Co-targeting CD47 and VEGF elicited potent anti-tumor effects in gastric cancer.

BACKGROUND: CD47, serving as an intrinsic immune checkpoint, has demonstrated efficacy as an anti-tumor target in hematologic malignancies. Nevertheless, the clinical relevance of CD47 in gastric cancer and its potential as a therapeutic target remains unclear. METHODS: The expression of CD47 in clinical gastric cancer tissues was assessed using immunohistochemistry and Western blot. Patient-derived cells were obtained from gastric cancer tissues and co-cultured with macrophages derived from human peripheral blood mononuclear cells. Flow cytometry analyses were employed to evaluate the rate of phagocytosis. Humanized patient-derived xenografts (Hu-PDXs) models were established to assess the efficacy of anti-CD47 immunotherapy or the combination of anti-CD47 and anti-VEGF therapy in treating gastric cancer. The infiltrated immune cells in the xenograft were analyzed by immunohistochemistry. RESULTS: In this study, we have substantiated the high expression of CD47 in gastric cancer tissues, establishing a strong association with unfavorable prognosis. Through the utilization of SIRPα-Fc to target CD47, we have effectively enhanced macrophage phagocytosis of PDCs in vitro and impeded the growth of Hu-PDXs. It is noteworthy that anti-CD47 immunotherapy has been observed to sustain tumor angiogenic vasculature, with a positive correlation between the expression of VEGF and CD47 in gastric cancer. Furthermore, the successful implementation of anti-angiogenic treatment has further augmented the anti-tumor efficacy of anti-CD47 therapy. In addition, the potent suppression of tumor growth, prevention of cancer recurrence after surgery, and significant prolongation of overall survival in Hu-PDX models can be achieved through the simultaneous targeting of CD47 and VEGF using the bispecific fusion protein SIRPα-VEGFR1 or by combining the two single-targeted agents. CONCLUSIONS: Our preclinical studies collectively offer substantiation that CD47 holds promise as a prospective target for gastric cancer, while also highlighting the potential of anti-angiogenic therapy to enhance tumor responsiveness to anti-CD47 immunotherapy.

METTL1/WDR4-mediated m7G tRNA modifications and m7G codon usage promote mRNA translation and lung cancer progression.

Mis-regulated epigenetic modifications in RNAs are associated with human cancers. The transfer RNAs (tRNAs) are the most heavily modified RNA species in cells; however, little is known about the functions of tRNA modifications in cancers. In this study, we uncovered that the expression levels of tRNA N7-methylguanosine (m7G) methyltransferase complex components methyltransferase-like 1 (METTL1) and WD repeat domain 4 (WDR4) are significantly elevated in human lung cancer samples and negatively associated with patient prognosis. Impaired m7G tRNA modification upon METTL1/WDR4 depletion resulted in decreased cell proliferation, colony formation, cell invasion, and impaired tumorigenic capacities of lung cancer cells in vitro and in vivo. Moreover, gain-of-function and mutagenesis experiments revealed that METTL1 promoted lung cancer growth and invasion through regulation of m7G tRNA modifications. Profiling of tRNA methylation and mRNA translation revealed that highly translated mRNAs have higher frequencies of m7G tRNA-decoded codons, and knockdown of METTL1 resulted in decreased translation of mRNAs with higher frequencies of m7G tRNA codons, suggesting that tRNA modifications and codon usage play an essential function in mRNA translation regulation. Our data uncovered novel insights on mRNA translation regulation through tRNA modifications and the corresponding mRNA codon compositions in lung cancer, providing a new molecular basis underlying lung cancer progression.

Using a new plateau hyperbaric chamber to alleviate high altitude hypoxia: Rabbit and human studies.

OBJECTIVES: To validate the effects of the new plateau hyperbaric chamber on alleviating high altitude hypoxia on Mount Kun Lun. METHODS: A prospective, controlled study of rabbits and adult volunteers was conducted at altitudes of 355, 2880 and 4532m. We obtained arterial blood samples from rabbits and volunteers before and after hyperbaric treatment. The respiratory rate, heart rate, and blood pressure (BP) of adult volunteers were monitored during hyperbaric treatment. RESULTS: The mean PaO2 levels of experimental group rabbits and volunteers increased significantly after 60min of hyperbaric treatment at 350, 2880 and 4532m. The mean PaCO2 and pH levels of rabbits were not significant different before and after hyperbaric treatment at each altitude. The mean PaCO2 and pH levels were not significant different at 355m in the human study. However, at 2880 and 4532m, pH fell with increasing PaCO2 levels in humans before and after hyperbaric treatment. CONCLUSIONS: The new multiplace plateau hyperbaric chamber may be used to alleviate plateau hypoxia by increasing patient PaO2. However, its value in treating AMS must be confirmed in field conditions.

Development and preliminary test of a new plateau hyperbaric chamber.

OBJECTIVE: The objective of this study is to validate the performance, define its limits, and provide details on a new plateau hyperbaric chamber at 355-, 2880-, and 4532-m high altitude. METHODS: A new multiplace plateau hyperbaric chamber was designed to satisfy the needed of patients who have acute mountain sickness. Tests were conducted inside the chamber at 355-, 2880-, and 4532-m high altitude. The safely and conveniences of the new plateau hyperbaric chamber were estimated. RESULTS: Minimum pressures of the main compartment can reach up to 0.029, 0.022, and 0.02 MPa at 355-, 2880-, and 4532-m high altitude. During pressurization, there was no leak of air around the chamber. The time lag of pressure equilibration between main and buffer compartment varies from 30.3±2.01 to 200.5±5.44 seconds and between buffer compartment and ambient pressure varies from 60.2±4.13 to 215.9±6.76 seconds. CONCLUSIONS: The chamber can be applicated for acute mountain sickness treatment safety and convenience. However, further experience about animals and human within the chamber is needed to improve the hardware and establish conditions of effective utilization of this equipment in the high altitude.