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author:("melchior, S")
1.  Entrapment of an EGFR inhibitor into nanostructured lipid carriers (NLC) improves its antitumor activity against human hepatocarcinoma cells 
Background
In hepatocellular carcinoma (HCC), different signaling pathways are de-regulated, and among them, the expression of the epidermal growth factor receptor (EGFR). Tyrphostin AG-1478 is a lipophilic low molecular weight inhibitor of EGFR, preferentially acting on liver tumor cells. In order to overcome its poor drug solubility and thus improving its anticancer activity, it was entrapped into nanostructured lipid carriers (NLC) by using safe ingredients for parenteral delivery.
Results
Nanostructured lipid carriers (NLC) carrying tyrphostin AG-1478 were prepared by using the nanoprecipitation method and different matrix compositions. The best system in terms of mean size, PDI, zeta potential, drug loading and release profile was chosen to evaluate the anti-proliferative effect of drug-loaded NLC versus free drug on human hepatocellular carcinoma HA22T/VGH cells.
Conclusions
Thanks to the entrapment into NLC systems, tyrphostin AG-1478 shows an enhanced in vitro anti-tumor activity compared to free drug. These finding raises hope of future drug delivery strategy of tyrphostin AG-1478 -loaded NLC targeted to the liver for the HCC treatment.
doi:10.1186/1477-3155-12-21
PMCID: PMC4033685  PMID: 24886097
Nanostructured lipid carriers; Tyrphostin AG-1478; Drug release; Hepatocellular carcinoma; EGFR inhibitor
2.  Oxidative Stress and Bone Resorption Interplay as a Possible Trigger for Postmenopausal Osteoporosis 
BioMed Research International  2014;2014:569563.
The underlying mechanism in postmenopausal osteoporosis (PO) is an imbalance between bone resorption and formation. This study was conducted to investigate whether oxidative stress (OxS) might have a role in this derangement of bone homeostasis. In a sample of 167 postmenopausal women, we found that increased serum levels of a lipid peroxidation marker, hydroperoxides, were negatively and independently associated with decreased bone mineral density (BMD) in total body (r = −0.192, P < 0.05), lumbar spine (r = −0.282, P < 0.01), and total hip (r = −0.282, P < 0.05), as well as with increased bone resorption rate (r = 0.233, P < 0.05), as assessed by the serum concentration of C-terminal telopeptide of type I collagen (CTX-1). On the contrary, the OxS marker failed to be correlated with the serum levels of bone-specific alkaline phosphatase (BAP), that is, elective marker of bone formation. Importantly, multiple regression analysis revealed that hydroperoxides is a determinant factor for the statistical association between lumbar spine BMD and CTX-1 levels. Taken together, our data suggest that OxS might mediate, by enhancing bone resorption, the uncoupling of bone turnover that underlies PO development.
doi:10.1155/2014/569563
PMCID: PMC3913453  PMID: 24524081
3.  TNFα Signals via p66Shc to Induce E-Selectin, Promote Leukocyte Transmigration and Enhance Permeability in Human Endothelial Cells 
PLoS ONE  2013;8(12):e81930.
Endothelial cells participate in inflammatory events leading to atherogenesis by regulating endothelial cell permeability via the expression of VE-Cadherin and β-catenin and leukocyte recruitment via the expression of E-Selectins and other adhesion molecules. The protein p66Shc acts as a sensor/inducer of oxidative stress and may promote vascular dysfunction. The objective of this study was to investigate the role of p66Shc in tumor necrosis factor TNFα-induced E-Selectin expression and function in human umbilical vein endothelial cells (HUVEC). Exposure of HUVEC to 50 ng/ml TNFα resulted in increased leukocyte transmigration through the endothelial monolayer and E-Selectin expression, in association with augmented phosphorylation of both p66Shc on Ser36 and the stress kinase c-Jun NH2-terminal protein kinase (JNK)-1/2, and higher intracellular reactive oxygen species (ROS) levels. Overexpression of p66Shc in HUVEC resulted in enhanced p66Shc phosphorylation on Ser36, increased ROS and E-Selectin levels, and amplified endothelial cell permeability and leukocyte transmigration through the HUVEC monolayer. Conversely, overexpression of a phosphorylation-defective p66Shc protein, in which Ser36 was replaced by Ala, did not augment ROS and E-Selectin levels, nor modify cell permeability or leukocyte transmigration beyond those found in wild-type cells. Moreover, siRNA-mediated silencing of p66Shc resulted in marked reduction of E-Selectin expression and leukocyte transmigration. In conclusion, p66Shc acts as a novel intermediate in the TNFα pathway mediating endothelial dysfunction, and its action requires JNK-dependent phosphorylation of p66Shc on Ser36.
