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1.
Biomolecules ; 11(11)2021 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-34827635

RESUMO

ß-thalassemia major (ßTM) patients require frequent blood transfusions, with consequences that span from allogenic reactions to iron overload. To minimize these effects, ßTM patients periodically receive leucodepleted packed red blood cells (P-RBCs) stored for maximum 14 days. The aim of this study was to compare two alternative routine procedures to prepare the optimal P-RBCs product, in order to identify differences in their content that may somehow affect patients' health and quality of life (QoL). In method 1, blood was leucodepleted and then separated to obtain P-RBCs, while in method 2 blood was separated and leucodepleted after removal of plasma and buffycoat. Forty blood donors were enrolled in two independent centers; couples of phenotypically matched whole blood units were pooled, divided in two identical bags and processed in parallel following the two methods. Biochemical properties, electrolytes and metabolic composition were tested after 2, 7 and 14 days of storage. Units prepared with both methods were confirmed to have all the requirements necessary for ßTM transfusion therapy. Nevertheless, RBCs count and Hb content were found to be higher in method-1, while P-RBCs obtained with method 2 contained less K+, iron and storage lesions markers. Based on these results, both methods should be tested in a clinical perspective study to determine a possible reduction of transfusion-related complications, improving the QoL of ßTM patients, which often need transfusions for the entire lifespan.

2.
Int J Mol Sci ; 22(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34445472

RESUMO

Background: Platelet-Rich Plasma (PRP) induces bone regeneration; however, there is low evidence supporting its efficacy in bone healing. The lack of a standardized protocol of administration represents the main obstacle to its use in the clinical routine for bone defects' treatment. The purpose of this study was to characterize PRP and elucidate its osteogenic potential. Methods: Platelet count, fibrinogen levels, and growth factors concentration were measured in PRP obtained by four apheresis procedures. HOB-01-C1, a pre-osteocytic cell line, was used to examine the effects of different PRP dilutions (from 1% to 50%) on cell viability, growth, and differentiation. Gene expression of RUNX2, PHEX, COL1A1, and OCN was also assayed. Results: PRP showed a mean 4.6-fold increase of platelets amount compared to whole blood. Among the 36 proteins evaluated, we found the highest concentrations for PDGF isoforms, EGF, TGF-ß and VEGF-D. PDGF-AA positively correlated with platelet counts. In three of the four tested units, 25% PRP induced a growth rate comparable to the positive control (10% FBS); whereas, for all the tested units, 10% PRP treatment sustained differentiation. Conclusions: This study showed that PRP from apheresis stimulates proliferation and differentiation of pre-osteocyte cells through the release of growth factors from platelets.


Assuntos
Remoção de Componentes Sanguíneos/métodos , Regulação da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Osteócitos/citologia , Osteogênese , Plasma Rico em Plaquetas/metabolismo , Medicina Regenerativa , Diferenciação Celular , Proliferação de Células , Sobrevivência Celular , Perfilação da Expressão Gênica , Humanos , Técnicas In Vitro , Osteócitos/metabolismo
3.
Vox Sang ; 2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34156107

RESUMO

BACKGROUND AND OBJECTIVES: The first wave of coronavirus disease-2019 (COVID-19) dramatically affected the Transfusion Medicine Unit of the Azienda Unità Sanitari Locale - Istituto di Ricovero e Cura a Carattere Scientifico (AUSL-IRCCS) di Reggio Emilia, which faced a total rearrangement of the procedures for donors and patients. This study aims to assess the major implications of COVID-19 on our department, focusing on the blood transfusion chain and therapies, in order to support transfusion specialists in seeking efficient ways to face similar future emergencies. MATERIALS AND METHODS: This retrospective study compares our Transfusion Medicine Unit data collected between February and May 2020 with the same period in 2017-2019. Data on red blood cells and platelets donations, transfusions and clinical procedures were collected as aggregates from our internal electronic database. RESULTS: During the lockdown, donor centres were re-organized to reduce the risk of contagion and avoid unnecessary blood collection. Blood donations were re-scheduled to meet the decrease in elective surgery; consequently, plateletapheresis was implemented to supply the reduction of buffycoat-derived platelets. Transfusions significantly decreased together with orthopaedic and vascular surgery, while they were only marginally diminished for both cancer and onco-haematological patients. Reduced procedures for inpatients and outpatients were matched by remote medicine, addressing the need of a constant healthcare support for patients with chronic diseases. CONCLUSIONS: The described measures were adopted to avoid excessive blood collection and expiration, guarantee the safety of our ward (for both patients and staff) and supply the necessary transfusion therapies. These measures may support the development of appropriate risk management plans and safety procedures for other hospitals and transfusion services that have to face similar events.

