Autotaxin and Lysophosphatidate Signaling: Prime Targets for Mitigating Therapy Resistance in Breast Cancer.

Overcoming and preventing cancer therapy resistance is the most pressing challenge in modern breast cancer management. Consequently, most modern breast cancer research is aimed at understanding and blocking these therapy resistance mechanisms. One increasingly promising therapeutic target is the autotaxin (ATX)-lysophosphatidate (LPA)-lipid phosphate phosphatase (LPP) axis. Extracellular LPA, produced from albumin-bound lysophosphatidylcholine by ATX and degraded by the ecto-activity of the LPPs, is a potent cell-signaling mediator of tumor growth, invasion, angiogenesis, immune evasion, and resistance to cancer treatment modalities. LPA signaling in the post-natal organism has central roles in physiological wound healing, but these mechanisms are subverted to fuel pathogenesis in diseases that arise from chronic inflammatory processes, including cancer. Over the last 10 years, our understanding of the role of LPA signaling in the breast tumor microenvironment has begun to mature. Tumor-promoting inflammation in breast cancer leads to increased ATX production within the tumor microenvironment. This results in increased local concentrations of LPA that are maintained in part by decreased overall cancer cell LPP expression that would otherwise more rapidly break it down. LPA signaling through six G-protein-coupled LPA receptors expressed by cancer cells can then activate virtually every known tumorigenic pathway. Consequently, to target therapy resistance and tumor growth mediated by LPA signaling, multiple inhibitors against the LPA signaling axis are entering clinical trials. In this review, we summarize recent developments in LPA breast cancer biology, and illustrate how these novel therapeutics against the LPA signaling pathway may be excellent adjuncts to extend the efficacy of evolving breast cancer treatments.

TNF-α induced NF-κB mediated LYRM7 expression modulates the tumor growth and metastatic ability in breast cancer.

Tumor microenvironment (TME) of solid tumors including breast cancer is complex and contains a distinct cytokine pattern including TNF-α, which determines the progression and metastasis of breast tumors. The metastatic potential of triple negative breast cancer subtypes is high as compared to other subtypes of breast cancer. NF-κB is key transcription factor regulating inflammation and mitochondrial bioenergetics including oxidative phosphorylation (OXPHOS) genes which determine its oxidative capacity and generating reducing equivalents for synthesis of key metabolites for proliferating breast cancer cells. The differential metabolic adaptation and OXPHOS function of breast cancer subtypes in inflammatory conditions and its contribution to metastasis is not well understood. Here we demonstrated that different subunits of NF-κB are differentially expressed in subtypes of breast cancer patients. RELA, one of the major subunits in regulation of the NF-κB pathway is positively correlated with high level of TNF-α in breast cancer patients. TNF-α induced NF-κB regulates the expression of LYRM7, an assembly factor for mitochondrial complex III. Downregulation of LYRM7 in MDA-MB-231 cells decreases mitochondrial super complex assembly and enhances ROS levels, which increases the invasion and migration potential of these cells. Further, in vivo studies using Infliximab, a monoclonal antibody against TNF-α showed decreased expression of LYRM7 in tumor tissue. Large scale breast cancer databases and human patient samples revealed that LYRM7 levels decreased in triple negative breast cancer patients compared to other subtypes and is determinant of survival outcome in patients. Our results indicate that TNF-α induced NF-κB is a critical regulator of LYRM7, a major factor for modulating mitochondrial functions under inflammatory conditions, which determines growth and survival of breast cancer cells.

Water-durability and high-performance all-fiber humidity sensor using methyldiethanolamine-photopolymer-PDMS structure.

In the context of optical fiber humidity sensing, the long-term stability of sensors in high humidity and dew environments such as bathrooms or marine climates remains a challenge, especially since many humidity sensitive materials are water soluble. In this study, we use methyldiethanolamine, pentaerythritol triacrylate and Eosin Y to form a liquid-solid structure humidity sensitive component, the outermost layer is coated with PDMS passivating layer to ensure the stability and durability of the humidity sensor under the conditions of dew and high humidity. The liquid microcavity of the sensor consists of methyldiethanolamine-pentaerythritol triacrylate composite solution, and the sensitivity is several times higher than that of the liquid-free cavity sensor. The sensitivity of the sensor to temperature is verified (0.43 nm/°C and 0.30 nm/°C, respectively) and temperature crosstalk is compensated using a matrix. The compact structure allows for ultra-fast response (602 ms) and recovery time (349 ms). Our work provides a promising platform for efficient and practical humidity and other gas monitoring systems.

