Rutin prevents retinal ganglion cell death and exerts protective effects by regulating transforming growth factor-β2/Smad2/3Akt/PTEN signaling in experimental rat glaucoma

Purpose: To investigate the protective effect of rutin against glaucoma in a rat model, and the mechanisms involved. Methods: Sprague-Dawley rats were injected hypertonic saline in the limbal vein for elevation of intraocular pressure (IOP). Rats in the treatment group were administered rutin at doses of 12.5, 25 or 50 mg/kg orally and daily for 21 days. Results: Rutin markedly (p < 0.05) reduced IOP and prevented loss of retinal ganglion cells (RGCs). The expression of apoptotic pathway proteins, i.e., Bcl-xL, Bcl-2, Bad and Bax were significantly (p < 0.05) regulated by rutin. Moreover, rutin caused a substantial decrease in TGF-β2 expression, and also down-regulated p-Smad2 and p-Smad3 dose-dependently (p < 0.05). Raised levels of collagen I, fibronectin and elastin were effectively down-regulated. Rutin substantially up-regulated the Akt pathway involved in cell survival, and markedly improved the survival of RGCs subjected to hypoxia in vitro (p < 0.05). Conclusion: These results reveal that rutin exerts protective effect against glaucoma in a rat model via a mechanism involving regulation of the TGF-β2/Smad2/3Akt/PTEN signaling pathways. Thus, rutin has potentials for use in the management of glaucoma

Mechanical Properties, Electronic Structures, and Debye Temperature of Ni<i>_x</i>B<i>_y</i> Compounds Obtained by the First Principles Calculations

Mechanical properties, electronic properties, and Debye temperatures of NixBy (Ni3B, Ni2B, Ni4B3 and NiB) compounds were obtained by the first principles calculations based on the density functional theory (DFT). The results showed that the formation enthalpy of the NixBy compounds were stable with negative formation enthalpy. NiB had the largest B, G, and E, and the smallest &#965;; it also had the highest hardness (10.8 GPa) and Debye temperature (681.8 K). Ni4B3 had the strongest anisotropy. It was found that the valence bonds of the NixBy compounds studied were composed of both metal bond and covalent bond, and the mechanical properties and Debye temperature of the NixBy compounds increased with the increase of the B atomic ratio

Evolutionary Trajectories of Primary and Metastatic Pancreatic Neuroendocrine Tumors Based on Genomic Variations

Liver metastases are common in pancreatic neuroendocrine tumors (PanNETs) patients and they are considered a poor prognostic marker. This study aims to analyze the spatiotemporal patterns of genomic variations between primary and metastatic tumors, and to identify the key related biomolecular pathways. We performed next-generation sequencing on paired tissue specimens of primary PanNETs (n = 11) and liver metastases (n = 12). Low genomic heterogeneity between primary PanNETs and liver metastases was observed. Genomic analysis provided evidence that polyclonal seeding is a prevalent event during metastatic progression, and may be associated with the progression-free survival. Besides this, copy number variations of BRCA1/BRCA2 seem to be associated with better prognosis. Pathways analysis showed that pathways in cancer, DNA repair, and cell cycle regulation-related pathways were significantly enriched in primary PanNETs and liver metastases. The study has shown a high concordance of gene mutations between the primary tumor and its metastases and the shared gene mutations may occur during oncogenesis and predates liver metastasis, suggesting an earlier onset of metastasis in patients with PanNETs, providing novel insight into genetic changes in metastatic tumors of PanNETs

Assessment of stromal SCD-induced drug resistance of PDAC using 3D-printed zPDX model chips

