Transforming cancer cells for long-term living with cancer: An inspiring new approach.

Cancer is the leading cause of human death and imposes a huge health burden. Currently, no matter what advanced therapeutic modalities or technologies are applied, it is still peculiarly rare for most cancers to be radically cured whereas therapy resistance and tumor recurrence are ever so common. The long-standing cytotoxic therapy is hard to achieve long-term tumor control, and produces side-effects or even promotes cancer progression. With growing understandings of tumor biology, we came to realize that it is possible to transform but not kill cancer cells to achieve long-term living with cancer, and directly altering cancer cells is a promising way. Remarkably, tissue microenvironment is involved in the fate determination of cancer cells. Of note, leveraging cell competition to combat malignant or therapy-resistant cells shows some therapeutic potentials. Furthermore, modulating tumor microenvironment to restore a normal state might help to transform cancer cells. Especially, reprogramming cancer-associated fibroblasts, and tumor-associated macrophages, or normalization of tumor vessel, tumor immune microenvironment, and tumor extracellular matrix or their combinations, et al., revealed some long-term therapeutic benefits. Despite the massive challenges ahead, it would be possible to transform cancer cells for long-term cancer control and living with cancer longevously. The related basic researches and corresponding therapeutic strategies are also ongoing.

Iodine-Promoted Oxidative Cyclization of Methyl Azaarenes and α-Amino Ketones for One-Pot Synthesis of 2-Azaaryl-5-aryl Oxazoles.

A high efficiency protocol was developed for the synthesis of 2,5-disubstituted oxazoles via iodine-promoted oxidative domino cyclization. These reactions were performed with readily available methyl azaarenes and α-amino ketones under metal-free conditions. This protocol is a simple method with high functional group compatibility, a wide range of substrates, and excellent yield, providing a new way to synthesize azaarene-attached oxazoles.

Synthesis of Diversified Pyrazolo[3,4-b]pyridine Frameworks from 5-Aminopyrazoles and Alkynyl Aldehydes via Switchable C≡C Bond Activation Approaches.

A cascade 6-endo-dig cyclization reaction was developed for the switchable synthesis of halogen and non-halogen-functionalized pyrazolo[3,4-b]pyridines from 5-aminopyrazoles and alkynyl aldehydes via C≡C bond activation with silver, iodine, or NBS. In addition to its wide substrate scope, the reaction showed good functional group tolerance as well as excellent regional selectivity. This new protocol manipulated three natural products, and the arylation, alkynylation, alkenylation, and selenization of iodine-functionalized products. These reactions demonstrated the potential applications of this new method.

Dying tumor cell-derived exosomal miR-194-5p potentiates survival and repopulation of tumor repopulating cells upon radiotherapy in pancreatic cancer.

BACKGROUND: Tumor repopulation is a major cause of radiotherapy failure. Previous investigations highlighted that dying tumor cells played vital roles in tumor repopulation through promoting proliferation of the residual tumor repopulating cells (TRCs). However, TRCs also suffer DNA damage after radiotherapy, and might undergo mitotic catastrophe under the stimulation of proliferative factors released by dying cells. Hence, we intend to find out how these paradoxical biological processes coordinated to potentiate tumor repopulation after radiotherapy. METHODS: Tumor repopulation models in vitro and in vivo were used for evaluating the therapy response and dissecting underlying mechanisms. RNA-seq was performed to find out the signaling changes and identify the significantly changed miRNAs. qPCR, western blot, IHC, FACS, colony formation assay, etc. were carried out to analyze the molecules and cells. RESULTS: Exosomes derived from dying tumor cells induced G1/S arrest and promoted DNA damage response to potentiate survival of TRCs through delivering miR-194-5p, which further modulated E2F3 expression. Moreover, exosomal miR-194-5p alleviated the harmful effects of oncogenic HMGA2 under radiotherapy. After a latent time, dying tumor cells further released a large amount of PGE2 to boost proliferation of the recovered TRCs, and orchestrated the repopulation cascades. Of note, low-dose aspirin was found to suppress pancreatic cancer repopulation upon radiation via inhibiting secretion of exosomes and PGE2. CONCLUSION: Exosomal miR-194-5p enhanced DNA damage response in TRCs to potentiate tumor repopulation. Combined use of aspirin and radiotherapy might benefit pancreatic cancer patients.

