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1.  Moving Medicine, Moving Minds: Helping Developing Countries Overcome Barriers to Outsourcing Health Commodity Distribution to Boost Supply Chain Performance and Strengthen Health Systems 
Senegal and other developing countries are improving access to health commodities by outsourcing supply chain logistics to private providers. To achieve broader, lasting reform, we must support further adoption of the outsourced model; assist country-led cost-benefit analyses; and help governments build capacity to manage contracts and overcome other barriers.
Senegal and other developing countries are improving access to health commodities by outsourcing supply chain logistics to private providers. To achieve broader, lasting reform, we must support further adoption of the outsourced model; assist country-led cost-benefit analyses; and help governments build capacity to manage contracts and overcome other barriers.
doi:10.9745/GHSP-D-16-00130
PMCID: PMC5042692  PMID: 27688714
2.  Everolimus induces Met inactivation by disrupting the FKBP12/Met complex 
Oncotarget  2016;7(26):40073-40084.
Inhibition of the mechanistic target of rapamycin (mTOR) is a promising treatment strategy for several cancer types. Rapamycin derivatives such as everolimus are allosteric mTOR inhibitors acting through interaction with the intracellular immunophilin FKBP12, a prolyl isomerase with different cellular functions. Although mTOR inhibitors have significantly improved survival of different cancer patients, resistance and lack of predictive factors of response remain unsolved issues. To elucidate the mechanisms of resistance to everolimus, we evaluated Met activation in everolimus-sensitive/resistant human cancer cells, in vitro and in vivo. Biochemical and computational analyses were performed. Everolimus-resistant cells were xenografted into mice (10/group) and studied for their response to everolimus and Met inhibitors. The statistical significance of the in vitro results was evaluated by Student's t test.
Everolimus reduced Met phosphorylation in everolimus-sensitive cells. This event was mediated by the formation of a Met-FKBP12 complex, which in turn is disrupted by everolimus. Aberrant Met activation in everolimus-resistant cells and overexpression of wild-type/mutant Met caused everolimus resistance. Pharmacological inhibition and RNA silencing of Met are effective in condition of everolimus resistance (P<0.01). In mice xenografted with everolimus-resistant cells, the combination of everolimus with the Met inhibitor PHA665752 reduced tumor growth and induced a statistically significant survival advantage (combination vs control P=0.0005).
FKBP12 binding is required for full Met activation and everolimus can inhibit Met. Persistent Met activation might sustain everolimus resistance. These results identify a novel everolimus mechanism of action and suggest the development of clinical strategies based on Met inhibitors in everolimus-resistant cancers.
doi:10.18632/oncotarget.9484
PMCID: PMC5129993  PMID: 27223077
everolimus; Met; FKBP12; everolimus resistance
3.  Oxidative Stress Mediates the Antiproliferative Effects of Nelfinavir in Breast Cancer Cells 
PLoS ONE  2016;11(6):e0155970.
The discovery of the anti-proliferative activity of nelfinavir in HIV-free models has encouraged its investigation as anticancer drug. Although the molecular mechanism by which nelfinavir exerts antitumor activity is still unknown, its effects have been related to Akt inhibition. Here we tested the effects of nelfinavir on cell proliferation, viability and death in two human breast cancer cell lines and in human normal primary breast cells. To identify the mechanism of action of nelfinavir in breast cancer, we evaluated the involvement of the Akt pathway as well as the effects of nelfinavir on reactive oxygen species (ROS) production and ROS-related enzymes activities. Nelfinavir reduced breast cancer cell viability by inducing apoptosis and necrosis, without affecting primary normal breast cells. The antitumor activity of nelfinavir was related to alterations of the cell redox state, coupled with an increase of intracellular ROS production limited to cancer cells. Nelfinavir treated tumor cells also displayed a downregulation of the Akt pathway due to disruption of the Akt-HSP90 complex, and subsequent degradation of Akt. These effects resulted to be ROS dependent, suggesting that ROS production is the primary step of nelfinavir anticancer activity. The analysis of ROS-producers and ROS-detoxifying enzymes revealed that nelfinavir-mediated ROS production was strictly linked to flavoenzymes activation. We demonstrated that ROS enhancement represents the main molecular mechanism required to induce cell death by nelfinavir in breast cancer cells, thus supporting the development of new and more potent oxidizing molecules for breast cancer therapy.
doi:10.1371/journal.pone.0155970
PMCID: PMC4900679  PMID: 27280849
4.  Metformin increases antitumor activity of MEK inhibitors through GLI1 downregulation in LKB1 positive human NSCLC cancer cells 
Oncotarget  2015;7(4):4265-4278.
