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1.
Spectrochim Acta A Mol Biomol Spectrosc ; 317: 124359, 2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-38704996

RESUMO

SERS (Surface Enhanced Raman Spectroscopy) is a new Raman spectroscopy which relies on Surface Plasmon Resonance (SPR) of metal nanoparticles. We have applied colloidal silver and gold nanoparticles as amplifier agents to enhance nucleotide Raman signals. It is observed that without these enhancing agents, it is impossible to investigate nucleotide spectrum due to weak Raman signals. Interaction mechanism of Melphalan, an anticancer drug with four nucleotides (Adenine, Cytosine, Guanine, Thymine) was investigated using SERS to detect and identify changes due to alkylating process in Raman spectra. After incubating Melphalan drug with nucleotides for 24 h at 37 °C, some changes occurred in SERS spectrum and interpretation of SERS spectra revealed the influence of the alkyl substitution on peaks and Raman shifts. After incubation of Melphalan with each nucleotide, intensity of relevant SERS signals assigned to Amid III group of Cytosine and Amid I of Thymine decreased significantly, confirming alkylating taking place. In this study, we also investigated the effect of nanoparticles type on nucleotide spectrum. We could not obtain useful information in the cases of guanine nucleotide. The SERS spectrum of Cytosine as an example of nucleotides in aqueous solution compared to solid state and results demonstrated that in solid state better signals were obtained than in liquid state.


Assuntos
Melfalan , Nanopartículas Metálicas , Nucleotídeos , Análise Espectral Raman , Análise Espectral Raman/métodos , Melfalan/química , Nucleotídeos/química , Nanopartículas Metálicas/química , Ouro/química , Alquilantes/química , Prata/química
2.
Pediatr Blood Cancer ; 71(6): e30976, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38577760

RESUMO

PURPOSE: Survival rates of patients with high-risk neuroblastoma are unacceptable. A time-intensified treatment strategy with delayed local treatment to control systemic diseases has been developed in Japan. We conducted a nationwide, prospective, single-arm clinical trial with delayed local treatment. This study evaluated the safety and efficacy of delayed surgery to increase treatment intensity. PATIENTS AND METHODS: Seventy-five patients with high-risk neuroblastoma were enrolled in this study between May 2011 and September 2015. Delayed local treatment consisted of five courses of induction chemotherapy (cisplatin, pirarubicin, vincristine, and cyclophosphamide) and myeloablative high-dose chemotherapy (melphalan, etoposide, and carboplatin), followed by local tumor extirpation with surgery and irradiation. The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall survival (OS), response rate, adverse events, and surgical complications. RESULTS: Seventy-five patients were enrolled, and 64 were evaluable (stage 3, n = 8; stage 4, n = 56). The estimated 3-year PFS and OS rates (95% confidence interval [CI]) were 44.4% [31.8%-56.3%] and 80.7% [68.5%-88.5%], resspectively. The response rate of INRC after completion of the treatment protocol was 66% (42/64; 95% CI: 53%-77%; 23 CR [complete response], 10 VGPR [very good partial response], and nine PR [partial response]). None of the patients died during the protocol treatment or within 30 days of completion. Grade 4 adverse effects, excluding hematological adverse effects, occurred in 48% of patients [31/64; 95% CI: 36%-61%]. Major Surgical complications were observed in 25% of patients [13/51; 95% CI: 14%-40%]. CONCLUSION: This study indicates that delayed local treatment is feasible and shows promising efficacy, suggesting that this treatment should be considered further in a comparative study of high-risk neuroblastoma.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Doxorrubicina/análogos & derivados , Neuroblastoma , Humanos , Neuroblastoma/tratamento farmacológico , Neuroblastoma/terapia , Neuroblastoma/mortalidade , Neuroblastoma/patologia , Feminino , Masculino , Pré-Escolar , Lactente , Criança , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Japão/epidemiologia , Estudos Prospectivos , Taxa de Sobrevida , Adolescente , Quimioterapia de Indução , Etoposídeo/administração & dosagem , Seguimentos , Vincristina/administração & dosagem , Vincristina/uso terapêutico , Terapia Combinada , Ciclofosfamida/administração & dosagem , Ciclofosfamida/uso terapêutico , Prognóstico , Doxorrubicina/administração & dosagem , Doxorrubicina/uso terapêutico , Melfalan/administração & dosagem , Melfalan/uso terapêutico , Cisplatino/administração & dosagem , Cisplatino/uso terapêutico
3.
Cardiovasc Intervent Radiol ; 47(6): 741-750, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38587534

