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Introduction: With depression's growing global prevalence and substantial impact, effective prevention and management strategies are imperative. Our study aims to perform a thorough bibliometric analysis of existing research on the impact of exercise on depression. Methods: A comprehensive analysis of Web of Science Core Collection publications from 2000 to 2020 was performed, highlighting trends, themes, and influential authors. The study focused on subject categories, source journals, countries/regions, institutions, and prolific authors. Co-citation and keyword analyses revealed key themes, hotspots and the thematic evolution. Results: The multidisciplinary nature of this research is evident across psychiatry, psychology, neuroscience, and sports science. Specific populations such as women, the elderly, and those with chronic illnesses were targeted. Mind-body exercises like yoga and tai chi gained prominence. Co-citation clusters showcased the evolution from early investigations on exercise's impact to recent dose-response and protocol studies. Conclusions: This bibliometric analysis provides insights into the dynamic field of exercise interventions for depression. It underscores the importance of individual differences, calls for guidelines considering comorbidities, and points towards future directions such as exploring mind-body exercise mechanisms and well-designed clinical trials. This study contributes to a comprehensive understanding of the research landscape and informs future endeavors aimed at refining depression treatment through exercise interventions.
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In this study, we analyzed the clinical efficacy of Zishen Yutai pills (ZSYTP) combined with metformin hydrochloride on infertile women diagnosed with polycystic ovary syndrome (PCOS) undergoing in vitro fertilization and embryo transfer (IVF-ET). Patients were assigned into 3 groups: the ZSYTP group (nâ =â 50), the metformin group (nâ =â 50), and the combination group (ZSYTP combined with metformin hydrochloride, nâ =â 50), based on their respective and the indicated treatments before undergoing IVF-ET. Then, their glucose metabolism indices, sex hormone indices, traditional Chinese medicine (TCM) syndrome scores, and outcomes of IVF-ET were compared. Baseline characteristics were not significantly different between the 2 groups. After treatment, various parameters such as body mass index (BMI), fasting plasma glucose (FPG), fasting insulin (FIN), homeostatic model assessment of insulin resistance (HOMA-IR), luteinizing hormone (LH), estradiol (E2), follicle-stimulating hormone (FSH), testosterone (T) levels, and TCM syndrome scores were found to be reduced compared to pretreatment levels in both groups. Moreover, the improvement observed in the treatment group exceeded that of the control group. Specifically, the observation group displayed significantly lower gonadotropin (Gn) dosage and duration, as well as a reduced abortion rate compared to the control group. Furthermore, the observation group had higher numbers of obtained eggs, high-quality embryos, eggs obtained through IVF-ET, average transferred embryos, clinical pregnancy rate, and embryo implantation rate compared to the control group. Pretreatment with ZSYTP combined with metformin before IVF-ET in PCOS patients improves the outcome of IVF-ET.
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Quimioterapia Combinada , Medicamentos de Ervas Chinesas , Fertilização in vitro , Hipoglicemiantes , Metformina , Síndrome do Ovário Policístico , Humanos , Síndrome do Ovário Policístico/tratamento farmacológico , Síndrome do Ovário Policístico/complicações , Feminino , Metformina/uso terapêutico , Metformina/administração & dosagem , Fertilização in vitro/métodos , Adulto , Medicamentos de Ervas Chinesas/uso terapêutico , Medicamentos de Ervas Chinesas/administração & dosagem , Gravidez , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/administração & dosagem , Infertilidade Feminina/tratamento farmacológico , Infertilidade Feminina/etiologia , Infertilidade Feminina/terapia , Transferência Embrionária/métodos , Taxa de Gravidez , Glicemia/efeitos dos fármacos , Resultado do TratamentoRESUMO
Chemically activated biochar is effective in supercapacitors and water splitting, but low conductivity hinders its application as a carbon support in carbon dioxide reduction reaction (CO2RR). Based on the observed CO2RR performance from potassium hydroxide (KOH)-activated biochar, increased microporosity was hypothesized to enhance the performance, leading to selection of potassium carbonate (K2CO3) for activation. K2CO3 activation at 600â increased microporosity significantly, yielding a total Faradaic efficiency of 72%, compared to 60% with KOH at 800â. Further refinement of thermal ramping rate enriched micropore content, directly boosting FEC to 82%. Additionally, K2CO3's lower activation temperature could preserve hydroxyl groups to improve ethylene selectivity. These findings demonstrate that optimizing microporosity and surface chemistry is critical for designing activated biochar-based CO2RR electrocatalysts. Despite lower electrical conductivity of activated biochar, selecting the appropriate activating agents and conditions can make it a viable alternative to carbon black-based electrocatalysts.
