Statins do not inhibit the FGFR signaling in chondrocytes.

OBJECTIVE: Statins are widely used drugs for cholesterol lowering, which were recently found to counteract the effects of aberrant fibroblast growth factor receptor (FGFR3) signaling in cell and animal models of FGFR3-related chondrodysplasia. This opened an intriguing therapeutic possibility for human dwarfing conditions caused by gain-of-function mutations in FGFR3, although the mechanism of statin action on FGFR3 remains unclear. Here, we determine the effect of statins on FGFR signaling in chondrocytes. DESIGN: Cultured chondrocyte cell lines, mouse embryonic tibia cultures and limb bud micromasses were treated with FGF2 to activate FGFR signaling. The effects of atorvastatin, fluvastatin, lovastatin and pravastatin on FGFR3 protein stability and on FGFR-mediated chondrocyte growth-arrest, loss of extracellular matrix (ECM), induction of premature senescence and hypertrophic differentiation were evaluated. RESULTS: Statins did not alter the level of FGFR3 protein expression nor produce any effect on FGFR-mediated inhibition of chondrocyte proliferation and hypertrophic differentiation in cultured chondrocyte cell lines, mouse tibia cultures or limb bud micromasses. CONCLUSION: We conclude that statins do not inhibit the FGFR signaling in chondrocytes. Therefore the statin-mediated rescue of FGFR3-related chondrodysplasia, described before, is likely not intrinsic to the growth plate cartilage.

[Metastatic Pituitary Disorders]. / Metastatické postizení hypofýzy.

BACKGROUND: Pituitary metastases are a rare complication of generalized cancer. Metastases to the pituitary gland occur in only 1% of patients operated on for sellar tumor. The most common presenting symptom in patients with pituitary metastases is diabetes insipidus, whereas this is rare in those with pituitary adenoma. MATERIAL AND METHODS: This publication presents the cases of two patients with pituitary metastases and a systematic review of the literature. English-language publications related to pituitary metastases and published from 1957 to 2016 were identified using the PubMed database. RESULTS: A total of 131 publications containing information about 259 patients (121 female and 138 male; mean age, 57.3 years) were identified. The most often metastasized breast carcinoma (24.6%) and lung carcinoma (23.8%), followed by thyroid carcinoma (11.3%), renal cell carcinoma (7.8%), hepatocellular carcinoma (4.3%), colorectal carcinoma (3.5%), and malignant melanoma (3.5%). The most frequent initial symptoms were manifestations of diabetes insipidus (39.6%), anterior pituitary deficiency (44.9%), perimeter disorders (51.6%), headache (37.6%), cranial nerve palsy (33.5%), and pseudoprolactinemia (16.7%). Radiotherapy (67.8%) and surgical treatment (63.9%) were the most frequently used treatment. CONCLUSION: The average survival time from the onset of metastatic disease was 11.8 months. Surgical therapy alone or in combination with radiation therapy does not prolong survival, but alleviates symptoms and improves quality of life.Key words: pituitary metastasis - diabetes insipidus - hypopituitarism - transsphenoidal surgery The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 13. 1. 2017Accepted: 4. 4. 2017.

[Autologous cranioplasty with a bone flap preserved subcutaneously in the mesogastrium]. / Autologní kranioplastika deponovanou kostní ploténkou v podkozí mezogastria.

INTRODUCTION: Cranioplasty with autologous bone flap is indicated in patients who have undergone decompressive craniectomy. Although it is an elective procedure, literature data indicate complication rates of up to 30%. The aim of this paper is to present our experience with cranioplasty with the patients own bone flap stored subcutaneously in the mesogastrium. METHODS: We retrospectively analyzed a set of 92 patients who had undergone cranioplasty after decompressive craniectomy using autologous graft preserved subcutaneously in the mesogastrium. The patients were clinically and radiologically examined before the surgery, and six weeks and one year after surgery. We evaluated the incidence of acute complications - wound hematoma, and late complications - infection and bone resorption. The postoperative cosmetic effect and patient discomfort from the stored bone flap also constituted an important aspect. RESULTS: The frequency of complications in our study group was 25%. Late complications were the most common, occurring with a frequency of 13%. These were mainly resorption of the bone flap (4.3%) and infectious complications (4.3%). Acute complications occurred with a frequency of 10.9% in our patient group. The most serious complication was cerebral edema of unknown origin leading to death of the patient. Unsatisfactory cosmetic effect as well as discomfort at the site where the flap was stored occurred in two cases. CONCLUSIONS: Cranioplasty is associated with a higher risk of complications in comparison with other elective procedures. Nevertheless, we regard cranioplasty with subcutaneously preserved bone flap as an inexpensive and suitable alternative to cryopreservation or alloplastic materials.Key words: cranioplasty complications of cranioplasty autologous cranioplasty decompressive craniectomy.

