Estimating the efficiency of primary health care services and its determinants: evidence from provincial panel data in China.

Background: The efficiency of primary health care services is drawing increased attention worldwide, especially in developing countries. Health care reform in China has moved into the 'deep water zone' phase and is facing the dilemma of inefficiency in primary health care services, which is a critical challenge for universal health coverage. Methods: In this study, we estimate the efficiency of primary health care services in China and its determinants. A combination of a super-SBM (Slack-Based Measure) model, a Malmquist productivity index model and a Tobit model is used to study provincial panel data, and the results demonstrate the inefficiency of primary health care services in China and the variations in efficiency values between regions. Results: Over time, the productivity of primary health care services shows a decreasing trend, mainly due to slowing technology change. Financial support is needed to improve the efficiency of primary health care services, but it is worth noting that existing social health insurance coverage decreases efficiency, while economic development, urbanization and education also have a significant impact. Conclusion: The findings suggest that increasing financial support should remain a priority in developing countries but that reasonable reimbursement design, appropriate payment methods and comprehensive supporting social health insurance policies are key to the next step of reform.

Near-infrared oxidative phosphorylation inhibitor integrates acute myeloid leukemia-targeted imaging and therapy.

Acute myeloid leukemia (AML) is a deadly hematological malignancy with frequent disease relapse. The biggest challenge for AML therapy is the lack of methods to target and kill the heterogeneous leukemia cells, which lead to disease relapse. Here, we describe a near-infrared (NIR) fluorescent dye, IR-26, which preferentially accumulates in the mitochondria of AML cells, depending on the hyperactive glycolysis of malignant cell, and simultaneously impairs oxidative phosphorylation (OXPHOS) to exert targeted therapeutic effects for AML cells. In particular, IR-26 also exhibits potential for real-time monitoring of AML cells with an in vivo flow cytometry (IVFC) system. Therefore, IR-26 represents a novel all-in-one agent for the integration of AML targeting, detection, and therapy, which may help to monitor disease progression and treatment responses, prevent unnecessary delays in administering upfront therapy, and improve therapeutic efficiency to the residual AML cells, which are responsible for disease relapse.

Improvement of obesity-associated disorders by a small-molecule drug targeting mitochondria of adipose tissue macrophages.

Pro-inflammatory activation of adipose tissue macrophages (ATMs) is causally linked to obesity and obesity-associated disorders. A number of studies have demonstrated the crucial role of mitochondrial metabolism in macrophage activation. However, there is a lack of pharmaceutical agents to target the mitochondrial metabolism of ATMs for the treatment of obesity-related diseases. Here, we characterize a near-infrared fluorophore (IR-61) that preferentially accumulates in the mitochondria of ATMs and has a therapeutic effect on diet-induced obesity as well as obesity-associated insulin resistance and fatty liver. IR-61 inhibits the classical activation of ATMs by increasing mitochondrial complex levels and oxidative phosphorylation via the ROS/Akt/Acly pathway. Taken together, our findings indicate that specific enhancement of ATMs oxidative phosphorylation improves chronic inflammation and obesity-related disorders. IR-61 might be an anti-inflammatory agent useful for the treatment of obesity-related diseases by targeting the mitochondria of ATMs.

Eye Drops of Metformin Prevents Fibrosis After Glaucoma Filtration Surgery in Rats via Activating AMPK/Nrf2 Signaling Pathway.