Purpose
Metformin, widely used as antidiabetic drug, showed antitumoral effects expecially in combination with chemotherapy. Our group recently has demonstrated that metformin and gefitinib are synergistic in LKB1-wild-type NSCLC cells. In these models, metformin as single agent induced an activation and phosphorylation of mitogen-activated-protein-kinase (MAPK) through an increased C-RAF/B-RAF heterodimerization.
Experimental design
Since single agent metformin enhances proliferating signals through the RAS/RAF/MAPK pathway, and several MEK inhibitors (MEK-I) demonstrated clinical efficacy in combination with other agents in NSCLC, we tested the effects of metformin plus MEK-I (selumetinib or pimasertib) on proliferation, invasiveness, migration abilities in vitro and in vivo in LKB1 positive NSCLC models harboring KRAS wild type and mutated gene.
Results
The combination of metformin with MEK-I showed a strong anti-proliferative and proapoptotic effect in Calu-3, H1299, H358 and H1975 human NSCLC cell lines, independently from the KRAS mutational status. The combination reduced the metastatic behaviour of NSCLC cells, via a downregulation of GLI1 trascritional activity, thus affecting the transition from an epithelial to a mesenchymal phenotype. Metformin and MEK-Is combinations also decreased the production and activity of MMP-2 and MMP-9 by reducing the NF-jB (p65) binding to MMP-2 and MMP-9 promoters.
Conclusions
Metformin potentiates the antitumor activity of MEK-Is in human LKB1-wild-type NSCLC cell lines, independently from the KRAS mutational status, through GLI1 downregulation and by reducing the NF-jB (p65)-mediated transcription of MMP-2 and MMP-9.
doi:10.18632/oncotarget.6559
PMCID: PMC4826204  PMID: 26673006
metformin; MEK; selumetinib; pimasertib; NSCLC
5.  Integr(at)in(g) EGFR therapy in HNSCC 
doi:10.3978/j.issn.2305-5839.2015.12.08
PMCID: PMC4691002  PMID: 26733003
6.  Src inhibitors act through different mechanisms in Non-Small Cell Lung Cancer models depending on EGFR and RAS mutational status 
Oncotarget  2015;6(28):26090-26103.
Resistance to the EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib, often related to Ras or secondary EGFR mutations, is a relevant clinical issue in Non-Small Cell Lung Cancer (NSCLC). Although Src TK has been involved in such resistance, clinical development of its inhibitors has been so far limited.
To better define the molecular targets of the Src TKIs saracatinib, dasatinib and bosutinib, we used a variety of in vitro/in vivo studies.
Kinase assays supported by docking analysis demonstrated that all the compounds directly inhibit EGFR TK variants. However, in live cells only saracatinib efficiently reduced EGFR activation, while dasatinib was the most effective agent in inhibiting Src TK. Consistently, a pronounced anti-proliferative effect was achieved with saracatinib, in EGFR mutant cells, or with dasatinib, in wt EGFR/Ras mutant cells, poorly dependent on EGFR and erlotinib-resistant. We then identified the most effective drug combinations to overcome resistance to EGFR inhibitors, both in vitro and in nude mice: in T790M EGFR erlotinib-resistant cells, saracatinib with the anti-EGFR mAb cetuximab; in Ras mutant erlotinib-resistant models, dasatinib with the MEK inhibitor selumetinib.
Src inhibitors may act with different mechanisms in NSCLCs, depending on EGFR/Ras mutational profile, and may be integrated with EGFR or MEK inhibitors for different cohorts of NSCLCs.
PMCID: PMC4694888  PMID: 26325669
Src; NSCLC; EGFR inhibitors; MEK inhibitors; drug resistance
7.  AXL is an oncotarget in human colorectal cancer 
Oncotarget  2015;6(27):23281-23296.
