(-)-Epicatechin ameliorates type 2 diabetes mellitus by reshaping the gut microbiota and Gut-Liver axis in GK rats.

As one of the most abundant plant polyphenols in the human diet, (-)-epicatechin (EC) can improve insulin sensitivity and regulate glucose homeostasis. However, the primary mechanisms involved in EC anti-T2DM benefits remain unclear. The present study explored the effects of EC on the gut microbiota and liver transcriptome in type 2 diabetes mellitus (T2DM) Goto-Kakizaki rats for the first time. The findings showed that EC protected glucose homeostasis, alleviated systemic oxidative stress, relieved liver damage, and increased serum insulin. Further investigation showed that EC reshaped gut microbiota structure, including inhibiting the proliferation of lipopolysaccharide (LPS)-producing bacteria and reducing serum LPS. In addition, transcriptome analysis revealed that the insulin signaling pathway may be the core pathway of the EC anti-T2DM effect. Therefore, EC may modulate the gut microbiota and liver insulin signaling pathways by the gut-liver axis to alleviate T2DM. As a diet supplement, EC has promising potential in T2DM prevention and treatment.

Effects of positive end-expiratory pressure on regional cerebral oxygen saturation in elderly patients undergoing thoracic surgery during one-lung ventilation: a randomized crossover-controlled trial.

BACKGROUND: A significant reduction in regional cerebral oxygen saturation (rSO2) is commonly observed during one-lung ventilation (OLV), while positive end-expiratory pressure (PEEP) can improve oxygenation. We compared the effects of three different PEEP levels on rSO2, pulmonary oxygenation, and hemodynamics during OLV. METHODS: Forty-three elderly patients who underwent thoracoscopic lobectomy were randomly assigned to one of six PEEP combinations which used a crossover design of 3 levels of PEEP-0 cmH2O, 5 cmH2O, and 10 cmH2O. The primary endpoint was rSO2 in patients receiving OLV 20 min after adjusting the PEEP. The secondary outcomes included hemodynamic and respiratory variables. RESULTS: After exclusion, thirty-six patients (36.11% female; age range: 60-76 year) were assigned to six groups (n = 6 in each group). The rSO2 was highest at OLV(0) than at OLV(10) (difference, 2.889%; [95% CI, 0.573 to 5.204%]; p = 0.008). Arterial oxygen partial pressure (PaO2) was lowest at OLV(0) compared with OLV(5) (difference, -62.639 mmHg; [95% CI, -106.170 to -19.108 mmHg]; p = 0.005) or OLV(10) (difference, -73.389 mmHg; [95% CI, -117.852 to -28.925 mmHg]; p = 0.001), while peak airway pressure (Ppeak) was lower at OLV(0) (difference, -4.222 mmHg; [95% CI, -5.140 to -3.304 mmHg]; p < 0.001) and OLV(5) (difference, -3.139 mmHg; [95% CI, -4.110 to -2.167 mmHg]; p < 0.001) than at OLV(10). CONCLUSIONS: PEEP with 10 cmH2O makes rSO2 decrease compared with 0 cmH2O. Applying PEEP with 5 cmH2O during OLV in elderly patients can improve oxygenation and maintain high rSO2 levels, without significantly increasing peak airway pressure compared to not using PEEP. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2200060112 on 19 May 2022.

Effect of Perineural or Intravenous Betamethasone on Femoral Nerve Block Outcomes in Knee Arthroplasty: A Randomized, Controlled Study.

