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Multisystem inflammatory syndrome in children (MIS-C) is a severe, post-infectious sequela of SARS-CoV-2 infection1,2, yet the pathophysiological mechanism connecting the infection to the broad inflammatory syndrome remains unknown. Here we leveraged a large set of samples from patients with MIS-C to identify a distinct set of host proteins targeted by patient autoantibodies including a particular autoreactive epitope within SNX8, a protein involved in regulating an antiviral pathway associated with MIS-C pathogenesis. In parallel, we also probed antibody responses from patients with MIS-C to the complete SARS-CoV-2 proteome and found enriched reactivity against a distinct domain of the SARS-CoV-2 nucleocapsid protein. The immunogenic regions of the viral nucleocapsid and host SNX8 proteins bear remarkable sequence similarity. Consequently, we found that many children with anti-SNX8 autoantibodies also have cross-reactive T cells engaging both the SNX8 and the SARS-CoV-2 nucleocapsid protein epitopes. Together, these findings suggest that patients with MIS-C develop a characteristic immune response to the SARS-CoV-2 nucleocapsid protein that is associated with cross-reactivity to the self-protein SNX8, demonstrating a mechanistic link between the infection and the inflammatory syndrome, with implications for better understanding a range of post-infectious autoinflammatory diseases.
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Anticorpos Antivirais , Autoanticorpos , COVID-19 , Reações Cruzadas , Epitopos , Mimetismo Molecular , SARS-CoV-2 , Síndrome de Resposta Inflamatória Sistêmica , Criança , Humanos , Anticorpos Antivirais/imunologia , Autoanticorpos/imunologia , Proteínas do Nucleocapsídeo de Coronavírus/química , Proteínas do Nucleocapsídeo de Coronavírus/imunologia , COVID-19/imunologia , COVID-19/virologia , COVID-19/complicações , Reações Cruzadas/imunologia , Epitopos/imunologia , Epitopos/química , Mimetismo Molecular/imunologia , Fosfoproteínas/química , Fosfoproteínas/imunologia , SARS-CoV-2/química , SARS-CoV-2/imunologia , SARS-CoV-2/metabolismo , SARS-CoV-2/patogenicidade , Nexinas de Classificação/química , Nexinas de Classificação/imunologia , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Síndrome de Resposta Inflamatória Sistêmica/patologia , Síndrome de Resposta Inflamatória Sistêmica/virologia , Linfócitos T/imunologiaRESUMO
The RNA exosome is a ribonuclease complex that mediates both RNA processing and degradation. This complex is evolutionarily conserved, ubiquitously expressed, and required for fundamental cellular functions, including rRNA processing. The RNA exosome plays roles in regulating gene expression and protecting the genome, including modulating the accumulation of RNA-DNA hybrids (R-loops). The function of the RNA exosome is facilitated by cofactors, such as the RNA helicase MTR4, which binds/remodels RNAs. Recently, missense mutations in RNA exosome subunit genes have been linked to neurological diseases. One possibility to explain why missense mutations in genes encoding RNA exosome subunits lead to neurological diseases is that the complex may interact with cell- or tissue-specific cofactors that are impacted by these changes. To begin addressing this question, we performed immunoprecipitation of the RNA exosome subunit, EXOSC3, in a neuronal cell line (N2A), followed by proteomic analyses to identify novel interactors. We identified the putative RNA helicase, DDX1, as an interactor. DDX1 plays roles in double-strand break repair, rRNA processing, and R-loop modulation. To explore the functional connections between EXOSC3 and DDX1, we examined the interaction following double-strand breaks and analyzed changes in R-loops in N2A cells depleted for EXOSC3 or DDX1 by DNA/RNA immunoprecipitation followed by sequencing. We find that EXOSC3 interaction with DDX1 is decreased in the presence of DNA damage and that loss of EXOSC3 or DDX1 alters R-loops. These results suggest EXOSC3 and DDX1 interact during events of cellular homeostasis and potentially suppress unscrupulous expression of genes promoting neuronal projection.
