PPAR-γ regulates the polarization of M2 macrophages to improve the microenvironment for autologous fat grafting.

The unpredictable survival rate of autologous fat grafting (AFG) seriously affects its clinical application. Improving the survival rate of AFG has become an unresolved issue in plastic surgery. Peroxisome proliferator-activated receptor-γ (PPAR-γ) regulates the adipogenic differentiation of adipocytes, but the functional mechanism in AFG remains unclear. In this study, we established an animal model of AFG and demonstrated the superior therapeutic effect of PPAR-γ regulation in the process of AFG. From day 3 after fat grafting, the PPAR-γ agonist rosiglitazone group consistently showed better adipose integrity, fewer oil cysts, and fibrosis. Massive macrophage infiltration was observed after 7 days. At the same time, M2 macrophages begin to appear. At day 14, M2 macrophages gradually became the dominant cell population, which suppressed inflammation and promoted revascularization and fat regeneration. In addition, transcriptome sequencing showed that the differentially expressed genes in the Rosiglitazone group were associated with the pathways of adipose regeneration, differentiation, and angiogenesis; these results provide new ideas for clinical treatment.

The Ideal Proportion of the Auricle Exposure via a Morphometric Analysis in Asian Women.

BACKGROUND: Ears are an important aesthetic feature that is vital to the overall attractiveness of the face. Although there have been many studies on the aesthetics of the auricle, there is currently a lack of consensus on the ideal proportion of auricle exposure for Asian women in frontal view. OBJECTIVES: This study aimed to investigate ideal proportion of auricle exposure in Asian women. METHODS: An observational study was carried out on the photographs of 84 women on the list of the 100 most beautiful faces in Asia (published by TCC Asia in 2020). The proportion of the distance between the outer canthus and the outermost point of auricle to the distance between the inner canthus and the outermost point of auricle was calculated as the auricle exposure proportion. Evaluators were asked to rank a set of photographs of the volunteer with varying auricle exposure proportions from most attractive to least attractive. RESULTS: Measurements of the photographs of the 84 women showed a mean ear exposure proportion of 0.600. With 487 questionnaire responses received, the proportion of auricle exposure that the evaluators considered most attractive was 0.600. People with aesthetic experience considered 0.625 the most attractive proportion, while the general group considered 0.600 the most attractive. CONCLUSIONS: The ideal proportion of the auricle exposure for Asian women is in the range of 0.60-0.625, which may help surgeons reconstruct aesthetically pleasing ears. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Obesity and cancer stem cells: Roles in cancer initiation, progression and therapy resistance.

Obesity, the global pandemic since industrialization, is the number one lifestyle-related risk factor for premature death, which increases the incidence and mortality of various diseases and conditions, including cancer. In recent years, the theory of cancer stem cells (CSCs), which have the capacity for self-renewal, metastasis and treatment resistance, has been bolstered by increasing evidence. However, research on how obesity affects CSCs to facilitate cancer initiation, progression and therapy resistance is still in its infancy, although evidence has already begun to accumulate. Regarding the ever-increasing burden of obesity and obesity-related cancer, it is pertinent to summarize evidence about the effects of obesity on CSCs, as elucidating these effects will contribute to the improvement in the management of obesity-related cancers. In this review, we discuss the association between obesity and CSCs, with a particular focus on how obesity promotes cancer initiation, progression and therapy resistance through CSCs and the mechanisms underlying these effects. In addition, the prospect of preventing cancer and targeting the mechanisms linking obesity and CSCs to reduce cancer risk or to improve the survival of patients with cancer is considered.

Prognostic Significance of Advanced Lung Cancer Inflammation Index, a Nutritional and Inflammation Index, in Patients With Gastrointestinal Cancers: A Meta-analysis.

