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Mass spectrometry (MS) can detect multiple myeloma-derived monoclonal proteins in peripheral blood (PB) with high sensitivity, potentially serving as a PB assay for measurable residual disease (MRD). This study evaluated the significance of PB MS MRD negativity during post-transplant therapy in patients with newly diagnosed multiple myeloma. Serum samples from 138 patients treated in the phase 3 ATLAS trial of post-transplant maintenance with either carfilzomib, lenalidomide, dexamethasone or lenalidomide alone were analyzed using EXENT MS methodology. We established feasibility of measuring MRD by MS in PB in the post-transplant setting, despite unavailability of pre-treatment calibration samples. There was high agreement between MRD by MS in PB and paired BM MRD results at the 10-5 threshold, assessed by either next generation sequencing (NGS) or multiparameter flow cytometry (MFC) (70% and 67%, respectively). Agreement between PB MS and both BM MRD methods was lowest early after transplant and increased with time. MS negativity was associated with improved progression-free survival (PFS), which in landmark analysis reached statistical significance after 18 cycles post-transplant. Combined PB/BM MRD negativity by MFC or NGS was associated with superior PFS compared to MRD negativity by only one modality. Sustained MS negativity carried similar prognostic performance to sustained BM MRD negativity at the 10-5 threshold. Overall, post-transplant MS assessment was feasible and provided additional prognostic information to BM MRD negativity. Further studies are needed to confirm the role and optimal timing of MS in disease evaluation algorithms. The ATLAS trial is registered at www.clinicaltrials.gov as #NCT02659293.
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Pancreatic cancer, particularly Pancreatic ductal adenocarcinoma, remains a highly lethal form of cancer with limited early diagnosis and treatment options. Infrared (IR) spectroscopy, combined with machine learning, has demonstrated great potential in detecting various cancers. This study explores the translation of a diagnostic model from Fourier Transform Infrared to Quantum Cascade Laser (QCL) microscopy for pancreatic cancer classification. Furthermore, QCL microscopy offers faster measurements with selected frequencies, improving clinical feasibility. Thus, the goals of the study include establishing a QCL-based model for pancreatic cancer classification and creating a fast surgical margin detection model using reduced spectral information. The research involves preprocessing QCL data, training Random Forest (RF) classifiers, and optimizing the selection of spectral features for the models. Results demonstrate successful translation of the diagnostic model to QCL microscopy, achieving high predictive power (AUC = 98%) in detecting cancerous tissues. Moreover, a model for rapid surgical margin recognition, based on only a few spectral frequencies, is developed with promising differentiation between benign and cancerous regions. The findings highlight the potential of QCL microscopy for efficient pancreatic cancer diagnosis and surgical margin detection within clinical timeframes of minutes per surgical resection tissue.
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Margens de Excisão , Neoplasias Pancreáticas , Humanos , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Microscopia/métodos , Neoplasias Pancreáticas/diagnóstico por imagem , BiópsiaRESUMO
In this paper, issues related to the technology of compound castings composed of two parts, i.e., the working layer and the supporting part, made of X46Cr13 high-chromium steel and EN-GJL-HB 255 grey cast iron, respectively, in a liquid-solid system by pre-installing a monolithic insert in the mould cavity are presented. As a part of the research, the mechanism of formation of transitional zones in the bonding area of the above-mentioned two alloys was identified and described. It was shown that the phenomenon that determines the formation of a permanent bond between the joined materials is the transport of C and heat from the "high-carbon and hot" material of the supporting part poured into the mould in the form of liquid cast iron to the "low-carbon and cold" material of the working layer placed in the form of a steel monolithic insert inside the mould cavity. In the paper, the suitability of the compound castings technology developed for use in the coke industry is also presented. Full-size high-chromium steel-grey cast iron compound casting plates designed for the coke quenching car lining were positively verified in real coke plant operating conditions.