RESUMO

PURPOSE: Percutaneous hepatic perfusion with melphalan (M-PHP) is a minimally invasive therapy with proven efficacy in patients with uveal melanoma (UM) liver metastases. M-PHP is associated with a short hospital admission time and limited systemic side effects. In this study, we assessed quality of life (QoL) in UM patients treated with M-PHP. MATERIALS AND METHODS: A prospective, single-center study including 24 patients treated with M-PHP for UM metastases to the liver. QoL questionnaires were collected at baseline, on day 2/3 after M-PHP, and on day 7 and day 21 after M-PHP, according to study protocol. The results were scored according to EORTC-QLQ C30 global health status (GHS), functional scales, and symptom scales. The difference in scores at baseline and subsequent time points was analyzed with the Wilcoxon signed-rank test and multiple testing Bonferroni correction. Adverse events (AE) were registered up to 30 days after M-PHP according to CTCAE v5.0. RESULTS: Twenty-four patients (14 males; median age 63.0 years) completed 96 questionnaires. Most scores on all scales declined on day 2/3 after M-PHP. On day 21 after M-PHP, 12 out of 15 scores returned to baseline, including median GHS scores. Three variables were significantly worse on day 21 compared to baseline: fatigue (6-33; p = 0.002), physical functioning (100 vs 86.7; p = 0.003), and role functioning (100 vs 66.7; p = 0.001). Grade 3/4 AEs consisted mainly of hematological complications, such as leukopenia and thrombopenia. CONCLUSION: M-PHP causes fatigue and a decline in physical and role functioning in the 1st weeks after treatment, but GHS returns to baseline levels within 21 days. LEVEL OF EVIDENCE 3: Cohort study.


Assuntos
Neoplasias Hepáticas , Melanoma , Melfalan , Qualidade de Vida , Neoplasias Uveais , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Prospectivos , Melanoma/secundário , Melanoma/tratamento farmacológico , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Inquéritos e Questionários , Idoso , Melfalan/administração & dosagem , Melfalan/uso terapêutico , Antineoplásicos Alquilantes/uso terapêutico , Antineoplásicos Alquilantes/administração & dosagem , Quimioterapia do Câncer por Perfusão Regional/métodos , Adulto , Resultado do Tratamento
4.
ACS Biomater Sci Eng ; 10(5): 3412-3424, 2024 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-38613483

RESUMO

Intratumoral injection of anticancer agents has limited efficacy and is not routinely used for most cancers. In this study, we aimed to improve the efficacy of intratumoral chemotherapy using a novel approach comprising peri-tumoral injection of sustained-release liposomal nanoparticles containing phenylephrine, which is a potent vasoconstrictor. Using a preclinical model of melanoma, we have previously shown that systemically administered (intravenous) phenylephrine could transiently shunt blood flow to the tumor at the time of drug delivery, which in turn improved antitumor responses. This approach was called dynamic control of tumor-associated vessels. Herein, we used liposomal phenylephrine nanoparticles as a "local" dynamic control strategy for the B16 melanoma. Local dynamic control was shown to increase the retention and exposure time of tumors to intratumorally injected chemotherapy (melphalan). C57BL/6 mice bearing B16 tumors were treated with intratumoral melphalan and peri-tumoral injection of sustained-release liposomal phenylephrine nanoparticles (i.e., the local dynamic control protocol). These mice had statistically significantly improved antitumor responses compared to melphalan alone (p = 0.0011), whereby 58.3% obtained long-term complete clinical response. Our novel approach of local dynamic control demonstrated significantly enhanced antitumor efficacy and is the subject of future clinical trials being designed by our group.


Assuntos
Lipossomos , Melanoma Experimental , Camundongos Endogâmicos C57BL , Nanopartículas , Fenilefrina , Animais , Fenilefrina/farmacologia , Fenilefrina/administração & dosagem , Nanopartículas/química , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/patologia , Camundongos , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacocinética , Melfalan/uso terapêutico , Melfalan/administração & dosagem , Melfalan/farmacologia , Linhagem Celular Tumoral , Melanoma/tratamento farmacológico , Melanoma/patologia
5.
PLoS One ; 19(4): e0299019, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38593113

RESUMO

Multiple myeloma (MM) is the second most prevalent hematologic malignancy which remains uncurable. Numerous drugs have been discovered to inhibit MM cells. Indisulam, an aryl sulfonamide, has a potent anti-myeloma activity in vitro and in vivo. This study aims to explore the new mechanism of indisulam and investigate its potential use in combination with melphalan. We examined DNA damage in MM cells through various methods such as western blotting (WB), immunofluorescence, and comet assay. We also identified the role of topoisomerase IIα (TOP2A) using bioinformatic analyses. The impact of indisulam on the RNA and protein levels of TOP2A was investigated through qPCR and WB. Cell proliferation and apoptosis were assessed using CCK-8 assays, Annexin V/PI assays and WB. We predicted the synergistic effect of the combination treatment based on calculations performed on a website, and further explored the effect of indisulam in combination with melphalan on MM cell lines and xenografts. RNA sequencing data and basic experiments indicated that indisulam caused DNA damage and inhibited TOP2A expression by decreasing transcription and promoting degradation via the proteasome pathway. Functional experiments revealed that silencing TOP2A inhibited cell proliferation and induced apoptosis and DNA damage. Finally, Indisulam/melphalan combination treatment demonstrated a strong synergistic anti-tumor effect compared to single-agent treatments in vitro and in vivo. These findings suggest that combination therapies incorporating indisulam and melphalan have the potential to enhance treatment outcomes for MM.


