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1.
Korean J Med Educ ; 36(2): 157-174, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38835309

RESUMO

PURPOSE: This study examines various aspects related to medical professionalism in medical students during coronavirus disease 2019 (COVID-19) pandemic, focusing on their medical professionalism attributes, KPA (knowledge, practices, and attitudes) toward COVID-19 and attitudes toward provision of care in pandemic. We assessed whether these aspects related to medical professionalism were varied by their demographics and mental health level. METHODS: Six questionnaires related to medical professionalism were distributed online to medical students in six grades at a single medical school. A one-way analysis of variance was used to examine differences in scores related to medical professionalism based on their demographics, for examples, gender, grade, residence, religion, as well as their mental health levels. Pearson correlation analysis was used to examine correlations between each variable. RESULTS: Female students scored higher on medical professionalism attributes and attitudes toward duty-to-care than male students. Medical professionalism attribute scores were higher with higher relationship satisfaction and resilience levels but lower with higher anxiety levels. Furthermore, these scores were significantly associated with attitudes toward COVID-19 preparedness. However, COVID-19 knowledge and practice scores were negatively associated with attitudes toward COVID-19 preparedness and careers after graduation. Meanwhile, students who took the leave of absence related to 2020 doctors' strike had significantly lower scores on attitudes toward COVID-19 preparedness and duty to care than those who did not. CONCLUSION: Our findings suggest that mental health of medical students is strongly related to their various aspects related to medical professionalism, especially their attitudes toward COVID-19 preparedness. Good mental health was positively linked to medical professionalism attributes and attitudes toward COVID-19 preparedness. However, knowledge and practice of COVID-19 were negatively associated with willingness to participate in the pandemic response. Additionally, the experience of the 2020 leave of absence impacted the attitudes of medical students toward COVID-19 preparedness (p=0.015) and their duty to care (p=0.012) negatively.


Assuntos
Atitude do Pessoal de Saúde , COVID-19 , Conhecimentos, Atitudes e Prática em Saúde , Saúde Mental , Profissionalismo , SARS-CoV-2 , Estudantes de Medicina , Humanos , COVID-19/epidemiologia , COVID-19/psicologia , Estudantes de Medicina/psicologia , Feminino , Masculino , Inquéritos e Questionários , Pandemias , Adulto , Adulto Jovem , República da Coreia
2.
Nat Commun ; 15(1): 4775, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38839750

RESUMO

The metal ion transporter SLC39A8 is associated with physiological traits and diseases, including blood manganese (Mn) levels and inflammatory bowel diseases (IBD). The mechanisms by which SLC39A8 controls Mn homeostasis and epithelial integrity remain elusive. Here, we generate Slc39a8 intestinal epithelial cell-specific-knockout (Slc39a8-IEC KO) mice, which display markedly decreased Mn levels in blood and most organs. Radiotracer studies reveal impaired intestinal absorption of dietary Mn in Slc39a8-IEC KO mice. SLC39A8 is localized to the apical membrane and mediates 54Mn uptake in intestinal organoid monolayer cultures. Unbiased transcriptomic analysis identifies alkaline ceramidase 1 (ACER1), a key enzyme in sphingolipid metabolism, as a potential therapeutic target for SLC39A8-associated IBDs. Importantly, treatment with an ACER1 inhibitor attenuates colitis in Slc39a8-IEC KO mice by remedying barrier dysfunction. Our results highlight the essential roles of SLC39A8 in intestinal Mn absorption and epithelial integrity and offer a therapeutic target for IBD associated with impaired Mn homeostasis.


Assuntos
Ceramidase Alcalina , Proteínas de Transporte de Cátions , Doenças Inflamatórias Intestinais , Mucosa Intestinal , Manganês , Camundongos Knockout , Animais , Proteínas de Transporte de Cátions/metabolismo , Proteínas de Transporte de Cátions/genética , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/patologia , Manganês/metabolismo , Camundongos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Ceramidase Alcalina/metabolismo , Ceramidase Alcalina/genética , Humanos , Camundongos Endogâmicos C57BL , Homeostase , Masculino , Colite/metabolismo , Colite/genética , Colite/patologia , Absorção Intestinal , Células Epiteliais/metabolismo
3.
Sci Rep ; 14(1): 11894, 2024 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-38789484

