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1.
Angew Chem Int Ed Engl ; : e202416764, 2024 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-39345025

RESUMO

Electron-rich phosphines play a crucial role in transition metal-based homogeneous catalysis. While alkyl groups have traditionally been employed to increase the phosphine donor strength, recent studies have shown that zwitterionic functional groups such as phosphorus ylides can result in a further enhancement. Herein we report the concept of twisting a C=C double bond to introduce a zwitterionic substituent by the synthesis and application of N-heterocyclic olefin phosphines with a sulfonyl substituent (sNHOP). This sulfonyl group enables the twisting of the olefin moiety due to steric and electronic stabilization of the carbanionic center. The resulting zwitterionic structure leads to a significant increase of the donor strength of the sNHOP ligands compared to conventional NHOP systems with a planar N-heterocyclic olefin moiety. The potential of this new ligand platform for catalysis is demonstrated by its application in the gold-catalyzed hydroamination and cyclo-isomerization of alkynes. Here, the ligands outperform the original NHOP ligands suggesting favorable properties for future catalysis applications.

2.
Biomed Phys Eng Express ; 10(6)2024 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-39288783

RESUMO

This study discussed comparing result accuracy and time cost under different tally methods using MCNP6 for a novel transmission x-ray tube which was designed for the Auger electron yield with specific material (e.g. iodine). The assessment included photon spectrum, percent depth dose, mass-energy absorption coefficient corresponding to air and water, and figure of merit comparison. The mean energy of in-air phantom was from 41.8 keV (0 mm) to 40.9 keV (100 mm), and the mean energy of in-water phantom was from 41.41 keV (0 mm) to 45.2 keV (100 mm). The specific dose conversion factors based mass-energy absorption coefficient corresponding to different materials was established and the difference was less than 2% for the dose conversion of FMESH comparing to measurement data. FMESH had better figure of merit (FOM) than the F6 tally for the dose parameter assessment, which mean the dose calculation that focused on the superficial region could be assessed with more calculation efficiency by FMESH tally for this novel transmission x-ray tube. The results of this study could help develop treatment planning system (TPS) to quickly obtain the calculated data for phase space data establishment and heterogeneous correction under different physical condition settings.


Assuntos
Método de Monte Carlo , Imagens de Fantasmas , Fótons , Radiometria , Radiometria/métodos , Raios X , Humanos , Doses de Radiação , Água/química , Simulação por Computador
3.
J Breast Imaging ; 2024 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-39304331

RESUMO

OBJECTIVE: Our objective was to compare the efficacy of digital breast tomosynthesis (DBT) and digital mammography (DM) in breast cancer screening and their impact on long-term overall survival (OS). METHODS: The study involved 48 549 consecutive mammography examinations between 2011 and 2015 at a medical center in Taiwan, identifying 545 women who were screened and diagnosed with breast cancer. Digital mammography and DBT examinations were alternated on different days. Patients were categorized based on mammographic modality, breast density, and American Joint Committee on Cancer (AJCC) stage. To determine the long-term outcome until August 2021, survival rates were analyzed using the Kaplan-Meier (K-M) survival analysis. RESULTS: The mean age at breast cancer diagnosis was 53.2 years. Digital breast tomosynthesis examinations were significantly associated with early breast cancer (AJCC stage 0 to 2) (P = .022). The 5- and 9-year OS rates for all patients were 96.8% and 93.0%, respectively. The 5- and 9-year OS was significantly greater in the DBT group (98.4% and 96.8%) compared with the DM group (95.0% and 90.4%) (P = .030 for all). The K-M survival analysis demonstrated a significantly higher OS in the DBT group than the DM group (P = .037). Furthermore, DBT significantly improved OS in a cohort of women with stage II and III cancer (P = .032) and heterogeneously dense breasts (P = .045). CONCLUSION: Screening with DBT is associated with early breast cancer diagnosis and higher survival rates compared with DM.

