Efficient plant regeneration through direct shoot organogenesis and two-step rooting in Eucommia ulmoides Oliver.

Eucommia ulmoides Oliver (E. ulmoides Oliver), a multipurpose woody plant, holds great economic significance due to its expansive medicinal, food and industrial applications. The rapid advancement of E. ulmoides in various fields has resulted in the inadequacy of existing breeding methods to meet its growth and annual production demands. Consequently, there is an urgent need for innovative propagation strategies. This study introduces an optimized micropropagation protocol for E. ulmoides, facilitating direct shoot organogenesis from nodal segments with axillary buds. We systematically examined the impact of basal medium composition, plant growth regulators, photosynthetic photon flux density, and sucrose concentration on bud sprouting. Employing cuttings with axillary buds as propagation material, we achieved a shortened cultivation period of merely 4 weeks for bud elongation and proliferation, marking a substantial enhancement in propagation efficiency. Notably, the Driver Kuniyuki Walnut medium, supplemented with 20.0 g L-1 sucrose and 2.0 mg L-1 trans-zeatin, induced shoots sprouting with a 100% success rate and an average length of 5.18 cm per nodal segment, equating to a great bud propagation rate of approximately 500%. Furthermore, a light source with an intensity of 80 µmol m-2 s-1 was shown the most economical choice. To address the primary challenge of inducing roots in regenerated plants, we employed a refined two-step rooting technique. This method yielded the optimal rooting frequency of 93.02%, producing an average of 5.90 adventitious roots per plantlet, each with an average length of 2.77 cm. The micropropagation program developed in this work will be the cornerstone for the preservation of the germplasm of E. ulmoides and its long-term use in medicinal and industrial applications.

Targeting MELK in tumor cells and tumor microenvironment: from function and mechanism to therapeutic application.

Maternal embryonic leucine zipper kinase (MELK), a member of the adenosine monophosphate-activated protein kinase (AMPK) protein family, has been reported to be involved in the regulation of many cellular events. The aberrant expression of MELK is associated with tumorigenesis and malignant progression of various tumors. Moreover, MELK plays an essential role in the regulation of tumor microenvironment (TME), which affects the function of immune cells and the responsiveness to immunotherapy. Currently, small molecule inhibitors targeting MELK have been developed and evaluated in clinical trials. A comprehensive understanding of MELK may provide clues and confidence for subsequent basic research and scientific transformation. In this review, we provide a comprehensive overview of the structural features, molecular biological functions, and critical roles of MELK in tumors and TME, as well as the targeted agents under development for the treatment of tumors and discuss the perspective for MELK-targeted therapies for tumors.

Upregulation of MELK promotes chemoresistance and induces macrophage M2 polarization via CSF-1/JAK2/STAT3 pathway in gastric cancer.

BACKGROUND: Gastric cancer (GC) stands out as one of the most prevalent malignancies affecting the digestive system, characterized by a substantial incidence rate and mortality. Maternal embryonic leucine zipper kinase (MELK) has been implicated in the advancement of various cancer types and the modulation of the tumor microenvironment. This study aims to delve into the involvement of MELK in chemoresistance and the tumor microenvironment of GC. METHODS: The MELK expression was detected using quantitative real-time polymerase chain reaction (qRT-PCR), western blotting and immunohistochemistry. Lentiviral transfection was employed to establish stable cell lines with either overexpressed or silenced MELK. The impact of MELK on the chemoresistance of GC cells and the polarization of macrophages was investigated through in vitro and in vivo functional assays. Additionally, the correlation between MELK and the cytokines colony-stimulating factor 1 (CSF-1), as well as stromal macrophages, was analysed. The prognostic significance of MELK, CSF-1, and CD206 expression levels in clinical samples was further investigated. RESULTS: MELK was found to be highly expressed in chemoresistant GC cells and tissues. Furthermore, both in vitro and in vivo assays indicated that MELK overexpression conferred chemoresistance in GC cells. Additionally, MELK overexpression was observed to induce M2 macrophage polarization via the CSF-1/JAK2/STAT3 pathway, thereby contributing to chemoresistance within the tumor microenvironment. The expression of MELK in GC tissues from neoadjuvant chemotherapy patients correlated positively with CSF-1 and CD206. Moreover, patients with higher expression levels of MELK, CSF-1, or CD206 exhibited significantly shorter OS and DFS rates. CONCLUSIONS: Our investigation underscores the critical role of MELK in promoting chemoresistance and inducing M2 macrophage polarization in GC. It proposes novel targets and methods for the treatment of GC, as well as prognostic factors for neoadjuvant chemotherapy.