AXL is a tyrosine kinase receptor activated by GAS6 and regulates cancer cell proliferation migration and angiogenesis. We studied AXL as new therapeutic target in colorectal cancer (CRC). Expression and activation of AXL and GAS6 were evaluated in a panel of human CRC cell lines. AXL gene silencing or pharmacologic inhibition with foretinib suppressed proliferation, migration and survival in CRC cells. In an orthotopic colon model of human HCT116 CRC cells overexpressing AXL, foretinib treatment caused significant inhibition of tumour growth and peritoneal metastatic spreading. AXL and GAS6 overexpression by immunohistochemistry (IHC) were found in 76,7% and 73.5%, respectively, of 223 human CRC specimens, correlating with less differentiated histological grading. GAS6 overexpression was associated with nodes involvement and tumour stage. AXL gene was found amplified by Fluorescence in situ hybridization (FISH) in 8/146 cases (5,4%) of CRC samples.
Taken together, AXL inhibition could represent a novel therapeutic approach in CRC.
PMCID: PMC4695118  PMID: 25966280
AXL; GAS6; colorectal cancer; foretinib; FISH
8.  Multidetector CT imaging of complications after laparoscopic nephron-sparing surgery 
Insights into Imaging  2015;6(4):465-478.
Purpose
Laparoscopic nephron-sparing surgery (L-NSS) is increasingly performed to treat localised renal lesions. However, the associated morbidity is non-negligible, with a rate of major complications approaching 10 %.
Methods and Results
This paper provides an overview of indications, surgical techniques and results of L-NSS; explains the incidence, risk factors and manifestations of postoperative complications; discusses the preferred multidetector computed tomography (CT) acquisition techniques; illustrates the appearance of normal postoperative images following L-NSS; and reviews, with example images, the most common and unusual iatrogenic complications. These include haematuria, haemorrhage, vascular injuries, infections and urinary leaks. Most emphasis is placed on CT, which provides rapid, reliable triage and follow-up of iatrogenic complications after L-NSS, identifying occurrences that require transarterial embolisation or repeated surgery.
Conclusions
Multidetector CT allows precise assessment of the surgical resection site; detection of pneumoperitoneum and subcutaneous emphysema; quantification of retroperitoneal blood; and identification of active bleeding, pseudoaneurysms, arterio-venous fistulas, abscess collections and extravasated urine.
Teaching Points
• Laparoscopic nephron-sparing surgery (NSS) is increasingly performed to treat renal lesions.
• Radiologists are increasingly requested to investigate suspected post-surgical NSS complications.
• Post-NSS complications include haemorrhage, haematuria, vascular injuries, infections and urinary leaks.
• Multidetector CT allows choice between conservative treatment, transarterial embolisation or surgery.
doi:10.1007/s13244-015-0413-1
PMCID: PMC4519814  PMID: 26104123
Laparoscopic nephron-sparing surgery; Haemorrhage; Pseudoaneurysm; Urine leak; Computed tomography (CT)
9.  Sphingosine analog fingolimod (FTY720) increases radiation sensitivity of human breast cancer cells in vitro 
Cancer Biology & Therapy  2014;15(6):797-805.
Radiotherapy is one of the most effective therapeutic strategies for breast cancer patients, although its efficacy may be reduced by intrinsic radiation resistance of cancer cells. Recent investigations demonstrate a link between cancer cell radio-resistance and activation of sphingosine kinase (SphK1), which plays a key role in the balance of lipid signaling molecules. Sphingosine kinase (SphK1) activity can alter the sphingosine-1-phosphate (S1P)/ceramide ratio leading to an imbalance in the sphingolipid rheostat. Fingolimod (FTY720) is a novel sphingosine analog and a potent immunosuppressive drug that acts as a SphK1 antagonist, inhibits the growth, and induces apoptosis in different human cancer cell lines. We sought to investigate the in vitro radiosensitizing effects of FTY720 on the MDA-MB-361 breast cancer cell line and to assess the effects elicited by radiation and FTY720 combined treatments. We found that FTY720 significantly increased anti-proliferative and pro-apoptotic effects induced by a single dose of ionizing radiation while causing autophagosome accumulation. At the molecular level, FTY720 significantly potentiated radiation effects on perturbation of signaling pathways involved in regulation of cell cycle and apoptosis, such as PI3K/AKT and MAPK. In conclusion, our data highlight a potent radiosensitizing effect of FTY720 on breast cancer cells and provide the basis of novel therapeutic strategies for breast cancer treatment.
doi:10.4161/cbt.28556
PMCID: PMC4049795  PMID: 24657936
FTY720; radiation therapy; sphingosine; autophagy; apoptosis; breast cancer; Akt; Erk
10.  Powerful anti-tumor and anti-angiogenic activity of a new anti-vascular endothelial growth factor receptor 1 peptide in colorectal cancer models 
Oncotarget  2015;6(12):10563-10576.