Previous studies have investigated the prognostic value of the advanced lung cancer inflammation index (ALI) in gastrointestinal (GI) cancers; however, the results are controversial. This meta-analysis aimed to evaluate the prognostic and clinicopathological role of ALI in patients with GI cancers. A systematic search of electronic databases was conducted to evaluate the prognostic and clinicopathological value of ALI in GI cancers. Nine studies comprising 3,750 patients were included in this meta-analysis. The pooled results showed that a low ALI was significantly associated with worse overall survival (OS, hazard ratio [HR] = 1.95, 95% confidence interval [CI] = 1.53-2.47, P < 0.001, I2 = 63.9%) and disease-free survival/relapse-free survival (DFS/RFS, HR = 1.49, 95% CI = 1.28-1.73, P < 0.001, I2 = 0%) in patients with GI cancers. In addition, decreased ALI correlated with the depth of tumor invasion and presence of distant metastasis and tended to be associated with male sex, high carcinoembryonic antigen levels, lymph node metastasis, and right-sided colon cancer. Low ALI was associated with adverse OS and DFS/RFS in patients with GI cancer. In addition, decreased ALI also correlated with clinicopathological factors, indicating higher stage of the malignancy.

A comparison of the da Vinci Xi vs. da Vinci Si surgical systems for radical prostatectomy.

BACKGROUND: To compare the perioperative and short-term efficacy and cost of the da Vinci Xi and da Vinci Si surgical systems for radical prostatectomy. METHODS: We retrospectively analyzed the clinical data of 175 patients with prostate cancer who underwent radical prostatectomy with the da Vinci Si or Xi surgical systems in our hospital from June 2019 to June 2020. Of the 175 patients, 82 underwent robot-assisted laparoscopic radical prostatectomy with the da Vinci Xi surgery system, and 93 patients underwent robot-assisted laparoscopic radical prostatectomy with the da Vinci Si surgical system. The perioperative outcomes, short-term efficacy and costs were compared between the two groups. RESULTS: The anesthesia time, operation time, docking time, indwelling catheter time and postoperative bed rest time in the Xi group were shorter than those in the Si group (respectively, 268.8 min vs. 219.3 min, P = 0.001; 228.2 min vs. 259.6 min, P < 0.001; 7.4 min vs. 12.7 min, P < 0.001; 8.6 d vs. 9.7 d, P = 0.036; 2.2 d vs. 2.6 d, P = 0.002). However, the total cost of hospitalization and the cost of intraoperative consumables in the Xi group were higher than those in the Si group (84,740.7 vs. 76,739.1 ¥, P = 0.003; 13,199.4 vs. 10,823.0 ¥, P = 0.019). CONCLUSIONS: Although the cost of robot-assisted radical prostatectomy is higher, compared with the Si system, the Xi system has better perioperative outcomes and can provide similar short-term efficacy and oncology outcomes.

Progress in Clinical Research on Gonadotropin-Releasing Hormone Receptor Antagonists for the Treatment of Prostate Cancer.

Gonadotropin-releasing hormone (GnRH) receptor agonists are still the most commonly used androgen deprivation treatment (ADT) drugs for prostate cancer in clinical practice. Currently, the GnRH receptor antagonists used for endocrine therapy for prostate cancer primarily include degarelix and relugolix (TAK-385). The former is administered by subcutaneous injection, while the latter is an oral drug. Compared to GnRH agonists, GnRH antagonists reduce serum testosterone levels more rapidly without an initial testosterone surge or subsequent microsurges. This review focuses on the mechanism of action of GnRH antagonists and agonists, the developmental history of GnRH antagonists, and emerging data from clinical studies of the two antagonists used as endocrine therapy for prostate cancer.

Development of prognostic signature based on RNA binding proteins related genes analysis in clear cell renal cell carcinoma.

RNA binding proteins (RBPs) play significant roles in the development of tumors. However, a comprehensive analysis of the biological functions of RBPs in clear cell renal cell carcinoma (ccRCC) has not been performed. Our study aimed to construct an RBP-related risk model for prognosis prediction in ccRCC patients. First, RNA sequencing data of ccRCC were downloaded from The Cancer Genome Atlas (TCGA) database. Three RBP genes (EIF4A1, CARS, and RPL22L1) were validated as prognosis-related hub genes by univariate and multivariate Cox regression analyses and were integrated into a prognostic model by least absolute shrinkage and selection operator (LASSO) Cox regression analysis. According to this model, patients with high risk scores displayed significantly worse overall survival (OS) than those with low risk scores. Moreover, the multivariate Cox analysis results indicated that risk score, tumor grade, and tumor stage were significantly correlated with patient OS. A nomogram was constructed based on the three RBP genes and showed a good ability to predict outcomes in ccRCC patients. In conclusion, this study identified a three-RBP gene risk model for predicting the prognosis of patients, which is conducive to the identification of novel diagnostic and prognostic molecular markers.