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Exossomos , RNA , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismo , DNA/metabolismo , Complexo Multienzimático de Ribonucleases do Exossomo/genética , Complexo Multienzimático de Ribonucleases do Exossomo/metabolismo , Exossomos/genética , Exossomos/metabolismo , Proteômica , Estruturas R-Loop , RNA/metabolismo , RNA Helicases/metabolismo , RNA Nuclear/metabolismo , Linhagem Celular , Animais , CamundongosRESUMO
INTRODUCTION: Periprocedural anxiety is common in pediatric patients and is characterized by tension, anxiety, irritability, and autonomic activation. Periprocedural anxiety increases during certain events including admission to the preoperative area, separation from caregivers, induction of anesthesia, and IV placement. A study of children aged 2-12 showed that perioperative anxiety in children may be influenced by high parental anxiety and low sociability of the child. While these are nonmodifiable variables in the perioperative setting, there are numerous ways to ameliorate both parental and patient anxiety including the use of certified child life specialists (CCLSs) to aid in child comfort. In this study, our objective was to evaluate the integration of CCLS in our perioperative setting on the rate of benzodiazepine use. METHODS: We used a prospectively maintained database to identify patients undergoing outpatient elective surgical and radiologic procedures from July 2022 to September 2023 and January 2023 to September 2023 respectively. CCLSs were used to work with appropriately aged children in order to decrease the use of benzodiazepines and reduce possible adverse events associated with their use. RESULTS: A total of 2175 pediatric patients were seen by CCLS in same day surgery from July 2022 to September 2023. During this period, midazolam use decreased by an average of 11.4% (range 6.2%-19.3%). An even greater effect was seen in the radiologic group with 73% reduction. No adverse events were reported during this period. CONCLUSIONS: CCLSs working with age-appropriate patients in the periprocedural setting is a useful adjunct in easing anxiety in pediatric patients, reducing the need for periprocedural benzodiazepine administration and the risk of exposure to unintended side effects.
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Ansiedade , Benzodiazepinas , Humanos , Projetos Piloto , Criança , Pré-Escolar , Feminino , Masculino , Benzodiazepinas/administração & dosagem , Benzodiazepinas/efeitos adversos , Ansiedade/prevenção & controle , Ansiedade/etiologia , Procedimentos Cirúrgicos Ambulatórios/efeitos adversos , Procedimentos Cirúrgicos Eletivos/efeitos adversos , Midazolam/administração & dosagem , Midazolam/efeitos adversos , Estudos ProspectivosRESUMO
PURPOSE: Blood culture (BC) is the gold standard for diagnosing blood stream infections (BSI) but is limited by long turnaround times (TAT) and low detection rate. The T2 Magnetic Resonance method (T2MR) offers a rapid, culture-independent alternative. The objective of this study was to compare the performance of the T2Bacteria assay to BCs in a real-world setting. METHODS: Retrospective comparative study consisting of T2Bacteria samples and BCs sampled within 72 h from the T2Bacteria sample. The primary outcome was detections by BC and T2Bacteria, respectively. The secondary outcome was difference in TAT. RESULTS: In total, 640 episodes were included, consisting of 640 T2Bacteria samples and 2,117 BCs. A median of three BCs was collected for each T2Bacteria sample. Overall positivity was 101 (15.8%) by either method. In 29 (28.7%) episodes, both T2Bacteria and BC were concordantly positive. In discordant episodes, 46/101 (45.5%) episodes were T2Bacteria positive/BC negative and 26/101 (25.7%) were T2Bacteria negative/BC positive (McNemar χ2, p < 0,05). In T2Bacteria positive/BC negative episodes, eight had growth of the same microorganism in a non-BC culture. Median (IQR) TAT for BC was 35 h and 30 min (25 h 50 min - 45 h 24 min), compared to 21 h and 3 min (17 h 6 min - 27 h 30 m) for T2Bacteria (p < 0.001), with longer delays for samplings occurring outside work hours. CONCLUSIONS: The study highlights a high discordance between T2Bacteria and BC and suggests complementary roles of the methods in BSI diagnostics. Furthermore, it is crucial to improve TAT by reducing preanalytical delays.