OBJECTIVES: Despite the use of multimodal analgesia, patients undergoing knee arthroplasty still encounter residual moderate pain. The addition of betamethasone to local anesthetic has been shown to improve postoperative pain. However, it remains uncertain whether the positive effects of perineural or intravenous administration of betamethasone on analgesia outcomes lead to better early mobility and postoperative recovery. METHODS: Between June 2022 and February 2023, a total of 159 patients who were undergoing knee arthroplasty were included in this study. These patients were allocated randomly into three groups: (i) the NS group, received ropivacaine 0.375% and intravenous 3mL 0.9% normal saline; (ii) the PNB group, received ropivacaine 0.375% plus perineural betamethasone (12mg) 3mL and intravenous 3mL 0.9% normal saline; and (iii) the IVB group, received ropivacaine 0.375% and intravenous betamethasone (12mg) 3mL. RESULTS: Both perineural and intravenous administration of betamethasone led to improved median (IQR) numeric rating scale (NRS) scores on the 6-meter walk test, with a score of 1.0 (1.0-2.0) for both groups, compared with 2.0 (1.0-2.0) for the NS group (p = 0.003). Compared to the NS group, both the PNB and IVB groups showed significant reductions in NRS scores at 24 and 36 h after surgery, along with a significant increase in ROM at 24, 36, and 48 h post-operation. Additionally, it exhibited lower levels of cytokine IL-1ß and TNF-α in fluid samples, as well as lower level of HS-CRP in blood samples in the PNB and IVB groups compared to the NS group. CONCLUSION: The administration of perineural and intravenous betamethasone demonstrated an enhanced analgesic effect following knee arthroplasty. Furthermore, it was associated with reduced levels of IL-1ß, TNF-α, and HS-CRP, as well as enhanced knee ROM, which is conducive to early ambulation and postoperative rehabilitation after knee arthroplasty.

Exposure risk to rural Residents: Insights into particulate and gas phase pesticides in the Indoor-Outdoor nexus.

Rural residents are exposed to both particulate and gaseous pesticides in the indoor-outdoor nexus in their daily routine. However, previous personal exposure assessment mostly focuses on single aspects of the exposure, such as indoor or gaseous exposure, leading to severe cognition bias to evaluate the exposure risks. In this study, residential dust and silicone wristbands (including stationary and personal wearing ones) were used to screen pesticides in different phases and unfold the hidden characteristics of personal exposure via indoor-outdoor nexus in intensive agricultural area. Mento-Carlo Simulation was performed to assess the probabilistic exposure risk by transforming adsorbed pesticides from wristbands into air concentration, which explores a new approach to integrate particulate (dust) and gaseous (silicone wristbands) pesticide exposures in indoor and outdoor environment. The results showed that particulate pesticides were more concentrated in indoor, whereas significantly higher concentrations were detected in stationary outdoor wristbands (p < 0.05). Carbendazim and chlorpyrifos were the most frequently detected pesticides in dust and stationary wristbands. Higher pesticide concentration was found in personal wristbands worn by farmers, with the maximum value of 2048 ng g-1 for difenoconazole. Based on the probabilistic risk assessment, around 7.1 % of farmers and 2.6 % of bystanders in local populations were potentially suffering from chronic health issues. One third of pesticide exposures originated mainly from occupational sources while the rest derived from remoting dissipation. Unexpectedly, 43 % of bystanders suffered the same levels of exposure as farmers under the co-existence of occupational and non-occupational exposures. Differed compositions of pesticides were found between environmental samples and personal pesticide exposure patterns, highlighting the need for holistic personal exposure measurements.

Preparation of healing-promoting and fibrosis-inhibiting asymmetric poly(ethylene glycol-b-L-phenylalanine)/cRGD-modified hyaluronate sponges and their applications in hemorrhage and nasal mucosa repair.

Acute or chromic bleeding, such as epistaxis, requires hemostatic materials to assist hemostasis. Even in complex cases, hemostatic materials must have other functions, including the promotion of healing and prevention of adhesion. Herein, a series of fibrosis-suppressive functional cRGD-modified crosslinking hyaluronic acid sponges were prepared. The in vitro hemostatic efficiency and mechanism were determined using blood clotting time, blood coagulation index, lactate dehydrogenase (LDH) and thromboxane B2 (TX-B2) ELISA, and proteomics. Among the prepared sponges, both poly(ethylene-b-L-Phe) (PEBP)-and cRGD contained SPN4 and exhibited the highest platelet concentration and activation efficiency as well as the most effective coagulative effect. In addition, no significant cytotoxicity was observed for the sponges in rat airway epithelial cells. The in vivo hemostatic and adhesion-preventive effects of the sponges were evaluated using rat models of liver injury and sidewall defect-cecum abrasion. PEBP-containing sponges effectively prevented postoperative adhesion and cRGD-modified sponges exhibited excellent hemostatic effects. Finally, the comprehensive repair effects of the sponges were evaluated using a rabbit maxillary sinus mucosal injury model, based on CT, MRI examination, and pathological staining. SPN4 exhibited the best comprehensive reparative effects, including the promotion of mucosal repair and infection inhibition. Thus, SPN4 is a promising multifunctional hemostatic material.

