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Hepatic ischemia-reperfusion injury (HIRI) is a critical complication after liver surgery that negatively affects surgical outcomes of patients with the end-stage liver-related disease. Reactive oxygen species (ROS) are responsible for the development of ischemia-reperfusion injury and eventually lead to hepatic dysfunction. Selenium-doped carbon quantum dots (Se-CQDs) with an excellent redox-responsive property can effectively scavenge ROS and protect cells from oxidation. However, the accumulation of Se-CQDs in the liver is extremely low. To address this concern, the fabrication of Se-CQDs-lecithin nanoparticles (Se-LEC NPs) is developed through self-assembly mainly driven by the noncovalent interactions. Lecithin acting as the self-assembly building block also makes a pivotal contribution to the therapeutic performance of Se-LEC NPs due to its capability to react with ROS. The fabricated Se-LEC NPs largely accumulate in the liver, effectively scavenge ROS and inhibit the release of inflammatory cytokines, thus exerting beneficial therapeutic efficacy on HIRI. This work may open a new avenue for the design of self-assembled Se-CQDs NPs for the treatment of HIRI and other ROS-related diseases.
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Pontos Quânticos , Traumatismo por Reperfusão , Selênio , Humanos , Antioxidantes/farmacologia , Espécies Reativas de Oxigênio , Carbono , Lecitinas , Fígado , Traumatismo por Reperfusão/tratamento farmacológicoRESUMO
Background: Human papillomavirus-positive (HPV+) cervical cancers are highly heterogeneous in clinical and molecular characteristics. Thus, an investigation into their heterogeneous immunological profiles is meaningful in providing both biological and clinical insights into this disease. Methods: Based on the enrichment of 29 immune signatures, we discovered immune subtypes of HPV+ cervical cancers by hierarchical clustering. To explore whether this subtyping method is reproducible, we analyzed three bulk and one single cell transcriptomic datasets. We also compared clinical and molecular characteristics between the immune subtypes. Results: Clustering analysis identified two immune subtypes of HPV+ cervical cancers: Immunity-H and Immunity-L, consistent in the four datasets. In comparisons with Immunity-L, Immunity-H displayed stronger immunity, more stromal contents, lower tumor purity, proliferation potential, intratumor heterogeneity and stemness, higher tumor mutation burden, more neoantigens, lower levels of copy number alterations, lower DNA repair activity, as well as better overall survival prognosis. Certain genes, such as MUC17, PCLO, and GOLGB1, showed significantly higher mutation rates in Immunity-L than in Immunity-H. 16 proteins were significantly upregulated in Immunity-H vs. Immunity-L, including Caspase-7, PREX1, Lck, C-Raf, PI3K-p85, Syk, 14-3-3_epsilon, STAT5-α, GATA3, Src_pY416, NDRG1_pT346, Notch1, PDK1_pS241, Bim, NF-kB-p65_pS536, and p53. Pathway analysis identified numerous immune-related pathways more highly enriched in Immunity-H vs. Immunity-L, including cytokine-cytokine receptor interaction, natural killer cell-mediated cytotoxicity, antigen processing and presentation, T/B cell receptor signaling, chemokine signaling, supporting the stronger antitumor immunity in Immunity-H vs. Immunity-L. Conclusion: HPV+ cervical cancers are divided into two subgroups based on their immune signatures' enrichment. Both subgroups have markedly different tumor immunity, progression phenotypes, genomic features, and clinical outcomes. Our data offer novel perception in the tumor biology as well as clinical implications for HPV+ cervical cancer.
