PARP1 Characterization as a Potential Biomarker for BCR::ABL1 p190+ Acute Lymphoblastic Leukemia.

Detection of t(9;22), and consequent BCR::ABL1 fusion, is still a marker of worse prognosis for acute lymphoblastic leukemia (ALL), with resistance to tyrosine-kinase inhibitor therapy being a major obstacle in the clinical practice for this subset of patients. In this study, we investigated the effectiveness of targeting poly-ADP-ribose polymerase (PARP) in a model of BCR::ABL1 p190+ ALL, the most common isoform to afflict ALL patients, and demonstrated the use of experimental PARP inhibitor (PARPi), AZD2461, as a therapeutic option with cytotoxic capabilities similar to that of imatinib, the current gold standard in medical care. We characterized cytostatic profiles, induced cell death, and biomarker expression modulation utilizing cell models, also providing a comprehensive genome-wide analysis through an aCGH of the model used, and further validated PARP1 differential expression in samples of ALL p190+ patients from local healthcare institutions, as well as in larger cohorts of online and readily available datasets. Overall, we demonstrate the effectiveness of PARPi in the treatment of BCR::ABL1 p190+ ALL cell models and that PARP1 is differentially expressed in patient samples. We hope our findings help expand the characterization of molecular profiles in ALL settings and guide future investigations into novel biomarker detection and pharmacological choices in clinical practice.

PD-1/PD-L1 Inhibition Enhances Chemotherapy-Induced Neuropathic Pain by Suppressing Neuroimmune Antinociceptive Signaling.

Cytotoxic agents synergize with immune checkpoint inhibitors and improve outcomes for patients with several cancer types. Nonetheless, a parallel increase in the incidence of dose-limiting side effects, such as peripheral neuropathy, is often observed. Here, we investigated the role of the programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis in the modulation of paclitaxel-induced neuropathic pain. We found that human and mouse neural tissues, including the dorsal root ganglion (DRG), expressed basal levels of PD-1 and PD-L1. During the development of paclitaxel-induced neuropathy, an increase in PD-L1 expression was observed in macrophages from the DRG. This effect depended on Toll-like receptor 4 activation by paclitaxel. Furthermore, PD-L1 inhibited pain behavior triggered by paclitaxel or formalin in mice, suggesting that PD-1/PD-L1 signaling attenuates peripheral neuropathy development. Consistent with this, we observed that the combined use of anti-PD-L1 plus paclitaxel increased mechanical allodynia and chronic neuropathy development induced by single agents. This effect was associated with higher expression of inflammatory markers (Tnf, Il6, and Cx3cr1) in peripheral nervous tissue. Together, these results suggest that PD-1/PD-L1 inhibitors enhance paclitaxel-induced neuropathic pain by suppressing PD-1/PD-L1 antinociceptive signaling.

Using an experimental model for the study of therapeutic touch.

OBJECTIVE: to verify whether the Paw Edema Model can be used in investigations about the effects of Therapeutic Touch on inflammation by measuring the variables pain, edema and neutrophil migration. METHOD: this is a pilot and experimental study, involving ten male mice of the same genetic strain and divided into experimental and control group, submitted to the chemical induction of local inflammation in the right back paw. The experimental group received a daily administration of Therapeutic Touch for 15 minutes during three days. RESULTS: the data showed statistically significant differences in the nociceptive threshold and in the paw circumference of the animals from the experimental group on the second day of the experiment. CONCLUSION: the experiment model involving animals can contribute to study the effects of Therapeutic Touch on inflammation, and adjustments are suggested in the treatment duration, number of sessions and experiment duration.

Efeito da nicotina sobre fagócitos ativados / Effect of the nicotine on actived phagocytes

Indivíduos fumantes apresentam aumento na proporção de leucócitos polimorfonucleares (LPMN), como por exemplo, no tecido pulmonar, resultando em aumento nos níveis de enzimas proteolíticas e espécies reativas de oxigênio, que ocasionam efeito destrutivo na matriz celular e contribuem para a progressão da doença pulmonar, além de favorecer o aparecimento de infecções microbianas, e determinam que as células fagocíticas estejam em frequente estado de ativação (fagocitose). Neste trabalho, avaliou-se a influência da nicotina (NIC) sobre a viabilidade de LPMN e macrófagos ativados ou não, pelos estímulos zymosan e acetato de forbol miristato. Os resultados indicaram que a NIC promove aumento na viabilidade de LPMN e macrófagos ativados em relação a essas células ativadas sem a presença de NIC, avaliada 'ex vivo' pelo teste de exclusão do azul de trypan. Esse efeito foi significativamente mais pronunciado sobre LPMN que sobre os macrófagos. Essa redução na citotoxicidade favorece a sobrevida da célula, podendo exacerbar os seus efeitos deletérios, especialmente em no seu estado ativado, pela maior produção de espécies reativas de oxigênio.

