Bioinformatics analyses of infiltrating immune cell participation on pancreatic ductal adenocarcinoma progression and in vivo experiment of the therapeutic effect of Shuangshen granules.

ETHNOPHARMACOLOGICAL RELEVANCE: Shuangshen granules (SSG), a nationally patented Chinese medicinal formula, including Panax quinquefolium L., Panax notoginseng (Burkill) F. H. Chen, and Cordyceps sinensis (Berk.) Sacc., has demonstrated remarkable therapeutic effects on pancreatic cancer in clinical treatment for nearly 10 years. Previous pharmacological researches have found that its main components, including ginsenosides and cordycepin have anticancer or preventive effects on pancreatic ductal adenocarcinoma (PDAC), which may be associated with immune metabolism. However, the underlying pharmacological mechanism of SSG in the truncation effect of PDAC progression is still unclear. AIM OF THE STUDY: To comprehensively understand the infiltrating immune cells during the different stages of the PDAC development chain and search for immune-related biomarkers that could potentially serve as drug targets through bioinformatic analysis. Meanwhile, the truncation effect of SSG on PDAC progression was also investigated. MATERIALS AND METHODS: The gene expression profiles at different PDAC developmental stages, including normal pancreas, pancreatic intraepithelial neoplasia (PanIN), and PDAC, were retrieved from the GEO database. The GEO2R tool was used to identify differentially expressed genes among the three groups. Functional enrichment analysis was performed with the GSEA software and Metascape platform. The CIBERSORT algorithm evaluated immune cell infiltration in the three groups, and immune-related biomarkers were identified. Correlation analysis was employed to examine the association between immune cells and the biomarkers. One of these biomarkers was selected for immunohistochemistry validation in human samples. Lastly, the effectiveness of SSG against PDAC progression and the influence on the selected biomarker were validated in vivo. The underlying pharmacological mechanisms were also explored. RESULTS: One dataset was obtained, where the functional enrichment of DEGs primarily involved immune effector processes and cytokine production of immune cells. The differential immune cells reflected during the progression from PanIN to PDAC were B memory cells, monocytes, M2 macrophages, and activated dendritic cells. The upregulation of ACTA2 was closely associated with M2 macrophage regulation. The immunohistochemistry on human samples validated significant differences in ACTA2 expression levels as the PDAC progressed. Moreover, animal experiments revealed that the national patented drug SSG ameliorated the pathological changes, decreased the expression of ACTA2 and its functional protein α-smooth muscle actin during PDAC progression. The underlying pharmacological mechanism was related to the regulation of macrophage polarization and downregulation of TGF-ß/Smad signaling pathway. CONCLUSIONS: The immunosuppressive environment changes during the PDAC progression. ACTA2 is a potential immuned-target for drug prevention of PDAC, while SSG could be a promising drug candidate.

Ginseng-containing traditional medicine preparations in combination with fluoropyrimidine-based chemotherapy for advanced gastric cancer: A systematic review and meta-analysis.

BACKGROUND: Ginseng-containing traditional medicine preparations (G-TMPs) in combination with fluoropyrimidine-based chemotherapy (FBC) are well-known treatments for advanced gastric cancer (AGC), with a superior efficacy to FBC alone. However, evidence regarding their efficacy remains limited. The purpose of this meta-analysis is to evaluate the efficacy and safety of G-TMPs in combination with FBC for the treatment of AGC. METHODS: Eight electronic databases were searched for randomized controlled trials (RCTs) using G-TMPs with FBC for the treatment of AGC. The primary outcome included the tumor response, while the secondary outcomes included the quality of life (QoL), proportions of peripheral blood lymphocytes, adverse drug reactions (ADRs), and levels of cancer biomarkers. The quality of evidence for each outcome was assessed using GRADE profilers. RESULTS: A total of 1,960 participants were involved in the 26 RCTs included. Patients treated with FBC plus G-TMPs had better objective response (risk ratio [RR] = 1.23, 95% confidence interval [CI]: 1.13 to 1.35, p < 0.00001) and disease control (RR = 1.13, 95% CI: 1.08 to 1.19, p < 0.00001) rates than those treated with FBC alone. Additionally, the combination group had a better QoL, higher proportions of CD3+ T cells, CD4+ T cells, and natural killer cells, as well as a higher CD4+/CD8+ T-cell ratio. Furthermore, lower levels of CA19-9, CA72-4, and CEA were confirmed in the combination treatment group. In addition, G-TMPs reduced the incidence of ADRs during chemotherapy. CONCLUSION: In combination with FBC, G-TMPs can potentially enhance efficacy, reduce ADRs, and improve prognosis for patients with AGC. However, high-quality randomized studies remain warranted. SYSTEMATIC REVIEW REGISTRATION: PROSPERO Number: CRD42021264938.