Optimal postoperative delirium prediction after coronary artery bypass grafting surgery: a prospective cohort study.

Background: Postoperative delirium (POD) presents as a serious neuropsychiatric syndrome in patients undergoing off-pump coronary artery bypass grafting (OPCABG) surgery. This is correlated with higher mortality, cognitive decline, and increased costs. The Age-adjusted Charlson Comorbidity Index (ACCI) is recognized as an independent predictor for mortality and survival rate. The purpose of our study is to estimate the predictive value of the ACCI on the POD in patients undergoing OPCABG surgery. Methods: This prospective cohort study enrolled patients undergoing OPCABG surgery between December 2020 and May 2021 in Qilu Hospital. Patients were divided into the low-ACCI group (score, 0-3) and the high-ACCI group (score ≥4) according to their ACCI scores. The Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) and CAM were used to diagnose POD within 7 days after surgery. The general, laboratory, and clinical data of the patients were recorded and collected. The characteristic ROC curve was applied to further assess the predictive value of the ACCI for POD in patients following OPCABG surgery. Results: A total of 89 patients were enrolled, including 45 patients in the low-ACCI group and 44 patients in the high-ACCI group. The incidence of POD was higher in the high-ACCI group than in the low-ACCI group (45.5% vs. 15.6%, P = 0.003). Multivariate logistic regression analyses showed that the ACCI (OR, 2.433; 95% CI, 1.468-4.032; P = 0.001) was an independent risk factor for POD. The ACCI accurately predicted POD in patients following OPCABG surgery with an AUC of 0.738, and the Hosmer-Lemeshow goodness of fit test yielded X2 = 5.391 (P = 0.145). Conclusion: The high-ACCI group showed a high incidence of POD. The ACCI was an independent factor associated with POD in patients following OPCABG surgery. In addition, the ACCI could accurately predict POD in patients following OPCABG surgery. Clinical Trial Registration: ClinicalTrials.gov, identifier CHiCTR2100052811.

Nanobody-based trispecific T cell engager (Nb-TriTE) enhances therapeutic efficacy by overcoming tumor-mediated immunosuppression.

BACKGROUND: T cell engagers (TCEs) have been established as an emerging modality for hematologic malignancies, but solid tumors remain refractory. However, the upregulation of programmed cell death 1 (PD-1) is correlated with T cell dysfunction that confer tumor-mediated immunosuppression. Developing a novel nanobody-based trispecific T cell engager (Nb-TriTE) would be a potential strategy to improve therapeutic efficacy. METHODS: Given the therapeutic potential of nanobodies (Nbs), we first screened Nb targeting fibroblast activation protein (FAP) and successfully generated a Nb-based bispecific T cell engager (Nb-BiTE) targeting FAP. Then, we developed a Nb-TriTE by fusing an anti-PD-1 Nb to the Nb-BiTE. The biological activity and antitumor efficacy of the Nb-TriTE were evaluated in vitro and in both cell line-derived and patient-derived xenograft mouse models. RESULTS: We had for the first time successfully selected a FAP Nb for the generation of novel Nb-BiTE and Nb-TriTE, which showed good binding ability to their targets. Nb-TriTE not only induced robust tumor antigen-specific killing, potent T cell activation and enhanced T cell function in vitro, but also suppressed tumor growth, improved survival and mediated more T cell infiltration than Nb-BiTE in mouse models of different solid tumors without toxicity. CONCLUSIONS: This novel Nb-TriTE provides a promising and universal platform to overcome tumor-mediated immunosuppression and improve patient outcomes in the future.

XPOT Disruption Suppresses TNBC Growth through Inhibition of Specific tRNA Nuclear Exportation and TTC19 Expression to Induce Cytokinesis Failure.

