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Lysophosphatidic acid receptors (LPARs) are six G-protein-coupled receptors that mediate LPA signaling to promote tumorigenesis and therapy resistance in many cancer subtypes, including breast cancer. Individual-receptor-targeted monotherapies are under investigation, but receptor agonism or antagonism effects within the tumor microenvironment following treatment are minimally understood. In this study, we used three large, independent breast cancer patient cohorts (TCGA, METABRIC, and GSE96058) and single-cell RNA-sequencing data to show that increased tumor LPAR1, LPAR4, and LPAR6 expression correlated with a less aggressive phenotype, while high LPAR2 expression was particularly associated with increased tumor grade and mutational burden and decreased survival. Through gene set enrichment analysis, it was determined that cell cycling pathways were enriched in tumors with low LPAR1, LPAR4, and LPAR6 expression and high LPAR2 expression. LPAR levels were lower in tumors over normal breast tissue for LPAR1, LPAR3, LPAR4, and LPAR6, while the opposite was observed for LPAR2 and LPAR5. LPAR1 and LPAR4 were highest in cancer-associated fibroblasts, while LPAR6 was highest in endothelial cells, and LPAR2 was highest in cancer epithelial cells. Tumors high in LPAR5 and LPAR6 had the highest cytolytic activity scores, indicating decreased immune system evasion. Overall, our findings suggest that potential compensatory signaling via competing receptors must be considered in LPAR inhibitor therapy.

The LPP family is comprised of three enzymes that dephosphorylate bioactive lipid phosphates both intracellularly and extracellularly. Pre-clinical breast cancer models have demonstrated that decreased LPP1/3 with increased LPP2 expression correlates to tumorigenesis. This though has not been well verified in human specimens. In this study, we correlate LPP expression data to clinical outcomes in over 5000 breast cancers from three independent cohorts (TCGA, METABRIC, and GSE96058), investigate biological function using gene set enrichment analysis (GSEA) and the xCell cell-type enrichment analysis, and confirm sources of LPP production in the tumor microenvironment (TME) using single-cell RNA-sequencing (scRNAseq) data. Decreased LPP1/3 and increased LPP2 expression correlated to increased tumor grade, proliferation, and tumor mutational burden (all p < 0.001), as well as worse overall survival (hazard ratios 1.3–1.5). Further, cytolytic activity was decreased, consistent with immune system invasion. GSEA data demonstrated multiple increased inflammatory signaling, survival, stemness, and cell signaling pathways with this phenotype across all three cohorts. scRNAseq and the xCell algorithm demonstrated that most tumor LPP1/3 was expressed by endothelial cells and tumor-associated fibroblasts and LPP2 by cancer cells (all p < 0.01). Restoring the balance in LPP expression levels, particularly through LPP2 inhibition, could represent novel adjuvant therapeutic options in breast cancer treatment.

Pancreatic ductal adenocarcinoma (PDAC) is an incurable, highly metastatic disease that is largely resistant to existing treatments. A better understanding of the genetic basis of PDAC metastasis should facilitate development of improved therapies. To that end, we developed a novel mouse xenograft model of PDAC metastasis to expedite testing of candidate genes associated with the disease. Human PDAC cell lines BxPC-3, MiaPaCa-2, and Panc-1 stably expressing luciferase were generated and introduced by intracardiac injections into immunodeficient mice to model hematogenous dissemination of cancer cells. Tumor development was monitored by bioluminescence imaging. Bioluminescent MiaPaCa-2 cells most effectively recapitulated PDAC tumor development and metastatic distribution in vivo. Tumors formed in nearly 90% of mice and in multiple tissues, including normal sites of PDAC metastasis. Effects of p14ARF, a known suppressor of PDAC, were tested to validate the model. In vitro, p14ARF acted through a CtBP2-dependent, p53-independent pathway to inhibit MiaPaCa-2–invasive phenotypes, which correlated with reduced tumor cell colonization in vivo. These findings establish a new bioluminescent mouse tumor model for rapidly assessing the biological significance of suspected PDAC metastasis genes. This system may also provide a valuable platform for testing innovative therapies. Mol Cancer Res; 9(7); 867–77. ©2011 AACR.

