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Background Cognitive dysfunction is increasingly recognized as an important complication of diabetes mellitus (DM). Accumulating evidence indicates that the abnormality of cerebrovascular structure and function plays an essential role in diabetic cognitive impairment (DCI), however, changes in cerebrovascular factors have been blurred during the development of diabetes. Objective To evaluate the changes in the structure and function of cerebrovascular in DCI mice and to investigate the changes of cerebral angiogenesis and stability factors during the development of DM. Methods Diabetes was induced by feeding with high-fat diet combined with intraperitoneal injection of streptozotocin (STZ,120 mg/kg). Cognitive function was evaluated at different stages of DM, cerebral neovascularization, blood-brain barrier (BBB) permeability and hippocampal neurons were measured of DCI mice, and the expression of vascular endothelial growth factor (VEGF) and platelet-derived growth factor receptor β (PDGFRβ) in hippocampus was detected during the development of DM. Results With the progress of diabetes, the learning and memory ability of mice gradually decreased, and DCI mice showed neuronal degeneration, increased BBB permeability and pathological cerebral neovascularization. Moreover, the expression of VEGF in the hippocampus increased first and then decreased at DM+8week, PDGFRβ decreased continuously with the development of diabetes. Conclusions Our results demonstrate that DCI may be attributed to the dynamic expression of VEGF/PDGFRβ in diabetic hippocampus, and pathological cerebral neovascularization, increased BBB permeability and neuronal degeneration are the key links.

Background and aim Activated hepatic stellate cells (HSCs) are the most critical cells responsible for liver fibrosis, and platelet-derived growth factor (PDGF) is the most prominent mitogen for HSCs in fibrogenesis. This study aimed to explore the potential of gadolinium (Gd)-labeled cyclic peptides (pPB) targeting PDGF receptor-β (PDGFR-β) as a magnetic resonance imaging (MRI) radiotracer to identify the progression of liver fibrosis by imaging hepatic PDGFR-β expression. Methods Mice treated with carbon tetrachloride (CCl4 ) were used to mimic hepatic fibrosis in vivo. The binding activity of FITC-labeled pPB to PDGFR-β was assessed in cultured human HSCs (HSC-LX2). MRI was performed to visualize hepatic PDGFR-β expression in mice with different degrees of liver fibrosis after Gd-labeled pPB was injected. Results Hepatic PDGFR-β expression level was correlated with the severity of liver fibrosis, and the majority of cells expressing PDGFR-β were found to be activated HSCs in fibrotic livers. Culture-activated human HSCs expressed abundant PDGFR-β, and FITC-labeled pPB could bind to these cells in a concentration-dependent and time-dependent manner. With Gd-labeled pPB as a tracer, an MRI modality demonstrated that the relative hepatic T1-weighted MRI signal value progressively increased with the severity of hepatic fibrosis and reduced with remission. Conclusions Hepatic PDGFR-β expression reflects the progression of hepatic fibrosis, and MRI using Gd-labeled pPB as a tracer exhibits potential for distinguishing liver fibrosis staging in mice.

Peritoneal metastases in colorectal cancer (CRC) belong to Consensus Molecular Subtype 4 (CMS4) and are associated with poor prognosis. Conventional imaging modalities, such as Computed Tomography (CT) and Fluorodeoxyglucose-Positron Emission Tomography (FDG-PET), perform very poorly in the detection of peritoneal metastases. However, the stroma-rich nature of these lesions provides a basis for developing molecular imaging strategies. In this study, conducted from 2019 to 2021, we aimed to generate a Platelet-Derived Growth Factor Receptor beta (PDGFRB)-binding molecular imaging tracer for the detection of CMS4 CRC, including peritoneal metastases. The expression of PDGFRB mRNA discriminated CMS4 from CMS1-3 (AUROC = 0.86 (95% CI 0.85–0.88)) and was associated with poor relapse-free survival. PDGFRB mRNA and protein levels were very high in all human peritoneal metastases examined (n = 66). Therefore, we generated a PDGFRB-targeting llama nanobody (VHH1E12). Biotin-labelled VHH1E12 bound to immobilized human and mouse PDGFRB with high affinity (EC50 human PDGFRB = 7 nM; EC50 murine PDGFRB = 0.8 nM), and to PDGFRB-expressing HEK293 cells grown in vitro. A pharmacokinetic analysis of IRDye-800CW-conjugated VHH1E12 in mice showed that the plasma half-life was 6 min. IRDye-800CW-conjugated VHH1E12 specifically accumulated in experimentally induced colorectal cancer peritoneal metastases in mice. A tissue analysis subsequently demonstrated co-localization of the nanobody with PDGFRB expression in the tumour stroma. Our results demonstrate the potential value of PDGFRB-targeted molecular imaging as a novel strategy for the non-invasive detection of CMS4 CRC, in particular, peritoneal metastases.

