Single-cell transcriptomics reveal distinct immune-infiltrating phenotypes and macrophage-tumor interaction axes among different lineages of pituitary neuroendocrine tumors.

BACKGROUND: Pituitary neuroendocrine tumors (PitNETs) are common gland neoplasms demonstrating distinctive transcription factors. Although the role of immune cells in PitNETs has been widely recognized, the precise immunological environment and its control over tumor cells are poorly understood. METHODS: The heterogeneity, spatial distribution, and clinical significance of macrophages in PitNETs were analyzed using single-cell RNA sequencing (scRNA-seq), bulk RNA-seq, spatial transcriptomics, immunohistochemistry, and multiplexed quantitative immunofluorescence (QIF). Cell viability, cell apoptosis assays, and in vivo subcutaneous xenograft experiments have confirmed that INHBA-ACVR1B influences the process of tumor cell apoptosis. RESULTS: The present study evaluated scRNA-seq data from 23 PitNET samples categorized into 3 primary lineages. The objective was to explore the diversity of tumors and the composition of immune cells across these lineages. Analyzed data from scRNA-seq and 365 bulk RNA sequencing samples conducted in-house revealed the presence of three unique subtypes of tumor immune microenvironment (TIME) in PitNETs. These subtypes were characterized by varying levels of immune infiltration, ranging from low to intermediate to high. In addition, the NR5A1 lineage is primarily associated with the subtype characterized by limited infiltration of immune cells. Tumor-associated macrophages (TAMs) expressing CX3CR1+, C1Q+, and GPNMB+ showed enhanced contact with tumor cells expressing NR5A1 + , TBX19+, and POU1F1+, respectively. This emphasizes the distinct interaction axes between TAMs and tumor cells based on their lineage. Moreover, the connection between CX3CR1+ macrophages and tumor cells via INHBA-ACVR1B regulates tumor cell apoptosis. CONCLUSIONS: In summary, the different subtypes of TIME and the interaction between TAM and tumor cells offer valuable insights into the control of TIME that affects the development of PitNET. These findings can be utilized as prospective targets for therapeutic interventions.

PLZF restricts intestinal ILC3 function in gut defense.

Group 3 innate lymphoid cells (ILC3s) play important roles in maintaining intestinal homeostasis by protecting the host from pathogen infections and tissue inflammation. The transcription factor PLZF (promyelocytic leukemia zinc finger), encoded by zinc finger BTB domain containing 16 (Zbtb16), is highly and transiently expressed in ILC precursors (ILCPs). However, the role of PLZF in regulating ILC3 development and function remains unknown. Here, we show that PLZF was specifically expressed in mature intestinal ILC3s compared with other ILC subsets. PLZF was dispensable for ILC3 development. However, PLZF deficiency in ILC3s resulted in increased innate interleukin-22 (IL-22) secretion and protection against gut infection and inflammation. Mechanistically, PLZF negatively regulated IL-22 expression by ILC3s in a cell-intrinsic manner by binding to the IL-22 promoter region for transcriptional repression. Together, our data suggest that PLZF restricts intestinal ILC3 function to regulate gut immune homeostasis.

Optimal information disclosure strategy in the primary healthcare service market: From the perspective of signaling theory.

The promotion of general practitioner (GP) contract service is one of the key components of China's healthcare reform. We consider GPs providing primary health services with private competency information over two periods, where patients decide when to sign. Two types of GPs are considered: those with higher and lower competency. Under asymmetric information, to spur the patients' incentive to sign, the GPs can move to offer competency disclosure schemes to patients, for example, separating or pooling, through which true competency information is revealed, respectively. We investigate three scenarios, which are referred to as "separating-separating," "pooling-separating," and "pooling-pooling." The results of the three scenarios yield intriguing insights into the impact of the GP's competency disclosure decisions. Findings include that GPs prefer the "pooling-separating" strategy, but patients prefer "separating-separating." Besides, an extremely low cure rate may enable GPs to conceal some competency information. Furthermore, low-competency GPs may exaggerate their competency level for profit, but greater efforts in disclosing competency information may result in diminished benefits. Therefore, to promote the services of GPs, the core is always to improve GPs' competency.

Payments for environmental services strategy for transboundary air pollution: A stochastic differential game perspective.

Air pollution has become a global threat to societal development. The main challenges of transboundary air pollution control include two perspectives: uneven socioeconomic development of regions and the diffusion of air pollution. This paper proposes an PES strategy to alleviate transboundary air pollution by coordinating regional economic interests and environmental preferences within the joint prevention and control of air pollution region. To make the model design more realistic, we introduce the stochastic differential game model to characterize the diffusion and uncertainty of air pollution. The optimal feedback Nash equilibrium is derived in three PES scenarios (no PES, dynamic PES, and fixed-fee PES) by using the Hamilton-Jacobi-Bellman equation. Numerical simulations and sensitivity analysis are implemented to compare the optimal strategies under the three PES scenarios. The dynamic PES strategy is shown to outperform the no PES strategy and the fixed-fee PES strategy by encouraging the backward region to cut more emissions. Besides, the confidence interval theory is used to estimate the variation range of air pollution stocks, which provides a powerful diagnostic tool for policy-makers.

