Fully automated artificial intelligence-based coronary CT angiography image processing: efficiency, diagnostic capability, and risk stratification.

OBJECTIVES: To prospectively investigate whether fully automated artificial intelligence (FAAI)-based coronary CT angiography (CCTA) image processing is non-inferior to semi-automated mode in efficiency, diagnostic ability, and risk stratification of coronary artery disease (CAD). MATERIALS AND METHODS: Adults with indications for CCTA were prospectively and consecutively enrolled at two hospitals and randomly assigned to either FAAI-based or semi-automated image processing using equipment workstations. Outcome measures were workflow efficiency, diagnostic accuracy for obstructive CAD (≥ 50% stenosis), and cardiovascular events at 2-year follow-up. The endpoints included major adverse cardiovascular events, hospitalization for unstable angina, and recurrence of cardiac symptoms. The non-inferiority margin was 3 percentage difference in diagnostic accuracy and C-index. RESULTS: In total, 1801 subjects (62.7 ± 11.1 years) were included, of whom 893 and 908 were assigned to the FAAI-based and semi-automated modes, respectively. Image processing times were 121.0 ± 18.6 and 433.5 ± 68.4 s, respectively (p <0.001). Scan-to-report release times were 6.4 ± 2.7 and 10.5 ± 3.8 h, respectively (p < 0.001). Of all subjects, 152 and 159 in the FAAI-based and semi-automated modes, respectively, subsequently underwent invasive coronary angiography. The diagnostic accuracies for obstructive CAD were 94.7% (89.9-97.7%) and 94.3% (89.5-97.4%), respectively (difference 0.4%). Of all subjects, 779 and 784 in the FAAI-based and semi-automated modes were followed for 589 ± 182 days, respectively, and the C-statistic for cardiovascular events were 0.75 (0.67 to 0.83) and 0.74 (0.66 to 0.82) (difference 1%). CONCLUSIONS: FAAI-based CCTA image processing significantly improves workflow efficiency than semi-automated mode, and is non-inferior in diagnosing obstructive CAD and risk stratification for cardiovascular events. CLINICAL RELEVANCE STATEMENT: Conventional coronary CT angiography image processing is semi-automated. This observation shows that fully automated artificial intelligence-based image processing greatly improves efficiency, and maintains high diagnostic accuracy and the effectiveness in stratifying patients for cardiovascular events. KEY POINTS: • Coronary CT angiography (CCTA) relies heavily on high-quality and fast image processing. • Full-automation CCTA image processing is clinically non-inferior to the semi-automated mode. • Full automation can facilitate the application of CCTA in early detection of coronary artery disease.

DNMT1 regulates hypermethylation and silences hsa_circ_401351 in hydroquinone-induced malignant TK6 cells.

BACKGROUND: Benzene and its metabolite hydroquinone (HQ) are widely used in daily life, and long-term exposure to benzene or HQ can induce acute myeloid leukemia (AML). Circular RNAs (circRNAs) are mostly produced by reverse splicing of gene exon mRNA precursors. The modulation of circRNA expression is connected to leukemia progression; however, the molecular mechanism is still unknown. MATERIALS AND METHODS: In this study, the cells were divided into four groups: PBS control group (PBS-TK6), TK6 malignantly transformed cells induced by 10.0 µmol/L HQ (HQ-TK6), and HQ-TK6 cells treated with 5 µmol/L 5-AzaC (DNA methyltransferase inhibitor) for 24 h (HQ + 5-AzaC). HQ-TK6 cells were treated with 200 nmol/L TSA (histone deacetylation inhibitor) for 24 h (HQ + TSA). qRT-PCR was used to identify the differential hsa_circ_401351 expression between the four groups. We further determined the hsa_circ_401351 promoter methylation level with methylation-specific PCR. DNMT1 and DNMT3b were knocked down by CRISPR/Cas9 to elucidate the specific molecular mechanism of hsa_circ_401351 in HQ-TK6 cells. CCK-8 and flow cytometry detected cell proliferation and apoptosis, respectively, after hsa_circ_401351 was overexpressed in HQ-TK6 cells. RESULTS: Compared with the PBS-TK6 group, the expression of hsa_circ_401351 was found to be lower in the HQ-TK6 group. Nevertheless, treatment with 5-AzaC or TSA increased hsa_circ_401351 expression, with the upregulation being more pronounced in the TSA group. The expression of hsa_circ_401351 in the DNMT1 knockdown group was dramatically increased by 50% compared to that in the control group, and the DNA methylation level of the hsa_circ_401351 promoter region was decreased. When hsa_circ_401351 was overexpressed, HQ-TK6 cell proliferation was significantly slowed after 48 h compared with the control group. Flow cytometry showed that cells were mainly arrested in G1 phase, and apoptosis was significantly enhanced. Similarly, qRT-PCR and Western blot data showed significant reductions in Caspase-3 mRNA and protein production, and Bcl-2 mRNA levels were also elevated. CONCLUSIONS: Overall, our research showed that elevated DNMT1 expression in HQ-TK6 cells increased methylation levels and decreased expression of the hsa_circ_401351 promoter region, limiting its ability to suppress HQ-TK6 cell growth and enhance apoptosis.

