FIZZ1 stimulation of myofibroblast differentiation

Bleomycin-induced pulmonary fibrosis is characterized by inflammation, emergence of myofibroblasts, and deposition of extracellular matrix. In an attempt to identify genes that may be involved in fibrosis, we used a 10,000 element (10 K) rat cDNA microarray to analyze the lung gene expression profiles in this model in the rat. Cluster analysis showed 628 genes were more than or equal to twofold up- or down-regulated, many of which were known to be involved in fibrosis. However, the most dramatic increase was observed with FIZZ1 (found in inflammatory zone; also known as RELM-alpha or resistin-like molecule-alpha), which was induced 17-fold to approximately 25-fold at the peak of expression. In situ hybridization analysis revealed FIZZ1 expression to localize primarily to alveolar and airway epithelium, which was confirmed in vitro by analysis of isolated type II alveolar epithelial cells. However FIZZ1 expression was not detected in isolated lung fibroblasts. Co-culture of FIZZ1-expressing type II cells with fibroblasts stimulated alpha-smooth muscle actin and type I collagen expression independent of transforming growth factor-beta. Transfection of a FIZZ1-expressing plasmid into fibroblasts or treatment with glutathione S-transferase-FIZZ1 fusion protein stimulated alpha-smooth muscle actin and collagen I production. These results suggest a novel role for FIZZ1 in myofibroblast differentiation in pulmonary fibrosis.     

The lncRNAs PCGEM1 and PRNCR1 are not implicated in castration resistant prostate cancer

Long noncoding RNAs (lncRNAs) are increasingly implicated in cancer biology, contributing to essential cancer cell functions such as proliferation, invasion, and metastasis. In prostate cancer, several lncRNAs have been nominated as critical actors in disease pathogenesis. Among these, expression of PCGEM1 and PRNCR1 has been identified as a possible component in disease progression through the coordination of androgen receptor (AR) signaling (Yang et al., Nature 2013, see ref. [1]). However, concerns regarding the robustness of these findings have been suggested. Here, we sought to evaluate whether PCGEM1 and PRNCR1 are associated with prostate cancer. Through a comprehensive analysis of RNA-sequencing data (RNA-seq), we find evidence that PCGEM1 but not PRNCR1 is associated with prostate cancer. We employ a large cohort of >230 high-risk prostate cancer patients with long-term outcomes data to show that, in contrast to prior reports, neither gene is associated with poor patient outcomes. We further observe no evidence that PCGEM1 nor PRNCR1 interact with AR, and neither gene is a component of AR signaling. Thus, we conclusively demonstrate that PCGEM1 and PRNCR1 are not prognostic lncRNAs in prostate cancer and we refute suggestions that these lncRNAs interact in AR signaling.     

Antibody-Based Detection of ERG Rearrangements in Prostate Core Biopsies, Including Diagnostically Challenging Cases: ERG Staining in Prostate Core Biopsies

Context.-Fusions of androgen-regulated genes and v-ets erythroblastosis virus E26 oncogene homolog (avian) (ERG) occur in approximately 50% of prostate cancers, encoding a truncated ERG product. In prostatectomy specimens, ERG rearrangements are greater than 99% specific for prostate cancer or high-grade prostatic intraepithelial neoplasia adjacent to ERG-rearranged prostate cancer by fluorescence in situ hybridization and immunohistochemistry. Objective.-To evaluate ERG staining by immunohistochemistry on needle biopsies, including diagnostically challenging cases. Design.-Biopsies from a retrospective cohort (n = 111) enriched in cores requiring diagnostic immunohistochemistry and a prospective cohort from all cases during 3?months (n = 311) were stained with an anti-ERG antibody (clone EPR3864). Results.-Among evaluable cores (n = 418), ERG staining was confined to cancerous epithelium (71 of 160 cores; 44%), high-grade prostatic intraepithelial neoplasia (12 of 68 cores; 18%), and atypical foci (3 of 28 cores; 11%), with staining in only 2 of 162 cores (1%) diagnosed as benign. The ERG was expressed in about 5 morphologically benign glands across 418 cores and was uniformly expressed by all cancerous glands in 70 of 71 cores (99%). Conclusions.-ERG staining is more prostate cancer-specific than α-methylacyl-coenzyme A racemase, and staining in an atypical focus supports a diagnosis of cancer if high-grade prostatic intraepithelial neoplasia can be excluded. Thus, ERG staining shows utility in diagnostically challenging biopsies and may be useful in molecularly subtyping prostate cancer and in stratifying isolated high-grade prostatic intraepithelial neoplasia by risk of subsequent cancer.     

Midwives' cell phone use and health knowledge in rural communities

This study developed and tested a theoretical model that explains the underlying process through which the use of cell phones can facilitate the capacity of community health care workers in developing regions. On the basis of a study conducted on 223 midwives in rural regions of Indonesia, the results showed that cell phone use was positively associated with midwives' access to institutional and peer information resources. Access to institutional resources was positively associated with midwives' health knowledge. Further, access to peer resources was associated with higher self-efficacy, which was positively associated with health knowledge. The study provides implications for technology intervention strategies targeted to community health workers in rural communities.     

An unusual ECG pattern in restrictive cardimyopathy

Restrictive cardiomyopathy is the least common type of primary cardiomyopathies. Electrocardiographic recording is abnormal in 99% of patients with RCM. Biatrial enlargement, obliquely elevated ST segment with notched or biphasic late peaking T waves are considered characteristic ECG finding. Significant ST depression with T inversion mimicking subendocardial ischemia has also been reported in patients with RCM and is even suggested as a predictor of sudden cardiac death. We noted a similar ECG pattern in a 16 yr girl with Idiopathic restrictive cardiomyopathy. Coronaries were normal, stress perfusion imaging did not show any perfusion defect. This diffuse resting ST depression with T inversion in precordial & inferior leads along with ST elevation in aVR was persistent for more than six months.     

