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Neuroendocrine transformation (NET) is a resistance mechanism for epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). We aimed to elucidate whether NET develops in TKI-naïve NSCLC by using molecular fingerprinting in paired pre- and post-NET tissues.NET cases were identified based on the following criteria: the pre- and post-NET lesions must harbor mutual somatic mutations; neuroendocrine component should be absent in the sampled specimens of pre-NET lesions; and re-biopsy should be performed in either previously biopsied baseline lesions or newly developed lesions, but not in baseline-existing non-biopsied lesions, excluding synchronous neuroendocrine malignancy. p53 and Rb expression were evaluated via immunohistochemistry. Clinical characteristics, treatments, and outcomes were recorded and analyzed.Fifteen NET cases were identified, including five EGFR/ALK wild-type, three EGFR-mutant TKI-naïve, and seven TKI-treated cases. All cases harbored mutual somatic mutations in paired pre- and post-NET lesions. Recurrent pre-NET mutations were detected in TP53 (44.4%), RB1 (33.3%), and PDGFRA (33.3%), but two of the three PDGFRA mutations were lost after NET, whereas pre-NET TP53 and RB1 mutations were retained in the corresponding post-NET lesions. Immunohistochemistry revealed inactivated p53/Rb in 90.9% and 72.7% of the pre-NET lesions, respectively.This proof-of-concept study demonstrated that NET develops in NSCLCs without TKI targets or treatments. This phenomenon could be under-recognized, because re-biopsy was less frequently performed in these patients. Tissue re-biopsy should be preferred over liquid biopsy at the time of progression to account for histology transformation. p53/Rb IHC should be considered in addition to genomic TP53/RB1 evaluation for NET risk prediction.

Osteoarthritis (OA) is the most common cause to lead to chronic pain. Sensitization of pain pathways including central sensitization and peripheral sensitization has been regarded as a major cause of OA pain refractory to treatment. Addressing peripheral sensitization or central sensitization alone may not adequately treat OA pain. In our previous studies, botulinum toxin type A (BoNT/A) has been shown to reduce peripheral sensitization for analgesic effects. In addition, transcranial direct current stimulation (tDCS) has also been suggested to reduce central sensitization for analgesia. The present study was designed to investigate whether BoNT/A in combination with tDCS has better analgesic effects than isolated treatment to alleviate OA-induced chronic pain in rats. The Von Frey and hot plate tests were applied to assess the pain-related behaviors at different time points. The expression level of N-methyl-D-aspartate receptor-2B (NMDAR2B) was evaluated in midbrain periaqueductal gray (PAG) by Western blot the Immunohistochemistry staining after different treatments. The results showed that the combined treatment of BoNT/A and tDCS better improved the pain-related behaviors and significantly increased the expression level of NMDAR2B protein in PAG than each isolated treatment. These results suggested that the combined treatments for relief of chronic pain were more obvious than each isolated treatment. The combination of BoNT/A and tDCS may relieve pain by increasing N-methyl-D-aspartate (NMDA) receptors in the PAG, and then the descending inhibitory systems were activated to modulate peripheral and central sensitization.

A water-soluble polysaccharide from the green alga Chaetomorpha linum, designated CHS2, was obtained by water extraction, preparative anion-exchange and size-exclusion chromatography. Results of chemical and spectroscopic analyses showed that CHS2 was a sulfated rhamnogalactoarabinan, and its backbone was mainly constituted by 4-linked and 3,4-linked β-l-arabinopyranose with sulfate groups at C-2/C-3 of 4-linked β-l-arabinopyranose. The branching contained 4-linked, 6-linked β-d-galactopyranose and terminal rhamnose residues. Based on the inhibition of human islet amyloid polypeptide (hIAPP) aggregation and morphology change of hIAPP aggregates in in vitro tests, it was proved that CHS2 effectively inhibited the hIAPP aggregation and possessed strong antidiabetic activity. CHS2 was nearly no toxicity in NIT-1 cells and could attenuate hIAPP-induced cytotoxicity. CHS2 may significantly reduce the generation of intracellular reactive oxygen species and hIAPP aggregation-induced oxidative stress in NIT-1 cells. CHS2 was co-localized with mitochondria, and largely protected mitochondria function from hIAPP aggregation-induced damage through stabilizing mitochondrial membrane potential and enhancing the mitochondrial complex I, II or III activity and ATP level. The data demonstrated that CHS2 could have potential prospect to become an antidiabetic drug for type 2 diabetes mellitus treatment.

Neuropathic pain in osteoarthritis is one of the reasons why the pain is difficult to treat, and P2X4R plays an important role in neuropathic pain. In addition, BoNT/A has been proven to have analgesic effects on both neuropathic pain and osteoarthritis, but its exact mechanism is still unknown. This study aims to investigate the relationship between the analgesic effect of BoNT/A on osteoarthritis and the expression of P2X4R in spinal cord microglia. The analgesic effect was compared between BoNT/A and compound betamethasone. Western blot analysis was used to examine the expression of P2X4R and BDNF proteins in the spinal cord. Immunohistochemistry was used to determine the cellular location of P2X4R. Mechanical allodynia and weight asymmetry were identified using the hind paw withdrawal threshold and weight bearing test. The results showed that intra-articular injection of MIA induced persistent mechanical allodynia and weight asymmetry in rats. Both BoNT/A and betamethasone could relieve pain behavior in rats, but BoNT/A had a more obvious effect and lasted longer. Furthermore, BoNT/A could reverse the MIA-induced overexpression of BDNF and P2X4R in the spinal dorsal horn. To sum up, BoNT/A is more effective than betamethasone in relieving MIA-induced osteoarthritis pain in rats, and its analgesic effect may be related to the regulation of P2X4R-mediated BDNF release in spinal microglia and the relief of neuropathic pain in osteoarthritis.

