Distinguishable Magnetic Reporter Coordination with Buoyancy-Magnetism Separation for Immobilization-Free Dual-Target Electrochemical Immunosensing.

Simultaneous sensitive and precise determination of multibiomarkers is of great significance for improving detection efficiency, reducing diagnosis and treatment expenses, and elevating survival rates. However, the development of simple and portable biosensors for simultaneous determination of multiplexed targets in biological fluids still faces challenges. Herein, a unique and versatile immobilization-free dual-target electrochemical biosensing platform, which combines distinguishable magnetic signal reporters with buoyancy-magnetism separation, was designed and constructed for simultaneous detection of carcinoembryonic (CEA) and α-fetoprotein (AFP) in intricate biological fluids. To construct such distinguishable magnetic signal reporters with signal transduction, amplification, and output, secondary antibodies of CEA and AFP were respectively functionalized on methylene blue (MB) and 6-(ferrocenyl)hexanethiol (FeC) modified Fe3O4@Au magnetic nanocomposites. Meanwhile, a multifunctional flotation probe with dual target recognition, capture, and isolation capability was prepared by conjugating primary antibodies (Ab1-CEA, Ab1-AFP) to hollow buoyant microspheres. The target antigens of CEA and AFP can trigger a flotation-mediated sandwich-type immunoreaction and capture a certain amount of the distinguishable magnetic signal reporter, which enables the conversion of the target CEA and AFP quantities to the signal of the potential-resolved MB and FeC. Thus, the MB and FeC currents of magnetically adsorbed distinguishable magnetic reporters can be used to determine the CEA and AFP targets simultaneously and precisely. Accordingly, the proposed strategy exhibited a delightful linear response for CEA and AFP in the range of 100 fg·mL-1-100 ng·mL-1 with detection limits of 33.34 and 17.02 fg·mL-1 (S/N = 3), respectively. Meanwhile, no significant nonspecific adsorption and cross-talk were observed. The biosensing platform has shown satisfactory performance in the determination of real clinical samples. More importantly, the proposed approach can be conveniently extended to universal detection just by simply substituting biorecognition events. Thus, this work opens up a new promising perspective for dual and even multiple targets and offers promising potential applications in clinical diagnosis.

Aldo-keto reductase family 1 member C3 mediates radioresistance of esophageal cancer cells through suppressing MAPK and AKT signaling.

BACKGROUND: Aldo-keto reductase family 1 member C3 (AKR1C3) is a radioresistance gene in esophageal cancer. This study aimed to investigate the signaling pathways that mediate the regulatory role of AKR1C3 in the radioresistance of esophageal cancer cells. METHODS: The protein levels of AKR1C3 in cancer tissue samples were compared between patients with radiosensitive and radioresistant esophageal cancer using immunohistochemical staining. AKR1C3-silenced stable KYSE170R esophageal cancer cells (KY170R-shAKR1C3) were established. Colony formation assay was employed to evaluate the radiosensitivity of cancer cells, while flow cytometry analysis was utilized to quantify reactive oxygen species (ROS) production in these cells. Additionally, Western blotting was conducted to determine protein expression levels. RESULTS: AKR1C3 protein exhibited significantly higher expression in radioresistant cancer tissue samples compared to radiosensitive samples. AKR1C3 silencing promoted radiosensitivity and ROS production of KYSE170R cells. At 32 h after X-ray radiation, the levels of total and phosphorylated ERK1/2, JNK, and AKT proteins were significantly elevated in KYSE170R-shAKR1C3 cells compared to untransfected KYSE170R cells. The inhibitor of AKR1C3 remarkably enhanced the radiosensitivity of KYSE170R cells. Conversely, treatment with either a MEK inhibitor or an AKT inhibitor significantly increased the radioresistance of KYSE170R-shAKR1C3 cells. CONCLUSIONS: Our results suggest that AKR1C3 mediates radioresistance of KYSE170R cells possibly through MAPK and AKT signaling.

Depletion of regulatory T cells enhancing the anti-tumor effect of in situ vaccination in solid tumors.

