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Hemophilic articular cartilage damage presents a significant challenge for surgeons, characterized by recurrent intraarticular bleeding, a severe inflammatory microenvironment, and limited self-repair capability of cartilage tissue. Currently, there is a lack of tissue engineering-based integrated therapies that address both early hemostasis, anti-inflammation, and long-lasting chondrogenesis for hemophilic articular cartilage defects. Herein, we developed an adhesive hydrogel using oxidized chondroitin sulfate and gelatin, loaded with exosomes derived from bone marrow stem cells (BMSCs) (Hydrogel-Exos). This hydrogel demonstrated favorable injectability, self-healing, biocompatibility, biodegradability, swelling, frictional and mechanical properties, providing a comprehensive approach to treating hemophilic articular cartilage defects. The adhesive hydrogel, featuring dynamic Schiff base bonds and hydrogen bonds, exhibited excellent wet tissue adhesiveness and hemostatic properties. In a pig model, the hydrogel could be smoothly injected into the knee joint cartilage defect site and gelled in situ under fluid-irrigated arthroscopic conditions. Our in vitro and in vivo experiments confirmed that the sustained release of exosomes yielded anti-inflammatory effects by modulating macrophage M2 polarization through the NF-κB pathway. This immunoregulatory effect, coupled with the extracellular matrix components provided by the adhesive hydrogel, enhanced chondrogenesis, promoted the cartilage repair and joint function restoration after hemophilic articular cartilage defects. In conclusion, our results highlight the significant application potential of Hydrogel-Exos for early hemostasis, immunoregulation, and long-term chondrogenesis in hemophilic patients with cartilage injuries. This innovative approach is well-suited for application during arthroscopic procedures, offering a promising solution for addressing the complex challenges associated with hemophilic articular cartilage damage.
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Fluid intelligence is an individual's innate ability to cope with complex situations and is gradually reduced across adults aging. The realization of fluid intelligence requires the simultaneous activity of multiple brain regions and depends on the structural connection of distributed brain regions. Uncovering the structural features of brain connections associated with fluid intelligence decline will provide reference for the development of intervention and treatment programs for cognitive decline. Using structural magnetic resonance imaging data of 454 healthy participants (18-87 years) from the Cam-CAN dataset, we constructed structural similarity network for each participant and calculated the node degree. Spearman correlation analysis showed that age was positively correlated with degree centrality in the cingulate cortex, left insula and subcortical regions, while negatively correlated with that in the orbito-frontal cortex, right middle temporal and precentral regions. Partial least squares (PLS) regression showed that the first PLS components explained 32â¯% (second PLS component: 20â¯%, p perm < 0.001) of the variance in fluid intelligence. Additionally, the degree centralities of anterior insula, supplementary motor area, prefrontal, orbito-frontal and anterior cingulate cortices, which are critical nodes of the multiple-demand network (MDN), were linked to fluid intelligence. Increased degree centrality in anterior cingulate cortex and left insula partially mediated age-related decline in fluid intelligence. Collectively, these findings suggest that the structural stability of MDN might contribute to the maintenance of fluid intelligence.
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This study investigates the relationship between self-rated health, social participation, spouse health, and depressive symptoms in older adults. It also analyzed the moderating effects of gender, drinking, visual function, diet, quality of life, and economic level on the model. We analyzed data from 5119 participants aged 60 and above, from the CLHLS. We used a partial least squares structural equation model to explore the correlation between self-rated health, spouse health, social participation, and depressive symptoms. Self-rated health was significantly correlated with spouse health, social participation, and depressive symptoms (P < 0.001). Social participation (ß=-0.034) and spouse health (ß=-0.029) were mediators of self-rated health to depressive symptoms. In addition, gender, drinking, visual function, diet, quality of life, and economic level were mediated factors. This study provides evidence that self-rated health has direct or indirect associations with depressive symptoms in older people, with social participation and spouse health playing a crucial mediating role.
