Prognostic analysis of children with Philadelphia chromosome-like acute lymphoblastic leukemia common genes / 中华儿科杂志

Objective: To summarize the clinical data and prognosis of children with Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) common genes. Methods: This was a retrospective cohort study.Clinical data of 56 children with Ph-like ALL common gene cases (Ph-like ALL positive group) treated from January 2017 to January 2022 in the First Affiliated Hospital of Zhengzhou University, Henan Children's Hospital, Henan Cancer's Hospital and Henan Provincial People's Hospital were collected, 69 children with other high-risk B cell acute lymphoblastic leukemia (B-ALL) at the same time and the same age were selected as the negative group. The clinical characteristics and prognosis of two groups were analyzed retrospectively. Comparisons between groups were performed using Mann-Whitney U test and χ2 test. Kaplan-Meier method was used for survival curve, Log-Rank test was used for univariate analysis, and the Cox regression model was used for multivariate prognosis analysis. Results: Among 56 Ph-like ALL positive patients, there were 30 males and 26 females, and 15 cases were over 10 years old. There were 69 patients in Ph-like ALL negative group. Compared with the negative group, the children in positive group were older (6.4 (4.2, 11.2) vs. 4.7 (2.8, 8.4) years), and hyperleukocytosis (≥50×109/L) was more common (25% (14/56) vs. 9% (6/69)), the differences were statistically significant (both P<0.05). In the Ph-like ALL positive group, 32 cases were positive for IK6 (1 case was co-expressed with IK6 and EBF1-PDGFRB), 24 cases were IK6-negative, of which 9 cases were CRLF2 positive (including 2 cases with P2RY8-CRLF2, 7 cases with CRLF2 high expression), 5 cases were PDGFRB rearrangement, 4 cases were ABL1 rearrangement, 4 cases were JAK2 rearrangement, 1 case was ABL2 rearrangement and 1 case was EPOR rearrangement. The follow-up time of Ph-like ALL positive group was 22 (12, 40) months, and 32 (20, 45) months for negative group. The 3-year overall survival (OS) rate of positive group was significantly lower than the negative group ((72±7) % vs. (86±5) %, χ2=4.59, P<0.05). Compared with the 24 IK6-negative patients, the 3-year event free survival (EFS) rate of 32 IK6 positive patients was higher, the difference was statistically significant ((88±9) % vs. (65±14) %, χ2=5.37, P<0.05). Multivariate Cox regression analysis showed that the bone marrow minimal residual disease (MRD) not turning negative at the end of first induction (HR=4.12, 95%CI 1.13-15.03) independent prognostic risk factor for patient with Ph-like ALL common genes. Conclusions: Children with Ph-like ALL common genes were older than other high-risk B-ALL patients at diagnosis, with high white blood cells and lower survival rate. The bone marrow MRD not turning negative at the end of first induction were independent prognostic risk factor for children with Ph-like ALL common gene.

Myeloid and lymphoid neoplasm with eosinophilia and abnormalities of PDGFRB presenting as congestive heart failure and hypereosinophilia

Hypereosinophilic syndrome (HES) is a heterogeneous disorder characterized by persistent hypereosinophilia with the evidence of organ dysfunction caused by eosinophilic involvement. HES can be induced by various secondary causes, including helminthic infections, adverse drug reactions, and allergic diseases. Primary/clonal bone marrow disease, including genetic mutations in platelet driven growth factor receptor alpha (PDGFRA), platelet driven growth factor receptor beta (PDGFRB), and fibroblast growth factor receptor 1 (FGFR1) could be its causes. Although corticosteroids are the mainstay of therapy in confirmed HES, imatinib is considered a definitive treatment for HES with these mutations. However, there have been few reports about HES with these genetic mutations in Korea. Here, we report a patient who presented with sudden onset of congestive heart failure and hypereosinophilia, proved to have PDGFRB rearrangement, and was controlled successfully with imatinib after left ventricle thrombectomy.

A Case of Myeloid Neoplasm with a PDGFRB Rearrangement and Eosinophilia / 대한내과학회지

Myeloid neoplasia with eosinophilia and platelet-derived growth factor receptor beta (PDGFRB) rearrangements is an uncommon Philadelphia-negative myeloproliferative neoplasm. Their most common morphological diagnosis is chronic myelomonocytic leukemia with eosinophilia, which is associated with t(5;12)(q33;p13) and results in the formation of the ETV6-PDGFRB fusion gene. Here, we report a 49-year-old man with a myeloid neoplasm with a PDGFRB rearrangement, who was incidentally diagnosed with hyperleukocytosis and eosinophilia during a health screening. A chromosome analysis of a bone marrow sample revealed 46, XY, t(5;12)(q33;p13), and fluorescence in situ hybridization analysis revealed the PDGFRB gene rearrangement. The patient was treated with imatinib and subsequently achieved complete hematological and molecular remission.

