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Background: South Korea's Ministry of Health and Welfare has developed clinical pathways for Korean Medicine (KM-CPs). As part of this initiative, a panel comprising Korean Medicine doctors (KMD) was assembled. This implementation study aimed to preliminarily explore how KM-CP implementation affects the appropriateness and efficiency of the clinical process and its relation to attitude. Methods: Through random sampling, 311 KMDs were recruited as panelists to participate in two surveys. The surveys included information regarding the KM clinical environment and KM-CP implementation. A panel management program and educational materials were provided to KMDs between the two survey periods. Only 262 KMDs who responded to both surveys were included in the analysis. Three analyses were conducted: 1) descriptive analysis of the study variables, 2) panel analysis using the ordered logit regression model to elucidate the impact of KM-CP on the appropriateness and efficiency of the clinical process, and 3) ordered logit regression analysis of the association between KM-CP implementation and attitude. Results: More than two-thirds of the KMDs attempted to adopt KM-CP, with mostly positive perception expressed by these doctors. However, expectations and concerns coexist with the standardization of KM-CP. Cases in which KM-CPs were partially and mostly implemented respectively had negative and positive effects on the appropriateness and efficiency of the clinical process compared to those in which KM-CPs were not implemented. Compared to neutral attitude, positive and very positive attitudes tended to be associated with increased implementation of KM-CP. However, statistical significances were not observed. Conclusions: The impact of KM-CP on the clinical process and its association with attitude were found to be statistically unclear or inconsistent. Considering the study limitations and implications, we suggest a policy and academic strategies aimed at fostering improvement to enhance its utility.
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Histone demethylases, enzymes responsible for removing methyl groups from histone proteins, have emerged as critical players in regulating gene expression and chromatin dynamics, thereby influencing various cellular processes. LSD2 and LSD1 have attracted considerable interest among these demethylases because of their associations with cancer. However, while LSD1 has received significant attention, LSD2 has not been recognized to the same extent. In this study, we conduct a comprehensive comparison between LSD2 and LSD1, with a focus on exploring LSD2's implications. While both share structural similarities, LSD2 possesses unique features as well. Functionally, LSD2 shows diverse roles, particularly in cancer, with tissue-dependent roles. Additionally, LSD2 extends beyond histone demethylation, impacting DNA methylation, cancer cell reprogramming, E3 ubiquitin ligase activity and DNA damage repair pathways. This study underscores the distinct roles of LSD2, providing insights into their contributions to cancer and other cellular processes.
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Metilación de ADN , Epigénesis Genética , Histona Demetilasas , Neoplasias , Histona Demetilasas/metabolismo , Histona Demetilasas/genética , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Metilación de ADN/genética , Histonas/metabolismo , Histonas/genética , Reparación del ADN , Regulación Neoplásica de la Expresión Génica , Proteínas F-Box , Histona Demetilasas con Dominio de JumonjiRESUMEN
Previously, we analyzed 316 herbal extracts to evaluate their potential nematocidal properties in Caenorhabditis elegans. In this study, our attention was directed towards Torenia sp., resulting in reduced survival and heightened larval arrest/lethality, alongside a noticeable decrease in DAPI-stained bivalent structures and disrupted meiotic progression, thus disrupting developmental processes. Notably, Torenia sp. extracts activated a DNA damage checkpoint response via the ATM/ATR and CHK-1 pathways, hindering germline development. LC-MS analysis revealed 13 compounds in the Torenia sp. extracts, including flavonoids, terpenoids, tanshinones, an analog of resveratrol, iridoids, carotenoids, fatty acids, and alkaloids. Of these, 10 are known for their antitumor activity, suggesting the potential of Torenia species beyond traditional gardening, extending into pharmaceutical and therapeutic applications.