The emergence of immune checkpoint inhibitors (ICIs) has revolutionized the clinical treatment for tumor. However, the low response rate of ICIs remains the major obstacle for curing patients and effective approaches for patients with primary or secondary resistance to ICIs remain lacking. In this study, immune stimulating agent unmethylated CG-enriched (CpG) oligodeoxynucleotide (ODN) was locally injected into the tumor to trigger a robust immune response to eradicate cancer cells, while anti-CD25 antibody was applied to remove immunosuppressive regulatory T cells, which further enhanced the host immune activity to attack tumor systematically. The combination of CpG and anti-CD25 antibody obtained notable regression in mouse melanoma model. Furthermore, rechallenge of tumor cells in the xenograft model has resulted in smaller tumor volume, which demonstrated that the combinational treatment enhanced the activity of memory T cells. Remarkably, this combinational therapy presented significant efficacy on multiple types of tumors as well and was able to prevent relapse of tumor partially. Taken together, our combinational immunotherapy provides a new avenue to enhance the clinical outcomes of patients who are insensitive or resistant to ICIs treatments.

Neural mechanism of non-adaptive cognitive emotion regulation in patients with non-suicidal self-injury.

BACKGROUND: The incidence of non-suicidal self-injury (NSSI) has been on the rise in recent years. Studies have shown that people with NSSI have difficulties in emotion regulation and cognitive control. In addition, some studies have investigated the cognitive emotion regulation of people with NSSI which found that they have difficulties in cognitive emotion regulation, but there was a lack of research on cognitive emotion regulation strategies and related neural mechanisms. METHODS: This study included 117 people with NSSI (age = 19.47 ± 5.13, male = 17) and 84 non-NSSI participants (age = 19.86 ± 4.14, male = 16). People with NSSI met the DSM-5 diagnostic criteria, and non-NSSI participants had no mental or physical disorders. The study collected all participants' data of Cognitive Emotion Regulation Questionnaire (CERQ) and functional magnetic resonance imaging (fMRI) to explore the differences in psychological performance and brain between two groups. Afterwards, Machine learning was used to select the found differential brain regions to obtain the highest correlation regions with NSSI. Then, Allen's Human Brain Atlas database was used to compare with the information on the abnormal brain regions of people with NSSI to find the genetic information related to NSSI. In addition, gene enrichment analysis was carried out to find the related pathways and specific cells that may have differences. RESULTS: The differences between NSSI participants and non-NSSI participants were as follows: positive refocusing (t = -4.74, p < 0.01); refocusing on plans (t = -4.11, p < 0.01); positive reappraisal (t = -9.22, p < 0.01); self-blame (t = 6.30, p < 0.01); rumination (t = 3.64, p < 0.01); catastrophizing (t = 9.10, p < 0.01), and blaming others (t = 2.52, p < 0.01), the precentral gyrus (t = 6.04, pFDR < 0.05) and the rolandic operculum (t = -4.57, pFDR < 0.05). Rolandic operculum activity was negatively correlated with blaming others (r = -0.20, p < 0.05). Epigenetic results showed that excitatory neurons (p < 0.01) and inhibitory neurons (p < 0.01) were significant differences in two pathways, "trans-synaptic signaling" (p < -log108) and "modulation of chemical synaptic transmission" (p < -log108) in both cells. CONCLUSIONS: People with NSSI are more inclined to adopt non-adaptive cognitive emotion regulation strategies. Rolandic operculum is also abnormally active. Abnormal changes in the rolandic operculum of them are associated with non-adaptive cognitive emotion regulation strategies. Changes in the excitatory and inhibitory neurons provide hints to explore the abnormalities of the neurological mechanisms at the cellular level of them. Trial registration number NCT04094623.

Basal forebrain mediates prosocial behavior via disinhibition of midbrain dopamine neurons.

Sociability is fundamental for our daily life and is compromised in major neuropsychiatric disorders. However, the neuronal circuit mechanisms underlying prosocial behavior are still elusive. Here we identify a causal role of the basal forebrain (BF) in the control of prosocial behavior via inhibitory projections that disinhibit the midbrain ventral tegmental area (VTA) dopamine (DA) neurons. Specifically, BF somatostatin-positive (SST) inhibitory neurons were robustly activated during social interaction. Optogenetic inhibition of these neurons in BF or their axon terminals in the VTA largely abolished social preference. Electrophysiological examinations further revealed that SST neurons predominantly targeted VTA GABA neurons rather than DA neurons. Consistently, optical inhibition of SST neuron axon terminals in the VTA decreased DA release in the nucleus accumbens during social interaction, confirming a disinhibitory action. These data reveal a previously unappreciated function of the BF in prosocial behavior through a disinhibitory circuitry connected to the brain's reward system.