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OBJECTIVE: To compare smartphone application (Colonoscopic Preparation) instructions versus paper instructions for bowel preparation for colonoscopy. BACKGROUND: Adhering to bowel preparation instructions is important to ensure a high-quality colonoscopy. PATIENTS AND METHODS: This randomized controlled trial included individuals undergoing colonoscopy at a tertiary care hospital. Individuals were randomized (1:1) to receive instructions through a smartphone application or traditional paper instructions. The primary outcome was the quality of the bowel preparation as measured by the Boston Bowel Preparation Score. Secondary outcomes included cecal intubation and polyp detection. Patient satisfaction was assessed using a previously developed questionnaire. RESULTS: A total of 238 individuals were randomized (n = 119 in each group), with 202 available for the intention-to-treat analysis (N = 97 in the app group and 105 in the paper group). The groups had similar demographics, indications for colonoscopy, and type of bowel preparation. The primary outcome (Boston Bowel Preparation Score) demonstrated no difference between groups (Colonoscopic Preparation app mean: 7.26 vs paper mean: 7.28, P = 0.91). There was no difference in cecal intubation (P = 0.37), at least one polyp detected (P = 0.43), or the mean number of polyps removed (P = 0.11). A higher proportion strongly agreed or agreed that they would use the smartphone app compared with paper instructions (89.4% vs 70.1%, P = 0.001). CONCLUSIONS: Smartphone instructions performed similarly to traditional paper instructions for those willing to use the application. Local patient preferences need to be considered before making changes in the method of delivery of medical instructions.
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BACKGROUND: The prevalence of fungal bloodstream infections (BSI), especially candidaemia, has been increasing globally during the last decades. Fungal diagnosis is still challenging due to the slow growth of fungal microorganisms and need for special expertise. Fungal polymicrobial infections further complicate the diagnosis and extend the time required. Epidemiological data are vital to generate effective empirical treatment strategies. OBJECTIVES: The overall aim of this project is to describe the epidemiology of monomicrobial candidaemia and polymicrobial BSI, both with mixed fungaemia and with mixed Candida/bacterial BSIs. METHODS: We conducted a single-centre retrospective epidemiological study that encompasses 950,161 blood cultures during the years 2010 to 2020. The epidemiology of monomicrobial and polymicrobial candidaemia episodes were investigated from the electronic records. RESULTS: We found that 1334 candidaemia episodes were identified belonging to 1144 individual patients during 2010 to 2020. Candida albicans was the most prevalent species detected in candidaemia patients, representing 57.7% of these episodes. Nakaseomyces (Candida) glabrata and Candida parapsilosis complex showed an increasing trend compared to previous studies, whereas Candida albicans demonstrated a decrease. 19.8% of these episodes were polymicrobial and 17% presented with mixed Candida/bacterial BSIs while 2.8% were mixed fungaemia. C. albicans and N. glabrata were the most common combination (51.4%) in mixed fungaemia episodes. Enterococcus and Lactobacillus spp. were the most common bacteria isolated in mixed Candida/bacterial BSIs. CONCLUSIONS: Polymicrobial growth with candidaemia is common, mostly being mixed Candida/bacterial BSIs. C. albicans was detected in more than half of all the candidaemia patients however showed a decreasing trend in time, whereas an increase is noteworthy in C. parapsilosis complex and N. glabrata.
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Candida , Candidemia , Humanos , Candidemia/epidemiologia , Candidemia/microbiologia , Estudos Retrospectivos , Candida/isolamento & purificação , Candida/classificação , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Prevalência , Coinfecção/epidemiologia , Coinfecção/microbiologia , Adulto Jovem , Adolescente , Idoso de 80 Anos ou mais , Candida albicans/isolamento & purificação , Criança , Pré-EscolarRESUMO
A useful theoretical lens that has emerged for understanding urban resilience is the four basic types of interdependencies in critical infrastructures: the physical, geographic, cyber, and logical types. This paper is motivated by a conceptual and methodological limitation-although logical interdependencies (where two infrastructures affect the state of each other via human decisions) are regarded as one of the basic types of interdependencies, the question of how to apply the notion and how to quantify logical relations remains under-explored. To overcome this limitation, this study focuses on institutions (rules), for example, rules and planned tasks guiding human interactions with one another and infrastructure. Such rule-mediated interactions, when linguistically expressed, have a syntactic form that can be translated into a network form. We provide a foundation to delineate these two forms to detect logical interdependence. Specifically, we propose an approach to quantify logical interdependence based on the idea that (1) there are certain network motifs indicating logical relations, (2) such network motifs can be discerned from the network form of rules, and that (3) the higher the frequency of these motifs between two infrastructures, the greater the extent of logical interdependency. We develop a set of such motifs and illustrate their usage using an example. We conclude by suggesting a revision to the original definition of logical interdependence. This rule-focused approach is relevant to understanding human error in risk analysis of socio-technical systems, as human error can be seen as deviations from constraints that lead to accidents.