The efficacy and safety of lenvatinib in the treatment of solid tumors: an up-to-date meta-analysis.

Aim: We performed an updated meta-analysis to evaluate the efficacy and safety of lenvatinib in cancer patients. Materials & methods: Databases were searched to identify relevant trials. Data were extracted to evaluate overall survival, progression-free survival, overall response rate and grade ≥3 adverse events. Results: The pooled analysis demonstrated that lenvatinib significantly improved progression-free survival (hazard ratio: 0.43; 95% CI: 0.23-0.80; p = 0.008), overall survival (hazard ratio: 0.85; 95% CI: 0.75-0.97; p = 0.013) and overall response rate (relative risk: 6.89; 95% CI: 2.22-21.36; p = 0.001) compared with control therapy. However, the use of lenvatinib can increase the risk of severe infection. Conclusion: Lenvatinib-containing regimens are associated with better progression-free survival, overall survival and overall response rate, but can induce severe infection.

Predicting highway freight transportation networks using radiation models.

Highway freight transportation (HFT) plays an important role in the economic activities. Predicting HFT networks is not only scientifically significant in the understanding of the mechanism governing the formation and dynamics of these networks, but also of practical significance in highway planning and design for policymakers and truck allocation and route planning for logistic companies. In this work we apply parameter-free radiation models to predict the HFT network in mainland China and assess their predictive performance using metrics based on links and fluxes, which can be done in reference to the real directed and weighted HFT network between 338 Chinese cities constructed from about 15.06 million truck transportation records in five months. It is found that the radiation models exhibit relatively high accuracy in predicting links but low accuracy in predicting fluxes on links. Similar to gravity models, radiation models also suffer difficulty in predicting long-distance links and the fluxes on them. Nevertheless, the radiation models perform well in reproducing several scaling laws of the HFT network. The adoption of population or gross domestic product in the model has a minor impact on the results, and replacing the geographic distance by the path length taken by most truck drivers does not improve the results.

Comparative Risks of High-Grade Adverse Events Among FDA-Approved Systemic Therapies in Advanced Melanoma: Systematic Review and Network Meta-Analysis.

Background: Head-to-head evidence is lacking in comparative risks of high-grade adverse events (AEs) among different systemic treatment options for advanced melanoma. Methods: An up-to-date systematic review and network meta-analysis (NMA) was performed. Randomized controlled trials (RCTs) of patients with advanced melanoma were eligible if at least one intervention was the Food and Drug Administration-approved targeted or immune checkpoint inhibitors. Risks of high-grade AEs were estimated by random-effects Bayesian NMAs, based on relative risks. Surface under the cumulative ranking probabilities was used to assess relative ranking of treatments. The summary incidences were calculated. Results: Twenty-five RCTs (12,925 patients) comparing 10 different systemic treatment options were included. BRAF/MEK had the highest risk of overall high-grade AEs (pooled incidence: 32.11%). BRAF had the highest risk of high-grade arthralgia (0.39%), whereas MEK had the highest risk of high-grade hypertension (2.28%) and nausea (0.37%). Cytotoxic T-lymphocyte antigen 4 (CTLA-4)/chemo had the highest risk of high-grade diarrhea (1.31%), alanine aminotransferase (0.60%), and aspartate aminotransferase elevation (0.59%). Programmed cell death 1 (PD-1)/CTLA-4 had the highest risks of high-grade pyrexia (1.14%) and rash (0.94%). Using PD-1 inhibitor alone had the lowest risks of overall high-grade AEs. Conclusions: Different systemic treatment options have varying high-grade AEs in advanced melanoma treatment. Current evidences highlight the important risks of BRAF/MEK, CTLA-4/chemo, and PD-1/CTLA-4.

Comparison of robot-assisted retroperitoneal laparoscopic adrenalectomy versus retroperitoneal laparoscopic adrenalectomy for large pheochromocytoma: a single-centre retrospective study.