Targeting tumor­associated macrophages: Critical players in tumor progression and therapeutic strategies (Review).

Tumor­associated macrophages (TAMs) are essential components of the tumor microenvironment (TME) and display phenotypic heterogeneity and plasticity associated with the stimulation of bioactive molecules within the TME. TAMs predominantly exhibit tumor­promoting phenotypes involved in tumor progression, such as tumor angiogenesis, metastasis, immunosuppression and resistance to therapies. In addition, TAMs have the potential to regulate the cytotoxic elimination and phagocytosis of cancer cells and interact with other immune cells to engage in the innate and adaptive immune systems. In this context, targeting TAMs has been a popular area of research in cancer therapy, and a comprehensive understanding of the complex role of TAMs in tumor progression and exploration of macrophage­based therapeutic approaches are essential for future therapeutics against cancers. The present review provided a comprehensive and updated overview of the function of TAMs in tumor progression, summarized recent advances in TAM­targeting therapeutic strategies and discussed the obstacles and perspectives of TAM­targeting therapies for cancers.

Nano protective membrane coated wheat to resist powdery mildew.

The plant pathogenic fungus Blumeria graminis f. sp. tritici infects wheat and reduces its yield. The policy of reducing fertilizer and biocide use in sustainable agriculture has prompted researchers to develop more green and efficient management strategies. In this study, a novel nanoprotective membrane (kaolin-nano titanium dioxide-liquid paraffin, referred to as KTP) that could effectively prevent powdery mildew of wheat was prepared by using 1 g/L kaolin, 2 g/L nanotitanium dioxide and 8% (v/v) liquid paraffin. The prevention and control effects of KTP spraying in advance in the pot and field experiments were 98.45% and 83.04%, respectively. More importantly, the weight of 1000 grains of wheat pretreated with KTP was 2.56 g higher than that of wheat infected with powdery mildew, significantly improving wheat yield. KTP delayed the germination of powdery mildew spores on the leaf surface, and inhibited the formation of mycelia. In addition, KTP did not affect the growth of wheat or the survival of earthworms. KTP nanoprotective membrane are a green and safe prevention and control materials that are which is expected to be widely used in agriculture to control wheat powdery mildew.

In vitro regeneration, photomorphogenesis and light signaling gene expression in Hydrangea quercifolia cv. 'Harmony' under different LED environments.

MAIN CONCLUSION: Plant growth regulators, sucrose concentration, and light quality significantly impact in vitro regeneration of 'Harmony'. Blue light promotes photomorphogenesis by enhancing light energy utilization, adjusting transcription of light signal genes, and altering hormone levels. Hydrangea quercifolia cv. 'Harmony', celebrated for lush green foliage and clusters of white flowers, has been extensively researched for its regenerative properties. Regeneration in stem segments, leaves, and petioles is facilitated by exogenous auxin and cytokinins (CTKs), with the concentration of sucrose (SC) being a key determinant for shoot regeneration from leaves. The study also highlights the significant impact of light conditions on photomorphogenesis. With an increase in the proportion of red (R) light, there is an inhibitory effect, leading to a reduction in leaf area, a decrease in the quantum yield of PSII (ΦPSII), and an increase in non-photochemical quenching (ΦNPQ) and non-regulated energy dissipation in PSII (ΦNO). Conversely, blue (B) light enhances growth, characterized by an increase in leaf area, elevated ΦPSII, and stable ΦNPQ and ΦNO levels. Additionally, B light induces the upregulation of HqCRYs, HqHY5-like, HqXTH27-like, and HqPHYs genes, along with an increase in endogenous CTKs levels, which positively influence photomorphogenesis independent of HqHY5-like regulation. This light condition also suppresses the synthesis of endogenous gibberellins (GA) and brassinosteroids (BR), further facilitating photomorphogenesis. In essence, B light is fundamental in expediting photomorphogenesis in 'Harmony', demonstrating the vital role in plant growth and development.

