Background
The aim of this study was to investigate differences in clinical features and HLA genotypes between adult‐onset and childhood‐onset patients with type 1 diabetes in a Chinese population.
...Materials and Methods
This study enrolled 716 Han Chinese patients with type 1 diabetes from Guangdong (258 childhood‐onset and 458 adult‐onset) to compare their clinical features. Of them 214 patients with classical type 1 diabetes (100 childhood‐onset and 114 adult‐onset) were selected for HLA DR and DQ genotyping by next‐generation sequencing.
Results
Adult‐onset patients were characterized by longer duration of symptoms before diagnosis, lower frequency of DKA at disease onset, less frequent autoantibody positivity, higher serum C‐peptide concentrations, and better glycemic control. These findings were replicated in the restricted cohort of 214 patients with classical type 1 diabetes. Compared with childhood‐onset patients, adult‐onset patients had a lower frequency of the DR9 haplotype, as well as lower frequency of high‐risk DR3/DR4 and DR3/DR9 genotypes, but higher frequency of DR3/DR3 genotype and DR3/X, DR4/X or DR9/X (X, non‐risk) genotypes.
Conclusions
Adult‐onset type 1 diabetic patients with susceptible haplotypes (DR3, DR4 or DR9) were more likely to carry protective DR‐DQ haplotypes than childhood‐onset patients, which suggested the association between less risk DR‐DQ genotypes and the less severe clinical manifestation in adult‐onset patients.
Mature T-cell lymphomas, including peripheral T-cell lymphoma (PTCL) and extranodal NK/T-cell lymphoma (NKTL), represent a heterogeneous group of non-Hodgkin lymphomas with dismal outcomes and ...limited treatment options. To determine the extent of involvement of the JAK/STAT pathway in this malignancy, we performed targeted capture sequencing of 188 genes in this pathway in 171 PTCL and NKTL cases. A total of 272 nonsynonymous somatic mutations in 101 genes were identified in 73% of the samples, including 258 single-nucleotide variants and 14 insertions or deletions. Recurrent mutations were most frequently located in STAT3 and TP53 (15%), followed by JAK3 and JAK1 (6%) and SOCS1 (4%). A high prevalence of STAT3 mutation (21%) was observed specifically in NKTL. Novel STAT3 mutations (p.D427H, E616G, p.E616K, and p.E696K) were shown to increase STAT3 phosphorylation and transcriptional activity of STAT3 in the absence of cytokine, in which p.E616K induced programmed cell death-ligand 1 (PD-L1) expression by robust binding of activated STAT3 to the PD-L1 gene promoter. Consistent with these findings, PD-L1 was overexpressed in NKTL cell lines harboring hotspot STAT3 mutations, and similar findings were observed by the overexpression of p.E616K and p.E616G in the STAT3 wild-type NKTL cell line. Conversely, STAT3 silencing and inhibition decreased PD-L1 expression in STAT3 mutant NKTL cell lines. In NKTL tumors, STAT3 activation correlated significantly with PD-L1 expression. We demonstrated that STAT3 activation confers high PD-L1 expression, which may promote tumor immune evasion. The combination of PD-1/PD-L1 antibodies and STAT3 inhibitors might be a promising therapeutic approach for NKTL, and possibly PTCL.
•Alterations in JAK/STAT signaling pathway are highly prevalent in PTCL and NKTL, where STAT3 and TP53 are the most frequently mutated genes.•STAT3 activation drives PD-L1 expression in NKTL, providing a rationale to combine STAT3 inhibitors with immune checkpoint inhibitors.
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Aims/hypothesis
The study aimed to investigate the effects of HLA class I genes on susceptibility to type 1 diabetes with different onset ages, in addition to the well-established effects of HLA ...class II genes.
Methods
A total of 361 patients with type 1 diabetes (192 patients with onset <18 years and 169 patients with onset ≥18 years) and 500 healthy control participants from China were enrolled and genotyped for the
HLA-A
,
-B
,
-C
,
-DQA1
,
-DQB1
and
-DRB1
genes using next-generation sequencing.