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PURPOSE: Proton therapy is sensitive to anatomical changes, often occurring in head-and-neck (HN) cancer patients. Although multiple studies have proposed online adaptive proton therapy (APT), there is still a concern in the radiotherapy community about the necessity of online APT. We have performed a retrospective study to investigate the potential dosimetric benefits of online APT for HN patients relative to the current offline APT. METHODS: Our retrospective study has a patient cohort of 10 cases. To mimic online APT, we re-evaluated the dose of the in-use treatment plan on patients' actual treatment anatomy captured by cone-beam CT (CBCT) for each fraction and performed a templated-based automatic replanning if needed, assuming that these were performed online before treatment delivery. Cumulative dose of the simulated online APT course was calculated and compared with that of the actual offline APT course and the designed plan dose of the initial treatment plan (referred to as nominal plan). The ProKnow scoring system was employed and adapted for our study to quantify the actual quality of both courses against our planning goals. RESULTS: The average score of the nominal plans over the 10 cases is 41.0, while those of the actual offline APT course and our simulated online course is 25.8 and 37.5, respectively. Compared to the offline APT course, our online course improved dose quality for all cases, with the score improvement ranging from 0.4 to 26.9 and an average improvement of 11.7. CONCLUSION: The results of our retrospective study have demonstrated that online APT can better address anatomical changes for HN cancer patients than the current offline replanning practice. The advanced artificial intelligence based automatic replanning technology presents a promising avenue for extending potential benefits of online APT.
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Neoplasias de Cabeça e Pescoço , Órgãos em Risco , Terapia com Prótons , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador , Radioterapia de Intensidade Modulada , Humanos , Estudos Retrospectivos , Neoplasias de Cabeça e Pescoço/radioterapia , Planejamento da Radioterapia Assistida por Computador/métodos , Terapia com Prótons/métodos , Radioterapia de Intensidade Modulada/métodos , Órgãos em Risco/efeitos da radiação , Tomografia Computadorizada de Feixe Cônico/métodos , PrognósticoRESUMO
The Compact Muon Solenoid (CMS) experiment is a general-purpose detector for high-energy collision at the Large Hadron Collider (LHC) at CERN. It employs an online data quality monitoring (DQM) system to promptly spot and diagnose particle data acquisition problems to avoid data quality loss. In this study, we present a semi-supervised spatio-temporal anomaly detection (AD) monitoring system for the physics particle reading channels of the Hadron Calorimeter (HCAL) of the CMS using three-dimensional digi-occupancy map data of the DQM. We propose the GraphSTAD system, which employs convolutional and graph neural networks to learn local spatial characteristics induced by particles traversing the detector and the global behavior owing to shared backend circuit connections and housing boxes of the channels, respectively. Recurrent neural networks capture the temporal evolution of the extracted spatial features. We validate the accuracy of the proposed AD system in capturing diverse channel fault types using the LHC collision data sets. The GraphSTAD system achieves production-level accuracy and is being integrated into the CMS core production system for real-time monitoring of the HCAL. We provide a quantitative performance comparison with alternative benchmark models to demonstrate the promising leverage of the presented system.