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Pancreatic intraepithelial neoplasia (PanIN) is manifested by noninvasive lesions in the epithelium of smaller pancreatic ducts. Generally, cancer development risk from low-grade PanIN is minor, whereas, invasive pancreatic ductal adenocarcinoma (PDAC) development is highly related to high-grade PanINs. Therefore, in the case of high-grade PanIN detection, additional surgical resection may be recommended. However, even the low-grade PanINs can indicate possible progression to PDAC. The definition of PanIN is constantly changing and there is a need for new tools to better characterize and understand its behavior. We have recently developed a comprehensive pancreatic cancer classification model with biopsies collected from over 600 biopsies from 250 patients. Here, we take the next step and employ Infrared (IR) spectroscopy to build the first classification model for PanINs detection. Furthermore, we created a Partial Least Squares Regression (PLSR) model to characterize ducts from benign to cancerous. This model was then used to predict and grade PanINs accordingly to their malignancy level.
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Carcinoma in Situ , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Espectroscopia de Infravermelho com Transformada de Fourier , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/patologia , Carcinoma Ductal Pancreático/patologia , Carcinoma in Situ/patologia , Aprendizado de MáquinaRESUMO
Radiotherapy is one of the most commonly used cancer therapies with many benefits including low toxicity to healthy tissues. However, a major problem in radiotherapy is cancer radioresistance. To enhance the effect of this kind of therapy several approaches have been proposed such as the use of radiosensitizers. A combined treatment of radiotherapy and radiosensitizing drugs leads to a greater effect on cancer cells than anticipated from the addition of both responses (synergism). In this study, high-definition FT-IR imaging was applied to follow lipid accumulation in prostate cancer cells as a response to X-ray irradiation, radiosensitizing drugs, and a combined treatment of X-rays and the drugs. Lipid accumulation induced in the cells by an increasing X-ray dose and the presence of the drugs was analyzed using Principal Component Analysis and lipid staining. Finally, the synergistic effect of the combined therapy (X-rays and radiosensitizers) was confirmed by calculations of the integral intensity of the 2850 cm-1 band.
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Neoplasias da Próstata , Radiossensibilizantes , Masculino , Humanos , Radiossensibilizantes/farmacologia , Radiossensibilizantes/uso terapêutico , Raios X , Espectroscopia de Infravermelho com Transformada de Fourier , Linhagem Celular Tumoral , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/radioterapia , Lipídeos/uso terapêuticoRESUMO
Cyclosporine A (CSA) is a commonly used immunosuppressive agent for the prophylaxis of graft-versus-host disease following allogeneic hematopoietic stem cell transplantation (alloHSCT). While tachycardia is a known adverse effect of CSA, bradycardia remains a phenomenon rarely described in the literature. We conducted a retrospective evaluation of the incidence of bradycardia in patients after alloHSCT treated with CSA between January 2020 and February 2023 at our center. Out of 206 patients, sinus bradycardia following the administration of CSA was observed in 6 (2.9%), comprising 3 women and 3 men, with the median age of 55 years (range: 20-65). The underlying diseases were myeloid malignancies in 4 and aggressive lymphoma in 2 patients. The patients received grafts from a matched unrelated (n=5) or a haploidentical family donor (n=1) following various conditioning regimens. Coexisting cardiovascular disorders were found in 5 of the 6 patients. All patients experienced symptomatic bradycardia within 1-4 days (median 2 days) after CSA introduction, which persisted until CSA withdrawal. One patient required treatment with atropine. All patients continued their immunosuppressive therapy with tacrolimus, which was well-tolerated Our study indicates CSA as a causative factor of sinus bradycardia in a small percentage of alloHSCT patients receiving CSA as graft-versus host disease (GvHD) prophylaxis. Importantly, these patients did not experience any cardiac complications when switched to tacrolimus. Although further research on the effects of CSA on heart automatation is needed, our single-center experience can help prompt diagnosis and therapeutic intervention in daily clinical practice.
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The 5-HT2A receptor is a molecular target of high pharmacological importance. Ligands of this protein, particularly atypical antipsychotics, are useful in the treatment of numerous mental disorders, including schizophrenia and major depressive disorder. Structure-based virtual screening using a 5-HT2A receptor complex was performed to identify novel ligands for the 5-HT2A receptor, serving as potential antidepressants. From the Enamine screening library, containing over 4 million compounds, 48 molecules were selected for subsequent experimental validation. These compounds were tested against the 5-HT2A receptor in radioligand binding assays. From the tested batch, six molecules were identified as ligands of the main molecular target and were forwarded to a more detailed inâ vitro profiling. This included radioligand binding assays at 5-HT1A, 5-HT7, and D2 receptors and functional studies at 5-HT2A receptors. These compounds were confirmed to show a binding affinity for at least one of the targets tested inâ vitro. The success rate for the inactive template-based screening reached 17 %, while it was 9 % for the active template-based screening. Similarity and fragment analysis indicated the structural novelty of the identified compounds. Pharmacokinetics for these molecules was determined using in silico approaches.
