Tyrosine kinase inhibitors. 15. 4-(Phenylamino)quinazoline and 4-(phenylamino)pyrido[d]pyrimidine acrylamides as irreversible inhibitors of the ATP binding site of the epidermal growth factor receptor.

A series of 6- and 7-acrylamide derivatives of the 4-(phenylamino)quinazoline and -pyridopyrimidine classes of epidermal growth factor receptor (EGFR) inhibitors were prepared from the corresponding amino compounds by reaction with either acryloyl chloride/base or acrylic acid/1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. All of the 6-acrylamides, but only the parent quinazoline 7-acrylamide, were irreversible inhibitors of the isolated enzyme, confirming that the former are better-positioned, when bound to the enzyme, to react with the critical cysteine-773. Quinazoline, pyrido[3,4-d]pyrimidine, and pyrido[3,2-d]pyrimidine 6-acrylamides were all irreversible inhibitors and showed similar high potencies in the enzyme assay (likely due to titration of the available enzyme). However the pyrido[3,2-d]pyrimidine analogues were 2-6-fold less potent than the others in a cellular autophosphorylation assay for EGFR in A431 cells. The quinazolines were generally less potent overall toward inhibition of heregulin-stimulated autophosphorylation of erbB2 (in MDA-MB-453-cells), whereas the pyridopyrimidines were equipotent. Selected compounds were evaluated in A431 epidermoid and H125 non-small-cell lung cancer human tumor xenografts. The compounds showed better activity when given orally than intraperitoneally. All showed significant tumor growth inhibition (stasis) over a dose range. The poor aqueous solubility of the compounds was a drawback, requiring formulation as fine particulate emulsions.     

Intestinal microsomal drug metabolism. A comparison of rat and guinea-pig enzymes, and of rat crypt and villous tip cell enzymes

A comparison was made of the properties of microsomes prepared from the small intestines of guinea pigs and rats. The NADPH2 cytochrome c reductase activity and cytochrome b5 and cytochrome P-450 content in rat microsomes was 42, 47 and 64% of that in the guinea pig, ethoxycoumarin deethylase activity was comparable, while arylesterase activity was twice as active in rats as guinea pigs. Investigation of the distribution of these and other parameters in rat intestinal epithelia revealed a preferential location of cytochrome P-450 in the villous tip while other parameters showed a more similar distribution between microsomes prepared from the villous tip and crypt.     

Mucinous epithelial ovarian cancer: a separate entity requiring specific treatment.

PURPOSE: Invasive mucinous carcinoma of the ovary (mucinous epithelial ovarian cancer [mEOC]) is a histologic subgroup of epithelial ovarian cancer (EOC). Chemotherapy for mEOC is chosen according to guidelines established for EOC. The purpose of this study is to determine whether this is appropriate. PATIENTS AND METHODS: Women with advanced mEOC (International Federation of Gynecology and Obstetrics stage III or IV) who underwent first-line platinum-based chemotherapy were compared with women with other histologic subtypes of EOC in a case-controlled study. RESULTS: Eighty-one patients (27 cases, 54 controls) treated with platinum-based regimens were analyzed. The response rates for cases and controls were 26.3% (95% CI, 9.2% to 51.2%) and 64.9% (95% CI, 47.5% to 79.8%), respectively (P=.01). The odds ratio for complete or partial response to chemotherapy for mEOC was 0.19 (95% CI, 0.06 to 0.66; P=.009) compared with other histologic subtypes of EOC. Median progression-free survival was 5.7 months (95% CI, 1.9 to 9.6 months) versus 14.1 months (95% CI, 12.0 to 16.2 months; P<.001) and overall survival was 12.0 months (95% CI, 8.0 to 15.6 months) versus 36.7 months (95% CI, 25.2 to 48.2 months; P<.001) for cases and controls, respectively. The hazard ratio for progression and death was 2.94 (95% CI, 1.71 to 5.07; P<.001) and 3.08 (95% CI, 1.69 to 5.6; P<.001), respectively, for mEOC patients as compared with controls. CONCLUSION: Patients with advanced mEOC have a poorer response to platinum-based first-line chemotherapy compared with patients with other histologic subtypes of EOC, and their survival is worse. Specific alternative therapeutic approaches should be sought for this group of patients, perhaps involving fluorouracil-based chemotherapy.     

The gynaecological management of women on tamoxifen: a national questionnaire survey.

Tamoxifen is the standard adjuvant treatment for women with breast carcinoma, decreasing the incidence of contralateral disease. However, the risk of endometrial cancer is increased. To establish current gynaecological management of women receiving tamoxifen in the United Kingdom we conducted a postal questionnaire of consultant gynaecologists, enquiring about frequency of, and methods used to investigate women on tamoxifen. Ninety-five per cent investigate women on tamoxifen only if they are symptomatic. Pelvic ultrasound and endometrial sampling are used for first-line investigation by 68.7%. Interpreting ultrasound findings, endometrial thickness is the parameter regarded as most important. An endometrial thickness of greater than 5 mm is regarded abnormal by 47.8% of respondents and of 4 mm by 23.6%. As there is no consensus of opinion regarding normal values for endometrial thickness, further data are required to ensure consistency when interpreting ultrasound reports of women on tamoxifen.     

激素治疗增加绝经后健康妇女尿失禁的发病率和严重程度

问题：在绝经后健康妇女中，激素治疗（hormone therapy，HT）对尿失禁（urinary incontinence，UI）的效果如何？     

Myocardial laser revascularization: the controversy and the data

The clinical and experimental data relevant to the theoretical mechanisms and clinical results of laser myocardial revascularization are reviewed. Both transmyocardial and percutaneous approaches are considered. Both types result in a reduction in anginal symptoms in patients refractory to conventional therapy and are likely to act through common pathways. The proximate mechanisms for the transmyocardial revascularization effect most likely relate to myocardial inflammation, secondary stimulation of growth factors, and denervation of the myocardium.     

Agminated segmental plaque‐type blue nevus associated with hypertrichosis and soft tissue hypertrophy: Report of a case and review of the literature

Blue nevi are common skin neoplasms that typically present as asymptomatic solitary papules, although they may rarely occur in an agminated configuration. We describe a case of agminated blue nevus in a segmental facial distribution associated with soft tissue hypertrophy and hypertrichosis in a 16‐year‐old boy and present a review of the literature. Although they are generally considered to be benign, concurrent soft tissue changes occurring within an agminated blue nevus should be investigated thoroughly to exclude alternate diagnoses.     

The Maladaptive Pursuit of Consumption: the Impact of Materialism,Pain of Paying,Social Anxiety,Social Support,and Loneliness on Compulsive Buying

The current research examined the capability of materialism, pain of paying, social anxiety, social support, and loneliness to predict compulsive buying. A sample of students attending a public university located in the northeast USA were surveyed. A multiple regression indicated materialism, pain of paying, anhedonia, coping with substances, and social support received from family were predictors of compulsive buying. Pain of paying was the strongest predictor of compulsive buying. Understanding factors that affect compulsive buying aids the identification of compulsive buying and informs the treatment of compulsive buying. Treatment models may be more effective if additional attention is given to addressing and developing social support networks of compulsive buyers. Such social support may act as a buffer against the social anxiety compulsive buyers experience and may help reduce feelings of anhedonia and use of substances to control social anxiety.