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Insect transient receptor potential vanilloid (TRPV) channels are critical targets for insecticides. In this study, various scaffold-hopping strategies were employed in the rational design of pyridylhydrazono derivatives as potential insect TRPV channels modulators. Insecticidal bioassay demonstrated that the initial target compounds exhibited lower insecticidal activity compared to pymetrozine, with the optimal compound B3 exhibiting a mortality rate of 53.3% against Aphis craccivora at 400 mg·L-1. Conformation analysis indicated that the high energy barrier required for the transition from the lowest-energy conformation to the active conformation may be a key factor contributing to the reduced insecticidal activities of the target compounds. Further structural optimizations aimed at reducing this energy barrier through binding mode-based conformation regulation led to the identification of optimal target 4-(3'-pyridylhydrazono)pyrazol-5-one derivatives C1 and C2. These compounds exhibited reduced transition energy barriers and improved insecticidal activity, with moderate mortality rate of 66.3% and 75.7% against A. craccivora at 400 mg·L-1, respectively. These findings provide valuable insights for future research on the discovery of insect TRPV modulators and have significant implications for the development of more effective agricultural insecticides.
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BACKGROUND: Web- and mobile-based physical activity interventions effectively promote physical and mental health among older adults, but participation and adherence are suboptimal. METHODS: This qualitative review used the mega-aggregation approach. Searches were conducted in five databases from the earliest to November 2023. Quality assessment and data extraction used JBI tools. Data synthesis used the COM-B model as a guide. RESULTS: Sixteen sub-themes were identified from the eight studies and categorized into the COM-B model. Subthemes were physical and psychological changes, digital skills and knowledge, older adult-friendly design, integration into daily routines, social influence, family engagement and support, health benefits and impairments, accessibility and flexibility, low cost, visibility and interaction, instructions and feedback, personalization and progression, incentives, self-efficacy, visual cues, self-monitoring. DISCUSSION: Web- and mobile-based interventions motivate older adults to engage in physical activity, but modifications are necessary. This includes age-appropriate interfaces and contents, tailored behavioral change techniques, and family engagement.
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Background: Chemotherapy plus immunotherapy has become the standard first-line treatment of advanced or metastatic esophageal squamous cell carcinoma (ESCC), but median duration of response is only 7.0-8.3 months and progression-free survival (PFS, â¼6 months) is still far from satisfactory. We aim to evaluate whether early involvement of radiotherapy might improve the treatment outcome if objective response to first-line chemo-immunotherapy was observed in locally advanced or metastatic ESCC. Methods: Patients were retrospectively collected from 3 institutions in China. Patients with histopathologically confirmed diagnoses of locally advanced or metastatic ESCC were identified, who objectively responded to first-line chemo-immunotherapy (complete or partial response, or stable disease) and also received radiotherapy of primary lesions with radiation dose of over 40 Gy, with or without radiotherapy of metastatic lesions before the first disease progression. Results: A total of 72 eligible patients were identified. With median follow-up duration of 14.6 (range, 7.1-34.8) months, median progression-free survival (PFS) and overall survival (OS) were 13.5 (95 % CI,10.4-NA) months and 31.8 (95 % CI, 23.0-NA) months, respectively. Median duration from initiation of chemo-immunotherapy to radiotherapy was 2.9 (range, 0-15.1) months. Besides lower tumor burden as a significant factor of better treatment outcome, radiation dose ≥ 50 Gy was associated with superior PFS, while OS might be mainly related to tumor response to the induction chemo-immunotherapy. A low incidence of Grade 3 or above treatment-related adverse events were observed (19 %), and no treatment-related death occurred. Conclusion: Our multi-center retrospective study showed survival benefit brought by early involvement of radiotherapy after first-line chemo-immunotherapy for patients with locally advanced or metastatic ESCC. However, further investigation is warranted in future prospective, controlled trials to assess the value of radio-immunotherapy in advanced or metastatic ESCC.
