Using Bland-Altman plot-based harmonization algorithm to optimize the harmonization for immunoassays.

OBJECTIVES: Harmonization has been recommended by the International Organization for Standard (ISO) to achieve equivalent results across in vitro diagnostic measurement devices (IVD-MDs). We aim to evaluate the effectiveness of Bland-Altman plot-based harmonization algorithm (BA-BHA) created in this study and compare it with weighted Deming regression-based harmonization algorithm (WD-BHA) proposed in ISO 21151:2020. METHODS: Eighty patient sera were used as the harmonization reference material (HRM) to develop IVD-MD-specific harmonization algorithms. Another panel of 40 patient sera was used to validate the effectiveness of harmonization algorithms. We compared regression slopes, intercepts, Bland-Altman plot layouts, percent differences, limits of agreement (LoAs), between-method coefficients of variation (CV) before and after harmonization. RESULTS: After harmonization by WD-BHA, acceptable slopes and intercepts between measured values and HRM targets were observed in weighted Deming regression, but not in Passing-Bablok analysis. Mean differences were -5.5 to 5.0 % and differences at specific levels were -33.9 to 23.9 %. LoAs were -64.6 to 74.6 %. Between-method CV was 22.9 % (±12.9 %). However, after harmonization by BA-BHA, both weighted Deming and Passing-Bablok regressions equations presented harmonized results. Mean differences were -0.3 to 0.2 % and differences at specific levels were -1.1 to 1.6 %. LoAs were -23.3 to 23.2 %. Between-method CV was 8.4 % (±4.0 %). The data points were evenly distributed at both sides of the mean in Bland-Altman plots. CONCLUSIONS: The inequivalence of test results between different methods can be improved but unacceptable analytical differences at specific levels may be hidden in terms of an acceptable slope and intercept on WD-BHA. The new protocol BA-BHA may be a viable alternative to optimize the harmonization for immunoassays.

VP5 protein of oncolytic herpes simplex virus type 2 induces apoptosis in A549 cells through TP53I3 protein.

Oncolytic virotherapy stands out as a burgeoning and promising therapeutic paradigm, harnessing the intrinsic cytotoxicity of oncolytic viruses for selective replication and dissemination within tumors. The primary mode of action revolves around the direct eradication of tumor cells. In our previous investigations, we formulated an oncolytic herpes simplex virus type 2 (OH2) and substantiated its anti-tumor efficacy both in vivo and in vitro. Subsequently, we embarked on a phase I/II clinical trial in China (NMPA, 2018L02743) and the USA (FDA, IND 27137) to assess OH2's safety, biodistribution, and anti-tumor activity as a standalone agent in patients with advanced solid tumors. In this investigation, our primary focus was to comprehend the influence of the major capsid protein VP5 of OH2 on its efficacy as an antitumor agent. Our findings underscore that the VP5 protein significantly amplifies OH2's oncolytic impact on A549 cells. Additionally, we observed that VP5 actively promotes the induction of apoptosis in A549 cells, both in vivo and in vitro. Through comprehensive transcriptional sequencing, we further authenticated that the VP5 protein triggers apoptosis-related signaling pathways and Gene Ontology (GO) terms in A549 cells. Moreover, we scrutinized differentially expressed genes in the p53-dependent apoptosis pathway and conducted meticulous in vitro validation of these genes. Subsequently, we delved deeper into unraveling the functional significance of the TP53I3 gene and conclusively affirmed that the VP5 protein induces apoptosis in A549 cells through the TP53I3 gene. These revelations illuminate the underlying mechanisms of OH2's antitumor activity and underscore the pivotal role played by the VP5 protein. The outcomes of our study harbor promising implications for the formulation of effective oncolytic virotherapy strategies in cancer treatment.