Role of PDGF/PDGFR Pathway in Essential Thrombocythemia and Its Action Mechanism / 中国实验血液学杂志

<p><b>OBJECTIVE</b>To study the role of PDGF/PDGFR in essential thrombocythemia (ET) by investigating the expression of PDGF-BB in bone marrow and the expression of PDGFR-β in bone marrow cells of patients with ET and explore the new target for treating ET patients through inhibiting the PDGFR of megakaryocytes.</p><p><b>METHODS</b>The expression level of PDGF-BB in bone marrow of ET patients and normal controls were assayed by using ELISA, the expression level of PDGFR-β (CD140) in bone marrow of ET patients and normal controls were detected by using flow cytometry, the effect of PDGF-BB in JAK2/STAT3 and PI3K/AKT pathway was detected by using flow cytometry or Werstern blot, and the effect of imatinib on the megakaryopoiesis of PDGF was observed.</p><p><b>RESULTS</b>The expression level of PDGF-BB in bone marrow of ET patients was significantly higher than that in normal controls; the expression level of PDGFR-β in bone marrow of ET patients was significantly higher than that in nornal controls; PDGF-BB could activate JAK2/STAT3 and PI3K/AKT pathway of megakaryocytes, while the imatinib could block the effect of PDGF-BB on megakaryocyte.</p><p><b>CONCLUSION</b>The elevated PDGF-BB and PDGFR-β may be involved in ET, and the physiopathologic mechanism is that the elevated PDGF-BB activates PDGFR with subsequent activation of the JAK2/STAT3 and PI3K/AKT pathways, stimulating megakaryopoiesis. Imatinib may have a therapeutical effect on ET via blocking of PDGFR.</p>

The study of 4 cases of myeloid neoplasm with t (5;12) (q33;p13) and the literatures review / 中华血液学杂志

<p><b>OBJECTIVE</b>To report clinical and laboratory features of 4 cases of myeloid neoplasm with t (5;12) (q33;p13).</p><p><b>METHODS</b>Cytogenetic examination of bone marrow cells obtained from patients was performed by 24 h culture method. R banding technical was used for karyotype analysis. PDGFRβ gene rearrangement was detected by FISH using dual color break apart PDGFRβ probe. ETV6-PDGFRβ fusion genes were detected by multiple-reverse transcription polymerase chain reaction (RT-PCR). Direct sequencing analysis was performed on the PCR products in case 1. Immunophenotype analysis was carried out by flow cytometry. Four cases were treated with imatinib (IM) and followed up.</p><p><b>RESULTS</b>The diagnoses included 3 MPN and 1 AML-M2. The t (5;12) (q33;p13) was a primary abnormality in 3 cases of MPN and a secondary abnormality in 1 case of AML-M2. PDGFRβ gene rearrangement and ETV6-PDGFRβ fusion genes were detected by FISH and multiple-RT-PCR in 4 cases, respectively. The immunophenotypical analysis of leukemia cells showed positive for CD13, CD33 and CD34. Two cases obtained MMR after the treatment of IM, one case complete hematologic and complete cytogenetic response. ETV6-PDGFRβ was negative detected by multiple-RT-PCR after the treatment of IM, but relapsed and died soon in case 4.</p><p><b>CONCLUSIONS</b>The t (5;12) myeloid neoplasm was a subtype with unique features. The t (5;12) maybe a primary chromosome abnormality in MPN and a secondary in AML. MPN with t (5;12) could benefit from IM, but not for AML. Dual-FISH was a reliable tool for detecting PDGFRβ rearrangement.</p>

Delta12-prostaglandinJ2-nano capsule up-regulates growth factor expression and enhances bone regeneration in rats / 中华口腔医学杂志

