Research on reliability mapping of 5G low orbit constellation network slice based on deep reinforcement learning.

Reliability mapping of 5G low orbit constellation network slice is an important means to ensure link network communication. The problem of state space explosion is a typical problem. The deep reinforcement learning method is introduced. Under the 5G low orbit constellation integrated network architecture based on software definition network (SDN) and network function virtualization (NFV), the resource requirements and resource constraints of the virtual network function (VNF) are comprehensively considered to build the 5G low orbit constellation network slice reliability mapping model, and the reliability mapping model parameters are trained and learned by using deep reinforcement learning, solve the problem of state space explosion in the reliability mapping process of 5G low orbit constellation network slices. In addition, node backup and link backup strategies based on importance are adopted to solve the problem that VNF/link reliability is difficult to meet in the reliability mapping process of 5G low orbit constellation network slice. The experimental results show that this method improves the network throughput, packet loss rate and intra slice traffic of 5G low orbit constellation, and can completely repair network faults within 0.3 s; For different number of 5G low orbit constellation network slicing requests, the reliability of this method remains above 98%; For SFC with different lengths, the average network delay of this method is less than 0.15 s.

Oxytocin Alleviates Colitis and Colitis-Associated Colorectal Tumorigenesis via Noncanonical Fucosylation.

Colon cancer is increasing worldwide and is commonly regarded as hormone independent, yet recent reports have implicated sex hormones in its development. Nevertheless, the role of hormones from the hypothalamus-hypophysis axis in colitis-associated colorectal cancer (CAC) remains uncertain. In this study, we observed a significant reduction in the expression of the oxytocin receptor (OXTR) in colon samples from both patient with colitis and patient with CAC. To investigate further, we generated mice with an intestinal-epithelium-cell-specific knockout of OXTR. These mice exhibited markedly increased susceptibility to dextran-sulfate-sodium-induced colitis and dextran sulfate sodium/azoxymethane-induced CAC compared to wild-type mice. Our findings indicate that OXTR depletion impaired the inner mucus of the colon epithelium. Mechanistically, oxytocin was found to regulate Mucin 2 maturation through ß1-3-N-acetylglucosaminyltransferase 7 (B3GNT7)-mediated fucosylation. Interestingly, we observed a positive correlation between B3GNT7 expression and OXTR expression in human colitis and CAC colon samples. Moreover, the simultaneous activations of OXTR and fucosylation by l-fucose significantly alleviated tumor burden. Hence, our study unveils oxytocin's promising potential as an affordable and effective therapeutic intervention for individuals affected by colitis and CAC.

Multiple brain abscesses caused by Nocardia farcinica infection after hand injury: A case report and literature review.

RATIONALE: Nocardia infection is commonly regarded as an opportunistic pulmonary pathogen affecting debilitated or immunocompromised individuals. Brain abscesses caused by Nocardia farcinica are rare and pose a diagnostic challenge. Traditional diagnostic techniques for identifying Nocardia species, such as blood culture, microscopy, and pathology, have shown inadequate performance. In the reported case, we applied metagenomic next-generation sequencing (mNGS) to diagnose a case of brain abscess due to N. farcinica. PATIENT CONCERNS: A 66-year-old female developed a brain abscess after sustaining a hand injury. The patient exhibited a gradual change in personality and experienced tremors in her right upper limb for a duration of 1 month. DIAGNOSES: The pathogen responsible for the multiple brain abscesses was identified in the cerebrospinal fluid as N. farcinica through mNGS. INTERVENTIONS: Antibiotic treatment included trimethoprim-sulfamethoxazole, linezolid, amikacin, meropenem, and moxifloxacin. OUTCOMES: The patient's symptoms and signs improved significantly after administration of antibiotics to which the pathogen is known to be sensitive. After 5 months of follow-up, magnetic resonance imaging of the head showed that the abscess was basically cured. The patient lived a normal life with no adverse drug reactions. LESSONS: Nocardia brain infection is characterized by an insidious onset and lacks distinctive clinical and imaging features. mNGS was advantageous for the timely identification and management of Nocardia-associated brain abscess in the present case and obviated the need for invasive brain surgery. Expeditious and precise diagnosis coupled with prompt antibiotic therapy can significantly reduce the mortality rate associated with this condition.