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Non-Hermitian degeneracies reveal intriguing and nontrivial behaviors in open physical systems. Examples like parity-time (PT) symmetry breaking, topological encircling chirality, and enhanced sensing near an exceptional point (EP) are often associated with the abrupt nature of the phase transition around these degeneracies. Here we experimentally observe a cavity-enhanced second-harmonic frequency (SHG) conversion on a PT symmetry line, i.e., a set consisting of open-ended isofrequency or isoloss lines, both terminated at EPs on the Riemann surface in parameter space. The enhancement factor can reach as high as 300, depending on the crossing point whether in the symmetry or the broken phase of the PT line. Moreover, such enhancement of SHG enables sensitive distance sensing with a nanometer resolution. Our works may pave the way for practical applications in sensing, frequency conversion, and coherent wave control.
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OBJECTIVES: Pregnancy outcomes of different ovarian stimulation protocols for in vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI) in patients with adenomyosis are not explicit. This meta-analysis aimed to systematically evaluate the effects of different IVF/ICSI protocols on pregnancy outcomes. DESIGN: Meta-analysis. DATA SOURCES: PubMed, Web of Science and Cochrane library were searched up to October 2023. ELIGIBILITY CRITERIA: Comparative studies on IVF/ICSI outcomes in the adenomyosis population were eligible. Studies on preimplantation genetic testing, reviews, case reports and animal experiments were excluded. DATA EXTRACTION AND SYNTHESIS: Valid information was extracted by two independent authors according to a standard data format. All analyses were conducted using Review Manager (RevMan, V.5.3). RESULTS: Compared with the non-adenomyosis population, adenomyosis was responsible for a 26% reduction in clinical pregnancy rate (CPR; 42.47% vs 55.89%, OR: 0.74, 95% CI: 0.66 to 0.82, p<0.00001), a 35% reduction in live birth rate (LBR; 30.72% vs 47.77%, OR: 0.65, 95% CI: 0.58 to 0.73, p<0.00001) and a 1.9-fold increase in miscarriage rate (MR; 27.82% vs 13.9%, OR: 1.90, 95% CI: 1.56 to 2.31, p<0.00001). Subgroup analysis suggested that, in fresh embryo transfer (ET) cycles, the CPR (34.4% vs 58.25%) in the long/short/antagonist protocol group was poorer than that in the ultralong protocol group. In frozen ET (FET) cycles, there were no statistical differences in CPR ((GnRHa+FET) AM(adenomyosis) vs non-AM: 51.32% vs 43.48%, p=0.31; (non-GnRHa+FET) AM vs non-AM: 50.25% vs 60.10%, p=0.82), MR ((GnRHa+FET) AM vs non-AM:12.82% vs 12.50%, p=0.97; (non-GnRHa+FET) AM vs non-AM: 30.5% vs 15.54%, p=0.15) and LBR ((GnRHa+FET) AM vs non-AM:44.74% vs 36.96%, p=0.31; (non-GnRHa+FET) AM vs non-AM: 34.42% vs 50.25%, p=0.28). The MR in the adenomyosis group was high in the fresh ET and FET cycles. CONCLUSIONS: FET might be a better choice for women with adenomyosis, especially those pretreated with GnRHa. In fresh ET cycles, pregnancy outcomes of the long/short/antagonist protocols were poorer than those of the ultralong protocol. TRIAL REGISTRATION NUMBER: CRD42022340743.