Assuntos
Melfalan , Mieloma Múltiplo , Humanos , Melfalan/farmacologia , Melfalan/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Linhagem Celular Tumoral , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico
6.
Hematology ; 29(1): 2335417, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38568018

RESUMO

Objectives: Primary graft failure (pGF) after hematopoietic stem-cell transplant is associated with considerable morbidity and mortality. The incidence in haplo-HSCT has been reported to be between 0% and 30%. In 2018, we identified a pGF incidence of 35% in our pediatric haplo-HSCT recipients with hematologic malignancies, which motivated us to enact changes to the conditioning regimen.Methods: We performed a single-center prospective, pre-post study of consecutive patients under 16 years with hematologic malignancies, from January 2015 to December 2022 who received a haplo-HSCT. Twenty-six pediatric patients received a haplo-HSCT before September 2018 (G1) and 36 patients after (G2). The main conditioning regimen for G1 was myeloablative with Flu/Cy/Bu, and for G2 the main regimen was reduced intensity Flu/Cy/Mel/TBI2.Results: Nine patients (35%) in G1 had primary graft failure, while in G2 there were no patients with pGF. The median follow-up for G1 was 15.9 months, and for G2 was 24.8 months, with an estimated overall survival at 12 months of 63% (95% CI 47-76) versus 85% (95% CI 73-93), and at 24 months of 47% (95% CI 31-64) versus 70% (95% CI 54-82) respectively (p = .007).Conclusion: After September 2018 conditioning regimen modifications were implemented with the objective of reducing primary failure, consisting mainly of switching from busulfan to melphalan as the alkylating agent of choice, and adding, when clinically possible TBI. Primary failure has been significantly reduced in our institution since then.


Assuntos
Neoplasias Hematológicas , Melfalan , Humanos , Criança , Estudos Prospectivos , Transplante Haploidêntico , Bussulfano
7.
Cancer Control ; 31: 10732748241246898, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38605434

RESUMO

BACKGROUND: Percutaneous Hepatic Perfusion (PHP) is a liver directed regional therapy recently FDA approved for metastatic uveal melanoma to the liver involving percutaneous isolation of liver, saturation of the entire liver with high-dose chemotherapy and filtration extracorporeally though in line filters and veno-venous bypass. The procedure is associated with hemodynamic shifts requiring hemodynamic support and blood product resuscitation due to coagulopathy. OBJECTIVE: To assess the cardiac safety and subsequent clinically significant sequalae of this therapy. METHODS: Consecutive PHP procedures done at our center between 2010-2022 were assessed retrospectively. Cardiac risk factors, post procedural cardiac enzymes, electrocardiograms, and transthoracic echocardiograms along with 90-day cardiac outcomes were reviewed. All data were reviewed by cardio-oncologists at our institution. RESULTS: Of 37 patients reviewed, mean age was 63 years and 57% were women. 132 procedures were performed with an average of 3.57 procedures per patient. 68.6% of patients had elevated troponin during at least 1 procedure. No patients were found to have acute coronary syndrome, heart failure, unstable arrhythmias, or cardiac death. No patients had notable echocardiographic changes. 10.8% of patients with positive troponin had asymptomatic transient electrocardiographic changes not meeting criteria for myocardial infarction. One patient had non-sustained ventricular tachycardiac intra-operatively which did not recur subsequently. Three patients died from non-cardiac causes within 90-days. There was no oncology treatment interruption, even in those with troponin elevation. In multivariable analysis, a history of hyperlipidemia was a predictor of postoperative troponin elevation. (P = .042). CONCLUSION: Percutaneous Hepatic Perfusion is safe and associated with a transient, asymptomatic troponin elevation peri-operatively without major adverse cardiac events at 90 days. The observed troponin elevation is likely secondary to coronary demand-supply mismatch related to procedural hemodynamic shifts, hypotension, and anemia.


Percutaneous hepatic perfusion using melphalan in patients with uveal melanoma and liver metastases carries no significant cardiac adverse events.


Assuntos
Neoplasias Hepáticas , Melanoma , Melfalan , Neoplasias Uveais , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Antineoplásicos Alquilantes , Estudos Retrospectivos , Quimioterapia do Câncer por Perfusão Regional/métodos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Recidiva Local de Neoplasia/tratamento farmacológico , Perfusão
8.
Clin Lymphoma Myeloma Leuk ; 24(6): e267-e275.e2, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38490927

RESUMO

BACKGROUND: Melflufen, a first-in-class alkylating peptide-drug conjugate, rapidly enters tumor cells and metabolizes to melphalan. In previous studies, melflufen was administered via central venous catheter (CVC). However, administration by peripheral venous catheter (PVC) may be preferable. PATIENTS AND METHODS: PORT was a two-period, phase 2 crossover study of CVC versus PVC melflufen administration in patients with relapsed/refractory multiple myeloma. Adults with ≥ 2 prior therapies refractory to/intolerant of an immunomodulatory drug and a proteasome inhibitor were randomized 1:1 to weekly oral dexamethasone plus melflufen (40 mg) via CVC or PVC infusion on day 1 of 28-day cycle 1. In cycle 2, patients continued dexamethasone and crossed over to the other melflufen administration route. In cycle 3, all patients received melflufen until progression; PVC or CVC routes were allowed based upon investigator decision. Pharmacokinetic sampling was performed during and after melflufen infusion. Primary endpoints were melphalan pharmacokinetic parameters (Cmax, AUC(0-t), and AUC(0-∞)) and frequency and severity of PVC-related local reactions. RESULTS: The 90% CIs for adjusted geometric mean ratios for pharmacokinetic parameters following CVC versus PVC administration were within the 0.8-1.25 bioequivalence range (Cmax 0.946 [90% CI: 0.849, 1.053]; AUC(0-t) 0.952 [90% CI: 0.861, 1.053]; AUC(0-∞) 0.955 [90% CI: 0.863, 1.058]). In both arms, adverse events were primarily hematological and similar; no phlebitis or local infusion-related reactions occurred. CONCLUSION: Melflufen PVC and CVC administrations are bioequivalent based on melphalan pharmacokinetic parameters. Melflufen via PVC was well tolerated, with no infusion-related reactions or new safety signals and may represent an alternative route of administration.


