Cadonilimab with chemotherapy in HER2-negative gastric or gastroesophageal junction adenocarcinoma: the phase 1b/2 COMPASSION-04 trial.

Treatment with anti-programmed cell death protein 1 (PD-1) therapy and chemotherapy prolongs the survival of patients with unresectable advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. The benefit from anti-PD-1 therapy is enriched in patients with programmed cell death 1 ligand 1 (PD-L1) combined positive score (CPS)-positive or CPS-high tumors compared with patients with PD-L1 CPS-negative or CPS-low tumors. In this phase 1b/2 study, we evaluated the efficacy and safety of cadonilimab, a bispecific antibody targeting PD-1 and cytotoxic T-lymphocyte antigen-4, plus chemotherapy as first-line treatment in patients with human epidermal growth factor receptor 2-negative unresectable advanced or metastatic gastric or GEJ adenocarcinoma. The primary endpoint was the recommended phase 2 dose (RP2D) for phase 1b and the objective response rate for phase 2. Secondary endpoints included disease control rate, duration of response, time to response, progression-free survival, overall survival (OS) and safety. The primary endpoint was met. No dose-limiting toxicities were observed during dose escalation in phase 1b; the recommended phase 2 dose was determined as 6 mg kg-1 every 2 weeks. The objective response rate was 52.1% (95% confidence interval (CI) = 41.6-62.5), consisting of complete and partial responses in 4.3% and 47.9% of patients, respectively. The median duration of response, progression-free survival and OS were 13.73 months (95% CI = 7.79-19.12), 8.18 months (95% CI = 6.67-10.48) and 17.48 months (95% CI = 12.35-26.55), respectively. The median OS in patients with a PD-L1 CPS ≥ 5 was 20.32 months (95% CI = 4.67-not estimable); in patients with a PD-L1 CPS < 1, the median OS reached 17.64 months (95% CI = 11.63-31.70). The most common treatment-related grade 3 or higher adverse events were decreased neutrophil count (19.1%), decreased platelet count (16.0%), anemia (12.8%) and decreased leukocyte count (8.5%). No new safety signal was identified. The current regimen showed promising clinical activity and manageable safety in patients with gastric or GEJ adenocarcinoma regardless of PD-L1 expression. Chinadrugtrials.org.cn registration: CTR20182027.

The "quadrant-sandwich" method in clockwise modular D2 lymph node dissection in laparoscopic total gastrectomy: a retrospective cohort study.

Background: For patients who need laparoscopic radical gastrectomy, lymph node dissection (LND) and optimization of surgical procedures are particularly important. This study introduces the "quadrant-sandwich" method in clockwise modular D2 LND and evaluates the advantages and safety of this method. Methods: The clinical data of 108 laparoscopic total gastrectomy patients admitted to the Affiliated Cancer Hospital of Zhengzhou University from January 2019 to January 2022 were retrospectively analyzed. Based on the different LND processes, 55 patients were allocated to the observation group, which underwent clockwise modular LND using the "quadrant-sandwich method", and 53 patients were allocated to the control group, which underwent traditional LND. The effectiveness and safety of the approach in terms of operation time, blood loss, lymph node yield, postoperative recovery and postoperative complications were observed in the two groups. Results: There was no statistical difference between the baseline data of the two groups. In relation to the surgery, the observation group had an operation time of 227.0±48.5 minutes, and intraoperative bleeding of 100.0 mL [inter-quartile range (IQR), 30.0-200.0 mL], while the control group had an operation time of 247±41.5 minutes, and intraoperative bleeding of 180.0 mL (IQR, 130.0-245.0 mL). There were statistically significant differences between the two groups in terms of the operation time and intraoperative bleeding (P=0.001, P=0.020). In relation to the LND, there were no statistically significant differences between the two groups in terms of the total number of lymph nodes in each division, and the number of positive lymph nodes. In relation to the post-operative results, there were no statistically significant differences between the two groups in terms of the post-operative pathological stage, first postoperative oral feeding, post-operative hospitalization time, and post-operative complications. Conclusions: Clockwise modular D2 LND using the "quadrant-sandwich method" is potentially safe and feasible in laparoscopic total gastrectomy. It not only ensures the thoroughness of the LND, but also ensures and efficient and fast surgical process, shortens the operation time, and reduces the amount of intraoperative bleeding.