Comparisons of in-hospital complications between total hip arthroplasty and hip resurfacing arthroplasty.

BACKGROUND: Hip resurfacing arthroplasty (HRA) is a less common but effective alternative method to total hip arthroplasty (THA) for hip reconstruction. In this study, we investigated the incidences of in-hospital complications between patients who had been subjected to THA and HRA. METHODS: The National Inpatient Sample data that had been recorded from 2005 to 2014 was used in this study. Based on the International Classification of Disease, Ninth Revision, Clinical Modification, patients who underwent THA or HRA were included. Data on demographics, preoperative comorbidities, length of hospital stay, total charges, and in-hospital mortality and complications were compared. Multiple logistic regression analysis was used to determine whether different surgical options are independent risk factors for postoperative complications. RESULTS: A total of 537,506 THAs and 9,744 HRAs were obtained from the NIS database. Patients who had been subjected to HRA exhibited less preoperative comorbidity rates, shorter length of stay and extra hospital charges. Moreover, HRA was associated with more in-hospital prosthesis loosening. Notably, patients who underwent HRA were younger and presented less preoperative comorbidities but did not show lower incidences in most complications. CONCLUSIONS: The popularity of HRA gradually reduced from the year 2005 to 2014. Patients who underwent HRA were more likely to be younger, male, have less comorbidities and spend more money on medical costs. The risk of in-hospital prosthesis loosening after HRA was higher. The HRA-associated advantages with regards to most in-hospital complications were not markedly different from those of THA. In-hospital complications of HRA deserve more attention from surgeons.

Hsa_circ_0001944 regulates apoptosis by regulating the binding of PARP1 and HuR in leukemia and malignant transformed cells induced by hydroquinone.

Hydroquinone (HQ) is one of the major metabolites of benzene and can cause abnormal gene expression. It is a known carcinogen that alters cell cycle disruption and cell proliferation. However, its chemical mechanism remain a mystery. Circular RNAs (circRNAs) are a subtype of noncoding RNAs (ncRNAs) that play a variety of roles in biological processes. Hsa_circ_001944 expression was upregulated in 30 leukemia patients and HQ-induced malignant transformed TK6 cells. Hsa_circ_001944 silencing inhibited the growth of HQ-TK6 cells and halted the cell cycle. The silencing of hsa_circ_0001944 led to increased cell accumulation in G1 versus S phase, increased apoptosis in the sh1944 versus the shNC group, and increased levels of DNA damage (γ-H2AX), leading to cell cycle arrest. In summary, inhibition of hsa_circ_001944 restricted cell growth by inhibiting cell cycle arrest and induced growth of HQ-TK6 cells by modulating PARP1 expression. Hsa_circ_0001944 targeted HuR, which is a kind of RNA-binding protein, to control PARP1 expression via RNAinter, RBPmap, and RBPdb. Fluorescence in situ hybridization combined with immunofluorescent labeling and western blotting experiments showed that hsa_circ_001944 was able to dissociate HuR and PARP1 binding in HQ-TK6 cells, control PARP1 production, and ultimately alter the PARP1/H-Ras pathway.

After-hour elective total knee arthroplasty does not affect clinical outcomes but negatively affects alignment.

INTRODUCTION: In cases of limited medical resources, elective total knee arthroplasty (TKA) sometimes needs to be performed after typical work hours. However, surgeon fatigue and logistical factors may potentially affect outcomes. This study aimed to detect whether after-hour procedures impair outcomes after TKA. MATERIALS AND METHODS: Elective unilateral TKA from Jan 1, 2016 to Nov 31, 2018 was retrospectively selected and separated into two groups. Procedures started from 8:00 A.M. to 5:29 P.M. were identified as day-time surgeries, whereas those started from 5:30 P.M. to 11:59 P.M. were considered after-hour surgeries. Operative period, Knee Society Score (KSS), range of motion (ROM), total blood loss, length of hospital stay (LOS), and postoperative adverse events and complications were compared. Additionally, the components were evaluated radiologically. RESULTS: A total of 321 patients were selected, including 258 (80.37%) patients in the day-time group and 63 (19.63%) patients in the after-hour group. Operative period, LOS, total blood loss were similar between groups. The overall and each specific incidence of postoperative complications were comparable between the two groups, but the incidence of postoperative vomiting (POV) was higher in the after-hour group. There was no significant difference in knee joint function as shown by the KSS and ROM, both on the 3rd day and at 2 years after surgeries. Radiologically, there were no significant differences between the two groups in the femoral notches (P = 0.592). However, better coronal alignment was detected in the day-time group (P = 0.002), consistent with which there were less outliers (P = 0.033). CONCLUSION: After-hour TKA procedure does not exert an impact on clinical outcomes, but negatively affects lower limb alignment. Besides, after-hour TKA surgery impairs patients' comfort by increasing POV.