Assuntos
Estudos Cross-Over , Mieloma Múltiplo , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Fenilalanina/análogos & derivados , Fenilalanina/administração & dosagem , Fenilalanina/farmacocinética , Adulto , Melfalan/administração & dosagem , Melfalan/uso terapêutico , Melfalan/análogos & derivados , Recidiva Local de Neoplasia/tratamento farmacológico , Administração Intravenosa , Idoso de 80 Anos ou mais , Resultado do Tratamento , Infusões Intravenosas
9.
Viruses ; 16(3)2024 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-38543782

RESUMO

The sudden emergence of SARS-CoV-2 demonstrates the need for new vaccines that rapidly protect in the case of an emergency. In this study, we developed a recombinant MVA vaccine co-expressing SARS-CoV-2 prefusion-stabilized spike protein (ST) and SARS-CoV-2 nucleoprotein (N, MVA-SARS-2-ST/N) as an approach to further improve vaccine-induced immunogenicity and efficacy. Single MVA-SARS-2-ST/N vaccination in K18-hACE2 mice induced robust protection against lethal respiratory SARS-CoV-2 challenge infection 28 days later. The protective outcome of MVA-SARS-2-ST/N vaccination correlated with the activation of SARS-CoV-2-neutralizing antibodies (nABs) and substantial amounts of SARS-CoV-2-specific T cells especially in the lung of MVA-SARS-2-ST/N-vaccinated mice. Emergency vaccination with MVA-SARS-2-ST/N just 2 days before lethal SARS-CoV-2 challenge infection resulted in a delayed onset of clinical disease outcome in these mice and increased titers of nAB or SARS-CoV-2-specific T cells in the spleen and lung. These data highlight the potential of a multivalent COVID-19 vaccine co-expressing S- and N-protein, which further contributes to the development of rapidly protective vaccination strategies against emerging pathogens.


Assuntos
COVID-19 , Melfalan , SARS-CoV-2 , Vacinas de DNA , Vacinas Virais , gama-Globulinas , Animais , Humanos , Camundongos , SARS-CoV-2/genética , COVID-19/prevenção & controle , Vacinas contra COVID-19 , Anticorpos Antivirais , Glicoproteína da Espícula de Coronavírus/genética , Vacinação , Anticorpos Neutralizantes
10.
Cancer Sci ; 115(6): 2002-2011, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38498976

RESUMO

Triplet regimen comprising proteasome inhibitors, immunomodulatory drugs, and dexamethasone (DEX) is a recommended induction/consolidation therapy for multiple myeloma (MM) patients eligible for transplant. In this Japanese phase II study conducted from 2017 to 2019, newly diagnosed MM patients aged 20-65 received four induction cycles with bortezomib (Bor), lenalidomide (Len), and DEX (VRD), followed by Bor and high-dose melphalan with autologous stem cell rescue. Subsequently, they underwent four consolidation cycles with carfilzomib, Len, and DEX (KRD), followed by Len maintenance until disease progression. A total of 141 patients were analyzed. In an intent-to-treat population, the complete or better response post induction was 19.9%, rising to 39.7%, 58.9%, and 62.4% after transplant, consolidation, and 1-year maintenance, respectively. With a median follow-up of 38 months, the 3-year progression-free survival (PFS) rate was 83.5% and the 3-year overall survival rate was 92.5%. Severe adverse events (≥grade 3) occurred in ~30% of patients; however, there was no treatment-related mortality. These findings clearly showed the tolerability and effectiveness of this protocol. Nevertheless, patients with high-risk cytogenetics showed a trend toward lower 3-year PFS than those without (77.8% vs. 89.4%, p = 0.051), and ultra-high-risk cytogenetics (≥2 high-risk cytogenetics) had an even worse prognosis, with 61.2% 3-year PFS. To overcome this situation, a more potent treatment strategy incorporating novel agents such as the CD38-antibody should be assessed in future studies.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Bortezomib , Dexametasona , Transplante de Células-Tronco Hematopoéticas , Lenalidomida , Mieloma Múltiplo , Transplante Autólogo , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/terapia , Lenalidomida/administração & dosagem , Lenalidomida/uso terapêutico , Pessoa de Meia-Idade , Feminino , Masculino , Idoso , Adulto , Transplante de Células-Tronco Hematopoéticas/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dexametasona/administração & dosagem , Dexametasona/uso terapêutico , Bortezomib/administração & dosagem , Bortezomib/uso terapêutico , Quimioterapia de Consolidação/métodos , Melfalan/administração & dosagem , Melfalan/uso terapêutico , Oligopeptídeos/uso terapêutico , Oligopeptídeos/administração & dosagem , Quimioterapia de Indução/métodos , Intervalo Livre de Progressão , Adulto Jovem , Quimioterapia de Manutenção/métodos
11.
J Vet Intern Med ; 38(3): 1693-1705, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38517293