Postoperative superior anastomotic leakage classification and treatment strategy for postoperative esophagogastric junction cancer.

Background: At present, anastomotic fistula cannot be avoided after adenocarcinoma of the esophagogastric junction (AEG). Once the anastomotic leakage occurs, the posterior mediastinum and the left thoracic cavity are often seriously infected, which further impairs respiratory and circulatory function, heightening the danger of the disease course. The aim of this study was to identify the characteristics of superior anastomotic leakage after surgery for AEG and recommend corresponding treatment strategies to improve the diagnosis and treatment of superior anastomotic leakage after surgery for AEG. Methods: The clinical data of 57 patients with superior anastomotic leakage after surgery for AEG in the Affiliated Cancer Hospital of Zhengzhou University from January 2017 to March 2019 were retrospectively analyzed, including 27 cases referred from external hospitals and 30 cases at the Affiliated Cancer Hospital of Zhengzhou University. According to the diameter and risk level of anastomotic leakage, the high anastomotic leakage is divided into types I, II, III, and IV. Results: Patients with preoperative comorbidities or those treated with the transabdominal approach or laparoscopic surgery often had type I and type II anastomotic leakage; meanwhile, patients with preoperative comorbidities and sacral perforation or those treated with a thoracic and abdominal approach or open surgery often had type III and IV fistula. The difference between types I-II and types III-IV was statistically significant (P<0.05). The mortality rate of patients with type III and type IV leakage was 14.8% within 90 days after operation, while no deaths occurred among patients with type I and type II leakage, and the difference in mortality between the two groups was statistically significant (P<0.05). Conclusions: After surgery for AEG, suitable treatment measures should be adopted according to the type of superior anastomotic leakage that occurs. Types III and IV superior anastomotic leakages are associated with higher mortality and require greater attention from surgeons.

Retrospective study of combined pelvic exenteration in the treatment of primary and recurrent pelvic malignant tumors.

Background: Pelvic malignant tumors often originate in the rectum, bladder, uterus, and other organs. In patients with locally advanced tumours in the presence of direct invasion of one or more organs, negative tumor resection margin (R0) resection can be very beneficial to patient survival if it can be performed. As a multidisciplinary and high-risk surgical method, the pelvic exenteration (PE) procedure has only been reported in a few medical centres internationally. We retrospectively analyzed the clinical data of patients who had undergone PE surgery in our hospital, in order to provide ideas for the best treatment of patients with pelvic malignant tumors. Methods: A retrospective analysis was conducted of 59 patients with pelvic malignant tumors admitted to the Affiliated Cancer Hospital of Zhengzhou University from January 2015 to July 2021, all of whom received PE surgery. They were divided into two groups according to the location of the disease: the rectal cancer group (n=40) and the cervical cancer group (n=19). Statistical analysis was performed on the baseline and follow-up data of the two groups of patients. Results: (I) Patient baseline data. Compared to the rectal cancer group, more patients in the cervical cancer group received preoperative radiotherapy and chemotherapy (P=0.013), and had a lower R0 resection rate (P=0.037). Postoperative complications in patients with rectal cancer and cervical cancer were 27.5% and 47.3%, respectively. (II) Patient survival analysis after PE surgery. The 5-year survival rate was 36.6% in the rectal cancer group and 25.3% in the cervical cancer group. In the rectal cancer group, for the primary tumor, if there was no lymph node metastasis or no postoperative complications in the postoperative pathology, the patient had a good survival prognosis. Univariate analysis showed that recurrent rectal cancer, postoperative lymph node metastasis, postoperative complications, and microsatellite stability (MSS) were significant predictors of poor survival outcomes. Multivariate analysis showed that lymph node metastasis and postoperative complications were independent prognostic factors for patient survival. Conclusions: PE is a viable option for pelvic malignancies; aggressive radical resection of lesions and reduced postoperative complications can effectively improve patient outcomes.

