Osr2 functions as a biomechanical checkpoint to aggravate CD8+ T cell exhaustion in tumor.

Alterations in extracellular matrix (ECM) architecture and stiffness represent hallmarks of cancer. Whether the biomechanical property of ECM impacts the functionality of tumor-reactive CD8+ T cells remains largely unknown. Here, we reveal that the transcription factor (TF) Osr2 integrates biomechanical signaling and facilitates the terminal exhaustion of tumor-reactive CD8+ T cells. Osr2 expression is selectively induced in the terminally exhausted tumor-specific CD8+ T cell subset by coupled T cell receptor (TCR) signaling and biomechanical stress mediated by the Piezo1/calcium/CREB axis. Consistently, depletion of Osr2 alleviates the exhaustion of tumor-specific CD8+ T cells or CAR-T cells, whereas forced Osr2 expression aggravates their exhaustion in solid tumor models. Mechanistically, Osr2 recruits HDAC3 to rewire the epigenetic program for suppressing cytotoxic gene expression and promoting CD8+ T cell exhaustion. Thus, our results unravel Osr2 functions as a biomechanical checkpoint to exacerbate CD8+ T cell exhaustion and could be targeted to potentiate cancer immunotherapy.

SPTAN1/NUMB axis senses cell density to restrain cell growth and oncogenesis through Hippo signaling.

The loss of contact inhibition is a key step during carcinogenesis. The Hippo-Yes-associated protein (Hippo/YAP) pathway is an important regulator of cell growth in a cell density-dependent manner. However, how Hippo signaling senses cell density in this context remains elusive. Here, we report that high cell density induced the phosphorylation of spectrin α chain, nonerythrocytic 1 (SPTAN1), a plasma membrane-stabilizing protein, to recruit NUMB endocytic adaptor protein isoforms 1 and 2 (NUMB1/2), which further sequestered microtubule affinity-regulating kinases (MARKs) in the plasma membrane and rendered them inaccessible for phosphorylation and inhibition of the Hippo kinases sterile 20-like kinases MST1 and MST2 (MST1/2). WW45 interaction with MST1/2 was thereby enhanced, resulting in the activation of Hippo signaling to block YAP activity for cell contact inhibition. Importantly, low cell density led to SPTAN1 dephosphorylation and NUMB cytoplasmic location, along with MST1/2 inhibition and, consequently, YAP activation. Moreover, double KO of NUMB and WW45 in the liver led to appreciable organ enlargement and rapid tumorigenesis. Interestingly, NUMB isoforms 3 and 4, which have a truncated phosphotyrosine-binding (PTB) domain and are thus unable to interact with phosphorylated SPTAN1 and activate MST1/2, were selectively upregulated in liver cancer, which correlated with YAP activation. We have thus revealed a SPTAN1/NUMB1/2 axis that acts as a cell density sensor to restrain cell growth and oncogenesis by coupling external cell-cell contact signals to intracellular Hippo signaling.

Glycogen accumulation and phase separation drives liver tumor initiation.

Glucose consumption is generally increased in tumor cells to support tumor growth. Interestingly, we report that glycogen accumulation is a key initiating oncogenic event during liver malignant transformation. We found that glucose-6-phosphatase (G6PC) catalyzing the last step of glycogenolysis is frequently downregulated to augment glucose storage in pre-malignant cells. Accumulated glycogen undergoes liquid-liquid phase separation, which results in the assembly of the Laforin-Mst1/2 complex and consequently sequesters Hippo kinases Mst1/2 in glycogen liquid droplets to relieve their inhibition on Yap. Moreover, G6PC or another glycogenolysis enzyme-liver glycogen phosphorylase (PYGL) deficiency in both human and mice results in glycogen storage disease along with liver enlargement and tumorigenesis in a Yap-dependent manner. Consistently, elimination of glycogen accumulation abrogates liver growth and cancer incidence, whereas increasing glycogen storage accelerates tumorigenesis. Thus, we concluded that cancer-initiating cells adapt a glycogen storing mode, which blocks Hippo signaling through glycogen phase separation to augment tumor incidence.

Weighted multiple model adaptive boundary control for a flexible manipulator.