H&E and immunohistochemistry staining for ATX and Bcl-2 in mouse breast tumor tissue. The border between tumor (red T) and stromal tissue (red S) is showed as red dash line. Scale bar = 100 mm.

Autotaxin catalyzes the formation of lysophosphatidic acid, which stimulates tumor growth and metastasis and decreases the effectiveness of cancer therapies. In breast cancer, autotaxin is secreted mainly by breast adipocytes, especially when stimulated by inflammatory cytokines produced by tumors. In this work, we studied the effects of an ATX inhibitor, GLPG1690, which is in phase III clinical trials for idiopathic pulmonary fibrosis, on responses to radiotherapy and chemotherapy in a syngeneic orthotopic mouse model of breast cancer. Tumors were treated with fractionated external beam irradiation, which was optimized to decrease tumor weight by approximately 80%. Mice were also dosed twice daily with GLPG1690 or vehicle beginning at 1 day before the radiation until 4 days after radiation was completed. GLPG1690 combined with irradiation did not decrease tumor growth further compared with radiation alone. However, GLPG1690 decreased the uptake of 3′-deoxy-3′-[18F]-fluorothymidine by tumors and the percentage of Ki67-positive cells. This was also associated with increased cleaved caspase-3 and decreased Bcl-2 levels in these tumors. GLPG1690 decreased irradiation-induced C-C motif chemokine ligand-11 in tumors and levels of IL9, IL12p40, macrophage colony-stimulating factor, and IFNγ in adipose tissue adjacent to the tumor. In other experiments, mice were treated with doxorubicin every 2 days after the tumors developed. GLPG1690 acted synergistically with doxorubicin to decrease tumor growth and the percentage of Ki67-positive cells. GLPG1690 also increased 4-hydroxynonenal-protein adducts in these tumors. These results indicate that inhibiting ATX provides a promising adjuvant to improve the outcomes of radiotherapy and chemotherapy for breast cancer.

We propose and demonstrate a single fiber optical tweezer for particle multi-dimensional arrangement based on a high-order Bessel-like beam produced by concatenating a few-mode fiber and a step-index multimode fiber. We use the mode division multiplexing technology to produce the high-order Bessel-like beam with uneven energy distribution. The LP11 and LP21 mode beams are excited by docking a 980 nm single-mode fiber at the outlet of the light source to a few-mode fiber with a defined offset. The few-mode fiber allows LP01, LP11, and LP21 mode beams to be spread in. The high-order Bessel-like beam is focused by a high refractive index glass microsphere integrated on the fiber end facet. The LP01 mode beam is used to trap particles and array them in a one-dimension space (linear arrangement), the LP01 and LP11 mode beams are used to trap and array particles in a two-dimension space (planar arrangement), and the LP01, LP11, and LP21 mode beams are used to trap and array particles in a three-dimension space (solid arrangement). The proposed fiber optical tweezer is simple in structure and will allow us to examine the interaction between the cells when held in close proximity.

In this paper, we propose and demonstrate a photosensitive polymer-based micro-nano long-period fiber grating (PPMN-LPFG) for refractive index (RI) sensing. We coat liquid photosensitive polymer on the surface of micro-nano fiber (MNF) and obtain a series of periodically distributed droplets on the MNF due to the Plateau-Rayleigh instability (PRI) property. Then we cure the polymer droplets by using the 532 nm laser illumination. We configure the cladding modulated LPFG based on the periodic polymer points along the MNF. The PPMN-LPFG combines with a strong evanescent field of MNF and cladding modulated LPFG, and thus, it is much more sensitive to the external environment. The experimental results indicate that the spectral dip redshifts from 1404 nm to 1654 nm when the RI changes from 1.3391 to 1.4164. The maximum RI sensitivity is 10419 nm/RIU in the RI range of 1.4102–1.4164. The temperature sensitivity is 0.89 nm/°C in the temperature range of 17.1 °C–50.5 °C. Compared with the RI sensitivity, the temperature crosstalk is negligible. Our simulated and experimental results verify the feasibility of the proposed sensor and show the advantages such as high sensitivity, compact size, and good stability.

