Synergistic Effects of Glutamine Deprivation and Metformin in Acute Myeloid Leukemia.

OBJECTIVE: The metabolic reprogramming of acute myeloid leukemia (AML) cells is a compensatory adaptation to meet energy requirements for rapid proliferation. This study aimed to examine the synergistic effects of glutamine deprivation and metformin exposure on AML cells. METHODS: SKM-1 cells (an AML cell line) were subjected to glutamine deprivation and/or treatment with metformin or bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl) ethyl sulfide (BPTES, a glutaminase inhibitor) or cytarabine. Cell viability was detected by Cell Counting Kit-8 (CCK-8) assay, and cell apoptosis and reactive oxygen species (ROS) by flow cytometry. Western blotting was conducted to examine the levels of apoptotic proteins, including cleaved caspase-3 and poly(ADP-ribose) polymerase (PARP). Moreover, the human long noncoding RNA (lncRNA) microarray was used to analyze gene expression after glutamine deprivation, and results were confirmed with quantitative RT-PCR (qRT-PCR). The expression of metallothionein 2A (MT2A) was suppressed using siRNA. Cell growth and apoptosis were further detected by CCK-8 assay and flow cytometry, respectively, in cells with MT2A knockdown. RESULTS: Glutamine deprivation or treatment with BPTES inhibited cell growth and induced apoptosis in SKM-1 cells. The lncRNA microarray result showed that the expression of MT family genes was significantly upregulated after glutamine deprivation. MT2A knockdown increased apoptosis, while proliferation was not affected in SKM-1 cells. In addition, metformin inhibited cell growth and induced apoptosis in SKM-1 cells. Both glutamine deprivation and metformin enhanced the sensitivity of SKM-1 cells to cytarabine. Furthermore, the combination of glutamine deprivation with metformin exhibited synergistic antileukemia effects on SKM-1 cells. CONCLUSION: Targeting glutamine metabolism in combination with metformin is a promising new therapeutic strategy for AML.

Cardiovascular magnetic resonance feature tracking derived strain analysis can predict return to training following exertional heatstroke.

BACKGROUND: Exertional heatstroke (EHS) is increasingly common in young trained soldiers. However, prognostic markers in EHS patients remain unclear. The objective of this study was to evaluate cardiovascular magnetic resonance (CMR) feature tracking derived left ventricle (LV) strain as a biomarker for return to training (RTT) in trained soldiers with EHS. METHODS: Trained soldiers (participants) with EHS underwent CMR cine sequences between June 2020 and August 2023. Two-dimensional (2D) LV strain parameters were derived. At 3 months after index CMR, the participants with persistent cardiac symptoms including chest pain, dyspnea, palpitations, syncope, and recurrent heat-related illness were defined as non-RTT. Multivariable logistic regression analysis was used to develop a predictive RTT model. The performance of different models was compared using the area under curve (AUC). RESULTS: A total of 80 participants (median age, 21 years; interquartile range (IQR), 20-23 years) and 27 health controls (median age, 21 years; IQR, 20-22 years) were prospectively included. Of the 77 participants, 32 had persistent cardiac symptoms and were not able to RTT at 3 months follow-up after experiencing EHS. The 2D global longitudinal strain (GLS) was significantly impaired in EHS participants compared to the healthy control group (-15.8 ± 1.7% vs -16.9 ± 1.2%, P = 0.001), which also showed significant statistical differences between participants with RTT and non-RTT (-15.0 ± 3.5% vs -16.5 ± 1.4%, P < 0.001). 2D-GLS (≤ -15.0%) (odds ratio, 1.53; 95% confidence interval: 1.08, 2.17; P = 0.016) was an independent predictor for RTT even after adjusting known risk factors. 2D-GLS provided incremental prognostic value over the clinical model and conventional CMR parameters model (AUCs: 0.72 vs 0.88, P = 0.013; 0.79 vs 0.88, P = 0.023; respectively). CONCLUSION: Two-dimensional global longitudinal strain (≤ -15.0%) is an incremental prognostic CMR biomarker to predict RTT in soldiers suffering from EHS.

Coronary CTA-based vascular radiomics predicts atherosclerosis development proximal to LAD myocardial bridging.