BACKGROUND AND AIMS Existing therapeutic approaches to treat cholangiocarcinoma (CCA) have limited effectiveness, prompting further study to develop therapies for CCA. We report a mechanistic role for the heparan sulfate editing enzyme sulfatase 2 (SULF2) in CCA pathogenesis. APPROACH AND RESULTS In silico analysis revealed elevated SULF2 expression in human CCA samples, occurring partly through gain of SULF2 copy number. We examined the effects of knockdown or overexpression of SULF2 on tumor growth, chemoresistance, and signaling pathway activity in human CCA cell lines in vitro. Up-regulation of SULF2 in CCA leads to increased platelet-derived growth factor receptor beta (PDGFRβ)-Yes-associated protein (YAP) signaling activity, promoting tumor growth and chemotherapy resistance. To explore the utility of targeting SULF2 in the tumor microenvironment for CCA treatment, we tested an anti-SULF2 mouse monoclonal antibody, 5D5, in a mouse CCA xenograft model. Targeting SULF2 by monoclonal antibody 5D5 inhibited PDGFRβ-YAP signaling and tumor growth in the mouse xenograft model. CONCLUSIONS These results suggest that SULF2 monoclonal antibody 5D5 or related agents may be potentially promising therapeutic agents in CCA.

Malignant pleural mesothelioma (MPM) has a rich stromal component containing mesenchymal fibroblasts. However, the properties and interplay of MPM tumor cells and their surrounding stromal fibroblasts are poorly characterized. Our objective was to spatially profile known mesenchymal markers in both tumor cells and associated fibroblasts and correlate their expression with patient survival. The primary study cohort consisted of 74 MPM patients, including 16 patients who survived at least 60 months. We analyzed location-specific tissue expression of seven fibroblast markers in clinical samples using multiplexed fluorescence immunohistochemistry (mfIHC) and digital image analysis. Effect on survival was assessed using Cox regression analyses. The outcome measurement was all-cause mortality. Univariate analysis revealed that high expression of secreted protein acidic and cysteine rich (SPARC) and fibroblast activation protein in stromal cells was associated with shorter survival. Importantly, high expression of platelet-derived growth factor receptor beta (PDGFRB) in tumor cells, but not in stromal cells, was associated with shorter survival (hazard ratio [HR] = 1.02, p

Eosinophilia is a common finding in the pediatric age group. While the majority of mild eosinophilia cases are benign and due to reactive causes, persistent hypereosinophilia is uncommon and requires prompt clinical evaluation because of the potential risk of end-organ damage associated with it. Given the broad differential diagnoses of eosinophilia, it is essential to have a systematic approach to the evaluation of unexplained eosinophilia in children. Here, we discuss the case of a 2-year-old child who presented with very high eosinophil counts. A systematic workup of the case helped us in arriving at a rare diagnosis of platelet-derived growth factor receptor-beta (PDGFRB)-rearranged clonal eosinophilia. Identification of such an entity is important as it has therapeutic implications, and early recognition helps in preventing associated end-organ damage by instituting appropriate therapy. Such cases of eosinophilia associated with platelet-derived growth factor receptor-alpha and PDGFRB rearrangement respond dramatically to imatinib.

