ATGL promotes the proliferation of hepatocellular carcinoma cells via the p‐AKT signaling pathway

Abnormal metabolism, including abnormal lipid metabolism, is a hallmark of cancer cells. Some studies have demonstrated that the lipogenic pathway might promote the development of hepatocellular carcinoma (HCC). However, the role of adipose triglyceride lipase (ATGL) in hepatocellular carcinoma cells has not been elucidated. We evaluated the function of ATGL in hepatocellular carcinoma using methyl azazolyl blue and migration assay through overexpression of ATGL in HepG2 cells. Quantitative reverse‐transcription polymerase chain reaction and Western blot analyses were used to assess the mechanisms of ATGL in hepatocellular carcinoma. In the current study, we first constructed and transiently transfected ATGL into hepatocellular carcinoma cells. Secondly, we found that ATGL promoted the proliferation of hepatoma cell lines via upregulating the phosphorylation of AKT, but did not affect the metastatic ability of HCC cells. Moreover, the p‐AKT inhibitor significantly eliminated the effect of ATGL on the proliferation of hepatoma carcinoma cells. Taken together, our results indicated that ATGL promotes hepatocellular carcinoma cells proliferation through upregulation of the AKT signaling pathway

Dynamic evolution of ceftazidime–avibactam resistance due to interchanges between blaKPC-2 and blaKPC-145 during treatment of Klebsiella pneumoniae infection

BackgroundThe emergence of ceftazidime–avibactam (CZA) resistance among carbapenem-resistant Klebsiella pneumoniae (CRKP) is of major concern due to limited therapeutic options.MethodsIn this study, 10 CRKP strains were isolated from different samples of a patient with CRKP infection receiving CZA treatment. Whole-genome sequencing (WGS) and conjugation experiments were performed to determine the transferability of the carbapenem resistance gene.ResultsThis infection began with a KPC-2-producing K. pneumoniae (CZA MIC = 2 μg/mL, imipenem MIC ≥ 16 μg/mL). After 20 days of CZA treatment, the strains switched to the amino acid substitution of T263A caused by a novel KPC-producing gene, blaKPC-145, which restored carbapenem susceptibility but showed CZA resistance (CZA MIC ≥ 256 μg/mL, imipenem MIC = 1 μg/mL). The blaKPC-145 gene was located on a 148,185-bp untransformable IncFII-type plasmid. The subsequent use of carbapenem against KPC-145-producing K. pneumoniae infection led to a reversion of KPC-2 production (CZA MIC = 2 μg/mL, imipenem MIC ≥ 16 μg/mL). WGS analysis showed that all isolates belonged to ST11-KL47, and the number of SNPs was 14. This implied that these blaKPC-positive K. pneumoniae isolates might originate from a single clone and have been colonized for a long time during the 120-day treatment period.ConclusionThis is the first report of CZA resistance caused by blaKPC-145, which emerged during the treatment with CZA against blaKPC-2-positive K. pneumoniae-associated infection in China. These findings indicated that routine testing for antibiotic susceptibility and carbapenemase genotype is essential during CZA treatment

The effects of in-plane and out-of-plane constraints on J-R curves for X80 steel: A study using clamped SENT specimens

In the present paper, an experimental program was carried out to develop J-R curves using clamped single edge notched tension (SENT) specimens. A wide range of geometrical parameter variations is considered including different crack depth to plate width ratios (a/W) and plate thickness to width ratios (B/W). The material studied is the oil and gas pipeline steel API X80. Power law curve fitting parameters and tearing modulus are obtained for the J-R curves using the unloading compliance (UC) method for the clamped SENT specimens. Moreover, in-plane and out-of-plane constraint effects on J-R curves using clamped SENT specimens are studied, the second terms in the Williams’ series expansion are used to quantify the constraint effects. Specifically, it is demonstrated that the normalized T11 and the independent portion of T33, which equals T33-νT11, can be used to quantify the in-plane and out-of-plane constraint effects, respectively. Comparisons show that the constraint dependent

Risk factors and mortality for elderly patients with bloodstream infection of carbapenem resistance Klebsiella pneumoniae: a 10-year longitudinal study

Abstract Background Bloodstream infection (BSI) caused by carbapenem resistant Klebsiella pneumoniae (CRKP), especially in elderly patients, results in higher morbidity and mortality. The purpose of this study was to assess risk factors associated with CRKP BSI and short-term mortality among elderly patients in China. Methods In this retrospective cohort study, we enrolled 252 inpatients aged ≥ 65 years with BSI caused by KP from January 2011 to December 2020 in China. Data regarding demographic, microbiological characteristics, and clinical outcome were collected. Result Among the 252 BSI patients, there were 29 patients (11.5%) caused by CRKP and 223 patients (88.5%) by carbapenem-susceptible KP (CSKP). The overall 28-day mortality rate of elderly patients with a KP BSI episode was 10.7% (27/252), of which CRKP BSI patients (14 / 29, 48.3%) were significantly higher than CSKP patients (13 / 223, 5.83%) (P < 0.001). Hypertension (OR: 13.789, [95% CI: 3.883–48.969], P < 0.001), exposure to carbapenems (OR: 8.073, [95% CI: 2.066–31.537], P = 0.003), and ICU stay (OR: 11.180, [95% CI: 2.663–46.933], P = 0.001) were found to be associated with the development of CRKP BSI in elderly patients. A multivariate analysis showed that isolation of CRKP (OR 2.881, 95% CI 1.228–6.756, P = 0.015) and KP isolated in ICU (OR 11.731, 95% CI 4.226–32.563, P < 0.001) were independent risk factors for 28-day mortality of KP BSI. Conclusion In elderly patients, hypertension, exposure to carbapenems and ICU stay were associated with the development of CRKP BSI. Active screening of CRKP for the high-risk populations, especially elderly patients, is significant for early detection and successful management of CRKP infection

Directed natural evolution generates a next-generation oncolytic virus with a high potency and safety profile

Abstract Oncolytic viruses (OVs) represent a type of encouraging multi-mechanistic drug for the treatment of cancer. However, attenuation of virulence, which is generally required for the development of OVs based on pathogenic viral backbones, is frequently accompanied by a compromised killing effect on tumor cells. By exploiting the property of viruses to evolve and adapt in cancer cells, we perform directed natural evolution on refractory colorectal cancer cell HCT-116 and generate a next-generation oncolytic virus M1 (NGOVM) with an increase in the oncolytic effect of up to 9690-fold. The NGOVM has a broader antitumor spectrum and a more robust oncolytic effect in a range of solid tumors. Mechanistically, two critical mutations are identified in the E2 and nsP3 genes, which accelerate the entry of M1 virus by increasing its binding to the Mxra8 receptor and antagonize antiviral responses by inhibiting the activation of PKR and STAT1 in tumor cells, respectively. Importantly, the NGOVM is well tolerated in both rodents and nonhuman primates. This study implies that directed natural evolution is a generalizable approach for developing next-generation OVs with an expanded scope of application and high safety