Immortal Time Bias-Corrected Effectiveness of Traditional Chinese Medicine in Non-Small Cell Lung Cancer (C-EVID): A Prospective Cohort Study.

Background: Relatively little is known about the effect of traditional Chinese medicine (TCM) on prognosis of non-small cell lung cancer (NSCLC). Methods: In this nationwide, multicenter, prospective, cohort study, eligible patients aged 18-75 years with radical resection, and histologically confirmed stage II-IIIA NSCLC were enrolled. All patients received 4 cycles of standard adjuvant chemotherapy. Patients who received Chinese herbal decoction and (or) oral Chinese patent medicine for a cumulative period of not less than 6 months were defined as TCM group, otherwise they were considered as control group. The primary endpoint was DFS calculated using the Kaplan-Meier method. A time-dependent Cox proportional hazards model was used to correct immortal time bias. The secondary endpoints included DFS in patients of different characteristics, and safety analyses. This study was registered with the Chinese Clinical Trial Registry (ChiCTR1800015776). Results: A total of 507 patients were included (230 patients in the TCM group; 277 patients in the control group). The median follow-up was 32.1 months. 101 (44%) in the TCM group and 186 (67%) in the control group had disease relapse. The median DFS was not reached in the TCM group and was 19.4 months (95% CI, 14.2 to 24.6) in the control group. The adjusted time-dependent HR was 0.61 (95% CI, 0.47 to 0.78), equalling to a 39% reduction in the risk of disease recurrence with TCM. the number needed to treat to prevent one patient from relapsing was 4.29 (95% CI, 3.15 to 6.73) at 5 years. Similar results were observed in most of subgroups. Patients had a significant improvement in white blood cell decrease, nausea, decreased appetite, diarrhea, pain, and fatigue in the TCM group. Conclusion: TCM may improves DFS and has a better tolerability profile in patients with stage II-IIIA NSCLC receiving standard chemotherapy after complete resection compared with those receiving standard chemotherapy alone. Further studies are warranted.

Clinical Efficacy and Safety of Traditional Medicine Preparations Combined With Chemotherapy for Advanced Pancreatic Cancer: A Systematic Review and Meta-Analysis.

Background: Traditional medicine preparations (TMPs) combined with chemotherapy is widely used for patients with advanced pancreatic cancer (APC); however, its efficacy and safety are still unclear. The purpose of this meta-analysis was to evaluate the clinical efficacy and safety of TMPs combined with chemotherapy for the treatment of APC. Methods: A systematic search of eight electronic databases for randomized controlled trials (RCTs) was conducted from inception to October 15, 2021. Tumor response was identified as primary outcome, whereas quality of life (QoL), cancer biomarkers, and adverse drug reactions (ADRs) were identified as secondary outcomes. Quality of the evidence for each outcome was evaluated by GRADE profiler. Results: In total, 31 RCTs involving 1,989 individuals were included. This meta-analysis showed that TMPs combined with chemotherapy significantly improved the objective response rate (ORR) (RR=1.64, 95% CI [1.43 to 1.88], p <0.00001), disease control rate (DCR) (RR=1.29, 95% CI [1.21 to 1.38], p <0.00001), and QoL (continuous data: SMD=0.81, 95% CI [0.44 to 1.18], p <0.0001, dichotomous data: RR=1.44, 95% CI [1.22 to 1.70], p<0.0001), compared to those with chemotherapy alone. In addition, the combined treatment group also had lower levels of CA19-9 (SMD=-0.46, 95% CI [-0.90 to -0.02], p=0.04) and CEA (SMD=-0.55, 95% CI [-0.93 to -0.17], p=0.004). Moreover, TMPs reduced the ADRs during chemotherapy. Conclusion: This systematic review suggests that TMPs combined with chemotherapy might be a potential option to enhance therapeutic effects and reduce ADRs during the treatment of APC. However, more high-quality randomized controlled trials with more participants are needed. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=209825, identifier PROSPERO Number: CRD42021264938.