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Alphapapillomavirus , Infecções por Papillomavirus , Neoplasias do Colo do Útero , Caspase 7 , Quimiocinas , Citocinas , Feminino , Humanos , NF-kappa B , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/patologia , Fosfatidilinositol 3-Quinases , Receptores de Antígenos de Linfócitos B , Receptores de Citocinas , Fator de Transcrição STAT5 , Proteína Supressora de Tumor p53 , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologiaRESUMO
Background: Both repetitive sacral root magnetic stimulation (rSMS) and transcutaneous posterior tibial nerve stimulation (TTNS) have demonstrated clinical benefits for lower urinary tract dysfunction. However it still remains unclear that which method is more effective and safer to treat neurogenic detrusor overactivity (NDO). Methods: From December 2020 to December 2021, 50 patients (31 men and 19 women, aged 47.9±12.4 years) with NDO secondary to suprasacral spinal cord injury (SCI) were enrolled and randomly allocated to the rSMS or TTNS group based on a computer-generated random numbers table. The stimulation was applied continuously 5 times per week for 20 sessions. Urodynamic test was conducted at baseline and the day after the final 20th treatment session. The primary outcome was the individual change (Δ) in maximum cystometric capacity (MCC) from baseline to post-treatment. Secondary outcomes included changes (Δ) for the following parameters: volume at 1st involuntary detrusor contraction (1st IDCV), maximal detrusor pressure (Pdetmax), bladder compliance (BC), postvoid residual (PVR) volume, and bladder voiding efficiency (BVE). Additionally, adverse reactions including pain and skin irritation during stimulation were observed and recorded as safety outcomes. Results: Finally 47 patients completed the study (23 in rSMS and 24 in TTNS group). A per-protocol (PP) analysis was performed, and Mann-Whitney U test and unpaired t-test were used for statistical analysis. Compared with the efficacy of TTNS, rSMS showed statistically greater ΔMCC [median +43 mL (IQR, 22-62 mL) vs. +20 mL (IQR, 15-25 mL), P=0.001, with a between-group difference of +22 mL (95% CI: +7 to +35 mL)] and ΔBVE [median +10.0% (IQR, 3.8-15.7%) vs. +3.5% (IQR, 0.0-7.8%), P=0.003, with a between-group difference of +5.9% (95% CI: +1.2% to +9.7%)]. No significant differences were found in Δ1st IDCV (P=0.40), ΔPdetmax (P=0.67), ΔBC (P=0.79) and ΔPVR (P=0.92) between the two groups. Meanwhile, patients exhibited high tolerance to both protocols, and no adverse reactions were observed. Conclusions: RSMS may be more effective to improve urodynamics in the treatment for NDO than TTNS, cause it led to a statistical improvement in bladder capacity and voiding efficiency, without any side effects. RSMS is thus worthy of further clinical promotion. Trial Registration: Chinese Clinical Trial Registry ChiCTR2100050663.
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PURPOSE: We present a framework for robust automated treatment planning using machine learning, comprising scenario-specific dose prediction and robust dose mimicking. METHODS: The scenario dose prediction pipeline is divided into the prediction of nominal dose from input image and the prediction of scenario dose from nominal dose, each using a deep learning model with U-net architecture. By using a specially developed dose-volume histogram-based loss function, the predicted scenario doses are ensured sufficient target coverage despite the possibility of the training data being non-robust. Deliverable plans may then be created by solving a robust dose mimicking problem with the predictions as scenario-specific reference doses. RESULTS: Numerical experiments are performed using a data set of 52 intensity-modulated proton therapy plans for prostate patients. We show that the predicted scenario doses resemble their respective ground truth well, in particular while having target coverage comparable to that of the nominal scenario. The deliverable plans produced by the subsequent robust dose mimicking were showed to be robust against the same scenario set considered for prediction. CONCLUSIONS: We demonstrate the feasibility and merits of the proposed methodology for incorporating robustness into automated treatment planning algorithms.
