Targeting Gli transcription activation by small molecule suppresses tumor growth.

Targeted inhibition of Hedgehog signaling at the cell membrane has been associated with anticancer activity in preclinical and early clinical studies. Hedgehog signaling involves activation of Gli transcription factors that can also be induced by alternative pathways. In this study, we identified an interaction between Gli proteins and a transcription coactivator TBP-associated factor 9 (TAF9), and validated its functional relevance in regulating Gli transactivation. We also describe a novel, synthetic small molecule, FN1-8, that efficiently interferes with Gli/TAF9 interaction and downregulate Gli/TAF9-dependent transcriptional activity. More importantly, FN1-8 suppresses cancer cell proliferation in vitro and inhibits tumor growth in vivo. Our results suggest that blocking Gli transactivation, an important control point of multiple oncogenic pathways, may be an effective anticancer strategy.

EMX2 is epigenetically silenced and suppresses growth in human lung cancer.

Lung cancer is a common cancer and the leading cause of cancer-related death worldwide. Aberrant activation of WNT signaling is implicated in lung carcinogenesis. EMX2, a human homologue of the Drosophila empty spiracles gene is a homeodomain-containing transcription factor. The function of EMX2 has been linked to the WNT signaling pathway during embryonic patterning in mice. However, little is known about the role of EMX2 in human tumorigenesis. In this study, we found that EMX2 was dramatically downregulated in lung cancer tissue samples and this downregulation was associated with methylation of the EMX2 promoter. Restoration of EMX2 expression in lung cancer cells lacking endogenous EMX2 expression suppressed cell proliferation and invasive phenotypes, inhibited canonical WNT signaling, and sensitized lung cancer cells to the treatment of the chemo cytotoxic drug cisplatin. On the other hand, knockdown of EMX2 expression in lung cancer cells expressing endogenous EMX2 promoted cell proliferation, invasive phenotypes and canonical WNT signaling. Taken together, our study suggests that EMX2 may have important roles as a novel suppressor in human lung cancer.

The hydroxyflavone, fisetin, suppresses mast cell activation induced by interaction with activated T cell membranes.

BACKGROUND AND PURPOSE: Cell-to-cell interactions between mast cells and activated T cells are increasingly recognized as a possible mechanism in the aetiology of allergic or non-allergic inflammatory disorders. To determine the anti-allergic effect of fisetin, we examined the ability of fisetin to suppress activation of the human mast cell line, HMC-1, induced by activated Jurkat T cell membranes. EXPERIMENTAL APPROACH: HMC-1 cells were incubated with or without fisetin for 15 min and then co-cultured with Jurkat T cell membranes activated by phorbol-12-myristate 13-acetate for 16 h. We determined gene expression in activated HMC-1 cells by DNA microarray and quantitative reverse transcription (RT)-PCR analysis. We also examined activation of the transcription factor NF-kappaB and MAP kinases (MAPKs) in activated HMC-1 cells. KEY RESULTS: Fisetin suppresses cell spreading and gene expression in HMC-1 cells stimulated by activated T cell membranes. Additionally, we show that these stimulated HMC-1 cells expressed granzyme B. The stimulatory interaction also induced activation of NF-kappaB and MAPKs; these activations were suppressed by fisetin. Fisetin also reduced the amount of cell surface antigen CD40 and intercellular adhesion molecule-1 (ICAM-1) on activated HMC-1 cells. CONCLUSIONS AND IMPLICATIONS: Fisetin suppressed activation of HMC-1 cells by activated T cell membranes by interfering with cell-to-cell interaction and inhibiting the activity of NF-kappaB and MAPKs and thereby suppressing gene expression. Fisetin may protect against the progression of inflammatory diseases by limiting interactions between mast cells and activated T cells.

Allelic diversification at the wx locus in landraces of Asian rice.

