This study aims to provide comprehensive insights into longitudinal immune landscape in acute myeloid leukemia (AML) development and treatment, which may contribute to predict prognosis and guide ...clinical decisions.
Periphery blood samples from 79 patients with AML (at diagnosis or/and after chemotherapy or at relapse) and 24 healthy controls were prospectively collected. We performed phenotypic and functional analysis of various lymphocytes through multiparametric flow cytometry and investigated prognostic immune-related risk factors.
Immune defects in AML were reflected in T and natural killer (NK) cells, whereas B-cell function remained unaffected. Both CD8
T and CD4
T cells exhibited features of senescence and exhaustion at diagnosis. NK dysfunction was supported by excessive maturation and downregulation of NKG2D and NKP30. Diseased γδ T cells demonstrated a highly activated or even exhausted state through PD-1 upregulation and NKG2D downregulation. Effective therapeutic response following chemotherapy correlated with T and NK function restoration. Refractory and relapsed patients demonstrated even worse immune impairments, and selective immune signatures apparently correlated clinical outcomes and survival. PD-1 expression in CD8
T cells was independently predictive of poor overall survival and event-free survival.
T-cell senescence and exhaustion, together with impaired NK and γδ T-cell function, are dominant aspects involved in immune dysfunction in AML. Noninvasive immune testing of blood samples could be applied to predict therapeutic reactivity, high risk for relapse, and unfavorable prognosis.
In this study, different probiotics commonly used to produce fermented dairy products were inoculated independently for Chenopodium formosanum Koidz. fermentation. The strain with the highest level ...of antioxidant activity was selected and the fermentation process was further optimized via response surface methodology (RSM). Lactobacillus plantarum BCRC 11697 was chosen because, compared to other lactic acid bacteria, it exhibits increased free radical scavenging ability and can produce more phenolic compounds, DPPH (from 72.6% to 93.2%), and ABTS (from 64.2% to 76.9%). Using RSM, we further optimize the fermentation protocol of BCRC 11697 by adjusting the initial fermentation pH, agitation speed, and temperature to reach the highest level of antioxidant activity (73.5% of DPPH and 93.8% of ABTS). The optimal protocol (pH 5.55, 104 rpm, and 24.4°C) resulted in a significant increase in the amount of phenolic compounds as well as the DPPH and ABTS free radical scavenging ability of BCRC 11697 products. The IC50 of the DPPH and ABTS free radical scavenging ability were 0.33 and 2.35 mg/mL, respectively, and both protease and tannase activity increased after RSM. An increase in lower molecular weight (<24 kDa) protein hydrolysates was also observed. Results indicated that djulis fermented by L. plantarum can be a powerful source of natural antioxidants for preventing free radical-initiated diseases.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective
Tracheal replacement is a crucial operation to enhance the quality of life for patients with extensive tracheal lesions. The most suitable surgical techniques for different clinical ...conditions remain a topic of debate. Through a reviewing of the relevant literature, this study investigated the association between surgical techniques and mortality rate.
Data Sources
Studies were collected from PubMed, Embase, the Web of Science, the Cochrane Center Register of Controlled Trials, and ClinicalTrials.gov.
Methods
This systematic review encompassed literature from the inception of each database to May 10, 2023, focusing on tracheal replacement for patients who underwent circumferential resection of the trachea or partial resection with preservation of the posterior membranous wall. Non‐human and non‐clinical studies were excluded.
Results
About 31 studies were included in the assessment comprising a combination of case reports and case series, and 118 patients underwent tracheal replacement through four underlying methodologies, including tracheal allotransplantation, autologous tissue reconstruction, bioprosthetic reconstruction, or tissue engineering surgery. Each modality exhibits unique advantages and disadvantages, leading to variable outcomes in clinical application.
Conclusion
Tracheal replacement is challenging due to the absence of an ideal substitution or graft material. Despite limited clinical successes observed across various modalities, we believe autologous tissue reconstruction for tracheal replacement has the advantage of broadest indications, low rejection rate, and avoidance of immunosuppressive agents. Future research should focus on achieving tracheal replacement that preserves mucociliary clearance, lateral rigidity, and longitudinal flexibility.