Transfer RNAs (tRNAs) impact the development and progression of various cancers, but how individual tRNAs are modulated during triple-negative breast cancer (TNBC) progression remains poorly understood. Here, we found that XPOT (Exportin-T), a nuclear export protein receptor of tRNAs, is associated with poor prognosis in breast cancer and directly orchestrates the nuclear export of a subset of tRNAs, subsequently promoting protein synthesis and proliferation of human TNBC cells. XPOT knockdown inhibited TNBC cell proliferation in vitro, and RNA-seq indicated that XPOT is involved in the completion of cytokinesis in TNBC cells. High-throughput sequencing of tRNA revealed that XPOT specifically influenced a subset of tRNA isodecoders involved in nucleocytoplasmic trafficking, including tRNA-Ala-AGC-10-1. Through codon preferential analysis and protein mass spectrometry, we found that XPOT preferentially transported nuclear tRNA-Ala-AGC-10-1 to the cytoplasm, driving the translation of TPR Repeat Protein 19 (TTC19). TTC19 is also indispensable for cytokinesis and proliferation of TNBC cells. Altogether, these findings provide a novel regulatory translation mechanism for preferential tRNA isodecoder nucleocytoplasmic transport through XPOT, which coordinates the spatial location of specific tRNA and the translation of mRNA to facilitate TNBC proliferation and progression. Targeting XPOT may be a novel therapeutic strategy for treating TNBC.

TRPV4 enhances the synthesis of fatty acids to drive the progression of ovarian cancer through the calcium-mTORC1/SREBP1 signaling pathway.

Transient receptor potential vanilloid 4 (TRPV4) is a nonselective cation channel activated by various stimuli, such as heat. A recent study reported that high expression of TRPV4 predicted a poor prognosis in ovarian cancer patients. This study demonstrated that TRPV4 was highly expressed in ovarian cancer and had the ability to promote proliferation and migration. Through RNA-seq and related experiments, we confirmed that the oncogenic pathway of TRPV4 in ovarian cancer may be related to the fatty acid synthesis. By correlation analysis and RNA-seq, we demonstrated that SREBP1 and mTORC1 were inseparably related to that. Therefore, we used inhibitors to perform experiments. Calcium fluorescent probe experiments suggest that the change of calcium content in ovarian cancer cells was related to the downstream mTORC1 signaling pathway and fatty acid synthesis. These results confirmed that TRPV4 affected the fatty acid synthesis through the calcium-mTOR/SREBP1 signaling pathway, thereby promoting ovarian cancer progression.

Effects of Microplastics on the Transport of Soil Dissolved Organic Matter in the Loess Plateau of China.

Microplastics (MPs) pollution and dissolved organic matter (DOM) affect soil quality and functions. However, the effect of MPs on DOM and underlying mechanisms have not been clarified, which poses a challenge to maintaining soil health. Under environmentally relevant conditions, we evaluated the major role of polypropylene particles at four micron-level sizes (20, 200, and 500 µm and mixed) in regulating changes in soil DOM content. We found that an increase in soil aeration by medium and high-intensity (>0.5%) MPs may reduce NH4+ leaching by accelerating soil nitrification. However, MPs have a positive effect on soil nutrient retention through the adsorption of PO43- (13.30-34.46%) and NH4+ (9.03-19.65%) and their leached dissolved organic carbon (MP-leached dissolved organic carbon, MP-DOC), thereby maintaining the dynamic balance of soil nutrients. The regulating ion (Ca2+) is also an important competitor in the MP-DOM adsorption system, and changes in its intensity are dynamically involved in the adsorption process. These findings can help predict the response of soil processes, especially nutrient cycling, to persistent anthropogenic stressors, improve risk management policies on MPs, and facilitate the protection of soil health and function, especially in future agricultural contexts.

A dendritic/tumor fusion cell vaccine enhances efficacy of nanobody-based CAR-T cells against solid tumor.