Solid-State Lithium Batteries with Ultrastable Cyclability: An Internal-External Modification Strategy.

A commonly used strategy to tackle the unstable interfacial problem between Li1.3Al0.3Ti1.7(PO4)3 (LATP) and lithium (Li) is to introduce an interlayer. However, this strategy has a limited effect on stabilizing LATP during long-term cycling or under high current density, which is due in part to the negative impact of its internal defects (e.g., gaps between grains (GBs)) that are usually neglected. Here, control experiments and theoretical calculations show clearly that the GBs of LATP have higher electronic conductivity, which significantly accelerates its side reactions with Li. Thus, a simple LiCl solution immersion method is demonstrated to modify the GBs and their electronic states, thereby stabilizing LATP. In addition to LiCl filling, composite solid polymer electrolyte (CSPE) interlayering is concurrently introduced at the Li/LATP interface to realize the internal-external dual modifications for LATP. As a result, electron leakage in LATP can be strictly inhibited from its interior (by LiCl) and exterior (by CSPE), and such dual modifications can well protect the Li/LATP interface from side reactions and Li dendrite penetration. Notably, thus-modified Li symmetrical cells can achieve ultrastable cycling for more than 3500 h at 0.4 mA cm-2 and 1500 h at 0.6 mA cm-2, among the best cycling performance to date.

Plant morphology, secondary metabolites and chlorophyll fluorescence of Artemisia argyi under different LED environments.

Different light spectra from light-emitting diodes (LEDs) trigger species-specific adaptive responses in plants. We exposed Artemisia argyi (A. argyi) to four LED spectra: white (the control group), monochromatic red light (R), monochromatic blue light (B), or a mixture of R and B light of photon flux density ratio is 3 (RB), with equivalent photoperiod (14 h) and light intensity (160 µmol s-1 m-2). R light accelerated photomorphogenesis but decreased biomass, while B light significantly increased leaf area and short-term exposure (7 days) to B light increased total phenols and flavonoids. HPLC identified chlorogenic acid, 3,5-dicaffeoylquinic acid, gallic acid, jaceosidin, eupatilin, and taxol compounds, with RB and R light significantly accumulating chlorogenic acid, 3,5-dicaffeoylquinic acid, and gallic acid, and B light promoting jaceosidin, eupatilin, and taxol. OJIP measurements showed that B light had the least effect on the effective quantum yield ΦPSII, with higher rETR(II), Fv/Fm, qL and PIabs, followed by RB light. R light led to faster photomorphology but lower biomass than RB and B lights and produced the most inadaptability, as shown by reduced ΦPSII and enlarged ΦNPQ and ΦNO. Overall, short-term B light promoted secondary metabolite production while maintaining effective quantum yield and less energy dissipation.

Silicon Nanowire Array Weaved by Carbon Chains for Stretchable Lithium-Ion Battery Anode.

To manufacture flexible batteries, it can be a challenge for silicon base anode materials to maintain structural integrity and electrical connectivity under bending and torsion conditions. In this work, 1D silicon nanowire array structures combined with flexible carbon chains consisting of short carbon nanofibers (CNFs) and long carbon nanotubes (CNTs) are proposed. The CNFs and CNTs serve as chain joints and separate chain units, respectively, weaving the well-ordered Si nanowire array into a robust and integrated configuration. The prepared flexible and stretchable silicon array anode exhibits excellent electrochemical performance during dynamic operation. A high initial specific capacity of 2856 mAh g-1 is achieved. After 1000 cycles, a capacity retention of 60% (1602 mAh g-1) is maintained. Additionally, the capacity attenuation is less than 1% after 100 bending cycles. This excellent cycling stability is obtained with a high Si loading of 6.92 mg cm-2. This novel approach offers great promise for the development of high-loading flexible energy-storage devices.