Summary: Lipid metabolism is extensively reprogrammed in pancreatic ductal adenocarcinoma (PDAC). Stearoyl-coenzyme A desaturase (SCD) is a critical lipid regulator that was unexplored in PDAC. Here, we characterized the existence of cancer-associated fibroblasts (CAFs) with high SCD expression, and revealed them as an unfavorable prognostic factor. Therefore, primary CAFs and pancreatic cancer cells were harvested and genetically labeled. The mixture of CAFs and cancer cells were co-injected into scd−/−; prkdc−/−, or hIGF1/INS-expressing zebrafish to generate patient-derived xenograft models (zPDX). The models were aligned in 3D-printed chips for semi-automatic drug administration and high-throughput scanning. The results showed that chaperoning of the SCD-high CAFs significantly improved the drug resistance of pancreatic cancer cells against gemcitabine and cisplatin, while the administration of SCD inhibitors neutralized the protective effect. Our studies revealed the prognostic and therapeutic value of stromal SCD in PDAC, and proposed the application of zPDX model chips for drug testing

Sintilimab plus bevacizumab, oxaliplatin and capecitabine as first-line therapy in RAS-mutant, microsatellite stable, unresectable metastatic colorectal cancer: an open-label, single-arm, phase II trialResearch in context

Summary: Background: Microsatellite stable (MSS) and RAS-mutant metastatic colorectal cancer (mCRC) patients are characterized by an immunosuppressive microenvironment and a low response rate to immunotherapy. Chemotherapy and anti-angiogenesis therapy have been reported to potentially promote immunotherapy response. This study aims to assess the preliminary anti-tumor activity and safety of sintilimab plus bevacizumab, oxaliplatin and capecitabine as a treatment option for patients with RAS-mutant MSS mCRC. Methods: This study was an open-label, single-arm, phase II trial in China. Patients with unresectable, RAS-mutant and MSS metastatic colorectal adenocarcinoma received treatment by intravenous sintilimab (200 mg, day 1) plus bevacizumab (7.5 mg/kg, day 1), oxaliplatin (135 mg/m2, day 1) and oral capecitabine (1 g/m2, day 1–14) in each 21-day cycle. The primary endpoints included objective response rate (ORR) and adverse events. Biomarker analysis was performed to identify potential predictors of good response to treatment. This study is registered with ClinicalTrials.gov, number NCT04194359. Findings: Between April 2021 and December 2021, 25 patients were enrolled. Two (8%) patients showed complete response (CR), 19 (76%) had partial response (PR) and 4 (16%) presented with stable disease. ORR reached 84% (95% CI, 63.9–95.5) and the disease control rate was 100% (95% CI, 86.3–100). The median progression-free survival (PFS) was 18.2 months for the full analysis set. The most common treatment-related adverse events (TRAEs) in all grades were anemia (21/25, 84%), neutropenia (20/25, 80%), and hand-foot syndrome (14/25, 56%). The most frequent grade 3 or 4 TRAEs were neutropenia (3/25, 12%) and increased alanine transaminase (2/25, 8%). No grade 5 adverse events occurred. In the exploration of biomarkers, 5 patients could be characterized as TTN/OBSCN “double-hit” after treatment, and the copy number variants burden was significantly decreased in tumor tissues after treatment compared with the baseline. Nanostring panel RNA sequencing analysis indicated a better tumor immune microenvironment cell infiltration in CR/PR patients compared with non-CR/PR patients as well as the PFS-long (≥12.5 months) group compared with the PFS-short group. Interpretation: Combination treatment with sintilimab plus bevacizumab, oxaliplatin and capecitabine as first-line treatment demonstrated a promising antitumor activity and a manageable safety profile in RAS-mutant, MSS and unresectable mCRC. Exploratory biomarker assessment analysis showed that some RAS-mutant and MSS patients changed into “immune-hot” subtype after the treatment. Funding: This study was supported by the Key R&D Program of Zhejiang Province (2021C03125 to Ying Yuan), the National Natural Science Foundation of China (81872481 to Ying Yuan, 82072624 to Kefeng Ding), the Fundamental Research Funds for the Central Universities (No. 226-2022-00009 to Kefeng Ding), and the Zhejiang Provincial Natural Science Foundation of China (No. LY22H160024 to Hanguang Hu)

Additional file 1 of Sintilimab plus bevacizumab and CapeOx (BBCAPX) on first-line treatment in patients with RAS mutant, microsatellite stable, metastatic colorectal cancer: study protocol of a randomized, open-label, multicentric study

Additional file 1: Supplementary file 1. A list of participating centers of BBCAPX trial