The volatile organic compounds generated from the Maillard reaction between l-ascorbic acid and l-cysteine in hot compressed water.

BACKGROUND: Hot compressed water (HCW), also known as subcritical water (SCW), refers to high-temperature compressed water in a special physical and chemical state. It is an emerging technology for natural product extraction. The volatile organic compounds (VOCs) generated from the Maillard reaction between l-ascorbic acid (ASA) and l-cysteine (Cys) have attracted significant interest in the flavor and fragrance industry. This study aimed to explore the formation mechanism of VOCs from ASA and Cys and examine the effects of reaction parameters such as temperature, time, and pH in HCW. RESULTS: The identified VOCs were predominantly thiophene derivatives, polysulfides, and pyrazine derivatives in HCW. The findings indicated that thiophene derivatives were formed under various pH conditions, with polysulfide formation favored under acidic conditions and pyrazine derivative formation preferred under weak alkaline conditions, specifically at pH 8.0. CONCLUSION: The Maillard reaction between ASA and Cys mainly produced thiophene derivatives, polysulfides, and pyrazine derivatives in HCW. The generation mechanism was significantly dependent on the surrounding pH conditions. © 2024 Society of Chemical Industry.

Prognostic impact of CD4+ and CD8+ tumor-infiltrating lymphocytes in patients with colorectal cancer.

OBJECTIVE: Tumor immune response has been suggested as an important indicator of cancer prognosis. This study was initiated to investigate the association between T lymphocytes and the prognosis of patients with colorectal cancer (CRC). METHODS: Included in this study were 129 CRC patients who received surgical treatment in Henan Provincial People's Hospital from January 2003 to January 2014. The level of CD4+ and CD8+ T lymphocytes in tissues was detected by immunohistochemistry (IHC). Survival analysis was conducted by the Kaplan-Meier method and Cox proportional hazards model. RESULTS: IHC staining showed that CD8+ T lymphocyte infiltration was high in 88 cases and low in 41 cases, while CD4+ T lymphocyte infiltration was high in 66 cases and low in 63 cases. The level of CD4+ and CD8+ T lymphocytes in CRC tissue was closely related to TNM stage and tumor invasion (p < 0.05). Follow-up analysis showed that both disease-free survival (DFS) and overall survival (OS) were better in patients with a high level of CD8+ and CD4 + CD8+ than those in patients with a low level (p < 0.05). Multivariate analysis showed that TNM stage, lymph node, CD8+ and CD4+ CD8+ were independent risk factors for DFS and OS (p < 0.05). CONCLUSION: High level of CD8+ and CD4+ CD8+ may prove to be a potential predictor of better prognosis of CRC patients.

Accelerated Dynamic Reconstruction in Metal-Organic Frameworks with Ligand Defects for Selective Electrooxidation of Amines to Azos Coupling with Hydrogen Production.

Electrosynthesis coupled hydrogen production (ESHP) mostly involves catalyst reconstruction in aqueous phase, but accurately identifying and controlling the process is still a challenge. Herein, we modulated the electronic structure and exposed unsaturated sites of metal-organic frameworks (MOFs) via ligand defect to promote the reconstruction of catalyst for azo electrosynthesis (ESA) coupled with hydrogen production overall reaction. The monolayer Ni-MOFs achieved 89.8 % Faraday efficiency and 90.8 % selectivity for the electrooxidation of 1-methyl-1H-pyrazol-3-amine (Pyr-NH2) to azo, and an 18.5-fold increase in H2 production compared to overall water splitting. Operando X-ray absorption fine spectroscopy (XAFS) and various in situ spectroscopy confirm that the ligand defect promotes the potential dependent dynamic reconstruction of Ni(OH)2 and NiOOH, and the reabsorption of ligand significantly lowers the energy barrier of rate-determining step (*Pyr-NH to *Pyr-N). This work provides theoretical guidance for modulation of electrocatalyst reconstruction to achieve highly selective ESHP.