Perioperative chemotherapy versus adjuvant chemotherapy treatment for resectable locally advanced gastric cancer: a retrospective cohort study.

BACKGROUND: Neoadjuvant chemotherapy (NAC) is increasingly used in locally advanced gastric cancer (LAGC), but the clinical safety and efficacy are still controversial. This study aims to compare perioperative chemotherapy (PEC) with adjuvant chemotherapy (AC) for resectable LAGC. METHODS: Patients who underwent D2 gastrectomy for resectable LAGC were retrospectively reviewed, and divided into NSA group (NAC plus surgery and AC) and SA group (surgery followed by AC). The baseline characteristics and perioperative data were compared. Survival analysis was based on Kaplan-Meier method. Multivariate analyses for prognostic factors were based on the Cox regression. RESULTS: A total of 450 patients were eligible for this study. 218 patients received NAC plus surgery and AC, while 232 upfront surgery followed by AC. The baseline characteristics were comparable between the two groups. NSA group showed significant superiority in R0 resection rate (P = 0.014), excised tumor size (P = 0.038), and tumor downstage (all P < 0.001). NAC did not affect postoperative complications or AC-related grade 3/4 adverse events. Patients in NSA group achieved significantly longer OS (P = 0.021) and DFS (P = 0.002). The Cox regression model showed that NAC was independently associated with better OS (HR 0.245, P = 0.039) and DFS (HR 0.591, P = 0.031). CONCLUSIONS: Compared with SA, the administration of NSA was considered safe and feasible for achieving higher R0 resection rate without increasing the postoperative complications or AC-related grade 3/4 adverse events, and NAC was independently associated with better OS and DFS for resectable LAGC.

Impact of intense physical activity in athletes on intestinal mucosal integrity and its role in acute gastric hemorrhage and postoperative infection risks

In the context of rising gastric disease prevalence, acute gastric hemorrhage presents a significant clinical challenge, particularly among athletes who engage in intense physical activity. This demographic may have unique vulnerabilities due to the stress and strain of their rigorous training and performance routines. Acute gastric bleeding can arise from various sources, including gastritis from Helicobacter pylori infection, gastric ulcers, or vascular abnormalities exacerbated by lifestyle factors like excessive alcohol consumption. However, the impact of high-intensity physical exertion, common in athletes, on these conditions remains underexplored. In athletes, the management of acute gastric bleeding often involves conservative drug therapy post-hemodilation, with proton pump inhibitors like omeprazole offering both anti-inflammatory and acid-inhibiting effects. Surgical intervention is reserved for severe cases, considering the heightened risk of postoperative abdominal infections due to the stomach's unique physiology and its microbial population. This study focuses on the intestinal mucosal barrier's function postoperatively in athletes who have undergone treatment for acute gastric bleeding. We explore how intense physical activity influences intestinal mucosal integrity and its subsequent role in postoperative infection risks. The role of high-mobility group box1 (HMGB1) and the receptor for advanced glycation end products (RAGE) in this context is also examined. HMGB1, a crucial pro-inflammatory cytokine and late inflammatory mediator, and RAGE, a significant HMGB1 receptor, are believed to play pivotal roles in the inflammatory response following acute gastric bleeding (AU)

Comparison of the predictive value of pathological response at primary tumor and lymph node status after neoadjuvant chemotherapy in locally advanced gastric cancer