Results
The susceptible
DR3
(β = −0.09,
p
= 0.0009) and
DR4-DQ8
(β = −0.13,
p
= 0.0059) haplotypes were negatively associated with onset age, while the protective
DR11
(β = 0.21,
p
= 0.0314) and
DR12
(β = 0.27,
p
< 0.0001) haplotypes were positively associated with onset age. After adjustment for linkage disequilibrium with
DR-DQ
haplotypes,
A*11:01:01
was positively associated with onset age (β = 0.06,
p
= 0.0370), while the susceptible
C*15:02:01
was negatively associated with onset age (β = −0.21,
p
= 0.0050). The unit for β was double square-root (fourth root) transformed years of change in onset age associated with per copy of the HLA haplotype/allele. In addition,
B*46:01:01
was protective (OR 0.41, 0.46;
p
c corrected for multiple comparisons = 0.0044, 0.0040), whereas
A*24:02:01
(OR 2.71, 2.25;
p
c = 0.0003, 0.0002) and
B*54:01:01
(OR 3.96, 3.79;
p
c = 0.0018, 0.0004) were predisposing in both the <18 group and the ≥18 group compared with healthy control participants. In the context of
DR4-DQ4
,
A*11:01:01
(61.29% vs 28.26%,
p
c = 0.0144) was increased while the predisposing
A*24:02:01
(19.35% vs 47.83%,
p
c = 0.0403) was decreased in patients with onset ≥18 years when compared with patients with onset <18 years.
Conclusions/interpretation
In addition to
DR-DQ
haplotypes, novel HLA class I alleles were detected to play a role in susceptibility to type 1 diabetes with different onset ages, which could improve the understanding of disease heterogeneity and has implications for the design of future studies.
Graphical abstract
Postinfarction cardiac remodeling presents a compensatory mechanism aimed at mitigating congestive heart failure. It is distinguished by progressive dilatation and hypertrophy of the ventricular ...chambers, fibrotic alterations, and prolonged apoptosis of cardiomyocytes. The primary objective of this study was to assess the effects of icariin on myocardial fibrosis and ventricular remodeling in rats subjected to myocardial infarction (MI).
Male Sprague‒Dawley (SD) rats were subjected to randomization and subsequently divided into distinct groups: the control group, the sham group (undergoing sham operation), the MI group (experiencing ligation of the left anterior descending artery), and the icariin group. Within the icariin group, rats were further categorized into three different dose groups based on the administered icariin dosage: the MI30 group (30 mg/kg/day), the MI60 group (60 mg/kg/day), and the MI120 group (120 mg/kg/day). Cardiac function evaluation was carried out using echocardiography. Histological examinations, including hematoxylin and eosin (HE) staining, Masson staining, and immunohistochemistry studies, were conducted 90 days after the occurrence of MI. Additionally, Western blotting was employed to assess TGF-β1, p-Smad2, and p-Smad3 levels.
The administration of icariin revealed a noteworthy enhancement in cardiac function among rats afflicted with left anterior descending coronary artery (LAD) ligation. In comparison to the icariin groups, the MI group exhibited reduced EF and FS, along with elevated LVEDD and LVESD. Furthermore, the cardiac fibrosis levels in the MI group rats exhibited a considerable increase compared to those in the icariin group. Notably, the levels of Collagen I, Collagen III, MMP2, and MMP9 were significantly higher in the MI group than in the icariin group, with evident distinctions. Moreover, the expression levels of TGF-β, IL-13, p-Smad2, and p-Smad3 were notably upregulated in the MI group compared to the icariin group.
In an experimental rat model of MI, the administration of icariin resulted in the amelioration of both cardiac function and remodeling processes, operating through the intricate TGF-β1/Smad signaling pathway.
Eighteen known susceptibility loci for IgAN account for only a small proportion of IgAN risk.
Genome-wide meta-analysis was performed in 2628 patients and 11,563 controls of Chinese ancestry, and a ...replication analysis was conducted in 6879 patients and 9019 controls of Chinese descent and 1039 patients and 1289 controls of European ancestry. The data were used to assess the association of susceptibility loci with clinical phenotypes for IgAN, and to investigate genetic heterogeneity of IgAN susceptibility between the two populations. Imputation-based analysis of the MHC/HLA region extended the scrutiny.
