R-2HG Exhibits Anti-tumor Activity by Targeting FTO/m6A/MYC/CEBPA Signaling.

R-2-hydroxyglutarate (R-2HG), produced at high levels by mutant isocitrate dehydrogenase 1/2 (IDH1/2) enzymes, was reported as an oncometabolite. We show here that R-2HG also exerts a broad anti-leukemic activity in vitro and in vivo by inhibiting leukemia cell proliferation/viability and by promoting cell-cycle arrest and apoptosis. Mechanistically, R-2HG inhibits fat mass and obesity-associated protein (FTO) activity, thereby increasing global N6-methyladenosine (m6A) RNA modification in R-2HG-sensitive leukemia cells, which in turn decreases the stability of MYC/CEBPA transcripts, leading to the suppression of relevant pathways. Ectopically expressed mutant IDH1 and S-2HG recapitulate the effects of R-2HG. High levels of FTO sensitize leukemic cells to R-2HG, whereas hyperactivation of MYC signaling confers resistance that can be reversed by the inhibition of MYC signaling. R-2HG also displays anti-tumor activity in glioma. Collectively, while R-2HG accumulated in IDH1/2 mutant cancers contributes to cancer initiation, our work demonstrates anti-tumor effects of 2HG in inhibiting proliferation/survival of FTO-high cancer cells via targeting FTO/m6A/MYC/CEBPA signaling.

Histone H3 trimethylation at lysine 36 guides m6A RNA modification co-transcriptionally.

DNA and histone modifications have notable effects on gene expression1. Being the most prevalent internal modification in mRNA, the N6-methyladenosine (m6A) mRNA modification is as an important post-transcriptional mechanism of gene regulation2-4 and has crucial roles in various normal and pathological processes5-12. However, it is unclear how m6A is specifically and dynamically deposited in the transcriptome. Here we report that histone H3 trimethylation at Lys36 (H3K36me3), a marker for transcription elongation, guides m6A deposition globally. We show that m6A modifications are enriched in the vicinity of H3K36me3 peaks, and are reduced globally when cellular H3K36me3 is depleted. Mechanistically, H3K36me3 is recognized and bound directly by METTL14, a crucial component of the m6A methyltransferase complex (MTC), which in turn facilitates the binding of the m6A MTC to adjacent RNA polymerase II, thereby delivering the m6A MTC to actively transcribed nascent RNAs to deposit m6A co-transcriptionally. In mouse embryonic stem cells, phenocopying METTL14 knockdown, H3K36me3 depletion also markedly reduces m6A abundance transcriptome-wide and in pluripotency transcripts, resulting in increased cell stemness. Collectively, our studies reveal the important roles of H3K36me3 and METTL14 in determining specific and dynamic deposition of m6A in mRNA, and uncover another layer of gene expression regulation that involves crosstalk between histone modification and RNA methylation.

RNA G-quadruplex secondary structure promotes alternative splicing via the RNA-binding protein hnRNPF.

It is generally thought that splicing factors regulate alternative splicing through binding to RNA consensus sequences. In addition to these linear motifs, RNA secondary structure is emerging as an important layer in splicing regulation. Here we demonstrate that RNA elements with G-quadruplex-forming capacity promote exon inclusion. Destroying G-quadruplex-forming capacity while keeping G tracts intact abrogates exon inclusion. Analysis of RNA-binding protein footprints revealed that G quadruplexes are enriched in heterogeneous nuclear ribonucleoprotein F (hnRNPF)-binding sites and near hnRNPF-regulated alternatively spliced exons in the human transcriptome. Moreover, hnRNPF regulates an epithelial-mesenchymal transition (EMT)-associated CD44 isoform switch in a G-quadruplex-dependent manner, which results in inhibition of EMT. Mining breast cancer TCGA (The Cancer Genome Atlas) data sets, we demonstrate that hnRNPF negatively correlates with an EMT gene signature and positively correlates with patient survival. These data suggest a critical role for RNA G quadruplexes in regulating alternative splicing. Modulation of G-quadruplex structural integrity may control cellular processes important for tumor progression.

NIR Absorbing Organic Chromophores Combination with NSAIDs for Remodeling of the Inflammatory Microenvironment to Amplify Tumor Ferroptosis-Photothermal Synergistic Therapy.