Gut microbial metabolites in lung cancer development and immunotherapy: Novel insights into gut-lung axis.

Metabolic derivatives of numerous microorganisms inhabiting the human gut can participate in regulating physiological activities and immune status of the lungs through the gut-lung axis. The current well-established microbial metabolites include short-chain fatty acids (SCFAs), tryptophan and its derivatives, polyamines (PAs), secondary bile acids (SBAs), etc. As the study continues to deepen, the critical function of microbial metabolites in the occurrence and treatment of lung cancer has gradually been revealed. Microbial derivates can enter the circulation system to modulate the immune microenvironment of lung cancer. Mechanistically, oncometabolites damage host DNA and promote the occurrence of lung cancer, while tumor-suppresive metabolites directly affect the immune system to combat the malignant properties of cancer cells and even show considerable application potential in improving the efficacy of lung cancer immunotherapy. Considering the crosstalk along the gut-lung axis, in-depth exploration of microbial metabolites in patients' feces or serum will provide novel guidance for lung cancer diagnosis and treatment selection strategies. In addition, targeted therapeutics on microbial metabolites are expected to overcome the bottleneck of lung cancer immunotherapy and alleviate adverse reactions, including fecal microbiota transplantation, microecological preparations, metabolite synthesis and drugs targeting metabolic pathways. In summary, this review provides novel insights and explanations on the intricate interplay between gut microbial metabolites and lung cancer development, and immunotherapy through the lens of the gut-lung axis, which further confirms the possible translational potential of the microbiome metabolome in lung cancer treatment.

Post-stroke cognitive impairment: exploring molecular mechanisms and omics biomarkers for early identification and intervention.

Post-stroke cognitive impairment (PSCI) is a major stroke consequence that has a severe impact on patients' quality of life and survival rate. For this reason, it is especially crucial to identify and intervene early in high-risk groups during the acute phase of stroke. Currently, there are no reliable and efficient techniques for the early diagnosis, appropriate evaluation, or prognostication of PSCI. Instead, plenty of biomarkers in stroke patients have progressively been linked to cognitive impairment in recent years. High-throughput omics techniques that generate large amounts of data and process it to a high quality have been used to screen and identify biomarkers of PSCI in order to investigate the molecular mechanisms of the disease. These techniques include metabolomics, which explores dynamic changes in the organism, gut microbiomics, which studies host-microbe interactions, genomics, which elucidates deeper disease mechanisms, transcriptomics and proteomics, which describe gene expression and regulation. We looked through electronic databases like PubMed, the Cochrane Library, Embase, Web of Science, and common databases for each omics to find biomarkers that might be connected to the pathophysiology of PSCI. As all, we found 34 studies: 14 in the field of metabolomics, 5 in the field of gut microbiomics, 5 in the field of genomics, 4 in the field of transcriptomics, and 7 in the field of proteomics. We discovered that neuroinflammation, oxidative stress, and atherosclerosis may be the primary causes of PSCI development, and that metabolomics may play a role in the molecular mechanisms of PSCI. In this study, we summarized the existing issues across omics technologies and discuss the latest discoveries of PSCI biomarkers in the context of omics, with the goal of investigating the molecular causes of post-stroke cognitive impairment. We also discuss the potential therapeutic utility of omics platforms for PSCI mechanisms, diagnosis, and intervention in order to promote the area's advancement towards precision PSCI treatment.

Geochemical Characteristics and Origin of Sinian-Cambrian Natural Gas in Penglai Gas Area, Sichuan Basin.