Reduced graphene oxide-gold nanoparticles-catalase-based dual signal amplification strategy in a spatial-resolved ratiometric electrochemiluminescence immunoassay.

A novel spatial-resolved electrochemiluminescent (ECL) ratiometry for cardiac troponin I (cTnI) analysis was developed using resonance energy transfer (RET) and a coreactant consumption strategy for signal amplification. Specifically, the spatial-resolved dual-disk glassy carbon electrodes were modified with CdS nanowires (CdS NWs) and luminol-gold nanoparticles (L-Au NPs) as potential-resolved ECL emitters, respectively. After stepwise immobilization of anti-cTnI and bovine serum albumin on the dual-disk electrodes, the CdS NWs-based electrode, with varied concentrations of cTnI, was used to provide a working signal, whereas the L-Au NPs-based electrode, with a fixed amount of cTnI, was employed to provide the reference signal. To efficiently amplify the working signal on the CdS NWs-based electrode, an anti-cTnI-reduced graphene oxide-gold nanoparticles-catalase probe (anti-cTnI-rGO-Au NPs-CAT) was loaded onto the electrode to form a sandwich immunocomplex. The RET from CdS NWs to Au NPs and the coreactant (i.e. H2O2) consumption by the CAT generate a significant ECL decrease on the CdS NWs-based electrode in the presence of cTnI. This novel and sensitive ratiometric detection mode for cTnI was achieved using the ratio values of the working signal of the CdS NWs-based electrode and the reference signal of the L-Au NPs-based electrode. The integration of RET and coreactant consumption strategy in the designed spatial-resolved ratiometric platform endows the immunosensor with a wide linear range of 5.0 × 10-13 - 1.0 × 10-7 g mL-1 and a low detection limit of 0.10 pg mL-1 for cTnI. Furthermore, the method exhibits high accuracy and sensitivity for cTnI determination in human serum samples.

Immuno-Electrochemiluminescent Imaging of a Single Cell Based on Functional Nanoprobes of Heterogeneous Ru(bpy)32+@SiO2/Au Nanoparticles.

It is valuable to develop a sensing platform for not only detecting a tumor marker in body fluids but also measuring its expression at single cells. In the present study, a simple closed bipolar electrodes-based electrochemiluminescence (BPEs-ECL) imaging strategy was developed for visual immunoassay of prostate specific antigen (PSA) at single cells using functional nanoprobes of heterogeneous Ru(bpy)32+@SiO2/Au nanoparticles. Multiple-assisted ECL signal amplification strategy was introduced into the detection system on the basis of the synergetic amplifying effect of the anodic and cathodic amplification. On the basis of the synergetic amplifying effect, the detection limits of PSA by using photomultiplier tube and charge-coupled device (CCD) imaging are 3.0 and 31 pg/mL, respectively. The obtained immunosensor was employed to evaluate PSA levels in serum samples with a satisfying result. Moreover, the obtained functional nanoprobes were used to visually profile the PSA expression on the surface of single LNCaP cells (a kind of prostate cancer cells) based on a bare BPE. The results show that the functional nanoprobes-based ECL imaging immunoassay provides a promising visual platform for detecting tumor markers (proteins and cancer cells) and thus shows a high potential in cancer diagnosis.

The Schlafen family: complex roles in different cell types and virus replication.

The Schlafen (slfn) gene family members express broadly, but the research has mainly focused on human slfn (h-slfn) and mouse slfn (m-slfn). The slfn members can be divided into three groups, and each group has its own characteristics and functions. Although the effects of slfns are still poorly understood, it has been confirmed that slfns are involved in the defense of immune system and regulate immune cells' proliferation and differentiation. In some malignant tumors, the slfn proteins can inhibit the growth and invasion of cancer cells, promote cancer cells sensibility to chemotherapeutics, and can be a promising new therapeutic target. In addition, the slfn proteins also disturb replication and virulence of viruses. In this review, we summarize the characteristics of the Schlafen family's structures and functions with the aim to achieve a more comprehensive understanding of slfns.