Breast cancer prognosis and P-cadherin expression: systematic review and study-level meta-analysis.

OBJECTIVE: P-cadherin can act both as a tumour suppressor and an oncogene. The clinical prognostic value of P-cadherin overexpression in breast cancer (BC) remains unclear. We conducted a study-level meta-analysis to determine whether P-cadherin expression can help predict prognosis in BC. METHODS: A systematic literature search was performed to review eligible studies and clarify the relationship between P-cadherin overexpression and overall survival (OS), disease-free survival (DFS), pathological features, molecular subtypes and molecular phenotypes in BC. RESULTS: Thirty-one studies including 12 332 patients were included. P-cadherin overexpression was correlated with significantly worse OS (HR=1.77, p<0.00001) and DFS (HR=1.96, p<0.00001) than P-cadherin-negative. P-cadherin overexpression could lead to high histological grade (OR=3.33, p<0.00001) and lymph node metastasis (OR=1.62, p<0.00001). Moreover, P-cadherin overexpression was associated with low odds of the luminal A subtype and high odds of the human epidermal growth factor receptor-2 (HER2)-positive and triple-negative subtypes. P-cadherin expression led to low expression of oestrogen and progesterone receptor (OR=0.37 and OR=0.36, respectively, both p<0.00001) and high expression of HER2 (OR=2.31, p<0.00001), Ki-67 (OR=2.79, p<0.00001), epidermal growth factor receptor (OR=5.85, p<0.00001) and cytokeratin 5/6 (OR=6.79, p<0.00001). CONCLUSIONS: P-cadherin was found to be associated with invasiveness and metastasis. P-cadherin expression can probably be a useful biomarker for predicting poor survival and may act as an independent prognostic predictor.

Efficacy and Safety of Astragalus-Containing Traditional Chinese Medicine Combined With Platinum-Based Chemotherapy in Advanced Gastric Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: Astragalus-containing traditional Chinese medicine (TCM) is widely used as adjunctive treatment to platinum-based chemotherapy (PBC) in patients with advanced gastric cancer (AGC) in China. However, evidence regarding its efficacy remains limited. This study aimed to evaluate the efficacy and safety of Astragalus-containing TCM combined with PBC in AGC treatment. METHODS: We searched for literature (up to July 19, 2020) in eight electronic databases. The included studies were reviewed by two researchers. The main outcomes were the objective response rate (ORR), disease control rate (DCR), survival rate, quality of life (QOL), adverse drug reactions (ADRs), and peripheral blood lymphocyte levels. The effect estimate of interest was the risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CIs). Trial sequential analysis (TSA) was used to detect the robustness of the primary outcome and to calculate the required information size (RIS). Certainty of the evidence was assessed using the GRADE profiler. RESULTS: Results based on available literature showed that, compared with patients treated with PBC alone, those treated with Astragalus-containing TCM had a better ORR (RR: 1.24, 95% CI: 1.15-1.34, P < 0.00001), DCR (RR: 1.10, 95% CI: 1.06-1.14, P < 0.00001), 1-year survival rate (RR: 1.41, 95% CI: 1.09-1.82, P = 0.009), 2-year survival rate (RR: 3.13, 95% CI: 1.80-5.46, P < 0.0001), and QOL (RR: 2.03, 95% CI: 1.70-2.43, P < 0.00001 and MD: 12.39, 95% CI: 5.48-19.30, P = 0.0004); higher proportions of CD3+ T cells and CD3+ CD4+ T cells; higher ratio of CD4+/CD8+ T cells; nature killer cells; and lower incidence of ADRs. Subgroup analysis showed that both oral and injection administration of Astragalus-containing TCM increased tumor response. Whether treatment duration was ≥8 weeks or <8 weeks, Astragalus-containing TCM could increase tumor response in AGC patients. Furthermore, Astragalus-containing TCM combined with oxaliplatin-based chemotherapy could increase the ORR and DCR; when with cisplatin, it could only increase the ORR. CONCLUSION: Current low to moderate evidence revealed that Astragalus-containing TCM combined with PBC had better efficacy and less side effects in the treatment of AGC; however, more high-quality randomized studies are warranted. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, identifier CRD42020203486.