Immunotherapy and drug sensitivity predictive roles of a novel prognostic model in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most significant causes of cancer-related deaths in the worldwide. Currently, predicting the survival of patients with HCC and developing treatment drugs still remain a significant challenge. In this study, we employed prognosis-related genes to develop and externally validate a predictive risk model. Furthermore, the correlation between signaling pathways, immune cell infiltration, immunotherapy response, drug sensitivity, and risk score was investigated using different algorithm platforms in HCC. Our results showed that 11 differentially expressed genes including UBE2C, PTTG1, TOP2A, SPP1, FCN3, SLC22A1, ADH4, CYP2C8, SLC10A1, F9, and FBP1 were identified as being related to prognosis, which were integrated to construct a prediction model. Our model could accurately predict patients' overall survival using both internal and external datasets. Moreover, a strong correlation was revealed between the signaling pathway, immune cell infiltration, immunotherapy response, and risk score. Importantly, a novel potential drug candidate for HCC treatment was discovered based on the risk score and also validated through ex vivo experiments. Our finds offer a novel perspective on prognosis prediction and drug exploration for cancer patients.

Peptide Transporter 1-Mediated Dipeptide Transport Promotes Hepatocellular Carcinoma Metastasis by Activating MAP4K4/G3BP2 Signaling Axis.

Cancer metastasis is the leading cause of mortality in patients with hepatocellular carcinoma (HCC). To meet the rapid malignant growth and transformation, tumor cells dramatically increase the consumption of nutrients, such as amino acids. Peptide transporter 1 (PEPT1), a key transporter for small peptides, has been found to be an effective and energy-saving intracellular source of amino acids that are required for the growth of tumor cells. Here, the role of PEPT1 in HCC metastasis and its underlying mechanisms is explored. PEPT1 is upregulated in HCC cells and tissues, and high PEPT1 expression is associated with poor prognosis in patients with HCC. PEPT1 overexpression dramatically promoted HCC cell migration, invasion, and lung metastasis, whereas its knockdown abolished these effects both in vitro and in vivo. Mechanistic analysis revealed that high PEPT1 expression increased cellular dipeptides in HCC cells that are responsible for activating the MAP4K4/G3BP2 signaling pathway, ultimately facilitating the phosphorylation of G3BP2 at Thr227 and enhancing HCC metastasis. Taken together, these findings suggest that PEPT1 acts as an oncogene in promoting HCC metastasis through dipeptide-induced MAP4K4/G3BP2 signaling and that the PEPT1/MAP4K4/G3BP2 axis can serve as a promising therapeutic target for metastatic HCC.

Visible-Light-Driven Bifunctional Photocatalytic Radical-Cascade Selenocyanation/Cyclization of Acrylamides with KSeCN.

A visible-light-induced radical-cascade selenocyanation/cyclization of N-alkyl-N-methacryloyl benzamides, 2-aryl-N-acryloyl indoles, and N-methacryloyl-2-phenylbenzimidazoles with potassium isoselenocyanate (KSeCN) was developed. The reactions were carried out with inexpensive KSeCN as a selenocyanation reagent, potassium persulfate as an oxidant, 2,4,6-triphenylpyrylium tetrafluoroborate as a bifunctional catalyst for phase-transfer catalysis, and photocatalysis. A library of selenocyanate-containing isoquinoline-1,3(2H,4H)-diones, indolo[2,1-a]isoquinoline-6(5H)-ones, and benzimidazo[2,1-a]isoquinolin-6(5H)-ones were achieved in moderate to excellent yields at room temperature under visible-light and ambient conditions. Importantly, the present protocol features mild reaction conditions, large-scale synthesis, simple manipulation, product derivatization, good functional group, and heterocycle tolerance.

Tyrosine hydroxylase inhibits HCC progression by downregulating TGFß/Smad signaling.