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We previously developed a FLASH planning framework for streamlined pin-ridge-filter (pin-RF) design, demonstrating its feasibility for single-energy proton FLASH planning. In this study, we refined the pin-RF design for easy assembly using reusable modules, focusing on its application in liver SABR. This framework generates an intermediate IMPT plan and translates it into step widths and thicknesses of pin-RFs for a single-energy FLASH plan. Parameters like energy spacing, monitor unit limit, and spot quantity were adjusted during IMPT planning, resulting in pin-RFs assembled using predefined modules with widths from 1 to 6 mm, each with a WET of 5 mm. This approach was validated on three liver SABR cases. FLASH doses, quantified using the FLASH effectiveness model at 1 to 5 Gy thresholds, were compared to conventional IMPT (IMPT-CONV) doses to assess clinical benefits. The highest demand for 6 mm width modules, moderate for 2-4 mm, and minimal for 1- and 5-mm modules were shown across all cases. At lower dose thresholds, the two-beam case showed significant dose reductions (>23%), while the other two three-beam cases showed moderate reductions (up to 14.7%), indicating the need for higher fractional beam doses for an enhanced FLASH effect. Positive clinical benefits were seen only in the two-beam case at the 5 Gy threshold. At the 1 Gy threshold, the FLASH plan of the two-beam case outperformed its IMPT-CONV plan, reducing dose indicators by up to 28.3%. However, the three-beam cases showed negative clinical benefits at the 1 Gy threshold, with some dose indicators increasing by up to 16% due to lower fractional beam doses and closer beam arrangements. This study evaluated the feasibility of modularizing streamlined pin-RFs in single-energy proton FLASH planning for liver SABR, offering guidance on optimal module composition and strategies to enhance FLASH planning.
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Resistance to radiotherapy is a major barrier during cancer treatment. Here using genome-scale CRISPR/Cas9 screening, we identify CD274 gene, which encodes PD-L1, to confer lung cancer cell resistance to ionizing radiation (IR). Depletion of endogenous PD-L1 delays the repair of IR-induced DNA double-strand breaks (DSBs) and PD-L1 loss downregulates non-homologous end joining (NHEJ) while overexpression of PD-L1 upregulates NHEJ. IR induces translocation of PD-L1 from the membrane into nucleus dependent on deglycosylation of PD-L1 at N219 and CMTM6 and leads to PD-L1 recruitment to DSBs foci. PD-L1 interacts with Ku in the nucleus and enhances Ku binding to DSB DNA. The interaction between the IgC domain of PD-L1 and the core domain of Ku is required for PD-L1 to accelerate NHEJ-mediated DSB repair and produce radioresistance. Thus, PD-L1, in addition to its immune inhibitory activity, acts as mechanistic driver for NHEJ-mediated DSB repair in cancer.
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Antígeno B7-H1 , Núcleo Celular , Quebras de DNA de Cadeia Dupla , Reparo do DNA por Junção de Extremidades , Autoantígeno Ku , Humanos , Quebras de DNA de Cadeia Dupla/efeitos da radiação , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Autoantígeno Ku/metabolismo , Autoantígeno Ku/genética , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Animais , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/patologia , Camundongos , Glicosilação , Radiação Ionizante , Sistemas CRISPR-CasRESUMO
BACKGROUND: FLASH radiotherapy (FLASH-RT) with ultra-high dose rate has yielded promising results in reducing normal tissue toxicity while maintaining tumor control. Planning with single-energy proton beams modulated by ridge filters (RFs) has been demonstrated feasible for FLASH-RT. PURPOSE: This study explored the feasibility of a streamlined pin-shaped RF (pin-RF) design, characterized by coarse resolution and sparsely distributed ridge pins, for single-energy proton FLASH planning. METHODS: An inverse planning framework integrated within a treatment planning system was established to design streamlined pin RFs for single-energy FLASH planning. The framework involves generating a multi-energy proton beam plan using intensity-modulated proton therapy (IMPT) planning based on downstream energy modulation strategy (IMPT-DS), followed by a nested pencil-beam-direction-based (PBD-based) spot reduction process to iteratively reduce the total number of PBDs and energy layers along each PBD for the IMPT-DS plan. The IMPT-DS plan is then translated into the pin-RFs and the single-energy beam configurations for IMPT planning with pin-RFs (IMPT-RF). This framework was validated on three lung cases, quantifying the FLASH dose of the IMPT-RF plan using the FLASH effectiveness model. The FLASH dose was then compared to the reference dose of a conventional IMPT plan to measure the clinical benefit of the FLASH planning technique. RESULTS: The IMPT-RF plans closely matched the corresponding IMPT-DS plans in high dose conformity (conformity index of <1.2), with minimal changes in V7Gy and V7.4 Gy for the lung (<3%) and small increases in maximum doses (Dmax) for other normal structures (<3.4 Gy). Comparing the FLASH doses to the doses of corresponding IMPT-RF plans, drastic reductions of up to nearly 33% were observed in Dmax for the normal structures situated in the high-to-moderate-dose regions, while negligible changes were found in Dmax for normal structures in low-dose regions. Positive clinical benefits were seen in comparing the FLASH doses to the reference doses, with notable reductions of 21.4%-33.0% in Dmax for healthy tissues in the high-dose regions. However, in the moderate-to-low-dose regions, only marginal positive or even negative clinical benefit for normal tissues were observed, such as increased lung V7Gy and V7.4 Gy (up to 17.6%). CONCLUSIONS: A streamlined pin-RF design was developed and its effectiveness for single-energy proton FLASH planning was validated, revealing positive clinical benefits for the normal tissues in the high dose regions. The coarsened design of the pin-RF demonstrates potential advantages, including cost efficiency and ease of adjustability, making it a promising option for efficient production.