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This study aimed to investigate the impact of racial residential segregation on healthcare utilization and perceived quality of care among informal caregivers in the US. It further assessed potential variations in the estimated impact across caregivers' race and socioeconomic status. We used data from the Health Information National Trends Survey Data Linkage Project (fielded in 2020) for a sample of 583 self-identified informal caregivers in the US. Fitting a series of regression models with the maximum likelihood estimation, we computed the beta coefficients (ß) of interest and their associated Wald 95% confidence limits (CI). Caregivers who resided in areas with higher segregation, compared to those living in lower segregated areas, were less likely to visit a healthcare professional [ß = - 2.08; Wald 95%CI - 2.093, - 2.067] (moderate); [ß = - 2.53; Wald 95%CI - 2.549, - 2.523] (high)]. Further, caregivers residing in moderate [ß = - 0.766; Wald 95%CI - 0.770, - 0.761] and high [ß = - 0.936; Wald 95%CI - 0.941, - 0.932] segregation regions were less likely to perceive a better quality of care compared to those located in low segregation areas. Moreover, as segregation level increased, Black caregivers were less likely to see a health professional, less frequently used healthcare services, and had poorer perceived healthcare quality when compared to Whites. Our findings indicate that higher residential segregation is associated with lower healthcare utilization, such as visiting a healthcare professional, and poorer perceived healthcare quality among informal caregivers. Given the essential role of informal caregivers in the current healthcare system, it is vital to investigate and address challenges associated with access to and quality of essential healthcare services to improve caregivers' health and well-being, specifically for caregivers of minority backgrounds.
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To probe the functions of Aster glehni (AG) extract containing various caffeoylquinic acids on dyslipidemia, obesity, and skeletal muscle-related diseases focused on the roles of skeletal muscle, we measured the levels of biomarkers involved in oxidative phosphorylation and type change of skeletal muscle in C2C12 cells and skeletal muscle tissues from apolipoprotein E knockout (ApoE KO) mice. After AG extract treatment in cell and animal experiments, western blotting, immunohistochemistry, and enzyme-linked immunosorbent assay (ELISA) were used to estimate the levels of proteins that participated in skeletal muscle type change and oxidative phosphorylation. AG extract elevated protein expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), phosphorylated 5'-AMP-activated protein kinase (p-AMPK), peroxisome proliferator-activated receptor beta/delta (PPARß/δ), myoblast determination protein 1 (MyoD), and myoglobin in skeletal muscle tissues. Furthermore, it elevated the ATP concentration. However, protein expression of myostatin was decreased by AG treatment. In C2C12 cells, increments of MyoD, myoglobin, myosin, ATP-producing pathway, and differentiation degree by AG were dependent on PPARß/δ and caffeoylquinic acids. AG extract can contribute to the amelioration of skeletal muscle inactivity and sarcopenia through myogenesis in skeletal muscle tissues from ApoE KO mice, and function of AG extract may be dependent on PPARß/δ, and the main functional constituents of AG are trans-5-O-caffeoylquinic acid and 3,5-O-dicaffeoylquinic acid. In addition, in skeletal muscle, AG has potent efficacies against dyslipidemia and obesity through the increase of the type 1 muscle fiber content to produce more ATP by oxidative phosphorylation in skeletal muscle tissues from ApoE KO mice.