BACKGROUND: To evaluate the feasibility and safety of robot-assisted retroperitoneal laparoscopic adrenalectomy (RARLA) for large pheochromocytomas (PHEOs; size≥6 cm) compared with retroperitoneal laparoscopic adrenalectomy (RLA). METHODS: Fifty-one patients who underwent adrenalectomy for large PHEOs between March 2016 and January 2019 were enrolled and divided into two groups, including 32 RLA cases and 19 RARLA cases. We compared the perioperative efficacy and long-term follow-up results between the two groups. RESULTS: Preoperative data, including demographics, comorbidities and tumour characteristics, were similar between the groups. Intraoperatively, the RARLA group had a lower incidence of haemodynamic instability (26.3% vs. 56.2%, P = 0.038) and less intraoperative blood loss (100 ml vs. Two hundred milliliter, P = 0.042) than the RLA group. The groups showed no significant differences in operative time or transfusion rates. Postoperatively, the time to diet resumption, time to ambulation, time to drainage removal and postoperative hospital stay were shorter in the RARLA group than in the RLA group (1 d vs. 2 d, P = 0.027; 1 d vs. 2 d, P = 0.034; 3 d vs. 5 d, P = 0.002; 5 d vs. 6 d, P = 0.02, respectively). The groups exhibited no significant differences in the duration of anaesthetic use, complications, or long-term follow-up results for the blood pressure (BP) improvement rate. CONCLUSIONS: Compared with RLA, RARLA is a safe, feasible and even optimized procedure for large PHEOs.

Astaxanthin suppresses lipopolysaccharide­induced myocardial injury by regulating MAPK and PI3K/AKT/mTOR/GSK3ß signaling.

Cardiac dysfunction is a significant manifestation of sepsis and it is associated with the prognosis of the disease. Astaxanthin (ATX) has been discovered to serve a variety of pharmacological effects, including anti­inflammatory, antioxidant and antiapoptotic properties. The present study aimed to investigate the role and mechanisms of ATX in sepsis­induced myocardial injury. Male C57BL/6 mice were divided into three groups (15 mice per group): Control group, lipopolysaccharide (LPS) group and LPS + ATX group. The cardiac dysfunction model was induced through an intraperitoneal injection of LPS (10 mg/kg) and ATX (40 mg/kg) was administered to the LPS + ATX group by intraperitoneal injection 30 min following the administration of LPS. All animals were sacrificed after 24 h. Inflammatory cytokine levels in the serum were detected using ELISAs, and cardiac B­type natriuretic peptide (BNP) levels were analyzed using western blot analysis and reverse transcription­quantitative PCR. Furthermore, the extent of myocardial injury was evaluated using pathological analysis, and cardiomyocyte apoptosis was analyzed using a TUNEL assay, in addition to determining the expression levels of Bcl­2 and Bax. The expression levels of proteins involved in the mitogen activated protein kinase (MAPK) and PI3K/AKT signaling pathways were also analyzed using western blot analysis. ATX significantly suppressed the LPS­induced increased production of TNF­α and IL­6 and suppressed the protein expression levels of BNP, Bax and Bcl­2 to normal levels. ATX also prevented the histopathological changes to the myocardial tissue and reduced the extent of necrosis. Furthermore, the treatment with ATX suppressed the LPS­activated MAPK and PI3K/AKT signaling. ATX additionally exerted a protective effect on cardiac dysfunction caused by sepsis by inhibiting MAPK and PI3K/AKT signaling.

[Mechanism of oxidative stress in skeletal muscle of rats induced by acute exhaustive exercise].

OBJECTIVE: To observe the effects of acute exhaustive exercise on the expressions of oxidative stress related enzymes in skeletal muscle of rats. METHODS: Forty male SD rats were divided into 4 groups, 10 rats in each group, which were the control group (C group), exhausted exercise group (E group), exercise + PKC inhibitor group (EC group), exercise + NOX inhibitor group (EA group). Three groups of exercise rats were familiarized with treadmill running for 3 days (5 m/min, once/d, no incline), then rested for one day. EC group was injected with PKC inhibitor chelerythrine (5 mg / kg) one day before and one hour before exercise, EA group was injected with NADPH oxidase inhibitor apocynin (10 mg / kg) at the same time, group C and group E were injected with the same dose of normal saline. Three groups of exercise rats were subjected to a one-time treadmill exhaustion exercise, and the plantaris were taken after exhaustion. Reactive oxygen species (ROS) were detected by DCF fluorescent probe, NOX2, NOX4, 3-NT were analyzed by Western blot, and PKC, NOX2, NOX4 were analyzed by immunoprecipitation. RESULTS: Compared with group C, ROS level, NOX2 and NOX4 protein expressions, PKC-NOX2 and PKC-NOX4 complex levels, and 3-NT production in group E were significantly increased (P＜0.01, P＜0.05), and ROS level was no significant difference in group EC and group EA (P＞0.05), and NOX4 protein expression in group EC was significantly increased (P ＜ 0.05). Compared with group E, ROS level, NOX2 and NOX4 protein expressions, PKC-NOX2 and PKC-NOX4 complex levels, 3-NT production were decreased significantly (P＜0.01, P＜0.05). CONCLUSION: Exhausted exercise induces increased expressions of NOX2 and NOX4 proteins in skeletal muscle, and PKC mediates the production of ROS by regulating NOX2.