Photothermal therapy has emerged as a promising approach for cancer treatment, which can cause ferroptosis to enhance immunotherapeutic efficacy. However, excessively generated immunogenicity will induce serious inflammatory response syndrome, resulting in a discounted therapeutic effect. Herein, a kind of NIR absorption small organic chromophore nanoparticles (TTHM NPs) with high photothermal conversion efficiency (68.33%) is developed, which can induce mitochondria dysfunction, generate mitochondrial superoxide, and following ferroptosis. TTHM NPs-based photothermal therapy is combined with Sulfasalazine (SUZ), a kind of nonsteroidal anti-inflammatory drugs, to weaken inflammation and promote ferroptosis through suppressing glutamate/cystine (Glu/Cys) antiporter system Xc- (xCT). Additionally, the combination of SUZ with PTT can induce immunogenic cell death (ICD), followed by promoting the maturation of DCs and the attraction of CD8+ T cell, which will secrete IFN-γ and trigger self-amplified ferroptosis via inhibiting xCT and simulating Acyl-CoA synthetase long-chain family member 4 (ACSL4). Moreover, the in vivo results demonstrate that this combination therapy can suppress the expression of inflammatory factors, enhance dendritic cell activation, facilitate T-cell infiltration, and realize effective thermal elimination of primary tumors and distant tumors. In general, this work provides an excellent example of combined medication and stimulates new thinking about onco-therapy and inflammatory response.

Enzyme-Inspired Coordination Polymers for Selective Oxidization of C(sp3)-H Bonds via Multiphoton Excitation.

Nature's blueprint provides the fundamental principles for expanding the use of abundant metals in catalysis; however, mimicking both the structure and function of copper enzymes simultaneously in one artificial system for selective C-H bond oxidation faces marked challenges. Herein, we report a new approach to the assembly of artificial monooxygenases utilizing a binuclear Cu2S2Cl2 cluster to duplicate the identical structure and catalysis of the CuA enzyme. The designed monooxygenase Cu-Cl-bpyc facilitates well-defined redox potential that initially activated O2via photoinduced electron transfer, and generated an active chlorine radical via a ligand-to-metal charge transfer (LMCT) process from the consecutive excitation of the in situ formed copper(II) center. The chlorine radical abstracts a hydrogen atom selectively from C(sp3)-H bonds to generate the radical intermediate; meanwhile, the O2•- species interacted with the mimic to form mixed-valence species, giving the desired oxidization products with inherent product selectivity of copper monooxygenases and recovering the catalyst directly. This enzymatic protocol exhibits excellent recyclability, good functional group tolerance, and broad substrate scope, including some biological and pharmacologically relevant targets. Mechanistic studies indicate that the C-H bond cleavage was the rate-determining step and the cuprous interactions were essential to stabilize the active oxygen species. The well-defined structural characters and the fine-modified catalytic properties open a new avenue to develop robust artificial enzymes with uniform and precise active sites and high catalytic performances.

The Biogenesis and Precise Control of RNA m6A Methylation.

N6-Methyladenosine (m6A) is the most prevalent internal RNA modification in mRNA, and has been found to be highly conserved and hard-coded in mammals and other eukaryotic species. The importance of m6A for gene expression regulation and cell fate decisions has been well acknowledged in the past few years. However, it was only until recently that the mechanisms underlying the biogenesis and specificity of m6A modification in cells were uncovered. We review up-to-date knowledge on the biogenesis of the RNA m6A modification, including the cis-regulatory elements and trans-acting factors that determine general de novo m6A deposition and modulate cell type-specific m6A patterns, and we discuss the biological significance of such regulation.

Cancer Immunotherapy Based on Cell Membrane-Coated Nanocomposites Augmenting cGAS/STING Activation by Efferocytosis Blockade.

Innate immunity triggered by the cGAS/STING pathway has the potential to improve cancer immunotherapy. Previously, the authors reported that double-stranded DNA (dsDNA) released by dying tumor cells can trigger the cGAS/STING pathway. However, owing to efferocytosis, dying tumor cells are engulfed and cleared before the damaged dsDNA is released; hence, immunologic tolerance and immune escape occur. Herein, a cancer-cell-membrane biomimetic nanocomposites that exhibit tumor-immunotherapeutic effects are synthesized by augmenting the cGAS/STING pathway and suppressing efferocytosis. Once internalized by cancer cells, a combined chemo/chemodynamic therapy would be triggered, which damages their nuclear and mitochondrial DNA. Furthermore, the releasing Annexin A5 protein could inhibit efferocytosis effect and promote immunostimulatory secondary necrosis by preventing phosphatidylserine exposure, resulting in the burst release of dsDNA. These dsDNA fragments, as molecular patterns to immunogenic damage, escape from the cancer cells, activate the cGAS/STING pathway, enhance cross-presentation inside dendritic cells, and promote M1-polarization of tumor-associated macrophages. In vivo experiments suggest that the proposed nanocomposite could recruit cytotoxic T-cells and facilitate long-term immunological memory. Moreover, when combined with immune-checkpoint blockades, it could augment the immune response. Therefore, this novel biomimetic nanocomposite is a promising strategy for generating adaptive antitumor immune responses.