4.
J Phys Ther Sci ; 36(8): 457-470, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39092409

RESUMO

[Purpose] Virtual reality has been increasingly used to improve the balance performance of older adults; however, the effect remains inconclusive. This study aimed to examine the effects of virtual reality on the balance performance of older adults through a systematic review and meta-analysis. [Methods] The PubMed, MEDLINE, CINAHL, Cochrane Library, and PEDro electronic databases were searched. Only randomized clinical trials published in English from January 1st, 1980, to September 30, 2022, were included and reviewed. Outcome measures included the Berg Balance Scale, Timed Up and Go Test and Activity-specific Balance Confidence scale. [Results] The results showed that virtual reality training for older adults led to significant improvements in Berg Balance Scale scores and Timed Up and Go Test times compared with non-virtual reality training. However, such an outcome was not observed with regard to the Activity-specific Balance Confidence scale. [Conclusion] Virtual reality training is effective in improving both static and dynamic balance among older adults. However, its effect on their self-confidence regarding balance is not significant.

5.
Int J Surg ; 2024 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-38959093

RESUMO

INTRODUCTION: The influence of deranged body composition on stage I/II HCC after surgery remains undetermined. The current study aimed to investigate the impact of low skeletal muscle bulk and disturbed body fat mass on the recurrence outcome of stage I/II HCC patients undergoing liver resection. The associated metabolomic alterations were also assessed. METHODS: From 2012 to 2021, stage I and II HCC patients who underwent liver resection at our institute were retrospectively reviewed. Their preoperative body composition including skeletal muscle mass and body fat volume was measured by computed tomography (CT). The recurrence outcome was recorded and analyzed. The preoperative serum was collected and subjected to metabolomic analysis. RESULTS: A total of 450 stage I and II HCC patients were included in the current study. Among them, 76% were male and around 60% had HBV infection. After stratified by normal cutoff values obtained from a healthy cohort, 6.4% of stage I/II HCC patients were found to have a low psoas muscle index (PMI), 17.8% a high subcutaneous adipose tissue (SAT) index, and 27.8% a high visceral adipose tissue (VAT) index. Cox regression multivariate analysis further demonstrated that low PMI and high SAT index were independent prognostic factors for time-to-recurrence (TTR) after surgery. Metabolomic analysis discovered that free fatty acid ß-oxidation was enhanced in with low PMI or high SAT index. CONCLUSION: The current study demonstrated that reduced psoas muscle mass may impair while elevated SAT may prolong the TTR of stage I/II HCC patients undergoing liver resections. VAT, on the other hand, was not associated with recurrence outcome after surgery. Further studies are warranted to validate our findings.

6.
Am J Pathol ; 194(10): 1967-1985, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39069169

RESUMO

Wnt-5a is a protein encoded by the WNT5A gene and is a ligand for the receptor tyrosine kinase-like orphan receptor 2 (ROR2). However, its biological impact on clear cell renal cell carcinoma (ccRCC) remains unclear. In this study, the prognostic significance of concurrent WNT5A and ROR2 expression levels was observed to predict unfavorable overall survival and disease-specific survival. High Wnt-5a expression was detected in a ccRCC cell line panel but not in HK-2 cells, a normal proximal tubular cell line. Inhibition of DNA methyltransferase by 5-azacytidine in 786-O and Caki-2 cells resulted in Wnt-5a up-regulation, indicating potential epigenetic modification. Furthermore, there was a repression of cell movement in vitro and metastatic colonization in vivo on WNT5A and ROR2 knockdown. Suppressions of angiogenesis in vivo and tubular-like structure formation in endothelial cells in vitro were also observed after silencing WNT5A and ROR2 expression. In addition, alteration in the downstream gene signature of the Wnt-5a-ROR2 signaling was similar to that in metastasis-associated gene 1-ß-catenin axis. Moreover, prunetin treatment reversed the gene signature derived from Wnt-5a-ROR2 signaling activation and to abolish ccRCC cell migration and proliferation. Overall, this study demonstrates the clinical and functional significance of the Wnt-5a-ROR2 axis and identifies prunetin as a potential precision medicine for patients with ccRCC harboring aberrant Wnt-5a-ROR2 signaling pathways.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Neovascularização Patológica , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase , Proteína Wnt-5a , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/tratamento farmacológico , Humanos , Proteína Wnt-5a/metabolismo , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/metabolismo , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/genética , Neoplasias Renais/patologia , Neoplasias Renais/metabolismo , Neoplasias Renais/genética , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Animais , Camundongos , Masculino , Transdução de Sinais/efeitos dos fármacos , Feminino , Movimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Metástase Neoplásica , Proliferação de Células/efeitos dos fármacos , Angiogênese
7.
J Cancer Res Clin Oncol ; 150(7): 354, 2024 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-39031214

