Emerging diagnostic, prognostic and therapeutic biomarkers for ovarian cancer

Abstract

Background

In spite of various treatment options currently available, ovarian cancer (OC) still remains a leading cause of death in women world-wide. Diagnosis at an early stage is one of the most important factors that determines survival. Current clinical diagnostic tools have, however, a limited efficacy in early OC detection. Therefore, there is a critical need for new (early) diagnostic biomarkers and tools. Through advances in genomic, proteomic and metabolomic techniques, several novel molecular OC biomarkers have recently been identified. These biomarkers are currently subject to validation. In addition, integration of genomic, proteomic and metabolomic data, in conjunction with epidemiologic and clinical data, is considered essential for obtaining useful results. Interesting recent work has already shown that specific diagnostic biomarkers, such as BRCA mutations, may have profound therapeutic implications. Here, we review the current state of OC research through literature and database searches, with a focus on various recently identified biomarkers via different technologies for the (early) diagnosis, prognosis and treatment of OC.

Conclusions

Multi-biomarker panels accompanied by a meticulous determination of their sensitivity and specificity, as well their validation, using multivariate analyses will be critical for its clinical application, including early OC detection and tailor-made OC treatment.

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Endocytosis, Metastasis and Beyond: Multiple Facets of SNX9

Publication date: Available online 16 December 2016
Source:Trends in Cell Biology
Author(s): Nawal Bendris, Sandra L. Schmid
Sorting nexin (SNX)9 was first discovered as an endocytic accessory protein involved in clathrin-mediated endocytosis. However, recent data suggest that SNX9 is a multifunctional scaffold that coordinates membrane trafficking and remodeling with changes in actin dynamics to affect diverse cellular processes. Here, we review the accumulated knowledge on SNX9 with an emphasis on its recently identified roles in clathrin-independent endocytic pathways, cell invasion, and cell division, which have implications for SNX9 function in human disease, including cancer.



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Pathways of Unconventional Protein Secretion

Publication date: Available online 16 December 2016
Source:Trends in Cell Biology
Author(s): Catherine Rabouille
Secretory proteins are conventionally transported through the endoplasmic reticulum to the Golgi and then to the plasma membrane where they are released into the extracellular space. However, numerous substrates also reach these destinations using unconventional pathways. Unconventional protein secretion (UPS) is complex and comprises cargos without a signal peptide or a transmembrane domain that can translocate across the plasma membrane, and cargos that reach the plasma membrane by bypassing the Golgi despite entering the endoplasmic reticulum (ER). With a few exceptions, unconventional secretion is largely triggered by stress. Here I review new results and concepts that are beginning to define these pathways.



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Actomyosin Pulsing in Tissue Integrity Maintenance during Morphogenesis

Publication date: Available online 16 December 2016
Source:Trends in Cell Biology
Author(s): Jonathan S. Coravos, Frank M. Mason, Adam C. Martin
The actomyosin cytoskeleton is responsible for many changes in cell and tissue shape. For a long time, the actomyosin cytoskeleton has been known to exhibit dynamic contractile behavior. Recently, discrete actomyosin assembly/disassembly cycles have also been observed in cells. These so-called actomyosin pulses have been observed in a variety of contexts, including cell polarization and division, and in epithelia, where they occur during tissue contraction, folding, and extension. In epithelia, evidence suggests that actomyosin pulsing, and more generally, actomyosin turnover, is required to maintain tissue integrity during contractile processes. This review explores possible functions for pulsing in the many instances during which pulsing has been observed, and also highlights proposed molecular mechanisms that drive pulsing.



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Pneumonia prevention: Cost-effectiveness analyses of two vaccines among refugee children aged under two years, Haemophilus influenzae type b-containing and pneumococcal conjugate vaccines, during a humanitarian emergency, Yida camp, South Sudan

Publication date: Available online 15 December 2016
Source:Vaccine
Author(s): Lisa M. Gargano, Rana Hajjeh, Susan T. Cookson
By September 2013, war between Sudan and South Sudan resulted in >70,000 Sudanese refugees and high pneumonia incidence among the 20,000 refugees in Yida camp, South Sudan. Using Médecins Sans Frontières (MSF)-provided data and modifying our decision-tree models, we estimated if administering Haemophilus influenzae type b (Hib)-containing (pentavalent vaccine, also with diphtheria pertussis and tetanus [DPT] and hepatitis B) and pneumococcal conjugate (PCV) vaccines were cost-effective against hospitalized pneumonia. Among children <2years old, compared with no vaccination, one- and two-doses of combined Hib-containing and PCV would avert an estimated 118 and 125 pneumonia cases, and 8.5 and 9.1 deaths, respectively. The cost per Disability-Adjusted-Life-Year averted for administering combined one- and two-doses was US$125 and US$209, respectively. MSF demonstrated that it was possible to administer these vaccines during an emergency and our analysis found it was highly cost-effective, even with just one-dose of either vaccine. Despite unknown etiology, there is strong field and now economic rationale for administering Hib and PCV during at least one humanitarian emergency.



