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Cancer metastasis is an extremely complex process affected by many factors. An acidic microenvironment can drive cancer cell migration towards blood vessels while also hampering immune cell activity. Here, we identified a mechanism mediated by sialyltransferases that induces an acidic tumor permissive microenvironment (ATPME) in BRCA1-mutant and most BRCA1-low breast cancers. Hypersialylation mediated by ST8SIA4 perturbed the mammary epithelial bilayer structure and generated an ATPME and immunosuppressive microenvironment with increased PD-L1 and PD1 expression. Mechanistically, BRCA1 deficiency increased expression of VEGF-A and IL6 to activate TGFβ-ST8SIA4 signaling. High levels of ST8SIA4 led to accumulation of polysialic acid (PSA) on mammary epithelial membranes that facilitated escape of cancer cells from immunosurveillance, promoting metastasis and resistance to αPD1 treatment. The sialyltransferase inhibitor 3Fax-Peracetyl Neu5Ac neutralized the ATPME, sensitized cancers to immune checkpoint blockade by activating CD8 T cells, and inhibited tumor growth and metastasis. Together, these findings identify a potential therapeutic option for cancers with a high level of PSA.

Objective: This study aimed to investigate the value of lactate/albumin ratio in prediction of mortality in intensive care unit (ICU) patients with post-operative intestinal obstruction. Method: A retrospective analysis was conducted with patient data from the eICU Collaborative Research Database (eICU-CRD). According to the outcome, the patients with post-operative intestinal obstruction who were admitted to ICU within 24 hours after surgery were separated into two groups: survivors (233 cases) and non-survivors (35 cases). Their clinical characteristics and scoring data were collected. Logistic regression analysis was used to evaluate the risk factors for death, and these risk factors were further included for the construction of the receiver operating characteristic curve (ROC) to evaluate the predictive value of death for these patients. Results: In-hospital mortality for patients admitted to ICU with post-operative intestinal obstruction was 13.1% (35/268). The level of lactate/albumin ratio was significantly higher in non-survivors than in survivors (1.36±1.54 versus 0.70±0.64; P

Lysine 2-hydroxyisobutyrylation (Khib) is a novel type of histone acylation whose prevalence and function in plants remain unclear. Here, we identified 41 Khib sites on histones in Arabidopsis thaliana, which did not overlap with frequently modified N-tail lysines (e.g. H3K4, H3K9 and H4K8). Chromatin immunoprecipitation-sequencing (ChIP-seq) assays revealed histone Khib in 35% of protein-coding genes. Most Khib peaks were located in genic regions, and they were highly enriched at the transcription start sites. Histone Khib is highly correlated with acetylation (ac), particularly H3K23ac, which it largely resembles in its genomic and genic distribution. Notably, co-enrichment of histone Khib and H3K23ac correlates with high gene expression levels. Metabolic profiling, transcriptome analyses, and ChIP-qPCR revealed that histone Khib and H3K23ac are co-enriched on genes involved in starch and sucrose metabolism, pentose and glucuronate interconversions, and phenylpropanoid biosynthesis, and help fine-tune plant response to dark-induced starvation. These findings suggest that Khib and H3K23ac may act in concert to promote high levels of gene transcription and regulate cellular metabolism to facilitate plant adaption to stress. Finally, HDA6 and HDA9 are involved in removing histone Khib. Our findings reveal Khib as a conserved yet unique plant histone mark acting with lysine acetylation in transcription-associated epigenomic processes.

