Pancreatic cancer (PC) is a serious threat to human health, with most patients diagnosed at the advanced stages of the disease. Treatment with gemcitabine (GEM) leads to PC GEM resistance. In addition, cancer stem cell (CSC)-derived exosomes play an important role in cancer progression. We aimed to investigate the role and mechanism of action of PC stem cell-derived exosomes in PC drug resistance and progression. CSC-derived exosomes increased the proportion of F4/80+/CD86 + cells and levels of M2 polarization factors. miR-210 is expressed in CSC-derived exosomes. Thus, following co-culture, miR-210 was taken up by macrophages. Transfection or the addition of miR-210 mimics increased the proportion of F4/80+/CD206 + cells and levels of M2 polarization factors. Further, the miR-210 targets inhibited the levels of FGFRL1. The FGFRL1 overexpression plasmid also inhibited miR-210-mediated M2 polarization. After co-culture of THP-M2 cells with PC cells and treatment with GEM, the survival rate, migration rate, and levels of MDR, YB-1, BCRP, p-PI3K, p-AKT, and p-mTOR in PC cells increased. And THP-M2 increased the tumor volume and MDR, YB-1, BCRP, p-PI3K, p-AKT, and p-mTOR levels. Overall, miR-210 from PC stem cell-derived exosome targets and inhibits FGFRL1 to promote macrophage M2 polarization, which activates the p-PI3K/p-AKT/p-mTOR pathway and increases GEM resistance.

Dysregulation of deubiquitination is essential for cancer growth. However, the role of 26 S proteasome non-ATPase regulatory subunit 14 (PSMD14) in the progression of triple-negative breast cancer (TNBC) remains to be determined. Gain- and loss-of-function experiments showed that silencing PSMD14 notably attenuated the growth, invasion, and metastasis of TNBC cells in vitro and in vivo. Overexpression of PSMD14 produced the opposite results. Mechanistically, PSMD14 decreased K63-linked ubiquitination on SF3B4 protein to de-ubiquitin and stabilize SF3B4 protein. Then, SF3B4/HNRNPC complex bound to FADS1 mRNA and promoted exon inclusion in the target mRNA through m ⁶ A site on FADS1 mRNA recognized by HNRNPC, thereby up-regulating the expression of FADS1 and activating Akt/mTOR signaling. Exogenous arachidonic acid supplementation combined with PSMD14 knockdown induced synthetic lethality, which was further confirmed in TNBC organoid (PDO) and TNBC patient-derived xenograft (PDX) mouse models. Overall, our findings reveal an oncogenic role of PSMD14 in TNBC progression, which indicates a potential biomarker and ferroptosis-mediated therapeutic strategy for TNBC.

Gemcitabine (Gem) is the first-line chemotherapy drug for pancreatic cancer, but the acquired chemoresistance also hinders its application. Therefore, research about Gem resistance plays a crucial role in enhancing the therapeutic effect of Gem. As a deubiquitinating enzyme, ubiquitin-specific protease 8 (USP8) was shown to play vital roles in the tumorigenesis processes of several cancers; however, the effect of USP8 on Gem resistance of pancreatic cancer still remains largely unknown. In the current study, we observed that the expression of USP8 was increased in pancreatic cancer patients, it is related to the recurrence of Gem chemotherapy, and USP8 expression could be induced by Gem application. Furthermore, USP8 was found to promote Gem resistance both in vivo and in vitro via regulating cell viability and apoptosis. Moreover, USP8 enhanced the activation of Nrf2 signaling which is dependent on its deubiquitinase ability. At last, we illustrated that USP8 interacted with Nrf2 directly and deubiquitinated K48-linked polyubiquitin chains from Nrf2, stabilizing the expression of Nrf2. In summary, the manuscript revealed the role of USP8 in Gem chemoresistance and suggested USP8 as a potential therapeutic target for pancreatic cancer.