RESUMO

BACKGROUND: Myeloma-related disorders (MRDs) are rare and poorly documented neoplasms of cats. HYPOTHESIS/OBJECTIVES: To describe clinical, clinicopathologic, and imaging findings, response to treatment, and survival time and to identify factors associated with shorter outcomes in cats with MRD. ANIMALS: Fifty cats with a diagnosis of MRD. METHODS: Cats with paraproteinemia confirmed by serum protein electrophoresis (SPE) and either intramedullary plasmacytosis >10%, marked cytonuclear atypia with intramedullary plasmacytosis that ranged between 5% and 10%, or cytologically or histologically confirmed visceral infiltration were retrospectively included from several veterinary referral centers. RESULTS: Bone marrow plasmacytosis and splenic or hepatic involvement were present in 17/27 cats (63%), 36/42 cats (86%), and 27/38 cats (71%), respectively. Anemia was reported in 33/49 cats (67%) and thrombocytopenia in 16/47 cats (34%). Some of the treatments that the cats received included melphalan and prednisolone (n = 19), cyclophosphamide and prednisolone (n = 10), chlorambucil and prednisolone (n = 4), prednisolone (n = 4), or other (n = 4). The overall response rates to melphalan, cyclophosphamide, and chlorambucil in combination with prednisolone were 87%, 90%, and 100%, respectively. Adverse events to melphalan or cyclophosphamide occurred in 65% and 23% of cats, respectively. Median survival time was 122 days (range, 0-1403) and was not significantly associated with chemotherapy protocol. Anemia (hazard ratio [HR], 3.1; 95% confidence interval [CI], 1.0-9.8) and thrombocytopenia (HR, 2.7; 95% CI, 1.2-6.0) were risk factors for shorter survival. CONCLUSIONS AND CLINICAL IMPORTANCE: Our study confirmed the guarded prognosis of MRD in cats and identified risk factors for shorter survival times.


Assuntos
Doenças do Gato , Mieloma Múltiplo , Gatos , Doenças do Gato/patologia , Doenças do Gato/tratamento farmacológico , Doenças do Gato/mortalidade , Animais , Estudos Retrospectivos , Feminino , Masculino , Mieloma Múltiplo/veterinária , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/complicações , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Prognóstico , Melfalan/uso terapêutico , Prednisolona/uso terapêutico , Ciclofosfamida/uso terapêutico , Anemia/veterinária , Anemia/etiologia
12.
Am J Hematol ; 99(6): 1180-1183, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38526002
13.
J Chem Theory Comput ; 20(7): 2947-2958, 2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38501645

RESUMO

The ordered assembly of Tau protein into filaments characterizes Alzheimer's and other neurodegenerative diseases, and thus, stabilization of Tau protein is a promising avenue for tauopathies therapy. To dissect the underlying aggregation mechanisms on Tau, we employ a set of molecular simulations and the Markov state model to determine the kinetics of ensemble of K18. K18 is the microtubule-binding domain of Tau protein and plays a vital role in the microtubule assembly, recycling processes, and amyloid fibril formation. Here, we efficiently explore the conformation of K18 with about 150 µs lifetimes in silico. Our results observe that all four repeat regions (R1-R4) are very dynamic, featuring frequent conformational conversion and lacking stable conformations, and the R2 region is more flexible than the R1, R3, and R4 regions. Additionally, it is worth noting that residues 300-310 in R2-R3 and residues 319-336 in R3 tend to form sheet structures, indicating that K18 has a broader functional role than individual repeat monomers. Finally, the simulations combined with Markov state models and deep learning reveal 5 key conformational states along the transition pathway and provide the information on the microsecond time scale interstate transition rates. Overall, this study offers significant insights into the molecular mechanism of Tau pathological aggregation and develops novel strategies for both securing tauopathies and advancing drug discovery.


Assuntos
Aprendizado Profundo , Melfalan , Tauopatias , gama-Globulinas , Humanos , Proteínas tau/metabolismo , Sequência de Aminoácidos , Estrutura Secundária de Proteína
14.
Nat Commun ; 15(1): 2349, 2024 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-38514609

RESUMO

Safe and effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are crucial to fight against the coronavirus disease 2019 pandemic. Most vaccines are based on a mutated version of the Spike glycoprotein [K986P/V987P (S-2P)] with improved stability, yield and immunogenicity. However, S-2P is still produced at low levels. Here, we describe the V987H mutation that increases by two-fold the production of the recombinant Spike and the exposure of the receptor binding domain (RBD). S-V987H immunogenicity is similar to S-2P in mice and golden Syrian hamsters (GSH), and superior to a monomeric RBD. S-V987H immunization confer full protection against severe disease in K18-hACE2 mice and GSH upon SARS-CoV-2 challenge (D614G or B.1.351 variants). Furthermore, S-V987H immunized K18-hACE2 mice show a faster tissue viral clearance than RBD- or S-2P-vaccinated animals challenged with D614G, B.1.351 or Omicron BQ1.1 variants. Thus, S-V987H protein might be considered for future SARS-CoV-2 vaccines development.