Background: Although preclinical studies have indicated that stroma cells can modulate the radiosensitivity of tumor cells, non-leukocytic stroma cells have not yet been explored as potential predictive markers for radiotherapy (RT) through systematic analyses of clinical samples. Platelet-derived growth factor receptor beta (PDGFRb) is a key regulator of fibroblasts, pericytes and smooth muscle cells. A high expression of PDGFRb in tumor-associated stroma has previously been associated with worse recurrence free and breast cancer specific survival as well as reduced tamoxifen sensitivity in invasive breast cancer. Purpose: To analyze the prognostic and predictive impact of stromal PDGFRb regarding ipsilateral breast tumor recurrence (IBTR) and any recurrence in a large randomized RT trial. Methods: Stromal PDGFRb expression was assessed by immunohistochemical staining of tissue microarrays (TMAs) with 958 tumors from the SweBCG91RT trial (Swedish Breast Cancer Group 91 Radiotherapy). The trial enrolled node-negative, stage I or IIA breast cancer patients, who were randomized to postoperative RT or not after breast conserving surgery. Stained TMAs were evaluated by two independent raters for PDGFRb staining intensity (0/negative; 1/low; 2/moderate; 3/high) and positive stroma fraction (0/0%; 1/1-10%; 2/11-50; 3/51-75%; 4/76-100%). The evaluations of both raters were averaged and the product between the two scoring metrics was formed. For final analysis the data was split in tertiles, as predefined, and referred to as PDGFRb low, medium or high score group. Outcomes were analyzed at 10 years of follow-up. Results: A high PDGFRb score was correlated with ER negativity (p=0.003,), young age (p With regard to prognosis, a significantly increased risk for any recurrence was detected in univariable analysis for patients with a medium (HR 1.57, CI95% 1.11-2.23, p=0.011) or high PDGFRb score (HR 1.49, CI95% 1.06-2.10, p=0.021) compared to the PDGFRb low score group. The significance remained for the PDGFRb medium (HR 1.47, CI95% 1.03-2.11, p=0.034) but not the PDGFRb high score group (HR 1.32, CI95% 0.93-1.88, p=0.125) in a multivariable analysis including grade, age and RT. The benefit of RT regarding the risk of IBTR was significant in the PDGFRb low (HR 0.28, CI95% 0.12-0.65, p=0.003) and medium (HR 0.32, CI95% 0.16-0.61, p=0.001) score groups but not in the PDGFRb high (HR 0.61, CI95% 0.35-1.07, p=0.086) score group in a multivariable analysis including grade and age. The risk reduction from RT regarding any recurrence was also less pronounced in the PDGFRb high (HR 0.73, CI95% 0.48-1.12, p=0.149) score group compared to the PDGFRb low (HR 0.57, CI95 0.32-1.03, p=0.065) and medium (HR 0.46, CI95% 0.28-0.75, p=0.002) score groups in multivariable analysis. No significant interaction between RT and PDGFRb expression could however be detected for IBTR (p=0.14) or any recurrence (p=0.33). Conclusion: A higher PDGFRb score conferred a negative prognosis with increased risk of any recurrence in univariable analyses, which in part can be explained by its association with ER negativity, young age and grade. A predictive effect of RT benefit from PDGFRb could not be confirmed although a tendency toward less benefit was observed in the patient group with the highest PDGFRb score. Citation Format: Carina Strell, Reidunn J Edelmann, Axel Stenmark Tullberg, Per Malmström, Mårten Fernö, Arne Östman, Erik Holmberg, Per Karlsson. Prognostic and predictive impact of stroma cells defined by platelet derived growth factor receptor beta in early breast cancer: Results from the randomized SweBGR91RT trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-08.

Background: With the introduction of mammography the detection of breast ductal carcinoma in situ (DCIS) has increased four- to sevenfold. Local recurrences occur only in a minority of patients. Radiotherapy (RT) is presently used without biomarker guidance. Therefore, novel biomarkers predicting benefit of radiotherapy are warranted to prevent overtreatment. Studies on RT response-predictive biomarkers in DCIS have focused on tumor cell features and often neglected the tumor-associated stroma, despite growing evidence of its active influence on treatment response including RT. The platelet derived growth factor receptors alpha and beta (PDGFRa and -b) signaling pathways are major regulators of stroma cells. Recent studies have indicated a loss of PDGFRa in the tumor-associated stroma of DCIS while PDGFRb remains high and patients with PDGFRa(low)/PDGFRb(high) expression had a significant increased risk for any tumor recurrence. A limitation of this study was though the usage of a population-based cohort, thus not allowing firm conclusions on the impact of the marker on natural course of the disease or benefit to treatment. Purpose: To explore if stromal expression of PDGFRb serves as prognostic as well as response-predictive biomarker for RT benefit with regard to ipsilateral breast tumor recurrence (IBTR) and overall survival (OS) for DCIS patients within a large and clinically well-annotated randomized trial. Method: Immunohistochemical staining of PDGFRb was performed on full tissue sections of 705 patients from the SwedDCIS cohort, a randomized RT trial after breast-conserving surgery. Stromal PDGFRb expression was evaluated by two independent raters in up to ten high power fields within the tumor associated stroma region and scored as 0/negative, 1/low average stroma intensity, 2/moderate average stroma intensity or 3/high average stroma intensity. An average PDGFRb score was calculated for each tumor. The final data was split at median defining PDGFRb low and high patient groups. Outcomes were analyzed at 10 years of follow-up. Results: High stromal PDGFRb was correlated with young age (p=0.003 Spearman’s Rank correlation). In multivariable Cox regression including RT, age, size, screen detection and tumor margin status, the PDGFRb high patient group showed a trend to worse prognosis with regard to IBTR (HR 1.40, CI95% 0.96-2.04, p=0.08) and OS (HR 1.76, CI95% 1.00-3.09, p=0.05). Benefit of radiotherapy on IBTR (in situ and invasive) was absent in the PDGFRb high patient group (HR 0.76, CI95% 0.47-1.22, p=0.25)), but clearly detected in the PDGFRb low group (HR 0.29, CI95% 0.15-0.55, p RT benefit was also restricted to the PDGFRb low patient group in separate analyses for in situ IBTR (PDGFRb low group HR 0.27, CI95% 0.12-0.60, p=0.001, versus PDGFRb high group HR 0.66, CI95% 0.34-1.29, p=0.22) or invasive IBTR (PDGFRb low group HR 0.33, CI95% 0.11-0.98, p=0.045, versus PDGFRb high group HR 0.88, CI95% 0.45-1.73, p=0.71). Significant interactions between PDGFRb group and RT were not detected in these sub-analyses (p=0.11 for in situ and p=0.15 for invasive IBTR). Conclusion: These data suggests high stromal PDGFRb as a marker of potential clinical utility for RT resistance regarding IBTR in DCIS patients. Furthermore, the study supports the hypothesis of a fibroblast-mediated modulation of RT-sensitivity in DCIS cells. Experimental model studies, investigating the biological mechanisms and potential therapeutic relevance are therefore highly motivated. Citation Format: Carina Strell, Dick Folkvaljon, Erik Holmberg, Per Karlsson, Jonas Bergh, Troy Bremer, Lars A. Akslen, Fredrik Wärnberg, Arne Östman. High stromal platelet derived growth factor receptor beta predicts absence of benefit of radiotherapy after breast conserving surgery in breast ductal carcinoma in situ within the SweDCIS randomized trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-10-24.

