Noonan syndrome (NS) is characterized by short stature, characteristic facial features, and heart defects. Recently, missense mutations of PTPN11, the gene encoding protein tyrosine phosphatase (PTP) SHP-2, were identified in patients with NS. Further, somatic mutations in PTPN11 were detected in childhood leukemia. Recent studies showed that the phosphatase activities of five mutations identified in NS and juvenile myelomonocytic leukemia (JMML) were increased. However, the functional properties of the other mutations remain unidentified. In this study, in order to clarify the differences between the mutations identified in NS and leukemia, we examined the phosphatase activity of 14 mutants of SHP-2. We identified nine mutations, including a novel F71I mutation, in 16 of 41 NS patients and two mutations, including a novel G503V mutation, in three of 29 patients with leukemia. Immune complex phosphatase assays of individual mutants transfected in COS7 cells showed that ten mutants identified in NS and four mutants in leukemia showed 1.4-fold to 12.7-fold increased activation compared with wild-type SHP-2. These results suggest that the pathogenesis of NS and leukemia is associated with enhanced phosphatase activity of mutant SHP-2. A comparison of the phosphatase activity in each mutant and a review of previously reported cases showed that high phosphatase activity observed in mutations at codons 61, 71, 72, and 76 was significantly associated with leukemogenesis. 相似文献
Since humans are under ceaseless orthostatic stress, the mechanism to maintain arterial pressure (AP) under orthostatic stress against gravitational fluid shift is of great importance. We hypothesized that (1) orthostatic stress resets the arterial baroreflex control of sympathetic nerve activity (SNA) to a higher SNA, and (2) resetting of the arterial baroreflex contributes to preventing postural hypotension. Renal SNA and AP were recorded in eight anaesthetized, vagotomized and aortic-denervated rabbits. Isolated intracarotid sinus pressure (CSP) was increased stepwise from 40 to 160 mmHg with increments of 20 mmHg (60 s for each CSP level) while the animal was placed supine and at 60 deg upright tilt. Upright tilt shifted the CSP–SNA relationship (the baroreflex neural arc) to a higher SNA, shifted the SNA–AP relationship (the baroreflex peripheral arc) to a lower AP, and consequently moved the operating point to marked high SNA while maintaining AP. A simulation study suggests that resetting in the neural arc would double the orthostatic activation of SNA and increase the operating AP in upright tilt by 10 mmHg, compared with the absence of resetting. In addition, upright tilt did not change the CSP–AP relationship (the baroreflex total arc). A simulation study suggests that although a downward shift of the peripheral arc could shift the total arc downward, resetting in the neural arc would compensate this fall and prevent the total arc from shifting downward to a lower AP. In conclusion, upright tilt increases SNA by resetting the baroreflex neural arc. This resetting may compensate for the reduced pressor responses to SNA in the peripheral cardiovascular system and contribute to preventing postural hypotension. 相似文献
CD4+CD56+ hematodermic neoplasms (HNs) with initial presentation in the skin are characterized by highly aggressive behavior and poor prognosis. Recent studies indicate that malignant cells, which are devoid of common T-, B-, NK-, and myeloid lineage markers, may be of plasmacytoid dendritic cell (pDC) origin. We undertook a study to assess the expression of several pDC-associated molecules on a series of 5 CD4+CD56+ HN cases. CD123 was expressed in all 5 cases, with some heterogeneity in individual cases. All but one case revealed fine membranous BDCA-2 staining of the dermal infiltrate. pDC-like phenotype of the malignant infiltrating cells was confirmed by costaining of BDCA-2+ cells with CD123 and CD4. MxA protein, representing the surrogate marker for lesional type I interferon activity, was expressed in 4 of 5 evaluated cases. Our findings further substantiate the putative pDC origin of CD4+CD56+ HNs. 相似文献
Transient thrombocytosis is commonly observed in preterm infants after birth, but its physiological mechanism is still unknown. To understand the mechanism of the transient thrombocytosis in preterm infants we firstly evaluated a correlation between platelet counts and thrombopoietin (TPO) levels in preterm infants and next c-mpl mRNA levels on platelets in healthy preterm infants longitudinally during a half-year of life. The mean platelet counts in 45 very low birth weight infants (mean gestational age 27.4±1.8 weeks, mean birth weight 1047±249 g) was 230±71×109/l just after birth and thereafter gradually increased to 579±178×109/l by 5 weeks of age. The platelet counts continued this level for about next 8 weeks. Serum TPO levels