Assuntos
COVID-19 , Melfalan , SARS-CoV-2 , gama-Globulinas , Cricetinae , Animais , Humanos , Camundongos , Mesocricetus , Vacinas contra COVID-19 , COVID-19/prevenção & controle , Glicoproteína da Espícula de Coronavírus/genética , Imunização , Glicoproteínas , Anticorpos Neutralizantes , Anticorpos Antivirais
15.
Cesk Slov Oftalmol ; 80(3): 123-129, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38538290

RESUMO

Retinoblastoma is the most common primary malignant intraocular tumor in children. Seeding, specifically the dispersion of the tumor into the adjacent compartments, represents a major parameter determining the degree of retinoblastoma according to the International Classification of Retinoblastoma. In this article we focused on vitreous seeding, one of the main limiting factors in the successful "eye preservation treatment" of retinoblastoma. This article presents an overview of the history of vitreous seeding of retinoblastoma, established treatment procedures and new-research modalities. The introduction of systemic chemotherapy in the treatment of retinoblastoma at the end of the 1990s represented a significant breakthrough, which enabled the progressive abandonment of radiotherapy with its attendant side effects. However, the attained concentrations of chemotherapeutics in the vitreous space during systemic chemotherapy are not sufficient for the treatment of vitreous seeding, and the toxic effects of systemic chemotherapy are not negligible. A significant change came with the advent of chemotherapy in situ, with the targeted administration of chemotherapeutic drugs, namely intra-arterial and intravitreal injections, contributing to the definitive eradication of external radiotherapy and a reduction of systemic chemotherapy. Although vitreous seeding remains the most common reason for the failure of intra-arterial chemotherapy, this technique has significantly influenced the original treatment regimen of children with retinoblastoma. However, intravitreal chemotherapy has made the greatest contribution to increasing the probability of preservation of the eyeball and visual functions in patients with advanced findings. Novel local drug delivery modalities, gene therapy, oncolytic viruses and immunotherapy from several ongoing preclinical and clinical trials may represent promising approaches in the treatment of vitreous retinoblastoma seeding, though no clinical trials have yet been completed for routine use.


Assuntos
Neoplasias da Retina , Retinoblastoma , Criança , Humanos , Retinoblastoma/induzido quimicamente , Retinoblastoma/tratamento farmacológico , Neoplasias da Retina/induzido quimicamente , Neoplasias da Retina/tratamento farmacológico , Melfalan/efeitos adversos , Antineoplásicos Alquilantes/farmacologia , Antineoplásicos Alquilantes/uso terapêutico , Corpo Vítreo/patologia , Injeções Intravítreas , Estudos Retrospectivos
16.
Lancet Haematol ; 11(5): e358-e367, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38555923

RESUMO

BACKGROUND: Chimeric antigen receptor (CAR) T cells targeting CD30 are safe and have promising activity when preceded by lymphodepleting chemotherapy. We aimed to determine the safety of anti-CD30 CAR T cells as consolidation after autologous haematopoietic stem-cell transplantation (HSCT) in patients with CD30+ lymphoma at high risk of relapse. METHODS: This phase 1 dose-escalation study was performed at two sites in the USA. Patients aged 3 years and older, with classical Hodgkin lymphoma or non-Hodgkin lymphoma with CD30+ disease documented by immunohistochemistry, and a Karnofsky performance score of more than 60% planned for autologous HSCT were eligible if they were considered high risk for relapse as defined by primary refractory disease or relapse within 12 months of initial therapy or extranodal involvement at the start of pre-transplantation salvage therapy. Patients received a single infusion of CAR T cells (2 × 107 CAR T cells per m2, 1 × 108 CAR T cells per m2, or 2 × 108 CAR T cells per m2) as consolidation after trilineage haematopoietic engraftment (defined as absolute neutrophil count ≥500 cells per µL for 3 days, platelet count ≥25 × 109 platelets per L without transfusion for 5 days, and haemoglobin ≥8 g/dL without transfusion for 5 days) following carmustine, etoposide, cytarabine, and melphalan (BEAM) and HSCT. The primary endpoint was the determination of the maximum tolerated dose, which was based on the rate of dose-limiting toxicity in patients who received CAR T-cell infusion. This study is registered with ClinicalTrials.gov (NCT02663297) and enrolment is complete. FINDINGS: Between June 7, 2016, and Nov 30, 2020, 21 patients were enrolled and 18 patients (11 with Hodgkin lymphoma, six with T-cell lymphoma, one with grey zone lymphoma) were infused with anti-CD30 CAR T cells at a median of 22 days (range 16-44) after autologous HSCT. There were no dose-limiting toxicities observed, so the highest dose tested, 2 × 108 CAR T cells per m2, was determined to be the maximum tolerated dose. One patient had grade 1 cytokine release syndrome. The most common grade 3-4 adverse events were lymphopenia (two [11%] of 18) and leukopenia (two [11%] of 18). There were no treatment-related deaths. Two patients developed secondary malignancies approximately 2 years and 2·5 years following treatment (one stage 4 non-small cell lung cancer and one testicular cancer), but these were judged unrelated to treatment. At a median follow-up of 48·2 months (IQR 27·5-60·7) post-infusion, the median progression-free survival for all treated patients (n=18) was 32·3 months (95% CI 4·6 months to not estimable) and the median progression-free survival for treated patients with Hodgkin lymphoma (n=11) has not been reached. The median overall survival for all treated patients has not been reached. INTERPRETATION: Anti-CD30 CAR T-cell infusion as consolidation after BEAM and autologous HSCT is safe, with low rates of toxicity and encouraging preliminary activity in patients with Hodgkin lymphoma at high risk of relapse, highlighting the need for larger studies to confirm these findings. FUNDING: National Heart Lung and Blood Institute, University Cancer Research Fund at the Lineberger Comprehensive Cancer Center.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Imunoterapia Adotiva , Antígeno Ki-1 , Transplante Autólogo , Humanos , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Imunoterapia Adotiva/métodos , Imunoterapia Adotiva/efeitos adversos , Idoso , Adolescente , Doença de Hodgkin/terapia , Doença de Hodgkin/imunologia , Adulto Jovem , Criança , Receptores de Antígenos Quiméricos/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Melfalan/uso terapêutico , Melfalan/administração & dosagem , Linfoma não Hodgkin/terapia , Linfoma não Hodgkin/imunologia , Carmustina/uso terapêutico , Carmustina/administração & dosagem , Etoposídeo/uso terapêutico , Etoposídeo/administração & dosagem , Pré-Escolar , Citarabina/uso terapêutico , Citarabina/administração & dosagem
17.
Cardiovasc Intervent Radiol ; 47(4): 407-415, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38509339

