Janus kinase inhibitor overcomes resistance to immune checkpoint inhibitor treatment in peritoneal dissemination of gastric cancer in C57BL/6 J mice.

BACKGROUND: Cancer immunotherapy aims to unleash the immune system's potential against cancer cells, providing sustained relief for tumors responsive to immune checkpoint inhibitors (ICIs). While promising in gastric cancer (GC) trials, the efficacy of ICIs diminishes in the context of peritoneal dissemination. Our objective is to identify strategies to enhance the impact of ICI treatment specifically for cases involving peritoneal dissemination in GC. METHODS: The therapeutic efficacy of anti-PD1, CTLA4 treatment alone, or in combination was assessed using the YTN16 peritoneal dissemination tumor model. Peritoneum and peritoneal exudate cells were collected for subsequent analysis. Immunohistochemical staining, flow cytometry, and bulk RNA-sequence analyses were conducted to evaluate the tumor microenvironment (TME). A Janus kinase inhibitor (JAKi) was introduced based on the pathway analysis results. RESULTS: Anti-PD1 and anti-CTLA4 combination treatment (dual ICI treatment) demonstrated therapeutic efficacy in certain mice, primarily mediated by CD8 + T cells. However, in mice resistant to dual ICI treatment, even with CD8 + T cell infiltration, most of the T cells exhibited an exhaustion phenotype. Notably, resistant tumors displayed abnormal activation of the Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) pathway compared to the untreated group, with observed infiltration of macrophages, neutrophils, and Tregs in the TME. The concurrent administration of JAKi rescued CD8 + T cells function and reshaped the immunosuppressive TME, resulting in enhanced efficacy of the dual ICI treatment. CONCLUSION: Dual ICI treatment exerts its anti-tumor effects by increasing tumor-specific CD8 + T cell infiltration, and the addition of JAKi further improves ICI resistance by reshaping the immunosuppressive TME.

Polarization-insensitive, shallow Ti-diffused near-stoichiometric LiTaO3 strip waveguide for integrated optics.

We report on a Ti-diffused near-stoichiometric (NS) LiTaO3 strip waveguide fabricated by diffusion of an 8 µm wide, 160 nm thick Ti-strip followed by Li-rich vapor transport equilibration. It is found that the waveguide surface caves in ∼60 nm below the crystal surface. X-ray single-crystal diffraction shows that the indentation is due to Ti-induced lattice contraction. Optical studies show that the waveguide is in an NS composition environment, supports TE and TM single-mode propagation at 1.5 µm wavelength, is polarization insensitive, and has a shallow mode field profile and a loss of 0.2/0.3 dB/cm for the TE/TM mode. Secondary ion mass spectrometry analysis shows that the Ti profile follows a sum of two error functions in the width direction and a Gaussian function in the depth direction of the waveguide. With the optimized fabrication condition, the waveguide is promising for developing an optical-damage-resistant device that requires a shallow mode field profile.

The antibacterial activity and mechanisms of Trp-containing peptides against multidrug-resistant Pseudomonas aeruginosa persisters.

Bacterial persisters avoid antibiotic-mediated death by entering a dormant state and are considered a major cause of antibiotic treatment failure. Antimicrobial peptides (AMPs) with membrane-disrupting activity are promising drugs to eradicate persister cells. In this study, carbonyl cyanide m-chlorophenylhydrazone (CCCP), ciprofloxacin (CIP), and rifampicin (RFP) were applied to induce the formation of multidrug-resistant Pseudomonas aeruginosa (MRPA0108) persisters, and the antibacterial activity and mechanisms of I1W and L12W (two Trp-containing peptides designed in our lab) against MRPA0108 persisters were investigated. The results showed that I1W and L12W displayed potent antibacterial activity against MRPA0108 persisters. Both Trp-containing peptides disturbed the inner and outer membrane of MRPA0108 persisters. In addition, I1W and L12W revealed novel antibacterial mechanisms by decreasing the enzymatic activities of superoxide dismutase (SOD) and catalase (CAT), increasing reactive oxygen species (ROS) and malondialdehyde (MDA) levels, consequently leading to oxidative stress. The transcriptome profile of I1W-treated MRPA0108 persisters revealed that the genes involved in carbon metabolism, biosynthesis of amino acids, and the TCA cycle were downregulated, indicating that I1W interfered with metabolism and energy synthesis processes. Furthermore, both Trp-containing peptides displayed synergistic activities with antibiotic tobramycin and showed additive activities with cefepime or ciprofloxacin, which revealed a potential therapeutic strategy for the eradication of MRPA0108 persisters.