PARP-1 inhibits DNMT1-mediated promoter methylation and promotes linc01132 expression in benzene-exposed workers and hydroquinone-induced malignant transformed cells.

Hydroquinone (HQ), one of the main active metabolites of benzene, can induce the abnormal expression of long non-coding RNA (lncRNA). Studies have shown that lncRNA plays an important role in the occurrence of hematologic tumors induced by benzene or HQ. However, the molecular mechanism remains to be elucidated. Here, we investigated the molecular mechanism by which poly(ADP-ribose)polymerase 1 (PARP-1) interacts with DNA methyltransferase 1 (DNMT1) to regulate promoter methylation mediated linc01132 expression in HQ-induced TK6 malignant transformed cells (HQ-MT). The results revealed that the expression of linc01132 was increased in benzene-exposed workers and HQ-MT cells. The methylation of linc01132 promoter region was inhibited. Furthermore, in HQ-MT cells treated with 5-Aza-2'-deoxycytidine (5-AzaC) (DNA methyltransferase inhibitor) or trichostatin A (TSA) (histone deacetylation inhibitor), the expression of linc01132 was increased due to the regulation of DNA promoter methylation level by inhibiting DNMT1 expression. The methylation level of linc01132 promoter was correlated negatively with the expression of linc01132 in benzene-exposed workers, indicating that DNA methylation may contribute the expression of linc01132. Knockout of DNMT1, not DNMT3b, increased the expression of linc01132 as well as the demethylation of linc01132 promoter in HQ-MT cells. It was found that by knockdown PARP-1, the expression of DNMT1 in the nucleus was increased by immunofluorescence confocal microscopy, leading to the inhibition of hypermethylation in the promoter region of linc01132. Therefore, PARP-1 inhibits DNA methyltransferase (DNMT)-mediated promoter methylation and plays a role in linc01132 expression in benzene-exposed workers or HQ-MT cells, and is associated with benzene or HQ induced leukemia progression.

PARP-1 modulates the expression of miR-223 through histone acetylation to involve in the hydroquinone-induced carcinogenesis of TK6 cells.

The upstream regulators of microRNAs were rarely reported. Hydroquinone (HQ) is the main metabolite of benzene, one of the important environmental factors contributing to leukemia and lymphoma. In HQ-induced malignant transformed TK6 (TK6-HT) cells, the expression of PARP-1 and miR-223 were upregulated. When in PARP-1 silencing TK6-HT cells, miR-223 was downregulated and the apoptotic cell number correspondingly increased. In TK6 cells treated with HQ for different terms, the expression of miR-223 and PARP-1 were dynamically observed and found to be decreased and increased, respectively. Trichostatin A could increase the expression of miR-223, then the expression of HDAC1-2 and nuclear factor kappa B were found to be increased, but that of mH2A was decreased. PARP-1 silencing inhibited the protein expression of H3Ac, mH2A, and H3K27ac. By co-immunoprecipitation experiment, PARP-1 and HDAC2 were found to form a regulatory complex. In conclusion, we demonstrated that the upregulation of PARP-1 mediated activation of acetylation to promote the transcription of miR-223 possibly via coregulating with HDAC2, an epigenetic regulation mechanism involved in cell malignant transformation resulting from long-term exposure to HQ, in which course, H3K27ac might be a specific marker for the activation of histone H3, which also gives hints for benzene exposure research.

Effect of First-Line Serplulimab vs Placebo Added to Chemotherapy on Survival in Patients With Extensive-Stage Small Cell Lung Cancer: The ASTRUM-005 Randomized Clinical Trial.