RESUMO

Retinoblastoma is the most common eye malignancy in children that if left untreated can invade intraocular structures, metastasize, and rarely lead to death. Traditionally treated with systemic chemotherapy, Intra-arterial chemotherapy is gaining popularity as it allows for the direct administration of chemotherapy through the ophthalmic artery, thus reducing systemic side effects. Intra-arterial chemotherapy procedures have evolved, with refinements to reduce risks and radiation exposure. Intra-arterial chemotherapy boasts an impressive technical success rate and one year ocular survival even amongst advanced cases. This review offers a thorough examination of the technique, indications, contraindications, outcomes, and alternative options for Intra-arterial chemotherapy.


Assuntos
Exposição à Radiação , Neoplasias da Retina , Retinoblastoma , Criança , Humanos , Lactente , Retinoblastoma/induzido quimicamente , Retinoblastoma/tratamento farmacológico , Neoplasias da Retina/induzido quimicamente , Neoplasias da Retina/tratamento farmacológico , Infusões Intra-Arteriais , Artéria Oftálmica/patologia , Melfalan/uso terapêutico , Estudos Retrospectivos
18.
Front Immunol ; 15: 1310752, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38504993

RESUMO

Background: Melphalan is the most common conditioning regimen used prior to autologous stem cell transplant (ASCT); however, there are varying data on optimal melphalan timing prior to transplant for best safety and efficacy. Historically, ASCT conditioning consisted of melphalan 200 mg/m2 on day 2 (D-2) (48 h prior to ASCT), but many institutions have since adopted a melphalan protocol with administration on day 1 (D-1) (24 h prior to SCT) or split dosing over the 2 days. The optimal timing of melphalan has yet to be determined. Methods: In this single-center retrospective study, we analyzed transplant outcomes for patients between March 2011 and September 2020 admitted for high-dose, single-agent melphalan 200 mg/m2 on D-1 vs. D-2. The primary outcomes were time to neutrophil and platelet engraftment. Secondary outcomes include incidence of hospital readmission within 30 days, 2-year progression-free survival, and 2-year overall survival. Results: A total of 366 patients were studied (D-2 n = 269 and D-1 n = 97). The incidence of high-risk cytogenetics was similar between the two groups (37% vs. 40%). Median days to absolute neutrophil count engraftment was similar at 11 days in the D-2 and D-1 cohort (n = 269, range 0-14, IQR 11-11 vs. n = 97, range 0-14, IQR 11-12). Median days to platelet engraftment >20,000/mcL was 18 days for D-2 melphalan (range: 0-28, IQR 17-20) versus 19 days for D-1 melphalan (range: 0-32, IQR 17-21). Overall survival at 2 years post-transplant was similar in both cohorts (94%; p = 0.76), and PFS was 70% in D-2 compared with 78% in D-1 (p = 0.15). In a multivariable model including age and performance status, hospital readmission within 30 days of transplant was higher in the D-1 cohort (odds ratio 1.9; p = 0.01). Conclusion: This study demonstrates similar neutrophil and platelet engraftment in D-1 and D-2 melphalan cohorts with similar 2-year PFS and OS. Either D-2 or D-1 melphalan dosing schedule is safe and effective.