Lysophosphatidate (LPA) and sphingosine 1-phosphate (S1P) promote vasculogenesis, angiogenesis, and wound healing by activating a plethora of overlapping signaling pathways that stimulate mitogenesis, cell survival, and migration. As such, maladaptive signaling by LPA and S1P have major effects in increasing tumor progression and producing poor patient outcomes after chemotherapy and radiotherapy. Many signaling actions of S1P and LPA are not redundant; each are vital in normal physiology and their metabolisms differ. In the present work, we studied how LPA signaling impacts S1P metabolism and signaling in MDA-MB-231 and MCF-7 breast cancer cells. LPA increased sphingosine kinase-1 (SphK1) synthesis and rapidly activated cytosolic SphK1 through association with membranes. Blocking phospholipase D activity attenuated the LPA-induced activation of SphK1 and the synthesis of ABCC1 and ABCG2 transporters that secrete S1P from cells. This effect was magnified in doxorubicin-resistant MCF-7 cells. LPA also facilitated S1P signaling by increasing mRNA expression for S1P1 receptors. Doxorubicin-resistant MCF-7 cells had increased S1P2 and S1P3 receptor expression and show increased LPA-induced SphK1 activation, increased expression of ABCC1, ABCG2 and greater S1P secretion. Thus, LPA itself and LPA-induced S1P signaling counteract doxorubicin-induced death of MCF-7 cells. We conclude from the present and previous studies that LPA promotes S1P metabolism and signaling to coordinately increase tumor growth and metastasis and decrease the effectiveness of chemotherapy and radiotherapy for breast cancer treatment.

Three-dimensional (3D) cell culture technology is a powerful tool in cancer research and drug development. It retains several critical components of the in vivo environment, including cell-cell and cell-extracellular matrix (ECM) interactions in a 3D fashion, gradients of oxygen, nutrients and metabolic waste, and it is thus more physiologically relevant than traditional two-dimensional (2D) cell culture. Here, we describe a simple and versatile method using commercially available chamber slides and Matrigel, a surrogate ECM hydrogel, to set up a 3D culture model for breast cancer cells. In this 3D culture model, cells form aggregates or spheroids on top of a thin layer of Matrigel, which can be fixed directly onto the chamber slides for cell imaging and immunofluorescence staining. Alternatively, RNA and protein can be extracted from the cells for further investigation. This 3D cell culture model provides a useful platform for cancer research and drug development, in which the effects of novel compounds or genetic modifications can be tested.

A 32 μm large-size microparticle is trapped by an all-fiber hollow Bessel-like beam. In order to realize the proposed high-order Bessel-like beam, we fabricate the optical fiber probe by splicing an annular core fiber with a step-index multimode fiber. We grind the fiber tip into a truncated cone shape to converge the hollow Bessel-like beam to obtain a large focal area. Simulation and experimental results show that the trapping field introduced by the Bessel-like beam provides a relatively strong optical force and has the capability of 3-D capture of a large particle (whose diameter is 32 μm). These highly integrated fiber tweezers provide hollow Bessel-like beams with strong optical force and large trapping area, which can be promisingly applied in biomedical and integrated optical research.