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Terapia com Prótons , Radioterapia de Intensidade Modulada , Humanos , Masculino , Órgãos em Risco , Terapia com Prótons/métodos , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador/métodos , Radioterapia de Intensidade Modulada/métodosRESUMO
Background: Human papillomavirus-positive (HPV+) cervical cancers are highly heterogeneous in molecular and clinical features. However, the molecular classification of HPV+ cervical cancers remains insufficiently unexplored. Methods: Based on the expression profiles of 50 genes having the largest expression variations across the HPV+ cervical cancers in the TCGA-CESC dataset, we hierarchically clustered HPV+ cervical cancers to identify new subtypes. We further characterized molecular, phenotypic, and clinical features of these subtypes. Results: We identified two subtypes of HPV+ cervical cancers, namely HPV+G1 and HPV+G2. We demonstrated that this classification method was reproducible in two validation sets. Compared to HPV+G2, HPV+G1 displayed significantly higher immune infiltration level and stromal content, lower tumor purity, lower stemness scores and intratumor heterogeneity (ITH) scores, higher level of genomic instability, lower DNA methylation level, as well as better disease-free survival prognosis. The multivariate survival analysis suggests that the disease-free survival difference between both subtypes is independent of confounding variables, such as immune signature, stemness, and ITH. Pathway and gene ontology analysis confirmed the more active tumor immune microenvironment in HPV+G1 versus HPV+G2. Conclusions: HPV+ cervical cancers can be classified into two subtypes based on the expression profiles of the 50 genes with the largest expression variations across the HPV+ cervical cancers. Both subtypes have significantly different molecular, phenotypic, and clinical features. This new subtyping method captures the comprehensive heterogeneity in molecular and clinical characteristics of HPV+ cervical cancers and provides potential clinical implications for the diagnosis and treatment of this disease.
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Regulação Neoplásica da Expressão Gênica , Papillomaviridae , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/virologia , Transcriptoma , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/etiologia , Biomarcadores , Biologia Computacional/métodos , Variações do Número de Cópias de DNA , Bases de Dados Genéticas , Epigênese Genética , Feminino , Perfilação da Expressão Gênica/métodos , Ontologia Genética , Humanos , Mutação , Prognóstico , Microambiente TumoralRESUMO
This study aimed to evaluate the effect of polysaccharides from Scutellaria barbata D. Don (PSB) on dextran sodium sulfate (DSS)-induced ulcerative colitis (UC) in C57BL/6 mice. PSB was isolated, and its chemical composition was preliminarily identified. The average molecular weight of PSB was 1.25 × 104 Da and it was mainly comprised of arabinose, galacturonic acid, galactose, glucose, and glucuronic acid in molar ratios of 1.00:2.09:4.52:4.73:4.90. PSB (25 and 50 mg/kg) and sulfasalazine (200 mg/kg) significantly relieved weight loss and symptoms and alleviated colonic pathological injury in mice with UC. In addition, PSB decreased the levels of inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-1ß (IL-1ß), IL-6, and IL-18 in the colon and suppressed DSS-induced activation of the nuclear factor kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) pathways. The improvement in the abundance of several bacterial genera, such as the Lachnospiraceae_NK4A136_group, Ruminococcus, Bacteroides, Parasutterella, and Eisenbergiella might be closely related to the reduction in the intestinal inflammatory response after PSB treatment. These results revealed that PSB could potentially be utilized to treat UC and other diseases associated with an imbalance in the intestinal flora.
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Colite Ulcerativa , Colite , Scutellaria , Animais , Colite/patologia , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/microbiologia , Colo , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Disbiose/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Polissacarídeos/efeitos adversosRESUMO
Objective.We propose a semiautomatic pipeline for radiation therapy treatment planning, combining ideas from machine learning-automated planning and multicriteria optimization (MCO).Approach.Using knowledge extracted from historically delivered plans, prediction models for spatial dose and dose statistics are trained and furthermore systematically modified to simulate changes in tradeoff priorities, creating a set of differently biased predictions. Based on the predictions, an MCO problem is subsequently constructed using previously developed dose mimicking functions, designed in such a way that its Pareto surface spans the range of clinically acceptable yet realistically achievable plans as exactly as possible. The result is an algorithm outputting a set of Pareto optimal plans, either fluence-based or machine parameter-based, which the user can navigate between in real time to make adjustments before a final deliverable plan is created.Main results.Numerical experiments performed on a dataset of prostate cancer patients show that one may often navigate to a better plan than one produced by a single-plan-output algorithm.Significance.We demonstrate the potential of merging MCO and a data-driven workflow to automate labor-intensive parts of the treatment planning process while maintaining a certain extent of manual control for the user.