RESUMO

Although immunotherapy has not yet been as successful in ovarian cancer (OC), it remains a potential therapeutic strategy. Preclinical models of OC are necessary to evaluate the efficacy of immuno-oncology (IO) drugs targeting human immune components but have been underutilized. Developing mouse models with a humanized (Hu) immune system can help understand the human immune response to IO drugs which have demonstrated limited effectiveness in OC patients. We established OC xenograft Hu-mouse models by intraperitoneally injecting luciferase-expressing SKOV-3 Luc and OVCAR-3 Luc OC cells into CD34+ Hu-mice. Tumor growth was monitored through bioluminescence imaging (BLI). In the SKOV-3 Luc Hu-mouse model, we assessed the efficacy of PD-1 blockade with pembrolizumab. We observed the presence of human lymphocyte and myeloid cell subsets within the tumors, lymph nodes, blood, and spleens in these models. Notably, these tumors exhibited a high prevalence of tumor-infiltrating macrophages. Furthermore, we identified HDAC class I target genes, and genes associated with epithelial-mesenchymal transition (EMT) and fibroblasts in the tumors of Hu-mice treated with pembrolizumab. Our xenograft Hu-mouse model of OC provides a valuable tool for investigating the efficacy of IO drugs. The insights gained from this model offer useful information to explore potential mechanisms associated with unresponsive anti-PD-1 treatment in OC.


Assuntos
Anticorpos Monoclonais Humanizados , Perfilação da Expressão Gênica , Neoplasias Ovarianas , Neoplasias Peritoneais , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/tratamento farmacológico , Feminino , Humanos , Camundongos , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Linhagem Celular Tumoral , Neoplasias Peritoneais/secundário , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Modelos Animais de Doenças , Transcriptoma
4.
Artigo em Inglês | MEDLINE | ID: mdl-38797499

RESUMO

PURPOSE: This study aimed to evaluate the efficacy of local ablative therapy (LAT) combined with pembrolizumab in patients with synchronous oligometastatic non-small cell lung cancer (NSCLC) and to identify patients who would most benefit from LAT. METHODS AND MATERIALS: We retrospectively identified patients who received diagnosis of synchronous oligometastatic NSCLC (≤5 metastatic lesions and ≤3 organs involved) and were treated with first-line pembrolizumab between January 2017 and December 2022. Patients who underwent LAT, including surgery or radiation therapy at all disease sites, were compared with those who did not undergo LAT. A recursive partitioning analysis (RPA) model was developed using prognostic factors for progression-free survival (PFS). RESULTS: Among the 258 patients included, 78 received LAT with pembrolizumab, and 180 received pembrolizumab alone. The median follow-up duration was 15.5 months (range, 3.0-71.2 months). In the entire cohort, LAT was independently associated with significantly improved PFS (hazard ratio [HR], 0.64; P = .015) and overall survival (OS) (HR, 0.61; P = .020). In the propensity score-matched cohort (N = 74 in each group), the median PFS was 19.9 months and 9.6 months, respectively (P = .003), and the median OS was 42.2 months and 20.5 months, respectively (P = .045), for the LAT and non-LAT groups. Based on the RPA model, incorporating the number of metastatic lesions, performance status, and programmed cell death-ligand 1 expression level, patients were stratified into 3 risk groups with distinct PFS. LAT significantly improved PFS and OS in the low- and intermediate-risk groups; however, no difference was observed in the high-risk group. LAT was more effective as a consolidative treatment after pembrolizumab initiation than as an upfront therapy. CONCLUSIONS: LAT combined with pembrolizumab was associated with higher PFS and OS compared with pembrolizumab alone in selected patients with synchronous oligometastatic NSCLC. The RPA model could serve as a valuable clinical tool for identifying appropriate patients for LAT.

5.
Nat Chem Biol ; 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38664586

RESUMO

The natural product hinokitiol mobilizes iron across lipid bilayers at low concentrations and restores hemoglobinization in iron transporter protein-deficient systems. But hinokitiol fails to similarly mobilize iron at higher concentrations, limiting its uses in chemical biology and medicine. Here we show that at higher concentrations, hinokitiol3:Fe(III) complexes form large, higher-order aggregates, leading to loss of transmembrane iron mobilization. Guided by this understanding and systematic structure-function studies enabled by modular synthesis, we identified FeM-1269, which minimally aggregates and dose-dependently mobilizes iron across lipid bilayers even at very high concentrations. In contrast to hinokitiol, FeM-1269 is also well-tolerated in animals at high doses for extended periods of time. In a mouse model of anemia of inflammation, FeM-1269 increases serum iron, transferrin saturation, hemoglobin and hematocrit. This rationally developed iron-mobilizing small molecule has enhanced potential as a molecular prosthetic for understanding and potentially treating iron transporter deficiencies.