Remediation of diesel contaminated soil by using activated persulfate with Fe3O4 magnetic nanoparticles: effect and mechanisms.

In this study, Fe3O4 magnetic nanoparticles (Fe3O4 MNPs) were assessed for their ability to enhance the activity of persulfate (PS). Various controlling factors including PS dosages, initial pH, water-soil ratio, ratio of Fe2+, and Fe3O4 MNPs to PS were considered in both the Fe2+/PS system and the Fe3O4 MNPs/PS system. Results showed that the Fe3O4 MNP-activated PS system exhibited high processing efficiency owing to the gradual release of Fe2+. This process occurred in a wide pH range (5-11), attributed to the synergistic action of sulfate radicals (SO4-·) and hydroxyl radicals (OH·) under alkaline conditions, effectively mitigating soil acidification. The ratio of Fe3O4 MNPs to PS and water-soil ratio significantly influenced the degradation rate with the highest petroleum hydrocarbon degradation rate exceeding 80% (82.31%). This rate was 3.1% higher than that achieved by the Fe2+/PS system under specific conditions: PS dosage of 0.05 mol/L, Fe3O4 MNPs to PS ratio of 1:10, water-soil ratio of 2:1, and initial pH of 11. Meanwhile, oxidant consumption in the Fe3O4 MNPs/PS system was halved compared to the Fe2+/PS system due to the slow release of Fe2+ and less ineffective consumption of SO4-·. Mechanistically, the possible degradation process was divided into three parts: the initial chain reaction, the proliferating chain reaction, and the terminating chain reaction. The introduction of Fe3O4 MNPs accelerated the degradation rate of pentadecane, heneicosane, eicosane, tritetracontane, and 9-methylnonadecane.

Differences in Physiological Characteristics, Seed Germination, and Seedling Establishment in Response to Salt Stress between Dimorphic Seeds in the Halophyte Suaeda liaotungensis.

Soil salinization is an increasing agricultural problem around the world, affecting crop productivity and quality. Seed germination and seedling establishment are susceptible to salt stress. Suaeda liaotungensis is a halophyte with strong salt tolerance that produces dimorphic seeds to adapt to the saline environment. Differences in physiological characteristics, seed germination, and seedling establishment in response to salt stress between dimorphic seeds in S. liaotungensis have not been reported. The results showed that brown seeds had significantly higher H2O2 and O2-. levels and betaine content, as well as POD and CAT activities, while they had significantly lower MDA and proline contents and SOD activity than black seeds. Light promoted the germination of brown seeds in a certain temperature range, and brown seeds could reach a higher germination percentage in a wide temperature range. However, light and temperature had no effect on the germination percentage of black seeds. Brown seeds had higher germination than black seeds under the same NaCl concentration. The final germination of brown seeds was significantly decreased as salt concentration increased, whereas this had no effect on the final germination of black seeds. POD and CAT activities, as well as MDA content, in brown seeds were significantly higher than those in black seeds during germination under salt stress. Additionally, the seedlings from brown seeds were more tolerant to salinity than those from black seeds. Therefore, these results will give an in-depth understanding of the adaptation strategies of dimorphic seeds to a salinization environment, and better exploitation and utilization of S. liaotungensis.

Association between hospital surgical case volume and postoperative mortality in patients undergoing gastrectomy for gastric cancer: a systematic review and meta-analysis.