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Receptor 5-HT2A de Serotonina , Receptor 5-HT2A de Serotonina/metabolismo , Receptor 5-HT2A de Serotonina/química , Ligantes , Humanos , Relação Estrutura-Atividade , Avaliação Pré-Clínica de Medicamentos , Descoberta de Drogas , Estrutura Molecular , Simulação de Acoplamento MolecularRESUMO
This paper presents the results of research conducted in the field of the technology of surface hardening of castings from unalloyed and low-alloy nodular cast iron using the laser remelting method. The range of studies included macro- and microhardness measurements using Rockwell and Vickers methods as well as metallographic microscopic examinations using a scanning electron microscope. Moreover, abrasive wear resistance tests were performed using the pin-on-disk method in the friction pair of nodular cast iron-SiC abrasive paper and the reciprocating method in the friction pair of nodular cast iron-unalloyed steel. Analysis of the test results shows that the casting surface layer remelting by laser for unalloyed nodular cast iron results in a greater improvement in its resistance to abrasive wear in the metal-mineral system, as compared to low-alloy cast iron. Additionally, carrying out the laser hardening treatment of the surface layer made of the tested grades of nodular cast iron is justified only if the tribological system of the cooperating working parts and allowable dimensional changes during their operation are known.
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Previously, we demonstrated that palmatine (PALM) - an isoquinoline alkaloid from Berberis sibrica radix, exerted antiseizure activity in the pentylenetetrazole (PTZ)-induced seizure assay in larval zebrafish. The aim of the present study was to more precisely characterize PALM as a potential anticonvulsant drug candidate. A range of zebrafish and mouse seizure/epilepsy models were applied in the investigation. Immunostaining analysis was conducted to assess the changes in mouse brains, while in silico molecular modelling was performed to determine potential targets for PALM. Accordingly, PALM had anticonvulsant effect in ethyl 2-ketopent-4-enoate (EKP)-induced seizure assay in zebrafish larvae as well as in the 6 Hz-induced psychomotor seizure threshold and timed infusion PTZ tests in mice. The protective effect in the EKP-induced seizure assay was confirmed in the local field potential recordings. PALM did not affect seizures in the gabra1a knockout line of zebrafish larvae. In the scn1Lab-/- zebrafish line, pretreatment with PALM potentiated seizure-like behaviour of larvae. Repetitive treatment with PALM, however, did not reduce development of PTZ-induced seizure activity nor prevent the loss of parvalbumin-interneurons in the hippocampus of the PTZ kindled mice. In silico molecular modelling revealed that the noted anticonvulsant effect of PALM in EKP-induced seizure assay might result from its interactions with glutamic acid decarboxylase and/or via AMPA receptor non-competitive antagonism. Our study has demonstrated the anticonvulsant activity of PALM in some experimental models of seizures, including a model of pharmacoresistant seizures induced by EKP. These results indicate that PALM might be a suitable new drug candidate but the precise mechanism of its anticonvulsant activity has to be determined.