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Neoplasias da Próstata , Radioterapia de Intensidade Modulada , Algoritmos , Humanos , Masculino , Neoplasias da Próstata/radioterapia , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador/métodos , Radioterapia de Intensidade Modulada/métodosRESUMO
E1A binding protein p300 (EP300) is mutated in diverse cancers. Nevertheless, a systematic investigation into the associations of EP300 mutations with genome instability and antitumor immunity in pan-cancer remains lacking. Using the datasets from The Cancer Genome Atlas, we analyzed the correlations between EP300 mutations and genome instability and antitumor immune response in 11 cancer types. Compared to EP300-wild-type cancers, EP300-mutated cancers had significantly higher tumor mutation burden (TMB) in 10 cancer types. EP300-mutated cancers harbored a much higher fraction of microsatellite instable cancers in the colon and gastric cancers. EP300 was co-mutated with genes involved in DNA damage repair pathways in multiple cancers. Furthermore, compared to EP300-wild-type cancers, EP300-mutated cancers had significantly higher immune cytolytic activity scores and ratios of immune-stimulatory over immune-inhibitory signatures in diverse cancers. Also, EP300-mutated cancers showed significantly higher programmed death-ligand 1 (PD-L1) expression levels than EP300-wild-type cancers. The increased TMB, antitumor immune activity, and PD-L1 expression indicated a favorable response to immune checkpoint inhibitors (ICIs) in EP300-mutated cancers, as evident in three cancer cohorts treated with ICIs. Thus, the EP300 mutation could be a predictive biomarker for the response to immunotherapy.
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Alterations in the spliceosome pathway (SP) have been associated with diverse human cancers. In this study, we explored associations of the SP activity with various clinical features, anti-tumor immune signatures, tumor immunity-related genomic and molecular features, and the response to immunotherapies and targeted therapies in 29 cancer types from The Cancer Genome Atlas (TCGA) database. We showed that the SP activity was an oncogenic signature, as evidenced by its hyperactivation in cancer and invasive cancer subtypes and correlations with unfavorable clinical outcomes and anti-tumor immunosuppression in various cancers. The SP activity showed positive correlations with tumor mutation burden (TMB) and aneuploidy in diverse cancers, suggesting its association with genomic instability. However, the negative association between the SP activity and anti-tumor immune response was independent of its associations with aneuploidy and TMB. Furthermore, we supported that the SP activity had a negative correlation with immunotherapy response in four cancer cohorts treated by immune checkpoint inhibitors. Moreover, elevated SP activity is correlated with increased drug sensitivity for a broad spectrum of anti-tumor targeted therapies. In conclusion, the SP activity is a negative biomarker for anti-tumor immune response, prognosis, and the response to immunotherapeutic and targeted drugs in pan-cancer.
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BACKGROUND: Inflammatory processes are known to be the key secondary effects of severe traumatic brain injury (sTBI). The aim of the present study was to assess the value of peripheral inflammatory markers in the chronic unconscious phase after sTBI. METHODS: This was a prospective cohort study. A total of 101 patients with prolonged disorder of consciousness (DoC) and 22 healthy controls (HC) were enrolled in the study. Serum levels of interleukin (IL)-1ß, -4, -6, -10, -13, and tumor necrosis factor-α (TNF-α) were investigated in patients with prolonged DoC after sTBI. In addition, the Coma Recovery Scale-revised (CRS-R) was used to quantify the consciousness level, and clinical outcomes at 12 months were determined using the Glasgow Outcome Scale (GOS). Predictive logistic model was built based on the demographic characteristics and cytokine levels. RESULTS: At baseline, IL-6, -10, -13, and TNF-α levels were significantly higher in patients with prolonged DoC compared with controls, while no differences in cytokine levels were observed between patients in a vegetative state (VS) and those in a minimally conscious state (MCS). IL-13 and TNF-α were found to be correlated with behavioral scores in patients with prolonged DoC, and were associated with recovery 12 months later. CONCLUSIONS: The results of the study provide information about long-term inflammatory responses in the chronic unconscious phase after brain trauma. Further larger studies are required to validate the value of these inflammatory markers.