The development of high-performance photosensitizers is the top priority in photodynamic therapy (PDT). Iridium complexes are widely used because of their many advantages such as high photostability, long T1 lifetime, high yield of singlet oxygen generation, and so on. Halogen-bridged binuclear complexes are often used as intermediates in the synthesis of photosensitizers but ignored in PDT applications. Here we found that halogen-bridged binuclear iridium complexes showed excellent performance in

Adsorption and photocatalysis are promising strategies to remove pollutants of dyes and antibiotics from wastewater. In this study, we demonstrate a rapid microwave-assisted hydrothermal route for the assembly of 2D copper-porphyrin Metal-Organic Frameworks (Cu-TCPP MOFs) within 1 h. The resulting 2D Cu-TCPP nanosheets with excellent crystallinity and a large surface area (342.72 m2/g) exhibited outstanding adsorption performance for typical dyes with adsorption capacities of about 185 mg/g for rhodamine B, 625 mg/g for methylene blue, and 290 mg/g for Congo red, respectively, as well as for representative antibiotics with adsorption capacities of about 130 mg/g for oxytocin, 150 mg/g for tetracycline, and 50 mg/g for norfloxacin, respectively. Meanwhile, the as-prepared 2D Cu-TCPP showed good photocatalytic degradation activity of pollutants after adsorption under irradiation by visible light, reaching removal efficiencies of 81.2 and 86.3% toward rhodamine B and norfloxacin, respectively. These results demonstrate the promising potential of 2D Cu-TCPP for use in the removal of contaminants from wastewater.

Recently, we discovered the H2S-mediated reductive cleavage of the CC bond, and applied this reaction to design probes for the detection of H2S. To extensively elucidate the structure–reactivity relationship, our current work further investigated the effect of substitutes that connected to the CC bond on the H2S-mediated reductive cleavage, wherein different kinds of electron-withdrawing groups (such as pyridine, bipyridine, terpyridine) and electron donating groups (such as carbazole, N,N-dimethylaniline and phenothiazine) were conjugated to the CC bond of interest. Experimental results and DFT calculations showed that the strength of the electron-donating and withdrawing substitutes could significantly affect the reductive cleavage of the CC bond. Unexpectedly, the reductive cleavage was not influenced by the change of the C(2) and C(3) positions in phenothiazine. On this basis, two probes (NPTZ-P1 and NPTZ-P2) with a C(3)-substituted phenothiazine were thus developed and successfully applied for sensing exogenous H2S in living HeLa cells, which implied their potential in bioimaging. This study provides further understanding on the structure–reactivity relationship of the H2S-mediated reductive cleavage of the CC bond, and is also valuable for exploring new reactions of the CC bond in organic synthesis.

By covalent combination of a chiral amino acid, lipid, and achiral phenothiazine derivative, a reaction-based chiroptical probe, PTZ-D, was obtained. PTZ-D could self-assemble into a chiral organogel realizing the chirality transformation from a chiral amino acid to a self-assembled system and displaying unprecedented chiroptical monitoring of ClO- with switchable CPL signals.

This contribution describes an efficient approach to constructing chiral spiro[pyrrol-benzopyran] (SPP) scaffold with high asymmetry. By combining chiral SPP and the achiral sensing moiety phenothiazine, the target probe P showed unprecedented reaction-based chiroptical sensing towards hypochlorite with switching CD signals.

To endow fluorescent functions to the inverse electron demand Diels–Alder (IEDDA) reaction products, introduction of extraneous fluorophores is usually inevitable. However, this strategy is blamed for complex construction and background fluorescence. It is desirable to construct IEDDA fluorescent products in a more convenient manner. In this work, we reported the in-situ generated green fluorescence in IEDDA reaction. The fluorescence intensity of IEDDA products RA-TZ-1 and RA-TZ-2 decreased in reduced pH values (from pH 7.0–3.0). Based on this novel property, we developed a ratiometric fluorescent probe RB–RA-TZ-2 by conjugation with another probe RB-NH2 (Em = 584 nm) with inverse response toward pH values. By single excitation, the fluorescence intensity ratio (I584/I488) showed a linear response (R = 0.9797) to H+ in pH range of 3.5–5.0. Colocalization imaging with LysoTracker Green indicated the capacity of RB–RA-TZ-2 to detect lysosomal pH (Pearson’s coefficient 0.81). Confocal microscopy was applied to measure and image intracellular pH in living cells.