The alteration of metabolic processes has been found to have significant impacts on the development of hepatocellular carcinoma (HCC). Nevertheless, the effects of dysfunction of tyrosine metabolism on the development of HCC remains to be discovered. This research demonstrated that tyrosine hydroxylase (TH), which responsible for the initial and limiting step in the bio-generation of the neuro-transmitters dopamine and adrenaline, et al. was shown to be reduced in HCC. Increased expression of TH was found facilitates the survival of HCC patients. In addition, decreased TH indicated larger tumor size, much more numbers of tumor, higher level of AFP, and the presence of cirrhosis. TH effectively impairs the growth and metastasis of HCC cells, a process dependent on the phosphorylation of serine residues (S19/S40). TH directly binds to Smad2 and hinders the cascade activation of TGFß/Smad signaling with the treatment of TGFß1. In summary, our study uncovered the non-metabolic functions of TH in the development of HCC and proposes that TH might be a promising biomarker for diagnosis as well as an innovative target for metastatic HCC.

Bis(2-ethylhexyl)-tetrabromophthalate Poses a Higher Exposure Risk and Induces Gender-Specific Metabolic Disruptions in Zebrafish Liver.

Bis(2-ethylhexyl)-tetrabromophthalate (TBPH), a typical novel brominated flame retardant, has been ubiquitously identified in various environmental and biotic media. Consequently, there is an urgent need for precise risk assessment based on a comprehensive understanding of internal exposure and the corresponding toxic effects on specific tissues. In this study, we first investigated the toxicokinetic characteristics of TBPH in different tissues using the classical pseudo-first-order toxicokinetic model. We found that TBPH was prone to accumulate in the liver rather than in the gonad, brain, and muscle of both female and male zebrafish, highlighting a higher internal exposure risk for the liver. Furthermore, long-term exposure to TBPH at environmentally relevant concentrations led to increased visceral fat accumulation, signaling potential abnormal liver function. Hepatic transcriptome analysis predominantly implicated glycolipid metabolism pathways. However, alterations in the profile of associated genes and biochemical indicators revealed gender-specific responses following TBPH exposure. Besides, histopathological observations as well as the inflammatory response in the liver confirmed the development of nonalcoholic fatty liver disease, particularly in male zebrafish. Altogether, our findings highlight a higher internal exposure risk for the liver, enhancing our understanding of the gender-specific metabolic-disrupting potential associated with TBPH exposure.

Targeting one-carbon metabolism for cancer immunotherapy.

BACKGROUND: One-carbon (1C) metabolism is a metabolic network that plays essential roles in biological reactions. In 1C metabolism, a series of nutrients are used to fuel metabolic pathways, including nucleotide metabolism, amino acid metabolism, cellular redox defence and epigenetic maintenance. At present, 1C metabolism is considered the hallmark of cancer. The 1C units obtained from the metabolic pathways increase the proliferation rate of cancer cells. In addition, anticancer drugs, such as methotrexate, which target 1C metabolism, have long been used in the clinic. In terms of immunotherapy, 1C metabolism has been used to explore biomarkers connected with immunotherapy response and immune-related adverse events in patients. METHODS: We collected numerous literatures to explain the roles of one-carbon metabolism in cancer immunotherapy. RESULTS: In this review, we focus on the important pathways in 1C metabolism and the function of 1C metabolism enzymes in cancer immunotherapy. Then, we summarise the inhibitors acting on 1C metabolism and their potential application on cancer immunotherapy. Finally, we provide a viewpoint and conclusion regarding the opportunities and challenges of targeting 1C metabolism for cancer immunotherapy in clinical practicability in the future. CONCLUSION: Targeting one-carbon metabolism is useful for cancer immunotherapy.

Artemether Attenuates Gut Barrier Dysfunction and Intestinal Flora Imbalance in High-Fat and High-Fructose Diet-Fed Mice.

