Annual Economic Burden of Productivity Losses Among Adult Survivors of Childhood Cancers.

PubMed

Guy, Gery P; Berkowitz, Zahava; Ekwueme, Donatus U; Rim, Sun Hee; Yabroff, K Robin

2016-11-01

Although adult survivors of childhood cancers have poorer health and greater health limitations than other adults, substantial gaps remain in understanding the economic consequences of surviving childhood cancer. Therefore, we estimated the economic burden of productivity losses among adult survivors of childhood cancers. We examined health status, functional limitations, and productivity loss among adult survivors of childhood cancers (n = 239) diagnosed at ≤14 years of age compared with adults without a history of cancer (n = 304 265) by using the 2004-2014 National Health Interview Survey. We estimated economic burden using the productivity loss from health-related unemployment, missed work days, missed household productivity, and multivariable regression models controlling for age, sex, race/ethnicity, education, comorbidities, and survey year. Childhood cancer survivorship is associated with a substantial economic burden. Adult survivors of childhood cancers are more likely to be in poorer health, need assistance with personal care and routine needs, have work limitations, be unable to work because of health, miss more days of work, and have greater household productivity loss compared with adults without a history of cancer (all P < .05). The annual productivity loss for adult survivors of childhood cancer is $8169 per person compared with $3083 per person for individuals without a history of cancer. These findings underscore the importance of efforts to reduce the health and economic burden among adult survivors of childhood cancer. In addition, this study highlights the potential productivity losses that could be avoided during adulthood from the prevention of childhood cancer in the United States. Copyright © 2016 by the American Academy of Pediatrics.

Screening, prevention, detection, and treatment of cancer therapy-induced bone loss in patients with breast cancer.

PubMed

Limburg, Connie E

2007-01-01

To identify protocols to screen, detect, prevent, and treat cancer therapy-induced bone loss resulting in osteoporosis in patients with breast cancer. Published books and articles. Normal bone remodeling is affected by hormonal stimulation. Breast cancer therapies target hormones that promote cancer cell growth. Chemotherapy regimens and hormone ablation may cause ovarian failure, resulting in decreased hormone levels. A decrease in hormones, in estrogen- and progesterone-positive and -negative patients, introduces an environment for decreased bone remodeling, which may result in thinning bone and osteoporosis. The acceleration of bone loss leading to osteoporosis can result in higher fracture rates among breast cancer survivors. With proper use of screening tools, patient education, and advice about lifestyle changes, all prior to cancer treatment, healthcare professionals may decrease or prevent bone loss in patients with breast cancer. Doing so minimizes healthcare costs and decreases morbidity and mortality rates in breast cancer survivors. As more individuals diagnosed with breast cancer are surviving for extended periods of time, oncology nurses are providing long-term follow-up care. Part of the care should include proper screening and patient education for healthier recovery and prevention of further healthcare complications as a result of cancer treatment.

Bariatric surgery in cancer survivorship: does a history of cancer affect weight loss outcomes?

PubMed

Philip, Errol J; Torghabeh, Mehyar H; Strain, Gladys W

2015-01-01

Weight loss is recommended for obese cancer survivors who are at increased risk of recurrence and non-cancer-related mortality. It remains unknown if this vulnerable population benefits from bariatric surgery to the same extent as those without a history of cancer. A retrospective chart review of 1013 patients identified 29 bariatric surgery patients with a history of cancer who were then matched to patients without a history of cancer. At 1-year postsurgical follow-up, individuals with a history of cancer had lost less weight than those without a history of cancer (14.2 versus 14.8); however, this difference was not significant (P = .76). Cancer survivors appear to draw similar benefit from bariatric surgery as those without a history of cancer, although a larger study with greater statistical power to detect differences is needed to confirm these results. These preliminary results are encouraging in light of the increasing focus on weight loss among this population. Copyright © 2015 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.

Clinicopathologic and prognostic relevance of ARID1A protein loss in colorectal cancer.

PubMed

Wei, Xiao-Li; Wang, De-Shen; Xi, Shao-Yan; Wu, Wen-Jing; Chen, Dong-Liang; Zeng, Zhao-Lei; Wang, Rui-Yu; Huang, Ya-Xin; Jin, Ying; Wang, Feng; Qiu, Miao-Zhen; Luo, Hui-Yan; Zhang, Dong-Sheng; Xu, Rui-Hua

2014-12-28

To explore the association between AT-rich interactive domain 1A (ARID1A) protein loss by immunohistochemistry and both clinicopathologic characteristics and prognosis in patients with colorectal cancer. We retrospectively collected clinicopathologic data and archived paraffin-embedded primary colorectal cancer samples from 209 patients, including 111 patients with colon cancer and 98 patients with rectal cancer. The tumor stage ranged from stage I to stage IV according to the 7(th) edition of the American Joint Committee on Cancer tumor-node-metastasis (TNM) staging system. All patients underwent resection of primary colorectal tumors. The expression of ARID1A protein in primary colorectal cancer tissues was examined by immunohistochemical staining. The clinicopathologic association and survival relevance of ARID1A protein loss in colorectal cancer were analyzed. ARID1A loss by immunohistochemistry was not rare in primary colorectal cancer tumors (25.8%). There were 7.4%, 24.1%, 22.2% and 46.3% of patients with ARID1A loss staged at TNM stage I, II, III and IV, respectively, compared with 20.0%, 22.6%, 27.7% and 29.7% of patients without ARID1A loss staged at TNM stage I, II, III and IV, respectively. In patients with ARID1A loss, the distant metastasis rate was 46.3%. However, only 29.7% of patients without ARID1A loss were found to have distant metastasis. In terms of pathologic differentiation, there were 25.9%, 66.7% and 7.4% with poorly, moderately and well differentiated tumors in patients with ARID1A loss, and 14.2%, 72.3% and 13.5% with poorly, moderately and well differentiated tumors in patients without ARID1A loss, respectively. ARID1A loss was associated with late TNM stage (P = 0.020), distant metastasis (P = 0.026), and poor pathological classification (P = 0.035). However, patients with positive ARID1A had worse overall survival compared to those with negative ARID1A in stage IV colorectal cancer (HR = 2.49, 95%CI: 1.13-5.51). ARID1A protein loss is

Differential Bone Loss in Mouse Models of Colon Cancer Cachexia.