4.
Transfus Apher Sci ; 60(4): 103155, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33975808

RESUMO

Allogeneic peripheral blood-derived (PBS) serum eye drops have been largely used in the treatment of dry eye disease (DED). Recently, cord blood has emerged as an effective alternative serum source (cord blood serum, CBS), containing a higher amount of growth factors than PBS, it holds the promise of a better capability to stimulate corneal healing. However, the lack of a standardized method for preparation, dispensation, storage and a poor biochemical characterization still hamper the establishment of a clinical consensus. Here the metabolomes of the two different serum eye drop preparations were compared using proton nuclear magnetic resonance spectroscopy. We found that both PBS and CBS contained several organic compounds, the majority of them already detected in human tears and may be thereby considered lacrimal substitutes. Metabolites having in the multivariate statistical analysis Partial least squares discriminant analysis (PLS-DA) a VIP scores > 1.0 were considered to be significantly different. All the metabolites identified were found to have a p < 0.05 in the univariate analysis. CBS, in particular, showed the highest amount of choline, myo-inositol, glutamine, creatine and ß-hydroxybutyrate. These evidences constitute relevant advances towards serum eye drops characterization and confirm that cord blood is a valid alternative source of serum eye drops.

5.
Diagnostics (Basel) ; 11(4)2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33923883

RESUMO

BACKGROUND: Increasing evidences support a correlation between magnesium (Mg) homeostasis and colorectal cancer (CRC). Nevertheless, the role of Mg and its transporters as diagnostic markers in CRC is still a matter of debate. In this study we combined X-ray Fluorescence Microscopy and databases information to investigate the possible correlation between Mg imbalance and CRC. METHODS: CRC tissue samples and their non-tumoural counterpart from four patients were collected and analysed for total Mg level and distribution by X-Ray Fluorescence Microscopy. We also reviewed the scientific literature and the main tissue expression databases to collect data on Mg transporters expression in CRC. RESULTS: We found a significantly higher content of total Mg in CRC samples when compared to non-tumoural tissues. Mg distribution was also impaired in CRC. Conversely, we evidenced an uncertain correlation between Mg transporters expression and colon malignancies. DISCUSSION: Although further studies are necessary to determine the correlation between different cancer types and stages, this is the first report proposing the measurement of Mg tissue localisation as a marker in CRC. This study represents thus a proof-of-concept that paves the way for the design of a larger prospective investigation of Mg in CRC.

