Objective: Analysis of the molecular characteristics of eosinophilia. Methods: Targeting sequence to 24 patients with chronic eosinophilic leukemia (CEL) with rearrangement of PDGFRA, PDGFRB, or FGFR1 and 62 patients with hyper-eosinophilic syndrome (HES). Mutation annotation and analysis of amino acid mutation using authoritative databases to speculate on possible pathogenic mutation. Results: Thirty-seven kinds of clonal variant were detected from 17 patients with CEL, no recurrent mutation site and hot spot region were found. No pathogenic mutation was detected in 19 patients with PDGFRA rearrangement, but pathogenic mutations of ASXL1, RUNX1 and NRAS were detected from 2 patients with FGFR1 rearrangement who progressed to acute myeloid leukemia and 1 patient with PDGFRB rearrangement who progressed to T lymphoblastic lymphoma, respectively. One hundred and two kinds of clonal abnormalities were detected in 49 patients with HES. The main hot spot mutation regions included: CEBPA Exon1, TET2 Exon3, ASXL1 Exon12, IDH1 Y208C, and FGFR3 L164V. CRRLF2 P224L and PDGFRB R370C point mutations were detected separately in 2 patients with HES who treated with imatinib monotherapy and achieved hematologic remission. Conclusion: The pathogenesis of CEL with PDGFRA, PDGFRB or FGFR1 rearrangement is usually single, and the progression of the disease may involve other driver mutation. A variety of genes with hot mutation regions may be involved in the pathogenesis of HES, and some mutation sites are sensitive to tyrosine kinase inhibitors.
Chronic Disease ; Humans ; Hypereosinophilic Syndrome ; Imatinib Mesylate ; Leukemia ; Receptor, Platelet-Derived Growth Factor alpha ; Receptor, Platelet-Derived Growth Factor beta

Under physiological conditions, the motility of smooth muscle in digestive tract is mainly regulated by enteric nervous system (ENS). However, how neural signal is transmitted to smooth muscle is not fully understood. Autonomic nerve endings in the smooth muscle layer form large number of varicosities which contain neurotransmitters. It was considered that nerve pulses arriving at the varicosities may cause the release of neurotransmitters, which may diffuse to the smooth muscle cells to induce contractile or relaxant responses. Over the past decade, a new understanding of the neurotransmission between ENS and smooth muscle has emerged, which emphasizes the role of a functional syncytium consisting of the interstitial cells of Cajal (ICC), the platelet-derived growth factor receptor α positive (PDGFRα) cells and the smooth muscle cells. Within the syncytium, purine neurotransmitters bind to P2Y1 receptors on PDGFRα cells, activating small-conductance calcium activated potassium channel (SK3) to hyperpolarize PDGFRα cells, and thus hyperpolarize smooth muscle cells through gap junction, resulting in relaxation of smooth muscle. In this paper, we review the research progress in the field of inhibitory purinergic neurotransmission in the gastrointestinal tract.
Interstitial Cells of Cajal ; Muscle, Smooth ; Myocytes, Smooth Muscle ; Receptor, Platelet-Derived Growth Factor alpha ; Synaptic Transmission

BACKGROUND/AIMS: Gastrointestinal stromal tumors (GISTs) strongly express a receptor tyrosine kinase (RTK, c-KIT-CD117) harboring a KIT mutation that causes constitutive receptor activation leading to the development and growth of tumors; 35% of GISTs without KIT mutations have platelet-derived growth factor receptor alpha (PDGFRA) mutations, and the type of mutation plays an important role in the response to treatment. This study aimed to establish the frequency of stop codon mutations in the RTKs, KIT, and PDGFRA, in GISTs and correlate this molecular alteration with protein expression and treatment responsiveness. METHODS: Seventy-nine GISTs were analyzed for both KIT and PDGFRA mutations. Immunohistochemical expression was studied in tissue microarray blocks. RESULTS: We found three rare KIT mutations in exon 11 that induced a stop codon, two at position 563 and one at position 589, which have never been described before. All three tumors were CD117-, DOG1-, and CD34-positive. Two patients with a KIT stop codon mutation did not respond to imatinib therapy and died shortly after treatment. CONCLUSIONS: The association between stop codon mutations in KIT and patient survival, if confirmed in a larger population, may be useful in choosing effective therapies.
Benzamides ; Codon, Terminator ; Exons ; Gastrointestinal Stromal Tumors ; Growth and Development ; Humans ; Piperazines ; Protein-Tyrosine Kinases ; Pyrimidines ; Receptor, Platelet-Derived Growth Factor alpha ; Receptors, Platelet-Derived Growth Factor