Metformin has effective therapeutic effects in anti-tumor and anti-fibrotic diseases. However, how the antifibrotic effect of metformin in the eye and how it is transferred are still unclear. Here, the eye drop of metformin treatment was studied in Sprague-Dawley (SD) rats of glaucoma filtrating surgery (GFS). Rats were administered randomly bilateral drops: control group (without surgery), GFS group, metformin group or mitomycin C (MMC) group (sponge application intraoperatively, 0.02%). Bleb features and intraocular pressure (IOP) were assessed for postoperative week 4. Metformin effectively inhibited fibrosis and improved the surgical outcomes of GFS. In vitro, we found that the degree of oxidative stress and fibrosis in metformin pretreated-Human Conjunctival Fibroblasts (HConFs) were reduced; the pro-fibrotic response of HConFs were decreased by inducing macrophagic polarity changes. Besides, the inhibition of nuclear factor erythroid 2-related factor 2 (Nrf2)/AMP-activated protein kinase (AMPK) and the competition of organic cation transporters (OCTs) effectively reduced the anti-fibrotic capability of metformin. Together, this experiment indicates that metformin enters into HConFs cell with OCTs, which can protect against filtrating blebs scar formation in SD rats of GFS via activating AMPK/Nrf2 axis and the downregulation of profibrogenic and inflammatory biomarkers.

PC4 serves as a negative regulator of skin wound healing in mice.

BACKGROUND: Human positive cofactor 4 (PC4) was initially characterized as a multifunctional transcriptional cofactor, but its role in skin wound healing is still unclear. The purpose of this study was to explore the role of PC4 in skin wound healing through PC4 knock-in mouse model. METHODS: A PC4 knock-in mouse model (PC4+/+) with a dorsal full-thickness wound was used to investigate the biological functions of PC4 in skin wound healing. Quantitative PCR, Western blot analysis and immunohistochemistry were performed to evaluate the expression of PC4; Sirius red staining and immunofluorescence were performed to explore the change of collagen deposition and angiogenesis. Proliferation and apoptosis were detected using Ki67 staining and TUNEL assay. Primary dermal fibroblasts were isolated from mouse skin to perform cell scratch experiments, cck-8 assay and colony formation assay. RESULTS: The PC4+/+ mice were fertile and did not display overt abnormalities but showed an obvious delay in cutaneous healing of dorsal skin. Histological staining showed insufficient re-epithelialization, decreased angiogenesis and collagen deposition, increased apoptosis and decreased cell proliferation in PC4+/+ skin. Our data also showed decreased migration rate and proliferation ability in cultured primary fibroblasts from PC4+/+ mice in vitro. CONCLUSIONS: This study suggests that PC4 might serve as a negative regulator of skin wound healing in mice.

Metformin mitigates gastrointestinal radiotoxicity and radiosensitises P53 mutation colorectal tumours via optimising autophagy.

BACKGROUND AND PURPOSE: There is an urgent but unmet need for mitigating radiation-induced intestinal toxicity while radio sensitising tumours for abdominal radiotherapy. We aimed to investigate the effects of metformin on radiation-induced intestinal toxicity and radiosensitivity of colorectal tumours. EXPERIMENTAL APPROACH: Acute and chronic histological injuries of the intestine from mice were used to assess radioprotection and IEC-6 cell line was used to investigate the mechanisms in vitro. The fractionated abdominal radiation model of HCT116 and HT29 tumour grafts was used to determine the effects on colorectal cancer. KEY RESULTS: Metformin alleviated radiation-induced acute and chronic intestinal toxicity by optimising mitophagy which was AMPK-dependent. In addition, our data indicated that metformin increased the radiosensitivity of colorectal tumours with P53 mutation both in vitro and in vivo. CONCLUSION AND IMPLICATIONS: Metformin may be a radiotherapy adjuvant agent for colorectal cancers especially those carrying P53 mutation. Our findings provide a new strategy for further precise clinical trials for metformin on radiotherapy.

Mitochondria-Targeting Immunogenic Cell Death Inducer Improves the Adoptive T-Cell Therapy Against Solid Tumor.

