RESUMO
Genomic surveillance based on sequencing the entire genetic code of SARS-CoV-2 involves monitoring and studying genetic changes and variations in disease-causing organisms such as viruses and bacteria. By tracing the virus, it is possible to prevent epidemic spread in the community, ensuring a 'precision public health' strategy. A peptide-based design was applied to provide an efficacious strategy that is able to counteract any emerging viral variant of concern dynamically and promptly to affect the outcomes of a pandemic at an early stage while waiting for the production of the anti-variant-specific vaccine, which require longer times. The inhibition of the interaction between the receptor-binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and one of the cellular receptors (DPP4) that its receptors routinely bind to infect human cells is an intriguing therapeutic approach to prevent the virus from entering human cells. Among the other modalities developed for this purpose, peptides surely offer unique advantages, including ease of synthesis, serum stability, low immunogenicity and toxicity, and small production and distribution chain costs. Here, we obtained a potent new inhibitor based on the rearrangement of a previously identified peptide that has been rationally designed on a cell dipeptidyl peptidase 4 (DPP4) sequence, a ubiquitous membrane protein known to bind the RBD-SPIKE domain of the virus. This novel peptide (named DPP4-derived), conceived as an endogenous "drug", is capable of targeting the latest tested variants with a high affinity, reducing the VSV* DG-Fluc pseudovirus Omicron's infection capacity by up to 14%, as revealed by in vitro testing in human Calu-3 cells. Surface plasmon resonance (SPR) confirmed the binding affinity of the new DPP4-derived peptide with Omicron variant RBD.
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Increased oxidative stress may contribute to cancer anorexia, which could be ameliorated by antioxidant supplementation. methylcholanthrene (MCA) sarcoma-bearing Fisher rats were studied. After tumour inoculation, rats were randomly assigned to standard diet (CTR group, n = 6), or to an antioxidant-enriched diet (AOX group, n = 8). Eight more rats (STD-AOX group) switched from standard to antioxidant diet when anorexia developed. At the end of the study, food intake (FI, g/d), body weight and tumour weight (g) were recorded, and plasma samples were obtained. On day 16, anorexia has appeared only in CTR and STD-AOX animals. At the end of the study, FI in AOX animals was still higher than in the other groups (p = 0.08). No differences in body and tumour weights were observed among groups. However, hydrogen peroxide and interleukin-1ß levels were significantly reduced only in AOX rats. Data obtained suggest that early antioxidant supplementation improves cancer anorexia, ameliorates oxidative stress and reduces inflammation.
Assuntos
Anorexia/tratamento farmacológico , Antioxidantes/uso terapêutico , Suplementos Nutricionais , Ingestão de Energia/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Sarcoma/complicações , Animais , Anorexia/sangue , Anorexia/etiologia , Antioxidantes/administração & dosagem , Ácido Ascórbico/administração & dosagem , Ácido Ascórbico/uso terapêutico , Peso Corporal/efeitos dos fármacos , Dieta , Modelos Animais de Doenças , Esquema de Medicação , Peróxido de Hidrogênio/sangue , Interleucina-1beta/sangue , Masculino , Metilcolantreno , Distribuição Aleatória , Ratos Endogâmicos F344 , Sarcoma/sangue , Sarcoma/induzido quimicamente , Vitamina E/administração & dosagem , Vitamina E/uso terapêuticoRESUMO
Despite the availability on the market of different anti-SARS-CoV-2 vaccines, there are still unanswered questions on whether they can stimulate long-lasting protection. A deep understanding of adaptive immune response to SARS-CoV-2 is important for optimizing both vaccine development and pandemic control measures. Among cytokines secreted by lymphocytes in response to viral infection, IFN-γ plays a pivotal role both in innate and adaptive immunity. In this study, we report on 28 naïve-to-SARS-Cov-2-infection and unvaccinated subjects, having reported a close and prolonged contact with COVID-19-positive patients. Samples were tested for defective genetic variants in interferon pathway genes by whole exome sequencing and anti-IFN autoantibodies production was investigated. Subject T-cells were cultured and infected with pseudotype particles bearing the S proteins and in parallel stimulated with two S-peptides designed on the RBD region of the spike protein. Our results showed that one of these peptides, RBD 484-508, induces a significant increase in IFN-γ gene expression and protein production in T-cells, comparable to those obtained in cells infected by SARS-CoV-2 pseudovirus. This work deepens our understanding of immune response and highlights the selected peptide as a reasonable approach to induce broad, potent, and variant concern-independent T-cell responses.
