IL-8 from CD248-expressing cancer-associated fibroblasts generates cisplatin resistance in non-small cell lung cancer.

Chemotherapy-resistant non-small cell lung cancer (NSCLC) presents a substantial barrier to effective care. It is still unclear how cancer-associated fibroblasts (CAFs) contribute to NSCLC resistance to chemotherapy. Here, we found that CD248+ CAFs released IL-8 in NSCLC, which, in turn, enhanced the cisplatin (CDDP) IC50 in A549 and NCI-H460 while decreasing the apoptotic percentage of A549 and NCI-H460 in vitro. The CD248+ CAFs-based IL-8 secretion induced NSCLC chemoresistance by stimulating nuclear factor kappa B (NF-κB) and elevating ATP-binding cassette transporter B1 (ABCB1). We also revealed that the CD248+ CAFs-based IL-8 release enhanced cisplatin chemoresistance in NSCLC mouse models in vivo. Relative to wild-type control mice, the CD248 conditional knockout mice exhibited significant reduction of IL-8 secretion, which, in turn, enhanced the therapeutic efficacy of cisplatin in vivo. In summary, our study identified CD248 activates the NF-κB axis, which, consecutively induces the CAFs-based secretion of IL-8, which promotes NSCLC chemoresistance. This report highlights a potential new approach to enhancing the chemotherapeutic potential of NSCLC-treating cisplatin.

Unexpected Intracranial Hemorrhage and Death After Cranioplasty in a Patient With Massive Hemispheric Infarction.

The benefits and common complications of cranioplasty are often mentioned, but fatal complications are rarely documented. Here, the authors report a patient of intracranial hemorrhage and death after cranioplasty and discussed the possible mechanism. A 42-year-old man was admitted with the diagnosis of massive cerebral infarction in left fronto-temporo- parietal lobe, emergency surgery for decompressive large craniotomy and Encephalo-Myo-Synangiosis were performed. One year after surgery, cranioplasty was performed using a titanium mesh plate. Intraoperative cerebrospinal fluid leakage was occurred and dura mater was repaired using pieces of silk. During the postoperative anesthesia emergence, the patient had epileptic seizures and did not wake after surgery. The authors also observed about 150 mL bloody cerebrospinal fluid (CSF) in the subcutaneous vacuum drainage system within 2 hours. Emergency computed tomography of the brain showed epidural, subdural, subarachnoid hemorrhages in the postischemic area, the middle line left, and the brain stem swelling. The patient's family refused to immediately remove the titanium mesh plate. Finally, nonoperative treatment is invalid and the patient's neurological condition did not recover and he died 3 days after the surgery. In the authors' mind, patients with previous massive cerebral infarction and Encephalo-Myo-Synangiosis undergoing cranioplasty might be at heightened risk of a fatal event than other cranioplasty. Therefore, the patients should be paid more attention to prevent and treat the fatal complications.

PI3K independent activation of mTORC1 as a target in lapatinib-resistant ERBB2+ breast cancer cells.

Therapies targeting the ERBB2 receptor, including the kinase inhibitor lapatinib (Tykerb, GlaxoSmithKline), have improved clinical outcome for women with ERBB2-amplified breast cancer. However, acquired resistance to lapatinib remains a significant clinical problem, and the mechanisms governing resistance remain poorly understood. We sought to define molecular alterations that confer an acquired lapatinib resistance phenotype in ER-/ERBB2+ human breast cancer cells. ERBB2-amplified SKBR3 breast cancer cells were rendered resistant to lapatinib via culture in increasing concentrations of the drug, and molecular changes associated with a resistant phenotype were interrogated using a collaborative enzyme-enhanced immunoassay platform and immunoblotting techniques for detection of phosphorylated signaling cascade proteins. Interestingly, despite apparent inactivation of the PI3K/AKT signaling pathway, resistant cells exhibited constitutive activation of mammalian target of rapamycin complex 1 (mTORC1) and were highly sensitive to mTOR inhibition with rapamycin and the dual PI3K/mTOR inhibitor NVP-BEZ235. These data demonstrate a role for downstream activation of mTORC1 in the absence of molecular alterations leading to PI3K/AKT hyperactivation as a potential mechanism of lapatinib resistance in this model of ERBB2+ breast cancer and support the rationale of combination or sequential therapy using ERBB2 and mTOR-targeting molecules to prevent or target resistance to lapatinib. Moreover, our data suggest that assessment of mTOR substrate phosphorylation (i.e., S6) may serve as a more robust biomarker to predict sensitivity to mTOR inhibitors in the context of lapatinib resistance than PI3K mutations, loss of PTEN and p-AKT levels.