7.
PLoS One ; 19(2): e0298815, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38363779

RESUMO

OBJECTIVE: To investigate the anti-cancer efficacy of ENB101-LNP, an ionizable lipid nanoparticles (LNPs) encapsulating siRNA against E6/E7 of HPV 16, in combination therapy with cisplatin in cervical cancer in vitro and in vivo. METHODS: CaSki cells were treated with ENB101-LNP, cisplatin, or combination. Cell viability assessed the cytotoxicity of the treatment. HPV16 E6/E7 gene knockdown was verified with RT-PCR both in vitro and in vivo. HLA class I and PD-L1 were checked by flow cytometry. A xenograft model was made using CaSki cells in BALB/c nude mice. To evaluate anticancer efficacy, mice were grouped. ENB101-LNP was given three times weekly for 3 weeks intravenously, and cisplatin was given once weekly intraperitoneally. Tumor growth was monitored. On day 25, mice were euthanized; tumors were collected, weighed, and imaged. Tumor samples were analyzed through histopathology, immunostaining, and western blot. RESULTS: ENB101-LNP and cisplatin synergistically inhibit CaSki cell growth. The combination reduces HPV 16 E6/E7 mRNA and boosts p21 mRNA, p53, p21, and HLA class I proteins. In mice, the treatment significantly blocked tumor growth and promoted apoptosis. Tumor inhibition rates were 29.7% (1 mpk ENB101-LNP), 29.6% (3 mpk), 34.0% (cisplatin), 47.0% (1 mpk ENB101-LNP-cisplatin), and 68.8% (3 mpk ENB101-LNP-cisplatin). RT-PCR confirmed up to 80% knockdown of HPV16 E6/E7 in the ENB101-LNP groups. Immunohistochemistry revealed increased p53, p21, and HLA-A expression with ENB101-LNP treatments, alone or combined. CONCLUSION: The combination of ENB101-LNP, which inhibits E6/E7 of HPV 16, with cisplatin, demonstrated significant anticancer activity in the xenograft mouse model of cervical cancer.


Assuntos
Lipossomos , Nanopartículas , Proteínas Oncogênicas Virais , Neoplasias do Colo do Útero , Feminino , Humanos , Animais , Camundongos , RNA Interferente Pequeno/genética , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/metabolismo , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia , Proteína Supressora de Tumor p53/genética , Camundongos Nus , Xenoenxertos , Linhagem Celular Tumoral , Proteínas Oncogênicas Virais/genética , Proteínas Oncogênicas Virais/metabolismo , Proteínas E7 de Papillomavirus/genética , Proteínas E7 de Papillomavirus/metabolismo , RNA Mensageiro/genética
8.
Cancer Res Treat ; 56(3): 785-794, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38228082

RESUMO

PURPOSE: This study aimed to assess the real-world clinical outcomes of consolidative durvalumab in patients with unresectable locally advanced non-small cell lung cancer (LA-NSCLC) and to explore the role of radiotherapy in the era of immunotherapy. MATERIALS AND METHODS: This retrospective study assessed 171 patients with unresectable LA-NSCLC who underwent concurrent chemoradiotherapy (CCRT) with or without consolidative durvalumab at Asan Medical Center between May 2018 and May 2021. Primary outcomes included freedom from locoregional failure (FFLRF), distant metastasis-free survival (DMFS), progression-free survival (PFS), and overall survival (OS). RESULTS: Durvalumab following CCRT demonstrated a prolonged median PFS of 20.9 months (p=0.048) and a 3-year FFLRF rate of 57.3% (p=0.008), compared to 13.7 months and 38.8%, respectively, with CCRT alone. Furthermore, the incidence of in-field recurrence was significantly greater in the CCRT-alone group compared to the durvalumab group (26.8% vs. 12.4%, p=0.027). While median OS was not reached with durvalumab, it was 35.4 months in patients receiving CCRT alone (p=0.010). Patients positive for programmed cell death ligand 1 (PD-L1) expression showed notably better outcomes, including FFLRF, DMFS, PFS, and OS. Adherence to PACIFIC trial eligibility criteria identified 100 patients (58.5%) as ineligible. The use of durvalumab demonstrated better survival regardless of eligibility criteria. CONCLUSION: The use of durvalumab consolidation following CCRT significantly enhanced locoregional control and OS in patients with unresectable LA-NSCLC, especially in those with PD-L1-positive tumors, thereby validating the role of durvalumab in standard care.