To examine continuous variation of amylose levels in Asian rice (Oryza sativa) landraces, the five putative alleles (Wx a, Wx in, Wx b, Wx op, and wx) at the wx locus were investigated in near-isogenic lines (NILs). Apparent amylose levels ranged from 0.5 to 29.9% in the NILs, showing a positive relation with the levels of Wx gene product, granule-bound starch synthase (GBSS) as well as the enzymatic activity per milligram starch granule. Only opaque (Wx op) accessions had an enzymatic activity per GBSS that was reduced to half the level of the others. Nucleotide sequences in the Wx gene were compared among 18 accessions harboring the five different alleles. Each of the Wx alleles had a unique replacement, frame-shift or splice donor site mutation, suggesting that these nucleotide changes could be reflected in phenotype alterations. A molecular phylogenetic tree constructed using the Wx gene indicated that ssp. japonica forms a distinct clade, whereas ssp. indica forms different clades together with the wild progenitor. Unexpectedly, the wx allele of 160 (indica from Taiwan) joined the japonica lineage; however, comparisons using linked genes for two Taiwanese accessions revealed that the wx gene was the product of gene flow from japonica to indica. Therefore, the japonica lineage frequently included Wx in, Wx b and wx, while Wx a and Wx op were found in the other lineages, strongly suggesting that allelic diversification occurred after divergence of the two subspecies. The present results were discussed in relation to the maintenance of agronomically valuable genes in various landraces.

[The evaluation of the complications and its management in 800 patients who underwent the thoracoscopic surgery].

Thoracoscopy has been applied to almost all thoracic surgery as shown (table 1). Besides an opportunity to follow and encounter a trouble during surgery using thoracoscopy, so that it is necessary to become skilled in the prediction and management of complication. Nowadays, there are two options on surgery using thoracoscopy, thoracoscopic surgery (TS) is performed only on in a port and on a mini-thoracotomy with a few ports (video-assisted thoracoscopic surgery: VATS). When changing into emergency or converting into open thoracotomy, a muscle sparing thoracotomy could be available. The symptoms which occurred in the thorax are fundamentally similar during both TS and VATS procedure. However, peculiar dangerous factor existed according to the difference in internal organs, procedures, and diseases. Critical complications during surgery were as follows, i.e., injury of pulmonary vessels and bronchus, tension pneumothorax of the opposite lung and tumor implantation of the chest wall. Basically, standard practice is the most important to avoid an accident and determine whether converting to open thoracotomy should be employed. In the present commentary, we would like to present our experiences and propose regarding management.

Down-regulation in human cancers of DRHC, a novel helicase-like gene from 17q25.1 that inhibits cell growth.

Frequent observations of allelic loss in chromosomal band 17q25.1 in a variety of human cancers have suggested that one or more tumor suppressor genes are normally present in this region. Moreover, a locus responsible for hereditary focal non-epidermolytic palmoplantar keratoderma (tylosis oesophageal cancer; TOC), a condition associated with esophageal cancer, has been mapped to the same band. During efforts to sequence, by shot-gun methods, a 1 Mb target region that we had defined as the DNA segment harboring the putative tumor suppressor gene(s) involved in these events, we identified a novel cDNA, DRHC (down-regulated in human cancers), that showed reduced expression in 28 of 95 (29%) cell lines derived from a variety of human cancers. The full-length cDNA, 6275 bp long, was expressed predominantly in thymus and brain. The predicted 1942-amino-acid product exhibited significant sequence homology to yeast enzymes belonging to the DEAD-helicase superfamily, and appeared to be a Uvr/Rep helicase with a DEXDc consensus domain. Transfection of a DRHC expression vector inhibited growth of cancer cells in liquid medium or soft agar. The results suggest that loss of expression of DRHC may play a role in human carcinogenesis.

Physician support and patient psychologic responses after surgery for nonsmall cell lung carcinoma: a prospective observational study.