doi:10.1371/journal.pone.0081930
PMCID: PMC3857848  PMID: 24349153
4.  Ectopic NGAL expression can alter sensitivity of breast cancer cells to EGFR, Bcl-2, CaM-K inhibitors and the plant natural product berberine 
Cell Cycle  2012;11(23):4447-4461.
Neutrophil gelatinase-associated lipocalin (NGAL, a.k.a Lnc2) is a member of the lipocalin family and has diverse roles. NGAL can stabilize matrix metalloproteinase-9 from autodegradation. NGAL is considered as a siderocalin that is important in the transport of iron. NGAL expression has also been associated with certain neoplasias and is implicated in the metastasis of breast cancer. In a previous study, we examined whether ectopic NGAL expression would alter the sensitivity of breast epithelial, breast and colorectal cancer cells to the effects of the chemotherapeutic drug doxorubicin. While abundant NGAL expression was detected in all the cells infected with a retrovirus encoding NGAL, this expression did not alter the sensitivity of these cells to doxorubicin as compared with empty vector-transduced cells. We were also interested in determining the effects of ectopic NGAL expression on the sensitivity to small-molecule inhibitors targeting key signaling molecules. Ectopic NGAL expression increased the sensitivity of MCF-7 breast cancer cells to EGFR, Bcl-2 and calmodulin kinase inhibitors as well as the natural plant product berberine. Furthermore, when suboptimal concentrations of certain inhibitors were combined with doxorubicin, a reduction in the doxorubicin IC50 was frequently observed. An exception was observed when doxorubicin was combined with rapamycin, as doxorubicin suppressed the sensitivity of the NGAL-transduced MCF-7 cells to rapamycin when compared with the empty vector controls. In contrast, changes in the sensitivities of the NGAL-transduced HT-29 colorectal cancer cell line and the breast epithelial MCF-10A cell line were not detected compared with empty vector-transduced cells. Doxorubicin-resistant MCF-7/DoxR cells were examined in these experiments as a control drug-resistant line; it displayed increased sensitivity to EGFR and Bcl-2 inhibitors compared with empty vector transduced MCF-7 cells. These results indicate that NGAL expression can alter the sensitivity of certain cancer cells to small-molecule inhibitors, suggesting that patients whose tumors exhibit elevated NGAL expression or have become drug-resistant may display altered responses to certain small-molecule inhibitors.
doi:10.4161/cc.22786
PMCID: PMC3552927  PMID: 23159854
NGAL; Lcn2; lipocalins; siderocalins; targeted therapy; inhibitor sensitivity; EGFR; rapamycin; berberine; BCL-2; calmodulin kinase; breast cancer; colorectal cancer
5.  Rheumatoid Arthritis 
Autoimmune Diseases  2013;2013:958437.
doi:10.1155/2013/958437
PMCID: PMC3863497  PMID: 24369497
6.  Accuracy of ultrasonography in the diagnosis of acute appendicitis in adult patients: review of the literature 
Critical Ultrasound Journal  2013;5(Suppl 1):S2.
Background
Ultrasound is a widely used technique in the diagnosis of acute appendicitis; nevertheless, its utilization still remains controversial.
Methods
The accuracy of the Ultrasound technique in the diagnosis of acute appendicitis in the adult patient, as shown in the literature, was searched for.