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Ratones Noqueados , Desarrollo de Músculos , Músculo Esquelético , PPAR delta , PPAR-beta , Extractos Vegetales , Ácido Quínico , Animales , Ratones , Ácido Quínico/análogos & derivados , Ácido Quínico/farmacología , Extractos Vegetales/farmacología , PPAR-beta/metabolismo , PPAR-beta/genética , Músculo Esquelético/metabolismo , Músculo Esquelético/efectos de los fármacos , Desarrollo de Músculos/efectos de los fármacos , PPAR delta/metabolismo , PPAR delta/genética , Masculino , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Humanos , Proteína MioD/metabolismo , Proteína MioD/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Ratones Endogámicos C57BL , Proteínas Quinasas Activadas por AMP/metabolismoRESUMEN
Proper cellular proteostasis, essential for viability, requires a network of chaperones and cochaperones. ATP-dependent chaperonin TRiC/CCT partners with cochaperones prefoldin (PFD) and phosducin-like proteins (PhLPs) to facilitate folding of essential eukaryotic proteins. Using cryoEM and biochemical analyses, we determine the ATP-driven cycle of TRiC-PFD-PhLP2A interaction. PhLP2A binds to open apo-TRiC through polyvalent domain-specific contacts with its chamber's equatorial and apical regions. PhLP2A N-terminal H3-domain binding to subunits CCT3/4 apical domains displace PFD from TRiC. ATP-induced TRiC closure rearranges the contacts of PhLP2A domains within the closed chamber. In the presence of substrate, actin and PhLP2A segregate into opposing chambers, each binding to positively charged inner surface residues from CCT1/3/6/8. Notably, actin induces a conformational change in PhLP2A, causing its N-terminal helices to extend across the inter-ring interface to directly contact a hydrophobic groove in actin. Our findings reveal an ATP-driven PhLP2A structural rearrangement cycle within the TRiC chamber to facilitate folding.
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Actinas , Proteínas del Ojo , Reguladores de Proteínas de Unión al GTP , Fosfoproteínas , Pliegue de Proteína , Actinas/metabolismo , Proteínas Portadoras/metabolismo , Chaperoninas/metabolismo , Adenosina Trifosfato/metabolismo , Chaperonina con TCP-1/metabolismoRESUMEN
Although Si is extensively used in micro-nano electronics, its inherent optical absorption cutoff at 1100-nm limits its photonic and optoelectronic applications in visible to partly near infrared (NIR) spectral range. Recently, strain engineering has emerged as a promising approach for extending device functionality via tuning the material properties, including change in optical bandgap. In this study, the reduction in bandgap with applied strain was used for extending the absorption limit of crystalline Si up to 1310 nm beyond its intrinsic bandgap, which was achieved by creating the crumpled structures in Si nanomembranes (NMs). The concept was used to develop a prototype NIR image sensor by organizing metal-semiconductor-metal-configured crumpled Si NM photosensing pixels in 6 × 6 array. The geometry-controlled, self-sustained strain induction in Si NMs provided an exclusive photon management with shortening of optical bandgap and enhanced photoresponse beyond the conventional Si absorption limit.
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Strain engineering has been employed as a crucial technique to enhance the electrical properties of semiconductors, especially in Si transistor technologies. Recent theoretical investigations have suggested that strain engineering can also markedly enhance the carrier mobility of two-dimensional (2D) transition-metal dichalcogenides (TMDs). The conventional methods used in strain engineering for Si and other bulk semiconductors are difficult to adapt to ultrathin 2D TMDs. Here, we report a strain engineering approach to apply the biaxial tensile strain to MoS2. Metal-organic chemical vapour deposition (MOCVD)-grown large-area MoS2 films were transferred onto SiO2/Si substrate, followed by the selective removal of the underneath Si. The release of compressive residual stress in the oxide layer induces strain in MoS2 on top of the SiO2 layer. The amount of strain can be precisely controlled by the thickness of oxide stressors. After the transistors were fabricated with strained MoS2 films, the array of strained transistors was transferred onto plastic substrates. This process ensured that the MoS2 channels maintained a consistent tensile strain value across a large area.
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Accurate folding of proteins in living cells often requires the cooperative support of molecular chaperones. Eukaryotic group II chaperonin Tailless complex polypeptide 1-Ring Complex (TRiC) accomplishes this task by providing a folding chamber for the substrate that is regulated by an Adenosine triphosphate (ATP) hydrolysis-dependent cycle. Once delivered to and recognized by TRiC, the nascent substrate enters the folding chamber and undergoes folding and release in a stepwise manner. During the process, TRiC subunits and cochaperones such as prefoldin and phosducin-like proteins interact with the substrate to assist the overall folding process in a substrate-specific manner. Coevolution between the components is supposed to consult the binding specificity and ultimately expand the substrate repertoire assisted by the chaperone network. This review describes the TRiC chaperonin and the substrate folding process guided by the TRiC network in cooperation with cochaperones, specifically focusing on recent progress in structural analyses.