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Adenomiose , Fertilização in vitro , Taxa de Gravidez , Injeções de Esperma Intracitoplásmicas , Humanos , Feminino , Adenomiose/terapia , Gravidez , Injeções de Esperma Intracitoplásmicas/métodos , Fertilização in vitro/métodos , Resultado da Gravidez , Indução da Ovulação/métodos , Infertilidade Feminina/terapiaRESUMO
BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra (SN). Activation of the neuroinflammatory response has a pivotal role in PD. Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic approach for various nerve injuries, but there are limited reports on their use in PD and the underlying mechanisms remain unclear. METHODS: We investigated the effects of clinical-grade hypoxia-preconditioned olfactory mucosa (hOM)-MSCs on neural functional recovery in both PD models and patients, as well as the preventive effects on mouse models of PD. To assess improvement in neuroinflammatory response and neural functional recovery induced by hOM-MSCs exposure, we employed single-cell RNA sequencing (scRNA-seq), assay for transposase accessible chromatin with high-throughput sequencing (ATAC-seq) combined with full-length transcriptome isoform-sequencing (ISO-seq), and functional assay. Furthermore, we present the findings from an initial cohort of patients enrolled in a phase I first-in-human clinical trial evaluating the safety and efficacy of intraspinal transplantation of hOM-MSC transplantation into severe PD patients. RESULTS: A functional assay identified that transforming growth factor-ß1 (TGF-ß1), secreted from hOM-MSCs, played a critical role in modulating mitochondrial function recovery in dopaminergic neurons. This effect was achieved through improving microglia immune regulation and autophagy homeostasis in the SN, which are closely associated with neuroinflammatory responses. Mechanistically, exposure to hOM-MSCs led to an improvement in neuroinflammation and neural function recovery partially mediated by TGF-ß1 via activation of the anaplastic lymphoma kinase/phosphatidylinositol-3-kinase/protein kinase B (ALK/PI3K/Akt) signaling pathway in microglia located in the SN of PD patients. Furthermore, intraspinal transplantation of hOM-MSCs improved the recovery of neurologic function and regulated the neuroinflammatory response without any adverse reactions observed in patients with PD. CONCLUSIONS: These findings provide compelling evidence for the involvement of TGF-ß1 in mediating the beneficial effects of hOM-MSCs on neural functional recovery in PD. Treatment and prevention of hOM-MSCs could be a promising and effective neuroprotective strategy for PD. Additionally, TGF-ß1 may be used alone or combined with hOM-MSCs therapy for treating PD.
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Modelos Animais de Doenças , Células-Tronco Mesenquimais , Mucosa Olfatória , Doença de Parkinson , Fator de Crescimento Transformador beta1 , Animais , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Transplante de Células-Tronco Mesenquimais/métodos , Doença de Parkinson/complicações , Doença de Parkinson/terapia , Recuperação de Função Fisiológica , Fator de Crescimento Transformador beta1/metabolismoRESUMO
Transposable elements (TEs), comprising nearly 50% of the human genome, have transitioned from being perceived as "genomic junk" to key players in cancer progression. Contemporary research links TE regulatory disruptions with cancer development, underscoring their therapeutic potential. Advances in long-read sequencing, computational analytics, single-cell sequencing, proteomics, and CRISPR-Cas9 technologies have enriched our understanding of TEs' clinical implications, notably their impact on genome architecture, gene regulation, and evolutionary processes. In cancer, TEs, including long interspersed element-1 (LINE-1), Alus, and long terminal repeat (LTR) elements, demonstrate altered patterns, influencing both tumorigenic and tumor-suppressive mechanisms. TE-derived nucleic acids and tumor antigens play critical roles in tumor immunity, bridging innate and adaptive responses. Given their central role in oncology, TE-targeted therapies, particularly through reverse transcriptase inhibitors and epigenetic modulators, represent a novel avenue in cancer treatment. Combining these TE-focused strategies with existing chemotherapy or immunotherapy regimens could enhance efficacy and offer a new dimension in cancer treatment. This review delves into recent TE detection advancements, explores their multifaceted roles in tumorigenesis and immune regulation, discusses emerging diagnostic and therapeutic approaches centered on TEs, and anticipates future directions in cancer research.
