Fibroblast growth factor-23 and cardiovascular disease among prevalent hemodialysis patients focusing on residual kidney function

BackgroundIn patients undergoing incident hemodialysis, increased fibroblast growth factor-23 (FGF-23) levels are associated with the development of cardiovascular disease (CVD), but the influence of residual kidney function (RFK) on this association is unclear. This study aimed to investigate the association between FGF-23 levels, RKF, and CVD in patients undergoing prevalent hemodialysis.MethodsThis cross-sectional and longitudinal observational study included 296 patients undergoing maintenance hemodialysis for at least three months who were followed up for a median of 44 months. RKF was defined as 24-h urine output >200 mL, left ventricular (LV) diastolic dysfunction as E/E’ >15 on echocardiographic parameters. CVD was defined as hospitalization or emergency room visits due to cardiovascular causes, such as angina, myocardial infarction, or congestive heart failure.ResultsThe median intact FGF-23 (iFGF-23) level was 423.8 pg/mL (interquartile range, 171–1,443). Patients with an FGF-23 level > 423.8 pg/mL significantly had a lower proportion of RKF (39.2% vs. 60.1%, P < 0.001) and a higher proportion of LV diastolic dysfunction (54. 1% vs. 29.1%, P < 0.001) than those with an iFGF-23 level ≤ 423.8 pg/mL. The odds ratio (OR) for LV diastolic dysfunction was significantly higher in patients with RFK (OR per one-unit increase in the natural log-transformed iFGF-23 levels, 1.80; 95% confidence interval [CI]: 1.11–2.93) than in patients without RKF (OR per one-unit increase in the natural log-transformed iFGF-23 levels: 1.42; 95% CI: 1.01–1.99) in multivariate analysis (p < 0.001). During the follow-up period, 55 patients experienced CVD. The hazard ratio (HR) for CVD development was also significantly higher in patients with RKF (HR per one-unit increase in the natural log-transformed iFGF-23 levels, 2.64; 95% CI: 1.29–5.40) than those without RKF (HR per one-unit increase in the natural log-transformed iFGF-23 levels: 1.44; 95% CI: 1.04–1.99) in multivariate analysis (p = 0.05).ConclusionsIncreased iFGF-23 levels were associated with LV diastolic dysfunction and CVD development in patients undergoing prevalent hemodialysis; however, the loss of RKF attenuated the magnitude of these associations. Therefore, in these patients, RKF strongly influenced the detrimental role of iFGF-23 in the development of CVD

Corneal keloid: four case reports of clinicopathological features and surgical outcome

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Abstract Background Surgical outcome of corneal keloid is largely variable depending on reports, although surgical management is inevitable in visually significant cases. We here report clinical features, histopathological findings, and surgical outcome of four cases of corneal keloid. Case presentation Four Korean male patients without a history of corneal trauma or disease were clinically and histologically evaluated for a slowly-growing, white opacity in the cornea. On slit lamp examination, corneal lesions appeared as a solitary, pearly white, well-circumscribed nodule with a smooth and glistening surface. Because the lesions involved the visual axis deteriorating the visual acuity, the nodules were surgically removed by superficial keratectomy in all patients. Amniotic membrane transplantation was combined in three patients, and an intraoperative mitomycin C application in two patients. Hematoxylin-eosin staining of the excised nodules revealed epithelial hyperplasia, Bowmans layer disruption, thick and irregularly-arranged collagen fibers in the stroma, and accumulation of prominent fibroblasts, which are consistent with the diagnosis of corneal keloid. The corneal keloids recurred in all patients within 10 months of surgical excision and outgrew the boundary of the excised area. Conclusion A diagnosis of corneal keloid should be suspected in patients presenting with an enlarging, white, glistening corneal nodule, even in the absence of a history of corneal trauma or disease. The recurrence is common after surgical excision, and the lesion can be exacerbated by surgery

Unusual Presentation of Cystic Lymphangioma of the Gallbladder

Cystic lymphangioma of the gallbladder is quite a rare tumor with only a few cases having been reported in the literature. We describe here a rare case of cystic lymphangioma of the gallbladder, which was unusual in that the patient presented with biliary pain and an abnormal liver test. Ultrasonography and computed tomography of the abdomen showed a multi-septated cystic mass in the gallbladder fossa and an adjacent compressed gallbladder. Endoscopic retrograde cholangiography showed there was no communication between the bile tract and the lesion, and there were no other abnormal findings with the exception of a laterally compressed gallbladder. After performing endoscopic sphincterotomy, a small amount of sludge was released from the bile duct. The histological findings were consistent with a cystic lymphangioma originating from the subserosal layer of the gallbladder. This unusual clinical presentation of a gallbladder cystic lymphangioma was attributed to biliary sludge, and this was induced by gallbladder dysfunction that was possibly from compression of the gallbladder due to the mass

HOXB13 promotes androgen independent growth of LNCaP prostate cancer cells by the activation of E2F signaling