Cathodic electrochemiluminescence behaviour of MoS2 quantum dots and its biosensing of microRNA-21.

The cathodic electrochemiluminescence (ECL) behaviour of nontoxic MoS2 quantum dots (QDs) was studied for the first time using potassium peroxydisulfate as the co-reactant. Ag-PAMAM NCs, serving as difunctional tags for quenching and enhancing ECL of MoS2-reduced graphene oxide composites, were introduced into the ECL detection system for signal amplification. By modulating the interparticle distance between MoS2 QDs and Ag-PAMAM NCs, the ECL quenching from resonance energy transfer and the ECL enhancement from surface plasma resonance were realized. Coupling the good ECL performance of MoS2 QDs with the excellent ECL quenching and enhancement effects of Ag-PAMAM NCs, a novel MoS2 QDs-based ECL biosensing platform for sensitive detection of microRNA-21 was achieved with a detection limit of 0.20 fmol L-1 (S/N = 3). This method was successfully applied to the determination of microRNA-21 in human serum samples with recoveries of 90.0-110.0%, suggesting great potential for its applications in biological and chemical analysis.

The epithelial to mesenchymal transition (EMT) and cancer stem cells: implication for treatment resistance in pancreatic cancer.

The mechanical properties of epithelial to mesenchymal transition (EMT) and a pancreatic cancer subpopulation with stem cell properties have been increasingly recognized as potent modulators of the effective of therapy. In particular, pancreatic cancer stem cells (PCSCs) are functionally important during tumor relapse and therapy resistance. In this review we have surveyed recent advances in the role of EMT and PCSCs in tumor progression, metastasis and treatment resistance, and the mechanisms of integrated with biochemical signals and the underlying pathways involved in treatment resistance of pancreatic cancer. These findings highlight the importance of confirming stem-cells markers and complex molecular signaling pathways controlling EMT and cancer stem cells in pancreatic cancer during tumor formation, progression, and response to therapy.

Pancreatic cancer cells hijack tumor suppressive microRNA-26a to promote radioresistance and potentiate tumor repopulation.

Pancreatic cancer is one of the most lethal cancers with significant radioresistance and tumor repopulation after radiotherapy. As a type of short non-coding RNA that regulate various biological and pathological processes, miRNAs might play vital role in radioresistance. We found by miRNA sequencing that microRNA-26a (miR-26a) was upregulated in pancreatic cancer cells after radiation, and returned to normal state after a certain time. miR-26a was defined as a tumor suppressive miRNA by conventional tumor biology experiments. However, transient upregulation of miR-26a after radiation significantly promoted radioresistance, while stable overexpression inhibited radioresistance, highlighting the importance of molecular dynamic changes after treatment. Mechanically, transient upregulation of miR-26a promoted cell cycle arrest and DNA damage repair to promote radioresistance. Further experiments confirmed HMGA2 as the direct functional target, which is an oncogene but enhances radiosensitivity. Moreover, PTGS2 was also the target of miR-26a, which might potentiate tumor repopulation via delaying the synthesis of PGE2. Overall, this study revealed that transient upregulation of miR-26a after radiation promoted radioresistance and potentiated tumor repopulation, highlighting the importance of dynamic changes of molecules upon radiotherapy.