Given the breadth of currently arising opportunities and concerns associated with nanoparticles for biomedical imaging, various types of nanoparticles have been widely exploited, especially for cellular/subcellular level probing. However, most currently reported nanoparticles either have inefficient delivery into cells or lack specificity for intracellular destinations. The absence of well-defined nanoplatforms remains a critical challenge hindering practical nano-based bio-imaging. Herein, the authors elaborate on a tailorable membrane-penetrating nanoplatform as a carrier with encapsulated actives and decorated surfaces to tackle the above-mentioned issues. The tunable contents in such a versatile nanoplatform offer huge flexibility to reach the expected properties and functions. Aggregation-induced emission luminogen (AIEgen) is applied to achieve sought-after photophysical properties, specific targeting moieties are installed to give high affinity towards different desired organelles, and critical grafting of cell-penetrating cyclic disulfides (CPCDs) to promote cellular uptake efficiency without sacrificing the specificity. Hereafter, to validate its practicability, the tailored nano products are successfully applied to track the dynamic correlation between mitochondria and lysosomes during autophagy. The authors believe that the strategy and described materials can facilitate the development of functional nanomaterials for various life science applications. Funding Agencies|STINT Joint China-Sweden Mobility Project [CH2017-7243]; Swedish Research Council (VR)Swedish Research Council [VR 2019-02409, 2020-05437]; China Scholarship Council (CSC)China Scholarship Council; Science and Technology Development Fund, Macau SAR [019/2017/AMJ, 0114/2019/A2]; Carl Tryggers Stiftelse [CTS 19:379]; Swedish Government strategic faculty grant in material science (SFO, MATLIU) in Advanced Functional Materials (AFM) (VR) [Dnr. 5.1-2015-5959]; Centre in Nano Science and technology at LiTH (CeNano); LiU Cancer network at Linkoping University

Objectives To identify potential metastases in the infundibulopelvic (IP) ligament and evaluate the necessity of high-level resection of the ligament during surgical treatment of epithelial ovarian cancer. Methods In this prospective study, 50 female patients with confirmed epithelial ovarian cancer underwent high-level resection of the IP ligament (10 cm or greater) as part of cytoreductive surgery. The resected IP ligaments were sectioned longitudinally at 10-mm intervals and labeled. Each segment was sectioned serially at a thickness of 4 µm, stained with hematoxylin and eosin (H&E), and examined by experienced pathologists for metastatic cells. Results Fifty pairs of IP ligaments were examined. Metastatic cells were found in the IP ligaments of 11 patients (22%) with FIGO stage III or IV epithelial ovarian cancer, 3–7 cm from the visual ovarian margin. Conclusions Our study demonstrates that metastases were occasionally present in the IP ligament of advanced epithelial ovarian cancer, and therefore, high-level resection of the IP ligament (10 cm or greater) is necessary as part of cytoreductive surgery to reduce residual tumors for advanced epithelial ovarian cancer.

Intracellular pH plays a significant role in all cell activities. Due to their precise imaging capabilities, fluorescent probes have attracted much attention for the investigation of pH-regulated processes. Detecting intracellular pH values with high throughput is critical for cell research and applications. In this work, hybrid semiconducting polymer dots (Pdots) were developed and characterized and were applied for cell imaging and exclusive ratiometric sensing of intracellular pH values. The reported Pdots were prepared by blending a synthesized block polymer (POMF) and a semiconducting polymer poly[2-methoxy-5-(2-ethylhexyloxy)-1,4-phenylenevinylene] (MEHPPV) to construct a fluorescence resonance energy transfer system for ratiometric sensing. Pdots showed many advantages, including high brightness, excellent photostability and biocompatibility, giving the pH probe high sensitivity and good stability. Our results proved the capability of POMF–MEHPPV Pdots for the detection of pH in living cells.