Safety and Efficacy of OGT-Assisted Overlap Oesophagojejunostomy Versus the Traditional Overlap Method in Laparoscopic Total Gastrectomy for Gastric/Gastroesophageal Junction (G/GEJ) Tumours.

INTRODUCTION: Overlap guiding tube (OGT)-assisted overlap oesophagojejunostomy (EJS), which was first designed and reported by our team, has shown feasibility. However, its safety and efficiency have not yet been compared with the conventional overlap approach. METHODS: We retrospectively analysed the data of 155 gastric/gastroesophageal junction (G/GEJ) cancer patients who underwent laparoscopic total gastrectomy by conventional (conventional group, n = 83) or OGT-assisted (OGT group, n = 72) overlap methods at Nanfang Hospital. The anastomotic efficiency and surgical outcomes were compared between the two groups. RESULTS: The success rate of inserting an anvil fork into the oesophageal lumen at the first attempt in the OGT group was much higher than in the conventional group (86.7% vs. 97.2%, P = 0.019). Consistently, the duration of EJS (P < 0.001) in the OGT group was significantly shorter than that in the conventional group. Operatively, there was one case in which oesophageal pseudocanals developed; another case was converted to thoracoscopic surgery in the conventional group, but there were no such cases in the OGT group. In terms of postoperative recovery, the OGT group was superior to the conventional group. The incidence of postoperative complications (28.9% vs. 20.8%, P = 0.247) and the classification of complication severity (P = 0.450) were milder in the OGT group, although the difference was not statistically significant. Notably, the conventional group had four cases (4.8%) of oesophagojejunal anastomotic leakage (EJAL) and one case (1.2%) of anastomotic stenosis. In the OGT group, two patients (2.8%) developed EJAL, but none developed anastomotic stenosis or anastomotic bleeding. Neither group had any cases of unplanned secondary surgery or perioperative deaths. CONCLUSIONS: The OGT-assisted method reduced the surgical difficulty of overlap EJS with good safety. This study provides new perspectives for optimizing EJS.

N(6)-methyladenosine-binding protein YTHDF1 suppresses EBV replication and promotes EBV RNA decay.

N6 -methyladenosine (m6 A) modification of mRNA mediates diverse cellular and viral functions. Infection with Epstein-Barr virus (EBV) is causally associated with nasopharyngeal carcinoma (NPC), 10% of gastric carcinoma, and various B-cell lymphomas, in which the viral latent and lytic phases both play vital roles. Here, we show that EBV transcripts exhibit differential m6 A modification in human NPC biopsies, patient-derived xenograft tissues, and cells at different EBV infection stages. m6 A-modified EBV transcripts are recognized and destabilized by the YTHDF1 protein, which leads to the m6 A-dependent suppression of EBV infection and replication. Mechanistically, YTHDF1 hastens viral RNA decapping and mediates RNA decay by recruiting RNA degradation complexes, including ZAP, DDX17, and DCP2, thereby post-transcriptionally downregulating the expression of EBV genes. Taken together, our results reveal the critical roles of m6 A modifications and their reader YTHDF1 in EBV replication. These findings contribute novel targets for the treatment of EBV-associated cancers.

N6-Methyladenosine RNA Modification in Normal and Malignant Hematopoiesis.

