Ceftazidime is a potential drug to inhibit cell proliferation by increasing cellular p27.

The development of new therapeutic uses for existing drugs is important for the treatment of some diseases. Cephalosporin antibiotics stand as the most extensively utilized antibiotics in clinical practice, effectively combating bacterial infections. Here, we found that the antimicrobial drug ceftazidime strongly upregulates p27 protein levels by inhibiting p27 ubiquitination. The p27 protein is a classic negative regulator of the cell cycle. Next, we demonstrated that ceftazidime can impede the cell cycle from G1 to S phase, thus inhibiting cell proliferation. Furthermore, we found that ceftazidime promotes p27 expression and inhibits cell proliferation by reducing Skp2, which is a substrate recognition component of the Skp2-Cullin-F-box (SCF) ubiquitin ligase. Moreover, ceftazidime downregulates transcriptional expression of Skp2. Importantly, we demonstrated that ceftazidime inhibited the proliferation of tumor cells in vivo. These findings reveal ceftazidime-mediated inhibition of cell proliferation through the Skp2-p27 axis, and could provide a potential strategy for anti-tumor therapy.

Immune checkpoint inhibitors combined with paclitaxel-based chemotherapy versus chemotherapy alone as first-line treatment in HER2-negative advanced gastric cancer: result of a multicenter retrospective study.

Background: Platinum-based chemotherapy combined with immune checkpoint inhibitors (ICIs) is now becoming the standard first-line therapy for human epidermal growth factor receptor 2 (HER2)-negative advanced gastric cancer (AGC). In China, paclitaxel has shown good efficacy and tolerability in AGC as an alternative for first-line therapy. Combining ICIs with paclitaxel-based chemotherapy may lead to improved tumor immune microenvironment, but evidence in paclitaxel combing with ICIs as first-line regimen is lacking. This multicenter, retrospective research aims to compare effectiveness and tolerability of paclitaxel-based chemotherapy combined with ICIs versus chemotherapy alone as a first-line treatment of HER2-negative AGC in a real-world setting. Methods: Eighty-six patients with HER2-negative AGC were included from 2017 to 2022. Among them, 57 patients received paclitaxel-based chemotherapy plus ICIs, and 29 patients received paclitaxel-based chemotherapy alone. We compared the efficacy and incidence of adverse events between the two therapy options. Results: Significant improvements in median progression-free survival (PFS) (8.77 versus 7.47 months; P=0.04) and median overall survival (OS) (15.70 versus 14.33 months; P=0.04) were observed in the ICIs combined with paclitaxel-based chemotherapy group. The use of ICIs also significantly prolonged the duration of response (DOR) (7.47 versus 4.59 months; P=0.02). Meanwhile, the ICIs plus chemotherapy group demonstrated significantly improved objective response rate (ORR) (50.9% vs. 27.6%; P=0.03) and disease control rate (DCR) (98.3% vs. 82.8%; P=0.01), and the side effects were tolerable. Conclusions: In summary, for HER2-negative AGC, ICIs plus paclitaxel-based chemotherapy is effective with mild toxicities, which should be considered as an alternative first-line therapy regimen.

Multi-parameter Inputted Logic-Gating on Aptamer-Encoded Extracellular Vesicles for Colorectal Cancer Diagnosis.

Extracellular vesicles (EVs) have emerged as a potential biomarker in liquid biopsy. However, cancer heterogeneity poses significant challenge to precise molecular diagnosis based on single-parameter input. Hence, strategies for analyzing multiple inputs with molecular computing were developed with the aim of improving diagnostic accuracy in liquid biopsy. In the present study, based on the surface of aptamer-encoded EVs, three toe-hold extended DNA aptamers served as specific inputs to perform AND-logic-gating to distinguish between healthy and cancerous EVs. In addition, this strategy has been successfully employed to analyze circulating EVs in clinical samples from colorectal cancer patients and healthy donors. The developed method has a promising future in the analysis of multiplex EV membrane proteins and the identification of early cancer.

Menthone inhibits type-I interferon signaling by promoting Tyk2 ubiquitination to relieve local inflammation of rheumatoid arthritis.