The Sichuan Basin in southern China is well-known for its large natural gas resource potential stored in Sinian-Cambrian systems. Recently, high-yield industrial gas flow has been discovered from the Dengying Formation (Sinian System) and Canglangpu Formation (Cambrian System) in the Penglai gas area, preluding the multilayer stereoscopic exploration in Sichuan Basin. However, the origin of the natural gas and its preserving mechanics is still debated, and thus, in this study the geochemical characteristics of the natural gas are systematically analyzed, based on the data from gas composition and hydrocarbon isotope of a series of local wells. On this basis, the geochemical characteristics of natural gas in different regions and layers are compared, and the reasons for these differences from the origin and influencing factors are analyzed. The results show the following: (1) The natural gas of the Penglai gas field is dry gas dominated by CH4, and the Sinian Dengying Formation gas has lower C2H6 content, larger dryness coefficient, heavier δ13C, and lighter δ2HCH4 than the Cambrian gas, which is associated with the high proportion of hydrocarbons from the high-maturity Dengying source rocks. (2) The natural gas from some wells in the lower part of the structure is characterized by high H2S content and low CH4 content, and heavy δ13C in the components, which seems to be affected by the thermochemical sulfate reduction (TSR) effect. (3) The natural gas from the Penglai gas area has a relatively low maturity, which appears to be attributed to the continuous sealing ability of the caprock, which can preserve both the early generated gas and the late thermal-cracked gas.

Cardiac electrophysiology, structure and diastolic function in patients with diabetic foot versus those without diabetic foot.

AIMS/INTRODUCTION: To evaluate the differences in cardiac autonomic function, cardiac structure and diastolic function between individuals with diabetic foot (DF) and those with diabetes but without DF. MATERIALS AND METHODS: A total of 413 individuals with DF and 437 without DF who underwent a 24-h electrocardiogram Holter and a Doppler echocardiogram were included. The heart rate variability parameters to evaluate cardiac autonomic function, and the indices for the assessment of cardiac structure and left ventricular (LV) diastolic function, including left atrium, LV posterior wall thickness, interventricular septum and E/e' ratio, were measured or calculated. Propensity score matching was used for the sensitivity analysis to minimize potential imbalance. RESULTS: In both the crude and propensity score matching analyses, significant differences were observed in heart rate variability between individuals with and without DF, as evidenced by lower standard deviation of the normal sinus interval, lower low-frequency power/high-frequency power ratio, lower standard deviation of the 5-min average RR intervals, lower low-frequency power, lower percentage of normal adjacent RR interval difference >50 ms, lower root mean square of successive RR interval differences and lower high-frequency power (all P < 0.05). In multivariate analysis, DF showed an independent negative correlation with the aforementioned indices of heart rate variability (all P < 0.05). Individuals with DF showed higher left atrium, LV posterior wall thickness, interventricular septum and a higher E/e' ratio than those without DF in the crude analysis (all P < 0.05), whereas these indices were no longer associated with DF in the multivariate analysis and the propensity score matching analyses. CONCLUSIONS: Cardiac autonomic modulation was more severely impaired in individuals with DF than in their counterparts without DF. There has been insufficient evidence to demonstrate the independent association of DF and LV diastolic dysfunction.

Adult ovarian and sellar region mixed germ cell tumor: a case report and literature review.

Mixed germ cell tumors (mGCTs) involving both the ovaries and sellar region have been rarely reported; thus, they pose significant challenges in clinical management. Our report of a case of a 26-year-old female with left ovarian mGCTs (dysgerminoma + yolk sac tumor) who presented with postoperative headaches and blurred vision contributes new information to the literature on treating mGCTs, which can lead to standardized regimens and sequencing guidelines. A physical examination revealed right temporal hemianopia, and elevated levels of alpha-fetoprotein were detected in serum and cerebrospinal fluid. Magnetic resonance imaging (MRI) of the sellar region revealed a space-occupying lesion. Pathological examination of the tumor after endoscopic transnasal resection confirmed the diagnosis of mGCTs (germinomas + yolk sac tumor). The patient received adjuvant chemotherapy and radiotherapy at reduced dosages. During follow-up, tumor markers remained within normal limits, and there was no evidence of tumor recurrence on sellar region MRI. This case highlights the rarity of the simultaneous occurrence of ovarian and sellar region mGCTs and emphasizes the importance of accurate diagnosis and multidisciplinary management.

Knowledge, Attitudes, and Practices about Hyperuricemia and Gout in Community Health Workers and Patients with Diabetes.