Background: Chimeric antigen receptor (CAR) T-cell therapy is practical in treating cancers of hematopoietic origin, but of that in solid tumors compromises efficacy for the loss of the antigen recognized by the CAR. However, dendritic cell (DC)/tumor fusion vaccines present a spectrum of known or unknown tumor antigens to stimulate T cell expansion and enhanced T cell response. Developing a new strategy of enhanced nanobody-based CAR-T (Nb-CAR-T) cells antitumor activity by DC/tumor fusion vaccines stimulation would provide guidance for more effective CAR-T cell therapies. Methods: Considering the therapeutic potential of nanobody (Nb), we first screened EGFRvIII Nb, then constructed and verified the function of EGFRvIII Nb-CAR-T cells in vitro and in vivo. We further combined DC/tumor fusion vaccines to boost EGFRvIII Nb-CAR-T cells antitumor effect, which was evaluated in vitro Nb-CAR-T cell function and in the tumor-bearing xenograft mouse models. Results: We had for the first time successfully selected EGFRvIII Nb for the generation of the novel EGFRvIII Nb-CAR-T cells. Importantly, our results suggested that DC/tumor fusion vaccines stimulate Nb-CAR-T cells response not only in improving T cell proliferation, T cell activation, cytokine secretion and tumor-specific cytotoxicity in vitro, but also significantly reducing tumor burden, prolonging survival and improving Nb-CAR-T cells infiltration. Conclusions: We have innovatively shown that DC/tumor fusion vaccines significantly enhance the efficacy of Nb-CAR-T cells against solid tumors. This new strategy has provided a promising therapeutic platform for promoting the clinical treatment of CAR-T cells therapy.

A p53/LINC00324 positive feedback loop suppresses tumor growth by counteracting SET-mediated transcriptional repression.

The p53 tumor suppressor exerts antitumor functions through its ability to regulate the transcription of its downstream targets. Long noncoding RNAs (lncRNAs) act as oncogenes or tumor suppressors implicated in tumorigenesis and tumor progression. Here, we identify the lncRNA LINC00324 (long intergenic noncoding RNA 00324) as a direct p53 transcriptional target. Knockdown of LINC00324 expression promotes tumor growth by reducing p53 transcriptional activity, whereas ectopic LINC00324 expression demonstrates a reverse effect. Notably, LINC00324 is present in the endogenous p53 complex in tumor cells and directly binds to the C-terminal domain of p53 in vitro. Mechanistically, LINC00324 enables p53 transactivation by competitively disrupting the p53-SET interaction, resulting in an increase of p300/CBP-mediated H3K18 and H3K27 acetylation on the p53 target promoters. Lower LINC00324 expression is associated with more aggressive disease status and predicts worse overall survival of patients with cancer. Our study identifies a p53/LINC00324 positive feedback loop that suppresses tumor growth by counteracting SET-mediated transcriptional repression.

Nucleolar HEAT Repeat Containing 1 Up-regulated by the Mechanistic Target of Rapamycin Complex 1 Signaling Promotes Hepatocellular Carcinoma Growth by Dominating Ribosome Biogenesis and Proteome Homeostasis.

BACKGROUND & AIMS: Hyperactivation of ribosome biogenesis leads to hepatocyte transformation and plays pivotal roles in hepatocellular carcinoma (HCC) development. We aimed to identify critical ribosome biogenesis proteins that are overexpressed and crucial in HCC progression. METHODS: HEAT repeat containing 1 (HEATR1) expression and clinical correlations were analyzed using The Cancer Genome Atlas and Gene Expression Omnibus databases and further evaluated by immunohistochemical analysis of an HCC tissue microarray. Gene expression was knocked down by small interfering RNA. HEATR1-knockdown cells were subjected to viability, cell cycle, and apoptosis assays and used to establish subcutaneous and orthotopic tumor models. Chromatin immunoprecipitation and quantitative polymerase chain reaction were performed to detect the association of candidate proteins with specific DNA sequences. Endogenous coimmunoprecipitation combined with mass spectrometry was used to identify protein interactions. We performed immunoblot and immunofluorescence assays to detect and localize proteins in cells. The nucleolus ultrastructure was detected by transmission electron microscopy. Click-iT (Thermo Fisher Scientific) RNA imaging and puromycin incorporation assays were used to measure nascent ribosomal RNA and protein synthesis, respectively. Proteasome activity, 20S proteasome foci formation, and protein stability were evaluated in HEATR1-knockdown HCC cells. RESULTS: HEATR1 was the most up-regulated gene in a set of ribosome biogenesis mediators in HCC samples. High expression of HEATR1 was associated with poor survival and malignant clinicopathologic features in patients with HCC and contributed to HCC growth in vitro and in vivo. HEATR1 expression was regulated by the transcription factor specificity protein 1, which can be activated by insulin-like growth factor 1-mammalian target of rapamycin complex 1 signaling in HCC cells. HEATR1 localized predominantly in the nucleolus, bound to ribosomal DNA, and was associated with RNA polymerase I transcription/processing factors. Knockdown of HEATR1 disrupted ribosomal RNA biogenesis and impaired nascent protein synthesis, leading to reduced cytoplasmic proteasome activity and inhibitory-κB/nuclear factor-κB signaling. Moreover, HEATR1 knockdown induced nucleolar stress with increased nuclear proteasome activity and inactivation of the nucleophosmin 1-MYC axis. CONCLUSIONS: Our study revealed that HEATR1 is up-regulated by insulin-like growth factor 1-mammalian target of rapamycin complex 1-specificity protein 1 signaling in HCC and functions as a crucial regulator of ribosome biogenesis and proteome homeostasis to promote HCC development.

