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1.
Chemistry ; 29(24): e202203990, 2023 Apr 25.
Article in English | MEDLINE | ID: mdl-36734519

ABSTRACT

A combined experimental and theoretical study has been carried out on 4-fluoro-threonine, the only naturally occurring fluorinated amino acid. Fluorination of the methyl group significantly increases the conformational complexity with respect to the parent amino acid threonine. The conformational landscape has been characterized in great detail, with special attention given to the inter-conversion pathways between different conformers. This led to the identification of 13 stable low-energy minima. The equilibrium population of so many conformers produces a very complicated and congested rotational spectrum that could be assigned through a strategy that combines several levels of quantum chemical calculations with the principles of machine learning. Twelve conformers out of 13 could be experimentally characterized. The results obtained from the analysis of the intra-molecular interactions can be exploited to accurately model fluorine-substitution effects in biomolecules.

2.
Anim Genet ; 49(3): 147-158, 2018 Jun.
Article in English | MEDLINE | ID: mdl-29624711

ABSTRACT

The 'omics revolution has made a large amount of sequence data available to researchers and the industry. This has had a profound impact in the field of bioinformatics, stimulating unprecedented advancements in this discipline. Mostly, this is usually looked at from the perspective of human 'omics, in particular human genomics. Plant and animal genomics, however, have also been deeply influenced by next-generation sequencing technologies, with several genomics applications now popular among researchers and the breeding industry. Genomics tends to generate huge amounts of data, and genomic sequence data account for an increasing proportion of big data in biological sciences, due largely to decreasing sequencing and genotyping costs and to large-scale sequencing and resequencing projects. The analysis of big data poses a challenge to scientists, as data gathering currently takes place at a faster pace than does data processing and analysis, and the associated computational burden is increasingly taxing, making even simple manipulation, visualization and transferring of data a cumbersome operation. The time consumed by the processing and analysing of huge data sets may be at the expense of data quality assessment and critical interpretation. Additionally, when analysing lots of data, something is likely to go awry-the software may crash or stop-and it can be very frustrating to track the error. We herein review the most relevant issues related to tackling these challenges and problems, from the perspective of animal genomics, and provide researchers that lack extensive computing experience with guidelines that will help when processing large genomic data sets.


Subject(s)
Computational Biology , Genomics , Sequence Analysis, DNA , Animals , Databases, Genetic , High-Throughput Nucleotide Sequencing , Internet , Software
3.
Chem Commun (Camb) ; 53(10): 1591-1594, 2017 Feb 04.
Article in English | MEDLINE | ID: mdl-28085164

ABSTRACT

Using ascorbate as a sacrificial reductant, iodo-Bodipy dye 1b is able to promote the ATRA reaction between bromoderivatives and alkenes. This finding expands the possibility of using Bodipy dyes to promote photocatalytic reactions in efficient ways.

4.
Nanoscale ; 8(28): 13678-86, 2016 Jul 14.
Article in English | MEDLINE | ID: mdl-27376633

ABSTRACT

Tuning the intermolecular interactions among suitably designed molecules forming highly ordered self-assembled monolayers is a viable approach to control their organization at the supramolecular level. Such a tuning is particularly important when applied to sophisticated molecules combining functional units which possess specific electronic properties, such as electron/energy transfer, in order to develop multifunctional systems. Here we have synthesized two tetraferrocene-porphyrin derivatives that by design can selectively self-assemble at the graphite/liquid interface into either face-on or edge-on monolayer-thick architectures. The former supramolecular arrangement consists of two-dimensional planar networks based on hydrogen bonding among adjacent molecules whereas the latter relies on columnar assembly generated through intermolecular van der Waals interactions. Scanning Tunneling Microscopy (STM) at the solid-liquid interface has been corroborated by cyclic voltammetry measurements and assessed by theoretical calculations to gain multiscale insight into the arrangement of the molecule with respect to the basal plane of the surface. The STM analysis allowed the visualization of these assemblies with a sub-nanometer resolution, and cyclic voltammetry measurements provided direct evidence of the interactions of porphyrin and ferrocene with the graphite surface and offered also insight into the dynamics within the face-on and edge-on assemblies. The experimental findings were supported by theoretical calculations to shed light on the electronic and other physical properties of both assemblies. The capability to engineer the functional nanopatterns through self-assembly of porphyrins containing ferrocene units is a key step toward the bottom-up construction of multifunctional molecular nanostructures and nanodevices.

