Hasil untuk "Diseases of the blood and blood-forming organs"

Guo Qiu, Zhao Yin, Xiaoyue Lu et al.

Abstract Background TP53-mutated acute myeloid leukemia (AML) represents one of the most adverse-risk subtypes of AML, yet the mechanisms underlying its resistance and relapse remain poorly defined. Methods We performed single-cell RNA sequencing on bone marrow samples from 30 de novo AML patients (11 TP53-mutated, 19 TP53-wild-type) and systematically analyzed leukemic, immune, and stromal compartments to delineate differentiation trajectories, transcriptional heterogeneity, and microenvironmental remodeling. We also performed in vitro assays to validate ferroptosis resistance, leukemia-T cell dysfunction, and stromal remodeling suggested by the single-cell data. Results TP53-mutated AML exhibited a differentiation bias toward granulocyte-monocyte and late myeloid progenitors rather than arrest at the stem cell stage, with enhanced anti-apoptotic and inflammatory programs and a transcriptionally and functionally supported ferroptosis resistance phenotype as a novel hallmark linked to poor prognosis. Functionally, CD8⁺ T cells were predominantly exhausted with an enrichment of dysfunctional subsets and a concomitant reduction of NK cells. B cells showed impaired activation with skewed plasma cell composition, and myeloid cells acquired immunosuppressive features. In the stromal compartment, mesenchymal cells lost hematopoietic and immune-supportive functions and shifted toward osteogenic programs, further reinforcing leukemic survival. We also established an integrated ecosystem score that, together with TP53 mutation burden and mono- versus multi-hit status, captured prognostic heterogeneity and enabled clinical stratification. Conclusions This study provides the first single-cell landscape of de novo TP53-mutated AML, highlighting its reprogrammed leukemic hierarchy and disrupted immune-stromal ecosystem, and offering mechanistic insights and potential therapeutic targets for this high-risk subtype. Graphical Abstract

Christian Göbl, Agnese Piersanti, Florian Heinzl et al.

<b>Background/Objectives</b>: In pregnancy, beta-cell function is of interest since not only insulin resistance but also beta-cell dysfunction is common, especially when gestational diabetes mellitus (GDM) occurs. Typically, model-based beta-cell function is assessed with (at least) five-sample oral glucose tolerance test (OGTT). The aim of this study was to investigate whether the clinically common three-sample OGTT is sufficient for model-based beta-cell function assessment in pregnancy. <b>Methods</b>: We studied a group of pregnant women undergoing a 2 h five-sample OGTT with glucose, insulin, and C-peptide measurement at early and/or mid-pregnancy, for a total of 152 OGTTs. The five-sample OGTT was used for model-based beta-cell function assessment, yielding three beta-cell function parameters, i.e., glucose sensitivity (GSENS), potentiation factor ratio (PFR), and rate sensitivity (RSENS). GSENS, PFR, and RSENS assessment was repeated with the three-sample OGTT (at 0, 60, 120 min) and related values were compared to those from the five-sample OGTT (reference). <b>Results</b>: We found that, for GSENS, regression and Bland–Altman analyses showed satisfactory results (conditional and marginal R² values: 0.56 and 0.75, <i>p</i> < 0.0001, and limits of agreement containing 94.2% of samples). Moreover, five-sample and three-sample OGTT GSENS versions were fully consistent in patient subgroup analyses. Results for PFR were less satisfactory but acceptable, whereas those for RSENS were not reliable. <b>Conclusions</b>: The three-sample OGTT is acceptable for model-based beta-cell function assessment in pregnancy, although not for all parameters. Our methodology may be used to explore the effect of time sample reduction in other in-silico models.