The effect of capnography on the incidence of hypoxia during sedation for EGD and colonoscopy in mildly obese patients: a randomized, controlled study.

BACKGROUND: By continually monitoring end-tidal carbon dioxide concentrations, capnography can detect abnormal ventilation or apnoea early. This randomized, controlled study explored the effect of early intervention with capnography on the incidence of hypoxia in mildly obese patients undergoing sedation for esophagogastroduodenoscopy (EGD) and colonoscopy. METHODS: This is a single-center, randomized, single-blind, parallel-assignment, controlled trial. Mildly obese patients (28 kg/m2 ≤ BMI < 40 kg/m2) undergoing sedation for EGD and colonoscopy were randomly assigned to either the standard or capnography group. Standard cardiopulmonary monitoring equipment was used in both groups, and additional capnography was performed in the capnography group. In the event of inadequate alveolar ventilation during sedation, five interventions were administered in sequence (a-e) : a: increasing oxygen flow (5 L/min); b: a chin lift or jaw thrust maneuver; c: placement of the nasopharyngeal airway and chin lift; d: mask positive-pressure ventilation, and e: ventilator-assisted ventilation with tube insertion. The primary outcome was the incidence of hypoxia (SpO2 < 90%, ≥ 10 s) in each group. The secondary outcomes included the incidence of severe hypoxia (SpO2 ≤ 85%), subclinical respiratory depression (90% ≤ SpO2 < 95%), interventions, minimum SpO2 during operation, patient satisfaction, endoscopist satisfaction, and other adverse events of anesthesia sedation. RESULTS: 228 patients were included (capnography group = 112; standard group = 113; three patients were excluded) in this study. The incidence of hypoxia was significantly lower in the capnography group than in the standard group (13.4% vs. 30.1%, P = 0.002). Subclinical respiratory depression in the capnography group was higher than that of the standard group (30.4% vs. 17.7%, P = 0.026). There was only a 5.4% incidence of severe hypoxia in the capnography group compared with 14.2% in the standard group (P = 0.026). During sedation, 96 and 34 individuals in the capnography and standard groups, respectively, underwent the intervention. There was a statistically significant difference (P < 0.0001) in the number of the last intraoperative intervention between the two groups ( a:47 vs. 1, b:46 vs. 26, c:2 vs. 5, d:1 vs. 2, e:0 vs. 0 ). No significant differences were found between the two groups in terms of minimum SpO2 during operation, patient satisfaction, or endoscopist satisfaction rating. There was no statistically significant difference in adverse events of anesthesia sedation between the two groups. CONCLUSION: Capnography during sedation for EGD and colonoscopy allows for the detection of apnea and altered breathing patterns in mildly obese patients before SpO2 is reduced. Effective intervention measures are given to patients within this time frame, which reduces the incidence of hypoxia and severe hypoxia in patients. TRIAL REGISTRATION: Ethical approval was granted by the Medical Ethics Committee (Chairperson Professor Tian Hui) of Qilu Hospital, Shandong University ((Ke) Lun Audit 2021 (186)) on 15/07/2021. The study was registered ( https://www.chictr.org.cn ) on 23/10/2021(ChiCTR2100052234). Designed and reported using CONSORT statements.

Transglutaminases are oncogenic biomarkers in human cancers and therapeutic targeting of TGM2 blocks chemoresistance and macrophage infiltration in pancreatic cancer.