The relationship between aging and restenosis are unclear. The purposes of this study were to investigate the possible pathological role and mechanism of aging on formation of restenosis. Our data indicated that cell proliferation and migration of the oxidative stress-induced senescent vascular smooth muscle cells were obviously desensitized to stimulation by platelet-derived growth factor (PDGF)-BB, which may have been caused by suppression of promoter activity, transcription, translation, and activation levels of PDGF receptor (PDGFR)-β. The analyzed data obtained from the binding array of transcription factors (TFs) showed that binding levels of eighteen TFs on the PDGFR-β promoter region (-523 to -1) were significantly lower in senescent cells compared to those of non-senescent cells. Among these TFs, the bioinformatics prediction suggested that the putative binding sites of ten TFs were found in this promoter region. Of these, transcriptional levels of seven TFs were markedly reduced in senescent cells. The clinical data showed that the proportion of restenosis was relatively lower in the older group than that in the younger group. Our study results suggested that a PDGFR-β-mediated pathway was suppressed in aging cells, and our clinical data showed that age and the vascular status were slightly negatively correlated in overall participants.

Aggressive therapies for patients with metastatic Wilms tumor (WT) with subsequent severe late effects warrant the search for novel therapies. The role of focal adhesion kinase (FAK), a non-receptor tyrosine kinase important in pediatric solid tumor development and progression, has not been examined in metastatic WT. Using a novel patient-derived xenograft (PDX) of a primary and matched, isogenic, metastatic WT, the hypothesis of the current study was that FAK would contribute to metastatic WT and small molecule inhibition would decrease tumor growth. Immunohistochemical staining, immunoblotting, cell viability and proliferation assays, cell cycle analysis, and cellular motility and attachment-independent growth assays were performed. FAK was present and phosphorylated in both WT PDXs and in the human samples from which they were derived. FAK inhibition decreased cellular survival, proliferation, and cell cycle progression in both PDXs but only significantly decreased migration, invasion, and attachment-independent growth in the primary WT PDX. Kinomic profiling revealed that platelet-derived growth factor receptor beta (PDGFRβ) may be affected by FAK inhibition in WT. Pharmacologic inhibition of FAK and PDGFRβ was synergistic in primary WT PDX cells. These findings broaden the knowledge of metastatic WT and support further investigations on the potential use of FAK and PDGFRβ inhibitors.