Fabrícia Petronilho, Amanda Della Giustina, Lucinéia Gainski Danielski

Nadia Bakhsheshi, Hamid Beigy

The reliable analysis of blood reports is important for health knowledge, but individuals often struggle with interpretation, leading to anxiety and overlooked issues. We explore the potential of general-purpose Vision-Language Models (VLMs) to address this challenge by automatically analyzing blood report images. We conduct a comparative evaluation of three VLMs: Qwen-VL-Max, Gemini 2.5 Pro, and Llama 4 Maverick, determining their performance on a dataset of 100 diverse blood report images. Each model was prompted with clinically relevant questions adapted to each blood report. The answers were then processed using Sentence-BERT to compare and evaluate how closely the models responded. The findings suggest that general-purpose VLMs are a practical and promising technology for developing patient-facing tools for preliminary blood report analysis. Their ability to provide clear interpretations directly from images can improve health literacy and reduce the limitations to understanding complex medical information. This work establishes a foundation for the future development of reliable and accessible AI-assisted healthcare applications. While results are encouraging, they should be interpreted cautiously given the limited dataset size.

Muhammed Furkan Dasdelen, Ivan Kukuljan, Peter Lienemann et al.

Peripheral blood smears remain a cornerstone in the diagnosis of hematological neoplasms, offering rapid and valuable insights that inform subsequent diagnostic steps. However, since neoplastic transformations typically arise in the bone marrow, they may not manifest as detectable aberrations in peripheral blood, presenting a diagnostic challenge. In this paper, we introduce cAItomorph, an explainable transformer-based AI model, trained to classify hematological malignancies based on peripheral blood cytomorphology. Our data comprises peripheral blood single-cell images from 6115 patients with diagnoses confirmed by cytomorphology, cytogenetics, molecular genetics, and immunophenotyping from bone marrow samples, and 495 healthy controls, eight coarse classes. cAItomorph leverages the DinoBloom hematology foundation model and aggregates image encodings via a transformer-based architecture into a single vector. It achieves an overall accuracy of 0.72 in eight disease classification, with F1 scores of 0.76 for acute leukemia, 0.80 for myeloproliferative neoplasms and 0.94 for healthy cases. The overall accuracy increases to 0.87 in top-2 predictions. cAItomorph achieves high sensitivity for acute leukemia cases in external test sets. By analyzing attention heads, we demonstrate clinically relevant cell-level attentions in both internal and external test sets. Moreover, our model's calibrated prediction probabilities reduce the false discovery rate from 13.5% to 8.7% without missing any acute leukemia cases, thereby decreasing the number of unnecessary bone marrow aspirations based on peripheral blood smears. This study highlights the potential of AI-assisted diagnostics in hematological malignancies, illustrating how models trained on real-world data could enhance diagnostic accuracy and reduce invasive procedures.

Nakul Sridhar, Meiou Song, Michael H. B. Stowell et al.

Sickle cell disease (SCD) remains a critical global health issue, with high child mortality in low-resource regions. Early screening and diagnosis is essential for improving health outcomes, but conventional screening methods are unsuitable for widespread use due to the high costs of laboratory equipment. There is an urgent need for portable, cost-effective, and user-friendly point-of-care tools that can quickly assess blood health. Here, we explore two new biomarkers enabled by acoustic probing for rapid SCD screening: cell membrane stability from measuring red blood cell (RBC) lysis temperature in whole blood, and plasma protein concentration from measuring relative protein precipitation in blood plasma. Both biomarkers effectively differentiate healthy HbAA samples from pre-/no transfusion HbSS samples with high accuracy. Additionally, the RBC lysis biomarker can distinguish post-transfusion exchange HbSS samples with a lower percentage of sickled cells, indicating the potential to initially screen for milder forms of SCD as well as sickle cell trait.

Ioanna Zografou, Panagiotis Doukelis, Theocharis Koufakis et al.

Aim: The aim of this study was to evaluate the specificity, sensitivity and accuracy of the Indicator Plaster Neuropad in detecting established Diabetic Autonomic Neuropathy (DAN). Methods: We studied 180 patients with Diabetes Mellitus (DM, mean age 49.5 ± 16 years, 82 with DM type 1). All patients underwent the following Cardiovascular Reflex Tests (CARTs): R-R variation during deep breathing (Mean Circular Resultant (MCR) and standard deviation (SD)), Valsalva maneuver, R-R variability after a rapid change from lying to standing position and postural hypotension. The presence of DAN was established if ≥2 CARTs were abnormal. According to the result the patients were divided into two groups, one with DAN and one without DAN. Assessment with Neuropad was performed also in all patients. Results: Abnormal perspiration with Neuropad (uncompleted or no change in color) was detected in 94 patients. Established DAN was detected in 85 patients. The sensitivity, specificity and accuracy of Neuropad for the diagnosis of established DAN were 87.1%, 78.9% and 82.8%, respectively and area under the curve was 0.846 and 95% CI (0.787, 0.905). Conclusions: Neuropad has high sensitivity, specificity, and accuracy in detecting established DAN, as defined by ≥2 abnormal CARTs.