Assuntos
Anticorpos Monoclonais , Carcinoma Pulmonar de Células não Pequenas , Quimiorradioterapia , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Masculino , Feminino , Quimiorradioterapia/métodos , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/tratamento farmacológico , Estudos Retrospectivos , Idoso , Pessoa de Meia-Idade , Anticorpos Monoclonais/uso terapêutico , Adulto , Antineoplásicos Imunológicos/uso terapêutico , Idoso de 80 Anos ou mais
10.
Cell Death Dis ; 15(1): 48, 2024 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-38218922

RESUMO

Valosin-containing protein (VCP)/p97, an AAA+ ATPase critical for maintaining proteostasis, emerges as a promising target for cancer therapy. This study reveals that targeting VCP selectively eliminates breast cancer cells while sparing non-transformed cells by inducing paraptosis, a non-apoptotic cell death mechanism characterized by endoplasmic reticulum and mitochondria dilation. Intriguingly, oncogenic HRas sensitizes non-transformed cells to VCP inhibition-mediated paraptosis. The susceptibility of cancer cells to VCP inhibition is attributed to the non-attenuation and recovery of protein synthesis under proteotoxic stress. Mechanistically, mTORC2/Akt activation and eIF3d-dependent translation contribute to translational rebound and amplification of proteotoxic stress. Furthermore, the ATF4/DDIT4 axis augments VCP inhibition-mediated paraptosis by activating Akt. Given that hyperactive Akt counteracts chemotherapeutic-induced apoptosis, VCP inhibition presents a promising therapeutic avenue to exploit Akt-associated vulnerabilities in cancer cells by triggering paraptosis while safeguarding normal cells.


Assuntos
Neoplasias , Proteínas Proto-Oncogênicas c-akt , Proteína com Valosina/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Paraptose , Adenosina Trifosfatases/metabolismo , Retículo Endoplasmático/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo
11.
Sci Data ; 10(1): 891, 2023 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-38086886

RESUMO

The Antarctic whitefin plunderfish Pogonophryne albipinna belongs to the family Artedidraconidae, a key component of Antarctic benthic ecosystems within the order Perciformes and the suborder Notothenioidei. While genome research on P. albipinna using short-read sequencing is available, high-quality genome assembly and annotation employing long-read sequencing have yet to be performed. This study presents a chromosome-scale genome assembly and annotation for P. albipinna, utilizing a combination of Illumina short-read, PacBio long-read, and Hi-C sequencing technologies. The resulting genome assembly spans approximately 1.07 Gb, with a longest scaffold measuring 59.39 Mb and an N50 length of 41.76 Mb. Of the 1,111 Hi-C scaffolds, 23 exceeded 10 Mb and were thus classified as chromosome-level. BUSCO completeness was assessed at 95.6%. The assembled genome comprises 50.68% repeat sequences, and a total of 31,128 protein-coding genes were predicted. This study will enhance our understanding of the genomic characteristics of cryonotothenioids and facilitate comparative analyses of their adaptation and evolution in extreme environments.


