In the present study, we first prove that progesterone can regulate NK cells via GR. It is valuable for further understanding the role of uNK in progesterone regulated gestation process.

Background Dual inhibition of activated MAPK and mTOR signaling pathways may enhance the antitumor efficacy of the MEK 1/2 inhibitor pimasertib and the mTOR inhibitor temsirolimus given in combination. Methods In this phase I study, patients with refractory advanced solid tumors (NCT01378377) received once-weekly temsirolimus plus once-daily oral pimasertib in 21-day cycles in a modified 3+3 dose-escalation design. The maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of pimasertib in combination with temsirolimus, safety and pharmacokinetics (PK) were investigated. Results Of 33 patients evaluated, all experienced ≥1 treatment-emergent adverse event (TEAE) and 31 had treatment-related TEAEs, most frequently stomatitis and thrombocytopenia. TEAEs were reversible. No deaths were attributed to treatment. Nine patients had dose-limiting toxicities (stomatitis, thrombocytopenia, serum creatinine phosphokinase increase, visual impairment) and the MTD was determined as 45 mg/day pimasertib plus 25 mg/week temsirolimus. However, due to overlapping toxicities no further investigations were performed and the RP2D was not defined. PK profiles of both agents were not adversely affected. Seventeen patients (17/26 patients) had a best response of stable disease; five had stable disease lasting >12 weeks. Conclusions The RP2D was not defined and the pimasertib plus temsirolimus combination investigated did not warrant further study.

BackgroundSeveral immune checkpoint inhibitors (ICIs), represented by programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) antibodies, have been approved for treatment of various malignant tumors (including advanced esophageal cancer) worldwide, and previous studies confirmed that they can significantly improve overall survival.1 However, there has been limited research on the use of ICIs as neoadjuvant therapy for patients with esophageal cancer. Toripalimab is a humanized IgG4 monoclonal antibody that targets PD-1. The objective of this study is to evaluate the efficacy and safety of toripalimab plus chemotherapy as a neoadjuvant therapy regimen for treatment of patients with locally advanced esophageal squamous cell carcinoma (ESCC).MethodsThis single-arm, single-center study enrolled patients with ESCC at clinical stage T2-T4/N0-N2/M0, who were eligible for radical resection and regional lymph node dissection. The patients received 2–3 cycles of toripalimab (240 mg d1, Q3W) in combination with nab-paclitaxel (260 mg/m2 d1, Q3W) and carboplatin (AUC=5 d1, Q3W) before surgery. Preoperative evaluation was performed within 4 weeks after the last administration of chemotherapy. The primary endpoints were pathologic complete response (PCR) and major pathologic response (MPR), and the secondary endpoints were safety and feasibility of the neoadjuvant immunotherapy.ResultsSeventeen patients diagnosed with ESCC at a pre-treatment clinical stage of T2-T4/N0-N2/M0 were included. After neoadjuvant therapy, 15 of 17 patients (88.2%) experienced downstaging and met the surgical criteria. Twelve patients (80.0%) underwent surgery without delay and 3 patients (20.0%) refused surgery. The tumors were completely removed in all 12 patients (R0 resection rate: 100%). Seven patients (58.3%) achieved MPR and 2 (16.7%) achieved PCR. The median post-surgical follow-up time was 4.5 months, and there were no recurrences. Treatment-related adverse events (TRAEs) of the neoadjuvant therapy were tolerable. Grade 3 or higher TRAEs occurred in 2 patients (11.8%), but these did not delay surgery.ConclusionsToripalimab in combination with chemotherapy as neoadjuvant therapy showed promising anti-tumor activity with acceptable tolerance for locally advanced ESCC, as demonstrated by reducing the tumor burden, improving the R0 resection rate, reducing the postoperative recurrence rate, and no delays in surgery.AcknowledgementsN/AEthics ApprovalThis study was approved by the Ethics Board of the Army Medical center of the PLA, approval number 142(2018).ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.ReferenceWu X, Gu Z, Chen Y, et al. Application of PD-1 blockade in cancer immunotherapy. Comput Struct Biotechnol J 2019;17:661–674.

344 Background: In metastatic pancreatic cancer (mPaCa), KRAS mutations lead to constitutive activation of the MAPK pathway in the vast majority of cases. Pimasertib (Pim) is a selective, non-competitive MEK 1/2 inhibitor with potent antitumor activity in preclinical models with constitutive MAPK activation. Methods: Following a phase I, dose-finding part to the trial, 88 patients (pts) with mPaCa were randomized 1:1 to receive Pim 60 mg BID (A, 44 pts) or placebo (B, 44 pts) in combination with weekly gemcitabine (Gem) 1000 mg/m2(7 of 8 wks in cycle 1, then 3 of 4 wks in subsequent cycles), in a phase II setting (NCT01016483). The primary endpoint was progression-free survival (PFS). Response rate (RR), overall survival (OS) and safety were secondary endpoints. Biomarker analysis was an exploratory endpoint. Results: Pt characteristics were balanced (median age 63.5 yrs, males 56%, stage IV at initial diagnosis 75%) except for PS 0, which was more frequent in arm A (59 vs 41%). Time on treatment was longer in arm B (10.6 vs 8.0 wks). A higher proportion of pts in arm A discontinued treatment during the first 4 wks (31 vs 19%), predominantly due to adverse events (AEs) and PD. Median PFS was 3.7 mo in arm A and 2.8 mo in arm B (HR=0.883, 95% CI: 0.549–1.42; p=0.608). No statistically significant differences were observed between arms for OS (median 7.3 mo in arm A vs 8.3 mo in arm B) and RECIST 1.0 RR (9.1% in both arms). Grade ≥3 thrombocytopenia (20.0 vs 0%), vomiting (15.6 vs 4.8%), fatigue (15.6 vs 7.1%), stomatitis (13.3 vs 0%) and diarrhea (11.1 vs 2.4%) were more common in arm A. Typical allosteric MEK inhibitor-related AEs, such as all grade retinal detachment (24.4%) and creatine phosphokinase elevation (20.0%), were observed almost exclusively in arm A. KRAS mutational status did not influence PFS or OS. Conclusions: The primary study endpoint was not met; secondary endpoints did not suggest clinically meaningful differences between arms, except for selected toxicities observed more frequently with the combination of Gem and Pim. The outcome does not support further development of this combination in the first-line setting in mPaCa. Pim is currently in development in other solid tumors. Clinical trial information: NCT01016483.

With the rapid development of the Internet era, the number of malware has reached an unprecedented peak, and therefore malware is threatening global network security seriously. In this paper, we propose an Android malware detection approach based on SIMGRU, which belongs to the static detection approach. The similarity of clustering is widely used in static analysis of android malware, so we introduce the similarity to improve Gated Recurrent Unit (GRU), and obtain three different structures of SimGRU: InputSimGRU, HiddenSimGRU, and InputHiddenSimGRU. The InputHiddenSimGRU is the combination of InputSimGRU and HiddenSimGRU. The experiment shows that InputSimGRU, HiddenSimGRU, and InputHiddenSimGRU outperform the conventional GRU model and other methods.