Yuepeng Jin

Background/Objectives: Decreases in skeletal muscle mass affect the efficacy of and tumor response to various therapies for hepatocellular carcinoma (HCC). This study aimed to investigate the relationship between changes in skeletal muscle mass during TACE-based combination therapy and tumor response and prognosis. Methods: This retrospective study analyzed 306 patients with unresectable HCC, divided into four groups according to the treatment received: TACE alone (n = 133), TACE plus targeted and immunotherapy combination (TACE + T + I, n = 68), TACE plus immunotherapy (TACE + I, n = 52), and TACE plus targeted therapy (TACE + T, n = 53). Skeletal muscle mass was assessed at the third lumbar vertebral level (L3) before treatment and at six months post-treatment using computed tomography (CT) scans. Patients were stratified based on changes in skeletal muscle index (SMI) values. Kaplan–Meier and Cox proportional hazards models were used to compare overall survival (OS) among groups classified by changes in SMI, while tumor response was assessed with univariate and multivariate analyses, using logistic regression analysis. Result: A total of 306 patients with unresectable HCC were included in this study. The median OS was 17.0 (0.9–83.0) months in the decreased-SMI group compared with 35.0 (2.0–113.0) months in the non-decreased-SMI group. The overall response rate (CR + PR) was 34.7% in the decreased-SMI group and 53.8% in the non-decreased group. Among different treatment regimens, significant differences in Kaplan–Meier survival curves were observed between the TACE and TACE + T + I groups. In multivariate analysis, decreased SMI remained an independent predictor of poor OS and tumor non-response, whereas a low-SMI pre-treatment was not an independent prognostic factor. Additionally, inadequate nutritional status and compromised liver function were associated with a greater decrease in SMI during comprehensive treatment. Conclusions: A decline in skeletal muscle index (SMI) among patients with unresectable hepatocellular carcinoma (HCC) undergoing TACE-based comprehensive treatment is associated with poor prognosis and unfavorable tumor response and is further linked to deteriorating nutritional status and impaired liver function. Monitoring SMI provides an effective approach for assessing overall patient condition and predicting clinical outcomes.

Supplementary figures 1-7 and table S1

BACKGROUND Acute pancreatitis (AP), the initially triggered inflammatory process in the pancreas, can be life-threatening. It has been reported that 15-lipoxygenase may promote the removal of damaged intracellular components, maintain intracellular homeostasis, and promote apoptosis by upregulating the activity of caspases. Despite an increased understanding of the lipoxygenase pathway in inflammation and immune diseases, the role of the Alox15 gene product in modulating the inflammatory changes during AP is not well defined. AIM To investigate the effect of Alox15 expression in cerulein-induced AP in rats. METHODS Model rats were transfected with Alox15 by injecting a recombinant lentivirus vector encoding Alox15 into the left gastric artery before inducing AP. The expression of Alox15 was then assessed at the mRNA and protein levels. RESULTS Our in vivo results showed that serum amylase activity and pancreatic tissue water content were significantly reduced in Alox15 -transfected rats. Further, the mRNA expression levels of tumor necrosis factor alpha, interleukin (IL)-1β, IL-6, and monocyte chemoattractant protein-1, as well as the protein expression of nuclear factor kappa B in pancreatic tissue were reduced. Additionally, we observed an upregulation of cleaved caspase-3 that implies an induction of apoptosis in pancreatic cells. The transfection of Alox15 resulted in a lower number of autophagic vacuoles in AP. CONCLUSION Our findings demonstrate a regulatory role of Alox15 in apoptosis and autophagy, making it a potential therapeutic target for AP.

Acute pancreatitis (AP) is among the most common hospital gastrointestinal diagnoses; understanding the mechanisms underlying the severity of AP is critical for development of new treatment options for this disease. Here, we evaluate the biological function of phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) in AP pathogenesis in 2 independent genetically engineered mouse models of AP. PFKFB3 was elevated in AP and severe AP (SAP), and KO of Pfkfb3 abrogated the severity of alcoholic SAP (FAEE-SAP). Using a combination of genetic, pharmacological, and molecular studies, we defined the interaction of PFKFB3 with inositol 1,4,5-trisphosphate receptor (IP3R) as a key event mediating this phenomenon. Further analysis demonstrated that the interaction between PFKFB3 and IP3R promotes FAEE-SAP severity by altering intracellular calcium homeostasis in acinar cells. Together, our results support a PFKFB3-driven mechanism controlling AP pathobiology and define this enzyme as a therapeutic target to ameliorate the severity of this condition.