Assuntos
Genoma , Perciformes , Animais , Regiões Antárticas , Cromossomos/genética , Ecossistema , Anotação de Sequência Molecular , Perciformes/genética , Filogenia
12.
BMC Med Ethics ; 24(1): 107, 2023 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-38041034

RESUMO

BACKGROUND: Conventional consent practices face ethical challenges in continuously evolving digital health environments due to their static, one-time nature. Dynamic consent offers a promising solution, providing adaptability and flexibility to address these ethical concerns. However, due to the immaturity of the concept and accompanying technology, dynamic consent has not yet been widely used in practice. This study aims to identify the facilitators of and barriers to adopting dynamic consent in real-world scenarios. METHODS: This scoping review, conducted in December 2022, adhered to the PRISMA Extension for Scoping Reviews guidelines, focusing on dynamic consent within the health domain. A comprehensive search across Web of Science, PubMed, and Scopus yielded 22 selected articles based on predefined inclusion and exclusion criteria. RESULTS: The facilitators for the adoption of dynamic consent in digital health ecosystems were the provision of multiple consent modalities, personalized alternatives, continuous communication, and the dissemination of up-to-date information. Nevertheless, several barriers, such as consent fatigue, the digital divide, complexities in system implementation, and privacy and security concerns, needed to be addressed. This study also investigated current technological advancements and suggested considerations for further research aimed at resolving the remaining challenges surrounding dynamic consent. CONCLUSIONS: Dynamic consent emerges as an ethically advantageous method for digital health ecosystems, driven by its adaptability and support for continuous, two-way communication between data subjects and consumers. Ethical implementation in real-world settings requires the development of a robust technical framework capable of accommodating the diverse needs of stakeholders, thereby ensuring ethical integrity and data privacy in the evolving digital health landscape.


Assuntos
Comunicação , Ecossistema , Humanos , Privacidade , Tecnologia , Consentimento Livre e Esclarecido
13.
Radiat Oncol J ; 41(3): 199-208, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37793629

RESUMO

PURPOSE: An optimal once-daily radiotherapy (RT) regimen is under investigation for definitive concurrent chemoradiotherapy (CCRT) in limited disease small cell lung cancer (LD-SCLC). We compared the efficacy and safety of dose escalation with intensity-modulated radiotherapy (IMRT). MATERIALS AND METHODS: Between January 2016 and March 2021, patients treated with definitive CCRT for LD-SCLC with IMRT were retrospectively reviewed. Patients who received a total dose <50 Gy or those with a history of thoracic RT or surgery were excluded. The patients were divided into two groups (standard and dose-escalated) based on the total biologically effective dose (BED, α/ß = 10) of 70 Gy. The chemotherapeutic regimen comprised four cycles of etoposide and cisplatin. RESULTS: One hundred and twenty-two patients were analyzed and the median follow-up was 27.8 months (range, 4.4 to 76.9 months). The median age of the patients was 63 years (range, 35 to 78 years) and the majority had a history of smoking (86.0%). The 1- and 3-year overall survival rates of the escalated dose group were significantly higher than those of the standard group (93.5% and 50.5% vs. 76.7% and 33.3%, respectively; p = 0.008), as were the 1- and 3-year freedom from in-field failure rates (91.4% and 66.5% vs. 73.8% and 46.9%, respectively; p = 0.018). The incidence of grade 2 or higher acute and late pneumonitis was not significantly different between the two groups (p = 0.062, 0.185). CONCLUSION: Dose-escalated once-daily CCRT with IMRT led to improved locoregional control and survival, with no increase in toxicity.

14.
Sci Data ; 10(1): 657, 2023 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-37752129

RESUMO

The blackfin Icefish (Chaenocephalus aceratus) belongs to the family Channichthyidae and the suborder Notothenioidei which lives in the Antarctic. We corrected the mis-scaffolds in the previous linkage map results by Hi-C analysis to obtain improved results for chromosome-level genome assembly. The final assembly analysis resulted in a total of 3,135 scaffolds, a genome size of 1,065.72 Mb, and an N50 of 33.46 Mb. 820.24 Mb, representing 88.88% of the total genome, is anchored to 24 chromosomes. The final gene set of 38,024 genes, including AFGPs, was annotated using RNA evidence, proteins, and ab-initio predictions. The complete percentage of BUSCO analysis is 92.7%. In this study, we aim to contribute to the study of polar fishes by improving the genome sequences of the blackfin icefish with the AFGP genes belonging to the Notothenoidei.


