Group IIa secretory phospholipase expression correlates with group IIa secretory phospholipase inhibition–mediated cell death in K-ras mutant lung cancer cells

ObjectiveThere are currently no targeted therapies against lung tumors with oncogenic K-ras mutations that are found in 25% to -40% of lung cancers and are characterized by their resistance to epidermal growth factor receptor inhibitors. The isozyme group IIa secretory phospholipase A2 (sPLA2IIa) is a potential biomarker and regulator of lung cancer cell invasion; however, the relationship between K-ras mutations and sPLA2IIa has yet to be investigated. We hypothesize that sPLA2IIa modulates lung cancer cell growth in K-ras mutant cells and that sPLA2IIa expression in human lung tumors is increased in K-ras mutant tumors.MethodsBaseline sPLA2IIa expression in K-ras mutant lung cancer cell lines (A549, SW1573, H358, H2009) was assessed. Cells were treated with a specific sPLA2IIa inhibitor and evaluated for apoptosis and cell viability. Nuclear factor kappa-b (NF-κB) and extracellular signal-regulated kinase 1/2 activity were detected by Western blot. Human tumor samples were evaluated for sPLA2IIa mRNA expression by quantitative reverse-transcription polymerase chain reaction.ResultsCytotoxicity of sPLA2IIa inhibition correlates with sPLA2IIa expression. Apoptosis in response to sPLA2 inhibition parallels attenuation in NF-κB activity. In addition, sPLA2IIa expression in human tumors correlates with squamous cell pathology and increasing stage of K-ras mutant lung tumors.ConclusionsBaseline sPLA2IIa expression predicts response to sPLA2IIa inhibition in some K-ras mutant lung cancer cells. This finding is independent of p53 mutation status. Furthermore, squamous tumors and advanced-stage K-ras mutant tumors express more sPLA2IIa. These data support a role for sPLA2IIa as a potential global therapeutic target in the treatment of lung cancer

Automatic Truss Design with Reinforcement Learning

Truss layout design, namely finding a lightweight truss layout satisfying all the physical constraints, is a fundamental problem in the building industry. Generating the optimal layout is a challenging combinatorial optimization problem, which can be extremely expensive to solve by exhaustive search. Directly applying end-to-end reinforcement learning (RL) methods to truss layout design is infeasible either, since only a tiny portion of the entire layout space is valid under the physical constraints, leading to particularly sparse rewards for RL training. In this paper, we develop AutoTruss, a two-stage framework to efficiently generate both lightweight and valid truss layouts. AutoTruss first adopts Monte Carlo tree search to discover a diverse collection of valid layouts. Then RL is applied to iteratively refine the valid solutions. We conduct experiments and ablation studies in popular truss layout design test cases in both 2D and 3D settings. AutoTruss outperforms the best-reported layouts by 25.1% in the most challenging 3D test cases, resulting in the first effective deep-RL-based approach in the truss layout design literature.Comment: IJCAI2023. The codes are available at https://github.com/StigLidu/AutoTrus

Re-visiting the extended Schmidt law: the important role of existing stars in regulating star formation

We revisit the proposed extended Schmidt law (Shi et al. 2011) which points that the star formation efficiency in galaxies depends on the stellar mass surface density, by investigating spatially-resolved star formation rates (SFRs), gas masses and stellar masses of star formation regions in a vast range of galactic environments, from the outer disks of dwarf galaxies to spiral disks and to merging galaxies as well as individual molecular clouds in M33. We find that these regions are distributed in a tight power-law as Sigma_SFR ~(Sigma_star^0.5 Sigma_gas )^1.09, which is also valid for the integrated measurements of disk and merging galaxies at high-z. Interestingly, we show that star formation regions in the outer disks of dwarf galaxies with Sigma_SFR down to 10^(-5) Msun/yr/kpc^2, which are outliers of both Kennicutt-Schmidt and Silk-Elmegreen law, also follow the extended Schmidt law. Other outliers in the Kennicutt-Schmidt law, such as extremely-metal poor star-formation regions, also show significantly reduced deviations from the extended Schmidt law. These results suggest an important role for existing stars in helping to regulate star formation through the effect of their gravity on the mid-plane pressure in a wide range of galactic environments.Comment: 15 pages, 6 figures, 3 tables; ApJ in pres

Semi-quantitative analysis of geological samples using laser plasma time-of-flight mass spectrometry