Julien Dereme, Konstantinos Asonitis, Francesco Grandoni et al.

ABSTRACT We present a case of a 71‐year‐old woman with a history of high‐grade serous ovarian adenocarcinoma, treated with neoadjuvant chemotherapy, surgery, and adjuvant chemotherapy. A maintenance treatment combining bevacizumab and olaparib was introduced consecutively. Bevacizumab was stopped 7 months later due to neurological complications. The patient developed severe, progressive anemia, leading to significant clinical management challenges, with hemoglobin levels as low as 54 g/L. Despite initially adapting and finally discontinuing olaparib, the patient remained transfusion dependent, without notable improvement. Common causes of anemia, such as iron deficiency, vitamin deficiency, autoimmune and infectious causes, were ruled out. Bone marrow biopsies revealed a clonal cytotoxic T‐LGL population and a DNMT3A mutation without evidence of myelodysplasia or metastatic infiltration. A further decline in reticulocytes and the appearance of warm autoantibodies (IgG) indicated an increasingly mixed anemia profile. High‐dose corticosteroids resulted in rapid hematological improvement. This case highlights a severe anemia of mixed origin with central hypo‐regenerative components due to prolonged PARP inhibitor toxicity and a hemolytic mechanism associated with warm autoantibodies. The prolonged toxic effect of olaparib, in conjunction with confounding factors (DNMT3A mutation, warm autoantibodies, T‐LGL clone), underscores the need for a comprehensive hematological assessment. The patient's response emphasizes the complexity of managing drug‐induced hematologic toxicity and the potential for overlapping hematologic conditions.

Etienne Jessen, Marc C. Steinbach, Dominik Schillinger

The understanding of the mechanisms driving vascular development is still limited. Techniques to generate vascular trees synthetically have been developed to tackle this problem. However, most algorithms are limited to single trees inside convex perfusion volumes. We introduce a new framework for generating multiple trees inside general nonconvex perfusion volumes. Our framework combines topology optimization and global geometry optimization into a single algorithmic approach. Our first contribution is defining a baseline problem based on Murray's original formulation, which accommodates efficient solution algorithms. The problem of finding the global minimum is cast into a nonlinear optimization problem (NLP) with merely super-linear solution effort. Our second contribution extends the NLP to constrain multiple vascular trees inside any nonconvex boundary while avoiding intersections. We test our framework against a benchmark of an anatomic region of brain tissue and a vasculature of the human liver. In all cases, the total tree energy is improved significantly compared to local approaches. By avoiding intersections globally, we can reproduce key physiological features such as parallel running inflow vessels and tortuous vessels. The ability to generate non-intersecting vascular trees inside nonconvex organs can improve the functional assessment of organs.

Philip Greulich

Blood clotting is an important physiological process to suppress bleeding upon injury, but when it occurs inadvertently, it can cause thrombosis, which can lead to life threatening conditions. Hence, understanding the microscopic mechanistic factors for inadvertent, spontaneous blood clotting, in absence of a vessel breach, can help in predicting and adverting such conditions. Here, we present a minimal model -- reminiscent of the SIR model -- for the initiating stage of spontaneous blood clotting, the collective activation of blood platelets. This model predicts that in the presence of very small initial activation signals, macroscopic activation of the platelet population requires a sufficient degree of heterogeneity of platelet sensitivity. To propagate the activation signal and achieve collective activation of the bulk platelet population, it requires the presence of, possibly only few, hyper-sensitive platelets, but also a sufficient proportion of platelets with intermediate, yet higher-than-average sensitivity. A comparison with experimental results demonstrates a qualitative agreement for high platelet signalling activity.