Intestinal inflammation is a key determinant of intestinal and systemic health, and when our intestines are damaged, there is disruption of the intestinal barrier, which in turn induces a systemic inflammatory response. However, the etiology and pathogenesis of inflammatory diseases of the intestine are still not fully understood. Artemether (ART), one of the artemisinin derivatives, has been widely used to treat malaria. Nevertheless, the effect of ART on intestinal inflammation remains unclear. The present study intended to elucidate the potential mechanism of ART in diet-induced intestinal injury. A high-fat and high-fructose (HFHF) diet-induced mouse model of intestinal injury was constructed, and the mice were treated with ART to examine their role in intestinal injury. RT-qPCR, Western blotting, immunohistochemical staining, and 16S rRNA gene sequencing were used to investigate the anti-intestinal inflammation effect and mechanism of ART. The results indicated that ART intervention may significantly ameliorate the intestinal flora imbalance caused by the HFHF diet and alleviate intestinal barrier function disorders and inflammatory responses by raising the expression of tight junction proteins ZO-1 and occludin and decreasing the expression of pro-inflammatory factors TNF-α and IL-1ß. Moreover, ART intervention restrained HFHF-induced activation of the TLR4/NF-κB p65 pathway in colon tissue, which may be concerned with the potential protective effect of ART on intestinal inflammation. ART might provide new insights into further explaining the mechanism of action of other metabolic diseases caused by intestinal disorders.

The SARS-CoV-2 nucleocapsid protein suppresses innate immunity by remodeling stress granules to atypical foci.

Viruses deploy multiple strategies to suppress the host innate immune response to facilitate viral replication and pathogenesis. Typical G3BP1+ stress granules (SGs) are usually formed in host cells after virus infection to restrain viral translation and to stimulate innate immunity. Thus, viruses have evolved various mechanisms to inhibit SGs or to repurpose SG components such as G3BP1. Previous studies showed that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection inhibited host immunity during the early stage of COVID-19. However, the precise mechanism is not yet well understood. Here we showed that the SARS-CoV-2 nucleocapsid (SARS2-N) protein suppressed the double-stranded RNA (dsRNA)-induced innate immune response, concomitant with inhibition of SGs and the induction of atypical SARS2-N+ /G3BP1+ foci (N+ foci). The SARS2-N protein-induced formation of N+ foci was dependent on the ability of its ITFG motif to hijack G3BP1, which contributed to suppress the innate immune response. Importantly, SARS2-N protein facilitated viral replication by inducing the formation of N+ foci. Viral mutations within SARS2-N protein that impair the formation of N+ foci are associated with the inability of the SARS2-N protein to suppress the immune response. Taken together, our study has revealed a novel mechanism by which SARS-CoV-2 suppresses the innate immune response via induction of atypical N+ foci. We think that this is a critical strategy for viral pathogenesis and has potential therapeutic implications.

Preparation and Photocatalytic Degradation Performance of Amine-Rich Carbon Nitride with Structural Modulation of the Precursor.

The photocatalytic performance of graphitic phase carbon nitride (g-C3N4) is strongly influenced by its own microstructure as well as the precursor structure that causes the microstructure changes. In this paper, a composite precursor of sodium chloride and cyanamide (NaCl/CA-2) was obtained by freeze-drying, which possess an aggregated state different from that of the non-freeze-drying method. This new aggregation state with the introduction of sodium ions into the cyanamide lattice results in a higher activation energy of NaCl/CA-2 in the thermal polycondensation process of the molten salt-assisted preparation of g-C3N4, which prevented the condensation of two cyanamides to one dicyandiamide, ultimately obtaining FD-CN with an amino-rich structure. The nitrogen atoms on the amino group can provide the photocatalyst with more unpaired electrons that can participate in the photoexcitation process, further improving its electron-hole separation ability and charge transfer efficiency, thus effectively enhancing its photocatalytic activity. Compared to the original g-C3N4, the photocatalytic activity of FD-CN for the degradation of methylene blue increased 2.19 times.

ISG15 and ISGylation modulates cancer stem cell-like characteristics in promoting tumor growth of anaplastic thyroid carcinoma.