Simultaneous Measurement of Microdisplacement and Temperature Based on Balloon-Shaped Structure.

An optical fiber sensor for the simultaneous measurement of microdisplacement and temperature based on balloon-shaped single-mode fibers cascaded with a fiber Bragg grating with two core-offset joints is proposed. The interference between the core mode and cladding mode is caused by the stimulation of the cladding mode by the core-offset joints' structure. The cladding of the core has a distinct refractive index, which causes optical path differences and interference. The balloon-shaped structure realizes mode selection by bending. As the displacement increases, the radius of the balloon-shaped interferometer changes, resulting in a change in the interference fringes of the interferometer, while the Bragg wavelength of the fiber grating remains unchanged. Temperature changes will cause the interference fringes of the interferometer and the Bragg wavelength of the fiber grating to shift. The proposed optical fiber sensor allows for the simultaneous measurement of microdisplacement and temperature. The results of the experiment indicate that the sensitivity of the interferometer to microdisplacement is 0.306 nm/µm in the sensing range of 0 to 200 µm and that the temperature sensitivity is 0.165 nm/°C, respectively. The proposed curvature sensor has the advantages of a compact structure, extensive spectrum of dynamic measurement, high sensitivity, and simple preparation, and has a wide range of potential applications in the fields of structural safety monitoring, aviation industry, and resource exploration.

Balloon-like optical fiber sensor for simultaneous displacement and temperature measurement based on an anti-resonance mechanism.

We propose and experimentally demonstrate a balloon-like optical fiber sensor with an anti-resonance mechanism for the simultaneous measurement of displacement and temperature. The sensor consists of a hollow-core fiber spliced between two single-mode fibers and bent into a balloon-like shape. The balloon-like structure not only increases the contrast of the spectral lines but also improves the displacement sensitivity. Theoretical and experimental results show that the incidence angle of light varies with the change in displacement, resulting in the variation of spectral intensity based on the anti-resonance mechanism. In addition, the temperature change causes the wavelength drift of the spectrum. Thus, by separately demodulating the intensity and wavelength of this sensor, it is possible to measure displacement and temperature simultaneously. The sensitivity of the displacement and temperature of the sensor is 0.043 dB/µm and 20.94 pm/°C, respectively. The proposed optical fiber sensor has a compact structure and simple preparation, making it an ideal choice for simultaneous measurement of displacement and temperature in the fields of micro-manufacturing and structural monitoring in the future.

Heterojunction photocatalyst FeS2/g-C3N5 for activating sulfites to degrade tetracycline: A stable degradation system based on heterogeneous processes.

The UV/sulfite system is a promising source of •SO4- and/or •OH, but its application is largely limited by the use of UV light due to its high cost and high energy consumption. Graphite carbon nitride (g-C3N5), as a new photocatalytic material, has better visible light absorption capacity and narrower band gap than g-C3N4, which is expected to activate sulfite under visible light to solve this problem. Herein, a novel FeS2/CN heterojunction material based on g-C3N5 was constructed by hydrothermal in-situ synthesis method and successfully activated sulfite, which was confirmed by tetracycline degradation experiments in water. Under optimized conditions, the degradation rate of TC in 1 h reached 96%. The experimental results revealed that the FeS2/CN heterostructure enhances the absorption of visible light and inhibits the recombination of carriers, enabling more electrons and holes to be utilized. Holes play a major role in the degradation reaction, promote the sulfite chain reaction, and effectively regulate the cycle of Fe2+ and Fe3+ in the solution. Iron ion leaching is negligible and the degradation reaction remains stable at pH 5-9.

Autotaxin production in the human breast cancer tumor microenvironment mitigates tumor progression in early breast cancers.