<p>Abstract</p> <p>Background</p> <p>Androgen signaling plays a critical role in the development of prostate cancer and its progression. However, androgen-independent prostate cancer cells emerge after hormone ablation therapy, resulting in significant clinical problems. We have previously demonstrated that the HOXB13 homeodomain protein functions as a prostate cancer cell growth suppressor by inhibiting androgen-mediated signals. However, the role of the HOXB13 in androgen-independent growth of prostate cancer cells remains unexplained.</p> <p>Results</p> <p>In this report, we first demonstrated that HOXB13 was highly overexpressed in hormone-refractory tumors compared to tumors without prostate-specific antigen after initial treatment. Functionally, in an androgen-free environment minimal induction of HOXB13 in LNCaP prostate cancer cells, to the level of the normal prostate, markedly promoted cell proliferation while suppression inhibited cell proliferation. The HOXB13-mediated cell growth promotion in the absence of androgen, appears to be mainly accomplished through the activation of RB-E2F signaling by inhibiting the expression of the p21^waftumor suppressor. Indeed, forced expression of HOXB13 dramatically decreased expression of p21^waf; this inhibition largely affected HOXB13-mediated promotion of E2F signaling.</p> <p>Conclusions</p> <p>Taken together, the results of this study demonstrated the presence of a novel pathway that helps understand androgen-independent survival of prostate cancer cells. These findings suggest that upregulation of HOXB13 is associated with an additive growth advantage of prostate cancer cells in the absence of or low androgen concentrations, by the regulation of p21-mediated E2F signaling.</p

Utility of Integrated Analysis of Pharmacogenomics and Pharmacometabolomics in Early Phase Clinical Trial: A Case Study of a New Molecular Entity

In this report, we present a case study of how pharmacogenomics and pharmacometabolomics can be useful to characterize safety and pharmacokinetic profiles in early phase new drug development clinical trials. During conducting a first-in-human trial for a new molecular entity, we were able to determine the mechanism of dichotomized variability in plasma drug concentrations, which appeared closely related to adverse drug reactions (ADRs) through integrated omics analysis. The pharmacogenomics screening was performed from whole blood samples using the Affymetrix DMET (Drug-Metabolizing Enzymes and Transporters) Plus microarray, and confirmation of genetic variants was performed using real-time polymerase chain reaction. Metabolomics profiling was performed from plasma samples using liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. A GSTM1 null polymorphism was identified in pharmacogenomics test and the drug concentrations was higher in GSTM1 null subjects than GSTM1 functional subjects. The apparent drug clearance was 13-fold lower in GSTM1 null subjects than GSTM1 functional subjects (p < 0.001). By metabolomics analysis, we identified that the study drug was metabolized by cysteinylglycine conjugation in GSTM functional subjects but those not in GSTM1 null subjects. The incidence rate and the severity of ADRs were higher in the GSTM1 null subjects than the GSTM1 functional subjects. Through the integrated omics analysis, we could understand the mechanism of inter-individual variability in drug exposure and in adverse response. In conclusion, integrated multi-omics analysis can be useful for elucidating the various characteristics of new drug candidates in early phase clinical trials

Liposomal irinotecan in metastatic pancreatic adenocarcinoma in Asian patients: Subgroup analysis of the NAPOLI-1 study

The global, randomized NAPOLI-1 phase 3 trial reported a survival benefit with liposomal irinotecan (nal-IRI) plus 5-fluorouracil/leucovorin (nal-IRI+5-FU/LV) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) after previous gemcitabine-based therapy. Median overall survival (OS) with nal-IRI+5-FU/LV was 6.1 vs 4.2 months with 5-FU/LV alone (unstratified hazard ratio [HR] = 0.67, P =.012). Herein, we report efficacy and safety results from a post-hoc subgroup analysis of Asian patients treated at Asian centers. Primary study endpoint was OS; secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety. Patients receiving nal-IRI+5-FU/LV (n = 34) had significantly longer median OS versus 5-FU/LV (n = 35) (8.9 vs 3.7 months; unstratified HR = 0.51, P =.025). Patients had significantly increased median PFS with nal-IRI+5-FU/LV versus 5-FU/LV (4.0 vs 1.4; unstratified HR = 0.48, P =.011), and increased ORR (8.8% vs 0; P =.114). nal-IRI monotherapy (n = 50) numerically improved efficacy endpoints versus 5-FU/ LV (n = 48): median OS was 5.8 versus 4.3 months (HR = 0.83, P =.423) a nd m edian PFS was 2.8 versus 1.4 months (HR = 0.69, P =.155). Grade =3 neutropenia was reported more frequently with nal-IRI+5-FU/LV versus 5-FU/LV (54.5% vs 3.4%), and incidence of grade =3 diarrhea was comparable between the two arms (3.0% vs 6.9%). This subgroup analysis confirms nal-IRI+5-FU/LV as an efficacious treatment option that improves survival in Asian patients with mPDAC that progressed after gemcitabine-based therapy, with a safety profile agreeing with previous findings. The nal-IRI+5-FU/LV regimen should represent a new standard of care for these patients in Asia. (Clinicaltrials. gov: NCT01494506)