Clinicopathological features and prognoses in younger and older patients with mismatch repair defects colorectal cancer: a retrospective comparative cohort study.

Background: Microsatellite instability-high (MSI-H) is an important biomarker for predicting the effects of immune checkpoint inhibitors (ICIs) in colorectal cancer (CRC) patients. However, due to the low mutation rate of MSI-H/deficient mismatch repair (dMMR) in the overall population, some doctors are of the view that testing this indicator increases the burden on patients, and consequently some patients fail to receive the most beneficial treatment methods. In order to provide testing criteria for younger patients with a higher proportion of MSI-H, we designed this retrospective controlled study. Methods: A retrospective analysis was conducted of 1,901 patients who were admitted to the Affiliated Cancer Hospital of Zhengzhou University from January 2017 to December 2019 and underwent CRC-related gene testing. For this analysis, 100 patients aged 40 or younger are defined as the young group, and 305 patients aged 71 and older but younger than 80 are defined as the elderly group. We included patients who met the following criteria: (I) underwent preoperative colonoscopy or gastroscopy and were diagnosed with CRC; (II) received perioperative adjuvant therapy; (III) underwent curative surgery for CRC. Each patient was followed up from the time of surgery until April 30, 2023, or death, with follow-up visits scheduled every 3 months for the first 2 years after surgery, and every 6 months thereafter. Clinical characteristics such as age, gender, body mass index (BMI), tumor depth (T), number of metastatic lymph nodes (N), distant metastasis (M), tumor, node, metastasis (TNM) stage, extent of surgical resection, tumor size, tumor location, differentiation grade, and carcinoembryonic antigen (CEA) levels were collected. The microsatellite instability (MSI) status was analyzed using fluorescence in situ hybridization (FISH). Results: In young CRC patients, the proportion of MSI-H is higher than in elderly CRC patients (33% vs. 10.16%, P<0.001). The proportion of poorly differentiated tumors is also higher in young CRC patients compared to elderly CRC patients (53% vs. 31.15%, P<0.001). However, there were no significant differences in clinical characteristics between young and elderly CRC patients. In terms of prognosis, survival analysis of the young group showed that MSI status [hazard ratio (HR) =0.26, 95% confidence interval (CI): 0.08-0.88, P=0.03], TNM staging (HR =3.84, 95% CI: 1.38-10.71, P=0.010) were associated with the prognosis of CRC patients. Conclusions: The mutation rate of MSI-H is higher in young CRC patients compared to older. Our study further confirms that MSI-H can serve as a favorable prognostic marker for CRC patients. This finding may provide valuable guidance for clinicians in terms of prognosis assessment and treatment selection. If feasible, we hope that MSI testing can be performed for all CRC patients to enable targeted testing, with particular attention to monitoring the MSI status in young patients. This will aid clinicians in selecting appropriate treatment strategies for these patients.

The long-term outcomes and prognostic factors about locally advanced right colon cancer: a retrospective cohort study.