In this article, a weighted multiple model adaptive boundary control scheme is proposed for a flexible manipulator with unknown large parameter uncertainties. First, the uncertainties are approximatively covered by a finite number of constant models. Second, based on Euler-Bernoulli beam theory and Hamilton principle, the distributed parameter model of the flexible manipulator is constructed in terms of partial differential equation for each local constant model. Correspondingly, local boundary controllers are designed to control the manipulator movement and suppress its vibration for each partial differential equation model, which are based on Lyapunov stability theory. Then, a novel weighted multiple model adaptive control strategy is developed based on an improved weighting algorithm. The stability of the overall closed-loop system is ensured by virtual equivalent system theory. Finally, numerical simulations are provided to illustrate the feasibility and effectiveness of the proposed control strategy.

FGF15 Activates Hippo Signaling to Suppress Bile Acid Metabolism and Liver Tumorigenesis.

The external factors that modulate Hippo signaling remain elusive. Here, we report that FGF15 activates Hippo signaling to suppress bile acid metabolism, liver overgrowth, and tumorigenesis. FGF15 is induced by FXR in ileal enterocytes in response to increased amounts of intestinal bile. We found that circulating enterohepatic FGF15 stimulates hepatic receptor FGFR4 to recruit and phosphorylate NF2, which relieves the inhibitory effect of Raf on the Hippo kinases Mst1/2, thereby switching FGFR4's role from pro-oncogenic to anti-tumor signaling. The activated Mst1/2 subsequently phosphorylates and stabilizes SHP to downregulate the key bile acid-synthesis enzyme Cyp7a1 expression, thereby limiting bile acid synthesis. In contrast, Mst1/2 deficiency impairs bile acid metabolism and remarkably increases Cyp7a1 expression and bile acid production. Importantly, pharmacological depletion of intestinal bile abrogates Mst1/2-mutant-driven liver overgrowth and oncogenesis. Therefore, FGF15-Hippo signaling along the gut-liver axis acts as a sensor of bile acid availability to restrain liver size and tumorigenesis.

Research on the Negotiation and Consultation Frame in Rural and Urban Residents Medical Insurance Provider Payment System Reform / 中国卫生经济

The establishment of negotiation and consultation mechanism between medical insurance management agency and medical institution,could proceed the development of provider payment system reforms.This paper discussed the policy basis and the basic principle of negotiation and consultation in provider payment system reforms,and the subject,level and model,content,the carrying out and so on.

Pharmacokinetics of paclitaxel loaded nanoparticles made with hydrophobically modified Rhizoma Bletillae polysaccharide in rats / 药学实践杂志

Objective To establish a simple and sensitive method for the determination of plasma drug concentration in rats after intragastrical and intravenous administration of paclitaxel loaded nanoparticles and to evaluate its pharmacokinetic characteristics .Methods AgilentTC-C18 column (250 mm × 4 .6 mm ,5 μm) was used for HPLC at the flow rate 1 ml/min with ketoconazole as internal standard and methanol acetonitrile water (45:20:35) as the mobile phase .The statistical mo-ment method was applied to calculate the pharmacokinetic parameters and to evaluate pharmacokinetic characteristics .Results There was a good liner relationship (r=0 .9997) when rat blood concentration of Paclitaxel ranged from 0 .5 to 20μg /ml .The accuracy and precision were in line with the requirements of biological sample analysis .The t1/2 were 3.86 ,3.76 ,3.35 and 2 .62 h after intravenous injection of three lab-made paclitaxel nanoparticles and paclitaxel solution via rat tail vein .The t1/2 were 5 .28 and 3 .72 h respectively after intragastrical administration of lab-made paclitaxel nanoparticles and paclitaxel suspen-sion .Conclusion This method can be used for the pharmacokinetic study of paclitaxel nanoparticles in rats .The paclitaxel loaded nanoparticles exhibited significantly longer in vivo retention time than paclitaxel injection and paclitaxel suspension .