BACKGROUND: Anaplastic thyroid carcinoma (ATC) was a rare and extremely malignant endocrine cancer with the distinct hallmark of high proportion of cancer stem cell-like characteristics. Therapies aiming to cancer stem-like cells (CSCs) were emerging as a new direction in cancer treatment, but targeting ATC CSCs remained challenging, mainly due to incomplete insights of the regulatory mechanism of CSCs. Here, we unveiled a novel role of ISG15 in the modulation of ATC CSCs. METHODS: The expression of ubiquitin-like proteins were detected by bioinformatics and immunohistochemistry. The correlation between ISG15 expression and tumor stem cells and malignant progression of ATC was analyzed by single-cell RNA sequence from the Gene Expression Omnibus. Flow cytometry combined with immunofluorescence were used to verify the enrichment of ISG15 and ISGyaltion in cancer stem cells. The effect and mechanism of ISG15 and KPNA2 on cancer stem cell-like characteristics of ATC cells were determined by molecular biology experiments. Mass spectrometry combined with immunoprecipitation to screen the substrates of ISG15 and validate its ISGylation modification. Nude mice and zebrafish xenograft models were utilized to demonstrate that ISG15 regulates stem cell characteristics and promotes malignant progression of ATC. RESULTS: We found that among several ubiquitin proteins, only ISG15 was aberrantly expressed in ATC and enriched in CSCs. Single-cell sequencing analysis revealed that abnormal expression of ISG15 were intensely associated with stemness and malignant cells in ATC. Inhibition of ISG15 expression dramatically attenuated clone and sphere formation of ATC cells, and facilitated its sensitivity to doxorubicin. Notably, overexpression of ISGylation, but not the non-ISGylation mutant, effectively reinforced cancer stem cell-like characteristics. Mechanistically, ISG15 mediated the ISGylation of KPNA2 and impeded its ubiquitination to promote stability, further maintaining cancer stem cell-like characteristics. Finally, depletion of ISG15 inhibited ATC growth and metastasis in xenografted mouse and zebrafish models. CONCLUSION: Our studies not only provided new insights into potential intervention strategies targeting ATC CSCs, but also uncovered the novel biological functions and mechanisms of ISG15 and ISGylation for maintaining ATC cancer stem cell-like characteristics.

CircRNA: a rising star in leukemia.

Non-coding RNA are a class of RNA that lack the potential to encode proteins. CircRNAs, generated by a post-splicing mechanism, are a newly discovered type of non-coding RNA with multi-functional covalent loop structures. CircRNAs may play an important role in the occurrence and progression of tumors. Research has shown that circRNAs are aberrantly expressed in various types of human cancers, including leukemia. In this review, we summarize the expression and function of circRNAs and their impact on different types of leukemia. We also illustrate the function of circRNAs on immune modulation and chemoresistance in leukemia and their impact on its diagnosis and prognosis. Herein, we provide an understanding of recent advances in research that highlight the importance of circRNAs in proliferation, apoptosis, migration, and autophagy in different types of leukemia. Furthermore, circRNAs make an indispensable difference in the modulation of the immunity and chemoresistance of leukemia. Increasing evidence suggests that circRNAs may play a vital role in the diagnostic and prognostic markers of leukemia because of their prominent properties. More detailed preclinical studies on circRNAs are needed to explore effective ways in which they can serve as biomarkers for the diagnosis and prognosis of leukemia in vivo.

Cu2+-regulated one-pot wet-chemical synthesis of uniform PdCu nanostars for electrocatalytic oxidation of ethylene glycol and glycerol.

The fabrication of effective and stable electrocatalysts is crucial for practical applications of direct alcohol fuel cells (DAFCs). In this study, bimetallic PdCu nanostars (PdCu NSs) were fabricated by a Cu2+-modulated one-pot wet-chemical method, where cetyltrimethyl ammonium bromide (CTAB) worked as a structure-regulating reagent. The morphology, compositions, crystal structures and formation mechanism of the as-prepared PdCu NSs were investigated by a series of techniques. The unique architectures created abundant active sites, which resulted in a large electrochemical active surface area (9.5 m2 g-1). The PdCu NSs showed negative shifts in the onset potentials and large forward peak current densities by contrast with those of commercial Pd black for the catalytic ethylene glycol oxidation reaction (EGOR) and glycerol oxidation reaction (GOR). It revealed that the PdCu NSs outperformed Pd black in the similar surroundings. This work provides a constructive strategy for fabrication of high-efficiency electrocatalysts for alcohol fuel cells.