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Anticonvulsivantes , Alcaloides de Berberina , Epilepsia , Camundongos , Animais , Anticonvulsivantes/efeitos adversos , Peixe-Zebra , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Epilepsia/tratamento farmacológico , Pentilenotetrazol/farmacologiaRESUMO
BACKGROUND: T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) molecule is a key regulator of the immune response by exerting an inhibitory effect on various types of immune cells. Understanding the role of TIM-3 in hematopoietic stem cell transplantation (HSCT) may improve transplant outcomes. Our study evaluated the potential association between TIM-3 polymorphisms, namely rs1036199 (A > C) or rs10515746 (C > A), changes which are located in exon 3 and the promoter region of the TIM-3 gene, and post-HSCT outcomes. METHODS: One-hundred and twenty allogeneic HSCT patients and their respective donors were enrolled and genotyped for TIM-3 single nucleotide polymorphisms (SNPs) using real-time PCR with TaqMan assays. RESULTS: We found that the presence of the rare alleles and heterozygous genotypes of studied SNP in recipients tended to protect against or increase the risk for acute graft-versus-host disease (aGvHD). For the rs1036199 polymorphism, recipients with the AC heterozygous genotype (p = 0.0287) or carrying the rarer C allele (p = 0.0334) showed a lower frequency of aGvHD development along all I-IV grades. A similar association was detected for the rs10515746 polymorphism as recipients with the CA genotype (p = 0.0095) or the recessive A allele (p = 0.0117) less frequently developed aGvHD. Furthermore, the rarer A allele of rs10515746 SNP was also associated with a prolonged aGvHD-free survival (p = 0.0424). Cytomegalovirus (CMV) infection was more common in patients transplanted with TIM-3 rs10515746 mismatched donors (p = 0.0229) and this association was also found to be independent of HLA incompatibility and pre-transplant CMV-IgG status. Multivariate analyses confirmed the role of these recessive alleles and donor-recipient TIM-3 incompatibility as an independent factor in aGvHD and CMV development. CONCLUSIONS: Polymorphism of TIM-3 molecule may affect the immune response in HSCT patients. The recessive alleles of rs1036199 and rs10515746 SNPs decreased the risk of developing aGvHD. TIM-3 donor-recipient genetic matching may also affect the risk of post-transplant CMV infection, indicating the potential value of genetic profiling in optimizing transplant strategies.
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Genótipo , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Receptor Celular 2 do Vírus da Hepatite A , Polimorfismo de Nucleotídeo Único , Transplante Homólogo , Humanos , Receptor Celular 2 do Vírus da Hepatite A/genética , Doença Enxerto-Hospedeiro/genética , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Adolescente , Adulto Jovem , Infecções por Citomegalovirus/genética , Criança , Alelos , Predisposição Genética para Doença , IdosoRESUMO
Introduction: Mixed-phenotype acute leukemia (MPAL) is a rare disease with poor prognosis. So far, no standard approach has been established as the "know-how" of MPAL is based only on retrospective analyses performed on small groups of patients. Materials and methods: In this study, a retrospective analysis of the outcomes of adult MPAL patients included in the PALG registry between 2005 and 2024 who received the CLAG-M hybrid protocol as induction or salvage therapy was performed. Results: Sixteen of 98 MPAL patients received CLAG-M: eight as first-line and eight as salvage therapy. In the first line, two patients achieved partial response (PR), and six achieved complete remission (CR), of whom four successfully underwent allogeneic hematopoietic stem cell transplantation (alloHSCT). Two patients who did not undergo alloHSCT promptly relapsed. Within the whole group, the overall response rate (ORR) was 75% (n = 12/16). With the median follow-up of 13 months, six out of eight patients remain in CR, however, two of them died due to acute graft versus host disease. Out of eight patients who received CLAG-M in the second line, four patients (50%) obtained CR. AlloHSCT was conducted in seven cases, six of which were in CR. Only two patients remained in CR at the time of the last follow-up. Tolerance to treatment was good. The median times for severe neutropenia and thrombocytopenia were 22 days (range, 16-24) and 17 days (range, 12-24), respectively. Overall, grade 3-4 infections were observed in 12 cases, and all infections presented successful outcomes. Conclusions: CLAG-M is an effective first-line salvage regimen for MPAL with an acceptable safety profile. Early achievement of CR with prompt alloHSCT allows for satisfactory disease control.
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The aim of the present study was to determine the associations between the MICB genetic variability and the expression and the risk of development of post-transplant complications after allogeneic hematopoietic stem cell transplantation (HSCT). HSCT recipients and their donors were genotyped for two MICB polymorphisms (rs1065075, rs3828903). Moreover, the expression of a soluble form of MICB was determined in the recipients' serum samples after transplantation using the Luminex assay. Our results revealed a favorable role of the MICB rs1065075 G allele. Recipients with donors carrying this genetic variant were less prone to developing chronic graft-versus-host disease (cGvHD) when compared to recipients without any symptoms of this disease (41.41% vs. 65.38%, p = 0.046). Moreover, the MICB rs1065075 G allele was associated with a lower incidence of cytomegalovirus (CMV) reactivation, both as a donor (p = 0.015) and as a recipient allele (p = 0.039). The MICB rs1065075 G variant was also found to be associated with decreased serum soluble MICB (sMICB) levels, whereas serum sMICB levels were significantly higher in recipients diagnosed with CMV infection (p = 0.0386) and cGvHD (p = 0.0008) compared to recipients without those complications. A protective role of the G allele was also observed for the rs3828903 polymorphism, as it was more frequently detected among donors of recipients without cGvHD (89.90% vs. 69.23%; p = 0.013). MICB genetic variants, as well as serum levels of sMICB, may serve as prognostic factors for the risk of developing cGvHD and CMV infection after allogeneic HSCT.