PubMed

Bonetto, Andrea; Kays, Joshua K; Parker, Valorie A; Matthews, Ryan R; Barreto, Rafael; Puppa, Melissa J; Kang, Kyung S; Carson, James A; Guise, Theresa A; Mohammad, Khalid S; Robling, Alexander G; Couch, Marion E; Koniaris, Leonidas G; Zimmers, Teresa A

2016-01-01

Cachexia is a distinctive feature of colorectal cancer associated with body weight loss and progressive muscle wasting. Several mechanisms responsible for muscle and fat wasting have been identified, however it is not known whether the physiologic and molecular crosstalk between muscle and bone tissue may also contribute to the cachectic phenotype in cancer patients. The purpose of this study was to clarify whether tumor growth associates with bone loss using several experimental models of colorectal cancer cachexia, namely C26, HT-29, and Apc Min/+ . The effects of cachexia on bone structure and strength were evaluated with dual energy X-ray absorptiometry (DXA), micro computed tomography (μCT), and three-point bending test. We found that all models showed tumor growth consistent with severe cachexia. While muscle wasting in C26 hosts was accompanied by moderate bone depletion, no loss of bone strength was observed. However, HT-29 tumor bearing mice showed bone abnormalities including significant reductions in whole-body bone mineral density (BMD), bone mineral content (BMC), femoral trabecular bone volume fraction (BV/TV), trabecular number (Tb.N), and trabecular thickness (Tb.Th), but no declines in strength. Similarly, cachexia in the Apc Min/+ mice was associated with significant decreases in BMD, BMC, BV/TV, Tb.N, and Tb.Th as well as decreased strength. Our data suggest that colorectal cancer is associated with muscle wasting and may be accompanied by bone loss dependent upon tumor type, burden, stage and duration of the disease. It is clear that preserving muscle mass promotes survival in cancer cachexia. Future studies will determine whether strategies aimed at preventing bone loss can also improve outcomes and survival in colorectal cancer cachexia.

ZIP4 silencing improves bone loss in pancreatic cancer

PubMed Central

Yang, Jingxuan; Ding, Hao; LeBrun, Drake; Ding, Kai; Houchen, Courtney W.; Postier, Russell G.; Ambrose, Catherine G.; Li, Zhaoshen; Bi, Xiaohong; Li, Min

2015-01-01

Metabolic bone disorders are associated with several types of human cancers. Pancreatic cancer patients usually suffer from severe nutrition deficiency, muscle wasting, and loss of bone mass. We have previously found that silencing of a zinc transporter ZIP4 prolongs the survival and reduces the severity of the cachexia in vivo. However, the role of ZIP4 in the pancreatic cancer related bone loss remains unknown. In this study we investigated the effect of ZIP4 knockdown on the bone structure, composition and mechanical properties of femurs in an orthotopic xenograft mouse model. Our data showed that silencing of ZIP4 resulted in increased bone tissue mineral density, decreased bone crystallinity and restoration of bone strength through the RANK/RANKL pathway. The results further support the impact of ZIP4 on the progression of pancreatic cancer, and suggest its potential significance as a therapeutic target for treating patients with such devastating disease and cancer related disorders. PMID:26305676

Differential Bone Loss in Mouse Models of Colon Cancer Cachexia

PubMed Central

Bonetto, Andrea; Kays, Joshua K.; Parker, Valorie A.; Matthews, Ryan R.; Barreto, Rafael; Puppa, Melissa J.; Kang, Kyung S.; Carson, James A.; Guise, Theresa A.; Mohammad, Khalid S.; Robling, Alexander G.; Couch, Marion E.; Koniaris, Leonidas G.; Zimmers, Teresa A.

2017-01-01

Cachexia is a distinctive feature of colorectal cancer associated with body weight loss and progressive muscle wasting. Several mechanisms responsible for muscle and fat wasting have been identified, however it is not known whether the physiologic and molecular crosstalk between muscle and bone tissue may also contribute to the cachectic phenotype in cancer patients. The purpose of this study was to clarify whether tumor growth associates with bone loss using several experimental models of colorectal cancer cachexia, namely C26, HT-29, and ApcMin/+. The effects of cachexia on bone structure and strength were evaluated with dual energy X-ray absorptiometry (DXA), micro computed tomography (μCT), and three-point bending test. We found that all models showed tumor growth consistent with severe cachexia. While muscle wasting in C26 hosts was accompanied by moderate bone depletion, no loss of bone strength was observed. However, HT-29 tumor bearing mice showed bone abnormalities including significant reductions in whole-body bone mineral density (BMD), bone mineral content (BMC), femoral trabecular bone volume fraction (BV/TV), trabecular number (Tb.N), and trabecular thickness (Tb.Th), but no declines in strength. Similarly, cachexia in the ApcMin/+ mice was associated with significant decreases in BMD, BMC, BV/TV, Tb.N, and Tb.Th as well as decreased strength. Our data suggest that colorectal cancer is associated with muscle wasting and may be accompanied by bone loss dependent upon tumor type, burden, stage and duration of the disease. It is clear that preserving muscle mass promotes survival in cancer cachexia. Future studies will determine whether strategies aimed at preventing bone loss can also improve outcomes and survival in colorectal cancer cachexia. PMID:28123369

Overcoming obstacles in the design of cancer anorexia/weight loss trials.

PubMed

Le-Rademacher, Jennifer G; Crawford, Jeffrey; Evans, William J; Jatoi, Aminah

2017-09-01

Most advanced cancer patients suffer loss of appetite (anorexia) and loss of weight. Despite the fact that cancer anorexia and weight loss are associated with a poor prognosis and detract from quality of life, no interventions have been demonstrated to palliate this syndrome in its entirety, particularly in patients with treatment-refractory malignancies. Recently, two registration trials - one with anamorelin and another with enobosarm - failed to reach their primary endpoints, thus raising questions. Were both these agents ineffective? Alternatively, did study design issues compromise the ability of these trials to identify effective agents? Thus, this review is timely insofar it serves as an introduction to study design, offers guidance on how to test promising agents for cancer anorexia/weight loss, and provides advice for overcoming trial design obstacles. Copyright © 2017 Elsevier B.V. All rights reserved.

Loss of the Nuclear Pool of Ubiquitin Ligase CHIP/STUB1 in Breast Cancer Unleashes the MZF1-Cathepsin Pro-oncogenic Program.