Smokers show increased rates of polymorphonuclear leukocytes (PMNL), including in pulmonary tissue, resulting increased levels of proteolytic enzymes and reactive oxygen species, which have a destructive effect on the cellular matrix and contribute to the progression of pulmonary disease, in addition to promoting the onset of microbial infections which cause phagocytic cells to be in a state of frequent activation (phagocytosis). This work evaluated the influence of nicotine (NIC) on the viability of PMNL and macrophages (activated or not), by stimuli zymosan and phorbol myristate acetate. The results indicated that NIC led to increased viability of PMNL and activated macrophages compared to these cells activated without NIC, measured ex vivo by trypan blue exclusion test. This effect was significantly higher on PMNL than on macrophages. This reduction in cytotoxicity favors cell survival, and may exacerbate its deleterious effect, especially in the active state, due to increased production of reactive oxygen species.

Using an experimental model for the study of therapeutic touch / Utilização de um modelo experimental para estudo sobre o toque terapêutico / Uso de un modelo experimental para estudio sobre el toque terapéutico

OBJECTIVE: to verify whether the Paw Edema Model can be used in investigations about the effects of Therapeutic Touch on inflammation by measuring the variables pain, edema and neutrophil migration. METHOD: this is a pilot and experimental study, involving ten male mice of the same genetic strain and divided into experimental and control group, submitted to the chemical induction of local inflammation in the right back paw. The experimental group received a daily administration of Therapeutic Touch for 15 minutes during three days. RESULTS: the data showed statistically significant differences in the nociceptive threshold and in the paw circumference of the animals from the experimental group on the second day of the experiment. CONCLUSION: the experiment model involving animals can contribute to study the effects of Therapeutic Touch on inflammation, and adjustments are suggested in the treatment duration, number of sessions and experiment duration.

OBJETIVO: verificar se o modelo de edema de pata pode ser utilizado nas investigações acerca dos efeitos do toque terapêutico sobre a inflamação, mensurando-se as variáveis dor, edema e migração de neutrófilos. MÉTODO: trata-se de estudo piloto, experimental, com 10 camundongos machos da mesma linhagem genética, divididos em grupo experimental e controle, submetidos à indução química de inflamação local na pata direita traseira. O grupo experimental recebeu uma aplicação diária de toque terapêutico com duração de quinze minutos, por três dias. RESULTADOS: os dados evidenciaram diferenças estatisticamente significativas no limiar nociceptivo e na circunferência das patas dos animais do grupo experimental, no segundo dia do experimento. CONCLUSÃO: o modelo de experimento com animal pode contribuir para o estudo dos efeitos do toque terapêutico sobre a inflamação. Sugere-se ajuste no tempo de exposição, número de sessões e tempo de duração do experimento.

OBJETIVO: verificar si el Modelo de Edema de Pata puede ser utilizado en las investigaciones acerca de los efectos del Toque Terapéutico sobre la inflamación, mensurándose las variables dolor, edema y migración de neutrófilos. MÉTODO: se trata de un estudio piloto, experimental, con 10 ratones machos del mismo linaje genético, divididos en grupo experimental y control, sometidos a inducción química de inflamación local en la pata derecha trasera. O grupo experimental recibió una aplicación diaria de Toque Terapéutico con duración de quince minutos, por tres días. RESULTADOS: Los datos evidenciaron diferencias estadísticamente significativas en el umbral de nocicepción y circunferencia de las patas de los animales del grupo experimental durante el segundo día del experimento. CONCLUSIÓN: El modelo de experimento con animal puede contribuir al estudio de los efectos del Toque Terapéutico sobre la inflamación: se sugiere ajuste en el tiempo de exposición, número de sesiones y duración del experimento.