Anesthesia/surgery activate MMP9 leading to blood-brain barrier disruption, triggering neuroinflammation and POD-like behavior in aged mice.

Anesthesia and surgery activate matrix metalloproteinase 9 (MMP9), leading to blood-brain barrier (BBB) disruption and postoperative delirium (POD)-like behavior, especially in the elderly. Aged mice received intraperitoneal injections of either the MMP9 inhibitor SB-3CT, melatonin, or solvent, and underwent laparotomy under 3 % sevoflurane anesthesia(anesthesia/surgery). Behavioral tests were performed 24 h pre- and post-operatively. Serum and cortical tissue levels of interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α (TNF-α) were measured using ELISA. Levels of PDGFRß, MMP9, tight junction, Mfsd2a, caveolin-1, synaptophysin, and postsynaptic densin (PSD)-95 proteins in the prefrontal cortex were assayed using Western blotting. BBB permeability was assessed by detecting IgG in the prefrontal cortex and serum S100ß levels. Anesthesia/surgery-induced peripheral inflammation activated MMP9, which in turn injured pericytes and tight junctions and increased transcytosis, thereby disrupting the BBB. Impaired BBB allowed the migration of peripheral inflammation into the central nervous system (CNS), thereby inducing neuroinflammation, synaptic dysfunction, and POD-like behaviors. However, MMP9 inhibition reduced pericyte and tight junction injury and transcytosis, thereby preserving BBB function and preventing the migration of peripheral inflammation into the CNS, thus attenuating synaptic dysfunction and POD-like behavior. In addition, to further validate the above findings, we showed that melatonin exerted similar effects through inhibition of MMP9. The present study shows that after anesthesia/surgery, inflammatory cytokines upregulation is involved in regulating BBB permeability in aged mice through activation of MMP9, suggesting that MMP9 may be a potential target for the prevention of POD.

Effect of hydrothermal treatment on the rheological properties of xanthan gum.

In this study, the effect of hydrothermal treatment with different temperatures (120-180 °C) on the rheological properties of xanthan gum was evaluated. When the temperature of hydrothermal treatment was relatively low (120 °C), the rheological properties of the hydrothermally treated xanthan gum was similar to the untreated xanthan gum (pseudoplastic and solid-like/gel-like behavior). However, as the temperature of hydrothermal treatment was higher, the rheological properties of the hydrothermally treated xanthan gum changed greatly (e.g., a wider range of Newtonian plateaus in flow curves, existence of a critical frequency between the storage modulus (G') and the loss modulus (G") in the dynamic viscoelasticity measurement, variation of complex viscosity). Although the hydrothermal treatment showed little influence on the functional groups of xanthan gum, it altered the micromorphology of xanthan gum from uneven and rough lump-like to thinner and smoother flake-like. In addition, higher concentration (2 %) of hydrothermally treated xanthan gum made its viscosity close to that of the untreated xanthan gum (1 %). Besides, hydrothermal treatment also affected the effect of temperature and salt (CaCl2) adding on the rheological properties of xanthan gum. Overall, this study can provide some useful information on the rheological properties of xanthan gum after hydrothermal treatment.

Anticancer Mechanism of Astragalus Polysaccharide and Its Application in Cancer Immunotherapy.

Astragalus polysaccharide (APS) derived from A. membranaceus plays a crucial role in traditional Chinese medicine. These polysaccharides have shown antitumor effects and are considered safe. Thus, they have become increasingly important in cancer immunotherapy. APS can limit the spread of cancer by influencing immune cells, promoting cell death, triggering cancer cell autophagy, and impacting the tumor microenvironment. When used in combination with other therapies, APS can enhance treatment outcomes and reduce toxicity and side effects. APS combined with immune checkpoint inhibitors, relay cellular immunotherapy, and cancer vaccines have broadened the application of cancer immunotherapy and enhanced treatment effectiveness. By summarizing the research on APS in cancer immunotherapy over the past two decades, this review elaborates on the anticancer mechanism of APS and its use in cancer immunotherapy and clinical trials. Considering the multiple roles of APS, this review emphasizes the importance of using APS as an adjunct to cancer immunotherapy and compares other polysaccharides with APS. This discussion provides insights into the specific mechanism of action of APS, reveals the molecular targets of APS for developing effective clinical strategies, and highlights the wide application of APS in clinical cancer therapy in the future.

A new technique to prevent conjunctival prolapse in Asian patients for correcting severe blepharoptosis.