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Lesões Encefálicas Traumáticas , Estado de Consciência , Transtornos da Consciência/etiologia , Humanos , Estado Vegetativo Persistente/etiologia , Estudos ProspectivosRESUMO
BACKGROUND: New therapeutics for hepatocellular carcinoma (HCC) are urgently needed and searching for new anti-cancer compounds in plant medicines may represent a promising approach. The present study was conducted to clarify the role of hyperoside (HP) and its underlying molecular mechanism in a cancer cell. METHODS: Bone morphogenetic protein 7 (BMP-7) protein expression was measure in Human HCC tissue. In in vitro experiments, HP effects on cell proliferation and the mechanism were investigated deeply. RESULTS: The result showed a higher expression of BMP-7 in human HCC compared to adjacent noncancerous counterparts, and that silencing of BMP-7 suppressed HepG2 cell proliferation, suggesting BMP-7 plays an anti-cancer role in HCC. Furthermore, we found that HP could induce cell cycle arrest in proliferating HepG2 cells at the G1 phase by decreasing BMP-7 expression and that the phosphorylation of AKT and expression of PI3K were significantly down-regulated upon treatment of HP or BMP-7 knockdown. In addition, silencing of BMP-7 abrogated the difference of AKT phosphorylation between cells with and without HP treatment. CONCLUSIONS: Our results indicated that HP suppressed cell proliferation by inhibiting the BMP-7-dependent PI3K/AKT signaling pathway in HepG2 HCC cells, and either HP supplement or targeting BMP-7 might be a promising treatment against HCC.
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PURPOSE: We propose a general framework for quantifying predictive uncertainties of dose-related quantities and leveraging this information in a dose mimicking problem in the context of automated radiation therapy treatment planning. METHODS: A three-step pipeline, comprising feature extraction, dose statistic prediction and dose mimicking, is employed. In particular, the features are produced by a convolutional variational autoencoder and used as inputs in a previously developed nonparametric Bayesian statistical method, estimating the multivariate predictive distribution of a collection of predefined dose statistics. Specially developed objective functions are then used to construct a probabilistic dose mimicking problem based on the produced distributions, creating deliverable treatment plans. RESULTS: The numerical experiments are performed using a dataset of 94 retrospective treatment plans of prostate cancer patients. We show that the features extracted by the variational autoencoder capture geometric information of substantial relevance to the dose statistic prediction problem and are related to dose statistics in a more regularized fashion than hand-crafted features. The estimated predictive distributions are reasonable and outperforms a non-input-dependent benchmark method, and the deliverable plans produced by the probabilistic dose mimicking agree better with their clinical counterparts than for a non-probabilistic formulation. CONCLUSIONS: We demonstrate that prediction of dose-related quantities may be extended to include uncertainty estimation and that such probabilistic information may be leveraged in a dose mimicking problem. The treatment plans produced by the proposed pipeline resemble their original counterparts well, illustrating the merits of a holistic approach to automated planning based on probabilistic modeling.
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Planejamento da Radioterapia Assistida por Computador , Radioterapia de Intensidade Modulada , Teorema de Bayes , Humanos , Masculino , Dosagem Radioterapêutica , Estudos RetrospectivosRESUMO
Following severe spinal cord injury (SCI), dysregulated neuroinflammation causes neuronal and glial apoptosis, resulting in scar and cystic cavity formation during wound healing and ultimately the formation of an atrophic microenvironment that inhibits nerve regrowth. Because of this complex and dynamic pathophysiology, a systemic solution for scar- and cavity-free wound healing with microenvironment remodeling to promote nerve regrowth has rarely been explored. A one-step solution is proposed through a self-assembling, multifunctional hydrogel depot that punctually releases the anti-inflammatory drug methylprednisolone sodium succinate (MPSS) and growth factors (GFs) locally according to pathophysiology to repair severe SCI. Synergistically releasing the anti-inflammatory drug MPSS and GFs in the hydrogel depot throughout SCI pathophysiology protects spared tissues/axons from secondary injury, promotes scar boundary- and cavity-free wound healing, and results in permissive bridges for remarkable axonal regrowth. Behavioral and electrophysiological studies indicate that remnants of spared axons, not regenerating axons, mediate functional recovery, strongly suggesting that additional interventions are still required to render the rebuilt neuronal circuits functional. These findings pave the way for the development of a systemic solution to treat acute SCI.