Hyperuricemia exhibits a high incidence among individuals with diabetes; however, the significance of hyperuricemia and gout is often underestimated. This study aimed to assess the knowledge, attitude, and practice of hyperuricemia and gout among community health workers and patients with diabetes. Two questionnaires were designed to investigate knowledge, attitudes, and practices of hyperuricemia and gout among community health workers and patients with diabetes in Chenghua District, Chengdu, from August 2021 to January 2022. A total of 709 community health workers were included, whose average score was 17.74/30. Approximately half of general practitioners (GPs) demonstrated knowledge regarding the target serum uric acid levels for hyperuricemia and gout. Only 11.2% of GPs were fully aware of the preferred medicine for acute gout. The majority of GPs (86.7%) demonstrated limited awareness regarding the contraindications associated with colchicine, while a significant proportion (65.1%) lacked knowledge about the specific classes of drugs that inhibit uric acid synthesis. Among the 508 patients with diabetes included in this survey, 32.3% demonstrated awareness of hyperuricemia, while 60.8% exhibited knowledge regarding gout. The average score attained by these individuals was recorded at 7.21 out of a total of 26 points. The majority of patients with diabetes (87.8%) held the mistaken belief that hyperuricemia definitely led to the development of gout. Almost 66% agreed that a massage or a hot compress could be used when acute gouty arthritis attacks. The knowledge rate of hyperuricemia and gout among community health workers was moderate, while it was low in patients with diabetes.

Analysis of Imaging and Pathologic Features in Eosinophilic Solid and Cystic Renal Cell Carcinoma.

OBJECTIVE: Eosinophilic solid and cystic renal cell carcinoma (ESC-RCC) is rare and difficult to diagnose. Therefore, we aim to investigate the imaging and pathologic features of ESC-RCC. METHODS: Fifteen cases of ESC-RCC with pathologically confirmed diagnoses were retrospectively collected: CT was performed in 15 cases and MRI in 9 cases. RESULTS: In these patients (6 males and 9 females) (age: mean, 53.3 ± 14.7 years; range, 27-72 years), all tumors were unilateral, renal, and solitary with no clinical symptoms and were classified into-type 1: cystic-solid component, with equal cystic and solid components, was the most common (8/15, 53.3%); type 2: predominantly cystic with a small solid component (4/15, 26.7%); and type 3: predominantly solid (3/15, 20%). The solid component showed equal/slightly higher density on the CT-plain-scan, equal/slightly high signal on the T1-weighted image (T1WI), and low signal on the T2-weighted image (T2WI). Ten cases showed progressive enhancement, while 5 showed a fast-wash-in and fast-wash-out enhancement. One patient experienced hemorrhage, while the others showed no signs of hemorrhage, necrosis, fat, or calcification. Pathologically, the tumor showed cystic solidity, with eosinophilic cytoplasm and granular basophilic-colored spots with focal or diffuse expression of CK20. Ten patients had componential nephrectomy and 5 had radical nephrectomy. No recurrence or metastasis was noted in any case at the follow-up (8-49 months). CONCLUSION: This study describes the imaging and pathologic features of a rare type of renal cancer and proposes 3 imaging types to enhance physicians' diagnosis of this disease and guide clinical diagnosis and treatment.

Sex-specific Difference for Small Cell Lung Cancer from Immunotherapy Advancement.

BACKGROUND: The treatment of lung cancer has witnessed significant progress, leading to improved survival rates among patients. It is important to assess the individual contributions of non-small cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) to overall lung-cancer incidence and mortality trends based population, especially sex difference. METHODS: We analyzed lung cancer mortality based on subtype, gender, and calendar year. The Joinpoint software was used to identify any changes in incidence and trends in mortality. RESULTS: Incidence and incidence-based mortality declined from 2001 to 2019 both NSCLC and SCLC annually. The most significant decrease occurred between 2016 and 2019 with annual percent change of 5.71%. From 2012 to 2016, the incidence-based mortality of SCLC in women changed by 2.7% in tandem with incidence decreased 2.84%. Remarkably, the incidence-based mortality for women declined notably by 5.23% between 2016 and 2019, even as the incidence showed a less extent of decreasing (-2.59%). The survival rate for women was 15.2% in 2001, 19.3% in 2016, it had increased to 21.3% in 2018 but similar trends not in men. The survival curve showed the change in survival outcomes over time among men and women (median overall survival: 13 vs 23months) receiving immunotherapy for SCLC. CONCLUSION: Population-level mortality from NSCLC and SCLC in the United States fell sharply from 2016 to 2019 as incidence deceased, and survival improved substantially. Our analysis suggests that approval for and use of immunotherapy may explain the mortality reduction observed during this period, with significant benefits especially for SCLC patient in women.