ILC1s and ILC3s Exhibit Inflammatory Phenotype in Periodontal Ligament of Periodontitis Patients.

Innate lymphoid cells (ILCs) are emerging as important players in inflammatory diseases. The oral mucosal barrier harbors all ILC subsets, but how these cells regulate the immune responses in periodontal ligament tissue during periodontitis remains undefined. Here, we show that total ILCs are markedly increased in periodontal ligament of periodontitis patients compared with healthy controls. Among them, ILC1s and ILC3s, particularly NKp44+ILC3 subset, are the predominant subsets accumulated in the periodontal ligament. Remarkably, ILC1s and ILC3s from periodontitis patients produce more IL-17A and IFN-γ than that from healthy controls. Collectively, our results highlight the role of ILCs in regulating oral immunity and periodontal ligament inflammation and provide insights into targeting ILCs for the treatment of periodontitis.

[Enoxaparin for the prevention of post surgical pulmonary embolism].

OBJECTIVE: To evaluate the efficacy and safety of the administration of enoxaparin, a low molecular weight heparin (LMWH), in the prevention of post surgical deep vein thrombosis (DVT) and pulmonary embolism (PE). METHODS: 1928 patients hospitalized for general surgery were randomly divided into: (1) test group (n = 960) to receive enoxaparin (40 mg, s.c., 12 hours before and after surgery, then once daily for 7 consecutive days); (2) control group (n = 968) without intervention. The incidence of DVT,PE and bleeding were recorded for statistical analysis during hospitalization and a 2 months follow-up after discharge. RESULTS: (1) No significant difference was found between the two groups in age, sex, average body mass index, type of surgery, and DVT / PE risk factors (obesity, varicose veins, and history of: venous thrombosis, chronic obstructive pulmonary disease, chronic heart failure, and hormone therapy). The percentage of non-malignant / malignant tumor surgery were 36.5% / 63.5% (average operation time 2.3 hours) in control group and 35.6% / 64.4% (2.2 hours) in test group (both P > 0.05). (2) During the hospitalization period, 59 cases (incidence=6.1%) of DVT and 14 cases (incidence=1.4%) of PE (among them 6 were fetal, 42.8% of all PE cases) were found in the control group, while 28 cases of DVT (2.9%) and 3 cases (0.3%) of PE (1 fetal, 33.3% of all PE cases) were found in test group. The incidence of DVT, PE (total), and PE (fetal) were significant lower in test group (P < 0.05 or P < 0.01). During the follow up, 14 more cases of DVT (1.4%) and 1 more case (0.1%) of PE (a fetal) were found in the control group, and 2 more DVT cases (0.2%) in test group, with the DVT incidence in test group significantly lower (P < 0.01). (3) During the enoxaparin administration, 30 cases (3.1%) minor bleeding and 8 cases (0.8%) major bleeding were found in the control group, while 33 cases (3.4%) minor bleeding events and 9 cases (0.9%) major bleeding events were found in the test group. THE RESULTS: in the two groups were not significantly different in either type of bleeding events (both P > 0.05). Also no significant difference was found in the bleeding events after the ending of enoxaparin administration and during the follow up. CONCLUSION: Enoxaparin may reduce the incidence of DVT and PE in patients undergoing general surgery without increased risk of bleeding.

Second-line combination chemotherapy with docetaxel and nedaplatin for Cisplatin-pretreated refractory metastatic/recurrent esophageal squamous cell carcinoma.

BACKGROUND: There is an urgent need for an effective second-line chemotherapy regimen after failure of the standard cisplatin and 5-fluorouracil therapy. PATIENTS AND METHODS: This study investigated the efficacy and toxicity of the combination of docetaxel (30 mg/m2) during a 1-hour infusion, followed by nedaplatin (50 mg/m2) during a 2-hour infusion (both drugs were administered on day 1 as an outpatient regimen and repeated every 2 weeks) as second-line chemotherapy for patients with cisplatin-pretreated refractory metastatic/recurrent esophageal squamous cell carcinoma after surgery. RESULTS: Forty-six of the 48 patients (95.8%) were assessable for response. Partial response was confirmed in 13 of 48 cases yielding a response rate of 27.1% (95% confidence interval [CI], 14.5-39.7%). The median overall time to progression and overall survival was 3.1 months (95% CI, 2.3-3.9 months) and 5.9 months (95% CI, 3.9-7.8 months), respectively. The estimate of overall survival at 12 months was 16.7% (95% CI, 6.1-27.2%). Grade 3 anemia leucopenia, grade 4 anemia leucopenia and neutropenia were detected in only 4 (8.7%), 8 (17.4%), and 9 patients (19.6%), respectively. CONCLUSIONS: The combination chemotherapy of docetaxel and nedaplatin in the outpatient setting is well tolerated and useful as second-line chemotherapy for cisplatin-pretreated refractory metastatic/recurrent esophageal squamous cell carcinoma.