Purpose As a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), osimertinib has a powerful ability to penetrate the blood-brain barrier and a high potency for controlling brain metastases (BMs) from EGFR-mutant non-small cell lung cancer (NSCLC). The clinical value of cranial radiation therapy in osimertinib-treated NSCLC with BMs remains largely unknown. Methods and Materials Patients with NSCLC and BMs and receiving osimertinib treatment as the standard of care were retrospectively enrolled from 2 institutions. Cranial radiation therapy (RT; whole-brain radiation therapy [WBRT] or/and stereotactic radiosurgery [SRS]) performed before disease progression (PD) to osimertinib was categorized as upfront cranial radiation therapy (ucRT group), excluding those treatments performed during prior EGFR-TKI treatment. Overall survival (OS), progression-free survival (PFS), and the time to intracranial progression (iTTP) were compared between the 2 groups, with adjustment by covariates in propensity-score matched (PSM) analyses. The state of having 1 to 3 BM lesions, with a maximal size of ≤3 cm, was defined as having oligo-BM; otherwise; the cases were defined as having multiple BMs. Results Of the 205 patients enrolled, osimertinib was used as first-line therapy in 74 and second-line therapy in 131. There were 48 patients who received ucRTs, including WBRT in 24 and SRS in 24. All patients with oligo-BM in the ucRT group received SRS alone (n = 17), whereas most (n = 28; 90.3%) patients with multiple BMs received WBRT. Failure pattern analyses indicated that in the non-ucRT group, 40.2% of the initial PD involved the brain and 76.9% of the cranial PD involved the original sites, indicating the potential roles of ucRT. Indeed, the iTTP was significantly prolonged (P = .010) in the ucRT group among the whole population. In the PSM oligo-BM cohort, the ucRT group showed superior PFS (P = .033) and OS (P = .026) compared with the non-ucRT group, and the differences remained after multivariate Cox analyses. No such differences were observed in the subpopulation with multiple BMs. Conclusions In osimertinib-treated NSCLC patients with BMs, oligo-BM status could be used as a potential factor to select patients for upfront cranial RT. Further investigation by well-designed clinical trials is warranted.

Tumor necrosis factor receptor-1 (TNFR1) and DEK are closely associated with the development of rheumatoid arthritis (RA). Taking advantage of the high adenosine triphosphate (ATP) in RA microenvironment and the interactions of DNA aptamers with their targets, an ATP-responsive DNA nanodrug was constructed that simultaneously targets TNFR1 and DEK for RA therapy. To this end, DEK target aptamer DTA and TNFR1 target aptamer Apt1-67 were equipped with sticky ends to hybridize with ATP aptamer (Apt

Osteosarcoma (OS) remains one of the most threatening primary malignant human tumors of the bone, especially in the first or second decade of life. Unfortunately, the clinical therapeutic efficacy has not substantially improved over the past four decades. Therefore, to achieve efficient tumor eradication, a new approach to prevent tumor recurrence is urgently needed. Here, we develop a new bisphosphonate (BP)-loaded microarc oxidation (MAO) coated magnesium-strontium (Mg-Sr) alloy pellet that can inhibit OS, and we illuminate the cellular and molecular mechanisms of the inhibiting effect. To generate such pellets, nitrogen-containing BP is chemically conjugated with a MAO coating on hollow Mg-Sr alloys. We demonstrate that BP coated Mg pellet has multiple desired features for OS therapy through in vitro and in vivo studies. At the cellular level, BP coated Mg pellets not only induce apoptosis and necrosis, as well as antitumor invasion of OS cells in the two-dimensional (2D) cell culture environment, but also damage the formation of multicellular tumor spheroids by OS cell lines in the three-dimensional (3D) cell culture environment. At the in vivo level, BP coated Mg pellets can destroy tumors and prevent neoplasm recurrence via synergistic Mg degradation and drug release. It is further suggested that the superior inhibitory effect on OS of our pellet is achieved by inhibiting the mevalonate pathway at the molecular level. Hence, these results collectively show that the BP coated Mg pellet is a promising candidate for future applications in repairing defects after tumor removal in OS therapy.

Objectives Central nervous system (CNS) metastases are common complications in epidermal growth factor receptor (EGFR) mutant non-small-cell lung cancer (NSCLC) treated with EGFR-tyrosine kinase inhibitors (TKIs). However, for patients without baseline CNS metastasis, data regarding the incidence of symptomatic CNS metastasis with EGFR-TKI treatment and its risk factors are still rare. Materials and Methods Patients with EGFR-mutant advanced NSCLC without baseline CNS metastasis who are receiving first- and/or third-generation EGFR-TKIs were included. Overall survival (OS), cumulative incidence of symptomatic CNS metastasis upon treatment failure, and their risk factors were evaluated. Results There were 813 patients enrolled, with 562, 106, and 32 received first-line gefitinib, erlotinib, and osimertinib, respectively, while 113 received second-line osimertinib. At a median follow-up of 18.1 months, the median OS was 45.5 months. There were 38 patients developed symptomatic CNS metastases. Osimertinib-treated patients tended to have a lower risk of CNS metastases compared with those treated with first-generation EGFR-TKIs (p = 0.059). However, the cumulative incidence curves of symptomatic CNS metastasis tended to reach a plateau after approximately 3 years regardless of which generation was used, and incidences beyond that period were similar in the two groups. Patients with L858R mutation exhibited a higher risk of developing CNS metastasis than patients with 19del mutation (p = 0.001). Interestingly, the presence of baseline neuroimaging was not associated with the risk of developing CNS metastasis or OS. Conclusion Compared with first-generation EGFR-TKIs, osimertinib can delay but not prevent the development of symptomatic CNS metastasis. L858R mutation is an independent risk factor for CNS metastasis.

