SHR1032, a novel STING agonist, stimulates anti-tumor immunity and directly induces AML apoptosis.

Stimulator of interferon genes (STING) activation induces type I interferons and pro-inflammatory cytokines which stimulate tumor antigen cross presentation and the adaptive immune responses against tumor. The first-generation of STING agonists, cyclic di-nucleotide (CDN), mimicked the endogenous STING ligand cyclic guanosine monophosphate adenosine monophosphate, and displayed limited clinical efficacy. Here we report the discovery of SHR1032, a novel small molecule non-CDN STING agonist. Compared to the clinical CDN STING agonist ADU-S100, SHR1032 has much higher activity in human cells with different STING haplotypes and robustly induces interferon ß (IFNß) production. When dosed intratumorally, SHR1032 induced strong anti-tumor effects in the MC38 murine syngeneic tumor model. Pharmacodynamic studies showed induction of IFNß, tumor necrosis factor α (TNFα) and interleukin-6 (IL-6) in the tumors and, to a lower extent, in the plasma. More importantly, we found SHR1032 directly causes cell death in acute myeloid leukemia (AML) cells. In conclusion, our findings demonstrate that in addition to their established ability to boost anti-tumor immune responses, STING agonists can directly eradicate AML cells, and SHR1032 may present a new and promising therapeutic agent for cancer patients.

A Clinical Study on the Effect of Different Ratios of Recombinant Human Bone Morphogenetic Protein-2 Compound to Autogenous Bone on Cervical Interbody Fusion Based on Smart Healthcare.

With an increasing elderly population worldwide, the incidence of spine degenerative diseases with neck and shoulder pain as the main symptom is rising obviously, which has now become one of the important and difficult problems in sociomedical science. This study was to explore the effects of different ratios of recombinant human bone morphogenetic protein-2 (rhBMP-2) compound to the autogenous bone on cervical interbody fusion. 90 cervical degeneration patients with the need of surgical treatment admitted to our hospital from January 2019 to January 2020 were selected as the research objects and equally divided into group A, group B, and group C according to the order of admission, with 30 cases in each group and the ratios of rhBMP-2 compound to autogenous bone being 2 : 1, 1 : 1, and 1 : 2 respectively, and standard anterior cervical diskectomy and fusion (ACDF) treatment was performed to all patients to compare their surgery-related indexes, the Japanese Orthopaedic Association (JOA) score, the visual analog scale (VAS) score, the effect of cervical interbody fusion, and the postoperative complication rate (CR). Compared with group A and group C, group B achieved the significantly better surgery-related indexes (P < 0.05), significantly higher postoperative JOA scores (P < 0.05), significantly lower postoperative neck and upper limb VAS scores (P < 0.05), significantly better effect of cervical interbody fusion (P < 0.05), and significantly lower postoperative CR (P < 0.05). 1 : 1 is the best ratio of rhBMP-2 compound to the autogenous bone, for it can optimize patients' perioperative indexes, reduce the postoperative pain, lower the possibility of complications, and improve the effect of cervical interbody fusion, which should be promoted and applied in practice.

Brain estrogen alters the effects of the antidepressant sertraline in middle-aged female and male mice.

Estrogens are important in regulating mood, especially for females. However, whether tissue-specific estrogen, such as brain estrogen, contributes to the effects of antidepressant treatment has not been determined. The present study used middle-aged aromatase gene knockout (Ar-/-) mice or overexpression (Thy1-Ar; hGFAP-Ar) mice as brain estrogen models to investigate whether brain estrogen synthesis alters the anti-depressive behaviors of sertraline treatment. Our results showed that depletion of brain estrogen increased depressive-like behavior in females, and elevated brain estrogen reduced depression-like behavior, regardless of sex. These genotype-related behaviors correlated with alterations of monoamine metabolism in the hippocampus (HPC) and the prefrontal cortex (PFC). We also demonstrated that male and female Ar-/- mice exhibited an attenuation of sertraline-induced anti-depressive behaviors compared to wild-type (WT) mice. The present data suggest that brain estrogen alters depressive-like behaviors and changes the effectiveness of antidepressants in middle-aged mice, regardless of sex.

Comparison of the sagittal profiles among thoracic idiopathic scoliosis patients with different Cobb angles and growth potentials.

BACKGROUND: Previous studies have demonstrated that pelvic incidence and sacral slope are significantly greater in idiopathic scoliosis patients compared with normal adolescents. However, whether these sagittal parameters are related to the progression of scoliosis remain unknown. The present was designed to determine the differences in the sagittal profiles among thoracic idiopathic scoliosis patients with different potentials for curve progression. METHODS: Ninety-seven outpatient idiopathic scoliosis patients enrolled from June 2008 to June 2011 were divided to three groups according to different Cobb angles and growth potentials: (1) non-progression of thoracic curve group, Risser sign of 5 and Cobb's angle < 40°; (2) moderate progression of thoracic curve group, Risser sign of 5 and Cobb's angle ≥ 40°; and (3) severe progression of thoracic curve group, Risser sign ≤ 3 and Cobb's angle ≥ 40°. All patients underwent whole spinal anteroposterior and lateral X-ray in standing position, and the sagittal parameters were measured, including thoracic kyphosis, lumbar lordosis, sacral slope, pelvic incidence, and pelvic tilt. RESULTS: The average thoracic scoliosis Cobb's angle in the non-progression group was significantly less than that in the moderate progression group (P < 0.01) and severe progression group (P < 0.01), but there was no statistical difference in the average thoracic scoliosis Cobb's angle between the severe progression group and moderate progression group. The average thoracic kyphosis angle in the severe progression group (9° ± 4°) was significantly smaller than that in the non-progression group (18° ± 6°, P < 0.01) and moderate progression group (14° ± 5°, P < 0.05). No statistical differences were present in the average lumbar lordosis, sacral slope, pelvic incidence, and pelvic tilt among the three groups. CONCLUSIONS: Thoracic hypokyphosis is strongly related with the curve progression in thoracic idiopathic scoliosis patients, but not pelvic sagittal profiles.