Stromal Liver Kinase B1 [STK11] Signaling Loss Induces Oviductal Adenomas and Endometrial Cancer by Activating Mammalian Target of Rapamycin Complex 1

Germline mutations of the Liver Kinase b1 (LKB1/STK11) tumor suppressor gene have been linked to Peutz-Jeghers Syndrome (PJS), an autosomal-dominant, cancer-prone disorder in which patients develop neoplasms in several organs, including the oviduct, ovary, and cervix. We have conditionally deleted Lkb1 in Müllerian duct mesenchyme-derived cells of the female reproductive tract and observed expansion of the stromal compartment and hyperplasia and/or neoplasia of adjacent epithelial cells throughout the reproductive tract with paratubal cysts and adenomyomas in oviducts and, eventually, endometrial cancer. Examination of the proliferation marker phospho-histone H3 and mammalian Target Of Rapamycin Complex 1 (mTORC1) pathway members revealed increased proliferation and mTORC1 activation in stromal cells of both the oviduct and uterus. Treatment with rapamycin, an inhibitor of mTORC1 activity, decreased tumor burden in adult Lkb1 mutant mice. Deletion of the genes for Tuberous Sclerosis 1 (Tsc1) or Tsc2, regulators of mTORC1 that are downstream of LKB1 signaling, in the oviductal and uterine stroma phenocopies some of the defects observed in Lkb1 mutant mice, confirming that dysregulated mTORC1 activation in the Lkb1-deleted stroma contributes to the phenotype. Loss of PTEN, an upstream regulator of mTORC1 signaling, along with Lkb1 deletion significantly increased tumor burden in uteri and induced tumorigenesis in the cervix and vagina. These studies show that LKB1/TSC1/TSC2/mTORC1 signaling in mesenchymal cells is important for the maintenance of epithelial integrity and suppression of carcinogenesis in adjacent epithelial cells. Because similar changes in the stromal population are also observed in human oviductal/ovarian adenoma and endometrial adenocarcinoma patients, we predict that dysregulated mTORC1 activity by upstream mechanisms similar to those described in these model systems contributes to the pathogenesis of these human diseases

Radial club hand managed with ulnar osteotomy and centralization of hand: a case report and review

Radial club hand also called radial longitudinal deficiency or radial dyspasia is a preaxial longitudinal failure of formation. As the defect is preaxial it is often associated with thumb hypoplasia or anomaly of the radial aspect of the carpus. It is diagnosed clinically and on X-rays. It is frequently syndromic so it is a must to look for associated congenital anomalies by doing a through clinical examination. The frequency of this anomaly is between 1:50000 to 1:100000 live births. The incidence of all radial ray-deficient limbs, including hypoplastic thumbs alone, is approximately 1:30000. The radial deficiency is bilateral in 50% of the cases and the male:female is 3:2. It includes a wide spectrum of disorders that encompass an absent thumb or thumb hypoplasia, a thin first metacarpal and an absent radius. We report here a 1.5 years old child with isolated type IV radial club hand without any restricted range of motion in elbow managed with osteotomy of ulna and centralization of hand

Mammalian Target of Rapamycin Is a Therapeutic Target for Murine Ovarian Endometrioid Adenocarcinomas with Dysregulated Wnt/β-Catenin and PTEN

Despite the fact that epithelial ovarian cancers are the leading cause of death from gynecological cancer, very little is known about the pathophysiology of the disease. Mutations in the WNT and PI3K pathways are frequently observed in the human ovarian endometrioid adenocarcinomas (OEAs). However, the role of WNT/β-catenin and PTEN/AKT signaling in the etiology and/or progression of this disease is currently unclear. In this report we show that mice with a gain-of-function mutation in β-catenin that leads to dysregulated nuclear accumulation of β-catenin expression in the ovarian surface epithelium (OSE) cells develop indolent, undifferentiated tumors with both mesenchymal and epithelial characteristics. Combining dysregulated β-catenin with homozygous deletion of PTEN in the OSE resulted in development of significantly more aggressive tumors, which was correlated with inhibition of p53 expression and cellular senescence. Induced expression of both mTOR kinase, a master regulator of proliferation, and phosphorylation of its downstream target, S6Kinase was also observed in both the indolent and aggressive mouse tumors, as well as in human OEA with nuclear β-catenin accumulation. Ectopic allotransplants of the mouse ovarian tumor cells with a gain-of-function mutation in β-catenin and PTEN deletion developed into tumors with OEA histology, the growth of which were significantly inhibited by oral rapamycin treatment. These studies demonstrate that rapamycin might be an effective therapeutic for human ovarian endometrioid patients with dysregulated Wnt/β-catenin and Pten/PI3K signaling