Breast cancer cells produce negligible quantities of autotaxin. Instead, previous work indicated that adipocytes in the inflamed adipose tissue adjacent to breast tumors are a major source of autotaxin secretion that drives breast tumor growth, metastasis, and the loss of efficacy for chemotherapy and radiotherapy. To test this hypothesis, we used mice with an adipocyte-specific knock out of autotaxin. The lack of autotaxin secretion from adipocytes failed to decrease the growth of orthotopic E0771 breast tumors in syngeneic C57BL/6 mice and the growth and lung metastasis of spontaneous breast tumors in MMTV-PyMT mice. However, the inhibition of autotaxin with IOA-289 decreased the growth of E0771 tumors, indicating that another source of autotaxin is responsible for tumor growth. Tumor-associated fibroblasts and leukocytes produce the majority of autotoxin transcripts in the E0771 breast tumors, and we hypothesize that they are the main sources of ATX that drive breast tumor growth. Autotaxin inhibition with IOA-289 increased the numbers of CD8α+-T-cells in the tumors. This was accompanied by decreases in the concentrations of CXCL10, CCL2, and CXCL9 in the plasma and LIF, TGFβ1, TGFβ2, and prolactin in the tumors. Bioinformatics analysis of human breast tumor databases showed that autotaxin (ENPP2) is expressed mainly in endothelial cells and fibroblasts. Autotaxin expression correlated significantly with increases in IL-6 cytokine receptor ligand interactions, signaling by LIF, TGFβ, and prolactin. This confirms the relevance of results from autotaxin inhibition in the mouse model. We propose that inhibiting autotaxin activity that is derived from cells presenting breast tumors such as fibroblasts, leukocytes, or endothelial cells changes the tumor micro-environment in such a way as to inhibit tumor growth.

In this Letter, we show stable suspension and directional manipulation of microdroplets on a liquid surface employing simple-mode fiber with a Gaussian beam at 1480-nm wavelength using the photothermal effect. The intensity of the light field generated by the single-mode fiber is used to generate droplets of different numbers and sizes. In addition, the effect of the heat generated at different heights from the liquid surface is discussed through numerical simulation. In this work, the optical fiber is not only free to move at any angle, solving the difficulty that a certain working distance is needed to generate microdroplets on free space, it can also allow the continuous generation and directional manipulation of multiple microdroplets, which is of tremendous scientific relevance and application value in promoting the development and cross-fertilization of life sciences and other interdisciplinary fields.

We propose and demonstrate an all-fiber probe to generate an active tractor beam by changing the gradients of optical intensity distributions. We grind the tip of a seven-core fiber (SCF) into a truncated hexagonal pyramid shape to integrate three equivalent two-core fiber optical tweezers in an SCF. Three optical tweezers produce three trapping locations along the fiber main axis. By adjusting and controlling the incident laser power in each core, we may perform multiple functions, including microparticles optical trapping, long-distance attraction, bidirectional transportation, and axial-direction position controllable adjustment. The proposed all-fiber active tractor beam generator is convenient to integrate and low cost. The all-fiber probe has the compatibility of optical tweezers and optical tractor beams. The increased effective range of optical pull broadens the scope of feasible optical trapping and will pave the way towards more efficient light-powered miniature machines, tools, and applications.

Digital instruments are widely used in industrial control, traffic, equipment displays and other fields because of the intuitive characteristic of their test data. Aiming at the character recognition scene of digital display Vernier caliper, this paper creatively proposes an intelligent instrument recognition system based on multi-step convolution neural network (CNN). Firstly, the image smples are collected from the Vernier caliper test site, and their resolution and size are normalized. Then the CNN model was established to train the image smples and extract the features. The digital display region in the image smples were extracted according to the image features, and the numbers in the Vernier caliper were cut out. Finally, using the MINIST datas set of Vernier caliper is established, and the CNN model is used to recognize it. The test results show that the overall recognition rate of the proposed CNN model is more than 95%, and has good robustness and generalization ability.

Human cytomegalovirus (HCMV) infects 40–70% of adults in developed countries. HCMV proteins and DNA are detected in tumors and metastases, suggesting an association with increased invasion. We investigated HCMV infection in human breast cancer cell lines compared to fibroblasts, a component of tumors, and the role of platelet-derived growth factor receptor-α (PDGFRα). HCMV productively infected HEL299 fibroblasts and, to a lesser extent, Hs578T breast cancer cells. Infection of another triple-negative cell line, MDA-MB-231, and also MCF-7 cells, was extremely low. These disparate infection rates correlated with expression of PDGFRA, which facilitates HCMV uptake. Increasing PDGFRA expression in T-47D breast cancer and BCPAP thyroid cancer cells markedly increased HCMV infection. Conversely, HCMV infection decreased PDGFRA expression, potentially attenuating signaling through this receptor. HCMV infection of fibroblasts promoted the secretion of proinflammatory factors, whereas an overall decreased secretion of inflammatory factors was observed in infected Hs578T cells. We conclude that HCMV infection in tumors will preferentially target tumor-associated fibroblasts and breast cancer cells expressing PDGFRα. HCMV infection in the tumor microenvironment, rather than cancer cells, will increase the inflammatory milieu that could enhance metastasis involving lysophosphatidate.

