Histidine triad nucleotide-binding protein 1 (HINT1), which belongs to the evolutionarily conserved HIT superfamily, has been shown to possess a tumor-suppressive function by binding to and ...inhibiting several oncogenic transcription factors, such as β-catenin and microphthalmia transcription factor (MITF), in various types of cancer cells. However, the regulatory mechanism that mediates the binding capacity of HINT1 for partner transcription factors remains elusive. Here, we report that HINT1 is acetylated by CBP at K21 and K30 and deacetylated by SIRT1. Deacetylation of HINT1 by SIRT1 increases the capacity of HINT1 to bind to β-catenin or MITF. As a result, the tumor-suppressive function of HINT1 is increased. In support of this, the deacetylation mimetic HINT1 mutant HINT1 2KR was found to significantly reduce cellular proliferation in colon cancer and melanoma cells and tumorigenesis in xenograft assays. Thus, this study reveals an acetylation-dependent regulatory mechanism that governs the tumor-suppressive function of HINT1.
N-α-acetyltransferase 20 (Naa20), which is a catalytic subunit of the N-terminal acetyltransferase B (NatB) complex, has recently been reported to be implicated in hepatocellular carcinoma (HCC) ...progression and autophagy, but the underlying mechanism remains unclear. Here, we report that based on bioinformatic analysis of Gene Expression Omnibus and The Cancer Genome Atlas data sets, Naa20 expression is much higher in HCC tumors than in normal tissues, promoting oncogenic properties in HCC cells. Mechanistically, Naa20 inhibits the activity of AMP-activated protein kinase (AMPK) to promote the mammalian target of rapamycin signaling pathway, which contributes to cell proliferation, as well as autophagy, through its N-terminal acetyltransferase (NAT) activity. We further show that liver kinase B1 (LKB1), a major regulator of AMPK activity, can be N-terminally acetylated by NatB in vitro, but also probably by NatB and/or other members of the NAT family in vivo, which may have a negative effect on AMPK activity through downregulation of LKB1 phosphorylation at S428. Indeed, p-LKB1 (S428) and p-AMPK levels are enhanced in Naa20-deficient cells, as well as in cells expressing the nonacetylated LKB1-MPE mutant; moreover, importantly, LKB1 deficiency reverses the molecular and cellular events driven by Naa20 knockdown. Taken together, our findings suggest that N-terminal acetylation of LKB1 by Naa20 may inhibit the LKB1-AMPK signaling pathway, which contributes to tumorigenesis and autophagy in HCC.
Chimeric antigen receptor (CAR)-T cell therapies have revolutionized cancer treatment, particularly in hematological malignancies. However, their application to solid tumors is limited, and they face ...challenges in safety, scalability, and cost. To enhance current CAR-T cell therapies, the integration of microfluidic technologies, harnessing their inherent advantages, such as reduced sample consumption, simplicity in operation, cost-effectiveness, automation, and high scalability, has emerged as a powerful solution. This review provides a comprehensive overview of the step-by-step manufacturing process of CAR-T cells, identifies existing difficulties at each production stage, and discusses the successful implementation of microfluidics and related technologies in addressing these challenges. Furthermore, this review investigates the potential of microfluidics-based methodologies in advancing cell-based therapy across various applications, including solid tumors, next-generation CAR constructs, T-cell receptors, and the development of allogeneic "off-the-shelf" CAR products.
This review outlines Chimeric antigen receptor (CAR)-T cell manufacturing, highlights challenges, and explores successful microfluidic approaches and related technologies to address them.
Item 9 of the Patient Health Questionnaire (PHQ) evaluates passive thoughts of death or self-injury within the last two weeks, and is often used to screen depressed patients for suicide risk. We ...aimed to validate the PHQ-9 item 9 with a brief electronic version of the Columbia Suicide Severity Rating Scale (eC-SSRS).
We analyzed data from 841 patients enrolled in the National Network of Depression Centers Clinical Care Registry. We performed a validation analysis of PHQ-9 item 9 for suicide risk and ideation, using the eC-SSRS as a gold standard (defined as positive response to suicidal ideation with intent to act or recent suicidal behavior).
Of the 841 patients, 13.4% and 41.1% were assessed as being positive for suicide risk by the eC-SSRS and PHQ-9 item 9, respectively. For the overall cohort, sensitivity was 87.6% (95%CI 80.2–92.5%), specificity was 66.1% (95%CI 62.6–69.4%), PPV was 28.6% (95%CI 24.1–33.6%), and NPV was 97.2% (95%CI 95.3–98.3%) for the PHQ-9 suicide item. These performance measures varied within subgroups defined by demographic and clinical characteristics. In addition, the validity of PHQ-9 item 9 (cutoff score of 1) with eC-SSRS-defined suicide ideation showed overall poor results.
The gold standard used in our study was a surrogate measure of suicidality based on eC-SSRS scores.
The results of our study suggest that item 9 of the PHQ-9 is an insufficient assessment tool for suicide risk and suicide ideation, with limited utility in certain demographic and clinical subgroups that requires further investigation.
•The PHQ-9 item 9 is an insufficient assessment tool for suicide risk and ideation.•The PHQ-9 item 9 has limited utility in certain subgroups.•The PHQ-9 item 9 should be used with a validated suicide risk inventory.
