Clinical manifestations and genetic mutation analysis of 20 patients with congenital Fibrinogen disorders / 中国输血杂志

【Objective】 To retrospectively analyze the clinical manifestations, related laboratory examinations and gene mutation of 20 patients with congenital Fibrinogen disorders (CFD) admitted to our hospital from February 2017 to December 2021, so as to improve the understanding of CFD diagnosis. 【Methods】 Clinical characteristics and laboratory examination of 20 CFD patients were collected, and common secondary hypoFibrinemia factors were excluded. Gene sequencing was performed on all exons and flanks of FGA, FGB and FGG genes of 20 patients to find gene mutation sites. The peripheral blood genomic DNA was collected from the family members of two CFD patients, and the genes of the corresponding mutation sites of the proband were detected. 【Results】 The 20 CFD patients had no history of bleeding; 11 female patients had no history of spontaneous abortion; all 20 patients had reduced Fib and prolonged thrombin time (TT). There were 13 gene mutations of different types in 20 patients, among which 90% (18/20) were missense mutations, 5% (1/20) was deletion mutation, and 5% (1/20) was frameshift mutation. Seven patients (35%) had Arg35His mutation at site 104 of the FGA chain, among which 3 new gene mutations have not been reported in China. 【Conclusion】 Most CFD patients with mild or asymptomatic symptoms can be diagnosed by genetic testing and screening. FGA chain Arg35His is a mutation hotspot in this region, and all of them are Uyghur. Whether the mutation of this site is related to ethnicity needs to be confirmed by further studies.

Primary myelofibrosis with thrombophilia as first symptom combined with thalassemia and Gilbert syndrome: A case report.

BACKGROUND: A 46-year-old Han man first had sigmoid sinus and transverse sinus venous thrombosis at the age of 42. At the age of 44, he once again developed thrombosis. Genetic testing showed heterozygous SERPINC1 mutation, bone marrow biopsy showed fibrosis grade 1 (MF-1), and JAK2 V617F mutation was positive, accompanied by UGT1A1 mutation and ß-thalassemia gene mutation. CASE SUMMARY: A 46-year-old Han man was first found to have sigmoid sinus and transverse sinus venous thrombosis at the age of 42 but had no individual or family thrombosis history, and he had been regularly taking warfarin anticoagulant therapy for a long period of time. At the age of 44, venous thrombosis reappeared in parts of the intrahepatic vein, main portal vein, splenic vein, and superior mesenteric vein, and his spleen was obviously enlarged. He had a history of jaundice for many years, and genetic testing revealed that he carried a heterozygous SERPINC1 mutation. Bone marrow biopsy showed multifocal fibrous tissue hyperplasia among trabeculae and focal fibrosis. He was positive for the JAK2 V617F mutation. At the same time, UGT1A1 and ß-thalassemia gene mutations existed, and a SERPINC1 mutation and UGT1A1 mutation were both found in his parents. CONCLUSION: The patient in this case had thrombophilia as the primary symptom, JAK2V617-positive myeloproliferative neoplasm (MPN) was the main potential cause, and hereditary AT-III deficiency may have been one of multiple secondary causes. It remains to be determined whether UGT1A1 and ß-thalassemia gene mutations are related to thrombophilia. However, the clinical features of MPN in this patient were hidden, and the relevant clinical features of coexisting thalassemia and hereditary Gilbert syndrome, reported here for the first time domestically and abroad, were complicating factors, causing great difficulties for a clear diagnosis. Thus, when thrombophilia has been determined, it is necessary to screen the relevant latent problems overall. When the clinical features cannot be perfectly explained by one etiology, a relevant comprehensive examination should also be initiated from the perspective of multiple etiologies.

Correlation analysis between JAK2, MPL, and CALR mutations in patients with myeloproliferative neoplasms of Chinese Uygur and Han nationality and their clinical characteristics.

BACKGROUND: Genetic factors play a role in the etiology of BCR-ABL-negative myeloproliferative neoplasms (MPNs). This study explored the relationship between mutations in the Janus kinase 2 gene ( JAK2), MPL, and the calreticulin gene ( CALR) in Uygur and Han Chinese patients with BCR-ABL fusion gene-negative MPN and corresponding clinical features. METHODS: A total of 492 BCR-ABL-negative MPN patients treated in our hospital from May 2013 to August 2016 were enrolled. Genomic DNA was extracted from peripheral blood and used for PCR amplification and DNA sequencing. Mutations including JAK2 V617F, MPL W515L/K, and those in JAK2 exon 12 and CALR were analyzed and compared with patient clinical characteristics. RESULTS: Of the 492 MPN patients, 169 were Uygur and 323 were Han. In these two patient groups, JAK2 mutations were detected in 39.64% and 52.63%, respectively, CALR mutations were detected in 10.06% and 20.43%, respectively, and MPL mutations were detected in 0.93% of Han patients. The age, white blood cell count, platelet levels, and hemoglobin levels in JAK2 in Han patients were higher than those in Uygur patients. CONCLUSION: Han MPN patients harboring JAK2 mutations had higher level of age, WBC, PLT, and Hb than Uyghur patients with the same mutations.

Tumor necrosis factor-α induces prostate cancer cell migration in lymphatic metastasis through CCR7 upregulation.

