Human C-reactive protein enhances thrombus formation after neointimal balloon injury in transgenic rabbits

Background:  High plasma levels of C-reactive protein (CRP) constitute a powerful predictive marker of cardiovascular events. Several lines of evidence suggest that CRP has prothrombogenic effects. However, whether CRP directly participates in the pathogenesis of thrombosis in vivo has not been fully clarified. Objective:  To test whether human CRP (hCRP) affects arterial thrombus formation after balloon injury of smooth muscle cell (SMC)-rich or macrophage-rich neointima. Methods:  We compared the susceptibility of transgenic (Tg) rabbits expressing hCRP (46.21 ± 13.85 mg L −1 , n  = 22) and non-Tg rabbits to arterial thrombus formation after balloon injury of SMC-rich or macrophage-rich neointima. Results:  Thrombus size on SMC-rich or macrophage-rich neointima was significantly increased, and was accompanied by an increase in fibrin content in hCRP-Tg rabbits, as compared with non-Tg rabbits. Thrombus size did not significantly differ between SMC-rich and macrophage-rich neointima in hCRP-Tg rabbits. Tissue factor (TF) mRNA expression and activity in these neointimal lesions were significantly increased in hCRP-Tg rabbits as compared with non-Tg rabbits. The degree of CRP deposition correlated with the elevated TF expression and thrombus size on injured neointima. In addition, hCRP isolated from hCRP-Tg rabbit plasma induced TF mRNA expression and activity in rabbit cultured vascular SMCs. Conclusions:  These results suggest that elevated plasma hCRP levels promote thrombus formation on injured SMC-rich neointima by enhancing TF expression, but have no additive effects in macrophage-rich neointima.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/79159/1/j.1538-7836.2010.04086.x.pd

Respiratory and Urinary Tract Infections, Arthritis, and Asthma Associated with HTLV-I and HTLV-II Infection

Human T-lymphotropic virus types I and II (HTLV-I and -II) cause myelopathy; HTLV-I, but not HTLV-II, causes adult T-cell leukemia. Whether HTLV-II is associated with other diseases is unknown. Using survival analysis, we studied medical history data from a prospective cohort of HTLV-I– and HTLV-II–infected and –uninfected blood donors, all HIV seronegative. A total of 152 HTLV-I, 387 HTLV-II, and 799 uninfected donors were enrolled and followed for a median of 4.4, 4.3, and 4.4 years, respectively. HTLV-II participants had significantly increased incidences of acute bronchitis (incidence ratio [IR] = 1.68), bladder or kidney infection (IR = 1.55), arthritis (IR = 2.66), and asthma (IR = 3.28), and a borderline increase in pneumonia (IR = 1.82, 95% confidence interval [CI] 0.98 to 3.38). HTLV-I participants had significantly increased incidences of bladder or kidney infection (IR = 1.82), and arthritis (IR = 2.84). We conclude that HTLV-II infection may inhibit immunologic responses to respiratory infections and that both HTLV-I and -II may induce inflammatory or autoimmune reactions

Integrated genetic and clinical prognostic factors for aggressive adult T-cell leukemia/lymphoma

成人T細胞白血病リンパ腫（ATL）におけるゲノム情報と臨床情報を統合したリスクモデルを確立 --ATLの個別化医療を推進--. 京都大学プレスリリース. 2023-04-10.The prognosis of aggressive adult T-cell leukemia/lymphoma (ATL) is poor, and allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is a curative treatment. To identify favorable prognostic patients after intensive chemotherapy, and who therefore might not require upfront allo-HSCT, we aimed to improve risk stratification of aggressive ATL patients aged <70 years. The clinical risk factors and genetic mutations were incorporated into risk modeling for overall survival (OS). We generated the m7-ATLPI, a clinicogenetic risk model for OS, that included the ATL prognostic index (PI) (ATL-PI) risk category, and non-silent mutations in seven genes, namely TP53, IRF4, RHOA, PRKCB, CARD11, CCR7, and GATA3. In the training cohort of 99 patients, the m7-ATLPI identified a low-, intermediate-, and high-risk group with 2-year OS of 100%, 43%, and 19%, respectively (hazard ratio [HR] 5.46, p < 0.0001). The m7-ATLPI achieved superior risk stratification compared to the current ATL-PI (C-index 0.92 vs. 0.85, respectively). In the validation cohort of 84 patients, the m7-ATLPI defined low-, intermediate-, and high-risk groups with a 2-year OS of 81%, 30%, and 0%, respectively (HR 2.33, p = 0.0094), and the model again outperformed the ATL-PI (C-index 0.72 vs. 0.70, respectively). The simplified m7-ATLPI, which is easier to use in clinical practice, achieved superior risk stratification compared to the ATL-PI, as did the original m7-ATLPI; the simplified version was calculated by summing the following: high-risk ATL-PI category (+10), low-risk ATL-PI category (−4), and non-silent mutations in TP53 (+4), IRF4 (+3), RHOA (+1), PRKCB (+1), CARD11 (+0.5), CCR7 (−2), and GATA3 (−3)

Detection of sentinel and non-sentinel lymph node micrometastases by complete serial sectioning and immunohistochemical analysis for gastric cancer

