Timing Is Critical for an Effective Anti-Metastatic Immunotherapy: The Decisive Role of IFNγ/STAT1-Mediated Activation of Autophagy

BACKGROUND: Immunotherapy is often recommended as an adjuvant treatment to reduce the chance of cancer recurrence or metastasis. Interestingly, timing is very important for a successful immunotherapy against metastasis, although the precise mechanism is still unknown. METHODS AND FINDINGS: Using a mouse model of melanoma metastasis induced by intravenous injection of B16-F10 cells, we investigated the mechanism responsible for the diverse efficacy of the prophylactic or therapeutic TLR4 and TLR9 agonist complex against metastasis. We found that the activation of TLR4 and TLR9 prevented, but did not reverse, metastasis because the potency of this combination was neither sufficient to overcome the tumor cell-educated immune tolerance nor to induce efficacious autophagy in tumor cells. The prophylactic application of the complex promoted antimetastatic immunity, leading to the autophagy-associated death of melanoma cells via IFNγ/STAT1 activation and attenuated tumor metastasis. IFNγ neutralization reversed the prophylactic benefit induced by the complex by suppressing STAT1 activation and attenuating autophagy in mice. However, the therapeutic application of the complex did not suppress metastasis because the complex could not reverse tumor cell-induced STAT3 activation and neither activate IFNγ/STAT1 signaling and autophagy. Suppressing STAT3 activation with the JAK/STAT antagonist AG490 restored the antimetastatic effect of the TLR4/9 agonist complex. Activation of autophagy after tumor inoculation by using rapamycin, with or without the TLR4/9 agonist complex, could suppress metastasis. CONCLUSION AND SIGNIFICANCE: Our studies suggest that activation of IFNγ/STAT1 signaling and induction of autophagy are critical for an efficacious anti-metastatic immunotherapy and that autophagy activators may overcome the timing barrier for immunotherapy against metastasis

Effects of In Vitro Maturation on Histone Acetylation in Metaphase II Oocytes and Early Cleavage Embryos

In vitro maturation (IVM) of oocyte is an effective procedure for avoiding ovarian hyperstimulation syndrome in patients with polycystic ovaries (PCOS) during in vitro fertilization (IVF). To investigate the influences of IVM on epigenetic reprogramming and to search for the possible reasons for the lower rates of fertilization and cleavage in IVM oocytes, we examined the expression of two enzymes controlling histone acetylation, histone acetyltransferase GCN5 (GCN5) and histone deacetylase 1 (HDAC1), as well as their common target, acetyl-histone H3 (Ac-H3), in mouse metaphase II (MII) oocytes and preimplantation embryos. Results showed that IVM downregulated the protein expression of GCN5 in MII oocytes and two-cell embryos and changed the distribution of GCN5 in two-cell embryos. Expression of HDAC1 mRNA in MII oocytes and two-cell embryos decreased in the IVM group. However, none of these changes persisted after two-cell embryos. Levels of Ac-H3 in both oocytes and embryos remained unchanged after IVM. Our studies indicated that IVM could affect the protein and gene expression related to histone acetylation in oocytes and early cleavage embryos. By function of selection, parts of the changes could be recovered in late embryo development

Spatial intratumoral heterogeneity and temporal clonal evolution in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is among the most common malignancies, but little is known about its spatial intratumoral heterogeneity (ITH) and temporal clonal evolutionary processes. To address this, we performed multiregion whole-exome sequencing on 51 tumor regions from 13 ESCC cases and multiregion global methylation profiling for 3 of these 13 cases. We found an average of 35.8% heterogeneous somatic mutations with strong evidence of ITH. Half of the driver mutations located on the branches of tumor phylogenetic trees targeted oncogenes, including PIK3CA, NFE2L2 and MTOR, among others. By contrast, the majority of truncal and clonal driver mutations occurred in tumor-suppressor genes, including TP53, KMT2D and ZNF750, among others. Interestingly, phyloepigenetic trees robustly recapitulated the topological structures of the phylogenetic trees, indicating a possible relationship between genetic and epigenetic alterations. Our integrated investigations of spatial ITH and clonal evolution provide an important molecular foundation for enhanced understanding of tumorigenesis and progression in ESCC

Geometry and optics calibration of WFCTA prototype telescopes using star light

The Large High Altitude Air Shower Observatory project is proposed to study high energy gamma ray astronomy ( 40 GeV-1 PeV ) and cosmic ray physics ( 20 TeV-1 EeV ). The wide field of view Cherenkov telescope array, as a component of the LHAASO project, will be used to study energy spectrum and compositions of cosmic ray by measuring the total Cherenkov light generated by air showers and shower maximum depth. Two prototype telescopes have been in operation since 2008. The pointing accuracy of each telescope is crucial to the direction reconstruction of the primary particles. On the other hand the primary energy reconstruction relies on the shape of the Cherenkov image on the camera and the unrecorded photons due to the imperfect connections between photomultiplier tubes. UV bright stars are used as point-like objects to calibrate the pointing and to study the optical properties of the camera, the spot size and the fractions of unrecorded photons in the insensitive areas of the camera.Comment: 5 pages, 6 figures, submitted to Chinese Physics

Review of CHINARE chemical oceanographic research in the Southern Ocean during 1984–2016

Between 1984 and 2016, China executed 33 Antarctic cruises with the icebreaker R/V Xuelong, which have provided opportunities for Chinese scientists to investigate the status and changes of the Southern Ocean. Research in chemical oceanography constitutes one of the primary missions of the Chinese National Antarctic Research Expedition (CHINARE). This paper reviews nearly 30 years of Chinese Antarctic expeditions, focusing on the major progress achieved in chemical oceanographic research. Specifically, the sea-surface distributions and air–sea fluxes of CO2 and N2O are considered, and the transport, flux, and budget of organic matter are investigated based on isotopes in the Southern Ocean, especially in Prydz Bay. In addition, the nutrient distribution and deep-water particle export in Prydz Bay and the study of aerosol heavy metal characteristics are considered. Finally, the prospects for future Chinese Antarctic chemical oceanographic research are outlined

Chinese Massage Combined with Herbal Ointment for Athletes with Nonspecific Low Back Pain: A Randomized Controlled Trial

Non-specific low back pain (NLBP) is an increasing health problem for athletes. This randomized controlled trial was designed to investigate the effects of Chinese massage combined with herbal ointment for NLBP. 110 athletes with NLBP were randomly assigned to experimental group with Chinese massage combined with herbal ointment or control group with simple massage therapy. The primary outcome was pain by Chinese Short Form McGill Pain Questionnaire (C-SFMPQ). The secondary outcome was local muscle stiffness by Myotonometer. After 4 weeks, the experimental group experienced significant improvements in C-SFMPQ and in local muscle stiffness compared with control group (between-group difference in mean change from baseline, −1.24 points, P = 0.005 in sensory scores; −3.14 points, P < 0.001 in affective scores; −4.39 points, P < 0.001 in total scores; −0.64 points, P = 0.002 in VAS; −1.04 points, P = 0.005 in local muscle stiffness during relaxation state). The difference remained at one month followup, but it was only significant in affective scores (−2.83 points, P < 0.001) at three months followup. No adverse events were observed. These findings suggest that Chinese massage combined with herbal ointment may be a beneficial complementary and alternative therapy for athletes with NLBP