Hollow cage-like PtCu nanozyme-regulated photo-activity of porous CdIn2S4/SnO2 heterojunctions for ultrasensitive PEC sensing of streptomycin.

Streptomycin (STR) is extensively employed for preventive and curative purposes in animals, which is accumulated in human body through food chain and induces serious health problems. Herein, highly photoactive type II heterojunctions of porous CdIn2S4/SnO2 microspheres were initially prepared, which can effectively inhibit the recombination of the charge-hole pairs. Besides, the peroxidase-mimicking catalytic property of the hollow PtCu nanocages (PtCu NCs) was carefully investigated by UV-vis spectroscopy, where catalytic oxidation of tetramethylbenzidine behaved as the benchmarked reaction. On such basis, a highly selective photoelectrochemical (PEC) aptasensor was established with the CdIn2S4/SnO2 heterojunctions for bioanalysis of streptomycin, coupled by the PtCu NCs nanozyme-catalyzed biocatalytic precipitation to achieve signal magnification. Specifically, the home-made nanozyme was applied for catalytic oxidation of 3,3'-diaminobenzidine to generate insulating precipitate in aqueous H2O2 system and thereby block the light harvesting on the photoanode, showing steeply declined PEC responses. The as-built aptasensor showed a broad linear range of 0.01-200 nM with a low limit of detection of 7.50 pM (S/N = 3) for such analysis, combined by exploring its practical detection in milk samples. This work shows excellent nanozyme-catalyzed signal amplification for fabrication of ultrasensitive PEC biosensors towards other antibiotics detection.

The effects of audio-visual perceptual characteristics on environmental health of pedestrian streets with traffic noise: A case study in Dalian, China.

The COVID-19 pandemic has affected city dwellers' physical and mental health and has raised concerns about the health of urban public spaces. This field investigation research in Dalian, China, examined the perceived audio-visual environment characteristics of urban pedestrian streets with traffic noise and their influences on the environmental health of the pedestrian streets. Five indicators reflecting psychological responses to environmental characteristics (willingness to walk, relaxation, safety, beauty, and comprehensive comfort) were used to measure environmental health of pedestrian streets with traffic noise. The results showed that safety was rated the highest, and willingness to walk was evaluated as the lowest among health evaluation indicators. The imageability and openness of the streetscape were associated with each health evaluation indicator. In contrast, the rhythm and continuity of the street buildings had a greater effect on willingness to walk than the other health indicators. There were negative correlations between L Aeq for traffic noise and health evaluations. Positive health evaluations were observed when L Aeq was less than 55 dBA. In contrast, soundscape indicators showed positive correlations with health evaluations, and acoustic comfort and noise annoyance, rather than sound preference and subjective loudness were associated with each health evaluation indicator. In terms of the combined audio-visual factors, acoustic comfort, the quantity of greening, annoyance, sky visibility, spatial scale, and building distance were examined as the determining factors affecting health evaluations, and 55.40% of the variance in health evaluations was explained by the soundscape and streetscape indicators. The findings provide references for better understanding the relationships between healthy experience and audio-visual perceptions. Moreover, they enable environmental health quality optimisation of pedestrian spaces considering audio-visual indicators and approaches in the post-epidemic era.

Ultrasensitive PEC cytosensor for breast cancer cells detection and inhibitor screening based on plum-branched CdS/Bi2S3 heterostructures.

Breast cancer is the most common malignant tumor in women, which seriously threatens the life and health of patients. Therefore, facile and sensitive detection of human breast cancer cells is crucial for cancer diagnosis. In this work, plum-branched CdS/Bi2S3 heterostructures (CdS/Bi2S3 HSs) were synthesized under hydrothermal condition, whose photoelectrochemical (PEC) property and biocompatibility were scrutinously investigated. In parallel, a signal amplification strategy was designed based on immune recognition between epidermal growth factor receptor (EGFR) overexpressed on membrane of breast cancer cells MDA-MB-231 and its aptamer. Integration of the above together, a highly sensitive PEC cytosensor was developed for analysis of target MDA-MB-231 cells, exhibiting a wider linear range of 1 × 102 âˆ¼ 3 × 105 cells mL-1 with a limit of detection (LOD) down to 6 cells mL-1 (S/N = 3). Further, the biosensor was explored for anticancer drug (e.g., dacomitinib) screening by monitoring the variations in the PEC signals of the expressed EGFR upon drug stimulation. The obtained CdS/Bi2S3 HSs are identified as promising and feasible photoactive material for determination of cancer cells and drug screening in clinic and related research.