5.
Cell Death Dis ; 5: e1437, 2014 Oct 02.
Article in English | MEDLINE | ID: mdl-25275598

ABSTRACT

The PI3K/Akt/mTOR pathway has a central role in cancer metastasis and radiotherapy. To develop effective therapeutics to improve radiosensitivity, understanding the possible pathways of radioresistance involved and the effects of a combination of the PI3K/Akt/mTOR inhibitors with radiotherapy on prostate cancer (CaP) radioresistant cells is needed. We found that compared with parent CaP cells, CaP-radioresistant cells demonstrated G0/G1 and S phase arrest, activation of cell cycle check point, autophagy and DNA repair pathway proteins, and inactivation of apoptotic proteins. We also demonstrated that compared with combination of single PI3K or mTOR inhibitors (BKM120 or Rapamycin) and radiation, low-dose of dual PI3K/mTOR inhibitors (BEZ235 or PI103) combined with radiation greatly improved treatment efficacy by repressing colony formation, inducing more apoptosis, leading to the arrest of the G2/M phase, increased double-strand break levels and less inactivation of cell cycle check point, autophagy and non-homologous end joining (NHEJ)/homologous recombination (HR) repair pathway proteins in CaP-radioresistant cells. This study describes the possible pathways associated with CaP radioresistance and demonstrates the putative mechanisms of the radiosensitization effect in CaP-resistant cells in the combination treatment. The findings from this study suggest that the combination of dual PI3K/Akt/mTOR inhibitors (BEZ235 or PI103) with radiotherapy is a promising modality for the treatment of CaP to overcome radioresistance.


Subject(s)
Autophagy , DNA End-Joining Repair , Enzyme Inhibitors/pharmacology , Homologous Recombination , Phosphoinositide-3 Kinase Inhibitors , Prostatic Neoplasms/physiopathology , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , TOR Serine-Threonine Kinases/antagonists & inhibitors , Apoptosis/drug effects , Apoptosis/radiation effects , Cell Cycle/drug effects , Cell Cycle/radiation effects , Cell Line, Tumor , DNA End-Joining Repair/drug effects , DNA End-Joining Repair/radiation effects , Homologous Recombination/drug effects , Homologous Recombination/radiation effects , Humans , Male , Phosphatidylinositol 3-Kinases/genetics , Phosphatidylinositol 3-Kinases/metabolism , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/genetics , Prostatic Neoplasms/radiotherapy , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , Radiation Tolerance/drug effects , Radiation Tolerance/radiation effects , Signal Transduction/drug effects , Signal Transduction/radiation effects , TOR Serine-Threonine Kinases/genetics , TOR Serine-Threonine Kinases/metabolism
6.
Cell Death Dis ; 4: e875, 2013 Oct 24.
Article in English | MEDLINE | ID: mdl-24157869

ABSTRACT

Radioresistance is a major challenge in prostate cancer (CaP) radiotherapy (RT). In this study, we investigated the role and association of epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs) and the PI3K/Akt/mTOR signaling pathway in CaP radioresistance. We developed three novel CaP radioresistant (RR) cell lines (PC-3RR, DU145RR and LNCaPRR) by radiation treatment and confirmed their radioresistance using a clonogenic survival assay. Compared with untreated CaP-control cells, the CaP-RR cells had increased colony formation, invasion ability and spheroid formation capability (P<0.05). In addition, enhanced EMT/CSC phenotypes and activation of the checkpoint proteins (Chk1 and Chk2) and the PI3K/Akt/mTOR signaling pathway proteins were also found in CaP-RR cells using immunofluorescence, western blotting and quantitative real-time PCR (qRT-PCR). Furthermore, combination of a dual PI3K/mTOR inhibitor (BEZ235) with RT effectively increased radiosensitivity and induced more apoptosis in CaP-RR cells, concomitantly correlated with the reduced expression of EMT/CSC markers and the PI3K/Akt/mTOR signaling pathway proteins compared with RT alone. Our findings indicate that CaP radioresistance is associated with EMT and enhanced CSC phenotypes via activation of the PI3K/Akt/mTOR signaling pathway, and that the combination of BEZ235 with RT is a promising modality to overcome radioresistance in the treatment of CaP. This combination approach warrants future in vivo animal study and clinical trials.