Using in vivo multiphoton fluorescent dosimetry, we demonstrate that the clearance dynamics of Indocyanine Green (ICG) in the blood can quickly reveal liver function reserve. In normal rats, the ICG retention rate was below 10% at the 15-minute post-administration; While in the rat with severe hepatocellular carcinoma (HCC), the 15-minute retention rate is over 40% due to poor liver metabolism. With a 785 nm CW laser, the fluorescence dosimeter can evaluate the liver function reserve at a 1/10 clinical dosage of ICG without any blood sampling. In the future, this low-dosage ICG 15-minute retention dosimetry can be applied for the preoperative assessment of hepatectomy or timely perioperative examination.

BACKGROUND The significant roles of circular ribonucleic acids (RNAs) in cancers have been discussed in many studies. This report aimed to investigate the biological functions of circKIAA0907 and its action mechanism in gastric cancer (GC). MATERIAL AND METHODS Relative RNA expression levels were determined using quantitative real-time polymerase chain reaction (qRT-PCR). The examination of cell proliferation was performed via 3-(4, 5-dimethylthiazol-2-y1)-2, 5-diphenyl tetrazolium bromide assay. Flow cytometry was used to analyze the apoptosis rate and cell cycle. Protein levels were quantified using western blot. Biotinylated RNA pull-down assay was used to find the microRNA target of circKIAA0907; target binding was validated through dual-luciferase reporter assay. The assay in vivo was executed via a xenograft tumor model to explore the role of circKIAA0907 in GC. RESULTS CircKIAA0907 was downregulated in GC and had higher stability than its linear isoform. Functionally, circKIAA0907 upregulation resulted in the repression of proliferation, cell cycle, and autophagy and promotion of apoptosis in GC cells. Mechanistically, circKIAA0907 bound to miR-452-5p as a specific sponge for it; lysine acetyltransferase 6B (KAT6B) was a target gene of miR-452-5p, so circKIAA0907 elevated KAT6B levels via sponging miR-452-5p. Reversion assays indicated that circKIAA0907 served as a tumor inhibitor by inhibiting miR-452-5p and increasing KAT6B; miR-452-5p inhibition impeded GC development by upregulating KAT6B. The miR-452-5p/KAT6B axis was also accountable for circKIAA0907-induced tumorigenesis suppression in vivo. CONCLUSIONS This work demonstrated that circKIAA0907 has diagnostic and therapeutic value in GC by acting as an oncogenic molecule via the miR-452-5p/KAT6B axis.

Adsorption and photocatalysis are promising strategies to remove pollutants of dyes and antibiotics from wastewater. In this study, we demonstrate a rapid microwave-assisted hydrothermal route for the assembly of 2D copper-porphyrin Metal-Organic Frameworks (Cu-TCPP MOFs) within 1 h. The resulting 2D Cu-TCPP nanosheets with excellent crystallinity and a large surface area (342.72 m

The grid load attributable to electric vehicles (EVs) is affected by the choice behaviors of EV users. To analyze the effects of factors such as travel demand and electricity prices on user behavior, a logit discrete choice model is introduced to simulate the users decisions to charge/travel. Based on a quasi-steady-state traffic network, a model for cluster electric vehicles considering the user's behavior is designed to obtain the probability distribution of the user's behavior and the charge and discharge curves of cluster EVs under various scenarios. The validity of the proposed model is verified using an IEEE 9-node traffic network case and an urban traffic network case. Furthermore, the impact of the electricity price, traffic conditions, and other factors on the load curves of urban EVs is analyzed.

Audit firms face conflicting incentives. On one hand, they are motivated to provide high quality audits in order to protect their reputations and avoid regulatory sanctions but, on the other hand, they also need to please their clients in order to increase their revenues. We argue that these conflicting incentives become apparent when comparing the partners who conduct audits (i.e., ‘engagement partners’) and the partners who are responsible for monitoring audit quality (i.e., ‘review partners’). Given their different responsibilities within the audit firm, we predict that review partners monitor audit quality more closely when they are motivated to work harder, whereas engagement partners tend to work harder by trying to please their clients. Consistent with these predictions we find that the associations between audit adjustments and partner ownership are: 1) significantly positive for review partners, 2) significantly negative or insignificant for engagement partners, and 3) significantly more positive for review partners than engagement partners. Our findings suggest that larger ownership stakes motivate review partners to monitor audit quality more closely, while larger ownership stakes do not motivate engagement partners to deliver higher quality audits.