Importance: Programmed cell death ligand 1 inhibitors combined with chemotherapy has changed the approach to first-line treatment in patients with extensive-stage small cell lung cancer (SCLC). It remained unknown whether adding a programmed cell death 1 (PD-1) inhibitor to chemotherapy provided similar or better benefits in patients with extensive-stage SCLC, which would add evidence on the efficacy of checkpoint inhibitors in the treatment of extensive-stage SCLC. Objective: To evaluate the efficacy and adverse event profile of the PD-1 inhibitor serplulimab plus chemotherapy compared with placebo plus chemotherapy as first-line treatment in patients with extensive-stage SCLC. Design, Setting, and Participants: This international, double-blind, phase 3 randomized clinical trial (ASTRUM-005) enrolled patients at 114 hospital sites in 6 countries between September 12, 2019, and April 27, 2021. Of 894 patients who were screened, 585 with extensive-stage SCLC who had not previously received systemic therapy were randomized. Patients were followed up through October 22, 2021. Interventions: Patients were randomized 2:1 to receive either 4.5 mg/kg of serplulimab (n = 389) or placebo (n = 196) intravenously every 3 weeks. All patients received intravenous carboplatin and etoposide every 3 weeks for up to 12 weeks. Main Outcomes and Measures: The primary outcome was overall survival (prespecified significance threshold at the interim analysis, 2-sided P < .012). There were 13 secondary outcomes, including progression-free survival and adverse events. Results: Among the 585 patients who were randomized (mean age, 61.1 [SD, 8.67] years; 104 [17.8%] women), 246 (42.1%) completed the trial and 465 (79.5%) discontinued study treatment. All patients received study treatment and were included in the primary analyses. As of the data cutoff (October 22, 2021) for this interim analysis, the median duration of follow-up was 12.3 months (range, 0.2-24.8 months). The median overall survival was significantly longer in the serplulimab group (15.4 months [95% CI, 13.3 months-not evaluable]) than in the placebo group (10.9 months [95% CI, 10.0-14.3 months]) (hazard ratio, 0.63 [95% CI, 0.49-0.82]; P < .001). The median progression-free survival (assessed by an independent radiology review committee) also was longer in the serplulimab group (5.7 months [95% CI, 5.5-6.9 months]) than in the placebo group (4.3 months [95% CI, 4.2-4.5 months]) (hazard ratio, 0.48 [95% CI, 0.38-0.59]). Treatment-related adverse events that were grade 3 or higher occurred in 129 patients (33.2%) in the serplulimab group and in 54 patients (27.6%) in the placebo group. Conclusions and Relevance: Among patients with previously untreated extensive-stage SCLC, serplulimab plus chemotherapy significantly improved overall survival compared with chemotherapy alone, supporting the use of serplulimab plus chemotherapy as the first-line treatment for this patient population. Trial Registration: ClinicalTrials.gov Identifier: NCT04063163.

The DNMT1-associated lncRNA UCA1 was upregulated in TK6 cells transformed by long-term exposure to hydroquinone and benzene-exposed workers via DNA hypomethylation.

Exposure to benzene or its metabolite hydroquinone (HQ) is a risk factor for a series of myeloid malignancies, and long noncoding RNAs play an important role in the process of pathogenesis. Urothelial cancer-associated 1 (UCA1) functions as an oncogene in the development of acute myeloid leukemia. However, the association between DNMT1 and UCA1 with benzene or HQ exposure has not been explored. We characterized UCA1 expression in cells briefly exposed to HQ (HQ-ST cells) and HQ-induced malignantly transformed (TK6-HT cells) treated with 5-aza-2'-deoxycytidine (5-AzaC) or trichostatin A (TSA). Compared to that in control cells, UCA1 expression was increased, whereas DNMT1 was decreased in HQ-ST cells and TK6-HT cells treated with 5-AzaC or TSA. Moreover, UCA1 expression was also upregulated and positively correlated with benzene exposure time in benzene-exposed workers. Furthermore, the expression of UCA1 was negatively associated with the DNA methylation level of its promoter in benzene-exposed workers. DNMT1 rather than DNMT3b knockout in TK6-HT cells activated the expression of UCA1 by inducing its promoter hypomethylation. These results suggest that benzene or HQ exposure leads to UCA1 upregulation via DNA hypomethylation in the UCA1 promoter, which is mediated by DNMT1.

Microbiological and clinical characteristics of cryptococcemia: a retrospective analysis of 85 cases in a Chinese hospital.