An Active and Regenerable Nanometric High-Entropy Catalyst for Efficient Propane Dehydrogenation.

Propane dehydrogenation (PDH) is crucial for propylene production, but commercially employed Pt-based catalysts face susceptibility to deactivation due to the Pt sintering during reaction and regeneration steps. Here, we report a SiO2 supported nanometric (MnCoCuZnPt) high-entropy PDH catalyst with high activity and stability. The catalyst exhibited a super high propane conversion of 56.6 % with 94 % selectivity of propylene at 600 °C. The propylene productivity reached 68.5 molC3H6 ⋅ gPt -1 ⋅ h-1, nearly three times that of Pt/SiO2 (23.5 molC3H6 ⋅ gPt -1 ⋅ h-1) under a weight hourly space velocity of 60 h-1. In a high-entropy nanoparticle, Pt atoms were atomically dispersed through coordination with other metals and exhibited a positive charge, thereby showcasing remarkable catalytic activity. The high-entropy effect contributes to the catalyst a superior stability with a low deactivation constant of 0.0004 h-1 during 200 hours of reaction under the industrial gas composition at 550 °C. Such high-entropy PDH catalyst is easy regenerated through simple air combustion of deposited coke. After the fourth consecutive regeneration cycle, satisfactory catalytic stability was observed, and the element distribution of spent catalysts almost returned to their initial state, with no detectable Pt sintering. This work provides new insights into designing active, stable, and regenerable novel PDH catalysts.

Universal DNA-Based Sensing Toolbox for Programming Cell Functions.

By recombining natural cell signaling systems and further reprogramming cell functions, use of genetically engineered cells and bacteria as therapies is an innovative emerging concept. However, the inherent properties and structures of the natural signal sensing and response pathways constrain further development. We present a universal DNA-based sensing toolbox on the cell surface to endow new signal sensing abilities for cells, control cell states, and reprogram multiple cell functions. The sensing toolbox contains a triangular-prismatic-shaped DNA origami framework and a sensing core anchored inside the internal confined space to enhance the specificity and efficacy of the toolbox. As a proof of principle, the sensing toolbox uses the customizable sensing core with signal sensing switches and converters to recognize unconventional signal inputs, deliver functional components to cells, and then control cell responses, including specific tumor cell death, immune cell disinhibition and adhesion, and bacterial expression. This work expands the diversity of cell sensing signals and reprograms biological functions by constructing nanomechanical-natural hybrid cells, providing new strategies for engineering cells and bacteria in diagnosis and treatment applications.

Dual-Gene Isothermal Amplification Coupled with Lateral Flow Strip for On-Site Accurate Detection of E. coli O157:H7 in Food Samples.

On-site field detection of E. coli O157:H7 in food samples is of utmost importance, since it causes a series of foodborne diseases due to infections-associated ready-to-eat foods. Due to the instrument-free nature, recombinase polymerase amplification (RPA) coupled with lateral flow assay (LFA) is well-suited for such goal. However, the high genomic similarity of different E. coli serotypes adds difficulty to accurate differentiation of E. coli O157:H7 from others. Dual-gene analysis could significantly improve the serotype selectivity, but will further aggravate the RPA artifacts. To address such issue, here we proposed a protocol of dual-gene RPA-LFA, in which the target amplicons were selectively recognized by peptide nucleic acid (PNA) and T7 exonuclease (TeaPNA), thus eliminating false-positives in LFA readout. Adapting rfbEO157 and fliCH7 genes as the targets, dual-gene RPA-TeaPNA-LFA was demonstrated to be selective for E. coli O157:H7 over other E. coli serotypes and common foodborne bacteria. The minimum detection concentration was 10 copies/µL for the genomic DNA (∼300 cfu/mL E. coli O157:H7), and 0.24 cfu/mL E. coli O157:H7 in food samples after 5 h bacterial preculture. For lettuce samples contaminated with E. coli O157:H7 (single-blind), the sensitivity and specificity of the proposed method were 85% and 100%, respectively. Using DNA releaser for fast genomic DNA extraction, the assay time could be reduced to ∼1 h, which is appealing for on-site food monitoring.

ß-Elemene enhances erlotinib sensitivity through induction of ferroptosis by upregulating lncRNA H19 in EGFR-mutant non-small cell lung cancer.