Liver fibrosis is a common characteristic of chronic liver diseases. The activation of hepatic stellate cells (HSCs) plays a key role in fibrogenesis in response to liver injury, yet the mechanism by which damaged hepatocytes modulate the activation of HSCs is poorly understood. Our previous studies have established that liver-specific deletion of O-GlcNAc transferase (OGT)leads to hepatocyte necroptosis and spontaneous fibrosis. Here, we report that OGT-deficient hepatocytes secrete trefoil factor 2 (TFF2) that activates HSCs and contributes to the fibrogenic process. The expression and secretion of TFF2 are induced in OGT-deficient hepatocytes but not in WT hepatocytes. TFF2 activates the platelet-derived growth factor receptor beta signaling pathway that promotes the proliferation and migration of primary HSCs. TFF2 protein expression is elevated in mice with carbon tetrachloride-induced liver injury. These findings identify TFF2 as a novel factor that mediates intercellular signaling between hepatocytes and HSCs and suggest a role of the hepatic OGT–TFF2 axis in the process of fibrogenesis.

Mosquito-borne Japanese encephalitis virus (JEV) causes serious illness worldwide and is associated with high morbidity and mortality. To identify potential host therapeutic targets, a high-throughput receptor tyrosine kinase small interfering RNA library screening was performed with recombinant JEV particles. Platelet-derived growth factor receptor beta (PDGFRβ) was identified as a hit after two rounds of screening. Knockdown of PDGFRβ blocked JEV infection and transcomplementation of PDGFRβ could partly restore its infectivity. The PDGFRβ inhibitor imatinib, which has been approved for the treatment of malignant metastatic cancer, protected mice against JEV-induced lethality by decreasing the viral load in the brain while abrogating the histopathological changes associated with JEV infection. These findings demonstrated that PDGFRβ is important in viral infection and provided evidence for the potential to develop imatinib as a therapeutic intervention against JEV infection.

Regorafenib is an oral multi‑kinase inhibitor which targets tumor angiogenesis, the tumor microenvironment and oncogenesis. Based on this mode of action, regorafenib has a broad spectrum of toxicities. However, at present, few reports have focused on autoimmune adverse events. We report a first case of regorafenib‑induced exacerbation of chronic immune thrombocytopenic purpura in remission during treatment for the patients with heavily treated advanced colorectal cancer. This case report highlights the need for caution with regard to regorafenib treatment in patients with cancer with concomitant immune thrombocytopenic purpura.

We have previously demonstrated that the transcription co-factor yes-associated protein 1 (YAP1) promotes vascular smooth muscle cell (VSMC) de-differentiation. Yet, the role and underlying mechanisms of YAP1 in neointima formation in vivo remain unclear. The goal of this study was to investigate the role of VSMC-expressed YAP1 in vascular injury-induced VSMC proliferation and delineate the mechanisms underlying its action. Experiments employing gain- or loss-of-function of YAP1 demonstrated that YAP1 promotes human VSMC proliferation. Mechanistically, we identified platelet-derived growth factor receptor beta (PDGFRB) as a novel YAP1 target gene that confers the YAP1-dependent hyper-proliferative effects in VSMCs. Furthermore, we identified TEA domain transcription factor 1 (TEAD1) as a key transcription factor that mediates YAP1-dependent PDGFRβ expression. ChIP assays demonstrated that TEAD1 is enriched at a PDGFRB gene enhancer. Luciferase reporter assays further demonstrated that YAP1 and TEAD1 co-operatively activate the PDGFRB enhancer. Consistent with these observations, we found that YAP1 expression is upregulated after arterial injury and correlates with PDGFRβ expression and VSMC proliferation in vivo. Using a novel inducible SM-specific Yap1 knockout mouse model, we found that the specific deletion of Yap1 in adult VSMCs is sufficient to attenuate arterial injury-induced neointima formation, largely due to inhibited PDGFRβ expression and VSMC proliferation. Our study unravels a novel mechanism by which YAP1/TEAD1 promote VSMC proliferation via transcriptional induction of PDGFRβ, thereby enhancing PDGF-BB downstream signaling and promoting neointima formation.