6.
J Med Chem ; 64(6): 3204-3221, 2021 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-33710891

RESUMO

Drug-target interaction, cellular internalization, and target engagement should be addressed to design a lead with high chances of success in further optimization stages. Accordingly, we have designed conjugates of folic acid with anticancer peptides able to bind human thymidylate synthase (hTS) and enter cancer cells through folate receptor α (FRα) highly expressed by several cancer cells. Mechanistic analyses and molecular modeling simulations have shown that these conjugates bind the hTS monomer-monomer interface with affinities over 20 times larger than the enzyme active site. When tested on several cancer cell models, these conjugates exhibited FRα selectivity at nanomolar concentrations. A similar selectivity was observed when the conjugates were delivered in synergistic or additive combinations with anticancer agents. At variance with 5-fluorouracil and other anticancer drugs that target the hTS catalytic pocket, these conjugates do not induce overexpression of this protein and can thus help combating drug resistance associated with high hTS levels.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Ácido Fólico/análogos & derivados , Peptídeos/química , Peptídeos/farmacologia , Timidilato Sintase/antagonistas & inibidores , Antineoplásicos/farmacocinética , Domínio Catalítico/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Feminino , Receptor 1 de Folato/metabolismo , Ácido Fólico/farmacocinética , Ácido Fólico/farmacologia , Humanos , Modelos Moleculares , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Peptídeos/farmacocinética , Timidilato Sintase/metabolismo
7.
Transfus Apher Sci ; 60(1): 102963, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33051093

RESUMO

The AUSL-IRCCS of Reggio Emilia Transfusion Unit operates in two blood donor centers. Plasmapheresis protocols and machines are identical in both centers, except for the final unit weight setting: 700 g in Center 1 and 720 g in Center 2. Within a wider study to assess the anticoagulant content in plasma units through proton nuclear magnetic resonance, we compared the efficiency of the two settings. We analyzed 215 and 100 consecutive samples from Centers 1 and 2, respectively. We collected processed blood volume, net plasma collected and anticoagulant volume in the plasma units. In our experience, setting the machine at 720 g instead of 700 g was associated with a small increase in plasma content of the final unit (only 4 mL), but implied an increase of more than 100 mL of the total processed blood and a higher amount of anticoagulant in the unit. On the contrary, the difference in donor's reinfused anticoagulant was negligible. Our findings come from an observational study suggesting that, in view of a minimal advantage in terms of collected net plasma, there might be relevant disadvantages for the donor in prolonging plasmapheresis over 700 g. Since observed differences may be attributed to confounding factors, we recommend always checking the marginal efficiency of the procedure when the balance target value of the setting is increased. Randomized cross-over studies are needed to find the optimal target weight for plasma units. These studies could also help defining personalized plasmapheresis procedures, thus further optimizing donor safety.


Assuntos
Plasma/metabolismo , Plasmaferese/métodos , Doadores de Sangue , Humanos , Pessoa de Meia-Idade , Plasma/citologia , Voluntários
8.
Blood Transfus ; 2020 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-33370225

RESUMO

BACKGROUND: Red blood cell (RBC) units may contain a variety of molecules that can activate the neutrophil cascade turning neutrophils into targets for immunomodulatory molecules. Our metabolomics profiling of RBC units revealed a significant increase of hypoxanthine concentration during storage. Hypoxanthine catabolism in vivo ends with the production of uric acid through a reaction catalysed by xanthine oxidase during which reactive oxygen species are generated. Some authors have described in vitro neutrophil activation after treatment with stored RBC medium. However, the response of neutrophils to the action of xanthine oxidase upon hypoxanthine accumulation in the supernatant of RBC units has never been investigated. MATERIALS AND METHODS: Neutrophils were isolated from peripheral whole blood and cultured at 37 °C in a humidified incubator with 5% CO2. Hypoxanthine and RBC supernatants were tested to verify neutrophil stimulation. To prove the involvement of hypoxanthine in neutrophil activation, xanthine oxidase was pre-incubated with or without allopurinol before addition to the neutrophil cultures. Intracellular expression of tumour necrosis factor-α (TNF-α) and interleukin-8 (IL-8) was assessed by a cytofluorimetric assay and early-stage release of IL-8 was detected by a Luminex® assay. RESULTS: In the presence of xanthine oxidase, hypoxanthine, alone and in combination with RBC supernatants, caused increases of TNF-α- and IL-8-positive cells after 5 hours of treatment. Moreover, IL-8 was quickly released, 30 min after stimulation. DISCUSSION: Here we show, for the first time, that neutrophil activation by stored RBC depends, in part, on the presence of hypoxanthine contained in the RBC units. Our results add hypoxanthine to the already known mediators of inflammation present in RBC units, supporting the evidence that medium from stored RBC may concur to boost inflammatory processes in transfusion recipients, potentially leading to negative post-transfusion outcomes.