BACKGROUND: Postoperative mortality is an important indicator for evaluating surgical safety. Postoperative mortality is influenced by hospital volume; however, this association is not fully understood. This study aimed to investigate the volume-outcome association between the hospital surgical case volume for gastrectomies per year (hospital volume) and the risk of postoperative mortality in patients undergoing a gastrectomy for gastric cancer. METHODS: Studies assessing the association between hospital volume and the postoperative mortality in patients who underwent gastrectomy for gastric cancer were searched for eligibility. Odds ratios were pooled for the highest versus lowest categories of hospital volume using a random-effects model. The volume-outcome association between hospital volume and the risk of postoperative mortality was analyzed. The study protocol was registered with Prospective Register of Systematic Reviews (PROSPERO). RESULTS: Thirty studies including 586 993 participants were included. The risk of postgastrectomy mortality in patients with gastric cancer was 35% lower in hospitals with higher surgical case volumes than in their lower-volume counterparts (odds ratio: 0.65; 95% CI: 0.56-0.76; P <0.001). This relationship was consistent and robust in most subgroup analyses. Volume-outcome analysis found that the postgastrectomy mortality rate remained stable or was reduced after the hospital volume reached a plateau of 100 gastrectomy cases per year. CONCLUSIONS: The current findings suggest that a higher-volume hospital can reduce the risk of postgastrectomy mortality in patients with gastric cancer, and that greater than or equal to 100 gastrectomies for gastric cancer per year may be defined as a high hospital surgical case volume.

Identification and initial validation of maximal tumor area as a novel prognostic factor for overall and disease-free survival in patients with resectable colon cancer: a retrospective study.

BACKGROUND: The tumor area may be a potential prognostic indicator. The present study aimed to determine and validate the prognostic value of tumor area in curable colon cancer. METHODS: This retrospective study included a training and validation cohorts of patients who underwent radical surgery for colon cancer. Independent prognostic factors for overall survival (OS) and disease-free survival (DFS) were identified using Cox proportional hazards regression models. The prognostic discrimination was evaluated using the integrated area under the receiver operating characteristic curves (iAUCs) for prognostic factors and models. The prognostic discrimination between tumor area and other individual factors was compared, along with the prognostic discrimination between the tumor-node-metastasis (TNM) staging system and other prognostic models. Two-sample Wilcoxon tests were carried out to identify significant differences between the two iAUCs. A two-sided P <0.05 was considered statistically significant. RESULTS: A total of 3051 colon cancer patients were included in the training cohort and 872 patients in the validation cohort. Tumor area, age, differentiation, T stage, and N stage were independent prognostic factors for both OS and DFS in the training cohort. Tumor area had a better OS and DFS prognostic discrimination characteristics than T stage, maximal tumor diameter, differentiation, tumor location, and number of retrieved lymph nodes. The novel prognostic model of T stage + N stage + tumor area (iAUC for OS, 0.714, P <0.001; iAUC for DFS, 0.694, P <0.001) showed a better prognostic discrimination than the TNM staging system (T stage + N stage; iAUC for OS, 0.664; iAUC for DFS, 0.658). Similar results were observed in an independent validation cohort. CONCLUSIONS: Tumor area was identified as an independent prognostic factor for both OS and DFS in curable colon cancer patients, and in cases with an adequate number of retrieved lymph nodes. The novel prognostic model of combining T stage, N stage, and tumor area may be an alternative to the current TNM staging system.

Global, Regional, and National Burdens with Temporal Trends of Early-, Intermediate-, and Later-Onset Gastric Cancer from 1990 to 2019 and Predictions up to 2035.

BACKGROUND: Evidence for estimating and predicting the temporal trends of gastric cancer in different age groups is lacking. METHODS: Data of early-, intermediate-, and later-onset gastric cancer (EOGC, IOGC, LOGC) was from the Global Burden of Diseases Study 2019. The incidences and deaths due to EOGC, IOGC, and LOGC were analyzed by period, sex, geographic location, and sociodemographic incidence. Temporal trends were evaluated by estimated annual percentage changes (EAPCs). The incidences and temporal trends were predicted until 2035. RESULTS: There were substantial differences in the incidence and death rates of the three populations at global, regional and national levels in 2019. From 1990 to 2019, EOGC (EAPC, -0.84) showed a slower decrease in incidence rate worldwide than IOGC (EAPC, -1.77) and LOGC (EAPC, -1.10), whereas EOGC and LOGC showed slower decreases in mortality than IOGC. The worldwide incidence rate of EOGC (EAPC, 1.44) was predicted to increase substantially from 2020 to 2035, while that for LOGC (EAPC, 0.43) was predicted to increase slightly and that for IOGC (EAPC, -0.01) was predicted to remain stable over the same period. CONCLUSIONS: This study revealed differences in the burdens and temporal trends of EOGC, IOGC, and LOGC, and highlighted the importance of tailored cancer-control measures in neglected subpopulations, especially in patients with EOGC.

