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Byline: Hyunsoo Kim, Jeff X. Zhou, Herbert C. Morse III, Haesun Park The identification of discriminative genes for categorical phenotypes in microarray gene expression data analysis has been extensively studied, especially for disease diagnosis. In recent biological experiments, continuous phenotypes have also been dealt with. For example, the extent of programmed cell death (apoptosis) can be measured by the level of caspase 3 enzyme. Thus, an effective gene selection method for continuous phenotypes is desirable. In this paper, we describe a three-stage framework for gene expression data analysis based on L1-norm support vector regression (L1-SVR). The first stage ranks genes by recursive multiple feature elimination based on L1-SVR. In the second stage, the minimal genes are determined by a kernel regression, which yields the lowest ten-fold cross-validation error. In the last stage, the final non-linear regression model is built with the minimal genes and optimal parameters found by leave-one-out cross-validation. The experimental results show a significant improvement over the current state-of-the-art approach, i.e., the two-stage process, which consists of the gene selection based on L1-SVR and the third stage of the proposed method.

INHBA (inhibin βA), a subunit of a ligand of the transforming growth factor-β superfamily, is known to play diverse roles in various solid tumors. However, its role in hematologic malignancies remains unexplored. Here, we investigated the function of INHBA in diffuse large B-cell lymphoma (DLBCL). Both mRNA and protein levels of INHBA were significantly downregulated in primary DLBCL tissues, irrespective of germinal center B-cell-like (GCB) or non-GCB subtype, compared to those in benign tonsils. The low level of INHBA in patients with de novo DLBCL was correlated with reduced overall and progression-free survival. Ectopic expression of INHBA in DLBCL cell lines (OCI-Ly01 and SUDHL-10) resulted in reduced cell proliferation, increased spontaneous apoptosis and arrested cell cycle in vitro and suppressed xenograft tumor growth in vivo. Moreover, INHBA enhanced the chemosensitivity of DLBCL cells. Thus, our results provide novel evidence that INHBA functions as a tumor suppressor in DLBCL. [ABSTRACT FROM AUTHOR]

Inhibin-β A (INHBA) is a ligand of the transforming growth factor β superfamily and associated with tumorigenesis and tumor progression in solid tumors. In this study, we investigated the expression levels and clinical significance ofINHBAin acute myeloid leukemia (AML). The results showed that high expression ofINHBAwas significantly correlated with elderly age (>60 years) (p = .038), adverse cytogenetic risks (p = .034), negativeNPM1mutation (p = .016), positiveFLT3internal tandem duplications (p = .011), and low hemoglobin levels (<60 g/dL) (p = .04). Patients with high levels ofINHBAhad poor responses to therapies as indicated by lower complete remission rate (p = .004), higher early death rate (p = .018), and shorter relapse-free survival (p = .04) and overall survival (p = .003). Moreover, multivariate analysis showed that high expression ofINHBAwas an independent adverse prognostic factor for AML. Taken together, our study suggested that high expression ofINHBAwas an adverse prognostic factor forde novoAML. [ABSTRACT FROM AUTHOR]

Background: Peritoneum metastasis of lung cancer is a rare event which, in addition to the peritoneum, usually involves multiple metastatic tissues. Here we report a case of a patient with lung adenosquamous cell carcinoma with the peritoneum as the sole distant metastatic site.Case Presentation: An 82-year-old Han Chinese man, in the teaching profession, was diagnosed with lung adenosquamous cell carcinoma in the upper lobe of his left lung with the involvement of ipsilateral hilar and mediastinal lymph nodes, and was initially staged as IIIa (cT2N2M0). Molecular testing identified a mutation at KRAS G12A. Due to his poor physical condition, our patient was given gamma knife radiotherapy with a total dose of 28.0 Gy. Two weeks later, our patient was diagnosed as peritoneal metastasis identified by using magnetic resonance imaging and confirmed with ascitic cytology and peritoneal histology. No other distant metastatic sites such as liver, brain, bone, paranephroi, and lungs were found. Subsequently, our patient received palliative intraperitoneal chemotherapy, and died within 2 months.Conclusions: Our patient represented a rare case of lung adenosquamous cell carcinoma harboring the KRAS G12A mutation, which metastasized distantly to the peritoneum only, and progressed rapidly. [ABSTRACT FROM AUTHOR]

Anaplastic lymphoma kinase (ALK) gene fusion is a driving mutation underlying the development of non-small cell lung cancer (NSCLC). Accurate detection of ALK fusion is critical for the use of ALK inhibitors in the treatment of NSCLC. Commonly utilized methods for ALK detection include fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). However, these methods are time-consuming and costly. In the present study, a method for assessing ALK gene fusion based on the differential expression levels of the ALK kinase and non-kinase domains was developed and evaluated, with the aim of providing a convenient and reliable method for the detection of ALK fusion. In addition, another method was established to determine the integrity of exons 19-20 and 20-21 of ALK, two genomic loci that are typically broken in ALK fusions. These novel methods were applied to detect ALK fusion in 100 NSCLC patients, and were compared with IHC and FISH methods. The novel methods developed in the present study successfully detected ALK fusions in 10 samples. The concordances between the novel methods and IHC and FISH were 100%. Furthermore, the differential expression method was able to detect ALK fusions in cell-free urine samples, which was advantageous over FISH and IHC. The novel methods developed in the present study are cost-effective and easy to perform, and may provide simple and convenient techniques for the clinical assessment of ALK fusions, facilitating the use of targeted therapy for NSCLC. [ABSTRACT FROM AUTHOR]