Placenta percreta leading to spontaneous complete uterine rupture in the second trimester. Example of a fatal complication of abnormal placentation following uterine scarring.

A 30-year-old gravida 2 para 1 was admitted to hospital 2 years after cesarean section at 20 weeks' gestation with acute onset of abdominal pain and hypovolaemic shock. Emergency laparotomy revealed a uterine rupture located in the anterior uterine wall caused by a placenta percreta and supracervical hysterectomy was performed. This site of invasion and finally rupture was in projection of the previous lower-segment cesarean section. This report illustrates the dramatic consequences of abnormal placentation after prior uterine surgery, which can already occur early during pregnancy and prior to the onset of labour.

Ciliopathy Protein Tmem107 Plays Multiple Roles in Craniofacial Development.

A broad spectrum of human diseases called ciliopathies is caused by defective primary cilia morphology or signal transduction. The primary cilium is a solitary organelle that responds to mechanical and chemical stimuli from extracellular and intracellular environments. Transmembrane protein 107 (TMEM107) is localized in the primary cilium and is enriched at the transition zone where it acts to regulate protein content of the cilium. Mutations in TMEM107 were previously connected with oral-facial-digital syndrome, Meckel-Gruber syndrome, and Joubert syndrome exhibiting a range of ciliopathic defects. Here, we analyze a role of Tmem107 in craniofacial development with special focus on palate formation, using mouse embryos with a complete knockout of Tmem107. Tmem107-/- mice were affected by a broad spectrum of craniofacial defects, including shorter snout, expansion of the facial midline, cleft lip, extensive exencephaly, and microphthalmia or anophthalmia. External abnormalities were accompanied by defects in skeletal structures, including ossification delay in several membranous bones and enlargement of the nasal septum or defects in vomeronasal cartilage. Alteration in palatal shelves growth resulted in clefting of the secondary palate. Palatal defects were caused by increased mesenchymal proliferation leading to early overgrowth of palatal shelves followed by defects in their horizontalization. Moreover, the expression of epithelial stemness marker SOX2 was altered in the palatal shelves of Tmem107-/- animals, and differences in mesenchymal SOX9 expression demonstrated the enhancement of neural crest migration. Detailed analysis of primary cilia revealed region-specific changes in ciliary morphology accompanied by alteration of acetylated tubulin and IFT88 expression. Moreover, Shh and Gli1 expression was increased in Tmem107-/- animals as shown by in situ hybridization. Thus, TMEM107 is essential for proper head development, and defective TMEM107 function leads to ciliary morphology disruptions in a region-specific manner, which may explain the complex mutant phenotype.

Prevention of human papilloma virus-induced preneoplasia and cancer by prophylactic HPV vaccines.

Persistent infection with human papilloma virus (HPV) is a necessary condition for the development of cervical, most of the vulvar and anal carcinoma and their precursors. HPV is the most common sexually transmitted virus throughout the world. About 70-80% of sexually active people are infected during their lifetime. Most infections are transient and asymptomatic and cleared by the host immune system within 12-18 months. Only persistent infections predispose to the development of genital preneoplasia and cancer. The first vaccine against HPV infection has been available in Italy since March 2006. The vaccine is a prophylactic, quadrivalent vaccine against the two most common oncogenic HPV types 16 and 18, responsible for more than 70% of cervical carcinomas and against the two low-risk types 6 and 11 responsible for 90% of cases of genital warts. A second, bivalent HPV 16/18 vaccine will be launched soon. The immunogenicity (100%) and efficacy of the vaccines is very high (96% against infection, 100% against disease). These vaccines constitute a milestone in the battle against cervical carcinoma, which is the second most common cancer in young women in Europe, with 33,500 new cases diagnosed every year.

Role of Primary Cilia in Odontogenesis.

