Comprehensive analysis on clinical significance and therapeutic targets of LDL receptor related protein 11 (LRP11) in liver hepatocellular carcinoma.

LDL lipoprotein receptor-related protein 11 (LRP11) plays a role in several tumors. However, their roles in hepatocellular carcinoma remain unclear. The present study aimed to explore the expression profile and prognostic value of LRP11 in liver hepatocellular carcinoma (LIHC) patients using various cancer databases and bioinformatic tools. In bioinformatics analysis, The Cancer Genome Atlas datasets showed increased LRP11 expression in tumor tissues compared to that in non-tumor tissues in various cancers. Moreover, patients with high expression LRP11 correlated with poor prognosis and clinical features. The LRP11 expression positively correlated with the infiltration of immune cells such as macrophages, neutrophils, and myeloid-derived suppressor cells and a combination of high LRP11 expression and high immune infiltrates was associated with the worst survival in LIHC tumors. Our results also indicated that LRP11 expression was closely associated with immune-modulate function, such as antigen presentation. In DNA methylation profiling, hypomethylation of LRP11 is widely observed in tumors and has prognostic value in LIHC patients. Functional enrichment analysis revealed that LIHC-specific LRP11 interacting genes are involved in protein binding, intracellular processing, and G-protein-related signaling pathways. Analyses of drug sensitivity and immune checkpoint inhibitor predict a number of drugs that could potentially be used to target LRP11. In addition, in vitro experiments verified the promoting effect of LRP11 on the migration, invasion, and colony formation capacity of hepatocellular carcinoma cells. Collectively, our results aided a better understanding of the clinical significance of LRP11 in gene expression, functional interactions, and epigenetic regulation in LIHC and suggested that it may be a useful prognostic biomarker for LIHC patients.

SAMD13 serves as a useful prognostic biomarker for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common form of liver cancer and the 5-year relative overall survival (OS) rate is less than 20%. Since there are no specific symptoms, most patients with HCC are diagnosed in an advanced stage with poor prognosis. Therefore, identifying novel prognostic biomarkers to improve the survival of patients with HCC is urgently needed. In the present study, we attempted to identify SAMD13 (Sterile Alpha Motif Domain-Containing Protein 13) as a novel biomarker associated with the prognosis of HCC using various bioinformatics tools. SAMD13 was found to be highly expressed pan-cancer; however, the SAMD13 expression was significantly correlated with the worst prognosis in HCC. Clinicopathological analysis revealed that SAMD13 upregulation was significantly associated with advanced HCC stage and high-grade tumor type. Simultaneously, high SAMD13 expression resulted in association with various immune markers in the immune cell subsets by TIMER databases and efficacy of immunotherapy. Methylation analysis showed SAMD13 was remarkably associated with prognosis. Furthermore, a six-hub gene signature associated with poor prognosis was correlated with the cell cycle, transcription, and epigenetic regulation and this analysis may support the connection between SAMD13 expression and drug-resistance. Our study illustrated the characteristics of SAMD13 role in patients with HCC using various bioinformatics tools and highlights its potential role as a therapeutic target and promising biomarker for prognosis in HCC.

Overcoming adaptive resistance to anti-VEGF therapy by targeting CD5L.

Antiangiogenic treatment targeting the vascular endothelial growth factor (VEGF) pathway is a powerful tool to combat tumor growth and progression; however, drug resistance frequently emerges. We identify CD5L (CD5 antigen-like precursor) as an important gene upregulated in response to antiangiogenic therapy leading to the emergence of adaptive resistance. By using both an RNA-aptamer and a monoclonal antibody targeting CD5L, we are able to abate the pro-angiogenic effects of CD5L overexpression in both in vitro and in vivo settings. In addition, we find that increased expression of vascular CD5L in cancer patients is associated with bevacizumab resistance and worse overall survival. These findings implicate CD5L as an important factor in adaptive resistance to antiangiogenic therapy and suggest that modalities to target CD5L have potentially important clinical utility.

Effects of the abdominal drawing-in maneuver on hamstring rotational activity and pelvic stability in females.