Purpose Despite the impressive response rate to osimertinib, acquired resistance remains an obstacle to achieving long-term tumor control in metastatic epidermal growth factor receptor–mutant non-small cell lung cancer. Stereotactic body radiation therapy (SBRT) plays a growing role in the management of oligometastatic disease. We investigated the patterns of residual disease and progression on osimertinib, as well as the predictors of candidates for consolidative SBRT. Methods and Materials The serial scans of patients with metastatic epidermal growth factor receptor–mutant non-small cell lung cancer treated with osimertinib were retrospectively reviewed. Disease progression in residual sites, new sites, and both residual and new sites were classified as residual-site recurrence (RR), new-site recurrence (NR), and combined RR and NR (RNR), respectively. Logistic regression analysis was performed to identify predictors of candidates for consolidative SBRT. Results Ninety-seven patients were enrolled. The median time to maximal osimertinib response was 2.6 months. Twenty-six patients (26.8%) with oligoresidual disease were identified as candidates for consolidative SBRT at time of maximal response. Stage T1-2 before initiation of osimertinib (P = .046) was the independent predictor of consolidative SBRT eligibility. During a median follow-up of 10.9 months, disease progression was documented in 50 (51.5%) patients, and 70% of them experienced oligoprogression. Twenty-five (50%) patients developed disease progression in originally involved sites, 11 (22%) had new metastases, and 14 (28%) experienced disease progression in both original and new metastatic sites. Forty-six patients had progressive disease after experiencing initial stable disease or objective response to osimertinib. RR occurred in 20 (43.5%) of these patients, NR in 14 (30.4%), and RNR in 12 (26.1%). Notably, within the subgroup of patients eligible for consolidative SBRT, RR was observed in 6 (54.5%) patients, RNR in 3 (27.3%), and NR in 2 (18.2%). Conclusions The majority of progressive disease on osimertinib was within residual lesions in initially involved sites. Consolidative SBRT may prolong time to progression in a selected subgroup of patients, which merits further investigation.

Chronic inflammatory pain is a serious clinical problem caused by inflammation of the joints and degenerative diseases and greatly affects patients' quality of life. Persistent pain states are thought to result from the central sensitization of nociceptive pathways in the spinal dorsal horn. Spinal microglia-mediated neuroinflammation plays a pivotal role in the development and maintenance of the central sensitization of chronic inflammatory pain. Botulinum toxin type A (BoNT/A) was recently reported to have analgesic and anti-inflammatory effects. However, the precise mechanism underlying its analgesic effect remains unclear. Although several studies have reported that BoNT/A could regulate neuroflammation, the reduction of neuroinflammation regulated by BoNT/A in chronic inflammatory pain in experimentally induced arthritis has not been reported. The aim of this study was to investigate whether BoNT/A could alleviate adjuvant-arthritis pain via modulating microglia-mediated neuroinflammation and intracellular molecular pathway. The pain behavioral tests were performed before and after CFA immunization as well as after BoNT/A injection. Western blotting and immunofluorescence staining were used to assess the changes of microglial activation markers (ionized calcium binding adaptor molecule 1, IBA-1) and phosphorylation of P38MAPK (P-p38MAPK) in the lumbar spinal cord. TNF-αand P2X4R gene expression were studied by real-time reverse transcriptase-polymerase chain reaction (RT-PCR). The results showed that (1) the activation of spinal microglia can be continued till 21 days after CFA injection, which suggested its role in the development and maintenance of chronic inflammatory pain. (2) The intra-articular administration of a single effective dose of BoNT/A (5U/10 U) on day 21 after CFA injection significantly reduced nociceptive behaviors and decreased protein overexpression and immunoreactivity for IBA-1 and P-p38MAPK in CFA induced rat. Simultaneously, BoNT/A (5 U) also inhibited the increase in TNF-α mRNA and P2X4R mRNA expression induced by CFA injection. These results suggested that BoNT/A is a potential therapeutic agent for relieving the neuroinflammation that occurs in chronic inflammatory pain by inhibiting the activation of microglial cells and the release of microglia-derived TNF-α. This effect is likely mediated by inhibiting the activation of the P2X4R-P38MAPK signaling pathways in spinal microglial cells.