Interferon (IFN) consensus sequence-binding protein/IFN regulatory factor 8 (IRF8) is a transcription factor that regulates the differentiation and function of macrophages, granulocytes, and dendritic cells through activation or repression of target genes. Although IRF8 is also expressed in lymphocytes, its roles in B cell and T cell maturation or function are ill defined, and few transcriptional targets are known. Gene expression profiling of human tonsillar B cells and mouse B cell lymphomas showed that IRF8 transcripts were expressed at highest levels in centroblasts. either from secondary lymphoid tissue or transformed cells. In addition, staining for IRF8 was most intense in tonsillar germinal center (GC) dark-zone centroblasts. To discover B cell genes regulated by IRF8. we transfected purified primary tonsillar B cells with enhanced green fluorescent protein-tagged IRF8, generated small interfering RNA knockdowns of IRF8 expression in a mouse B cell lymphoma cell line, and examined the effects of a null mutation of IRF8 on B cells. Each approach identified activation-induced cytidine deaminase (AICDA] and BCL6 as targets of transcriptional activation. Chromatin immunoprecipitation studies demonstrated in vivo occupancy of 5′ sequences of both genes by IRF8 protein. These results suggest previously unappreciated roles for IRF8 in the transcriptional regulation of B cell GC reactions that include direct regulation of AICDA and BCL6. [ABSTRACT FROM AUTHOR]

INHBA (inhibin βA), a subunit of a ligand of the transforming growth factor-β superfamily, is known to play diverse roles in various solid tumors. However, its role in hematologic malignancies remains unexplored. Here, we investigated the function of INHBA in diffuse large B-cell lymphoma (DLBCL). Both mRNA and protein levels of INHBA were significantly downregulated in primary DLBCL tissues, irrespective of germinal center B-cell-like (GCB) or non-GCB subtype, compared to those in benign tonsils. The low level of INHBA in patients with de novo DLBCL was correlated with reduced overall and progression-free survival. Ectopic expression of INHBA in DLBCL cell lines (OCI-Ly01 and SUDHL-10) resulted in reduced cell proliferation, increased spontaneous apoptosis and arrested cell cycle in vitro and suppressed xenograft tumor growth in vivo. Moreover, INHBA enhanced the chemosensitivity of DLBCL cells. Thus, our results provide novel evidence that INHBA functions as a tumor suppressor in DLBCL.

Our previous studies illustrated that a steady increase of intracellular calcium concentration ([Ca2+]i) was important for maintaining microtubules (MTs) rearrangement in apoptotic cells. However, little is known about the effect of calcium sensing receptor (CaSR)-mediated increase in [Ca2+]i on cytoskeleton gene expression. We examined the impact of taxol or CaSR agonist/antagonist on the regulation of [Ca2+]i concentration, cytoskeleton arrangement, phosphorylated CREB and cytoskeleton gene expressions in HeLa cells with dominant negative plasmid of CREB (PM). This study demonstrated that Gdcl3 (a specific CaSR agonist) evoked a rapid increase of [Ca2+]i, formed a rigid bundle of MTs which surrounded the nucleus and decreased the cytoskeleton gene expressions in HeLa cells. These effects were rescued by addition of NPS2390 (a specific CaSR antagonist). Moreover, CaSR activity affected cytoskeleton gene expression through transcription factor CREB. Histoscores of pCREB immunoreactivity in tissues of cervical adenocarcinoma, renal clear cell carcinoma, and diffuse large B-cell lymphoma were markedly increased compared with non malignant tissue. These data demonstrate, for the first time, that CaSR-mediated increase in [Ca2+]i probably modulate cytoskeleton organization and gene expression via transcription factor., (© 2014 Wiley Periodicals, Inc.)

Background: Excision repair cross complementation group 1 (ERCC1) is a nucleotide excision repair pathway gene which provides protection against platinum-based chemotherapy-induced DNA damage., Methods: ERCC1 mRNA expression was quantified by quantitative real-time reverse-transcription PCR in paraffin-embedded non-small cell lung cancer (NSCLC; n = 357), gastric cancer (n = 106), and breast cancer (n = 363) tissues. Survival curves were generated by Kaplan-Meier analysis; Cox proportional multivariate regression analysis was applied., Results: ERCC1 mRNA expression was significantly higher in breast cancer than gastric cancer or NSCLC (both P < 0.0001), but not significantly different in NSCLC and gastric cancer (P = 0.119). In NSCLC, the low ERCC1 group had significantly longer disease free survival (DFS) than the high ERCC1 group (29.1 vs. 21.0 months, P < 0.0001); in the surgery alone and postoperative platinum-containing chemotherapy subgroups, DFS was significantly longer for the low ERCC1 groups than high ERCC1 groups (30.2 vs. 25.1 months, P = 0.018; 27.0 vs. 19.4 months, P < 0.0001, respectively). In gastric cancer patients receiving surgery alone, the low ERCC1 group had significantly longer overall survival than the high ERCC1 group (47.54 vs. 27.47 months, P = 0.018)., Conclusions: High ERCC1 mRNA expression of the NSCLC tumor tissues was associated with poor disease-free survival (DFS), in both the surgery alone and postoperative platinum-containing chemotherapy subgroups. Meanwhile, low ERCC1 mRNA expression had significantly longer overall survival in gastric cancer patients receiving surgery alone. Therefore, ERCC1 expression was a prognostic factor and predictive marker in NSCLC, and gastric cancer after surgery alone, but was not a prognostic factor in breast cancer.