BACKGROUND: The medial hamstring (MH) and lateral hamstring (LH) can be selectively trained through tibial internal and external rotation during prone knee flexion. However, no study has identified how a combined tibial rotation and lumbo-pelvic stability strategy influences MH and LH muscle activities. OBJECTIVE: To investigate the combined effects of tibial rotation and the abdominal drawing-in maneuver (ADIM) on MH and LH muscle activities as well as pelvic rotation during prone knee flexion. METHODS: Fifteen female volunteers performed prone knee flexion with tibial internal and external rotation, with and without the ADIM. Under each condition, MH and LH muscle activities were measured by surface electromyography (EMG), and the pelvic rotation angle by a smartphone inclinometer application. RESULTS: The results showed increased MH (without the ADIM: p< 0.001, effect size (d) = 2.05; with the ADIM: p< 0.001, d= 1.71) and LH (without the ADIM: p< 0.001, d= 1.64; with the ADIM: p= 0.001, d= 1.58) muscle activities under internal and external tibial rotation, respectively. However, addition of the ADIM led to increased MH (internal tibial rotation: p= 0.001, d= 0.67; external tibial rotation: p= 0.019, d= 0.45) and LH (internal tibial rotation: p= 0.003, d= 0.79; external tibial rotation: p< 0.001, d= 1.05) muscle activities combined with reduced pelvic rotation (internal tibial rotation: p< 0.001, d= 3.45; external tibial rotation: p< 0.001, d= 3.01) during prone knee flexion. CONCLUSIONS: These findings suggest that the ADIM could be useful for reducing compensatory pelvic rotation and enhancing selective muscle activation in the MH and LH, according to the direction of tibial rotation, during prone knee flexion.

Differences in Function and Healthcare Cost of Older Adults with Dementia by Long-Term Care Service Type: A National Dataset Analysis.

This study aims to analyze the function and cost changes among long-term care insurance (LTCI) beneficiaries with low-severity dementia according to their LTCI service type. Data were collected from the Korean LTCI and national health insurance (NHI) datasets. Participants were 4414 beneficiaries with dementia aged 65 or older who received LTC services continuously for 4 years (2008-2011). LTCI service types were classified into home care (HC), institutional care (IC), and combined care (CC). Activities of daily living (ADL), cognitive function, medical cost, and benefit-cost were assessed. Linear mixed models and multiple regression models were used to analyze the changes in function and costs of the beneficiaries. ADL, cognitive function, medical cost, and benefit-cost differed significantly depending on the service type and time (p < 0.001). LTCI service types affected the degree of changes in ADL, cognitive function, medical cost, and benefit-cost over four years and showed negative changes in IC and CC beneficiaries than HC beneficiaries. HC is a cost-effective way to maintain the function of beneficiaries with low-severity dementia. Thus, efforts are needed to actively promote HC services.

The hidden role of paxillin: localization to nucleus promotes tumor angiogenesis.

Paxillin (PXN), a key component of the focal adhesion complex, has been associated with cancer progression, but the underlying mechanisms are poorly understood. The purpose of this study was to elucidate mechanisms by which PXN affects cancer growth and progression, which we addressed using cancer patient data, cell lines, and orthotopic mouse models. We demonstrated a previously unrecognized mechanism whereby nuclear PXN enhances angiogenesis by transcriptionally regulating SRC expression. SRC, in turn, increases PLAT expression through NF-ĸB activation; PLAT promotes angiogenesis via LRP1 in endothelial cells. PXN silencing in ovarian cancer mouse models reduced angiogenesis, tumor growth, and metastasis. These findings provide a new understanding of the role of PXN in regulating tumor angiogenesis and growth.

PRKRA/PACT Expression Promotes Chemoresistance of Mucinous Ovarian Cancer.

For mucinous ovarian cancer (MOC), standard platinum-based therapy is largely ineffective. We sought to identify possible mechanisms of oxaliplatin resistance of MOC and develop strategies to overcome this resistance. A kinome-based siRNA library screen was carried out using human MOC cells to identify novel targets to enhance the efficacy of chemotherapy. In vitro and in vivo validations of antitumor effects were performed using mouse MOC models. Specifically, the role of PRKRA/PACT in oxaliplatin resistance was interrogated. We focused on PRKRA, a known activator of PKR kinase, and its encoded protein PACT because it was one of the five most significantly downregulated genes in the siRNA screen. In orthotopic mouse models of MOC, we observed a significant antitumor effect of PRKRA siRNA plus oxaliplatin. In addition, expression of miR-515-3p was regulated by PACT-Dicer interaction, and miR-515-3p increased the sensitivity of MOC to oxaliplatin. Mechanistically, miR-515-3p regulated chemosensitivity, in part, by targeting AXL. The PRKRA/PACT axis represents an important therapeutic target in MOC to enhance sensitivity to oxaliplatin.

Inhibiting Nuclear Phospho-Progesterone Receptor Enhances Antitumor Activity of Onapristone in Uterine Cancer.