Results
The gold standard for the diagnosis of appendicitis still remains pathologic confirmation after appendectomy. In the published literature, graded-compression Ultrasound has shown an extremely variable diagnostic accuracy in the diagnosis of acute appendicitis (sensitivity range from 44% to 100%; specificity range from 47% to 99% ). This is due to many reasons, including lack of operator skill, increased bowel gas content, obesity, anatomic variants, and limitations to explore patients with previuos laparotomies.
Conclusions
Graded-compression Ultrasound still remains our first-line method in patients referred with clinically suspected acute appendicitis: nevertheless, due to variable diagnostic accuracy, individual skill is requested not only to perform a successful exam, but also in order to triage those equivocal cases that, subsequently, will have to undergo assessment by means of Computed Tomography.
doi:10.1186/2036-7902-5-S1-S2
PMCID: PMC3711731  PMID: 23902717
Acute appendicitis; Ultrasound; Abdomen (US); Abdominal Pain
7.  Contrast enhanced ultrasound (CEUS) in blunt abdominal trauma 
Critical Ultrasound Journal  2013;5(Suppl 1):S9.
In the assessment of polytrauma patient, an accurate diagnostic study protocol with high sensitivity and specificity is necessary. Computed Tomography (CT) is the standard reference in the emergency for evaluating the patients with abdominal trauma. Ultrasonography (US) has a high sensitivity in detecting free fluid in the peritoneum, but it does not show as much sensitivity for traumatic parenchymal lesions. The use of Contrast-Enhanced Ultrasound (CEUS) improves the accuracy of the method in the diagnosis and assessment of the extent of parenchymal lesions. Although the CEUS is not feasible as a method of first level in the diagnosis and management of the polytrauma patient, it can be used in the follow-up of traumatic injuries of abdominal parenchymal organs (liver, spleen and kidneys), especially in young people or children.
doi:10.1186/2036-7902-5-S1-S9
PMCID: PMC3711741  PMID: 23902930
Ultrasonography (US); Ultrasound contrast agent (USCA); Contrast-enhanced Ultrasound (CEUS); Computed Tomography (CT); Blunt abdominal trauma
8.  Novel Combination of Sorafenib and Celecoxib Provides Synergistic Anti-Proliferative and Pro-Apoptotic Effects in Human Liver Cancer Cells 
PLoS ONE  2013;8(6):e65569.
Molecular targeted therapy has shown promise as a treatment for advanced hepatocellular carcinoma (HCC). Sorafenib, a multikinase inhibitor, recently received FDA approval for the treatment of advanced HCC. However, although sorafenib is well tolerated, concern for its safety has been expressed. Celecoxib (Celebrex®) is a selective cyclooxygenase-2 (COX-2) inhibitor which exhibits antitumor effects in human HCC cells. The present study examined the interaction between celecoxib and sorafenib in two human liver tumor cell lines HepG2 and Huh7. Our data showed that each inhibitor alone reduced cell growth and the combination of celecoxib with sorafenib synergistically inhibited cell growth and increased apoptosis. To better understand the molecular mechanisms underlying the synergistic antitumor activity of the combination, we investigated the expression profile of the combination-treated liver cancer cell lines using microarray analysis. Combination treatment significantly altered expression levels of 1,986 and 2,483 transcripts in HepG2 and Huh7 cells, respectively. Genes functionally involved in cell death, signal transduction and regulation of transcription were predominantly up-regulated, while genes implicated in metabolism, cell-cycle control and DNA replication and repair were mainly down-regulated upon treatment. However, combination-treated HCC cell lines displayed specificity in the expression and activity of crucial factors involved in hepatocarcinogenesis. The altered expression of some of these genes was confirmed by semi-quantitative and quantitative RT-PCR and by Western blotting. Many novel genes emerged from our transcriptomic analyses, and further functional analyses may determine whether these genes can serve as potential molecular targets for more effective anti-HCC strategies.