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Infecções por Citomegalovirus , Predisposição Genética para Doença , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Antígenos de Histocompatibilidade Menor , Transplante Homólogo , Humanos , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/etiologia , Infecções por Citomegalovirus/genética , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Masculino , Feminino , Transplante Homólogo/efeitos adversos , Adulto , Pessoa de Meia-Idade , Doença Crônica , Antígenos de Histocompatibilidade Menor/genética , Antígenos de Histocompatibilidade Classe I/genética , Polimorfismo de Nucleotídeo Único , Alelos , Genótipo , Adulto Jovem , Citomegalovirus/fisiologia , Adolescente , Risco , Fatores de RiscoRESUMO
Metastable binding sites (MBS) have been observed in a multitude of molecular dynamics simulations and can be considered low affinity allosteric binding sites (ABS) that function as stepping stones as the ligand moves toward the orthosteric binding site (OBS). Herein, we show that MBS can be utilized as ABS in ligand design, resulting in ligands with improved binding kinetics. Four homobivalent bitopic ligands (1-4) were designed by molecular docking of (S)-alprenolol ((S)-ALP) in the cocrystal structure of the ß2 adrenergic receptor (ß2AR) bound to the antagonist ALP. Ligand 4 displayed a potency and affinity similar to (S)-ALP, but with a >4-fold increase in residence time. The proposed binding mode was confirmed by X-ray crystallography of ligand 4 in complex with the ß2AR. This ligand design principle can find applications beyond the ß2AR and G protein-coupled receptors (GPCRs) as a general approach for improving the pharmacological profile of orthosteric ligands by targeting the OBS and an MBS simultaneously.
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Simulação de Acoplamento Molecular , Receptores Adrenérgicos beta 2 , Receptores Adrenérgicos beta 2/metabolismo , Receptores Adrenérgicos beta 2/química , Ligantes , Humanos , Sítios de Ligação , Cristalografia por Raios X , Alprenolol/química , Alprenolol/farmacologia , Alprenolol/metabolismo , Antagonistas de Receptores Adrenérgicos beta 2/química , Antagonistas de Receptores Adrenérgicos beta 2/farmacologia , Antagonistas de Receptores Adrenérgicos beta 2/metabolismo , Simulação de Dinâmica Molecular , Desenho de FármacosAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Dexametasona , Lenalidomida , Mieloma Múltiplo , Oligopeptídeos , Qualidade de Vida , Humanos , Mieloma Múltiplo/tratamento farmacológico , Lenalidomida/uso terapêutico , Dexametasona/uso terapêutico , Dexametasona/administração & dosagem , Oligopeptídeos/uso terapêutico , Masculino , Feminino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Pessoa de Meia-Idade , Idoso , Talidomida/uso terapêuticoRESUMO
Background and Objectives: An interaction between neuroticism and burden of illness supports depressive symptoms even at subclinical level. We have assessed its effect in groups of patients with different kind of somatic illness. Methods: Depressive symptoms (SCAN 2.1) and a level of neuroticism (EPQ-R) were assessed in in patients from 3 different hospital wards, namely the general internal, hematological and infectious wards, and in controls from the general population. Results: A total of 184 adult subjects were examined (45 with haematological malignancies, 46 treated for other, non-malignant internal diseases, 48 with HCV infection beforetreatment and 45 healthy persons as control). Differences in mean neuroticism scores were not statistically significant (ANOVA, F = 1.44, p = 0.23) where as differences in mean depression scores were statistically significant (ANOVA, F = 6.34, p < 0.001). Results of ANCOVA for separate-slopes model analysis revealed a statistically significant level of interaction between groups and neuroticism in their influence on depression mean scores (F= 22.9, p < 0.001). The residual effect of the group variable was weak (F = 0.54, p = 0.21). Conclusions: The interaction is a significant factor related to depressive symptoms and can be used in estimating the extent of the psychological impact of a burden of illness (AU)