Clinical outcomes of second-line chemotherapy in patients with advanced pancreatic adenocarcinoma:a real-world study

Objective:Little progress has been made in recent years using first-line chemotherapy,including gemcitabine combined with nab-paclitaxel,FOLFIRINOX,and NALIRIFOX,for advanced pancreatic adenocarcinoma(APC).In addition,the optimal second-line chemotherapy regimen has not been determined.This study aimed to compare the effectiveness of different types of second-line chemotherapy for APC.Methods:Patients with APC who received first-line treatment from January 2008 to January 2021 were considered eligible for this retrospective analysis.The primary and secondary endpoints were overall survival(OS)and progression-free survival(PFS),respectively.Results:Four hundred and thirty-seven and 617 patients were treated with 5-fluorouracil-and gemcitabine-based chemotherapy as first-line treatment,respectively.Demographic and clinical features,except age and liver metastasis,were comparable between the two groups(P<0.05).The median OS was 8.8 and 7.8 months in patients who received a 5-fluorouracil-and gemcitabine-based combined regimen for first-line therapy,respectively(HR=1.244,95%CI=1.090–1.419;P<0.001).The median OS was 5.6 and 1.9 months in patients who received second-line chemotherapy and supportive care,respectively(HR=0.766,95%CI=0.677–0.867;P<0.001).The median PFS was not significantly differently between gemcitabine or 5-fluorouracil monotherapy and combination therapy.Conclusions:A 5-fluorouracil-or gemcitabine-based combined regimen was shown to be as effective as a single 5-fluorouracil or gemcitabine regimen as second-line therapy for patients with APC.

Study on Flow Field Optimization of Flow Distribution Disk of Double-unloaded Groove Piston Pump

By referring to all kinds of research data and summarizing the analysis and research of various kinds of distribution disks,a new type of distribution disc with double V-shaped unloading slots is designed again.Then,the new designed disk is loaded into the piston pump by CFD software to simulate.Finally,through simulation,it is concluded that the width of the triangle slot of the distribution plate is about 10°,the slope angle is about 12°,and the diameter of the unloading hole is about 0.8mm.When the diameter of the perforated hole is about 1.5mm,the flow curve of the unloading hole is the smoother.Pressure shock and noise are also minimized at this time.Draw By improving the damping tank,the flow noise and cavitation change are smaller than before.

Non-fragile Dynamic Output Feedback H∞Control for a Class of Un­certain Switched Systems with Time-varying Delay

The problem of non-fragile dynamic output feedback H∞control for a class of uncertain switched systems with time-varying delay is discussed.Firstly,the form of non-fragile dynamic output feedback H∞controller is given.Under the condition that the upper bound of time delay and the upper bound of delay derivative are limited simultaneously,Lyapunov functional and its corresponding switching rules are constructed by using single Lyapunov function method and convex combination technique;Secondly,we use the inequality lemma to scale the derived Lyapunov functional in order to eliminate the time-varying delay term in the in­equality,and then introduce the J-function to obtain a nonlinear matrix in­equality that satisfies the H∞performance indexγ,we also employ Schur complement lemma to transform the nonlinear matrix inequality into set of linear matrix inequalities consisting of two linear matrix inequalities,a sufficient condition for the existence of a non-fragile dynamic output feedback H∞controller and satisfying the H∞performance indexγis concluded for a class of uncertain switching systems with variable time delay;Finally,a switched system composed of two subsystems is consid­ered and the effectiveness and practicability of the theorem are illustrated by numerical simulation with LMI toolbox.

Highly efficient base editing in rabbit by using near-PAMless engineered CRISPR/Cas9 variants

Dear Editor,Base editors can achieve targeted C-to-T and A-to-G conversion without the generation of DNA double-strand breaks(DSBs)or the requirement of a donor template,showing the potential to generate new mutations or to correct pathogenic mutations(Gaudelli et al.,2018).However,for conventional base editors,efficient base editing requires the presence of an NGG protospacer adjacent motif(PAM)that lies 12–16 nt downstream of the target bases,which generally limits the application of these base editors(Gaudelli et al.,2018).

Efficient and high-fidelity base editor with expanded PAM compatibility for cytidine dinucleotide

Cytidine base editor(CBE),which is composed of a cytidine deaminase fused to Cas9 nickase,has been widely used to induce C-to-T conversions in a wide range of organisms.However,the targeting scope of current CBEs is largely restricted to protospacer adjacent motif(PAM)sequences containing G,T,or A bases.In this study,we developed a new base editor termed“nNme2-CBE”with excellent PAM compatibility for cytidine dinucleotide,significantly expanding the genome-targeting scope of CBEs.Using nNme2-CBE,targeted editing efficiencies of 29.0%-55.0%and 17.3%—52.5%were generated in human cells and rabbit embryos,respectively.In contrast to conventional nSp-CBE,the nNme2-CBE is a natural high-fidelity base editing platform with minimal DNA off-targeting detected in vivo.Significantly increased efficiency in GC context and precision were determined by combining nNme2Cas9 with rationally engineered cytidine deaminases.In addition,the Founder rabbits with accurate single-base substitutions at Fgf5 gene loci were successfully generated by using the nNme2-CBE system.These novel nNme2-CBEs with expanded PAM compatibility and high fidelity will expand the base editing toolset for efficient gene modification and therapeutic applications.