Assuntos
COVID-19 , Humanos , Linfócitos T , SARS-CoV-2 , Interferon gama , Peptídeos , Anticorpos Antivirais , Glicoproteína da Espícula de Coronavírus/genéticaRESUMO
Electrochemotherapy is a tumor treatment that adapts the systemic or local delivery of anticancer drugs by the application of permeabilizing electric pulses with appropriate amplitude and waveforms. This allows the use of lipophobic drugs, which frequently have a narrow therapeutic index, with a decreased morbidity for the patient, while maintaining appropriate anticancer efficacy. Electrochemotherapy is used in humans for the treatment of cutaneous neoplasms or the palliation of skin tumor metastases, and a standard operating procedure has been devised. In veterinary oncology, the electrochemotherapy approach is gaining popularity, becoming a first-line treatment in consideration of its high efficacy and low toxicity. This review summarizes the state of the art in veterinary oncology as a preclinical model.
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Antineoplásicos/administração & dosagem , Eletroquimioterapia/métodos , Neoplasias/veterinária , Animais , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica , Bleomicina/farmacocinética , Bleomicina/farmacologia , Carcinoma/tratamento farmacológico , Doenças do Gato/tratamento farmacológico , Gatos , Cisplatino/farmacocinética , Cisplatino/farmacologia , Doenças do Cão/tratamento farmacológico , Cães , Avaliação Pré-Clínica de Medicamentos , Eletroquimioterapia/veterinária , Epirubicina , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Melanoma/veterinária , Mitoxantrona/farmacocinética , Mitoxantrona/farmacologia , Neoplasias/tratamento farmacológico , Quinazolinas , Sarcoma/tratamento farmacológico , TiofenosRESUMO
The global health emergency for SARS-CoV-2 (COVID-19) created an urgent need to develop new treatments and therapeutic drugs. In this study, we tested, for the first time on human cells, a new tetravalent neutralizing antibody (15033-7) targeting Spike protein and a synthetic peptide homologous to dipeptidyl peptidase-4 (DPP4) receptor on host cells. Both could represent powerful immunotherapeutic candidates for COVID-19 treatment. The infection begins in the proximal airways, namely the alveolar type 2 (AT2) cells of the distal lung, which express both ACE2 and DPP4 receptors. Thus, to evaluate the efficacy of both approaches, we developed three-dimensional (3D) complex lung organoid structures (hLORGs) derived from human-induced pluripotent stem cells (iPSCs) and resembling the in vivo organ. Afterward, hLORGs were infected by different SARS-CoV-2 S pseudovirus variants and treated by the Ab15033-7 or DPP4 peptide. Using both approaches, we observed a significant reduction of viral entry and a modulation of the expression of genes implicated in innate immunity and inflammatory response. These data demonstrate the efficacy of such approaches in strongly reducing the infection efficiency in vitro and, importantly, provide proof-of-principle evidence that hiPSC-derived hLORGs represent an ideal in vitro system for testing both therapeutic and preventive modalities against COVID-19.
Assuntos
Tratamento Farmacológico da COVID-19 , Células-Tronco Pluripotentes Induzidas , Dipeptidil Peptidase 4/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Pulmão/metabolismo , Organoides/metabolismo , SARS-CoV-2RESUMO
BACKGROUND: Cancer is one of the most difficult current health challenges, being responsible for millions of deaths yearly. Systemic chemotherapy is the most common therapeutic approach, and the prevailing orientation calls for the administration of the maximum tolerated dose; however, considerable limitations exist including toxicities to healthy tissues and low achievable drug concentrations at tumor sites. Electrochemotherapy (ECT) is a tumor treatment that combines the systemic or local delivery of anticancer drugs with the application of permeabilizing electric pulses. In this article we evaluate the capability of ECT to allow the use of cisplatin despite its high toxicity in a spontaneous feline model of soft tissue sarcoma. METHODS: A cohort of sixty-four cats with incompletely excised sarcomas were treated with cisplatin-based adjuvant ECT and monitored for side effects. Their response was compared to that of fourteen cats treated with surgery alone. RESULTS: The toxicities were minimal and mostly treated symptomatically. ECT resulted in increased local control (median not reached at the time of writing) with a mean time to recurrence of 666 days versus 180 of controls. CONCLUSIONS: We conclude that ECT is a safe and efficacious therapy for solid tumors; its use may be considered as part of strategies for the reintroduction of drugs with a narrow therapeutic index in the clinical protocols.