Assuntos
Perciformes , Animais , Regiões Antárticas , Mapeamento Cromossômico , Cromossomos/genética , Perciformes/genética , RNA , Genoma
15.
Cancer Sci ; 114(9): 3583-3594, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37650703

RESUMO

Radiotherapy (RT) plays an important role in localized lung cancer treatments. Although RT locally targets and controls malignant lesions, RT resistance prevents RT from being an effective treatment for lung cancer. In this study, we identified phosphomevalonate kinase (PMVK) as a novel radiosensitizing target and explored its underlying mechanism. We found that cell viability and survival fraction after RT were significantly decreased by PMVK knockdown in lung cancer cell lines. RT increased apoptosis, DNA damage, and G2/M phase arrest after PMVK knockdown. Also, after PMVK knockdown, radiosensitivity was increased by inhibiting the DNA repair pathway, homologous recombination, via downregulation of replication protein A1 (RPA1). RPA1 downregulation was induced through the ubiquitin-proteasome system. Moreover, a stable shRNA PMVK mouse xenograft model verified the radiosensitizing effects of PMVK in vivo. Furthermore, PMVK expression was increased in lung cancer tissues and significantly correlated with patient survival and recurrence. Our results demonstrate that PMVK knockdown enhances radiosensitivity through an impaired HR repair pathway by RPA1 ubiquitination in lung cancer, suggesting that PMVK knockdown may offer an effective therapeutic strategy to improve the therapeutic efficacy of RT.


Assuntos
Neoplasias Pulmonares , Humanos , Animais , Camundongos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/radioterapia , Fosfotransferases (Aceptor do Grupo Fosfato) , Tolerância a Radiação/genética , Ubiquitinação , Modelos Animais de Doenças
16.
Cancer Cell Int ; 23(1): 172, 2023 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-37596639

RESUMO

BACKGROUND: The B7-H3 protein, encoded by the CD276 gene, is a member of the B7 family of proteins and a transmembrane glycoprotein. It is highly expressed in various solid tumors, such as lung and breast cancer, and has been associated with limited expression in normal tissues and poor clinical outcomes across different malignancies. Additionally, B7-H3 plays a crucial role in anticancer immune responses. Antibody-drug conjugates (ADCs) are a promising therapeutic modality, utilizing antibodies targeting tumor antigens to selectively and effectively deliver potent cytotoxic agents to tumors. METHODS: In this study, we demonstrate the potential of a novel B7-H3-targeting ADC, ITC-6102RO, for B7-H3-targeted therapy. ITC-6102RO was developed and conjugated with dHBD, a soluble derivative of pyrrolobenzodiazepine (PBD), using Ortho Hydroxy-Protected Aryl Sulfate (OHPAS) linkers with high biostability. We assessed the cytotoxicity and internalization of ITC-6102RO in B7-H3 overexpressing cell lines in vitro and evaluated its anticancer efficacy and mode of action in B7-H3 overexpressing cell-derived and patient-derived xenograft models in vivo. RESULTS: ITC-6102RO inhibited cell viability in B7-H3-positive lung and breast cancer cell lines, inducing cell cycle arrest in the S phase, DNA damage, and apoptosis in vitro. The binding activity and selectivity of ITC-6102RO with B7-H3 were comparable to those of the unconjugated anti-B7-H3 antibody. Furthermore, ITC-6102RO proved effective in B7-H3-positive JIMT-1 subcutaneously xenografted mice and exhibited a potent antitumor effect on B7-H3-positive lung cancer patient-derived xenograft (PDX) models. The mode of action, including S phase arrest and DNA damage induced by dHBD, was confirmed in JIMT-1 tumor tissues. CONCLUSIONS: Our preclinical data indicate that ITC-6102RO is a promising therapeutic agent for B7-H3-targeted therapy. Moreover, we anticipate that OHPAS linkers will serve as a valuable platform for developing novel ADCs targeting a wide range of targets.