Subject(s)
Epithelial-Mesenchymal Transition , Neoplastic Stem Cells/pathology , Phosphatidylinositol 3-Kinases/metabolism , Prostatic Neoplasms/pathology , Proto-Oncogene Proteins c-akt/metabolism , Radiation Tolerance , TOR Serine-Threonine Kinases/metabolism , Animals , Apoptosis/drug effects , Apoptosis/radiation effects , Cell Cycle Checkpoints/drug effects , Cell Cycle Checkpoints/radiation effects , Cell Line, Tumor , Enzyme Activation/drug effects , Enzyme Activation/radiation effects , Epithelial-Mesenchymal Transition/drug effects , Epithelial-Mesenchymal Transition/radiation effects , Humans , Imidazoles/pharmacology , Imidazoles/therapeutic use , Male , Models, Biological , Neoplasm Invasiveness , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/enzymology , Phenotype , Phosphoinositide-3 Kinase Inhibitors , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/enzymology , Prostatic Neoplasms/radiotherapy , Quinolines/pharmacology , Quinolines/therapeutic use , Radiation Tolerance/drug effects , Radiation Tolerance/radiation effects , Reproducibility of Results , Signal Transduction/drug effects , Signal Transduction/radiation effects , Spheroids, Cellular/drug effects , Spheroids, Cellular/pathology , Spheroids, Cellular/radiation effects , TOR Serine-Threonine Kinases/antagonists & inhibitors
7.
Br J Cancer ; 106(4): 638-45, 2012 Feb 14.
Article in English | MEDLINE | ID: mdl-22274410

ABSTRACT

BACKGROUND: Men diagnosed with localised prostate cancer (LPC) face difficult choices between treatment options that can cause persistent problems with sexual, urinary and bowel function. Controlled trial evidence about the survival benefits of the full range of treatment alternatives is limited, and patients' views on the survival gains that might justify these problems have not been quantified. METHODS: A discrete choice experiment (DCE) was administered in a random subsample (n=357, stratified by treatment) of a population-based sample (n=1381) of men, recurrence-free 3 years after diagnosis of LPC, and 65 age-matched controls (without prostate cancer). Survival gains needed to justify persistent problems were estimated by substituting side effect and survival parameters from the DCE into an equation for compensating variation (adapted from welfare economics). RESULTS: Median (2.5, 97.5 centiles) survival benefits needed to justify severe erectile dysfunction and severe loss of libido were 4.0 (3.4, 4.6) and 5.0 (4.9, 5.2) months. These problems were common, particularly after androgen deprivation therapy (ADT): 40 and 41% overall (n=1381) and 88 and 78% in the ADT group (n=33). Urinary leakage (most prevalent after radical prostatectomy (n=839, mild 41%, severe 18%)) needed 4.2 (4.1, 4.3) and 27.7 (26.9, 28.5) months survival benefit, respectively. Mild bowel problems (most prevalent (30%) after external beam radiotherapy (n=106)) needed 6.2 (6.1, 6.4) months survival benefit. CONCLUSION: Emerging evidence about survival benefits can be assessed against these patient-based benchmarks. Considerable variation in trade-offs among individuals underlines the need to inform patients of long-term consequences and incorporate patient preferences into treatment decisions.


Subject(s)
Patient Preference , Prostatic Neoplasms/therapy , Aged , Androgen Antagonists/adverse effects , Disease-Free Survival , Erectile Dysfunction/epidemiology , Humans , Intestinal Diseases/epidemiology , Male , Middle Aged , Prostatectomy/adverse effects , Prostatic Neoplasms/mortality , Prostatic Neoplasms/psychology , Quality of Life , Radiotherapy/adverse effects , Urologic Diseases/epidemiology
8.
Br J Cancer ; 103(7): 1008-18, 2010 Sep 28.
Article in English | MEDLINE | ID: mdl-20736947