Cancer immunotherapy including adoptive T cell therapy (ACT) is widely used in the clinic and is highly beneficial for patients with hematological malignancies; however, it remains a challenge to develop effective immunotherapy strategies for the treatment of solid cancers, due to the inefficiency of the immune response and the immunosuppressive tumor microenvironment (TME). Immunogenic cell death (ICD) converts dying cancer cells into a therapeutic vaccine and stimulate a systemic antigen-specific antitumor immune response, which can effectively subvert the immunosuppressive TME and enhance the efficiency of immune responses, relative to conventional immunotherapeutic regimens. However, the application of traditional inducers of ICD in anti-cancer immunotherapy has been limited because of low levels of ICD induction and a lack of tumor-targeting accumulation. Mitochondria are important for tumor-targeting strategies and have emerged as organelles with key roles in the immune system. We hypothesized that the alteration of mitochondria in cancer cells could be an important target for the development of an efficient ICD inducer for use in cancer immunotherapy. Here, we report the evaluation of a mitochondria-targeted small molecule, IR-780, that acts as an ICD inducer and exhibits exceptional antineoplastic activity. IR-780 specifically accumulated in tumor cells to elicit ICD in vitro and in vivo, effectively suppressed tumor growth and lung metastasis, and enhanced adoptive T-cell therapy effects against solid tumors in mouse models. These anticancer effects were linked to dendritic cell maturation and synergistic effector T cell priming and infiltration into tumors. The underlying mechanism involves the direct targeting of the mitochondria by IR-780, to destroy cancer cells, including drug-resistant cancer cells, leading to the full exposure of tumor-associated antigens (TAAs), thereby enhancing antigen-specific antitumor immune responses. These features of IR-780 suggest that it has the advantage of leading to complete TAA exposure and the stimulation of efficient antitumor immune responses in the TME. IR-780 has potential for use as a preparative ICD inducer, in combination with conventional immunostimulatory regimens for cancer immunotherapy, particularly in the context of solid tumor treatment.

The human positive cofactor 4 promotes androgen-independent prostate cancer development and progression through HIF-1α/ß-catenin pathway.

Androgen-dependent prostate cancer (ADPC) eventually progresses to androgen-independent prostate cancer (AIPC), that has a poor prognosis owing to its unclear mechanism and lack of effective therapeutic targets. The human positive cofactor 4 (PC4) is a transcriptional cofactor, and plays a potential role in cancer development. However, the significance and mechanism of PC4 in AIPC progression are unclear. By analyzing the clinical data, we find that PC4 is overexpressed in prostate cancer and closely correlated with the progression, metastasis and prognosis of patients. Additionally, PC4 is significantly upregulated in AIPC cells compared with ADPC cells, implying its importance in the development and progression of AIPC. Then, in vivo and in vitro studies reveal that loss of PC4 inhibits cell growth by suppressing c-Myc/P21 pathway and inducing cell cycle arrest at G1/S phase transition in AIPC. PC4 knockdown also attenuates EMT-mediated metastasis in AIPC. Moreover, for the first time, we find that PC4 exerts its oncogenic functions by promoting the expression of HIF-1α and activating ß-catenin signaling. Therefore, our findings determine the signatures and molecular mechanisms of PC4 in AIPC, and indicate that PC4 might be a promising therapeutic target for AIPC.

Senolytics (DQ) Mitigates Radiation Ulcers by Removing Senescent Cells.

Radiation ulcers are a prevalent toxic side effect in patients receiving radiation therapy. At present, there is still no effective treatment for the complication. Senescent cells accumulate after radiation exposure, which can induce cell and tissue dysfunction. Here we demonstrate increased expression of p16 (a senescence biomarker) in human radiation ulcers after radiotherapy and radiation-induced persistent cell senescence in animal ulcer models. Furthermore, senescent cells secreted the senescence-associated secretory phenotype (SASP) and induced cell senescence in adjacent cells, which was alleviated by JAK inhibition. In addition, the clearance of senescent cells following treatment with a senolytics cocktail, Dasatinib plus Quercetin (DQ), mitigated radiation ulcers. Finally, DQ induced tumor cell apoptosis and enhanced radiosensitivity in representative CAL-27 and MCF-7 cell lines. Our results demonstrate that cell senescence is involved in the development of radiation ulcers and that elimination of senescent cells might be a viable strategy for patients with this condition.