A method has been developed that allows the direct measurement of the elemental composition of geological samples based on a newly developed laser plasma time-of-flight mass spectrometer with a collisional cooling system. This technique has the merits of small sample consumption and rapid elemental analysis. Four geological reference materials were used in the experiment. The system has shown a satisfactory resolving power with few interferences in the spectra. The limits of detection were about 10(-6)-10(-7) g g(-1) for most of the metal elements. The relative sensitivity coefficients (RSCs) of the elements with mass heavier than 30 amu could be used for direct semi-quantitative analysis.National 863 program ; Fujian Province Department of Science Technology ; National Natural Science Foundation of Chin

Mini percutaneous nephrolithotomy is a noninferior modality to standard percutaneous nephrolithotomy for the management of 20-40 mm renal calculi: A Multicenter randomized controlled trial

Background: High quality of evidence comparing mini percutaneous nephrolithotomy (mPNL) with standard percutaneous nephrolithotomy (sPNL) for the treatment of larger-sized renal stones is lacking. Objective: To compare the efficacy and safety of mPNL and sPNL for the treatment of 20–40 mm renal stones. Design, setting, and participants: A parallel, open-label, and noninferior randomized controlled trial was performed at 20 Chinese centers (2016–2019). The inclusion criteria were patients 18–70 yr old, with normal renal function, and 20–40 mm renal stones. Intervention: Percutaneous nephrolithotomy PNL was performed using either 18 F or 24 F percutaneous nephrostomy tracts. Outcome measurements and statistical analysis: The primary outcome was the one-session stone-free rate (SFR). The secondary outcomes included operating time, visual analog pain scale (VAS) score, blood loss, complications as per the Clavien-Dindo grading system, and length of hospitalization. Results and limitations: The 1980 intention-to-treat patients were randomized. The mPNL group achieved a noninferior one-session SFR to the sPNL group by the one-side noninferiority test (0.5% [difference], p < 0.001). The transfusion and embolization rates were comparable; however, the sPNL group had a higher hemoglobin drop (5.2 g/l, p < 0.001). The sPNL yielded shorter operating time (–2.2 min, p = 0.008) but a higher VAS score (0.8, p < 0.001). Patients in the sPNL group also had longer hospitalization (0.6 d, p < 0.001). There was no statistically significant difference in fever or urosepsis occurrences. The study's main limitation was that only 18F or 24F tract sizes were used. Conclusions: Mini mPNL achieves noninferior SFR outcomes to sPNL, but with reduced bleeding, less postoperative pain, and shorter hospitalization. Patient summary: We evaluated the surgical outcomes of percutaneous nephrolithotomy using two different sizes of nephrostomy tracts in a large population. We found that the smaller tract might be a sensible alternative for patients with 20–40 mm renal stones. This multicenter, parallel, open-label, and noninferior randomized controlled trial showed that mini percutaneous nephrolithotomy achieved noninferior stone-free rate with advantages of reduced blood loss, less postoperative pain, and shorter hospitalization. Mini percutaneous nephrolithotomy should be considered a sensible alternative treatment of 20–40 mm renal stones.grants from high-level development funding of Guangzhou Medical Universit

ULK1/2 Constitute a Bifurcate Node Controlling Glucose Metabolic Fluxes in Addition to Autophagy

揭示了在外界能量供应缺乏时，细胞通过激活ULK1来介导葡萄糖分解代谢重编程以维持胞内的能量与氧化还原稳态的详细机制，并创新地发现了ULK1独立于自噬的关键功能。基于自噬和糖代谢与人类健康的重要相关性，该研究将很可能为我们预防和治疗各类代谢疾病提供新的思路和药物靶点。Metabolic reprogramming is fundamental to biological homeostasis, enabling cells to adjust metabolic routes after sensing altered availability of fuels and growth factors. ULK1 and ULK2 represent key integrators that relay metabolic stress signals to the autophagy machinery. Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1). Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels. These results identify ULK1/2 as a bifurcate-signaling node that sustains glucose metabolic fluxes besides initiation of autophagy in response to nutritional deprivation.State Key Program of National Natural Science of China， the 973 Program；National Natural Science Foundation of China for Fostering Talents in Basic Research ；the Foundation for Innovative Research Groups of the National Natural Science Foundation of China； and the 111 Project of Education of China