Nearly half of all Asian non-small cell lung cancer (NSCLC) patients harbour epidermal growth factor receptor (EGFR) mutations, and first-generation EGFR tyrosine kinase inhibitors (TKIs) are one of the first-line treatments that have improved the outcomes of these patients. Unfortunately, 20% of these patients can not benefit from the treatment. The basis of this primary resistance is poorly understood. Therefore, overcoming EGFR-TKI primary resistance and maintaining the efficacy of TKIs has become a key issue. ß-Elemene, a sesquiterpene compound extracted from Curcuma aromatica Salisb. (wenyujing), has shown potent antitumor effects. In this research, we found that ß-elemene combined with erlotinib enhanced the cytotoxicity of erlotinib to primary EGFR-TKI-resistant NSCLC cells with EGFR mutations and that ferroptosis was involved in the antitumor effect of the combination treatment. We found that lncRNA H19 was significantly downregulated in primary EGFR-TKI-resistant NSCLC cell lines and was upregulated by the combination treatment. Overexpression or knockdown of H19 conferred sensitivity or resistance to erlotinib, respectively, in both in vitro and in vivo studies. The high level of H19 enhanced the cytotoxicity of erlotinib by inducing ferroptosis. In conclusion, our data showed that ß-elemene combined with erlotinib could enhance sensitivity to EGFR-TKIs through induction of ferroptosis via H19 in primary EGFR-TKI-resistant lung cancer, providing a promising strategy to overcome EGFR-TKI resistance in NSCLC patients.

Short- and long-term outcomes of laparoscopic versus open liver resection for large hepatocellular carcinoma: a propensity score study.

PURPOSE: Laparoscopic liver resection (LLR) for hepatocellular carcinoma (HCC) remains controversial, especially for tumors larger than 5 cm. We compared the short- and long-term outcomes of laparoscopic and open liver resection (OLR) for large HCC. METHODS: Patients with large HCC after curative hepatectomy were enrolled. To compare the short-term outcomes, propensity score matching (PSM) and inverse probability treatment weighting (IPTW) were performed to reduce the effect of confounding factors, respectively. Subsequently, Cox-regression analyses were conducted to identify the independent risk factors associated with decreased recurrence-free survival (RFS) and poor overall survival (OS). RESULT: There were 265 patients enrolled in the final analysis: 146 who underwent OLR and 119 who underwent LLR. There was no significant difference between the OLR and LLR groups according to PSM and IPTW analysis (all P > 0.05). Multivariable analysis revealed that LLR was not independently associated with poorer OS (HR 1.15, 95% CI 0.80-1.67, P = 0.448) or RFS (HR 1.22, 95% CI 0.88-1.70, P = 0.238). CONCLUSION: There were no significant differences in perioperative complications or long-term prognosis between LLR and OLR for large HCC, which provides evidence for standard laparoscopic surgical practice with adequate surgeon experience and careful patient selection.

Polymer-like Inorganic Double Helical van der Waals Semiconductor.

In high-performance flexible and stretchable electronic devices, conventional inorganic semiconductors made of rigid and brittle materials typically need to be configured into geometrically deformable formats and integrated with elastomeric substrates, which leads to challenges in scaling down device dimensions and complexities in device fabrication and integration. Here we report the extraordinary mechanical properties of the newly discovered inorganic double helical semiconductor tin indium phosphate. This spiral-shape double helical crystal shows the lowest Young's modulus (13.6 GPa) among all known stable inorganic materials. The large elastic (>27%) and plastic (>60%) bending strains are also observed and attributed to the easy slippage between neighboring double helices that are coupled through van der Waals interactions, leading to the high flexibility and deformability among known semiconducting materials. The results advance the fundamental understanding of the unique polymer-like mechanical properties and lay the foundation for their potential applications in flexible electronics and nanomechanics disciplines.

eHealth Literacy of Chinese Residents During the Coronavirus Disease 2019 Pandemic: A Cross-sectional Survey.