Assuntos
Técnicas de Ablação , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Cisplatino/uso terapêutico , Eletroquimioterapia/métodos , Fibrossarcoma/tratamento farmacológico , Fibrossarcoma/cirurgia , Animais , Gatos , Estimativa de Kaplan-Meier , Resultado do TratamentoRESUMO
BACKGROUND: The treatment of human cancer has been seriously hampered for decades by resistance to chemotherapeutic drugs. Mechanisms underlying this resistance are far from being entirely known. A very efficient mechanism of tumor resistance to drugs is related to the modification of tumour microenvironment through changes in the extracellular and intracellular pH. The acidification of tumor microenvironment depends on proton pumps that actively pump protons outside the cells, mostly to avoid intracellular acidification. In fact, we have shown in pre-clinical settings as pre-treatment with proton-pumps inhibitors (PPI) increase tumor cell and tumor responsiveness to chemotherapeutics. In this study pet with spontaneously occurring cancer proven refractory to conventional chemotherapy have been recruited in a compassionate study. METHODS: Thirty-four companion animals (27 dogs and 7 cats) were treated adding to their chemotherapy protocols the pump inhibitor lansoprazole at high dose, as suggested by pre-clinical experiments. Their responses have been compared to those of seventeen pets (10 dogs and 7 cats) whose owners did not pursue any other therapy than continuing the currently ongoing chemotherapy protocols. RESULTS: The drug was overall well tolerated, with only four dogs experiencing side effects due to gastric hypochlorhydria consisting with vomiting and or diarrhea. In terms of overall response twenty-three pets out of 34 had partial or complete responses (67.6%) the remaining patients experienced no response or progressive disease however most owners reported improved quality of life in most of the non responders. On the other hand, only three animals in the control group (17%) experienced short lived partial responses (1-3 months duration) while all the others died of progressive disease within two months. CONCLUSIONS: high dose proton pump inhibitors have been shown to induce reversal of tumor chemoresistance as well as improvement of the quality of life in pets with down staged cancer and in the majority of the treated animals PPI were well tolerated. Further studies are warranted to assess the efficacy of this strategy in patients with advanced cancers in companion animals as well as in humans.
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2-Piridinilmetilsulfinilbenzimidazóis/farmacologia , 2-Piridinilmetilsulfinilbenzimidazóis/uso terapêutico , Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias/veterinária , 2-Piridinilmetilsulfinilbenzimidazóis/efeitos adversos , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Gatos , Ensaios de Uso Compassivo , Cães , Feminino , Humanos , Lansoprazol , Masculino , Neoplasias/tratamento farmacológico , Resultado do TratamentoRESUMO
Increased cytokine expression contributes to the pathogenesis of cancer anorexia?cachexia syndrome. Carnitine may reduce inflammation in chronic diseases. We tested the effects of L-propionylcarnitine (PC group) or saline (C group) on food intake (FI), body composition, and inflammatory status of MCA-sarcoma-bearing rats. On tumor appearance, rats were randomly assigned to daily i.p. injection of L-propionylcarnitine (250 mg/kgBW/d; n = 8) or saline (equal volume; n = 8). FI and fat-free mass wasting improved in PC rats only (p < .01 vs. controls). Cytokines? levels decreased in PC rats vs. controls (p < .02). Results suggest that carnitine may ameliorate cancer anorexia?cachexia, via reduction of the inflammatory status.