doi:10.1371/journal.pone.0065569
PMCID: PMC3680460  PMID: 23776502
9.  [5,11,17,23-Tetra-tert-butyl-25,27-(3,6-dioxaoctan-1,8-di­oxy)-26,28-bis­(pyridin-2-ylmeth­oxy)calix[4]arene]sodium iodide–1,2,4,5-tetra­fluoro-3,6-diiodo­benzene–methanol (2/3/4) 
The title compound, [Na(C62H76N2O6)]I·1.5C6F4I2·2CH3OH, is composed of five components: a calix[4]arene derivative (hereinafter C4), a sodium cation, an iodide anion, a 1,2,4,5-tetra­fluoro-3,6-diiodo­benzene (tFdIB) mol­ecule and a methanol mol­ecule in a 1:1:1:1.5:2 ratio. The complex shows several inter­esting features: (i) the polyoxygenated loop of C4 effectively chelates a sodium cation in the form of a distorted octahedron and separates it from the iodide counter-ion, the shortest Na+⋯I− distance being greater than 6.5 Å; (ii) the cavity of C4 is filled by a methanol mol­ecule; (iii) a second methanol mol­ecule is hydrogen-bonded to the N atom of a pyridinyl substituent pendant of C4 and halogen-bonded to the I atom of a tFdIB mol­ecule; (iv) the two I atoms of another tFdIB mol­ecule are halogen-bonded to two iodide anions, which act as monodentate halogen-bond acceptorss; (v) one of the two tFdIB molecules is located about a centre of inversion.
doi:10.1107/S1600536813007757
PMCID: PMC3647790  PMID: 23723756
10.  Social Support, Socio-Economic Status, Health and Abuse among Older People in Seven European Countries 
PLoS ONE  2013;8(1):e54856.
Background
Social support has a strong impact on individuals, not least on older individuals with health problems. A lack of support network and poor family or social relations may be crucial in later life, and represent risk factors for elder abuse. This study focused on the associations between social support, demographics/socio-economics, health variables and elder mistreatment.
Methods
The cross-sectional data was collected by means of interviews or interviews/self-response during January-July 2009, among a sample of 4,467 not demented individuals aged 60–84 years living in seven European countries (Germany, Greece, Italy, Lithuania, Portugal, Spain, and Sweden).
Results
Multivariate analyses showed that women and persons living in large households and with a spouse/partner or other persons were more likely to experience high levels of social support. Moreover, frequent use of health care services and low scores on depression or discomfort due to physical complaints were indicators of high social support. Low levels of social support were related to older age and abuse, particularly psychological abuse.
Conclusions
High levels of social support may represent a protective factor in reducing both the vulnerability of older people and risk of elder mistreatment. On the basis of these results, policy makers, clinicians and researchers could act by developing intervention programmes that facilitate friendships and social activities in old age.
doi:10.1371/journal.pone.0054856
PMCID: PMC3559777  PMID: 23382989
11.  Advances in Targeting Signal Transduction Pathways 
Oncotarget  2012;3(12):1505-1521.
Over the past few years, significant advances have occurred in both our understanding of the complexity of signal transduction pathways as well as the isolation of specific inhibitors which target key components in those pathways. Furthermore critical information is being accrued regarding how genetic mutations can affect the sensitivity of various types of patients to targeted therapy. Finally, genetic mechanisms responsible for the development of resistance after targeted therapy are being discovered which may allow the creation of alternative therapies to overcome resistance. This review will discuss some of the highlights over the past few years on the roles of key signaling pathways in various diseases, the targeting of signal transduction pathways and the genetic mechanisms governing sensitivity and resistance to targeted therapies.
PMCID: PMC3681490  PMID: 23455493
Targeted Therapy; Therapy Resistance; Cancer Stem Cells; Raf; Akt; PI3K; mTOR; AMPK; Metformin
12.  Somatic complaints and refrain from buying prescribed medications. Results from a cross-sectional study on people 60 years and older living in Kaunas (Lithuania) 
Background
The use of medicines by elderly people is a growing area of concern in social pharmacy. A significant proportion of older people do not follow the recommendations from physicians and refrain from buying prescribed medications. The aim of this study is to evaluate associations between self-rated health, somatic complaints and refraining from buying prescribed medications by elderly people.