9.
Blood Transfus ; 18(5): 359-365, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32931414

RESUMO

BACKGROUND: While patient blood management (PBM) principles are not specific to cancer patients, their application contains the pathophysiological premises that could also benefit this patient population. In this study, we assessed the effects of implementing a PBM bundle for cancer patients in the postoperative period. MATERIALS AND METHODS: The Azienda USL-IRCCS of Reggio Emilia implemented a two-step PBM bundle for the postoperative period of cancer patients hospitalised in the semi-intensive post-surgery (SIPO) ward. Step 1 included seminars and lessons specifically targeting SIPO personnel; Step 2 introduced Points of Care (POCs) for the continuous monitoring of haemoglobin (Radical7, Masimo Corp, Irvine, CA, USA). We conducted 3 audits on 600 cancer patients recruited between 2014 and 2017: Audit 1 on 200 patients before the application of our PBM bundle; Audit 2 after Step 1 on 200 patients; Audit 3 after Step 2 on 200 patients monitored with POCs. Red blood cell (RBC) transfusion appropriateness in the postoperative period was evaluated using the Italian Society of Transfusion Medicine and Immunohaematology (SIMTI) recommendations. RESULTS: RBC transfusion appropriateness in the postoperative period of cancer patients rose from 38% to 75% after seminars, and reached 79% after the introduction of POC. The mean number of RBC units each patient received remained unchanged after training sessions (1.8 units/patient) while the introduction of POCs saw a simultaneous decrease in the number of prescribed units (1.3 units/patient). DISCUSSION: Our PBM bundle positively impacted RBC transfusion appropriateness in postsurgical cancer patients, both in terms of quality and quantity. A structured PBM programme specifically dedicated to surgical oncology should cover the entire perioperative period and might further improve transfusion appropriateness in these patients. The publication of guidelines on the management of anaemia in surgical oncology should be a priority.


Assuntos
Perda Sanguínea Cirúrgica , Transfusão de Eritrócitos , Auditoria Médica , Neoplasias/cirurgia , Cuidados Pós-Operatórios , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sistemas Automatizados de Assistência Junto ao Leito , Período Pós-Operatório
10.
Blood Transfus ; 18(3): 170-175, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32281927

RESUMO

BACKGROUND: Anticoagulant concentration in plasma units is extremely variable. Understanding the underlying causes of this variability could help personalise plasmapheresis procedures in order to optimise the risk-benefit ratio. We studied the association between anticoagulant solution A (usually ACD-A, Citrate Dextrose Solution A) volume in plasma units and donor characteristics to build a model to determine the needed weight of the final plasma unit to have an 80% probability of reaching 600 mL net plasma. MATERIALS AND METHODS: We experimentally measured ACD-A in 296 plasma units from an Italian blood donor centre, where machines are set for the collection of 700 g of plasma. Next, we built a statistical model to predict how the final volume of the unit should be set to obtain 50%, 80% or 90% probability of having at least 600 mL net plasma. RESULTS: ACD-A volume was associated with haemoglobin, total proteins and triglycerides. Donors with low haemoglobin reach an 80% probability of at least 600 mL net plasma with units of approximately 690 g, while 720 g are needed for donors with high haemoglobin levels. For total proteins and triglycerides, plasma units may vary within a range of ±20 g. DISCUSSION: Our model, based on easily measurable individual characteristics, makes it possible to customise plasmapheresis procedures by determining the blood volume to be processed for each donor. Tailored plasma donations might result in both a reduction in adverse events and an increase in the quality of collected plasma.


