The expression patterns and prognostic significance of pleckstrin homology-like domain family A (PHLDA) in lung cancer and malignant mesothelioma

BackgroundPleckstrin homology domain family A (PHLDA) genes play important roles in cancer cellular processes, including inhibiting Akt activation, repressing growth factor signaling, inhibiting the negative feedback of EGFR/ErbB2 signaling cells, and inducing apoptosis. However, the prognostic significance of PHLDA in non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MM) remains unclear. The present study investigates the associations between PHLDA expression patterns and their prognostic value in lung adenocarcinoma (LUAD) and MM.MethodsWe analyzed PHLDA family members at the genomic level in silico to explore their mRNA expression pattern and predictive significance in LUAD and MM. We then created a PHLDA–drug interaction network and a protein-protein interaction (PPI) network using different databases. Finally, we immunohistochemically assessed the protein expression of each PHLDA family member on tissue microarrays (TMAs) in both LUAD and MM cohorts with long-term follow-up.ResultsWhile PHLDA1 mRNA expression in both LUAD and MM was lower than that of normal tissue, PHLDA2 mRNA was significantly overexpressed in LUAD, and PHLDA3 mRNA was overexpressed in MM. In NSCLC, both low PHLDA1 mRNA expression and high PHLDA3 mRNA expression correlated with worse overall survival (OS) (P<0.01), whereas high PHLDA2 mRNA expression was associated with better OS (P<0.01). In MM, patients presenting high PHLDA1 and PHLDA2 mRNA expression had poor OS (P=0.01 and P<0.01, respectively). In addition, the PHLDA-drug interaction network indicated that several common drugs could potentially modulate PHLDA expression, and the PPI network suggested that PHLDA1 interacts with Notch family members, whereas PHLDA3 interacts with TP53. Our results also showed that the expression of PHLDA2 and PHLDA3 was significantly higher in LUAD and MM than that of PHLDA1 (P<0.05) and was associated with the risk of death. While patients with PHLDA2 >85.09 cells/mm² had a low risk of death (P=0.01) and a median survival time of 48 months, those with PHLDA3 <70.38 cells/mm² had a high risk of death (P=0.03) and a median survival time of 34 months.ConclusionsWe shed light on the role of the PHLDA family as promising predictive biomarkers and potential therapeutic targets in LUAD and MM.     

Elevated levels of soluble fibrin in patients with venous thromboembolism

The fibrin-related markers (FRMs), including soluble fibrin (SF), d-dimer and fibrin and fibrinogen degradation products (FDP) are considered to be useful for the diagnosis of thrombosis; however, evidence for the diagnosis of thrombosis by SF is still not well established. The present study was designed to evaluate the usefulness of SF in the diagnosis of venous thromboembolism (VTE). The plasma concentrations of FRMs were measured in 551 in-patients suspected to have a VTE. The plasma levels of SF, d-dimer and FDP were significantly higher in patients with VTE than patients without VTE and those were significantly higher in patients without VTE than in healthy volunteers. In a receiver operating characteristic analysis for the diagnosis of VTE, the area under the curve was 0.950 for SF, 0.933 for FDP and 0.805 for d-dimer. The appropriate cut-off values for the diagnosis were as follows SF 5.9 μg/ml, FDP 2.1 μg/ml and d-dimer 4.8 μg/ml. To obtain a 100% negative predictive value for the diagnosis of VTE, the SF was less than 5.2 μg/ml, FDP was less than 1.3 μg/ml, and d-dimer was less than 0.5 μg/ml. Our findings suggest that the SF assay is useful for the diagnosis and exclusion of VTE.     

Expression of galectin‐3 involved in prognosis of patients with hepatocellular carcinoma

Aims: Galectins are multifunctional lectins binding to the β‐galactoside of glycoproteins that affect diverse physiological and pathophysiological processes such as development, inflammation and tumor growth. In hepatocellular carcinoma (HCC), the over‐expression of galectin‐1, 3, and 4 has been reported, although their function and correlation with tumor progression remain unknown. Thus, we aimed to assess the role of galectin‐3 during HCC progression. Methods: Specimens were obtained during curative operations and used for immunohistochemical analysis of galectin‐3 (n = 52), and statistically assessed for correlations with the clinical profiles and the prognoses of the patients. The serum galectin‐3 levels from the patients with liver diseases including HCC were assessed by ELISA. Results: In total, galectin‐3 expression was found in 34 of 52 tumors (65%) and was statistically correlated with histological differentiation and vascular invasion. Kaplan‐Meier's analysis showed that patients with galectin‐3 expression tended to relapse in the earlier phase and had worse overall survival. In particular, a higher expression rate of nuclear galectin‐3 showed a markedly worse prognosis, and it was independent in the multivariate analysis for overall survival. Serum galectin‐3 levels were significantly increased in HCC compared with chronic liver disease. The sensitivity and specificity of galectin‐3 were equivalent to alpha‐fetoprotein and Vitamin K absence or antagonist II, and the combination of HCC biomarkers with galectin‐3 improved the diagnostic performance. Conclusions: Galectin‐3 expression was involved in the tumor progression and related to the prognosis of HCC. Our observations suggested that galectin‐3 could be a novel tumor marker and therapeutic target.     

