Targeting STAT3-VISTA axis to suppress tumor aggression and burden in acute myeloid leukemia.

The acute myeloid leukemia (AML) patients obtain limited benefits from current immune checkpoint blockades (ICBs), although immunotherapy have achieved encouraging success in numerous cancers. Here, we found that V-domain Ig suppressor of T cell activation (VISTA), a novel immune checkpoint, is highly expressed in primary AML cells and associated with poor prognosis of AML patients. Targeting VISTA by anti-VISTA mAb boosts T cell-mediated cytotoxicity to AML cells. Interestingly, high expression of VISTA is positively associated with hyperactive STAT3 in AML. Further evidence showed that STAT3 functions as a transcriptional regulator to modulate VISTA expression by directly binding to DNA response element of VISTA gene. We further develop a potent and selective STAT3 inhibitor W1046, which significantly suppresses AML proliferation and survival. W1046 remarkably enhances the efficacy of VISTA mAb by activating T cells via inhibition of STAT3 signaling and down-regulation of VISTA. Moreover, combination of W1046 and VISTA mAb achieves a significant anti-AML effect in vitro and in vivo. Overall, our findings confirm that VISTA is a potential target for AML therapy which transcriptionally regulated by STAT3 and provide a promising therapeutic strategy for immunotherapy of AML.

Discovery of small molecule Gαq/11 protein inhibitors against uveal melanoma.

Constitutively activated G proteins caused by specific mutations mediate the development of multiple malignancies. The mutated Gαq/11 are perceived as oncogenic drivers in the vast majority of uveal melanoma (UM) cases, making directly targeting Gαq/11 to be a promising strategy for combating UM. Herein, we report the optimization of imidazopiperazine derivatives as Gαq/11 inhibitors, and identified GQ262 with improved Gαq/11 inhibitory activity and drug-like properties. GQ262 efficiently blocked UM cell proliferation and migration in vitro. Analysis of the apoptosis-related proteins, extracellular signal-regulated kinase (ERK), and yes-associated protein (YAP) demonstrated that GQ262 distinctly induced UM cells apoptosis and disrupted the downstream effectors by targeting Gαq/11 directly. Significantly, GQ262 showed outstanding antitumor efficacy in vivo with good safety at the testing dose. Collectively, our findings along with the favorable pharmacokinetics of GQ262 revealed that directly targeting Gαq/11 may be an efficient strategy against uveal melanoma.

Inhibition of STAT3-ferroptosis negative regulatory axis suppresses tumor growth and alleviates chemoresistance in gastric cancer.

Chemotherapy is still one of the principal treatments for gastric cancer, but the clinical application of 5-FU is limited by drug resistance. Here, we demonstrate that ferroptosis triggered by STAT3 inhibition may provide a novel opportunity to explore a new effective therapeutic strategy for gastric cancer and chemotherapy resistance. We find that ferroptosis negative regulation (FNR) signatures are closely correlated with the progression and chemoresistance of gastric cancer. FNR associated genes (GPX4, SLC7A11, and FTH1) and STAT3 are upregulated in 5-FU resistant cells and xenografts. Further evidence demonstrates that STAT3 binds to consensus DNA response elements in the promoters of the FNR associated genes (GPX4, SLC7A11, and FTH1) and regulates their expression, thereby establishing a negative STAT3-ferroptosis regulatory axis in gastric cancer. Genetic inhibition of STAT3 activity triggers ferroptosis through lipid peroxidation and Fe2+ accumulation in gastric cancer cells. We further develop a potent and selective STAT3 inhibitor, W1131, which demonstrates significant anti-tumor effects in gastric cancer cell xenograft model, organoids model, and patient-derived xenografts (PDX) model partly by inducing ferroptosis, thus providing a new candidate compound for advanced gastric cancer. Moreover, targeting the STAT3-ferroptosis circuit promotes ferroptosis and restores sensitivity to chemotherapy. Our finding reveals that STAT3 acts as a key negative regulator of ferroptosis in gastric cancer through a multi-pronged mechanism and provides a new therapeutic strategy for advanced gastric cancer and chemotherapy resistance.

Rapid BMI Increases and Persistent Obesity in Small-for-Gestational-Age Infants.