Identification of three novel loci (rs6427389 on 1q23.1
=8.18×10
, OR=1.132, rs6942325 on 6p25.3
=1.62×10
, OR=1.165, and rs2240335 on 1p36.13
=5.10×10
, OR=1.114), implicates
,
, and
as susceptibility genes for IgAN. Rs2240335 is associated with the expression level of
, and rs6427389 is in high linkage disequilibrium with rs11264799, which showed a strong expression quantitative trail loci effect on
. Of the 24 confirmed risk SNPs, six showed significant heterogeneity of genetic effects and
showed clear evidence of allelic heterogeneity between the populations. Imputation-based analysis of the MHC region revealed significant associations at three HLA polymorphisms (HLA allele DPB1*02, AA_DRB1_140_32657458_T, and AA_DQA1_34_32717152) and two SNPs (rs9275464 and rs2295119).
A meta-analysis of GWAS data revealed three novel genetic risk loci for IgAN, and three HLA polymorphisms and two SNPs within the MHC region, and demonstrated the genetic heterogeneity of seven loci out of 24 confirmed risk SNPs. These variants may explain susceptibility differences between Chinese and European populations.
Energy metabolism has recently gained interest as a target space for antibiotic drug development in mycobacteria. Of particular importance is bedaquiline (Sirturo), which kills mycobacteria by ...inhibiting the F1F0 ATP synthase. Other components of the electron transport chain such as the NADH dehydrogenases (NDH-2 and NdhA) and the terminal respiratory oxidase bc1:aa3 are also susceptible to chemical inhibition. Because antituberculosis drugs are prescribed as part of combination therapies, the interaction between novel drugs targeting energy metabolism and classical first and second line antibiotics must be considered to maximize treatment efficiency. Here, we show that subinhibitory concentration of drugs targeting the F1F0 ATP synthase and the cytochrome bc1:aa3, as well as energy uncouplers, interfere with the bactericidal potency of isoniazid and moxifloxacin. Isoniazid- and moxifloxacin-induced mycobacterial death correlated with a transient increase in intracellular ATP that was dissipated by co-incubation with energy metabolism inhibitors. Although oxidative phosphorylation is a promising target space for drug development, a better understanding of the link between energy metabolism and antibiotic-induced mycobacterial death is essential to develop potent drug combinations for the treatment of tuberculosis.
SHROOM2 is a key mediator of RhoA-ROCK pathway that regulates cell motility and actin cytoskeleton organization. However, the functions of SHROOM2 beyond RhoA/ROCK signaling remain poorly understood. ...Here, we report that SHROOM2 not only participates in RhoA-ROCK-induced stress fiber formation and focal adhesion, but also had an unanticipated role in suppressing epithelial-to-mesenchymal transition (EMT) and tumor metastasis. Depletion of SHROOM2 in nasopharyngeal carcinoma (NPC) cells enhances mesenchymal characteristics and reduces epithelial markers, concomitant with increased motility, enabling the development of invasion and tumor metastasis, which are largely ROCK-independent, as ROCK inhibitor Y-27632 did not cause EMT phenotype; furthermore, combination of ROCK inhibition and SHROOM2 depletion resulted in the most robust increases in cell migration and invasion, indicating that SHROOM2 and ROCK work synergistically rather than epistatic. Analysis of clinical samples suggested that SHROOM2 is downregulated in NPC and the expression of SHROOM2 in metastatic NPC was even lower than in the primary tumors. Our findings uncover a non-canonical role of SHROOM2 as a potent antagonist for EMT and NPC metastasis.
STUDY DESIGN.A cross-sectional study.
OBJECTIVE.To assess the effectiveness of a new assessment tool, myelopathy-hand functional evaluation system (MFES), in evaluating the hand dysfunction of ...patients with cervical myelopathy in the 10-second grip-and-release test (10 second G-R test).
SUMMARY OF BACKGROUND DATA.Clumsy fingers movement is a common symptom of myelopathy patients. Evaluating the impaired hand function can provide a strong basis in assessing the severity of myelopathy. Currently, no objective and effective evaluation method is widely accepted in clinical practice.
METHODS.MFES mainly consists of a pair of wise-gloves and a computer with software. One hundred and ninety-eight consecutive participants were asked to wear the wise-gloves and then perform 10 seconds G-R test. The movements of each finger were recorded by MFES and converted into waveforms. Relevant waveform parameters were measured and analyzed. The Japanese Orthopedics Association (JOA) scores of each patient were marked and the maximum spinal cord compression (MSCC) was measured on midsagittal T2-weighted magnetic resonance imaging (MRI).