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Novel immunological insights in accelerating RSV vaccine development

Publication date: Available online 16 December 2016
Source:Vaccine
Author(s): Christopher Chiu




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Development of bioluminescence imaging of respiratory syncytial virus (RSV) in virus-infected live mice and its use for evaluation of therapeutics and vaccines

Publication date: Available online 15 December 2016
Source:Vaccine
Author(s): Sandra Fuentes, Diego Arenas, Martin M. Moore, Hana Golding, Surender Khurana
Respiratory Syncytial virus (RSV) is one of the leading causes of pneumonia among infants with no human vaccine or efficient curative treatments. Efforts are underway to develop new RSV vaccines and therapeutics. There is a dire need for animal models for preclinical evaluation and selection of products against RSV. Herein, we developed a whole body bioluminescence imaging to follow replication of RSV A2 virus strain expressing firefly luciferase (RSVA2-line19-FFL) in live BALB/c mice that can be used as an extremely sensitive readout for studying effects of antiviral and vaccines in living mice. Strong bioluminescence signal was detected in the nasal cavity and in the lungs following intranasal infection of mice with RSVA2-line19-FFL. The kinetics of viral replication in lungs quantified by daily live imaging strongly correlated with viral titers measured by ex-vivo plaque assay and by assessing viral RNA by qRT-PCR. Vaccination of mice with a pre-fusion F protein elicited high neutralizing antibody titers conferring strong protective immunity against virus replication in the nasal cavity and lungs. In contrast, post-challenge treatment of mice with the monoclonal antibody Palivizumab two days after infection reduced viral replication in the nasal cavity at day 4, but only modestly reduced virus loads in the lungs by day 5. In contrast to RSV bioluminescence, plaque assay did not detect viral titers in lungs on day 5 in Palivizumab-treated animals. This difference between viral loads measured by the two assays was found to be due to coating of virions with the Palivizumab that blocked infection of target cells in vitro and shows importance of live imaging in evaluation of RSV therapeutics. This recombinant RSV based live imaging animal model is convenient and valuable tool that can be used to study host dissemination of RSV and evaluation of antiviral compounds and vaccines against RSV.



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Impact of pre-gestational and gestational diabetes mellitus on the expression of glucose transporters GLUT-1, GLUT-4 and GLUT-9 in human term placenta

Abstract

Purpose

Various studies in placental tissue suggest that diabetes mellitus alters the expression of glucose transporter (GLUT) proteins, with insulin therapy being a possible modulatory factor. The aim of the present study was quantitative evaluation of the expression of glucose transporters (GLUT-1, GLUT-4, GLUT-9) in the placenta of women in both, uncomplicated and diabetic pregnancy. Additionally, the effect of insulin therapy on the expression of selected glucose transporter isoforms was analyzed.

Methods

Term placental samples were obtained from healthy control (n = 25) and diabetic pregnancies, including diet-controlled gestational diabetes mellitus (GDMG1) (n = 16), insulin-controlled gestational diabetes mellitus (GDMG2) (n = 6), and pre-gestational diabetes mellitus (PGDM) (n = 6). Computer-assisted quantitative morphometry of stained placental sections was performed to determine the expression of selected glucose transporter proteins.

Results

Morphometric analysis revealed a significant increase in the expression of GLUT-4 and GLUT-9 in insulin-dependent diabetic women (GDMG2 + PGDM) as compared to both, control and GDMG1 groups (p < .05). Significantly increased GLUT-1 expression was observed only in placental specimens from patients with PGDM (p < .05). No statistically significant differences in GLUT expression were found between GDMG1 patients and healthy controls.

Conclusions

The results of the study confirmed the presence of GLUT-1, GLUT-4 and GLUT-9 proteins in the trophoblast from both, uncomplicated and diabetic pregnancies. In addition, insulin therapy may increase placental expression of GLUT-4 and GLUT-9, and partially GLUT-1, in women with GDMG2/PGDM.