To assess the therapeutic outcome of selective block of VEGFR1, we have evaluated the activity of a new specific antagonist of VEGFR1, named iVR1 (inhibitor of VEGFR1), in syngenic and xenograft colorectal cancer models, in an artificial model of metastatization, and in laser-induced choroid neovascularization. iVR1 inhibited tumor growth and neoangiogenesis in both models of colorectal cancer, with an extent similar to that of bevacizumab, a monoclonal antibody anti-VEGF-A. It potently inhibited VEGFR1 phosphorylation in vivo, determining a strong inhibition of the recruitment of monocyte-macrophages and of mural cells as confirmed, in vitro, by the ability to inhibit macrophages migration. iVR1 was able to synergize with irinotecan determining a shrinkage of tumors that became undetectable after three weeks of combined treatment. Such treatment induced a significant prolongation of survival similar to that observed with bevacizumab and irinotecan combination. iVR1 also fully prevented lung invasion by HCT-116 cells injected in mouse tail vein. Also, iVR1 impressively inhibited choroid neovascularization after a single intravitreal injection. Collectively, data showed the strong potential of iVR1 peptide as a new anti-tumor and anti-metastatic agent and demonstrate the high flexibility of VEGFR1 antagonists as therapeutic anti-angiogenic agents in different pathological contexts.
PMCID: PMC4496375  PMID: 25868854
colorectal cancer; VEGFR1; angiogenesis; metastasis; choroid neovascularization
11.  Cross-sectional imaging of common and unusual complications after endoscopic retrograde cholangiopancreatography 
Insights into Imaging  2015;6(3):323-338.
Endoscopic retrograde cholangiopancreatography (ERCP) is currently a primarily therapeutic procedure that is extensively employed to treat several biliopancreatic disorders. Although widely considered a safe procedure, ERCP is associated with a non-negligible morbidity and occasional mortality. Due to the number and complexity of operative ERCPs performed, radiologists are increasingly faced with urgent requests for investigation of suspected post-procedural complications, which often have similar clinical and laboratory manifestations. This pictorial essay reviews the usual post-procedural CT findings, the clinical features and imaging appearances of common and unusual post-ERCP occurrences including interstitial oedematous and necrotising acute pancreatitis, haemorrhages, retroperitoneal and intraperitoneal duodenal perforations, infections and stent-related complications. Emphasis is placed on the pivotal role of multidetector CT, which is warranted after complex or prolonged ERCP procedures as it represents the most effective modality to detect and grade ERCP-related complications and to monitor nonsurgically treated patients. Timely diagnosis and optimal management require a combination of clinical and laboratory data with imaging appearances; therefore, this article aims to provide an increased familiarity with interpretation of early post-ERCP studies, particularly to triage those occurrences that require interventional or surgical treatment. In selected patients MRI allows imaging pancreatitis and abnormal collections without the use of ionising radiation.
Teaching Points
• Endoscopic retrograde cholangiopancreatography (ERCP) allows treating many biliopancreatic disorders.
• Due to the number and complexity of procedures, post-ERCP complications are increasingly encountered.
• Main complications include acute pancreatitis, haemorrhages, duodenal perforation and infections.
• Diagnosis and management of complications rely on combined clinical, laboratory and imaging data.
• Multidetector CT is most effective to diagnose, categorise and monitor post-ERCP complications.
doi:10.1007/s13244-015-0393-1
PMCID: PMC4444795  PMID: 25716101
Endoscopic retrograde cholangiopancreatography (ERCP); Complications; Computed tomography (CT); Acute pancreatitis; Duodenal perforation
12.  Pictorial review of normal postoperative cross-sectional imaging findings and infectious complications following laparoscopic appendectomy 
Insights into Imaging  2014;6(1):65-72.