RESULTS.Myelopathy patients had a lower number of G-R cycles and a longer time per cycle than healthy subjects. There were significant differences in adduction and abduction time in patients with JOA scores greater than 6, but not in healthy subjects and patients with JOA scores less than 6. The waveforms of ulnar three fingers in myelopathy patients were lower and wider than those in healthy individuals. The average ratio value of wave height to wave width (a/b) could quantitatively reflect such differences of waveforms. According to receiver operating characteristic (ROC) curve analysis, the optimal threshold value of the normal average ratio was more than 1.92. The average a/b value was correlated with the JOA scores of the motor function in the upper extremities (r = 0.842).
CONCLUSION.MFES appears to be an objective and quantitative assessment tool for patients with cervical myelopathy.Level of Evidence3
Abstract
Background
Radiation-induced brain injury is a nonnegligible issue in the management of cancer patients treated by partial or whole brain irradiation. In particular, temporal lobe injury ...(TLI), a deleterious late complication in nasopharyngeal carcinoma, greatly affects the long-term life quality of these patients. Although genome-wide association studies (GWASs) have successfully identified single nucleotide polymorphisms (SNPs) associated with radiation toxicity, genetic variants contributing to the radiation-induced brain injury have not yet been assessed.
Methods
We recruited and performed follow-up for a prospective observational cohort, Genetic Architecture of Radiotherapy Toxicity and Prognosis, using magnetic resonance imaging for TLI diagnosis. We conducted genome-wide association analysis in 1082 patients and validated the top associations in two independent cohorts of 1119 and 741 patients, respectively. All statistical tests were two-sided.
Results
We identified a promoter variant rs17111237 (A > G, minor allele frequency MAF = 0.14) in CEP128 associated with TLI risk (hazard ratio = 1.45, 95% confidence interval = 1.26 to 1.66, Pcombined=3.18 × 10–7) which is in moderate linkage disequilibrium (LD) with rs162171 (MAF = 0.18, R2 = 0.69), the top signal in CEP128 (hazard ratio = 1.46, 95% confidence interval = 1.29–1.66, Pcombined= 6.17 × 10–9). Combining the clinical variables with the top SNP, we divided the patients into different subgroups with varying risk with 5-year TLI-free rates ranging from 33.7% to 95.5%. CEP128, a key component of mother centriole, tightly interacts with multiple radiation-resistant genes and plays an important role in maintaining the functional cilia, which otherwise will lead to a malfunction of the neural network. We found that A > G alteration at rs17111237 impaired the promoter activity of CEP128 and knockdown of CEP128 decreased the clonogenic cell survival of U87 cells under radiation. Noteworthy, 12.7% (27/212) of the GWAS-based associated genes (P < .001) were enriched in the neurogenesis pathway.
Conclusions
This three-stage study is the first GWAS of radiation-induced brain injury that implicates the genetic susceptibility gene CEP128 involved in TLI development and provides the novel insight into the underlying mechanisms of radiation-induced brain injury.
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. In China, chronic hepatitis B virus (HBV) infection remains the major risk factor for HCC. In this study, we performed a ...genome-wide association study (GWAS) among Chinese populations to identify novel genetic loci contributing to susceptibility to HBV-related HCC.
GWAS scan is performed in a collection of 205 HBV-related HCC trios (each trio includes an affected proband and his/her both parents), and 355 chronic HBV carriers with HCC (cases) and 360 chronic HBV carriers without HCC (controls), followed by two rounds of replication studies totally consisting of 3,796 cases and 2,544 controls.
We identified a novel association signal within the
gene at 7q21.13 (index rs10272859, OR = 1.28,
= 9.46 × 10
). Furthermore, we observed that the at-risk rs10272859G allele was significantly associated with higher mRNA expression levels of
in liver tissues. Chromosome conformation capture assays in liver cells confirmed that a physical interaction exists between the promoter region of
and the risk-associated SNPs in strong linkage disequilibrium with the index rs10272859 at 7q21.13. This index rs10272859 also showed significant association with the survival of HCC patients.
Our findings highlight a novel locus at 7q21.13 conferring both susceptibility and prognosis to HBV-related HCC, and suggest the
gene to be the functional target of the 7q21.13 locus.
.
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