The mother-offspring transfer of chlorothalonil through human breast milk: A multi-city cross-sectional study.

4-Hydroxychlorothalonil (4-OH CHT), the main metabolite of chlorothalonil and the most widely used fungicide, has been frequently detected in human samples during monitoring. 4-OH CHT may exhibit higher toxicity and persistence in the environment compared to its prototype. In this study, a total of 540 paired serum and breast milk samples from pregnant women in three provinces in China were monitored for contaminant residues. 4-OH CHT was analyzed in the samples using ultra high-performance liquid chromatography - high-resolution mass spectrometry with a detection limit of 20 ng/L. The study investigated the effects of demographic factors, such as BMI, region of residence, and education level, on the levels of 4-OH CHT residues in serum and breast milk. Among the three provinces, the highest median concentration of 4-OH CHT in serum samples was observed in Hebei (1.04 × 103 ng/L), while the highest median concentration of 4-OH CHT in breast milk samples was observed in Hubei and Guangdong (491 ng/L). Multiple linear regression was used to investigate the significant positive correlation between 4-OH CHT in serum and breast milk (p = 0.000) after adjusting for personal characteristics. Based on this, the study further explored the influencing factors of transfer efficiencies (TEs) in conjunction with the individual TEs and the personal characteristics of the participants. Our results demonstrated that the age of the volunteers and their exercise habits had an effect on TEs, but further studies are needed to determine whether exercise leads to an increase in TEs.

Dual inhibitors of DNMT and HDAC remodels the immune microenvironment of colorectal cancer and enhances the efficacy of anti-PD-L1 therapy.

Colorectal cancer is the second most prevalent and deadly cancer worldwide. The emergence of immune checkpoint therapy has provided a revolutionary strategy for the treatment of solid tumors. However, less than 5 % of colorectal cancer patients respond to immune checkpoint therapy. Thus, it is of great scientific significance to develop "potentiators" for immune checkpoint therapy. In this study, we found that knocking down different DNMT and HDAC isoforms could increase the expression of IFNs in colorectal cancer cells, which can enhance the effectiveness of immune checkpoint therapy. Therefore, the combined inhibition of DNMT and HDAC cloud synergistically enhance the effect of immunotherapy. We found that dual DNMT and HDAC inhibitors C02S could inhibit tumor growth in immunocompetent mice but not in immunocompromised nude mice, which indicates that C02S exerts its antitumor effects through the immune system. Mechanistically, C02S could increase the expression of ERVs, which generated the intracellular levels of dsRNA in tumor cells, and then promotes the expression of IFNs through the RIG-I/MDA5-MAVS signaling pathway. Moreover, C02S increased the immune infiltration of DCs and T cells in microenvironment, and enhanced the efficacy of anti-PD-L1 therapy in MC38 and CT26 mice model. These results confirmed that C02S can activate IFNs through the RIG-I/MDA5-MAVS signaling pathway, remodel the tumor immune microenvironment and enhance the efficacy of immune checkpoint therapy, which provides new evidence and solutions for the development of "potentiator" for colorectal cancer immunotherapy.

A Cytochrome P450 Enzyme Catalyses Oxetane Ring Formation in Paclitaxel Biosynthesis.

Oxetane synthase (TmCYP1), a novel cytochrome P450 enzyme from Taxus×media cell cultures, has been functionally characterized to efficiently catalyse the formation of the oxetane ring in tetracyclic taxoids. Transient expression of TmCYP1 in Nicotiana benthamiana using 2α,5α,7ß,9α,10ß,13α-hexaacetoxytaxa-4(20),11(12)-diene (1) as a substrate led to the production of a major oxetane derivative, 1ß-dehydroxybaccatin IV (1 a), and a minor 4ß,20-epoxide derivative, baccatin I (1 b). However, feeding the substrate decinnamoyltaxinine J (2), a 5-deacetylated derivative of 1, yielded only 5α-deacetylbaccatin I (2 b), a 4ß,20-epoxide. A possible reaction mechanism was proposed on the basis of substrate-feeding, 2H and 18O isotope labelling experiments, and density functional theory calculations. This reaction could be an intramolecular oxidation-acetoxyl rearrangement and the construction of the oxetane ring may occur through a concerted process; however, the 4ß,20-epoxide might be a shunt product. In this process, the C5-O-acetyl group in substrate is crucial for the oxetane ring formation but not for the 4(20)-epoxy ring formation by TmCYP1. These findings provide a better understanding of the enzymatic formation of the oxetane ring in paclitaxel biosynthesis.