Mutations of the KRAS, BRAF, and PIK3CA genes have been reported in colorectal cancer (CRC), associated with resistance to epidermal growth factor receptor (EGFR)-targeted monoclonal antibody therapy. These reports have mainly emanated from Western countries, however, and little is known about the mutation frequencies of these genes and their prognostic value in Asian patients with CRC. In this study, we analyzed the mutation frequencies of these three genes together with EGFR, and their association with overall survival in 61 Chinese patients with metastatic CRC (mCRC). Gene mutations were examined using pyrosequencing. Kaplan-Meier survival analysis and multivariate Cox proportional hazard analysis were used to assess the prognostic significance of mutations of these four genes for patients' survival. We found that the mutations of KRAS, BRAF, PIK3CA, and EGFR were present in 12 (19.7%), 3 (4.9%), 3 (4.9%), and 0 patients, respectively. Kaplan-Meier survival analysis showed that none of these gene mutations correlated significantly with patients' overall survival. Multivariate Cox proportional hazard analysis showed only treatment regimens and age to be independent prognostic factors. Our findings indicate that EGFR signaling network genes are frequently mutated in Chinese mCRC patients, and these gene mutations do not seem to be associated with patients' overall survival., (2010. © 2010 Wiley-Liss, Inc.)

Detection of serum markers for pancreatic cancer has been elusive. Although CA 19-9 is most commonly used, its sensitivity and specificity are modest. We used large-scale proteomics to identify potential serum markers for pancreatic cancer. Samples were analyzed using high-resolution two-dimensional gel electrophoresis to identify differentially expressed proteins in 32 normal and 30 pancreatic cancer patients. Up to 1,744 protein spots were resolved for each serum sample. Candidate proteins were identified using mass spectrometry. ANOVA was used to identify proteins that could discriminate cancer from normal sera. Serum fibrinogen level was also measured using enzymatic assay. Immunohistochemistry was used to detect fibrinogen in resected pancreatic cancers. One hundred fifty-four proteins were commonly overexpressed in all pancreatic cancers. Nine protein spots (four with identifications by mass spectrometry) could effectively separate cancer from normal controls using cross-validation. These proteins successfully discriminated all pancreatic cancer samples (30 of 30) and 94% of normal (30 of 32) samples. Prominent among these candidates was fibrinogen gamma, which was subsequently confirmed to be overexpressed in pancreatic cancer sera by enzymatic analysis (54.1 +/- 64.1 versus 0.0 +/- 0.0 mg/dL, P < 0.05) and tissue by immunohistochemistry (67% versus 29%, P < 0.05) relative to normal pancreas. Proteomic analysis combining two-dimensional gel electrophoresis and mass spectrometry successfully identified 154 potential serum markers for pancreatic cancer. Of these, fibrinogen gamma, a protein associated with the hypercoagulable state of pancreatic cancer, discriminated cancer from normal sera. Fibrinogen is a potential tumor marker in pancreatic cancer.

Interferon (IFN) consensus sequence-binding protein/IFN regulatory factor 8 (IRF8) is a transcription factor that regulates the differentiation and function of macrophages, granulocytes, and dendritic cells through activation or repression of target genes. Although IRF8 is also expressed in lymphocytes, its roles in B cell and T cell maturation or function are ill defined, and few transcriptional targets are known. Gene expression profiling of human tonsillar B cells and mouse B cell lymphomas showed that IRF8 transcripts were expressed at highest levels in centroblasts, either from secondary lymphoid tissue or transformed cells. In addition, staining for IRF8 was most intense in tonsillar germinal center (GC) dark-zone centroblasts. To discover B cell genes regulated by IRF8, we transfected purified primary tonsillar B cells with enhanced green fluorescent protein-tagged IRF8, generated small interfering RNA knockdowns of IRF8 expression in a mouse B cell lymphoma cell line, and examined the effects of a null mutation of IRF8 on B cells. Each approach identified activation-induced cytidine deaminase (AICDA) and BCL6 as targets of transcriptional activation. Chromatin immunoprecipitation studies demonstrated in vivo occupancy of 5' sequences of both genes by IRF8 protein. These results suggest previously unappreciated roles for IRF8 in the transcriptional regulation of B cell GC reactions that include direct regulation of AICDA and BCL6.