Proper alloying magnesium with element scandium (Sc) could transform its microstructure from α phase with hexagonal closed-packed (hcp) structure into β phase with body-cubic centered (bcc) structure. In the present work, the Mg-30 wt% Sc alloy with single α phase, dual phases (α + β) or β phase microstructure were developed by altering the heat-treatment routines and their suitability for usage within bone was comprehensively investigated. The β phased Mg-30 wt% Sc alloy showed the best mechanical performance with ultimate compressive strength of 603 ± 39 MPa and compressive strain of 31 ± 3%. In vitro degradation test showed that element scandium could effectively incorporate into the surface corrosion product layer, form a double-layered structure, and further protect the alloy matrix. No cytotoxic effect was observed for both single α phased and β phased Mg-30 wt% Sc alloys on MC3T3 cell line. Moreover, the β phased Mg-30 wt%Sc alloy displayed acceptable corrosion resistance in vivo (0.06 mm y−1) and maintained mechanical integrity up to 24 weeks. The degradation process did not significantly influence the hematology indexes of inflammation, hepatic or renal functions. The bone-implant contact ratio of 75 ± 10% after 24 weeks implied satisfactory integration between β phased Mg-30 wt%Sc alloy and the surrounding bone. These findings indicate a potential usage of the bcc-structured Mg-Sc alloy within bone and might provide a new strategy for future biomedical magnesium alloy design. Statement of Significance Scandium is the only rare earth element that can transform the matrix of magnesium alloy into bcc structure, and Mg-30 wt%Sc alloy had been recently reported to exhibit shape memory effect. The aim of the present work is to study the feasibility of Mg-30 wt%Sc alloy with different constitutional phases (single α phase, single β phase or dual phases (α + β)) as biodegradable orthopedic implant by in vitro and in vivo testings. Our findings showed that β phased Mg-30 wt%Sc alloy which is of bcc structure exhibited improved strength and superior in vivo degradation performance (0.06 mm y−1). No cytotoxicity and systematic toxicity were shown for β phased Mg-30 wt%Sc alloy on MC3T3 cell model and rat organisms. Moreover, good osseointegration, limited hydrogen gas release and maintained mechanical integrity were observed after 24 weeks’ implantation into the rat femur bone.

This study experimentally investigates the condensation of dielectric fluid HFE-7100 in a micro-channel heat sink with the hydraulic diameter of 1.21 mm. Tests are conducted at a fixed pressure of 110 kPa, with vapor mass quality (xin) ranging from 0.1 to 0.9, mass fluxes (G) from 150 to 250 kg·m−2·s−1, inclined angle (θ) from −90° to +90°. A novel trapezoid drainage design is proposed to enhance the condensation heat transfer by effectively entraining condensation film. When G is lower than 200 kg·m−2·s−1, the two phase heat transfer coefficient (htp) for the trapezoid drainage design exceeds the conventional rectangular micro-channel heat sink by 10–26% while the corresponding pressure drop is about 22–45% lower. When G is increased to 250 kg·m−2·s−1, the drainage design can still dramatically decrease the pressure drop, however, it shows a negative effect on htp when the xin is greater than 0.2. With inclined arrangements, the pressure drop would dramatically increase due to gravity effect. Besides, at the conditions of θ = −45° and −90°, the trapezoid drainage channel can improve the htp by 43–45% when G is lower than 200 kg·m−2·s−1. On the contrary, with the arrangement of θ = +45° and +90°, the trapezoid drainage channels may decrease the htp by 8–15%. This phenomenon is especially pronounced at a high xin. In addition, the heat transfer enhancement and deterioration are both analyzed based on stress distribution at vapor phase and condensation film.

In this study, a novel passive heat sink with triangular fins having alternating layout to promote heat transfer performance of a passive heat sink is proposed and verified by experimental and numerical examinations. The heat sinks with rectangular fins (case A), triangular fins with right angle, 90° (case B), triangular fins with right angle having alternating layout (case C), triangular fins with obtuse angle of 120° (case D) and triangular fins with obtuse angle of 120° having alternating layout (case E) are tested with vacuum pressure ranging from 400 Pa to atmosphere pressure. It is indicated that the triangular fin having alternating layout offer some benefits like entraining more airflow into the heat sink and a higher effective view factor, thereby showing an appreciable increase of effective heat transfer coefficient (HTC). Results obtained in low vacuum pressure show that the effective HTC of cases B, C, D and E can be improved by 1.5%, 5.5%, 3.0% and 12.1%, respectively as compared to the reference case A. Yet the effective HTC can be improved by 3.2%, 6.1%, 4.6% and 13.0%, respectively in atmosphere pressure. The numerical study is in line with the experimental results and the simulations suggest that the optimum angle of the proposed triangular fins having alternating layout can improve the effective HTC by up to 14.6% and 16.0% with obtuse angles of 150° and 140° when fin area is 2000 mm2 and 3000 mm2, respectively. The benefits of triangular fins having alternating layout show even more superior performance when the heat sink is placed vertically and the effective heat transfer coefficient for triangular fins having alternating layout with 150° is improved by up to 20.3%.

Radical therapy takes advantage of the reactive oxygen species produced in greater quantities within tumor cells than in normal cells. Here, for the first time, we explore a TiO2 nanoparticle mediated microwave induced radical therapy (termed as Microdynamic Therapy) as a new cancer treatment method. The experiments in vitro and in vivo demonstrate that colloidal TiO2 nanoparticles could significantly suppress the growth of osteosarcomas, even under low power (5 W) microwave (MW) irradiation for 5 min. The high photocatalytic activity of TiO2 nanoparticles efficiently utilizes the microwave-induced plasmonic effect for the formation of reactive oxygen species (ROS). Furthermore, TiO2 nanoparticles exhibit a higher cytotoxicity on cancer cells (osteosarcoma UMR-106 cells) than on normal cells (mouse fibroblast L929 cells). The effectiveness of TiO2 nanoparticles for microwave induced radical therapy demonstrates that this is a new landmark approach to treating cancers.