Background Preoperative chemotherapy has been increasingly used in locally advanced gastric cancer (LAGC). However, the prognostic factors are still insufficient. This study aimed to investigate the prognostic significance of pathological response of the primary tumor to neoadjuvant chemotherapy (NACT) and the lymph node status after NACT. Methods Data from 160 patients with LAGC treated with NACT followed by gastrectomy and met the inclusion criteria between March 2016 and December 2019 were retrospectively reviewed. Pathological evaluation after NACT was based on the grade of pathological response of the primary tumor and the status of lymph node. Survival curves for overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan–Meier method, and the log-rank test was used to compare survival difference. Univariate and multivariate analyses for prognostic factors were based on the Cox regression. Results Among 160 selected cases, 90 had pathological response (PR), while 70 had no pathological response (nPR) to NACT. Smaller tumor size was presented in PR group, which also had lower level of signet ring cell features, compared to nPR group (all p < 0.05). Based on the status of lymph nodes, nodal status (−) group showed smaller tumor size, lower depth of tumor invasion, better differentiated degree, lower level of signet ring cell features, lower rate of lymphatic and venous invasion and less advanced ypTNM stage (all p < 0.05). Survival was equivalent between PR and nPR group (all p > 0.05), while patients with no lymph node metastasis had better DFS than that with lymph node metastasis (HR 0.301, 95% CI 0.194–0.468, p = 0.002) (AU)

Comparison of the predictive value of pathological response at primary tumor and lymph node status after neoadjuvant chemotherapy in locally advanced gastric cancer.

BACKGROUND: Preoperative chemotherapy has been increasingly used in locally advanced gastric cancer (LAGC). However, the prognostic factors are still insufficient. This study aimed to investigate the prognostic significance of pathological response of the primary tumor to neoadjuvant chemotherapy (NACT) and the lymph node status after NACT. METHODS: Data from 160 patients with LAGC treated with NACT followed by gastrectomy and met the inclusion criteria between March 2016 and December 2019 were retrospectively reviewed. Pathological evaluation after NACT was based on the grade of pathological response of the primary tumor and the status of lymph node. Survival curves for overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method, and the log-rank test was used to compare survival difference. Univariate and multivariate analyses for prognostic factors were based on the Cox regression. RESULTS: Among 160 selected cases, 90 had pathological response (PR), while 70 had no pathological response (nPR) to NACT. Smaller tumor size was presented in PR group, which also had lower level of signet ring cell features, compared to nPR group (all p < 0.05). Based on the status of lymph nodes, nodal status (-) group showed smaller tumor size, lower depth of tumor invasion, better differentiated degree, lower level of signet ring cell features, lower rate of lymphatic and venous invasion and less advanced ypTNM stage (all p < 0.05). Survival was equivalent between PR and nPR group (all p > 0.05), while patients with no lymph node metastasis had better DFS than that with lymph node metastasis (HR 0.301, 95% CI 0.194-0.468, p = 0.002). Multivariable Cox regression analysis identified that lymph node status after NACT was an independent prognostic factor associated with survival (OS: hazard ratio 1.756, 95% CI 1.114-3.278, p = 0.029; DFS: hazard ratio 1.901, 95% CI 1.331-3.093, p = 0.012). CONCLUSION: Lymph node status is a potential independent prognostic factor for LAGC patients treated with NACT and may be more efficient than pathological response in primary tumor.

Association between Plasma FGF21 Levels and Body Composition in Patients with Gastric Cancer.

BACKGROUND: Accumulating evidence has suggested that Fibroblast growth factor 21 (FGF21) plays an important role in metabolic diseases. This study aimed to investigate the relationship between plasma FGF21 levels and body composition parameters in gastric cancer (GC) patients. METHODS: This study was cross-sectional based on a prospective cohort of GC patients in a single center. Computer tomography (CT) and bioelectrical impedance analysis (BIA) were used to estimate skeletal muscle and adipose tissue mass. Blood samples were collected and plasma concentrations of FGF21 were measured by ELISA. Spearman's rank correlation test and logistic regression analysis were performed to assess associations between plasma FGF21 levels and these body composition parameters. RESULTS: A total of 66 GC patients were enrolled in this study. Plasma FGF21 levels were significantly higher in women compared with men. The plasma FGF21 levels were positively correlated with fat mass index (FMI), fat mass percentage (FM%), and subcutaneous adipose tissue index (SATI). Furthermore, after adjustment for confounders, the lower plasma FGF21 levels were remain associated with increased odds for low SATI. CONCLUSIONS: Plasma FGF21 levels were positively associated with FMI, FM%, and SATI in GC patients, suggesting a potential mechanistic link between FGF21 and subcutaneous adipose tissue in GC.