<p><b>OBJECTIVE</b>To investigate the effect of local delivery of delta12-prostaglandinJ2-loaded poly (lactic-co-glycolic acid) (Δ(12)-PGJ2-NC) on growth factors expression and bone formation.</p><p><b>METHODS</b>Δ(12)-PGJ2-NC was prepared by the emulsion solvent diffusion method. The physical and chemical properties of the nanoparticles were evaluated by particle size analysis, transmission electron microscopy, drug-loading ratio and the in vitro release study. Then standardized transcortical defect (5.0 mm × 1.5 mm) was conducted in the femur of 48 male Wistar rats which were randomly divided into four groups (n = 12), S, K, F, and N. Thirty microliter of saline (S), unloaded nanoparticles (K), Δ(12)-PGJ2 (F) and Δ(12)-PGJ2-NC(N) in a collagen vehicle were delivered inside a titanium chamber fixed over the defect. Then, four subgroups were randomly divided in each group named as D3, D7, D14, and D28 (n = 3) according to the days 3, 7, 14, and 28 after the surgery. At days 3, 7, 14, and 28, the mRNA expression of the bone morphogenetic protein-6 (BMP-6), platelet-derived growth factor-B (PDGF-B) in defect aera was analyzed by real time quantitive-polymerase blotting. HE staining was employed to reveal new bone formation in weeks 2 and 4.</p><p><b>RESULTS</b>Δ(12)-PGJ2-NC appeared opalescent white and remained relatively stable, with an average particle size of (135.2 ± 0.85) nm. The images from transmission electron microscopy showed that Δ(12)-PGJ2-NC was spherical in shape and homogeneously distributed. The encapsulation efficiency of Δ(12)-PGJ2 with the poly (lactic-co-glycolic acid) (PLGA) nanocapsules was about 92%. The in vitro release of Δ(12)-PGJ2-NC at 37 °C showed a sustained fashion and the average accumulated amount was 30%, 52%, 77%, 91%, and 98% respectively, at 0.5, 1, 2, 4 and 6 h. Compared with the animals treated with saline, after dose of 100 mg/L Δ(12)-PGJ2 and Δ(12)-PGJ2-NC apllication, the mRNA expression level of BMP-6, PDGF-B increased significantly (P < 0.05, P < 0.001). The protein expression of BMP-6, Ephrin-B2 also was up-regulated. Histomorphometry revealed that new bone formation increased at the same dose of 100 mg/L. But the unloaded nanoparticles did not have the same effect (P > 0.05).</p><p><b>CONCLUSIONS</b>A stable Δ(12)-PGJ2 loaded nanoparticle was successfully prepared. Δ(12)-PGJ2-NC may upregulate the expression of BMP-6, PDGF-B and Ephrin-B2, and promote new bone formation in bone defect area.</p>

Effect of Curcumin on TGF-β2 Regulated PPAR-γ/PDGF-β Signaling Pathway in Lung Fibroblasts of Mice / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To explore the effect of curcumin on TGF-β2 regulated peroxisome proliferater activated receptor y (PPAR-γ)/platelet derived growth factor β (PDGF-β) signaling pathway in lung fibroblasts of mice.</p><p><b>METHODS</b>C57BL/6 mouse lung fibroblasts were in vitro cultured with TGF-β2, curcumin, or TGF-β2 plus curcumin. The cell proliferation was detected by cell growth counting in the blank control group, low, middle, and high dose curcumin groups (5, 25, 50 μmol/L), the TGF-β2 (10 ng/mL) group, TGF-β2 (10 ng/mL) plus curcumin (5, 25, 50 μmol/L) groups. mRNA expressions of PPAR-γ, platelet-derived growth factor receptor β (PDGFR-β), fibroblast growth factor R1 (FGFR1) were detected using reverse transcription PCR. Protein levels of PPAR-γ and collagen-1 were detected using Western blot and ELISA in the blank control group, the TGF-β2 group, the TGF-β2 (10 ng/mL) plus curcumin 50 μmol/L group.</p><p><b>RESULTS</b>Compared with the blank control group, curcumin 50 μmol/L showed the most significant inhibition on cell proliferation at 48 h and 72 h. Compared with the TGF-β2 group, TGF-β2 (10 ng/mL) plus curcumin 50 mol/L also showed the most significant inhibition on cell proliferation at 48 h and 72 h. Compared with the blank control group, mRNA expressions of PPAR-γ and PDGF-β, as well as protein expression of PPAR-γ increased, the collagen-1 expression also increased in the TGF-β2 group (P < 0.05). Compared with the TGF-β2 group, mRNA expressions of PPAR-γ obviously increased in the TGF-β2 (10 ng/mL) plus curcumin 25 μmol/L group and the TGF-β2 (10 ng/mL) plus curcumin 50 μmol/L group, higher than that in the TGF-β2 (10 ng/mL) plus curcumin 5 [μmol/L group (P < 0.05). mRNA expressions of PPAR-γ was higher in the TGF-β2 (10 ng/mL) plus curcumin 50 μmol/L group than in the TGF-β2 (10 ng/mL) plus curcumin 25 μmol/L group (P < 0.05). mRNA expressions of PDGF-β was lower in TGF-β2 (10 ng/mL) plus curcumin groups than in the TGF-β2 group (P < 0.05). Besides, PDGF-β mRNA expressions were lower in the TGF-β2 (10 ng/mL) plus curcumin 50 μmol/L group than in the TGF-β2 (10 ng/mL) plus curcumin 5 μmol/L group and the TGF-β2 (10 ng/mL) plus curcumin 25 μmol/L group (P < 0.05). There was no statistical difference in FGFR1 mRNA expressions between the TGF-β2 group and 3 TGF-β2 plus curcumin groups (P > 0.05). Compared with the TGF-β2 group, PPAR-γ protein expressions increased and collagen-1 protein expressions decreased in the TGF-β2 (10 ng/mL) plus curcumin 50 μLmol/L group (P < 0.05, P < 0.01).</p><p><b>CONCLUSIONS</b>Curcumin not only could inhibit TGF-β2 induced proliferation of lung fibroblasts, but also could inhibit the synthesis of collagens. These might be associated with up-regulating PPAR-γ expressions and down-regulating PDGF-β expressions. Therefore, curcumin might inhibit the occurrence and developing of lung fibrosis through blocking PPAR-γ/PDGF-β signaling pathway.</p>