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AIM: To explore frail older adults' preferences and needs regarding mobile health (mHealth) exercise interventions in China. Additionally, it sought to identify the nudge strategies necessary for initiating and sustaining exercise behaviours among frail older adults. DESIGN: A qualitative study. METHOD: The semi-structured interviews were conducted between April and May 2024 from two communities in Changsha, China. The data were analysed using a deductive framework analysis aligned to nudge theory, and an inductive thematic analysis to gather relevant needs and preferences. RESULTS: This study involved 14 participants with pre-frailty or frailty, aged 60-82 years (median age of 64 years). While participants were generally receptive to new technologies, lower levels of health literacy and competing priorities often hindered their participation. Three primary functionality requirements were as follows. (1) Profession engagement: tailored exercise prescription, professional and timely feedback and guidance; (2) personalised knowledge encompassing pain management, successful cases and inspiration; (3) beneficial, tailored, dynamic, fragmented, challenging exercise courses. Participants showed positive attitudes towards simplification nudges, gamification nudges, social nudges, trustworthy nudges, reminder nudges, economic nudges, feedback nudges and pre-commitment nudges. Addressing privacy concerns was essential to build trust and acceptance among older adults. CONCLUSION: These findings emphasised the importance of designing mHealth interventions that address frail older adults' specific needs and preferences while incorporating effective nudge strategies to promote engagement and adherence. Future researchers should explore wearables, ChatGPT language models, virtual coaching assistants, exercise snack to further optimise the experience and analyse the effects of nudges in mHealth exercise interventions among older adults. IMPLICATION FOR THE PROFESSION AND/OR PATIENT CARE: Exercise systems or app development for frail older adults should meet three basic functionality and essential nudge strategies. REPORTING METHOD: The consolidated criteria for reporting qualitative research (COREQ) guidelines were used for reporting. PATIENT OR PUBLIC CONTRIBUTION: Older adults' engagement and interview data contribute a lot.
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Histone deacetylases (HDACs) are highly attractive targets in the drug development process, and the development of subtype-selective HDAC inhibitors is the research direction for HDAC inhibitors. As an important member of the HDAC family, HDAC3 has been found to be closely related to the pathological progression of many diseases due to its abnormal expression. In previous studies, we discovered compound 13a, which has potent inhibitory activity against HDAC1, 2, and 3. In this work, we improved the HDAC3 isotype selectivity of 13a, and obtained compound 9c through rational drug design. 9c shows a selectivity of 71 fold for HDAC3 over HDAC1 and can significantly inhibit the proliferation activity of MV4-11 cells in vitro. Furthermore, when combined with Venetoclax, 9c can effectively induce apoptosis in MV4-11 cells in vitro and reduce the expression of anti-apoptotic proteins, the development of HDAC3 selective inhibitors may serve as a potential lead compound to reverse Venetoclax resistance.
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Antineoplásicos , Apoptosis , Compuestos Bicíclicos Heterocíclicos con Puentes , Proliferación Celular , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores de Histona Desacetilasas , Histona Desacetilasas , Leucemia Mieloide Aguda , Sulfonamidas , Humanos , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/química , Histona Desacetilasas/metabolismo , Sulfonamidas/farmacología , Sulfonamidas/química , Sulfonamidas/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Relación Estructura-Actividad , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Apoptosis/efectos de los fármacos , Estructura Molecular , Línea Celular Tumoral , Relación Dosis-Respuesta a DrogaRESUMEN
HDAC11, as a rising star in the histone deacetylase (HDAC) family, has attracted widespread interest in the biomedical field in recent years specially owing to its high defatty-acylase activity compared its innate deacetylase activity. Numerous studies have provided evidence indicating the crucial involvement of HDAC11 in cancers, immune responses, and metabolic processes. Several potent and selective HDAC11 inhibitors have been discovered and identified, which is crucial for exploring the function of HDAC11 and its potential therapeutic applications. Herein, we present a critical overview of the current advances in the biological function of HDAC11 and its inhibitors. We initially discuss the physiological functions of HDAC11 and its pathological roles in relevant diseases. Subsequently, our main focus centers on the design strategy and development process of HDAC11 inhibitors. Additionally, we address significant challenges and outline future directions in this field. This perspective may provide guidance for the further development of HDAC11 inhibitors and their prospects in disease treatment.
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Inhibidores de Histona Desacetilasas , Histona Desacetilasas , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/síntesis química , Histona Desacetilasas/metabolismo , Humanos , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Estructura Molecular , Animales , Relación Estructura-ActividadRESUMEN
Charge transfer efficiencies in all-inorganic lead halide perovskite nanocrystals (NCs) are crucial for applications in photovoltaics and photocatalysis. Herein, CsPbBr3 NCs with different sizes are synthesized by varying the ligand contents of didodecyl dimethylammonium bromide at room temperature. Adding benzoquinone (BQ) molecules leads to a decrease in the PL intensities and PL decay times in NCs. The electron transfer (ET) efficiency (ηET) increases with NC size in complexes of CsPbBr3 NCs and BQ molecules (NC-BQ complexes), when the same concentration of BQ is maintained, as investigated by transient photobleaching and photoluminescence spectroscopies. Controlling the same number of attached BQ acceptor molecules per NC induces the same ηET in NC-BQ complexes even though with different NC sizes. Our findings provide new insights into ultrafast charge transfer behaviors in perovskite NCs, which is important for designing efficient light energy conversion devices.