Over 170 nucleotide variants have been discovered in messenger RNAs (mRNAs) and non-coding RNAs so far. However, only a few of them, including N6-methyladenosine (m6A), 5-methylcytidine (m5C), and N1-methyladenosine (m1A), could be mapped in the transcriptome. These RNA modifications appear to be dynamically regulated, with writer, eraser, and reader proteins being identified for each modification. As a result, there is a growing interest in studying their biological impacts on normal bioprocesses and tumorigenesis over the past few years. As the most abundant internal modification in eukaryotic mRNAs, m6A plays a vital role in the post-transcriptional regulation of mRNA fate via regulating almost all aspects of mRNA metabolism, including RNA splicing, nuclear export, RNA stability, and translation. Studies on mRNA m6A modification serve as a great example for exploring other modifications on mRNA. In this chapter, we will review recent advances in the study of biological functions and regulation of mRNA modifications, specifically m6A, in both normal hematopoiesis and malignant hematopoiesis. We will also discuss the potential of targeting mRNA modifications as a treatment for hematopoietic disorders.

Influence of Centrifugation and Transmembrane Treatment on Determination of Polyphenols and Antioxidant Ability for Sea Buckthorn Juice.

When the total phenolic content (TPC) and antioxidant activity of sea buckthorn juice were assayed by spectrophotometry, the reaction solutions were not clarified, so centrifugation or membrane treatment was needed before determination. In order to find a suitable method for determining TPC and antioxidant activity, the effects of centrifugation and nylon membrane treatment on the determination of TPC and antioxidant activity in sea buckthorn juice were studied. TPC was determined by the Folin-Ciocalteau method, and antioxidant activity was determined by DPPH, ABTS, and FRAP assays. For Treatment Method (C): the sample was centrifuged for 10 min at 10,000 rpm and the supernatant was taken for analysis. Method (CF): The sample was centrifuged for 10 min at 4000 rpm, filtered by Nylon 66 filtration membranes with pore size of 0.22 µm, and taken for analysis. Method (F): the sample was filtered by Nylon 66 filtration membranes with pore size of 0.22 µm and taken for analysis. Method (N): after the sample of ultrasonic extract solution reacted completely with the assay system, the reaction solution was filtered by Nylon 66 filtration membranes with pore size of 0.22 µm and colorimetric determination was performed. The results showed that centrifugation or transmembrane treatment could affect the determination of TPC and antioxidant activity of sea buckthorn juice. There was no significant difference (p > 0.05) between methods (CF) and (F), while there was a significant difference (p < 0.05) between methods (C) (F) (N) or (C) (CF) (N). The TPC and antioxidant activity of sea buckthorn juice determined by the four treatment methods showed the same trend with fermentation time, and the TPC and antioxidant activity showed a significant positive correlation (p < 0.05). The highest TPC or antioxidant activity measured by method (N) indicates that method (N) has the least loss of TPC or antioxidant activity, and it is recommended for sample assays.

Impact of preoperative therapy on surgical outcomes of laparoscopic total gastrectomy for gastric/gastroesophageal junction cancer.

Objective: As laparoscopic surgery is widely applied for primarily treated gastric cancer (GC)/gastroesophageal junction cancer (GEJC) and gains many advantages, the feasibility of laparoscopic total gastrectomy (LTG) for GC/GEJC patients who have received preoperative therapy (PT) has come to the fore. This study aims to analyze the safety and feasibility of LTG after PT for GC/GEJC patients. Methods: We retrospectively analyzed the data of 511 patients with GC/GEJC undergoing LTG, of which 405 received LTG (LTG group) and 106 received PT+LTG (PT-LTG group) at Nanfang Hospital between June 2018 and September 2022. The surgical outcomes were compared between the two groups. Results: The surgical duration was significantly longer in the PT-LTG group (P<0.001), while the incidence of intraoperative complications (P=1.000), postoperative complications (LTG group vs. PT-LTG group: 26.2% vs. 23.6%, P=0.587), the classification of complication severity (P=0.271), and postoperative recovery was similar between two groups. Notably, the incidence of anastomotic complications of esophagojejunostomy was also comparable between the two groups (LTG group vs. PT-LTG group: 5.9% vs. 5.7%, P=0.918). The univariate and multivariate analysis confirmed that positive proximal margin [positive vs. negative: odds ratio (OR)=14.094, 95% confidence interval (95% CI): 2.639-75.260, P=0.002], rather than PT, has an impact on anastomotic complications after LTG (OR=0.945, 95% CI: 0.371-2.408, P=0.905). Conclusions: PT did not increase the surgical risk of LTG for GC/GEJC. Therefore, considering the positive effect of PT on long-term survival, the broader application of PT and LTG for GC/GEJC is supported by our findings.

Snow Albedo Feedbacks Enhance Snow Impurity-Induced Radiative Forcing in the Sierra Nevada.