17.
Medicine (Baltimore) ; 102(30): e34358, 2023 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-37505153

RESUMO

BACKGROUND: Hemodynamic variations during the induction of general anesthesia are more profound in hypertensive patients, and the risk of hypoperfusion-induced organ damage followed by hypotensive episodes is higher in hypertensive patients than in normotensive patients. Thus, we compared the effects of remimazolam and propofol on hemodynamics during general anesthesia induction in hypertensive patients. METHODS: Patients were randomly divided into the remimazolam (Group R, n = 48) and propofol (Group P, n = 48) groups: remimazolam was continued at 6 mg/kg/hour until the patient lost consciousness, followed by 1 mg/kg/hour until 5 minutes after tracheal intubation. Propofol was administered as a slow bolus of 1.5 to 2 mg/kg, followed by 3 to 6 mg/kg/hour 5 minutes after tracheal intubation. Hemodynamic parameters including mean blood pressure (MBP), systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate, and incidence of hypotension were analyzed during the induction period, pre-induction (T1), immediately after loss of consciousness (T2), at 1 and 3 minutes after neuromuscular blockade (T3, T4), immediately after tracheal intubation (T5), and at 1, 3, and 5 minutes after tracheal intubation (T6, T7, T8). RESULTS: The MBP, SBP, and DBP were significantly lower in the propofol group than in the remimazolam group (MBP: at T2, T3, T4, and T5; SBP: at T2, T3, and T4; DBP: at T5). HR was significantly lower in the propofol group at T3, T4, and T8. The incidence of hypotension was significantly higher in the propofol group than that in the remimazolam group. The incidence of bradycardia was comparable between the groups. CONCLUSIONS: Remimazolam induction was more stable than propofol induction in preserving normal hemodynamics and was associated with a relatively lower incidence of hypotension. Remimazolam may be preferable to propofol for induction of anesthesia in patients with hypertension.


Assuntos
Hipertensão , Hipotensão , Propofol , Humanos , Hemodinâmica , Anestesia Geral , Hipotensão/etiologia
18.
J Korean Med Sci ; 38(22): e169, 2023 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-37272558

RESUMO

BACKGROUND: Healthcare professionals often experience moral distress while providing end-of-life care. This study explored how physicians and nurses experienced moral distress when they cared for critically and terminally ill patients in tertiary hospitals in South Korea. METHODS: This study used semi-structured in-depth interviews. A total of 22 people in two tertiary hospitals were interviewed, nine (40.9%) of which were physicians and 13 (59.1%) were nurses. The recorded interview files and memos were analyzed using grounded theory. RESULTS: Most physicians and nurses encountered similar feelings of anger, helplessness, and burden owing to a lack of appropriate resources for end-of-life care. However, the factors and contexts of their moral distress differed. Nurses mainly addressed poorly organized end-of-life care, intensive labor conditions without support for nurses, and providing care without participation in decision-making. Meanwhile, physicians addressed the prevailing misperceptions on end-of-life care, communication failure between physicians owing to hierarchy and fragmented disciplines, the burden of responsibility in making difficult decisions, and the burden of resource allocation. CONCLUSION: Differences in moral distress between physicians and nurses leave them isolated and can affect communication regarding healthcare. Mutual understanding between job disciplines will enhance their communication and help resolve conflicts in end-of-life care.


Assuntos
Enfermeiras e Enfermeiros , Médicos , Assistência Terminal , Humanos , Hospitais Universitários , Atitude do Pessoal de Saúde , Princípios Morais , Estresse Psicológico , Inquéritos e Questionários
19.
World J Clin Cases ; 11(10): 2349-2354, 2023 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-37122517

RESUMO

BACKGROUND: Functional vocal cord disorders can be a differential diagnosis for postoperative upper airway obstruction requiring urgent intervention. However, this may be unfamiliar to anesthesiologists who would favor inappropriate airway intervention and increased morbidity. CASE SUMMARY: A 61-year-old woman underwent cervical laminectomy, followed by laparoscopic cholecystectomy 10 mo later. Despite adequate reversal of neuromuscular blockade, the patient experienced repetitive respiratory difficulty with inspiratory stridor after extubation. After the second operation, the patient was diagnosed with paradoxical vocal fold motion (PVFM) by an otolaryngologist based on the clinical features and fiberoptic bronchoscopy results, and the patient was successfully treated. CONCLUSION: PVFM should be considered a differential diagnosis if a patient presents with stridor after general anesthesia.

20.
Children (Basel) ; 10(4)2023 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-37189880

RESUMO

Miller-Dieker syndrome (MDS) is a genetic disorder characterized by classic lissencephaly, distinctive facial features, intellectual disability, seizures, and early death. The anesthetic management of patients with MDS should focus on airway manipulation with the risk of potentially difficult intubation, seizure control due to lissencephaly, and any other clinical complications. Herein, we report a case of anesthetic management in a child with MDS and describe relevant clinical features in a perioperative anesthetic setting. This case highlights the importance of difficult airway manipulation using a videolaryngoscope, seizure management with regard to anesthetics use, and the low validity of BIS monitoring in patients with MDS.

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