Assuntos
Composição Corporal/efeitos dos fármacos , Carnitina/análogos & derivados , Citocinas/sangue , Ingestão de Alimentos/efeitos dos fármacos , Neoplasias Experimentais/metabolismo , Animais , Anorexia/tratamento farmacológico , Caquexia/tratamento farmacológico , Carnitina/farmacologia , Masculino , Ratos , Ratos Endogâmicos F344RESUMO
BACKGROUND: To evaluate the association between polymorphisms involved in DNA repair and oxidative stress genes and mean dose to whole breast on acute skin reactions (erythema) in breast cancer (BC) patients following single shot partial breast irradiation (SSPBI) after breast conservative surgery. MATERIALS AND METHODS: Acute toxicity was assessed using vers.3 criteria. single nucleotides polymorphisms(SNPs) in genes: XRCC1(Arg399Gln/Arg194Trp), XRCC3 (A4541G-5'UTR/Thr241Met), GSTP1(Ile105Val), GSTA1 and RAD51(untranslated region). SNPs were determined in 57 BC patients by the Pyrosequencing analysis. Univariate(ORs and 95% CI) and logistic multivariate analyses (MVA) were performed to correlate polymorphic genes with the risk of developing acute skin reactions to radiotherapy. RESULTS: After SSPBI on the tumour bed following conservative surgery, grade 1 or 2 acute erythema was observed in 19 pts(33%). Univariate analysis indicated a higher significant risk of developing erythema in patients with polymorphic variant wt XRCC1Arg194Trp, mut/het XRCC3Thr241Met, wt/het XRCC3A4541G-5'UTR. Similarly a higher erythema rate was also found in the presence of mut/het of XRCC1Arg194Trp or wt of GSTA1. Whereas, a lower erythema rate was observed in patients with mut/het of XRCC1Arg194Trp or wt of XRCC1Arg399Gln. The mean dose to whole breast(p = 0.002), the presence of either mut/het XRCC1Arg194Trp or wt XRCC3Thr241Met (p = 0.006) and the presence of either mut/het XRCC1Arg194Trp or wt GSTA1(p = 0.031) were confirmed as predictors of radiotherapy-induced erythema by MVA. CONCLUSIONS: The Whole breast mean dose together with the presence of some polymorphic genes involved in DNA repair or oxidative stress could explain the erythema observed after SSPBI, but further studies are needed to confirm these results in a larger cohort.
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Neoplasias da Mama/genética , Neoplasias da Mama/radioterapia , Eritema/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único , Dosagem Radioterapêutica , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/cirurgia , Reparo do DNA/genética , Proteínas de Ligação a DNA/genética , Eritema/etiologia , Feminino , Genótipo , Glutationa S-Transferase pi/genética , Glutationa Transferase/genética , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Análise Multivariada , Estresse Oxidativo/genética , Estudos Prospectivos , Rad51 Recombinase/genética , Radioterapia Conformacional/efeitos adversos , Radioterapia Conformacional/métodos , Fatores de Risco , Proteína 1 Complementadora Cruzada de Reparo de Raio-XRESUMO
Inflammation contributes to the pathogenesis of cancer anorexia-cachexia syndrome. Nicotine administration reduces cytokine levels and mortality during sepsis. Therefore, nicotine administration may result in improved anorexia-cachexia. Sixteen male Fischer rats inoculated with MCA sarcoma were assigned to random injections of nicotine (NIC; 200 mg/kg BW/d) or saline (C). Food intake (FI), body weight, body composition, interleukin (IL)-1, IL-6 levels were evaluated. Data were analyzed via Student's t-test for paired and unpaired data and ANOVA. FI started declining 12 days after tumor inoculation both in C and NIC rats, but the decline was significantly attenuated by nicotine administration. At the end of the study, lean body mass wasting was more severe in C rats than in NIC rats (P<0.05), whereas a trend toward attenuation of fat mass depletion was observed. IL-1 circulating levels were significantly lower in NIC rats than in C rats (114±21 pg/mL vs. 190±35 pg/mL, respectively; P<0.01), whereas the reduction of IL-6 levels in NIC rats was only marginally not significant when compared to C rats (555±174 pg/mL vs. 721±160 pg/mL, respectively; P=0.06). Our data suggest that the nicotinic antiinflammatory pathway may represent an interesting and possibly effective therapy for anorexia-cachexia syndrome.