This study employs a fully coupled meteorology-chemistry-snow model to investigate the impacts of light-absorbing particles (LAPs) on snow darkening in the Sierra Nevada. After comprehensive evaluation with spatially and temporally complete satellite retrievals, the model shows that LAPs in snow reduce snow albedo by 0.013 (0-0.045) in the Sierra Nevada during the ablation season (April-July), producing a midday mean radiative forcing of 4.5 W m-2 which increases to 15-22 W m-2 in July. LAPs in snow accelerate snow aging processes and reduce snow cover fraction, which doubles the albedo change and radiative forcing caused by LAPs. The impurity-induced snow darkening effects decrease snow water equivalent and snow depth by 20 and 70 mm in June in the Sierra Nevada bighorn sheep habitat. The earlier snowmelt reduces root-zone soil water content by 20%, deteriorating the forage productivity and playing a negative role in the survival of bighorn sheep.

Cell type-restricted activity of hnRNPM promotes breast cancer metastasis via regulating alternative splicing.

Tumor metastasis remains the major cause of cancer-related death, but its molecular basis is still not well understood. Here we uncovered a splicing-mediated pathway that is essential for breast cancer metastasis. We show that the RNA-binding protein heterogeneous nuclear ribonucleoprotein M (hnRNPM) promotes breast cancer metastasis by activating the switch of alternative splicing that occurs during epithelial-mesenchymal transition (EMT). Genome-wide deep sequencing analysis suggests that hnRNPM potentiates TGFß signaling and identifies CD44 as a key downstream target of hnRNPM. hnRNPM ablation prevents TGFß-induced EMT and inhibits breast cancer metastasis in mice, whereas enforced expression of the specific CD44 standard (CD44s) splice isoform overrides the loss of hnRNPM and permits EMT and metastasis. Mechanistically, we demonstrate that the ubiquitously expressed hnRNPM acts in a mesenchymal-specific manner to precisely control CD44 splice isoform switching during EMT. This restricted cell-type activity of hnRNPM is achieved by competition with ESRP1, an epithelial splicing regulator that binds to the same cis-regulatory RNA elements as hnRNPM and is repressed during EMT. Importantly, hnRNPM is associated with aggressive breast cancer and correlates with increased CD44s in patient specimens. These findings demonstrate a novel molecular mechanism through which tumor metastasis is endowed by the hnRNPM-mediated splicing program.

Graphene oxide (GO)-based nanosheets with combined chemo/photothermal/photodynamic therapy to overcome gastric cancer (GC) paclitaxel resistance by reducing mitochondria-derived adenosine-triphosphate (ATP).

BACKGROUND: Paclitaxel (PTX) has been suggested to be a promising front-line drug for gastric cancer (GC), while P-glycoprotein (P-gp) could lead to drug resistance by pumping PTX out of GC cells. Consequently, it might be a hopeful way to combat drug resistance by inhibiting the out-pumping function of P-gp. RESULTS: In this study, we developed a drug delivery system incorporating PTX onto polyethylene glycol (PEG)-modified and oxidized sodium alginate (OSA)-functionalized graphene oxide (GO) nanosheets (NSs), called PTX@GO-PEG-OSA. Owing to pH/thermal-sensitive drug release properties, PTX@GO-PEG-OSA could induced more obvious antitumor effects on GC, compared to free PTX. With near infrared (NIR)-irradiation, PTX@GO-PEG-OSA could generate excessive reactive oxygen species (ROS), attack mitochondrial respiratory chain complex enzyme, reduce adenosine-triphosphate (ATP) supplement for P-gp, and effectively inhibit P-gp's efflux pump function. Since that, PTX@GO-PEG-OSA achieved better therapeutic effect on PTX-resistant GC without evident toxicity. CONCLUSIONS: In conclusion, PTX@GO-PEG-OSA could serve as a desirable strategy to reverse PTX's resistance, combined with chemo/photothermal/photodynamic therapy.

IGF2BP1 promotes SRF-dependent transcription in cancer in a m6A- and miRNA-dependent manner.