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Visceral adiposity index as an indicator of cardiometabolic risk in patients treated for craniopharyngioma

Abstract

Purpose

Craniopharyngioma is associated with metabolic alterations leading to increased cardiovascular mortality. Recently, the visceral adiposity index has been proposed as a marker of visceral adipose tissue dysfunction and of the related cardiometabolic risk. The role of the visceral adiposity index has never been explored in craniopharyngioma patients. We assessed the cardiometabolic risk on the basis of the visceral adiposity index in craniopharyngioma patients.

Methods

We evaluated data of 24 patients treated for craniopharyngioma in a single-centre. We investigated the relationship among patients' clinical and biochemical features, cardiovascular risk -assessed by the Framingham and the atherosclerotic cardiovascular disease risk scores-, visceral adiposity index and adipose tissue dysfunction severity.

Results

Increased visceral adiposity index was found in 8 patients (33%). Adipose tissue dysfunction resulted to be severe, moderate or mild in 5, 2 and 1 cases. Increased visceral adiposity index significantly correlated with the occurrence of metabolic syndrome (p 0.027), IRI (p 0.001), triglycerides (p < 0.001), HOMA-IR (p < 0.001) and with lower ISI-Matsuda (p 0.005) and HDL-cholesterol (p < 0.001). Higher degree of adipose tissue dysfunction associated with increased insulin resistance. No gender difference was found for visceral adiposity index, adipose tissue dysfunction severity, and cardiovascular risk scores. Patients with adulthood onset craniopharyngioma showed higher Framingham risk score (p 0.004), atherosclerotic cardiovascular disease 10-year (p < 0.001) and lifetime (p 0.018) risk scores than those with childhood onset disease.

Conclusions

Visceral adiposity index is increased in one third of our patients with craniopharyngioma, even if metabolic syndrome does not occur. Increased visceral adiposity index and adipose tissue dysfunction severity correlate with insulin sensitivity parameters, do not correlate with Framingham or atherosclerotic cardiovascular disease risk scores, and are not influenced by gender and age of disease onset.

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Leptin directly stimulates parathyroid hormone secretion

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Craniopharyngiomas: a life-changing tumor

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Growth hormone and the heart in growth hormone deficiency—what have we learned so far?

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Reduced serum levels of oestradiol and brain derived neurotrophic factor in both diabetic women and HFD-feeding female mice

Abstract

The estrogen levels in the pre and post menstrual phases interact with brain-derived neurotrophic factor in a complex manner, which influences the overall state of the body. To study the role of oestradiol and brain-derived neurotrophic factor in modulating obesity related type 2 diabetes and the interactions between two factors, we enrolled 15 diabetic premenopausal women and 15 diabetic postmenopausal women respectively, the same number of healthy pre and postmenopausal women were recruited as two control groups. The fasting blood glucose, insulin, lipids, estrogen, and brain-derived neurotrophic factor levels were measured through clinical tests. Additionally, we set up obese female mouse model to mimic human trial stated above, to verify the relationship between estrogen and brain-derived neurotrophic factor. Our findings revealed that there is a moderately positive correlation between brain-derived neurotrophic factor and oestradiol in females, and decreased brain-derived neurotrophic factor may worsen impaired insulin function. The results further confirmed that high fat diet-fed mice which exhibited impaired glucose tolerance, showed lower levels of oestradiol and decreased expression of brain-derived neurotrophic factor mRNA in the ventromedial hypothalamus. The level of brain-derived neurotrophic factor reduced on condition that the level of oestradiol is sufficiently low, such as women in postmenopausal period, which aggravates diabetes through feeding-related pathways. Increasing the level of brain-derived neurotrophic factor may help to alleviate the progression of the disease in postmenopausal women with diabetes.