Maryam Samavaki, Santtu Söderholm, Arash Zarrin Nia et al.

Background and Objective: This proof of concept study investigates mathematical modelling of blood flow and oxygen transport in cerebral microcirculation, focusing on understanding hemodynamic responses. By coupling oxygen transport models and blood flow dynamics, the research aims to predict spatiotemporal hemodynamic responses and their impact on blood oxygenation levels, particularly in the context of deoxygenated and total blood volume (DBV and TBV) fractions. Methods: A coupled spatiotemporal model is developed using Fick's law for diffusion, combined with the hemodynamic response function derived from a damped wave equation. The diffusion coefficient in Fick's law is based on Hagen-Poiseuille flow, and arterial blood flow is approximated numerically through pressure-Poisson equation (PPE). The equations are then numerically solved with the finite element method (FEM). Numerical experiments are performed on a high-resolution 7-Tesla Magnetic Resonance Imaging (MRI) dataset for head segmentation, which facilitates the differentiation of arterial blood vessels and various brain tissue compartments. Results: The applicability of the model is further demonstrated through numerical experiments utilizing a 7 Tesla magnetic resonance imaging (MRI) dataset for head segmentation, which facilitates the differentiation of arterial blood vessels and various brain tissue compartments. By simulating hemodynamical responses and analyzing their impact on volumetric DBV and TBV, this study offers valuable insights into spatiotemporal modelling of brain tissue and blood flow. Conclusions: This study utilizes spatiotemporal modelling with high-resolution 7 Tesla-MRI head data to explore cerebral blood flow, oxygen transport, and brain dynamics. It enhances understanding of cardiovascular conditions, improves simulation accuracy, and offers potential clinical applications for targeted interventions.

Comlan Affo, Carine Schmidt, Antoine Bosquet et al.

Abstract Sickle cell disease is a rare genetic disease resulting from an abnormality in hemoglobin. Hemostasis in the steady state, defined as ≥2 months without vaso‐occlusive crises, is poorly described in the literature. We report the routine hemostasis profile in steady state patients with sickle cell disease (SCD), including during pregnancy and according to phenotype. This retrospective study collected data over the period 2010 to 2021. Data on routine hemostasis parameters (prothrombin time [PT] activated partial thromboplastin time [aPTT], and platelets) were collected from medical records and were compared with laboratory norms including during pregnancy; the HbSS phenotype was compared with the HbSC, HbSB°thalassemia, and HbSB+thalassemia phenotypes. we included 119 adults (representing 190 day‐hospitals) with SCD who had attended at least one checkup in the steady state. Seven patients (15 day‐hospitals) on anticoagulants were excluded. Eleven (17 day‐hospitals) were pregnant. Mean routine hemostasis parameters were within normal values regardless of pregnancy. Mean PT was lower during pregnancy (12.3 ± 0.6 s vs. 13.2 ± 1.0 s; P = .01). PT and platelet counts were higher (P = .01) and aPTT was lower (P = .03) in men and nonpregnant women in the HbSS group compared with those in the HbSC group. routinely collected hemostasis parameters in steady state patients were within normal laboratory values, including in pregnant women. PT values differed significantly between pregnant women and nonpregnant women, and PT, aPTT, and platelet counts differed between HbSS, HbSC, and HbSB+thalassemia phenotypes.

Giulia Bertaglia, Lorenzo Pareschi

In this paper, a multiscale constitutive framework for one-dimensional blood flow modeling is presented and discussed. By analyzing the asymptotic limits of the proposed model, it is shown that different types of blood propagation phenomena in arteries and veins can be described through an appropriate choice of scaling parameters, which are related to distinct characterizations of the fluid-structure interaction mechanism (whether elastic or viscoelastic) that exist between vessel walls and blood flow. In these asymptotic limits, well-known blood flow models from the literature are recovered. Additionally, by analyzing the perturbation of the local elastic equilibrium of the system, a new viscoelastic blood flow model is derived. The proposed approach is highly flexible and suitable for studying the human cardiovascular system, which is composed of vessels with high morphological and mechanical variability. The resulting multiscale hyperbolic model of blood flow is solved using an asymptotic-preserving Implicit-Explicit Runge-Kutta Finite Volume method, which ensures the consistency of the numerical scheme with the different asymptotic limits of the mathematical model without affecting the choice of the time step by restrictions related to the smallness of the scaling parameters. Several numerical tests confirm the validity of the proposed methodology, including a case study investigating the hemodynamics of a thoracic aorta in the presence of a stent.

