Decreased LRIG1 in fulvestrant-treated luminal breast cancer cells permits ErbB3 upregulation and increased growth.

ErbB3, a member of the ErbB family of receptor tyrosine kinases, is a potent activator of phosphatidyl inositol-3 kinase (PI3K) and mammalian target of rapamycin (mTOR) signaling, driving tumor cell survival and therapeutic resistance in breast cancers. In luminal breast cancers, ErbB3 upregulation following treatment with the antiestrogen fulvestrant enhances PI3K/mTOR-mediated cell survival. However, the mechanism by which ErbB3 is upregulated in fulvestrant-treated cells is unknown. We found that ErbB3 protein levels and cell surface presentation were increased following fulvestrant treatment, focusing our attention on proteins that regulate ErbB3 at the cell surface, including Nrdp1, NEDD4 and LRIG1. Among these, only LRIG1 correlated positively with ERα, but inversely with ErbB3 in clinical breast cancer data sets. LRIG1, an estrogen-inducible ErbB downregulator, was decreased in a panel of fulvestrant-treated luminal breast cancer cells. Ectopic LRIG1 expression from an estrogen-independent promoter uncoupled LRIG1 from estrogen regulation, thus sustaining LRIG1 and maintaining low ErbB3 levels in fulvestrant-treated cells. An LRIG1 mutant lacking the ErbB3 interaction motif was insufficient to downregulate ErbB3. Importantly, LRIG1 overexpression improved fulvestrant-mediated growth inhibition, whereas cells expressing the LRIG1 mutant were poorly sensitive to fulvestrant, despite effective ERα downregulation. Consistent with these results, LRIG1 expression correlated positively with increased disease-free survival in antiestrogen-treated breast cancer patients. These data suggest that ERα-dependent expression of LRIG1 dampens ErbB3 signaling in luminal breast cancer cells, and by blocking ERα activity with fulvestrant, LRIG1 is decreased thus permitting ErbB3 accumulation, enhanced ErbB3 signaling to cell survival pathways and blunting therapeutic response to fulvestrant.

A case of congenital central hypoventilation syndrome in a three-generation family with non-polyalanine repeat PHOX2B mutation.

We describe a three generation family in whom multiple individuals are variably affected due to a PHOX2B non-polyalanine repeat mutation. This family demonstrates extreme phenotypic variability and autosomal dominant transmission over three generations not previously reported in the wider literature. Novel findings also inclue a history of recurrent second trimester miscarriage. Pediatr Pulmonol. 2014; 49:E140-E143. © 2014 Wiley Periodicals, Inc.

Cancer linked to Alzheimer disease but not vascular dementia.

OBJECTIVE: To investigate whether cancer is associated with Alzheimer disease (AD) and vascular dementia (VaD). METHODS: Cox proportional hazards models were used to test associations between prevalent dementia and risk of future cancer hospitalization, and associations between prevalent cancer and risk of subsequent dementia. Participants in the Cardiovascular Health Study-Cognition Substudy, a prospective cohort study, aged 65 years or older (n = 3,020) were followed a mean of 5.4 years for dementia and 8.3 years for cancer. RESULTS: The presence of any AD (pure AD + mixed AD/VaD; hazard ratio [HR] = 0.41, 95% confidence interval [CI] = 0.20-0.84) and pure AD (HR = 0.31, 95% CI = 0.12-0.86) was associated with a reduced risk of future cancer hospitalization, adjusted for demographic factors, smoking, obesity, and physical activity. No significant associations were found between dementia at baseline and rate of cancer hospitalizations for participants with diagnoses of VaD. Prevalent cancer was associated with reduced risk of any AD (HR = 0.72; 95% CI = 0.52-0.997) and pure AD (HR = 0.57; 95% CI = 0.36-0.90) among white subjects after adjustment for demographics, number of APOE epsilon4 alleles, hypertension, diabetes, and coronary heart disease; the opposite association was found among minorities, but the sample size was too small to provide stable estimates. No significant association was found between cancer and subsequent development of VaD. CONCLUSIONS: In white older adults, prevalent Alzheimer disease (AD) was longitudinally associated with a reduced risk of cancer, and a history of cancer was associated with a reduced risk of AD. Together with other work showing associations between cancer and Parkinson disease, these findings suggest the possibility that cancer is linked to neurodegeneration.

Subtalar arthroscopy: indications, technique, and results.

The purpose of this study was to present the indications, technique, and results for subtalar arthroscopy in 50 consecutive patients. In each case, ankle arthroscopy was performed concomitantly to assess the exact source of the patient's pain. Surgical indications included chronic pain, swelling, buckling, and/or locking that failed conservative treatment. Arthroscopy of the ankle and subtalar joints were performed using both 2.7- and 1.9-mm arthroscopes through standard and accessory portals; distraction was used in all cases. All patients were followed-up for an average of 48 months (range, 36 to 70 months). Group 1 included 21 patients (42%) with chronic lateral ankle pain following an inversion injury. In this group, the subtalar joints were completely normal and the pathology was found to be limited only to the ankle joint. In group 2, 29 patients (58%) had the following diagnoses at arthroscopy: synovitis, 7; degenerative joint disease, 5; subtalar dysfunction, 5; chondromalacia, 4; nonunion of os trigonum, 4; arthrofibrosis, 2; loose bodies, 1; and osteochondral lesions of the talus, 1. Overall, the results were 86% good-to-excellent in group 2.