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Neoplasias , Terapia com Prótons , Radioterapia de Intensidade Modulada , Humanos , Prótons , Planejamento da Radioterapia Assistida por Computador/métodos , Radioterapia de Intensidade Modulada/métodos , Terapia com Prótons/métodos , Dosagem Radioterapêutica , Órgãos em RiscoRESUMO
PURPOSE: Radiation-induced bystander effect (RIBE) frequently is seen as DNA damage in unirradiated bystander cells, but the repair processes initiated in response to that DNA damage are not well understood. RIBE-mediated formation of micronuclei (MN), a biomarker of persistent DNA damage, was previously observed in bystander normal fibroblast (AG01522) cells, but not in bystander human chondrosarcoma (HTB94) cells. The molecular mechanisms causing this disparity are not clear. Herein, we investigate the role of DNA repair in the bystander responses of the two cell lines. METHODS: Cells were irradiated with X-rays and immediately co-cultured with un-irradiated cells using a trans-well insert system in which they share the same medium. The activation of DNA damage response (DDR) proteins was detected by immunofluorescence staining or Western blotting. MN formation was examined by the cytokinesis-block MN assay, which is a robust method to detect persistent DNA damage. RESULTS: Immunofluorescent foci of γH2AX and 53BP1, biomarkers of DNA damage and repair, revealed a greater capacity for DNA repair in HTB94 cells than in AG01522 cells in both irradiated and bystander populations. Autophosphorylation of ATR at the threonine 1989 site was expressed at a greater level in HTB94 cells compared to AG01522 cells at the baseline and in response to hydroxyurea treatment or exposure to 1 Gy of X-rays. An inhibitor of ATR, but not of ATM, promoted MN formation in bystander HTB94 cells. In contrast, no effect of either inhibitor was observed in bystander AG01522 cells, indicating that ATR signaling might be a pivotal pathway to preventing the MN formation in bystander HTB94 cells. Supporting this idea, we found an ATR-dependent increase in the fractions of bystander HTB94 cells with pRPA2 S33 and RAD51 foci. A blocker of RAD51 facilitated MN formation in bystander HTB94 cells. CONCLUSION: Our results indicate that HTB94 cells were likely more efficient in DNA repair than AG01522 cells, specifically via ATR signaling, which inhibited the bystander signal-induced MN formation. This study highlights the significance of DNA repair efficiency in bystander cell responses.
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Proteínas Mutadas de Ataxia Telangiectasia , Efeito Espectador , Condrossarcoma , Reparo do DNA , Rad51 Recombinase , Transdução de Sinais , Humanos , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Efeito Espectador/efeitos da radiação , Linhagem Celular Tumoral , Condrossarcoma/metabolismo , Condrossarcoma/radioterapia , Dano ao DNA , Histonas/metabolismo , Rad51 Recombinase/metabolismoRESUMO
BACKGROUND: Cone-beam computed tomography (CBCT) scans, performed fractionally (e.g., daily or weekly), are widely utilized for patient alignment in the image-guided radiotherapy (IGRT) process, thereby making it a potential imaging modality for the implementation of adaptive radiotherapy (ART) protocols. Nonetheless, significant artifacts and incorrect Hounsfield unit (HU) values hinder their application in quantitative tasks such as target and organ segmentations and dose calculation. Therefore, acquiring CT-quality images from the CBCT scans is essential to implement online ART in clinical settings. PURPOSE: This work aims to develop an unsupervised learning method using the patient-specific diffusion model for CBCT-based synthetic CT (sCT) generation to improve the image quality of CBCT. METHODS: The proposed method is in an unsupervised framework that utilizes a patient-specific score-based model as the image prior alongside a customized total variation (TV) regularization to enforce coherence across different transverse slices. The score-based model is unconditionally trained using the same patient's planning CT (pCT) images to characterize the manifold of CT-quality images and capture the unique anatomical information of the specific patient. The efficacy of the proposed method was assessed on images from anatomical sites including head and neck (H&N) cancer, pancreatic cancer, and lung cancer. The performance of the proposed CBCT correction method was evaluated using quantitative metrics including mean absolute error (MAE), peak signal-to-noise ratio (PSNR), and normalized cross-correlation (NCC). Additionally, the proposed algorithm was benchmarked against two other unsupervised diffusion model-based CBCT correction algorithms.