Effective tumor regression has been observed with chimeric antigen receptor (CAR) T cells; however, the development of an affordable, safe, and effective CAR-T cell treatment remains a challenge. One ...of the major obstacles is that the suboptimal genetic modification of T cells reduces their yield and antitumor activity, necessitating the development of a next-generation T cell engineering approach. In this study, we developed a nonviral T cell nanoengineering system that allows highly efficient delivery of diverse functional nanomaterials into primary human T cells in a genetically stable and scalable manner. Our platform leverages the unique cell deformation and restoration process induced by the intrinsic inertial flow in a microchannel to create nanopores in the cellular membrane for macromolecule internalization, leading to effective transfection with high scalability and viability. The proposed approach demonstrates considerable potential as a practical alternative technique for improving the current CAR-T cell manufacturing process.
This meta-analysis aimed to examine the association of child abuse with adult coronary heart disease risk and separately by abuse subtypes, including emotional abuse, sexual abuse, and physical ...abuse.
Data were extracted from studies published up through December 2021 and on the basis of research from PubMed, Embase, CINAHL, and PsycINFO. Studies were selected if they included adults with or without any type of child abuse and measured the risk of any type of coronary heart disease. Statistical analyses were conducted in 2022. The random effects model was used to pool the effect estimates presented by RRs with 95% CIs. Heterogeneity was assessed using Q and I2 statistics.
The pooled estimates were synthesized using 24 effect sizes from 10 studies with a sample size of 343,371 adults. Adults with child abuse were associated with a higher risk of coronary heart disease than those without (RR=1.52; 95% CI=1.29, 1.79), and the association was similar for myocardial infarction (RR=1.50; 95 % CI=1.08, 2.10) and unspecified coronary heart disease (RR=1.58; 95% CI=1.23, 2.02). Moreover, emotional (RR=1.48; 95% CI=1.29, 1.71), sexual (RR=1.47; 95% CI=1.15, 1.88), and physical (RR=1.48; 95% CI=1.22, 1.79) abuse were associated with increased risk of coronary heart disease.
Child abuse was associated with an increased risk of adult coronary heart disease. Results were generally consistent across abuse subtypes and sex. This study advocates further research on biological mechanisms linking child abuse to coronary heart disease as well as improvement in coronary heart disease risk prediction and targeted prevention approaches.
Delays in autism spectrum disorder (ASD) diagnosis and treatment are significant clinical problems that can be addressed by timely, community-based assessment. This study examined tools for ...identifying ASD in community settings using machine learning (ML) models.
This study analyzed population-based cross-sectional studies (2005-2017) of ASD in South Korea. A community sample of 62,083 children was screened using the Autism Spectrum Screening Questionnaire (ASSQ) and teacher/caregiver referrals. Caregivers completed the Behavior Assessment System for Children–2nd Edition (BASC-2) and the Social Responsiveness Scale (SRS). Screen positives were offered a comprehensive clinical evaluation. Among the first-graders in regular elementary schools who completed the diagnostic evaluation (N = 746), supervised ML models (generalized linear model with elastic net regularization GLMNET, classification and regression tree, random forest, and gradient boosting GB) were developed and validated for classification of ASD. Models were developed in the single questionnaire and combined questionnaire datasets, using questionnaire responses and demographic and developmental information.
ASD was diagnosed in 46.2% of children (median age, 6.8 years interquartile range, 6.5-7.1 years; 71.7% boys). Among single questionnaire models, the BASC GB model demonstrated the best discrimination ability (area under the curve 0.80, 95% CI 0.75-0.83). Area under the curve of the GLMNET model with combined ASSQ, BASC-2, and SRS was the highest, 0.82 (95% CI 0.77-0.89); the predicted risk of ASD by the GB model of combined questionnaires agreed the best with the observed risk of ASD compared with other ML models.
Caregiver questionnaire ML models showed future promise for identifying children with ASD in community settings.
The purpose of this study was to develop a software tool and evaluate different T1 map calculation methods in terms of computation time in cardiac magnetic resonance imaging.
The modified Look-Locker ...inversion recovery (MOLLI) sequence was used to acquire multiple inversion time (TI) images for pre- and post-contrast T1 mapping. The T1 map calculation involved pixel-wise curve fitting based on the T1 relaxation model. A variety of methods were evaluated using data from 30 subjects for computational efficiency: MRmap, python Levenberg-Marquardt (LM), python reduced-dimension (RD) non-linear least square, C++ single- and multi-core LM, and C++ single- and multi-core RD.
Median (interquartile range) computation time was 126 s (98-141) for the publicly available software MRmap, 261 s (249-282) for python LM, 77 s (74-80) for python RD, 3.4 s (3.1-3.6) for C++ multi-core LM, and 1.9 s (1.9-2.0) for C++ multi-core RD. The fastest C++ multi-core RD and the publicly available MRmap showed good agreement of myocardial T1 values, resulting in 95% Bland-Altman limits of agreement of (- 0.83 to 0.58 ms) and (- 6.57 to 7.36 ms) with mean differences of - 0.13 ms and 0.39 ms, for the pre- and post-contrast, respectively.
The C++ multi-core RD was the fastest method on a regular eight-core personal computer for pre- or post-contrast T1 map calculation. The presented software tool (fT1fit) facilitated rapid T1 map and extracellular volume fraction map calculations.
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