RESUMO

BACKGROUND: Patients with autoimmune diseases (AD) generally carry an increased risk of developing cancer. However, the effect of AD in hepatocellular carcinoma (HCC) patients receiving surgical treatment is uncertain. The present study aimed to investigate the potential influence of AD on the survival of HCC patients undergoing hepatectomies. METHODS: Operated HCC patients were identified from the Chang Gung Research Database, and the survival outcomes of HCC patients with or without AD were analyzed ad compared. Cox regression model was performed to identify significant risk factors associated with disease recurrence and mortality. RESULTS: From 2002 to 2018, a total of 5532 patients underwent hepatectomy for their HCC. Among them, 229 patients were identified to have AD and 5303 were not. After excluding cases who died within 30 days of surgery, the estimated median overall survival (OS) was 43.8 months in the AD (+) group and 47.4 months in the AD (-) group (P = 0.367). The median liver-specific survival and disease-free survival (DFS) were also comparable between the two groups. After Cox regression multivariate analysis, the presence of AD did not lead to a higher risk of all-cause mortality, liver-specific mortality, or disease recurrence. CONCLUSION: Our study demonstrated that autoimmune disease does not impair the OS and DFS of HCC patients undergoing liver resections. AD itself is not a risk factor for tumor recurrence after surgery. Patients eligible for liver resections, as a result, should be considered for surgery irrespective of the presence of AD. Further studies are mandatory to validate our findings.


Assuntos
Doenças Autoimunes , Carcinoma Hepatocelular , Hepatectomia , Neoplasias Hepáticas , Humanos , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Carcinoma Hepatocelular/cirurgia , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Masculino , Feminino , Hepatectomia/mortalidade , Doenças Autoimunes/complicações , Doenças Autoimunes/mortalidade , Doenças Autoimunes/cirurgia , Pessoa de Meia-Idade , Idoso , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Estudos Retrospectivos , Fatores de Risco , Adulto , Taxa de Sobrevida , Prognóstico
8.
Sci Rep ; 14(1): 13220, 2024 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-38851820

RESUMO

University nursing students have been shown to experience psychological stress. A mindfulness-based intervention (MBI) may be a helpful tool for stress management. The aim of this study was to examine the effects of a MBI on improving mindfulness and reducing perceived stress in nursing students. A quasi-experimental study was conducted between July 2021 and February 2022. The intervention group participated in an 8-week mindfulness awareness course, which included 50 min of training and practice in mindfulness meditation techniques each week. Over the same 8 weeks, the control group watched a 50-min film each week. The mindful attention awareness scale (MAAS) and perceived stress scale (PSS) were administered before the intervention, intervention completion, and 2 and 6 months after the intervention. Data were analyzed using t test and generalized estimating equation. Overall, that the MBI showed a substantial effect on felt stress in comparison to the control group. When compared to the control group, the MBI showed a substantial impact on trait mindfulness. The MBI was beneficial for nursing students and could be considered a viable approach in nursing education to enhance mental wellbeing. It could be an effective method of relieving stress in a high-stress population.


Assuntos
Atenção Plena , Estresse Psicológico , Estudantes de Enfermagem , Humanos , Atenção Plena/métodos , Estudantes de Enfermagem/psicologia , Estresse Psicológico/terapia , Feminino , Masculino , Adulto Jovem , Adulto , Universidades , Meditação/métodos , Meditação/psicologia
9.
Sci Rep ; 14(1): 14917, 2024 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-38942819