BACKGROUND: In Asian patients with severe ptosis,the use of conjoint fascia sheath (CFS) suspension or levator aponeurosis fascia complex shortening surgery can correct the ptosis. During these surgery, a significant amount of levator aponeurosis fascia shortening is performed, which often leads to serious complications such as conjunctival prolapse.This study compares two surgical approaches for correcting severe blepharoptosis:Conjoint fascial sheath (CFS) + levator aponeurosis and muller's muscle complex (LM complex) suspension and conjoint fascial sheath (CFS) + LM complex+conjunctival suspension.The postoperative efficacy and the incidence of complications such as conjunctival prolapse are investigated for both procedures. METHODS: This study retrospectively analyzed 70 patients (77eyes) with severe blepharoptosis from January 2019 to December 2021. The patients were divided into the experimental group (34 cases, 38 eyes) and the control group (36 cases, 39 eyes). The experimental group was treated with CFS+LM complex + conjunctival suspension, and the control group was treated with CFS+LM complex suspension.The curative effect of blepharoptosis, the incidence of complications such as conjunctival prolapse and patient satisfaction were compared between the two different surgical methods. RESULTS: There was no significant difference in the correction effective rate between the experimental group (84.21%) and the control group (82.05%) (P > 0.05). There was no significant difference in the total incidence of complications between the experimental group (23.68%) and the control group (38.46%) (P > 0.05), but in the complication of conjunctival prolapse, the incidence of conjunctival prolapse in the experimental group was significantly lower than that in the control group. The difference was statistically significant (P < 0.05). In the survey of patient satisfaction rate, the satisfaction rate of the experimental group was significantly higher than that of the control group,which was statistically significant (P < 0.05). CONCLUSIONS: Compared to CFS+LM complex suspension surgery, the CFS+LM complex + conjunctival suspension has a definite effect in preventing postoperative conjunctival prolapse .The procedure has a high feasibility, good corrective effect, and improves patient satisfaction after surgery.

Brain circuits for retching-like behavior.

Nausea and vomiting are important defensive responses to cope with pathogens and toxins that invade the body. The nucleus of the solitary tract (NTS) is important for initiating these responses. However, the molecular heterogeneities and cellular diversities of the NTS occlude a better understanding of these defensive responses. Here, we constructed the single-nucleus transcriptomic atlas of NTS cells and found multiple populations of NTS neurons that may be involved in these defensive responses. Among these, we identified Calbindin1-positive (Calb1+) NTS neurons that are molecularly distinct from Tac1+ neurons. These Calb1+ neurons are critical for nausea and retching induced by cereulide; an emetic toxin secreted by Bacillus Cereus. Strikingly, we found that cereulide can directly modulate vagal sensory neurons that innervate Calb1+ NTS neurons, a novel mechanism distinct from that for nausea and retching induced by Staphylococcal enterotoxin A. Together, our transcriptomic atlas of NTS neurons and the functional analyses revealed the neural mechanism for cereulide-induced retching-like behavior. These results demonstrate the molecular and cellular complexities in the brain that underlie defensive responses to the diversities of pathogens and toxins.

Potassium xanthate-promoted reductive sulfuration reaction: from aldehydes to thiol, disulfide, and thioester derivatives.

Herein, we developed a synthetic strategy for the direct construction of C-S bonds to obtain biologically active sulfur-containing compounds and a methodology involving the reductive sulfuration of aldehydes or ketones to obtain diverse substituted thiol, disulfide, and thioester derivatives. EtOCS2K is demonstrated as a potential substitute for the Berzelius reagent or Lawesson's reagent for the construction of C-S bonds.

Spatiotemporal transcriptome atlas reveals the regional specification of the developing human brain.

Different functional regions of brain are fundamental for basic neurophysiological activities. However, the regional specification remains largely unexplored during human brain development. Here, by combining spatial transcriptomics (scStereo-seq) and scRNA-seq, we built a spatiotemporal developmental atlas of multiple human brain regions from 6-23 gestational weeks (GWs). We discovered that, around GW8, radial glia (RG) cells have displayed regional heterogeneity and specific spatial distribution. Interestingly, we found that the regional heterogeneity of RG subtypes contributed to the subsequent neuronal specification. Specifically, two diencephalon-specific subtypes gave rise to glutamatergic and GABAergic neurons, whereas subtypes in ventral midbrain were associated with the dopaminergic neurons. Similar GABAergic neuronal subtypes were shared between neocortex and diencephalon. Additionally, we revealed that cell-cell interactions between oligodendrocyte precursor cells and GABAergic neurons influenced and promoted neuronal development coupled with regional specification. Altogether, this study provides comprehensive insights into the regional specification in the developing human brain.

