The diagnostic value of human epididymis protein 4 as a novel biomarker in patients with renal dysfunction.

PURPOSE: In this study, we investigated the diagnostic value of human epididymis protein 4 (HE4) in acute and chronic renal dysfunction and analyzed the correlation between HE4 levels and the results of routine renal function tests. We aimed to provide evidence to establish HE4 as a novel biomarker of renal injury and its appropriate application as a marker of ovarian cancer. METHODS: We collected 259 serum samples from hospitalized patients with different causes of renal damage. HE4 serum levels were detected by chemiluminescence and the levels of serum creatinine, urea, and cystatin C were tested by conventional clinical chemical methods. RESULTS: The levels of HE4 were highest in the acute kidney injury groups and chronic kidney disease groups, although other groups were also significantly higher than the control group. HE4 and creatinine, urea, and cystatin C had a positive linear correlation. In contrast, HE4 and estimated glomerular filtration rate (eGFR) had a negative linear correlation, with a correlation coefficient of - 0.674 (P < 0.01). Area under the receiver-operating characteristic curve analysis showed that HE4 has higher diagnostic value compared with creatinine, urea, and cystatin C in both acute and chronic renal injury patients; however, HE4 and creatinine have a similar diagnostic value. Notably, HE4 concentration gradually increased with a decline of glomerular filtration rate, with significant differences evident between different eGFR stages. CONCLUSION: HE4 is a potential biomarker of kidney injury in acute and chronic renal dysfunction. Importantly, clinicians should be aware of this when using HE4 to diagnose ovarian cancer.

Bcl-3 is a novel biomarker of renal fibrosis in chronic kidney disease.

Progressive renal fibrosis in chronic kidney disease (CKD) greatly contributes to end-stage renal failure and is associated with high mortality. The identification of renal fibrosis biomarkers for the diagnosis and the monitoring of disease progression in CKD is urgently needed. Whole-transcriptomic analysis of renal tissues in a unilateral ureteral obstruction (UUO) mouse model revealed that the mRNA level of Bcl-3, an atypical member of the IκB family, was induced 6.3-fold 2 days after UUO. Compared with renal tissues in sham-operated mice, increases in Bcl-3 mRNA and protein in the renal tissues in the UUO model were accompanied with increases in other markers of renal fibrosis, including human epididymis protein 4 (HE4), a recently identified biomarker of renal fibrosis. Immunohistochemical analysis revealed that both Bcl-3 and HE4 were located in the plasma of renal tubule cells. Serum protein levels of Bcl-3 and HE4 rose with the development of renal fibrosis in UUO mouse model. We found that the serum protein levels of both HE4 and Bcl-3 were elevated in CKD patients compared with healthy controls. Moreover, a significant positive correlation between Bcl-3 and HE4 (r = 0.939, p < 0.0001) was observed in CKD patients. These data suggest that Bcl-3 can serve as a novel valuable biomarker of renal fibrosis in CKD.

[Identification of B (A) Blood Group and Blood Transfusion for patients with B (A) Blood Group].

OBJECTIVE: To investigate the serological and molecular biological identification of B(A) blood group and its reasonable method of blood transfusion for patient with B(A) blood group. METHODS: The blood group of patient was detected by serological method, at the some time, the genotype of patient was detected by using the ABO-TYPE Variant kit and sequence analysis of 6 and 7 exons in ABO gene; the washed O red blood cells were used to cross matching blood of difficultly matching blood by the three step analysis method. RESULTS: The A weak and B strong agglutination were found in positive type, and A1C(3+), BC(-) were observed in negative type; the molecular biological identification showed B(A)04, 640 A > G; the matching blood main side of washed O red blood cells displayed no agglutination. CONCLUSION: The identification and analysis of rare blood or subtype should be very careful; if necessary, the molecular biological detection should carried out; the blood transfusion for patient with rate blood group or subtype should be safe, correct and reasonable.

Blockage of tropomyosin receptor kinase a (TrkA) enhances chemo-sensitivity in breast cancer cells and inhibits metastasis in vivo.