Léonie Courcoul, Christophe Tzourio, Mark Woodward et al.

Given the high incidence of cardio and cerebrovascular diseases (CVD), and its association with morbidity and mortality, its prevention is a major public health issue. A high level of blood pressure is a well-known risk factor for these events and an increasing number of studies suggest that blood pressure variability may also be an independent risk factor. However, these studies suffer from significant methodological weaknesses. In this work we propose a new location-scale joint model for the repeated measures of a marker and competing events. This joint model combines a mixed model including a subject-specific and time-dependent residual variance modeled through random effects, and cause-specific proportional intensity models for the competing events. The risk of events may depend simultaneously on the current value of the variance, as well as, the current value and the current slope of the marker trajectory. The model is estimated by maximizing the likelihood function using the Marquardt-Levenberg algorithm. The estimation procedure is implemented in a R-package and is validated through a simulation study. This model is applied to study the association between blood pressure variability and the risk of CVD and death from other causes. Using data from a large clinical trial on the secondary prevention of stroke, we find that the current individual variability of blood pressure is associated with the risk of CVD and death. Moreover, the comparison with a model without heterogeneous variance shows the importance of taking into account this variability in the goodness-of-fit and for dynamic predictions.

MIG Migueis, ILS Pinto, LR Borges et al.

Introdução: O mesilato de imatinibe (MI) é o primeiro inibidor oral de tirosina quinase que atua impedindo a proliferação celular da linhagem de células mieloides que expressam o gene BCR-ABL, sendo usado no tratamento de Leucemia Mieloide Crônica (LMC). O advento dos inibidores da tirosina quinase (ITQ) revolucionou o tratamento destes pacientes no alcance de remissões citogenéticas e moleculares duráveis e melhora da sobrevida. Os ITQs apresentam efeitos colaterais leves relatados como citopenias, edemas, efeitos gastrointestinais, insuficiência cardíaca, hepatotoxicidade e raramente manifestações neurológicas. Esse caso visa estabelecer a relação do processo de desmielinização do sistema nervoso central (SNC) ocorrendo após o início do tratamento com MI. Objetivo: Apresentar um caso de neurite óptica (NO) devido ao uso crônico de MI no tratamento de LMC. Material e métodos: Relato de caso, os dados foram obtidos por meio de revisão do prontuário. Resultado: Paciente do sexo masculino, 68 anos, com diagnostico de LMC fase crônica (FC) em dezembro de 2013, iniciou tratamento no mesmo mês com imatinibe, 400 mg ao dia e obteve resposta molecular (RM) profunda. Em fevereiro de 2021, apresentou redução da acuidade visual bilateralmente. Ao exame apresentava acuidade visual reduzida, com apenas percepção de luz em olho esquerdo (OE), ausência de reflexos pupilares e no fundo de olho observou-se palidez de papila bilateralmente, sugerindo o diagnóstico de NO. Feita RM de crânio e órbitas com contraste, visualizada assimetria dos nervos ópticos, notando-se afilamento e hipersinal em T2 à direita, sem realce de contraste, sugerindo sequela de neurite. Realizada extensa investigação com a neurologia e oftalmologia, feito avaliação de líquor sem alterações. Foram excluídas causas autoimunes, infecciosas e inflamatórias como possíveis diagnósticos para o quadro. Optado pela suspensão do MI e iniciado pulsoterapia com metilprednisolona por 5 dias. Apresentou reversão parcial do quadro em olho direito e manteve amaurose em OE. Realizado troca de ITQ para dasatinibe em março de 2021. Após a troca do ITQ, manteve estabilidade do quadro. Discussão: Os ITQs são drogas promissoras no tratamento da LMC com a maioria dos pacientes atingindo RM maior em uso dessas. O MI apresenta boa eficácia e tolerabilidade como terapia de primeira linha. Seu uso está associado à toxicidade hematológica, gastrintestinal, cardíaca, renal e hepatoxicidade. As manifestações neurológicas são raras, podendo ocorrer em qualquer momento do tratamento e permanecendo após sua interrupção, sugerindo risco cumulativo de neurotoxicidade. A NO é caracterizada por uma condição inflamatória e desmielinizante do nervo óptico, levando a perda visual aguda monocular. As manifestações clínicas mais recorrentes são a perda repentina da visão e a dor periorbitária e retroorbitária, principalmente durante a movimentação dos olhos. A NO pode estar associada a infecções, fármacos e doenças autoimunes. O caso citado sugere potencial relação entre MI e o processo de desmielinização. Seu mecanismo de ação permanece incerto. Poucos estudos descrevem a associação entre NO e MI. Conclusão: Este trabalho apresentou um caso raro de NO relacionada ao uso crônico de MI, na ausência de outros fatores de risco. Oferecendo evidências clínicas da associação de ITQ com neurotoxicidade, embora não possa estabelecer a causa. Mais estudos são necessários para elucidar a potencial relação do uso de MI com a NO.