This study provides a review upon airflow management in data centers. Based on the available airflow path, cooling systems in data centers are categorized as long-distance cooling or short-distance cooling systems. Investigations on airflow management include tests in real data center or in simulated data center. Besides, the computational fluid dynamics (CFD) had been widely employed upon the thermal and airflow management of the data centers. For the long-distance cooling system, the airflow management normally adopts raised-floor configuration and hot/cold aisle arrangement. The major problems in airflow management include hot-air recirculation, cold-air bypass, leakages, over-provisioned and under-provisioned air supply, and airflow/temperature non-uniformity. The aforementioned effects often interact with the geometry layout of the data center. Related literatures regarding the effect of plenum depth, perforated tiles, enhanced facility such as induced bypass fans, infrastructure layout, aisle containment and leakage are discussed and compared. In addition, studies on the overhead air supply method are also examined and compared with the raised-floor ones. For the short-distance cooling system, the effect of server layout and heat exchanger layout concerning the airflow uniformity are investigated. It is found that the appropriate management of the original design into centralized server layout can ease the mal-distribution of airflow into the severs by 30%. This review aims to emphasize the criteria of implementing airflow management to data centers that serve as a reference guide for energy saving in data center as far as airflow arrangement is concerned. Moreover, some recommended future research efforts are also addressed.

Background Chemoresistance is the major cause of neoadjuvant treatment failure in breast cancer patients. Despite recent progress, the mechanism underlying chemoresistance remains to be further defined. Methods Expression of G protein-coupled receptor 120 (GPR120) was analyzed by immunohistochemistry in the biopsies of primary breast cancer who subsequently underwent preoperative neoadjuvant chemotherapy. In vitro and in vivo loss- and gain-of -function studies were performed to reveal the effects and related mechanism of GPR120 signaling pathway in the chemoresistance of breast cancer cells. Findings We identified that GPR120, a receptor for long-chain fatty acids, was important for the acquisition of chemoresistance in breast cancer cells. We showed that GPR120 expression was positively associated with clinical response to neoadjuvant chemotherapy in patients. In breast cancer cells, GPR120 enhanced the de novo synthesis of fatty acids that served as GPR120 ligands to activate GPR120 signaling via a feedback mechanism. Upregulated GPR120 signaling rendered cells resistant to epirubicin-induced cell death by upregulating ABC transporters expression and thus decreasing the intracellular accumulation of epirubicin. Akt/NF-κB pathway was responsible for the GPR120-mediated expression of ABC transporters leading to modulation of the concentration of chemotherapeutic drugs in cells. The functional importance of GPR120 in chemoresistance was further validated using epirubicin-treated tumor xenografts, in which we showed that blockade of GPR120 signaling with AH7614 or GPR120-siRNA significantly compromised chemoresistance. Interpretation Our results highlight that GPR120 might be a promising therapeutic target for breast cancer chemoresistance. Fund National Natural Science Foundation of China, Ministry of Science and Technology of China, Program of Science and Technology Commission of Shanghai Municipality.

Non-small cell lung cancer (NSCLC) is one of the most common malignancies, and Taxol is a cornerstone in the treatment. However, taxol-resistance eventually limits the clinical effects and applications. Daurinoline could restore the sensitivity of resistant MCF-7/adr and KBv200 cells. Whereas, the effect of daurinoline on the chemo-resistant NSCLC cells and the mechanism has not been elucidated. In this study, daurinoline was firstly demonstrated that inhibited the proliferation, migration, invasion and EMT phenotype of chemo-resistant NSCLC cells. And these effects were associated with EMT and Notch-1 reversal. Moreover, daurinoline could significantly enhance the anti-tumor effect of Taxol rather than epirubicin, adriamycin and cisplatin. And the reverse fold (RF) value of daurinoline was greater than terfenadine reported before. There are little cytotoxic effects of daurinoline and its derivatives reported by L.W. Fu, et al. (2001). Therefore, daurinoline may be a potential anti-tumor agent or chemosensitizer for chemo-resistant NSCLC patients.

Printed circuit heat exchangers (PCHEs) can be used as the recuperator and condenser in the supercritical CO2 (sCO2) Brayton cycle of fast cooled reactor (FCR) systems. Most researchers focused on heat transfer improvement of the core structure in previous literatures. However, the flow non-uniformity may seriously decrease the comprehensive performance of PCHEs by increasing the pressure loss. The sCO2 temperature in partial channels may be lower than the pseudo-critical temperature due to non-uniform flow distribution. Thereby, it is possible that the condenser may deviate from the steady operating condition and work inefficiently. In this paper, the flow non-uniformity of a straight-channel PCHE condenser with four different inlet headers is analyzed. Based on the streamline profile, a novel modified hyperbolic inlet header is proposed, which can reduce the flow non-uniformity by 46% compared with the current practical manufactured model. Simultaneously, the improvement of flow uniformity by the novel inlet header may increase the overall performance by 39.5%. Furthermore, the effect of core length is also investigated, and it is found that the flow non-uniformity can be minimized by varying the core length. Additionally, the relationship between the standard deviation of flow non-uniformity and the shape factor is quantitatively investigated and analyzed. Result shows that the flow non-uniformity can be expressed as a function of the shape factor and dimensionless core length. Finally, the correlations of the thermo-hydraulic performance of the straight-channel PCHE with corrections for flow non-uniformity are proposed.

