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.

A Clinical Comparative Analysis of Retroperitoneal Laparoscopic Tuberculous Nephrectomy and Open Tuberculous Nephrectomy.

Background: This study aimed to investigate the efficacy and safety of retroperitoneal laparoscopic tuberculous nephrectomy (RLTN) and open tuberculous nephrectomy (OTN). Materials and Methods: One hundred fifty-eight patients treated with RLTN were enrolled in the RLTN group. One hundred patients treated with OTN were enrolled in the control group. Surgical parameters and postoperative conditions were recorded to assess the effect of the operation, and complications were recorded throughout the follow-up time. The follow-up time was 2-72 months. Results: Eight cases in the RLTN group were moved to the OTN group due to intraoperative bleeding. There were significant differences in the diameter of the incision between the 2 groups (P < .01). The resumed time and length of hospitalization in the RLTN group were significantly shorter than those in the OTN group (P < .05). During surgery, 6 cases (3.79%) in the RLTN group presented pus overflow due to a rupture of the empyema space. The same happened to 3 cases (3.00%) in the OTN group. After surgery, there was 1 case of abdominal tuberculosis (TB) in the RLTN group. There was no tuberculous sinus or systemic disseminated TB during the follow-up period. Conclusions: Both treatment approaches were safe and effective, but RLTN presented more advantages. Therefore, RLTN can be used as a first-line method for tuberculous nephrectomy.

Mini-percutaneous Nephrolithotomy Under Total Ultrasonography in Patients Aged Less Than 3 Years: A Single-center Initial Experience from China.

BACKGROUND: Urolithiasis in pediatric population is a serious problem with the incidence increased these years. In the management of larger stones (diameters >2 cm), percutaneous nephrolithotomy (PCNL) is considered to be the gold standard. This study aimed to investigate the efficacy and safety of mini-PCNL under total ultrasonography in patients aged <3 years. METHODS: We reviewed 68 patients (80 renal units) aged <3 years between August 2006 and December 2014 in Peking University People's Hospital and Beijing Tsinghua Changung Hospital, including 36 renal units with a single stone, 6 with staghorn stones, 14 with upper ureteral stones, and 24 with multiple stones. The mean age of the patients was 24.2 months (range 6-36 months), and the mean maximum stone diameter was 19.2 mm (range 10-35 mm). The puncture site selection and tract dilation were guided by Doppler ultrasonography solely. All procedures were performed using 12-16 Fr tracts. Stones were fragmented using pneumatic lithotripsy and a holmium laser with an 8/9.8 Fr rigid ureteroscope. RESULTS: Fifty-six patients with unilateral stones underwent a single session procedure, and 12 patients with bilateral stones underwent two procedures. The mean time to establish access was 2.8 min (range 1.8-5.0 min), the mean operative time was 36.5 min (range 20-88 min), the mean decrease in hemoglobin concentration was 8.9 g/L (2-15 g/L), and the stone-free rate (SFR) at hospital discharge was 94.0%. The mean postoperative hospital stay was 7.1 days (range 3-13 days). Postprocedure complications included fever (>38.5°C) in five patients and reactive pleural effusion in one patient. Blood loss requiring transfusion, sepsis, adjacent organ injury, and kidney loss were not observed. CONCLUSIONS: This study indicated that ultrasound-guided mini-PCNL is feasible and safe in patients aged <3 years, without major complications or radiation exposure.