Background: Activated hepatic stellate cells (HSCs) are the most critical cell responsible for liver fibrosis. In liver fibrogenesis, platelet-derived growth factor (PDGF) is the most prominent mitogen for HSCs. This study aims to explore the potential of gadolinium (Gd)-labeled cyclic peptides (pPB) targeted to PDGF receptor-β (PDGFR-β) as an MRI radiotracer to identify the progress of liver fibrosis by imaging hepatic PDGFR-β expression. Methods: Mouse models of liver fibrosis caused by bile duct ligation (BDL) and CCl 4 treatment were both used to determine the association of hepatic PDGFR-β expression and the progress of hepatic fibrosis. The binding activity of FITC-labeled pPB to PDGFR-β was assessed in culture-activated human HSCs (HSC-LX2). MR imaging was performed to visualize hepatic PDGFR-β expression in mice with different degrees of liver fibrosis after Gd-labeled pPB were injected. Findings: Hepatic PDGFR-β expression level was found to be paralleled with the severity of liver fibrosis, which was increased with the progression of fibrosis and reduced with the regression. Majority of cells expressing PDGFR-β was determined to be activated HSCs in fibrotic livers. Culture-activated HSC-LX2 expressed abundant PDGFR-β, and FITC-labeled pPB could bind to HSC-LX2 in a concentration and time dependent manner. Interpretation: With Gd-labeled pPB as a tracer, the relative hepatic T1-weighed MR signal value was increased progressively along with severity of hepatic fibrosis and reduced with the remission, suggesting that hepatic PDGFR-β expression reflects the progress of hepatic fibrosis. MR imaging using Gd-labeled pPB as a tracer may distinguish different stages of liver fibrosis in mice. Funding Statement: This work was supported by the National Natural Science Foundation of China (Grant NO. 81270007 & 81670513 to Li F), Shanghai Talent Development Funds (Grant NO. 201304 to Li F), Shanghai Rising-Star Program (Grant NO. 13QA1400700 to Li F), And Shanghai Outstanding Young Talent Training Plan in Health System (Grant NO. 13YO56 to Li F). Declaration of Interests: The authors declare no conflict of interests. Ethics Approval Statement: The study was approved by Institutional Ethical Committee of Animal Experimentation, all experiments and postoperative animal care procedures were performed according to the governmental and international guidelines on animal experimentation.

Wei Xiao,1,2 Yi Que,1,2 Ruiqing Peng,1,2 Ya Ding,1,2 Jingjing Zhao,1,2 Xizhi Wen,1,2 Desheng Weng,1,2 Xiaoshi Zhang,1,2 Yuanxiang Guan,2,3,* Xing Zhang1,2,* 1Melanoma and Sarcoma Medical Oncology Unit, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China; 2State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China; 3Department of Gastric Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China *These authors equally contributed to the work Abstract: While traditional cytotoxic agents play a limited role in advanced dermatofibrosarcoma protuberans (DFSP), the treatment of sunitinib for patients with advanced DFSP after imatinib failure is not well defined. The objective of this case report was to analyze the relationship between molecular mechanisms and clinical outcomes of sunitinib treatment in patients with advanced DFSP after imatinib failure. In this case report, a 37-year-old man suffered from advanced DFSP progression after surgical operation, microwave ablation, and chemotherapy. The immunohistochemistry in this patient revealed abundant expression of platelet-derived growth factor receptor-beta on tumor cells, which is one of the drug targets of sunitinib. The nucleotide sequence analysis revealed COL1A1-PDGFB fusion transcripts in this patient. Thus, we treated the patient with sunitinib, a multi-targeted tyrosine kinase inhibitor, after imatinib failure. After treatment with sunitinib, the patient exhibited a partial response and 9 months’ progression-free survival without significant adverse drug effects. In our case, the patient with advanced DFSP experienced a favorable outcome in 9-months’ progression-free survival and a significant improvement of quality of life without serious side effects after sunitinib treatment. Therefore, sunitinib could serve as another treatment option for patients with advanced DFSP. Keywords: COL1A1-PDGFB fusion gene, dermatofibrosarcoma protuberans, platelet-derived growth factor receptor-beta, sunitinib

The present study aimed to investigate the effects of ethanol extract from Brucea javanicaseed (EEBJS) on the angiogenesis of human umbilical vein endothelial cells (HUVECs) and the possible molecular signal involved. Firstly, a Matrigel-based in vitro angiogenesis assay demonstrated that EEBJS inhibited the angiogenesis of HUVECs in a dose-dependent manner. Then by using porcine aortic endothelial cells which stably express human PDGFR-beta, we found that the inhibition of angiogenesis was mediated by PDGFR-beta. Taken together, we conclude that EEBJS inhibited the angiogenesis function of the vascular endothelial cells mediated by PDGFR-beta, and postulate that it might contribute to the therapeutic effects of EEBJS on malignant tumors.

Objective: microvascular angina (MVA) is a coronary microcirculation disease. Research on microcirculatory dysfunction has revealed several biomarkers involved in the etiopathogenesis of MVA. Platelet-derived growth factor receptor β (PDGFR-β) and brain-derived neurotrophic factor (BDNF) are 2 biomarkers associated with microcirculation, particularly pericytes function. The aim of this study was to investigate the role of PDGFR-β and BDNF in MVA. Methods: ninety-one patients (median age, 56 y; age range, 40–79 y; 36 men) with MVA and 61 control group subjects (median age, 52 y; age range, 38–76 y; 29 men) were included in the study. Serum concentrations of PDGFR-β and BDNF were measured with commercially available enzyme-linked immunosorbent assay kits. Results: PDGFR-β [2.82 ng/ml; interquartile range (IQR), 0.57–7.79 ng/ml vs. 2.27 ng/ml; IQR, 0.41–7.16 ng/ml; p, NA