RESUMO

In tuberculosis (TB), chest radiography (CXR) patterns are highly variable, mimicking pneumonia and many other diseases. This study aims to evaluate the efficacy of Google teachable machine, a deep neural network-based image classification tool, to develop algorithm for predicting TB probability of CXRs. The training dataset included 348 TB CXRs and 3806 normal CXRs for training TB detection. We also collected 1150 abnormal CXRs and 627 normal CXRs for training abnormality detection. For external validation, we collected 250 CXRs from our hospital. We also compared the accuracy of the algorithm to five pulmonologists and radiological reports. In external validation, the AI algorithm showed areas under the curve (AUC) of 0.951 and 0.975 in validation dataset 1 and 2. The accuracy of the pulmonologists on validation dataset 2 showed AUC range of 0.936-0.995. When abnormal CXRs other than TB were added, AUC decreased in both human readers (0.843-0.888) and AI algorithm (0.828). When combine human readers with AI algorithm, the AUC further increased to 0.862-0.885. The TB CXR AI algorithm developed by using Google teachable machine in this study is effective, with the accuracy close to experienced clinical physicians, and may be helpful for detecting tuberculosis by CXR.


Assuntos
Algoritmos , Aprendizado Profundo , Radiografia Torácica , Tuberculose Pulmonar , Humanos , Tuberculose Pulmonar/diagnóstico por imagem , Tuberculose Pulmonar/diagnóstico , Radiografia Torácica/métodos , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Área Sob a Curva
10.
J Chin Med Assoc ; 87(6): 635-642, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38690873

RESUMO

BACKGROUND: Liver transplantation is treatment option for patients with end-stage liver disease and hepatocellular carcinoma. Renal function deterioration significantly impacts the survival rates of liver recipients, and serum uric acid (SUA) is associated with both acute and chronic renal function disorders. Thus, our study aimed to assess the relationship and predictive value of preoperative SUA level and postoperative acute kidney injury (AKI) in living donor liver transplantation (LDLT). METHODS: We conducted a prospective observational study on 87 patients undergoing LDLT. Blood samples were collected immediately before LDLT, and renal function status was followed up for 3 consecutive days postoperatively. RESULTS: Low SUA levels (cutoff value 4.15 mg/dL) were associated with a high risk of early posttransplantation AKI. The area under the curve was 0.73 (sensitivity, 79.2%; specificity, 59.4%). Although not statistically significant, there were no deaths in the non-AKI group but two in the early AKI group secondary to liver graft dysfunction in addition to early AKI within the first month after LDLT. CONCLUSION: AKI after liver transplantation may lead to a deterioration of patient status and increased mortality rates. We determined low preoperative SUA levels as a possible risk factor for early postoperative AKI.


Assuntos
Injúria Renal Aguda , Transplante de Fígado , Doadores Vivos , Ácido Úrico , Humanos , Transplante de Fígado/efeitos adversos , Ácido Úrico/sangue , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/sangue , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto , Complicações Pós-Operatórias/sangue , Complicações Pós-Operatórias/etiologia
11.
Biomedicines ; 12(3)2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38540268

RESUMO

BACKGROUND: The perioperative outcomes of a partial hepatectomy for hepatocellular carcinoma (HCC) have improved. However, high recurrence rates after a curative hepatectomy for HCC is still an issue. This study aimed to analyze the difference between various recurrence patterns. METHODS: We retrospectively reviewed 754 patients with HCC who underwent a curative hepatectomy between January 2012 and March 2021. Patients with recurrent events were categorized into three types: regional recurrence (type I), multiple intrahepatic recurrence (type II), or presence of any distant metastasis (type III). RESULTS: The median follow-up period was 51.2 months. Regarding recurrence, 375 (49.7%) patients developed recurrence, with 244 (32.4%), 51 (6.8%), and 80 (10.6%) patients having type I, II, and III recurrence, respectively. Type III recurrence appeared to be more common in male patients and those with major liver resection, vascular invasion, a large tumor size (>5 cm), a higher tumor grade, and higher levels of AST and AFP (p < 0.05). Patients who had distant metastasis at recurrence had the shortest recurrence time and the worst overall survival (p < 0.001 and p < 0.001). CONCLUSIONS: our study demonstrated that recurrence with distant metastasis occurred earliest and had the worst outcome compared to regional or multiple intrahepatic recurrences.