Assuntos
Anti-Inflamatórios/farmacologia , Composição Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Neoplasias/terapia , Nicotina/farmacologia , Análise de Variância , Animais , Anorexia/metabolismo , Peso Corporal , Caquexia/metabolismo , Citocinas/sangue , Interleucina-1/análise , Interleucina-6/análise , Masculino , Modelos Animais , Neoplasias/complicações , Nicotina/administração & dosagem , Ratos , Ratos Endogâmicos F344RESUMO
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in a global pandemic causing over 195 million infections and more than 4 million fatalities as of July 2021.To date, it has been demonstrated that a number of mutations in the spike glycoprotein (S protein) of SARS-CoV-2 variants of concern abrogate or reduce the neutralization potency of several therapeutic antibodies and vaccine-elicited antibodies. Therefore, the development of additional vaccine platforms with improved supply and logistic profile remains a pressing need. In this work, we have validated the applicability of a peptide-based strategy focused on a preventive as well as a therapeutic purpose. On the basis of the involvement of the dipeptidyl peptidase 4 (DPP4), in addition to the angiotensin converting enzyme 2 (ACE2) receptor in the mechanism of virus entry, we analyzed peptides bearing DPP4 sequences by protein-protein docking and assessed their ability to block pseudovirus infection in vitro. In parallel, we have selected and synthetized peptide sequences located within the highly conserved receptor-binding domain (RBD) of the S protein, and we found that RBD-based vaccines could better promote elicitation of high titers of neutralizing antibodies specific against the regions of interest, as confirmed by immunoinformatic methodologies and in vivo studies. These findings unveil a key antigenic site targeted by broadly neutralizing antibodies and pave the way to the design of pan-coronavirus vaccines.
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Dipeptidil Peptidase 4/química , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/farmacologia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Enzima de Conversão de Angiotensina 2/química , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Anticorpos Amplamente Neutralizantes/imunologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/imunologia , Chlorocebus aethiops , Dipeptidil Peptidase 4/metabolismo , Epitopos de Linfócito T/imunologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/metabolismo , Ligação Proteica , Domínios Proteicos , Receptores de Coronavírus/química , Receptores de Coronavírus/metabolismo , SARS-CoV-2/química , SARS-CoV-2/fisiologia , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismo , Células Vero , Internalização do Vírus , Tratamento Farmacológico da COVID-19RESUMO
Endometriosis is a chronic gynecological disease characterized by the growth of endometrial tissue outside the uterine cavity. Exposure to endocrine disruptors during critical period of development causes long-lasting effects, being the genital system one of the targets. This study describes the effects on female genital system caused by developmental exposure to the endocrine-disrupting chemical bisphenol A (BPA) during pre- and peri-natal development in mice. To this end, timed pregnant Balb-C mice were treated from day 1 of gestation to 7 days after delivery with BPA (100, or 1000 microg/kg/day). After delivery, pups were held for 3 months; then, pelvic organs were analyzed in their entirety and livers of both pups and moms were studied for the presence of BPA. We found in the adipose tissue surrounding the genital tracts of a consistent number of treated animals, endometriosis-like structure with the presence of both glands and stroma and expressing both estrogen receptor and HOXA-10. Moreover, cystic ovaries, adenomatous hyperplasia with cystic endometrial hyperplasia and atypical hyperplasia were significantly more frequent in treated animals respect to the controls. Finally, BPA was found in the livers of exposed moms and female offspring. In conclusion, we describe for the first time an endometriosis-like phenotype in mice, elicited by pre-natal exposition to BPA. This observation may induce to thoroughly reconsider the pathogenesis and treatment of endometriosis, considering the high incidence of endometriosis and the problems caused by associated infertility.
