receptor (ER) status, i.e., ER-negative infiltrating ductal carcinoma, ER-positive infiltrating ductal carcinoma, and ER-positive infiltrating lobular carcinoma. We observed a consistent association between loss in regions of 5q and ER-negative infiltrating ductal carcinoma, as well as more frequent loss in 4p16, 8p23, 8p21, 10q25, and 17p11.2 in ER-negative infiltrating ductal carcinoma compared with ER-positive infiltrating ductal carcinoma (adjusted P values < or = 0.05). We also observed high-level amplifications in ER-negative infiltrating ductal carcinoma in regions of 8q24 and 17q12 encompassing the c-myc and c-erbB-2 genes and apparent homozygous deletions in 3p21, 5q33, 8p23, 8p21, 9q34, 16q24, and 19q13. ER-positive infiltrating ductal carcinoma showed a higher frequency of gain in 16p13 and loss in 16q21 than ER-negative infiltrating ductal carcinoma. Correlation analysis highlighted regions of change commonly seen together in ER-negative infiltrating ductal carcinoma. ER-positive infiltrating lobular carcinoma differed from ER-positive infiltrating ductal carcinoma in the frequency of gain in 1q and loss in 11q and showed high-level amplifications in 1q32, 8p23, 11q13, and 11q14. These results indicate that array comparative genomic hybridization can identify significant differences in the genomic alterations between subtypes of breast cancer.     

The use of dual phase 201Tl SPECT for differentiating pulmonary malignancies from benign lesions

BACKGROUND: This study examines the usefulness of thallium-201 single photon emission computed tomography ((201)Tl SPECT) in differentiating pulmonary malignancies from benign lesions by using dual phase (201)Tl scintigraphy. METHODS: One hundred and six patients with thoracic lesions and confirmed diagnoses were assessed by (201)Tl chest SPECT examinations; of these 106 enrolled thoracic lesions, 59 were malignancies and 47 were benign lesions. Dual phase (201)Tl SPECT was performed with an early image acquired at 10-20 min and a delayed image at 2-3 h after intravenous injection of 2-3 mCi of (201)Tl. The results of (201)Tl SPECT images were classified as either malignant or benign lesions by visual interpretation: the lesion was interpreted as positive for malignancy if the uptake of (201)Tl in the lung lesion in the delayed phase was increased or persistent as compared with that in the early phase image; otherwise, it was considered as a benign lesion. Simultaneously, the traditional method of retention index (RI) was also calculated to help in the differential diagnosis of pulmonary lesions. Then, both methods of dual phase (201)Tl SPECT, visual reading and traditional RI, were compared to differentiate pulmonary malignancies from benign lesions. RESULTS: Analyzing the image results, we found that dual phase (201)Tl SPECT could differentiate pulmonary malignancies from benign lesions with a sensitivity of 83%, a specificity of 91% and an accuracy of 87%. Moreover, by using the traditional RI method of (201)Tl SPECT, it could differentiate pulmonary malignancy from benign lesions with a sensitivity of 79.3%, a specificity of 80.8% and an accuracy of 80%. CONCLUSIONS: We conclude that using dual phase (201)Tl SPECT with visual interpretation is a simpler and potentially more effective method for differentiating pulmonary malignancies from benign lesions, with results compatible with the traditional RI method of (201)Tl SPECT.     

Association between diet and esophageal cancer in Taiwan

BACKGROUND: Several studies have reported the importance of dietary factors in the development of esophageal cancer. The purpose of the present study was to evaluate the effects of several common dietary factors on the risk of squamous cell carcinoma of the esophagus in a Taiwanese population. METHODS: The association between diet and esophageal cancer was examined in 284 male patients and 480 male controls, who were recruited during 6 year period. RESULTS: Consumption of preserved and overheated foods was found to be associated with increased risk of esophageal cancer, whereas intake of fresh fruits, vegetables, and tea was inversely associated with this risk. Men who consumed fermented bean products, salted food and preserved/pickled vegetables more than once a week after age 40 years had a 3.4-fold risk (95% confidence interval (CI): 1.9-6.2), 2.3-fold risk (95%CI: 1.2-4.2), and 2.5-fold risk (95%CI: 1.3-4.5), respectively, compared to men eating these items less than once a week. It was further found that these preserved foods were more strongly associated with esophageal cancer among men who consumed fruit less than once per day than those who consumed fruits one or more times per day. CONCLUSIONS: These results suggest that a high intake of preserved foods and overheated drinks might increase the risk of esophageal cancer, and intake of fruit, vegetables, and tea might be negatively associated with risk of esophageal cancer. The results also suggest that diet is an important factor in the development of esophageal cancer in Taiwan.