Background: Recently, low-density lipoprotein receptor (LDLR)-related protein 6 (LRP6) has been the focus of molecular targeted therapy for breast cancer; however, its role in breast cancer is still controversial. The purpose of this study was to investigate the effect of LRP6 overexpression on the prognosis of breast cancer. Methods: We used immunohistochemistry to detect the expression of LRP6 via tissue microarrays in breast cancer samples, Chi-square test analyze the relationship between LRP6 expression and clinicopathological features of breast cancer, the Kaplan-Meier method to perform survival analysis, and the Cox proportional hazards regression model to explore the potential risk factors of breast cancer. The role of LRP6 in the proliferation, invasion, and metastasis of breast cancer was studied by colony formation, Transwell migration and invasion assay and scratch assay. The tumor-bearing model of LRP6 knockdown was established using MCF-7 cells, and corresponding negative control was set up to observe the growth rate of the two models. Results: High expression of LRP6 was observed in 89 out of 150 (59.3%) breast cancer cases, as detected by microarray of breast cancer tissue. Chi-square tests showed no significant correlation between LRP6 expression and tumor size, lymph node staging, or mitosis. Survival analysis showed that the overall survival rate of tumor patients with high LRP6 expression was significantly lower than that of patients with low LRP6 expression. Univariate and multivariate regression analyses revealed that LRP6 was an independent risk factor for breast cancer and was negatively correlated with the prognosis of breast cancer. Compared with the control group, small interference RNA (si-RNA) knockdown of LRP6 significantly reduced the clonogenic rate as well as the migration and invasion abilities of MCF-7 cells. In the scratch experiment, the wound healing ability of the LRP6 knockdown was significantly weaker than that of the control group. There were significant differences in tumor growth weight and volume between lentivirus transfected LRP6 knockdown MCF-7 cell line and control MCF-7 cell line in nude mice. Conclusions: LRP6 could be a useful biomarker of poor prognosis of breast cancer, as it plays an important role in tumor growth, migration, and invasion.

Background: Isthmic papillary thyroid carcinoma (IPTC) is an aggressive thyroid cancer associated with a poor prognosis. Guidelines elaborating on the extent of surgery for IPTC are yet to be developed. This study aims to construct and validate a model to predict central lymph node metastasis (CLNM) in patients with IPTC, which could be used as a risk stratification tool to determine the best surgical approach for patients.Methods: Electronic medical records for patients diagnosed with isolated papillary thyroid carcinoma who underwent surgery at Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, from January 2010 to December 2021 were reviewed. All patients who underwent thyroidectomy with central neck dissection (CND) for isolated IPTC were included. We conducted univariate and multivariate logistic regression analyses to assess risk factors for ipsilateral and contralateral CLNM and the number of CLNM in IPTC patients. Based on the analysis, the nomogram construction and internal validations were performed.Results: A total of 147 patients with isolated IPTC were included. The occurrence of CLNM was 53.7% in the patients. We identified three predictors of ipsilateral CLNM, including age, gender, and size. For contralateral CLNM, three identified predictors were age, gender, and capsular invasion. Predictors for the number of CLNM included age, gender, capsular invasion, tumor size, and chronic lymphocytic thyroiditis (CLT). The concordance index(C-index) of the models predicting ipsilateral CLNM, contralateral CLNM, 1-4 CLNM, and ≥5 CLNM was 0.779 (95%CI, 0.704, to 0.854), 0.779 (95%CI, 0.703 to 0.855), 0.724 (95%CI, 0.629 to 0.818), and 0.932 (95%CI, 0.884 to 0.980), respectively. The corresponding indices for the internal validation were 0.756 (95%CI, 0.753 to 0.758), 0.753 (95%CI, 0.750 to 0.756), 0.706 (95%CI, 0.702 to 0.708), and 0.920 (95%CI, 0.918 to 0.922). Receiver operating characteristic (ROC) curves, calibration, and decision curve analysis (DCA) results confirmed that the three nomograms could precisely predict CLNM in patients with isolated IPTC.Conclusion: We constructed predictive nomograms for CLNM in IPTC patients. A risk stratification scheme and corresponding surgical treatment recommendations were provided accordingly. Our predictive models can be used as a risk stratification tool to help clinicians make individualized surgical plans for their patients.

Magnetic nanoparticles (MNPs) are temperature sensitive, making them useful as probes for measuring cellular temperature. In this paper, we propose a remote non-invasive thermometer that replaces a traditional magnetic sensor with linearly polarized light as the transmission medium, utilizing the Faraday rotation of MNPs. This method not only overcomes the limitations of distance on temperature measurement accuracy but also offers strong anti-interference capabilities. Using this thermometer, we measured the cooling process of MNPs within a temperature range of 310–316 K, achieving an estimated temperature root mean square error (RMSE) of 0.14 K. This approach shows promise for integration with microscopy systems for temperature imaging of cells or biological tissues, potentially revealing new biological insights.