The TGF-βs are multifunctional proteins whose activities are believed to be controlled by interaction with the latent TGF-β binding proteins (LTBPs). In spite of substantial effort, the precise in vivo significance of this interaction remains unknown. To examine the role of the Ltbp-3, we made an Ltbp-3–null mutation in the mouse by gene targeting. Homozygous mutant animals develop cranio-facial malformations by day 10. At 2 mo, there is a pronounced rounding of the cranial vault, extension of the mandible beyond the maxilla, and kyphosis. Histological examination of the skulls from null animals revealed ossification of the synchondroses within 2 wk of birth, in contrast to the wild-type synchondroses, which never ossify. Between 6 and 9 mo of age, mutant animals also develop osteosclerosis and osteoarthritis. The pathological changes of the Ltbp-3–null mice are consistent with perturbed TGF-β signaling in the skull and long bones. These observations give support to the notion that LTBP-3 is important for the control of TGF-β action. Moreover, the results provide the first in vivo indication for a role of LTBP in modulating TGF-β bioavailability.

Amplification of Her-2/neu in breast carcinoma is associated with poor prognosis, short disease-free interval, and short survival time in both nodenegative and -positive patients. Little is known about the starting point of amplification of Her-2/ neu and how it progresses from benign to malignant breast lesions. We attempted to address these questions by evaluating amplification of Her-2/neu in benign, premalignant, and malignant lesions using fluorescence in situ hybridization (FISH). Twentysix patients with Her-2/neu-overexpressing invasive ductal carcinomas (as judged by strong immunoreactivity with Her-2/neu antibody) and coexisting lesions of ductal hyperplasia (DH), atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS) in the vicinity of the invasive tumor (as judged by review of the hematoxylin and eosin-stained sections), as well as metastatic carcinoma in axillary lymph nodes (mets) were selected for this study. In the primary carcinomas, a close relationship was present between overexpression as detected by immunohistochemistry (IHC) and amplification as demonstrated by FISH (85% concordance). Among these patients, amplification of Her-2/neu in ADH was demonstrated in 7 of 13 cases with ADH, and in DCIS, in 21 of 22 cases with DCIS. There was no amplification in DH or normal ductal epithelium. Significantly, in all 12 patients with synchronous positive axillary lymph nodes, there was concordant amplification of Her-2/neu in the primary and metastatic carcinoma. Amplification was consistent in multifocal metastases, despite morphological heterogeneity in some patients. Amplification ratios increased from ADH to DCIS to invasive carcinoma (P < .01, ADH versus DCIS; P < .05, DCIS versus invasive cancer), but there was no difference in amplification ratios between primary cancers and synchronous axillary metastases (P > .05). We also evaluated Her-2/neu amplification in 21 patients without Her-2/neu overexpression in their primary carcinomas (as judged by absent immunoreactivity with Her-2/neu antibody). Three showed amplification in both primary and metastatic lesions, with a low amplification ratio (approximately 2). One patient had amplification in the primary tumor but not in an axillary metastasis. Two patients exhibited slight amplification in the metastatic carcinoma (ratios 1.6 and 2), but not in their primary cancers. This FISH study indicates that amplification of Her-2/neu can emerge de novo in any stage of the disease process, from ADH to metastatic lesions, but most often appears first in ADH or DCIS. The degree of Her-2/neu amplification increases with progression to invasive carcinoma, there being no further increase in synchronous metastasis. Our data suggest that amplification of Her-2/neu appears to be mainly involved in initiation of breast oncogenesis and that its role in progression of breast cancers is uncertain. Her-2/neu, a proto-oncogene located on chromosome 17q, encodes a transmembrane tyrosine kinase with substantial homology to the epidermal growth factor receptor...

Overexpression of HMGA2 is common in uterine leiomyomas (ULM). The expression of HMGA2 in its malignant counterpart – uterine leiomyosarcomas (ULMS) remains undetermined. Recently it has been shown that repression of HMGA2 by microRNA let-7s is a critical molecular regulatory mechanism associated with tumour growth in many tumours and cell types, including leiomyomas. To test whether HMGA2 and let-7s play a role in ULMS, we examined the levels of endogenous HMGA2 and let-7 expression and found a significant correlation between these two molecules in a case-matched cohort of human ULMS. We found that overexpression of HMGA2 and let-7-mediated HMGA2 repression is a relevant molecular alteration in ULMS. Disrupting the control of HMGA2 and let-7 pairs promotes ULMS cell growth in vitro.

Purpose To estimate the prevalence of chromosomally abnormal related miscarriages in an infertile population. Methods Retrospective analysis of cytogenetics obtained by chorionic villi harvesting of the first miscarriage cycle of infertile patients at our center from 2001-2010 were reviewed. Abnormal results were characterized as trisomy, monosomy X, structural, or other. Age, # of eggs, #2PN, # embryos transferred, day of transfer, and performance of intracytoplasmic sperm injection (ICSI) were recorded. Results In a study population of 299 patients with a mean age of 38.0±4.5 y, 276(92 %) patients had some form of assisted reproductive technologies (ART), and 244(82 %) had IVF. Of all results, 71.6 % had an abnormal karyotype. Patients with abnormal cytogenetics were older (38.6±4.1 vs. 36.3± 4.9, p<0.001), and more likely to have a day 3 transfer (age <38(20.7 %) vs. age 38 (46.3 %), p0<0.001) with more embryos transferred (3.0±1.2, vs. 2.3±0.9, p<0.001). The performance of ICSI did not affect the rate of cytogenetically abnormal products of conception (ICSI 68.3 % vs. no ICSI 70.7 %). In comparing patients, monosomy X was more common in <38 y. Rates of trisomy, although not statistically significant, were higher in older patients. Conclusions The classic associations between advancing age and chromosomal abnormalities, and younger age and monosomy X, are affirmed in our infertile population. There was no increase in chromosomal abnormalities in cycles where ICSI was performed. Older patients are more likely to have day 3 transfers and more embryos transferred. Our chromosomal abnormality rates are higher than classic estimates but comparable to recent studies. The limitation of this study was a lack in uniformity among practitioners in recommending all patients have a Dilation and Curettage (D&C) at time of diagnosis. Such information may serve to improve the counseling of patients after miscarriage.

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