Primary cilium is a solitary organelle that emanates from the surface of most postmitotic mammalian cells and serves as a sensory organelle, transmitting the mechanical and chemical cues to the cell. Primary cilia are key coordinators of various signaling pathways during development and maintenance of tissue homeostasis. The emerging evidence implicates primary cilia function in tooth development. Primary cilia are located in the dental epithelium and mesenchyme at early stages of tooth development and later during cell differentiation and production of hard tissues. The cilia are present when interactions between both the epithelium and mesenchyme are required for normal morphogenesis. As the primary cilium coordinates several signaling pathways essential for odontogenesis, ciliary defects can interrupt the latter process. Genetic or experimental alterations of cilia function lead to various developmental defects, including supernumerary or missing teeth, enamel and dentin hypoplasia, or teeth crowding. Moreover, dental phenotypes are observed in ciliopathies, including Bardet-Biedl syndrome, Ellis-van Creveld syndrome, Weyers acrofacial dysostosis, cranioectodermal dysplasia, and oral-facial-digital syndrome, altogether demonstrating that primary cilia play a critical role in regulation of both the early odontogenesis and later differentiation of hard tissue-producing cells. Here, we summarize the current evidence for the localization of primary cilia in dental tissues and the impact of disrupted cilia signaling on tooth development in ciliopathies.

The putative tumor suppressor gene FHIT at 3p14.2 is rarely affected by loss of heterozygosity in primary human brain tumors.

To elucidate the role of the recently identified FHIT gene, located at 3p14.2 in human brain tumor carcinogenesis, a total of 259 tumors were analyzed for loss of heterozygosity (LOH) at microsatellite loci D3S1313, D3S1234, D3S1300, and D3S1481. In primary brain tumors, LOH was detected at a frequency of 8.4% (n = 214). Low-grade gliomas exhibited insignificantly lower LOH rates in comparison to high-grade gliomas (5.3%, n = 19, versus 11.1%, n = 90). Notably, no allelic loss was observed in 12 recurrent glioblastomas analyzed in comparison to their corresponding primary tumor lesions and in two astrocytomas with progression to higher grades of malignancy. Our data indicate that allelic loss of the FHIT gene is neither a critical event in carcinogenesis of primary brain tumors nor tumor grade-associated in astrocytic tumors. In contrast, observed LOH rate for brain metastases was as high as 54.5% (n = 45), in accordance with data thus far accumulated from analyses of corresponding primary tumors.

Diagnosis, Therapy and Follow-up Care of Vulvar Cancer and its Precursors. Guideline of the DGGG and DKG (S2k-Level, AWMF Registry Number 015/059, November 2015.

Purpose: This is an official guideline, published and coordinated by the Arbeitsgemeinschaft Gynäkologische Onkologie (AGO, Study Group for Gynecologic Oncology) of the Deutsche Krebsgesellschaft (DKG, German Cancer Society) and the Deutsche Gesellschaft für Gynäkologie und Geburtshilfe (DGGG, German Society for Gynecology and Obstetrics). The number of cases with vulvar cancer is on the rise, but because of the former rarity of this condition and the resulting lack of literature with a high level of evidence, in many areas knowledge of the optimal clinical management still lags behind what would be required. This updated guideline aims to disseminate the most recent recommendations, which are much clearer and more individualized, and is intended to create a basis for the assessment and improvement of quality care in hospitals. Methods: This S2k guideline was drafted by members of the AGO Committee on Vulvar and Vaginal Tumors; it was developed and formally completed in accordance with the structured consensus process of the Association of Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF). Recommendations: 1. The incidence of disease must be taken into consideration. 2. The diagnostic pathway, which is determined by the initial findings, must be followed. 3. The clinical and therapeutic management of vulvar cancer must be done on an individual basis and depends on the stage of disease. 4. The indications for sentinel lymph node biopsy must be evaluated very carefully. 5. Follow-up and treatment for recurrence must be adapted to the individual case.

Loss of heterozygosity accumulation in primary breast carcinomas and additionally in corresponding distant metastases is associated with poor outcome.

The occurrence of distant metastases is the most feared manifestation of breast cancer, often occurring years after the primary surgery and associated with poor survival. The dominant metastatic clone is characterized by an accumulation of genetic alterations, but it is not actually known at what stage of the metastatic cascade these alterations have occurred. We investigated allelic losses during breast cancer progression in a series of 17 primary breast carcinomas and 22 corresponding brain, liver, lung, and bone metastases (mean metastasis-free interval, 31 months) by analyzing 19 microsatellite markers on seven breast cancer- or metastasis-related chromosomal regions and correlated the incidence of combined loss of heterozygosity (LOH) with metastasis-free and postmetastatic survival. We found that, in comparison with the corresponding primary tumor, additional LOH events are frequently found in metastases and that the incidence of combined LOH in the primary tumor, plus the occurrence of additional LOH events in the distant metastases, correlated significantly with decreased postmetastatic survival. Combined LOH of the three breast cancer-related chromosomal regions alone or in combination with allelic loss at the p53 gene region seems to have a specific influence on the aggressive behavior of metastases. We hypothesize that the occurrence of additional LOH events is either involved in termination of dormancy of micrometastatic tumor cells at distant organ sites or acquired during further progression of metastases.