Trp-Containing Antibacterial Peptides Impair Quorum Sensing and Biofilm Development in Multidrug-Resistant Pseudomonas aeruginosa and Exhibit Synergistic Effects With Antibiotics.

Pseudomonas aeruginosa uses quorum sensing (QS) to control virulence, biofilm formation and antibiotic efflux pump expression. The development of effective small molecules targeting the QS system and biofilm formation represents a novel attractive strategy. In this present study, the effects of a series of Trp-containing peptides on the QS-regulated virulence and biofilm development of multidrug-resistant P. aeruginosa, as well as their synergistic antibacterial activity with three classes of traditional chemical antibiotics were investigated. The results showed that Trp-containing peptides at low concentrations reduced the production of QS-regulated virulence factors by downregulating the gene expression of both the las and rhl systems in the strain MRPA0108. Biofilm formation was inhibited in a concentration-dependent manner, which was associated with extracellular polysaccharide production inhibition by downregulating pelA, algD, and pslA transcription. These changes correlated with alterations in the extracellular production of pseudomonal virulence factors and swarming motility. In addition, the combination of Trp-containing peptides at low concentration with the antibiotics ceftazidime and piperacillin provided synergistic effects. Notably, L11W and L12W showed the highest synergy with ceftazidime and piperacillin. A mechanistic study demonstrated that the Trp-containing peptides, especially L12W, significantly decreased ß-lactamase activity and expression of efflux pump genes OprM, MexX, and MexA, resulting in a reduction in antibiotic efflux from MRPA0108 cells and thus increasing the antibacterial activity of these antibiotics against MRPA0108.

Signaling Responses to N Starvation: Focusing on Wheat and Filling the Putative Gaps With Findings Obtained in Other Plants. A Review.

Wheat is one of the most important food crops worldwide. In recent decades, fertilizers, especially nitrogen (N), have been increasingly utilized to maximize wheat productivity. However, a large proportion of N is not used by plants and is in fact lost into the environment and causes serious environmental pollution. Therefore, achieving a low N optimum via efficient physiological and biochemical processes in wheat grown under low-N conditions is highly important for agricultural sustainability. Although N stress-related N capture in wheat has become a heavily researched subject, how this plant adapts and responds to N starvation has not been fully elucidated. This review summarizes the current knowledge on the signaling mechanisms activated in wheat plants in response to N starvation. Furthermore, we filled the putative gaps on this subject with findings obtained in other plants, primarily rice, maize, and Arabidopsis. Phytohormones have been determined to play essential roles in sensing environmental N starvation and transducing this signal into an adjustment of N transporters and phenotypic adaptation. The critical roles played by protein kinases and critical kinases and phosphatases, such as MAPK and PP2C, as well as the multifaceted functions of transcription factors, such as NF-Y, MYB, DOF, and WRKY, in regulating the expression levels of their target genes (proteins) for low-N tolerance are also discussed. Optimization of root system architecture (RSA) via root branching and thinning, improvement of N acquisition and assimilation, and fine-tuned autophagy are pivotal strategies by which plants respond to N starvation. In light of these findings, we attempted to construct regulatory networks for RSA modification and N uptake, transport, assimilation, and remobilization.

Low-power-consumption CMOS inverter array based on CVD-grown p-MoTe2 and n-MoS2.

Two-dimensional (2D) semi-conductive transition metal dichalcogenides (TMDCs) have shown advantages for logic application. Complementary metal-oxide-semiconductor (CMOS) inverter is an important component in integrated circuits in view of low power consumption. So far, the performance of the reported TMDCs-based CMOS inverters is not satisfactory. Besides, most of the inverters were made of mechanically exfoliated materials, which hinders their reproducible production and large-scale integration in practical application. In this study, we demonstrate a practical approach to fabricate CMOS inverter arrays using large-area p-MoTe2 and n-MoS2, which are grown via chemical vapor deposition method. The current characteristics of the channel materials are balanced by atomic layer depositing Al2O3. Complete logic swing and clear dynamic switching behavior are observed in the inverters. Especially, ultra-low power consumption of ∼0.37 nW is achieved. Our work paves the way for the application of 2D TMDCs materials in large-scale low-power-consumption logic circuits.