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease. RA development is mediated by the abnormal activation of multiple signaling pathways. Recent studies have revealed that type-I interferon (IFN-I) signaling plays an essential role in the occurrence and development of RA. However, how to target IFN-I signaling to develop anti-rheumatoid arthritis drugs remains largely unexplored. Here, our study showed that IFN-I signaling was over-activated in articular synovial cells from collagen II-induced arthritis (CIA) mice. Interestingly, we found that a small molecule compound, menthone, strongly inhibited the activation of the IFN-I signaling pathway. Further studies revealed that menthone promoted K48-linked polyubiquitination of Tyk2, thus lowering the protein level and stability of Tyk2. Importantly, menthone administration in the local articulus of CIA mice significantly attenuated the local inflammation in CIA mice. This study could promote our understanding of rheumatoid arthritis, and also suggests a potential strategy to develop anti-RA drugs.

Gp350-anchored extracellular vesicles: promising vehicles for delivering therapeutic drugs of B cell malignancies.

Although chimeric antigen receptor-modified (CAR) T cell therapy has been successfully applied in the treatment of acute B lymphocytic leukemia, its effect on Burkitt lymphoma (BL) and chronic B lymphocytic leukemia (B-CLL) is unsatisfactory. Moreover, fatal side effects greatly impede CAR T cell application. Extracellular vesicles (EVs) are excellent carriers of therapeutic agents. Nevertheless, EVs mainly accumulate in the liver when administered without modification. As an envelope glycoprotein of Epstein-Barr viruses, gp350 can efficiently bind CD21 on B cells. Here, gp350 was directly anchored onto red blood cell EVs (RBC-EVs) via its transmembrane region combined with low-voltage electroporation. The results showed that gp350 could anchor to RBC-EVs with high efficiency and that the resulting gp350-anchored RBC-EVs (RBC-EVs/gp350Etp) exhibited increased targeting to CD21+ BL and B-CLL relative to RBC-EVs. After the loading of doxorubicin or fludarabine, RBC-EVs/gp350Etp had powerful cytotoxicity and therapeutic efficacy on CD21+ BL or B-CLL, respectively. Moreover, RBC-EVs/gp350Etp loaded with a drug did not exhibit any apparent systemic toxicity and specifically induced the apoptosis of tumor B cells but not normal B cells. Therefore, our findings indicate that drug-loaded RBC-EVs/gp350Etp may be adopted in the treatment of CD21+ B cell malignancies.

Quantitative Relationship Between Solar Radiation and Grain Filling Parameters of Maize.

A quantitative understanding of the factors driving changes in grain filling is essential for effective prioritization of increasing maize yield. Grain filling is a significant stage in maize yield formation. Solar radiation is the energy source for grain filling, which is the ultimate driving factor for final grain weight and grain filling capacity that determine maize yield. Here, we first confirmed the quantitative relationships between grain filling parameters and photosynthetically active radiation (PAR) by conducting field experiments using different shading and plant density conditions and cultivars in 2019 and 2020 in Xinjiang, China. The results showed that with every 100 MJ m-2 increase in PAR, the average grain filling rate (G ave), maximum grain-filling rate (G max), and the kernel weight at the time of maximum grain-filling rate (W max) increased by 0.073 mg kernel-1 day-1, 0.23 mg kernel-1 day-1, and 0.24 mg kernel-1, and the time of maximum grain-filling rate (T max) delayed by 0.91 day. Relative changes in PAR were significantly and positively correlated with relative changes in yield and G ave. With every 1% change in PAR, yield and G ave changed by 1.16 and 0.17%, respectively. From the perspective of grain filling capacity, DH618 was a more shade-resistant cultivar than XY335 and ZD958. It is urgent to breed maize cultivars with low light tolerance and high grain yield in the face of climate change, particularly the decrease in solar radiation.

WISP3 suppresses ESCC progression by inhibiting the IGF-2-IGF1R-AKT signaling cascade.

Esophageal squamous cell carcinoma (ESCC) is a major health problem worldwide, especially in the Chinese population. However, the intrinsic molecular mechanisms of ESCC progression are largely unclear, thus there is an unmet need to identify essential genes governing this disease. Here, we discovered WISP3, an important member of the CCN family, is markedly downregulated in ESCC tissues compared to the normal esophageal epithelium. Downregulation of WISP3 in cancer tissue correlates with worse overall survival of ESCC patients. Using ESCC cell lines as models, we found that forced expression of WISP3 not only suppressed proliferation and migration of cancer cells in vitro, but also inhibited ESCC tumor growth and metastasis in vivo. On the contrary, WISP3 depletion strongly promoted the tumorigenicity of ESCC cells. Mechanistically, we found that WISP3 negates the activity of AKT via inhibiting the IGF-2-IGF1R signaling cascade, which mediates the tumor-suppressive function of WISP3 in esophageal cancers. Together, we identified a novel factor driving the development of ESCC, and revealed a potential therapeutic target for ESCC treatment.