The Coronavirus Disease 2019 (COVID-19) pandemic has become a leading societal concern. eHealth literacy is important in the prevention and control of this pandemic. The purpose of this study is to identify eHealth literacy of Chinese residents about the COVID-19 pandemic and factors influencing eHealth literacy. A total of 15 694 individuals clicked on the link to the questionnaire, and 15 000 agreed to participate and completed the questionnaire for a response rate of 95.58%. Descriptive statistics, χ 2 test, and logistic regression analysis were conducted to analyze participants' level of eHealth literacy about COVID-19 and its influencing factors. The results showed 52.2% of participants had relatively lower eHealth literacy regarding COVID-19 (eHealth literacy score ≤ 48). The scores of the information judgment dimension (3.09 ± 0.71) and information utilization dimension (3.18 ± 0.67) of the eHealth literacy scale were relatively lower. The logistics regression showed that sex, age, education level, level of uncertainty, having people around the respondent diagnosed with COVID-19, relationship with family, and relationship with others were associated to eHealth literacy (χ 2 = 969.135, P < .001). The public's eHealth literacy about COVID-19 needs to be improved, especially the ability to judge and utilize online information. Close collaboration among global health agencies, governments, healthcare institutions, and media is needed to provide reliable online information to the public. Interventions to improve eHealth literacy should take into account and accentuate the importance of sex, age, educational background, level of uncertainty, exposure to disease, and social support.

A Lesson of Immunosuppression in Renal Transplant: Retreat or Hold?

Background: Aiming at understanding whether there are cases of near-tolerance among long-term surviving kidney transplant recipients in our center, or even operant tolerance can be attempted based on their immune status, we analyzed changes of immune cell subsets and cytokines in various groups, and evaluated immune status of long-term survival recipients. Methods: A real-world, observational, retrospective cohort study was conducted in our hospital. Twenty-eight long-term recipients were selected as study subjects, 15 recent postoperative stable recipients, and 15 healthy subjects as controls. T and B lymphocyte subsets, MDSCs, and cytokines were detected and analyzed. Results: Treg/CD4 T cells, total B and B10 cells in long-term and recent renal recipients were lower than healthy controls (HC). The level of IFN-γ and IL-17A in long-term survival patients was obviously higher than that in recent postoperative stable recipients and HC, while TGF-ß1 level was significantly lower in long-term survival group than in short-term postoperative group and HC. Notably, compared with short-term recipients, it has been found that the IL-6 level in both positive and negative HLA groups were obviously lower (all P<0.05). In the long-term survival group, 43% of recipients were positive for urinary protein and 50% were positive for HLA antibody. Conclusion: This "real-world" study validates the findings of real status of long-term survival recipients observed in clinical trials. Contrary to a state of proper tolerance as expected, the group recipients in long-term survival were accompanied by the increased indicators of immune response, while those related to immune tolerance were not significantly increased. Long-term survival recipients with stable renal function may be in an immune equilibrium state where immunosuppression and rejection coexist under the action of low-intensity immune agents. If immunosuppressive agents are reduced or even removed, rejection may occur.

[Advances in mechanism of traditional Chinese medicine in inhibiting angiogenesis in ovarian cancer].

Ovarian cancer is one of the three major cancers in gynecology. Ovarian cancer has insidious symptoms in its early stages and mostly has progressed to advanced stages when detected. Surgical treatment combined with chemotherapy is currently the main treatment, but the 5-year survival rate is still less than 45%. Angiogenesis is a key step in the growth and metastasis of ovarian cancer. The inhibition of ovarian cancer angiogenesis has become a new hotspot in anti-tumor targeted therapy, which has many advantages such as less drug resistance, high specificity, few side effects, and broad anti-tumor spectrum. Modern research has confirmed that traditional Chinese medicine(TCM) can inhibit tumor angiogenesis by inhibiting the expression of pro-angiogenic factors, up-regulating the expression of anti-angiogenic factors, inhibiting the proliferation of vascular endothelial cells, reducing the density of tumor microvessels, and regulating related signaling pathways, with unique advantages in the treatment of ovarian cancer. This paper presented a review of the role of TCM in inhibiting ovarian cancer angiogenesis in order to provide references for the optimization of clinical ovarian cancer treatment strategies.

Bone marrow mesenchymal stem cell-derived extracellular vesicles facilitate endometrial injury repair by carrying the E3 ubiquitin ligase WWP1.