Findings
Data was collected in a cross-sectional study in 2009. We received 624 completed questionnaires (response rate – 48.9%) from persons aged 60–84 years living in Kaunas (Lithuania). Somatic complaints were measured with the 24 item version of the Giessen Complaint List (GBB-24). Logistic regression (Enter model) was used for evaluation of the associations between refraining from buying medications and somatic complaints. These associations were measured using odds ratio (OR) and calculating the 95% confidence interval (CI).
The mean scores in total for the GBB scale and sub-scales (exhaustion, gastrointestinal and cardiovascular) were lowest among respondents who did not refrain from buying prescribed medications (means for GBB-24 scale: 21.04 vs. 24.82; p=0.001). Logistic regression suggests that somatic complaints were associated with a increased risk of refraining from buying prescribed medications (OR=1.35, 95% CI=1.15-1.60).
Conclusions
Somatic complaints were significantly associated with the decision to refrain from buying prescribed medications.
doi:10.1186/2008-2231-20-78
PMCID: PMC3556035  PMID: 23351159
Use of medication; Somatic complaints; Self-rated health; Elderly; Accessibility; Non-adherence; Lithuania
13.  Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR Cascade Inhibitors: How Mutations Can Result in Therapy Resistance and How to Overcome Resistance 
Oncotarget  2012;3(10):1068-1111.
The Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades are often activated by genetic alterations in upstream signaling molecules such as receptor tyrosine kinases (RTK). Targeting these pathways is often complex and can result in pathway activation depending on the presence of upstream mutations (e.g., Raf inhibitors induce Raf activation in cells with wild type (WT) RAF in the presence of mutant, activated RAS) and rapamycin can induce Akt activation. Targeting with inhibitors directed at two constituents of the same pathway or two different signaling pathways may be a more effective approach. This review will first evaluate potential uses of Raf, MEK, PI3K, Akt and mTOR inhibitors that have been investigated in pre-clinical and clinical investigations and then discuss how cancers can become insensitive to various inhibitors and potential strategies to overcome this resistance.
PMCID: PMC3717945  PMID: 23085539
Targeted Therapy; Therapy Resistance; Cancer Stem Cells; Raf; Akt; PI3K; mTOR
14.  Effects of Ectopic Expression of NGAL on Doxorubicin Sensitivity 
Oncotarget  2012;3(10):1236-1245.
Neutrophil gelatinase-associated lipocalin (NGAL, a.k.a Lnc2) is a member of the lipocalin family which has diverse roles including stabilizing matrix metalloproteinase-9 from auto-degradation and as siderocalins which are important in the transport of iron. NGAL also has important biological functions involved in immunity and inflammation as well as responses to kidney damage. NGAL expression has also been associated with certain neoplasia and is important in the metastasis of breast cancer. Many advanced cancer patients have elevated levels of NGAL in their urine and it has been proposed that NGAL may be a prognostic indicator for certain cancers (e.g. breast, brain, and others). NGAL expression is detected in response to various chemotherapeutic drugs including doxorubicin and docetaxel. We were interested in the roles of NGAL expression in cancer and whether it is associated with chemotherapeutic drug resistance. In the present study, we investigated whether increased NGAL expression led to resistance to the chemotherapeutic drug doxorubicin in normal breast epithelial cells (MCF-10A), breast cancer cells (MCF-7), and colorectal cancer cells (HT-29). We infected the various cell lines with a retrovirus encoding NGAL which we constructed. Increased NGAL expression was readily detected in the NGAL-infected cells but not the empty vector-infected cells. However, increased NGAL expression did not alter the sensitivity of the cells to the chemotherapeutic drug doxorubicin. Thus, although NGAL expression is often detected after chemotherapeutic drug treatment, it by itself, does not lead to doxorubicin resistance.
PMCID: PMC3717946  PMID: 23100449
NGAL; Lcn2; Doxorubicin; lipocalins; siderocalins; iron transport; MMP-9; drug resistance
15.  Mutations and Deregulation of Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR Cascades Which Alter Therapy Response 
Oncotarget  2012;3(9):954-987.
The Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades are often activated by genetic alterations in upstream signaling molecules such as receptor tyrosine kinases (RTK). Certain components of these pathways, RAS, NF1, BRAF, MEK1, DUSP5, PP2A, PIK3CA, PIK3R1, PIK3R4, PIK3R5, IRS4, AKT, NFKB1, MTOR, PTEN, TSC1, and TSC2 may also be activated/inactivated by mutations or epigenetic silencing. Upstream mutations in one signaling pathway or even in downstream components of the same pathway can alter the sensitivity of the cells to certain small molecule inhibitors. These pathways have profound effects on proliferative, apoptotic and differentiation pathways. Dysregulation of components of these cascades can contribute to: resistance to other pathway inhibitors, chemotherapeutic drug resistance, premature aging as well as other diseases. This review will first describe these pathways and discuss how genetic mutations and epigenetic alterations can result in resistance to various inhibitors.
PMCID: PMC3660063  PMID: 23006971
Targeted Therapy; Therapy Resistance; Mutations; Raf; Akt; PI3K; mTOR
16.  Critical US visibility with tissue harmonic imaging of subcutaneous nodules☆ 
Journal of Ultrasound  2011;14(3):152-156.
Introduction
Assessment of US ability to identify subcutaneous nodular lesions using conventional B mode imaging (CBMI) and tissue second harmonic imaging (THI).
Materials and Methods
Three different types of equipment were used (Philips Envisor HDC, Philips HD 11 XE and GE Logic E) with 12–13 MHz probes and THI probes with variable frequency. One experienced operator studied 31 patients (24 women, 7 men, mean age 49 ± 15) with 52 subcutaneous nodular lesions of which 43 were palpable and 9 were nonpalpable. Statistical analysis was carried out using chi-square test.
Results
19/52 subcutaneous nodular lesions were hyperechoic, 10/52 were isoechoic and 23/52 were hypoechoic. Of the hyperechoic nodules, 8/19 (42%) (p < 0.005) were not detected using THI, as they “disappeared” when THI was activated. Of the isoechoic nodules only 1/10 was not detected using THI, and of the hypoechoic nodules only 2/23 were not detected. Of the nodular lesions detected using CBMI and also using THI (41/52), 16/41 were shown more clearly using THI than using BMCI. No nodule was detected with the exclusive use of THI.
Conclusions
The statistical significance of the “disappearing” lesions (p < 0.005), mainly hyperechoic (42%), at the activation of THI must lead to a reconsideration of routine activation of THI during the entire US examination in the evaluation of subcutaneous lesions in order to avoid the risk of missing important lesions. The present results suggest that both BMCI and THI should be used in the study of subcutaneous lesions.
doi:10.1016/j.jus.2011.06.002
PMCID: PMC3558069  PMID: 23396896
Ultrasound; Harmonic imaging; Contrast resolution; Subcutaneous tumors
17.  Targeted therapy for hepatocellular carcinoma: novel agents on the horizon 
Oncotarget  2012;3(3):236-260.
Hepatocellular carcinoma (HCC) is the most common liver cancer, accounting for 90% of primary liver cancers. In the last decade it has become one of the most frequently occurring tumors worldwide and is also considered to be the most lethal of the cancer systems, accounting for approximately one third of all malignancies.
Although the clinical diagnosis and management of early-stage HCC has improved significantly, HCC prognosis is still extremely poor. Furthermore, advanced HCC is a highly aggressive tumor with a poor or no response to common therapies. Therefore, new effective and well-tolerated therapy strategies are urgently needed.
Targeted therapies have entered the field of anti-neoplastic treatment and are being used on their own or in combination with conventional chemotherapy drugs. Molecular-targeted therapy holds great promise in the treatment of HCC. A new therapeutic opportunity for advanced HCC is the use of sorafenib (Nexavar). On the basis of the recent large randomized phase III study, the Sorafenib HCC Assessment Randomized Protocol (SHARP), sorafenib has been approved by the FDA for the treatment of advanced HCC. Sorafenib showed to be able to significantly increase survival in patients with advanced HCC, establishing a new standard of care. Despite this promising breakthrough, patients with HCC still have a dismal prognosis, as it is currently the major cause of death in cirrhotic patients. Nevertheless, the successful results of the SHARP trial underscore the need for a comprehensive understanding of the molecular pathogenesis of this devastating disease.