Cryptococcemia is a life-threatening fungal infection. Sometimes, it is hard to diagnose. The studies to describe the characteristics of cryptococcemia specifically were limited. We performed this retrospective analysis in a Chinese hospital during 2002-2015, including 85 cryptococcemia cases and 52 Cryptococcus spp. isolates. The species, mating type, antifungal susceptibility and multilocus sequence typing of Cryptococcus spp. were determined. C. neoformans var. grubii MATα of sequence type (ST) 5 is the representative strain of cryptococcemia, accounting for 51 isolates. The MIC50/90 values were 0.5/0.5, 1.0/1.0, 2.0/4.0, ≤0.06/0.25, and ≤0.06/≤0.06 µg/ml for amphotericin B, flucytosine, fluconazole, itraconazole, and voriconazole, respectively. Cryptococcemia was the first diagnostic proof of cryptococcosis in 37 patients (43.5%, 37/85). Compared with the patients initially diagnosed of cryptococcosis in other sites (mainly cerebrospinal fluid), the patients firstly diagnosed by blood culture had prolonged time from admission to diagnosis of cryptococcosis (9 days vs. 2 days, P < .001) and higher 30-day mortality (54.1% vs. 20.8%, P = .003), while fewer symptoms of meningitis (45.9% vs. 100%, P < .001). For the patients receiving lumbar puncture, the occurrence of meningitis was similar between the patients firstly diagnosed by blood culture and those firstly diagnosed in other sites (94.1% vs. 100%, P = .26). However, the patients first diagnosed by blood culture had lower baseline intracranial pressure (250 mm H2O vs. 342.5 mm H2O, P = .001). In conclusion, patients with cryptococcemia as the first diagnostic proof of cryptococcosis usually had neglected subtle symptoms of meningitis, which may result in delayed diagnosis and catastrophic outcome.

E4F1 silencing inhibits the cell growth through cell-cycle arrest in malignant transformed cells induced by hydroquinone.

Hydroquinone (HQ), one of the most significant metabolic activation products of benzene in an organism, can cause hematological toxicity, such as acute myeloid leukemia. It is a clear carcinogen that can cause changes in the disorder of cell cycle and cell growth. However, its molecular mechanisms remain unclear. E4 transcription factor 1 (E4F1), an important transcription factor, participating in the regulation of cell cycle may be related to the occurrence of tumor. Here, we examined the HQ-induced malignant transformed TK6 cells (TK6-HT) to illustrate the role of E4F1 in carcinogenesis. The present study showed that both the expressions of E4F1 messenger RNA and protein increased obviously in TK6-HT, preliminarily indicating that E4F1 is associated with HQ-induced carcinogenesis. To further explore the role of E4F1, we established E4F1 silencing TK6-HT (pLVX-shE4F1) and its control cells (pLVX-shNC) using lentiviral short hairpin RNA (shRNA) interference expression plasmid vector pLVX-shRNA. Flow cytometry and cell counting kit-8 assay were used to determine the effects of E4F1 silencing on cell cycle and cell growth, respectively. E4F1 silencing inhibited cell growth in TK6-HT. The results from flow cytometry indicated that the inhibitory effect on cell growth may be the results of the E4F1 silencing-induced accumulation in G2/M compared with TK6-HT-shNC. Meanwhile, levels of DNA damage (γ-H2AX), proteins of Rb and phosphorylated Rb, and reactive oxygen species were increased in TK6-HT-shRNA2 cells, which is the critical reason of cell-cycle arrest. In conclusion, E4F1 silencing inhibits the cell growth through cell-cycle arrest in malignant transformed cells induced by HQ.

Crizotinib in patients with anaplastic lymphoma kinase-positive advanced non-small cell lung cancer versus chemotherapy as a first-line treatment.

BACKGROUND: To compare the efficacy of crizotinib, pemetrexed and other chemotherapy regimens as a first-line treatment in patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) in real world clinical use and to evaluate the +86-571-87,236,876 predictive clinical factors of the efficacy of crizotinib. METHODS: The 73 patients with ALK-positive advanced NSCLC were divided into three groups based on the first-line treatment: first-line crizotinib group (1-CRZ group, n = 32); first-line platinum-based pemetrexed treatment group (1-PP group, n = 28), and first-line chemotherapy platinum-based non-pemetrexed group (N1-PP, n = 12). Sixty eight of the 73 patients received crizotinib treatment and followed up in our hospital. Differences in the objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS) were compared in the different groups. The clinical factors were evaluated to predict the efficacy of crizotinib by the Kaplan-Meier survival analysis and Cox proportional hazards model. RESULTS: The PFS, ORR, DCR were 16.1 months, 78.1% (25/32) and 100% (32/32) in the 1-CRZ group; were 6.0 months, 17.9% (5/28) and 57.2% (16/28) in the 1-PP group; and were 2.9 months, 15.4% (2/13) and 46.2% (6/13) in the N1-PP group. The PFS of the 1-CRZ group was significantly longer than that of the 1-PP group (P < 0.001) and the N1-PP group (P < 0.001). The ORR and DCR of the 1-CRZ group was significantly greater than that of the 1-PP group and the N1-PP group (all the P < 0.001). Higher Eastern Cooperative Oncology Group (ECOG) performance status score (> = 2) (HR 2.345, 95% CI 1.137-4.834, P = 0.021) and patients received crizotinib after N1-PP chemotherapy (HR 2.345, 95% CI 1.137-4.834, P = 0.021) were two factors associated with shorter PFS after crizotinib treatment. CONCLUSIONS: In patients with ALK-positive NSCLC who did not receive previous treatment, crizotinib was superior to standard chemotherapy for the longer PFS and greater ORR and DCR. Higher ECOG score (> = 2) and patients received crizotinib after N1-PP chemotherapy predict poor efficacy of crizotinib.