12.
J Gastrointest Surg ; 28(3): 267-275, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38445919

RESUMO

BACKGROUND: Studies on prognostic factors for patients undergoing surgery to treat solitary liver metastases originating from colorectal cancer (CRC) are limited. This study aimed to analyze significant prognostic factors associated with tumor recurrence and long-term survival after liver resection for solitary colorectal liver metastasis. METHODS: Data from 230 patients with solitary liver metastases from CRC who received liver resection between 2010 and 2019 were retrospectively analyzed. Recurrence-free survival (RFS) and overall survival (OS) were accessed with the Kaplan-Meier method and log-rank test. Cox regression multivariate analysis identified independent variables associated with RFS and OS. Nomograms were developed to predict patient outcomes after surgery. RESULTS: The 3- and 5-year OS rates were 72.3% and 59.8%, respectively. The 3- and 5-year RFS rates were 40.0% and 27.1%, respectively. Multivariate analysis revealed age ≥ 70 years, resection margin width < 10 mm, initial N2 stage, hypoalbuminemia before surgery, and neutrophil-to-lymphocyte ratio (NLR) ≥ 3 after surgery as independent prognostic factors for OS. For RFS, initial N2 stage, hypoalbuminemia before surgery, NLR ≥ 3 after surgery, elevated carcinoembryonic antigen (CEA) levels after surgery, and CEA ratio (after/before liver resection) < 0.3 were identified as independent prognostic factors. CONCLUSION: This study demonstrated that initial N2 stage, hypoalbuminemia before liver resection, and NLR ≥ 3 after liver resection exert a significant association on the RFS and OS of patients undergoing surgery for solitary liver metastases from CRC. Thus, upfront chemotherapy, prompt postoperative chemotherapy, and intensive postoperative surveillance are mandatory for patients having these adverse factors.


Assuntos
Neoplasias Colorretais , Hipoalbuminemia , Neoplasias Hepáticas , Humanos , Idoso , Antígeno Carcinoembrionário , Prognóstico , Estudos Retrospectivos , Neoplasias Hepáticas/cirurgia
13.
Heliyon ; 10(5): e27072, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38449621

RESUMO

Rationale and objectives: To develop a prognostic nomogram using mammography data and AJCC staging to predict breast cancer survival. Materials and methods: A prognostic nomogram was created using data from 1000 women diagnosed with breast cancer at a medical cancer center in Taiwan between 2011 and 2015. The variables included age at diagnosis (≤60 or > 60 years), mammography purpose (screening or diagnostic), mammography modality (digital mammogram or digital breast tomosynthesis), and the 7th American Joint Committee on Cancer (AJCC) stage. The outcome predicted was breast cancer-related mortality. The nomogram utilized Kaplan-Meier analysis for all subsets and Cox proportional hazards regression analysis for prediction. The nomogram's accuracy was internally validated using the concordance index and receiver operating characteristic (ROC) curve analysis, focusing on 3-year and 5-year survival predictions. Results: Participants' mean age at breast cancer diagnosis was 54 years (SD = 11.2 years). The 1-year, 3-year, and 5-year overall survival (OS) rates were found to be 99.7%, 95.3%, and 91.4%, respectively. The bootstrap-corrected concordance indices indicated the following: nomogram, 0.807 and AJCC, 0.759. A significant difference was observed between the nomogram's area under the curve (AUC) and the AJCC stage in predicting the probability of 5-year survival (p = 0.005). A nomogram, constructed based on mammography and AJCC, demonstrated excellent calibration through internal validation using bootstrapping. Conclusion: The utilization of a nomogram that incorporates mammography data and the AJCC registry data has been demonstrated to be a reliable predictor of breast cancer survival.

