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1.
Mol Cell Proteomics ; 23(9): 100824, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39097268

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) suffers from a lack of an effective diagnostic method, which hampers improvement in patient survival. Carbohydrate antigen 19-9 (CA19-9) is the only FDA-approved blood biomarker for PDAC, yet its clinical utility is limited due to suboptimal performance. Liquid chromatography-mass spectrometry (LC-MS) has emerged as a burgeoning technology in clinical proteomics for the discovery, verification, and validation of novel biomarkers. A plethora of protein biomarker candidates for PDAC have been identified using LC-MS, yet few has successfully transitioned into clinical practice. This translational standstill is owed partly to insufficient considerations of practical needs and perspectives of clinical implementation during biomarker development pipelines, such as demonstrating the analytical robustness of proposed biomarkers which is critical for transitioning from research-grade to clinical-grade assays. Moreover, the throughput and cost-effectiveness of proposed assays ought to be considered concomitantly from the early phases of the biomarker pipelines for enhancing widespread adoption in clinical settings. Here, we developed a fit-for-purpose multi-marker panel for PDAC diagnosis by consolidating analytically robust biomarkers as well as employing a relatively simple LC-MS protocol. In the discovery phase, we comprehensively surveyed putative PDAC biomarkers from both in-house data and prior studies. In the verification phase, we developed a multiple-reaction monitoring (MRM)-MS-based proteomic assay using surrogate peptides that passed stringent analytical validation tests. We adopted a high-throughput protocol including a short gradient (<10 min) and simple sample preparation (no depletion or enrichment steps). Additionally, we developed our assay using serum samples, which are usually the preferred biospecimen in clinical settings. We developed predictive models based on our final panel of 12 protein biomarkers combined with CA19-9, which showed improved diagnostic performance compared to using CA19-9 alone in discriminating PDAC from non-PDAC controls including healthy individuals and patients with benign pancreatic diseases. A large-scale clinical validation is underway to demonstrate the clinical validity of our novel panel.


Assuntos
Biomarcadores Tumorais , Carcinoma Ductal Pancreático , Detecção Precoce de Câncer , Neoplasias Pancreáticas , Humanos , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/sangue , Biomarcadores Tumorais/sangue , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/sangue , Detecção Precoce de Câncer/métodos , Proteômica/métodos , Cromatografia Líquida , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Espectrometria de Massas/métodos
2.
J Biol Chem ; 299(8): 104984, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37390988

RESUMO

HIV-1 replication in primary monocyte-derived macrophages (MDMs) is kinetically restricted at the reverse transcription step due to the low deoxynucleoside triphosphates (dNTP) pools established by host dNTPase, SAM and HD domain containing protein 1 (SAMHD1). Lentiviruses such as HIV-2 and some Simian immunodeficiency virus counteract this restriction using viral protein X (Vpx), which proteosomally degrades SAMHD1 and elevates intracellular dNTP pools. However, how dNTP pools increase after Vpx degrades SAMHD1 in nondividing MDMs where no active dNTP biosynthesis is expected to exists remains unclear. In this study, we monitored known dNTP biosynthesis machinery during primary human monocyte differentiation to MDMs and unexpectedly found MDMs actively express dNTP biosynthesis enzymes such as ribonucleotide reductase, thymidine kinase 1, and nucleoside-diphosphate kinase. During differentiation from monocytes the expression levels of several biosynthesis enzymes are upregulated, while there is an increase in inactivating SAMHD1 phosphorylation. Correspondingly, we observed significantly lower levels of dNTPs in monocytes compared to MDMs. Without dNTP biosynthesis availability, Vpx failed to elevate dNTPs in monocytes, despite SAMHD1 degradation. These extremely low monocyte dNTP concentrations, which cannot be elevated by Vpx, impaired HIV-1 reverse transcription in a biochemical simulation. Furthermore, Vpx failed to rescue the transduction efficiency of a HIV-1 GFP vector in monocytes. Collectively, these data suggest that MDMs harbor active dNTP biosynthesis and Vpx requires this dNTP biosynthesis to elevate dNTP levels to effectively counteract SAMHD1 and relieve the kinetic block to HIV-1 reverse transcription in MDMs.


Assuntos
HIV-1 , Proteínas Monoméricas de Ligação ao GTP , Nucleotídeos , Proteína 1 com Domínio SAM e Domínio HD , Proteínas Virais Reguladoras e Acessórias , Animais , Humanos , HIV-1/metabolismo , Lentivirus/metabolismo , Macrófagos/metabolismo , Monócitos/metabolismo , Proteínas Monoméricas de Ligação ao GTP/genética , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Nucleotídeos/metabolismo , Proteína 1 com Domínio SAM e Domínio HD/metabolismo , Proteínas Virais Reguladoras e Acessórias/metabolismo
3.
Ann Surg ; 2024 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-39258374

