SMAD4 endows TGF-ß1-induced highly invasive tumor cells with ferroptosis vulnerability in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive malignancy prone to recurrence and metastasis. Studies show that tumor cells with increased invasive and metastatic potential are more likely to undergo ferroptosis. SMAD4 is a critical molecule in the transforming growth factor ß (TGF-ß) pathway, which affects the TGF-ß-induced epithelial-mesenchymal transition (EMT) status. SMAD4 loss is observed in more than half of patients with PDAC. In this study, we investigated whether SMAD4-positive PDAC cells were prone to ferroptosis because of their high invasiveness. We showed that SMAD4 status almost determined the orientation of transforming growth factor ß1 (TGF-ß1)-induced EMT via the SMAD4-dependent canonical pathway in PDAC, which altered ferroptosis vulnerability. We identified glutathione peroxidase 4 (GPX4), which inhibited ferroptosis, as a SMAD4 down-regulated gene by RNA sequencing. We found that SMAD4 bound to the promoter of GPX4 and decreased GPX4 transcription in PDAC. Furthermore, TGF-ß1-induced high invasiveness enhanced sensitivity of SMAD4-positive organoids and pancreas xenograft models to the ferroptosis inducer RAS-selective lethal 3 (RSL3). Moreover, SMAD4 enhanced the cytotoxic effect of gemcitabine combined with RSL3 in highly invasive PDAC cells. This study provides new ideas for the treatment of PDAC, especially SMAD4-positive PDAC.

Drought stress-induced the formation of heteromorphic leaves of Populus euphratica Oliv: evidence from gene transcriptome.

Populus euphratica Oliv., a dominant species of arid desert community, grows heteromorphic leaves at different crown positions. Whether heteromorphic leaves are a strategy of plant adaptation to drought stress is rarely reported. This study sequenced the transcriptome of three typical heteromorphic leaves (lanceolate, ovate and broad-ovate leaves) of P. euphratica, and measured their drought stress. We wanted to reveal the molecular mechanisms underlying the formation of heteromorphic leaves. Drought stress was increased significantly from lanceolate to ovate to broad-ovate leaves. Gene ontology (GO) and KEGG enrichment analysis showed that the MADs-box gene regulated the expression of peroxidase (POD) in the phenylpropane biosynthetic pathway. The up-regulated expression of the chalcone synthase (CHS) gene in broad-ovate leaves significantly activated the flavonoid biosynthetic pathway. In the process of leaf shape change, the different expressions of homeodomain leucine zipper (HD-ZIP) among the three heteromorphic leaves had potential interactions on the AUX and ABA pathways. The expression of Sucrose phosphate synthase (SPS) and sucrose synthase (SUS) increased from lanceolate to broad-ovate leaves, resulting in a consistent change in starch and sucrose content. We concluded that these resistance-related pathways are expressed in parallel with leaf formation genes, thereby inducing the formation of heteromorphic leaves. Our work provided a new insights for desert plants to adapt to drought stress.

Clinical Application of the Musculoperiosteal Iliac Flap for Osteonecrosis of the Femoral Head.

BACKGROUND: Osteonecrosis of the femoral head (ONFH) often affects young, active patients, and the femoral head's preservation is the primary goal of treatment for this disease. Vascularized iliac crest bone grafting is one of the many vascularized procedures used in treating ONHF. In some cases, we selectively performed this procedure using the musculoperiosteal iliac flap with the ascending branch of the lateral femoral circumflex artery for ONFH treatment. METHODS: Twelve patients (12 hips) with nontraumatic femoral head necrosis underwent musculoperiosteal iliac flap transfer with the ascending branch of the lateral femoral circumflex artery. The Harris Hip Score (HHS), visual analog scale score, and double-hip X-ray findings were used to analyze hip function changes within 10 days preoperatively and 6 and 12 months postoperatively. RESULTS: The mean HHS increased from 52.33 ± 3.34 preoperatively to 65.92 ± 5.04 6 months postoperatively and 79.75 ± 3.84 12 months postoperatively, and the data showed a statistical significance difference between preoperative and postoperative (F = 131.90, P < 0.01). The HHS at 6 and 12 months after surgery were significantly different (P < 0.01). The visual analog scale score showed the same trend. The x-ray of hip joints at 6 and 12 months after surgery showed that the femoral heads' shape and contour were good, femoral heads did not collapse, and the transferred bone flaps healed well. CONCLUSIONS: Musculoperiosteal iliac flap transfer with the ascending branch of the lateral femoral circumflex artery may be an effective method with a high clinical success rate for treating young patients with early to midstage ONFH.

In vivo biocompatibility evaluation of Zn-0.05Mg-(0, 0.5, 1wt%)Ag implants in New Zealand rabbits.

Bio-absorbable Zn alloys have been attractive replacements for the traditionally permanent implants due to their reasonable mechanical strength and elongation, degradation rate, and biocompatibility. The hybridization addition of Mg and Ag elements could greatly improve the mechanical properties and antibacterial ability of Zn, respectively. In the present paper, in vivo biocompatibility for the Zn-0.05Mg-(0, 0.5, 1 wt%) Ag implants in New Zealand rabbit was qualitatively evaluated during the implantation periods of 4, 12, and 24 weeks. The blood serum biochemical parameters and in vivo integrity of the implants in the live rabbits were monitored by using clinical chemistry analyzing and X-ray radiographic imaging techniques during the implantation process, respectively. There is no great difference in the serum biochemical indicator between the implanted rabbits and the control group. Especially the levels of serum Zn and serum Mg normalize after implantation of 24 weeks. The interfacial adherence between the implants and newly formed bones, and the histopathological morphology of heart, liver, and kidney were observed morphologically under the microscope. The new bones formed and grew surrounding the implants after 12 weeks' post-operation, which were well joined with the original cortical bones after post-implantation of 24 weeks. The heart, liver and kidney were not negatively influenced as evidenced from the serum biochemical indicators and morphologies of the tissues. Zn-0.05Mg-(0, 0.5, 1 wt%) Ag alloys are proved to be in vivo biocompatible and potential candidates for the biodegradable medical implants.