Therapeutic effects of viral vector-mediated antiangiogenic gene transfer in malignant ascites.

Malignant ascites is a common complication of advanced intraabdominal neoplasms for which standard treatments are suboptimal. Evidence suggests that tumor-mediated angiogenesis and enhanced vascular permeability in the peritoneal wall due to high levels of vascular endothelial growth factor play a fundamental role in the pathogenesis of malignant ascites. To explore the advantage of viral vector-mediated "targeted antiangiogenic therapy" in ascites formation, we constructed and administered adenoviral vectors encoding several different antiangiogenic proteins (angiostatin, endostatin, platelet factor 4, and a fusion protein between angiostatin and endostatin) alone or in combination intraperitoneally in mice with peritoneal carcinomatosis from breast cancer (TA3 cells) and ovarian cancer (SKOV-3 i.p. and ES-2 cell lines) to explore the potential of additive or synergistic activity. Our data demonstrated statistically significant downregulation of ascites formation, tumor growth, vascularity, and prolongation of animal survival after intraperitoneal treatment with antiangiogenic adenoviral vectors in three different ascites tumor models. Combined treatment proved to be more effective than treatment with one vector alone. Reduced ascites formation was accompanied by decreased microvascular density in the peritoneal wall and increased apoptosis of tumor cells after administration of antiangiogenic vectors in vivo. Of interest was the observation that AdPF4 caused a significant decrease in the level of VEGF secreted by tumor cells both in vitro and in TA3 ascites tumor-bearing animals in vivo. These data suggest that adenoviral vector-mediated delivery of genes encoding antiangiogenic proteins may represent a potentially new treatment modality for malignant ascites.

An intronic germline transition in the HNPCC gene hMSH2 is associated with sporadic colorectal cancer.

The aim of this study was to determine whether an intronic germline substitution in the hereditary non-polyposis colorectal cancer (HNPCC) gene hMSH2 represents a genetic risk factor for sporadic CRC. Possible effects of this substitution were investigated by assessment of microsatellite instability and hMSH2 cDNA sequencing. Constitutional DNA from patients with sporadic CRC and healthy controls from the same region in Germany was analysed for the intronic germline T-->C transition six bases upstream of exon 13 of hMSH2. 29 of 106 patients (27%) were found to harbour the germline T-->C transition as opposed to only 13 of 125 controls (10%; P < 0.001; OR 3.2, CI 1.58-6.63). CRCs from patients with the substitution displayed neither clinical HNPCC-like features nor an increased rate of microsatellite instability. No abnormal cDNA sequence was found at the exon 12-13 border. These data suggest a 3.2-fold increased risk of sporadic CRC for individuals with the intronic hMSH2 transition. However, this substitution might not be pathogenic itself, but may be linked to a locus nearby that is.

Loss of BRCA2 correlates with reduced long-term survival of sporadic breast cancer patients.

BACKGROUND: The present study was undertaken to analyze the prognostic value of loss of heterozygosity (LOH) at 13q12-13, 17q21 and 17p13, harboring BRCA2, BRCA1 and p53 to predict the clinical course of sporadic breast cancer patients. MATERIALS AND METHODS: LOH analysis was performed by PCR amplification of genomic DNA using nine microsatellite markers. Fifty-three sporadic breast cancer patients were followed clinically for a median of 55 months. Disease-free and overall survival was documented as the endpoint for statistical evaluation. RESULTS: Patients presenting with LOH in their tumor samples at at least one of the loci examined were found to have a reduced overall survival time compared to those retaining heterozygosity (61% versus 48%). Focusing on the three target regions, patients with LOH at the BRCA2 locus died earlier compared to patients retaining heterozygosity (69% versus 50%) and, in addition, BRCA2 LOH-positive patients showed a shorter metastasis-free interval (30 versus 37 months). In a multivariate analysis, LOH at the 13q12-13 locus was found to be a significant predictor for reduced long-term survival (risk ratio 2.33, 95% C.I., 1.0-5.3; p<0.05) and earlier metastases manifestation (risk ratio 2.32, 95% C.I., 1.0-5.3, p<0.05). CONCLUSION: Allelic loss at the BRCA2 locus may be of use as a negative predictor for metastases-free and overall survival.

Hibernation-induction trigger. II. In vitro effects of prairie dog plasma albumin on mouse vas deferens contractility.

