METHODS: Expression of SPRY genes in human and mice PDAC was analyzed using The Cancer Genome Atlas and Gene Expression Omnibus datasets, and by immunohistochemistry analysis. Gain-of-function, loss-of-function of Spry1 and orthotopic xenograft model were adopted to investigate the function of Spry1 in mice PDAC. Bioinformatics analysis, transwell and flowcytometry analysis were used to identify the effects of SPRY1 on immune cells. Co-immunoprecipitation and K-ras4B G12V overexpression were used to identify molecular mechanism.
RESULTS: SPRY1 expression was remarkably increased in PDAC tissues and positively associated with poor prognosis of PDAC patients. SPRY1 knockdown suppressed tumor growth in mice. SPRY1 was found to promote CXCL12 expression and facilitate neutrophil and macrophage infiltration via CXCL12-CXCR4 axis. Pharmacological inhibition of CXCL12-CXCR4 largely abrogated the oncogenic functions of SPRY1 by suppressing neutrophil and macrophage infiltration. Mechanistically, SPRY1 interacted with ubiquitin carboxy-terminal hydrolase L1 to induce activation of nuclear factor κB signaling and ultimately increase CXCL12 expression. Moreover, SPRY1 transcription was dependent on KRAS mutation and was mediated by MAPK-ERK signaling.
CONCLUSION: High expression of SPRY1 can function as an oncogene in PDAC by promoting cancer-associated inflammation. Targeting SPRY1 might be an important approach for designing new strategy of tumor therapy.
Methods: We conducted a retrospective review of 70 patients with LPD (35 with lymphoma and 35 with multiple myeloma) who had undergone APBSCT between January 2008 and December 2016. Data obtained included disease type, treatment, and stem cell characteristics. Kaplan-Meier analysis was performed for probabilities of neutrophil and platelet engraftment occurred and was compared by the log-rank test. The multivariate Cox proportional hazards regression model was used for the analysis of potential independent factors influencing engraftment. A p-value < 0.050 was considered statistically significant.
Results: Most patients were ethnic Malay, the median age at transplantation was 49.5 years. Neutrophil and platelet engraftment occurred in a median time of 18 (range 4-65) and 17 (range 6-66) days, respectively. The majority of patients showed engraftment with 65 (92.9%) and 63 (90.0%) showing neutrophil and platelet engraftment, respectively. We observed significant differences between neutrophil engraftment and patient's weight (< 60/≥ 60 kg), stage of disease at diagnosis, number of previous chemotherapy cycles (< 8/≥ 8), and pre-transplant radiotherapy. While for platelet engraftment, we found significant differences with gender, patient's weight (< 60/≥ 60 kg), pre-transplant radiotherapy, and CD34+ dosage (< 5.0/≥ 5.0 × 106/kg and < 7.0/≥ 7.0 × 106/kg). The stage of disease at diagnosis (p = 0.012) and pre-transplant radiotherapy (p = 0.025) were found to be independent factors for neutrophil engraftment whereas patient's weight (< 60/≥ 60 kg, p = 0.017), age at transplantation (< 50/≥ 50 years, p = 0.038), and CD34+ dosage (< 7.0/≥ 7.0 × 106/kg, p = 0.002) were found to be independent factors for platelet engraftment.
Conclusions: Patients with LPD who presented at an early stage and with no history of radiotherapy had faster neutrophil engraftment after APBSCT, while a younger age at transplantation with a higher dose of CD34+ cells may predict faster platelet engraftment. However, additional studies are necessary for better understanding of engraftment kinetics to improve the success of APBSCT.