14.
Heliyon ; 10(5): e27200, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38486759

RESUMO

Arrhythmia, a frequently encountered and life-threatening cardiac disorder, can manifest as a transient or isolated event. Traditional automatic arrhythmia detection methods have predominantly relied on QRS-wave signal detection. Contemporary research has focused on the utilization of wearable devices for continuous monitoring of heart rates and rhythms through single-lead electrocardiogram (ECG), which holds the potential to promptly detect arrhythmias. However, in this study, we employed a convolutional neural network (CNN) to classify distinct arrhythmias without QRS wave detection step. The ECG data utilized in this study were sourced from the publicly accessible PhysioNet databases. Taking into account the impact of the duration of ECG signal on accuracy, this study trained one-dimensional CNN models with 5-s and 10-s segments, respectively, and compared their results. In the results, the CNN model exhibited the capability to differentiate between Normal Sinus Rhythm (NSR) and various arrhythmias, including Atrial Fibrillation (AFIB), Atrial Flutter (AFL), Wolff-Parkinson-White syndrome (WPW), Ventricular Fibrillation (VF), Ventricular Tachycardia (VT), Ventricular Flutter (VFL), Mobitz II AV Block (MII), and Sinus Bradycardia (SB). Both 10-s and 5-s ECG segments exhibited comparable results, with an average classification accuracy of 97.31%. It reveals the feasibility of utilizing even shorter 5-s recordings for detecting arrhythmias in everyday scenarios. Detecting arrhythmias with a single lead aligns well with the practicality of wearable devices for daily use, and shorter detection times also align with their clinical utility in emergency situations.

15.
Nat Commun ; 15(1): 1726, 2024 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-38409174

RESUMO

Electronic processors are reaching the physical speed ceiling that heralds the era of optical processors. Multifunctional all-optical logic gates (AOLGs) of massively parallel processing are of great importance for large-scale integrated optical processors with speed far in excess of electronics, while are rather challenging due to limited operation bandwidth and multifunctional integration complexity. Here we for the first time experimentally demonstrate a reconfigurable all-in-one broadband AOLG that achieves nine fundamental Boolean logics in a single configuration, enabled by ultrabroadband (400-4000 nm) plasmon-enhanced thermo-optical nonlinearity (TONL) of liquid-metal Galinstan nanodroplet assemblies (GNAs). Due to the unique heterogeneity (broad-range geometry sizes, morphology, assembly profiles), the prepared GNAs exhibit broadband plasmonic opto-thermal effects (hybridization, local heating, energy transfer, etc.), resulting in a huge nonlinear refractive index under the order of 10-4-10-5 within visual-infrared range. Furthermore, a generalized control-signal light route is proposed for the dynamic TONL modulation of reversible spatial-phase shift, based on which nine logic functions are reconfigurable in one single AOLG configuration. Our work will provide a powerful strategy on large-bandwidth all-optical circuits for high-density data processing in the future.

16.
J Chem Inf Model ; 64(5): 1615-1627, 2024 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-38356220

RESUMO

Cancer immunotherapy harnesses the immune system to combat tumors and has emerged as a major cancer treatment modality. The PD-1/PD-L1 immune checkpoint modulates interactions between tumor cells and T cells and has been extensively targeted in cancer immunotherapy. However, the monoclonal antibodies known to target this immune checkpoint have considerable side effects, and novel PD-1/PD-L1 inhibitors are therefore required. Herein, a peptide inhibitor to disrupt PD-1/PD-L1 interactions was designed through structure-driven phage display engineering coupled to computational modification and optimization. BetaPb, a novel peptide library constructed by using the known structure of PD-1/PD-L, was used to develop inhibitors against the immune checkpoint, and specific peptides with high affinity toward PD-1 were screened through enzyme-linked immunosorbent assays, homogeneous time-resolved fluorescence, and biolayer interferometry. A potential inhibitor, B8, was preliminarily screened through biopanning. The binding affinity of B8 toward PD-1 was confirmed through computation-aided optimization. Assessment of B8 variants (B8.1, B8.2, B8.3, B8.4, and B8.5) demonstrated their attenuation of PD-1/PD-L1 interactions. B8.4 exhibited the strongest attenuation efficiency at a half-maximal effective concentration of 0.1 µM and the strongest binding affinity to PD-1 (equilibrium dissociation constant = 0.1 µM). B8.4 outperformed the known PD-1/PD-L1 interaction inhibitor PL120131 in disrupting PD-1/PD-L1 interactions, revealing that B8.4 has remarkable potential for modification to yield an antitumor agent. This study provides valuable information for the future development of peptide-based drugs, therapeutics, and immunotherapies for cancer.