Urolithin A suppresses tumor progression and induces autophagy in gastric cancer via the PI3K/Akt/mTOR pathway.

Urolithin A (UA) is a microbial metabolite of natural polyphenols ellagitannins and ellagic acid with well-established antitumor properties against various malignancies. However, the exact role of UA in gastric cancer (GC) progression remains largely unclear. In the present study, we investigated the effects and potential mechanisms of UA in GC in vitro and in vivo. Our results revealed that UA could suppress GC cell proliferation, inhibit migration and invasion, promote apoptosis, and induce autophagy via the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin pathway in vitro. The autophagy inhibitors 3-methyladenine and chloroquine augmented the inhibitory effect of UA on proliferation and promoted apoptosis, implying that UA mediated the cytoprotective role of autophagy. Meanwhile, the in vivo experiments showed that UA effectively suppressed tumor growth, enhanced the therapeutic effects, and alleviated chemotherapy toxicity in xenograft models. Overall, these findings offer novel insights into the role of UA in tumor therapy and suggest that UA may possess potential therapeutic applications for GC.

Does postoperative chemotherapy improve overall survival of patients with ypT1-2N0 cancer?

BACKGROUND: Perioperative chemotherapy combined with curative gastrectomy has been increasingly represented the standard therapeutic strategy for resectable gastric cancer (GC). However, it is still unclear whether postoperative chemotherapy has a survival benefit for ypT1-2N0 gastric cancer patients who have undergone preoperative chemotherapy followed curative gastrectomy. METHODS: The data of patients who undergone neoadjuvant chemotherapy followed by gastrectomy and had pathological classification of ypT1-2N0 between March 2016 and December 2020 at Peking Union Medical College Hospital were retrospectively reviewed. Chi-square test was adopted to compare the difference between the patients with postoperative chemotherapy (pCHT) and without postoperative chemotherapy (no pCHT). Survival curves for overall survival (OS) were estimated using the Kaplan-Meier method, and the log-rank test was used to compare survival difference. Univariate and multivariate analyses for prognostic factors were based on the Cox regression. RESULTS: A total of 134 patients met the inclusion criteria and 56 (41.8%) of them have undergone postoperative chemotherapy. There were no statistically significant differences in demographic and clinicopathologic characteristics between pCHT group and no pCHT group (all p > 0.05). Postoperative chemotherapy was not associated with a significant improvement in overall survival (OS) (Hazard ratio [HR] 0.815, 95% confidence interval [CI] 0.403-1.650; p = 0.474). Subgroup analyses demonstrated survival was equivalent between pCHT and no CHT group in ypT1N0 patients (HR 0.832, CI 0.222-3.121; p = 0.786) and ypT2N0 patients (HR 1.284, CI 0.564-2.924; p = 0.551). Multivariable analysis identified that clinical T stage independently influenced prognosis (cT3 vs. cT2: HR 2.875, 95% CI 0.998-8.281, p = 0.050; cT4 vs. cT2: HR 7.382, 95% CI 2.569-21.211, p < 0.001). In clinical T3-4 patients, there was an overall survival benefit for postoperative chemotherapy (HR 0.270, 95% CI 0.114-0.634; p = 0.006). No survival benefit of postoperative chemotherapy was identified in clinical T2 patients (HR 0.689, 95% CI 0.200-2.372; p = 0.579). Furthermore, postoperative chemotherapy was proved to be an independently positive prognostic factor for clinical T3-4 patients (HR 0.132, 95% CI 0.051-0.345; p < 0.001). CONCLUSION: Postoperative chemotherapy might offer survival benefit to patients with ypT1-2N0 gastric cancer whose clinical T stage was T3-4 before preoperative chemotherapy.