Although progesterone receptor (PR)-targeted therapies are modestly active in patients with uterine cancer, their underlying molecular mechanisms are not well understood. The clinical use of such therapies is limited because of the lack of biomarkers that predict response to PR agonists (progestins) or PR antagonists (onapristone). Thus, understanding the underlying molecular mechanisms of action will provide an advance in developing novel combination therapies for cancer patients. Nuclear translocation of PR has been reported to be ligand-dependent or -independent. Here, we identified that onapristone, a PR antagonist, inhibited nuclear translocation of ligand-dependent or -independent (EGF) phospho-PR (S294), whereas trametinib inhibited nuclear translocation of EGF-induced phospho-PR (S294). Using orthotopic mouse models of uterine cancer, we demonstrated that the combination of onapristone and trametinib results in superior antitumor effects in uterine cancer models compared with either monotherapy. These synergistic effects are, in part, mediated through inhibiting the nuclear translocation of EGF-induced PR phosphorylation in uterine cancer cells. Targeting MAPK-dependent PR activation with onapristone and trametinib significantly inhibited tumor growth in preclinical uterine cancer models and is worthy of further clinical investigation. Mol Cancer Ther; 17(2); 464-73. ©2017 AACR.

Differential Effects of EGFL6 on Tumor versus Wound Angiogenesis.

Angiogenesis inhibitors are important for cancer therapy, but clinically approved anti-angiogenic agents have shown only modest efficacy and can compromise wound healing. This necessitates the development of novel anti-angiogenesis therapies. Here, we show significantly increased EGFL6 expression in tumor versus wound or normal endothelial cells. Using a series of in vitro and in vivo studies with orthotopic and genetically engineered mouse models, we demonstrate the mechanisms by which EGFL6 stimulates tumor angiogenesis. In contrast to its antagonistic effects on tumor angiogenesis, EGFL6 blockage did not affect normal wound healing. These findings have significant implications for development of anti-angiogenesis therapies.

Role of ADP receptors on platelets in the growth of ovarian cancer.

We investigated the effect of platelets on ovarian cancer and the role of adenosine diphosphate (ADP) receptors (P2Y12 and P2Y1) on platelets in the growth of primary ovarian cancer tumors. We showed that in murine models of ovarian cancer, a P2Y12 inhibitor (ticagrelor) reduced tumor growth by 60% compared with aspirin and by 75% compared with placebo. In P2Y12-/- mice, the growth of syngeneic ovarian cancer tumors was reduced by >85% compared with wild-type (WT) mice. In contrast, there was no difference in tumor growth between P2Y1-/- and WT mice. Reconstitution of hematopoiesis in irradiated P2Y12-/- mice by hematopoietic progenitor cells from WT mice (WT→P2Y12-/-) restored tumor growth in P2Y12-/- mice. Finally, knockdown of ecto-apyrase (CD39) on ovarian cancer cells increased tumor growth in tumor-bearing mice. Although in the absence of platelets, ADP, the P2Y12 inhibitor, recombinant apyrase, or knockdown of CD39 did not affect cancer cell proliferation, in the presence of platelets, the P2Y12 inhibitor and recombinant apyrase reduced and knockdown of CD39 increased platelet-enhanced cancer cell proliferation. These results suggest that P2Y12 on platelets and ADP concentration at the interface between cancer cells and platelets affect the growth of primary ovarian cancer tumors in mice. If additional studies in mice and in pilot human trials confirm our results, inhibition of P2Y12 might be a new therapeutic option that can be used in adjuvant to the traditional surgery and chemotherapy in patients with ovarian cancer.

Role of YAP1 as a Marker of Sensitivity to Dual AKT and P70S6K Inhibition in Ovarian and Uterine Malignancies.