Assuntos
Bacteriófagos , Neoplasias , Humanos , Inibidores de Checkpoint Imunológico , Receptor de Morte Celular Programada 1/química , Antígeno B7-H1/química , Peptídeos/farmacologia , Peptídeos/química , Bacteriófagos/metabolismo
17.
Acta Neuropathol ; 147(1): 9, 2024 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-38175301

RESUMO

Nuclear clearance and cytoplasmic accumulations of the RNA-binding protein TDP-43 are pathological hallmarks in almost all patients with amyotrophic lateral sclerosis (ALS) and up to 50% of patients with frontotemporal dementia (FTD) and Alzheimer's disease. In Alzheimer's disease, TDP-43 pathology is predominantly observed in the limbic system and correlates with cognitive decline and reduced hippocampal volume. Disruption of nuclear TDP-43 function leads to abnormal RNA splicing and incorporation of erroneous cryptic exons in numerous transcripts including Stathmin-2 (STMN2, also known as SCG10) and UNC13A, recently reported in tissues from patients with ALS and FTD. Here, we identify both STMN2 and UNC13A cryptic exons in Alzheimer's disease patients, that correlate with TDP-43 pathology burden, but not with amyloid-ß or tau deposits. We also demonstrate that processing of the STMN2 pre-mRNA is more sensitive to TDP-43 loss of function than UNC13A. In addition, full-length RNAs encoding STMN2 and UNC13A are suppressed in large RNA-seq datasets generated from Alzheimer's disease post-mortem brain tissue. Collectively, these results open exciting new avenues to use STMN2 and UNC13A as potential therapeutic targets in a broad range of neurodegenerative conditions with TDP-43 proteinopathy including Alzheimer's disease.


Assuntos
Doença de Alzheimer , Esclerose Lateral Amiotrófica , Demência Frontotemporal , Doença de Pick , Humanos , Doença de Alzheimer/genética , Proteínas de Ligação a DNA/genética , Splicing de RNA , RNA Mensageiro/genética , Estatmina/genética
18.
Int J Radiat Oncol Biol Phys ; 118(3): 712-724, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-37778426

RESUMO

PURPOSE: Our purpose was to report the clinical and dosimetric attributes of patients with large unresectable hepatocellular carcinoma (HCC) undergoing proton or photon radiation therapy. METHODS AND MATERIALS: We retrospectively analyzed the outcomes and dosimetric indices of 159 patients with >5 cm nonmetastatic HCC who underwent definitive radiation therapy using either protons (N = 105) or photons (N = 54) between 2014 and 2018. Additional photon plans were performed in the 105 proton-treated patients using the same dose prescription criteria for intragroup dosimetric comparison. RESULTS: After a median follow-up of 47 months, patients with biologically effective dose (BED10) ≥ 75 Gy exhibited significantly better local control (LC; 2-year: 85.6% vs 20.5%; P < .001), progression-free survival (PFS; median, 7.4 vs 3.2 months; P < .001), and overall survival (OS; median, 18.1 vs 7.3 months; P < .001) compared with those with BED10 < 75 Gy. Notably, proton-treated patients had a significantly higher BED10 (96 vs 67 Gy; P < .001) and improved LC (2-year: 88.5% vs 33.8%; P < .001), PFS (median, 7.4 vs 3.3 months; P = .001), and OS (median, 18.9 vs 8.3 months; P < .001) than those undergoing photon radiation therapy. Furthermore, patients treated with protons had significantly lower V1 of the liver (P < .001), mean upper gastrointestinal tract dose (P < .001), and mean splenic dose (P < .001), with significantly decreased incidences of radiation-induced liver disease (P = .007), grade ≥3 upper gastrointestinal bleeding (P = .001), and grade ≥3 lymphopenia (P = .003). On multivariate analysis, proton radiation therapy consistently correlated with superior LC (P < .001), PFS (P < .001), and OS (P < .001). In intragroup dosimetric comparison, photon plans demonstrated significantly higher mean liver dose (P < .001) compared with actually delivered proton treatments, and 72 (69%) of them had mean liver dose exceeding 28 Gy, which necessitated target dose de-escalation. CONCLUSIONS: In the context of large HCC radiation therapy, a higher target BED10 was associated with improved outcomes. Notably, proton therapy has demonstrated the capability to deliver ablative doses while also being accompanied by fewer instances of severe toxicity.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Terapia com Prótons , Lesões por Radiação , Humanos , Carcinoma Hepatocelular/patologia , Prótons , Estudos Retrospectivos , Neoplasias Hepáticas/patologia , Lesões por Radiação/etiologia , Terapia com Prótons/efeitos adversos , Terapia com Prótons/métodos , Dosagem Radioterapêutica
19.
J Formos Med Assoc ; 123(2): 238-247, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37586970