Hyper-activation of the Neurotrophin Receptor Signaling contributes to the development and metastasis of breast cancer. The inhibition of growth factor-dependent growth of breast cancer cell demonstrated a promising way for cancer therapy. In this study, the signaling pathway of tropomyosin receptor kinase A (TrkA) had been investigated for the role it played in the proliferation of chemo-resistance of breast cancer cells. Small interference RNA (siRNA) was used to down-regulate the expression of TrkA in breast cancer cell and tumor xenograft mice model. Our results indicated that siRNA mediated down-regulation of TrkA lead to the proliferation inhibition of cancer cells and arrested cells cycle at G0/G1 phase via inactivation of NF-κBp65. Application of TrkA siRNA to cancer cell also increased the chemo-sensitivity to paclitaxel, and further promoted apoptosis in cancer cell through the activation of caspase-3. Moreover, TrkA siRNA increased the efficacy of paclitaxel and decreased the incidence of lung metastasis in tumor xenografted mice. In sum, these results indicate that TrkA signaling plays an important role in breast cancer chemo-resistance and metastasis. It could be a potential pharmacologic target to enhance the effectiveness of chemo-therapy for breast cancer.

A microRNA 221- and 222-mediated feedback loop maintains constitutive activation of NFκB and STAT3 in colorectal cancer cells.

BACKGROUND & AIMS: Constitutive activation of the transcription factors nuclear factor κB (NF-κB) and STAT3 is involved in the development and progression of human colorectal cancer (CRC). Little is known about how these factors become activated in cancer cells. We investigated whether microRNA miR-221 and miR-222 regulate NF-κB and signal transducer and activator of transcription 3 (STAT3) activation in human CRC cell lines. METHODS: CRC cell lines (HCT116 and RKO) were transfected with miR-221 or miR-222 mimics or inhibitors. The activity levels of NF-κB and STAT3 were measured in dual luciferase reporter assays. We used immunoblot and real-time polymerase chain reaction analyses to measure protein and messenger RNA (mRNA) levels. Cells were analyzed by proliferation, viability, and flow cytometry analyses. Mice were given injections of azoxymethane, followed by dextran sodium sulfate, along with control lentivirus or those expressing mRNAs that bind miR-221 and miR-222 (miR-221/miR-222 sponge). The levels of miR-221 and miR-222 as well as RelA, STAT3, and PDLIM2 mRNAs were measured in 57 paired CRC and adjacent nontumor tissues from patients. RESULTS: In CRC cell lines, mimics of miR-221 and miR-222 activated NF-κB and STAT3, further increasing expression of miR-221 and miR-222. miR-221 and miR-222 bound directly to the coding region of RelA mRNA, increasing its stability. miR-221 and miR-222 also reduced the ubiquitination and degradation of the RelA and STAT3 proteins by binding to the 3' untranslated region of PDLIM2 mRNA (PDLIM2 is a nuclear ubiquitin E3 ligase for RelA and STAT3). Incubation of CRC cells with miR-221 and miR-222 inhibitors reduced their proliferation and colony formation compared with control cells. In mice with colitis, injection of lentiviruses expressing miR-221/miR-222 sponges led to formation of fewer tumors than injection of control lentiviruses. Human CRC tissues had higher levels of miR-221 and miR-222 than nontumor colon tissues; increases correlated with increased levels of RelA and STAT3 mRNAs. Levels of PDLIM2 mRNA were lower in CRC than nontumor tissues. CONCLUSIONS: In human CRC cells, miR-221 and miR-222 act in a positive feedback loop to increase expression levels of RelA and STAT3. Antagonism of miR-221 and miR-222 reduces growth of colon tumors in mice with colitis.

NF-kappaB signaling pathway, inflammation and colorectal cancer.

There is growing evidence for a connection between inflammation and tumor development, and the nuclear factor kappa B (NF-kappaB), a proinflammatory transcription factor, is hypothesized to promote tumorigenesis. Although the genetic evidence for the hypothesis has been lacking, recent papers have lent credence to this hypothesis. It has been reported that constitutive NF-kappaB activation in inflammatory bowel diseases (IBDs) increases risk of colorectal cancer (CRC) in the patients with the number of years of active disease. NF-kappaB activation might induce cellular transformation, mediate cellular proliferation, prevent the elimination of pre-neoplastic and fully malignant cells by up-regulating the anti-apoptosis proteins. Furthermore, NF-kappaB may contribute to the progression of CRC by regulating the expression of diverse target genes that are involved in cell proliferation (Cyclin D1), angiogenesis (VEGF, IL-8, COX2), and metastasis (MMP9). These findings implicate NF-kappaB inhibition as an important therapeutic target in CRC. However, due to lack of knowledge about the specific roles of different NF-kappaB subunits in different stage of carcinogenesis, and compounds to block specific subunits of NF-kappaB family, it will be a long time before the coming of targeting NF-kappaB in CRC therapy.