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Chaperonina con TCP-1 , Pliegue de Proteína , Chaperonina con TCP-1/química , Chaperonina con TCP-1/metabolismoRESUMEN
PURPOSE: The current study investigates associations between mHealth apps and healthcare decision-making and health communication among informal caregivers in the US. DESIGN: Cross-sectional study employing secondary data. SETTING: The Health Information National Trends Survey (HINTS5, Cycles 2 through 4, 2018 - 2020). SAMPLE: Self-identified informal caregivers (n = 1386; had mHealth apps = 61.3%, female = 63.2%, some college or more in education = 80.3%) who reported owning at least a smartphone or a tablet computer (i.e., ownership of a "smart device"). MEASURES: Sociodemographic characteristics, reports of having mHealth apps, smart device utilization in healthcare decision-making and health communication. ANALYSIS: Accounting for the complex design features of the HINTS data, we constructed multiple hierarchical logistic regressions to compute adjusted odds ratios (aOR) and their 95% confidence intervals (CI). RESULTS: Compared to caregivers without mHealth apps, those with the apps had higher odds of utilizing their smart devices to make a health-related decision, such as how to treat a disease or a medical condition (aOR = 1.65; 95% CI: 1.13-2.39, P < .01), or engage in health-related discussions with a healthcare provider (aOR = 2.36; 95% CI: 1.54-3.61, P < .001). CONCLUSION: Having mHealth apps was associated with a higher likelihood of using smart devices in healthcare decision-making and health communication by informal caregivers. Empowering caregivers to make informed health-related decisions and communicate effectively with healthcare providers are both crucial to health promotion and well-being. Future studies should investigate facilitators as well as barriers to using mHealth apps and smart devices in health-promoting strategies involving informal caregivers.
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Comunicación en Salud , Neoplasias , Telemedicina , Estados Unidos , Humanos , Femenino , Masculino , Cuidadores , Estudios Transversales , National Cancer Institute (U.S.)RESUMEN
Background: Meningiomas are the most common primary central nervous system tumors, and magnetic resonance imaging (MRI), especially contrast-enhanced T1 weighted image (CE T1WI), is used as a fundamental imaging modality for the detection and analysis of the tumors. In this study, we propose an automated deep-learning model for meningioma detection using the dural tail sign. Methods: The dataset included 123 patients with 3,824 dural tail signs on sagittal CE T1WI. The dataset was divided into training and test datasets based on specific time point, and 78 and 45 patients were comprised for the training and test dataset, respectively. To compensate for the small sample size of the training dataset, 39 additional patients with 69 dural tail signs from the open dataset were appended to the training dataset. A You Only Look Once (YOLO) v4 network was trained with sagittal CE T1WI to detect dural tail signs. The normal group dataset, comprised of 51 patients with no abnormal finding on MRI, was employed to evaluate the specificity of the trained model. Results: The sensitivity and false positive average were 82.22% and 29.73, respectively, in the test dataset. The specificity and false positive average were 17.65% and 3.16, respectively, in the normal dataset. Most of the false-positive cases in the test dataset were enhancing vessels, misinterpreted as dural thickening. Conclusions: The proposed model demonstrates an automated detection system for the dural tail sign to identify meningioma in general screening MRI. Our model can facilitate and alleviate radiologists' reading process by notifying the possibility of incidental dural mass based on dural tail sign detection.