Assuntos
Endometriose/induzido quimicamente , Endometriose/etiologia , Fenóis/toxicidade , Animais , Compostos Benzidrílicos , Endometriose/metabolismo , Feminino , Genitália Feminina/efeitos dos fármacos , Genitália Feminina/embriologia , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos BALB C , Fenóis/administração & dosagem , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Útero/efeitos dos fármacos , Útero/embriologiaRESUMO
BACKGROUND AND OBJECTIVES: Gemcitabine (2,2-difluorodeoxycytidine [dFdC]) can be administered in a standard 30-minute infusion or in a fixed-dose-rate (FDR) infusion to maximize the rate of accumulation of triphosphate, its major intracellular metabolite. The standard 30-minute infusion requires dose adjustment in patients with organ dysfunction, especially in patients with elevated baseline serum bilirubin levels. On the other hand, the FDR infusion is burdened by increased haematological toxicity. The primary aim of this study was to evaluate the pharmacokinetics of dFdC and its metabolite difluorodeoxyuridine (dFdU) in patients with normal and impaired hepatic function. PATIENTS AND METHODS: In this prospective study, patients with pancreatic or biliary tract carcinoma and normal or impaired hepatic function tests were considered eligible for recruitment. Patients were recruited according to the following criteria: (i) serum bilirubin <1.6 mg/dL and AST and ALT <2 times the upper the limit of normal (ULN) [cohort I]; and (ii) serum bilirubin >1.6 mg/dL and/or AST/ALT >2 times the ULN (cohort II). An FDR infusion of gemcitabine 1000 mg/m2 was administered on days 1, 8 and 15 every 4 weeks. The pharmacokinetic analysis of gemcitabine and dFdU was performed with high-performance liquid chromatography-tandem mass spectrometry assay in cycles 1 and 2. RESULTS: Thirteen patients were enrolled, four in cohort I and nine in cohort II. All patients were assessable for toxicity and pharmacokinetic analysis. The grade and rate of toxicities were similar in both groups, and patients with elevation of bilirubin and/or transaminases did not require dose reduction of gemcitabine. Pharmacokinetic analysis revealed a reduction of the experimental area under the plasma concentration-time curve for gemcitabine and dFdU in patients with hepatic dysfunction when compared with patients with normal hepatic function. All other pharmacokinetic parameters were similar in the two cohorts. No statistical difference was demonstrated for all parameters evaluated between cycle 1 and cycle 2 in the two groups. CONCLUSION: Gemcitabine 1000 mg/m2 can be administered as an FDR infusion in patients with altered hepatic function without causing additional toxicity compared with patients with normal hepatic function.
Assuntos
Adenocarcinoma/sangue , Antimetabólitos Antineoplásicos/farmacocinética , Neoplasias do Sistema Biliar/sangue , Desoxicitidina/análogos & derivados , Hepatopatias/sangue , Neoplasias Pancreáticas/sangue , Adenocarcinoma/complicações , Adenocarcinoma/tratamento farmacológico , Adulto , Idoso , Antimetabólitos Antineoplásicos/uso terapêutico , Área Sob a Curva , Neoplasias do Sistema Biliar/complicações , Neoplasias do Sistema Biliar/tratamento farmacológico , Cromatografia Líquida de Alta Pressão , Desoxicitidina/farmacocinética , Desoxicitidina/uso terapêutico , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Floxuridina/análogos & derivados , Floxuridina/farmacocinética , Humanos , Infusões Intravenosas , Hepatopatias/complicações , Hepatopatias/fisiopatologia , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/tratamento farmacológico , Estudos Prospectivos , Espectrometria de Massas em Tandem , GencitabinaRESUMO
Squamous cell carcinomas (SCC) of the skin are commonly described in cats. Reported treatments include surgery, radiation therapy and photodynamic therapy. This preliminary study reports on the management of these lesions combining the local administration of bleomycin (plus hyaluronidase for a more uniform distribution) with permeabilizing biphasic electric pulses. Nine cats with SCC graded T(2)-T(4) were treated over a 5 year period, and each cat received two sessions of electrochemotherapy (ECT) 1 week apart. The side effects of this treatment were minimal and limited to mild erythema of the nose. Seven of the cats (77.7%) had a complete response lasting up to 3 years. ECT seems to be a safe and effective option for the treatment of feline sun-induced squamous cell carcinomas and warrants further investigation.