soon after birth and at 1 month of age were significantly higher than those at the age of 2–6 months. There was a significant negative correlation between platelet counts and serum TPO values. The c-mpl expression levels on platelets at birth and at 1 month of age tended to be lower than those on platelets from adults, and the c-mpl levels gradually increased through 6 months of age, although they were still lower than those of adults. Our results suggest that low expression of TPO receptor on platelets until 1 month after birth cause a decreased TPO clearance and keep a high level of free TPO in blood, thereby promoting platelet production from megakaryocytes or their progenitors in bone marrow, resulting in the subsequent thrombocytosis in preterm infants. 相似文献
Alleles encoding HLA-C antigens in Japanese were identified by polymerase chain reaction followed by single strand conformation polymorphism (PCR-SSCP) and nucleotide sequencing analyses. The results showed that at least sixteen different alleles code for eight serologically detectable antigen groups and undetectable blanks. Cwl was mainly encoded by Cw*0102, whereas two split antigens of Cw3, Cw9 and Cw10, were encoded by Cw*0303 and Cw*0304, respectively. Cw4 and Cw6 were encoded by Cw*0401 and Cw*0602, respectively. Seven alleles, Cw*0801, Cw*0803, Cw*1202, Cw*1203, Cw*1402, Cw*1403 and Cw*1502, were found to encode serological HLA-C "blanks" in Japanese. Moreover, errors in the published nucleotide sequences of Cw*0501 and Cw*1201 were corrected. Twenty-one HLA-C alleles were distinguished from each other by means of group-specific PCR amplification followed by the SSCP method developed in the present study. The system using genomic DNAs can be used effectively for identification of new HLA-C alleles. 相似文献
Objective: The long-term administration of erythromycin (EM), clarithromycin (CAM) or azithromycin (AZM) has generally resulted in a favorable outcome for patients with diffuse panbronchiolitis (DPB) infected with mucoid Pseudomonas aeruginosa. To elucidate the mechanism involved, the influence of macrolides on mucoid alginate production by P. aeruginosa was investigated in vitro. Methods: The macrolides used in this study were EM with a 14-membered ring, AZM with a 15-membered ring, midecamycin (MDM) with a 16-membered ring, and CP-4305, which has had mycarose removed from MDM, The effects of macrolides on mucoid P. aeruginosa were investigated by quantitative assay of alginate production and inhibition of guanosine diphospho-D-mannose dehydrogenase activity. Results: After incubation with EM, AZM and CP-4305, the structural material of P. aeruginosa biofilm was distorted, and the enzymatic activity of GDP-D-mannose dehydrogenase, the most important enzyme in mucoid alginate biosynthesis, was inhibited. However, these effects were not observed with the 16-membered macrolide MDM. Conclusions: The basic mechanism of clinical efficacy seen characteristically in 14- or 15-membered macrolides for patients with airway biofilm disease depends on the ability of such macrolides to inhibit alginate production by P. aeruginosa. Furthermore, this suggests that the inhibitory effect observed with 14-, 15- and 16-membered macrolides may depend on the sugar chain connected with the macrolide ring. 相似文献
The optimal regimens of neoadjuvant chemotherapy (NAC) and its biological and physiological modification of the tumor microenvironment (TME) in patients with borderline resectable pancreatic ductal adenocarcinoma (BR PDAC) remain unknown. A deeper understanding of the complex stromal biology of the TME will identify new avenues to establish treatment strategies for PDAC patients. Herein, we sought to clarify whether stromal remodeling by NAC affects recurrence patterns and prognosis in BR PDAC patients. We retrospectively analyzed data from 104 BR PDAC patients who underwent pancreatectomy with or without NAC (upfront surgery [UpS], n?=?44; gemcitabine?+?nab-paclitaxel [GnP], n?=?28; and gemcitabine?+?S-1 [GS], n?=?32) to assess the correlations of treatment with early recurrence, the stromal ratio, and Ki-67 levels. Eighty-six patients experienced recurrence, and those with liver metastasis had significantly shorter recurrence-free survival than those with other recurrence patterns. The frequency of liver metastasis was significantly higher in patients with a low stromal ratio than in those with a high stromal ratio in the NAC group but not in the UpS group. Patients in the GnP group had significantly higher Ki-67 than those in the GS and UpS groups. A low stromal ratio was positively correlated with high Ki-67 in the NAC group but not in the UpS group. The low stromal ratio induced by NAC promoted early liver metastasis in patients with BR PDAC. Our findings provide new insights into the complexity of stromal biology, leading to consideration of the optimal NAC regimen.