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Experimental decoupling of the effects of plasmon resonance energy transfer (PRET) and metal-enhanced fluorescence (MEF) within the same nanometal-fluorophore pair is fascinating but challenging. In this study, we presented a possible solution for this by coating plasmonic Au nanoparticles (AuNPs) with temperature-sensitive poly(N-isopropylacrylamide) (pNIPAM) shells and R6G hybrids, termed the Au@p-R nanoplatform, which could reversibly adjust the separation between dyes and the AuNP surface, enabling an ON/OFF switch between MEF and PRET. In our optimization process, we discovered that 20 kDa of pNIPAM causes an MEF effect owing to an appropriate shrinking distance of 6.86 ± 0.85 nm. This dual-model nanoplatform exhibits great potential for tracking temperature-dependent transitions.
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A photonic topological insulator features robust directional propagation and immunity to defect perturbations of the edge/surface state. Exciton-polaritons, that is, the hybrid quasiparticles of excitons and photons in semiconductor microcavities, have been proposed as a tunable nonlinear platform for emulating topological phenomena. However, mainly due to excitonic material limitations, experimental observations so far have not been able to enter the nonlinear condensation regime or only show localized condensation in one dimension. Here we show a topological propagating edge state with polariton condensation at room temperature and without any external magnetic field. We overcome material limitations by using excitonic CsPbCl3 halide perovskites with a valley Hall lattice design. The polariton lattice features a large bandgap of 18.8 meV and exhibits strong nonlinear polariton condensation with clear long-range spatial coherence across the critical pumping density. The geometric parameters and material composition of our nonlinear many-body photonic system platform can in principle be tailored to study topological phenomena of other interquasiparticle interactions.
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BACKGROUND: Quality study monitoring is fundamental to patient safety and data integrity. Regulators and industry consortia have increasingly advocated for risk-based monitoring (RBM) and central statistical monitoring (CSM) for more effective and efficient monitoring. Assessing which statistical methods underpin these approaches can best identify unusual data patterns in multi-center clinical trials that may be driven by potential systematic errors is important. METHODS: We assessed various CSM techniques, including cross-tests, fixed-effects, mixed-effects, and finite mixture models, across scenarios with different sample sizes, contamination rates, and overdispersion via simulation. Our evaluation utilized threshold-independent metrics such as the area under the curve (AUC) and average precision (AP), offering a fuller picture of CSM performance. RESULTS: All CSM methods showed consistent characteristics across center sizes or overdispersion. The adaptive finite mixture model outperformed others in AUC and AP, especially at 30% contamination, upholding high specificity unless converging to a single-component model due to low contamination or deviation. The mixed-effects model performed well at lower contamination rates. However, it became conservative in specificity and exhibited declined performance for binary outcomes under high deviation. Cross-tests and fixed-effects methods underperformed, especially when deviation increased. CONCLUSION: Our evaluation explored the merits and drawbacks of multiple CSM methods, and found that relying on sensitivity and specificity alone is likely insufficient to fully measure predictive performance. The finite mixture method demonstrated more consistent performance across scenarios by mitigating the influence of outliers. In practice, considering the study-specific costs of false positives/negatives with available resources for monitoring is important.