BACKGROUND: In patients with cancer, depression and coping have been suggested to be important psychologic responses that may be associated with quality of life. Social support, especially from physicians, is considered important for cancer patients during their illness. The authors have investigated the impact of physician support on psychologic responses, including depression, psychologic distress and coping (such as fighting spirit and helplessness/hopelessness) in a cohort of patients with early-stage lung carcinoma. METHODS: After curative resection for nonsmall cell lung carcinoma, 226 patients were enrolled in a longitudinal study. The extent of social support, including physician support, was measured in structured interviews conducted 1 and 3 months after surgery. During the interviews, psychologic responses were measured using the Structured Clinical Interview for DSM-III-R, the Profiles of Mood States, and the Mental Adjustment to Cancer scale. Univariate and multivariate analyses were used to examine the impact of physician support on psychologic responses. RESULTS: Physician support had no effect on depression, but correlated negatively with psychologic distress (P < 0.05) and helplessness/hopelessness (P < 0.05), and positively with fighting spirit (P < 0.01). Multivariate analyses controlling for confounding biomedical and psychosocial variables revealed only physician support had a significant impact on fighting spirit, independently. However, this effect was limited to female patients or patients with no history of depression. CONCLUSION: In postoperative patients with nonsmall cell lung carcinoma, physician support may have a significant impact on fighting spirit, but this effect appears to be limited to female patients or patients with no history of depression.

Comparison of changes in hemodynamics between unilateral and bilateral lung volume reduction for pulmonary emphysema.

This study was aimed to compare changes in hemodynamics between unilateral (UL) or simultaneous bilateral (BL) lung volume reduction surgery (LVRS) for chronic obstructive lung disease. Sixteen patients underwent LVRS by stapler resection with neodymium: yttrium-alminum-garnet (Nd: YAG) laser ablation; five underwent BL-LVRS (four by median sternotomy and one by thoracoscopy) and 11 underwent UL-LVRS by thoracoscopy. Four patients had multiple bullae within pulmonary emphysema. At preoperation and 6, 12, 24, and 48 hours postoperatively, hemodynamics and right ventricular performance were evaluated. UL- and BL-LVRS reduced afterload of the right and left ventricle postoperatively. Although the pulmonary arterial resistance increased after surgery, the total pulmonary resistance decreased (p=0.001) in association with the reduced systemic vascular resistance (p=0.001). These reductions improved cardiopulmonary circulation, resulting in increased stroke volume and cardiac output (p=0.003). The right ventricular ejection fraction showed minimal change 48 hours postoperation. Two patients died of pneumonia caused by persistent air leakage. In conclusion, both the UL- and BL-LVRS showed similar effectiveness in terms of improvement in the systemic and cardiopulmonary circulation after LVRS, if there were no postoperative complications. We concluded that we had to reduce and repair the persistent air leakage after LVRS.

Down-regulation in multiple human cancers of a novel gene, DMHC, from 17q25.1 that encodes an integral membrane protein.

Frequent observations of allelic loss in chromosomal band 17q25.1 in a variety of human cancers have suggested that one or more tumor suppressor genes are present in that region. Moreover, a genetic locus for hereditary focal non-epidermolytic palmoplantar keratoderma, a condition associated with cancer of the esophagus (TOC; Tylosis with Oesophageal Cancer), lies in the same region. We screened cell lines derived from a variety of human cancers by reverse transcription-polymerase chain reaction (RT-PCR) to detect alterations in expression of genes within the region in question, by examining expressed sequence tags located there. These experiments identified an 1834-bp full-length cDNA encoding a novel, 441-amino acid integral membrane protein with seven putative transmembrane domains. This gene showed loss or extreme decrease of expression in 6 of 10 uterine cancer-cell lines, 2 of 11 hepatic cell carcinoma-cell lines, 2 of 7 lung cancer-cell lines, 1 of 6 gastric cancer-cell lines, and 1 of 10 breast cancer-cell lines. (We named it DMHC ("down-regulated in multiple human cancers").) Our results suggest that loss of expression of DMHC at 17q25.1 may play an important role in development of variety of human cancers.

Molecular cloning, tissue expression, and chromosomal assignment of a novel gene encoding a subunit of the human signal-recognition particle.

Human cancers derived from breast, esophageal, or ovarian tissues frequently show allelic losses on chromosome band 17q25. Moreover, a locus responsible for hereditary focal nonepidermolytic palmoplantar keratoderma, a condition associated with esophageal cancer (TOC; tylosis with oesophageal cancer), has been mapped to the same band. During efforts to sequence, by shotgun methods, a 1-Mb target region that we had defined as the DNA segment harboring the putative tumor suppressor gene(s) involved in these events, we identified a novel cDNA. The full-length cDNA is 2495bp long and is expressed predominantly in skeletal muscle, heart, kidney, and placenta. The predicted product, a 627-amino-acid protein, exhibited significant sequence homology to the canine 68-kd subunit of the signal recognition particle that has been implicated in the transport of secreted and membrane proteins to the endoplasmic reticulum for proper processing. We confirmed the location of this gene at chromosome 17q25.1 by radiation-hybrid mapping and by fluorescence in situ hybridization.