Laparoscopic appendectomy is increasingly accepted as the preferred surgical treatment for acute appendicitis and represents one of the most common emergency operations performed in both adult and paediatric populations. However, in patients with perforated appendicitis laparoscopy is associated with an increased incidence of postoperative intraabdominal infections compared to open appendectomy. Nowadays urgent imaging is commonly requested by surgeons when postoperative complications are suspected. Due to the widespread use of laparoscopy, in hospitals with active surgical practices clinicians and radiologists are increasingly faced with suspected postappendectomy complications. This pictorial essay illustrates the normal cross-sectional imaging findings observed shortly after laparoscopic appendectomy and the spectrum of appearances of iatrogenic intraabdominal infections observed in adults and adolescents, aiming to provide radiologists with an increased familiarity with early postoperative imaging. Emphasis is placed on the role of multidetector CT, which according to the most recent World Society of Emergency Surgery (WSES) guidelines is the preferred and most accurate modality to promptly investigate suspected intraabdominal infections and highly helpful for correct therapeutic choice, particularly to identify those occurrences that require in-hospital treatment, drainage or surgical reintervention. In teenagers and young adults MRI represents an attractive alternative modality to detect or exclude iatrogenic abscesses without ionising radiation.
Teaching points
• Laparoscopic appendectomy is the preferred surgical treatment for uncomplicated acute appendicitis
• In perforated appendicitis laparoscopy results in increased incidence of intraabdominal infections
• Multidetector CT promptly assesses suspected iatrogenic intraabdominal infections
• Interpretation of early postoperative CT requires knowledge of normal postsurgical imaging findings
• Postsurgical infections include right-sided peritonitis, intraabdominal, pelvic or liver abscesses
doi:10.1007/s13244-014-0369-6
PMCID: PMC4330234  PMID: 25431189
Appendectomy; Laparoscopic surgery; Acute appendicitis; Infectious complications; Abscess; Computed tomography (CT); Magnetic resonance imaging (MRI)
13.  High mobility group A1 protein expression reduces the sensitivity of colon and thyroid cancer cells to antineoplastic drugs 
BMC Cancer  2014;14:851.
Background
Development of resistance to conventional drugs and novel biological agents often impair long-term chemotherapy. HMGA gene overexpression is often associated with antineoplastic drug resistance and reduced survival. Inhibition of HMGA expression in thyroid cancer cells reduces levels of ATM protein, the main cellular sensor of DNA damage, and enhances cellular sensitivity to DNA-damaging agents. HMGA1 overexpression promotes chemoresistance to gemcitabine in pancreatic adenocarcinoma cells through an Akt-dependent mechanism.
Methods
To elucidate the role of HMGA1 proteins in chemoresistance we analyzed resistance to conventional drugs and targeted therapies of human colon carcinoma cells (GEO) that are sensitive to the epidermal growth factor receptor inhibitor cetuximab, and express minimal levels of HMGA1 and cetuximab-resistant (GEO CR) cells expressing high HMGA1 protein levels.
Results
GEO CR cells were less sensitive than GEO cells to cetuximab and 5-fluorouracil. GEO CR cells silenced for HMGA1 expression were more susceptible than empty vector-transfected cells to the drugs’ cytotoxicity. Similar results were obtained with anaplastic thyroid carcinoma cells expressing or not HMGA1 proteins, treated with doxorubicin or the HDAC inhibitor LBH589. Finally, HMGA1 overexpression promoted the DNA-damage response and stimulated Akt phosphorylation and prosurvival signaling.
Conclusions
Our findings suggest that the blockage of HMGA1 expression is a promising approach to enhance cancer cell chemosensitivity, since it could increase the sensitivity of cancer cells to antineoplastic drugs by inhibiting the survival signal and DNA damage repair pathways.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2407-14-851) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2407-14-851
PMCID: PMC4247615  PMID: 25409711
HMGA1; Chemoresistance; Colon cancer; Thyroid cancer
15.  Hemorrhage and thrombosis with different LVAD technologies: a matter of flow? 
Annals of Cardiothoracic Surgery  2014;3(6):582-584.
Background
Much of the morbidity and mortality associated with ventricular assist devices (VADs) is due to haemorrhagic and thrombotic complications. To manage antithrombotic therapy, interactions between the patient and pump should be better understood.
Methods
We have compared the Jarvik 2000, an axial flow left ventricular assist device (LVAD), with the HeartWare ventricular assist device (HVAD) centrifugal pump, regarding conventional laboratory findings, thromboelastometric and aggregometric tests.
Results
Patients with the Jarvik 2000 experienced a significant reduction in platelet count following implantation, a phenomenon not seen with the HeartWare model. Conversely, we observed that levels of platelet activation, as assessed by a platelet function analyzer, and activation of the coagulation system, as assessed by thromboelastometry, were significantly greater in the HeartWare group.