Comparative Safety of PD-1/PD-L1 Inhibitors for Cancer Patients: Systematic Review and Network Meta-Analysis.

Background: Comprehensive evidence comparing treatment-related adverse events (trAEs) among PD-1/PD-L1 inhibitors is unavailable. Methods: A systematic review and network meta-analysis (NMA) was conducted. Randomized controlled trials in cancer patients treated with PD1/PD-L1 inhibitors or their combinations with chemotherapy/placebo and compared with PD1/PD-L1 inhibitors/chemotherapy/placebo were identified through comprehensive searches of multiple databases. Bayesian NMA was performed using random-effects model. Relative ranking of treatments was assessed with surface under the cumulative ranking (SUCRA) probabilities. Incidences and odds ratios of trAEs and immune-related adverse events (irAEs) of all-grade (Grade 1-5) and high-grade (Grade 3-5) were estimated. Results: Twenty-three RCTs (14,204 patients) comparing six different strategies were included. The incidence of trAEs was lowest for PD-L1 inhibitors (all-grade: pooled incidence = 60.4%, SUCRA = 77.2%; high-grade: 6.4, 73.8%). PD-L1 inhibitors plus chemotherapy had the highest incidence of all-grade trAEs (88.6, 10.1%), while PD-1 inhibitors plus chemotherapy had the highest incidence of high-grade trAEs (8.2, 9.3%). The use of PD-1/PD-L1 inhibitors alone was associated with significant reductions on high-grade trAEs, compared with PD-1/PD-L1 inhibitors plus chemotherapy. PD-1 inhibitors had the highest incidence of irAEs (all-grade: 15.1, 9.5%; high-grade: 3.5, 16.8%). Compared with PD-L1 inhibitors, PD-1 inhibitors neither increased trAEs nor irAEs significantly. Results from sensitivity analyses were consistent. Conclusions: Current data showed that PD-L1 inhibitors had the best safety on both trAEs and irAEs. Awareness of the comparative safety could promote further appropriate utilization of PD-1/PD-L1 inhibitors in clinical practice.

A New VMAT-2 Inhibitor NBI-641449 in the Treatment of Huntington Disease.

AIMS: To evaluate the effectiveness of a new VMAT-2 inhibitor NBI-641449 in controlling hyperkinetic movements of Huntington disease (HD) and to investigate its possible therapeutic effects. METHODS: We applied three different doses of NBI-641449 (1, 10, 100 mg/kg/day) for 2 weeks in 4-month-old YAC128 mice and wild-type (WT) mice. Rotarod performance and locomotive activities were tested during the administration of the drug. The concentration of dopamine (DA) and its metabolites was quantified in the striatal tissues by high-performance liquid chromatography (HPLC). Neuron survival in striatum and huntingtin protein aggregates were assessed with immunostaining. Expression levels of endoplasmic reticulum (ER) stress proteins were detected by immunoblotting. RESULTS: Rotarod performance was significantly improved after treatment with low or middle dose of NBI-641449 in YAC128 mice. Open field test showed that NBI-641449 treatment could attenuate the increased horizontal activity (HACTV), total vertical movement, moving time, and moving distance in YAC128 mice. High dose of NBI-641449 might cause sedative effects in WT and YAC128 mice. HPLC showed that NBI-641449 caused a dose-dependent decrease of DA, 3,4-dihydroxyphenylacetic acid, and homovanillic acid levels in the striatum. NeuN and DARPP-32 immunostaining revealed that NBI-641449 had no significant effect on the neuron survival in the striatum. However, NBI-641449 treatment reduced the huntingtin protein aggregates in the cortex of YAC128 mice. In addition, the levels of ER stress proteins were increased in YAC128 mice, which can be suppressed by NBI-641449. CONCLUSIONS: These findings suggest that this new VMAT-2 inhibitor NBI-641449 may have therapeutic potential for the treatment of HD.