Rhamnogalacturonan-I enriched pectin from steamed ginseng ameliorates lipid metabolism in type 2 diabetic rats via gut microbiota and AMPK pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Panax ginseng C. A. Meyer (Ginseng) has traditionally been used to treat diabetes. Polysaccharide is the main active component of ginseng, and has been proved to have hypoglycaemic and hypolipidaemic effects, but its mechanism remains unclear. AIM OF THE STUDY: This study aimed to evaluate the effect and the potential mechanism of rhamnogalacturonan-I enriched pectin (GPS-1) from steamed ginseng on lipid metabolism in type 2 diabetes mellitus (T2DM) rats. MATERIALS AND METHODS: GPS-1 was prepared by water extraction, ion-exchange and gel chromatography. High-glucose/high-fat diet combined with streptozotocin was used to establish T2DM rat models, and lipid levels in serum and liver were tested. 16S rRNA sequencing and gas chromatography-mass spectrometry were used to detect the changes of gut microbiota and metabolites. The protein and mRNA levels of lipid synthesis-related genes were detected by Western blot and quantitative real-time polymerase chain reaction. RESULTS: The polyphagia, polydipsia, weight loss, hyperglycaemia, hyperlipidaemia and hepatic lipid accumulation in T2DM rats were alleviated after GPS-1 intervention. GPS-1 modulated the gut microbiota composition of T2DM rats, increased the levels of short-chain fatty acids, and promoted the secretion of glucagon-like peptide-1 and peptide tyrosine tyrosine. Further, GPS-1 activated AMP-activated protein kinases, phosphorylated acetyl-CoA carboxylase, reduced the expression of sterol regulatory element-binding protein-1c and fatty acid synthases in T2DM rats. CONCLUSIONS: The regulation effects of GPS-1 on lipid metabolism in T2DM rats are related to the regulation of gut microbiota and activation of AMP-activated protein kinase pathway.

cGAS-STING signalings potentiate tumor progression via sustaining cancer stemness.

The cytosolic DNA-sensing cGAS-STING pathway has been proved to be involved in tumor progression and influence the effect of cancer immunotherapy. However, little attentions have been paid to the role of cGAS-STING pathway on cancer stemness. Herein, we found that the cGAS-STING pathway was activated in different tumor cells. cGAS- or STING-knockout impaired the capability of tumor formation in vivo and tumorsphere formation in vitro. In addition, loss of cGAS-STING cascade promoted tumor apoptosis, but inhibited tumor growth and metastasis. We further demonstrated that cGAS-STING pathway potentiated tumor formation by sustaining cancer stemness. Moreover, analysis of RNA-seq showed that cGAS-STING pathway maintained cancer stemness probably by activating STAT3. Our findings highlight the role of intrinsic activation of cGAS-STING pathway in tumorigenesis, and reveal a new mechanism of its regulation of tumor progression via sustaining cancer stemness through STAT3 activation.

Characterisation, Chain Conformation and Antifatigue Effect of Steamed Ginseng Polysaccharides With Different Molecular Weight.

Two polysaccharides were obtained from steamed ginseng via ultrafiltration, and their physical-chemical properties, solution properties and antifatigue activities were studied. WSGP-S3 and WSGP-G3 were acid heteropolysaccharides with the molecular weights of 2.03 × 104 and 4.86 × 104, respectively. They were composed of different molar ratios of the monosaccharides Rha, GlcA, GalA, Glc, Gal, and Ara. The results of size-exclusion chromatography-multiangle laser light scattering analysis, Conge red staining and Circular dichroism spectroscopy revealed that WSGP-S3 exhibited a random conformation of branched clusters in solution. By contrast, WSGP-G3 exhibited an ordered conformation, including helix-like conformations in aqueous solution. Antifatigue activity tests proved that WSGP-S3 markedly prolonged the exhaustive swimming time of fatigued mice; increased liver and muscle glycogen levels and superoxide dismutase, catalase, glutathione peroxidase activities and decreased blood lactic acid, nitrogen and malondialdehyde levels compared with the control treatment. Moreover, it enhanced spleen cell proliferation in fatigued mice. By contrast, WSGP-G3 had no significant effect on fatigued mice. The results showed that WSGP-S3 might have a major contribution to the antifatigue effects of steamed ginseng polysaccharides and could be a potential anti-fatigue polysaccharide.

ATM Expression Is Elevated in Established Radiation-Resistant Breast Cancer Cells and Improves DNA Repair Efficiency.