Chinese herbal medicine for small cell lung cancer patients: A protocol for a systematic review and meta-analysis.

BACKGROUND: Small cell lung cancer (SCLC) is an aggressive disease. Chemotherapy is the standard treatment for SCLC, but the resistance and the adverse effects of Chemotherapy still remains a major problem. Although Chinese herbal medicine (traditional Chinese medicine) is wildly applied for patients with SCLC in China, the evidence of traditional Chinese medicine in the treatment for SCLC is limited. METHOD: We conducted a systematic search of PubMed, EMBASE, the Chinese National Knowledge Infrastructure, the VIP Information Database, and the Wanfang Database for relevant studies. Only randomized controlled trials were included. Two investigators independently reviewed the included studies and extracted relevant data. The effect estimate of interest was the relative risk or mean difference with 95% confidence intervals. ETHICS AND DISSEMINATION: Ethical approval is not required, as this study is based on the review of published research. This review will be published in a peer-reviewed journal and disseminated both electronically and in print. INPLASY REGISTRATION NUMBER: INPLASY2020110055.

Efficacy and safety of TCM combined with chemotherapy for SCLC: a systematic review and meta-analysis.

BACKGROUND: Chemotherapy is the standard treatment for small cell lung cancer (SCLC), but chemotherapy resistance and adverse reactions remain major problems. Although Traditional Chinese Medicine (TCM) is wildly applied for patients with SCLC in China, the evidence of TCM in the treatment for SCLC is limited. PURPOSE: To evaluate the efficacy and safety of TCM combined with chemotherapy for patients with SCLC. METHOD: We conducted a systematic search of PubMed, EMBASE, the Chinese National Knowledge Infrastructure, the VIP Information Database, and the Wanfang Database for randomized-controlled trials (RCTs) that are relevant. The included studies were reviewed by two investigators, with relevant data extracted independently. The effect estimate of interest was the relative risk (RR) or mean difference with 95% confidence intervals (95% CIs). RESULTS: 22 RCTs involving 1887 patients were included in this study. Compared with patients treated with chemotherapy© alone, those with Chinese herbal medicine and chemotherapy (TCM-C) had better therapeutic effects (RR = 1.295, 95% CI 1.205-1.391, P < 0.001), KPS scores (RR = 1.310, 95% CI 1.210-1.418, P < 0.001), 1-year survival rate (RR = 1.282, 95% CI 1.129-1.456, P < 0.001), 3-year survival rate (RR = 2.109, 95% CI 1.514-2.939, P < 0.001), and 5-year survival rate (RR = 2.373, 95% CI 1.227-4.587, P = 0.01). The incidence of gastrointestinal reaction (RR of = 0.786, 95% CI 0.709-0.870, P < 0.000) and bone marrow depression (RR = 0.837, 95% CI 0.726-0.965, P = 0.014) in TCM-C group were lower than that in the C group. CONCLUSION: The systematic review indicated that TCM combined with chemotherapy may improve therapeutic effect, quality of life, and prolong survival time. More large-scale and higher quality RCTs are warranted to support our findings. PROSPERO REGISTRATION NUMBER: CRD42016038016.

Prognostic significance of E-cadherin expression in prostatic carcinoma: A protocol for systematic review and meta-analysis.

BACKGROUND: Increasing studies were performed to explore the prognostic value of E-cadherin in prostatic carcinoma, however, with inconsistent results. Hence, this systematic review is aimed to evaluate the prognostic role of E-cadherin in patients with prostatic carcinoma (PCa). METHODS: A comprehensive literature search in all available databases will be conducted to identify eligible studies. We will employ hazard ratios (HRs) and 95% confidence intervals (95% CIs) to estimate the correlations between E-cadherin expression and overall survival (OS), disease-free survival (DFS), relapse-free survival (RFS), progression-free survival (PFS) and clinicopathological features. Meta-analysis will be performed using Review Manager (Revman) 5.3.5 software (Cochrane Community, London, United Kingdom) and STATA 14 software (version 14.0; Stata Corp, College Station, TX). RESULTS: This study will provide a high-quality synthesis of current evidence of the correlations between snail expression and OS, DFS/RFS, PFS and clinicopathological features. CONCLUSION: The study will provide updated evidence to assess whether the expression of E-cadherin is in association with poor prognosis in patients with PCa. ETHICS AND DISSEMINATION: It is not necessary for ethical approval because individuals cannot be identified. The protocol will be disseminated in a peer-reviewed journal or presented at a relevant conference. PROSPERO REGISTRATION NUMBER: This systematic review protocol has been registered in the PROSPERO network (No. CRD42019128353).