De-escalated radiotherapy for HER2-overexpressing breast cancer patients with 1-3 positive lymph nodes undergoing anti-HER2 targeted therapy.

Background: In the era of anti-HER2 targeted therapy, the potential clinical feasibility of considering HER2-overexpressing breast cancer cases presenting with 1-3 positive axillary lymph nodes as low-risk, and thereby contemplating postoperative radiotherapy reduction, remains an important subject for in-depth examination. The aim of this retrospective study was to evaluate the effectiveness of de-escalated radiotherapy in T1-2N1M0 HER2-overexpressing breast cancer patients receiving anti-HER2 targeted therapy. Specifically, omitting regional lymph node irradiation (RNI) after breast-conserving surgery and only performing whole-breast irradiation or omitting postmastectomy radiation therapy. Methods: A retrospective analysis was conducted on 429 patients with stage T1-2N1M0 primary invasive HER2-overexpressing breast cancer from our center between 2004 and 2018. Patients who received anti-HER2 targeted therapy were divided into an RNI group and a no RNI group to assess the role of RNI. The prognostic role of RNI was investigated via the Kaplan-Meier method and Cox proportional hazards modeling. Results: The median follow-up time was 46.8 months (range 7.1-225.8 months). In the anti-HER2 targeted therapy group RNI yielded no significant improvements in invasive disease-free survival (IDFS) (p = 0.940), local-regional recurrence-free survival (p = 0.380), distant metastases-free survival (p = 0.698), or overall survival (p = 0.403). Estrogen receptor (ER) status (hazard ratio [HR] 0.105, 95% confidence interval [CI] 0.023-0.749, p = 0.004) and lymph vascular invasion status (LVI) (HR 5.721, 95% CI 1.586-20.633, p = 0.008) were identified as independent prognostic factors for IDFS, and ER-positive and LVI-negative patients exhibited better prognoses. Conclusion: Omitting RNI may be a safe option in T1-2N1 HER2-overexpressing breast cancer patients receiving standardized anti-HER2 targeted therapy; particularly in ER-positive or LVI-negative subgroups.

Effect of raw electroencephalogram-guided anesthesia administration on postoperative outcomes in elderly patients undergoing abdominal major surgery: a randomized controlled trial.

BACKGROUND: EEG monitoring techniques are receiving increasing clinical attention as a common method of reflecting the depth of sedation in the perioperative period. The influence of depth of sedation indices such as the bispectral index (BIS) generated by the processed electroencephalogram (pEEG) machine to guide the management of anesthetic depth of sedation on postoperative outcome remains controversial. This research was designed to decide whether an anesthetic agent exposure determined by raw electroencephalogram (rEEG) can influence anesthetic management and cause different EEG patterns and affect various patient outcomes. METHODS: A total of 141 participants aged ≥ 60 years undergoing abdominal major surgery were randomized to rEEG-guided anesthesia or routine care group. The rEEG-guided anesthesia group had propofol titrated to keep the rEEG waveform at the C-D sedation depth during surgery, while in the routine care group the anesthetist was masked to the patient's rEEG waveform and guided the anesthetic management only through clinical experience. The primary outcome was the presence of postoperative complications, the secondary outcomes included intraoperative anesthetic management and different EEG patterns. RESULTS: There were no statistically significant differences in the occurrence of postoperative respiratory, circulatory, neurological and gastrointestinal complications. Further EEG analysis revealed that lower frontal alpha power was significantly associated with a higher incidence of POD, and that rEEG-guidance not only reduced the duration of deeper anesthesia in patients with lower frontal alpha power, but also allowed patients with higher frontal alpha power to receive deeper and more appropriate depths of anesthesia than in the routine care group. CONCLUSIONS: In elderly patients undergoing major abdominal surgery, rEEG-guided anesthesia did not reduce the incidence of postoperative respiratory, circulatory, neurological and gastrointestinal complications. rEEG-guided anesthesia management reduced the duration of intraoperative BS in patients and the duration of over-deep sedation in patients with lower frontal alpha waves under anesthesia, and there was a strong association between lower frontal alpha power under anesthesia and the development of POD. rEEG-guided anesthesia may improve the prognosis of patients with vulnerable brains by improving the early identification of frail elderly patients and providing them with a more effective individualized anesthetic managements.