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Área Sob a Curva , Simulação por Computador , Modelos Estatísticos , Estudos Multicêntricos como Assunto , Humanos , Estudos Multicêntricos como Assunto/métodos , Interpretação Estatística de Dados , Projetos de Pesquisa , Tamanho da AmostraRESUMO
Background: Previous studies have showed that lycorine can restrain the development of multiple tumor types, containing hepatocellular carcinoma (HCC), but the underlying mechanisms remain unknown. Methods: We assessed the impact of lycorine on hepatocellular cancer cell proliferation, migration, colony formation, cell cycle, and apoptosis. The possible inhibitory effect of lycorine on the activity of HCC cells was analyzed by RNA-seq, and transketolase (TKT) expression in HCC and nontumorous tissues was detected using RT-PCR. The expression of TKT protein in HCC and tumor adjacent non-cancerous tissues was detected by immunohistochemistry. We evaluated the association of expression of TKT in HCC tissues with prognosis, and investigated the inhibitory effect of lycorine on tumor growth in vivo. Results: Lycorine significantly inhibited the proliferation, invasion, migration, colony formation, cell cycle of HCC cells, but had no obvious impact on apoptosis. Twenty-eight genes were found to be down-regulated in HuH7 and HepG2 cells after lycorine treatment, and the difference of TKT gene expression was significantly. The expression of TKT protein was significantly higher in HCC than in non-tumorous tissues. The expression of TKT was correlated with tumor size, Edmondson grade, AFP, and overall survival. Survival analysis suggested that high expression of TKT was associated with a poor survival. The average tumor volume and weight were significantly reduced in the lycorine injection group, but the body weights of the mice did not change significantly. Conclusion: Lycorine can restrict the migration and proliferation of HCC cells by down-regulating TKT expression, and it may be a potential meaningful drug for the prevention and treatment of HCC.
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A new naphtho-γ-pyrone dimer, asperosperma A, and a new methyl nicotinate derivative, asperosperma B, with 12 known compounds were isolated from the endophytic fungus Aspergillus niger from the stem of Camellia flavida. Their structure was elucidated by NMR, ECD spectrum, and HR-ESI-MS data. Asperosperma A exhibited a highly cytotoxicity against H460 and 4T1 cancer cells with the IC50 values were 0.37 ± 0.06 and 2.04 ± 0.79 µM, respectively. Moreover, it showed a highly sensitive against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and methicillin-resistant S. aureus.
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Although schizophrenia patients exhibit structural abnormalities in the striatum, it remains largely unknown for the role of the striatum subregions in the treatment response of antipsychotic drugs. The purpose of this study was to investigate the associations between the striatal subregions and improved clinical symptoms in first-episode drug-naïve (FEDN) schizophrenia. Forty-two FEDN schizophrenia patients and 29 healthy controls (HCs) were recruited. At baseline, the Positive and Negative Syndrome Scale (PANSS) was used to assess the clinical symptoms of patients, MRI scanner was used to obtain anatomical images of patients and HCs. After 12-week stable doses of risperidone treatment, clinical symptoms were obtained in 38 patients and anatomical images in 26 patients. After 12 weeks of treatment, the left nucleus accumbens volume decreased, whereas the left pallidum volume increased in schizophrenia patients. The decreased left nucleus accumbens volume was positively correlated with cognitive factor improvement measured by PANSS. Intriguingly, greater left nucleus accumbens volume at baseline predicted greater cognitive improvements. Furthermore, the responders who had >50 % improvement in cognitive symptoms exhibited significantly greater baseline left nucleus accumbens volume compared to non-responders. The left striatum volume at baseline and after treatment predicted the cognitive improvements in FEDN schizophrenia, which could be a potential biomarker for the development of precision medicine approaches targeting cognitive function.
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MAIN CONCLUSION: Overexpression and loss of function of OsGEX3 reduce seed setting rates and affect pollen fertility in rice. OsGEX3 positively regulates osmotic stress response by regulating ROS scavenging. GEX3 proteins are conserved in plants. AtGEX3 encodes a plasma membrane protein that plays a crucial role in pollen tube guidance. However, the function of its homolog in rice, OsGEX3, has not been determined. Our results demonstrate that OsGEX3 is localized in the plasma membrane and the nucleus as shown by a transiently transformed assay using Nicotiana benthamiana leaves. The up-regulation of OsGEX3 was detected in response to treatments with polyethylene glycol (PEG) 4000, hydrogen peroxide, and abscisic acid (ABA) via RT-qPCR analysis. Interestingly, we observed a significant decline in the seed setting rates of OsGEX3-OE lines and mutants, compared to the wild type. Further investigations reveal that overexpression and loss of function of OsGEX3 affect pollen maturation. TEM observation revealed a significant decrease in the fertile pollen rates of OsGEX3-OE transgenic lines and Osgex3 mutants due to a delay in pollen development at the late vacuolated stage. Overexpression of OsGEX3 improved osmotic stress and oxidative stress tolerance by enhancing reactive oxygen species (ROS) scavenging in rice seedlings, whereas Osgex3 mutants exhibited an opposite phenotype in osmotic stress. These findings highlight the multifunctional roles of OsGEX3 in pollen development and the response to abiotic stress. The functional characterization of OsGEX3 provides a fundamental basis for rice molecular breeding and can facilitate efforts to cultivate drought resistance and yield-related varieties.