Solar Radiation Effects on Dry Matter Accumulations and Transfer in Maize.

Solar radiation is the energy source for crop growth, as well as for the processes of accumulation, distribution, and transfer of photosynthetic products that determine maize yield. Therefore, learning the effects of different solar radiation amounts on maize growth is especially important. The present study focused on the quantitative relationships between solar radiation amounts and dry matter accumulations and transfers in maize. Over two continuous years (2017 and 2018) of field experiments, maize hybrids XY335 and ZD958 were grown at densities of 4.5 × 104 (D1), 7.5 × 104 (D2), 9 × 104 (D3), 10.5 × 104 (D4), and 12 × 104 (D5) plants/ha at Qitai Farm (89°34'E, 44°12'N), Xinjiang, China. Shading levels were 15% (S1), 30% (S2), and 50% (S3) of natural light and no shading (CK). The results showed that the yields of the commonly planted cultivars XY335 and ZD958 at S1, S2, and S3 (increasing shade treatments) were 7.3, 21.2, and 57.6% and 11.7, 31.0, and 61.8% lower than the control yields, respectively. Also, vegetative organ dry matter translocation (DMT) and its contribution to grain increased as shading levels increased under different densities. The dry matter assimilation amount after silking (AADMAS) increased as solar radiation and planting density increased. When solar radiation was <580.9 and 663.6 MJ/m2, for XY335 and ZD958, respectively, the increase in the AADMAS was primarily related to solar radiation amounts; and when solar radiation was higher than those amounts for those hybrids, an increase in the AADMAS was primarily related to planting density. Photosynthate accumulation is a key determinant of maize yield, and the contributions of the vegetative organs to the grain did not compensate for the reduced yield caused by insufficient light. Between the two cultivars, XY335 showed a better resistance to weak light than ZD958 did. To help guarantee a high maize yield under weak light conditions, it is imperative to select cultivars that have great stay-green and photosynthetic efficiency characteristics.

Marginal superiority of maize: an indicator for density tolerance under high plant density.

Marginal superiority is a common phenomenon in crops, and is caused by the competitiveness of individual plant for resources and crop adaptability to crowded growth conditions. In this study, in order to clarify the response of marginal superiority to maize morphology and plant-density tolerance, field experiments without water and nutrition stress were conducted at Qitai Farm in Xinjiang, China, in 2013-2014 and 2016-2019. The results showed that no more than three border rows of all the cultivars had marginal superiority under high density, about 90% of all the cultivars had no more than two border row that had marginal superiority and a significant negative correlation was observed between marginal superiority and population grain yield (first border row: y = - 2.193x + 213.9, p < 0.05; second border row: y = - 2.076x + 159.2, p < 0.01). Additionally, marginal superiority was found to have a significant positive relationship with plant density (first border row: y = 6.049x + 73.76, p < 0.01; second border row: y = 1.88x + 95.41, p < 0.05) and the average leaf angle above the ear (first border row: y = 2.306x + 103.1, p < 0.01). These results indicated that the smaller the leaf angle above the ear, the weaker the marginal superiority and the higher the grain yield. It suggests that the magnitude of marginal superiority in the border rows can be an indicator for plant-density tolerance under high density. What's more, cultivars with small leaf angle above the ear can be selected to weaken the marginal superiority and improve grain yield under high plant density. Conversely, cultivars with a large leaf angle above the ear can be selected to achieve higher individual yield in intercropping systems with no more than four rows alternated with other crops.

Author Correction: EpCAM-dependent extracellular vesicles from intestinal epithelial cells maintain intestinal tract immune balance.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

ST6GAL2 Downregulation Inhibits Cell Adhesion and Invasion and is Associated with Improved Patient Survival in Breast Cancer.