Efficacy and safety of Yiqi Huoxue Jiedu decoction for the treatment of advanced epithelial ovarian cancer patients: a double-blind randomized controlled clinical trial.

OBJECTIVE: To further evaluate the complementary effect of Yiqi Huoxue Jiedu decoction (YHJD) on patients with advanced epithelial ovarian cancer (EOC). METHODS: All 330 enrolled participants diagnosed with stage Ⅲc EOC were randomly divided into two groups that received YHJD or a placebo. The primary end point was health-related quality of life (HRQL) measured by the functional assessment of cancer therapy-ovary cancer (FACT-O) questionnaire. The secondary end point was progression-free survival (PFS). RESULTS: A total of 299 participants completed the trial with 153 and 146 in YHJD and control groups, respectively. After 6 months of treatment, YHJD increased physical wellbeing (PWB), functional wellbeing (FWB), additional concerns (AC), and the trial outcome index (TOI) (P < 0.05) by various degrees compared with the baseline. YHJD also had notable advantages over the placebo at 3 and 6 months in terms of PWB, FWB, AC (P < 0.05), and TOI (P < 0.01). In addition, YHJD had a significant advantage in terms of PFS compared with the placebo (21 vs 18 months, P < 0.05). No adverse events were reported. CONCLUSION: YHJD is an effective and safe choice as a complementary therapy to improve HRQL and prolong PFS of stage Ⅲc EOC patients.

Study on the treatment of pancreatic cancer with integrated traditional Chinese and Western medicine: A study protocol of a multicenter prospective cohort study.

INTRODUCTION: Pancreatic cancer is one of the most lethal malignancies worldwide. Most patients are diagnosed at an advanced stage, which leads to a poor prognosis and a low survival rate. At present, treatment options for pancreatic cancer are limited, so it is vital to explore new treatments and strategies. Traditional Chinese medicine (TCM) is an important method for cancer prevention and treatment in China. We will conduct a multicenter, prospective cohort study to evaluate the survival and quality of life of patients with advanced pancreatic cancer treated with integrated traditional Chinese and Western medicine, further refine the core pathogenesis of TCM for pancreatic cancer, form a core prescription, and provide clinical data support for the clinical plan of integrated treatment of pancreatic cancer using Chinese and Western medicine; this will aid in the development of the best comprehensive treatment plan for patients. METHODS AND ANALYSIS: This study will recruit patients with stage 3 to 4 pancreatic cancer in 12 medical units from April 2019 to June 2020. Patients will be divided into a Western medicine treatment group and an integrated traditional Chinese and Western medicine treatment group, with a total of 148 patients. Overall survival is the main efficacy index, while the secondary efficacy indexes are progression-free survival, tumor markers, TCM symptom grading scale, quality of life assessment, Eastern Cooperative Oncology Group (ECOG) score, and imaging assessment. A follow-up will be performed every 6 weeks ±1 week. The end point is the death of the patient or the end of the study (October 31, 2021). Statistical analysis will be performed using Statistical Packages of Social Sciences software (SPSS). ETHICS AND DISSEMINATION: This work was supported by Beijing Municipal Science and Technology Commission and approved by the ethics committee of Guang'anmen Hospital, China Academy of Chinese Medical Sciences (Approval No. 2019-016-KY). All patients will sign a written informed consent prior to data collection. The results will be disseminated through peer-reviewed journals and conference presentations and will be openly shared after completion of the trial. TRIAL REGISTRATION: The trial was registered with the Chinese Clinical Trials Registry (ChiCTR1900022632, pre-registration).

Taxane-based chemotherapy and risk of breast cancer-related lymphedema: Protocol for a systematic review and meta-analysis.