Autotaxin (ATX) is a secreted enzyme that produces extracellular lysophosphatidate in physiological wound healing. ATX is overexpressed in many cancers to promote growth, metastasis, and treatment resistance. However, ATX expression is very low in breast cancer cells, and is instead secreted by the tumor microenvironment (TME). Paracrine ATX expression, and its effects on tumor progression, has not been robustly studied in human breast tumors. In this study, ATX expression was analyzed in over 5000 non-metastatic breast cancers from databases TCGA, METABRIC and GSE96058, dichotomized by the median. Gene set enrichment analysis (GSEA) and the xCell algorithm investigated biological functions of ATX and correlation to TME cell populations. TME ATX production was verified by single cell RNA sequencing. The highest ATX expression occurred in endothelial cells and cancer-associated fibroblasts (P<0.0001). High tumor ATX expression correlated to increased adipocyte, fibroblast, and endothelial cell fractions (P<0.01), and GSEA demonstrated enriched immune system, tumor suppressor, pro-survival, stemness, and pro-inflammatory signaling in multiple gene sets. Tumor mutational burden was decreased, Ki67 scores were decreased, tumor infiltrating immune cell populations increased, and immune cytolytic activity scores increased (all P<0.01) for ATX-high tumors. Overall survival trends favored ATX-high tumors (hazard ratios 0.75-0.80). In summary, in human breast cancers, ATX is produced by the TME, and in non-metastatic tumors, high levels correlate with an anti-tumor phenotype. Because pre-clinical models use aggressive pro-metastatic cell lines where ATX-mediated signaling promotes tumorigenesis, further research is required to verify an anti-to-pro-tumor phenotype switch with breast cancer progression and/or treatment resistance.

Autotaxin Inhibition with IOA-289 Decreases Breast Tumor Growth in Mice Whereas Knockout of Autotaxin in Adipocytes Does Not.

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, TGFß1, TGFß2, 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, TGFß, 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.

Lysophosphatidic Acid Receptor Signaling in the Human Breast Cancer Tumor Microenvironment Elicits Receptor-Dependent Effects on Tumor Progression.

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.

Decreased Lipid Phosphate Phosphatase 1/3 and Increased Lipid Phosphate Phosphatase 2 Expression in the Human Breast Cancer Tumor Microenvironment Promotes Tumor Progression and Immune System Evasion.

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.

Light-induced microdroplet suspension and directional self-driving.

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.

Infliximab, a Monoclonal Antibody against TNF-α, Inhibits NF-κB Activation, Autotaxin Expression and Breast Cancer Metastasis to Lungs.

An inflammatory milieu in the tumor microenvironment leads to immune evasion, resistance to cell death, metastasis and poor prognosis in breast cancer patients. TNF-α is a proinflammatory cytokine that regulates multiple aspects of tumor biology from initiation to progression. TNF-α-induced NF-κB activation initiates inflammatory pathways, which determine cell survival, death and tumor progression. One candidate pathway involves the increased secretion of autotaxin, which produces lysophosphatidate that signals through six G-protein-coupled receptors. Significantly, autotaxin is one of the 40-50 most upregulated genes in metastatic tumors. In this study, we investigated the effects of TNF-α by blocking its action with a monoclonal antibody, Infliximab, and studied the effects on autotaxin secretion and tumor progression. Infliximab had little effect on tumor growth, but it decreased lung metastasis by 60% in a syngeneic BALB/c mouse model using 4T1 breast cancer cells. Infliximab-treated mice also showed a decrease in proliferation and metastatic markers like Ki-67 and vimentin in tumors. This was accompanied by decreases in NF-κB activation, autotaxin expression and the concentrations of plasma and tumor cytokines/chemokines which are involved in metastasis. We also demonstrated a positive correlation of TNF-α -NF-κB and ATX expression in breast cancer patients using cancer databases. Studies in vitro showed that TNF-α-induced NF-κB activation increases autotaxin expression and the clone forming ability of 4T1 breast cancer cells. This report highlights the potential role of Infliximab as an additional approach to attenuate signaling through the autotaxin-lysophosphatidate-inflammatory cycle and decrease mortality from metastatic cancer.

