Xiaoping Chen’s research while affiliated with Indiana University Southeast and other places

Surgery-based multimodality therapy is currently the primary treatment for liver cancer. In 1958, the Second Affiliated Hospital of Wuhan Medical College (now Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science & Technology) reported the first case of hepatectomy for liver cancer, marking the beginning of surgical treatment of liver cancer in China. The continuous advancement in liver surgery techniques has brought tremendous benefits to liver cancer patients. An epidemiological study was conducted by the Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science & Technology and the Liver Surgery Group of the Chinese Surgical Society, Chinese Medical Association on 42,573 patients who underwent hepatectomy (67% of whom had hepatocellular carcinoma; Fig. 10.1). The data collected from 112 medical institutions in China showed that the median overall survival time after hepatectomy was 631 days, and the 3- and 5-year overall survival rates were 28.8% and 19.6%, respectively (Fig. 10.2). The joint efforts of liver surgeons in the past decade have led to remarkable achievements in the surgical treatment of liver cancer in China.

Liver cancer with portal vein tumor thrombosis (PVTT) is a significant adverse prognostic factor for patients with liver cancer. However, the incidence of PVTT is 12.5–39.7% in patients with liver cancer, up to 64.7% in autopsied patients with liver cancer, up to 90% in patients with advanced liver cancer, and 20–30% in patients with small liver cancer. The median survival time of patients with liver cancer complicated with PVTT in the natural course of the disease is 2.7–4.0 months, whereas that of patients with liver cancer without PVTT is 24.4 months. According to the Barcelona Clinic Liver Cancer (BCLC) staging system widely applied internationally, liver cancer with PVTT is classified as BCLC stage C. At present, there is no unified international standard for the treatment of liver cancer with PVTT, and the American Association for the Study of Liver Diseases (AASLD) and European Association for the Study of the Liver (EASL) recommend molecular targeted therapy (sorafenib/lenvatinib) as the only first-line treatment regimen, based on the BCLC staging system. The Hong Kong Liver Cancer Staging System recommends TACE as the first-line therapy for liver cancer with PVTT, but for tumors smaller than 5 cm in diameter with Child-Pugh class A liver function and intrahepatic vascular invasion, surgical resection is recommended. The Japan Society of Hepatology and the Asian Pacific Association for the Study of the Liver both recommend surgical resection as an option of the multiple treatment strategies for liver cancer with PVTT.

Background Intrahepatic cholangiocarcinoma (ICC) is a challenging cancer with an increasing incidence. The Phase III TOPAZ‐1/KEYNOTE‐966 study demonstrated chemo‐immunotherapy (CIT) as a significant advancement, potentially replacing traditional chemotherapy for advanced biliary tract cancer. Ferroptosis is a crucial process that affects cancer cell survival and therapy resistance. Although AKT hyperactivation is prevalent in numerous cancers, including ICC, its role in ferroptosis resistance remains unclear. This study explored whether targeting ferroptosis can enhance CIT response rates, specifically in ICC patients with AKT hyperactivation. Methods In vivo metabolic CRISPR screening in a KrasG12D/Tp53−/− ICC mouse model was used to identify primary regulators of ferroptosis during CIT (gemcitabine, cisplatin, and anti‐mouse programmed cell death 1 ligand 1). Phosphoenolpyruvate carboxykinase 1 (PCK1) was assessed for its role in ferroptosis and treatment resistance in preclinical models under AKT activation levels. Molecular and biochemical techniques were used to explore PCK1‐related resistance mechanisms in AKT‐hyperactivated ICC. Results Under AKT hyperactivation condition, phosphorylated PCK1 (pPCK1) promoted metabolic reprogramming, enhancing ubiquinol and menaquinone‐4 synthesis through the mevalonate (MVA) pathway. This cascade was mediated by the pPCK1‐pLDHA‐SPRINGlac axis. Inhibiting PCK1 phosphorylation or using simvastatin significantly augmented CIT efficacy in preclinical models. Clinical data further indicated that phosphorylated AKT (pAKT)‐pPCK1 levels might serve as a biomarker to predict CIT response in ICC. Conclusion This study identified the pAKT‐pPCK1‐pLDHA‐SPRINGlac axis as a novel mechanism driving ferroptosis resistance in AKT‐hyperactivated ICC by associating glycolytic activation with MVA flux reprogramming. Targeting this axis, potentially through statin‐based therapies, may offer a strategy to sensitize ICC cells to ferroptosis and improve treatment outcomes.