Visceral Adipose Tissue Assessment Enhances the Prognostic Value of GLIM Criteria in Patients with Gastric Cancer Undergoing Radical Gastrectomy after Neoadjuvant Treatment.

BACKGROUND: The Global Leadership Initiative on Malnutrition (GLIM) criteria has been recently published for diagnosing malnutrition in adults. However, the validity of the GLIM criteria has not been well-established in patients with gastric cancer (GC) treated with neoadjuvant treatment (NT) followed by radical gastrectomy. The present study aimed to explore the prognostic value of GLIM-defined malnutrition before NT and after NT in GC patients and to investigate whether additional visceral adipose tissue (VAT) assessment could improve the predictive power of the GLIM criteria for NT-related adverse events (AEs) and long-term survival. METHODS: GC patients who underwent radical surgery after NT from June 2016 to June 2020 were enrolled in this study. The cross-sectional areas of total skeletal muscle (TSM) and VAT were measured using computed tomography (CT) before NT and after NT. GLIM-defined malnutrition was diagnosed using the two-step approach, including nutritional risk screening and diagnostic assessment. Low VAT was also added to the diagnosis of malnutrition in this study. The predictive value of these malnutrition diagnoses for NT-related AEs, and long-term survival was evaluated in GC patients. RESULTS: A total of 182 GC patients were included in this study, of which 66 (36.3%) patients before NT and 55 (30.2%) patients after NT were diagnosed with GLIM-defined malnutrition, respectively. In addition to GLIM-defined malnutrition, 54 (29.7%) patients had additional low VAT before NT, and 39 (21.4%) patients had additional low VAT after NT. GLIM-defined malnutrition alone before NT was not associated with NT-related AEs in GC patients. The addition of low VAT to GLIM-defined malnutrition led to a significant predictive value for NT-related AEs. Furthermore, GLIM-defined malnutrition before NT and after NT were both identified as independent risk factors for overall survival (OS) and disease-free survival (DFS). The combination of low VAT and GLIM-defined malnutrition showed a higher hazard ratio for the prediction of OS and DFS both before NT and after NT. CONCLUSIONS: The addition of VAT assessment using CT improved the predictive value of GLIM-defined malnutrition for NT-related AEs and long-term survival in GC patients treated with NT followed by radical gastrectomy, which further supports the prognostic importance of assessing adipose tissue simultaneously during the routine nutritional assessment in patients with cancer.

Crosstalk between tumor-associated macrophages and tumor cells promotes chemoresistance via CXCL5/PI3K/AKT/mTOR pathway in gastric cancer.

BACKGROUND: 5-fluorouracil (5-FU)-based chemotherapy regimen has been widely used for the treatment of gastric cancer, but meanwhile the development of chemotherapeutic resistance remains a major clinical challenge. Tumor microenvironment (TME) frequently correlates with the development of chemoresistance in human cancer. As a major component of TME, the role of tumor-associated macrophages (TAMs) in the chemoresistance of gastric cancer has not been fully elucidated. METHODS: Immunohistochemistry (IHC) was applied to detect the density of TAMs in clinical samples of 103 patients with gastric cancer who had undergone 5-FU-based neoadjuvant chemotherapy. 5-FU-resistant gastric cell lines MKN45-R and HGC27-R were established, macrophages were then separately co-cultured with MKN45-R, HGC27-R cells and their parental cells. The effect of gastric cancer cells on the polarization of macrophages, the biological function of M2-polaried macrophages and the mechanism for promoting 5-FU-resistance were investigated. Then the correlation between the expression of CXC motif chemokine ligand 5 (CXCL5) and the infiltration of hemoglobin scavenger receptor (CD163) positive and mannose receptor (CD206) positive macrophages was analyzed, the prognostic value of CXCL5 expression in clinical samples was further explored. RESULTS: The high infiltration of macrophages marked by CD68 in gastric cancer samples was significantly associated with the resistance of gastric cancer to chemotherapy. Gastric cancer cells could modulate macrophages to M2-like polarization through indirect co-culture, and chemoresistant cells were more efficient in inducing macrophages polarization to M2 phenotype. Co-culturing M2-polarized macrophages in turn enhanced 5-FU-resistance of gastric cancer cells, and it was further verified that CXCL5 derived from M2-polarized macrophages promoted chemoresistance through activing the PI3K/AKT/mTOR pathway. Besides, high level of CXCL5 could recruit monocytes to form more M2-polarized macrophages. Clinically, high expression of CXCL5 in gastric cancer samples was associated with the high infiltration of CD163 positive macrophages and CD206 positive macrophages, and patients with high expression of CXCL5 presented lower overall survival (OS) rates than those with low expression of CXCL5. CONCLUSION: Interaction between TAMs and gastric cancer cells promoted chemoresistance in gastric cancer via CXCL5/PI3K/AKT/mTOR pathway. Thus, targeting TAMs and blocking the cell-cell crosstalk between TAMs and gastric cancer cells may represent prospective therapeutic strategies for patients with gastric cancer.