OBJECTIVE: Breast cancer is one of the most common and serious types of cancer, with a particularly unfavorable prognosis. Although dysregulation of ß-galactoside α 2,6-sialyltransferase 2 (ST6GAL2) has been observed in multiple cancers, the mechanism involved remains to be clarified. In this study, we focused on the potential function of ST6GAL2 in the regulation of breast cancer. METHODS: Flow cytometry and CCK-8 were used to measure markers of the cell cycle proliferation, adhesion, and invasion. Real-time PCR and immunohistochemistry analysis were used to detect the expression levels of ST6GAL2 in breast cancer tissues. Western blot was used to analyze the expression level of genes correlated with focal adhesion and metastasis pathways in breast cancer cells. RESULTS: ST6GAL2 expression levels were higher in breast cancer tissues as compared to healthy tissues. ST6GAL2 expression was associated with tumor stage, survival time, and estrogen receptor (ER)/progesterone receptor (PR)/human epidermal growth factor receptor 2 (HER2) status of breast cancer patients. Silence of ST6GAL2 inhibited cancer progression by arresting cell cycle progression at G0/G1 phase and inhibiting cell adhesion and invasion. ST6GAL2 was positively correlated with focal adhesion and metastasis pathways, and its downregulation inhibited the expression of ICAM-1, VCAM-1, CD24, MMP2, MMP9, and CXCR4. CONCLUSION: These findings indicated that ST6GAL2 might serve as a useful potential target for treatment of breast cancer.

Correction to: Surface anchorage of superantigen SEA promotes induction of specific antitumor immune response by tumor-derived exosomes.

The corrected Fig. 1 image and caption is presented in this paper.

Improving maize grain yield by matching maize growth and solar radiation.

Matching of maize growth with solar radiation is of great importance for achieving high yield. We conducted experiments using different maize cultivars and planting densities under different solar radiations during grain filling to quantitatively analyze the relationships among these factors. We found that a decrease in solar radiation after silking caused a drop in maize grain yield and biomass, with lower solar radiation intensities leading to worse grain yields and biomass. Cultivar ZD958 was more sensitive to solar radiation changes than cultivar XY335; slight decreases in solar radiation (i.e., 15% shading) caused significant declines in ZD958 grain yield. When total solar radiation during grain filling was less than 486.9 MJ m-2 for XY335 and less than 510.9 MJ m-2 for ZD958, the two cultivars demonstrated high yields at lower planting density of 7.5 × 104 plants ha-1; average yields were 13.36 and 11.09 Mg ha-1, respectively. When radiation intensities were higher than 549.5 MJ m-2 for XY335 and higher than 605.8 MJ m-2 for ZD958, yields were higher at a higher planting density of 12 × 104 plants ha-1, with average yields of 20.58 Mg ha-1 for XY335 and 19.65 Mg ha-1 for ZD958.

Specific Decrease in B-Cell-Derived Extracellular Vesicles Enhances Post-Chemotherapeutic CD8+ T Cell Responses.

Systemic immunosuppression greatly affects the chemotherapeutic antitumor effect. Here, we showed that CD19+ extracellular vesicles (EVs) from B cells through CD39 and CD73 vesicle-incorporated proteins hydrolyzed ATP from chemotherapy-treated tumor cells into adenosine, thus impairing CD8+ T cell responses. Serum CD19+ EVs were increased in tumor-bearing mice and patients. Patients with fewer serum CD19+ EVs had a better prognosis after chemotherapy. Upregulated hypoxia-inducible factor-1α (HIF-1α) promoted B cells to release CD19+ EVs by inducing Rab27a mRNA transcription. Rab27a or HIF-1α deficiency in B cells inhibited CD19+ EV production and improved the chemotherapeutic antitumor effect. Silencing of Rab27a in B cells by inactivated Epstein-Barr viruses carrying Rab27a siRNA greatly improved chemotherapeutic efficacy in humanized immunocompromised NOD PrkdcscidIl2rg-/- mice. Thus, decreasing CD19+ EVs holds high potential to improve the chemotherapeutic antitumor effect.

A near-infrared fluorescent sensor with large Stokes shift for rapid and highly selective detection of thiophenols in water samples and living cells.

The development of simple methods with high sensitivity and selectivity to differentiate toxic aromatic thiols (thiophenols) from aliphatic thiols (cysteine, homocysteine, and glutathione) and hydrogen sulfide (H2S) is of great significance. Herein, we report on the fabrication of a novel near-infrared (NIR) fluorescent sensor for rapid and highly selective detection of thiophenols through the photoinduced electron transfer (PET) mechanism. In the presence of the thiophenols, an obvious enhancement of NIR fluorescence at 658 nm could be visualized with the aid of nucleophilic aromatic substitution (SNAr) reaction. The sensor displays large Stokes shift (~ 227 nm), fast response time (< 30 s), high sensitivity (~ 8.3 nM), and good biocompatibility. Moreover, the as-prepared sensor possesses an excellent anti-interference feature even when other possible interferents exist (aliphatic thiols and H2S) and has been successfully utilized for thiophenol detection in both water samples and living cells. Graphical abstract Illustration of the sensor for thiophenol imaging in living cells.