PURPOSE: Transglutaminases (TGs) are multifunctional enzymes exhibiting transglutaminase crosslinking, as well as atypical GTPase/ATPase and kinase activities. Here, we used an integrated comprehensive analysis to assess the genomic, transcriptomic and immunological landscapes of TGs across cancers. METHODS: Gene expression and immune cell infiltration patterns across cancers were obtained from The Cancer Genome Atlas (TCGA) database and Gene Set Enrichment Analysis (GSEA) datasets. Western blotting, immunofluorescence staining, enzyme-linked immunosorbent assays, and orthotopic xenograft models were used to validate our database-derived results. RESULTS: We found that the overall expression of TGs (designated as the TG score) is significantly upregulated in multiple cancers and related to a worse patient survival. The expression of TG family members can be regulated through multiple mechanisms at the genetic, epigenetic and transcriptional levels. The expression of transcription factors crucial for epithelial-to-mesenchymal transition (EMT) is commonly correlated with the TG score in many cancer types. Importantly, TGM2 expression displays a close connection with chemoresistance to a wide range of chemotherapeutic drugs. We found that TGM2 expression, F13A1 expression and the overall TG score were positively correlated with the infiltration of immune cells in all cancer types tested. Functional and clinical verification revealed that a higher TGM2 expression is linked with a worse patient survival, an increased IC50 value of gemcitabine, and a higher abundance of tumor-infiltrating macrophages in pancreatic cancer. Mechanistically, we found that increased C-C motif chemokine ligand 2 (CCL2) release mediated by TGM2 contributes to macrophage infiltration into the tumor microenvironment. CONCLUSIONS: Our results reveal the relevance and molecular networks of TG genes in human cancers and highlight the importance of TGM2 in pancreatic cancer, which may provide promising directions for immunotherapy and for addressing chemoresistance.

Vacuolar protein sorting 35 (VPS35) acts as a tumor promoter via facilitating cell cycle progression in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is insidious and highly malignant with extremely poor prognosis and drug resistance to current chemotherapies. Therefore, there is a critical need to investigate the molecular mechanism underlying PDAC progression to develop promising diagnostic and therapeutic interventions. In parallel, vacuolar protein sorting (VPS) proteins, involved in the sorting, transportation, and localization of membrane proteins, have gradually attracted the attention of researchers in the development of cancers. Although VPS35 has been reported to promote carcinoma progression, the specific molecular mechanism is still unclear. Here, we determined the impact of VPS35 on the tumorigenesis of PDAC and explored the underlying molecular mechanism. We performed a pan-cancer analysis of 46 VPS genes using RNAseq data from GTEx (control) and TCGA (tumor) and predicted potential functions of VPS35 in PDAC by enrichment analysis. Furthermore, cell cloning experiments, gene knockout, cell cycle analysis, immunohistochemistry, and other molecular and biochemical experiments were used to validate the function of VPS35. Consequently, VPS35 was found overexpressed in multiple cancers and correlated with the poor prognosis of PDAC. Meanwhile, we verified that VPS35 could modulate the cell cycle and promote tumor cell growth in PDAC. Collectively, we provide solid evidence that VPS35 facilitates the cell cycle progression as a critical novel target in PDAC clinical therapy.

PEDOT Films Doped with Titanyl Oxalate as Chemiresistive and Colorimetric Dual-Mode Sensors for the Detection of Hydrogen Peroxide Vapor.

Hydrogen peroxide (H2O2) is commonly used as an oxidizing, bleaching, or antiseptic agent. It is also hazardous at increased concentrations. It is therefore crucial to monitor the presence and concentration of H2O2, particularly in the vapor phase. However, it remains a challenge for many state-of-the-art chemical sensors (e.g., metal oxides) to detect hydrogen peroxide vapor (HPV) because of the interference of moisture in the form of humidity. Moisture, in the form of humidity, is guaranteed to be present in HPV to some extent. To meet this challenge, herein, we report a novel composite material based on poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS) doped with ammonium titanyl oxalate (ATO). This material can be fabricated as a thin film on electrode substrates for use in chemiresistive sensing of HPV. The adsorbed H2O2 will react with ATO, causing a colorimetric response in the material body. Combining colorimetric and chemiresistive responses resulted in a more reliable dual-function sensing method that improved the selectivity and sensitivity. Moreover, the composite film of PEDOT:PSS-ATO could be coated with a layer of pure PEDOT via in situ electrochemical synthesis. The pure PEDOT layer was hydrophobic, shielding the sensor material underneath from coming into contact with moisture. This was shown to mitigate the interference of humidity when detecting H2O2. A combination of these material properties makes the double-layer composite film, namely PEDOT:PSS-ATO/PEDOT, an ideal sensor platform for the detection of HPV. For example, upon a 9 min exposure to HPV at a concentration of 1.9 ppm, the electrical resistance of the film increased threefold, surpassing the bounds of the safety threshold. Meanwhile, the colorimetric response observed was 2.55 (defined as the color change ratio), a ratio at which the color change could be easily seen by the naked eye and quantified. We expect that this reported dual-mode sensor will find extensive practical applications in the fields of health and security with real-time, onsite monitoring of HPV.