OBJECTIVE To examine the incidence of stroke in Chinese adults with newly diagnosed type 2 diabetes (NDD), impaired glucose tolerance (IGT), and normal glucose tolerance (NGT) over a 34-year follow-up period. RESEARCH DESIGN AND METHODS This cohort study included participants with NDD, IGT, and NGT initially identified in 1986 in the Da Qing Diabetes Prevention Study who were followed up for 34 years. Patients with IGT were randomized into a 6-year lifestyle intervention or control group. The stroke incidence and hazard ratios (HRs) were determined across the three glucose-level groups. RESULTS Over 34 years, the cumulative stroke incidence in the NDD, IGT nonintervention, and IGT intervention groups were 65.4%, 62.8%, and 49.8%, respectively. The annual incidence in the NDD group was significantly higher than that in the NGT group (24.3 vs. 18.5 per 1,000 person-years), after adjusting for age and sex. After adjusting for risk factors, the risk of stroke was significantly higher in the NDD (HR 1.80, 95% CI 1.46–2.21, P < 0.001), IGT nonintervention (HR 1.52, 95% CI 1.11–2.07, P = 0.008), and IGT intervention (HR 1.33, 95% CI 1.17–1.63, P = 0.01) groups than in the NGT group. A reduced stroke risk was observed in the overall IGT intervention group compared with the NDD group (HR 0.77, 95% CI 0.64–0.94, P = 0.009), especially in women (HR 0.64, 95% CI 0.47–0.88, P = 0.006). CONCLUSIONS Over 34 years, ∼50% of Chinese adults with NDD and IGT experienced stroke. Further efforts in diabetes management and intervention are required.

The transmembrane and coiled‐coil domains 3 (TMCO3) are highly expressed in many tumors. However, the underlying mechanisms governing the way in which TMCO3 affects the progression of hepatocellular carcinoma (HCC) remain unclear. This study screens out the molecule TMCO3 with high N6‐methyladenosine (m⁶A) modification level in tumor samples compared to the adjacent non‐cancerous tissues of three pairs of HCC patients through Methylated RNA Immunoprecipitation Sequencing (MeRIP‐seq) and RNA sequencing (RNA‐seq). Subsequently, the oncogenic effect of TMCO3 in HCC is verified through in vivo and in vitro experiments. AlkB Homolog 5 (ALKBH5), an m⁶A demethylase of TMCO3 is then screened out. The following experiments demonstrate that TMCO3 can activate AKT directly through the Phosphatidylinositol‐3–Kinase (PI3K) pathway, thus promoting the progression of HCC. Meanwhile, the phosphorylation site on TMCO3: the 85th amino acid‐serine, and mutation of this site can directly impair the activity and membrane translocation of AKT is found. Finally, the carcinogenic effect of TMCO3 is further elucidated in HCC through the orthotopic treatment model and the hydrodynamic tail vein injection treatment model. The findings can provide a potential target for targeted AKT treatment in patients with HCC and verify a possible prognostic marker in HCC.

Background We investigated the association between younger-onset type 2 diabetes, duration of diabetes, and cancer risk based on data from the Da Qing Diabetes Prevention Outcome Study (DQDPOS). Methods The analysis recruited 620 younger-onset (age≤50 years) and 649 older-onset (age>50 years) patients with type 2 diabetes, and 310 younger non-diabetes controls (age≤50 years). Multiple regression analysis was used to test the influence of younger-onset diabetes and duration of diabetes on the long-term risk of cancer. Results The annual incidence of all cancer among the non-diabetes, younger-, and older-onset type 2 diabetes was significantly different (3.7, 5.5, and 4.0/1000 person-years, respectively). The standard Cox analysis revealed that the patients with younger-onset diabetes had a significantly higher risk of cancer than those with older-onset diabetes (hazard ratio [HR]:1.81; 95% confidence interval [CI]:1.20–2.73) and younger non-diabetic controls (HR:2.43; 95% CI:1.34–4.41) after adjustment for diabetes duration and other confounders. Stepwise general linear regression model analysis revealed that a longer diabetes-free time was associated with longer lifetime cancer-free years (partial R² = 0.36, p < 0.001), in addition to the non-modifiable predictor duration of diabetes. Conclusions Younger-onset type 2 diabetes was significantly associated with an increased risk of cancer beyond the influence of diabetes duration.