Animals ; Eosinophilia ; genetics ; pathology ; Gene Rearrangement ; Humans ; Lymphoma ; genetics ; pathology ; Myeloproliferative Disorders ; genetics ; pathology ; Receptor, Fibroblast Growth Factor, Type 1 ; genetics ; Receptor, Platelet-Derived Growth Factor alpha ; genetics ; Receptor, Platelet-Derived Growth Factor beta ; genetics

OBJECTIVE: To investigate the effect of PDGFRα stromal cells derived SCF on hematopoiesis of adult mice. METHODS: Pdgfrα-CreER; R26-tdTomato mice model was constructed, and the proportion and distribution of PDGFRα cells in the liver, spleen, lung, kidney and bone marrow were analyzed by flow cytometry and confocal microscopy. Then the Pdgfrα-CreER; Scf mice model was further constructed, the Scf in PDGFRα was knocked out specifically, the effect of Scf-knocked out in PDGFRα stromal cells in the propitiation of HSPCs in the bone marrow was analyzed by flow cytometry. The effect of SCF on the proportion on number of peripheral blood cells in mice was analyzed by whole blood analyzer. RESULTS: After Scf was knocked out in PDGFRα stromal cells, the propitiation and number of LKS- cell, LKS+ cell, HSC, MPP1, MKP, PreGM, PreMegE, and CFU-E in the bone marrow of mice was decreased, as well as in the number of red blood cells and hemoglobin concentration of peripheral blood. However, Scf knocked out from PDGFRα cells showed no effect on the hematopoiesis in spleen. CONCLUSION specific knocked out of Scf in PDGFRα stromal cells in adult mice can decrease the proportion of HSPCs in the bone marrow and the number of red blood cells in peripheral blood, and finally lead to anemia in mice.
Animals ; Bone Marrow ; Bone Marrow Cells ; Hematopoiesis ; Mice ; Receptor, Platelet-Derived Growth Factor alpha ; Stem Cell Factor

Objective: To study the effects of Nintedanib associated with Shenfu Injection on lung injury induced by paraquat (PQ) intoxication. Methods: In September 2021, a total of 90 SD rats were divided into 5 groups in random, namely control group, PQ poisoning group, Shenfu Injection group, Nintedanib group and associated group, 18 rats in each group. Normal saline was given by gavage route to rats of control group, 20% PQ (80 mg/kg) was administered by gavage route to rats of other four groups. 6 hours after PQ gavage, Shenfu Injection group (12 ml/kg Shenfu Injection), Nintedanib group (60 mg/kg Nintedanib) and associated group (12 ml/kg Shenfu Injection and 60 mg/kg Nintedanib) were administered with medicine once a day. The levels of serum transforming growth factor beta1 (TGF-β1), interleukin-1 beta (IL-1β) were determined at 1, 3 and 7 d, respectively. The pathological changes of lung tissue, the ratio of wet weight and dry weight (W/D) of lung tissue, the levels of superoxide dismutase (SOD) and malondialdehyde (MDA) in lung tissue were observed and determined after 7 d. Western blot was used to analyse the expression levels of fibroblast growth factor receptor 1 (FGFR1), platelet derivation growth factor receptor alpha (PDGFRα), vascular endothelial growth factor receptor 2 (VEGFR2) in lung tissue after 7 d. Results: The levels of TGF-β1, IL-1β in all poisoning groups went up first and then went down. The levels of TGF-β1, IL-1β in associated group at 1, 3, 7 d were lower than that of PQ poisoning group, Shenfu Injection group and Nintedanib group at the same point (P<0.05). Pathological changes of lung tissue under the light microscopes showed that the degrees of hemorrhage, effusion and infiltration of inflammatory cells inside the alveolar space of Shenfu Injection group, Nintedanib group and associated group were milder than that of PQ poisoning group, and the midest in associated group. Compared with control group, the W/D of lung tissue was higher, the level of MDA in lung tissue was higher, while the level of SOD was lower, the expressions of FGFR1, PDGFRα and VEGFR2 in lung tissue were higher in PQ poisoning group (P<0.05). Compared with PQ poisoning group, Shenfu Injection group and Nintedanib group, the W/D of lung tissue was lower, the level of MDA in lung tissue was lower, while the level of SOD was higher, the expressions of FGFR1, PDGFRα and VEGFR2 in lung tissue were lower in associated group (P<0.05) . Conclusion: Nintedanib associated with Shenfu Injection can relieve lung injury of rats induced by PQ, which may be related to Nintedanib associated with Shenfu Injection can inhibit the activation of TGF-β1 and the expressions of FGFR1, PDGFRα, VEGFR2 in lung tissue of rats.
Animals ; Rats ; Rats, Sprague-Dawley ; Paraquat ; Transforming Growth Factor beta1 ; Receptor, Platelet-Derived Growth Factor alpha ; Vascular Endothelial Growth Factor A ; Acute Lung Injury/drug therapy*