LPP2 is one of three enzymes in the lipid phosphate phosphatase family (LPP1-3) that dephosphorylate extracellular and intracellular bioactive lipid phosphates and pyrophosphates. LPP2 increases cell growth and LPP2 expression is elevated in a variety of malignancies, implying that LPP2 is a pro-tumorigenic factor.

Summary LPIN1 mutations are responsible for inherited recurrent rhabdomyolysis, a life-threatening condition with no efficient therapeutic intervention. Here, we conduct a bedside-to-bench-and-back investigation to study the pathophysiology of lipin1 deficiency. We find that lipin1-deficient myoblasts exhibit a reduction in phosphatidylinositol-3-phosphate close to autophagosomes and late endosomes that prevents the recruitment of the GTPase Armus, locks Rab7 in the active state, inhibits vesicle clearance by fusion with lysosomes, and alters their positioning and function. Oxidized mitochondrial DNA accumulates in late endosomes, where it activates Toll-like receptor 9 (TLR9) and triggers inflammatory signaling and caspase-dependent myolysis. Hydroxychloroquine blocks TLR9 activation by mitochondrial DNA in vitro and may attenuate flares of rhabdomyolysis in 6 patients treated. We suggest a critical role for defective clearance of oxidized mitochondrial DNA that activates TLR9-restricted inflammation in lipin1-related rhabdomyolysis. Interventions blocking TLR9 activation or inflammation can improve patient care in vivo., Graphical abstract, Highlights Lipin1 deficiency causes mitophagosome and late endosome dysfunction in human myoblasts Damaged mitochondria trigger TLR9-mediated inflammation and myoblast death Mitochondrial DNA elimination or blockade of TLR9 activation prevent myoblast death Hydroxychloroquine sulfate treatment may prevent rhabdomyolysis episodes in patients, Hamel et al. investigate the mechanism underlying life-threatening rhabdomyolysis in human lipin1 deficiency. They find that endosomal accumulation of mitochondrial DNA in myoblasts induces inflammation and cell death mediated by TLR9 activation in vitro. Treatment of 6 patients with hydroxychloroquine sulfate suggests benefits in preventing rhabdomyolysis episodes.

We propose and demonstrate an optical trap on the basis of a normal single-mode fiber (SMF), which is used to trap two particles in the axial direction at the same time without contact based on mode division multiplexing technology. We design and manufacture a tapered fiber probe. The L P 11 mode beam is excited by docking a normal SMF to a 980 nm SMF with a 2 µm offset. Then the beams of L P 01 and L P 11 are both transmitted in the fiber. To converge the L P 11 mode beam, a SMF with a tapered end is used to produce a cage for trapping the first microparticle. This particle acts as a lens to converge the L P 01 mode beam to trap the second microparticle. We verify the feasibility of trapping two particles simultaneously through simulation. With this function, the proposed optical trap is easier to manipulate different individual particles for comparison and testing, which can promote the development of the biological, biophysical, colloidal, and soft matter fields.