PubMed

Luan, Haitao; Mohapatra, Bhopal; Bielecki, Timothy A; Mushtaq, Insha; Mirza, Sameer; Jennings, Tameka A; Clubb, Robert J; An, Wei; Ahmed, Dena; El-Ansari, Rokaya; Storck, Matthew D; Mishra, Nitish K; Guda, Chittibabu; Sheinin, Yuri M; Meza, Jane L; Raja, Srikumar; Rakha, Emad A; Band, Vimla; Band, Hamid

2018-05-15

CHIP/STUB1 ubiquitin ligase is a negative co-chaperone for HSP90/HSC70, and its expression is reduced or lost in several cancers, including breast cancer. Using an extensive and well-annotated breast cancer tissue collection, we identified the loss of nuclear but not cytoplasmic CHIP to predict more aggressive tumorigenesis and shorter patient survival, with loss of CHIP in two thirds of ErbB2 + and triple-negative breast cancers (TNBC) and in one third of ER + breast cancers. Reduced CHIP expression was seen in breast cancer patient-derived xenograft tumors and in ErbB2 + and TNBC cell lines. Ectopic CHIP expression in ErbB2 + lines suppressed in vitro oncogenic traits and in vivo xenograft tumor growth. An unbiased screen for CHIP-regulated nuclear transcription factors identified many candidates whose DNA-binding activity was up- or downregulated by CHIP. We characterized myeloid zinc finger 1 (MZF1) as a CHIP target, given its recently identified role as a positive regulator of cathepsin B/L (CTSB/L)-mediated tumor cell invasion downstream of ErbB2. We show that CHIP negatively regulates CTSB/L expression in ErbB2 + and other breast cancer cell lines. CTSB inhibition abrogates invasion and matrix degradation in vitro and halts ErbB2 + breast cancer cell line xenograft growth. We conclude that loss of CHIP remodels the cellular transcriptome to unleash critical pro-oncogenic pathways, such as the matrix-degrading enzymes of the cathepsin family, whose components can provide new therapeutic opportunities in breast and other cancers with loss of CHIP expression. Significance: These findings reveal a novel targetable pathway of breast oncogenesis unleashed by the loss of tumor suppressor ubiquitin ligase CHIP/STUB1. Cancer Res; 78(10); 2524-35. ©2018 AACR . ©2018 American Association for Cancer Research.

Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer.

PubMed

Varambally, Sooryanarayana; Cao, Qi; Mani, Ram-Shankar; Shankar, Sunita; Wang, Xiaosong; Ateeq, Bushra; Laxman, Bharathi; Cao, Xuhong; Jing, Xiaojun; Ramnarayanan, Kalpana; Brenner, J Chad; Yu, Jindan; Kim, Jung H; Han, Bo; Tan, Patrick; Kumar-Sinha, Chandan; Lonigro, Robert J; Palanisamy, Nallasivam; Maher, Christopher A; Chinnaiyan, Arul M

2008-12-12

Enhancer of zeste homolog 2 (EZH2) is a mammalian histone methyltransferase that contributes to the epigenetic silencing of target genes and regulates the survival and metastasis of cancer cells. EZH2 is overexpressed in aggressive solid tumors by mechanisms that remain unclear. Here we show that the expression and function of EZH2 in cancer cell lines are inhibited by microRNA-101 (miR-101). Analysis of human prostate tumors revealed that miR-101 expression decreases during cancer progression, paralleling an increase in EZH2 expression. One or both of the two genomic loci encoding miR-101 were somatically lost in 37.5% of clinically localized prostate cancer cells (6 of 16) and 66.7% of metastatic disease cells (22 of 33). We propose that the genomic loss of miR-101 in cancer leads to overexpression of EZH2 and concomitant dysregulation of epigenetic pathways, resulting in cancer progression.

Truncation- and motif-based pan-cancer analysis reveals tumor-suppressing kinases.

PubMed

Hudson, Andrew M; Stephenson, Natalie L; Li, Cynthia; Trotter, Eleanor; Fletcher, Adam J; Katona, Gitta; Bieniasz-Krzywiec, Patrycja; Howell, Matthew; Wirth, Chris; Furney, Simon; Miller, Crispin J; Brognard, John

2018-04-17

A major challenge in cancer genomics is identifying "driver" mutations from the many neutral "passenger" mutations within a given tumor. To identify driver mutations that would otherwise be lost within mutational noise, we filtered genomic data by motifs that are critical for kinase activity. In the first step of our screen, we used data from the Cancer Cell Line Encyclopedia and The Cancer Genome Atlas to identify kinases with truncation mutations occurring within or before the kinase domain. The top 30 tumor-suppressing kinases were aligned, and hotspots for loss-of-function (LOF) mutations were identified on the basis of amino acid conservation and mutational frequency. The functional consequences of new LOF mutations were biochemically validated, and the top 15 hotspot LOF residues were used in a pan-cancer analysis to define the tumor-suppressing kinome. A ranked list revealed MAP2K7, an essential mediator of the c-Jun N-terminal kinase (JNK) pathway, as a candidate tumor suppressor in gastric cancer, despite its mutational frequency falling within the mutational noise for this cancer type. The majority of mutations in MAP2K7 abolished its catalytic activity, and reactivation of the JNK pathway in gastric cancer cells harboring LOF mutations in MAP2K7 or the downstream kinase JNK suppressed clonogenicity and growth in soft agar, demonstrating the functional relevance of inactivating the JNK pathway in gastric cancer. Together, our data highlight a broadly applicable strategy to identify functional cancer driver mutations and define the JNK pathway as tumor-suppressive in gastric cancer. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Efficacy of a Weight Loss Intervention for African American Breast Cancer Survivors.

PubMed

Stolley, Melinda; Sheean, Patricia; Gerber, Ben; Arroyo, Claudia; Schiffer, Linda; Banerjee, Anjishnu; Visotcky, Alexis; Fantuzzi, Giamila; Strahan, Desmona; Matthews, Lauren; Dakers, Roxanne; Carridine-Andrews, Cynthia; Seligman, Katya; Springfield, Sparkle; Odoms-Young, Angela; Hong, Susan; Hoskins, Kent; Kaklamani, Virginia; Sharp, Lisa

2017-08-20

Purpose African American women with breast cancer have higher cancer-specific and overall mortality rates. Obesity is common among African American women and contributes to breast cancer progression and numerous chronic conditions. Weight loss interventions among breast cancer survivors positively affect weight, behavior, biomarkers, and psychosocial outcomes, yet few target African Americans. This article examines the effects of Moving Forward, a weight loss intervention for African American breast cancer survivors (AABCS) on weight, body composition, and behavior. Patients and Methods Early-stage (I-III) AABCS were randomly assigned to a 6-month interventionist-guided (n = 125) or self-guided (n = 121) weight loss program supporting behavioral changes to promote a 5% weight loss. Anthropometric, body composition, and behavioral data were collected at baseline, postintervention (6 months), and follow-up (12 months). Descriptive statistics and mixed models analyses assessed differences between groups over time. Results Mean (± standard deviation) age, and body mass index were 57.5 (± 10.1) years and 36.1 (± 6.2) kg/m 2 , respectively, and 82% had stage I or II breast cancer. Both groups lost weight. Mean and percentage of weight loss were greater in the guided versus self-guided group (at 6 months: 3.5 kg v 1.3kg; P < .001; 3.6% v 1.4%; P < .001, respectively; at 12 months: 2.7 kg v 1.6 kg; P < .05; 2.6% v 1.6%; P < .05, respectively); 44% in the guided group and 19% in the self-guided group met the 5% goal. Body composition and behavioral changes were also greater in the interventionist-guided group at both time points. Conclusion The study supports the efficacy of a community-based interventionist-guided weight loss program targeting AABCS. Although mean weight loss did not reach the targeted 5%, the mean loss of > 3% at 6 months is associated with improved health outcomes. Affordable, accessible health promotion programs represent a critical resource for

Allelic loss and linkage studies in prostate cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Johnson, D.R.; Bale, A.E.; Lytton, B.