Relationship of redundant Th17 cells and IL-17A, but not IL-17 F, with the severity of obstructive sleep apnoea/hypopnoea syndrome (OSAHS).

BACKGROUND: The pathogenesis of obstructive sleep apnoea/hypopnoea syndrome (OSAHS), a highly prevalent disease, is not completely understood. The purpose of this study was to investigate the contributions of Th17 cells and the Th17-associated cytokines IL-17A and IL-17 F to OSAHS. METHODS: 46 male patients with a clinical suspicion of OSAHS were enrolled and divided into four groups based on their polysomnography results: controls and mild, moderate, and severe OSAHS. The serum levels of IL-17A and IL-17 F were determined by enzyme linked immunosorbent assay (ELISA), pulmonary arterial pressure (PAP) was determined by echocardiography, and Th17 cell frequencies in peripheral blood were measured by flow cytometry. RESULTS: Serum IL-17A levels in the severe group were elevated (median value: control group 0.89 pg/ml, mild OSAHS 1.02 pg/ml, moderate OSAHS 1.18 pg/ml, and severe OSAHS 1.62 pg/ml; p < 0.05) and positively correlated with AHI (r = 0.52, p < 0.05) but negatively related to the mean O2 saturation and lowest O2 saturation (r = -0.349, p < 0.05; and r = -0.336, p < 0.05, respectively). Although the frequencies of Th17 cells in the OSAHS groups were higher than that in the control group, these differences were not significant (p = 0.275). Pulmonary arterial hypertension was not present in our patients as the median PAP of the normal control and the mild, moderate, and severe OSAHS groups were 26, 27.5, 24.5, and 25.5 mmHg, respectively (p = 0.676). CONCLUSION: IL-17A may be involved in the pathogenesis of OSAHS and may represent a target for therapeutic intervention.

Advanced glycation end products promote meniscal calcification by activating the mTOR-ATF4 positive feedback loop.

The meniscus is vital for maintaining knee homeostasis and function. Meniscal calcification is one of the earliest radiological indicators of knee osteoarthritis (KOA), and meniscal calcification is associated with alterations in biomechanical properties. Meniscal calcification originates from a biochemical process similar to vascular calcification. Advanced glycation end products (AGEs) and their receptors (RAGEs) reportedly play critical roles in vascular calcification. Herein, we investigated whether targeting AGE-RAGE is a potential treatment for meniscal calcification. In our study, we demonstrated that AGE-RAGE promotes the osteogenesis of meniscal cells and exacerbates meniscal calcification. Mechanistically, AGE-RAGE activates mTOR and simultaneously promotes ATF4 accumulation, thereby facilitating the ATF4-mTOR positive feedback loop that enhances the osteogenic capacity of meniscal cells. In this regard, mTOR inhibits ATF4 degradation by reducing its ubiquitination, while ATF4 activates mTOR by increasing arginine uptake. Our findings substantiate the unique role of AGE-RAGE in the meniscus and reveal the role of the ATF4-mTOR positive feedback loop during the osteogenesis of meniscal cells; these results provide potential therapeutic targets for KOA.

Evolving Into a Transformer: From a Training-Free Retrieval-Based Method for Anomaly Obstacle Segmentation.

As a key problem of auto-vehicle applications, the goal of Anomaly Obstacle Segmentation (AOS) is to detect some strange and unexpected obstacles (possibly are unseen previously) on the drivable area, thereby equipping the semantic perceptual model to be tolerant of unknown things. Due to its practicality, recently AOS is drawing attentions and a long line of works are proposed to tackle the obstacles with almost infinite diversity. However, these methods usually focus less on the priors of driving scenarios and involve image re-generation or the retraining of perceptual model, which lead to large computational quantity or the degradation of perceptual performance. In this paper, we propose to pay more attention to the characteristics of driving scenarios, lowering the difficulty of this tricky task. A training-free retrieval based method is thereby proposed to distinguish road obstacles from the surrounding road texture by computing the cosine similarity based on their appearance features, and significantly outperforms methods of the same category by around 20 percentage points. Besides, we find that there is a deep relation between our method and self-attention mechanism, and as a result a novel Transformer evolves from our retrieval based method, further boosting the performance.