The energy consumptions of data centers are increasing dramatically and cooling systems using for controlling the operating temperature usually consume more than half of these energy. Thus, effective strategies on thermal management in data centers may have benefit on energy savings. In order to improve the power usage effectiveness (PUE) of data centers, the effects of air supply flowrate by computer room air handler (CRAH), intake flowrate of rack cooling fans, air supply grilles and heat load distribution on the cooling performance of a typical small container data center having overhead air supply system are investigated in this paper. The rack cooling index (RCI) and supply heat index (SHI) are incorporated to evaluate the local and average cooling performance of data racks. It is found that the intake flowrate of rack cooling fans plays dominant role, which is suggested to be greater than the air supply flowrate in normal operation. Meanwhile, the volumetric flowrate distribution of grilles is studied. The additional front grille before entering the cold aisle may improve the RCI and SHI of front rack (rack A ), in which severe hot-air recirculation may occur in typical operation. Conversely, additional rear grille at the exit of cold aisle has negative effect on cooling performance of the last rack (rack E). Based on the measurement of local temperature distribution, the non-uniform heat load distribution in racks is proposed. Result shows that the RCI can be improved to 64% if more power is placed at lower half part, which is eligible for energy saving. However, the non-uniform heat load distribution shows limited improvement on the rear rack (rack E).

The induction of a suitable immune microenvironment by implant is essential for fast bone regeneration. Surface potential is a critical factor that influences immune cells behavior. We apply polydopamine coatings on a titanium (Ti) surface to decrease its surface potential. A lower surface potential favored the expression of adhesion-related genes in bone marrow-derived monocytes (BMDMs) by activating the focal adhesion kinase signaling pathway. A lower negative surface potential results in higher electronic repulsion between the surface and the BMDMs, because the cells exhibit negative charged membrane. To resist the repulsive force, Integrin β1 and Integrin β3 in the cell membrane for low surface potential group are upregulated. Furthermore, BMDMs cultured on Ti with low surface potential are more inclined polarize towards anti-inflammatory phenotype (M2) in vitro and in vivo. Whole gene expression analysis reveals that inhibition of the PI3K-Akt-mTOR signaling axis is responsible for the immune regulation ability of Ti with low surface potential. The cytokines secreted by M2 BMDMs promote osteogenic differentiation of a mouse embryo cell line (C3H10T1/2) and increase osteointegration between the implant and newly formed bone. These findings reveal that surface potential regulation is a promising strategy to reprogram the immune microenvironment for bone regeneration and provide insights into developing biomaterials with immunomodulatory functions.

Copper (Cu) has drawn considerable attention in the design of biomaterials due to its multifunction, such as antibacterial property, osteogenic and angiogenic ability. However, the effect of Cu on chondrogenic differentiation of mesenchymal stem cells (MSCs) and its potential for cartilage repair biomaterials has been rarely studied. Here, we report that Cu can significantly enhance chondrogensis of MSCs. Specifically, in vitro studies showed that Cu could promote MSCs cytoskeleton change, extracellular glycosaminoglycan (GAG) deposition and the chrodrogenic genes (Sox9, Aggrecan, and Col-2) up-regulation. Furthermore, we prepared a Cu-containing alginate (Alg) porous scaffold to assess the chondroinductivity of Cu in vivo. In eight weeks, we found that Alg/Cu scaffolds could induce better formation of new cartilage tissue compared to the pure Alg scaffolds fabricated by the same procedure but without adding Cu. These encouraging results indicate that Cu can bring considerable benefits to the development and application of cartilage repair biomaterials.

A transient solidification model was developed and coupled to ASYST code to simulate the transient behavior of the direct reactor auxiliary cooling system (DRACS) of the fluoride-salt-cooled high-temperature reactor (FHR) during the loss of heat sink (LOHS) accident. The model was firstly validated by comparing the experimental data with the simulation results that deriving from available heat transfer and friction factor correlations. The simulation results are found to be well-fitted with the experimental data. The transient solidification model successfully predicted the occurrence of solidification and the complete blockage of the heat transfer pipes in DRACSs. The solidified layer is found to be beneficial for the decay heat removal at the early stage of solidification, however, a sudden clog is found at the end stage of the solidification. Based on the simulation results, an optimization attempt was made to extend the failure time of DRACS by reducing the length of heat transfer tubes. The model is applicable to all the reactors where solidification may occur, such as other molten salt reactors (MSRs) and lead-cooled fast reactors (LFRs).

Interleukin-33 (IL-33) is a potent contributor to antiviral immune responses and antitumor immunity. We recently discovered that IL-33 is overexpressed in dectin-1-activated dendritic cells (DCs). However, mechanisms of dectin-1-induced IL-33 expression in DCs remain elusive. Curdlan, an agonist of dectin-1, was used to mature DCs in this study. We found that dectin-1-induced IL-33 expression in DCs relies on Syk and Raf-1 pathways. By using nuclear factor (NF)-κB inhibitors, we also found that dectin-1-induced IL-33 expression relies on NF-κB signaling. Furthermore, through Syk/Raf-1-NF-κB pathway, dectin-1 signaling stimulates DCs to overexpress interferon regulatory factor 4 (IRF4), which directly upregulates the expression of IL-33 in dectin-1-activated DCs. Thus, our study provides new insights into the mechanisms of dectin-1-induced IL-33 expression in DCs and may provide new targets for improving DC-based cancer immunotherapy.