Assuntos
Doadores de Sangue , Modelos Biológicos , Plasma , Plasmaferese , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
11.
J Clin Apher ; 35(3): 146-153, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32087045

RESUMO

Low-density lipoprotein (LDL) apheresis (LA) selectively eliminates lipoproteins containing apolipoprotein B 100 (ApoB100) on patients affected by severe dyslipidemia. In addition to lowering lipids, LA is thought to exert pleiotropic effects altering a number of other compounds associated with atherosclerosis, such as pro- and anti-inflammatory cytokines or pro-thrombotic factors. More knowledge needs to be gathered on the effects of LA, and particularly on its ability to modify blood components other than lipids. We performed a multiparametric assessment of the inflammatory, metabolic and proteomic profile changes after Heparin-induced lipoprotein precipitation (H.E.L.P.) apheresis on serum samples from nine dyslipidemic patients evaluating cholesterol and lipoproteins, plasma viscosity and density, metabolites, cytokines, PCSK9 levels and other proteins selectively removed after the treatment. Our results show that H.E.L.P. apheresis is effective in lowering lipoprotein and PCSK9 levels. Although not significantly, complement and inflammation-related proteins are also affected, indicating a possible transient epiphenomenon induced by the extracorporeal procedure.


Assuntos
Remoção de Componentes Sanguíneos/métodos , Dislipidemias/sangue , Dislipidemias/terapia , Heparina/efeitos adversos , Lipoproteínas/química , Idoso , Fenômenos Biomecânicos , Eletroforese em Gel Bidimensional , Feminino , Humanos , Inflamação , Lipoproteína(a)/sangue , Masculino , Espectrometria de Massas , Metabolômica , Pessoa de Meia-Idade , Pró-Proteína Convertase 9/sangue , Qualidade de Vida , Viscosidade
12.
Blood Transfus ; 17(6): 459-464, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31403929

RESUMO

BACKGROUND: Within the context of Patient Blood Management (PBM) policy for the peri-operative period, the transfusion medicine unit of our institution adopted a series of strategies to support and enhance red blood cell (RBC) transfusion best practices. This study aimed to evaluate the appropriateness of RBC transfusion therapy in the post-operative period, before and after starting a multifactorial PBM policy. MATERIALS AND METHODS: A 2-phase observational study was conducted on patients who underwent major surgery. The study was designed as follows: 3 months of preliminary audit, followed by multifactorial PBM policy, and a final audit. The policy comprised seminars, teaching lessons, periodic consultations and the insertion of Points of Care. RBC transfusion appropriateness was evaluated in both audits. RESULTS: The preliminary audit, performed on 168 patients, showed that 37.7% of the patients were appropriately transfused. The final audit, performed on 205 patients, indicated a significant increase of RBC transfusion appropriateness to 65.4%. DISCUSSION: In our experience, our multifactorial PBM policy improved the RBC transfusion appropriateness in the post-operative period. We believe that our multifactorial PBM policy, which comprises the insertion of Points of Care, supported the healthcare workers in the transfusion decision-making process. This enhancement of transfusion appropriateness implies clinical and managerial advantages, such as reduced transfusion-related risks, optimisation of health care resources, and reduction in costs.


Assuntos
Transfusão de Eritrócitos , Auditoria Médica , Sistemas Automatizados de Assistência Junto ao Leito , Cuidados Pós-Operatórios , Procedimentos Cirúrgicos Operatórios , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
13.
Transfusion ; 59(6): 2113-2120, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30875439

