Cancer-associated fibroblasts (CAF) play a crucial role in angiogenesis in the complex tumor microenvironment. However, fibroblasts show extensive heterogeneity and their dynamic functions against stressors remain largely unknown.We collected patient-derived CAF and carried out perturbation-based monitoring of the dynamic functions. Clinically relevant experimental stimuli were defined as follows: hypoxia, cisplatin, fluorouracil, coculture with cancer spheroids (interaction through paracrine signals). We selected 18 marker genes that encode components for fibroblast activation, intracellular communication, and extracellular matrix remodeling. Quantitative reverse transcription polymerase chain reaction was carried out for data collection and statistical analyses were carried out using SPSS software.Kruskal-Wallis multivariate analysis of variance showed that variations in expression of 11 marker genes were explained, in part, by a difference in tissue of origin. Friedman and two-sided Wilcoxon signed rank tests detected significant perturbations in expression of marker genes. Paracrine signal from cancer spheroids induced vascular endothelial growth factor A (VEGFA) in CAF but not in fetal lung fibroblasts.We have established perturbation-based monitoring of patients' CAF. Further data collection and individual patient follow up is ongoing to identify critical determinants of disease outcome.
Two cases of "Inflammatory" aneurysm of the abdominal aorta and a review of this type of lesion were presented. The incidence of inflammatory aneurysm of the abdominal aorta in the literature is 2.5 to 15%, but there were no detail reports concerning with this in Japan. The pathogenesis is not clear, but it is evident both macroscopically and microscopically that the inflammatory aneurysms are different from athelosclerotic ones. They are characterized by perivascular peel of inflammatory fibrous tissue. It is possible that this type of aneurysms are merely a variant of Takayasu's disease. Until recently, the diagnosis of this type of aneurysm has not been made before surgery. The symptom of abdominal pain, weight loss, elevated ESR in a patient with abdominal aortic aneurysm are highly suggestive an inflammatory aneurysm. Characteristics of CT scan lead to more frequent preoperative diagnosis of inflammatory aneurysms of the aorta. It reveals a thickened often calcified aortic wall surrounded by a soft tissue mantle. Dynamic scanning shows an enhancing perianeurysnal mass. Graft replacement in these patients is often difficult and associated with increase in morbidity and mortality. At surgery, no attempt should be made to mobilize adjacent viscela in order to avoid injury. Arterial control should be obtained with as little as possible dissection. Some reports refer to successful steroid therapy resolving the inflammatory process and alleviating symptoms. Further research may resolve the treatment of choice for this type of lesion and optimize the timing of surgery.
A 76-year-old woman with unstable angina underwent coronary stent implantation. At the same time, rosuvastatin therapy was started. However, she experienced repeated in-stent restenosis (ISR). Treatment with a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor along with rosuvastatin (5 mg/day) reduced plasma low-density lipoprotein cholesterol to 10 mg/dL, but failed to prevent further ISR. Eventually, an increase in the rosuvastatin dose to the permitted maximum of 20 mg/day succeeded in preventing further in-stent restenosis. Rather than using PCSK9 inhibitors, intensive statin treatment, using the maximum dose of statins, should be prioritized for the secondary prevention of coronary artery disease.
Abstract Background Aggressive lipid lowering by high-dose statin treatment has been established for the secondary prevention of coronary artery disease (CAD). Regarding the low-density lipoprotein cholesterol (LDL-C) level, however, the “The lower is the better” concept has been controversial to date. We hypothesized that there is an optimal LDL-C level, i.e., a “threshold” value, below which the incidence of cardiovascular events is no longer reduced. We undertook a subanalysis of the REAL-CAD study to explore whether such an optimal target LDL-C level exists by a novel analysis procedure to verify the existence of a monotonic relationship. Methods For a total of 11,105 patients with CAD enrolled in the REAL-CAD study, the LDL-C level at 6 months after randomization and 5-year cardiovascular outcomes were assessed. We set the “threshold” value of the LDL-C level under which the hazards were assumed to be constant, by including an artificial covariate max (0, LDL-C − threshold) in the Cox model. The analysis was repeated with different LDL-C thresholds (every 10 mg/dl from 40 to 100 mg/dl) and the model fit was assessed by log-likelihood. Results For primary outcomes such as the composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, and unstable angina requiring emergency hospitalization, the model fit assessed by log-likelihood was best when a threshold LDL-C value of 70 mg/dl was assumed. And in the model with a threshold LDL-C ≥ 70 mg/dl, the hazard ratio was 1.07 (95% confidence interval 1.01–1.13) as the LDL-C increased by 10 mg/dl. Therefore, the risk of cardiovascular events decreased monotonically until the LDL-C level was lowered to 70 mg/dl, but when the level was further reduced, the risk was independent of LDL-C. Conclusions Our analysis model suggests that a “threshold” value of LDL-C might exist for the secondary prevention of cardiovascular events in Japanese patients with CAD, and this threshold might be 70 mg/dl for primary composite outcomes. Trial registration http://www.clinicaltrials.gov . Unique identifier: NCT01042730.
Sarcopenia is closely associated with postoperative prognosis in patients undergoing cardiovascular surgery. Growth differentiation factor (GDF)-15 is involved in the pathogenesis of cardiovascular disease. We examined the relationship between the serum GDF-15 concentration and muscle function in patients receiving aortic valve replacement and healthy elderly subjects.Forty-three female patients undergoing aortic valve surgery (79.9 ± 6.4 years; transcatheter aortic valve replacement [TAVR] n = 19, conventional surgical aortic valve replacement [SAVR] n = 24) and 64 healthy elderly female subjects (75.9 ± 6.1 years) were included. Walking speed, grip strength, and skeletal muscle mass index (SMI) by a multifrequency bioelectrical impedance analyzer were measured to determine the presence of sarcopenia. Preoperative serum GDF-15 concentration was measured by enzyme-linked immunosorbent assay.The GDF-15 level was higher in patients receiving aortic valve replacement than in healthy elderly subjects (aortic valve replacement: 1624 ± 1186 pg/mL vs. healthy: 955 ± 368 pg/mL, p < 0.001). Multivariate linear regression analysis showed that the serum GDF-15 level determined grip strength independently of the high-sensitivity C-reactive protein level and eGFR, even after adjusting for age (β = -0.318, p = 0.025). Sarcopenia was found in 12.5% of healthy elderly subjects, 83.3% of patients with TAVR, and 64.3% of patients with SAVR. The GDF-15 concentration that defined sarcopenia was 1109 pg/mL in subjects including patients receiving aortic valve replacement.The preoperative serum GDF-15 concentration, which was higher in female patients receiving aortic valve replacement than in healthy elderly subjects, may be a serum marker of sarcopenia.
