Mass in the Inferior Vena Cava Chao, Chih-Chung; Tsao, Teng-Fu; Lee, Kun-Yu ...
The Journal of emergency medicine,
08/2023, Letnik:
65, Številka:
2
Journal Article
Cardiac arrhythmias have a strong association with pneumonia due to the cardiovascular response to infection. Electrocardiographic (ECG) changes in patients with pneumonia are associated with greater ...disease severity. Atrial fibrillation (AF) is the most common type of cardiac arrhythmia.
This population-based cohort study investigated the incidence of AF among Taiwanese adults with pneumonia using data from the National Health Insurance Research Database in Taiwan.
A total of 34,883 patients with pneumonia and an equal number of individuals without pneumonia were eligible after excluding those with a previous diagnosis of AF and matching 1:1 by age, sex, and comorbidities. The Cox proportional hazards model was used to estimate hazard ratios for AF in both groups.
Patients were more likely to develop AF throughout the 1-year follow-up period after the diagnosis of pneumonia. The incidence of AF was 1.2 (414/334,746) per 1000 person-months. Patients with pneumonia had a 4.08-fold (95% confidence interval 3.37–4.95) increased risk for AF compared to patients without pneumonia.
Patients with pneumonia exhibited an increased risk for AF, especially in the early period after diagnosis of pneumonia.
The adoption of CRISPR-Cas9 technology for functional genetic screens has been a transformative advance. Due to its modular nature, this technology can be customized to address a myriad of questions. ...To date, pooled, genome-scale studies have uncovered genes responsible for survival, proliferation, drug resistance, viral susceptibility, and many other functions. The technology has even been applied to the functional interrogation of the non-coding genome. However, applications of this technology to neurological diseases remain scarce. This shortfall motivated the assembly of a review that will hopefully help researchers moving in this direction find their footing. The emphasis here will be on design considerations and concepts underlying this methodology. We will highlight groundbreaking studies in the CRISPR-Cas9 functional genetics field and discuss strengths and limitations of this technology for neurological disease applications. Finally, we will provide practical guidance on navigating the many choices that need to be made when implementing a CRISPR-Cas9 functional genetic screen for the study of neurological diseases.
L-arginine (L-Arg) depletion induced by randomly PEGylated arginine deiminase (ADI-PEG20) can treat arginosuccinate synthase (ASS)-negative cancers, and ADI-PEG20 is undergoing phase III clinical ...trials. Unfortunately, ASS-positive cancers are resistant to ADI-PEG20. Moreover, the yield of ADI production is low because of the formation of inclusion bodies. Here, we report a thermostable arginine-depleting enzyme,
arginase mutant (BCA-M: Ser
->Cys
). An abundant amount of BCA-M was easily obtained via high cell-density fermentation and heat treatment purification. Subsequently, we prepared BCA-M-PEG20, by conjugating a single 20 kDa PEG monomer onto the Cys
residue via thio-chemistry. Unlike ADI-PEG20, BCA-M-PEG20 significantly inhibited ASS-positive lung cancer cell growth. Pharmacodynamic studies showed that a single intraperitoneal injection (i.p). administration of 250 U/mouse of BCA-M-PEG20 induced low L-Arg level over 168 h. The mono-PEGylation of BCA-M prolonged its elimination half-life from 6.4 to 91.4 h (a 14-fold increase). In an A549 lung cancer xenograft model, a weekly administration of 250 U/mouse of BCA-M-PEG20 suppressed tumor growth significantly. We also observed that BCA-M-PEG20 did not cause any significant safety issue in mouse models. Overall, BCA-M-PEG20 showed excellent results in drug production, potency, and stability. Thereby, it has great potential to become a promising candidate for lung cancer therapy.