The oncofetal mRNA-binding protein IGF2BP1 and the transcriptional regulator SRF modulate gene expression in cancer. In cancer cells, we demonstrate that IGF2BP1 promotes the expression of SRF in a conserved and N6-methyladenosine (m6A)-dependent manner by impairing the miRNA-directed decay of the SRF mRNA. This results in enhanced SRF-dependent transcriptional activity and promotes tumor cell growth and invasion. At the post-transcriptional level, IGF2BP1 sustains the expression of various SRF-target genes. The majority of these SRF/IGF2BP1-enhanced genes, including PDLIM7 and FOXK1, show conserved upregulation with SRF and IGF2BP1 synthesis in cancer. PDLIM7 and FOXK1 promote tumor cell growth and were reported to enhance cell invasion. Consistently, 35 SRF/IGF2BP1-dependent genes showing conserved association with SRF and IGF2BP1 expression indicate a poor overall survival probability in ovarian, liver and lung cancer. In conclusion, these findings identify the SRF/IGF2BP1-, miRNome- and m6A-dependent control of gene expression as a conserved oncogenic driver network in cancer.

Homoharringtonine exhibits potent anti-tumor effect and modulates DNA epigenome in acute myeloid leukemia by targeting SP1/TET1/5hmC.

Homoharringtonine, a plant alkaloid, has been reported to suppress protein synthesis and has been approved by the US Food and Drug Administration for the treatment of chronic myeloid leukemia. Here we show that in acute myeloid leukemia (AML), homoharringtonine potently inhibits cell growth/viability and induces cell cycle arrest and apoptosis, significantly inhibits disease progression in vivo, and substantially prolongs survival of mice bearing murine or human AML. Strikingly, homoharringtonine treatment dramatically decreases global DNA 5-hydroxymethylcytosine abundance through targeting the SP1/TET1 axis, and TET1 depletion mimics homoharringtonine's therapeutic effects in AML. Our further 5hmC-seq and RNA-seq analyses, followed by a series of validation and functional studies, suggest that FLT3 is a critical down-stream target of homoharringtonine/SP1/TET1/5hmC signaling, and suppression of FLT3 and its downstream targets (e.g. MYC) contributes to the high sensitivity of FLT3-mutated AML cells to homoharringtonine. Collectively, our studies uncover a previously unappreciated DNA epigenome-related mechanism underlying the potent antileukemic effect of homoharringtonine, which involves suppression of the SP1/TET1/5hmC/FLT3/MYC signaling pathways in AML. Our work also highlights the particular promise of clinical application of homoharringtonine to treat human AML with FLT3 mutations, which accounts for more than 30% of total cases of AML.

Biodegradable hollow mesoporous organosilica nanotheranostics (HMON) for multi-mode imaging and mild photo-therapeutic-induced mitochondrial damage on gastric cancer.

BACKGROUND: CuS-modified hollow mesoporous organosilica nanoparticles (HMON@CuS) have been preferred as non-invasive treatment for cancer, as near infrared (NIR)-induced photo-thermal effect (PTT) and/or photo-dynamic effect (PDT) could increase cancer cells' apoptosis. However, the certain role of HMON@CuS-produced-PTT&PDT inducing gastric cancer (GC) cells' mitochondrial damage, remained unclear. Moreover, theranostic efficiency of HMON@CuS might be well improved by applying multi-modal imaging, which could offer an optimal therapeutic region and time window. Herein, new nanotheranostics agents were reported by Gd doped HMON decorated by CuS nanocrystals (called HMON@CuS/Gd). RESULTS: HMON@CuS/Gd exhibited appropriate size distribution, good biocompatibility, L-Glutathione (GSH) responsive degradable properties, high photo-thermal conversion efficiency (82.4%) and a simultaneous reactive oxygen species (ROS) generation effect. Meanwhile, HMON@CuS/Gd could efficiently enter GC cells, induce combined mild PTT (43-45 °C) and PDT under mild NIR power density (0.8 W/cm2). Surprisingly, it was found that PTT might not be the only factor of cell apoptosis, as ROS induced by PDT also seemed playing an essential role. The NIR-induced ROS could attack mitochondrial transmembrane potentials (MTPs), then promote mitochondrial reactive oxygen species (mitoROS) production. Meanwhile, mitochondrial damage dramatically changed the expression of anti-apoptotic protein (Bcl-2) and pro-apoptotic protein (Bax). Since that, mitochondrial permeability transition pore (mPTP) was opened, followed by inducing more cytochrome c (Cyto C) releasing from mitochondria into cytosol, and finally activated caspase-9/caspase-3-depended cell apoptosis pathway. Our in vivo data also showed that HMON@CuS/Gd exhibited good fluorescence (FL) imaging (wrapping fluorescent agent), enhanced T1 imaging under magnetic resonance imaging (MRI) and infrared thermal (IRT) imaging capacities. Guided by FL/MRI/IRT trimodal imaging, HMON@CuS/Gd could selectively cause mild photo-therapy at cancer region, efficiently inhibit the growth of GC cells without evident systemic toxicity in vivo. CONCLUSION: HMON@CuS/Gd could serve as a promising multifunctional nanotheranostic platform and as a cancer photo-therapy agent through inducing mitochondrial dysfunction on GC.