Assuntos
Mieloma Múltiplo , Humanos , Mieloma Múltiplo/terapia , Melfalan/efeitos adversos , Estudos Retrospectivos , Transplante de Células-Tronco
19.
Pol J Vet Sci ; 27(1): 61-74, 2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-38511603

RESUMO

This study aimed to develop an equine-derived hyperimmune serum against SARS-CoV-2 and evaluate its efficacy as a potential immunotherapy tool for the treatment of known and potential variants of COVID-19 in preclinical trials. The novelty of this study is the whole virus and ALUM gel adjuvant formula. The horses were immunized using a whole inactivated SARS-CoV-2 antigen, and the final purified hyperimmune serum showed high plaque reduction neutralization (PRNT 50) neutralizing titers. The efficacy of the hyperimmune serum was evaluated histopathologically and biochemically in the lungs, hearts, and serum of K18 hACE2 transgenic mice (n=45), which is an accepted model organism for SARS-CoV-2 studies and was challenged with live SARS-CoV-2. Serum treatment improved the general condition, resulting in lower levels of proinflammatory cytokines in the blood plasma, as well as reduced viral RNA titers in the lungs and hearts. Additionally, it reduced oxidative stress significantly and lessened the severity of interstitial pneumonia in the lungs when compared to infected positive controls. The study concluded that equine-derived anti-SARS-CoV-2 antibodies could be used for COVID-19 prevention and treatment, especially in the early stages of the disease and in combination with antiviral drugs and vaccines. This treatment will benefit special patient populations such as immunocompromised individuals, as specific antibodies against SARS-CoV-2 can neutralize the virus before it enters host cells. The rapid and cost-effective production of the serum allows for its availability during the acute phase of the disease, making it a critical intervention in preventing the spread of the disease and saving lives in new variants where a vaccine is not yet developed.


Assuntos
Compostos de Alúmen , COVID-19 , Doenças dos Cavalos , Melfalan , Doenças dos Roedores , gama-Globulinas , Camundongos , Animais , Cavalos , COVID-19/veterinária , SARS-CoV-2 , Anticorpos Antivirais , Camundongos Transgênicos , Modelos Animais de Doenças , Doenças dos Cavalos/prevenção & controle
20.
Cytotherapy ; 26(5): 456-465, 2024 05.
Artigo em Inglês | MEDLINE | ID: mdl-38385909

RESUMO

BACKGROUND AIMS: The combination therapy of autologous hematopoietic stem cell transplantation (ASCT) and chimeric antigen receptor T-cell (CART) therapy has been employed to improve outcomes for relapsed or refractory (R/R) B-cell non-Hodgkin-lymphoma (B-NHL). The widely used conditioning regimen before ASCT plus CART therapy reported in the literature was carmustine, etoposide, cytarabine and melphalan (BEAM). However, whether adding fludarabine to the BEAM regimen (BEAMF) can improve the survival of patients with R/R B-NHL remains unknown. METHODS: In total, 39 and 19 patients with R/R B-NHL were enrolled to compare clinical outcomes in the BEAM and BEAMF regimens before ASCT plus CD19/22 CART therapy, respectively. RESULTS: The objective response (OR) rates at 3 months to BEAM and BEAMF regimens before ASCT plus CD19/22 CART therapy were 71.8% and 94.7%, respectively (P = 0.093). The BEAMF regimen showed a trend towards a superior duration of response compared with the BEAM regimen (P = 0.09). After a median follow-up of 28 months (range: 0.93-51.9 months), the BEAMF regimen demonstrated superior 2-year progression-free survival (PFS) (89.5% versus 63.9%; P = 0.048) and 2-year overall survival (OS) (100% vs 77.3%; P = 0.035) compared with the BEAM regimen. In the multivariable Cox regression analysis, OR at month 3 (responders) was remarkably correlated with better OS (hazard ratio: 0.112, P = 0.005) compared with OR (non-responders). CONCLUSIONS: For patients with R/R B-NHL, the BEAMF regimen before ASCT plus CD19/22 CART therapy was correlated with superior PFS and OS than the BEAM regimen, and the BEAMF regimen is a promising alternative conditioning regimen for ASCT plus CAR-T therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Carmustina , Citarabina , Etoposídeo , Transplante de Células-Tronco Hematopoéticas , Melfalan , Transplante Autólogo , Vidarabina , Vidarabina/análogos & derivados , Humanos , Masculino , Carmustina/uso terapêutico , Carmustina/administração & dosagem , Melfalan/uso terapêutico , Melfalan/administração & dosagem , Citarabina/uso terapêutico , Citarabina/administração & dosagem , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Pessoa de Meia-Idade , Adulto , Transplante Autólogo/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Etoposídeo/uso terapêutico , Etoposídeo/administração & dosagem , Vidarabina/administração & dosagem , Vidarabina/uso terapêutico , Prognóstico , Idoso , Linfoma de Células B/terapia , Linfoma de Células B/mortalidade , Podofilotoxina/uso terapêutico , Podofilotoxina/administração & dosagem , Imunoterapia Adotiva/métodos , Adulto Jovem , Terapia Combinada , Condicionamento Pré-Transplante/métodos , Receptores de Antígenos Quiméricos/uso terapêutico
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