Background: Breakfast is deemed the most important meal of the day. We examined the prospective associations of breakfast habits with emotional/behavioral problems in adolescents and potential effect ...modification.Methods: 115,217 Primary 6 students (United States Grade 6; mean age, 11.9; standard deviation SD, 0.59 years) who attended the Student Health Service of Department of Health in Hong Kong in 2004/05, 2006/07, 2008/09 were followed till Secondary 6 (United States Grade 12). Emotional/behavioral problems were biennially examined using Youth Self-Report since Secondary 2 (United States Grade 8). Lifestyles were biennially examined using standardized questionnaires since Primary 6. Prospective associations of breakfast habit with emotional/behavioral problems and potential effect modification were examined using generalized estimating equations.Results: Compared with eating breakfast at home, eating breakfast away from home was significantly associated with total emotional/behavioral problems and seven syndromes, including withdrawal, somatic complaints, anxiety/depression, thought problems, attention problems, delinquent behaviors, and aggressive behaviors (adjusted odds ratios AORs 1.22–2.04), while skipping breakfast showed stronger associations with the above problems and social problems (AORs 1.34–2.29). Stronger associations were observed in younger students for total and attention problems (P < 0.03) and in those with lower weight status for delinquent behaviors (P = 0.005).Conclusion: Eating breakfast away from home and especially skipping breakfast were prospectively associated with adolescent emotional/behavioral problems. The associations weakened with increasing age for total emotional/behavioral and attention problems, and weakened with higher weight status for delinquent behaviors, highlighting the vulnerability of younger and underweight children. If the associations are causal, increasing home breakfast may reduce adolescent emotional/behavioral problems and benefit psychosocial health.
Contrasting the well-described effects of early intervention (EI) services for youth-onset psychosis, the potential benefits of the intervention for adult-onset psychosis are uncertain. This paper ...aims to examine the effectiveness of EI on functioning and symptomatic improvement in adult-onset psychosis, and the optimal duration of the intervention.
360 psychosis patients aged 26-55 years were randomized to receive either standard care (SC,
= 120), or case management for two (2-year EI,
= 120) or 4 years (4-year EI,
= 120) in a 4-year rater-masked, parallel-group, superiority, randomized controlled trial of treatment effectiveness (Clinicaltrials.gov: NCT00919620). Primary (i.e. social and occupational functioning) and secondary outcomes (i.e. positive and negative symptoms, and quality of life) were assessed at baseline, 6-month, and yearly for 4 years.
Compared with SC, patients with 4-year EI had better Role Functioning Scale (RFS) immediate interaction estimate = 0.008, 95% confidence interval (CI) = 0.001-0.014,
= 0.02 and extended social network (interaction estimate = 0.011, 95% CI = 0.004-0.018,
= 0.003) scores. Specifically, these improvements were observed in the first 2 years. Compared with the 2-year EI group, the 4-year EI group had better RFS total (
= 0.01), immediate (
= 0.01), and extended social network (
= 0.05) scores at the fourth year. Meanwhile, the 4-year (
= 0.02) and 2-year EI (
= 0.004) group had less severe symptoms than the SC group at the first year.
Specialized EI treatment for psychosis patients aged 26-55 should be provided for at least the initial 2 years of illness. Further treatment up to 4 years confers little benefits in this age range over the course of the study.
l
-Arginine (L-Arg) depletion has attracted great attention in cancer therapy. Although two types of arginine-depleting enzymes, arginine deiminase (ADI) and human arginase I, are undergoing clinical ...trials, random site of PEGylation, low efficacy of heavy metal as co-factor, and immunogenicity limit the performance of these drugs and cause difficulty in a homogeneous production. Here we screened ten catalytic metal ions and have successfully produced a site-specific mono-PEGylated human arginase I mutant by conjugating the Cys
45
residue to PEG-maleimide to minimize the decrease in activity and produce a homogeneous product. The catalytic efficiency trend of metal ion–enriched human arginase I mutant (HAI) was Co
2+
> Ni
2+
≫ Mn
2+
. The overall k
cat
/K
M
values of Co-HAI and Ni-HAI were higher than Mn-HAI by ~ 8.7- and ~ 5.2-folds, respectively. Moreover, the results of enzyme kinetics and circular dichroism spectrometry demonstrated that the 20 or 40 kDa linear and branched PEG attached on the HAI surface did not affect the enzyme activity and the protein secondary structures. In vitro studies showed that both Co-HAI-PEG20L and Ni-HAI-PEG20L inhibited the growth of eight types of cancer cell lines. The pharmacodynamic study in mice demonstrated that the i.p. administration of Co-HAI-PEG20L at 13 mg/kg and Ni-HAI-PEG20L at 15 mg/kg was able to maintain a L-Arg level below its detection limit for over 120 h after one injection. The body weights of mice could return to normal levels within 5 days after injection, showing that the doses were well-tolerated. Therefore, both the Ni-HAI-PEG20L and Co-HAI-PEG20L are promising candidates for cancer therapy.
Key Points
• Mono-PEGylation applied on human arginase I mutant (HAI) successfully.
• The catalytic efficiency of Co- and Ni-enriched HAI was higher than the wild type.