Identification of DMC1, a novel gene in the TOC region on 17q25.1 that shows loss of expression in multiple human cancers.

Frequent allelic losses within chromosomal band 17q25.1 in a variety of human cancers have suggested the presence of one or more tumor suppressor genes in this region. Furthermore, a genetic locus responsible for familial focal nonepidermolytic palmoplantar keratoderma, a condition associated with cancer of the esophagus, lies in the same region. This esophageal-cancer susceptibility locus, TOC (tylosis with oesophageal cancer), might be a target of deletions at 17q25.1 in multiple types of malignancy. Using the reverse transcriptase-polymerase chain reaction (RT-PCR) to examine cancer cell lines for alterations in the expression of transcripts from this portion of 17q, we identified a novel gene that we designated DMC1 (downregulated in multiple cancer-1). The full-length cDNA is 3293bp long. Its putative product is an integral membrane protein of 788 amino acids, belonging to the class of so-called 'inside-out" membrane proteins; it lacks a signal sequence but contains an N-terminal cytoplasmic domain, a single transmembrane peptide, and a C-terminal extracellular domain. We documented loss of expression of DMC1 in 2 of 10 breast-cancer cell lines, in 7 of 10 cervical-cancer lines, in 7 of 13 hepatocellular-cancer lines, in 3 of 7 lung-cancer lines, in 3 of 6 thyroid-cancer lines, in 2 of 6 gastric-cancer lines, and in 2 of 4 renal cell-cancer lines. Our results suggest that loss of expression of the DMC1 gene at 17q25.1 may play an important role in the development of cancers in a broad range of human tissues.

Changes in right ventricular performance in elderly patients who underwent lobectomy using video-assisted thoracic surgery for primary lung cancer.

OBJECTIVE: Even though lobectomy using video-assisted thoracic surgery for primary lung cancer has been reported to be beneficial in terms of the perioperative outcome, changes in the right ventricular performance have not yet been reported. The aim of this study was to determine whether lobectomy by video-assisted thoracic surgery is also advantageous with respect to the right ventricular performance in elderly patients who are 70 years old or older. SUBJECTS AND METHODS: Thirteen patients (mean age: 76 years) who underwent lobectomy using video-assisted thoracic surgery (Video-assisted Thoracic Surgery Group), and 10 patients (mean age: 76 years) who underwent lobectomy using a standard thoracotomy as a historical control group (Standard Thoracotomy Group) were studied. The hemodynamics and right ventricular ejection fraction were evaluated preoperatively, and at 6, 12, 24, and at 48 hours postoperatively. RESULTS: Postoperative values were expressed as a percentage of the preoperative values. The systemic vascular resistance index decreased to a greater extent in the Video-assisted Thoracic Surgery Group than in the Standard Thoracotomy Group. The pulmonary arteriolar resistance index at 24 hours postoperation tended to be higher in the Standard Thoracotomy Group than in the Video-assisted Thoracic Surgery Group. The stroke index, cardiac index, and right ventricular ejection fraction at 24 hours postoperation were each significantly higher in the Video-assisted Thoracic Surgery Group than in the Standard Thoracotomy Group. CONCLUSION: Lobectomy using video-assisted thoracic surgery for elderly patients offers not only beneficial effects in the right ventricular afterload but also acceleration in the expected compensatory hyperdynamics during the acute postoperative phase.

Prediction of the postoperative pulmonary function and complication rate in elderly patients.