The efficacy of sodium bicarbonated Ringer's solution versus lactated Ringer's solution in elderly patients undergoing gastrointestinal surgery: a prospective randomized controlled trial.

OBJECTIVE: To investigate the effect of sodium bicarbonated Ringer's solution (BRS) on lactate metabolism, acid-base balance, and clinical outcomes in elderly patients undergoing gastrointestinal surgery. METHODS: A total of 60 elderly patients undergoing gastrointestinal surgery were enrolled in this prospective, randomized controlled study. The participants were randomly assigned to the BRS group (n = 30) or sodium lactated Ringer's solution (LRS) group (n = 30) where they received goal-directed fluid therapy with BRS or LRS, respectively. The primary outcome was the incidence of postoperative hyperlactatemia, whereas the secondary outcomes included pH, bicarbonate, base excess (BE), liver function, and postoperative complications within 30 days. Linear regression was conducted to screen the factors affecting lactate concentration. RESULTS: After fluid therapy, the probability of hyperlactatemia was lower in the BRS group than in the LRS group (3.3% vs. 40.0%, P < 0.001). No significant difference in bicarbonate, pH, and BE was observed between the groups (P > 0.05). Furthermore, the incidence of major complications and the length of hospital stay were not significantly different (P > 0.05). However, the BRS group had a lower risk of minor complications than the LRS group (50.0% vs. 76.7%, P = 0.032), particularly in terms of impaired liver function (16.7% vs. 43.3%, P = 0.024). Diabetes, hypotension, and volume of LRS infused were highly correlated with lactate concentration. CONCLUSION: BRS is more beneficial to the reduction of the incidence of postoperative hyperlactatemia and the risk of minor postoperative complications in elderly patients undergoing gastrointestinal surgery. Therefore, BRS may be a better option for perioperative fluid therapy in elderly patients undergoing gastrointestinal surgery.

Epigenetic architecture of Pseudotaxus chienii: Revealing the synergistic effects of climate and soil variables.

Whether conifers can withstand environmental changes especially temperature fluctuations has been controversial. Epigenetic analysis may provide new perspectives for solving the issue. Pseudotaxus chienii is an endangered gymnosperm species endemic to China. In this study, we have examined the genetic and epigenetic variations in its natural populations aiming to disentangle the synergistic effects of climate and soil on its population (epi)genetic differentiation by using amplified fragment length polymorphism (AFLP) and methylation-sensitive AFLP (MSAP) techniques. We identified 23 AFLP and 26, 7, and 5 MSAP outliers in P. chienii. Twenty-one of the putative adaptive AFLP loci were found associated with climate and/or soil variables including precipitation, temperature, K, Fe, Zn, and Cu, whereas 21, 7, and 4 MSAP outliers were significantly related to precipitation of wettest month (Bio13), precipitation driest of month (Bio14), percent tree cover (PTC), and soil Fe, Mn, and Cu compositions. Total precipitation and precipitation in the driest seasons were the most influential factors for genetic and epigenetic variation, respectively. In addition, a high full-methylation level and a strong correlation between genetic and epigenetic variation were detected in P. chienii. Climate is found of greater importance than soil in shaping adaptive (epi)genetic differentiation, and the synergistic effects of climate and climate-soil variables were also observed. The identified climate and soil variables should be considered when applying ex situ conservation.

Cross-species comparison illuminates the importance of iron homeostasis for splenic anti-immunosenescence.

Although immunosenescence may result in increased morbidity and mortality, many mammals have evolved effective immune coping strategies to extend their lifespans. Thus, the immune systems of long-lived mammals present unique models to study healthy longevity. To identify the molecular clues of anti-immunosenescence, we first built high-quality reference genome for a long-lived myotis bat, and then compared three long-lived mammals (i.e., bat, naked mole rat, and human) versus the short-lived mammal, mouse, in splenic immune cells at single-cell resolution. A close relationship between B:T cell ratio and immunosenescence was detected, as B:T cell ratio was much higher in mouse than long-lived mammals and significantly increased during aging. Importantly, we identified several iron-related genes that could resist immunosenescence changes, especially the iron chaperon, PCBP1, which was upregulated in long-lived mammals but dramatically downregulated during aging in all splenic immune cell types. Supportively, immune cells of mouse spleens contained more free iron than those of bat spleens, suggesting higher level of ROS-induced damage in mouse. PCBP1 downregulation during aging was also detected in hepatic but not pulmonary immune cells, which is consistent with the crucial roles of spleen and liver in organismal iron recycling. Furthermore, PCBP1 perturbation in immune cell lines would result in cellular iron dyshomeostasis and senescence. Finally, we identified two transcription factors that could regulate PCBP1 during aging. Together, our findings highlight the importance of iron homeostasis in splenic anti-immunosenescence, and provide unique insight for improving human healthspan.