Metastasis is the leading cause of mortality in breast cancer patients and lysophosphatidate (LPA) signaling promotes this process. LPA signaling is attenuated by lipid phosphate phosphatase-1 (LPP1) whose activity is decreased in cancers. Consequently, increasing LPP1 levels suppresses breast tumor growth and metastasis. This study shows that increasing LPP1 in breast cancer cells decreases transcription through cFos and cJun. This decreases production of cyclin D1/D3 and matrix metalloproteinases (MMPs), which provides new insights into the role of LPP1 in controlling tumor growth and metastasis. Methods: Invasiveness was determined by a Matrigel invasion assay. MMP expression was measured by qPCR, multiplex LASER bead technology and gelatin zymography. Levels of cJUN, cFOS, FRA1, cyclin D1, and cyclin D3 were determined by qPCR and western blotting. Collagen was determined by Picro-Sirius Red staining. Results: Increasing LPP1 expression inhibited invasion of MDA-MB-231 breast cancer cells through Matrigel. This was accompanied by decreases in expression of MMP-1, -3, -7, -9, -10, -12 and -13, which are transcriptionally regulated by the AP-1 complex. Increasing LPP1 attenuated the induction of mRNA of MMP-1, -3, cFOS, and cJUN by EGF or TNFα, but increased FRA1. LPP1 expression also decreased the induction of protein levels for cFOS and cJUN in nuclei and cytoplasmic fractions by EGF and TNFα. Protein levels of cyclin D1 and D3 were also decreased by LPP1. Although FRA1 in total cell lysates or cytoplasm was increased by LPP1, nuclear FRA1 was not affected. LPP1-induced decreases in MMPs in mouse tumors created with MDA-MB-231 cells were accompanied by increased collagen in the tumors and fewer lung metastases. Knockdown of LPP1 in MDA-MB-231 cells increased the protein levels of MMP-1 and -3. Human breast tumors also have lower levels of LPP1 and higher levels of cJUN, cFOS, MMP-1, -7, -8, -9, -12, -13, cyclin D1, and cyclin D3 relative to normal breast tissue. Conclusion: This study demonstrated that the low LPP1 expression in breast cancer cells is associated with high levels of cyclin D1/D3 and MMPs as a result of increased transcription by cFOS and cJUN. Increasing LPP1 expression provides a novel approach for decreasing transcription through AP-1, which could provide a strategy for decreasing tumor growth and metastasis.

We propose and experimentally demonstrate the simultaneous trapping of a high-refractive-index particle and a low-refractive-index particle by using a single fiber optical Bessel beam. The experimental and simulated results verify the stable trapping.

We achieve the particle size measurement based on a fiber-tweezer-based dual-beam interference approach. We may obtain the particle size information from the FSR of the interference spectrum. Our method is non-contact, real-time and label-free.

To maintain sustainable economic growth, China has created a national innovation system (NIS) and strengthened the central status of firms. Our data show that the effect of turnover growth in small and medium-sized enterprises (SMEs) on China&rsquo, s aggregate Gross Domestic Product (GDP)growth is significant, but the status of SMEs in the NIS and related policies is not significant. To determine whether there is a correspondence between the sustainability of innovation in SMEs and the support of China&rsquo, s NIS, we developed a framework for China&rsquo, s innovation policy under the NIS framework, taking into account its transition characteristics, to examine the texts of SME innovation policies and reveal the sustainability of SMEs&rsquo, innovation. The relevant national government policy texts were collected from the yearbooks of Chinese SMEs between 1999 and 2017 and government notices between 1994 and 2017. On this basis, we also compared with some other countries&rsquo, innovation systems. The findings indicate that China&rsquo, s NIS pays little attention to the sustainability of SMEs&rsquo, innovation activities for two reasons. First, the scope of the NIS is very narrowly defined. Second, the top-down, government-oriented Research and Development (R&amp, D) system that focuses on large state-owned firms leaves little room for innovation policies in SMEs.