Small molecules with circularly polarized luminescence (CPL) are especially valuable in solution-based applications, like chiroptical probes for effective sensing. However, such application has not been well explored due in part to hard introduction of appropriate triggerable fluorophores. Herein, we report an easily post-modifiable CPL-active scaffold (4) and further propose a feasible strategy to construct chiroptical probes for sensing hypochlorous acid. Helically chiral 4 with a 4, 4′-bicarbazole scaffold exhibits a large Stokes shift up to 142 nm and glum value of 0.9 × 10−3. Through facile construction of phenothiazine moiety on 4, red-emitting compound 5 was obtained in high yield (85.3%), showing distinct optical and chiroptical responses towards hypochlorous acid with good liner relationships and CPL sign blue-shifting of 120 nm in vitro. The probe is also applied to detect endogenous hypochlorous acid in living macrophages and can serve as a CPL sensor. Taking 5 as an application example, we envision that CPL-enabling scaffold 4 could find broad use in the design of more chiroptical probes.

China’s public accounting service profession has experienced rapid development in the past decade, and the major means of expansion are mainly characterized by merging with local audit firm...

Colorectal cancer (CRC) is the third‐most common cancer around the world, accounting for approximately 10% of cancer‐related mortality. Deeper molecular understanding of colorectal carcinogenesis will provide evidences for identification of early diagnostic indicators and novel therapeutic strategies for CRC treatment. The p21cdc42/rac1‐activated kinase 5 (PAK5) has been reported to be involved in a variety of tumor‐promoting behaviors, whereas the underlying mechanisms of PAK5 in CRC progression are still obscure. Our current study revealed an upregulated expression of PAK5 in human CRC tissues as compared with normal adjacent biopsies, which was associated with tumor progression and metastasis. We further unraveled that inhibition of PAK5 was correlated with restrained proliferation, migration, and invasion of CRC cells in vitro and in vivo. Moreover, we showed an indispensable role of PAK5 in interacting with Cdc42 and Integrin β1, β3, thus, to facilitate the migration and invasion of CRC cells. Collectively, we pointed out a potential of PAK5 to serve as a novel therapeutic target in restricting CRC proliferation and metastasis. The uncovered mechanisms will deepen the comprehension with regard to the mechanisms of CRC progression, as well as providing new insights for therapeutic intervention in colorectal cancer., PAK5 was highly expressed in human CRC samples, which was correlated with cancer progression and metastasis. Inhibition of PAK5 was associated with restrained tumor cell proliferation, migration, and invasion in vitro and in vivo models. Interacting with Cdc42 and integrin β1 and β3 was indispensable for PAK5 to facilitate the migration and invasion of CRC cells.

An energy-transfer metal–organic nanoprobe is designed for ratiometric sensing with dual response to both peroxynitrite (ONOO–) and hypochlorite (ClO–). Here, a nanoscale metal–organic framework (NMOF) acts as the energy donor and molecular probe as the acceptor to construct a Förster resonance energy transfer (FRET) nanosystem. Biocompatible dextran conveniently binds to the NMOF surface through multiple weak coordination interactions to improve water dispersibility and cell uptake. Dextran can also coordinate with the molecular probe with arylboronic acid group, which enables the convenient grafting of molecular probes to the NMOF surface to construct energy-transfer nanoprobes. Because of efficient FRET, the bright blue fluorescence of NMOF is quenched, whereas red emission from the acceptor is enhanced. Upon reacting with ONOO–, the probe departs from NMOF and the fluorescence of NMOF is recovered because of the interruption of FRET. When reacting with ClO–, the phenothiazine moiety in the molecular probe is oxidized into phenothiazine-5-oxide, which leads to more efficient energy transfer and the fluorescence shifts from red to orange. The nanoprobes are also successfully applied to the detection of ONOO– and ClO– in living cells.

