Gut microbiota shed new light on the management of immune-related adverse events.

Immunotherapy has dramatically revolutionized the therapeutic landscape for patients with cancer. Although immune checkpoint inhibitors are now accepted as effective anticancer therapies, they introduce a novel class of toxicity, termed immune-related adverse events, which can lead to the temporary or permanent discontinuation of immunotherapy and life-threatening tumor progression. Therefore, the effective prevention and treatment of immune-related adverse events is a clinical imperative to maximize the utility of immunotherapies. Immune-related adverse events are related to the intestinal microbiota, baseline gut microbiota composition is an important determinant of immune checkpoint inhibitor-related colitis, and antibiotics exacerbate these undesirable side-effects. Supplementation with specific probiotics reduces immune checkpoint inhibitor-related colitis in mice, and fecal microbiota transplantation has now been shown to effectively treat refractory immune checkpoint inhibitor-related colitis in the clinic. Hence, modifying the microbiota holds great promise for preventing and treating immune-related adverse events. Microbiomes and their metabolites play important roles in the potential underlying mechanisms through interactions with both innate and adaptive immune cells. Here we review the gut microbiota and immune regulation; the changes occurring in the microbiota during immune checkpoint inhibitor therapy; the relationship between the microbiota and immune-related adverse events, antibiotics, probiotics/prebiotics, and fecal microbiota transplantation in immune checkpoint inhibitor-related colitis; and the protective mechanisms mediated by the microbiome and metabolites in immune-related adverse events.

Intrathecally administered pizotifen alleviates neuropathic and inflammatory pain in mice by enhancing GABAergic inhibition.

Chronic pain, such as chronic neuropathic pain and chronic inflammatory pain, is often difficult to manage and bring great trouble to patients. 5-HT plays a key role in the process of pain transmission both in centrally and peripherally. Tricyclic antidepressants (TCA) such as amitriptyline are classical 5-HT reuptake inhibitors, are recommended as the first-line treatment for chronic pain. Pizotifen, a 5-HT2 receptor antagonist, is currently used in the prevention of vascular headaches. However, the antinociceptive effect of pizotifen on non-headache pain especially chronic pain in the spinal level is still unknown. Here we find that intrathecal pizotifen attenuates neuropathic and inflammatory pain mainly due to elevated GABAergic synaptic inhibition. Neuropathic pain is induced by segmental spinal nerve ligation (SNL), and inflammatory pain is induced by intraplantar injection of complete Freund's adjuvant (CFA). Both in SNL and CFA mice, spinally administered pizotifen reduced mechanical and thermal hyperalgesia dose-dependently. Since the levels of GAD65/67 were increased, and the frequency of mIPSCs in the spinal dorsal horn was increased, together with the antinociceptive effect being reversed by both GABAAR and GAD blockade, this antinociceptive effect might be generated from strengthened GABAergic inhibition. Furthermore, high dose of pizotifen (5 µg) weakly affected motor performance and did not influence the locomotor activity in normal animals. In summary, our findings suggest that pizotifen strengthens the inhibitory synaptic transmission and exerts antinociceptive effect on both neuropathic pain and inflammatory pain in the spinal cord, and may serve as a promising remedy for chronic pain.

[Frequency up-conversion properties of Er3+ /Yb3+ co-doped zinc oxide powders].

Er3+ /Yb3+ co-doped ZnO powders were prepared by the high temperature sintering method with starting composition of (mol%) 95ZnF2-4. 8Yb2 O3-0. 2Er2 O3. Microstructure analysis by X-ray diffraction (XRD) showed that the sample consists of two phases, i. e. ZnO and YbF3, which verified that the ZnF2 was oxidized during the high temperatue sintering Composition analysis by scanning electron microscope (SEM) and spectroscopic measurements showed that the Er3+ and Yb3+ ons were successfully used in doping the lattice of ZnO, but most of Yb3+ ions were in the YbF3 phase. These results indicated that the up-conversion luminescence was emitted from ZnO, not from YbF3. Under the excitation of 980 nm diodelaser, four strong up-conversion emissions peaks centered at 658, 538, 522 and 409 nm, corresponding to the transitions 4F9/2 --> 4I15/2, 4S3/2 --> 4I15/2, 2 H11/2 --> 4I15/2 and 2 H9/2 --> I15/2, respectively, were observed. Especially, a strong red up-conversion emission was observed, which is different from that the green up-converted luminescence is dominated in glass and ceramics. Three important cross energy transfer (CRET) processes between Er3+ ions played an important role for this. Under 488 nm Ar+ laser excitation, intense violet (409 nm), weak blue (466, 450 nm) and ultraviolet (379 nm) up-conversion luminescence originating from the transitions 2 H9/2 --> 4I15/2, 2P3/2 --> 4I11/2, 4 F3/2 /4 F5/2 --> 4I15/ 2 and 4G11/2 --> 4 I15/2, respectively, were obtained. The dependence of up-conversion intensities on excitation power indicated that two-photon absorption processes were responsible for the violet luminescence under 488 nm excitation, and the violet up-converted luminescence was achieved through the forward and back energy transfer between Er3+ and Yb3+ ions. Our results show that ZnO as a host material has the potential applications in the up-conversion red phosphors and ultraviolet laser materials.

[Spectroscopic properties of Er3+-doped germanium bismuthate glass].

Er(3+)-Doped Germanium Bismuthate Glass was fabricated and characterized. The absorption spectrum and up-conversion spectrum of glass were studied. The Judd-Oflet intensity parameters omega(t) (t = 2, 4, 6), determined based on Judd-Ofelt theory, were found to be omega2 = 3.35 x 10(-20) cm2, omega4 = 1.34 x 10(-20) cm2, omega6 = 0.67 x 10(-20) cm2. Frequency up-conversion of Er(3+)-doped germanium bismuthate glass has been investigated. The up-conversion mechanisms are discussed under 808 nm and 980 nm excitation. Stimulated emission cross-section of 4I(13/2) --> 4I(15/2) transition was calculated by McCumber theory. Compared to other host glasses, the emission property of Er(3+)-doped germanium bismuthate glasses has advantage over those of silicate, phosphate and germinate glasses. Er(3+)-doped germanium bismuth glasses are promising upconversion optical and optic-communication materials.