Generation of an mESC model with a human hemophilia B nonsense mutation via CRISPR/Cas9 technology.

BACKGROUND: Hemophilia B is a rare inherited genetic bleeding disorder caused by a deficiency or lack of coagulation factor IX, the gene for which (F9) is located on the X chromosome. Hemophilia B is currently incurable and the standard treatment is coagulation factor replacement therapy. Although gene therapy has the potential to cure hemophilia, significant barriers are still needed to be overcome, e.g., off-target effects and immunoreactivity, so new approaches must be explored. Nonsense mutations account for 8% of all the hemophilia B mutation types and can result in the development of coagulation factor inhibitors. In this study, CRISPR/Cas9 technology was used to construct a mouse embryonic stem cell model with a hemophilia B nonsense mutation (F9 c.223C > T) in humans to investigate the pathogenesis and treatment of nonsense mutations in hemophilia B. METHODS: First, a donor plasmid with a mutation (F9 c.223 C > T) and sgRNAs were constructed. Second, both the donor plasmid and the px330-sgRNA were electroporated into mouse embryonic stem cell, and the mutant cells were then screened using puromycin and red fluorescence. Third, the mutant cell lines were tested for pluripotency and the ability to differentiate into three layers. Finally, the effect of mutation on gene function was studied in the differentiation system. RESULTS: The mutant vector and effective sgRNA were constructed, and the mutant cell line was screened. This mutant cell line exhibited pluripotency and the ability to differentiate into three layers. This point mutation affects F9 expression at both the RNA and protein levels in the differentiation system. CONCLUSIONS: The mutant cell line obtained in the current study had a single-base mutation rather than a base deletion or insertion in the exon, which is more similar to clinical cases. In addition, the mutant has the characteristics of mouse embryonic stem cells, and this point mutation affects F9 gene transcription and translation, which can be used as a disease model for studying the pathogenesis and treatment of hemophilia at the stem cell level.

Progress in neoadjuvant therapy for gastric cancer.

Gastric cancer is one of the most common malignant tumor types in the world and the majority of patients have already reached the advanced stage at the time of initial diagnosis, owing to the subtle symptoms of gastric cancer in the early stage and the low rate of screening in the population. Surgical resection is one of the main treatments for advanced gastric cancer; however, the efficacy of surgery is limited by factors such as low radical resection rate and high distant metastasis rate. A large number of clinical trials have indicated that neoadjuvant therapy (NAT), which consists of neoadjuvant chemotherapy, neoadjuvant chemoradiotherapy and NAT combined with targeted therapy, may improve the therapeutic effect and prognosis of patients to different degrees. However, the benefit of NAT remains controversial due to the heterogeneity of clinical trials and gastric cancer itself. The present review summarizes the main research progress and key breakthrough of NAT for advanced gastric cancer and discusses its prospects.