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Hidrogéis , Traumatismos da Medula Espinal , Axônios , Humanos , Regeneração Nervosa , Recuperação de Função Fisiológica , Medula Espinal , Traumatismos da Medula Espinal/tratamento farmacológicoRESUMO
BACKGROUND: Patients who undergo cardiac valve surgery undertake routine physical therapy program. Despite its routine use, its influence on physical activity level post- surgery has not been illustrated. This study was to investigate whether 5 days of in-hospital physiotherapy could improve physical activity levels after cardiac valve surgery. METHODS: The study is a single-blind randomized controlled trial which performed in Cardiothoracic Surgery Department. Patients who underwent cardiac valve surgery (n=34) for confirmed cardiac valve disorders were assessed during hospitalization. The intervention group received a daily post-operative physiotherapy intervention, consisting of individualized mobilization, breathing exercises, ambulation with or without a walking aid. There was no physiotherapy treatment in the control group. Measurements: physical activity was assessed with the handgrip strength test and the timed up and go test. RESULTS: The treatment group showed significantly greater handgrip strength [20.58 (7.17) vs. 12.96 (4.65) kg] and less time on the timed up and go test [5.92 (2.91) vs. 6.53 (1.60) s] compared to the control group on the 5th post-operative day. Whilst there was no significant difference on the timed up and go test between the 2 groups, handgrip strength on the 5th post-operative day was significantly different between the 2 groups. CONCLUSIONS: Patients who received physiotherapy during hospitalization showed increased levels of handgrip strength and physical activity on the 5th day after cardiac valve surgery compared to the control group. The clinical value of increased levels of physical activity after in-hospital physiotherapy following cardiac valve surgery requires further investigation.
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Força da Mão , Equilíbrio Postural , Exercício Físico , Valvas Cardíacas , Hospitais , Humanos , Modalidades de Fisioterapia , Método Simples-Cego , Estudos de Tempo e MovimentoRESUMO
We demonstrate the application of mixture density networks (MDNs) in the context of automated radiation therapy treatment planning. It is shown that an MDN can produce good predictions of dose distributions as well as reflect uncertain decision making associated with inherently conflicting clinical tradeoffs, in contrast to deterministic methods previously investigated in the literature. A two-component Gaussian MDN is trained on a set of treatment plans for postoperative prostate patients with varying extents to which rectum dose sparing was prioritized over target coverage. Examination on a test set of patients shows that the predicted modes follow their respective ground truths well, both spatially and in terms of their dose-volume histograms. A special dose mimicking method based on the MDN output is used to produce deliverable plans and thereby showcase the usability of voxel-wise predictive densities. Thus, this type of MDN may serve to support clinicians in managing clinical tradeoffs and has the potential to improve the quality of plans produced by an automated treatment planning pipeline.
