SUMO1 degrader induces ER stress and ROS accumulation through deSUMOylation of TCF4 and inhibition of its transcription of StarD7 in colon cancer.

Small molecule degraders of small ubiquitin-related modifier 1 (SUMO1) induce SUMO1 degradation in colon cancer cells and inhibits the cancer cell growth; however, it is unclear how SUMO1 degradation leads to the anticancer activity of the degraders. Genome-wide CRISPR-Cas9 knockout screen has identified StAR-related lipid transfer domain containing 7 (StarD7) as a critical gene for the degrader's anticancer activity. Here, we show that both StarD7 mRNA and protein are overexpressed in human colon cancer and its knockout significantly reduces colon cancer cell growth and xenograft progression. The treatment with the SUMO1 degrader lead compound HB007 reduces StarD7 mRNA and protein levels and increases endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) production in colon cancer cells and three-dimensional (3D) organoids. The study further provides a novel mechanism of the compound anticancer activity that SUMO1 degrader-induced decrease of StarD7 occur through degradation of SUMO1, deSUMOylation and degradation of T cell-specific transcription 4 (TCF4) and thereby inhibition of its transcription of StarD7 in colon cancer cells, 3D organoids and patient-derived xenografts (PDX).

Ubiquitination and degradation of SUMO1 by small-molecule degraders extends survival of mice with patient-derived tumors.

Discovery of small-molecule degraders that activate ubiquitin ligase­mediated ubiquitination and degradation of targeted oncoproteins in cancer cells has been an elusive therapeutic strategy. Here, we report a cancer cell­based drug screen of the NCI drug-like compounds library that enabled identification of small-molecule degraders of the small ubiquitin-related modifier 1 (SUMO1). Structure-activity relationship studies of analogs of the hit compound CPD1 led to identification of a lead compound HB007 with improved properties and anticancer potency in vitro and in vivo. A genome-scale CRISPR-Cas9 knockout screen identified the substrate receptor F-box protein 42 (FBXO42) of cullin 1 (CUL1) E3 ubiquitin ligase as required for HB007 activity. Using HB007 pull-down proteomics assays, we pinpointed HB007's binding protein as the cytoplasmic activation/proliferation-associated protein 1 (CAPRIN1). Biolayer interferometry and compound competitive immunoblot assays confirmed the selectivity of HB007's binding to CAPRIN1. When bound to CAPRIN1, HB007 induced the interaction of CAPRIN1 with FBXO42. FBXO42 then recruited SUMO1 to the CAPRIN1-CUL1-FBXO42 ubiquitin ligase complex, where SUMO1 was ubiquitinated in several of human cancer cells. HB007 selectively degraded SUMO1 in patient tumor­derived xenografts implanted into mice. Systemic administration of HB007 inhibited the progression of patient-derived brain, breast, colon, and lung cancers in mice and increased survival of the animals. This cancer cell­based screening approach enabled discovery of a small-molecule degrader of SUMO1 and may be useful for identifying other small-molecule degraders of oncoproteins.

[Spectral Response and Inversion Models for Prediction of Total Copper Content in Soil of Xifanping Mining Area].

In order to solve the problem of high cost and low efficiency by using the traditional soil geochemical survey methods, this paper studied the simple detection method of soil heavy metal content with visible and near-infrared reflectance spectroscopy. The study collected visible and near-infrared reflectance spectroscopy of soil samples in Xifanping mining area; then treated the reflectance spectroscopy with six mathematic changes such as differentials and continuum removal in advance; the next step was to select characteristic wavelengths that were sensitive to soil copper content by using stepwise regression method and Pearson correlation coefficient as set of comprehensive characteristic variables; finally, utilized different methods and parameters of characteristic variable selection to build the soil total copper content models and tested them. Results showed that: to extract the information of copper content in soil, the performance of different spectral transform methods varied, and each spectrum transform method corresponded to its certain sensitive spectral ranges; the inversion models based on the integrated spectrum transform information were better than that based on only one kind of spectrum transform information; as for establishing the prediction model of soil copper content by using the integrated spectrum transform information, backward elimination was better than forward selection and stepwise selection, and when the Removal is 0.20, the optimum model was obtained, its coefficients of determination(R(2))and determination coefficients of prediction(R(2)(pre))reached 0.851 and 0.830, root mean square error of calibration(RMSEC)and root mean square error of prediction(RMSEP)were 0.349 and 0.468 mg·kg(-1). The model has a good precision, and it provides a train of thought for the detection of other soil heavy metal elements with visible and near-infrared reflectance spectroscopy.

Enhanced recovery after surgery with laparoscopic radical gastrectomy for stomach carcinomas.

AIM: To study the efficacy of the enhanced recovery after surgery (ERAS) program in laparoscopic radical gastrectomy for stomach carcinomas. METHODS: From June 2010 to December 2012, 61 gastric cancer patients who underwent laparoscopic-assisted radical gastrectomy with D2 lymphadenectomy at First Hospital of Jilin University were enrolled in this randomized controlled trial. (Clinical Trials.gov, registration ID: NCT01955096). The subjects were divided into the ERAS program group and the conventional control group. The clinical characteristics, recovery variables, and complications of patients were analyzed. RESULTS: The time to first ambulation, oral food intake, and time to defecation were significantly shorter in the ERAS group (n = 30), compared to the conventional group (n = 31; P = 0.04, 0.003, and 0.01, respectively). The postoperative hospital stay was less in the ERAS group (6.8 ± 1.1 d) compared to the conventional group (7.7 ± 1.1 d) (P = 0.002). There was no significant difference in postoperative complications between the ERAS (1/30) and conventional care groups (2/31) (P = 1.00). There were no readmissions or mortality during the 30-d follow-up period. CONCLUSION: The ERAS program is associated with a shorter hospital stay in gastric cancer patients undergoing laparoscopic radical gastrectomy. The ERAS protocol is useful in the treatment of gastric cancer.