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BACKGROUND: Innominate artery aneurysms (IAAs) are rare and may result in rupture, distal arterial embolization, or local compression without timely treatment. Rupture is the most dangerous of these complications. This article reports a case of innominate artery bifurcation pseudoaneurysm. CASE PRESENTATION: The patient was a 45-year-old man who was admitted to the emergency department due to chest discomfort. The computed tomographic angiography (CTA) imaging indicated the presence of a 3.6*2.4 cm saccular aneurysm in the bifurcation of the innominate artery, involving both the right proximal subclavian and common carotid arteries. The patient's vital signs were normal, there was equal blood pressure in the upper arms and no neurological dysfunction was observed. Gadolinium-enhanced magnetic resonance angiography indicated that the circle of Willis was intact. The treatment involved open surgery combined with endovascular therapy. The external carotid artery was first transposed to the right subclavian artery (RSA) and an 8-mm woven Dacron graft was inserted in the middle. The covered stent graft was then placed in the proximal part of the innominate artery to close the entrance of the aneurysm. Lastly, an occluder was implanted at the origin of the RSA. There were no perioperative or postoperative complications. At 1-year follow-up, no aneurysm was observed on CTA and the right vertebral artery was patent. CONCLUSIONS: This study indicated that the combined use of endovascular therapy and open repair surgery is an effective strategy to treat innominate artery bifurcation pseudoaneurysm.
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Aneurisma Falso , Implantación de Prótesis Vascular , Tronco Braquiocefálico , Procedimientos Endovasculares , Stents , Humanos , Masculino , Persona de Mediana Edad , Aneurisma Falso/diagnóstico por imagen , Aneurisma Falso/cirugía , Aneurisma Falso/etiología , Aneurisma Falso/terapia , Tronco Braquiocefálico/diagnóstico por imagen , Tronco Braquiocefálico/cirugía , Procedimientos Endovasculares/instrumentación , Resultado del Tratamiento , Implantación de Prótesis Vascular/instrumentación , Prótesis Vascular , Angiografía por Tomografía Computarizada , Angiografía por Resonancia MagnéticaRESUMEN
Impaired angiogenesis is a major factor contributing to delayed wound healing in diabetes. Dysfunctional mitochondria promote the formation of neutrophil extracellular traps (NETs), obstructing angiogenesis during wound healing. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have shown promise in promoting tissue repair and regeneration in diabetes; however, the precise pathways involved in this process remain unclear. In this study, NET-induced ferroptosis of endothelial cells (ECs) and angiogenesis were assessed in diabetic wound samples from both patients and animal models. In vitro and in vivo experiments were performed to examine the regulatory mechanisms of NETs in ECs using specific inhibitors and gene-knockout mice. MSC-EVs encapsulating dysfunctional mitochondria were used to trigger mitochondrial fusion and restore mitochondrial function in neutrophils to suppress NET formation. Angiogenesis in wound tissue was evaluated using color laser Doppler imaging and vascular density analysis. Wound healing was evaluated via macroscopic analysis and histological evaluation of the epithelial gap. NET-induced ferroptosis of ECs was validated as a crucial factor contributing to the impairment of angiogenesis in diabetic wounds. Mechanistically, NETs regulated ferroptosis by suppressing the PI3K/AKT pathway. Furthermore, MSC-EVs transferred functional mitochondria to neutrophils in wound tissue, triggered mitochondrial fusion, and restored mitochondrial function, thereby reducing NET formation. These results suggest that inhibiting NET formation and EC ferroptosis or activating the PI3K/AKT pathway can remarkably improve wound healing. In conclusion, this study reveals a novel NET-mediated pathway involved in wound healing in diabetes and suggests an effective therapeutic strategy for accelerating wound healing.