Zerumbone,a Sesquiterpene,Controls Proliferation and Induces Cell Cycle Arrest in Human Laryngeal Carcinoma Cell Line Hep-2

Zerumbone (ZER), a sesquiterpene found in Zingiber zerumbet Smith, has been shown to possess antiproliferative, anticancer, antioxidant, and anti-inflammatory activity against various types of human carcinoma. The molecular mechanism by which ZER mediates its activity against many cancer types is revealed by many studies. Upregulation of proapoptotic molecules and suppression of antiapoptotic gene expression are few of the mechanisms by which ZER mediates its effect. The present study is focused on investigating the effect of ZER on proliferation of laryngeal carcinoma cells (Hep-2). MTT assay results showed that ZER (0.01–100 μM) induced death of Hep-2 cells in a concentration-dependent manner; significant suppression of proliferation of Hep-2 cells was seen with a IC₅₀ value of 15 µM. ZER at a concentration of 15 and 30 μM for 48 h showed early signs of apoptosis as evidenced by confocal microscopy imaging. Flow cytometry studies showed that ZER induced cell cycle arrest. ZER arrested Hep-2 proliferation at S and G2/M phases of cell cycle. In conclusion, these results indicate that ZER has antiproliferative effect and arrests cell cycle in Hep-2 cells in vitro. This could be a potential anticancer drug against laryngeal carcinoma.     

Detailed pathologic analysis on the co-occurrence of non-seminomatous germ cell tumor subtypes in matched orchiectomy and retroperitoneal lymph node dissections

The frequency of co-occurrence between germ cell tumor (GCT) components in non-seminomatous germ cell tumor (NSGCT) orchiectomy specimens and their correlation with histologic findings in subsequent retroperitoneal lymph node dissection (RPLND) specimens have not been well characterized. The objective of the study was to report the first detailed clinicopathologic analysis of NSGCT orchiectomy and RPLND samples to determine the likelihood and agreement of the co-occurrence of GCT components. A total of 118 consecutive patients with NSGCT treated between 1988 and 2012 who underwent both orchiectomy and RPLND at a single academic tertiary care center were analyzed. Statistical analysis of co-occurrence likelihood and agreement of GCT components was performed, both within and between orchiectomy and RPLND specimens. Embryonal carcinoma was the most frequent component present in orchiectomy specimens, and there were multiple significant associations between orchiectomy GCT components; seminoma occurred less frequently with embryonal carcinoma (OR 0.29 [95% confidence interval (CI) 0.11–0.75]; p < 0.01), and teratoma more frequently occurred with choriocarcinoma (OR 9.64 [95% CI 1.22–76.12]; p = 0.01). Presence of teratoma in the orchiectomy specimen predicted for a fourfold increase in distant metastasis on multivariate analysis (HR 4.92 [1.14–18.9]; p = 0.02). The only significant association of co-occurrence in the RPLND specimen was between embryonal carcinoma and teratoma (OR 0.01 [95% CI 0–0.07]; p < 0.001), where it was significantly less likely for them to occur together. Our findings are limited by their retrospective nature. The co-occurrence of GCT components within orchiectomy specimens does not appear to be a completely random process. However, there is less agreement and more randomness between the occurrence of the GCT components in matched orchiectomy and RPLND samples. In this report, we look at the co-occurrence of different GCT components within matched orchiectomy and RPLND pathology specimens and show that co-occurrence is not a completely random process.     

Association of ERG/PTEN status with biochemical recurrence after radical prostatectomy for clinically localized prostate cancer

We have previously demonstrated a significant correlative relationship between PTEN deletion and ERG rearrangement, both in the development of clinically localized prostate cancers and metastases. Herein, we evaluate the cooperative role of ERG and PTEN in oncological outcomes after radical prostatectomy for clinically localized prostate cancer. We evaluated ERG and PTEN status using three previously described cohorts. The first cohort included 235 clinically localized prostate cancer cases represented on tissue microarrays (TMA), evaluated using previously validated FISH assays for ERG and PTEN. The second cohort included 167 cases of clinically localized prostate cancer on TMAs evaluated for PTEN by FISH, and for PTEN and ERG by dual IHC. The third cohort comprised 59 clinically localized prostate cancer cases assessed by array comparative genomic hybridization (aCGH). Kaplan–Meir plots and long rank tests were used to assess the association of ERG and PTEN status with biochemical recurrence after radical prostatectomy for clinically localized prostate cancer. Of the 317 cases eligible for analyses with evaluable ERG and PTEN status, 88 (27.8%) patients developed biochemical recurrence over a median follow-up of 5.7 years. Overall, 45% (142/317) of cases demonstrated ERG rearrangement and 20% (62/317) of cases demonstrated PTEN loss. Hemizygous and homozygous deletion of PTEN was seen in 10% (18/175) and 3% (5/175) of ERG-negative cases, respectively. In contrast, hemizygous and homozygous deletion of PTEN was seen in 11% (15/142) and 17% (24/123) of ERG-positive cases, respectively. PTEN loss (heterozygous or homozygous) was significantly associated with shorter time to biochemical recurrence compared to no PTEN loss (p?<?0.001). However, ERG rearrangement versus no rearrangement was not associated with time to PSA recurrence (p?=?0.15). Patients who exhibited ERG rearrangement and loss of PTEN had no significant difference in time to recurrence compared to patients with wild-type ERG and loss of PTEN (p?=?0.30). Our findings confirm a mutual cooperative role of ERG and PTEN in the pathogenesis of prostate cancer, particularly for homozygous PTEN deletion. ERG did not stratify outcome either alone or in combination with PTEN in this cohort.