Assuntos
Carcinoma de Células Escamosas/veterinária , Doenças do Gato/tratamento farmacológico , Eletroquimioterapia/veterinária , Neoplasias Cutâneas/veterinária , Animais , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Doenças do Gato/patologia , Gatos , Eletroquimioterapia/métodos , Feminino , Masculino , Segurança , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Fatores de Tempo , Resultado do TratamentoRESUMO
Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), encoded by the OLR1 gene, is a scavenger receptor that plays a central role in the pathogenesis of atherosclerosis. We have recently identified a truncated naturally occurring variant of the human receptor LOX-1, named LOXIN, which lacks part of the C-terminus lectin-like domain. In vivo and in vitro studies support that the new splicing isoform is protective against acute myocardial infarction. The mechanism by which LOXIN exerts its protective role is unknown. In this paper we report studies on the heterologous expression and functional characterization of LOXIN variant in mammalian fibroblasts and human endothelial cells. We found that LOXIN, when expressed in the absence of LOX-1, shows diminished plasma membrane localization and is deficient in ox-LDL ligand binding. When co-transfected with the full-length counterpart LOX-1, the two isoforms interact to form LOX-1 oligomers and their interaction leads to a decrease in the appearance of LOX-1 receptors in the plasma membrane and a marked impairment of ox-LDL binding and uptake. Co-immunoprecipitation studies confirmed the molecular LOX-1/LOXIN interaction and the formation of non-functional hetero-oligomers. Our studies suggest that hetero-oligomerization between naturally occurring isoforms of LOX-1 may represent a general paradigm for regulation of LOX-1 function by its variants.
Assuntos
Processamento Alternativo/genética , Receptores Depuradores Classe E/metabolismo , Animais , Western Blotting , Células COS , Membrana Celular/metabolismo , Chlorocebus aethiops , Dimerização , Imunofluorescência , Humanos , Imunoprecipitação , Lipoproteínas LDL/metabolismo , Mutação , Infarto do Miocárdio/metabolismo , Ligação Proteica , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Receptores Depuradores Classe E/química , Receptores Depuradores Classe E/genéticaRESUMO
Heat shock protein B (HspB) is one of the dominant proteins recognized by most Helicobacter pylori-infected persons and is being considered as potential candidates for subunit vaccines. In the present study we describe the generation of an antibody against HspB and its use in immunohistochemical assays on gastric biopsies. We have demonstrated that our rabbit polyclonal antibody against HspB did not recognize any protein in lysates from a lung human epithelial cell (H1299) line and did not cross-react with the other members of human heat shock proteins. Secondly, we have observed that in gastric biopsies, HspB immunostaining was present inside the cytoplasm of human epithelial cells with a particular localization in the apical portion of gastric epithelial cells other than in the extracellular spaces among gastric cells of human stomach. Finally, we have demonstrated a cytoplasmic HspB immunostaining in groups of neoplastic cells of MALT lymphoma. In conclusion, our observations suggest a possible involvement of HspB in the pathogenesis of H. pylori-related pathologies such as gastritis, ulcer and gastric cancer.
Assuntos
Proteínas de Bactérias/metabolismo , Mucosa Gástrica/metabolismo , Proteínas de Choque Térmico/metabolismo , Helicobacter pylori/metabolismo , Linfoma de Zona Marginal Tipo Células B/metabolismo , Animais , Antígenos de Bactérias/genética , Antígenos de Bactérias/metabolismo , Proteínas de Bactérias/genética , Vacinas Bacterianas/metabolismo , Biópsia , Linhagem Celular , Mucosa Gástrica/citologia , Mucosa Gástrica/microbiologia , Mucosa Gástrica/patologia , Proteínas de Choque Térmico/genética , Infecções por Helicobacter/metabolismo , Infecções por Helicobacter/patologia , Humanos , Imuno-Histoquímica , Linfoma de Zona Marginal Tipo Células B/patologia , CoelhosRESUMO
Local management of soft tissue sarcoma in humans generally involves multi-modality approaches whose cornerstones are surgery combined with radiation therapy. The usual radiation protocols are based on preoperative, intraoperative, or postoperative external beam treatment or adjuvant brachytherapy. The aim of these strategies is to maximize tumor control while minimizing side effects, especially in the case of limb sarcomas. Unfortunately, the rate of local wound complication associated with aggressive surgical management and radiation therapy are still elevated. Electrochemotherapy is an anticancer technique that gained popularity over the past 15 years. It involves the administration of anticancer agents to the application of permeabilizing pulses so to increase the uptake of antitumor molecules. Goal of this review is to underline the advances in this field obtained from animal studies in order to point out the possible therapeutic applications of this technique for the treatment of soft tissue sarcomas in humans.