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Células Endoteliales , Trampas Extracelulares , Vesículas Extracelulares , Ferroptosis , Células Madre Mesenquimatosas , Cicatrización de Heridas , Animales , Ferroptosis/fisiología , Cicatrización de Heridas/fisiología , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/trasplante , Células Madre Mesenquimatosas/metabolismo , Ratones , Humanos , Células Endoteliales/metabolismo , Trampas Extracelulares/metabolismo , Masculino , Ratones Endogámicos C57BL , Neutrófilos/metabolismo , Mitocondrias/metabolismo , Ratones Noqueados , Fosfatidilinositol 3-Quinasas/metabolismoRESUMEN
Osteosarcoma (OS) is a bone malignant tumor affecting children, adolescents and young adults. Currently, osteosarcoma is treated with chemotherapy regimens established over 40 years ago. The investigation of novel therapeutic strategies for the treatment of osteosarcoma remains an important clinical need. Cyclin-dependent kinases (CDKs) have been considered promising molecular targets in cancer therapy. Among these, CDK12 has been shown to play a crucial role in the pathogenesis of malignancies, but its clinical significance and biological mechanisms in osteosarcoma remain unclear. In the present study, we aim to determine the expression and function of CDK12, and evaluate its prognostic and therapeutic value in metastatic osteosarcoma. We found that overexpression of CDK12 was associated with high tumor grade, tumor progression and reduced patient survival. Underlying mechanism revealed that knockdown of CDK12 expression with siRNA or functional inhibition with the CDK12-targeting agent THZ531 effectively exhibited time- and dose-dependent cytotoxicity. Downregulation of CDK12 paused transcription by reducing RNAP II phosphorylation, interfered with DNA damage repair with increased γH2AX, and decreased cell proliferation through the PI3K-AKT pathway. This was accompanied by the promotion of apoptosis, as evidenced by enhanced Bax expression and reduced Bcl-xL expression. Furthermore, the CDK12 selective inhibitor THZ531 also hindered ex vivo 3D spheroid formation, growth of in vitro 2D cell colony, and prevented cell mobility. Our findings highlight the clinical importance of CDK12 as a potentially valuable prognostic biomarker and therapeutic target in metastatic osteosarcoma.
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Psammaplin A (PsA), a symmetrical bromotyrosine-derived disulfide marine metabolite, has been reported could inhibit HDAC1/2/3 through its thiol monomer. Inspired by the disuflide bond structure of this marine natural product, we designed and synthesized a series of PsA analogues, in which the disulfide bond of PsA was replaced with diselenide bond or cyclic disulfide/diselenide/selenenylsulfide motifs. We also studied the HDAC inhibition, cell growth inhibition, and apoptosis induction of these PsA analogues. The results showed that, all the synthetic diselenide analogues and cyclic selenenyl sulfide compounds exhibited better antiproferative activity than their counterpart of disulfide analogues. Among the prepared analogues, diselenide analogue P-503 and P-116 significantly increased the ability of inhibiting HDAC6 and induced apoptosis and G2/M cell cycle arrest. However, cyclic selenenylsulfides analogues P-111 lost its HDAC inhibitory ability and exhibited no effect on cell cycle and apoptosis, indicating that the anti-proliferative mechanism of cyclic selenenylsulfides analogues has changed.
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Apoptosis , Proliferación Celular , Disulfuros , Inhibidores de Histona Desacetilasas , Histona Desacetilasas , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/química , Disulfuros/química , Disulfuros/farmacología , Disulfuros/síntesis química , Humanos , Apoptosis/efectos de los fármacos , Histona Desacetilasas/metabolismo , Proliferación Celular/efectos de los fármacos , Relación Estructura-Actividad , Estructura Molecular , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Línea Celular Tumoral , Tirosina/análogos & derivadosRESUMEN
Extreme thermal conditions with heat flux densities exceeding 1 MW·m-2 or temperatures reaching up to 1000 °C are prevalent in various situations. However, the ability of thermal protection either depends on specialized materials or is currently limited with existing cooling schemes. Herein, we propose an innovative cooling scheme that relies on evaporation-driven capillary flow enhanced by nanoengineering-designed porous structures with common materials. Experimentally-obtained capillary flow cooling curve identifies critical heat flux corresponding to evaporation-driven flow stage, where coolants cool the surface and subsequent vapor impedes heat transfer from thermal boundaries. Nanoengineering provides opportunities for enhanced capillary flow, which proves to endow bronze, TC4, and Al2O3 with thermal protection ability 50%-180% higher than that without nanoengineering-designed. Our scheme achieves critical heat flux up to 2.0-3.1 MW·m-2, and performs thermal dissipation capacity almost twice higher than inherent latent heat of coolant. Furthermore, in a supersonic wind tunnel with total temperature reaching up to 1792 K, our scheme effectively protects surfaces by cooling them to surface temperatures below 500 K. Nanoengineering-enhanced capillary cooling gives access to the application of common materials for high-temperature and high-heat-flux environments and paves the way for the development of lightweight, long-lasting, and large-scale solutions for thermal protection. This article is protected by copyright. All rights reserved.