1994-09-01

Prostate cancer is the most common malignancy in U.S. males. Many examples of familial aggregation have been reported, and segregration analysis suggests that an autosomal dominant gene with a penetrance of 88% by age 85 accounts for 9% of all cases. Because many dominant cancer predisposition syndromes are related to germline mutations in tumor suppressor genes, we analyzed a series of sporadic and hereditary tumors for allelic loss. High grade sporadic, paraffin-embedded, primary prostate tumors were obtained from the archival collection in the Department of Pathology at Yale and hereditary tumors from three families were obtained by an advertisement inmore » the New York Times and from referrals by urologists. PCR analysis showed loss in 4/7 informative sporadic prostate tumors with NEFL (8p21), in 8/22 informative tumors with D10S169 (10q26-qter), in 2/8 informative tumors with D10S108 (10q) and in 4/23 informative tumors with D10S89 (10p) in agreement with previous studies. PYGM on chromosome 11 and D9S127 on chromosome 9 showed no loss. Linkage analysis with NEFL in 3 prostate cancer families gave strongly negative results for close linkage (Z=-2.1 at {theta}=0.01) but LOD scores were very dependent on parameters, e.g. gene frequency, phenocopy rate, and penetrance. Linkage analysis with chromosome 10 markers and systematic analysis of the genome for other area of allelic loss are underway.« less

Detrimental social interactions predict loss of dignity among patients with cancer.

PubMed

Philipp, R; Mehnert, A; Lehmann, C; Oechsle, K; Bokemeyer, C; Krüll, A; Vehling, S

2016-06-01

This prospective study aimed to determine the extent to which cancer patients experience loss of dignity during primary cancer care (baseline) and at 3-month follow-up and the contribution of positive social support and detrimental social interactions on loss of dignity at follow-up. At baseline, we enrolled N = 270 cancer patients (advanced cancer 57 %) undergoing oncological treatment. At follow-up, n = 178 patients (72 %) participated. Patients completed the following questionnaires: sense of dignity item (SDI), physical problem list of the NCCN Distress Thermometer, Illness-Specific Social Support Scale (SSUK), Patient Health Questionnaire (PHQ-9), and Generalized Anxiety Disorder Questionnaire (GAD-7). We conducted ordinal regression analyses controlling for age, gender, tumor stage, number of physical symptoms, depression, and anxiety. At baseline, 18 % of the patients experienced moderate to extreme loss of dignity (follow-up 23 %, p = 0.27). Detrimental interactions significantly predicted loss of dignity (OR = 1.42, 95 % CI 1.06-1.90) in a model including positive support (OR = 1.10, 95 % CI 0.82-1.49), depression (OR = 1.55, 95 % CI 0.96-2.51), and anxiety (OR = 1.20, 95 % CI 0.83-1.74). Items in relation to detrimental interactions with significant others such as "made you feel like you couldn't take care of yourself" (r = 0.29, p < 0.001) and "felt uncomfortable in illness conversations" (r = 0.24, p = 0.002) showed the highest associations with perceived loss of dignity. Loss of dignity was a frequent problem in our mixed cancer patient sample. Detrimental interactions that weaken the sense of dignity may result from discrepancies with patients' needs for autonomy and security. Tailoring social support to attachment-related patient needs may help to conserve patients' sense of dignity.

Serum and urine metabolomics study reveals a distinct diagnostic model for cancer cachexia

PubMed Central

Yang, Quan‐Jun; Zhao, Jiang‐Rong; Hao, Juan; Li, Bin; Huo, Yan; Han, Yong‐Long; Wan, Li‐Li; Li, Jie; Huang, Jinlu; Lu, Jin

2017-01-01

Abstract Background Cachexia is a multifactorial metabolic syndrome with high morbidity and mortality in patients with advanced cancer. The diagnosis of cancer cachexia depends on objective measures of clinical symptoms and a history of weight loss, which lag behind disease progression and have limited utility for the early diagnosis of cancer cachexia. In this study, we performed a nuclear magnetic resonance‐based metabolomics analysis to reveal the metabolic profile of cancer cachexia and establish a diagnostic model. Methods Eighty‐four cancer cachexia patients, 33 pre‐cachectic patients, 105 weight‐stable cancer patients, and 74 healthy controls were included in the training and validation sets. Comparative analysis was used to elucidate the distinct metabolites of cancer cachexia, while metabolic pathway analysis was employed to elucidate reprogramming pathways. Random forest, logistic regression, and receiver operating characteristic analyses were used to select and validate the biomarker metabolites and establish a diagnostic model. Results Forty‐six cancer cachexia patients, 22 pre‐cachectic patients, 68 weight‐stable cancer patients, and 48 healthy controls were included in the training set, and 38 cancer cachexia patients, 11 pre‐cachectic patients, 37 weight‐stable cancer patients, and 26 healthy controls were included in the validation set. All four groups were age‐matched and sex‐matched in the training set. Metabolomics analysis showed a clear separation of the four groups. Overall, 45 metabolites and 18 metabolic pathways were associated with cancer cachexia. Using random forest analysis, 15 of these metabolites were identified as highly discriminating between disease states. Logistic regression and receiver operating characteristic analyses were used to create a distinct diagnostic model with an area under the curve of 0.991 based on three metabolites. The diagnostic equation was Logit(P) = −400.53 – 481.88�

Cholesteryl Ester Accumulation Induced by PTEN Loss and PI3K/AKT Activation Underlies Human Prostate Cancer Aggressiveness

PubMed Central

Yue, Shuhua; Li, Junjie; Lee, Seung-Young; Lee, Hyeon Jeong; Shao, Tian; Song, Bing; Cheng, Liang; Masterson, Timothy A.; Liu, Xiaoqi; Ratliff, Timothy L.; Cheng, Ji-Xin