Repair of damaged DNA induced by radiation plays an important role in the development of radioresistance, which greatly restricts patients' benefit from radiotherapy. However, the relation between radioresistance development and DNA double-strand break repair pathways (mainly non-homologous end joining and homologous recombination) and how these pathways contribute to radioresistance are unclear. Here, we established a radioresistant breast cancer cell line by repeated ionizing radiation and studied the alteration in DNA repair capacity. Compared with parental sham-treated cells, radioresistant breast cancer cells present elevated radioresistance, enhanced malignancy, increased expression of Ataxia-telangiectasia mutated (ATM), and increased DNA damage repair efficiency, as reflected by accelerated γ-H2AX kinetic. These defects can be reversed by ATM inhibition or ATM knockdown, indicating a potential link between ATM, DNA repair pathway and radiosensitivity. We propose that cancer cells develop elevated radioresistance through enhanced DNA damage repair efficiency mediated by increased ATM expression. Our work might provide a new evidence supporting the potential of ATM as a potential target of cancer therapy.

A novel electrochemiluminescence resonance energy transfer system for simultaneous determination of two acute myocardial infarction markers using versatile gold nanorods as energy acceptors.

A novel electrochemiluminescence resonance energy transfer (ECL-RET) system using versatile gold nanorods as energy acceptors was introduced into the ECL biochemical analysis. A spatial- and potential-resolved platform coupled with the ECL-RET strategy was developed for simultaneous determination of two acute myocardial infarction markers.

Electrochemiluminescence energy resonance transfer in 2D/2D heterostructured g-C3N4/MnO2 for glutathione detection.

The energy transfer efficiency, strongly depending on the distance of donor-acceptor pair, is always a crucial factor for the construction of elegant electrochemiluminescence resonance energy transfer (ECL-RET)-based biosensors. In this paper, a novel and efficient ECL-RET in 2D/2D heterostructured g-C3N4/MnO2 was developed using g-C3N4 nanosheets (g-C3N4 NSs) as energy donor and MnO2 nanosheets (MnO2 NSs) as energy acceptor. In this system, MnO2 NSs in-situ grew on g-C3N4 NSs to form the 2D/2D heterostructure, greatly shortening the distance of the donor-acceptor pair (g-C3N4-MnO2) and thus greatly enhancing the RET efficiency. To demonstrate the performance of the system, a signal "off-on" ECL sensor was designed for glutathione (GSH) analysis. In the absence of GSH, MnO2 significantly quenched the ECL intensity of g-C3N4 owing to ECL-RET in this 2D/2D g-C3N4/MnO2 heterostructure (ECL signal "off"). Upon the addition of GSH, MnO2 was reduced to Mn2+ by GSH and g-C3N4 was released from the heterostructured g-C3N4/MnO2, generating a recovery of ECL intensity (ECL signal "on"). Under the optimal conditions, the designed ECL-RET signal "off-on" sensor realized the sensitive detection of GSH ranged from 0.2-100 µM with the detection limit of 0.05 µM. Furthermore, the as-prepared ECL-RET sensor exhibits good performance in the determination of GSH in human serum samples. The ECL-RET in 2D/2D heterostructure provides an ingenious way for the exploitation of novel ECL biosensing systems.

SMARCAD1 Promotes Pancreatic Cancer Cell Growth and Metastasis through Wnt/ß-catenin-Mediated EMT.

Pancreatic cancer (PC) is one of the most lethal diseases, characterized by early metastasis and high mortality. Subunits of the SWI/SNF complex have been identified in many studies as the regulators of tumor progression, but the role of SMARCAD1, one member of the SWI/SNF family, in pancreatic cancer has not been elucidated. Based on analysis of GEO database and immunohistochemical detection of patient-derived pancreatic cancer tissues, we found that SMARCAD1 is more highly expressed in pancreatic cancer tissues and that its expression level negatively correlates with patients' survival time. With further investigation, it shows that SMARCAD1 promotes the proliferation, migration, invasion of pancreatic cancer cells. Mechanistically, we first demonstrate that SMARCAD1 induces EMT via activating Wnt/ß-catenin signaling pathway in pancreatic cancer. Our results provide the role and potential mechanism of SMARCAD1 in pancreatic cancer, which may prove useful marker for diagnostic or therapeutic applications of PC disease.