Impact of diabetes on prognosis of gastric cancer patients performed with gastrectomy.

OBJECTIVE: This study aimed to determine the impact of type 2 diabetes mellitus (T2DM) on clinical outcomes of gastric cancer (GC) patients and explore whether metformin use and good glycemic control could reverse it. METHODS: Clinicopathologic data of consecutive GC patients who underwent gastrectomy at Nanfang Hospital between October 2004 and December 2015 were included. Propensity score matching (PSM) was performed to balance the important factors of the disease status between non-T2DM and T2DM group. The last follow-up time was January 2019. RESULTS: A total of 1,692 eligible patients (1,621 non-T2DM vs. 71 T2DM) were included. After PSM, non-T2DM group (n=139) and T2DM group (n=71) were more balanced in baseline variables. The 5-year cancer-specific survival (CSS) rate in T2DM group (47.0%) was inferior to that in non-T2DM group (58.0%), but did not reach statistical significance [hazard ratio (HR)=1.319, 95% confidence interval (95% CI): 0.868-2.005, P=0.192]. While the 5-year progress-free survival (PFS) rate of T2DM group (40.6%) is significantly worse than that in non-T2DM group (56.3%) (HR=1.516, 95% CI: 1.004-2.290, P=0.045). Univariate and multivariate analyses showed that T2DM was an independent risk factor for PFS but not for CSS. In T2DM group, metformin use subgroup was associated with superior 5-year CSS and PFS in compared with non-metformin use subgroup, although the difference was not statistically significant (5-year CSS: 48.0%vs. 45.4%, HR=0.680, 95% CI: 0.352-1.313, P=0.246; 5-year PFS: 43.5%vs. 35.7%, HR=0.763, 95% CI: 0.400-1.454, P=0.406). The 5-year CSS rate was 47.5% in good glycemic control subgroup and 44.1% in poor glycemic control subgroup (HR=0.826, 95% CI: 0.398-1.713, P=0.605). And both two subgroups yielded a similar 5-year PFS rate (42.2%vs. 36.3%, HR=0.908, 95% CI: 0.441-1.871, P=0.792). CONCLUSIONS: DM promoted disease progress of GC after gastrectomy but had not yet led to the significant discrepancy of CSS. For GC patients with T2DM, metformin use was associated with superior survival but without statistical significance, while better glycemic control could not improve the prognosis.

RNA N 6-Methyladenosine Modification in Normal and Malignant Hematopoiesis.

As the most abundant internal modification in eukaryotic messenger RNAs (mRNAs), N 6-methyladenosine (m6A) modification has been shown recently to posttranscriptionally regulate expression of thousands of messenger RNA (mRNA) transcripts in each mammalian cell type in a dynamic and reversible manner. This epigenetic mark is deposited by the m6A methyltransferase complex (i.e., the METTL3/METTL14/WTAP complex and other cofactor proteins) and erased by m6A demethylases such as FTO and ALKBH5. Specific recognition of these m6A-modified mRNAs by m6A-binding proteins (i.e., m6A readers) determines the fate of target mRNAs through affecting splicing, nuclear export, RNA stability, and/or translation. During the past few years, m6A modification has been demonstrated to play a critical role in many major normal bioprocesses including self-renewal and differentiation of embryonic stem cells and hematopoietic stem cells, tissue development, circadian rhythm, heat shock or DNA damage response, and sex determination. Thus, it is not surprising that dysregulation of the m6A machinery is also closely associated with pathogenesis and drug response of both solid tumors and hematologic malignancies. In this chapter, we summarize and discuss recent findings regarding the biological functions and underlying mechanisms of m6A modification and the associated machinery in normal hematopoiesis and the initiation, progression, and drug response of acute myeloid leukemia (AML), a major subtype of leukemia usually associated with unfavorable prognosis.