2014-01-01

Summary Altered lipid metabolism is increasingly recognized as a signature of cancer cells. Enabled by label-free Raman spectromicroscopy, we performed quantitative analysis of lipogenesis at single cell level in human patient cancerous tissues. Our imaging data revealed an unexpected, aberrant accumulation of esterified cholesterol in lipid droplets of high-grade prostate cancer and metastases. Biochemical study showed that such cholesteryl ester accumulation was a consequence of loss of tumor suppressor PTEN and subsequent activation of PI3K/AKT pathway in prostate cancer cells. Furthermore, we found that such accumulation arose from significantly enhanced uptake of exogenous lipoproteins and required cholesterol esterification. Depletion of cholesteryl ester storage significantly reduced cancer proliferation, impaired cancer invasion capability, and suppressed tumor growth in mouse xenograft models with negligible toxicity. These findings open opportunities for diagnosing and treating prostate cancer by targeting the altered cholesterol metabolism. PMID:24606897

Ribosomal DNA copy number amplification and loss in human cancers is linked to tumor genetic context, nucleolus activity, and proliferation

PubMed Central

2017-01-01

Ribosomal RNAs (rRNAs) are transcribed from two multicopy DNA arrays: the 5S ribosomal DNA (rDNA) array residing in a single human autosome and the 45S rDNA array residing in five human autosomes. The arrays are among the most variable segments of the genome, exhibit concerted copy number variation (cCNV), encode essential components of the ribosome, and modulate global gene expression. Here we combined whole genome data from >700 tumors and paired normal tissues to provide a portrait of rDNA variation in human tissues and cancers of diverse mutational signatures, including stomach and lung adenocarcinomas, ovarian cancers, and others of the TCGA panel. We show that cancers undergo coupled 5S rDNA array expansion and 45S rDNA loss that is accompanied by increased estimates of proliferation rate and nucleolar activity. These somatic changes in rDNA CN occur in a background of over 10-fold naturally occurring rDNA CN variation across individuals and cCNV of 5S-45S arrays in some but not all tissues. Analysis of genetic context revealed associations between cancer rDNA CN amplification or loss and the presence of specific somatic alterations, including somatic SNPs and copy number gain/losses in protein coding genes across the cancer genome. For instance, somatic inactivation of the tumor suppressor gene TP53 emerged with a strong association with coupled 5S expansion / 45S loss in several cancers. Our results uncover frequent and contrasting changes in the 5S and 45S rDNA along rapidly proliferating cell lineages with high nucleolar activity. We suggest that 5S rDNA amplification facilitates increased proliferation, nucleolar activity, and ribosomal synthesis in cancer, whereas 45S rDNA loss emerges as a byproduct of transcription-replication conflict in rapidly replicating tumor cells. The observations raise the prospects of using the rDNA arrays as re-emerging targets for the design of novel strategies in cancer therapy. PMID:28880866

Illustrating the (in)visible: Understanding the impact of loss in adults living with secondary lymphedema after cancer

PubMed Central

Thomas, Roanne; Hamilton, Ryan

2014-01-01

Life with a disability is often riddled with paradoxes, one of which is being visibly marked, while personal experiences, losses, and challenges remain hidden. Our article draws attention to this paradox among people who live with secondary lymphedema after cancer (SLC). SLC is a relatively unfamiliar chronic condition within medical and lay discourses of cancer, which proves challenging for the many cancer survivors who are in search of information and understanding. Thirteen men and women with SLC were recruited from two research sites (Fredericton, NB, and Ottawa, ON, Canada) to participate in semi-structured interviews about the physical and psychosocial aspects of SLC. Using a methodology of interpretive description, our analysis of participant interviews reveals the complex ways in which men and women felt both visible and invisible within various contexts. We discuss three majors themes: (in)visibility and appearance related to material losses; (in)visibility and action connected to visible losses in function, as well as invisible struggles to care for oneself; and the loss of present and future well-being, as SLC renders some limitations visible while potentially obscuring a hopeful future indefinitely. Our research indicates that timely diagnosis of SLC would be an immediate first step in recognizing the physical and emotional dimensions of the condition. To accomplish this, increased awareness is needed. To enhance quality of life for those living with SLC, the development of new resources and psychosocial supports is also required. PMID:25148936

Target sequencing and CRISPR/Cas editing reveal simultaneous loss of UTX and UTY in urothelial bladder cancer.

PubMed

Ahn, Jinwoo; Kim, Kwang Hyun; Park, Sanghui; Ahn, Young-Ho; Kim, Ha Young; Yoon, Hana; Lee, Ji Hyun; Bang, Duhee; Lee, Dong Hyeon

2016-09-27

UTX is a histone demethylase gene located on the X chromosome and is a frequently mutated gene in urothelial bladder cancer (UBC). UTY is a paralog of UTX located on the Y chromosome. We performed target capture sequencing on 128 genes in 40 non-metastatic UBC patients. UTX was the most frequently mutated gene (30%, 12/40). Of the genetic alterations identified, 75% were truncating mutations. UTY copy number loss was detected in 8 male patients (22.8%, 8/35). Of the 9 male patients with UTX mutations, 6 also had copy number loss (66.7%). To evaluate the functional roles of UTX and UTY in tumor progression, we designed UTX and UTY single knockout and UTX-UTY double knockout experiments using a CRISPR/Cas9 lentiviral system, and compared the proliferative capacities of two UBC cell lines in vitro. Single UTX or UTY knockout increased cell proliferation as compared to UTX-UTY wild-type cells. UTX-UTY double knockout cells exhibited greater proliferation than single knockout cells. These findings suggest both UTX and UTY function as dose-dependent suppressors of UBC development. While UTX escapes X chromosome inactivation in females, UTY may function as a male homologue of UTX, which could compensate for dosage imbalances.