RESUMO

BACKGROUND: To date, the quantification of the anticoagulant (ACD-A) in plasma units has been based on theoretical calculations. An accurate quantification could help minimize the risks associated with plasmapheresis, given that the total ACD-A used during the procedure is distributed between the donor and the plasma unit. Our aim was to experimentally quantify the volume of ACD-A in units collected by plasmapheresis. STUDY DESIGN AND METHODS: We used proton nuclear magnetic resonance spectroscopy to measure the ACD-A volume in 295 plasma units collected by the Azienda USL-IRCCS of Reggio Emilia, Italy. We analyzed the determinants of the differences between estimated and measured ACD-A through multivariate regression models. RESULTS: The experimentally measured ACD-A in plasma units was variable, with 45% of the samples showing a discrepancy of more than 15 mL compared to the manufacturer's estimate. ACD-A was underestimated for higher density of the units (p < 0.0005); a weak association was also observed with triglycerides (underestimated for higher levels, p = 0.015) and sex (overestimated in females, p = 0.008), but our model explained only 35% of the individual variability. CONCLUSION: The manufacturer's algorithms do not accurately estimate the ACD-A in units collected by plasmapheresis. Donor-related characteristics may affect ACD-A distribution between donor and plasma unit, thereby explaining the discrepancies between estimate and measurement. Errors in the estimate of the ACD-A actually received by donors could hamper studies on dose-response relationship between anticoagulant and adverse reactions. Our work should stimulate research on tailored procedures aimed at minimizing the anticoagulant received by donors and increasing plasmapheresis safety.


Assuntos
Anticoagulantes/análise , Plasma/química , Plasmaferese , Adulto , Doadores de Sangue , Coleta de Amostras Sanguíneas/métodos , Feminino , Humanos , Itália , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Plasmaferese/métodos
14.
J Med Chem ; 61(16): 7374-7380, 2018 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-30035541

RESUMO

LR and [d-Gln4]LR peptides bind the monomer-monomer interface of human thymidylate synthase and inhibit cancer cell growth. Here, proline-mutated LR peptides were synthesized. Molecular dynamics calculations and circular dichroism spectra have provided a consistent picture of the conformational propensities of the [Pro n]-peptides. [Pro3]LR and [Pro4]LR show improved cell growth inhibition and similar intracellular protein modulation compared with LR. These represent a step forward to the identification of more rigid and metabolically stable peptides.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Peptídeos/farmacologia , Timidilato Sintase/antagonistas & inibidores , Antineoplásicos/química , Linhagem Celular Tumoral , Dicroísmo Circular , Inibidores Enzimáticos/química , Feminino , Humanos , Simulação de Dinâmica Molecular , Mutação , Neoplasias Ovarianas/patologia , Peptídeos/química , Peptídeos/genética , Prolina/genética , Conformação Proteica , Timidilato Sintase/genética , Timidilato Sintase/metabolismo
15.
Ann Hematol ; 97(10): 1909-1917, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29881883

RESUMO

The upholding of red blood cells (RBC) quality and the removal of leukocytes are two essential issues in transfusion therapy. Leukodepletion provides optimum results, nonetheless there are cases where irradiation is recommended for some groups of hematological patients such as the ones with chronic graft-vs-host disease, congenital cellular immunodeficiency, and hematopoietic stem cell transplant recipients. The European guidelines suggest irradiation doses from 25 to 50 Gray (Gγ). We evaluated the effect of different prescribed doses (15 to 50 Gγ) of X-ray irradiation on fresh leukodepleted RBCs bags using a novel protocol that provides a controlled irradiation. Biochemical assays integrated with RBCs metabolome profile, assessed by nuclear magnetic resonance spectroscopy, were performed on RBC units supernatant, during 14 days storage. Metabolome analysis evidenced a direct correlation between concentration increase of three metabolites, glycine, glutamine and creatine, and irradiation dose. Higher doses (35 and 50 Gγ) effect on RBC mean corpuscular volume, hemolysis, and ammonia concentration are considerable after 7 and 14 days of storage. Our data show that irradiation with 50 Gγ should be avoided and we suggest that 35 Gγ should be the upper limit. Moreover, we suggest for leukodepleted RBCs units the irradiation with the prescribed dose of 15 Gγ, value at center of bag, and ranging between 13.35-15 Gγ, measured over the entire bag volume, may guarantee the same benefits of a 25 Gγ dose assuring, in addition, a better quality of RBCs.