RESUMO

OBJECTIVE: To evaluate the diagnostic performance of surgical indications of the revised International Association of Pancreatology (IAP) 2023 guidelines compared to the IAP 2017 and European 2018 guidelines. SUMMARY BACKGROUND DATA: The revised IAP guidelines for surgical indications for branch duct (BD) intraductal papillary mucinous neoplasms (IPMN) include the presence of at least two worrisome features without mandatory endoscopic ultrasound. METHODS: Among 663 patients who underwent resection for pathologically confirmed IPMN in a tertiary hospital between 2013 and 2023, 556 patients with BD or mixed-type IPMN were retrospectively reviewed. Diagnostic performances of the three guidelines for predicting high-grade dysplasia or IPMN with invasive carcinoma were compared. The primary outcome was the malignancy rate. Clinicopathological and radiological imaging data were analyzed. RESULTS: A total of 540, 451, and 490 patients met the surgical indications of the IAP, 2017, 2023, and European guidelines, respectively. Malignant IPMN was observed in 229 (41.2%) patients (high-grade dysplasia, n=99; invasive carcinoma, n=130). Surgical indication by the IAP 2023 guidelines showed higher specificity (29.1 vs. 4.9%, P<0.001), positive predictive value (48.6 vs. 42.4%, P=0.031), and accuracy (55.5 vs. 44.1%, P<0.001) than the IAP 2017 guidelines. It also had higher specificity than the European guidelines (18.7%, P=0.024). The IAP 2023 guidelines showed a superior AUC of surgical indication (0.623 vs. 0.582 for the European guidelines, P<0.001; and 0.524 for the IAP guidelines, P=0.008). CONCLUSIONS: The IAP 2023 guidelines showed better malignancy prediction than the IAP 2017 and European guidelines, potentially reducing unnecessary surgeries.

4.
Ann Surg Oncol ; 31(2): 1336-1346, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37991581

RESUMO

BACKGROUND: In this era of increasing neoadjuvant chemotherapy, methods for evaluating responses to neoadjuvant chemotherapy are still diverse among institutions. Additionally, the efficacy of adjuvant chemotherapy for patients undergoing neoadjuvant chemotherapy remains unclear. Therefore, this retrospective study was performed to evaluate the effectiveness of methods for assessing response to neoadjuvant chemotherapy and the need for adjuvant chemotherapy in treating patients with non-metastatic pancreatic ductal adenocarcinoma. METHODS: The study identified 150 patients who underwent neoadjuvant FOLFIRINOX chemotherapy followed by curative-intent pancreatectomy. The patients were stratified by biochemical response based on the normalization of carbohydrate antigen 19-9 and by radiologic response based on size change at imaging. RESULTS: The patients were classified into the following three groups based on their response to neoadjuvant chemotherapy and prognosis: biochemical responders (BR+), radiology-only responders (BR-/RR+), and non-responders (BR-/RR-). The 3-year overall survival rate was higher for BR+ (71.0%) than for BR-/RR+ (53.6%) or BR-/RR- (33.1%) (P < 0.001). Response to neoadjuvant chemotherapy also was identified as a significant risk factor for recurrence in a comparison between BR-/RR+ and BR+ (hazard ratio [HR], 2.15; 95% confidence interval [CI] 1.19-3.88; P = 0.011) and BR-/RR- (HR, 3.82; 95% CI 2.41-6.08; P < 0.001). Additionally, regardless of the response to neoadjuvant chemotherapy, patients who completed adjuvant chemotherapy had a significantly higher 3-year overall survival rate than those who did not. CONCLUSIONS: This response evaluation criterion for neoadjuvant chemotherapy is feasible and can significantly predict prognosis. Additionally, completion of adjuvant chemotherapy could be helpful to patients who undergo neoadjuvant chemotherapy regardless of their response to neoadjuvant chemotherapy.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Radiologia , Humanos , Neoplasias Pancreáticas/cirurgia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Neoadjuvante , Estudos Retrospectivos , Fluoruracila , Carcinoma Ductal Pancreático/cirurgia , Prognóstico , Pancreatectomia/métodos
5.
Cancer Cell Int ; 24(1): 43, 2024 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-38273381

RESUMO

BACKGROUND: The FGF/FGFR signaling pathway plays a critical role in human cancers. We analyzed the anti-tumor effect of AZD4547, an inhibitor targeting the FGF/FGFR pathway, in epithelial ovarian cancer (EOC) and strategies on overcoming AZD4547 resistance. METHODS: The effect of AZD4547 on cell viability/migration was evaluated and in vivo experiments in intraperitoneal xenografts using EOC cells and a patient-derived xenograft (PDX) model were performed. The effect of the combination of AZD4547 with SU11274, a c-Met-specific inhibitor, FGF19-specific siRNA, or an FGFR4 inhibitor was evaluated by MTT assay. RESULTS: AZD4547 significantly decreased cell survival and migration in drug-sensitive EOC cells but not drug-resistant cells. AZD4547 significantly decreased tumor weight in xenograft models of drug-sensitive A2780 and SKOV3ip1 cells and in a PDX with drug sensitivity but not in models with drug-resistant A2780-CP20 and SKOV3-TR cells. Furthermore, c-Met expression was high in SKOV3-TR and HeyA8-MDR cells, and co-administration of SU11274 and AZD4547 synergistically induced cell death. In addition, expressions of FGF19 and FGFR4 were high in A2780-CP20 cells. Combining AZD4547 with FGF19 siRNA or with a selective FGFR4 inhibitor led to significantly reduced cell proliferation in A2780-CP20 cells. CONCLUSIONS: This study showed that AZD4547 has significant anti-cancer effects in drug-sensitive cells and PDX models but not in drug-resistant EOC cells. In drug-resistant cells, the expression level of c-Met or FGF19/FGFR4 may be a predictive biomarker for AZD4547 treatment response, and a combination strategy of drugs targeting c-Met or FGF19/FGFR4 together with AZD4547 may be an effective therapeutic strategy for EOC.

