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The association between sarcopenia and the effectiveness of neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) remains uncertain. This study aims to examine the potential of sarcopenia as a predictive factor for the response to NAC in TNBC, and to assess whether its combination with MRI radiomic signatures can improve the predictive accuracy. We collected clinical and pathological information, as well as pretreatment breast MRI and abdominal CT images, of 121 patients with TNBC who underwent NAC at our hospital between January 2012 and September 2021. The presence of pretreatment sarcopenia was assessed using the L3 skeletal muscle index. Clinical models were constructed based on independent risk factors identified by univariate regression analysis. Radiomics data were extracted on breast MRI images and the radiomics prediction models were constructed. We integrated independent risk factors and radiomic features to build the combined models. The results of this study demonstrated that sarcopenia is an independent predictive factor for NAC efficacy in TNBC. The combination of sarcopenia and MRI radiomic signatures can further improve predictive performance.
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Mammalian hair cells (HCs) are arranged spirally along the cochlear axis and correspond to different frequency ranges. Serving as primary sound detectors, HCs spatially segregate component frequencies into a topographical map. HCs display significant diversity in anatomical and physiological characteristics, yet little is known about the organization of the cochleotopic map of HCs or the molecules involved in this process. Using single-cell RNA sequencing, we determined the distinct molecular profiles of inner hair cells and outer hair cells, and we identified numerous position-dependent genes that were expressed as gradients. Newly identified genes such as Ptn, Rxra, and Nfe2l2 were found to be associated with tonotopy. We employed the SCENIC algorithm to predict the transcription factors that potentially shape these tonotopic gradients. Furthermore, we confirmed that Nfe2l2, a tonotopy-related transcription factor, is critical in mice for sensing low-to-medium sound frequencies in vivo. the analysis of cell-cell communication revealed potential receptor-ligand networks linking inner hair cells to spiral ganglion neurons, including pathways such as BDNF-Ntrk and PTN-Scd4, which likely play essential roles in tonotopic maintenance. Overall, these findings suggest that molecular gradients serve as the organizing principle for maintaining the selection of sound frequencies by HCs.
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Exosomes, nano-sized small extracellular vesicles, have been shown to serve as mediators between intercellular communications by transferring bioactive molecules, such as non-coding RNA, proteins, and lipids from secretory to recipient cells, modulating a variety of physiological and pathophysiological processes. Recent studies have gradually demonstrated that altered exosome charges may represent a key mechanism driving the pathological process of ferroptosis. This review summarizes the potential mechanisms and signal pathways relevant to ferroptosis and then discusses the roles of exosome in ferroptosis. As well as transporting iron, exosomes may also indirectly convey factors related to ferroptosis. Furthermore, ferroptosis may be transmitted to adjacent cells through exosomes, resulting in cascading effects. It is expected that further research on exosomes will be conducted to explore their potential in ferroptosis and will lead to the creation of new therapeutic avenues for clinical diseases.
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Background: Acute myocardial infarction (AMI) is a severe acute coronary syndrome, demonstrating a trend toward affecting younger individuals in recent years. The association between early-onset myocardial infarction and single nucleotide polymorphism necessitates further exploration and evaluation. Case description: We present a case of a patient experiencing early-onset and recurrent myocardial infarction. The patient underwent stent implantation for myocardial infarction at the age of 53 and subsequently encountered two more myocardial infarctions within a span of 16 years. Following interventional therapy, genetic testing was conducted to assess the efficacy of subsequent anti-heart failure medications, with the aim to preemptively address heart failure risks. Genetic testing revealed a mutation in the angiotensin-converting enzyme (ACE) gene (rs577350502, g.63488533C>A), characterized by an intron-deletion single nucleotide variant. Conclusion: While this variant has not been previously reported to be associated with any specific disease, we hypothesize that it may contribute to the susceptibility and risk of myocardial infarction and coronary heart disease in the patient under consideration. This observation underscores the significance of investigating the insertion/deletion polymorphisms of the ACE gene in the context of AMI and emphasizes the necessity for further validation of this variant and other genetic markers associated with AMI in related diseases.
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Targeting the metabolic dependencies of acute myeloid leukemia (AML) cells is a promising therapeutical strategy. In particular, the cysteine and methionine metabolism pathway (C/M) is significantly altered in AML cells compared to healthy blood cells. Moreover, methionine has been identified as one of the dominant amino acid dependencies of AML cells. Through RNA-seq, we found that the two nucleoside analogs 8-chloro-adenosine (8CA) and 8-amino-adenosine (8AA) significantly suppress the C/M pathway in AML cells, and methionine-adenosyltransferase-2A (MAT2A) is one of most significantly downregulated genes. Additionally, mass spectrometry analysis revealed that Venetoclax (VEN), a BCL-2 inhibitor recently approved by the FDA for AML treatment, significantly decreases the intracellular level of methionine in AML cells. Based on these findings, we hypothesized that combining 8CA or 8AA with VEN can efficiently target the Methionine-MAT2A-S-adenosyl-methionine (SAM) axis in AML. Our results demonstrate that VEN and 8CA/8AA synergistically decrease the SAM biosynthesis and effectively target AML cells both in vivo and in vitro. These findings suggest the promising potential of combining 8CA/8AA and VEN for AML treatment by inhibiting Methionine-MAT2A-SAM axis and provide a strong rationale for our recently activated clinical trial.