Assuntos
Eritrócitos/metabolismo , Eritrócitos/efeitos da radiação , Metaboloma/efeitos da radiação , Raios X , Adulto , Preservação de Sangue/métodos , Transplante de Medula Óssea/métodos , Sobrevivência Celular/efeitos da radiação , Relação Dose-Resposta à Radiação , Transfusão de Eritrócitos/métodos , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Leucemia/terapia , Masculino , Pessoa de Meia-Idade , Doses de Radiação
16.
Front Pharmacol ; 9: 454, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29867465

RESUMO

Proteomics and bioinformatics are a useful combined technology for the characterization of protein expression level and modulation associated with the response to a drug and with its mechanism of action. The folate pathway represents an important target in the anticancer drugs therapy. In the present study, a discovery proteomics approach was applied to tissue samples collected from ovarian cancer patients who relapsed after the first-line carboplatin-based chemotherapy and were treated with pemetrexed (PMX), a known folate pathway targeting drug. The aim of the work is to identify the proteomic profile that can be associated to the response to the PMX treatment in pre-treatement tissue. Statistical metrics of the experimental Mass Spectrometry (MS) data were combined with a knowledge-based approach that included bioinformatics and a literature review through ProteinQuest™ tool, to design a protein set of reference (PSR). The PSR provides feedback for the consistency of MS proteomic data because it includes known validated proteins. A panel of 24 proteins with levels that were significantly different in pre-treatment samples of patients who responded to the therapy vs. the non-responder ones, was identified. The differences of the identified proteins were explained for the patients with different outcomes and the known PMX targets were further validated. The protein panel herein identified is ready for further validation in retrospective clinical trials using a targeted proteomic approach. This study may have a general relevant impact on biomarker application for cancer patients therapy selection.

17.
Chemosphere ; 201: 595-602, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29533810

RESUMO

Sediments dredged by an industrial port, slightly contaminated by heavy metals and petroleoum hydrocarbons, were phytoremediated and used as peat-free growing media for the red robin photinia (Photinia x fraseri L.). Plants were grown on sediment only (S), sediment mixed with composted pruning residues (S + PR), sediment fertilized with controlled release fertilizers (S + F) and peat-based growing media as control (C). Plant elongation and dry weight, leaf contents of chlorophyll, malondialdehyde (MDA), macronutrients and heavy metals were determined at the end of one growing season. Environmental impact related to the use of sediment-based as compared to peat-based growing media was assessed by the Life Cycle Analysis (LCA). Sediment-based growing media presented significantly higher bulk density, pH and electrical conductivity values, lower C and N contents, and significantly higher total and available P. Red robin photinia grown on S + F growing media showed morphological and chemical parameters similar to those of control plants (C), whereas plants grown on S and S + PR showed lower growth. Leaf concentration of nutrients and heavy metals varied depending on the considered element and growing media, but were all within the common values for ornamental plants, whereas the highest MDA concentrations were found in plants grown on traditional growing media. The LCA indicated the use of sediments as growing media reduced the C footprint of ornamental plant production and the contribute of growing media to the environmental impact per produced plant. We concluded that sediments phytoremediation and use in plant nursery is a practical alternative re-use option for dredged sediments.


Assuntos
Clorofila/análise , Sedimentos Geológicos/química , Photinia/crescimento & desenvolvimento , Poluentes do Solo/análise , Solo/química , Animais , Biodegradação Ambiental , Metais Pesados/análise , Petróleo/análise , Photinia/química
18.
Nat Protoc ; 12(3): 461-471, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28151463