Nitrate alleviates ammonium toxicity in wheat (Triticum aestivum L.) by regulating tricarboxylic acid cycle and reducing rhizospheric acidification and oxidative damage.

Ammonium (NH4+) is one of the most important nutrients required by plants. However, a high concentration of NH4+ as the sole nitrogen source suppresses plant growth. Although nitrate (NO3-) can alleviate NH4+ toxicity, the mechanisms underlying this ability have not been fully elucidated. In this study, wheat plants were cultivated in hydroponic solution with 7.5 mM NO3- (control), 7.5 mM NH4+ (sole ammonium, SA) or 7.5 mM NH4+ plus 1.0 mM NO3- (ammonium and nitrate, AN). The results showed that compared with the control, the SA treatment significantly decreased root growth, protein content and the concentrations of most intermediates and the activity of enzymes from the tricarboxylic acid (TCA) cycle. Moreover, increased the activity of plasma membrane H+-ATPase and the rate of H+ efflux along roots, caused solution acidification, and increased the activity of mitochondrial respiratory chain complexes I-IV and the contents of protein-bound carbonyls and malondialdehyde in roots. SA treatment induced ultrastructure disruption and reduced the viability of root cells. Compared with the SA treatment, the AN treatment increased root growth, protein content, the concentrations of most intermediates and the activity of enzymes from the TCA cycle. Furthermore, AN treatment decreased the rate of H+ efflux, retarded medium acidification, decreased protein carbonylation and lipid peroxidation in roots and relieved ultrastructure disruption and increased the viability of root cells. Taken together, these results indicate that NO3--dependent alleviation of NH4+ toxicity in wheat seedlings is closely associated with physiological processes that mediate TCA cycle, relieve rhizospheric acidification and decrease the production of ROS and oxidative damage.

p-MoS2/n-InSe van der Waals heterojunctions and their applications in all-2D optoelectronic devices.

A library of two-dimensional (2D) semiconductors with different band gaps offers the construction of van der Waals (vdWs) heterostructures with different band alignments, providing a new platform for developing high-performance optoelectronic devices. Here, we demonstrate all-2D optoelectronic devices based on type-II p-MoS2/n-InSe vdWs heterojunctions operating at the near infrared (NIR) wavelength range. The p-n heterojunction diode exhibits a rectification ratio of ∼102 at V ds = ±2 V and a turn-on voltage of ∼0.8 V. Under a forward bias exceeding the turn-on voltage and a proper positive back-gate voltage, the all-2D vdWs heterojunction diode exhibits an electroluminescence with an emission peak centered at ∼1020 nm. Besides, this p-MoS2/n-InSe heterojunction shows a photoresponse at zero external bias, indicating that it can serve as a photodiode working without an external power supply. The as-demonstrated all-2D vdWs heterojunction which can work as both a light-emitting diode and a self-powered photodetector may find applications in flexible wear, display, and optical communication fields, etc.

Experimental and clinical study of influence of high-frequency electric surgical knives on healing of abdominal incision.

AIM: To study the influence of high-frequency electric surgical knives on healing of abdominal incision. METHODS: Two hundred and forty white rats were divided into 10(0), 10(2), 10(5), and 10(8) groups and rat models of abdominal operation were induced by using electric surgical knives and common lancets respectively. Then they were respectively given hypodermic injections of normal saline and 0.2 mL quantitative mixture of Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa at a concentration of 10(2), 10(5) and 10(8). On the basis of the animal experiment, 220 patients undergoing abdominal operations (above type II) were randomly allocated into one of following three groups: electric knife (EK, 93 cases), electro-coagulation (EC, 55 cases) and control (72 cases). High-frequency electric surgical knives were used to dissect abdominal tissues and electro-coagulation for hemostasis in EK group. Common lancets and electro-coagulation were applied in EC group. Common lancets and tying silk suture were used in the controls. RESULTS: In all the groups except group 10(0), infection rate of incisional wounds made by electric surgical knives were remarkably higher than that with common lancets. Furthermore, there were significant differences in groups 10(2), 10(5), and 10(8) (P<0.05), but not in group 10(0) (P>0.05) between EK and EC groups. Clinical studies showed a delayed wound healing in 16 cases (17.20%) in EK, 11 cases (16.36%) in EC and 2 cases (2.86%) in the control groups. A significant difference between EK and the control groups (chi2 = 8.57, P<0.01), and between EC and the control groups (chi2 = 5.66, P<0.05) was observed, but not between EK and EC (chi2 = 0.017, P>0.05). CONCLUSION: High-frequency electric knives may remarkably delay abdominal incision healing. Its application should be minimized so as to reduce the possibility of postoperative complications.