Carlos Jimenez-Vicente, Francesca Guijarro, Monica Lopez-Guerra et al.

LFM Fontes, LSL Vieira, GLT Caneschi et al.

Introdução: A lesão pulmonar aguda relacionada à transfusão (TRALI), reação que pode ocorrer dentro de 6 horas, é uma condição rara e que há indícios do envolvimento de anticorpos anti-antígeno leucocitário humano (HLA) e anti-antígeno neutrofílico humano (HNA). Objetivos: Avaliar, por meio de uma revisão sistemática, pacientes que tiveram TRALI e a sua associação com anticorpos anti-HLA e anti-HNA do doador ou receptor. Material e métodos: Para a seleção dos estudos, foi utilizada a base de dados MedLine aplicando os filtros case reports, english, 10 years e usando as seguintes palavras chaves e suas respectivas variações no DeCS/MeSH: Transfusion-Related Acute Lung Injury; HLA Antigens; HNA Antigens. Foram incluídos estudos que relacionavam a TRALI e a presença de anticorpos anti-HLA e anti-HNA no doador ou receptor e excluídos estudos sem dados completos. A partir disso, três artigos foram selecionados para compor o escopo dessa revisão. Resultados: Os estudos envolveram 10 pacientes com TRALIsendo cinco mulheres e cinco homens. Em relação ao sangue do doador, ocorreram cinco casos de TRALI causados por uma doadora multípara anti-HNA positiva que nunca recebeu transfusão. Por outro lado, em cinco pacientes receptores foram encontrados anti-HLA prévios no plasma sendo que um caso ocorreu em uma mulher multípara que recebeu soro de doador com anti-HLA. Por fim, essa revisão não discrimina se os casos de TRALI foram provenientes dos anticorpos do doador, receptor ou ambos. Discussão: Os resultados ratificam que a fisiopatologia envolve anticorpos anti-HLA e anti-HNA do doador, predisposição individual e desenvolvimento de aloanticorpos (TRALI reversa). Por outro lado, receptoras multíparas poderiam estar em maior risco de desenvolver TRALI reversa ressaltando a importância da triagem também nos receptores. Conclusão: Essa revisão evidenciou que a fisiopatologia da TRALI é mediada por anticorpos anti-HLA e anti-HNA destacando a necessidade de triagem não só nos doadores como também nos receptores para mitigar a ocorrência de TRALI.

HP Vicari, RC Gomes, K Lima et al.