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Activation of oncogenic gene expression from long-range enhancers is initiated by the assembly of DNA-binding transcription factors (TF), leading to recruitment of co-activators such as CBP/p300 to modify the local genomic context and facilitate RNA-Polymerase 2 (Pol2) binding. Yet, most TF-to-coactivator recruitment relationships remain unmapped. Here, studying the oncogenic fusion TF PAX3-FOXO1 (P3F) from alveolar rhabdomyosarcoma (aRMS), we show that a single cysteine in the activation domain (AD) of P3F is important for a small alpha helical coil that recruits CBP/p300 to chromatin. P3F driven transcription requires both this single cysteine and CBP/p300. Mutants of the cysteine reduce aRMS cell proliferation and induce cellular differentiation. Furthermore, we discover a profound dependence on CBP/p300 for clustering of Pol2 loops that connect P3F to its target genes. In the absence of CBP/p300, Pol2 long range enhancer loops collapse, Pol2 accumulates in CpG islands and fails to exit the gene body. These results reveal a potential novel axis for therapeutic interference with P3F in aRMS and clarify the molecular relationship of P3F and CBP/p300 in sustaining active Pol2 clusters essential for oncogenic transcription.
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ARN Polimerasa II , Rabdomiosarcoma Alveolar , Humanos , ARN Polimerasa II/genética , ARN Polimerasa II/metabolismo , Cisteína/metabolismo , Factores de Transcripción/metabolismo , Factor de Transcripción PAX3/genética , Rabdomiosarcoma Alveolar/genética , ARN/metabolismo , Activación Transcripcional , Unión Proteica , Proteína Forkhead Box O1/metabolismoRESUMEN
Pseudoaneurysms are among the most serious complications of percutaneous balloon angioplasty. Although pseudoaneurysm rupture rarely happens, when it does, the result can be fatal; thus, early detection and management are crucial. In this report, we disclose the case of a 34-year-old male with end-stage renal disease who presented with a huge symptomatic pseudoaneurysm of the left popliteal artery, following percutaneous balloon angioplasty three months prior. The pseudoaneurysm was successfully excluded using interventional treatment. The patient recovered well, and the follow-up was uneventful, with excellent patency of the covered stent.
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Introduction: Iloprost, a prostacyclin analog, has lung cancerpreventive activity in preclinical models and improved dysplasia in former smokers in a phase IIb trial. Oral iloprost is currently unavailable. We performed a phase Ib trial of inhaled iloprost in former smokers to assess tolerance and compliance. Methods: Participants self-administered nebulized iloprost (5ug) or placebo four (QID) or two (BID) times daily. As QID dose was well tolerated and due to expiration of the placebo, the BID dosing and placebo were eliminated early on in the trial. Bronchoscopy with biopsyat six standard sites was performed at treatment initiation and two months post-iloprost, with exploratory histological analysis. Bulk RNA sequencing, single cell RNA sequencing and an in vitro assay of epithelial progenitor cell iloprost response were performed on a subset of biopsies in an exploratory investigation of response mechanisms and predictive biomarkers. Results and discussion: Thirty-four of a planned 48 participants were recruited to the trial.Inhaled iloprost was well tolerated with no adverse events > grade 2. Compliance was 67% in the QID group. The trial was not powered to detect histologic response and none was found. Bulk RNA sequencing of biopsies pre/post iloprost suggest that iloprost is immunomodulatory and downregulates cell proliferation pathways. Single cell RNA sequencing showed an increase in CD8-positive T cells with upregulation of genes in interferon γ signaling. In vitro iloprost response by epithelial progenitor cells correlated with histologic response with kappa coefficient of 0.81 (95% CI 0.47, 1.0). Inhaled iloprost was well tolerated with suboptimal compliance. Molecular analysis suggested that iloprosthas immunomodulatory and antiproliferative effects.The progenitor cell iloprost response assay may be a promising avenue to develop predictive biomarkers. Clinical trial registration: https://clinicaltrials.gov/study/NCT02237183, identifier NCT02237183.