6.
BMC Cancer ; 24(1): 1048, 2024 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-39187784

RESUMO

BACKGROUND: Pancreatic cancer is anatomically divided into pancreatic head and body/tail cancers, and some studies have reported differences in prognosis. However, whether this discrepancy is induced from the difference of tumor biology is hotly debated. Therefore, we aimed to evaluate the differences in clinical outcomes and tumor biology depending on the tumor location. METHODS: In this retrospective cohort study, we identified 800 patients with pancreatic ductal adenocarcinoma who had undergone upfront curative-intent surgery. Cox regression analysis was performed to explore the prognostic impact of the tumor location. Among them, 153 patients with sufficient tumor tissue and blood samples who provided informed consent for next-generation sequencing were selected as the cohort for genomic analysis. RESULTS: Out of the 800 patients, 500 (62.5%) had pancreatic head cancer, and 300 (37.5%) had body/tail cancer. Tumor location in the body/tail of the pancreas was not identified as a significant predictor of survival outcomes compared to that in the head in multivariate analysis (hazard ratio, 0.94; 95% confidence interval, 0.77-1.14; P = 0.511). Additionally, in the genomic analyses of 153 patients, there were no significant differences in mutational landscapes, distribution of subtypes based on transcriptomic profiling, and estimated infiltration levels of various immune cells between pancreatic head and body/tail cancers. CONCLUSIONS: We could not find differences in prognosis and tumor biology depending on tumor location in pancreatic ductal adenocarcinoma. Discrepancies in prognosis may represent a combination of lead time, selection bias, and clinical differences, including the surgical burden between tumor sites.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/cirurgia , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/mortalidade , Masculino , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Idoso , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/cirurgia , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/mortalidade , Prognóstico , Genômica/métodos , Mutação , Sequenciamento de Nucleotídeos em Larga Escala , Biomarcadores Tumorais/genética
7.
Pancreatology ; 24(3): 463-488, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38480047

RESUMO

BACKGROUND: The management of branch-duct type intraductal papillary mucinous neoplasms (BD-IPMN) varies in existing guidelines. This study investigated the optimal surveillance protocol and safe discontinuation of surveillance considering natural history in non-resected IPMN, by systematically reviewing the published literature. METHODS: This review was guided by PRISMA. Research questions were framed in PICO format "CQ1-1: Is size criteria helpful to determine surveillance period? CQ1-2: How often should surveillance be carried out? CQ1-3: When should surveillance be discontinued? CQ1-4: Is nomogram predicting malignancy useful during surveillance?". PubMed was searched from January-April 2022. RESULTS: The search generated 2373 citations. After screening, 83 articles were included. Among them, 33 studies were identified for CQ1-1, 19 for CQ1-2, 26 for CQ1-3 and 12 for CQ1-4. Cysts <1.5 or 2 cm without worrisome features (WF) were described as more indolent, and most studies advised an initial period of surveillance. The median growth rate of cysts <2 cm ranged from 0.23 to 0.6 mm/year. Patients with cysts <2 cm showing no morphological changes and no WF after 5-years of surveillance have minimal malignancy risk of 0-2%. Two nomograms created with over 1000 patients had AUCs of around 0.8 and appear to be feasible in a real-world practice. CONCLUSIONS: For patients with suspected BD-IPMN <2 cm and no other WF, less frequent surveillance is recommended. Surveillance may be discontinued for cysts that remain stable during 5-year surveillance, with consideration of patient condition and life expectancy. With this updated surveillance strategy, patients with non-worrisome BD-IPMN should expect more streamlined management and decreased healthcare utilization.


Assuntos
Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/patologia , Neoplasias Intraductais Pancreáticas/patologia , Carcinoma Ductal Pancreático/patologia
8.
Gynecol Oncol ; 188: 60-70, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38936282

RESUMO

OBJECTIVE: Ovarian cancer, a leading cause of cancer-related deaths in women, remains a formidable challenge, especially in the context of platinum-resistant disease. This study investigated the potential of the benzimidazole derivative BNZ-111 as a novel treatment strategy for platinum-resistant ovarian cancer. METHODS: The human EOC cell lines A2780, HeyA8, SKOV3ip1, A2780-CP20, HeyA8-MDR, and SKOV3-TR were treated with BNZ-111, and cell proliferation, apoptosis, and cell cycle were assessed. RESULTS: It demonstrated strong cytotoxicity in both chemo-sensitive and chemo-resistant epithelial ovarian cancer cell lines, inducing apoptosis and G2/M cell cycle arrest. In vivo experiments using orthotopic and patient-derived xenograft models showed significant tumor growth inhibition without apparent toxicity to vital organs. Unlike paclitaxel, BNZ-111 proved effective in paclitaxel-resistant cells, potentially by bypassing interaction with MDR1 and modulating ß-3 tubulin expression to suppress microtubule dynamics. CONCLUSION: BNZ-111, with favorable drug-like properties, holds promise as a therapeutic option for platinum-resistant ovarian cancer, addressing a critical clinical need in gynecologic oncology.