Axin2+ endometrial stem cells: the source of endometrial regeneration and cancer

Menstruation is one of the basic but poorly understood life processes in primates during which females shed inner uterine lining every month only to be completely regenerated back within a week. The definitive evidence for the existence and/or identity of stem cells responsible for this process has remained elusive for more than six decades now. Recently, we reported Axin2, a classical Wnt reporter gene, as a marker for endometrial stem cells that also serve as the cells of origin for endometrial cancer

Dynamic expression of bone morphogenetic protein 4 in reproductive organs of female mice

Various members of the bone morphogenetic protein (BMP) family have been shown to regulate mammalian follicular development by affecting granulosa cell proliferation and steroidogenesis. In situ hybridization studies have shown expression of BMPR1A, BMPR1B, and BMPR2 in the granulosa cells and oocyte of most of the follicles in the ovary, suggesting that these cells have the capacity to respond to BMP signaling. Although much is known about BMP4 signaling, its expression pattern in the female reproductive tract (FRT) is still unclear. The objective of the current study was to characterize the expression of BMP4 and its downstream target proteins (pSMAD1/5/8) in the FRT. In the ovary, BMP4 protein was detected in all the stages of follicular development. Staining for pSMAD1/5/8 was observed in granulosa cells and oocytes of all the stages of follicular development including primordial follicles, suggesting that these follicles are responsive to autocrine/paracrine BMP signaling. In the uterus, BMP4 and pSMAD1/5/8 staining was observed in all three compartments and strongest expression was observed during the estrus phase. BMP4- and pSMAD1/5/8-specific staining was also observed in oviductal epithelium. Different forms (apparent MW: 50, 35, and 15 kDa) of BMP4 were detected in mouse ovary by western blot analysis. In conclusion, these results have defined BMP4 and pSMAD1/5/8 protein expression in the mouse FRT and highlighted the importance of BMP4 in folliculogenesis

Sustainable Development Through Smart Cities: Issues and Challenges

Smart city is about incorporating ‘smart thinking’ in the city’s urban design and planning with a focus on people place and planet. Cities around the world have taken a conscious effort in adopting smart city concepts and strategies to shape better cities for our environment. However, smart and sustainable city concepts need to be viewed together by integrating good planning and design into their physical and social fabric with a focus on people, place and planet along with information and communication technologies (ICT) to improve the quality of life of the city and its people. Through technology, cities can function more efficiently and adapt to their new environments better by utilising real-time data monitoring, assessment and sharing as information is received and can optimise decision-making to better understand and improve the status quo and quality of city life. A smart and sustainable city should be discussed together and should focus on encompassing three core values—people, place and planet while highlighting planning and design with ‘smart thinking’ as the central themes of developing smart and sustainable cities. This article will explore how smart and sustainable environment is achieved when applying ‘smart thinking’ to the city’s development with various cities as a case study of the principles

The Role of Bone Morphogenetic Protein-4 in Mammalian Reproduction

The BMPs comprise the largest subgroup of the TGF-β superfamily. Various members of the BMP family have been shown to regulate mammalian folliculogenesis by affecting granulosa cell proliferation, steroidogenesis and by modulating the production of various endocrine factors such as activin A, follistatin, inhibin, estradiol and progesterone. 'In situ' hybridization studies have shown expression of BMPR-IA, BMPR-IB and BMPRII in the granulosa cells and oocyte of most of the follicles in the ovary suggesting that these cells have capacity to respond to BMP signaling. In addition, the mRNA for BMP-4 and BMP-7 has been in detected in the theca layer of rat follicles. In 'in vitro' conditions, physiological concentrations of BMP-4 and BMP-7 enhanced and attenuated respectively,the stimulatory action of FSH on estradiol and progesterone production. The objective of the current study was to elucidate the role of BMP-4 in mammalian follicular development and spermatogenesis by using mouse and sheep as experimental models