Background: The first case of treatment with en bloc right hemicolectomy with pancreatoduodenectomy (RHCPD) for locally advanced right-sided colon cancer (LARCC) invading the pancreas, duodenum, or other organs, was reported in 1953 by Van Prohaska. Right-sided colon cancers invading the pancreas and duodenum are rare. Surgery can be technically challenging, with unclear oncologic consequences, hence there are few reports on the clinical outcomes and factors associated with survival in this patient cohort. The need for neoadjuvant chemotherapy in patients with LARCC is controversial, and the long-term survival of these patients as well as the preferred treatment regimen needs to be explored. This paper reports our experience in right hemicolectomy with en bloc resection for LARCC. We conducted this study to analyze the clinical features and surgical outcomes of LARCC. Methods: A retrospective study was performed using a database of all patients who underwent RHCPD due to the tumour directly invading the duodenum and/or pancreas in a 19-year period [2003-2022]. We included patients whose primary tumor site was the right hemicolon and who had undergone a negative tumor resection margin (R0) resection. In addition, the adhesions between the colon and other organs in these patients were malignant adhesions. The primary outcome was the overall survival after surgery. The secondary endpoints of the study included 30-day postoperative mortality, postoperative complications, prognostic factors, and tumour genetics. All patients were followed up with postoperative imaging at an interval of 3 months for the first 3 years and at an interval of 6 months for the next 2 years, and annual follow-up thereafter. Survival was estimated using Kaplan-Meier analysis. Variables with P values <0.05 in univariate analysis were entered into multivariate Cox proportional risk regression to identify independent predictors of survival. Results: There were 47 patients (23 males and 24 females) who underwent en bloc resection for LARCC. The median age of the patients was 61 years (range, 38-80 years). R0 resection was achieved in all cases. The overall complication rate was 27.7% (n=13). Two patients died within 30 days of surgery. The overall survival was 80.9%, 63.5%, and 51.7% at 1, 3, and 5 years, respectively. Univariate survival analysis identified pancreatic invasion, regional lymph node positivity, more than two organs invaded, and no neoadjuvant treatment as predictors of poor survival (log-rank P<0.05). Multivariate analysis showed that regional lymph node positivity [95% confidence interval (CI): 1.145-7.736; P=0.025] and more than two organs invaded (95% CI: 1.321-26.981; P=0.020) were predictors of poor survival. Conclusions: Relatively optimistic clinical outcomes from en bloc resection were demonstrated for patients with LARCC. For LARCC patients, en bloc resection can be carefully considered.

Corrigendum: Single-cell RNA sequencing reveals the role of phosphorylation-related genes in hepatocellular carcinoma stem cells.

[This corrects the article DOI: 10.3389/fcell.2021.734287.].

Ferritinophagy-mediated apoptosis and paraptosis induction involved MAPK and PI3K/AKT pathway in mechanism of an iron chelator.

Melanoma cells were more resistant to ferroptosis with still poor therapy outcomes. Sensitizing melanoma cell to the ferroptosis inducer was a crucial strategy for treatment of melanoma. In the present study, 2,2'-di-pyridylketone hydrazone dithiocarbamate s-butyric acid (DpdtbA) displayed superior inhibitory activity than ferroptosis inducer Erastin in melanoma cells, which prompt us to explore the underlying mechanism. The analyses from flow cytometry and Western blot showed that the growth inhibition of DpdtbA against SK-MEL-28 and A375 cells involved apoptosis induction and G1 phase arrest. Surprisingly, the cytoplasmic vacuoles were found upon the treatment; transmission electron microscopy and endoplasmic reticulum (ER) staining revealed that the cytoplasmic vacuoles were in ER; while down-regulation of alix and requirement of protein synthesis suggested there was an occurrence of paraptosis. However, both NAC and 3-MA could significantly attenuate the cytoplasmic vacuolization and growth inhibition, hinting that both ROS and autophagy involved the paraptosis induction. The additional evidence revealed that there was an occurrence of continuous ferritinophagy, which was responsible for the ROS production. Downregulation of NCOA4 clearly attenuated the apoptosis and paraptosis induction. In addition, activation of MAPK involved regulation of paraptosis, but only ERK and JNK had role in the formation of cytoplasmic vacuoles and growth inhibition. Furthermore, a ROS dependent regulation of PI3K/AKT pathway was also involved. Taken together, our result firstly demonstrated that a continuous ferritinophagy contributed to the apoptosis and paraptosis induction, highlighting that the lysosomal labile iron pool had a crucial role in control of melanoma cell fate.