Assuntos
Benzimidazóis , Resistencia a Medicamentos Antineoplásicos , Neoplasias Ovarianas , Paclitaxel , Ensaios Antitumorais Modelo de Xenoenxerto , Feminino , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Benzimidazóis/farmacologia , Paclitaxel/farmacologia , Linhagem Celular Tumoral , Animais , Camundongos , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/patologia , Apoptose/efeitos dos fármacos , Camundongos Nus , Proliferação de Células/efeitos dos fármacos
9.
Am J Respir Crit Care Med ; 207(6): 704-720, 2023 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-36215036

RESUMO

Rationale: Data suggest that altered antimicrobial concentrations are likely during extracorporeal membrane oxygenation (ECMO). Objectives: The primary aim of this analysis was to describe the pharmacokinetics (PKs) of antimicrobials in critically ill adult patients receiving ECMO. Our secondary aim was to determine whether current antimicrobial dosing regimens achieve effective and safe exposure. Methods: This study was a prospective, open-labeled, PK study in six ICUs in Australia, New Zealand, South Korea, and Switzerland. Serial blood samples were collected over a single dosing interval during ECMO for 11 antimicrobials. PK parameters were estimated using noncompartmental methods. Adequacy of antimicrobial dosing regimens were evaluated using predefined concentration exposures associated with maximal clinical outcomes and minimal toxicity risks. Measurements and Main Results: We included 993 blood samples from 85 patients. The mean age was 44.7 ± 14.4 years, and 61.2% were male. Thirty-eight patients (44.7%) were receiving renal replacement therapy during the first PK sampling. Large variations (coefficient of variation of ⩾30%) in antimicrobial concentrations were seen leading to more than fivefold variations in all PK parameters across all study antimicrobials. Overall, 70 (56.5%) concentration profiles achieved the predefined target concentration and exposure range. Target attainment rates were not significantly different between modes of ECMO and renal replacement therapy. Poor target attainment was observed across the most frequently used antimicrobials for ECMO recipients, including for oseltamivir (33.3%), piperacillin (44.4%), and vancomycin (27.3%). Conclusions: Antimicrobial PKs were highly variable in critically ill patients receiving ECMO, leading to poor target attainment rates. Clinical trial registered with the Australian New Zealand Clinical Trials Registry (ACTRN12612000559819).


Assuntos
Anti-Infecciosos , Oxigenação por Membrana Extracorpórea , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antibacterianos/uso terapêutico , Anti-Infecciosos/uso terapêutico , Austrália , Estado Terminal/terapia , Oxigenação por Membrana Extracorpórea/métodos , Estudos Prospectivos
10.
BMC Pulm Med ; 24(1): 7, 2024 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-38166950

RESUMO

BACKGROUND: Bacterial colonization is an essential aspect of bronchiectasis. Although Haemophilus influenzae is a frequent colonizer in some regions, its clinical impacts are poorly understood. This study aimed to elucidate the impact of H. influenzae colonization in patients with bronchiectasis. METHODS: This retrospective study screened adult patients diagnosed with bronchiectasis at a tertiary referral center between April 1, 2003, and May 16, 2021, in South Korea. Propensity score matching was used to match patients with and without H. influenzae colonization. We assessed the severity of bronchiectasis as per the bronchiectasis severity index, the incidence of exacerbation, differences in lung function, and all-cause mortality. RESULTS: Out of the 4,453 patients with bronchiectasis, 79 (1.8%) were colonized by H. influenzae. After 1:2 propensity score matching, 78 and 154 patients were selected from the H. influenzae colonizer and non-colonizer groups, respectively. Although there were no significant differences between the groups regarding baseline demographics, patients colonized with H. influenzae had a higher bronchiectasis severity index (median 6 [interquartile range 4-8] vs. 4 [2-7], p = 0.002), associated with extensive radiographic involvement (52.2% vs. 37.2%, p = 0.045) and mild exacerbation without hospitalization (adjusted incidence rate ratio 0.15; 95% confidence interval 0.12-0.24). Lung function and mortality rates did not reveal significant differences, regardless of H. influenzae colonization. CONCLUSION: H. influenzae colonization in bronchiectasis was associated with more severe disease and greater incidence of mild exacerbation, but not lung function and mortality. Attention should be paid to patients with bronchiectasis with H. influenzae colonization.


Assuntos
Bronquiectasia , Haemophilus influenzae , Adulto , Humanos , Estudos Retrospectivos , Bronquiectasia/complicações , República da Coreia/epidemiologia
11.
BMC Pulm Med ; 24(1): 162, 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38570737