RESUMO

BACKGROUND: The percentage of and factors associated with the regression of Barrett's esophagus (BE) or its characteristic intestinal metaplasia (IM) remain unclear, and conflicting results have been reported because of diverse regression and sampling error definitions. Thus, we investigated the rates of IM regression, sampling error, and associated factors. METHODS: Forty-two patients with proven short-segment BE with IM who underwent two follow-up endoscopies with biopsies of Barrett's mucosa were retrospectively analyzed. Additional Alcian blue and MUC2 staining were done on the biopsy specimens without IM in hematoxylin-eosin staining. Only patients with negative hematoxylin-eosin, Alcian blue, and MUC2 staining for IM in both follow-up endoscopies were considered to have true regression. When all three stains were negative for IM in the first, but positive in the second follow-up endoscopy, we considered IM persisting and declared sampling error. RESULTS: Among the 18 patients without IM at the first follow-up endoscopy, only five (11.9%) were judged to have true regression. Prolonged proton-pump inhibitor use was significantly associated with regression. Limited experience of the endoscopist, and insufficient biopsy number were significantly related to sampling error. Receiver operating characteristic (ROC) curve analysis showed the best cut-off value of the biopsy number/maximal-length (cm) ratio to predict sampling error was 2.25. CONCLUSION: In our patients with short-segment BE, 11.9% experienced regression of IM. Prolonged proton-pump inhibitors treatment was associated with regression. An insufficient biopsy number was related to a missed IM, which may be eliminated by maintaining biopsy number/maximal-length (cm) ratio ≥2.25.


Assuntos
Esôfago de Barrett , Gastroenteropatias , Humanos , Azul Alciano , Amarelo de Eosina-(YS) , Seguimentos , Hematoxilina , Estudos Retrospectivos , Viés de Seleção , Endoscopia , Inibidores da Bomba de Prótons/uso terapêutico , Metaplasia
20.
Healthcare (Basel) ; 11(23)2023 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-38063631

RESUMO

Colorectal cancer (CRC) is a prevalent cancer globally, including in Vietnam where its incidence is rapidly increasing. The aim of this study was to evaluate the awareness of signs, symptoms, and risk factors of colorectal cancer among outpatients at Hoa Hao Medic Company Limited, Ho Chi Minh City, Vietnam. A cross-sectional study was conducted, and a total of 441 people who visited Hoa Hao Medic Company Limited for a general health check-up and voluntarily agreed to participate in this study were recruited through the convenience sampling method. Data were collected through face-to-face structured interviews using the Bowel CAM questionnaire. According to the results, the highest percentage of well-recalled warning signs were "change in bowel habit" (36.7%) followed by abdominal pain (35.4%). Other warning signs such as weight loss and rectal bleeding were reported by 19.0% and 18.1% of participants, respectively. Over 42% of participants stated that they were unaware of any signs or symptoms. The most commonly identified risk factors for CRC were pollution (66.9%), genetics (50.6%), and an unhealthy/poor diet (53.7%) for unprompted questions. The overall awareness score of participants was 3.46/9 (SD ± 2.91) for signs and symptoms of CRC and 5.90/10 (SD ± 1.62) for risk factors. Univariate linear regression identified education level and occupation as predictors of higher CRC awareness. In conclusion, this study highlights that overall awareness of CRC is low among outpatients at Hoa Hao Medic Company Limited. Strategies to increase awareness, knowledge, and education programs are necessary to promote early detection of CRC and reduce its burden in Vietnam.

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