ATF4 renders human T-cell acute lymphoblastic leukemia cell resistance to FGFR1 inhibitors through amino acid metabolic reprogramming.

Abnormalities of FGFR1 have been reported in multiple malignancies, suggesting FGFR1 as a potential target for precision treatment, but drug resistance remains a formidable obstacle. In this study, we explored whether FGFR1 acted a therapeutic target in human T-cell acute lymphoblastic leukemia (T-ALL) and the molecular mechanisms underlying T-ALL cell resistance to FGFR1 inhibitors. We showed that FGFR1 was significantly upregulated in human T-ALL and inversely correlated with the prognosis of patients. Knockdown of FGFR1 suppressed T-ALL growth and progression both in vitro and in vivo. However, the T-ALL cells were resistant to FGFR1 inhibitors AZD4547 and PD-166866 even though FGFR1 signaling was specifically inhibited in the early stage. Mechanistically, we found that FGFR1 inhibitors markedly increased the expression of ATF4, which was a major initiator for T-ALL resistance to FGFR1 inhibitors. We further revealed that FGFR1 inhibitors induced expression of ATF4 through enhancing chromatin accessibility combined with translational activation via the GCN2-eIF2α pathway. Subsequently, ATF4 remodeled the amino acid metabolism by stimulating the expression of multiple metabolic genes ASNS, ASS1, PHGDH and SLC1A5, maintaining the activation of mTORC1, which contributed to the drug resistance in T-ALL cells. Targeting FGFR1 and mTOR exhibited synergistically anti-leukemic efficacy. These results reveal that FGFR1 is a potential therapeutic target in human T-ALL, and ATF4-mediated amino acid metabolic reprogramming contributes to the FGFR1 inhibitor resistance. Synergistically inhibiting FGFR1 and mTOR can overcome this obstacle in T-ALL therapy.

Treatment Status of Elderly Patients With Severe Mental Disorders in Rural China.

This study was performed to compare the treatment status between older (≥65 years) and younger adults (18-64 years) with severe mental illness (SMI) and explore factors associated with treatment status in rural China. Persons with SMI were identified in one mental health survey in 2015 in 6 townships of Xinjin County, Chengdu, China. Logistic regressions were conducted to explore factors associated with treatment status. Older adults with SMI, especially major depressive disorder, reported significantly lower rates of treatment than younger group. Older age, longer duration of illness, and poor mental status were risk factors for never-treated status in these patients. Never-treated status (46.3%) and poor treatment status in these older patients are serious issues. Different treatment statuses in these patients had various influencing factors. It is crucial to develop culture-specific, community-based mental health services to improve early identification, diagnosis, treatment, and recovery of older adults with SMI in rural China.

Depressive disorders among children in the transforming China: an epidemiological survey of prevalence, correlates, and service use.

BACKGROUND: To date, no one-phase survey of childhood depression has been performed in China that involves both urban and rural community children. The objective of this study was to determine the prevalence, correlates, and mental health service utilization of depressive disorders (DDs) in a community-based sample of 6-14-year-old children in south-central China. METHODS: Children (3,582) were approached through multistage sampling and interviewed using a Chinese version of the Mini International Neuropsychiatric Interview for Children and Adolescents 5.0, which is a structured interview that is administered by trained psychiatrists to obtain information from children and their guardians. RESULTS: The overall prevalence of all current DDs was found to be 2.8% (95%CI: 1.5-3.9). The risk factors for depression included being 9-14-year old, not attending school, having unmarried parents, living in a non-nuclear family (single parent or parentless family), being taken care of by people other than two parents (single parent, grandparent(s), other relatives, or others) during the past year, and not being breastfed prior to 1 year of age. Only 5.8% of the depressed children had received professional help prior to the interview. CONCLUSIONS: The prevalence of DDs among children in this part of China is relatively high compared with most figures reported in other countries. Depression in this age group has been a major public health concern, but it is often underrecognized. There is an urgent need to develop efficacious interventions aimed at the prevention and early recognition of childhood depression.