ABSTRACT

BACKGROUND: The aim of this study is to seek an association between markers of metastatic potential, drug resistance-related protein and monocarboxylate transporters in prostate cancer (CaP). METHODS: We evaluated the expression of invasive markers (CD147, CD44v3-10), drug-resistance protein (MDR1) and monocarboxylate transporters (MCT1 and MCT4) in CaP metastatic cell lines and CaP tissue microarrays (n=140) by immunostaining. The co-expression of CD147 and CD44v3-10 with that of MDR1, MCT1 and MCT4 in CaP cell lines was evaluated using confocal microscopy. The relationship between the expression of CD147 and CD44v3-10 and the sensitivity (IC(50)) to docetaxel in CaP cell lines was assessed using MTT assay. The relationship between expression of CD44v3-10, MDR1 and MCT4 and various clinicopathological CaP progression parameters was examined. RESULTS: CD147 and CD44v3-10 were co-expressed with MDR1, MCT1 and MCT4 in primary and metastatic CaP cells. Both CD147 and CD44v3-10 expression levels were inversely related to docetaxel sensitivity (IC(50)) in metastatic CaP cell lines. Overexpression of CD44v3-10, MDR1 and MCT4 was found in most primary CaP tissues, and was significantly associated with CaP progression. CONCLUSIONS: Our results suggest that the overexpression of CD147, CD44v3-10, MDR1 and MCT4 is associated with CaP progression. Expression of both CD147 and CD44v3-10 is correlated with drug resistance during CaP metastasis and could be a useful potential therapeutic target in advanced disease.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Basigin/metabolism , Hyaluronan Receptors/metabolism , Monocarboxylic Acid Transporters/metabolism , Prostatic Neoplasms/metabolism , ATP Binding Cassette Transporter, Subfamily B , Adult , Aged , Animals , Biomarkers, Tumor/metabolism , Cell Line, Tumor , Disease Progression , Docetaxel , Drug Resistance, Neoplasm , Humans , Male , Middle Aged , Neoplasm Metastasis , Prostatic Neoplasms/drug therapy , Taxoids/therapeutic use , Up-Regulation
9.
Minerva Anestesiol ; 76(7): 550-3, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20613697

ABSTRACT

The aim of this paper was to describe a case of acute liver failure treated with total hepatectomy, recombinant activated factor VII and rescue liver transplantation. We reported our experience with a 51-year-old-woman who developed a massive portal thrombosis after cadaveric liver transplantation for hepatic epithelioid hemangioendothelioma and who then required a total hepatectomy and porto-caval shunt as a bridge procedure while waiting for an urgent new liver transplantation. Subsequently, the patient developed severe hemodynamic instability, massive abdominal and mucosal bleeding and acute renal failure that were managed with infusion of high doses of inotropes, red blood cells and fresh frozen plasma as well as continuous veno-venous hemofiltration. Due to persistent, uncontrolled bleeding, we considered the off-label use of rFVIIa. This caused a correction of the prothrombin times and allowed for sufficient hemostasis. The patient received a new cadaveric liver that was reperfused 38 hours after the first graft was removed. The transplanted liver showed immediate recovery, the hemodynamics ameliorated and the patient was fully awake at day five. In the case of an anhepatic phase complicated by severe bleeding that is unresponsiveness to several transfusions, a single administration of rFVIIa should be considered as a rescue therapy to control massive bleeding.


Subject(s)
Factor VIIa/therapeutic use , Hepatectomy , Liver Failure, Acute/therapy , Liver Transplantation , Combined Modality Therapy , Female , Hepatectomy/methods , Humans , Middle Aged , Recombinant Proteins/therapeutic use
10.
Curr Cancer Drug Targets ; 10(3): 287-306, 2010 May.
Article in English | MEDLINE | ID: mdl-20370680

ABSTRACT

Prostate cancer (CaP) is a major health problem in males in Western countries. Current therapeutic approaches are limited and many patients die of secondary disease (metastases). There is no cure for metastatic castration-resistant prostate cancer (CRPC). Targeting tumor-associated antigens is fast emerging as an area of promise to treat late stage and recurrent CaP. Extracellular matrix metalloproteinase inducer, EMMPRIN (CD147) is a multifunctional glycoprotein that can modify the tumor microenvironment by activating proteinases, inducing angiogenic factors in tumor and stromal cells, and regulating growth and survival of anchorage-independent tumor cells (micrometastases) and multidrug resistance (MDR). CD44 is a multifunctional protein involved in cell adhesion, migration and drug resistance, and is a primary receptor for hyaluronan (HA), a major component of the extracellular matrix (ECM) with a critical role in cell signaling and cell-ECM interactions in cancer. Our recent studies indicate both CD147 and CD44 are involved in cancer drug resistance and play very important roles in CaP metastasis. Thus, CD147 and CD44 may be ideal therapeutic targets to control metastatic and CRPC disease. This review will discuss their putative roles in CaP metastasis and MDR, and give an overview of literature regarding their expression on human CaP tissues. Additional focus will be on the potential of therapeutic strategies targeting CD147 and CD44 to prevent CaP metastasis and overcome drug resistance.


