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author:("melchior, S")
1.  Non invasive tools for the diagnosis of liver cirrhosis 
World Journal of Gastroenterology : WJG  2014;20(48):18131-18150.
Liver cirrhosis (LC), the end stage of many forms of chronic hepatitis of different etiologies is a diffuse process characterized by fibrosis and the conversion of normal liver architecture into structurally abnormal nodules surrounded by annular fibrosis. This chronic progressive clinical condition, leads to liver cell failure and portal hypertension, which can favour the onset of hepatocellular carcinoma. Defining the phase of the natural history is crucial for therapeutic choice and prognosis. Liver biopsy is currently considered the best available standard of reference but it has some limits, so alternative tools have been developed to substitute liver biopsy when assessing liver fibrosis. Serum markers offer a cost-effective alternative to liver biopsy being less invasive and theoretically without complications. They can be classified into direct and indirect markers which may be used alone or in combination to produce composite scores. Diagnostic imaging includes a number of instruments and techniques to estimate liver fibrosis and cirrhosis like ultrasound (US), US Doppler, contrast enhanced US and Elastography. US could be used for the diagnosis of advanced LC while is not able to evaluate progression of fibrosis, in this case Elastography is more reliable. This review aims to revise the most recent data from the literature about non invasive methods useful in defining liver fibrosis.
doi:10.3748/wjg.v20.i48.18131
PMCID: PMC4277952  PMID: 25561782
Liver fibrosis; Liver biopsy; Ultrasound; Elastography; Serum markers
2.  Tako-tsubo syndrome as a consequence and cause of stroke 
Functional Neurology  2014;29(2):135-137.
Summary
Since tako-tsubo syndrome (TS) frequently appears soon after stroke (usually stroke involving the insular cortex), it is believed to be a consequence rather than a cause of stroke.
Herein, we describe a 70-year-old woman presenting with a left middle cerebral artery stroke (involving the insular cortex) who developed a further contralateral ischemic stroke with concomitant detection of a transient intracardiac mural thrombus attributable to TS. It can reasonably be maintained that that in our patient insular stroke triggered the TS, which in turn became the embolic cause of a further stroke.
Given the association between TS and the risk of embolic stroke, congestive heart failure and sudden death, stroke physicians need to promptly detect and appropriately manage this condition.
PMCID: PMC4198162  PMID: 25306124
cardioembolic; insular stroke; stroke; stroke cause; Tako-tsubo syndrome
3.  Expression of Animal Anti-Apoptotic Gene Ced-9 Enhances Tolerance during Glycine max L.–Bradyrhizobium japonicum Interaction under Saline Stress but Reduces Nodule Formation 
PLoS ONE  2014;9(7):e101747.
The mechanisms by which the expression of animal cell death suppressors in economically important plants conferred enhanced stress tolerance are not fully understood. In the present work, the effect of expression of animal antiapoptotic gene Ced-9 in soybean hairy roots was evaluated under root hairs and hairy roots death-inducing stress conditions given by i) Bradyrhizobium japonicum inoculation in presence of 50 mM NaCl, and ii) severe salt stress (150 mM NaCl), for 30 min and 3 h, respectively. We have determined that root hairs death induced by inoculation in presence of 50 mM NaCl showed characteristics of ordered process, with increased ROS generation, MDA and ATP levels, whereas the cell death induced by 150 mM NaCl treatment showed non-ordered or necrotic-like characteristics. The expression of Ced-9 inhibited or at least delayed root hairs death under these treatments. Hairy roots expressing Ced-9 had better homeostasis maintenance, preventing potassium release; increasing the ATP levels and controlling the oxidative damage avoiding the increase of reactive oxygen species production. Even when our results demonstrate a positive effect of animal cell death suppressors in plant cell ionic and redox homeostasis under cell death-inducing conditions, its expression, contrary to expectations, drastically inhibited nodule formation even under control conditions.
doi:10.1371/journal.pone.0101747
PMCID: PMC4106779  PMID: 25050789
4.  Deregulation of the EGFR/PI3K/PTEN/Akt/mTORC1 pathway in breast cancer: possibilities for therapeutic intervention 
Oncotarget  2014;5(13):4603-4650.
The EGFR/PI3K/PTEN/Akt/mTORC1/GSK-3 pathway plays prominent roles in malignant transformation, prevention of apoptosis, drug resistance and metastasis. The expression of this pathway is frequently altered in breast cancer due to mutations at or aberrant expression of: HER2, ERalpha, BRCA1, BRCA2, EGFR1, PIK3CA, PTEN, TP53, RB as well as other oncogenes and tumor suppressor genes. In some breast cancer cases, mutations at certain components of this pathway (e.g., PIK3CA) are associated with a better prognosis than breast cancers lacking these mutations. The expression of this pathway and upstream HER2 has been associated with breast cancer initiating cells (CICs) and in some cases resistance to treatment. The anti-diabetes drug metformin can suppress the growth of breast CICs and herceptin-resistant HER2+ cells. This review will discuss the importance of the EGFR/PI3K/PTEN/Akt/mTORC1/GSK-3 pathway primarily in breast cancer but will also include relevant examples from other cancer types. The targeting of this pathway will be discussed as well as clinical trials with novel small molecule inhibitors. The targeting of the hormone receptor, HER2 and EGFR1 in breast cancer will be reviewed in association with suppression of the EGFR/PI3K/PTEN/Akt/mTORC1/GSK-3 pathway.