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Oryza , Espécies Reativas de Oxigênio/metabolismo , Oryza/fisiologia , Pressão Osmótica , Reprodução , Estresse Oxidativo , Estresse Fisiológico/genética , Plantas Geneticamente Modificadas/genética , Regulação da Expressão Gênica de Plantas , Secas , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismoRESUMO
RATIONALE: Nonsecretory multiple myeloma (NSMM) is a rare subtype of multiple myelom, occurring in 1% to 2% of multiple myelom and characterized by the inability of clonal plasma cells to synthesize or secrete immunoglobulins. We describe a 71-year-old male patient who began with bone pain and was referred to hospital several times, but was not properly diagnosed and effectively treated. PATIENT CONCERNS: A 71-year-old male patient visited our hematology department, complaining of lumbago for 1 year and back pain for half a year. DIAGNOSES: Low-dose whole-body bone computed tomography: multiple bone destruction of the sternum, ribs, multiple vertebrae and accessories of the spine, pelvis, bilateral humerus, and proximal femur. Monoclonal plasma cells accounted for 17.5% of nuclear cells in bone marrow puncture smear. Fluorescence in situ hybridization detected amplification of CKS1B (1q21) gene. Immunofixation electrophoresis negative. About 10.72% of monoclonal plasma cells were detected by flow cytometry. Finally, he was diagnosed with NSMM. INTERVENTIONS: The patients received VCD chemotherapy (bortezomib 1.3 mg/m2, d1, d4, d8, d11; cyclophosphamide 300 mg/m2, d1-2, d8-9; dexamethasone sodium phosphate 20 mg, d1-2, d4-5, d8-9, d11-12, once every 21 days). OUTCOMES: After 2 cycles of VCD treatment, the symptoms of bone pain were significantly relieved, and the efficacy was evaluated as partial response. Follow-up chemotherapy will continue to be completed on schedule. We will continue to follow up to further evaluate the overall survival and progression-free survival. LESSONS: This case shows that NSMM is easily missed or misdiagnosed.
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Mieloma Múltiplo , Masculino , Humanos , Idoso , Mieloma Múltiplo/complicações , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/tratamento farmacológico , Hibridização in Situ Fluorescente , Ciclofosfamida/uso terapêutico , Coluna Vertebral , Dor nas Costas , Bortezomib/uso terapêutico , Dexametasona/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
BACKGROUND: The wounds failing to heal through a timely and orderly standard of care (SOC) treatment are considered as chronic wounds, which add significant burden to healthcare systems around the world. SOC treatment has been commonly applied for management of chronic wounds, but SOC alone may not be adequate to heal all ulcers effectively. Fish skin graft (FSG) is a xenogenic skin substitute which could be used for accelerating skin healing. The current study was performed with the view of evaluating the effectiveness of FSG as an adjuvant treatment of SOC for chronic ulcer treatment. METHODS: Two authors independently searched the following electronic databases: PubMed, Embase, and CENTRAL, using keywords including "diabetic foot ulcer," "fish skin graft," and "wound healing." Clinical studies that evaluated the clinical outcomes of FSG in treatment of chronic ulcers were included in this meta-analysis. Random- or fixed-effect modeled meta-analyses were performed according to the heterogeneity test result (i.e., I2), to analyze the clinical outcome of FSG. RESULTS: A total of 8 studies were included in qualitative synthesis and meta-analysis, with 145 patients treated by SOC and 245 patients treated by SOC plus FSG. There was no significant difference between two groups for time to healing (MD = 1.99, 95% CI: -3.70~7.67, p = 0.493). The complete healing rate was significantly higher in FSG group compared with SOC alone (OR = 3.44, 95% CI: 2.03~5.82, p < 0.001***). Mean percentage area reduction (PAR) was reported in six studies, with a range of 71.6~97.3%. However, many of these studies did not report the value of standard deviation (SD), so we could not pool the data. No significantly different ulcer recurrence rate (RR = 0.60, 95% CI: 0.07~5.27, p = 0.645) and severe adverse events (SAEs) risk (RR = 1.67, 95% CI: 0.42~6.61, p = 0.467) were found between two groups. CONCLUSIONS: The application of FSG treatment for patients with chronic ulcers that do not respond well to SOC management could significantly increase the complete healing rate compared with SOC alone, without increased recurrence rate and SAEs risk.