<p>Abstract</p> <p>Background</p> <p>We investigated the presence and distribution of the sentinel and the non-sentinel node micrometastases using complete serial sectioning and immunohistochemical staining (IHC), to inspect whether lymph node micrometastases spread to the sentinel lymph nodes first.</p> <p>Methods</p> <p>A total of 35 patients, who underwent gastrectomy with a sentinel lymph node biopsy for gastric cancer, were enrolled in this study. Total of 1028 lymph nodes of 35 patients having gastric cancer without metastasis of lymph node by permanent section with hematoxylin and eosin staining (H&E) were selected. There were 252 sentinel nodes and the other 776 were non-sentinel nodes. All nodes were sectioned serially and stained alternately with H&E and IHC. Lymph node micrometastases was defined as proving to be positive first either the IHC or the complete serial sectioning.</p> <p>Results</p> <p>Micrometastases were detected in 4 (11%) of the 35 patients, 6 (0.58%) of 1028 nodes. Of these 4 patients, 3 had micrometastases exclusively in sentinel nodes, and the other had micrometastasis in both sentinel and non-sentinel nodes. There was no patient who had the micrometasitases only in non-sentinel nodes.</p> <p>Conclusion</p> <p>These results support the concept that lymph node micrometastasis of gastric cancer spreads first to sentinel nodes.</p

Phase I trial of intravesical Suramin in recurrent superficial transitional cell bladder carcinoma

Suramin is an antitrypanosomal agent with antineoplastic activity, but with serious systemic side effects. We administered Suramin intravesically to determine a concentration with low toxicity but with evidence of a pharmacodynamic effect, to recommend a dose level for phase II trials. This was an open-labelled, nonrandomised dose-escalation phase I study. In all, 12 patients with a history of recurrent superficial bladder cancer were grouped into four dose levels (10–150 mg ml−1 in 60 ml saline). Six catheter instillations at weekly intervals were used. Cystoscopy and biopsy were performed before and 3 months after the start of treatment. Suramin was assayed using high-performance liquid chromatography, vascular endothelial growth factor (VEGF) using ELISA (enzyme-linked immunosorbent assay), and urinary protein profile using surface-enhanced laser desorption ionisation mass spectroscopy (SELDI). Minimal systemic absorption of Suramin was found at the highest dose of 150 mg ml−1. Urinary VEGF was affected by Suramin at doses above 50 mg ml−1, corresponding to the estimated threshold of saturation of Suramin binding to urine albumin. SELDI showed a specific disappearance of urinary protein peaks during treatment. Intravesical Suramin shows lack of toxicity and low systemic absorption. The results of this phase I trial support expanded clinical trials of efficacy at a dose of 100 mg ml−1 intravesically

Prospective validation of quantitative CEA mRNA detection in peritoneal washes in gastric carcinoma patients

Prediction of peritoneal relapse is extremely important for gastric cancer patients after curative surgery. The present study prospectively validates the prognostic ability of quantifying carcinoembryonic antigen (CEA) mRNA in peritoneal washes by real-time reverse transcriptase–polymerase chain reaction. Based on a retrospective study of 197 curatively resected gastric cancer patients (training set), we determined a cutoff value of CEA mRNA using receiver-operating characteristic curve. We used this cutoff value to validate the risk of peritoneal recurrence in a new cohort of 86 gastric cancer patients (validation set) between July 2000 and December 2002 in a prospective study. During the median 30 months of postoperative surveillance, 20 of the 86 patients died, and 13 of the 20 developed peritoneal metastases. Peritoneal recurrence-free survival as well as overall survival was significantly worse in patients with positive CEA mRNA (P<0.0001). Multivariate analysis with the Cox proportional hazards model showed that positive CEA mRNA was a significant independent risk factor with both survival (P=0.0130) and peritoneal recurrence-free survival (P=0.0006) as end points. These results indicate that quantitation of CEA mRNA in peritoneal washes is a reliable prognostic indicator of peritoneal recurrence in the clinical setting

Expression of uPAR mRNA in peripheral blood is a favourite marker for metastasis in gastric cancer cases

Urokinase-type plasminogen activator receptor (uPAR) plays a central role in the plasminogen activation cascade and participates in extracellular matrix degradation, cell migration and invasion. We evaluated the expression level of uPAR mRNA and the presence of isolated tumour cells (ITCs) in bone marrow (BM) and peripheral blood (PB) in gastric cancer patients and clarified its clinical significance. We assessed specific uPAR mRNA expression by quantitative real-time reverse transcriptase- polymerase chain reaction (RT–PCR) in BM and PB in 846 gastric cancer patients as well as three epithelial cell markers, carcinoembryonic antigen (CEA), cytokeratin (CK)-19 and CK-7. The uPAR mRNA expression in bone marrow and peripheral blood expressed significantly higher than normal controls (P<0.0001). The uPAR mRNA in BM showed concordant expression with the depth of tumour invasion, distant metastasis, and the postoperative recurrence (P=0.015, 0.044 and 0.010, respectively); whereas in PB, we observed more intimate significant association between uPAR expression and clinicopathologic variables, such as depth of tumour invasion, the distant metastasis, the venous invasion and the clinical stage (P=0.009, 0.002, 0.039 and 0.008, respectively). In addition, the uPAR mRNA expression in PB was an independent prognostic factor for distant metastasis by multivariate analysis. We disclosed that it was possible to identify high-risk patients for distant metastasis by measuring uPAR mRNA especially in peripheral blood at the timing of operation in gastric cancer patients