Elastic Knowledge Distillation by Learning From Recollection.

Model performance can be further improved with the extra guidance apart from the one-hot ground truth. To achieve it, recently proposed recollection-based methods utilize the valuable information contained in the past training history and derive a "recollection" from it to provide data-driven prior to guide the training. In this article, we focus on two fundamental aspects of this method, i.e., recollection construction and recollection utilization. Specifically, to meet the various demands of models with different capacities and at different training periods, we propose to construct a set of recollections with diverse distributions from the same training history. After that, all the recollections collaborate together to provide guidance, which is adaptive to different model capacities, as well as different training periods, according to our similarity-based elastic knowledge distillation (KD) algorithm. Without any external prior to guide the training, our method achieves a significant performance gain and outperforms the methods of the same category, even as well as KD with well-trained teacher. Extensive experiments and further analysis are conducted to demonstrate the effectiveness of our method.

Increased DNMT1 Involvement in the Activation of LO2 Cell Death Induced by Silver Nanoparticles via Promoting TFEB-Dependent Autophagy.

The accumulation of exogenous silver nanoparticles (AgNPs) will terminally bring about liver injury, including cell death, where DNA methylation tends to be a crucial epigenetic modulator. The change in the cell autophagy level verified to be closely associated with hepatocyte death has been followed with wide interest. But the molecular toxicological mechanisms of AgNPs in relation to DNA methylation, autophagy, and cell death remain inconclusive. To address the issue above, in LO2 cells treated with increasing concentrations of AgNPs (0, 5, 10, and 20 µg/mL), a cell cytotoxicity assay was performed to analyze the level of cell death, which also helped to choose an optimal concentration for next experiments. An immunofluorescence assay was used to determine the autophagic flux as well as TFEB translocation, with qRT-PCR and western blot being used to analyze the expression level of autophagy-related genes and proteins. According to our findings, in the determination of cell viability, 20 µg/mL (AgNPs) was adopted as the best working concentration. LO2 cell death, autophagy, and TFEB nuclear translocation were induced by AgNPs, which could be inhibited by lysosome inhibitor chloroquine (CQ) or siRNA specific for TFEB. Moreover, AgNP exposure led to DNA hypermethylation, with DNMT1 taking part mainly, which could be obviously prevented by 5-Aza-2'-deoxycytidine (5-AzaC) or trichostatin A (TSA) treatment or DNMT1 knockout in LO2 cells. Our studies suggest that through TFEB-dependent cell autophagy, increased DNMT1 may facilitate cell death induced by AgNPs.

Predictive Equations for Adult Pulmonary Function in Zhejiang Province, China.

Background: Accurate interpretation of lung function tests requires appropriate spirometry reference values derived from large-scale population-specific epidemiological surveys. The aim of this cross-sectional study was to establish normal spirometric values for the population of healthy, nonsmoking Han Chinese adults residing in Zhejiang province, China. Methods: We measured lung function parameters such as forced expiratory volume in 1 s, forced vital capacity, peak expiratory flow, maximal midexpiratory flow, and diffusion capacity for carbon monoxide and considered age, height, and weight as independent factors that may modify these parameters. The clinical data were divided into the study arm and validation group. The study arms were used to construct predictive equations using stepwise multiple linear regression, and data from the validation group were used to assess the robustness of the equations. Results: The 3866 participants were randomized into a study arm (n = 1,949) and a validation arm (n = 1,917). Lung function parameters had a negative association with age and a positive association with height. Data from the two groups were similar. Predictive equations were constructed from the study arm, and the validation group was used to test the feasibility of the reference equations. Conclusions: The reference values we derived can be used to evaluate lung function in this cohort in both epidemiological studies and clinical practice.

LINC00173 Interacts With DNMT1 to Regulate LINC00173 Expression via Promoter Methylation in Hydroquinone-Induced Malignantly Transformed TK6 Cells and Benzene-Exposed Workers.