RESUMO

BACKGROUND: Endobronchial valve (EBV) therapy, a validated method for bronchoscopic lung volume reduction (BLVR) in severe emphysema, has been explored for persistent air-leak (PAL) management. However, its effectiveness and safety in the Asian population require further real-world evaluation. In this study, we assessed the outcomes of treatment with EBV within this demographic. METHODS: We conducted a retrospective analysis of medical records from 11 Korean centers. For the emphysema cohort, inclusion criteria were patients diagnosed with emphysema who underwent bronchoscopy intended for BLVR. We assessed these patients for clinical outcomes of chronic obstructive pulmonary disease. All patients with PAL who underwent treatment with EBV were included. We identified the underlying causes of PAL and evaluated clinical outcomes after the procedure. RESULTS: The severe emphysema cohort comprised 192 patients with an average age of 70.3 years, and 95.8% of them were men. Ultimately, 137 underwent treatment with EBV. Three months after the procedure, the BLVR group demonstrated a significant improvement in forced expiratory volume in 1 s (+160 mL vs. +30 mL; P = 0.009). Radiographic evidence of lung volume reduction 6 months after BLVR was significantly associated with improved survival (adjusted hazard ratio 0.020; 95% confidence interval 0.038-0.650; P = 0.010). Although pneumothorax was more common in the BLVR group (18.9% vs. 3.8%; P = 0.018), death was higher in the no-BLVR group (38.5% vs. 54.5%, P = 0.001), whereas other adverse events were comparable between the groups. Within the subset of 18 patients with PAL, the predominant causes of air-leak included spontaneous secondary pneumothorax (44.0%), parapneumonic effusion/empyema (22.2%), and post-lung resection surgery (16.7%). Following the treatment, the majority (77.8%) successfully had their chest tubes removed. Post-procedural complications were minimal, with two incidences of hemoptysis and one of empyema, all of which were effectively managed. CONCLUSIONS: Treatment with EBV provides substantial clinical benefits in the management of emphysema and PAL in the Asian population, suggesting a favorable outcome for this therapeutic approach.


Assuntos
Enfisema , Empiema , Pneumotórax , Enfisema Pulmonar , Masculino , Humanos , Idoso , Feminino , Pneumotórax/etiologia , Pneumotórax/cirurgia , Estudos Retrospectivos , Pneumonectomia/efeitos adversos , Volume Expiratório Forçado , Broncoscopia/métodos , Empiema/etiologia , Empiema/cirurgia , Resultado do Tratamento
12.
J Biol Chem ; 298(3): 101635, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35085552

RESUMO

The lack of antiviral innate immune responses during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections is characterized by limited production of interferons (IFNs). One protein associated with Aicardi-Goutières syndrome, SAMHD1, has been shown to negatively regulate the IFN-1 signaling pathway. However, it is unclear whether elevated IFN signaling associated with genetic loss of SAMHD1 would affect SARS-CoV-2 replication. In this study, we established in vitro tissue culture model systems for SARS-CoV-2 and human coronavirus OC43 infections in which SAMHD1 protein expression was absent as a result of CRISPR-Cas9 gene KO or lentiviral viral protein X-mediated proteosomal degradation. We show that both SARS-CoV-2 and human coronavirus OC43 replications were suppressed in SAMHD1 KO 293T and differentiated THP-1 macrophage cell lines. Similarly, when SAMHD1 was degraded by virus-like particles in primary monocyte-derived macrophages, we observed lower levels of SARS-CoV-2 RNA. The loss of SAMHD1 in 293T and differentiated THP-1 cells resulted in upregulated gene expression of IFNs and innate immunity signaling proteins from several pathways, with STAT1 mRNA being the most prominently elevated ones. Furthermore, SARS-CoV-2 replication was significantly increased in both SAMHD1 WT and KO cells when expression and phosphorylation of STAT1 were downregulated by JAK inhibitor baricitinib, which over-rode the activated antiviral innate immunity in the KO cells. This further validates baricitinib as a treatment of SARS-CoV-2-infected patients primarily at the postviral clearance stage. Overall, our tissue culture model systems demonstrated that the elevated innate immune response and IFN activation upon genetic loss of SAMHD1 effectively suppresses SARS-CoV-2 replication.


Assuntos
COVID-19 , Proteína 1 com Domínio SAM e Domínio HD , SARS-CoV-2 , Antivirais/farmacologia , Doenças Autoimunes do Sistema Nervoso , COVID-19/genética , COVID-19/imunologia , COVID-19/virologia , Humanos , Imunidade Inata , Interferons , Malformações do Sistema Nervoso , RNA Viral , Proteína 1 com Domínio SAM e Domínio HD/genética , Proteína 1 com Domínio SAM e Domínio HD/imunologia , SARS-CoV-2/imunologia , SARS-CoV-2/fisiologia , Replicação Viral/imunologia
13.
Crit Care ; 27(1): 346, 2023 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-37670324

RESUMO

BACKGROUND: Retrospective studies have demonstrated that the deep learning-based cardiac arrest risk management system (DeepCARS™) is superior to the conventional methods in predicting in-hospital cardiac arrest (IHCA). This prospective study aimed to investigate the predictive accuracy of the DeepCARS™ for IHCA or unplanned intensive care unit transfer (UIT) among general ward patients, compared with that of conventional methods in real-world practice. METHODS: This prospective, multicenter cohort study was conducted at four teaching hospitals in South Korea. All adult patients admitted to general wards during the 3-month study period were included. The primary outcome was predictive accuracy for the occurrence of IHCA or UIT within 24 h of the alarm being triggered. Area under the receiver operating characteristic curve (AUROC) values were used to compare the DeepCARS™ with the modified early warning score (MEWS), national early warning Score (NEWS), and single-parameter track-and-trigger systems. RESULTS: Among 55,083 patients, the incidence rates of IHCA and UIT were 0.90 and 6.44 per 1,000 admissions, respectively. In terms of the composite outcome, the AUROC for the DeepCARS™ was superior to those for the MEWS and NEWS (0.869 vs. 0.756/0.767). At the same sensitivity level of the cutoff values, the mean alarm counts per day per 1,000 beds were significantly reduced for the DeepCARS™, and the rate of appropriate alarms was higher when using the DeepCARS™ than when using conventional systems. CONCLUSION: The DeepCARS™ predicts IHCA and UIT more accurately and efficiently than conventional methods. Thus, the DeepCARS™ may be an effective screening tool for detecting clinical deterioration in real-world clinical practice. Trial registration This study was registered at ClinicalTrials.gov ( NCT04951973 ) on June 30, 2021.