The spectrum of clinical consequences of variants in the Platelet derived growth factor receptor beta (PDGFRB) gene is wide. Missense variants leading to variable loss of signal transduction in vitro have been reported in the idiopathic basal ganglia calcification (IBGC) syndrome Type 4. In contrast, gain-of-function variants have been reported in infantile myofibromatosis, Penttinen syndrome, and Kosaki overgrowth syndrome. Here, we report a patient harboring a novel postzygotic variant in PDGFRB (c.1682_1684del, p.[Arg561_Tyr562delinsHis]) and presenting severe cerebral malformations, intracerebral calcifications, and infantile myofibromatosis. This observation expands the phenotype associated with PDGFRB variants and illustrates the wide clinical spectrum linked to dysregulation of PDGFRB.

Specific classes of de novo heterozygous gain-of-function pathogenic variants of the PDGFRB (platelet-derived growth factor receptor-beta) cause a distinctive overgrowth syndrome, named the Kosaki overgrowth syndrome (KOGS) (OMIM #616592). Until now, six patients with this condition have been reported in the literature. In addition to skeletal overgrowth, these patients exhibit hyperelastic, translucent, and fragile skin, scoliosis, progressive loss of subcutaneous adipose tissue, skull deformity, infantile myofibromas, neuropsychiatric symptoms, and arachnoid cysts in the posterior fossa and periventricular white matter signal abnormalities on neuroimaging. This constellation of phenotypes clearly distinguishes KOGS from other PDGFRB-related disorders, including idiopathic basal ganglia calcification, infantile myofibroma, and Penttinen-type premature aging syndrome. From a molecular standpoint, PDGFRB is a dimeric receptor tyrosine kinase that plays critical roles in cell growth and tumorigenesis. The two known types of pathogenic variants (p.(Pro584Arg) and p.(Trp566Arg)) of the PDGFRB that cause KOGS are exclusively located in the juxtaglomerular domain that regulates autoactivation/inhibition of PDGFRB. In-vitro evidence suggests that p.(Pro584Arg) represents a gain-of-function pathogenic variant. Inhibition of PDGFRB activity using multi-kinase inhibitors appears to be a potentially promising therapeutic approach. Investigation of the molecular mechanisms underlying the pathogenesis of this disease using induced pluripotent stem cells is under way. Presence of skeletal overgrowth, distinctive facial features, characteristic hyperelastic and fragile skin, and cerebral white matter lesions with neuropsychiatric symptoms should prompt genetic analysis of the PDGFRB.

Malignant pleural mesothelioma (MPM) is a cancer of the pleural cavity resistant to chemotherapy. The identification of novel therapeutic targets is needed to improve its poor prognosis. Following a review of literature and a screening of specimens we found that platelet-derived growth factor receptor beta (PDGFRB) is over-expressed, but not somatically mutated, in MPM tissues. We aimed to ascertain whether PDGFRB is a MPM-cancer driver gene. The approaches employed included the use of gene silencing and the administration of small molecules, such as crenolanib and imatinib (PDGFR inhibitors) on MPM cell lines (IstMes2, Mero-14, Mero-25). Met5A cells were used as non-malignant mesothelial cell line. PDGFRB-silencing caused a decrease in the proliferation rate, and a reduced colony formation capacity, as well as an increase of the share of cells in sub-G1 and in G2 phase, and increased apoptotic rate of MPM cell lines. Loss of migration ability was also observed. Similar, or even further enhanced, results were obtained with crenolanib. Imatinib showed the least effective activity on the phenotype. In conclusion, our study highlights PDGFRB as target with a clear role in MPM tumorigenesis and provided a rationale to explore further the efficacy of crenolanib in MPM patients, with promising results.

Abnormal platelet-derived growth factor receptor (PDGFR)-mediated signaling may cause hematologic neoplasm. The PDGFR beta (PDGFRB) gene, located at chromosome band 5q31-33, forms a fusion gene as a result of chromosome translocation. Although patients with PDGFRB rearrangement mostly present with myeloproliferative neoplasm and eosinophilia, acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) have also been reported in this population. Treatment with imatinib mesylate alone has been shown to have excellent long-term efficacy against myeloproliferative neoplasms; however, its long-term effects on ALL and AML have not been elucidated. A 75-year-old man was diagnosed with acute myeloid leukemia having the PDGFRB and cGMP-dependent protein kinase 2 fusion gene with additional genetic abnormalities. Continuous therapy with single-agent imatinib mesylate resulted in cytogenetic remission and decreased molecular burden for 9 months; however, the leukemia subsequently recurred, and the patient died 1 year after initiation of treatment. This case report supports the importance of cytogenetic analysis during patient screening.

