Functional redundancy between Apc and Apc2 regulates tissue homeostasis and prevents tumorigenesis in murine mammary epithelium.

Aberrant Wnt signaling within breast cancer is associated with poor prognosis, but regulation of this pathway in breast tissue remains poorly understood and the consequences of immediate or long-term dysregulation remain elusive. The exact contribution of the Wnt-regulating proteins adenomatous polyposis coli (APC) and APC2 in the pathogenesis of human breast cancer are ill-defined, but our analysis of publically available array data sets indicates that tumors with concomitant low expression of both proteins occurs more frequently in the 'triple negative' phenotype, which is a subtype of breast cancer with particularly poor prognosis. We have used mouse transgenics to delete Apc and/or Apc2 from mouse mammary epithelium to elucidate the significance of these proteins in mammary homeostasis and delineate their influences on Wnt signaling and tumorigenesis. Loss of either protein alone failed to affect Wnt signaling levels or tissue homeostasis. Strikingly, concomitant loss led to local disruption of ß-catenin status, disruption in epithelial integrity, cohesion and polarity, increased cell division and a distinctive form of ductal hyperplasia with 'squamoid' ghost cell nodules in young animals. Upon aging, the development of Wnt activated mammary carcinomas with squamous differentiation was accompanied by a significantly reduced survival. This novel Wnt-driven mammary tumor model highlights the importance of functional redundancies existing between the Apc proteins both in normal homeostasis and in tumorigenesis.

Design and validation of an improved nonferrous smoking device for self-administration of smoked drugs with concurrent fMRI neuroimaging.

Several popularly abused drugs, such as nicotine (tobacco) and THC (delta9-tetrahydrocannabinol) (marihuana) are commonly self-administered by the smoked route. Although the neuronal substrates mediating the effect of smoked drugs are of interest, studies of their acute actions in living human brain has been difficult due to the unique constraints imposed by neuroimaging equipment and scanning environments. We have previously reported a device for the self-administration of smoked drugs with concurrent blood oxygen level dependent (BOLD) fMRI imaging. Here we report improvements to the device which result in improved drug delivery to the smoker. Gas chromatography/mass spectrometry (GCMS) analysis of nicotine recovered from filter extracts revealed that the amount of nicotine delivered to subjects smoking with our original device was reduced by approximately 44% compared to nicotine delivered by cigarettes smoked normally. Improvements were made to the smoke delivery component of our apparatus in an attempt to improve drug delivery, while not interfering with collection of MRI data. Nicotine plasma levels in 9 subjects smoking both with and without the improved smoking device in the laboratory were not significantly different. Similarly, the device produced no significant difference in either ratings of the subjective effects of nicotine, or changes in cardiovascular parameters in this experiment. The improved device does not interfere with typical drug effects produced by normal smoking. Phantom scans revealed that BOLD signal was not found to be altered by the (in-bore) installation and operation of the improved device. Preliminary data analysis of smoking induced changes in the BOLD response to visual stimulation suggest that this response is not affected by the improved device, the act of smoking, air puffing, nicotine, or other components of cigarette smoke. The improved device does not interfere with the collection of MRI neuroimaging data. Use of this device will facilitate investigations of the acute neuronal effects of smoked drugs.

The effect of interobserver variation in dating endometrial histology on the diagnosis of luteal phase defects.

Endometrial biopsy specimens (n = 62) were evaluated by five pathologists to assess the effect of interobserver variation on histologic dating of the endometrium. The potential effect of this variation on the diagnosis of luteal phase defects (LPDs) and resulting clinical management was also determined. Mean (+/- standard error) interobserver variation was 0.96 +/- 0.08 days, comparable to results reported by other investigators. The magnitude of the variation was not affected by whether the biopsy specimen was obtained in the mid or late luteal phase, the degree of lag between the dating and subsequent menses, or the presence of an LPD. Redating of a specimen by another pathologist would have resulted in a change in the determination of "in" or "out" of phase in 22% of cases. The subsequent probability of changing patient management altered ranged from 22% to 39% depending on the clinical setting.

Visualization of hepatic adenoma with Tc-99m di-isopropyl IDA.

A case of hepatic adenoma is reported, presenting as a defect on sulfur colloid liver image and visualized on a biliary scintigram. Although biliary imaging in the evaluation of sulfur colloid defects may be of value in selected patients, combination imaging in this case could not distinguish a benign from a malignant process.

Enhanced uptake of liposomes by bovine macrophages after opsonization with antibodies to Brucella abortus.

Phosphatidylcholine:cholesterol liposomes containing 4(5) carboxyfluorescein were modified by incorporation of Brucella abortus lipopolysaccharide. These vesicles were opsonized with bovine anti-B abortus or anti-B abortus plus complement. The fluorescent marker entrapped in antibody-opsonized liposomes was taken up by cultured bovine macrophages more effectively than was the same compound which had been loaded into nonopsonized liposomes. The addition of bovine complement to antibody-opsonized liposomes did not increase the extent of 4(5) carboxyfluorescein uptake over that caused by antibodies alone. The system, described in this report, could be used as a model for evaluation of the efficacy of selectively directing liposomes containing antibiotics to macrophages infected with intracellular B abortus, since macrophages possess Fc receptors capable of binding antibody-opsonized liposomes.