Comparison of two rapid enzyme immunoassays with standard enzyme immunoassay and latex agglutination for the detection of human rotavirus in stools.

We evaluated the performance of six commercially available immunoassays for their ability to detect rotaviruses in stool specimens. Four of the assays were enzyme-linked immunosorbent assays (ELISA), including two rapid enzyme immunoassays (Testpack, Abbott Laboratories, Chicago and Pinpoint, Cambridge Biomedical, UK), and the remaining two were latex agglutination tests. A total of 100 specimens from children with gastroenteritis were tested with the commercial immunoassays and compared with electron microscopy (EM) and polyacrylamide gel electrophoresis (PAGE) as reference tests for the detection of rotavirus. Discordant results were further evaluated by a standard blocking ELISA. The rapid EIAs were found to be highly sensitive (100% for the Testpack and 97% for the Pinpoint) and more sensitive than the other immunoassays tested. High specificity was also recorded with both rapid EIAs (96% and 100% for Testpack and Pinpoint, respectively). The rapid EIA tests were easy to perform, required no specialized equipment, and could yield a result in less than 15 min. The results show that each of the commercial assays evaluated could accurately detect rotavirus in the stools of children with gastroenteritis, although the suitability of choice of assay will ultimately depend upon the requirements of the individual laboratory.

The Buford complex--the "cord-like" middle glenohumeral ligament and absent anterosuperior labrum complex: a normal anatomic capsulolabral variant.

Two hundred consecutive shoulder arthroscopy videotapes were retrospectively reviewed, paying specific attention to the anatomy of the anterosuperior glenoid quadrant and especially the labroligamentous complex. Normal glenohumeral anatomy and all variations were carefully evaluated and recorded. Twenty-four (12%) patients had a sublabral foramen below the anterosuperior labrum; a "cord-like" middle glenohumeral ligament was present in 75% (18 of 24) of those cases or 9% of the study population. A smaller group of patients demonstrated a unique variant of normal capsulolabral anatomy that, for convenience, is termed the "Buford complex." This unusual variant was noted in 3 of the 200 (1.5%) shoulders and was distinguished by a "cord-like" middle glenohumeral ligament that originated directly from the superior labrum at the base of the biceps tendon and crossed the subscapularis tendon to insert on the humerus. There was no anterior-superior labral tissue present between this attachment and the midglenoid notch. This unusual-appearing anatomical variation may lead the surgeon to confuse this complex with a sublabral hole or a pathologic labral detachment. The labral tissue of the remaining three glenoid quadrants was normal. If the Buford complex is mistakenly reattached to the neck of the glenoid, as illustrated in our case example, severe painful restriction of rotation and elevation will occur.

Regulation of interleukin-1 and tumour necrosis factor gene expression in myelomonocytic cell lines by 1,25-dihydroxyvitamin D3.

1,25-dihydroxyvitamin D3[1,25-(OH)2D3] is capable of regulating cells in the immune system and affects cytokine production by both T lymphocytes and by monocytes. We examined the effects of 1,25-(OH)2D3 on the regulation of interleukin-1 beta (IL-1 beta) and tumour necrosis factor-alpha (TNF-alpha) genes in HL-60 and U937 cells. 1,25-(OH)2D3 alone only induced low level expression of the genes for these cytokines. Phorbol 12-myristate 13-acetate (PMA) strongly induced the transcription of these genes, whilst the addition of 1,25-(OH)2D3 to PMA-stimulated cells caused a further dose-dependent synergistic increase in the mRNA for both cytokines in U937 cells. In PMA-stimulated HL-60 cells, 1,25-(OH)2D3 increased the mRNA for IL-1 beta but not that for TNA-alpha, These differences may be related to the different stage of myeloid differentiation in HL-60 and U937 cells.

Early regulation of c-myc mRNA by 1,25-dihydroxyvitamin D3 in human myelomonocytic U937 cells.

The effects of 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3; 10 nmol/l) on the human monomyelocytic cell line U937 were investigated. Addition of 1,25-(OH)2D3 led to a decrease in cell proliferation which fell at 72 h to 67.8 +/- 4.3% (mean +/- S.E.M.) of control values. The presence of CD14, a surface marker found on mature monocytes/macrophages but not on U937 cells, was detectable as early as 18 h and peaked at 48 h, when 63.6 +/- 4.2% of the cells were positive. However, changes in c-myc mRNA levels were detected earlier, starting within 4 h of exposure to the hormone and being reduced to 38 +/- 8.2% of control values of 24 h. These effects were reversible after removal of the hormone, with the same sequence of events seen following addition of the hormone. There was first an increase in c-myc mRNA levels, starting within 2 h and reaching control values by 24 h. These changes were followed by loss of CD14 which became undetectable after 72 h. Proliferation recovered slowly and incompletely, since it was 81.7 +/- 0.7% of control after 72 h. A constant reciprocal relationship between c-myc mRNA and CD14 levels was found both in the presence and after removal of 1,25-(OH)2D3. Regulation of U937 cell proliferation and maturation by 1,25-(OH)2D3 is thus preceded by early modulation of c-myc mRNA.