Preoperative prediction of adverse outcome after elective gastrointestinal surgery in older patients: three leading frailty instruments and the American Society of Anesthesiologists physical status.

OBJECTIVE: This study aimed to compare the ability of three frailty assessments to predict adverse outcomes after elective gastrointestinal surgery and analyze how frailty assessments impact the American Society of Anesthesiologists (ASA) risk prediction model. METHODS: Frailty was measured using the FRAIL scale, Fried Phenotype (FP), and Clinical Frailty Scale (CFS), alongside ASA assessments before surgery. Univariate and logistic regression analyses were used to determine the predictive value of each method. The predictive abilities of the tools were assessed by the area under the receiver operating characteristic curves (AUCs) and their 95% confidence intervals (CIs). RESULTS: After adjusting for age and other risk factors, logistic regression analysis revealed significant positive associations between preoperative frailty and postoperative total adverse systemic complications (odds ratios [ORs] [95% CIs]: FRAIL, 1.297 [0.943-1.785]; FP, 1.317 [0.965-1.798]; CFS, 2.046 [1.413-3.015]; P < 0.001). The CFS was the best predictor of any adverse systemic complications (AUC, 0.696; 95% CI, 0.640-0.748). The predictive abilities of the FRAIL scale (AUC, 0.613; 95% CI, 0.555-0.669) and FP (AUC, 0.615; 95% CI, 0.557-0.671) were similar. The CFS and ASA assessment combined (AUC, 0.697; 95% CI, 0.641-0.749) had a statistically improved AUC compared to the ASA assessment alone (AUC, 0.636; 95% CI, 0.578-0.691), illustrating their value for predicting any adverse systemic complications. CONCLUSION: Frailty instruments enhance the accuracy of predicting postoperative outcome in older adults. Clinicians should add frailty assessments before preoperative ASA, particularly the CFS, given its ease of use and clinical feasibility.

Sewage sludge application stimulated soil N2O emissions with a low heavy metal pollution risk in Eucalyptus plantations.

Sewage sludge (SS) has been extensively used as an alternative fertilizer in forest plantations, which are beneficial in supplying timbers and mitigating climate change. However, whether the extra nitrogen (N) applied by SS would enhance the soil nitrous oxide (N2O) emission, an important greenhouse gas, in forest plantations have not been well understood. The objective of this study is to evaluate the ecological effects of SS application on soils, by investigating the soil N2O emission and the toxicity of the potentially toxic elements (PTEs) in soil. A field fertilization experiment was conducted in Eucalyptus plantations with four fertilization rates (0 kg m-2, 1.5 kg m-2, 3.0 kg m-2, and 4.5 kg m-2). The soil N2O emissions were monitored at a soil depth of 0-10 cm using static chamber method, soil chemical properties, and PTEs were determined at soil depths of 0-10 cm, 10-20 cm, and 20-40 cm. The average soil N2O emission rate was 8.1 µg N2O-N h-1 m-2 in plots without SS application (control). The application of SS significantly increased the soil N2O emissions by 7-10 times as to control. The increased N2O emissions were positively related to the soil total phosphorus and nitrogen and negatively correlated with copper and zinc, which increased with the SS application. However, the potential ecological risk index (Ei) and the comprehensive potential ecological risk index (RI) of PTEs were lower than 40 and 150 respectively, which indicating a low toxicity of PTEs to soil health. After seven months of SS application, the priming effects of SS on soil N2O emissions gradually diminished. These findings suggest that the application of SS may increase N2O emissions at the initial stages of application (<7 months) and may have a low PTEs pollution risk, even at a high SS addition rate (4.5 kg m-2).

Effect of optimizing the use of endoscope on the efficiency of microdynamic bromhidrosis removal operation.