Effect of platelet derived growth factor-B and its receptor expression on the proliferation of renal cell carcinoma ACHN cells / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To study the effect of platelet derived growth factor-B and its receptor expression on the proliferation of renal cell carcinoma ACHN cells in vitro and in vivo.</p><p><b>METHODS</b>PDGF-B gene was transfected into human renal carcinoma cell line ACHN cells, and the proliferation capability of ACHN cells transfected with or without PDGF-B was assessed by MTT assay. The effect of PDGF-B on the expression of p-PDGFR-β in endothelial cells and vascular smooth muscle cells (VSMC) was detected by Western blot. ACHN cells transfected with PDGF-B were injected into mice (untransfected ACHN as control) to induce tumor formation. Immunohistochemical staining was used to detect the expression of Ki-67 in tumor cells and the tumor volume was measured to compare the tumor growth in the two groups.</p><p><b>RESULTS</b>The PDGF-B expression of ACHN cells in transfected group was significantly increased than that in the untransfected group. MTT assay showed that the proliferation capability of ACHN cells in the transfected and untransfected groups had no significant differences at different time points (P>0.05). The expression of p-PDGFR-β in VSMC was significantly increased when cultured with PDGF-B overexpression culture medium. The mean tumor size of the PDGF-B group and control group was (0.305±0.108) cm(3) and (0.577±0.218) cm(3), respectively (P=0.007). Ki-67-positive tumor cells were (41.00±5.34)/HPF in the PDGF-B-transfected group and (55.80±2.95)/HPF in the untransfected group (P=0.001).</p><p><b>CONCLUSION</b>PDGF-B overexpression may up-regulate p-PDGFR-β expression of VSMC in renal cell carcinoma, and inhibit the tumor cell proliferation and tumor growth through paracrine signaling.</p>

Imatinib atenua a fibrose miocárdica em associação com a inibição da atividade do PDGFRα / Imatinib attenuates myocardial fibrosis in association with inhibition of the PDGFRα activity

FUNDAMENTO: O Imatinib é um inibidor do receptor tirosina-quinase que foi confirmada como exercendo um efeito inibidor sobre a atividade do receptor do PDGF, fator de crescimento plaquetário (PDGFRα e PDGFRβ). OBJETIVO: Investigar o efeito protetor do Imatinib na fibrose miocárdica em acetato de deoxicorticosterona (DOCA)/ratos com hipertensão induzida por sal. MÉTODOS: Sessenta ratos Sprague-Dawley machos, uninefrectomizados foram distribuídos em três grupos: ratos controles (grupo CON): grupo deoxicorticosterona (grupo DOCA); grupo deoxicorticosterona e Imatinib (grupo DOCA IMA). A Pressão Arterial Sistólica (PAS) foi medida quinzenalmente. Foi estudada a porção apical do ventrículo esquerdo. Foram empregados: coloração vermelho sirius, coloração de hematoxilina-eosina, imuno-histoquímica e ensaio de western blot. RESULTADOS: A PAS nos grupos DOCA e IMA+DOCA foi maior que no grupo CON nos dias 14 e 28. Os animais do grupo DOCA apresentaram fibrose intersticial e perivascular grave no dia 28, e as expressões de PI, PIII, tenascina-C e fibronectina foram significativamente maiores que nos grupos DOCA+IMA e CON. Quando comparados com o grupo CON, os grupos DOCA e DOCA+IMA apresentaram resposta inflamatória de tecido miocárdico e infiltração de monócitos/macrófagos de diferentes graus. As expressões proteicas do PDGF-A, PDGF-C e PDGFRα foram significativamente maiores nos grupos DOCA e DOCA+IMA que no grupo CON, mas a expressão proteica do p-PDGFRα no grupo DOCA+IMA foi menor que no DOCA. CONCLUSÃO: O Imatinib pode exercer efeitos inibitórios sobre a fibrose miocárdica em ratos com hipertensão induzida por DOCA/sal, os quais podem ser atribuídos à inibição da atividade do PDGFR-α.