PMCID: PMC4148087  PMID: 25051360
Targeted Therapy; Therapy Resistance; Mutations; PI3K; mTOR; rapamycin
5.  Nanotechnology applications for the therapy of liver fibrosis 
Chronic liver diseases represent a major global health problem both for their high prevalence worldwide and, in the more advanced stages, for the limited available curative treatment options. In fact, when lesions of different etiologies chronically affect the liver, triggering the fibrogenesis mechanisms, damage has already occurred and the progression of fibrosis will have a major clinical impact entailing severe complications, expensive treatments and death in end-stage liver disease. Despite significant advances in the understanding of the mechanisms of liver fibrinogenesis, the drugs used in liver fibrosis treatment still have a limited therapeutic effect. Many drugs showing potent antifibrotic activities in vitro often exhibit only minor effects in vivo because insufficient concentrations accumulate around the target cell and adverse effects result as other non-target cells are affected. Hepatic stellate cells play a critical role in liver fibrogenesis , thus they are the target cells of antifibrotic therapy. The application of nanoparticles has emerged as a rapidly evolving area for the safe delivery of various therapeutic agents (including drugs and nucleic acid) in the treatment of various pathologies, including liver disease. In this review, we give an overview of the various nanotechnology approaches used in the treatment of liver fibrosis.
doi:10.3748/wjg.v20.i23.7242
PMCID: PMC4064070  PMID: 24966595
Liver fibrosis; Nanotechnology; Nanoparticles; Hepatic stellate cells; Antifibrotic drugs, Cirrhosis
6.  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
7.  GSK-3 as potential target for therapeutic intervention in cancer 
Oncotarget  2014;5(10):2881-2911.
The serine/threonine kinase glycogen synthase kinase-3 (GSK-3) was initially identified and studied in the regulation of glycogen synthesis. GSK-3 functions in a wide range of cellular processes. Aberrant activity of GSK-3 has been implicated in many human pathologies including: bipolar depression, Alzheimer's disease, Parkinson's disease, cancer, non-insulin-dependent diabetes mellitus (NIDDM) and others. In some cases, suppression of GSK-3 activity by phosphorylation by Akt and other kinases has been associated with cancer progression. In these cases, GSK-3 has tumor suppressor functions. In other cases, GSK-3 has been associated with tumor progression by stabilizing components of the beta-catenin complex. In these situations, GSK-3 has oncogenic properties. While many inhibitors to GSK-3 have been developed, their use remains controversial because of the ambiguous role of GSK-3 in cancer development. In this review, we will focus on the diverse roles that GSK-3 plays in various human cancers, in particular in solid tumors. Recently, GSK-3 has also been implicated in the generation of cancer stem cells in various cell types. We will also discuss how this pivotal kinase interacts with multiple signaling pathways such as: PI3K/PTEN/Akt/mTORC1, Ras/Raf/MEK/ERK, Wnt/beta-catenin, Hedgehog, Notch and others.
PMCID: PMC4102778  PMID: 24931005
GSK-3; cancer stem cells; Wnt/beta-catenin; PI3K; Akt; mTOR; Hedgehog; Notch; Targeted Therapy; Therapy Resistance; Mutations; Rapamycin
8.  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
9.  Heat Shock Protein 70 Serum Levels Differ Significantly in Patients with Chronic Hepatitis, Liver Cirrhosis, and Hepatocellular Carcinoma 
Members of the heat shock protein 70 (HSP70) family play an important role in assisting protein folding, preventing protein aggregation and transport of proteins across membranes under physiological conditions. Following environmental (i.e., irradiation, chemotherapy), physiological (i.e., cell growth, differentiation), and pathophysiological (i.e., inflammation, tumorigenesis) stress, the synthesis of heat shock proteins (HSPs) is highly up-regulated, whereas protein synthesis in general is reduced. In contrast to normal cells, many tumor entities including hepatocellular carcinoma (HCC) overexpress HSP70, the major-stress-inducible member of the HSP70 family, present it on their cell surface and secrete it into the extracellular milieu. Herein, the prognostic relevance of serum HSP70 levels in patients with chronic hepatitis (CH; n = 50), liver cirrhosis (LC; n = 46), and HCC (n = 47) was analyzed. Similar to other tumor entities, HSP70 is also present on the surface of primary HCC cells. The staining intensity of intracellular HSP70 in HCC tissue is stronger compared to control and cirrhotic liver sections. HSP70 serum levels in all HCC patients were significantly higher compared to a control group without liver disease (n = 40). No significant age- and gender-related differences in HSP70 serum levels were observed in male and female healthy human volunteers (n = 86). Patients with CH (n = 50) revealed significantly higher HSP70 serum levels compared to the control group, however, these values were significantly lower than those of HCC patients (n = 47). Furthermore, a subgroup of patients with LC who subsequently developed HCC (LC-HCC, n = 13) revealed higher HSP70 serum levels than patients with LC (n = 46, p = 0.05). These data indicate that serum HSP70 levels are consecutively increased in patients with CH, LC and liver carcinomas and thus might have a prognostic value.
doi:10.3389/fimmu.2014.00307
PMCID: PMC4076752  PMID: 25071768
HCC; serum HSP70; prognostic biomarker; chronic hepatitis; inflammation; liver cirrhosis
10.  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
11.  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
12.  Rheumatoid Arthritis 
Autoimmune Diseases  2013;2013:958437.
doi:10.1155/2013/958437
PMCID: PMC3863497  PMID: 24369497
13.  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
14.  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
15.  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
16.  [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
17.  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
18.  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
19.  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
20.  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
21.  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
22.  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
23.  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
24.  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

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