Level of Evidence
NA Laryngoscope, 134:1517–1522, 2024
Tracheal replacement is challenging due to the lack of ideal graft materials. We believe that autologous tissue reconstruction is a promising approach due to its broad applicability, lower risks of rejection, and avoids the need for immunosuppression. Future research should aim to preserve essential tracheal function during replacement.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Swertia chirayita, has been commonly used under the name “Zang-yin-chen” for the treatment of liver infections, inflammation, abdominal pain, and bacterial infection in traditional Tibetan medicine. ...However, the bioactive components with anti-inflammatory activities and underlying mechanisms remain poorly evaluated.
Repeated column chromatography yielded two main xanthones from petroleum ether (PE) and ethyl acetate fractions of whole plants of S. chirayita, and their structures were determined as bellidifolin (1) and swerchirin (2) on the basis of spectroscopic data and literature analysis. The anti-inflammatory activities and mechanisms of anti-inflammation of these two isolated xanthones were determined via enzyme-linked immunosorbent assay (ELISA) and western blot in lipopolysaccharide (LPS)-stimulated RAW 264.7 murine macrophages in vitro.
Anti-inflammation assay demonstrated that 1 and 2 inhibit the production of the pro-inflammatory cytokines interleukin-6 (IL-6) and TNF-α in LPS-stimulated RAW 264.7 macrophages. Xanthone 1 also potently inhibited the production of prostaglandin E2 (PGE2) by suppressing the protein expression of cyclooxygenase-2 (COX-2) in LPS-stimulated RAW 264.7 macrophages. Western blot showed that the phosphorylation of c-Jun N-terminal kinases (JNK), extracellular signal-regulated kinase (ERK), and p38 MAPKs were remarkably attenuated by 1 in a concentration-dependent manner. Particularly, Compound 1 suppressed the phosphorylation of the inhibitor κB kinase-β (IKK-β), Akt, and p65 subunit of nuclear factor-kappaB (NF-κB).
The potent suppressive effects of 1 from S. chirayita on inflammatory mediators by blocking the expression of COX-2 and phosphorylation of Akt, IKK-β, MAPK and NF-κB, activation in LPS-stimulated macrophages suggest that 1 can be a preventive therapeutic candidate for the management of inflammatory-mediated immune disorders.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Summary
The mediator complex is highly conserved in eukgaryotes and is integral for transcriptional responses. Mediator subunits associate with signal‐responsive transcription factors (TF) to ...activate expression of specific signal‐responsive genes. As the key TF of Arabidopsis thaliana senescence, ORESARA1 (ORE1) is required for nitrogen deficiency (−N) induced senescence; however, the mediator subunit that associates with ORE1 remains unknown.
Here, we show that Arabidopsis MED19a associates with ORE1 to activate −N senescence‐responsive genes. Disordered MED19a forms inducible nuclear condensates under −N that is regulated by decreasing MED19a lysine acetylation. MED19a carboxyl terminus (cMED19a) harbors a mixed‐charged intrinsically disordered region (MC‐IDR) required for ORE1 interaction and liquid–liquid phase separation (LLPS).
Plant and human cMED19 are sufficient to form heterotypic condensates with ORE1. Human cMED19 MC‐IDR, but not yeast cMED19 IDR, partially complements med19a suggesting functional conservation in evolutionarily distant eukaryotes. Phylogenetic analysis of eukaryotic cMED19 revealed that the MC‐IDR could arise through convergent evolution.