Background: The PI3K/AKT/P70S6K pathway is an attractive therapeutic target in ovarian and uterine malignancies because of its high rate of deregulation and key roles in tumor growth. Here, we examined the biological effects of MSC2363318A, which is a novel inhibitor of AKT1, AKT3, and P70S6K. Methods: Orthotopic murine models of ovarian and uterine cancer were utilized to study the effect of MSC2363318A on survival and regression. For each cell line, 10 mice were treated in each of the experimental arms tested. Moreover, in vitro experiments in 21 cell lines (MTT, immunoblot analysis, plasmid transfection, reverse phase protein array [RPPA]) were carried out to characterize underlying mechanisms and potential biomarkers of response. All statistical tests were two-sided. Results: MSC2363318A decreased tumor growth and metastases in multiple murine orthotopic models of ovarian (SKOV3ip1, HeyA8, and Igrov1) and uterine (Hec1a) cancer by reducing proliferation and angiogenesis and increasing cell death. Statistically significant prolonged overall survival was achieved with combination MSC2363318A and paclitaxel in the SKUT2 (endometrioid) uterine cancer mouse model ( P < .001). Mice treated with combination MSC2363318A and paclitaxel had the longest overall survival (mean = 104.2 days, 95% confidence interval [CI] = 97.0 to 111.4) compared with those treated with vehicle (mean = 61.9 days, 95% CI = 46.3 to 77.5), MSC2363318A alone (mean = 89.7 days, 95% CI = 83.0 to 96.4), and paclitaxel alone (mean = 73.6 days, 95% CI = 53.4 to 93.8). Regression and stabilization of established tumors in the Ishikawa (endometrioid) uterine cancer model was observed in mice treated with combination MSC2363318A and paclitaxel. Synergy between MSC2363318A and paclitaxel was observed in vitro in cell lines that had an IC50 of 5 µM or greater. RPPA results identified YAP1 as a candidate marker to predict cell lines that were most sensitive to MSC2363318A (R = 0.54, P = .02). After establishment of a murine ovarian cancer model of adaptive anti-angiogenic resistance (SKOV3ip1-luciferase), we demonstrate that resensitization to bevacizumab occurs with the addition of MSC2363318A, resulting in improved overall survival ( P = .01) using the Kaplan-Meier method. Mice treated with bevacizumab induction followed by MSC2363318A had the longest overall survival (mean = 66.0 days, 95% CI = 53.9 to 78.1) compared with mice treated with control (mean = 42.0 days, 95% CI = 31.4 to 52.6) and bevacizumab-sensitive mice (mean = 47.2 days; 95% CI = 37.5 to 56.9). Conclusions: MSC2363318A has therapeutic efficacy in multiple preclinical models of ovarian and uterine cancer. These findings support clinical development of a dual AKT/P70S6K inhibitor.

Differences in performance on the functional movement screen between chronic low back pain patients and healthy control subjects.

[Purpose] Differences in scores on the Functional Movement Screen between patients with chronic lower back pain and healthy control subjects were investigated. [Subjects and Methods] In all, 20 chronic lower back pain patients and 20 healthy control subjects were recruited. Chronic lower back pain patients and healthy controls performed the Functional Movement Screen (deep squat, hurdle step, inline lunge, shoulder mobility, active straight leg raise, trunk stability pushup, and rotary stability). The Mann-Whitney test was used to analyze differences in Functional Movement Screen scores between the two groups. [Results] Chronic lower back pain patients scored lower on the Functional Movement Screen total composite compared with healthy control subjects. Chronic lower back pain patients scored lower on Functional Movement Screen subtests including the deep squat, hurdle step, active straight leg raise, and rotary stability tests. [Conclusion] The deep squat, hurdle step, active straight leg raise, and rotary stability tasks of the Functional Movement Screen can be recommended as a functional assessment tools to identify functional deficits in chronic lower back pain patients.

Complement Component 3 Is Regulated by TWIST1 and Mediates Epithelial-Mesenchymal Transition.

We have previously shown that complement component 3 (C3) is secreted by malignant epithelial cells. To understand the mechanism of upregulation of C3 expression in tumor cells, we studied the C3 promoter and identified that twist basic helix-loop-helix transcription factor 1 (TWIST1) binds to the C3 promoter and enhances its expression. Because TWIST1 mediates epithelial-mesenchymal transition (EMT), we studied the effect of C3 on EMT and found that C3 decreased E-cadherin expression on cancer cells and promoted EMT. We showed that C3-induced reduction in E-cadherin expression in ovarian cancer cells was mediated by C3a and is Krüppel-like factor 5 dependent. We investigated the association between TWIST1 and C3 in malignant tumors and in murine embryos. TWIST1 and C3 colocalized at the invasive tumor edges, and in the neural crest and limb buds of mouse embryos. Our results identified TWIST1 as a transcription factor that regulates C3 expression during pathologic and physiologic EMT.

Erythropoietin Stimulates Tumor Growth via EphB4.

While recombinant human erythropoietin (rhEpo) has been widely used to treat anemia in cancer patients, concerns about its adverse effects on patient survival have emerged. A lack of correlation between expression of the canonical EpoR and rhEpo's effects on cancer cells prompted us to consider the existence of an alternative Epo receptor. Here, we identified EphB4 as an Epo receptor that triggers downstream signaling via STAT3 and promotes rhEpo-induced tumor growth and progression. In human ovarian and breast cancer samples, expression of EphB4 rather than the canonical EpoR correlated with decreased disease-specific survival in rhEpo-treated patients. These results identify EphB4 as a critical mediator of erythropoietin-induced tumor progression and further provide clinically significant dimension to the biology of erythropoietin.