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Perianal fistulas in Crohn's disease (CD) are a poor prognostic phenotype requiring a combination of medical and surgical management. Perianal fistulas in CD are characterized by more complex and multi-branched fistulas, association with skin tags, and frequent presence of proctitis. A comprehensive approach with clinical examination, endoscopic and MR assessment is required, and in particular, MR interpretation provides detailed information on the type of fistula with its internal component and activity, secondary tracts and extension, internal, external openings, associated abscess, and presence of proctitis. Structured reporting of these items would be recommended for further discussion and management planning both at initial diagnosis and for disease monitoring during treatment follow-up. Management strategy would be individualized for each patient, and control of luminal disease activity could be an important determinant in the selection of treatment options. In this review, we provide an overview of the MRI evaluation of perianal fistulas in CD with a proposed structured MR report.
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Enfermedad de Crohn , Fístula Cutánea , Proctitis , Fístula Rectal , Humanos , Enfermedad de Crohn/complicaciones , Enfermedad de Crohn/diagnóstico por imagen , Fístula Rectal/diagnóstico por imagen , Fístula Rectal/etiología , Imagen por Resonancia Magnética , Pronóstico , Proctitis/complicaciones , Resultado del TratamientoRESUMEN
PURPOSE: This study aimed to provide an overview of accelerometer-derived physical activity (PA) and sedentary behavior (SB) patterns among Korean adults. We also investigated the association between participant characteristics and the likelihood of adherence to moderate-to-vigorous physical activity (MVPA), SB, and the MVPA-SB guidelines. METHODS: Data from the 2014-2017 Korea National Health and Nutrition Examination Survey were used. The study involved a nationally representative sample of 2,260 Korean adults aged ≥20 years. Accelerometers were used to measure PA and SB for seven days. Multivariate logistic regression models were used to assess the association between the participant characteristics and the likelihood of adhering to the MVPA, SB, and MVPA-SB guidelines. RESULTS: SB (60.61%), light intensity (26.22%), and lifestyle activities (9.4%) accounted for the majority of the participants' days. MVPA and vigorous physical activity (VPA) accounted for 3.72% and 0.06% of the days, respectively. The MVPA guidelines were more likely to be adhered to by men, older adults, participants with higher education, non-smokers, and individuals without multimorbidity. Participants with higher education and household income were less likely to adhere to the SB guidelines. Women (OR=0.51), participants with high education levels (OR=0.54), current smokers (OR=0.47), and patients with multimorbidity (OR=0.46) were less likely to adhere to the MVPA-SB guidelines. CONCLUSION: This study found that participants were predominantly sedentary, with only a small proportion engaging in VPA. There were differences related to demographic factors and health status. Most Korean adults do not adhere to the recommended MVPA-SB guidelines, and that is a serious public health concern. These findings highlight the need to promote PA and reduce SB through public health policies and interventions, particularly for adults facing PA barriers.
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A large volume of security events, generally collected by distributed monitoring sensors, overwhelms human analysts at security operations centers and raises an alert fatigue problem. Machine learning is expected to mitigate this problem by automatically distinguishing between true alerts, or attacks, and falsely reported ones. Machine learning models should first be trained on datasets having correct labels, but the labeling process itself requires considerable human resources. In this paper, we present a new selective sampling scheme for efficient data labeling via unsupervised clustering. The new scheme transforms the byte sequence of an event into a fixed-size vector through content-defined chunking and feature hashing. Then, a clustering algorithm is applied to the vectors, and only a few samples from each cluster are selected for manual labeling. The experimental results demonstrate that the new scheme can select only 2% of the data for labeling without degrading the F1-score of the machine learning model. Two datasets, a private dataset from a real security operations center and a public dataset from the Internet for experimental reproducibility, are used.