Enhanced selectivity for convenient extraction of acidic mycotoxins using a miniaturized centrifugal integrated cold-induced phase separation: Determination of fumonisins and ochratoxins in cereals as a proof-of-concept study.

Starches-rich and protein-rich cereal samples commonly need tedious sample preparation steps before instrumental analysis. This study developed a miniaturized centrifugal integrated cold-induced phase separation (CIPS) method for convenient sample preparation. A small-sized centrifuge tube (2 mL) and a low-temperature centrifuge, both of which are easily accessible, make up the basic components of the system. Unlike conventional sample preparation methods that need a step-by-step extraction, enrichment, purification, and centrifugation, this centrifugal integrated CIPS method can be performed by a one-step combination protocol under a low-temperature centrifuge. As a proof-of-concept study, satisfactory recoveries and enrichment factors were demonstrated for the extraction of fumonisins and ochratoxins from cereals. A sensitive and selective quantification method was yielded by combining LC-HRMS using tSIM acquisition mode, with good linearity (R2 > 0.998), accuracy (82.9-106.5%), and precision (<13.4%). This strategy is convenient, low-cost, repeatable, and easy to semi-automate, further expanding the extraction potential for other acidic mycotoxins.

LILRB2 inhibition enhances radiation sensitivity in non-small cell lung cancer by attenuating radiation-induced senescence.

Radiotherapy (RT) in non-small cell lung cancer (NSCLC) triggers cellular senescence, complicating tumor microenvironments and affecting treatment outcomes. This study examines the role of lymphocyte immunoglobulin-like receptor B2 (LILRB2) in modulating RT-induced senescence and radiosensitivity in NSCLC. Through methodologies including irradiation, lentivirus transfection, and various molecular assays, we assessed LILRB2's expression and its impact on cellular senescence levels and tumor cell behaviors. Our findings reveal that RT upregulates LILRB2, facilitating senescence and a senescence-associated secretory phenotype (SASP), which in turn enhances tumor proliferation and resistance to radiation. Importantly, LILRB2 silencing attenuates these effects by inhibiting the JAK2/STAT3 pathway, significantly increasing radiosensitivity in NSCLC models. Clinical data correlate high LILRB2 expression with reduced RT response and poorer prognosis, suggesting LILRB2's pivotal role in RT-induced senescence and its potential as a therapeutic target to improve NSCLC radiosensitivity.

Clinical characteristics of liver transplant recipients with COVID-19 and analysis of risk factors for the severe disease.

INTRODUCTION: Liver transplant (LT) recipients were at a high risk of infection during the coronavirus disease 2019 (COVID-19) pandemic. Our purpose was to compare the clinical characteristics of severe and non-severe groups of LT recipients with COVID-19, and to analyze their risk factors for severe disease. METHODOLOGY: 79 LT recipients with COVID-19 were divided into a non-severe group (n = 60) and a severe group (n = 19), and differences in clinical characteristics, laboratory tests, and chest computed tomography (CT) performance were analyzed. Logistic regression was used to identify risk factors with severe COVID-19. Receiver operating characteristic (ROC) curves were plotted and the area under curve (AUC) values were calculated to assess the predictive value for severe COVID-19. RESULTS: Age was statistically different (p < 0.001) between the two groups. The difference in neutrophil-to-lymphocyte ratio (NLR), serum creatinine (Scr), D-dimer, urea, C-reactive protein (CRP), lactate dehydrogenase (LDH), and the number of lung segments involved in inflammation between the two groups were statistically significant (p < 0.05). The results revealed that age (OR = 1.255, 95% CI 1.079-1.460), NLR (OR = 1.172, 95% CI 1.019-1.348), and Scr (OR = 1.041, 95% CI 1.016-1.066) were independent risk factors for severe COVID-19. The ROC results showed that high values for age, NLR and Scr predicted severe COVID-19, with AUC values of 0.775, 0.841 and 0.820, respectively, and 0.925 for the three factors combined. CONCLUSIONS: Advanced age, and elevated NLR and Scr are independent risk factors for severe COVID-19 in LT recipients.