Comparison of lumbar repositioning error according to different lumbar angles in a flexion pattern (FP) subgroup of patients with non-specific chronic low back pain.

[Purpose] This study determined the change in lumbar position sense according to lumbar angles in a flexion pattern (FP) subgroup of patients with non-specific chronic low back pain (NCSLBP). [Subjects] Thirteen subjects with FP low back pain participated. [Methods] The lumbar repositioning error (RE) of subjects was measured between a neutral starting position and re-position phases at three angles, in sitting and standing upright positions. [Results] Lumbar RE was significantly greater during lumbar flexion at a 30° angle in the sitting position than in the other tasks. [Conclusion] In the flexion-related subgroup, the lumbar RE measurement may be a more sensitive evaluation method using a lumbar flexion angle of 30° while in the sitting position, compared with other angles in sitting or standing positions.

A sloped seat wedge can change the kinematics of the lumbar spine of seated workers with limited hip flexion.

[Purpose] The purpose of this study was to determine whether a wedge type seat decreases the lumbar flexion angle of seated workers with limited hip flexion. [Subjects] Twelve sedentary workers with limited hip flexion were recruited. [Methods] Three seat surfaces were used: a level surface, a forward-inclining wedge, and a backward-reclining wedge. The angles of lumbar flexion and pelvic tilt were measured using a three-dimensional motion analysis system. Differences in kinematic data of the subjects seated on the three seat surfaces were analyzed using repeated one-way analysis of variance. [Results] The degree of lumbar flexion decreased significantly when using the forward-inclining wedge compared with the level surface and backward-reclining wedge. [Conclusion] These findings suggest that sitting on a forward-inclining wedge may be useful for minimizing the compensatory lumbar flexion of individuals with limited hip flexion who work in a seated position.

The Influence of Dual Pressure Biofeedback Units on Pelvic Rotation and Abdominal Muscle Activity during the Active Straight Leg Raise in Women with Chronic Lower Back Pain.

[Purpose] This study was performed to assess the influence of applying dual pressure biofeedback units (DPBUs) on the angle of pelvic rotation and abdominal muscle activity during the active straight leg raise (ASLR). [Subjects] Seventeen patients with low-back pain (LBP) participated in this study. [Methods] The subjects were asked to perform an active straight leg raise (ASLR) without a PBU, with a single PBU, and with DPBUs. The angles of pelvic rotation were measured using a three-dimensional motion-analysis system, and the muscle activity of the bilateral internal oblique abdominis (IO), external oblique abdominis (EO), and rectus abdominis (RA) was recorded using surface electromyography (EMG). One-way repeated-measures ANOVA was performed to determine the rotation angles and muscle activity under the three conditions. [Results] The EMG activity of the ipsilateral IO, contralateral EO, and bilateral RA was greater and pelvic rotation was lower with the DPBUs than with no PBU or a single PBU. [Conclusion] The results of this study suggest that applying DPBUs during ASLR is effective in decreasing unwanted pelvic rotation and increasing abdominal muscle activity in women with chronic low back pain.

Chlorella dichloromethane extract ameliorates NO production and iNOS expression through the down-regulation of NF kappa B activity mediated by suppressed oxidative stress in RAW 264.7 macrophages.

BACKGROUND: It has been proposed that chlorella extracts have antioxidative and anti-inflammatory effects. METHODS: RAW 264.7 murine macrophage cell line was preincubated with various concentrations (0-100 mug/ml) of chlorella dichloromethane extract (CDE) and stimulated with lipopolysaccharide (LPS) to induce oxidative stress and inflammation. RESULTS: Treatments of CDE reduced thiobarbituric acid-reactive substances (TBARS) accumulation, enhancing glutathione level and activities of antioxidative enzymes including superoxide dismutase (SOD), catalase, glutathione peroxidase (GSH-px), and glutathione reductase in LPS-stimulated macrophages than LPS-only treated cells. Nitric oxide (NO) production was significantly suppressed in a dose-dependent manner (p<0.05) with an IC(50) of 30.5 microg/ml. Treatment of CDE at 50 microg/ml suppressed NO production to 6% of LPS-control. Treatment with CDE suppressed the levels of inducible nitric oxide synthase (iNOS) protein and mRNA expressions. The specific DNA binding activities of nuclear factor kappa B (NF kappa B) on nuclear extracts from CDE treatments were significantly suppressed with an IC(50) of 62.7 mug/ml in a dose-dependent manner. CONCLUSIONS: CDE ameliorates NO production and iNOS expression through the down-regulation of NF kappa B activity, which may be mediated by attenuated oxidative stress in RAW 264.7 macrophages.