A cross-sectional assessment of oxidative DNA damage and muscle strength among elderly people living in the community

Objectives

The mechanism by which muscle weakness leads to an increased risk of death remains a subject of interest. In this context, the aim of this study is to assess the relationship between urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG) and muscle strength, and other risk factors contributing to poor muscle strength in older persons.

Methods

This was a cross-sectional study in which a total of 86 participants, both men and women, aged 65 years or above were screened for urinary 8-OHdG, and muscle strength as measured by handgrip strength.

Results

Handgrip strength was lower in participants who had history of acute or chronic disease. Urinary 8-OHdG level was negatively associated with muscle strength, and the association remained after adjusting for confounding factors.

Conclusions

Urinary 8-OHdG is associated with muscle strength. These findings may be clinically relevant as there is a possibility of controlling oxidative DNA damage by healthy behaviors related to lifestyle.     

Remineralization capacity of carious and non-carious white spot lesions: clinical evaluation using ICDAS and SS-OCT

Objectives

To assess the remineralization capacity of carious, non-carious, and combined white spot lesions (WSLs) using the ICDAS and SS-OCT.

Materials and methods

This clinical trial was based on a quasi-experimental design. Forty-two healthy subjects (median age 26.6 years), who visited university hospital and had at least one WSL with an ICDAS score of 2 or 1, were recruited. The subjects chewed a non-blind sugar-free gum containing bioavailable calcium and fluoride for 3 months. The remineralization capacities of carious and non-carious 121 WSLs were assessed using ICDAS by two calibrated non-blind examiners and optical boundary depth (BD) by SS-OCT at a monthly recall. The outcome variables, transitions of ICDAS score, mean BD, and mean BD recovery rate (RR%), were statistically analyzed using the chi-square test, two way-repeated measures ANOVA, and Wilcoxon rank sum test, respectively (alpha = 0.05).

Results

Based on the visual inspection, OCT images at the baseline, 72 WSLs were purely carious, 20 were non-carious (developmental) lesions, while 29 were combined (carious-developmental). The responses of WSLs over time showed to be highly variable. There was a significant difference in transitions of ICDAS scores after 3 months between carious and non-carious WSLs (p < 0.05) and non-carious and combined WSLs (p < 0.05). Carious and combined WSLs underwent significant changes in the mean BD between baseline (161.8 ± 56.8 μm) and 2 months (130.7 ± 57.4 μm) or 3 months (119.1 ± 57.5 μm) (p < 0.05), while there was no significant difference between baseline (132.2 ± 26.2 μm) and 2 months (122.8 ± 24.1 μm) or 3 months (119.8 ± 22.6 μm) in non-carious WSLs (p > 0.05). There was a significant difference in mean RR% after 2 and 3 months between carious and non-carious WSLs (p < 0.05).

Conclusions

The remineralization capacity of WSL was variable among the cases and subjects, and depended on the WSLs history, etiology (carious, non-carious, or combined lesion) and structure (histological pattern).

Clinical relevance

Carious WSLs showed the highest remineralization potential.

     

Anti-erythropoietin receptor antibody-associated pure red cell aplasia accompanied by Coombs-negative autoimmune hemolytic anemia in a patient with T cell/histiocyte-rich large B cell lymphoma

A 79-year-old female diagnosed with T cell/histiocyte-rich large B cell lymphoma in complete remission after six cycles of rituximab-combined chemotherapy developed severe anemia, reticulocytopenia, and bone marrow erythroid hypoplasia. She was diagnosed with pure red cell aplasia (PRCA) accompanied by Coombs-negative autoimmune hemolytic anemia evidenced by a lack of glycophorin-A-positive cells in the bone marrow, haptoglobin under the detection level, and a high titer of RBC-bound IgG. Anti-erythropoietin receptor (EPOR) antibody was detected in the serum, and oligoclonal α/β and γ/δ T cells were also detected in her peripheral blood by Southern blotting analysis. Parvovirus B19 DNA was not detected by PCR. Although the treatment with rituximab had limited efficacy (specifically, only for hemolysis), subsequent cyclosporine therapy led to prompt recovery of erythropoiesis with the disappearance of anti-EPOR antibody and oligoclonal T cells. This is the first case report of anti-EPOR antibody-associated PRCA in a patient with malignant lymphoma treated successfully with cyclosporine.