BACKGROUND: Bromhidrosis, also known as body odor, is a common disease in life, which often occurs in young adults. The histological basis of bromhidrosis is the hyperplasia of apocrine sweat glands. OBJECTIVE: To compare the effects of different methods of endoscopy in microdynamic axillary osmidrosis removal on curative effect, complications, and surgical efficiency. METHODS: A total of 149 patients with axillary osmidrosis were treated in our hospital from January 2020 to December 2021. They were treated with endoscopic assistance in the whole process of operation (Group A) and endoscope-assisted exploration after blind rotary cutter suction (Group B), respectively, and the curative effect, complication rate, and surgical efficiency were evaluated. RESULTS: There was no significant difference in the curative effect and complication rate between the two groups, but the endoscope-assisted exploration group after suction with rotary cutter (Group B) had higher surgical efficiency. CONCLUSION: On the basis of professional use of rotary cutter, it is efficient to choose endoscope to check the excision of sweat gland in the operation area and stop bleeding in time after blind suction.

Regulatory mucosa-associated invariant T cells controlled by ß1 adrenergic receptor signaling contribute to hepatocellular carcinoma progression.

BACKGROUND AND AIMS: The innate-like mucosa-associated invariant T (MAIT) cells are enriched in human liver and have been linked to human HCC. However, their contributions to the progression of HCC are controversial due to the heterogeneity of MAIT cells, and new MAIT cell subsets remain to be explored. APPROACH AND RESULTS: Combining single cell RNA sequencing (scRNA-seq) and flow cytometry analysis, we performed phenotypic and functional studies and found that FOXP3 + CXCR3 + MAIT cells in HCC patients were regulatory MAIT cells (MAITregs) with high immunosuppressive potential. These MAITregs were induced under Treg-inducing condition and predominantly from FOXP3 - CXCR3 + MAIT cells, which displayed mild Treg-related features and represented a pre-MAITreg reservoir. In addition, the induction and function of MAITregs were promoted by ß1 adrenergic receptor signaling in pre-MAITregs and MAITregs, respectively. In HCC patients, high proportion of the intratumoral MAITregs inhibited antitumor immune responses and was associated with poor clinical outcomes. CONCLUSIONS: Together, we reveal an immunosuppressive subset of MAIT cells in HCC patients that contributes to HCC progression, and propose a control through neuroimmune crosstalk.

CO2 fractional laser combined with triamcinolone acetonide injection for the hypertrophic scars: which is first?

The aim of this study is to investigate and analyze the effect of different application sequences of CO2 fractional laser and triamcinolone acetonide injection on the application effect of hypertrophic scar in one operation. Patients with hypertrophic scars who received CO2 lattice laser combined with triamcinolone acetonide injection from January 2021 to December 2022 were retrospectively analyzed. According to the different initial operations, they were divided into CO2 FL-TA group and TA-CO2 FL group. The Vancouver Scar Scale score and scar thickness of the two groups before and after treatment were analyzed. The complications occurred in the two groups during the treatment period. The clinical efficacy of the two groups before and after the treatment was calculated. Before treatment, there was no difference in scar thickness and VSS score between the two groups (P > 0.05). After treatment, the above indexes in CO2 FL-TA group were significantly better than those in TA-CO2 FL group (P < 0.05); the incidence of adverse reactions in CO2 FL-TA group was 9.38%, which was significantly lower than that in TA-CO2 FL group (18.75%) (P < 0.05); the total effective rate of CO2 FL-TA group was 90.63%, which was significantly higher than that in TA-CO2 FL group (65.63%) (P < 0.05). In the process of combined CO2 fractional laser and triamcinolone acetonide injection in the treatment of hypertrophic scars, CO2 fractional laser treatment first, and then triamcinolone acetonide injection can reduce the number of treatments, reduce the incidence of adverse reactions, and achieve more satisfactory treatment effect.

PRR11 promotes cell proliferation by regulating PTTG1 through interacting with E2F1 transcription factor in pan-cancer.