Intratumoral heterogeneity analysis reveals hidden associations between protein expression losses and patient survival in clear cell renal cell carcinoma

PubMed Central

Devarajan, Karthik; Parsons, Theodore; Wang, Qiong; O'Neill, Raymond; Solomides, Charalambos; Peiper, Stephen C.; Testa, Joseph R.; Uzzo, Robert; Yang, Haifeng

2017-01-01

Intratumoral heterogeneity (ITH) is a prominent feature of kidney cancer. It is not known whether it has utility in finding associations between protein expression and clinical parameters. We used ITH that is detected by immunohistochemistry (IHC) to aid the association analysis between the loss of SWI/SNF components and clinical parameters.160 ccRCC tumors (40 per tumor stage) were used to generate tissue microarray (TMA). Four foci from different regions of each tumor were selected. IHC was performed against PBRM1, ARID1A, SETD2, SMARCA4, and SMARCA2. Statistical analyses were performed to correlate biomarker losses with patho-clinical parameters. Categorical variables were compared between groups using Fisher's exact tests. Univariate and multivariable analyses were used to correlate biomarker changes and patient survivals. Multivariable analyses were performed by constructing decision trees using the classification and regression trees (CART) methodology. IHC detected widespread ITH in ccRCC tumors. The statistical analysis of the “Truncal loss” (root loss) found additional correlations between biomarker losses and tumor stages than the traditional “Loss in tumor (total)”. Losses of SMARCA4 or SMARCA2 significantly improved prognosis for overall survival (OS). Losses of PBRM1, ARID1A or SETD2 had the opposite effect. Thus “Truncal Loss” analysis revealed hidden links between protein losses and patient survival in ccRCC. PMID:28445125

Risk Factors for the Loss of Lean Body Mass After Gastrectomy for Gastric Cancer.

PubMed

Aoyama, Toru; Sato, Tsutomu; Segami, Kenki; Maezawa, Yukio; Kano, Kazuki; Kawabe, Taiichi; Fujikawa, Hirohito; Hayashi, Tsutomu; Yamada, Takanobu; Tsuchida, Kazuhito; Yukawa, Norio; Oshima, Takashi; Rino, Yasushi; Masuda, Munetaka; Ogata, Takashi; Cho, Haruhiko; Yoshikawa, Takaki

2016-06-01

Lean body mass loss after surgery, which decreases the compliance of adjuvant chemotherapy, is frequently observed in gastric cancer patients who undergo gastrectomy for gastric cancer. However, the risk factors for loss of lean body mass remain unclear. The current study retrospectively examined the patients who underwent curative gastrectomy for gastric cancer between June 2010 and March 2014 at Kanagawa Cancer Center. All the patients received perioperative care for enhanced recovery after surgery. The percentage of lean body mass loss was calculated by the percentile of lean body mass 1 month after surgery to preoperative lean body mass. Severe lean body mass loss was defined as a lean body mass loss greater than 5 %. Risk factors for severe lean body mass loss were determined by both uni- and multivariate logistic regression analyses. This study examined 485 patients. The median loss of lean body mass was 4.7 %. A lean body mass loss of 5 % or more occurred for 225 patients (46.4 %). Both uni- and multivariate logistic analyses demonstrated that the significant independent risk factors for severe lean body mass loss were surgical complications with infection or fasting (odds ratio [OR] 3.576; p = 0.001), total gastrectomy (OR 2.522; p = 0.0001), and gender (OR 1.928; p = 0.001). Nutritional intervention or control of surgical invasion should be tested in future clinical trials for gastric cancer patients with these risk factors to maintain lean body mass after gastrectomy.

The burden of mortality with costs in productivity loss from occupational cancer in Italy.

PubMed

Binazzi, Alessandra; Scarselli, Alberto; Marinaccio, Alessandro

2013-11-01

The costs of productivity loss due to occupational cancer mortality are rarely investigated. An estimate of occupational cancer deaths in Italy in 2006 and an approximation of the resultant costs from medical and non-medical expenditures together with figures of remuneration lost are provided. Occupational cancer deaths, obtained from the application of the attributable fraction (AF) to mortality data (source: Italian National Institute of Statistics), were used to calculate the Potential Years of Life Lost (PYLLs), the Potential Years of Working Life Lost (PYWLLs) and the costs of the loss of productive life. The health care costs for any cancer was applied to the estimated number of occupational cancer cases to obtain the total cost. Around 8,000-8,500 deaths/year from occupational cancer are estimated to occur in Italy, corresponding to 170,000 PYLLs and more than 16,000 PYWLLs, leading to around 360,000,000 euros in indirect economic loss. Health care costs of occupational cancer are estimated at 456,000,000 euros. Occupational cancer is of major concern in terms of mortality and economic productivity loss. Preventive efforts in evaluating ongoing risks and current exposures are strongly recommended to health policy-makers. Copyright © 2013 Wiley Periodicals, Inc.

Coping with losses, grief, and mourning in prostate cancer.

PubMed

Wittmann, Daniela

2015-01-01

Prostate cancer is a highly prevalent disease with a high likelihood of survival. If treated, survivors live with significant and lasting treatment-related side effects. Surgical treatment is associated with urinary incontinence and erectile dysfunction, and radiation leads to urinary and bowel irritability as well as erectile dysfunction. Patients who undergo hormonal treatment cope with sexual dysfunction, bone density loss, hot flashes, mood symptoms, and cardiac and metabolic disorders. Functional losses have a significant impact on patients and their partners' quality of life and are associated with distress and psychosocial morbidity. Psychosocial treatment is largely unavailable in usual care, but has been shown to reduce distress, to increase positive reappraisal of the illness, and to contribute to the recovery of sexual intimacy. Treatment for grief and mourning, typical reactions to loss, has not been introduced into psychosocial interventions but is increasingly recognized as a path toward a 'new normal' after prostate cancer treatment. © 2015 S. Karger AG, Basel.

Effect of weight loss on bone health in overweight/obese postmenopausal breast cancer survivors.

PubMed

Toriola, Adetunji T; Liu, Jingxia; Ganz, Patricia A; Colditz, Graham A; Yang, Lin; Izadi, Sonya; Naughton, Michael J; Schwartz, Anna L; Wolin, Kathleen Y

2015-08-01

Current guidelines recommend weight loss in obese cancer survivors. Weight loss, however, has adverse effects on bone health in obese individuals without cancer but this has not been evaluated in breast cancer survivors. We investigated the associations of intentional weight loss with bone mineral density (BMD) and bone turn-over markers in overweight/obese postmenopausal breast cancer survivors. Participants were overweight/obese breast cancer survivors (N = 81) with stage I, II or IIIA disease enrolled in the St. Louis site of a multi-site Exercise and Nutrition to Enhance Recovery and Good health for You (ENERGY) study; a randomized-controlled clinical trial designed to achieve a sustained ≥7 % loss in body weight at 2 years. Weight loss was achieved through dietary modification with the addition of physical activity. Generalized estimating equations were used to assess differences in mean values between follow-up and baseline. Mean weight decreased by 3 and 2.3 % between baseline and 6-month follow-up, and 12-month follow-up, respectively. There were decreases in osteocalcin (10.6 %, p value < 0.001), PINP (14.5 %, p value < 0.001), NTx (19.2 % p value < 0.001), and RANK (48.5 %, p value < 0.001), but not BALP and CTX-1 levels between baseline and 12-month follow-up. No significant changes occurred in mean T-scores, pelvis and lumbar spine BMD between baseline and 12-month follow-up. A 2.3 % weight loss over 12 months among overweight/obese women with early-stage breast cancer does not appear to have deleterious effect on bone health, and might even have beneficial effect. These findings warrant confirmation, particularly among breast cancer survivors with a larger magnitude of weight loss.