Assuntos
Aprendizado Profundo , Parada Cardíaca , Adulto , Humanos , Quartos de Pacientes , Estudos Prospectivos , Estudos de Coortes , Estudos Retrospectivos , Hospitais de Ensino , Unidades de Terapia Intensiva , Gestão de Riscos
14.
Surg Endosc ; 37(12): 9089-9097, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37798528

RESUMO

BACKGROUND: Although laparoscopic cholecystectomy is applicable for the treatment of early gallbladder cancer (GBC), minimally invasive surgery is not widely used for advanced GBC. This is because advanced GBCs necessitate complicated surgical techniques, including lymph node dissection and liver resection. Robotic extended cholecystectomy (REC) is thought to overcome the limitations of laparoscopic surgery, but oncological safety studies are lacking. Therefore, in this study, we aimed to evaluate the oncologic outcomes of REC compared with those of open extended cholecystectomy (OEC). METHODS: A total of 125 patients, who underwent extended cholecystectomy for GBC with tentative T2 or higher stage between 2018 and 2021, were included and stratified by surgical methods. To minimize the confounding factors, 1:1 propensity-score matching was performed between the patients who underwent REC and those who underwent OEC. RESULTS: Regarding short-term outcomes, the REC group showed significantly lower estimated blood loss (382.7 vs. 717.2 mL, P = 0.020) and shorter hospital stay (6.9 vs. 8.5 days, P = 0.042) than the OEC group. In addition, the REC group had significantly lower subjective pain scores than the OEC group from the day of surgery through the 5th postoperative day (P = 0.006). Regarding long-term outcomes, there were no significant differences in the 3-year [5-year] overall survival (OS) and disease-free survival (DFS) rates between the REC group [OS, 92.3% (92.3%); DFS, 84.6% (72.5%)] and the OEC group [OS, 96.8% (96.8%); DFS, 78.2% (78.2%)] (P = 0.807 for OS and 0.991 for DFS). CONCLUSIONS: In this study, REC showed superior short-term outcomes to OEC and no difference in long-term survival outcomes. Additionally, REC was superior to OEC in terms of postoperative pain. Therefore, REC may be a feasible option with early recovery compared with OEC for patients with advanced GBC.


Assuntos
Carcinoma in Situ , Carcinoma , Colecistectomia Laparoscópica , Neoplasias da Vesícula Biliar , Laparoscopia , Procedimentos Cirúrgicos Robóticos , Humanos , Neoplasias da Vesícula Biliar/patologia , Procedimentos Cirúrgicos Robóticos/efeitos adversos , Resultado do Tratamento , Colecistectomia/efeitos adversos , Colecistectomia/métodos , Colecistectomia Laparoscópica/efeitos adversos , Colecistectomia Laparoscópica/métodos , Excisão de Linfonodo/métodos , Carcinoma/cirurgia , Carcinoma in Situ/cirurgia , Estudos Retrospectivos
15.
J Korean Med Sci ; 38(10): e75, 2023 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-36918029

RESUMO

BACKGROUND: Administration of adequate antibiotics is crucial for better outcomes in sepsis. Because no uniform tool can accurately assess the risk of multidrug-resistant (MDR) pathogens, a local antibiogram is necessary. We aimed to describe the antibiogram of MDR bacteria based on locations of sepsis onset in South Korea. METHODS: We performed a prospective observational study of adult patients diagnosed with sepsis according to Sepsis-3 from 19 institutions (13 tertiary referral and 6 university-affiliated general hospitals) in South Korea. Patients were divided into four groups based on the respective location of sepsis onset: community, nursing home, long-term-care hospital, and hospital. Along with the antibiogram, risk factors of MDR bacteria and drug-bug match of empirical antibiotics were analyzed. RESULTS: MDR bacteria were detected in 1,596 (22.7%) of 7,024 patients with gram-negative predominance. MDR gram-negative bacteria were more commonly detected in long-term-care hospital- (30.4%) and nursing home-acquired (26.3%) sepsis, whereas MDR gram-positive bacteria were more prevalent in hospital-acquired (10.9%) sepsis. Such findings were consistent regardless of the location and tier of hospitals throughout South Korea. Patients with long-term-care hospital-acquired sepsis had the highest risk of MDR pathogen, which was even higher than those with hospital-acquired sepsis (adjusted odds ratio, 1.42; 95% confidence interval, 1.15-1.75) after adjustment of risk factors. The drug-bug match was lowest in patients with long-term-care hospital-acquired sepsis (66.8%). CONCLUSION: Gram-negative MDR bacteria were more common in nursing home- and long-term-care hospital-acquired sepsis, whereas gram-positive MDR bacteria were more common in hospital-acquired settings in South Korea. Patients with long-term-care hospital-acquired sepsis had the highest the risk of MDR bacteria but lowest drug-bug match of initial antibiotics. We suggest that initial antibiotics be carefully selected according to the onset location in each patient.