Bone marrow mesenchymal stem cells-derived extracellular vesicles (BMSC-EVs) relieve endometrial injury. This study aimed to elucidate the BMSC-EV mechanism in alleviating endometrial injury. Endometrial injury model in vivo was induced using 95% ethanol, and endometrial epithelial cells (EECs) treated with mifepristone were applied as an endometrial injury model in vitro. After BMSCs and BMSC-EVs were isolated and identified, the BMSC-EV function was evaluated by hematoxylin-eosin and Masson staining, immunohistochemistry, quantitative real-time PCR, Cell Counting Kit-8 assay, flow cytometry, enzyme-linked immunosorbent assay, and Transwell and tubule formation assays. The BMSC-EV mechanism was assessed using Western blot, ubiquitination, and cycloheximide-chase assays. After isolation and identification, BMSC-EVs were effective in endometrial injury repair in vivo and facilitated EEC proliferation and repressed cell apoptosis in vitro; the EEC supernatants accelerated human umbilical vein endothelial cell proliferation, migration, and invasion and facilitated angiogenesis after endometrial injury in vitro. For the BMSC-EV mechanism, E3 ubiquitin ligase WWP1 in BMSC-EVs mediated the ubiquitination of peroxisome proliferator-activated receptor gamma (PPARγ), thus relieving the PPARγ inhibition on vascular endothelial growth factor expression. Furthermore, the WWP1 in BMSC-EVs alleviated endometrial injury in vitro and in vivo. BMSC-EVs facilitated endometrial injury repair by carrying WWP1.

Tumor PKCδ instigates immune exclusion in EGFR-mutated non-small cell lung cancer.

BACKGROUND: The recruitment of a sufficient number of immune cells to induce an inflamed tumor microenvironment (TME) is a prerequisite for effective response to cancer immunotherapy. The immunological phenotypes in the TME of EGFR-mutated lung cancer were characterized as non-inflamed, for which immunotherapy is largely ineffective. METHODS: Global proteomic and phosphoproteomic data from lung cancer tissues were analyzed aiming to map proteins related to non-inflamed TME. The ex vivo and in vivo studies were carried out to evaluate the anti-tumor effect. Proteomics was applied to identify the potential target and signaling pathways. CRISPR-Cas9 was used to knock out target genes. The changes of immune cells were monitored by flow cytometry. The correlation between PKCδ and PD-L1 was verified by clinical samples. RESULTS: We proposed that PKCδ, a gatekeeper of immune homeostasis with kinase activity, is responsible for the un-inflamed phenotype in EGFR-mutated lung tumors. It promotes tumor progression by stimulating extracellular matrix (ECM) and PD-L1 expression which leads to immune exclusion and assists cancer cell escape from T cell surveillance. Ablation of PKCδ enhances the intratumoral penetration of T cells and suppresses the growth of tumors. Furthermore, blocking PKCδ significantly sensitizes the tumor to immune checkpoint blockade (ICB) therapy (αPD-1) in vitro and in vivo model. CONCLUSIONS: These findings revealed that PKCδ is a critical switch to induce inflamed tumors and consequently enhances the efficacy of ICB therapy in EGFR-mutated lung cancer. This opens a new avenue for applying immunotherapy against recalcitrant tumors.

Decline of suspended particulate matter concentrations in Lake Taihu from 1984 to 2020: observations from Landsat TM and OLI.

Suspended particulate matter (SPM) affects the optical properties of water, which can be used as a marker of water quality. The water quality of Lake Taihu has changed immensely since the 1980's. However, despite the link between water quality and SPM, long-term systematic studies on SPM have not been conducted in this lake. Here, we used Landsat-5 TM and Landsat-8 OLI data to model changes in the SPM concentration of Lake Taihu from 1984 to 2020. Various models were generated, calibrated, and finally validated using in situ SPM, remote sensing reflectance (Rrs) data, and synchronous satellite data. After comparing various commonly used models, it was found that the exponential model based on band combination [Rrs(red) + Rrs(NIR)/Rrs(green)] had the highest accuracy, with an average unbiased relative error greater than 35%. Subsequently, the SPM products of Lake Taihu during 1984-2020 were generated. Overall, the SPM concentration showed a downward trend over the study period, which might be primarily attributable to a decline in wind speed. These findings may assist in the conservation of Lake Taihu and its associated water resources.