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Algoritmos , Internet , Humanos , Reproducibilidad de los Resultados , Análisis por Conglomerados , Aprendizaje AutomáticoRESUMEN
Chromatin structure plays a fundamental role in regulating gene expression, with histone modifiers shaping the structure of chromatin by adding or removing chemical changes to histone proteins. The p53 transcription factor controls gene expression, binds target genes, and regulates their activity. While p53 has been extensively studied in cancer research, specifically in relation to fundamental cellular processes, including gene transcription, apoptosis, and cell cycle progression, its association with histone modifiers has received limited attention. This review explores the interplay between histone modifiers and p53 in regulating gene expression. We discuss how histone modifications can influence how p53 binds to target genes and how this interplay can be disrupted in cancer cells. This review provides insights into the complex mechanisms underlying gene regulation and their implications for potential cancer therapy.
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Histonas , Proteína p53 Supresora de Tumor , Histonas/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Cromatina , Regulación de la Expresión Génica , Expresión GénicaRESUMEN
PARP inhibitors (PARPi) kill cancer cells by stalling DNA replication and preventing DNA repair, resulting in a critical accumulation of DNA damage. Resistance to PARPi is a growing clinical problem in the treatment of high grade serous ovarian carcinoma (HGSOC). Acetylation of histone H3 lysine 14 (H3K14ac) and associated histone acetyltransferases (HATs) and epigenetic readers have known functions in DNA repair and replication. Our objectives are to examine their expression and activities in the context of PARPi-resistant HGSOC, and to determine if targeting H3K14ac or associated proteins has therapeutic potential. Using mass spectrometry profiling of histone modifications, we observed increased H3K14ac enrichment in PARPi-resistant HGSOC cells relative to isogenic PARPi-sensitive lines. By reverse-transcriptase quantitative PCR and RNA-seq, we also observed altered expression of numerous HATs in PARPi-resistant HGSOC cells and a PARPi-resistant PDX model. Knockdown of HATs only modestly altered PARPi response, although knockdown and inhibition of PCAF significantly increased resistance. Pharmacologic inhibition of HBO1 depleted H3K14ac but did not affect PARPi response. However, knockdown and inhibition of BRPF3, a bromodomain and PHD-finger containing protein that is known to interact in a complex with HBO1, did reduce PARPi resistance. This study demonstrates that depletion of H3K14ac does not affect PARPi response in HGSOC. Our data suggest that the bromodomain function of HAT proteins, such as PCAF, or accessory proteins, such as BRPF3, may play a more direct role compared to direct HATs function in PARPi response.
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Neoplasias Ováricas , Femenino , Humanos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Línea Celular Tumoral , Histonas/metabolismo , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacologíaRESUMEN
An in vitro culture period of at least 2 weeks is required to produce sufficient natural killer (NK) cells for immunotherapy, which are the key effectors in hematological malignancy treatment. Mitochondrial damage and fragmentation reduce the NK cell immune surveillance capacity. Thus, we hypothesized that the transfer of healthy mitochondria to NK cells could enhance their anticancer effects. Allogeneic healthy mitochondria isolated from WRL-68 cells were transferred to NK cells. We evaluated NK cells' proliferative capacity, cell cycle, and cytotoxic capacity against various cancer cell types by analyzing specific lysis and the cytotoxic granules released. The relationship between the transferred allogenic mitochondrial residues and NK cell function was determined. After mitochondrial transfer, the NK cell proliferation rate was 1.2-fold higher than that of control cells. The mitochondria-treated NK cells secreted a 2.7-, 4.1-, and 5-fold higher amount of granzyme B, perforin, and IFN-γ, respectively, when co-cultured with K562 cells. The specific lysis of various solid cancer cells increased 1.3-1.6-fold. However, once allogeneic mitochondria were eliminated, the NK cell activity returned to the pre-mitochondrial transfer level. Mitochondria-enriched NK cells have the potential to be used as a novel solid cancer treatment agent, without the need for in vitro cytokine-induced culture.