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Transplante de Pele , Cicatrização , Humanos , Animais , Transplante de Pele/métodos , Doença Crônica , Peixes , Pé Diabético/cirurgia , Resultado do Tratamento , Derme AcelularRESUMO
HER2-positive (HER2+) metastatic breast cancer (mBC) is highly aggressive and a major threat to human health. Despite the significant improvement in patients' prognosis given the drug development efforts during the past several decades, many clinical questions still remain to be addressed such as efficacy when combining different therapeutic modalities, best treatment sequences, interindividual variability as well as resistance and potential coping strategies. To better answer these questions, we developed a mechanistic quantitative systems pharmacology model of the pathophysiology of HER2+ mBC that was extensively calibrated and validated against multiscale data to quantitatively predict and characterize the signal transduction and preclinical tumor growth kinetics under different therapeutic interventions. Focusing on the second-line treatment for HER2+ mBC, e.g., antibody-drug conjugates (ADC), small molecule inhibitors/TKI and chemotherapy, the model accurately predicted the efficacy of various drug combinations and dosing regimens at the in vitro and in vivo levels. Sensitivity analyses and subsequent heterogeneous phenotype simulations revealed important insights into the design of new drug combinations to effectively overcome various resistance scenarios in HER2+ mBC treatments. In addition, the model predicted a better efficacy of the new TKI plus ADC combination which can potentially reduce drug dosage and toxicity, while it also shed light on the optimal treatment ordering of ADC versus TKI plus capecitabine regimens, and these findings were validated by new in vivo experiments. Our model is the first that mechanistically integrates multiple key drug modalities in HER2+ mBC research and it can serve as a high-throughput computational platform to guide future model-informed drug development and clinical translation.
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Neoplasias da Mama , Receptor ErbB-2 , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Humanos , Feminino , Receptor ErbB-2/metabolismo , Receptor ErbB-2/antagonistas & inibidores , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Imunoconjugados/uso terapêutico , Imunoconjugados/farmacologia , Farmacologia em Rede , Modelos Biológicos , Antineoplásicos/uso terapêutico , Antineoplásicos/administração & dosagem , Camundongos , Linhagem Celular Tumoral , Metástase NeoplásicaRESUMO
Triple-negative breast cancer (TNBC) is an aggressive disease characterized by remarkable intratumor heterogeneity (ITH), which poses therapeutic challenges. However, the clinical relevance and key determinant of ITH in TNBC are poorly understood. Here, we comprehensively characterized ITH levels using multi-omics data across our center's cohort (n = 260), The Cancer Genome Atlas cohort (n = 134), and four immunotherapy-treated cohorts (n = 109). Our results revealed that high ITH was associated with poor patient survival and immunotherapy resistance. Importantly, we identified zinc finger protein 689 (ZNF689) deficiency as a crucial determinant of ITH formation. Mechanistically, the ZNF689-TRIM28 complex was found to directly bind to the promoter of long interspersed element-1 (LINE-1), inducing H3K9me3-mediated transcriptional silencing. ZNF689 deficiency reactivated LINE-1 retrotransposition to exacerbate genomic instability, which fostered ITH. Single-cell RNA sequencing, spatially resolved transcriptomics and flow cytometry analysis confirmed that ZNF689 deficiency-induced ITH inhibited antigen presentation and T-cell activation, conferring immunotherapy resistance. Pharmacological inhibition of LINE-1 significantly reduced ITH, enhanced antitumor immunity, and eventually sensitized ZNF689-deficient tumors to immunotherapy in vivo. Consistently, ZNF689 expression positively correlated with favorable prognosis and immunotherapy response in clinical samples. Altogether, our study uncovers a previously unrecognized mechanism underlying ZNF689 deficiency-induced ITH and suggests LINE-1 inhibition combined with immunotherapy as a novel treatment strategy for TNBC.