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Compostos Bicíclicos Heterocíclicos com Pontes , Sinergismo Farmacológico , Leucemia Mieloide Aguda , Metionina Adenosiltransferase , Metionina , S-Adenosilmetionina , Sulfonamidas , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Humanos , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Sulfonamidas/farmacologia , Metionina/metabolismo , Metionina/análogos & derivados , Metionina Adenosiltransferase/metabolismo , Metionina Adenosiltransferase/antagonistas & inibidores , Metionina Adenosiltransferase/genética , Animais , Camundongos , S-Adenosilmetionina/farmacologia , S-Adenosilmetionina/metabolismo , Adenosina/análogos & derivados , Adenosina/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Linhagem Celular TumoralRESUMO
Introduction: Glial fibrillary acidic protein (GFAP) astrocytopathy is a novel autoimmune neurological disorder and is diagnosed by GFAP-IgG in cerebrospinal fluid (CSF) measurement. Case report: Herein, we described a 10-year-old boy with abnormal neurological symptoms and signs. GFAP-IgG was detected in CSF using cell-based assay (CBA), and his CSF showed an increase in lymphocytes, a slight decrease in glucose and an increase in protein level in the early stage. The cranial MRI showed multiple strips of T2-FLAIR hyperintense signal changes on the surface of medulla oblongata, pons, and gyrus in bilateral cerebral hemispheres. He was treated with immunoglobulin (IVIG) and high-dose methylprednisolone pulse treatment, and his clinical presentations gradually improved. Conclusion: We highlight that patients with normal inflammatory markers in peripheral blood have obvious meningitis-like symptoms, and clinicians need to consider GFAP astrocytopathy. The early diagnosis and treatment of GFAP astrocytopathy are important for improving the prognosis.
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The natural healing of diabetic wounds is collectively impeded by multiple factors, including hyperglycemia, angiogenesis disorders, acute oxidative stress, and prolonged inflammation. Although considerable effort has been devoted to solving these problems, the treatment of diabetic wounds remains a major clinical obstacle. In light of this, we developed an innovative wound microenvironment self-adaptive hydrogel to promote the healing of diabetic wounds. The hydrogel was constructed by the crosslinking of 3-aminobenzeneboronic acid (PBA)-modified gelatin (Gel) and polyvinyl alcohol (PVA) by borate ester bonds, which showed high responsiveness to glucose. Meanwhile, the liposomes that encapsulated metformin, L-arginine, and L(+)-ascorbic acid were incorporated into the hydrogel framework. The hydrogel@lipo composite demonstrated shape adaptability, glucose responsiveness, and all-in-one capability, thereby effectively improving the intricate microenvironment of diabetic wounds. In vitro and in vivo experiments demonstrated the ability of hydrogel@lipo to mitigate oxidative stress, enhance angiogenesis, and attenuate inflammatory responses. Consequently, the hydrogel@lipo could accelerate diabetic wound healing (within two weeks). The cumulative findings strongly suggest the potential of hydrogel@lipo as a highly promising therapeutic dressing for advancing diabetic wound recovery.
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Diabetes Mellitus , Hidrogéis , Humanos , Hidrogéis/farmacologia , Arginina , Ácido Ascórbico , GlucoseRESUMO
The therapeutic potential for human type 2 innate lymphoid cells (ILC2s) has been underexplored. Although not observed in mouse ILC2s, we found that human ILC2s secrete granzyme B (GZMB) and directly lyse tumor cells by inducing pyroptosis and/or apoptosis, which is governed by a DNAM-1-CD112/CD155 interaction that inactivates the negative regulator FOXO1. Over time, the high surface density expression of CD155 in acute myeloid leukemia cells impairs the expression of DNAM-1 and GZMB, thus allowing for immune evasion. We describe a reliable platform capable of up to 2,000-fold expansion of human ILC2s within 4 weeks, whose molecular and cellular ILC2 profiles were validated by single-cell RNA sequencing. In both leukemia and solid tumor models, exogenously administered expanded human ILC2s show significant antitumor effects in vivo. Collectively, we demonstrate previously unreported properties of human ILC2s and identify this innate immune cell subset as a member of the cytolytic immune effector cell family.