Spatial interaction and functional status of CD68+SHP2+ macrophages in tumor microenvironment correlate with overall survival of NSCLC.

Background: Tumor-associated macrophages (TAMs) constitute a plastic and heterogeneous cell population of the tumor microenvironment (TME) that can regulate tumor proliferation and support resistance to therapy, constituting promising targets for the development of novel anticancer agents. Our previous results suggest that SHP2 plays a crucial role in reprogramming the phenotype of TAMs. Thus, we hypothesized that SHP2+ TAM may predict the treatment efficacy of non-small cell lung cancer NSCLC patients as a biomarker. Methods: We analyzed cancer tissue samples from 79 NSCLC patients using multiplex fluorescence (mIF) staining to visualize various SHP-2+ TAM subpopulations (CD68+SHP2+, CD68+CD86+, CD68 + 206+, CD68+ CD86+SHP2+, CD68+ CD206+SHP2+) and T cells (CD8+ Granzyme B +) of immune cells. The immune cells proportions were quantified in the tumor regions (Tumor) and stromal regions (Stroma), as well as in the overall tumor microenvironment (Tumor and Stroma, TME). The analysis endpoint was overall survival (OS), correlating them with levels of cell infiltration or effective density. Cox regression was used to evaluate the associations between immune cell subsets infiltration and OS. Correlations between different immune cell subsets were examined by Spearman's tests. Results: In NSCLC, the distribution of different macrophage subsets within the TME, tumor regions, and stroma regions exhibited inconsistency. The proportions of CD68+ SHP2+ TAMs (P < 0.05) were higher in tumor than in stroma. And the high infiltration of CD68+SHP2+ TAMs in tumor areas correlated with poor OS (P < 0.05). We found that the expression level of SHP2 was higher in M2-like macrophages than in M1-like macrophages. The CD68+SHP2+ subset proportion was positively correlated with the CD68+CD206+ subset within TME (P < 0.0001), tumor (P < 0.0001) and stroma (P < 0.0001). Conclusions: The high infiltration of CD68+SHP2+ TAMs predict poor OS in NSCLC. Targeting SHP2 is a potentially effective strategy to inhibit M2-phenotype polarization. And it provides a new thought for SHP2 targeted cancer immunotherapy.

Membrane Fusion Liposomes Deliver Antifibrotic and Chemotherapeutic Drugs Sequentially to Enhance Tumor Treatment Efficacy by Reshaping Tumor Microenvironment.

The intricate tumor microenvironment in triple-negative breast cancer (TNBC) hampers chemotherapy and immunotherapy efficacy due to dense extracellular matrix (ECM) by tumor-associated fibroblasts (TAFs). Nanoparticle-based therapies, especially "all-in-one" nanoparticles, have shown great potential in combined drug delivery strategies to reshape the tumor microenvironment and enhance therapeutic efficiency. However, these "all-in-one" nanoparticles suffer from limitations in targeting different target cells, uncontrollable dosing ratio, and disregarding the impact of delivery schedules. This study prepared cell membrane fusion liposomes (TAFsomes and CCMsomes) to load FDA-approved antifibrotic drug pirfenidone (PFD/TAFsomes) and antitumor drug doxorubicin (DOX/CCMsomes). These liposomes can specifically target TAFs cells and tumor cells, and combined administration can effectively inhibit TAFs activity, reshape the tumor microenvironment (TME), and significantly enhance the tumor chemotherapy efficacy. Combined drug delivery defeats "all-in-one" liposomes (DOX/PFD/Liposomes, DOX/PFD/TAFsomes, and DOX/PFD/CCMsomes) by flexibly adjusting the drug delivery ratio. Moreover, an asynchronous delivery strategy that optimizes the administration schedule not only further improves the therapeutic effect, but also amplifies the effectiveness of α-PD-L1 immunotherapy by modulating the tumor immune microenvironment. This delivery strategy provides a personalized treatment approach with clinical translation potential, providing new ideas for enhancing the therapeutic effect against solid tumors such as TNBC.