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Neoplasias de Mama Triplo Negativas , Humanos , Imunoterapia , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/terapia , Fatores de Transcrição/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Resistencia a Medicamentos Antineoplásicos/genéticaRESUMO
Hypoxic-ischemic brain damage (HIBD) frequently induces cognitive impairments. Investigating the role of sevoflurane postconditioning (SPC) in HIBD, we conducted experiments involving HIBD modeling, SPC treatment, and interventions with the PERK inhibitor GSK2656157 or the PERK activator CCT020312, administered 30 min before modeling, followed by SPC treatment. Behavioral testing using the Morris water maze test and Neurological Deficiency Scale (NDS) was conducted. Additionally, Nissl staining assessed hippocampal CA1 area neuronal density, TUNEL staining evaluated hippocampal CA1 area neuronal apoptosis, and Western blot determined hippocampal CA1 area protein levels, including Bax, Bcl-2, p-PERK/PERK, p-eIF2/eIF2, ATF4, CHOP, GRP78, Bax, and Bcl-2 protein levels. Following SPC treatment, HIBD rats exhibited improved spatial learning and memory abilities, reduced neuronal apoptosis, increased neuronal density in the hippocampal CA1 area, elevated Bcl-2 protein level, decreased Bax protein levels, and decreased levels of endoplasmic reticulum stress pathway related proteins (p-PERK/PERK, p-eIF2/eIF2, ATF4, CHOP and GRP78). Pre-modeling treatment with the PERK inhibitor treatment improved outcomes in HIBD rats. However, pre-modeling treatment with the PERK activator CCT020312 counteracted the protective effects of SPC against HIBD in rats. In conclusion, SPC alleviates neuronal apoptosis in the hippocampus CA1 area of HIBD rats by inhibiting the endoplasmic reticulum stress pathway PERK/ATF4/CHOP, thereby mitigating HIBD in rats.
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Chaperona BiP do Retículo Endoplasmático , Estresse do Retículo Endoplasmático , Hipóxia-Isquemia Encefálica , Sevoflurano , Animais , Ratos , Apoptose , Proteína X Associada a bcl-2/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fator de Iniciação 2 em Eucariotos/metabolismo , Fator de Iniciação 2 em Eucariotos/farmacologia , Hipocampo/metabolismo , Hipóxia-Isquemia Encefálica/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos Sprague-Dawley , Sevoflurano/farmacologiaRESUMO
Biomarker discovery is essential for the understanding, diagnosis, targeted therapy and prognosis assessment of malignant diseases. However, it remains a huge challenge due to the lack of sensitive methods to identify disease-specific rare molecules. Here we present MORAC, molecular recognition based on affinity and catalysis, which enables the effective identification of candidate biomarkers with low abundance. MORAC relies on a class of DNAzymes, each cleaving a sole RNA linkage embedded in their DNA chain upon specifically sensing a complex system with no prior knowledge of the system's molecular content. We show that signal amplification from catalysis ensures the DNAzymes high sensitivity (for target probing); meanwhile, a simple RNA-to-DNA mutation can shut down their RNA cleavage ability and turn them into a pure affinity tool (for target pulldown). Using MORAC, we identify previously unknown, low-abundance candidate biomarkers with clear clinical value, including apolipoprotein L6 in breast cancer and seryl-tRNA synthetase 1 in polyps preceding colon cancer.