Objetivos: Em estudos anteriores, nosso grupo de pesquisa identificou um composto sintético inédito derivado da classe dos ciclopenta[b]indois que apresentou citotoxicidade seletiva em modelos celulares de leucemia promielocítica aguda através da interrupção da dinâmica de microtúbulos. No presente estudo, nós expandimos a investigação dos efeitos celulares e moleculares do ciclopenta[b]indol C2 sobre o fenótipo leucêmico de um amplo painel, molecularmente heterogêneo, de linhagens celulares de leucemias agudas. Material e métodos: Um painel contendo 13 linhagens celulares de neoplasias mieloides e 12 linfoides foi utilizado. As linhagens Kasumi-1, MV4-11, Jurkat e Namalwa foram selecionadas para análises adicionais detalhadas. Dois enantiômeros de C2 foram utilizados (C2E1 e C2EB). A viabilidade celular foi avaliada por MTT e a clonogenicidade por ensaio de formação de colônias. Por citometria de fluxo foram avaliados a apoptose (marcação com anexina V/iodeto de propídio [IP]) e o ciclo celular (marcação com IP). A morfologia celular foi avaliada por coloração H&E e microscopia óptica. Os marcadores moleculares de proliferação (STMN1), apoptose (PARP1) e dano ao DNA (γH2AX) foram investigados por Western Blot. Experimentos de re-docagem e docagem molecular dos ligantes colchicina, C2E1 e C2EB foram realizados utilizando os dímeros de α/β-tubulina como receptor (PDB:4O2B) através dos softwares Autodock Vina e Gold. As análises estatísticas foram realizadas por ANOVA e pós-teste de Bonferroni. Um valor de p < 0,05 foi considerado significativo. Resultados: O C2E1 apresentou alta citotoxicidade em células malignas do sangue e apenas 4 das 25 células foram consideradas resistentes ao composto (IC50 > 50 μM). O C2EB não apresentou atividade citotóxica considerável nos modelos testados e 19 das 25 linhagens foram consideradas resistentes. As análises de docagem molecular indicam que apenas o C2E1 apresenta maior sobreposição na região de ancoramento do anel A da colchicina, o que pode ser a causa para baixa atividade do C2EB. Sendo assim, apenas o composto C2E1 foi utilizado nos ensaios posteriores. O C2E1 apresentou efeito citotóxico dependente de concentração e tempo (IC50 variou de 1,8 a 31,5 μM em 72 h). Em células de leucemia aguda, o composto C2E1 diminuiu a clonogenicidade, induziu apoptose, resultou no acúmulo de células em subG1 e parada do ciclo celular na fase G2/M após 48 h de exposição ao fármaco (todos p < 0,05). As análises morfológicas indicaram aberrações mitóticas nas células tratadas. O C2E1 aumentou a fosforilação e reduziu a expressão de STMN1 e elevou a expressão de PARP1 clivada e γH2AX. Discussão: Nossos resultados evidenciaram que o composto inédito derivado da classe dos ciclopenta[b]indois reduziu a viabilidade de células de leucemia aguda. No cenário molecular, C2E1 reduziu marcadores de proliferação (STMN1) e induziu marcadores de apoptose (PARP1 clivada) e dano no DNA (γH2AX). Portanto, o composto indólico C2E1 mostrou-se capaz reproduzir seu mecanismo de ação inicialmente caracterizado, sendo este o colapso mitótico gerado pela perturbação da dinâmica de microtúbulos. Conclusão: Nosso estudo apresentou evidências pré-clínicas de uma nova classe de inibidores de microtúbulos como potencial opção terapêutica em neoplasias hematológicas. Apoio: FAPESP, CNPq e CAPES.

Setti Sudharsan Meenambiga, Punniavan Sakthiselvan, Sowmya Hari et al.

Stephen C. Anco, Almudena P. Marquez, Tamara M. Garrido et al.

Two aspects of a widely used 1D model of blood flow in a single blood vessel are studied by symmetry analysis, where the variables in the model are the blood pressure and the cross-section area of the blood vessel. As one main result, all travelling wave solutions are found by explicit quadrature of the model. The features, behaviour, and boundary conditions for these solutions are discussed. Solutions of interest include shock waves and sharp wave-front pulses for the pressure and the blood flow. Another main result is that three new conservation laws are derived for inviscid flows. Compared to the well-known conservation laws in 1D compressible fluid flow, they describe generalized momentum and generalized axial and volumetric energies. For viscous flows, these conservation laws get replaced by conservation balance equations which contain a dissipative term proportional to the friction coefficient in the model.