Lipid phosphate phosphatase-2 promotes tumor growth through increased c-Myc expression.

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. Methods: LPP2 expression in human breast tumors and normal breast tissue was measured by qPCR. To understand the role of LPP2, we knocked out its expression in multiple cell lines using CRISPR/Cas9. Cell proliferation and migration were compared between wild type and LPP2 knockout cells. Cell cycle was measured by flow cytometry, and cell cycle proteins were determined by western blotting. Effects of LPP2 on tumor growth were investigated using syngeneic and xenograft mouse breast cancer models. Results: LPP2 mRNA levels were higher in ER/PR positive, ER/HER2 positive, and triple negative human breast tumors, relative to normal breast tissue. Higher levels of LPP2 in breast tumors, hepatocellular carcinoma, pancreatic adenocarcinoma, and melanomas were prognostic of poorer survival. LPP2 mRNA expression is also increased in Hs-578T, MDA-MB-231, MCF7 and MDA-MB-468 breast cancer cell lines, relative to non-malignant Hs-578Bst, MCF10A and MCF-12A cells. LPP2 knockout in breast cancer cells decreased cell growth by inhibiting G1/S transition, whereas, increasing LPP2 levels in Hs-578Bst and MCF10A cells promoted proliferation. The effects of LPP2 on cell cycle were associated with changes in cyclin A2, cyclin B1, and cell cycle inhibitors, p27 or p21. The level of c-Myc was downregulated by knocking out LPP2, and it was partly restored by re-expressing LPP2. The positive correlation between the expression of LPP2 and c-Myc exists in multiple cancer cell lines including breast, lung, upper aerodigestive tract and urinary tract cancer. LPP2 knockout in MDA-MB-231 or 4T1 cells suppressed tumor formation in mouse breast cancer models, and decreased the in vivo expression of Ki67 and c-Myc of the cancer cells. Conclusion: Targeting LPP2 could provide a new strategy for decreasing c-Myc expression and tumor growth.

Analysis of Cell Proliferation by Three-Dimensional Culture.

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.

Human Cytomegalovirus Seropositivity and Viral DNA in Breast Tumors Are Associated with Poor Patient Prognosis.

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.

PDGFRα Enhanced Infection of Breast Cancer Cells with Human Cytomegalovirus but Infection of Fibroblasts Increased Prometastatic Inflammation Involving Lysophosphatidate Signaling.

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.

Compromised mitochondrial quality control triggers lipin1-related rhabdomyolysis.

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.

Lysophosphatidate Promotes Sphingosine 1-Phosphate Metabolism and Signaling: Implications for Breast Cancer and Doxorubicin Resistance.

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.

Mode division multiplexing for multiple particles noncontact simultaneous trap.

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 LP11 mode beam is excited by docking a normal SMF to a 980 nm SMF with a 2 µm offset. Then the beams of LP01 and LP11 are both transmitted in the fiber. To converge the LP11 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 LP01 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.

Esophageal squamous cell cancer coincides with myelodysplastic syndrome/acute myelogenous leukemia: A case report and review of the literature.

Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors, and has high incidence and mortality rates, worldwide. Myelodysplastic syndrome (MDS), a disorder of hematopoietic stem or progenitor cells, results in marrow failure, which increases the risk of acute myeloid leukemia (AML). Few studies had reported patients who have suffered from both ESCC and MDS/AML simultaneously. To identify possible potential associations between ESCC and MDS/AML, the present case report describes a patient with both types of these tumors at the same time. Following endoscopic biopsy, the patient was revealed to have moderately differentiated SCC. MDS with excess blasts was subsequently diagnosed following bone marrow aspiration. The results of next-generation sequencing revealed that TP53 and ROS1 were both found in ESCC and MDS/AML tumors. The patient refused therapeutic intervention and died within 20 days. The current report demonstrated that hematologic malignancies presenting alongside solid tumors should be considered clinically. In addition, the report indicated that bone marrow puncture should be performed in patients with solid tumors and abnormal blood test results. Next-generation sequencing may be a useful technique for the investigation of patients with two or more neoplasms. However, more research regarding the co-existence of solid tumors with hematological malignancy are required.