c-Myc-Targeting PROTAC Based on a TNA-DNA Bivalent Binder for Combination Therapy of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is highly aggressive with a poor clinical prognosis and no targeted therapy. The c-Myc protein is a master transcription factor and a potential therapeutic target for TNBC. In this study, we develop a PROTAC (PROteolysis TArgeting Chimera) based on TNA (threose nucleic acid) and DNA that effectively targets and degrades c-Myc. The TNA aptamer is selected in vitro to bind the c-Myc/Max heterodimer and appended to the E-box DNA sequence to create a high-affinity, biologically stable bivalent binder. The TNA-E box-pomalidomide (TEP) conjugate specifically degrades endogenous c-Myc/Max, inhibits TNBC cell proliferation, and sensitizes TNBC cells to the cyclin-dependent kinase inhibitor palbociclib in vitro. In a mouse TNBC model, combination therapy with TEP and palbociclib potently suppresses tumor growth. This study offers a promising nucleic acid-based PROTAC modality for both chemical biology studies and therapeutic interventions of TNBC.

Selection of RNA-Cleaving TNA Enzymes for Cellular Mg2+ Imaging.

Catalytic DNA-based fluorescent sensors have enabled cellular imaging of metal ions such as Mg2+ . However, natural DNA is prone to nuclease-mediated degradation. Here, we report the in vitro selection of threose nucleic acid enzymes (TNAzymes) with RNA endonuclease activities. One such TNAzyme, T17-22, catalyzes a site-specific RNA cleavage reaction with a kcat of 0.017 min-1 and KM of 675 nM. A fluorescent sensor based on T17-22 responds to an increasing concentration of Mg2+ with a limit of detection at 0.35 mM. This TNAzyme-based sensor also allows cellular imaging of Mg2+ . This work presents the first proof-of-concept demonstration of using a TNA catalyst in cellular metal ion imaging.

Associations of ambient ozone exposure and CD4+ T cell levels with mortality among people living with HIV: An eight-year longitudinal study.

There has been a consistent upward trend in ground-level ozone (O3) concentration in China. People living with HIV (PLWH) may be more vulnerable to the health impacts of O3 exposure due to their immunosuppressed state. This study aims to investigate the association between ambient O3 exposure and mortality among PLWH, as well as the potential exacerbating effects of a decreased CD4+ T cell level. Daily maximum 8-hour O3 concentrations were assigned to 7270 PLWH at a county level in Guangxi, China. Every 10-unit increase in ambient O3 concentration was associated with a significant rise in all-cause mortality ranging from 7.3 % to 28.7 % and a significant rise in AIDS-related mortality ranging from 8.4 % to 14.5 %. When PLWH had a higher CD4+ count (≥350 cells/µL), elevated O3 concentration was associated with increased blood CD4+ count at lag0 [percent change with 95 % confidence interval, 0.20(0.00, 0.40)], lag1 [0.26(0.06, 0.47)], and lag2 [0.23(0.03, 0.44)]; however, an opposite association was observed when CD4+ count was <350 cells/µL for half-year average [-2.45(-4.71, -0.14)] and yearly average [-3.42(-5.51, -1.29)] of O3 exposure. The association of O3 exposure with all-cause and AIDS-related mortality was more prominent among those with higher CD4+ count. Exploratory analysis revealed possible associations between O3 exposure and respiratory infections and clinical symptoms. These findings suggest potential synergistic effects between a compromised immune status and elevated O3 exposure levels on mortality risk among PLWH. Ambient O3 exposure should be considered as an emerging mortality risk factor for PLWH in the era of antiretroviral therapy, requiring further attention from researchers and healthcare professionals.

Knowledge, attitude, and practice of healthcare workers on early gastrointestinal cancer in China.

Objective: Gastrointestinal cancer is the leading cause of cancer-related death in China, and its early screening is largely recommended by healthcare workers. This study investigated the knowledge, attitudes, and practice (KAP) of healthcare workers on early gastrointestinal cancer (EGC). Methods: This cross-sectional study was conducted on healthcare workers who volunteered to participate from 30 hospitals in China between September and December 2022. A self-administered questionnaire including 37 questions was developed. Results: A total of 545 completed questionnaires were finally obtained. Healthcare workers had moderate knowledge level [9.22 ± 1.80 (65.88±12.89%), total score: 14], positive attitude [21.84 ± 2.67 (91.01 ± 11.14%), total score: 24], and excellent practice level [19.07 ± 4.43 (79.47 ± 18.44%), total score: 24] on EGC. Pearson's correlation analysis suggested that knowledge score was positively correlated with attitude (r = 0.264, P < 0.001) and practice score (r = 0.140, P = 0.001), and higher attitude score was significantly correlated with higher practice score (r = 0.380, P < 0.001), which were supported and reinforced by structural equation modeling. In addition, subgroup analysis showed that knowledge scores might be influenced by sex, age, education, type of hospital, type of occupation, professional title, and years of working (all P < 0.05); attitude scores might be influenced by years of working (P < 0.05); and practice scores were statistically distinct among groups of different sex, department, and years of working (all P < 0.05). Conclusion: Healthcare workers have moderate knowledge level, positive attitude, and excellent practice levels on EGC. Good knowledge and positive attitude might be correlated with excellent practice. KAP level might be influenced by sociodemographic characteristics.