Reductive cleavage of alkenes is rarely reported in synthetic chemistry. Here we report a unique H2S-mediated reductive cleavage of C[double bond, length as m-dash]C bonds under mild conditions, which is a successful new strategy for the design of probes for effective sensing of H2S with turn-on dual-color fluorescence. A short series of phenothiazine ethylidene malononitrile derivatives were shown to react with H2S, via reductive cleavage of C[double bond, length as m-dash]C bonds with intramolecular cyclization reactions to form thiophene rings. Enlightened by this new reaction mechanism, four effective probes with turn-off to turn-on fluorescence switches were successfully applied for sensing H2S, an important gaseous signalling molecule in living systems, among which PTZ-P4 exhibited two fluorescent colors after reductive cleavage. The dual-color probe was applied for imaging endogenous H2S and showed distinct differences in brightness in living C. elegans for wild type N2, glp-1 (e2144) mutants (higher levels of endogenous H2S), and cth-1 (ok3319) mutants (lower levels of endogenous H2S). The discovery of H2S-mediated reductive cleavage of C[double bond, length as m-dash]C bonds is expected to be valuable for chemical synthesis, theoretical studies, and the design of new fluorescent H2S probes.

Circularly polarized luminescence (CPL) is a preferential emission from chiral systems. Introducing CPL to traditional small fluorescence probes will greatly enhance selectivity and sensitivity due to avoiding the background fluorescence. Small-molecule probes are practically useful for bioimaging and sensing but always suffer from weak CPL properties. To optimize chiral perturbation, the study of structure-CPL correlation is an urgent necessity. Here, we investigated the influence of 3, 3′-substituent of BINOL on optical properties and found that iodization could significantly enhance the fluorescence quantum yield (ΦF) and dissymmetry factor (|glum|). Based on this finding, we presented a strategy to design dual-readout probes emiting both robust total fluorescence and CPL upon activation. As an application example, we first designed a pair of thiols probes, R/S-P1, with the fluorescence readout showing good linear response to cysteine, and CPL signal displaying significant enhancement with |glum| from undetectable value to 0.7 × 10−3.

Molecular nanomaterials built with well-defined chemical structures, accurate molecular weights and high synthetic reproducibility, have emerged as an exciting new branch of nanomaterials. Meaningfully, they perfectly fill the gap between small molecules and conventional nanomaterials. Nevertheless, coordination-based molecular nanomaterials are especially attractive due to their diverse structures and multifunctionalities combining merits of both organic components and metal ions. This review highlights recent progresses of coordination-based molecular nanomaterials mainly involving biomedically relevant applications, such as biosensing, bioimaging and therapy. Three typical coordination-based molecular nanomaterials were emphasized: (1) Organometallic carborane nanoclusters showed high amount of boron, as well as varieties of optical properties by the incorporation between metals/metal complexes and carborane, make a great contribution to bioimaging and boron neutron capture therapy. (2) Atomically precise metal nanoclusters cascading metals as a whole, thus possessing intriguing structures and diverse optical properties, which are superior in biosensing, bioimaging and phototherapy. (3) Metal-organic nanocages assembled as containers play an important role in biosensing and biomolecular delivery because of host–guest interactions, and they also display excellent DNA binding for antitumor. Finally, the current challenges and perspectives for the further trend are also discussed. The overview will lead timely recognition of coordination-based molecular nanomaterials and hopefully stimulate their fast development.

BACKGROUND: The influence of pretreatment anemia on the prognosis of patients with advanced gastric cancer (GC) remains controversial. We retrospectively examined the impact of pretreatment anemia on the overall survival (OS) of patients with GC with nonhypoalbuminemia undergoing curative resection. METHODS: The clinicopathological data of 2,916 patients with advanced GC who received a radical gastrectomy from 1994 to 2015 were analyzed. The patients were divided into two subgroups by hemoglobin level