Purpose: In order to compensate for the early intrauterine growth restriction, small-for-gestational age (SGA) infants have "catch-up growth" after birth. Increased caloric intake has been suggested for SGA infants conventionally. It is important to determine if the early growth rate of body mass index (BMI) is associated with risk of persistent obesity later in life. In this longitudinal cohort study, we assessed the BMI of a large cohort of children who were SGA at birth to determine their risk of persistent obesity at school age (6-7 years) due to excessive weight gain in the first 3 years of life. Methods: We collected the height and weight data of 23,871 SGA babies. A polynomial function was used to fit the BMI-for-age z-score (BAZ) values of 0-6 years old SGA children and interpolate their growth trajectory. In addition, we screened out 6,959 children from 23,871 children to further evaluate the dynamic changes of early childhood BMI. We divided the school-age children into groups as non-obese (BAZ < 2) and obese (BAZ > 2), and determined the association between changes in BMI and school-age obesity. Results: From the perspective of BMI distribution, the interpolated growth trajectory indicated that SGA children reaching overweight status or developing obesity by 3 years of age, continued to have obesity until school age (R2, 0.65; R2, 0.21). The retrospective analysis showed that children who were overweight and had obesity during school age had a high BMI from early age. By analyzing the changes in early BMI, we found that the fastest growth of SGA children occurred in the early infancy before 6 months and they continued to grow rapidly for a period of time. Interestingly, former SGA children who maintained a near overweight (1 < BAZ < 2) status before the age of 2 maintained an appropriate growth rate and usually did not develop obesity. Conclusions: A rapid increase in BMI during early infancy in former SGA newborns leads to a persistent risk of obesity. The energy intake of SGA infants should appropriately meet the infants' growth needs and early BMI changes should be closely monitored for an optimal integrated management.

Taste-masking and colloidal-stable cubosomes loaded with Cefpodoxime proxetil for pediatric oral delivery.

Drug administration failure has been often witnessed in pediatric due to children's resistance to take medicines with bitter taste. Taste-masking is the key requirement among the scanty drugs available for children. Solid taste-masking systems, such as tablets and capsules, are difficult to swallow for children. Therefore, a liquid taste-masking system based on lyotropic liquid crystalline nanoparticles (LLCNs) was developed in this study. Cefpodoxime proxetil (CFP), a typically bitter drug used as antibiotic in pediatric, was selected as the model drug, and the encapsulation of CFP into the LLCNs was envisaged to improve their taste. Pluronic F127 was added to improve the colloidal stability of CFP-LLCNs. The optimized CFP-LLCNs showed the particle size of 187.29 ± 4.12 nm and the encapsulation efficiency of 85.80%. The mesophase analysis by polarized light microscopy and small angle X-ray scattering confirmed the cubic phase of CFP-LLCNs. It showed a sustained-release profile well fitted to Higuchi model, indicating that diffusion and erosion were both responsible for the CFP release. The taste-masking ability of CFP-LLCNs was confirmed by electronic tongue, compared to CFP and commercial product. The colloidal stability was verified after 3 months storage in room condition (25 ± 2 °C, 70 ± 2%RH). To sum up, the taste-masking and colloidal-stable CFP-LLCNs showed great potential for pediatric oral delivery.

Applicability of the Chinese version of the Personal and Social Performance scale in patients with severe mental disorders.

INTRODUCTION: This study was designed to determine the reliability and validity of the Chinese version of the Personal and Social Performance scale (PSP-CHN) and assess the applicability of using the PSP-CHN in patients with severe mental disorders. METHODS: A total of 285 outpatients with severe mental disorders, 220 with schizophrenia and 65 with major depressive disorder, were enrolled into the study. Both diagnoses were made using the DSM-IV. All the patients were assessed with the PSP-CHN, the GAF, and the CGI-S. In addition, the PANSS and the MADRS were used to assess the patients with schizophrenia and major depressive disorder, respectively. RESULTS: The PSP-CHN showed good internal consistency (Cronbach α = 0.839, n = 285), high interrater reliability for total scores (intraclass correlation coefficient, ICC = 0.865, n = 48), and good test-retest reliability (ICC = 0.892, n = 130). The PSP-CHN total score showed a statistically significant positive correlation with the GAF score (r = 0.927, P < .01, n = 285), as well as a significant negative correlation with the CGI-S total score (r = -0.793, P < .01, n = 285), the PANSS total score (r = -0.694, P < .01, n = 220), and the MADRS total score (r = -0.721, P < .01, n = 65). DISCUSSION: We were able to demonstrate that the PSP-CHN is a reliable and valid measurement tool to assess the personal and social functioning in patients with severe mental disorders.