Subject(s)
Antineoplastic Agents/therapeutic use , Basigin/metabolism , Biomarkers, Tumor/metabolism , Genetic Therapy , Hyaluronan Receptors/metabolism , Immunotherapy , Prostatic Neoplasms/therapy , Animals , Basigin/genetics , Biomarkers, Tumor/genetics , Cell Adhesion , Cell Movement , Drug Resistance, Neoplasm , Humans , Hyaluronan Receptors/genetics , Hyaluronic Acid/metabolism , Male , Monocarboxylic Acid Transporters/metabolism , Neoplasm Invasiveness , Neoplastic Stem Cells/immunology , Neoplastic Stem Cells/pathology , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/immunology , Neovascularization, Pathologic/prevention & control , Prostatic Neoplasms/blood supply , Prostatic Neoplasms/genetics , Prostatic Neoplasms/immunology , Prostatic Neoplasms/secondary , Treatment Outcome
11.
Cancer Treat Rev ; 33(6): 521-7, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17658220

ABSTRACT

Prostate cancer (CaP) is one of the most common malignancies in men, with an increasing incidence. Despite significant advances in surgery, chemotherapy and radiotherapy to treat CaP, many patients unfortunately succumb to secondary disease (metastases). The invasive ability of tumour cells plays a key role in CaP metastasis and is a major cause of treatment failure. Urokinase plasminogen activator (uPA) and its receptor (uPAR)-mediated signalling have been implicated in tumour cell invasion, survival, and metastasis in a variety of cancers including CaP. Both uPA and uPAR are expressed at much higher levels in CaP tissues than in benign and normal prostate tissues. They are used as diagnostic markers as well as therapeutic targets due to their aberrant and unique expression pattern during cancer progression. Current therapeutic options for patients with metastatic hormone-refractory CaP (HRPC) are very limited. Therefore, much effort is currently being directed toward targeting aberrant uPA or uPAR activity in CaP. This review summarizes some important new findings supporting the role of uPA/uPAR in CaP progression and establishing the potential therapeutic efficacy of uPA/uPAR-targeted therapies in CaP.


Subject(s)
Prostatic Neoplasms/therapy , Receptors, Cell Surface/antagonists & inhibitors , Urokinase-Type Plasminogen Activator/antagonists & inhibitors , Animals , Antineoplastic Agents/pharmacology , Cell Proliferation , Cell Survival , Enzyme Inhibitors/pharmacology , Humans , Male , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , RNA Interference , Receptors, Urokinase Plasminogen Activator , Urokinase-Type Plasminogen Activator/genetics , Urokinase-Type Plasminogen Activator/metabolism
12.
Curr Cancer Drug Targets ; 7(3): 259-71, 2007 May.
Article in English | MEDLINE | ID: mdl-17504123

ABSTRACT

Prostate cancer (CaP) is one of the most common malignancies in men, and the incidence of CaP is increasing. Because of the limitations of current therapeutic approaches, many patients die of secondary disease (metastases). Mucins are used as diagnostic markers as well as therapeutic targets due to their aberrant and unique expression pattern during cancer progression. There is a growing interest in mucins as treatment targets in human malignancies, including CaP. So far, 21 mucin genes have been identified. Of these, MUC1 has been investigated most extensively. In neoplastic tissues, MUC1 is underglycosylated compared with that in normal tissues. The reduced glycosylation permits the immune system to access the peptide core of the tumor-associated underglycosylated MUC1 antigen (uMUC1) and reveal epitopes that are masked in the normal cell. This feature makes it possible to design an antibody that discriminates between normal and adenocarcinoma cells and target tumor-associated MUC1 with toxins or radionuclides, or use a vaccine targeting tumor-associated MUC1 antigen. The results from our recent study have shown that over-expression of MUC1 plays a very important role in CaP progression and MUC1 is an ideal target for targeted therapy to control micrometastases and hormone refractory disease. This review will cover our current understanding of the structure and functions of MUC1, summarize its expression on human CaP tissues and focus on the MUC1-based immunotherapy for control of metastatic CaP.