Note: Electro-optic coefficients of Li-deficient MgO-doped LiNbO3 crystal.

A number of Li-deficient MgO-doped LiNbO3 (LN) crystals with different Li2O contents ranging from 43.4 mol. % to 44.5 mol. % were prepared by carrying out the Li-poor vapor transport equilibration treatment on 5 mol. % (in growth melt) MgO-doped LN crystals. Unclamped electro-optic (EO) coefficients γ13 and γ33 of these crystals were measured by Mach-Zehnder interferometry. The results show that γ13 (γ33) increases linearly by ∼14% (11%) as the Li2O content decreases from 44.5 mol. % of the as-grown state to 43.4 mol. % of the Li-deficient state. This feature is desired for the EO application of the Li-deficient MgO:LN crystal.

[Influence of high-frequency electric surgical knife on healing of abdominal incision, experimental and clinical studies].

OBJECTIVE: To study the influence of high-frequency electric surgical knife on abdominal incision healing. METHODS: Two hundred and forty Wistar rats were randomly divided into two groups of 120 rats to undergo abdominal incision by high-frequency electric knife or common lancet respectively. Each of these two groups was redivided into four subgroups that were injected hypodermically with 0.2 ml of quantitative mixture of Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa at the concentrations of 0.24 x 10(2) bacteria (10(2) group), 4.49 x 10(4) bacteria (10(5) group), and 4.11 x 10(7) bacteria (10(8) group) respectively, and normal saline of the same volume (10(0) group). Eight days after the operation, the rats were killed. The infection rate of the operational wound was observed and the tissues around the wounds were examined pathologically. On the basis of the animal experiment, 220 patients undergoing abdominal operation above type II were randomly allocated into one of following three groups: high-frequency electric knife (EK) group (93 cases, high-frequency electric knife was used to cut the abdominal tissues and electro-coagulation was used for hemostasis), electro-coagulation (EC) group (55 cases, the abdominal tissues were cut with common lancet and electro-coagulation was used for hemostasis) and control group (72 cases, common lancet and silk thread suture were used). The healing of wound was observed after operation. RESULTS: Four rats died of anesthetic accident; the other 236 rats were killed 8 days after. The wound infection rates were 23.33% and 6.60% in the experimental 10(0) group and the control 10(0) group respectively (chi(2) = 3.28, P > 0.05); 37.04% and 13.33% in the experimental 10(2) group and the control 10(2) group respectively (chi(2) = 4.31, P > 0.05), 50.00% and 24.14% in the experimental 10(5) group and the control 10(5) group respectively (chi(2) = 4.22, P > 0.05); and 63.33% and 36.67% in the experimental 10(8) group and the control 10(8) group respectively (chi(2) = 4.27, P > 0.05). Clinical observation showed a delayed wound healing rate of 17.20% (16 cases) in EK group, 16.36% (11 cases) in EC group, and 2.86% (2 cases) in the control group. There was a statistically significant difference in delayed wound healing rate between the EK and control groups (chi(2) = 8.57, P < 0.01) and between the EC and control groups (chi(2) = 5.66, P < 0.05). However, no significant difference in the delayed wound healing rate was seen between the EK and EC groups (chi(2) = 0.017, P > 0.05). CONCLUSION: High-frequency electric knife remarkably delays the healing of abdominal incision. Its application should be minimized so as to reduce the possibility of postoperative complications.