Assuntos
Sepse , Adulto , Humanos , Sepse/diagnóstico , Sepse/tratamento farmacológico , Sepse/microbiologia , Farmacorresistência Bacteriana Múltipla , Hospitais Universitários , Estudos Prospectivos , República da Coreia , Testes de Sensibilidade Microbiana , Bactérias , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Fatores de Risco
16.
Antimicrob Agents Chemother ; 66(1): e0137721, 2022 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-34633852

RESUMO

Our study aimed to describe the population pharmacokinetics (PK) of vancomycin in critically ill patients receiving extracorporeal membrane oxygenation (ECMO), including those receiving concomitant renal replacement therapy (RRT). Dosing simulations were used to recommend maximally effective and safe dosing regimens. Serial vancomycin plasma concentrations were measured and analyzed using a population PK approach on Pmetrics. The final model was used to identify dosing regimens that achieved target exposures of area under the curve (AUC0-24) of 400-700 mg · h/liter at steady state. Twenty-two patients were enrolled, of which 11 patients received concomitant RRT. In the non-RRT patients, the median creatinine clearance (CrCL) was 75 ml/min and the mean daily dose of vancomycin was 25.5 mg/kg. Vancomycin was well described in a two-compartment model with CrCL, the presence of RRT, and total body weight found as significant predictors of clearance and central volume of distribution (Vc). The mean vancomycin renal clearance and Vc were 3.20 liters/h and 29.7 liters respectively, while the clearance for patients on RRT was 0.15 liters/h. ECMO variables did not improve the final covariate model. We found that recommended dosing regimens for critically ill adult patients not on ECMO can be safely and effectively used in those on ECMO. Loading doses of at least 25 mg/kg followed by maintenance doses of 12.5-20 mg/kg every 12 h are associated with a 97-98% probability of efficacy and 11-12% probability of toxicity, in patients with normal renal function. Therapeutic drug monitoring along with reductions in dosing are warranted for patients with renal impairment and those with concomitant RRT. (This study is registered with the Australian New Zealand Clinical Trials Registry [ANZCTR] under number ACTRN12612000559819.).


Assuntos
Oxigenação por Membrana Extracorpórea , Vancomicina , Adulto , Antibacterianos/farmacocinética , Austrália , Estado Terminal/terapia , Humanos , Vancomicina/farmacocinética
17.
Gynecol Oncol ; 165(2): 270-280, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35305818

RESUMO

OBJECTIVE: Poly (ADP)-ribose polymerase inhibitors (PARPi) are effective clinical agents for treatment of epithelial ovarian cancer (EOC) harboring BRCA mutations as well as those without BRCA mutations. In this study, we evaluate the efficacy of combined PARPi and DNA methyltransferase inhibitor (DNMTi) in EOCs. METHODS: Expression levels of DNMT1 and PARP1 proteins in EOC cells were assessed using western blot analysis and immunohistochemistry. To evaluate the effects of co-treatment of PARPi (olaparib) and DNMTi (5-azacitidine, 5-AZA), we performed cell proliferation, apoptosis, and wound-healing assays in EOC cells. In addition, we performed in vivo experiments using both cell-line and patient-derived xenograft (PDX) models of EOC. RESULTS: The combination of olaparib and 5-AZA significantly inhibited cell proliferation and migration and induced apoptosis compared with olaparib or 5-AZA alone in EOC cell lines including A2780, HeyA8, A2780-CP20, and HeyA8-MDR. Moreover, in vivo experiments with this combination showed significantly decreased weight and nodule numbers of tumors in cell-line xenograft models with A2780 cells and a PDX model compared with control, olaparib, and 5-AZA groups. As a potential mechanism, the expression of intracellular reactive oxygen species (ROS) and its related proteins, including p-ERK, NRF2, p-p38, HO-1, and γH2AX, was affected in EOC cells. CONCLUSIONS: Co-treatment with PARPi and DNMTi had a significant anti-tumor effect in EOC cells. This combination might be a potential therapeutic strategy for EOCs.


Assuntos
Antineoplásicos , Neoplasias Ovarianas , Difosfato de Adenosina/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma Epitelial do Ovário/patologia , Linhagem Celular Tumoral , DNA , Feminino , Humanos , Neoplasias Ovarianas/patologia , Ftalazinas/farmacologia , Ftalazinas/uso terapêutico , Poli(ADP-Ribose) Polimerase-1 , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Ribose/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
18.
BMC Pulm Med ; 22(1): 56, 2022 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-35135503

RESUMO

BACKGROUND: Acute fibrinous and organizing pneumonia (AFOP) is a rare interstitial pneumonia characterized by intra-alveolar fibrin deposition and organizing pneumonia. The clinical manifestations and long-term prognosis of AFOP are unclear. Our objective was to investigate the clinical features and prognosis of AFOP. METHODS: We identified patients diagnosed with AFOP by surgical lung biopsy between January 2011 and May 2018 at Seoul National University Bundang Hospital. We retrospectively reviewed clinical and radiologic findings, treatment, and outcomes of AFOP. RESULTS: Fifteen patients with histologically confirmed lung biopsies were included. The median follow-up duration was 2.4 (range, 0.1-82) months. The median age was 55 (range, 33-75) years, and four patients were immunocompromised. Fever was the most common clinical presentation (86.7%). Patchy ground-glass opacities and/or consolidations were the most predominant findings on chest computed tomography images. Nine patients (60%) received mechanical ventilator care, and eight patients (53.3%) died. The non-survivors tended to have slightly higher body mass index (BMI) and a long interval between symptom onset and diagnosis than the survivors, but these findings were not statistically significant. Among seven survivors, five patients were discharged without dyspnea and oxygen supplement. CONCLUSIONS: The clinical course of AFOP was variable. Although AFOP was fatal, most of the patients who recovered from AFOP maintained normal life without supplemental oxygen therapy and respiratory symptoms.