The upregulated proline rich 11 (PRR11) plays a critical role in cancer progression. The relevant biological functions of PRR11 in pan-cancer development are not well understood. In the current study, we found that PRR11 was upregulated in 19 cancer types compared with that of normal tissues and high-expressed PRR11 was a predictor of poor prognosis in 10 cancer types by bioinformatics. Then we showed that interfering PRR11 on three cancer cell lines could greatly inhibit cell proliferation and migration and arrest cells to S phase in vivo. Based on RNA-seq, downregulation of PRR11 expression could extremely suppress the expression of PTTG1 and the cell cycle pathway identified by a differentially expressed gene analysis and an enrichment analysis. The expression of PRR11 and PTTG1 was positively correlated in TCGA and independent GEO data sets. Importantly, we revealed that the PRR11 could express itself in the nucleus and interact with E2F1 on the PTTG1 promoter region to increase the expression of PTTG1. Further results indicated that the expression of PTTG1 was also associated with poor prognosis in 10 cancer types, while downregulation of PTTG1 expression could inhibit cancer cell proliferation and migration. Therefore, we found that PRR11 served as an oncogene in pan-cancer and could influence the cell cycle progression through regulating the expression of PTTG1 by interacting with the transcription factor E2F1.

Coassembling functionalized glycopolypeptides to prepare pH-responsive self-indicating nanocomplexes to manipulate self-assembly/drug delivery and visualize intracellular drug release.

The pH-responsive polymeric micelles (PMs) have been widely used as smart nano drug delivery systems to treat tumors. However, synchronously manipulating these PMs' self-assembly properties, drug release dynamics and tracing their pH-dependent intracellular fate remain challenges. Herein, we have first synthesized hyaluronic acid (HA) based glycopolypeptides modified by tetraphenylethylene (TPE) and a pH-sensitive doxorubicin (DOX) prodrug through Diels-Alder reaction, respectively. Then, the pH-responsive nanocomplexes (NCs) were prepared by coassembling the two obtained glycopolypeptides with different formulations. Controllable size within the range of 60-125 nm and morphologies like spherical, vesicular and oblate micelles can be easily accomplished by using this method; High drug encapsulating and loading efficiency can be easily realized and adjusted within a range of 86-97% and 7-25%, respectively; Acid sensitive drug release dynamics of these NCs are also tunable by using this way. Additionally, the programmed drug release induced by subtle pH variations can be extracellularly self-indicated by detecting the blue AIE changes of the TPE units through fluorescence resonance energy transfer (FRET) effect between DOX and TPE. More importantly, the dynamic pH-triggered DOX release can be easily traced inside the tumor cells by visualizing blue emission changes of the TPE through the FRET effect. In addition, both the size and the shape can affect the endocytic routes of the NCs; The HA coated NCs targeting the tumor cells can effectively inhibit the proliferation of the HeLa cells. This work can provide a new route to acquire the stimuli-responsive self-indicating PMs with the ability to adjust their self-assembly properties and their pH-triggered drug release dynamics, and even to simultaneously visualize the PMs' intracellular fate in a real-time.

Characterizing Intercellular Communication of Pan-Cancer Reveals SPP1+ Tumor-Associated Macrophage Expanded in Hypoxia and Promoting Cancer Malignancy Through Single-Cell RNA-Seq Data.

Hypoxia is a characteristic of tumor microenvironment (TME) and is a major contributor to tumor progression. Yet, subtype identification of tumor-associated non-malignant cells at single-cell resolution and how they influence cancer progression under hypoxia TME remain largely unexplored. Here, we used RNA-seq data of 424,194 single cells from 108 patients to identify the subtypes of cancer cells, stromal cells, and immune cells; to evaluate their hypoxia score; and also to uncover potential interaction signals between these cells in vivo across six cancer types. We identified SPP1+ tumor-associated macrophage (TAM) subpopulation potentially enhanced epithelial-mesenchymal transition (EMT) by interaction with cancer cells through paracrine pattern. We prioritized SPP1 as a TAM-secreted factor to act on cancer cells and found a significant enhanced migration phenotype and invasion ability in A549 lung cancer cells induced by recombinant protein SPP1. Besides, prognostic analysis indicated that a higher expression of SPP1 was found to be related to worse clinical outcome in six cancer types. SPP1 expression was higher in hypoxia-high macrophages based on single-cell data, which was further validated by an in vitro experiment that SPP1 was upregulated in macrophages under hypoxia-cultured compared with normoxic conditions. Additionally, a differential analysis demonstrated that hypoxia potentially influences extracellular matrix remodeling, glycolysis, and interleukin-10 signal activation in various cancer types. Our work illuminates the clearer underlying mechanism in the intricate interaction between different cell subtypes within hypoxia TME and proposes the guidelines for the development of therapeutic targets specifically for patients with high proportion of SPP1+ TAMs in hypoxic lesions.