Subject(s)
Antineoplastic Agents/administration & dosage , Drug Delivery Systems/methods , Mucin-1/metabolism , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/metabolism , Animals , Antineoplastic Agents/therapeutic use , Humans , Male , Mucin-1/biosynthesis , Mucin-1/chemistry , Mucin-1/genetics , Neoplasm Metastasis/drug therapy , Neoplasm Metastasis/pathology , Neoplasm Metastasis/prevention & control , Prostatic Neoplasms/genetics , Prostatic Neoplasms/pathology
13.
Bone Marrow Transplant ; 39(10): 631-5, 2007 May.
Article in English | MEDLINE | ID: mdl-17384656

ABSTRACT

Antifungal therapy may be unable to eradicate invasive mycosis in leukemia patients. The presence of persisting pulmonary nodules owing to mycosis seems to increase the risk of fungal relapse after chemotherapy and transplant procedures. Between 1997 and 2004, 10 acute leukemia patients underwent pulmonary surgery for invasive mycosis. The median time from diagnosis of mycosis to surgery was 135 days (range 21-147). Three patients underwent emergency surgery, owing to hemoptysis. In the other seven patients with nodule/cavitation remaining after antifungal treatment, surgery (three wedge resections, four lobectomies) was scheduled before transplant. Pathologic examination confirmed two aspergillosis and three zygomycosis. The only side effect was pneumothorax in one case. Nine patients were considered cured. Six patients underwent bone marrow transplantation (three allogeneic, three autologous) with antifungal prophylaxis without relapse during the transplant procedure. In selected patients scheduled for bone marrow transplantation, surgical resection of localized pulmonary fungus nodules combined with antifungal prophylaxis seem to be an effective treatment for preventing mycotic relapse.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bone Marrow Transplantation/adverse effects , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/therapy , Lung Diseases, Fungal/etiology , Lung Diseases, Fungal/surgery , Adult , Aged , Antifungal Agents/therapeutic use , Aspergillosis/drug therapy , Aspergillosis/etiology , Aspergillosis/prevention & control , Aspergillosis/surgery , Female , Humans , Leukemia, Myeloid, Acute/complications , Lung Diseases, Fungal/drug therapy , Lung Diseases, Fungal/prevention & control , Male , Middle Aged , Mucormycosis/drug therapy , Mucormycosis/etiology , Mucormycosis/prevention & control , Mucormycosis/surgery , Recurrence
15.
Cancer Immunol Immunother ; 53(11): 995-1004, 2004 Nov.
Article in English | MEDLINE | ID: mdl-15449043

ABSTRACT

BACKGROUND: Monoclonal antibodies (MAbs) can be used to detect, image and treat cancers. This study aimed to characterise the binding of BLCA-38 MAbs to human prostate cancer cell lines, human prostate cancer biopsy samples and normal tissues to enable future targeted studies. METHODS: BLCA-38 antigen expression on cancer lines was determined by flow cytometry; that on patient specimens from normal tissues and cancers was tested by immunohistochemistry using fresh frozen tissues or paraffin-embedded tissues that had undergone antigen retrieval. RESULTS: Cell surface BLCA-38 antigen expression was seen on DU-145, PC-3, PC-3 M and PC-3 M-MM2 prostate cancer lines, but LNCaP, MDA PCa 2a or MDA PCa 2b lines were negative. Other human lines, including 8/12 bladder cancer and A431 vulval epidermoid cells, but not breast cancer lines, expressed BLCA-38 antigen. Staining occurred in glandular epithelial cells in the majority of frozen, and paraffin-embedded prostate cancer tissues and was occasionally seen in prostatic intraepithelial neoplasia (PIN). No staining was observed in normal cadaver tissues or in benign areas from various other cancer tissues. CONCLUSIONS: The BLCA-38 antibody binds to the majority of human prostate cancers but not to normal cells, and has potential for targeting novel therapies in patients with this disease.


Subject(s)
Antibodies, Monoclonal/chemistry , Biomarkers, Tumor , Immunohistochemistry/methods , Prostatic Neoplasms/diagnosis , Prostatic Neoplasms/metabolism , Animals , Antibodies, Monoclonal/immunology , Antigens, Neoplasm , Cell Line, Tumor , Female , Flow Cytometry , Humans , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Neoplasm Transplantation
17.
J Vasc Access ; 5(4): 168-73, 2004.
Article in English | MEDLINE | ID: mdl-16596561