Our result of MED19 MC‐IDR suggests that plant MED19 is regulated by phase separation during stress responses.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
In magnetic topological insulators (TIs), the interplay between magnetic order and nontrivial topology can induce fascinating topological quantum phenomena, such as the quantum anomalous Hall effect, ...chiral Majorana fermions, and axion electrodynamics. Recently, a great deal of attention has been focused on the intrinsic magnetic TIs, where disorder effects can be eliminated to a large extent, which is expected to facilitate the emergence of topological quantum phenomena. Despite intensive efforts, experimental evidence of the topological surface states (SSs) remains elusive. Here, by combining first-principles calculations and angle-resolved photoemission spectroscopy (ARPES) experiments, we reveal thatEuSn2As2is an antiferromagnetic TI with the observation of Dirac SSs consistent with our prediction. We also observe nearly gapless Dirac SSs in antiferromagnetic TIsMnBi2nTe3n+1(n=1and 2), which are absent in previous ARPES results. These results provide clear evidence for nontrivial topology of these intrinsic magnetic TIs. Furthermore, we find that the topological SSs show no observable changes across the magnetic transition within the experimental resolution, indicating that the magnetic order has a quite small effect on the topological SSs, which can be attributed to weak hybridization between the localized magnetic moments, from either4for3dorbitals, and the topological electronic states. This finding provides insights for further research that the correlations between magnetism and topological states need to be strengthened to induce larger gaps in the topological SSs, which will facilitate the realization of topological quantum phenomena at higher temperatures.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UL, UM, UPUK
Accumulation of saturated fatty acids in the liver can cause nonalcoholic fatty liver disease (NAFLD). This study investigated saturated fatty acid induction of endoplasmic reticulum (ER) stress and ...apoptosis in human liver cells and the underlying causal mechanism. Human liver L02 and HepG2 cell lines were exposed to the saturated fatty acid sodium palmitate. MTT assay was used for cell viability, flow cytometry and Hoechst 33258 staining for apoptosis, RT-PCR for mRNA expression, and Western blot for protein expression. Silence of PRK-like ER kinase (PERK) expression in liver cells was through transient transfection of PERK shRNA. Treatment of L02 and HepG2 cells with sodium palmitate reduced cell viability through induction of apoptosis. Sodium palmitate also induced ER stress in the cells, indicated by upregulation of PERK phosphorylation and expression of BiP, ATF4, and CHOP proteins. Sodium palmitate had little effect on activating XBP-1, a common target of the other two canonical sensors of ER stress, ATF6, and IRE1. Knockdown of PERK gene expression suppressed the PERK/ATF4/CHOP signaling pathway during sodium palmitate-induced ER stress and significantly inhibited sodium palmitate-induced apoptosis in L02 and HepG2 cells. Saturated fatty acid-induced ER stress and apoptosis in these human liver cells were enacted through the PERK/ATF4/CHOP signaling pathway. Future study is warranted to investigate the role of these proteins in mediating saturated fatty acid-induced NAFLD in animal models.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The clinical presentation and outcomes of non-alcoholic fatty liver disease (NAFLD)-related hepatocellular carcinoma are unclear when compared with hepatocellular carcinoma due to other causes. We ...aimed to establish the prevalence, clinical features, surveillance rates, treatment allocation, and outcomes of NAFLD-related hepatocellular carcinoma.
In this systematic review and meta-analysis, we searched MEDLINE and Embase from inception until Jan 17, 2022, for articles in English that compared clinical features, and outcomes of NAFLD-related hepatocellular carcinoma versus hepatocellular carcinoma due to other causes. We included cross-sectional and longitudinal observational studies and excluded paediatric studies. Study-level data were extracted from the published reports. The primary outcomes were (1) the proportion of hepatocellular carcinoma secondary to NAFLD, (2) comparison of patient and tumour characteristics of NAFLD-related hepatocellular carcinoma versus other causes, and (3) comparison of surveillance, treatment allocation, and overall and disease-free survival outcomes of NAFLD-related versus non-NAFLD-related hepatocellular carcinoma. We analysed proportional data using a generalised linear mixed model. Pairwise meta-analysis was done to obtain odds ratio (OR) or mean difference, comparing NAFLD-related with non-NAFLD-related hepatocellular carcinoma. We evaluated survival outcomes using pooled analysis of hazard ratios.
Of 3631 records identified, 61 studies (done between January, 1980, and May, 2021; 94 636 patients) met inclusion criteria. Overall, the proportion of hepatocellular carcinoma cases secondary to NAFLD was 15·1% (95% CI 11·9–18·9). Patients with NAFLD-related hepatocellular carcinoma were older (p<0·0001), had higher BMI (p<0·0001), and were more likely to present with metabolic comorbidities (diabetes p<0·0001, hypertension p<0·0001, and hyperlipidaemia p<0·0001) or cardiovascular disease at presentation (p=0·0055) than patients with hepatocellular carcinoma due to other causes. They were also more likely to be non-cirrhotic (38·5%, 27·9–50·2 vs 14·6%, 8·7–23·4 for hepatocellular carcinoma due to other causes; p<0·0001). Patients with NAFLD-related hepatocellular carcinoma had larger tumour diameters (p=0·0087), were more likely to have uninodular lesions (p=0·0003), and had similar odds of Barcelona Clinic Liver Cancer stages, TNM stages, alpha fetoprotein concentration, and Eastern Cooperative Oncology Group (ECOG) performance status to patients with non-NAFLD-related hepatocellular carcinoma. A lower proportion of patients with NAFLD-related hepatocellular carcinoma underwent surveillance (32·8%, 12·0–63·7) than did patients with hepatocellular carcinoma due to other causes (55·7%, 24·0–83·3; p<0·0001). There were no significant differences in treatment allocation (curative therapy, palliative therapy, and best supportive care) between patients with NAFLD-related hepatocellular carcinoma and those with hepatocellular carcinoma due to other causes. Overall survival did not differ between the two groups (hazard ratio 1·05, 95% CI 0·92–1·20, p=0·43), but disease-free survival was longer for patients with NAFLD-related hepatocellular carcinoma (0·79, 0·63–0·99; p=0·044). There was substantial heterogeneity in most analyses (I2>75%), and all articles had low-to-moderate risk of bias.