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This study aims to develop a digital twin (DT) framework to enhance adaptive proton stereotactic body radiation therapy (SBRT) for prostate cancer. Prostate SBRT has emerged as a leading option for external beam radiotherapy due to its effectiveness and reduced treatment duration. However, interfractional anatomy variations can impact treatment outcomes. This study seeks to address these uncertainties using DT concept, with the goal of improving treatment quality, potentially revolutionizing prostate radiotherapy to offer personalized treatment solutions. Our study presented a pioneering approach that leverages DT technology to enhance adaptive proton SBRT. The framework improves treatment plans by utilizing patient-specific CTV setup uncertainty, which is usually smaller than conventional clinical setups. This research contributes to the ongoing efforts to enhance the efficiency and efficacy of prostate radiotherapy, with ultimate goals of improving patient outcomes and life quality.
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BACKGROUND: Pharmacist-led medication regimen simplification using a structured approach can reduce unnecessary medication regimen complexity in residential aged care facilities (RACFs), but no studies have investigated simplification by different health professionals, nor the extent to which simplification is recommended during comprehensive medication reviews. OBJECTIVES: To compare medication regimen simplification opportunities identified by pharmacists, general medical practitioners (GPs), and geriatricians and to determine if pharmacists identified simplification opportunities during routinely conducted comprehensive medication reviews in RACFs for these same residents. METHODS: Three pharmacists, three GPs and three geriatricians independently applied the Medication Regimen Simplification Guide for Residential Aged CarE (MRS GRACE) to medication data for 83 residents taking medications at least twice daily. Interrater agreement was calculated using Fleiss's kappa. Pharmacist medication review reports for the same 83 residents were then examined to identify if the pharmacists conducting these reviews had recommended any of the simplification strategies. RESULTS: Overall, 77 residents (92.8 %) taking medications at least twice daily could have their medication regimen simplified by at least one health professional. Pharmacists independently simplified 53.0-77.1 % of medication regimens (Κ = 0.60, 95%CI 0.46-0.75, indicating substantial agreement), while GPs simplified 74.7-89.2 % (Κ = 0.44, 95%CI 0.24-0.64, moderate agreement) and geriatricians simplified 41.0-66.3 % (Κ = 0.30, 95%CI 0.16-0.44, fair agreement). No simplification recommendations were included in the reports previously prepared by pharmacists as part of the comprehensive medication reviews undertaken for these residents. CONCLUSION: Pharmacists, GPs, and geriatricians can all identify medication regimen simplification opportunities, although these opportunities differ within and between professional groups. Although opportunities to simplify medication regimens during comprehensive medication reviews exist, simplification is not currently routinely recommended by pharmacists performing these reviews in Australian RACFs.
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Instituição de Longa Permanência para Idosos , Farmacêuticos , Humanos , Farmacêuticos/organização & administração , Idoso , Masculino , Feminino , Idoso de 80 Anos ou mais , Clínicos Gerais , Geriatras , Conduta do Tratamento Medicamentoso/organização & administração , Médicos , Papel ProfissionalRESUMO
Radiotherapy (RT) and anti-PD-L1 synergize to enhance local and distant (abscopal) tumor control. However, clinical results in humans have been variable. With the goal of improving clinical outcomes, we investigated the underlying synergistic mechanism focusing on a CD8+ PD-1+ Tcf-1+ stem-like T cell subset in the tumor-draining lymph node (TdLN). Using murine melanoma models, we found that RT + anti-PD-L1 induces a novel differentiation program in the TdLN stem-like population which leads to their expansion and differentiation into effector cells within the tumor. Our data indicate that optimal synergy between RT + anti-PD-L1 is dependent on the TdLN stem-like T cell population as either blockade of TdLN egress or specific stem-like T cell depletion reduced tumor control. Together, these data demonstrate a multistep stimulation of stem-like T cells following combination therapy which is initiated in the TdLN and completed in the tumor.