Metastasis causes most cancer-related deaths, and the role and mechanism of periostin (POSTN) in the metastasis of hepatocellular carcinoma (HCC) remain undiscovered. In this study, DEN and HTVi HCC models were performed in hepatic-specific Postn ablation and Postn knock-in mouse to reveal the role of POSTN in HCC metastasis. Furthermore, POSTN was positively correlated with circulating EPCs level and promoted EPC mobilization and tumour infiltration. POSTN also mediated the crosstalk between HCC and EPCs, which promoted metastasis ability and upregulated CD36 expression in HCC through indirect crosstalk. Chemokine arrays further revealed that hepatic-derived POSTN induced elevated CCL2 expression and secretion in EPCs, and CCL2 promoted prometastatic traits in HCC. Mechanistic studies showed that POSTN upregulated CCL2 expression in EPCs via the αvβ3/ILK/NF-κB pathway. CCL2 further induced CD36 expression via the CCR2/STAT3 pathway by directly binding to the promoter region of CD36. Finally, CD36 was verified to have a prometastatic role in vitro and to be correlated with POSTN expression, metastasis and recurrence in HCC in clinical samples. Our findings revealed that crosstalk between HCC and EPCs is mediated by periostin/CCL2/CD36 signalling which promotes HCC metastasis and emphasizes a potential therapeutic strategy for preventing HCC metastasis.

Neutrophils act as a “double-edged sword” in the tumor microenvironment by either supporting or suppressing tumor progression. Thus, eliciting a neutrophil antitumor response remains challenging. Here, we showed that tumor cell–derived microparticles induced by methotrexate (MTX-MP) acts as an immunotherapeutic agent to activate neutrophils, increasing the tumor-killing effect of the cells and augmenting T-cell antitumor responses. We found that lactate induced tumor-associated neutrophils to elevate expression of programmed cell death protein 1 (PD-1) and that PD-1+ neutrophils had the properties of N2 neutrophils and suppressed T-cell activation through PD-1/programmed death-ligand 1 (PD-L1) signaling. By performing ex vivo experiments, we found that MTX-MPs–activated neutrophils had reduced surface expression of PD-1 as a result of PD-1 internalization and degradation in the lysosomes, leading to the cells showing a decreased capacity to suppress T-cell responses. In addition, we also found that MTX-MP–activated neutrophils released neutrophil elastase which could kill tumor cells and disrupt tumor stroma, leading to increased T-cell infiltration. Furthermore, using a combination of anti–PD-L1 and MTX-MPs, we observed that long-term survival increased in a mouse model of lung cancer. Collectively, these findings highlight the potential use of a combination of anti–PD-L1 and MTX-MPs to enhance the therapeutic effect of anti–PD-L1 alone.

Supplementary figures 1-7 and table S1

Neutrophils act as a “double-edged sword” in the tumor microenvironment by either supporting or suppressing tumor progression. Thus, eliciting a neutrophil antitumor response remains challenging. Here, we showed that tumor cell–derived microparticles induced by methotrexate (MTX-MP) acts as an immunotherapeutic agent to activate neutrophils, increasing the tumor-killing effect of the cells and augmenting T-cell antitumor responses. We found that lactate induced tumor-associated neutrophils to elevate expression of programmed cell death protein 1 (PD-1) and that PD-1+ neutrophils had the properties of N2 neutrophils and suppressed T-cell activation through PD-1/programmed death-ligand 1 (PD-L1) signaling. By performing ex vivo experiments, we found that MTX-MPs–activated neutrophils had reduced surface expression of PD-1 as a result of PD-1 internalization and degradation in the lysosomes, leading to the cells showing a decreased capacity to suppress T-cell responses. In addition, we also found that MTX-MP–activated neutrophils released neutrophil elastase which could kill tumor cells and disrupt tumor stroma, leading to increased T-cell infiltration. Furthermore, using a combination of anti–PD-L1 and MTX-MPs, we observed that long-term survival increased in a mouse model of lung cancer. Collectively, these findings highlight the potential use of a combination of anti–PD-L1 and MTX-MPs to enhance the therapeutic effect of anti–PD-L1 alone.