NAFLD-related hepatocellular carcinoma is associated with a higher proportion of patients without cirrhosis and lower surveillance rates than hepatocellular carcinoma due to other causes. Surveillance strategies should be developed for patients with NAFLD without cirrhosis who are at high risk of developing hepatocellular carcinoma.
None.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Accumulating epidemiological evidence shows that life event stressors are major vulnerability factors for psychiatric diseases such as major depression. It is also well known that social isolation in ...male mice results in aggressive behavior. However, it is not known how social isolation-induced aggression affects anxiety and depressive-like behavior in isolated male mice subjected to unpredictable chronic mild stress (CMS), an animal model of depression.
C57/B6 male mice were divided into 3 groups; non-stressed controls, in Group I; isolated mice subjected to the CMS protocol in Group II and aggression by physical contact in socially isolated mice subjected to the CMS protocol in Group III. In the sucrose intake test, ingestion of a 1% sucrose solution by mice in Groups II and III was significantly lower than in Group I. Furthermore, intake of this solution in Group III mice was significantly lower than in Group II mice. In the open field test, mice in Group III, showed reduced locomotor activity and reduced entry and retention time in the central zone, compared to Groups I and II mice. Moreover, the distances moved in 1 hour by Group III mice did not differ between night and morning. In the light/black box test, Groups II and III animals spent significantly less time in the light box compared to Group I animals. In the tail suspension test (TST) and forced swimming test (FST), the immobility times of Group II and Group III mice were significantly longer than in Group I mice. In addition, immobility times in the FST were significantly longer in Group III than in Group II mice.
These findings show that social isolation-induced aggression could potentiate anxiety and depressive-like behaviors in isolated male mice subjected to CMS.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
BACKGROUND & AIMS
Liver fibrosis score (LFS) has been used for predicting the cardiovascular outcomes (CVOs) in diverse populations. However, the association of LFS with CVOs in patients with ...previous myocardial infarction (MI) remains undetermined. We aimed to examine the prognostic value of LFS in patients with prior MI in a prospective cohort.
METHODS
A total of 3718 patients with previous MI were consecutively enrolled from March 2009 to January 2019. Five LFSs including the fibrosis‐4 (FIB‐4) score, non‐alcohol fatty liver disease fibrosis score (NFS), Forns score, HUI score and BARD score were used. The CVOs covered major adverse cardiac event (MACEs), cardiovascular mortality and all‐cause mortality. Cox proportional hazards model was used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs).
RESULTS
During a mean follow‐up of 47.4 ± 24.8 months, 431 (11.6%) MACEs occurred. Kaplan‐Meier analysis demonstrated that higher LFSs resulted in a significantly higher probability of CVOs. Compared to the lowest score group, multivariable‐adjusted HRs (95% CIs) of the highest group of FIB‐4, NFS, Forns score, HUI score and BARD score were 1.75 (1.32‐2.33), 2.37 (1.70‐3.33), 2.44 (1.61‐3.73), 1.58 (1.16‐2.14) and 1.27 (1.03‐1.57) respectively. These LFSs were also independent predictors of cardiovascular mortality and all‐cause mortality. Similar results were observed across subgroups analysis. The addition of LFSs to a prediction model significantly increased the C‐statistic for CVOs.
CONCLUSIONS
The present study firstly demonstrated that LFS could be used as a risk stratification tool for predicting CVOs in patients with previous MI, which should be evaluated further.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
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