Safety and antitumour activity of cadonilimab, an anti-PD-1/CTLA-4 bispecific antibody, for patients with advanced solid tumours (COMPASSION-03): a multicentre, open-label, phase 1b/2 trial.

BACKGROUND: Immune checkpoint inhibitors targeting PD-1 or CTLA-4 individually have shown substantial clinical benefits in the treatment of malignancies. We aimed to assess the safety and antitumour activity of cadonilimab monotherapy, a bispecific PD-1/CTLA-4 antibody, in patients with advanced solid tumours. METHODS: This multicentre, open-label, phase 1b/2 trial was conducted across 30 hospitals in China. Patients aged 18 years or older with histologically or cytologically confirmed, unresectable advanced solid tumours, unsuccessful completion of at least one previous systemic therapy, and an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible for inclusion. Patients who had previously received anti-PD-1, anti-PD-L1, or anti-CTLA-4 treatment were not eligible for inclusion. In the dose escalation phase of phase 1b, patients received intravenous cadonilimab at 6 mg/kg and 10 mg/kg every 2 weeks. In the dose expansion phase of phase 1b, cadonilimab at 6 mg/kg and a fixed dose of 450 mg were given intravenously every 2 weeks. In phase 2, cadonilimab at 6 mg/kg was administered intravenously every 2 weeks in three cohorts: patients with cervical cancer, oesophageal squamous cell carcinoma, and hepatocellular carcinoma. The primary endpoints were the safety of cadonilimab in phase 1b and objective response rate in phase 2, based on the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. The safety analysis was done in all patients who received at least one dose of cadonilimab. Antitumour activity was assessed in the full analysis set for the cervical cancer cohort, and in all patients with measurable disease at baseline and who received at least one dose of cadonilimab in the oesophageal squamous cell carcinoma and hepatocellular carcinoma cohorts. The study is registered on ClinicalTrial.gov, NCT03852251, and closed to new participants; follow-up has been completed. FINDINGS: Between Jan 18, 2019, and Jan 8, 2021, 240 patients (83 [43 male and 40 female] in phase 1b and 157 in phase 2) were enrolled. Phase 2 enrolled 111 female patients with cervical cancer, 22 patients with oesophageal squamous cell carcinoma (15 male and seven female), and 24 patients with hepatocellular carcinoma (17 male and seven female). During dose escalation, no dose-limiting toxicities occurred. Grade 3-4 treatment-related adverse events occurred in 67 (28%) of 240 patients; the most frequent grade 3 or worse treatment-related adverse events were anaemia (seven [3%]), increased lipase (four [2%]), decreased bodyweight (three [1%]), decreased appetite (four [2%]), decreased neutrophil count (three [1%]), and infusion-related reaction (two [1%]). 17 (7%) patients discontinued treatment due to treatment-related adverse events. 54 (23%) of 240 patients reported serious treatment-related adverse events, including five patients who died (one due to myocardial infarction; cause unknown for four). In phase 2, in the cervical cancer cohort, with a median follow-up of 14·6 months (IQR 13·1-17·5), the objective response rate was 32·3% (32 of 99; 95% CI 23·3-42·5). In the oesophageal squamous cell carcinoma cohort, with a median follow-up of 17·9 months (IQR 4·0-15·1), the objective response rate was 18·2% (four of 22; 95% CI 5·2-40·3). In the hepatocellular carcinoma cohort, with a median follow-up of 19·6 months (IQR 8·7-19·8), the objective response rate was 16·7% (four of 24; 95% CI 4·7-37·4). INTERPRETATION: Cadonilimab showed an encouraging tumour response rate, with a manageable safety profile, suggesting the potential of cadonilimab for the treatment of advanced solid tumours. FUNDING: Akeso Biopharma. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Protocol for high-sensitivity western blot on murine hematopoietic stem cells.