Understanding the mechanism of lymph node metastasis, a poor prognostic sign for prostate cancer, and the further dissemination of the disease is important to develop novel treatment strategies. Recent studies have reported that C-C chemokine receptor 7 (CCR7), whose ligand is CCL21, is abundantly expressed in lymph node metastasis and promotes cancer progression. Tumor necrosis factor-α (TNF-α) is chronically produced at low levels within the tumor microenvironment. The aim of this study was to determine whether TNF-α promotes prostate cancer dissemination from metastatic lymph nodes through activation of the CCL21/CCR7 axis. First, human prostate cancer cells were determined to express both TNF-α and CCR7. Second, low concentrations of TNF-α were confirmed to induce CCR7 in prostate cancer cells through phosphorylation of ERK. Finally, CCL21 was found to promote the migration of prostate cancer cells through phosphorylation of the protein kinase p38. Our results suggest that TNF-α leads to the induction of CCR7 expression and that the CCL21/CCR7 axis might increase the metastatic potential of prostate cancer cells in lymph node metastasis.

C-C motif ligand 5 promotes migration of prostate cancer cells in the prostate cancer bone metastasis microenvironment.

Chemokines and their receptors have key roles in cancer progression. The present study investigated chemokine activity in the prostate cancer bone metastasis microenvironment. Growth and migration of human prostate cancer cells were assayed in cocultures with bone stromal cells. The migration of LNCaP cells significantly increased when co-cultured with bone stromal cells isolated from prostate cancer bone metastases. Cytokine array analysis of conditioned medium from bone stromal cell cultures identified CCL5 as a concentration-dependent promoter of LNCaP cell migration. The migration of LNCaP cells was suppressed when C-C motif ligand 5 (CCL5) neutralizing antibody was added to cocultures with bone stromal cells. Knockdown of androgen receptor with small interfering RNA increased the migration of LNCaP cells compared with control cells, and CCL5 did not promote the migration of androgen receptor knockdown LNCaP. Elevated CCL5 secretion in bone stromal cells from metastatic lesions induced prostate cancer cell migration by a mechanism consistent with CCL5 activity upstream of androgen receptor signaling.

Tumor-associated macrophages promote prostate cancer migration through activation of the CCL22-CCR4 axis.

Previous studies have found that tumor-associated macrophages (TAMs) promote cancer progression. We previously reported that TAMs promote prostate cancer metastasis via activation of the CCL2-CCR2 axis. The CCR4 (receptor of CCL17 and CCL22) expression level in breast cancer was reported to be associated with lung metastasis. The aim of this study was to elucidate the role of CCR2 and CCR4 in prostate cancer progression. CCR2 and CCR4 were expressed in human prostate cancer cell lines and prostate cancer tissues. In vitro co-culture of prostate cancer cells and macrophages resulted in increased CCL2 and CCR2 levels in prostate cancer cells. The addition of CCL2 induced CCL22 and CCR4 production in prostate cancer cells. The migration and invasion of prostate cancer cells via enhanced phosphorylation of Akt were promoted by CCL17 and CCL22. CCR4 may be a potential candidate for molecular-targeted therapy.

Detection of p53 gene deletion in Xinjiang patients with chronic lymphocytic leukemia by fluorescence in situ hybridization and its clinical significance / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To investigate the presence of p53 gene deletion in Xinjiang patients with chronic lymphocytic leukemia and its clinical significance.</p><p><b>METHODS</b>Interphase fluorescence in situ hybridization (FISH) was used to detect the p53 gene deletion in 77 patients with CLL. Presence of the deletion and its association with clinical and laboratory features as well as prognostic factors were analyzed. Kaplan-Meier method was used to calculate survivals, and the results were compared using a Log-rank test.</p><p><b>RESULTS</b>p53 gene deletion was found in 10 (12.9%) of the patients but none from the control group (P<0.05). The deletion was found in 12.5% (4/32) of ethnic Hans and 13.3% (6/45) of ethnic Uyghurs (P>0.05). No significant different distribution of p53 gene deletion was found in regard to sex, age, ethnicity, peripheral blood cell count (except for Hb) or the levels of lactate dehydrogenase, β2-micro globulin and CD38 (P>0.05). The deletion rate was higher in the group with high expression of ZAP-70 and patients with advanced stage disease than that in the group of low expression and early-stage CLL (P<0.05). Among 20 patients who received fludarabine therapy, the overall remission rate for those with p53 gene deletion (20%) was lower than those without (75%) (P<0.05). With a median follow-up time of 39.0 (8.0-136.0) months, 11 cases had died (14.3%), among them, 7 cases died from CLL and related complications, and all of them were founded p53 gene deletion. In patients with p53 gene deletion, the progression-free survival (18 months) was shorter than those without the deletion (55 months) (P<0.05).</p><p><b>CONCLUSION</b>The p53 gene deletion has been found in more than 10% of patients with CLL, and the deletion rate did not significantly differ between ethnic Han and Uyghur patients. The deletion is associated with advanced stage of the disease. High-level ZAP-70 expression and the presence of p53 deletion are associated with shorter survival and poor response to fludarabine containing therapy. Therefore, drugs affecting the p53 signaling pathway should be avoided.</p>