BACKGROUND: Imatinib is a tyrosine kinase receptor inhibitor that has been confirmed to exert inhibitory effect on the platelet derived growth factor PDGF receptor (PDGFRα and PDGFRβ) activity. OBJECTIVE: To investigate the protective effect of imatinib on the myocardial fibrosis in deoxycorticosterone-acetate (DOCA)/salt induced hypertensive rats. METHODS: Sixty male uninephrectomized Sprague-Dawley rats were assigned to three groups: control rats (CON group); deoxycorticosterone group (DOCA group); deoxycorticosterone and imatinib group (DOCA+IMA group). Systolic blood pressure (SBP) was measured biweekly. The apical portion of the left ventricle was studied. Sirius-Red staining, Hematoxylin-Eosin staining, immunohistochemistry and Western blot assay were employed. RESULTS: SBP in the DOCA group and DOCA+IMA group was higher than that in the CON group on day 14 and 28. Animals in the DOCA group showed severe interstitial and perivascular fibrosis on day 28, and the expressions of PI, PIII, tenascin-C and fibronectin were significantly higher than those in the DOCA+IMA group and CON group. When compared with the CON group, myocardial tissue inflammatory response and monocyte/macrophage infiltration of different degrees were observed in the DOCA group and DOCA+IMA group. Protein expressions of PDGF-A, PDGF-C and PDGFRα were signiflcantly higher in the DOCA and DOCA+IMA groups than those in the CON group, but the p-PDGFRα protein expression in the DOCA+IMA group was lower than that in the DOCA group. CONCLUSION: Imatinib can exert inhibitory effects on myocardial fibrosis in DOCA/salt induced hypertensive rats, which may be attributed to the inhibition of PDGFR-α activity.

Pulmonary capillary hemangiomatosis: a clinicopathologic analysis of 2 cases with review of literature / 中华病理学杂志

<p><b>OBJECTIVE</b>To investigate the clinicopathologic features of pulmonary capillary hemangiomatosis (PCH).</p><p><b>METHODS</b>The clinical and pathologic profiles of 2 PCH cases were evaluated. Immunohistochemical study (EnVision method) was performed on fixed tissues. The biologic behavior was analyzed with follow-up data.</p><p><b>RESULTS</b>The main presenting symptom was dyspnea. Chest radiography of the two cases depicted diffuse, ground-glass nodules, accompanied by enlarged central pulmonary arteries. Microscopically, the most distinctive feature was proliferation of capillary channels within pulmonary interstitium and alveolar walls, accompanied by muscularization of arterioles. Immunohistochemical study showed an abundance of mast cells in the lesion, and staining for platelet-derived growth factor receptor-beta (PDGFR-β) localized to vascular smooth muscles surrounding the proliferating capillaries and the mast cells. The index of Ki-67 was less than 1 percent and the p53 was negative.</p><p><b>CONCLUSIONS</b>PCH is a rare vascular proliferative disease of yang patients. Increased number of mast cell and the up-regulation of PDGFR-β may suggest mechanism for PCH. The clinical and radiologic diagnosis of PCH can be very difficult, and the histological examination is regarded as the most reliable means to establish the diagnosis. Pathologists should improve their knowledge on PCH.</p>

Heterogenous abnormality polymorphism of gene PDGFRB in myeloid neoplasms and its clinical characteristics / 中国实验血液学杂志

Myeloid neoplasms with eosinophilia and abnormalities of PDGFRB gene are a new kind of myeloid disorders in the revised 2008 WHO classification. Out of detected 2000 cases of myeloid cell abnormalities in our hospital, 12 cases of myeloid neoplasms with eosinophilia and abnormalities of PDGFRB were found. This study was purposed to summarize and analyze the clinical and laboratorial characteristics of the 12 cases with PDGFRB gene abnormalities. The results indicated that among 12 cases of myeloid neoplasms with PDGFRB abnormalities, 5 cases with TEL/PDGFRB fusion gene, 2 cases with HEPI/PDGFRB, 1 case with PDGFRB mutation, 1 case with RABAPTIN-5/PDGFRB, 1 case with GIT2/PDGFRB, 1 case with TP53/PDGFRB, 1 case with WDR43/PDGFRB fusion gene were detected, showing the polymorphism of PDGFRB gene abnormalities. Among this kind of myeloid neoplasm patients, almost all patients manifested monocytosis and eosinophilia in different degree, the thrombocytosis mainly was observed in atypical myeloid neoplasms, acute leukemia, chromic myelo-monocytic leukemia patients. The treatment with imatinib mesylate for this kind of patients was effective in some cases. It is concluded that the myeloid neoplasms with PDGFRB gene abnormalities are a kind of heterogenetic myeloid neoplasms, their gene abnormal types and clinical manifestations show polymorphism too. The monocytosis and eosinophilia appear in this kind myeloid neoplasms which may be treated with tyrosine kinase inhibitors such as imatinib mesylate.

