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ObjectiveTo identify the proteins involved the compensatory adaptive response to paclitaxel in ovarian cancer cells and to determine whether inhibition of the compensatory adaptive response increases the efficacy of paclitaxel in decreasing the viability of cancer cells.MethodsWe used a reverse-phase protein array and western blot analysis to identify the proteins involved in the compensatory mechanism induced by paclitaxel in HeyA8 and SKOV3 ovarian cancer cells. We used a cell viability assay to examine whether inhibition of the proteins involved in the compensatory adaptive response influenced the effects of paclitaxel on cancer cell viability. All experiments were performed in three-dimensional cell cultures.ResultsPaclitaxel induced the upregulation of pS6 (S240/S244) and pS6 (S235/S236) in HeyA8 and SKOV3 cells, and pPRAS40 (T246) in HeyA8 cells. BX795 and CCT128930 were chosen as inhibitors of pS6 (S240/S244), pS6 (S235/S236), and pPRAS40 (T246). BX795 and CCT128930 decreased pS6 (S240/S244) and pS6 (S235/S236) expression in HeyA8 and SKOV3 cells. However, pPRAS40 (T246) expression was inhibited only by BX795 and not by CCT128930 in HeyA8 cells. Compared with paclitaxel alone, addition of BX795 or CCT128930 to paclitaxel was more effective in decreasing the viability of HeyA8 and SKOV3 cells.ConclusionAddition of BX795 or CCT128930 to inhibit pS6 (S240/S244) or pS6 (S235/S236) restricted the compensatory adaptive response to paclitaxel in HeyA8 and SKOV3 cells. These inhibitors increased the efficacy of paclitaxel in reducing cancer cell viability.

We aimed to present the incidence and risk factors for pancreatic cancer in a multicenter retrospective cohort of patients with chronic pancreatitis (CP). Patients with ICD-10 codes for CP (K86.0, K86.1) who underwent abdominal CT or MRI between January 2010 and December 2021 in seven academic hospitals were analyzed. After exclusions, we identified 727 patients with definite CP with a median follow-up of 3.6 years (range 1.0‒12.9). During 3290 person-years of observation, pancreatic cancers were diagnosed in 16 patients (2.20%, 0.49% per year) after a median follow-up of 2.4 years (range 1.4‒6.6), with an age- and sex-standardized incidence ratio of 18.1 (95% CI 10.4‒29.5). The underlying CPs in the 16 pancreatic cancers were classified as chronic obstructive pancreatitis (10, 63%), chronic obstructive and calcifying pancreatitis (4, 25%), chronic calcifying pancreatitis (1, 6%), and autoimmune pancreatitis (1, 6%). Factors associated with pancreatic cancer development included age (HR 4.830, p = 0.006), parenchymal calcification (HR 0.213, p = 0.003), pancreatic duct stricture (HR 2.706, p = 0.048), and serum CA 19‒9 level (HR 3.567, p = 0.014). After adjustment, age over 60 years (HR 4.540, p = 0.009) and serum CA 19‒9 levels greater than 100 U/mL (HR 3.528, p = 0.015) were independent risk factors for pancreatic cancer.