Gastrointestinal smooth muscle layer contains two kinds of interstitial cells with special differentiation, i.e., interstitial cells of Cajal (ICC) and platelet-derived growth factor receptor &alpha;-positive (PDGFR&alpha;) cells. The ICC and PDGFR&alpha;cells contact with smooth muscle cells (SMCs) by gap junctions and regulate contractive function of the SMCs. Therefore, these three kinds of cells constitute a functional syncytium, i.e., the SMC, ICC and PDGFR&alpha;cells syncytium (SIP syncytium). Various neurotransmitters, humoral factors, endogenous bioactive molecules, as well as drugs regulate gastrointestinal motility through the SIP syncytium. In this review, we introduce the concept of SIP syncytium and summarize functions of the syncytium, as well as its physiological and pathological significances.
Gastrointestinal Motility ; Giant Cells ; Humans ; Interstitial Cells of Cajal ; Muscle, Smooth ; Myocytes, Smooth Muscle ; Receptor, Platelet-Derived Growth Factor alpha

The incidence of gastrointestinal stromal tumor(GIST) is 1-2 per 100 000. Micro GIST with a size less than 1 cm are found in 3%-35% elderly population. These small-size GIST are usually located in the middle or upper stomach, with gain-function KIT or PDGFRA mutation. In this review, the clinicopathological features and management of these small-size GISTs are discussed.
Gastrointestinal Neoplasms ; pathology ; Gastrointestinal Stromal Tumors ; Humans ; Mutation ; Proto-Oncogene Proteins c-kit ; Receptor, Platelet-Derived Growth Factor alpha

OBJECTIVETo elucidate the mutation profiles of c-kit/PDGFR&alpha; and its associations with clinicopathological characteristics in large scale Chinese gastrointestinal stromal tumors(GISTs).

METHODSClinicopathological data and tumor samples of 1002 GIST patients treated in the Peking University Cancer Hospital from September 2002 to January 2014 were retrospectively collected. Mutation status of c-kit(exons 9, 11, 13, and 17) and PDGFR&alpha;(exons 12 and 18) genes were detected by direct sequencing. Association between mutation profiles and clinicopathological features of mutant patients were statistically analyzed.

RESULTSAmong all the 827 mutant patients, c-kit and PDGFR&alpha; mutations were found in 798 cases(96.5%, exons 11, 9, 13, and 17 mutations in 669, 99, 18, 12) and 29 cases (3.5%, exons 12 and 18 in 2 and 27), respectively. As for c-kit gene, deletion mutation was most frequent in exon 11(n=325), and then point mutation(n=172), mixed mutation(n=135), and duplication mutation(n=37). The duplication of codons 502-503 was the unique genotype for exon 9 of c-kit gene, and point mutation was the single mutation type for exons 13 and 17 of c-kit gene. Point mutation was the most common mutation for PDGFR&alpha; gene with few deletion or mixed mutations. Most deletion mutations of c-kit gene were located in 5' region of exon 11, duplication mutations were mainly located in 3' region of exon 11, and point mutations were focused on codons 556-560. Mutation type of exon 11 was associated with age, gender, primary location, tumor size, karyokinesis image and CD 34 expression(all P<0.05).

CONCLUSIONGISTs are featured by frequent gene mutations, many mutation types, and specificity for mutations in same exons or different exons.

Gastrointestinal stromal tumors(GISTs) are the most common gastrointestinal mesenchymal tumors of the gastrointestinal tract. Most of GISTs are characterized by mutation in the c-kit or PDGFR-&alpha; genes. In recent years, detection of gene mutation in GISTs has been widely used. In addition to the contribution to the diagnosis of difficult cases, such detection also has important value in predicting the efficacy of therapeutic drugs targeting, guiding clinical treatment and evaluating the prognosis of patients. In a word, gene mutation detection should be considered as the important standard for exact diagnosis and treatment of GISTs.
Gastrointestinal Neoplasms ; Gastrointestinal Stromal Tumors ; Humans ; Mutation ; Prognosis ; Proto-Oncogene Proteins c-kit ; Receptor, Platelet-Derived Growth Factor alpha