We analyzed the risk factors predisposing elderly patients to develop postoperative respiratory complications (PRCs) and investigated the possibility of predicting the postoperative pulmonary function and PRC rate. The postoperative pulmonary functions were predicted according to a simplified system, which we developed using plain chest roentgenograms from patients with primary lung cancer. Both univariate and multivariate analyses of PRCs were performed in 39 elderly patients with lung cancer from July 1982 to March 1991 (the early period). Based on the results obtained, the permissible extent of lung resection to achieve a predicted postoperative % forced expiratory volume in 1 s (ppo%FEV1.0) and a predicted postoperative % vital capacity (ppo%VC) of more than 55% was selected as the basic criteria for undergoing such an operation after April 1991 (the recent period). A ppo%FEV1.0 and/or ppo%VC of 55% or less was the most significant risk factor for developing PRCs. The PRC rate decreased from 33.3% to 9.8% (P = 0.0251) and the operative mortality rate decreased from 10.3% to 0%. The survival rates for stage I, II. and III cases were not significantly different between the early and recent periods. Decisions made on the operability and the permissible extent of lung resection based on our system using plain chest roentgenograms therefore appeared to reduce the PRC rate and operative mortality rate in elderly patients.

Depression after successful treatment for nonsmall cell lung carcinoma.

BACKGROUND: There have been few studies of depression in nonsmall cell lung carcinoma (NSCLC) patients after successful treatment. The purpose of the study was to clarify the prevalence and the correlated factors of depression after surgery. METHODS: A structured interview was conducted for patient characteristics and social support with NSCLC patients at baseline. One-month prevalence of depression at 1 and 3 months after surgery was obtained by follow-up interviews at 1 and 3 months after surgery, respectively, whereas that of depression at 2 months after surgery was by the latter interview retrospectively. Three-month prevalence of depression was determined as presence of depression during any month in of a period of 3 months after surgery. A logistic analysis was used to examine the correlated factors of depression during the 3 months after surgery. RESULTS: Of 223 consecutive cancer patients who participated in the study between June 1996 and April 1999, 33 (14.8%) met the criteria for major or minor depression during the 3 months after surgery. One-month prevalence of depression at 1, 2, and 3 months after surgery were 9.0%, 9.4%, and 5.8%, respectively. The results of logistic regression analysis revealed that only satisfaction with confidants before surgery, of patient characteristics and social support factors, was significantly associated with depression during the 3 months after surgery. CONCLUSIONS: These results suggest that depression is not rare after successful treatment for NSCLC and that social support may play an important role for NSCLC patients with depression after successful treatment.

[Methods of single-nucleotide polymorphism analysis and application to hereditary cancer syndrome].

Single-nucleotide polymorphism analysis is important in all areas of molecular biology. The causative genes of hereditary cancer syndrome have been isolated. Recently, molecular diagnosis of hereditary cancer syndrome has been performed using methods of single-nucleotide polymorphism analysis and the usefulness has been reported. It is considered that progression of molecular biology will be able to contribute to diagnosis (especially pre-symptomatic diagnosis), prevention and treatment of hereditary cancer syndrome in the future.

Prevalence, predictive factors, and screening for psychologic distress in patients with newly diagnosed head and neck cancer.

BACKGROUND: High levels of distress are a concern regarding patients with head and neck cancer. Early detection of and intervention for such distress are needed to predict patients' adaptation to treatment or rehabilitation, but few studies have investigated the detection of their distress in a patient population of significant size. METHODS: The authors examined 107 consecutive patients with head and neck cancer to assess their psychologic distress (adjustment disorders or major depression) or other psychiatric problems by structured psychiatric interview before the initial cancer treatment. They also evaluated predictive factors for psychologic distress and assessed the ability of a self-rating questionnaire (Hospital Anxiety and Depression Scale, HADS) to screen for distress. RESULTS: Of 107 subjects, 18 (16.8%) had an adjustment disorder or major depression. Thirty-six (33.6%), 7 (6. 5%), and 35 (32.7%) met criteria for alcohol dependence, alcohol abuse, and nicotine dependence, respectively. Logistic regression analysis revealed that having advanced stage cancer (odds ratio, 5. 77; 95% confidence interval [CI], 1.41-39.7; P = 0.03) and living alone (odds ratio, 4.83; 95% CI, 1.04-22.2; P = 0.04) were significantly associated with having psychologic distress. The optimal cutoff point for the HADS screening for psychologic distress was 15. This cutoff point gave 72.2% sensitivity and 81.4% specificity. CONCLUSIONS: Head and neck cancer patients who have advanced disease or live alone should be assessed so that psychologic distress can be detected and intervention made. HADS is a useful clinical instrument to screen for their distress.