Polyvalent vaccines against more than one species of pathogens are especially important due to the complex ecosystem in aquaculture. We have previously shown that the development of polyvalent vaccines by shuffling six ompA genes from different bacteria with V. parahaemolyticus VP0764 primers. Here, we used the same 6 genes, V. alginolyticus VA0764 and VA1186, V. parahaemolyticus VP0764 and VP1186, E. tarda ompA and E. coli ompA, but with E. tarda ompA primers to develop new polyvalent vaccines. By this approach, we identified 7 potential polyvalent vaccines that were effective against both V. alginolyticus and E. tarda infections. Furthermore, the innate immunity triggered by the vaccines were also explored in three groups, no protection (group I), protection against V. alginolyticus (group II), and protection against both V. alginolyticus and E. tarda (group III). The transcription of IL-1β, IL-6, IL-8, C3b and NF-kB were significantly increased in group II and group III but not group I, where the expression level of group III was higher than group II. In addition, differential activities of succinate dehydrogenase were detected among the three groups. These results indicate the expansion of polyvalent vaccine reservoir with the same shuffling genes but different primers, and promote the understanding of the mechanisms of polyvalent vaccines based on vaccine-induced innate immunity.

Our previous studies demonstrated that molecular breeding via DNA shuffling directs the evolution of polyvalent vaccines with desired traits, which leads to generation of polyvalent ompA vaccines using Vibrio alginolyticus VA0764 primers. Here, we replaced VA0764 primers with Edwardsiella tarda ompA primers to generate new polyvalent ompA vaccines by DNA shuffling of the same five ompA genes from four species of bacteria E. tarda, V. parahaemolyticus, V. alginolyticus and Escherichia coli. We identified four polyvalent vaccine candidates from a eukaryotic expressing library EompAs-FE containing 82 ompAs using active immune protection against V. alginolyticus and E. tarda. Furthermore, we explored mechanisms of polyvalent vaccine candidates by investigation of the innate immune response to these ompAs, and found that expression of IL-1β, IL-8, IL-15, COX-2, IFN-γ, TLR-1, TLR-3 and C3b genes was elevated as a characteristic feature of these polyvalent vaccine candidates. These results indicate that use of different primers to construct a DNA library selects new evolution of polyvalent vaccines with desired traits, and polyvalent ompA vaccines elicit high innate immune response.

Up to 14% of the U.S. population is estimated to have obstructive sleep apnea (OSA), while the outcomes of the treatments have variable results. In the current study, a three-dimensional fluid-structure interaction modeling was applied to simulate the upper airway to identify the precise location, severity, and characteristic of airway collapse. This was accomplished using Simpleware® and ANSYS® software applied to a 3-D rendering of the airway in a real patient with severe OSA. During this simulation, areas which are prone to collapse and precipitate apneic episodes were identified at the tip of the soft palate and the base of the tongue, with intrathoracic pressure as low as −1370 Pa. These results are consistent with anatomical structures currently indicated and targeted in the treatment of OSA. This improved FSI modeling simulation, which is the first to completely model the whole upper airway without consideration of the nasal cavity in OSA, and can allow virtual modification of the airway prior to actual treatment by doctors.

The flow boiling process of refrigerants indicates significant influence on the refrigeration system performance. With the development of environmental standards in the last two decades, various refrigerants with low Global Warming Potential (GWP) and none ozone depletion potential (ODP). This study provides a review upon flow boiling behavior of refrigerants impacting by lubricant oil. Experimental studies on flow regimes of refrigerant/oil mixtures in macro-scale and that in mini- and micro-scale flow channels are respectively summarized in this review. Meanwhile, correlations with applicable ranges involving refrigerant mass velocities, heat fluxes, vapor mass qualities and oil concentrations are also examined and concluded for predicting the two-phase heat transfer coefficient (HTC) and pressure drop. For achieving better comprehensive thermal performance, experimental studies on augmentation structures with the application of microfin and metal-foam tubes are also reviewed. Moreover, the effect of nanoparticles on the flow boiling heat transfer is considered, which sometimes shows negative effect, but not always. This review aims to serve as a reference guide for experimental measurement of refrigerant flow boiling as far as the effect of lubricant oil is concerned. Moreover, some research efforts in the further studies as well as potential enhancement measures are also addressed.

The acquired resistance of non-small cell lung cancer (NSCLC) to taxanes eventually leads to the recurrence and metastasis of tumours. Thus, the development of therapeutic strategies based on the mechanisms by which cells acquire resistance to prolong their survival rate in chemotherapy drug treatment failure patients are warranted. In this study, we found that the resistant cells acquired increased migratory and invasive capabilities, and this transformation was correlated with epithelial-mesenchymal transition (EMT) and Notch pathway deregulation in the resistant cells. Finally, we reported for the first time that terfenadine augmented the effect of epirubicin (EPI) better than Taxol and cisplatin (DDP) by inhibiting migration, invasion, and the EMT phenotype, and the combination therapy also reversed Notch signalling pathway and enhanced the accumulation of fluorescent P-gp substrate rhodamine 123 (Rh123). Similar activities of terfenadine on EPI were observed in xenografts. All of our results confirmed that terfenadine combined with EPI synergistically inhibits the growth and metastatic processes of resistant cells both in vitro and in vivo. Therefore, terfenadine or its derivatives are a promising approach for the clinical challenge of resistance in patients with advanced NSCLC.