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Planejamento da Radioterapia Assistida por Computador/métodos , Automação , Humanos , Masculino , Órgãos em Risco/efeitos da radiação , Probabilidade , Neoplasias da Próstata/radioterapia , Dosagem Radioterapêutica , Radioterapia de Intensidade Modulada/efeitos adversos , Reto/efeitos dos fármacosRESUMO
We present a method of directly optimizing on deviations in clinical goal values in radiation therapy treatment planning. Using a new mathematical framework in which metrics derived from the dose-volume histogram are regarded as functionals of an auxiliary random variable, we are able to obtain volume-at-dose and dose-at-volume as infinitely differentiable functions of the dose distribution with easily evaluable function values and gradients. Motivated by the connection to risk measures in finance, which is formalized in this framework, we also derive closed-form formulas for mean-tail-dose and demonstrate its capability of reducing extreme dose values in tail distributions. Numerical experiments performed on a prostate and a head-and-neck patient case show that the direct optimization of dose-volume histogram metrics produced marginally better results than or outperformed conventional planning objectives in terms of clinical goal fulfilment, control of low- and high-dose tails of target distributions and general plan quality defined by a pre-specified evaluation measure. The proposed framework eliminates the disconnect between optimization functions and evaluation metrics and may thus reduce the need for repetitive user interaction associated with conventional treatment planning. The method also has the potential of enhancing plan optimization in other settings such as multicriteria optimization and automated treatment planning.
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Benchmarking , Humanos , Masculino , Próstata , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador , Radioterapia de Intensidade ModuladaRESUMO
BACKGROUND Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a functional long non-coding RNA involved in many biologic processes. The study was aimed to explore the functional roles of MALAT1 in osteosarcoma progression. MATERIAL AND METHODS A total of 76 osteosarcoma tissues and paired adjacent non-tumor tissues were collected from surgical resection. MALAT1, miRNAs, and genes mRNA expression levels were detected using quantitative real-time PCR (qRT-PCR). Protein expression level, cell proliferation, migration, and invasion were assessed using western blot, Cell Counting Kit-8 (CCK-8), wound-healing assay, and Matrigel invasion assay respectively. The target relationships among miRNAs, MALAT1, and mRNA were detected via dual-luciferase reporter assay. RESULTS We found that MALAT1 was frequently upregulated in osteosarcoma samples and cell lines and a high level of MALAT1 predicted poor overall survival in osteosarcoma patients. Knockdown of MALAT1 inhibited proliferation, migration, and invasion of osteosarcoma cells. Further study showed a positive correlation between MALAT1 and c-Met or SOX4 expression. Mechanistic investigations demonstrated that MALAT1, as a competing endogenous RNA (ceRNA), regulated osteosarcoma proliferation and metastasis through competitively binding to miR-34a/c-5p and miR-449a/b. CONCLUSIONS Taken together, our study illustrates a new regulatory mechanism for MALAT1 and may provide a novel therapeutic strategy for the treatment of osteosarcoma.
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Neoplasias Ósseas/metabolismo , MicroRNAs/metabolismo , Osteossarcoma/metabolismo , RNA Longo não Codificante/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Fatores de Transcrição SOXC/metabolismo , Adolescente , Adulto , Apoptose/fisiologia , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Criança , Feminino , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Invasividade Neoplásica , Metástase Neoplásica , Osteossarcoma/genética , Osteossarcoma/patologia , RNA Longo não Codificante/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Receptores Proteína Tirosina Quinases/genética , Fatores de Transcrição SOXC/genética , Transdução de Sinais , Regulação para CimaRESUMO
Although total hip replacement (THR) has been proven to be effective, the effect of THR on employment in ankylosing spondylitis (AS) in Chinese population is still unknown. We aimed to demonstrate whether or not patients with AS returned to work following THR and factors associated with the work ability after THR. We performed a retrospective study including a total number of 128 AS patients undergoing THR between 2009 and 2013. Presurgery and postsurgery data including disease state, work status, type of job, and time of resuming work were collected. Factors associated with early return to work were assessed through ordinal regression. Eighty-seven of 128 patients (68 %) were employed within 1 year before THR and 98 returned to work after surgery. Among them, 21, 46, and 31 resumed work by 3, 6, and 12 months postoperation, respectively. Multivariate ordinal regression showed that patients with unilateral THR, younger age, lower BASFI score, employed presurgery, and low or moderate physical demand were more likely to resume work earlier. Most individuals working presurgery returned to work after THR. For young AS patients with hip involvement, THR is an effective treatment for improving and maintaining work ability.