Anti-parkinsonian effects of Nurr1 activator in ubiquitin-proteasome system impairment induced animal model of Parkinson's disease.

Nurr1 is a member of the nuclear receptor superfamily and is a potential susceptibility gene for Parkinson's disease (PD). Several lines of studies in vitro and in vivo reported that defects in the Nurr1 gene cause nigrostriatal neuronal deficiency as seen in PD. In the present study, we used a a synthetic low molecular weight Nurr1 activator which increases the transcription of Nurr1 to investigate whether it has anti-parkinsonian effects against nigrostriatal neuronal degeneration induced by proteasome inhibitor lactacystin. Adult C57BL/6 mice were treated orally with the Nurr1 activator and an inactive structural analog as a control at a dose of 10mg/kg per day, starting 3 days before microinjection of proteasome inhibitor lactacystin into the medial forebrain bundle and the treatment continued for a total of 4 weeks. Animal behavior tests, and pathological and biochemical examinations were performed to determine the anti-parkinsonian effects of the Nurr1 activator. We found that treatment with the Nurr1 activator significantly improved rotarod performance, attenuated dopamine neuron loss and nigrostriatal dopamine reduction, increased expression of Nurr1, dopamine transporter and vesicular monoamine transporter 2, and alleviated microglial activation in the substantia nigra of lactacystin-lesioned mice. These results suggest that the Nurr1 activator may become an innovative strategy for the treatment of PD.

A mechanistic study of proteasome inhibition-induced iron misregulation in dopamine neuron degeneration.

Ubiquitin proteasome system (UPS) impairment and iron misregulation have been implicated in dopamine (DA) neuron degeneration in Parkinson's disease. As previously shown, proteasome inhibition in a rodent model can cause nigral neuron degeneration accompanied by iron accumulation. To investigate the involvement of iron in DA neuron degeneration, we generated an in vitro model by applying proteasome inhibitor lactacystin in DAergic cell line MES23.5 culture. We found that lactacystin caused marked increase in labile iron, reactive oxygen species and ubiquitin-conjugated protein aggregation prior to cell injury. These effects were attenuated by iron chelators or antioxidants. Furthermore, we demonstrated that the iron regulatory protein (IRP)/iron response element system contributed to UPS impairment-mediated DA neuron injury. We documented that IRP2 disruption resulted in an increase in transferrin receptor 1 (TfR1), a decrease in ferritin heavy chain (H-Frt), and eventually cell death. These findings provide insight into the mechanistic interplay between UPS impairment and iron misregulation and suggest that the disturbances in IRP2, TfR1 and H-Frt may contribute to DA neuron degeneration.

Blocking TLR2 activity attenuates pulmonary metastases of tumor.

BACKGROUND: Metastasis is the most pivotal cause of mortality in cancer patients. Immune tolerance plays a crucial role in tumor progression and metastasis. METHODS AND FINDINGS: In this study, we investigated the potential roles and mechanisms of TLR2 signaling on tumor metastasis in a mouse model of intravenously injected B16 melanoma cells. Multiple subtypes of TLRs were expressed on B16 cells and several human cancer cell lines; TLR2 mediated the invasive activity of these cells. High metastatic B16 cells released more heat shock protein 60 than poor metastatic B16-F1 cells. Importantly, heat shock protein 60 released by tumor cells caused a persistent activation of TLR2 and was critical in the constitutive activation of transcription factor Stat3, leading to the release of immunosuppressive cytokines and chemokines. Moreover, targeting TLR2 markedly reduced pulmonary metastases and increased the survival of B16-bearing mice by reversing B16 cells induced immunosuppressive microenvironment and restoring tumor-killing cells such as CD8(+) T cells and M1 macrophages. Combining an anti-TLR2 antibody and a cytotoxic agent, gemcitabine, provided a further improvement in the survival of tumor-bearing mice. CONCLUSIONS AND SIGNIFICANCE: Our results demonstrate that TLR2 is an attractive target against metastasis and that targeting immunosuppressive microenvironment using anti-TLR2 antibody is a novel therapeutic strategy for combating a life-threatening metastasis.