Hematopoietic stem cells (HSCs) sustain hematopoiesis during homeostasis and regeneration. However, their limited availability poses a challenge for protein analysis. Here, we present a protocol for performing high-sensitivity western blot on HSCs using two techniques that enhance HSC isolation from mice and boost sensitivity for low cell numbers. We describe steps for isolating murine bone marrow cells, antibody staining, and cell sorting and post-sort analysis. We then detail a western blot procedure suitable for low numbers of HSCs. For complete details on the use and execution of this protocol, please refer to Li et al (2022).1,2.

DpdtpA, A Multi-metal Ion Chelator, Attenuates Tau Phosphorylation and Microglial Inflammatory Response via Regulating the PI3K/AKT/GSK-3ß Signal Pathways.

Tau protein hyperphosphorylation and formation of intracellular neurofibrillary tangles (NFTs) are one of the histopathological hallmarks of Alzheimer's disease (AD) and positively correlated with the severity of AD symptoms. NFTs contain a large number of metal ions that play an important role in regulating tau protein phosphorylation and AD progression. Extracellular tau induces primary phagocytosis of stressed neurons and neuronal loss by activating microglia. Here, we studied the effects of a multi-metal ion chelator, DpdtpA, on tau-induced microglial activation and inflammatory responses and the underlying mechanisms. Treatment with DpdtpA attenuated the increase in the expression of NF-κB and production of inflammatory cytokines, IL-1ß, IL-6 and IL-10, in rat microglial cells induced by expression of human tau40 proteins. Treatment with DpdtpA also suppressed tau protein expression and phosphorylation. Moreover, treatment with DpdtpA prevented tau-induced activation of glycogen synthase kinase-3ß (GSK-3ß) and inhibition of phosphatidylinositol-3-hydroxy kinase (PI3K)/AKT. Collectively, these results show that DpdtpA can attenuate tau phosphorylation and inflammatory responses of microglia by regulating the PI3K/AKT/GSK-3ß signal pathways, providing a new option to alleviate neuroinflammation for the treatment of AD.

Loss of sphingosine kinase 2 promotes the expansion of hematopoietic stem cells by improving their metabolic fitness.

Hematopoietic stem cells (HSCs) have reduced capacities to properly maintain and replenish the hematopoietic system during myelosuppressive injury or aging. Expanding and rejuvenating HSCs for therapeutic purposes has been a long-sought goal with limited progress. Here, we show that the enzyme Sphk2 (sphingosine kinase 2), which generates the lipid metabolite sphingosine-1-phosphate, is highly expressed in HSCs. The deletion of Sphk2 markedly promotes self-renewal and increases the regenerative potential of HSCs. More importantly, Sphk2 deletion globally preserves the young HSC gene expression pattern, improves the function, and sustains the multilineage potential of HSCs during aging. Mechanistically, Sphk2 interacts with prolyl hydroxylase 2 and the Von Hippel-Lindau protein to facilitate HIF1α ubiquitination in the nucleus independent of the Sphk2 catalytic activity. Deletion of Sphk2 increases hypoxic responses by stabilizing the HIF1α protein to upregulate PDK3, a glycolysis checkpoint protein for HSC quiescence, which subsequently enhances the function of HSCs by improving their metabolic fitness; specifically, it enhances anaerobic glycolysis but suppresses mitochondrial oxidative phosphorylation and generation of reactive oxygen species. Overall, targeting Sphk2 to enhance the metabolic fitness of HSCs is a promising strategy to expand and rejuvenate functional HSCs.

Amino acid catabolism regulates hematopoietic stem cell proteostasis via a GCN2-eIF2α axis.