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The role of AIP mutations in pituitary adenomas: 10 years on

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Preliminary data of VEGF-A and VEGFR-2 polymorphisms as predictive factors of radiological response and clinical outcome in iodine-refractory differentiated thyroid cancer treated with sorafenib

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Physical activity and hypocaloric diet recovers osteoblasts homeostasis in women affected by abdominal obesity

Abstract

Obesity is a multifactorial disease linked to metabolic chronic disorders such as diabetes, and hypertension. Also, it has recently been associated with skeletal alterations and low bone mineral density. We previously demonstrated that exposure of osteoblasts to sera of sedentary subjects affected by obesity alters cell homeostasis in vitro, leading to disruption of intracellular differentiation pathways and cellular activity. Thus, the purpose of the present study has been to evaluate whether sera of sedentary obese women, subjected to physical activity and hypocaloric diet, could recover osteoblast homeostasis in vitro as compared to the sera of same patients before intervention protocol. To this aim, obese women were evaluated at time 0 and after 4, 6, and 12 months of individualized prescribed physical activity and hypocaloric diet. Dual-energy-X-ray absorptiometry measurements were performed at each time point, as well as blood was collected at the same points. Cells were incubated with sera of subjects before and after physical activity as described: obese at baseline and after for 4, 6, and 12 months of physical activity and nutritional protocol intervention. Osteoblasts exposed to sera of patients, who displayed increased lean and decreased fat mass (from 55.5 ± 6.5 to 57.1 ± 5.6% p ≤ 0.05; from 44.5 ± 1.1 to 40.9 ± 2.6% p ≤ 0.01 respectively), showed a time-dependent increase of Wnt/β-catenin signaling, versus cells exposed to sera of obese patients before intervention protocol, suggesting recovery of osteoblast homeostasis upon improvement of body composition. An increase in β-catenin nuclear accumulation and nuclear translocation was also observed, accompanied by an increase in Adiponectin receptor 1 protein expression, suggesting positive effect on cell differentiation program. Furthermore, a decrease in sclerostin amount and an increase of type 1 procollagen amino-terminal-propeptide were depicted as compared to baseline, proportionally to the time of physical activity, suggesting a recovery of bone remodeling modulation and an increase of osteoblast activity induced by improvement of body composition. In conclusion, our results show for the first time that sera of obese sedentary women who increased lean mass and decreased fat mass, by physical activity and hypocaloric diet, rescue osteoblasts differentiation and activity likely due to a reactivation of Wnt/β-catenin-pathway, suggesting that a correct life style can improve skeletal metabolic alteration induced by obesity.

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The emergence of levothyroxine as a treatment for hypothyroidism

Abstract

Objective

To describe the historical refinements, understanding of physiology and clinical outcomes observed with thyroid hormone replacement strategies.

Methods

A Medline search was initiated using the search terms, levothyroxine, thyroid hormone history, levothyroxine mono therapy, thyroid hormone replacement, combination LT4 therapy, levothyroxine Bioequivalence. Pertinent articles of interest were identified by title and where available abstract for further review. Additional references were identified in the course of review of the literature identified.

Results

Physicians have intervened in cases of thyroid dysfunction for more than two millennia. Ingestion of animal thyroid derived preparations has been long described but only scientifically documented for the last 130 years. Refinements in hormone preparation, pharmaceutical production and regulation continue to this day. The literature provides documentation of physiologic, pathologic and clinical outcomes which have been reported and continuously updated. Recommendations for effective and safe use of these hormones for reversal of patho-physiology associated with hypothyroidism and the relief of symptoms of hypothyroidism has documented a progressive refinement in our understanding of thyroid hormone use. Studies of thyroid hormone metabolism, action and pharmacokinetics have allowed evermore focused recommendations for use in clinical practice. Levothyroxine mono-therapy has emerged as the therapy of choice of all recent major guidelines.

Conclusions

The evolution of thyroid hormone therapies has been significant over an extended period of time. Thyroid hormone replacement is very useful in the treatment of those with hypothyroidism. All of the most recent guidelines of major endocrine societies recommend levothyroxine mono-therapy for first line use in hypothyroidism.

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« Conditions hygiéniques actuelles de Beyrouth » (Boyer) : premier document épidémiologique de vénéréologie libanaise

Publication date: Available online 16 December 2016
Source:Annales de Dermatologie et de Vénéréologie
Author(s): I. Maatouk




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Lipome périsudoral

Publication date: Available online 16 December 2016
Source:Annales de Dermatologie et de Vénéréologie
Author(s): F. Bourlond, C. Velter, B. Blouard, B. Cribier




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Safer delivery of surgical services: a programme of controlled before-and-after intervention studies with pre-planned pooled data analysis.

The study found that the effects on team performance of single interventions employing lean, teamwork training or standard operating procedures were inconsistent. A combination of teamwork training plus systems improvement training appears more effective in improving team performance than either approach alone. Combining all three strategies did not increase the percentage of successful projects.

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