ABSTRACT

BACKGROUND: Indwelling central venous catheters (CVCs) are essential devices in the management of patients with hematological disorders treated with chemotherapy. However, their nature predisposes patients to unwanted complications. METHODS: CVC-related complications were retrospectively analyzed in 227 hematologic patients who were consecutively admitted to our hematology department between May 2002 and April 2004. Patients' diagnoses comprised acute myeloid leukemia (36.8%), acute lymphoid leukemia (7.3%), lymphoproliferative disorders (28.3%), multiple myeloma (19.5%), myeloproliferative syndromes (5%) and others (3.1%). The CVCs used were polyurethane three lumen 7-Fr (111 patients) for chemotherapy and 12-Fr (114 patients) for chemotherapy and peripheral blood stem cell apheresis, plus two tunneled catheters. RESULTS: The pathological events were: bacteriaemias (n=46); occlusions (n=10); exit tunnel infections (n=8); thrombosis (n=6); lung emboli (n=2). Among febrile patients the bacteriemia frequency was 20%, of which 13.6% were CVC-related (with a higher incidence in leukemia patients (p=0.027). Among the isolates, gram-positive bacteria were found in 29 cases (23 CVC-related cases), and gram-negative bacteria in 16 cases (8 CVC-related cases). Only one patient had Candida albicans sepsis. At univariate and multivariate analysis significant risk factors for infection (p<0.0001) were only the number of days/catheters and neutropenia duration. CONCLUSIONS: In our hematologic patients, the CVC complications were mainly septic, with only 10.1% of CVC-related bacteriemias, despite prolonged catheterization duration. Acute leukemia patients were at major risk for sepsis, probably due to a more severe neutropenia and prolonged catheterization duration.

19.
Org Lett ; 3(8): 1153-5, 2001 Apr 19.
Article in English | MEDLINE | ID: mdl-11348182

ABSTRACT

[reaction: see text]. Chiral Cr(Salen) complex (1) prepared in situ from CrCl3 promotes the enantioselective addition of 1,3-dichloropropene to aromatic aldehydes in the presence of Mn as the stoichiometric reductant and Me3SiCl as a scavenger. The resulting 1,2-chlorohydrins obtained in good enantiomeric and diastereoisomeric excesses can be easily transformed into the corresponding chiral vinyl epoxides.


Subject(s)
Aldehydes/chemistry , Allyl Compounds/chemistry , Chlorides/chemistry , Chromium Compounds/chemistry , Ethylenediamines/chemistry , Chromatography, High Pressure Liquid , Hydrocarbons, Chlorinated , Manganese/chemistry , Models, Chemical
20.
Farmaco ; 56(1-2): 57-65, 2001.
Article in English | MEDLINE | ID: mdl-11347968

ABSTRACT

DNA minor groove binders represent a class of cytotoxic antitumor agents whose DNA sequence specificity may lead to a high selectivity of action. Tallimustine, benzoyl nitrogen mustard derivative of distamycin A, showed excellent antitumor activity in preclinical tests but also a severe myelotoxicity. Novel nitrogen mustard derivatives of distamycin showing improved activity profile were recently identified. In particular, cinnamic nitrogen mustard and cinnamic ethyl half-mustard analogs of tallimustine showed increased potency and more favorable cytotoxicity/myelotoxicity ratio. However a series of alpha-halogenoacrylamido derivatives of distamycin-like frames showed an activity profile substantially improved in comparison to tallimustine. In particular PNU-166196, alpha-bromo-acrylamido derivative of four pyrrole distamycin-like frame ending with a guanidino moiety, showed high cytotoxic potency even on tumor cell lines resistant to alkylating agents and camptothecin, broad antitumor activity and myelotoxicity dramatically reduced in comparison to tallimustine. This compound was found to bind to minor groove TA-rich sequences but appeared unreactive in classical in vitro DNA alkylation assays. With respect to the apparent lack of DNA alkylation we speculated that an intracellular reactive nucleophilic species, e.g. glutathione (GSH), could activate the reactivity of the compound leading to alkylation of DNA in vivo. Recent evidence of both covalent interaction of PNU-166196 with plasmidic DNA in the presence of GSH and of enhanced cytotoxicity in tumor cells characterized by high levels of GSH were obtained. PNU-166196, in view of its excellent activity profile and its outstanding favorable cytotoxicity/myelotoxicity ratio, was selected for clinical development and is undergoing phase I studies.


Subject(s)
Acrylamides/pharmacology , Antineoplastic Agents/pharmacology , DNA/metabolism , Alkylation , Distamycins/pharmacology , Glutathione/metabolism , Glutathione Transferase/metabolism , Humans , Nitrogen Mustard Compounds/pharmacology , Structure-Activity Relationship
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