In this review we summarize the most important studies on the signaling pathways implicated in the pathogenesis of HCC, as well as the newest emerging drugs and their potential use in HCC management.
PMCID: PMC3359882  PMID: 22470194
HCC; targeted therapy; VEGF; Ras/Raf/MEK/ERK; PI3K/Akt/PTEN/mTOR; signal transduction inhibitors; cancer
20.  Happy Aged People Are All Alike, While Every Unhappy Aged Person Is Unhappy in Its Own Way 
PLoS ONE  2011;6(9):e23377.
Aging of the world's population represents one of the most remarkable success stories of medicine and of humankind, but it is also a source of various challenges. The aim of the collaborative cross-cultural European study of adult well being (ESAW) is to frame the concept of aging successfully within a causal model that embraces physical health and functional status, cognitive efficacy, material security, social support resources, and life activity. Within the framework of this project, we show here that the degree of heterogeneity among people who view aging in a positive light is significantly lower than the degree of heterogeneity of those who hold a negative perception of aging. We base this conclusion on our analysis of a survey involving 12,478 people aged 50 to 90 from six West European countries. We treat the survey database as a bipartite network in which individual respondents are linked to the actual answers they provide. Taking this perspective allows us to construct a projected network of respondents in which each link indicates a statistically validated similarity of answers profile between the connected respondents, and to identify clusters of individuals independently of demographics. We show that mental and physical well-being are key factors determining a positive perception of aging. We further observe that psychological aspects, like self-esteem and resilience, and the nationality of respondents are relevant aspects to discriminate among participants who indicate positive perception of aging.
doi:10.1371/journal.pone.0023377
PMCID: PMC3169534  PMID: 21931596
21.  Home care in Europe: a systematic literature review 
Background
Health and social services provided at home are becoming increasingly important. Hence, there is a need for information on home care in Europe. The objective of this literature review was to respond to this need by systematically describing what has been reported on home care in Europe in the scientific literature over the past decade.
Methods
A systematic literature search was performed for papers on home care published in English, using the following data bases: Cinahl, the Cochrane Library, Embase, Medline, PsycINFO, Sociological Abstracts, Social Services Abstracts, and Social Care Online. Studies were only included if they complied with the definition of home care, were published between January 1998 and October 2009, and dealt with at least one of the 31 specified countries. Clinical interventions, instrument developments, local projects and reviews were excluded. The data extracted included: the characteristics of the study and aspects of home care 'policy & regulation', 'financing', 'organisation & service delivery', and 'clients & informal carers'.
Results
Seventy-four out of 5,133 potentially relevant studies met the inclusion criteria, providing information on 18 countries. Many focused on the characteristics of home care recipients and on the organisation of home care. Geographical inequalities, market forces, quality and integration of services were also among the issues frequently discussed.
Conclusions
Home care systems appeared to differ both between and within countries. The papers included, however, provided only a limited picture of home care. Many studies only focused on one aspect of the home care system and international comparative studies were rare. Furthermore, little information emerged on home care financing and on home care in general in Eastern Europe. This review clearly shows the need for more scientific publications on home care, especially studies comparing countries. A comprehensive and more complete insight into the state of home care in Europe requires the gathering of information using a uniform framework and methodology.
doi:10.1186/1472-6963-11-207
PMCID: PMC3170599  PMID: 21878111
home care; European Union; care systems; international comparison
22.  Roles of the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways in controlling growth and sensitivity to therapy-implications for cancer and aging 
Aging (Albany NY)  2011;3(3):192-222.
Dysregulated signaling through the Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways is often the result of genetic alterations in critical components in these pathways or upstream activators. Unrestricted cellular proliferation and decreased sensitivity to apoptotic-inducing agents are typically associated with activation of these pro-survival pathways. This review discusses the functions these pathways have in normal and neoplastic tissue growth and how they contribute to resistance to apoptotic stimuli. Crosstalk and commonly identified mutations that occur within these pathways that contribute to abnormal activation and cancer growth will also be addressed. Finally the recently described roles of these pathways in cancer stem cells, cellular senescence and aging will be evaluated. Controlling the expression of these pathways could ameliorate human health.