RESUMO

Magnesium plays a crucial role in many physiological functions and pathological states. Therefore, the evolution of specific and sensitive tools capable of detecting and quantifying this element in cells is a very desirable goal in biological and biomedical research. We developed a Mg2+-selective fluorescent dye that can be used to selectively detect and quantify the total magnesium pool in a number of cells that is two orders of magnitude smaller than that required by flame atomic absorption spectroscopy (F-AAS), the reference analytical method for the assessment of cellular total metal content. This protocol reports itemized steps for the synthesis of the fluorescent dye based on diaza-18-crown-6-hydroxyquinoline (DCHQ5). We also describe its application in the quantification of total intracellular magnesium in mammalian cells and the detection of this ion in vivo by confocal microscopy. The use of in vivo confocal microscopy enables the quantification of magnesium in different cellular compartments. As an example of the sensitivity of DCHQ5, we studied the involvement of Mg2+ in multidrug resistance in human colon adenocarcinoma cells sensitive (LoVo-S) and resistant (LoVo-R) to doxorubicin, and found that the concentration was higher in LoVo-R cells. The time frame for DCHQ5 synthesis is 1-2 d, whereas the use of this dye for total intracellular magnesium quantification takes 2.5 h and for ion bioimaging it takes 1-2 h.


Assuntos
Técnicas de Química Sintética/métodos , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/metabolismo , Espaço Intracelular/metabolismo , Magnésio/metabolismo , Microscopia de Fluorescência , Linhagem Celular Tumoral , Corantes Fluorescentes/química , Humanos , Hidroxiquinolinas/síntese química , Hidroxiquinolinas/química , Hidroxiquinolinas/metabolismo
20.
Drug Resist Updat ; 23: 20-54, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26690339

RESUMO

Our current understanding of the mechanisms of action of antitumor agents and the precise mechanisms underlying drug resistance is that these two processes are directly linked. Moreover, it is often possible to delineate chemoresistance mechanisms based on the specific mechanism of action of a given anticancer drug. A more holistic approach to the chemoresistance problem suggests that entire metabolic pathways, rather than single enzyme targets may better explain and educate us about the complexity of the cellular responses upon cytotoxic drug administration. Drugs, which target thymidylate synthase and folate-dependent enzymes, represent an important therapeutic arm in the treatment of various human malignancies. However, prolonged patient treatment often provokes drug resistance phenomena that render the chemotherapeutic treatment highly ineffective. Hence, strategies to overcome drug resistance are primarily designed to achieve either enhanced intracellular drug accumulation, to avoid the upregulation of folate-dependent enzymes, and to circumvent the impairment of DNA repair enzymes which are also responsible for cross-resistance to various anticancer drugs. The current clinical practice based on drug combination therapeutic regimens represents the most effective approach to counteract drug resistance. In the current paper, we review the molecular aspects of the activity of TS-targeting drugs and describe how such mechanisms are related to the emergence of clinical drug resistance. We also discuss the current possibilities to overcome drug resistance by using a molecular mechanistic approach based on medicinal chemistry methods focusing on rational structural modifications of novel antitumor agents. This paper also focuses on the importance of the modulation of metabolic pathways upon drug administration, their analysis and the assessment of their putative roles in the networks involved using a meta-analysis approach. The present review describes the main pathways that are modulated by TS-targeting anticancer drugs starting from the description of the normal functioning of the folate metabolic pathway, through the protein modulation occurring upon drug delivery to cultured tumor cells as well as cancer patients, finally describing how the pathways are modulated by drug resistance development. The data collected are then analyzed using network/netwire connecting methods in order to provide a wider view of the pathways involved and of the importance of such information in identifying additional proteins that could serve as novel druggable targets for efficacious cancer therapy.


Assuntos
Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Antagonistas do Ácido Fólico/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Neoplasias/tratamento farmacológico , Timidilato Sintase/antagonistas & inibidores , Ensaios Clínicos como Assunto , Resistencia a Medicamentos Antineoplásicos/genética , Inibidores Enzimáticos/uso terapêutico , Ácido Fólico/metabolismo , Redes Reguladoras de Genes/efeitos dos fármacos , Humanos , Redes e Vias Metabólicas/efeitos dos fármacos , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Medicina de Precisão , Transdução de Sinais , Timidilato Sintase/genética , Timidilato Sintase/metabolismo
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