AIMS: Cardiac cycle morphological changes can accelerate plaque growth proximal to myocardial bridging (MB) in the left anterior descending artery (LAD). To assess coronary computed tomography angiography (CCTA)-based vascular radiomics for predicting proximal plaque development in LAD MB. METHODS AND RESULTS: Patients with repeated CCTA scans showing LAD MB without proximal plaque in index CCTA were included from Jinling Hospital as a development set. They were divided into training and internal testing in an 8:2 ratio. Patients from four other tertiary hospitals were set as external validation set. The endpoint was proximal plaque development of LAD MB in follow-up CCTA. Four vascular radiomics models were built: MB centreline (MB CL), proximal MB CL (pMB CL), MB cross-section (MB CS), and proximal MB CS (pMB CS), whose performances were evaluated using area under the receiver operating characteristic curve (AUC), integrated discrimination improvement (IDI), and net reclassification improvement (NRI). In total, 295 patients were included in the development (n = 192; median age, 54 ± 11 years; 137 men) and external validation sets (n = 103; median age, 57 ± 9 years; 57 men). The pMB CS vascular radiomics model exhibited higher AUCs in training, internal test, and external sets (AUC = 0.78, 0.75, 0.75) than the clinical and anatomical model (all P < 0.05). Integration of the pMB CS vascular radiomics model significantly raised the AUC of the clinical and anatomical model from 0.56 to 0.75 (P = 0.002), along with enhanced NRI [0.76 (0.37-1.14), P < 0.001] and IDI [0.17 (0.07-0.26), P < 0.001] in the external validation set. CONCLUSION: The CCTA-based pMB CS vascular radiomics model can predict plaque development in LAD MB.

Identification of the novel allele, HLA-B*48:58, in a patient with chronic myelogenous leukemia.

HLA-B*48:58 differs from HLA-B*48:01:01 by one nucleotide substitution in codon 17 in exon 2.

Characterization of the novel HLA-A*26:233 allele by sequencing based typing.

HLA-A*26:233 differs from HLA-A*26:01:01:01 by one nucleotide substitution in codon 129 in exon 3.

Detection of cytomegalovirus (CMV) by digital PCR in stool samples for the non-invasive diagnosis of CMV gastroenteritis.

BACKGROUND: CMV gastroenteritis is common in patients receiving allogeneic hematopoietic stem cell transplantation and it is difficult to distinguish from acute graft-versus-host disease (aGvHD), which has very similar symptoms but needs quite different treatment. CMV gastroenteritis is caused by local infection or reactivation of CMV in the gastrointestinal tract while aGvHD is due to immune rejection. The gold standard of diagnosis of CMV gastroenteritis and aGvHD is gastrointestinal biopsy under endoscopy, which is invasive and can potentially lead to severe side effects. Stool samples testing with quantitative polymerase chain reaction (qPCR) may be an alternative, while the application in trace level measurements and precision are not all satisfactory enough in reported research. METHODS: In this study, we designed a novel method that extracted the cell free DNA (cfDNA) from the fecal supernatant to perform digital PCR (dPCR) for the detection of CMV, analyzed the performance and compared it with the total DNA extracted by the current procedure. RESULTS: Twenty-two paired stool samples using two DNA extraction methods proved that the cfDNA extraction method had markedly higher DNA concentrations and control gene copy number, suggesting that cfDNA may be more informative and more useful for the detection of CMV DNA segment. The dPCR approach in detecting CMV DNA segment also exhibit good linearity (R2 = 0.997) and higher sensitivity (limit of detection at 50% was 3.534 copies/µL). Eighty-two stool samples from 44 immunocompromised patients were analyzed, CMV-positive rate was 28%, indicating that more than one-quarter of the gastrointestinal symptoms within these patients may be caused by CMV infection or reactivation. CONCLUSION: The combined results suggest that detection of CMV by dPCR in cfDNA of stool supernatant is a powerful method to identify CMV gastroenteritis and helps in clinical treatment decision making.

Randomized Clinical Study on the Efficacy of Direct Anterior Approach Combined With Tendon Release and Repair After Total Hip Arthroplasty.

Background: To study the effect of reconstruction of the joint capsule and conjoint tendon on the functional recovery of the hip joint during direct anterior approach (DAA) total hip arthroplasty. Methods: A total of 60 patients who underwent their first total hip arthroplasty surgery were selected. According to the set criteria, the selected patients were divided into observation group A (n = 30) and control group B (n = 30). In group A, the joint capsule and conjoint tendon (superior muscle, internal obturator muscle, and inferior muscle) were repaired in situ, while in group B, only the joint capsule was repaired in situ, and the conjoint tendon was not repaired. The surgical indicators, including hip joint function and clinical efficacy of the two groups, were compared. Results: After 6 months of follow-up in groups A and B, no dislocation occurred. The Harris Hip scores of group A were higher than those of group B at 1-month post-operation, i.e., p < 0.05, as well as the valid muscle strength and conjoint tendon valid tension, were higher in group A than group B at 1-month postoperative follow-up, i.e., p < 0.05. Conclusion: DAA for total hip arthroplasty on the premise of reconstructing the joint capsule structure can rebuild the tension of the conjoint tendon, enhance its muscle strength, and significantly improve the joint stability and function of the patient early stage. It is beneficial for the patient's rapid recovery and is worth implementing.