BACKGROUND: Many studies were performed to explore the correlation between taxane-based chemotherapy and the risk of breast cancer-related lymphedema (BCRL), however, with inconsistent results. Hence, the purpose of this study is to evaluate whether taxane-based chemotherapy is a risk factor for BCRL. METHODS: A comprehensive systematic search of clinical trials published in the PubMed, Embase and the Cochrane Library databases will be conducted to identify eligible studies up to the date of December 31, 2018. We will employ risk ratios with 95% confidence intervals (95% CIs) to estimate the correlations between taxane-based chemotherapy and BCRL. Meta-analysis will be performed using Stata SE version 12.0 software. RESULTS: The results of this systematic review and meta-analysis will provide a high-quality synthesis of existing evidence of the correlations between taxane-based chemotherapy and the risk of BCRL. CONCLUSION: The protocol will provide updated evidence for the use of taxane-based chemotherapy in postoperative breast cancer patients. ETHICS AND DISSEMINATION: It is not necessary for ethical approval because it is based on published studies. The protocol will be disseminated in a peer-reviewed journal or presented at a topic-related conference. TRIAL REGISTRATION: This systematic review protocol has been registered with a number of CRD42019123989.

TCM therapies combined with chemotherapy for preventing recurrence and metastasis in postoperative II to IIIA NSCLC: A protocol for a systematic review and meta-analysis.

BACKGROUND: Traditional Chinese Medicine (TCM) therapies have been combined with chemotherapy for preventing Recurrence and metastasis in postoperative II to IIIA non-small-cell lung cancer (NSCLC) and the associated better disease-free survival (DFS), but its effects remain elusive. The purpose of this review is to assess the efficacy of TCM therapies as a treatment for postoperative II to IIIA NSCLC. METHODS AND ANALYSIS: Seventh databases will be searched for relevant studies from inception to the present date. We will include randomized controlled trials assessing TCM therapies combined with chemotherapy for preventing Recurrence and metastasis in postoperative II to IIIA NSCLC. The methodological qualities, including the risk of bias, will be evaluated using the Cochrane risk of bias assessment tool, while confidence in the cumulative evidence will be evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. ETHICS AND DISSEMINATION: Ethical approval is not required, as this study is based on the review of published research. This review will be published in a peer-reviewed journal and disseminated both electronically and in print. PROSPERO REGISTRATION NUMBER: The protocol for this systematic review has been registered on PROSPERO under the number CRD42019116594.

Traditional Chinese Medicine Bionic Tiger Bone Powder for the Treatment of AI-Associated Musculoskeletal Symptoms.

Background. Aromatase inhibitors (AIs) are used for adjuvant therapy of breast cancer; however AIMSS (AI-Associated Musculoskeletal Symptoms) can negatively affect quality of life and compliance. Most patients in China moved to TCM (traditional Chinese medicine) for help. TB (tiger bone) is used to treat bone disease, whose main ingredients are calcium and collagen. The objective of this study was to evaluate whether the TB prevented AIMSS in postmenopausal women with ER/PR+ breast cancer. Methods. We conducted a randomized, blind, controlled study of comparing TB versus placebo for 12 weeks in postmenopausal women with breast cancer who have taken AI for less than a month. Patients completed the M-BPI, VAS, and FACT-B at baseline, 6 weeks, and 12 weeks. M-BPI and VAS were used as the primary outcomes. FACT-B was used as the secondary outcome. Serum E2 and FSH were tested every 6 weeks. Results. Of 70 evaluable cases, 8 of 35 patients (22.9%) developed new or worsening point symptoms in TB group, compared to 21 of 35 (60%) in placebo group (P < 0.001). We also found differences between 2 groups in average pain (2 to 5.6), worst pain (3.9 to 8), pain interference severity (1.9 to 5.3), stiffness (2.4 to 6.9), and joint symptom interference (1.8 to 5.7), all P < 0.001; similar findings were seen in VAS value (3 to 6.6) at the end of intervention. HRQoL measured by FACT-B (P < 0.05) was improved. No change of serum estradiol and FSH between two groups. Conclusions. TB appeared to be effective and safe in the prevention of AIMSS. This trial is registered with ChiCTR-IPR-15007081.