The MTOR signaling pathway regulates macrophage differentiation from mouse myeloid progenitors by inhibiting autophagy.

Understanding of the mechanism for myeloid differentiation provides important insights into the hematopoietic developmental processes. By using an ESC-derived myeloid progenitor cell model, we found that CSF2/GM-CSF triggered macrophage differentiation and activation of the MTOR signaling pathway. Activation or inhibition of the MTOR signaling enhanced or attenuated macrophage differentiation, respectively, suggesting a critical function. We further showed that macroautophagy/autophagy was inhibited with the addition of CSF2. Furthermore, pharmacological inhibition and genetic modification of autophagy enhanced macrophage differentiation and rescued the inhibitory effect on differentiation caused by MTOR inhibition. Thus, the MTOR signaling pathway regulates macrophage differentiation of myeloid progenitors by inhibiting autophagy. Our results provide new insights into the mechanisms for myeloid differentiation and may prove useful for therapeutic applications of hematopoietic and myeloid progenitor cells. Abbreviations: 2-DG: 2-deoxy-D-glucose; ADGRE1/F4/80: adhesion G protein-coupled receptor E1; BM: bone marrow; CQ: chloroquine; ECAR: extracellular acidification rate; ESC: embryonic stem cell; CSF2/GM-CSF: colony stimulating factor 2; CSF3/G-CSF: colony stimulating factor 3; HPC: hematopoietic progenitor cell; ITGAM/CD11b: integrin alpha M; LPS: lipopolysaccharide; MFI: median fluorescence intensity; MTOR: mechanistic target of rapamycin kinase; RPS6KB1/p70S6K1: ribosomal protein S6 kinase, polypeptide 1; shRNA: short hairpin RNA; SQSTM1/p62: sequestosome 1.

Spatial-resolved dual-signal-output electrochemiluminescent ratiometric strategy for accurate and sensitive immunoassay.

The identification of tumor markers is of great importance for clinical diagnosis but accurate detection with high sensitivity is still a great challenge. In present work, a spatial-resolved dual-signal-output electrochemiluminescent (ECL) ratiometric assay platform was constructed for sensitive detection of prostate specific antigen (PSA) on a dual-disk glassy carbon electrode. To fabricate the platform, flower-like CdS three-dimensional (3D) assemblies and Ru(bpy)32+-conjugated silica nanoparticles (Ru(bpy)32+@RuSi NPs), were immobilized onto the two disks as cathodic and anodic ECL emitters, respectively. After the stepwise modification of the gold nanoparticles, antibody for PSA, and bovine serum albumin onto the two disks respectively, the Ru(bpy)32+@RuSi NPs-based disk were incubated with varied concentration of PSA as working electrode, whereas the flower-like CdS 3D assemblies-based disk with fixed concentration of PSA were taken as internal reference electrode. The label free assay of PSA was realized by the ratio of anodic ECL signal from working electrode to the cathodic ECL signal from the internal reference electrode (ECLanode/ECLcathode). On the basis of the spatial-resolved dual-signal-output ratiometric ECL sensor, the PSA can be detected accurately with a linear range of 0.001 - 50ng/mL at a concentration as low as 0.34pg/mL. Furthermore, the proposed method was applied for PSA determination in human serum samples with satisfying results. Thanks to the same modified process of the two disks, this universal design well avoids environmental errors including the interference caused in the biological recognition process, which effectively reduces the false positive or negative errors, exhibiting a greatly improved accuracy, reliability and sensitivity.

An in situ electron donor consumption strategy for photoelectrochemical biosensing of proteins based on ternary Bi2S3/Ag2S/TiO2 NT arrays.

An ascorbic acid oxidase (AAO)-ascorbic acid bioevent-based electron donor consumption mode was introduced into the PEC bioassay for the first time. Ternary hybrid bismuth sulfide/silver sulfide/TiO2 nanotube arrays as the photoelectrode coupled with AAO attached to SiO2 as a dual signal quenching strategy were employed for sensitivity enhancement.