The supercritical CO 2 Brayton cycle (SCO 2 -BC) is proposed to be used as the concept of fast cooled reactor (FCR), which is a typical application in the 4th generation reactors. The recuperator and cooler, which acted as important components in SCO 2 -BC, are required for long-term operation especially at the high pressure condition. However, the traditional shell-and-tube heat exchanger, which already has mature fabrication technology, is not appropriate in the developing miniaturized thermal system because of its low compactness. In the present paper, the compact printed circuit heat exchanger (PCHE) with straight ribs is manufactured by the photochemical etching technology and the diffusion bonding method independently. Then, the thermohydraulic performance of PCHE is tested on the SCO 2 -water experiment platform. Considering the difference of thermal properties of working fluid, the comparison of thermal and hydraulic performance between SCO 2 and water in the tested PCHE is studied at the same mass flow rate, which shows that the SCO 2 has better heat transfer capability than water fluid. Further, the heat transfer rate and pressure loss of PCHE are investigated at different SCO 2 operating pressure, which indicates that the PCHE has better comprehensive performance when it operates at higher pressure condition. Meanwhile, the extreme operating condition due to the pseudo-critical point of CO 2 working in the PCHE is analyzed comparing with the normal operating condition. The results show that the comprehensive performance of PCHE is significantly reduced nearly 17.6% when operates at the transcritical state. The heat transfer correlation of PCHE with straight ribs is fitted by experimental data in both the supercritical and transcritical states in order to simplifying design process.

Monoallelic gene expression refers to the phenomenon that all transcripts of a gene in a cell are expressed from only one of the two alleles in a diploid organism. Although monoallelic gene expression has been occasionally reported with bulk transcriptome analysis in plants, how prevalent it is in individual plant cells remains unknown. Here, we developed a single-cell RNA-seq protocol in rice and investigated allelic expression patterns in mesophyll cells of indica (93-11) and japonica (Nipponbare) inbred lines, as well as their F1 reciprocal hybrids. We observed pervasive monoallelic gene expression in individual mesophyll cells, which could be largely explained by stochastic and independent transcription of two alleles. By contrast, two mechanisms that were proposed previously based on bulk transcriptome analyses, parent-of-origin effects and allelic repression, were not well supported by our data. Furthermore, monoallelically expressed genes exhibited a number of characteristics, such as lower expression levels, narrower H3K4me3/H3K9ac/H3K27me3 peaks, and larger expression divergences between 93-11 and Nipponbare. Taken together, the development of a single-cell RNA-seq protocol in this study offers us an excellent opportunity to investigate the origins and prevalence of monoallelic gene expression in plant cells.

High temperature resistance and corrosion resistance make ceramic materials available for heat exchangers operating under high temperature or harsh chemical conditions. And the importance of the effect of flow maldistribution on thermal-hydraulic performance of heat exchangers has been demonstrated by a lot of researches. In this work, the nonuniformity of fluid flow is focused on to improve the performance of a microchannel ceramic heat exchanger. The inlet part of a microchannel ceramic heat exchanger is optimized using surrogate model coupled with genetic algorithm. Specifically, 30 sample points are designed by Latin hypercube sampling method and calculated by computational fluid dynamics. Radial basis neural network is established with the sample data and employed to predict the specific fluid flow distribution within design space as a surrogate model. Specifically, the surrogate model predicts the specific flow distribution instead of a single target value of nonuniformity in previous surrogate model. The results indicate that such a method has a significant advantage over the previous surrogate model. The genetic algorithm is implemented to search for the optimal point. The nonuniformity of fluid flow is reduced by 68.2% and pressure drop is increased by 6.6% by the optimization, which means the uniformity of fluid flow in the heat exchanger is improved significantly with just a little cost of pressure drop.

Myocyte enhancer factor 2D (MEF2D) is involved in many aspects of cancer progression, including cell proliferation, invasion, and migration. However, little is known about the role of MEF2D in tumor angiogenesis. Using clinical specimens, colorectal cancer (CRC) cell lines and a mouse model in the present study, we found that MEF2D expression was positively correlated with CD31-positive microvascular density in CRC tissues. MEF2D promoted tumor angiogenesis in vitro and in vivo and induced the expression of proangiogenic cytokines in CRC cells. MEF2D was found to be a downstream effector of hypoxia-inducible factor (HIF)-1α in the induction of tumor angiogenesis. HIF-1α transactivates MEF2D expression by binding to the MEF2D gene promoter. These results demonstrate that the HIF-1α/MEF2D axis can serve as a therapeutic target for the treatment of CRC.

Makerspaces have become some of the most important environments for nurturing creativity in the 21st century. This study proposed that a rounded versus an angular physical work environment (RA-PWE) in makerspaces has different effects on makers’ divergent and convergent creativity. The results of a survey with makers in 15 makerspaces and two experiments indicated that a rounded physical work environment (Rounded-PWE) was more likely to enhance divergent creativity than an angular physical work environment (Angular-PWE), while an Angular-PWE was more likely to enhance convergent creativity than a Rounded-PWE. The underlying process identified showed that a Rounded-PWE was more likely to activate approach motivation, while an Angular-PWE was more likely to activate avoidance motivation, in turn enhancing divergent or convergent creativity. This study makes theoretical contributions to research on PWE, creativity, and motivation and provides practical implications for managers and designers of makerspaces and other spaces.

The print circuit heat exchanger (PCHE) is a new kind of compact and high efficiency plate-heat-exchangers which can be used for high pressure and high temperature systems, such as the supercritical CO2 Brayton cycle. In this study, the geometrical parameters of airfoil fins are investigated by the numerical simulation. The local and overall heat transfer characteristics as well as the dynamic performance are analyzed with different pitches. The result shows that the heat transfer rate decreases because of the strong variation of properties of supercritical CO2, but the pressure loss remains almost constant along the main flow direction. Meanwhile, the effect of transverse pitch and staggered longitudinal pitch are analyzed comprehensively. Furthermore, the correlations of j and f factors are fitted for the studied airfoil printed circuited heat transfer surfaces. It is proved that a large windward area and a short length can lead to a better comprehensive heat transfer performance.