Factors correlated with fatigue in disease-free breast cancer patients: application of the Cancer Fatigue Scale.

Fatigue is one of the most frequent symptoms in cancer patients. However, the precise causes of this fatigue are still unknown, and this situation makes it difficult to combat the problem. The present study was conducted to investigate factors correlated with fatigue in disease-free breast cancer patients. A group of 134 randomly selected ambulatory breast cancer patients who had undergone successful surgical treatment participated. They completed the Cancer Fatigue Scale, the Hospital Anxiety and Depression Scale, the Mental Adjustment to Cancer Scale, and an ad hoc questionnaire detailing physical symptoms, social support, and demographic variables at home and returned them by mail the following day. Multiple regression analysis revealed that fatigue was significantly correlated with dyspnea, insufficient sleep, and depression, and that these three variables accounted for a total of 46% of variance in fatigue. Factors concerned with the cancer and treatment, such as disease stage, lymph node metastasis, number of days since operation, past intravenous chemotherapy, radiotherapy, current use of fluoropyrimidine compounds, and current use of tamoxifen citrate were not correlated with fatigue. The results suggest that fatigue in this population is determined by current physical and psychological distress rather than by the cancer itself and prior cancer treatments, and that the management of dyspnea, insomnia, and depression might be important in reducing fatigue in this population.

Suicidal thoughts in cancer patients: clinical experience in psycho-oncology.

Because cancer is a life-threatening illness, its impact on the patient's emotional well-being, such as suicidal thoughts, has become a significant problem in public health as well as in clinical oncology. Factors such as the pain and hopelessness are suggested as making cancer patients more vulnerable to suicide. On the other hand, euthanasia and physician-assisted suicide are now important medical and social issues all over the world. However, little is known about the relationship between the characteristics of cancer patients and suicidal thoughts. The present study investigated the characteristics of patients who were referred to the Psychiatry Division, National Cancer Center Hospital East, due to risk of suicide or suicide attempts. Fourteen patients were referred, representing 3.9% of all consultations. Most of these patients suffered from advanced cancer and poor physical functioning. The most frequent psychiatric diagnosis was mood disorder (57%), and the next was delirium (29%). In patients with mood disorders (8 cases), suicidal thoughts disappeared after psychiatric treatment in 5 cases, but not in 3 cases. Those three patients survived a significantly shorter time than the others after psychiatric consultation. These empirical data might indicate that most suicidal thoughts experienced by cancer patients are not rational, and a careful evaluation, including psychiatric assessment, should be conducted in such patients.

Screening for nicotine dependence among smoking-related cancer patients.

To identify lung and head-and-neck cancer patients who will have difficulty stopping smoking it is necessary to measure the severity of their nicotine dependence. In this study, we compiled a Japanese version of the Fagerstrom test for nicotine dependence (FTND) and examined its reliability and validity. One hundred and fifty-one cancer patients participated in this study and took our Japanese version of the FTND. Socio-demographic and medical data and information about smoking habits were obtained from a semi-structured interview, and the patients' nicotine dependence was evaluated according to the Diagnostic and Statistical Manual of Mental Disorders, 3rd Ed., Rev. (DSM-III-R). The mean FTND scores+/-SD of the group with nicotine dependence and the group without nicotine dependence were 6.85+/-2.00 and 3.70+/-2.13 respectively, and the difference was significant (P<0.001, Mann-Whitney's U-test). The test-retest correlation was 0.75. Cronbach's alpha of the FTND was 0.66. The FTND score correlated significantly with the number of satisfied criteria of nicotine dependence (r=0.70; P<0.001, Pearson's correlation). By using a receiver-operating-characteristic curve, we determined a score of 5/6 as a suitable cut-off point for nicotine dependence; this point gave high sensitivity and specificity (0.75 and 0.80, respectively). These results suggest that our Japanese version of FTND is a reliable and valid measure of nicotine dependence in patients with smoking-related cancers.