Characteristics of cytogenetics and molecular biology in patients with eosinophilia / 中国实验血液学杂志

The aim of study is to explore the characteristics of cytogenetics and molecular biology in patients with eosinophilia. Bone marrow samples from 79 cases of eosinophilia (AEoC ≥ 1.5×10(9)/L) were detected for PDGFRA/B and FGFR1 gene rearrangement by fluorescence in situ hybridization and reverse transcription polymerase chain reaction (RT-PCR). Forty-four samples were detected for T cell receptor (TCR) clonal rearrangement by PCR. The results showed that among 76 cases the FIP1L1/PDGFRA (F/P) fusion gene was detected in 19 cases, the CHIC2 deletion was detected in 19 cases, the PDGFRA rearrangement was detected in 4 cases, and no FIP1L1 rearrangement was detected. According to the 2008 WHO classification, diagnosis were revised as myeloid neoplasms with PDGFRA/B rearrangement in 20 (42%) of 48 patients and 5 (83%) of 6 patients with hypereosinophilia syndrome (HES) or chronic eosinophilic leukemia (CEL), respectively. The diagnosis in (17%) of 6 patients with CEL was revised as chronic eosinophilic leukemia, not otherwise as specified (CEL-NOS). Clonal cytogenetic abnormalities were detected in 1 case of CEL-NOS and 3 cases with PDGFRB rearrangement. Karyotypic abnormalities involved in chromosome 4q12 were not detected in all of the 21 cases with PDGFRA rearrangement. The clonal TCR gene rearrangement were detected in 33% (5/15), 40% (6/15), and 36% (5/14) cases with PDGFRA/B rearrangement, HES, or secondary eosinophilia, respectively. There was no statistical difference in incidence rate among 3 subgroups. It is concluded that PDGFRA/B rearrangement can be detected in many cases of HES or CEL. Interphase FISH and PCR testing can enhance the diagnostic rate of myeloid neoplasms with PDGFRA/B rearrangement.

Application of reverse transcription-multiplex nested PCR to detect PDGFRB gene rearrangement in myeloproliferative disorders / 中国实验血液学杂志

In order to explore the value of reverse transcription(RT)-multiplex nested PCR for detecting PDGFRB gene rearrangement in myeloproliferative disorders (MPD), the PDGFRB rearrangement was detected qualitatively in 146 MPD cases by reverse transcription multiplex nested PCR. The results showed that 8 cases with PDGFRB fusion gene were found in 146 cases, the positive rate was 5.5%. Out of 8 cases with PDGFRB fusion gene, TEL-PDGRB fusion gene was found in 3 cases; HIP1-PDGFRB fusion gene in 2 cases; GIT2-PDGFRB, TP53BP1-PDGFRB and WDP48-PDGFRB fusion gene in 1 case, respectively. It is concluded that RT-multiplex nested PCR is a powerful tool for the detection of PDGFRB rearrangement, which helps to tentatively diagnose MPD and to provide the clues for targeting therapy.

A Case of Atypical Chronic Myeloid Leukemia with the JAK2V617F Mutation

Atypical chronic myeloid leukemia (aCML) is a rare leukemic disorder that shows myelodysplastic and myeloproliferative features simultaneously. The Janus kinase 2 gene V617F mutation (JAK2V617F) in aCML has been the source of much controversy. Some JAK2V617F positive cases have been reported but others observed no JAK2V617F mutation in aCML as defined by WHO classification. Recently, we experienced a case of aCML with JAK2V617F mutation with typical myelodysplastic/myeloproliferative features in peripheral blood and bone marrow aspirates. The karyotype was normal and no BCR/ABL1, PDGFRA or PDGFRB gene rearrangement was noted with FISH analysis. JAK2V617F mutation of the case was identified with amplification refractory mutation system PCR and direct sequencing. We also studied JAK2V617F mutation status in 3 additional cases of previously diagnosed aCML in our institution, but no mutation was identified.

Eosinofilia reacional, leucemia eosinofílica crônica e síndrome hipereosinofílica idiopática / Reactive eosinophilia, chronic eosinophilic leukemia and idiopathic hypereosinophilic syndrome

A eosinofilia é freqüente na prática clínica, principalmente quando os valores estão entre 500 e 1000 eosinófilos/uL e indica a presença de doença parasitária, alérgica ou reação a medicamentos. Afora essas situações, a eosinofilia pode ser devida a doenças do tecido conjuntivo, infecções e, mais raramente, a doença hematológica maligna ou a tumores sólidos. Os critérios estabelecidos na década de 70 para a definição para a definição da síndrome hipereosinofílica idiopática se tornaram insuficientes para caracterizar todas as entidades albergadas sob o termo eosinofilia e, hoje, melhor compreendidas graças aos avanços na biologia celular e molecular, que proporcionaram a caracterização de doenças distintas e que envolvem células das linhagens mieloide e linfoide. Nesse contexto, as eosinofilias sanguíneas são categorizadas como reacionais, clonais e idiopáticas (SHE). O advento de terapia antitirosinoquinase (a exemplo do mesilato de imatinibe), eficaz para os casos com o rearranjo gênico FIP1L1/PDGFR, também abriu novas perspectivas para o controle ideal da leucemia eosinofílica crônica. Daí a importância do diagnóstico preciso e rápido para a indicação terapêutica ideal, antes que se instalem as complicações orgânicas, em especial cardíacas, que são irreversíveis. O presente manuscrito objetiva rever as situações de eosinofilia sanguínea e oferecer uma atualização da investigação diagnóstica e terapêutica.