Autotaxin (ATX) is a secreted enzyme that hydrolyzes lysophosphatidylcholine to produce lysophosphatidate (LPA), which signals through six G-protein coupled receptors (GPCRs). Signaling through LPA is terminated by its degradation by a family of three lipid phosphate phosphatases (LPPs). LPP1 also attenuates signaling downstream of the activation of LPA receptors and some other GPCRs. The ATX-LPA axis mediates a plethora of activities such as cell proliferation, survival, migration, angiogenesis and inflammation, which perform an important role in facilitating wound healing. This wound healing response is hijacked by cancers where there is decreased expression of LPP1 and LPP3 and increased expression of ATX. This maladaptive regulation of LPA signaling also causes chronic inflammation, which has been recognized as one of the hallmarks in cancer. The increased LPA signaling promotes cell survival and migration and attenuates apoptosis, which stimulates tumor growth and metastasis. The wound healing functions of increased LPA signaling also protect cancer cells from effects of chemotherapy and radiotherapy. In this review, we will summarize knowledge of the ATX-LPA axis and its role in the development of resistance to chemotherapy and radiotherapy. We will also offer insights for developing strategies of targeting ATX-LPA axis as a novel part of cancer treatment. This article is part of a Special Issue entitled Lysophospholipids and their receptors: New data and new insights into their function edited by Susan Smyth, Viswanathan Natarajan and Colleen McMullen.

After a decade of intense preclinical investigations, the first in-class autotaxin inhibitor, GLPG1690, has entered Phase III clinical trials for idiopathic pulmonary fibrosis. In the intervening time, a deeper understanding of the role of the autotaxin–lysophosphatidate (LPA)–lipid phosphate phosphatase axis in breast cancer progression and treatment resistance has emerged. Concordantly, appreciation of the tumor microenvironment and chronic inflammation in cancer biology has matured. The role of LPA as a central mediator behind these concepts has been exemplified within the breast cancer field. In this review, we will summarize current challenges in breast cancer therapy and delineate how blocking LPA signaling could provide novel adjuvant therapeutic options for overcoming therapy resistance and adverse side effects, including radiation-induced fibrosis. The advent of autotaxin inhibitors in clinical practice could herald their applications as adjuvant therapies to improve the therapeutic indexes of existing treatments for breast and other cancers.

Human cytomegalovirus (HCMV) infects 40–70% of adults in developed countries. Detection of HCMV DNA and/or proteins in breast tumors varies considerably, ranging from 0–100%. In this study, nested PCR to detect HCMV glycoprotein B (gB) DNA in breast tumors was shown to be sensitive and specific in contrast to the detection of DNA for immediate early genes. HCMV gB DNA was detected in 18.4% of 136 breast tumors while 62.8% of 94 breast cancer patients were seropositive for HCMV. mRNA for the HCMV immediate early gene was not detected in any sample, suggesting viral latency in breast tumors. HCMV seropositivity was positively correlated with age, body mass index and menopause. Patients who were HCMV seropositive or had HCMV DNA in their tumors were 5.61 (CI 1.77–15.67, p = 0.003) or 5.27 (CI 1.09–28.75, p = 0.039) times more likely to develop Stage IV metastatic tumors, respectively. Patients with HCMV DNA in tumors experienced reduced relapse-free survival (p = 0.042). Being both seropositive with HCMV DNA-positive tumors was associated with vascular involvement and metastasis. We conclude that determining the seropositivity for HCMV and detection of HCMV gB DNA in the breast tumors could identify breast cancer patients more likely to develop metastatic cancer and warrant special treatment.

In this paper, Nd3+/Yb3+ codoped SrWO4 phosphors for temperature sensing are investigated. Firstly, the doping ratio of Nd3+ and Yb3+ was optimized. Then, under a 980 nm excitation, the temperature response of the near infrared (NIR) upconversion emission spectra in the temperature range of 313 K–453 K was characterized. The results show that the NIR emission peaks increase notably with the increase of temperature. With the fluorescence intensity ratio (FIR) technique, thermal sensing property of the optimized phosphor was investigated. A maximum thermal sensitivity of 0.02857 K−1 (I801/I869) at 453 K was achieved, which is higher than that of the other previously reported similar materials. The minimum temperature uncertainty is about 1 K at 453 K. The results reveal that SrWO4: Nd3+/Yb3+ is a promising material for optical thermometry.