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Acute myeloid leukemia (AML) is a hematologic malignancy characterized by infiltration of the blood and bone marrow, exhibiting a low remission rate and high recurrence rate. Current research has demonstrated that class I HDAC inhibitors can downregulate anti-apoptotic proteins, leading to apoptosis of AML cells. In the present investigation, we conducted structural modifications of marine cytotoxin Santacruzamate A (SCA), a compound known for its inhibitory activity towards HDACs, resulting in the development of a novel series of potent class I HDACs hydrazide inhibitors. Representative hydrazide-based compound 25c exhibited concentration-dependent induction of apoptosis in AML cells as a single agent. Moreover, 25c exhibited a synergistic anti-AML effect when combined with Venetoclax, a clinical Bcl-2 inhibitor employed in AML therapy. This combination resulted in a more pronounced downregulation of anti-apoptotic proteins Mcl-1 and Bcl-xL, along with a significant upregulation of the pro-apoptotic protein cleaved-caspase3 and the DNA double-strand break biomarker γ-H2AX compared to monotherapy. These results highlighted the potential of 25c as a promising lead compound for AML treatment, particularly when used in combination with Venetoclax.
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Antineoplásicos , Apoptosis , Compuestos Bicíclicos Heterocíclicos con Puentes , Sinergismo Farmacológico , Inhibidores de Histona Desacetilasas , Leucemia Mieloide Aguda , Sulfonamidas , Humanos , Sulfonamidas/farmacología , Sulfonamidas/química , Leucemia Mieloide Aguda/tratamiento farmacológico , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/química , Histona Desacetilasa 1/antagonistas & inhibidores , Histona Desacetilasas/metabolismo , Animales , Caspasa 3/metabolismo , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/antagonistas & inhibidoresRESUMEN
The efficacy of anthracycline-based chemotherapeutics, which include doxorubicin and its structural relatives daunorubicin and idarubicin, remains almost unmatched in oncology, despite a side effect profile including cumulative dose-dependent cardiotoxicity, therapy-related malignancies and infertility. Detoxifying anthracyclines while preserving their anti-neoplastic effects is arguably a major unmet need in modern oncology, as cardiovascular complications that limit anti-cancer treatment are a leading cause of morbidity and mortality among the 17 million cancer survivors in the U.S. In this study, we examined different clinically relevant anthracycline drugs for a series of features including mode of action (chromatin and DNA damage), bio-distribution, anti-tumor efficacy and cardiotoxicity in pre-clinical models and patients. The different anthracycline drugs have surprisingly individual efficacy and toxicity profiles. In particular, aclarubicin stands out in pre-clinical models and clinical studies, as it potently kills cancer cells, lacks cardiotoxicity, and can be safely administered even after the maximum cumulative dose of either doxorubicin or idarubicin has been reached. Retrospective analysis of aclarubicin used as second-line treatment for relapsed/refractory AML patients showed survival effects similar to its use in first line, leading to a notable 23% increase in 5-year overall survival compared to other intensive chemotherapies. Considering individual anthracyclines as distinct entities unveils new treatment options, such as the identification of aclarubicin, which significantly improves the survival outcomes of AML patients while mitigating the treatment-limiting side-effects. Building upon these findings, an international multicenter Phase III prospective study is prepared, to integrate aclarubicin into the treatment of relapsed/refractory AML patients.