Mild eosinophilia with values of less than 1000 eosinophils/µL is commonly seen in the clinical practice and can be secondary to parasitic, inflammatory or allergic diseases or to drug reactions. Additionally, eosinophilia may be due to connective tissue disorders, infections and occasionally to hematopoietic malignancies or solid tumors. The criteria established in the 1970s, for the definition of idiopathic hypereosinophilic syndrome is today unsatisfactory to characterize all conditions described as eosinophilia. Now these conditions are better understood due to the evolution of cellular and molecular biology. This knowledge has helped to characterize distinct disorders involving myeloid and lymphoid lineages. Hence, eosinophilia is categorized as reactive, clonal or idiopathic. With the introduction of anti-tyrosine kinase (imatinib mesylate) therapy, which is effective for the FIP1L1/PDGFRa rearrangement, there is a possibility to control or cure chronic eosinophilic leukemia. For this reason, precise and fast diagnosis is necessary for ideal therapeutic decisions before organic lesions that are irreversible, such as heart injury, become established. The aim of this manuscript is to review eosinophilia and offer an update on diagnostic and therapeutic investigations.

A case of myeloid neoplasm with the PDGFRB rearrangement and eosinophilia / 대한내과학회지

Myeloid neoplasm with the platelet-derived growth factor receptor beta (PDGFRB) rearrangement is a myeloproliferative neoplasm. Patients with this disease often have prominent eosinophilia or monocytosis and the presence of t(5;12)(q31~33;p12) or a variant translocation with expression of an ETV6-PDGFRB fusion gene or the PDGFRB rearrangement. We report an 82-year-old woman with a myeloid neoplasm, with the PDGFRB rearrangement, who presented with a dry cough, eosinophilia and thrombocytosis. The chromosome study of the bone marrow showed 46,XX,ins(1;5)(q22;q33q13.3), and fluorescence in situ hybridization (FISH) analysis revealed rearrangement of the PDGFRB gene. The patient was successfully treated with low-dose imatinib.

Clinical and laboratory study of myleodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) with PDGFRβ abnormalities / 中华血液学杂志

<p><b>OBJECTIVE</b>To explore the clinical and laboratory characteristics of myleodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) with PDGFRβ abnormalities.</p><p><b>METHODS</b>Chromosome specimens were prepared directly and/or short-time culture of bone marrow cells. Karyotyping was performed with R-binding technique. Fluorescence in situ hybridization (FISH) was performed using PDGFRβ, PDGFRα, FGFR1 break-apart probes and whole chromosome 5 and 12 painting probes, respectively. The expression of JAK2 V617F was measured with quantitative PCR.</p><p><b>RESULTS</b>The clinical and hematological findings of 27 patients were compatible with diagnosis of MDS/MPN. PDGFRβ rearrangement was detected in 4 patients with D-FISH, and 2 of which were confirmed as t(5;12) by chromosome painting. PDGFRα, FGFR1 and JAK2 V617F mutation were not detected in these 4 PDGFRβ positive MDS/MPN patients with.</p><p><b>CONCLUSIONS</b>PDGFRβ gene rearrangement may be detected in some MDS/MPN patients. FISH is a convenient and reliable approach to detect PDGFRβ gene.</p>

Expressão do P16 e do PDGFR-Beta no adenocarcinoma gástrico / Expression of P16 and PDGFR-Beta in gastric adenocarcinoma

OBJETIVO: Detectar a expressão imunoistoquímica do p16 e do PDGFR-beta no adenocarcinoma gástrico. MÉTODOS: Foram estudados 36 pacientes submetidos a cirurgia para adenocarcinoma gástrico entre 1998 e 2002 no Hospital da Santa Casa de Porto Alegre. As variáveis investigadas foram: idade, sexo, tamanho e localização do tumor, número de linfonodos dissecados, número de linfonodos metastáticos, tipo histológico, extensão da ressecção cirúrgica e estadiamento patológico. RESULTADOS: Não foi detectada expressão do PDGFR-beta nas peças cirúrgicas. Em relação ao p16, detectou-se perda de expressão menor que 10 por cento e menor que 1 por cento respectivamente em 89 por cento e 79 por cento das peças estudadas. CONCLUSÃO: Não houve correlação entre a perda de p16 e as variáveis estudadas.