Erratum: IGFBP7 remodels the tumor microenvironment of esophageal squamous cell carcinoma by activating the TGFß1/SMAD signaling pathway.

[This corrects the article DOI: 10.3892/ol.2022.13371.].

DNA-catalysed alternative RNA splicing.

We report DNA-catalysed alternative RNA splicing in vitro. Using modular DNA catalysts with RNA endonuclease and RNA ligase activities, we show that DNA can modulate RNA structure and activity. Furthermore, we illustrate that such DNA-catalysed reactions can yield, from a common precursor, different splicing isoforms with distinct functions.

IGFBP7 remodels the tumor microenvironment of esophageal squamous cell carcinoma by activating the TGFß1/SMAD signaling pathway.

Esophageal squamous cell carcinoma (ESCC) is the most common type of esophageal cancer, and its development, growth, and invasiveness are regulated by the tumor microenvironment (TME). Insulin-like growth factor-binding protein-7 (IGFBP7), which is closely related to various tumors, transforming growth factor-ß1 (TGFß1), which is a key signal mediator in oncogenesis, α-smooth muscle actin (α-SMA), and collagen I are important components of the TME. IGFBP7 can upregulate the expression of TGFß1 and activate the TGFß1/SMAD signaling pathway, which leads to an increase in collagen I in hepatic stellate cells (HSCs). However, the contribution of IGFBP7 to TGFß1 and the TME in the progression of ESCC remains unknown. In the present study, we investigated IGFBP7 expression and its effects on TGFß1 and the TME in ESCC. A total of 45 patients were divided into three groups: early-tumor group (n=15), advanced-tumor group (n=15), and paracancer control group (n=15). The EC109 cell line was cultured and treated with AdIGFBP7 and LvshTGFß1, and the expression levels of IGFBP7, TGFß1, α-SMA, collagen I, and p-SMAD2/3 were determined by immunohistochemical staining and western blotting analysis. IGFBP7, TGFß1, α-SMA, and collagen I were upregulated in the ESCC samples compared with the control samples (P<0.05), and the values peaked in the advanced-tumor group (P<0.05). Compared with the control group, the TGFß1, α-SMA, p-SMAD2/3, and collagen I proteins were gradually increased from 24 to 72 h in the EC109 cells treated with AdIGFBP7 (P<0.05). Inhibition of TGFß1 expression in the EC109 cells treated with AdIGFBP7 gradually reduced the expression of α-SMA, collagen I, and p-SMAD2/3 from 24 to 72 h (P<0.05). These findings suggest that increased IGFBP7 may accelerate the progression of ESCC by upregulating TGFß1, α-SMA, and collagen I via activating the TGFß1/SMAD signaling pathway, which could remodel the TME.

A Nucleic Acid Sequence That is Catalytically Active in Both RNA and TNA Backbones.

Threose nucleic acid (TNA) is considered a potential RNA progenitor due to its chemical simplicity, base pairing property, and capability of folding into a functional tertiary structure. However, it is unknown whether the functional property can be maintained during transition from TNA to RNA. Here, we use a toggle in vitro selection to identify nucleic acid catalyst sequences that are active in both TNA and RNA backbones. One such nucleic acid enzyme with exchangeable backbone (CAMELEON) catalyzes an RNA cleavage reaction when prepared as TNA (T) and RNA (R). Further biochemical characterization reveals that CAMELEON R and T exhibit different catalytic behaviors such as rate enhancement and magnesium dependence. Structural probing and mutagenesis experiments suggest that they likely fold into distinct tertiary structures. This work demonstrates that the catalytic activity can be preserved during backbone transition from TNA to RNA and provides further experimental support for TNA as an RNA precursor in evolution.

Examining long-term natural vegetation dynamics in the Aral Sea Basin applying the linear spectral mixture model.

BACKGROUND: Associated with the significant decrease in water resources, natural vegetation degradation has also led to many widespread environmental problems in the Aral Sea Basin. However, few studies have examined long-term vegetation dynamics in the Aral Sea Basin or distinguished between natural vegetation and cultivated land when calculating the fractional vegetation cover. METHODS: Based on the multi-temporal Moderate Resolution Imaging Spectroradiometer, this study examined the natural vegetation coverage by introducing the Linear Spectral Mixture Model to the Google Earth Engine platform, which greatly reduces the experimental time. Further, trend line analysis, Sen trend analysis, and Mann-Kendall trend test methods were employed to explore the characteristics of natural vegetation cover change in the Aral Sea Basin from 2000 to 2018. RESULTS: Analyses of the results suggest three major conclusions. First, the development of irrigated agriculture in the desert area is the main reason for the decrease in downstream water. Second, with the reduction of water, the natural vegetation coverage in the Aral Sea Basin showed an upward trend of 17.77% from 2000 to 2018. Finally, the main driving factor of vegetation cover changes in the Aral Sea Basin is the migration of cultivated land to the desert.