Long-term exposure to benzene or its metabolite, hydroquinone (HQ), can causally contribute to acute myeloid leukemia. Long-noncoding RNAs are essential epigenetic regulators with critical roles in tumor initiation and malignant progression; however, the mechanism by which aberrantly expressed LINC00173 (long intergenic nonprotein coding RNA 173) regulates the pathogenesis of acute myeloid leukemia is not fully understood. Here, we found that the expression of LINC00173 decreased while the expression of DNA methyltransferase 1 (DNMT1) increased, and the methylation of LINC00173 promoter was negatively correlated with LINC00173 expression in GEPIA, CCLE databases, benzene-exposed workers, B-cell non-Hodgkin's lymphoma, K562, U937, or HQ-induced malignantly transformed TK6 (HQ-MT cells). Furthermore, in 5-aza-2'-deoxycytidine (DNA methyltransferase inhibitor) or trichostatin A (histone deacetylation inhibitor)-treated HQ-MT cells, the expression of LINC00173 was restored by reduced DNA promoter methylation levels. HQ-MT cells with DNMT1 knockout by CRISPR/Cas9 restored the expression of LINC00173 and inhibited the DNA methylation of its promoter as well as enrichment of DNMT1 to promoter. Overexpression of LINC00173 inhibited the expression of DNMT1, cell proliferation, tumor growth, enhanced chemosensitivity to cisplatin, and apoptosis in HQ-MT cells. LINC00173 interacts with DNMT1 to regulate the methylation of LINC00173 promoter. Overall, this study provides evidence that interaction between DNMT1 and LINC00173 regulates the expression of LINC00173 by regulating its promoter methylation level, thus regulating the function of HQ-MT cells in vitro and in vivo, providing a new therapeutic target for benzene-induced tumor.

Efficacy and Safety of Limertinib (ASK120067) in Patients With Locally Advanced or Metastatic EGFR Thr790Met-Mutated NSCLC: A Multicenter, Single-Arm, Phase 2b Study.

INTRODUCTION: Limertinib (ASK120067) is a newly developed third-generation EGFR tyrosine kinase inhibitor targeting both sensitizing EGFR and EGFR Thr790Met (T790M) mutations. This study aimed to evaluate the efficacy and safety of limertinib in patients with locally advanced or metastatic EGFR T790M-mutated NSCLC. METHODS: This is a single-arm, open-label, phase 2b study conducted at 62 hospitals across the People's Republic of China. Patients with locally advanced or metastatic NSCLC with centrally confirmed EGFR T790M mutations in tumor tissue or blood plasma who progressed after first- or second-generation EGFR tyrosine kinase inhibitors or with primary EGFR T790M mutations were enrolled. Patients received limertinib 160 mg orally twice daily until disease progression or unacceptable toxicity. The primary end point was objective response rate (ORR) assessed by independent review committee per the Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included disease control rate, progression-free survival (PFS), duration of response (DoR), overall survival, and safety. Safety was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. RESULTS: From July 16, 2019, to March 10, 2021, a total of 301 patients were enrolled and started the treatment of limertinib. All patients entered the full analysis set and safety set. By the data cutoff date on September 9, 2021, 76 (25.2%) remained on treatment. The median follow-up time was 10.4 months (range: 0.3-26.3). On the basis of full analysis set, the independent review committee-assessed ORR was 68.8% (95% confidence interval [CI]: 63.2%-74.0%) and disease control rate was 92.4% (95% CI: 88.8%-95.1%). The median PFS was 11.0 months (95% CI: 9.7-12.4), median DoR was 11.1 months (95% CI: 9.6-13.8), and median OS was not reached (95% CI 19.7 months-not evaluable). Objective responses were achieved across all prespecified subgroups. For 99 patients (32.9%) with central nervous system (CNS) metastases, the ORR was 64.6% (95% CI: 54.4%-74.0%), median PFS was 9.7 months (95% CI: 5.9-11.6), and median DoR was 9.6 months (95% CI: 8.1-15.2). For 41 patients who had assessable CNS lesion, the confirmed CNS-ORR was 56.1% (95% CI: 39.7%-71.5%) and median CNS-PFS was 10.6 months (95% CI: 5.6-not evaluable). In safety set, 289 patients (96.0%) experienced at least one treatment-related adverse event (TRAE), with the most common being diarrhea (81.7%), anemia (32.6%), rash (29.9%), and anorexia (28.2%). Grade ≥3 TRAEs occurred in 104 patients (34.6%), with the most common including diarrhea (13.0%), hypokalemia (4.3%), anemia (4.0%), and rash (3.3%). TRAEs leading to dose interruption and dose discontinuation occurred in 24.6% and 2% of patients, respectively. No TRAE leading to death occurred. CONCLUSIONS: Limertinib (ASK120067) was found to have promising efficacy and an acceptable safety profile for the treatment of patients with locally advanced or metastatic EGFR T790M-mutated NSCLC. CLINICAL TRIAL INFORMATION: NCT03502850.