Lysophosphatidate (LPA) signaling through 6 receptors is regulated by the balance of LPA production by autotaxin (ATX) vs. LPA degradation by lipid phosphate phosphatases (LPPs). LPA promotes an inflammatory cycle by increasing the synthesis of cyclooxygenase-2 and multiple inflammatory cytokines that stimulate further ATX production. We aimed to determine whether the anti-inflammatory glucocorticoid (GC) dexamethasone (Dex) functions partly by decreasing the ATX-LPA inflammatory cycle in adipose tissue, a major site of ATX secretion. Treatment of human adipose tissue with 10-1000 nM Dex decreased ATX secretion, increased LPP1 expression, and decreased mRNA expressions of IL-6, TNF-α, peroxisome proliferator-activated receptor (PPAR)-γ, and adiponectin. Cotreatment with rosiglitazone (an insulin sensitizer), insulin, or both abolished Dex-induced decreases in ATX and adiponectin secretion, but did not reverse Dex-induced decreases in secretions of 20 inflammatory cytokines and chemokines. Dex-treated mice exhibited lower ATX activity in plasma, brain, and adipose tissue; decreased mRNA levels for LPA and sphingosine 1-phosphate (S1P) receptors in brain; and decreased plasma concentrations of LPA and S1P. Our results establish a novel mechanism for the anti-inflammatory effects of Dex through decreased signaling by the ATX-LPA-inflammatory axis. The GC action in adipose tissue has implications for the pathogenesis of insulin resistance and obesity in metabolic syndrome and breast cancer treatment.-Meng, G., Tang, X., Yang, Z., Zhao, Y., Curtis, J. M., McMullen, T. P. W., Brindley, D. N. Dexamethasone decreases the autotaxin-lysophosphatidate-inflammatory axis in adipose tissue: implications for the metabolic syndrome and breast cancer.

In this essay, we study the sufficient and necessary conditions for a Randers metric F = α + β (α is a Riemann metric, β is a 1-form) to be of constant Ricci curvature, without the restriction of strong convexity (regularity). A classification result for the case ‖ β ‖ α > 1 is provided, which is similar to the famous Bao–Robles–Shen's result for strongly convex Randers metrics ( ‖ β ‖ α 1 ). Based on some famous vacuum Einstein metrics in General Relativity, many non-regular Einstein–Randers metrics are constructed. Besides, we find that the case ‖ β ‖ α ≡ 1 is very distinctive. These metrics will be called singular Randers metrics or parabolic Finsler metrics since their indicatrixs are parabolic hypersurfaces. A preliminary discussion for such metrics is provided.

Sm3+ doped SrWO4 was synthesized by the high temperature solid-state reaction method to explore its possible application in optical thermometry. Under a 404 nm excitation, the fluorescence intensity ratios (FIRs) between the down conversion emissions of the Sm3+:4G5/2 → 6H5/2 (564 nm) to the Sm3+:4G5/2 → 6H7/2 (600 nm) and Sm3+:4G5/2 → 6H9/2 (647 nm), respectively, were measured as a function of temperature in the range of 300–573 K. A maximum temperature sensitivity of 0.016 K−1 at 300 K is achieved. The results indicate that the SrWO4:Sm3+ is a promising candidate for optical thermometry.

In this paper, Tm3+/Yb3+ codoped SrWO4 materials for optical thermometry is synthetized and characterized. Under a 980 nm diode laser excitation, the upconversion emission spectra of the material under different temperature were measured in the temperature range of 308 K–573 K. The fluorescence intensity ratios (FIRs) of the Tm3+:3F2 → 3H6 (684 nm) and Tm3+:3F3 → 3H6 (696 nm) emissions to the Tm3+:3H4 → 3H6 (814 nm) emission were respectively calculated. The results show that the natural logarithm of both FIRs change linearly with the reciprocal of temperature. The maximum absolute sensitivities are 0.00544 K−1 and 0.00617 K−1 at 323 K, respectively, which are about one order higher than that of most of the previously reported Tm3+/Yb3+ doped materials with other hosts. The results indicate that SrWO4:Tm3+/Yb3+ is a very promising material for highly sensitive optical thermometry.