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Aclarubicina , Antraciclinas , Leucemia Mieloide Aguda , Animales , Femenino , Humanos , Masculino , Aclarubicina/farmacología , Aclarubicina/uso terapéutico , Antraciclinas/uso terapéutico , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/efectos adversos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/mortalidad , Resultado del TratamientoRESUMEN
Objectives: To study the frequency, causes, and consequences of seizure-related falls and near falls in LGI1-IgG autoimmune encephalitis. Methods: We retrospectively reviewed 136 patients seen at Mayo Clinic with (1) LGI1-IgG seropositivity, (2) clinical phenotypes compatible with LGI1-IgG autoimmune encephalitis, and (3) falls or near falls related to seizures. The clinical documentation, MRI, and EEG data were collected and reviewed. Results: In this cohort of 136 patients, 27% (n = 36) had falls or near falls related to seizures. The median age was 67 years (range 49-86 years) and 23/36 (64%) were male. Facio-brachio-crural dystonic seizures (21/36, 58%) and drop attacks (9/36, 25%) were the most common causes. Seizure-related falls resulted in injuries in 18/30 (60%), ranging from skin lacerations, joint dislocations, bone fractures to life-threatening intracranial hemorrhage. The injuries occurred most with drop attacks 8/9 (89%). Seizure-related falls or near falls resolved with immunotherapy in 24/32 (75%) whereas the responsiveness to anti-seizure medication alone was poor (4/32, 13%). Discussion: Our study demonstrates that seizure-related falls and near falls are common in LGI1-IgG autoimmune encephalitis. Early diagnosis, prompt immunotherapy initiation, and proper counseling are key to improving functional outcomes and preventing secondary injuries.
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Background: Benign prostatic hyperplasia (BPH) is prevalent among the aging male population and often presents with distressing lower urinary tract symptoms. There is emerging evidence that commercial oral poly-herbal traditional Chinese medicine (TCM) formulation combined with Western medicine (WM) may offer enhanced therapeutic effects compared to WM alone in BPH treatment. Nevertheless, determining the optimal formulations for BPH remains controversial. We aimed to employ a network meta-analysis to compare and assess differences among commonly used and recommended poly-herbal TCM formulations outlined in the Chinese guidelines for BPH treatment, providing clinical medication recommendations and guidance. Methods: We extensively searched for RCTs of BPH patients that had oral poly-herbal TCM formulations and WM treatment, covering both English and Chinese databases up to 31 October 2023. The quality of the included studies was evaluated using the Cochrane risk-of-bias tool Version 2 (ROB2). A Bayesian network meta-analysis was performed to assess the effectiveness of various formulations, followed by sensitivity and subgroup analyses. Results: Our meta-analysis included 107 RCTs involving 11,037 patients across 16 oral poly-herbal TCM formulations. The quality of the selected studies was assessed as "Some concerns". Most formulations combined with WM demonstrated superior therapeutic efficacy compared to WM alone. For clinical effective rate, Jingui Shenqi pill (JGSQ) + WM had the highest-ranking probability (87.38%). Concerning International Prostate Symptom Score (IPSS) and maximum flow rate of urine, Guizhi Fuling capsule (GZFL) + WM was most effective (91.10% and 98.55%). Regarding the quality of life score and postvoid residual urine, Pulean tablet (PLA) + WM ranked first (86.71% and 91.81%). In controlling prostate volume, Huange capsule (HE) + WM demonstrated the highest efficacy (95.65%). Additionally, among the interventions, Lingze (LZ) + WM capsule exhibited the lowest incidence of adverse drug reactions (2.32%). Conclusion: Combining oral poly-herbal TCM formulations with WM may provide greater therapeutic benefits in BPH treatment compared to WM alone. JGSQ, GZFL, PLA, and HE emerged as promising treatment options. However, further rigorous empirical studies are essential to substantiate these findings. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=459651, CRD 42023459651.
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We examined the occurrence and levels of 19 legacy and emerging per- and polyfluoroalkyl substances (PFASs) in 7 species of marine bivalve molluscs collected from four coastal cities of Shandong Province, China. Perfluorooctanoic acid (PFOA) was the most prevalent component, accounting for 68.1 % of total PFASs. The total PFASs in bivalve molluscs ranged from 0.86 to 6.55 ng/g wet weight, with the highest concentration found in Meretrix meretrix L. The concentration of total PFASs in bivalve molluscs showed the following trend: clams > scallops > oysters > mussels. Estimation on the human intake of PFASs from consumption of bivalve molluscs resulted in hazard ratios (HR) ranging from 0.12 to 6.40. Five of the seven species had HR >1, indicating high exposure risks associated with PFASs. Therefore, the occurrence of PFASs in marine biota is particularly concerning and further investigations on the sources of PFASs in Shandong are warranted.