Hematopoietic stem cells (HSCs) adapt their metabolism to maintenance and proliferation; however, the mechanism remains incompletely understood. Here, we demonstrated that homeostatic HSCs exhibited high amino acid (AA) catabolism to reduce cellular AA levels, which activated the GCN2-eIF2α axis, a protein synthesis inhibitory checkpoint to restrain protein synthesis for maintenance. Furthermore, upon proliferation conditions, HSCs enhanced mitochondrial oxidative phosphorylation (OXPHOS) for higher energy production but decreased AA catabolism to accumulate cellular AAs, which inactivated the GCN2-eIF2α axis to increase protein synthesis and coupled with proteotoxic stress. Importantly, GCN2 deletion impaired HSC function in repopulation and regeneration. Mechanistically, GCN2 maintained proteostasis and inhibited Src-mediated AKT activation to repress mitochondrial OXPHOS in HSCs. Moreover, the glycolytic metabolite, NAD+ precursor nicotinamide riboside (NR), accelerated AA catabolism to activate GCN2 and sustain the long-term function of HSCs. Overall, our study uncovered direct links between metabolic alterations and translation control in HSCs during homeostasis and proliferation.

Disulfiram Protects Against Radiation-Induced Intestinal Injury in Mice.

Radiation-induced intestinal injury (RIII) occurs after high doses of radiation exposure. RIII restricts the therapeutic efficacy of radiotherapy in cancer and increases morbidity and mortality in nuclear disasters. Currently, there is no approved agent for the prevention or treatment of RIII. Here, we reported that the disulfiram, an FDA-approved alcohol deterrent, prolonged the survival in mice after lethal irradiation. Pretreatment with disulfiram inhibited proliferation within 24 h after irradiation, but improved crypt regeneration at 3.5 days post-irradiation. Mechanistically, disulfiram promoted Lgr5+ intestinal stem cells (ISCs) survival and maintained their ability to regenerate intestinal epithelium after radiation. Moreover, disulfiram suppresses DNA damage accumulation, thus inhibits aberrant mitosis after radiation. Unexpectedly, disulfiram treatment did not inhibit crypt cell apoptosis 4 h after radiation and the regeneration of crypts from PUMA-deficient mice after irradiation was also promoted by disulfiram. In conclusion, our findings demonstrate that disulfiram regulates the DNA damage response and survival of ISCs through affecting the cell cycle. Given its radioprotective efficacy and decades of application in humans, disulfiram is a promising candidate to prevent RIII in cancer therapy and nuclear accident.

Ferritinophagy-Mediated Ferroptosis and Activation of Keap1/Nrf2/HO-1 Pathway Were Conducive to EMT Inhibition of Gastric Cancer Cells in Action of 2,2'-Di-pyridineketone Hydrazone Dithiocarbamate Butyric Acid Ester.

In metastasis of cancer cells, the epithelial-mesenchymal transition (EMT) is prerequired. Ferroptosis is an iron-mediated cellular death process, but whether it involves EMT regulation remains elusive. In addition, how stress responders (Nrf2) respond to the redox alteration and cross-talking between them needs to be determined. Our data revealed that DpdtbA (2,2'-di-pyridineketone hydrazone dithiocarbamate butyric acid ester) resisted TGF-ß1-induced EMT in gastric cancer lines (SGC-7901 and MGC-823) through ferritinophagy-mediated ROS production. Furthermore, the depletion of Gpx4 and xCT as well as enhanced lipid peroxidation indicated that DpdtbA acted as Erastin did in ferroptosis induction, which thus provided chance to explore the causal relationship between ferroptosis and EMT. Our data illustrated that ferritinophagy-mediated ferroptosis promoted the EMT inhibition. In addition, activated Nrf2 involved the regulation on both ferroptosis and EMT in response to the alteration in the cellular redox environment. In brief, ferritinophagy-mediated ferroptosis and activation of the Keap1/Nrf2/HO-1 pathway were conducive to the EMT inhibition.