金沢大学疾患モデル総合研究センター, Platelet-derived growth factor receptor beta (PDGFRβ) affects in numerous human cancers and has been recognized as a promising molecular target for cancer therapies. The overexpression of PDGFRβ could be a biomarker for cancer diagnosis. Radiolabeled ligands having high affinity for the molecular target could be useful tools for the imaging of overexpressed receptors in tumors. In this study, we aimed to develop radiobrominated PDGFRβ ligands and evaluate their effectiveness as PDGFRβ imaging probes. The radiolabeled ligands were designed by modification of 1-{2-[5-(2-methoxyethoxy)-1H- benzo[d]imidazol-1-yl]quinolin-8-yl}piperidin-4-amine (1), which shows selective inhibition profile toward PDGFRβ. The bromine atom was introduced directly into C-5 of the quinoline group of 1, or indirectly by the conjugation of 1 with the 3-bromo benzoyl group. [77Br]1-{5-Bromo-2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinoline-8-yl}piperidin-4-amine ([77Br]2) and [77Br]-N-3-bromobenzoyl-1-{2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinolin-8-yl}-piperidin-4-amine ([77Br]3) were prepared using a bromodestannylation reaction. In a cellular uptake study, [77Br]2 and [77Br]3 more highly accumulatd in BxPC3-luc cells (PDGFRβ-positive) than in MCF7 cells (PDGFRβ-negative), and their accumulation was significantly reduced by pretreatment with inhibitors. In biodistribution experiments, [77Br]2 accumulation was higher than [77Br]3 accumulation at 1 h postinjection. These findings suggest that [76Br]2 is more promising for positron emission tomography (PET) imaging of PDGFRβ than [76Br]3. © 2018 The Author(s)., CC-BY 4.0

The establishment of a fully functional blood vascular system requires elaborate angiogenic and vascular maturation events in order to fulfill organ-specific anatomical and physiological needs. Although vascular mural cells, i.e. pericytes and vascular smooth muscle cells, are known to play fundamental roles during these processes, their characteristics during vascular development remain incompletely understood. In this report, we utilized transgenic reporter mice in which mural cells are genetically labeled to examine developing vascular mural cells in the central nervous system (CNS). We found platelet-derived growth factor receptor β gene ( Pdgfrb)-driven EGFP reporter expression as a suitable marker for vascular mural cells at the earliest stages of mouse brain vascularization. Furthermore, the combination of Pdgfrb and NG2 gene (Cspg4) driven reporter expression increased the specificity of brain vascular mural cell labeling at later stages. The expression of other known pericyte markers revealed time-, region- and marker-specific patterns, suggesting heterogeneity in mural cell maturation. We conclude that transgenic reporter mice provide an important tool to explore the development of CNS pericytes in health and disease.

Background Myelofibrosis (MF) is characterized by accumulation of stromal cells and extracellular matrix. Progression of fibrosis is an important clinical issue and monitoring is required for new therapeutic approaches. Currently, the quantification is based on semiquantitative evaluation of reticulin silver stained slides. We recently reported that platelet derived growth factor receptor beta (PDGFRβ) expression in fibroblasts is a useful marker of stromal activation. PDGFRβ expression based scores represent significant differences in different MF grade which provides optimal source of quantification. In this study, slide-based measurements were performed to support correlations of PDGFRβ expression with MF grade. Methods Scanned image tiles from 79 bone marrow samples (BM) with different MF grades were evaluated for PDGFRβ-related IHC parameters. Following the determination of immunopositive (brown component) and total area (region of interest) of the BM, PDGFRβ related image parameters were defined and evaluated in comparison with the classical reticulin based grading. Results Eight PDGFRβ expression related image parameters showed excellent correlation with the MF grade (correlation coefficient ranging between 0.79 and 0.83) and with PDGFRβ score (0.76–0.87). Despite the significant sample heterogeneity, the parameters showed significant differences between fibrotic and nonfibrotic cases and between mild and advanced fibrosis. Distribution of values within a particular specimen emphasizes the heterogeneity of bone marrow involvement which may cause difficulties in semiquantitative methods. Conclusions Our results clearly demonstrated the correlation between MF and PDGFRβ expression considering all relevant areas in BM samples. This method provides good basis for follow-up comparison of the fibrotic samples. © 2014 International Clinical Cytometry Society