Stromal loss of TGFβ drives cancer growth in the epithelium via inflammation | Center for Cancer Research

Cancer.gov

Interactions between epithelial and stromal cells play an important role in cancer development and progression. Epithelial cancers develop when changes occur to tumor suppressor genes in stromal fibroblast cells. For example, loss of tumor suppressor, p53, in stromal fibroblasts leads to p53 inactivation in the epithelium in a prostate cancer model, and disruption of the

Identifying allelic loss and homozygous deletions in pancreatic cancer without matched normals using high-density single-nucleotide polymorphism arrays.

PubMed

Calhoun, Eric S; Hucl, Tomas; Gallmeier, Eike; West, Kristen M; Arking, Dan E; Maitra, Anirban; Iacobuzio-Donahue, Christine A; Chakravarti, Aravinda; Hruban, Ralph H; Kern, Scott E

2006-08-15

Recent advances in oligonucleotide arrays and whole-genome complexity reduction data analysis now permit the evaluation of tens of thousands of single-nucleotide polymorphisms simultaneously for a genome-wide analysis of allelic status. Using these arrays, we created high-resolution allelotype maps of 26 pancreatic cancer cell lines. The areas of heterozygosity implicitly served to reveal regions of allelic loss. The array-derived maps were verified by a panel of 317 microsatellite markers used in a subset of seven samples, showing a 97.1% concordance between heterozygous calls. Three matched tumor/normal pairs were used to estimate the false-negative and potential false-positive rates for identifying loss of heterozygosity: 3.6 regions (average minimal region of loss, 720,228 bp) and 2.3 regions (average heterozygous gap distance, 4,434,994 bp) per genome, respectively. Genomic fractional allelic loss calculations showed that cumulative levels of allelic loss ranged widely from 17.1% to 79.9% of the haploid genome length. Regional increases in "NoCall" frequencies combined with copy number loss estimates were used to identify 41 homozygous deletions (19 first reports), implicating an additional 13 regions disrupted in pancreatic cancer. Unexpectedly, 23 of these occurred in just two lines (BxPc3 and MiaPaCa2), suggesting the existence of at least two subclasses of chromosomal instability (CIN) patterns, distinguished here by allelic loss and copy number changes (original CIN) and those also highly enriched in the genomic "holes" of homozygous deletions (holey CIN). This study provides previously unavailable high-resolution allelotype and deletion breakpoint maps in widely shared pancreatic cancer cell lines and effectively eliminates the need for matched normal tissue to define informative loci.

Weight loss after head and neck cancer: A dynamic relationship with depressive symptoms.

PubMed

Van Liew, Julia R; Brock, Rebecca L; Christensen, Alan J; Karnell, Lucy Hynds; Pagedar, Nitin A; Funk, Gerry F

2017-02-01

Weight loss and depressive symptoms are critical head and neck cancer outcomes, yet their relation over the illness course is unclear. Associations between self-reported depressive symptoms and objective weight loss across the year after head and neck cancer diagnosis were examined using growth curve modeling techniques (n = 564). A reciprocal covariation pattern emerged-changes in depressive symptoms over time were associated with same-month changes in weight loss (t [1148] = 2.05; p = .041), and changes in weight loss were associated with same-month changes in depressive symptoms (t [556] = 2.43; p = .015). To the extent that depressive symptoms increased, patients lost incrementally more weight than was lost due to the passage of time and vice versa. Results also suggested that pain and eating-related quality of life might explain the reciprocal association between depressive symptoms and weight loss. In head and neck cancer, a transactional interplay between depressive symptoms and weight loss unfolds over time. © 2016 Wiley Periodicals, Inc. Head Neck 39: 370-379, 2017. © 2016 Wiley Periodicals, Inc.

Chromosome 3p allele loss in early invasive breast cancer: detailed mapping and association with clinicopathological features

PubMed Central

Martinez, A; Walker, R A; Shaw, J A; Dearing, S J; Maher, E R; Latif, F

2001-01-01

Aims—Chromosome 3p allele loss is a frequent event in many common sporadic cancers including lung, breast, kidney, ovarian, and head and neck cancer. To analyse the extent and frequency of 3p allelic losses in T1N0 and T1N1 invasive sporadic breast cancer, 19 microsatellite markers spread along 3p were analysed in 40 such breast carcinomas with known clinicopathological parameters. Methods—Loss of heterozygosity analysis was carried out using 3p microsatellite markers that were non-randomly distributed and chosen to represent regions that show hemizygous and/or homozygous losses in lung cancer (lung cancer tumour suppressor gene region 1 ( LCTSGR1) at 3p21.3 and LCTSGR2 at 3p12), and regions demonstrating suppression of tumorigenicity in breast, kidney, lung, and ovarian cancer. Results—Allelic loss was seen at one or more loci in 22 of these clinically early stage sporadic breast tumours, but none had complete 3p allele loss. Several regions with non-overlapping deletions were defined, namely: (1) 18 tumours showed loss at 3p21–22, a physical distance of 12 Mb; (2) 11 tumours showed loss at 3p12 within a physical distance of 1 Mb, this region is contained within LCTSGR2; (3) six tumours showed loss at 3p25–24, including the von Hippel-Lindau (VHL) locus; (4) five tumours showed loss at 3p14.2, including the fragile histidine triad (FHIT) locus. Conclusions—This is the largest study to date defining the extent and range of 3p allelic losses in early stage invasive breast cancer and the results indicate that region 3p21–22 containing LCTSGR1 and a region at 3p12 within LCTSGR2 are the most frequent sites of 3p allelic loss in these breast carcinomas. This suggests that tumour suppressor genes located in these regions may play important roles in the development of breast cancer. There was an association between increasing 3p allelic loss and increasing tumour grade and loss of progesterone (p = 0.0098) and oestrogen (p = 0.0472) receptor expression

Chromosome 3p allele loss in early invasive breast cancer: detailed mapping and association with clinicopathological features.