Assuntos
Pneumonias Intersticiais Idiopáticas/diagnóstico , Pneumonias Intersticiais Idiopáticas/epidemiologia , Adulto , Idoso , Biópsia/métodos , Feminino , Humanos , Pneumonias Intersticiais Idiopáticas/patologia , Pneumonias Intersticiais Idiopáticas/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , República da Coreia/epidemiologia , Respiração Artificial/estatística & dados numéricos , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida
19.
BMC Pulm Med ; 22(1): 319, 2022 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-35986257

RESUMO

BACKGROUND: Electromagnetic navigation bronchoscopy (ENB) is an emerging advanced imaging-guided bronchoscopy technique for diagnosing peripheral lung lesions. However, the selection strategy for the optimal biopsy device and whether adopting a multi-tool strategy increases the diagnostic yield remains undetermined. The CONFIDENT-ENB trial (NCT05110131) is a prospective randomized study on ENB, performed in a least-invasive setting. The primary aim is to evaluate whether a combination of needle aspiration and forceps biopsy improves the diagnostic performance, and assess the comparative diagnostic value and discordance of the two devices. METHODS: The trial will recruit 142 participants with lung lesions suspected of malignancy who are eligible for an elective ENB procedure under moderate sedation. Participants will undergo ENB-guided needle aspiration and forceps biopsy in a randomized order without the use of any complementary techniques. All participants will be followed up subsequently for up to 12 months to conclude the final diagnosis of the biopsied lesions. Primary outcomes include the diagnostic yield and sensitivity of each biopsy modality and the diagnostic yield of the combined modalities. DISCUSSION: The CONFIDENT-ENB trial will prospectively evaluate the synergistic effectiveness and comparative accuracy of ENB-guided needle aspiration and forceps biopsy in a least-invasive setting. The results are expected to improve our understanding of the optimal tool-selection strategy for ENB. TRIAL REGISTRATION: ClinicalTrials.gov (NCT05110131). Prospectively registered on 5 November 2021.


Assuntos
Broncoscopia , Neoplasias Pulmonares , Biópsia/métodos , Broncoscopia/métodos , Fenômenos Eletromagnéticos , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Estudos Prospectivos , Instrumentos Cirúrgicos
20.
J Korean Med Sci ; 37(34): e262, 2022 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-36038958

RESUMO

BACKGROUND: This study aimed to investigate the effects of comprehensive rehabilitation management on functional recovery and examine the correlation between clinical parameters and improvements in functional outcomes in severe-to-critical inpatients with coronavirus disease 2019 (COVID-19) in a tertiary hospital. METHODS: Post-acute COVID-19 patients who had a World Health Organization (WHO) ordinal scale of 5-7, underwent intensive care, and received comprehensive rehabilitation management, including exercise programs, nutritional support, dysphagia evaluation, and psychological care were included. The appendicular skeletal muscle mass index (SMI), Medical Research Council sum score, handgrip strength, number of repetitions in the 1-minute sit-to-stand test, gait speed, Berg Balance Scale (BBS), and Functional Ambulation Classification (FAC) were evaluated at hospital stay, discharge, and 1-month follow-up. The correlation between the rehabilitation dose and improvement in each outcome measure was analyzed. RESULTS: Overall, 37 patients were enrolled, of whom 59.5% and 32.4% had a score of 6 and 7 on the WHO ordinal scale, respectively. Lengths of stay in the intensive care unit and hospital were 33.6 ± 23.9 and 63.8 ± 36.5 days. Outcome measures revealed significant improvements at discharge and 1-month follow-up. The SMI was significantly increased at the 1-month follow-up (6.13 [5.24-7.76]) compared with that during the hospital stay (5.80 [5.39-7.05]). We identified dose-response associations between the rehabilitation dose and FAC (ρ = 0.46) and BBS (ρ = 0.50) scores. Patients with older age, longer hospitalization, longer stay at the intensive care unit, longer duration of mechanical ventilation, tracheostomy, a more depressive mood, and poorer nutritional status revealed poorer improvement in gait speed at the 1-month follow-up. CONCLUSION: Comprehensive rehabilitation management effectively improved muscle mass, muscle strength, and physical performance in severe-to-critical COVID-19 patients. Dose-response relationship of rehabilitation and functional improvement emphasizes the importance of intensive post-acute inpatient rehabilitation in COVID-19 survivors. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05104411.


Assuntos
COVID-19 , Estudos de Coortes , Força da Mão , Humanos , Pacientes Internados , Unidades de Terapia Intensiva , Centros de Atenção Terciária
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