Exosomes from heat-stressed tumour cells inhibit tumour growth by converting regulatory T cells to Th17 cells via IL-6.

Exosomes derived from heat-stressed tumour cells (HS-TEXs), which contain abundant heat shock protein (HSP) 70, strongly induce antitumour immune responses. HSP70-induced interleukin (IL)-6 promotes IL-17 expression and causes rejection of established prostate tumours. However, it remains unclear whether HS-TEXs exhibit antitumour effects by converting regulatory T cells (Tregs ) into T helper type 17 (Th17) cells. In this study, we found that compared with TEXs, HS-TEXs were more potent in stimulating secretion of IL-6 from dendritic cells. In vitro, IL-6 blocked tumour cell-derived transforming growth factor beta 1-induced Treg differentiation and promoted Th17 cell differentiation. HS-TEXs exerted strong antitumour effects, converting Tregs into Th17 cells with high efficiency, a process that was entirely dependent upon IL-6. Neutralization of IL-17 completely abolished the antitumour effect of TEXs, but only partially inhibited that of HS-TEXs. In addition, we found higher levels of IL-6 and IL-17 in serum from tumour patients treated with hyperthermia, and an increase in Th17 cells and a decrease in Tregs was detected in peripheral blood mononuclear cells isolated from these patients after hyperthermia. Therefore, our results demonstrate that HS-TEXs possess a powerful capacity to convert immunosuppressive Tregs into Th17 cells via IL-6, which contributes to their potent antitumour effect.

Tumor-derived exosomes educate dendritic cells to promote tumor metastasis via HSP72/HSP105-TLR2/TLR4 pathway.

How the tumor microenvironment educates dendritic cells (DCs) to promote tumorigenesis remains largely unknown, and the role of tumor-derived exosomes (TEXs) in tumorigenesis is controversial. Here, we report that in addition to the activation of DCs, TEXs induce DCs to produce increased interleukin-6 (IL-6), which dramatically promotes tumor invasion by increasing signal transducer and activator of transcription 3 (STAT3)-dependent matrix metalloproteinases 9 transcription activity in tumor cells. HSP72 and HSP105 on the TEX surface induce IL-6 secretion of DCs in a TLR2- and TLR4-dependent manner. In addition, HSP72 and HSP105 are predominantly present on exosomes from sera of tumor patients but not healthy people, indicating their value in tumor prediction. Furthermore, TEXs are powerful activators of DCs, and the depletion of IL-6 converts TEXs from tumor promoters to tumor inhibitors in vivo. Therefore, our results reveal a novel mechanism for the TEX-mediated education of DCs and shed light on the conundrum that TEXs present by playing dual roles in tumorigenesis.

Corrigendum: EpCAM-dependent extracellular vesicles from intestinal epithelial cells maintain intestinal tract immune balance.

This corrects the article DOI: 10.1038/ncomms13045.

The significance of multi-line chemotherapy for advanced gastric cancer: A retrospective analysis.

Palliative chemotherapy is known to benefit patients with advanced gastric cancer by palliating symptoms and improving survival. The aim of the present study was to evaluate the efficacy and toxicity of chemotherapy regimens that are commonly used in patients with advanced or recurrent gastric cancer. Patients with advanced or recurrent gastric cancer who were treated by at least two chemotherapy regimens between May 2006 and July 2014 at Zhejiang Cancer Hospital (Hangzhou, China) were retrospectively investigated. Survival was evaluated using the Kaplan-Meier method. A total of 248 patients were reviewed, and 158 were evaluated in the final analysis, with a median age of 57 years and a Karnofsky performance status score of ≥80. The median progression-free survival (PFS) time was 168 days for first-line chemotherapy, 96 days for second-line chemotherapy, and the median overall survival (OS) time was 356 days. Further analysis revealed that patients with the disease controlled [complete response (CR) + partial response (PR) + stable disease (SD)], no matter whether they received first-or second-line chemotherapy, may have had an improved OS compared with patients with disease progression (PD). Patients who were treated with >2 lines of chemotherapy had an improved OS compared those who ceased treatment following failure of the second-line chemotherapy. The cycle number of chemotherapy that patients received was associated with OS. The site of the primary and metastatic tumors was also associated with OS. Other factors, including gender, age, histological type, whether a radical operation was received, and chemotherapy regimens, had no evident association with survival. The toxicities were generally tolerated. Taken together, the results from the present study have demonstrated that an increased cycle number of effective chemotherapy may prolong the survival of patients with advanced gastric cancer. Differences among the chemotherapy regimens had no clear correlation with survival.