• At least eight types of cancer cell lines were inhibited by Co- and Ni-HAI-PEG20L.
• Co- and Ni-HAI-PEG20L were able to achieve weekly depletion of L-Arg.
Graphical abstract
Nasopharyngeal carcinoma (NPC) is an Epstein‐Barr virus (EBV)‐associated epithelial malignancy. The high expression of BART‐miRNAs (miR‐BARTs) during latent EBV infection in NPC strongly supports ...their pathological importance in cancer progression. Recently, we found that several BART‐miRNAs work co‐operatively to modulate the DNA damage response (DDR) by reducing Ataxia‐telangiectasia‐mutated (ATM) activity. In this study, we further investigated the role of miR‐BARTs on DDR. The immunohistochemical study showed that the DNA repair gene, BRCA1, is consistently down‐regulated in primary NPCs. Using computer prediction programs and a series of reporter assays, we subsequently identified the negative regulatory role of BART2‐3p, BART12, BART17‐5p and BART19‐3p in BRCA1 expression. The ectopic expression of these four miR‐BARTs suppressed endogenous BRCA1 expression in EBV‐negative epithelial cell lines, whereas BRCA1 expression was enhanced by repressing endogenous miR‐BARTs activities in C666‐1 cells. More importantly, suppressing BRCA1 expression in nasopharyngeal epithelial cell lines using miR‐BART17‐5p and miR‐BART19‐3p mimics reduced the DNA repair capability and increased the cell sensitivity to the DNA‐damaging chemotherapeutic drugs, cisplatin and doxorubicin. Our findings suggest that miR‐BARTs play a novel role in DDR and may facilitate the development of effective NPC therapies.
Nasopharyngeal carcinoma (NPC) is a unique EBV-associated epithelial malignancy, showing highly invasive and metastatic phenotype. Despite increasing evidence demonstrating the critical role of ...cancer stem-like cells (CSCs) in the maintenance and progression of tumors in a variety of malignancies, the existence and properties of CSC in EBV-associated NPC are largely unknown. Our study aims to elucidate the presence and role of CSCs in the pathogenesis of this malignant disease. Sphere-forming cells were isolated from an EBV-positive NPC cell line C666-1 and its tumor-initiating properties were confirmed by in vitro and in vivo assays. In these spheroids, up-regulation of multiple stem cell markers were found. By flow cytometry, we demonstrated that both CD44 and SOX2 were overexpressed in a majority of sphere-forming C666-1 cells. The CD44+SOX2+ cells was detected in a minor population in EBV-positive xenografts and primary tumors and considered as potential CSC in NPC. Notably, the isolated CD44+ NPC cells were resistant to chemotherapeutic agents and with higher spheroid formation efficiency, showing CSC properties. On the other hand, microarray analysis has revealed a number of differentially expressed genes involved in transcription regulation (e.g. FOXN4, GLI1), immune response (CCR7, IL8) and transmembrane transport (e.g. ABCC3, ABCC11) in the spheroids. Among these genes, increased expression of CCR7 in CD44+ CSCs was confirmed in NPC xenografts and primary tumors. Importantly, blocking of CCR7 abolished the sphere-forming ability of C666-1 in vitro. Expression of CCR7 was associated with recurrent disease and distant metastasis. The current study defined the specific properties of a CSC subpopulation in EBV-associated NPC. Our findings provided new insights into developing effective therapies targeting on CSCs, thereby potentiating treatment efficacy for NPC patients.
The lack of representative nasopharyngeal carcinoma (NPC) models has seriously hampered research on EBV carcinogenesis and preclinical studies in NPC. Here we report the successful growth of five NPC ...patient-derived xenografts (PDXs) from fifty-eight attempts of transplantation of NPC specimens into NOD/SCID mice. The take rates for primary and recurrent NPC are 4.9% and 17.6%, respectively. Successful establishment of a new EBV-positive NPC cell line, NPC43, is achieved directly from patient NPC tissues by including Rho-associated coiled-coil containing kinases inhibitor (Y-27632) in culture medium. Spontaneous lytic reactivation of EBV can be observed in NPC43 upon withdrawal of Y-27632. Whole-exome sequencing (WES) reveals a close similarity in mutational profiles of these NPC PDXs with their corresponding patient NPC. Whole-genome sequencing (WGS) further delineates the genomic landscape and sequences of EBV genomes in these newly established NPC models, which supports their potential use in future studies of NPC.
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