Conclusions
It seems that axial flow pumps, being more destructive on blood cells, tend to reduce platelet numbers. On the other hand, centrifugal flow is associated with a hypercoagulable state, possibly resulting from the activation of the coagulation system in the absence of platelet destruction.
doi:10.3978/j.issn.2225-319X.2014.08.21
PMCID: PMC4250552  PMID: 25512898
Ventricular assist device (VAD); bleeding; thrombosis; axial flow; centrifugal flow
16.  Cross-sectional imaging of iatrogenic complications after extracorporeal and endourological treatment of urolithiasis 
Insights into Imaging  2014;5(6):677-689.
Extracorporeal shock wave lithotripsy (ESWL), percutaneous nephrolithotomy (PCNL) and ureteroscopy (URS) currently represent the mainstay treatment options for the vast majority of patients with urolithiasis, with limited contraindications and high success rates. However, minimally invasive extracorporeal and endourological treatments are associated with a non-negligible morbidity including occasional life-threatening occurrences. These complications represent a source of concern for urologists since they may result in prolonged hospitalisation, need for surgical, endoscopic or interventional treatment, long-term renal impairment, and sometimes even medical malpractice claims. Due to the increasing prevalence of urolithiasis and the large number of therapeutic procedures performed, in hospitals with active urologic practices radiologists are increasingly requested to investigate suspected post-procedural complications following ESWL, PCNL or ureteroscopic stone removal. Based upon our experience, this pictorial essay provides an overview of current extracorporeal and endourological treatment modalities for urolithiasis, including indications and possible complications according to the most recent guidelines from the European Association of Urology (EAU). Afterwards, we review the clinical features and cross-sectional imaging appearances of common and unusual complications with case examples, including steinstrasse, subcapsular, perirenal and suburothelial haemorrhages, severe urinary tract infections (such as pyeloureteritis, pyelonephritis, renal abscesses and pyonephrosis), ureteral injuries and delayed strictures.
Teaching points
• Extracorporeal lithotripsy, percutaneous nephrolitotomy and ureteroscopy allow treating urolithiasis.
• Minimally invasive extracorporeal and endourological treatment have non-negligible morbidity.
• Multidetector CT allows confident assessment of stone-free status and postprocedural complications.
• Main complications include steinstrasse, bleeding, severe infections, ureteral injuries and strictures.
• Imaging triage allows the choice among conservative, surgical, endoscopic or interventive treatment.
doi:10.1007/s13244-014-0355-z
PMCID: PMC4263803  PMID: 25256564
Urolithiasis; Lithotripsy; Ureteroscopy; Complications; Computed Tomography (CT)
19.  Decellularized Allogeneic Heart Valves Demonstrate Self-Regeneration Potential after a Long-Term Preclinical Evaluation 
PLoS ONE  2014;9(6):e99593.
Tissue-engineered heart valves are proposed as novel viable replacements granting longer durability and growth potential. However, they require extensive in vitro cell-conditioning in bioreactor before implantation. Here, the propensity of non-preconditioned decellularized heart valves to spontaneous in body self-regeneration was investigated in a large animal model. Decellularized porcine aortic valves were evaluated for right ventricular outflow tract (RVOT) reconstruction in Vietnamese Pigs (n = 11) with 6 (n = 5) and 15 (n = 6) follow-up months. Repositioned native valves (n = 2 for each time) were considered as control. Tissue and cell components from explanted valves were investigated by histology, immunohistochemistry, electron microscopy, and gene expression. Most substitutes constantly demonstrated in vivo adequate hemodynamic performances and ex vivo progressive repopulation during the 15 implantation months without signs of calcifications, fibrosis and/or thrombosis, as revealed by histological, immunohistochemical, ultrastructural, metabolic and transcriptomic profiles. Colonizing cells displayed native-like phenotypes and actively synthesized novel extracellular matrix elements, as collagen and elastin fibers. New mature blood vessels, i.e. capillaries and vasa vasorum, were identified in repopulated valves especially in the medial and adventitial tunicae of regenerated arterial walls. Such findings correlated to the up-regulated vascular gene transcription. Neoinnervation hallmarks were appreciated at histological and ultrastructural levels. Macrophage populations with reparative M2 phenotype were highly represented in repopulated valves. Indeed, no aspects of adverse/immune reaction were revealed in immunohistochemical and transcriptomic patterns. Among differentiated elements, several cells were identified expressing typical stem cell markers of embryonic, hematopoietic, neural and mesenchymal lineages in significantly higher number and specific topographic distribution in respect to control valves. Following the longest follow-up ever realized in preclinical models, non-preconditioned decellularized allogeneic valves offer suitable microenvironment for in vivo cell homing and tissue remodeling. Manufactured with simple, timesaving and cost-effective procedures, these promising valve replacements hold promise to become an effective alternative, especially for pediatric patients.