OBJECTIVES: To detect immunohistochemistry expression of p16 and PDGFR-beta on gastric adenocarcinoma. METHODS: Thirty six patients submitted to surgery for gastric adenocarcinoma between 1998 and 2002 at Santa Casa de Porto Alegre Hospital have been studied. Variables investigated were: age, gender, tumour size and localization, number of dissected and metastatic nodes, histological type, surgical resection extension and pathological staging. RESULTS: No expression of PDGFR-beta has been detected on surgical specimens. Concerning to p16, loss of expression lower than 10 percent and 1 percent has been detected respectively on 89 percent and 79 percent of the specimens studied. CONCLUSION: There has been no correlation among p16 loss and variables studied.

Expression and gene mutation of phospho-platelet derived growth factor receptor alpha and C-kit in gastrointestinal and extra-gastrointestinal stromal tumors / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To investigate the expression of phospho-platelet derived growth factor receptor alpha (P-PDGFR-alpha) in gastrointestinal stromal tumors (GIST) and extra-gastrointestinal stromal tumors (EGIST) and its clinical significance.</p><p><b>METHODS</b>Expression of P-PDGFR-alpha in 28 samples of positive CD117 and 13 samples of negative CD117 was detected by Envision immunohistochemical staining. Direct PCR sequencing was used to investigate the mutation status of c-kit gene exons 9, 11, 13, 17 and PDGFR-alpha gene exons 12 and 18.</p><p><b>RESULTS</b>The positive rate of P-PDGFR-alpha expression in GISTs with negative CD117 was 69.2%, which was significantly higher than that in GISTs with positive CD117 (7.1%, P<0.05). The positive rates of P-PDGFR-alpha expression in epithelioid GISTs(27.3%) and mixed GIST(63.3%) were both significantly higher than that in fusiform GISTs (9%, P<0.05). The positive rate of CD117 expression in fusiform GISTs (53.6%)was significantly higher than that in epithelioid GISTs (7.1%) and mixed GISTs(39.3%, P<0.05). C-kit gene mutation was found in 19 GIST cases with positive CD117. C-kit gene mutation was found in 19 of 28 GIST patients with positive CD117, among them, mutation of exon 11 occurred in 15 cases and exon 13 in 4 cases. No C-kit gene mutation was seen in 13 GIST patients with negative CD117. PDGFR-alpha gene mutation was found in 4 of 11 GIST cases with positive P-PDGFR-alpha and all occurred in exon 18.</p><p><b>CONCLUSIONS</b>Examination of P-PDGFR-alpha expression may provide reliable evidence for the further improvement of pathological diagnosis,pathological typing and treatment for GISTs with negative CD117. Phosphorylated protein induced by PDGFR-alpha mutation may be associated with the important alternative molecular mechanism and the biological behavior of GIST development.</p>

Crosstalk between angiotensin II and platelet derived growth factor-BB mediated signal pathways in cardiomyocytes / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Angiotensin II (AngII) and platelet-derived growth factor (PDGF)-BB can induce hypertrophy in the cultured rat cardiomyocytes through different signal transduction pathways. AngII stimulates growth through G protein coupled receptor (GPCR), while PDGF-BB acts via receptor tyrosine kinase (RTK). Although there has been much development on the individual AngII and PDGF-BB mediated signal pathways, little is known about the interactions between these two factors. Therefore, the crosstalk between AngII and PDGF-BB mediated signal pathways in the rat cardiomyocytes was investigated in this study.</p><p><b>METHODS</b>Primary culture of neonatal rat ventricular myocytes was prepared. The amount of tyrosine-phosphorylated and non-phosphorylated PDGF-beta receptor, G(alphaq/11), and phospholipase C (PLC) beta(3) were measured by immunoblotting analysis. The statistical analysis was done by one-way ANOVA.</p><p><b>RESULTS</b>Tyrosine-phosphorylated PDGF-beta receptor was increased by 120.60% at 1 minute and recovered to the control level at 10 minutes after AngII stimulation. Phosphorylation of PDGF-beta receptor triggered by AngII was blocked by losartan, a specific antagonist of AT1 receptor. PLC inhibitor U73122, protein kinase C (PKC) inhibitor staurosporine (STS) and mitogen-activated ERK activating kinase (MEK) inhibitor PD98059 also inhibited the AngII-induced phosphorylation of PDGF-beta receptor. PDGF-BB slightly increased the expression of G(alphaq/11) protein.</p><p><b>CONCLUSION</b>AngII transactivates PDGF-beta receptor via AT(1) receptor-G(alphaq/11)-PLC-PKC pathway in the rat cardiomyocytes. ERK also participates in the transactivation of PDGF-beta receptor triggered by AngII.</p>