Assuntos
Modelos Animais de Doenças , Eletroquimioterapia , Sarcoma/tratamento farmacológico , Neoplasias de Tecidos Moles/tratamento farmacológico , Animais , Avaliação Pré-Clínica de Medicamentos , Humanos , Modelos Biológicos , Sarcoma/patologia , Neoplasias de Tecidos Moles/patologiaRESUMO
Peripheral administration of interleukin-1 (IL-1) reduces food intake and affects brain serotonergic activity, suggesting a causal relationship. Furthermore, IL-1 increases the brain concentrations of the serotonin precursor, tryptophan (TRP), by unclear mechanism(s). We aimed at confirming the link between IL-1 administration, raised brain TRP concentrations and the development of anorexia, and at investigating the mechanisms of TRP entry into the brain. Thirty adult, overnight fasted Sprague-Dawley rats were randomly assigned to i.p. injections of 1 mug/kg BW of IL-1 alpha (n=10) or vehicle (n=10), or to pair-feeding with IL-1 animals (n=10). After 2 h, food intake, blood plasma concentrations of total TRP, free TRP, large neutral amino acids (LNAA; competing with TRP for brain entry) were measured. Cerebral spinal fluid (CSF) TRP concentrations were also measured. TRP brain availability was assessed by calculating the plasma ratio free TRP/LNAA. Following IL-1 injection, food intake significantly declined in IL-1 rats, which was paralleled by decreased plasma free TRP and increased plasma LNAA. Despite a decrease in the free TRP/LNAA ratios in plasma, IL-1 significantly increased concentrations of TRP in CSF. These data show that the acute peripheral administration of IL-1 induces anorexia and raises CSF TRP levels. Considering the possible role of the raised CSF TRP in influencing brain serotonin activity, it is postulated that increased serotonergic neurotransmission could be involved in IL-1 induced anorexia.
Assuntos
Aminoácidos Neutros/sangue , Anorexia/sangue , Anorexia/induzido quimicamente , Interleucina-1 , Triptofano/sangue , Triptofano/líquido cefalorraquidiano , Animais , Anorexia/líquido cefalorraquidiano , Peso Corporal/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
A ten-year-old intact male Rottweiler dog was examined for sudden onset of stranguria and pollakiuria. The dog had an intestinal lymphoma treated three years before with chemotherapy. Ultrasonographic examination of the abdomen showed a large dyshomogeneous prostate with an over-distended bladder. Cytological examination of the fine-needle aspirate from the prostate yielded a diagnosis of lymphoma. The diagnosis was confirmed by histopathological examination. The dog was treated with multi-drug chemotherapy and achieved a complete remission. The dog remained in complete remission for one year from the re-institution of chemotherapy before dying of recurrence. Lymphoma rarely invades the prostate in the dog. To the best of our knowledge this is the first report of prostatic recurrence of lymphoma in a canine patient originally affected by intestinal lymphoma and treated with chemotherapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doenças do Cão/patologia , Linfoma/patologia , Neoplasias da Próstata/patologia , Animais , Doenças do Cão/tratamento farmacológico , Cães , Linfoma/diagnóstico por imagem , Linfoma/tratamento farmacológico , Masculino , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/tratamento farmacológico , Recidiva , Resultado do Tratamento , UltrassonografiaRESUMO
A three-year-old male African hedgehog was presented for a non healing crusty proliferation on the left pinna. The lesion failed to respond to topical therapy and systemic antibiotic therapy. Whole body radiography and abdominal ultrasonograpy were within normal limits. The lesion was surgically removed. The patient recovered well from the procedure and remained in remission for nine months when he came back as an emergency case and died of an unrelated disease. The histopathology report enabled a diagnosis of completely excised cutaneous T-cell lymphoma. This report represents the first successful treatment of a cutanous T-cell lymphoma in this species and might help to plan future therapies.