Secretory phospholipase A2-IIa is a target gene of the HER/HER2-elicited pathway and a potential plasma biomarker for poor prognosis of prostate cancer.

BACKGROUND: Our previous study showed that prostate cancer cells overexpress and secrete secretory phospholipases A2 group IIa (sPLA2-IIa) and plasma sPLA2-IIa was elevated in prostate cancer patients. The current study further explored the underlying mechanism of sPLA2-IIa overexpression and the potential role of sPLA2-IIa as a prostate cancer biomarker. METHODS: Plasma and tissue specimens from prostate cancer patients were analyzed for sPLA2-IIa levels. Regulation of sPLA2-IIa expression by Heregulin-α was determined by Western blot and reporter assay. RESULTS: We found that Heregulin-α enhanced expression of the sPLA2-IIa gene via the HER2/HER3-elicited pathway. The EGFR/HER2 dual inhibitor Lapatinib and the NF-kB inhibitor Bortezomib inhibited sPLA2-IIa expression induced by Heregulin-α. Heregulin-α upregulated expression of the sPLA2-IIa gene at the transcriptional level. We further confirmed that plasma sPLA2-IIa secreted by mouse bearing human prostate cancer xenografts reached detectable plasma concentrations. A receiver operating characteristic (ROC) analysis of patient plasma specimens revealed that high levels of plasma sPLA2-IIa, with the optimum cutoff value of 2.0 ng/ml, were significantly associated with high Gleason score (8-10) relative to intermediate Gleason score (6-7) prostate cancers and advanced relative to indolent cancers. The area under the ROC curve (area under curve, AUC) was 0.73 and 0.74, respectively. CONCLUSION: We found that Heregulin-α, in addition to EGF, contributes to sPLA2-IIa overexpression in prostate cancer cells. Our findings support the notion that high levels of plasma sPLA2-IIa may serve as a poor prognostic biomarker capable of distinguishing aggressive from indolent prostate cancers, which may improve decision-making and optimize patient management.

Secretory phospholipase A2-IIa is involved in prostate cancer progression and may potentially serve as a biomarker for prostate cancer.

The majority of prostate cancers are indolent, whereas a significant portion of patients will require systemic treatment during the course of their disease. To date, only high Gleason scores are best associated with a poor prognosis in prostate cancer. No validated serum biomarker has been identified with prognostic power. Previous studies showed that secretory phospholipase A2-IIa (sPLA2-IIa) is overexpressed in almost all human prostate cancer specimens and its elevated levels are correlated with high tumor grade. Here, we found that sPLA2-IIa is overexpressed in androgen-independent prostate cancer LNCaP-AI cells relative to their androgen-dependent LNCaP cell counterparts. LNCaP-AI cells also secrete significantly higher levels of sPLA2-IIa. Blocking sPLA2-IIa function compromises androgen-independent cell growth. Inhibition of the ligand-induced signaling output of the HER network, by blocking PI3K-Akt signaling and the nuclear factor-kappaB (NF-κB)-mediated pathway, compromises both sPLA2-IIa protein expression and secretion, as a result of downregulation of sPLA2-IIa promoter activity. More importantly, we demonstrated elevated serum sPLA2-IIa levels in prostate cancer patients. High serum sPLA2-IIa levels are associated significantly with high Gleason score and advanced disease stage. Increased sPLA2-IIa expression was confirmed in prostate cancer cells, but not in normal epithelium and stroma by immunohistochemistry analysis. We showed that elevated signaling of the HER/HER2-PI3K-Akt-NF-κB pathway contributes to sPLA2-IIa overexpression and secretion by prostate cancer cells. Given that sPLA2-IIa overexpression is associated with prostate development and progression, serum sPLA2-IIa may serve as a prognostic biomarker for prostate cancer and a potential surrogate prostate biomarker indicative of tumor burden.

Intracranial treatment for solitary prostatic adenocarcinoma brain metastasis is curative.

Solitary metastasis to the brain from prostate cancer is rare. We present a young patient with a prostate-specific antigen value of 26 ng/dL and pathologic Gleason score 4 + 5 = 9 prostatic adenocarcinoma who developed a solitary cerebral metastasis 4 years after radical prostatectomy. With aggressive treatment involving resection of the solitary metastasis and use of local brachytherapy, the patient remains with an undetectable PSA level and without evidence of disease 5 years later. Our experience suggests that delayed solitary metastasis may be curable with treatment.

On tracking the course of cerebral oxygen saturation and pilot performance during gravity-induced loss of consciousness.

OBJECTIVE: The aim of this study was to track the course of cerebral tissue oxygen saturation (rSO2) and pilot performance during an episode of gravity-induced loss of consciousness (GLOC). BACKGROUND: GLOC, a major problem facing pilots of high-performance aircraft, is brought about by a sudden reduction in rSO2 as a result of increased +Gz force. It consists of 24 s of complete functional impairment followed by a prolonged period of performance recovery. This study tested the hypothesis that delayed recovery in GLOC is caused by a slow return of rSO2 following removal of the g-force that induced the episode. METHOD: GLOC was induced in U.S. Air Force personnel via a centrifuge with math and tracking tasks emulating flight performance. A near-infrared spectroscopy unit provided the rSO2 measure. RESULTS: Declines in rSO2 from baseline pinpointed when pilots would cease active flight control and when GLOC would set in. Counter to expectation, rSO2 returned to baseline levels shortly after the centrifuge came to a complete stop following GLOC onset. Nevertheless, performance deficits continued for 49.45 s thereafter. CONCLUSION: The prolonged performance recovery time in GLOC cannot be attributed to delays in the return of rSO2. This finding explains why previous ergonomic efforts to shorten the duration of GLOC episodes by increasing the rate of return of rSO2 have not been fruitful. Evidently, another approach is needed. APPLICATION: Such an approach might use the close linkage between loss of rSO2, performance deterioration, and GLOC onset to develop a warning system that would permit pilots to take effective action to avoid GLOC incapacitation.