PMCID: PMC3091517  PMID: 21422497
Raf; MEK; PI3K; mTOR; cancer; kinases; protein phosphorylation; signal transduction; apoptosis
23.  Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR Inhibitors: Rationale and Importance to Inhibiting These Pathways in Human Health 
Oncotarget  2011;2(3):135-164.
The Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades are often activated by genetic alterations in upstream signaling molecules such as receptor tyrosine kinases (RTK). Integral components of these pathways, Ras, B-Raf, PI3K, and PTEN are also activated/inactivated by mutations. These pathways have profound effects on proliferative, apoptotic and differentiation pathways. Dysregulation of these pathways can contribute to chemotherapeutic drug resistance, proliferation of cancer initiating cells (CICs) and premature aging. This review will evaluate more recently described potential uses of MEK, PI3K, Akt and mTOR inhibitors in the proliferation of malignant cells, suppression of CICs, cellular senescence and prevention of aging. Ras/Raf/MEK/ERK and Ras/PI3K/PTEN/Akt/mTOR pathways play key roles in the regulation of normal and malignant cell growth. Inhibitors targeting these pathways have many potential uses from suppression of cancer, proliferative diseases as well as aging.
PMCID: PMC3260807  PMID: 21411864
Targeted Therapy; Combination Therapy; Drug Resistance; Cancer Stem Cells; Aging; Senescence; Raf; Akt; PI3K; mTOR
24.  Sonographic evaluation of the temporomandibular joints in juvenile idiopathic arthritis☆ 
Journal of Ultrasound  2009;13(1):34-37.
Introduction
Juvenile idiopathic arthritis (JIA) may cause damage to the temporomandibular joint (TMJ). In oligoarticular forms of JIA, TMJ involvement is often asymptomatic and consequently overlooked. The aim of this study was to evaluate the presence of TMJ joint effusion (JE) by ultrasonography (US) in patients with early arthritis.
Materials and methods
We examined 68 children (57 girls, 11 boys, age range 9.1–16.0 years, mean age 11.0 years) recently diagnosed with JIA. None had received any specific treatment for inflammation. Symptomatic TMJ involvement was diagnosed when one or more of the following were present: 1) recurrent pain (spontaneous or on movement of the jaw); 2) crepitation; 3) feeling of stiffness or fatigue of the jaw; 4) intermittent locking. US of the TMJ was performed in static and dynamic phases with a General Electric LOGIQ7 scanner and a linear transducer (8.5 MHz) positioned along the axis of the mandibular ramus. JE was diagnosed when the joint capsule was ≥1.5 mm thick.
Results
Forty-six out (68%) of 68 children had US evidence of TMJ effusions (bilateral in 16 [35%] cases), but only 2/46 were symptomatic.
Conclusions
These data suggest that children with early stage oligoarticular JIA children are likely to have inflammation of the TMJs even in the absence of symptoms. US is a simple-to-use, noninvasive, radiation-free tool that can provide useful information in the assessment and follow-up of TMJ involvement in children and young adults with JIA.
doi:10.1016/j.jus.2009.09.008
PMCID: PMC3552829  PMID: 23396613
Ultrasonography; TMJ; Oligo-articular onset; Early JIA
25.  Abdominal wall actinomycosis simulating a malignant neoplasm: Case report and review of the literature 
Abdominal wall actinomycosis is a rare disease frequently associated with the presence of an intra uterine device. We report on a case of a 47-year-old woman who had used an intrauterine device for many years and had removed it about a month prior to the identification of an abdominal wall abscess caused by Actinomyces israelii. The abscess mimicked a malignancy and the patient underwent a demolitive surgical treatment. The diagnosis was obtained only after histopathological examination. Postoperatively, the patient developed an infection of the wound which was treated with daily medication. The combination of long-term high dose antibiotic therapy with surgery led to successful treatment.
doi:10.4240/wjgs.v2.i7.247
PMCID: PMC2999246  PMID: 21160882
Actinomycosis; Abdominal wall; Intra uterine device; Abscess; Neoplasm

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