Paclitaxel loaded nanoparticles with cholesterol succinyl bletilla striata polysac-charide as a carrier / 药学实践杂志

Objective To explore the feasibility of bletilla striata polysaccharide as a drug delivery material .Method With hydrophobic cholesterol succinyl bletilla striata polysaccharide (CHSB) as the carrier ,the model drug paclitaxel (PTX) loaded nanoparticles were prepared via dialysis method .The morphology of nanoparticles was observed by Transmission Elec-tron Microscope (TEM) .The particle size ,distribution and zeta potential were characterized by Dynamic Light Scattering in-strument (DLS) .The entrapment efficiency ,drug loading and in vitro release were determined by high performance liquid chromatography (HPLC) .Differential Scanning Calorimetry (DSC) was used to confirm the drug form in the drug loaded nan-oparticles .The in vitro antitumor activity of nanoparticles was assayed by MTT .The uptake of nanoparticles by QGY-7703 liver cancer cells was observed by fluorescence labeling method .Results The prepared nanoparticles had spherical shape with uniform particle size distribution .The drug was loaded in the interior of the nanoparticles .Drug loading and encapsulation effi-ciency were affected by the CHSB in certain range .The cytotoxicity of drug loaded nanoparticles on liver cancer cells was stron-ger than the free drug .The fluorescence of Rhodamine B labeled drug nanoparticles were observed in the cells .Conclusion Cholesterol succinyl bletilla striata polysaccharide (CHSB) is highly feasible as an insoluble drug carrier .It can be used as a po-tential Nano carrier material .

Case-control study on related risk factors of aortic-esophageal fistula after esophageal carcinoma operation / 重庆医学

Objective To explore the related risk factors of aortic esophageal fistula (AEF) after esophageal carcinoma operation.Methods According to the design of case-control study and matching proportion of 1:3,18 cases of AEF after esophageal carcinoma operation treated in the thoracic surgery department of Daping Hospital of Third Military Medical University from 2000 to 2015 served as the observation group,and contemporaneous 54 cases of esophageal carcinoma operation,who had approximate basic diseases or risk factors,were selected as the control group,18 pairs were formed.The risk factors possessed by the observation group before disease onset such as age,sex,tumor TNM stage and tumor location served as the matching variables.The non-matching variables including operation time,preoperative body mass index (BMI),amount of intraoperative hemorrhage,preoperative LDL level,anastomosis mode,postoperative pulmonary complications,postoperative arrhythmia,preoperative hypertension,preoperative diabetes and number of removed lymph nodes were performed the case-control study.Results The univariate Logistic analysis preliminarily screened out 5 risk factors,including preoperative obesity,preoperative LDL level,postoperative pulmonary complications,anstomosis mode and number of removed lymph nodes,the difference in other factors was not statistically significant (P＞ 0.05).The multivariate non-conditional Logistic stepwise regression analysis revealed that preoperative obesity (OR =8.63,95 ％ CI=1.35-17.60),preoperative LDL level (OR =0.81,95 ％ CI =0.23-0.98) and the number of intraoperatively removed lymph nodes (OR =0.32,95 ％ CI =0.14-0.59) had statistical differences between the observation group and control group,but the difference in other factors had no statistical significance.Conclusion Preoperative obesity,preoperative LDL level and number of removed lymph nodes might be the risk factors for AEF occurrence after esophageal carcinoma operation.

Clinical and laboratory features of acute monocytic leukemia with B lymphoproliferative disorders / 中华血液学杂志

<p><b>OBJECTIVE</b>To identify the clinical and pathological features of acute myeloid leukemia with B lymphoproliferative disorders.</p><p><b>METHODS</b>The characteristics of 3 cases of acute monocytic leukemia with untreated chronic lymphocytic leukemia/monoclonal B-cell lymphocytosis were reported with literatures review.</p><p><b>RESULTS</b>The patients presented with a history of anemia, bleeding and/or fever. Acute monocytic leukemia was diagnosed by bone marrow morphology, cytochemistry and pathology studies. Immunophenotyping by flow cytometry analysis showed a significant population of absolute B-lymphocyte count of > 5×10(9)/L in a patients, similar to that of chronic lymphocytic leukemia.</p><p><b>CONCLUSIONS</b>The association of acute monocytic leukemia and untreated chronic lymphocytic leukemia/monoclonal B-cell lymphocytosis was a rare event. The abnormal B lymphocytes was likely to be misdiagnosis. Thus, it was important to combine several kinds of laboratory studies, especially flow cytometry to identify this rare disorder.</p>