Involvement of opioid molecules in hibernation is well established, with the delta opioid receptor implicated in hibernation induction. Previous studies have shown that plasma albumin fractions (PAFs) from hibernating mammals contain an uncharacterized ligand called "hibernation-induction trigger" (HIT), which causes inhibition of induced contractility in the guinea pig ileum (GPI). In part I of this study, we described effects of PAF from two species of prairie dogs on induced contractility of the GPI. In the present study (part II), we examine the response of the mouse vas deferens (MVD), which is populated with the delta receptor subtype, to increasing concentrations of PAF from the white-tailed prairie dog (WT) and the black-tailed prairie dog (BT). Dose-response curves of lyophilized PAF yielded IC50 values (mg) (mean dose that inhibits contractility to 50% of control) of 11.0 for summer WT, 10.6 for hibernating WT, 9.4 for summer BT, 12.2 for winter active BT, and 4.7 for winter hibernating BT. These results suggest that delta opioid (HIT) is present in both species throughout the calendar year and that the induction of hibernation may involve not only levels of opioid but also dynamic interactions between endogenous opioid and its receptors.

[Mammographic screening starting in the fifth or sixth decade of life]. / Mammographisches Screening ab 5. oder 6. Lebensjahrzehnt?

Mammography is an established diagnostic procedure for breast cancer. Data concerning screening mammography are available from nine prospectively controlled trials, the largest series being presented from Sweden. Mammographic screening leads to a significant reduction of breast cancer of 30% in women ages 50-59 years. In younger women (40-49 years) the benefit accounts to only 20% and has not proven to be statistically significant. Nevertheless, the major advantage of mammographic screening is detection of the non-palpable tumor < or = 10 mm in size. The treatment of these small breast carcinomas leads to long-term survival rates of > or = 90%. Mammographic screening programs have been introduced in the USA, Canada, Iceland and Sweden for women in their 5th decade of life. Starting yearly lifelong mammography-screening at the age of 40, the theoretical cancer induction by radiation exposure does not exceed 0.1%. Under highly qualified conditions, it should be possible to minimize false-positive and false-negative screening results. In Germany, screening-mammography is only introduced in patients at high risk for breast cancer. Based on medical data, mammography must be a part of screening for women with an average risk--starting at the age of 40, although there are still open questions needing further clinical research.

Benefits of vaccinating young adult women with a prophylactic quadrivalent human papillomavirus (types 6, 11, 16 and 18) vaccine.

Cervical cancer is a leading cause of cancer-related deaths worldwide. The causal role of human papillomavirus (HPV) infection in the pathogenesis of cervical cancer has prompted the development of vaccines against HPV. The highest risk of HPV infection is in women aged 16-25 years. Almost all young adult women can benefit from HPV vaccination. There is strong epidemiological and clinical support for vaccination programmes that target sexually active women in this age group to prevent HPV infection, and thus avert the development of HPV-related disease. Furthermore, the implementation of HPV vaccination programmes may benefit the development or awareness of cervical cancer prevention strategies and ultimately reduce the burden of cervical cancer and improve cervical cancer control.

[Value of general human papillomavirus vaccination in sexually active women]. / Nutzen einer generellen HPV-Impfung bei sexuell aktiven Frauen.

Most cervical cancers are caused by human papillomavirus (HPV) genotypes 16 or 18, while almost all the anogenital warts are related to HPV 6 and 11. In placebo-controlled trials, a vaccine against HPV (6, 11, 16, 18) almost completely prevented infections and associated clinical lesions in primarily not infected women. Furthermore, new data demonstrate that sexually active women, as well as those with prior infection, also benefit from the vaccine. These results suggest that a general vaccination programme for sexually active women will be beneficial.

[Trends of population concentration in the Czech Socialist Republic from 1869 to 1970]. / Vyvoj hlavnich prostoru koncentrace obyvatelstva v CSR v letech 1869-1970

PIP: Trends and patterns of population concentration in the Czech Socialist Republic for the period 1869-1970 are examined, with a focus on the relationship between changes in population concentration and employment opportunities. The creation of new urban centers, as well as the advance and decline of existing urban areas, is analyzed in relation to differences in productivity throughout the country. (summary in ENG, RUS)^ieng

[The hierarchy of reality and the assessment of demographic and geo-demographic systems]. / Hierarchie reality a hodnoceni demografickych a geodemografickych systemu

PIP: The author presents a theoretical discussion of the hierarchy of real systems and then uses this framework to assess the specific features of demographic and geo-demographic systems (SUMMARY IN ENG)^ieng