Dynamic m6A-ncRNAs association and their impact on cancer pathogenesis, immune regulation and therapeutic response.

Several types of modifications have been proven to participate in the metabolism and processing of different RNA types, including non-coding RNAs (ncRNAs). N-6-methyladenosine (m6A) is a dynamic and reversible RNA modification that is closely involved in the ncRNA homeostasis, and serves as a crucial regulator for multiple cancer-associated signaling pathways. The ncRNAs usually regulate the epigenetic modification, mRNA transcription and other biological processes, displaying enormous roles in human cancers. In this review, we summarized the significant implications of m6A-ncRNA interaction in various types of cancers. In particular, the interplay between m6A and ncRNAs in cancer pathogenesis and therapeutic resistance are being widely recognized. We also discussed the relevance of m6A-ncRNA interaction in immune regulation, followed by the interference on cancer immunotherapeutic procedures. In addition, we briefly highlighted the computation tools that could identify the accurate features of m6A methylome among ncRNAs. In summary, this review would pave the way for a better understanding of the biological functions of m6A-ncRNA crosstalk in cancer research and treatment.

Let-7b-5p inhibits breast cancer cell growth and metastasis via repression of hexokinase 2-mediated aerobic glycolysis.

Hexokinase 2 (HK2), a critical rate-limiting enzyme in the glycolytic pathway catalyzing hexose phosphorylation, is overexpressed in multiple human cancers and associated with poor clinicopathological features. Drugs targeting aerobic glycolysis regulators, including HK2, are in development. However, the physiological significance of HK2 inhibitors and mechanisms of HK2 inhibition in cancer cells remain largely unclear. Herein, we show that microRNA-let-7b-5p (let-7b-5p) represses HK2 expression by targeting its 3'-untranslated region. By suppressing HK2-mediated aerobic glycolysis, let-7b-5p restrains breast tumor growth and metastasis both in vitro and in vivo. In patients with breast cancer, let-7b-5p expression is significantly downregulated and is negatively correlated with HK2 expression. Our findings indicate that the let-7b-5p/HK2 axis plays a key role in aerobic glycolysis as well as breast tumor proliferation and metastasis, and targeting this axis is a potential therapeutic strategy for breast cancer.

Checkerboard arranged G4 nanostructure-supported electrochemical platform and its application to unique bio-enzymes examination.

In this study, a checkerboard arranged G4 nanostructure-supported electrochemical platform is developed well for the application to unique bio-enzymes examination. Herein, we focus on the two bio-enzymes involving histone acetyltransferase (HAT) and terminal deoxynucleotidyl transferase (TdT); the former leads to the acetyl transfer of acetyl coenzyme A to the lysine residue of the substrate peptide and the latter achieves the polymeric extension of DNA without template under a unique pool of dATP and dGTP (4: 6). A complex of antibody and short DNA is introduced onto the electrode surface based on the affinity interaction between acetyl in acetylated peptide and its antibody. and used for initiating reaction. Then, TdT-yielded rich-G sequence is formed to act as the backbone of checkerboard, and subsequently free G-DNAs can be stacked continually on the backbone under Mg2+. An excellent electrocatalytic signal to H2O2 emerges noticeably, which is related with the activity of HAT p300 and TdT with a low detection limit of 2.3 pM and 0.38 mU/mL, respectively. Finally, this strategy is also used successfully for the inhibitor screening and complex sample analysis, which has important implications for the advancement of HAT- and TdT-related electrochemical bioassay and drug discovery.