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Diffuse large B-cell lymphoma (DLBCL) is a commonly diagnosed, aggressive non-Hodgkin's lymphoma. While R-CHOP chemoimmunotherapy is potentially curative, about 40% of DLBCL patients will fail, highlighting the need to identify biomarkers to optimize management. SAMHD1 has a dNTPase-independent role in promoting resection to facilitate DNA double-strand break (DSB) repair by homologous recombination. We evaluated the relationship of SAMHD1 levels with sensitivity to DSB-sensitizing agents in DLBCL cells and the association of SAMHD1 expression with clinical outcomes in 79 DLBCL patients treated with definitive therapy and an independent cohort dataset of 234 DLBCL patients. Low SAMHD1 expression, Vpx-mediated, or siRNA-mediated degradation/depletion in DLBCL cells was associated with greater sensitivity to doxorubicin and PARP inhibitors. On Kaplan-Meier log-rank survival analysis, low SAMHD1 expression was associated with improved overall survival (OS), which on subset analysis remained significant only in patients with advanced stage (III-IV) and moderate to high risk (2-5 International Prognostic Index (IPI)). The association of low SAMHD1 expression with improved OS remained significant on multivariate analysis independent of other adverse factors, including IPI, and was validated in an independent cohort. Our findings suggest that SAMHD1 expression mediates doxorubicin resistance and may be an important prognostic biomarker in advanced, higher-risk DLBCL patients.
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Given the global surge in autoimmune diseases, it is critical to evaluate emerging therapeutic interventions. Despite numerous new targeted immunomodulatory therapies, comprehensive approaches to apply and evaluate the effects of these treatments longitudinally are lacking. Here, we leveraged advances in programmable-phage immunoprecipitation methodology to explore the modulation, or lack thereof, of autoantibody profiles, proteome-wide, in both health and disease. Using a custom set of over 730,000 human-derived peptides, we demonstrated that each individual, regardless of disease state, possesses a distinct and complex constellation of autoreactive antibodies. For each individual, the set of resulting autoreactivites constituted a unique immunological fingerprint, or "autoreactome," that was remarkably stable over years. Using the autoreactome as a primary output, we evaluated the relative effectiveness of various immunomodulatory therapies in altering autoantibody repertoires. We found that therapies targeting B cell maturation antigen (BCMA) profoundly altered an individual's autoreactome, while anti-CD19 and anti-CD20 therapies had minimal effects. These data both confirm that the autoreactome comprises autoantibodies secreted by plasma cells and strongly suggest that BCMA or other plasma cell-targeting therapies may be highly effective in treating currently refractory autoantibody-mediated diseases.
Assuntos
Autoanticorpos , Autoimunidade , Proteoma , Humanos , Autoanticorpos/imunologia , Feminino , Doenças Autoimunes/imunologia , Doenças Autoimunes/terapia , Masculino , Imunoterapia Adotiva/métodos , Antígeno de Maturação de Linfócitos B/imunologia , Antígeno de Maturação de Linfócitos B/metabolismo , Adulto , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Antígenos CD19/imunologia , Pessoa de Meia-IdadeRESUMO
R loops are RNA-DNA hybrid containing structures involved in diverse cellular processes, including DNA double-strand break (DSB) repair. R loop homeostasis involving the formation and resolution of R loops is critical for DSB repair, and its dysregulation leads to genome instability. Here we show that the HELZ helicase promotes R loop resolution to facilitate DSB repair by homologous recombination (HR). HELZ depletion causes hypersensitivity to DSB-inducing agents, and HELZ localizes and binds to DSBs. HELZ depletion further leads to genomic instability in a R loop dependent manner and the accumulation of R loops globally and at DSBs. HELZ binds to R loops in response to DSBs and promotes their resolution, thereby facilitating HR to promote genome integrity. Our findings thus define a role for HELZ in promoting the resolution of R loops critical for DSB repair by HR.