doi:10.1371/journal.pone.0099593
PMCID: PMC4062459  PMID: 24940754
20.  Epidermal growth factor-receptor activation modulates Src-dependent resistance to lapatinib in breast cancer models 
Introduction
Src tyrosine kinase overactivation has been correlated with a poor response to human epidermal growth factor receptor 2 (HER2) inhibitors in breast cancer. To identify the mechanism by which Src overexpression sustains this resistance, we tested a panel of breast cancer cell lines either sensitive or resistant to lapatinib.
Methods
To determine the role of Src in lapatinib resistance, we evaluated the effects of Src inhibition/silencing in vitro on survival, migration, and invasion of lapatinib-resistant cells. In vivo experiments were performed in JIMT-1 lapatinib-resistant cells orthotopically implanted in nude mice. We used artificial metastasis assays to evaluate the effect of Src inhibition on the invasiveness of lapatinib-resistant cells. Src-dependent signal transduction was investigated with Western blot and ELISA analyses.
Results
Src activation was higher in lapatinib-resistant than in lapatinib-sensitive cells. The selective small-molecule Src inhibitor saracatinib combined with lapatinib synergistically inhibited the proliferation, migration, and invasion of lapatinib-resistant cells. Saracatinib combined with lapatinib significantly prolonged survival of JIMT-1-xenografted mice compared with saracatinib alone, and impaired the formation of lung metastases. Unexpectedly, in lapatinib-resistant cells, Src preferentially interacted with epidermal growth factor receptor (EGFR) rather than with HER2. Moreover, EGFR targeting and lapatinib synergistically inhibited survival, migration, and invasion of resistant cells, thereby counteracting Src-mediated resistance. These findings demonstrate that Src activation in lapatinib-resistant cells depends on EGFR-dependent rather than on HER2-dependent signaling.
Conclusions
Complete pharmacologic EGFR/HER2 inhibition is required to reverse Src-dependent resistance to lapatinib in breast cancer.
doi:10.1186/bcr3650
PMCID: PMC4076622  PMID: 24887236
21.  Multidetector CT imaging of post-robot-assisted laparoscopic radical prostatectomy complications 
Insights into Imaging  2013;4(5):711-721.
Background
Robot-assisted laparoscopic radical prostatectomy (RALRP) is currently accepted as the preferred minimally invasive surgical treatment for localised prostate cancer, with optimal oncologic and functional results. Despite growing surgical experience, reduced postoperative morbidity and hospital stays, RALRP-related complications may occur, which are severe in 5–7 % of patients and sometimes require reoperation. Therefore, in hospitals with an active urologic surgery, urgent diagnostic imaging is increasingly requested to assess suspected early complications following RALRP surgery.
Methods
Based upon our experience, this pictorial review discusses basic principles of the surgical technique, the optimal multidetector CT (MDCT) techniques to be used in the postoperative urologic setting, the normal postoperative anatomy and imaging appearances.
Results
Afterwards, we review and illustrate the varied spectrum of RALRP-related complications including haemorrhage, urinary leaks, anorectal injuries, peritoneal changes, surgical site infections, abscess collections and lymphoceles, venous thrombosis and port site hernias.
Conclusion
Knowledge of surgical procedure details, appropriate MDCT acquisition techniques, and familiarity with normal postoperative imaging appearances and possible complications are needed to correctly perform and interpret early post-surgical imaging studies, particularly to identify those occurrences that require prolonged in-hospital treatment or surgical reintervention.
Teaching points
• Robot-assisted laparoscopic radical prostatectomy allows minimally invasive surgery of localised cancer
• Urologic surgeons may request urgent imaging to assess suspected postoperative complications
• Main complications include haemorrhage, urine leaks, anorectal injuries, infections and lymphoceles
• Correct multidetector CT techniques allow identifying haematomas, active bleeding and extravasated urine
• Imaging postoperative complications is crucial to assess the need for surgical reoperation
doi:10.1007/s13244-013-0280-6
PMCID: PMC3781251  PMID: 24018752
Prostatectomy; Robotic surgery; Laparoscopic surgery; Complications; Haemorrhage; Anastomotic leak; Urine leak; Computed tomography (CT); Cystography
22.  Combination of a Toll-like receptor 9 agonist with everolimus interferes with the growth and angiogenic activity of renal cell carcinoma 
Oncoimmunology  2013;2(8):e25123.