Ecological risk assessment of pesticides on soil biota: An integrated field-modelling approach.

Pesticide residues in soils can cause negative impacts on soil health as well as soil biota. However, research related to the toxicity and exposure risks of pesticides to soil biota are scarce, especially in the North China Plain (NCP) where pesticides are intensively applied. In this study, the occurrence and distribution of 15 commonly used pesticides in 41 fields in Quzhou county in the NCP were determined during the growing season in 2020. The ecological risks of pesticides to the soil biota, including earthworms, enchytraeids, springtails, mites and nitrogen mineralization microorganisms, were assessed using toxicity exposure ratios (TERs) and risk quotient (RQ) methods. Based on pesticide detection rates and RQs, pesticide hazards were ranked using the Hasse diagram. The results showed that pesticides were concentrated in the 0-2 cm soil depth. Chlorantraniliprole was the most frequently detected pesticide with a detection rate of 37%, while the highest concentration of 1.85 mg kg-1 was found for carbendazim in apple orchards. Chlorpyrifos, carbendazim and imidacloprid posed a chronic exposure risk to E. fetida, F. candida and E. crypticus with the TERs exceeding the trigger value. Pesticide mixtures posed ecological risks to soil biota in 70% of the investigated sites. 47.5% of samples were ranked as high-risk, with the maximum RQ exceeding 490. According to the Hasse diagram, abamectin, tebuconazole, chlorantraniliprole and chlorpyrifos were ranked as the most hazardous pesticides for soil biota in the study region, indicating that alternative methods of pest management need to be considered. Therefore, practical risk mitigation solutions are recommended, in which the use of hazardous pesticides would be replaced with low-risk pesticides with similar functions from the Hasse diagram, or with biopesticides.

Human Resistin Induces Cardiac Dysfunction in Pulmonary Hypertension.

Background Cardiac failure is the primary cause of death in most patients with pulmonary arterial hypertension (PH). As pleiotropic cytokines, human resistin (Hresistin) and its rodent homolog, resistin-like molecule α, are mechanistically critical to pulmonary vascular remodeling in PH. However, it is still unclear whether activation of these resistin-like molecules can directly cause PH-associated cardiac dysfunction and remodeling. Methods and Results In this study, we detected Hresistin protein in right ventricular (RV) tissue of patients with PH and elevated resistin-like molecule expression in RV tissues of rodents with RV hypertrophy and failure. In a humanized mouse model, cardiac-specific Hresistin overexpression was sufficient to cause cardiac dysfunction and remodeling. Dilated hearts exhibited reduced force development and decreased intracellular Ca2+ transients. In the RV tissues overexpressing Hresistin, the impaired contractility was associated with the suppression of protein kinase A and AMP-activated protein kinase. Mechanistically, Hresistin activation triggered the inflammation mediated by signaling of the key damage-associated molecular pattern molecule high-mobility group box 1, and subsequently induced pro-proliferative Ki67 in RV tissues of the transgenic mice. Intriguingly, an anti-Hresistin human antibody that we generated protected the myocardium from hypertrophy and failure in the rodent PH models. Conclusions Our data indicate that Hresistin is expressed in heart tissues and plays a role in the development of RV dysfunction and maladaptive remodeling through its immunoregulatory activities. Targeting this signaling to modulate cardiac inflammation may offer a promising strategy to treat PH-associated RV hypertrophy and failure in humans.