A Novel Genetic Neural Network Algorithm with Link Switches and Its Application in University Professional Course Evaluation.

This study exploits a novel enhanced genetic neural network algorithm with link switches (EGA-NNLS) to model the professional university course evaluating system. Various indices should be employed to evaluate the learning effect of a professional course comprehensively and objectively, and the traditional artificial evaluation methods cannot achieve this goal. The presented data-driven modeling method, EGA-NNLS, combines a neural network with link switches (NN-LS) with an enhanced genetic algorithm (EGA) and the Levenberg-Marquardt (LM) algorithm. It employs an optimized network structure combined with EGA and NN-LS to learn the relationships between the system's input and output from historical data and uses the network's gradient information via the LM algorithm. Compared with the traditional backpropagation neural network (BPNN), EGA-NNLS achieves a faster convergence speed and higher evaluation precision. In order to verify the efficiency of EGA-NNLS, it is applied to a collection of experimental data for modeling the professional university course evaluating system.

Micro-irrigation improves grain yield and resource use efficiency by co-locating the roots and N-fertilizer distribution of winter wheat in the North China Plain.

Water use efficiency (WUE) and nitrogen fertilizer use efficiency (NUE) of winter wheat are urgently needed to further improve in the North China Plain (NCP). In this study, a 3-year field experiment was conducted during the 2014-2017 growing seasons to clarify the effect of traditional flood irrigation (TI), surface drip irrigation (DI), and micro-sprinkling irrigation (MSI) on grain yield, WUE, and NUE of winter wheat. Across the 3 years, grain yield of DI and MSI improved by 9.79% and 14.1%, WUE of DI and MSI increased by 12.3% and 17.7%, and NUE of DI and MSI increased by 9.77% and 14.0%, respectively compared with those of TI. Wheat subjected to the micro-irrigation treatments (DI and MSI) had higher chlorophyll content in flag leaves 10 days post-anthesis; this postponed senescence of the flag leaves, which increased dry matter accumulation post-anthesis, and increased 1000-grain weight and grain yield. The micro-irrigation treatments reduced pre-anthesis water consumption but increased post-anthesis water consumption and ensured the water supply in the top soil layer at the critical stage, thus increasing WUE. Root length density (RLD) of TI in the 0-80-cm soil layer was significantly higher than that of micro-irrigation, whereas micro-irrigation had higher RLD than TI below the 80-cm soil layer, which promoted the absorption and utilization of water and nitrogen in deep soil. The micro-irrigation treatments increased total nitrogen accumulation of the plants, reduced soil nitrate nitrogen (NO3--N) content at maturity, ensured the nitrogen supply in the top soil layer, thus increasing NUE. Overall, micro-irrigation with water and fertilizer as an integrated pattern significantly improved grain yield, WUE, and NUE of winter wheat in the NCP by co-locating the root, water, and N-fertilizer distribution and reducing NO3--N accumulation in deep soil. The best treatment was micro-sprinkling irrigation.

N-oleoyldopamine enhances glucose homeostasis through the activation of GPR119.

G protein-coupled receptor 119 (GPR119) is largely restricted to pancreatic insulin-producing beta-cells and intestinal glucagon-like peptide-1-producing L-cells. Synthetic agonists of this receptor elicit glucose-dependent release of these endocrine factors, thereby enhancing glycemic control. Oleoylethanolamide also activates GPR119, but it remains unclear whether endogenous production of this lipid modulates GPR119 activity under normal or dysglycemic conditions. We show here that a relatively diverse set of lipid amides activate GPR119. Among these, the endovallinoid N-oleoyldopamine (OLDA) stimulated cAMP accumulation in GPR119-transfected cells as effectively as oleoylethanolamide and the previously described synthetic agonist AR231453. None of these lipid amides increased cAMP in control-transfected cells or in cells transfected with a number of other G protein-coupled receptors. OLDA stimulated both cAMP accumulation and insulin release in HIT-T15 cells, which express GPR119 endogenously, and in GPR119-transfected RIN-5F cells. Oral administration of OLDA to C57bl/6 mice elicited significant improvement in glucose tolerance, whereas GPR119-deficient mice were essentially unresponsive. OLDA also acutely elevated plasma gastric inhibitory peptide levels, a known hallmark of GPR119 activation. OLDA represents a possible paracrine modulator of GPR119 in pancreatic islets, where markers of dopamine synthesis correlated well with GPR119 expression. However, no such correlation was seen in the colon. Collectively, these studies indicate that multiple, distinct classes of lipid amides, acting via GPR119, may be important modulators of glucose homeostasis.