The mTOR inhibitor everolimus is currently approved for the treatment of renal cell carcinoma (RCC) and several Toll-like receptor 9 (TLR9) agonists, including immunomodulatory oligonucleotides (IMOs), have been tested for their therapeutic potential against advanced RCC. However, no clinical trials investigating the combination of mTOR inhibitors with TLR9 agonists in RCC patients have been performed to date. Our results may pave the way to translate this combinatorial approach to the clinical setting.
doi:10.4161/onci.25123
PMCID: PMC3782521  PMID: 24083076
mTOR; TLR9; everolimus; renal cell carcinoma; microenvironment
23.  Early non-aneurysmal infectious aortitis: Cross-sectional imaging diagnosis 
In patients without history of vascular surgery, infectious aortitis is a very uncommon, life-threatening condition with nonspecific clinical manifestations, which exposes the patient to uncontrolled sepsis and to the risk of retroperitoneal rupture. State-of-the-art cross-sectional imaging with contrast-enhanced multidetector computed tomography and magnetic resonance imaging allows confident diagnosis and characterization of unsuspected aortitis in septic patients at an early stage before the development of aneurysmal dilatation. The asymmetric distribution of periaortic inflammatory tissue is helpful for the differentiation of this exceptional disorder from other periaortic abnormalities such as retroperitoneal fibrosis or lymphoma.
doi:10.4103/0974-2700.110811
PMCID: PMC3665067  PMID: 23723629
Aortitis; computed tomography; magnetic resonance imaging; sepsis; Staphylococcus aureus
24.  Water enema multidetector CT technique and imaging of diverticulitis and chronic inflammatory bowel diseases 
Insights into Imaging  2013;4(3):309-320.
Background
Water enema multidetector computed tomography (WE-MDCT) is currently considered the most accurate imaging modality to provide high-resolution multiplanar visualisation of the colonic wall and surrounding structures.
Methods
This pictorial review presents our experience with WE-MDCT applications outside colorectal tumour staging, particularly for investigating diverticular disease and chronic inflammatory bowel diseases. A detailed explanation of the technique is provided, including patient preparation, the acquisition protocol, and study interpretation.
Results
WE-MDCT allows accurate preoperative visualisation of diverticular disease, acute and complicated diverticulitis. Ulcerative, indeterminate, or Crohn’s colitis can be assessed including longitudinal distribution, mural thickening and enhancement patterns, pseudopolyps, associated perivisceral changes, adjacent organ involvement, and features suggesting carcinoma. Elective WE-MDCT represents a useful complementary technique in patients with impossible, incomplete, or inconclusive endoscopy, can allow study of a stricture’s features and the upstream bowel, and helps planning medical, endoscopic, or surgical treatments.
Conclusion
Urgent WE-MDCT with limited or no bowel preparation may prove useful in acutely symptomatic patients, as it may obviate a risky or contraindicated endoscopy, can determine disease severity, and allows making correct therapeutic choices.
Teaching Points
• Water enema multidetector CT provides high-resolution multiplanar visualisation of the colonic wall.
• WE-MDCT allows accurate visualisation of diverticular disease, acute and complicated diverticulitis.
• In chronic inflammatory bowel diseases WE-MDCT depicts the distribution, mural and perivisceral changes.
• Elective WE-MDCT usefully complements incomplete endoscopy to assess strictures and upstream colon.
• Urgent WE-MDCT with limited or no bowel preparation in acute diseases may obviate endoscopy.
doi:10.1007/s13244-013-0239-7
PMCID: PMC3675246  PMID: 23508934
Contrast enema; Computed tomography (CT); Colonoscopy; Diverticular disease; Acute diverticulitis; Chronic inflammatory bowel diseases; Ulcerative colitis; Crohn’s disease; Indeterminate colitis
25.  Erratum to: MRI and CT of anal carcinoma: a pictorial review 
Insights into Imaging  2013;4(1):63.
doi:10.1007/s13244-013-0221-4
PMCID: PMC3579988  PMID: 23361151

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