PubMed

Martinez, A; Walker, R A; Shaw, J A; Dearing, S J; Maher, E R; Latif, F

2001-10-01

Chromosome 3p allele loss is a frequent event in many common sporadic cancers including lung, breast, kidney, ovarian, and head and neck cancer. To analyse the extent and frequency of 3p allelic losses in T1N0 and T1N1 invasive sporadic breast cancer, 19 microsatellite markers spread along 3p were analysed in 40 such breast carcinomas with known clinicopathological parameters. Loss of heterozygosity analysis was carried out using 3p microsatellite markers that were non-randomly distributed and chosen to represent regions that show hemizygous and/or homozygous losses in lung cancer (lung cancer tumour suppressor gene region 1 ( LCTSGR1) at 3p21.3 and LCTSGR2 at 3p12), and regions demonstrating suppression of tumorigenicity in breast, kidney, lung, and ovarian cancer. Allelic loss was seen at one or more loci in 22 of these clinically early stage sporadic breast tumours, but none had complete 3p allele loss. Several regions with non-overlapping deletions were defined, namely: (1) 18 tumours showed loss at 3p21-22, a physical distance of 12 Mb; (2) 11 tumours showed loss at 3p12 within a physical distance of 1 Mb, this region is contained within LCTSGR2; (3) six tumours showed loss at 3p25-24, including the von Hippel-Lindau (VHL) locus; (4) five tumours showed loss at 3p14.2, including the fragile histidine triad (FHIT) locus. This is the largest study to date defining the extent and range of 3p allelic losses in early stage invasive breast cancer and the results indicate that region 3p21-22 containing LCTSGR1 and a region at 3p12 within LCTSGR2 are the most frequent sites of 3p allelic loss in these breast carcinomas. This suggests that tumour suppressor genes located in these regions may play important roles in the development of breast cancer. There was an association between increasing 3p allelic loss and increasing tumour grade and loss of progesterone (p = 0.0098) and oestrogen (p = 0.0472) receptor expression, indicating a link between 3p allelic loss and the

A comparison of cancer burden and research spending reveals discrepancies in the distribution of research funding.

PubMed

Carter, Ashley J R; Nguyen, Cecine N

2012-07-17

Ideally, the distribution of research funding for different types of cancer should be equitable with respect to the societal burden each type of cancer imposes. These burdens can be estimated in a variety of ways; "Years of Life Lost" (YLL) measures the severity of death in regard to the age it occurs, "Disability-Adjusted Life-Years" (DALY) estimates the effects of non-lethal disabilities incurred by disease and economic metrics focus on the losses to tax revenue, productivity or direct medical expenses. We compared research funding from the National Cancer Institute (NCI) to a variety of burden metrics for the most common types of cancer to identify mismatches between spending and societal burden. Research funding levels were obtained from the NCI website and information for societal health and economic burdens were collected from government databases and published reports. We calculated the funding levels per unit burden for a wide range of different cancers and burden metrics and compared these values to identify discrepancies. Our analysis reveals a considerable mismatch between funding levels and burden. Some cancers are funded at levels far higher than their relative burden suggests (breast cancer, prostate cancer, and leukemia) while other cancers appear underfunded (bladder, esophageal, liver, oral, pancreatic, stomach, and uterine cancers). These discrepancies indicate that an improved method of health care research funding allocation should be investigated to better match funding levels to societal burden.

Stromal loss of TGFβ drives cancer growth in the epithelium via inflammation | Center for Cancer Research

Cancer.gov

Interactions between epithelial and stromal cells play an important role in cancer development and progression. Epithelial cancers develop when changes occur to tumor suppressor genes in stromal fibroblast cells. For example, loss of tumor suppressor, p53, in stromal fibroblasts leads to p53 inactivation in the epithelium in a prostate cancer model, and disruption of the transforming growth factor-b receptor II (TGF-βRII) in stromal fibroblasts results in intraepithelial dysplasia in prostate cancer and invasive squamous cell carcinoma (SCC) in mouse forestomach.

The cancer anorexia/weight loss syndrome: exploring associations with single nucleotide polymorphisms (SNPs) of inflammatory cytokines in patients with non-small cell lung cancer.

PubMed

Jatoi, Aminah; Qi, Yingwei; Kendall, Glenda; Jiang, Ruoxiang; McNallan, Sheila; Cunningham, Julie; Mandrekar, Sumithra; Yang, Ping

2010-10-01

The cancer anorexia/weight loss syndrome commonly occurs in patients with non-small cell lung cancer (NSCLC) and is characterized by loss of weight and appetite as well as diminished survival. The current study explored whether any of 22 single nucleotide polymorphisms (SNPs) of certain previously implicated inflammatory cytokines (interleukin-1 beta, interleukin-1RN, interleukin-6, and tumor necrosis factor) are associated with this syndrome. All NSCLC patients who had been enrolled in the Mayo Clinic Lung Cancer Cohort, had completed a health-related questionnaire approximately 6 months after enrollment, and had blood drawn were included in this study, thus yielding a sample size of 471 patients. Sixty-six (14%) patients manifested weight loss shortly after diagnosis, and 152 (32%) reported appetite loss. Only tumor necrosis factor alpha rs800629 was associated with anorexia (odds ratio: 0.46; 95% confidence interval: 0.29, 0.72; p < 0.001); patients who were heterozygous and minor homozygous were less likely to suffer anorexia. Otherwise, there were no statistically significant associations between any of the other 21 SNPs and weight loss and/or anorexia. In univariate analyses, weight loss, anorexia, more advanced cancer stage, and interleukin-1 beta rs1143627 were associated with a worse survival, and interleukin-6 rs2069835 was associated with better survival. However, in multivariate analyses, cancer stage and patient age were the only statistically significant predictors of worse survival. No specific SNP was associated with all aspects of the cancer anorexia/weight loss syndrome, but rs800629 may merit further study in cancer-associated anorexia.

A negative genetic interaction map in isogenic cancer cell lines reveals cancer cell vulnerabilities

PubMed Central

Vizeacoumar, Franco J; Arnold, Roland; Vizeacoumar, Frederick S; Chandrashekhar, Megha; Buzina, Alla; Young, Jordan T F; Kwan, Julian H M; Sayad, Azin; Mero, Patricia; Lawo, Steffen; Tanaka, Hiromasa; Brown, Kevin R; Baryshnikova, Anastasia; Mak, Anthony B; Fedyshyn, Yaroslav; Wang, Yadong; Brito, Glauber C; Kasimer, Dahlia; Makhnevych, Taras; Ketela, Troy; Datti, Alessandro; Babu, Mohan; Emili, Andrew; Pelletier, Laurence; Wrana, Jeff; Wainberg, Zev; Kim, Philip M; Rottapel, Robert; O'Brien, Catherine A; Andrews, Brenda; Boone, Charles; Moffat, Jason

2013-01-01

Improved efforts are necessary to define the functional product of cancer mutations currently being revealed through large-scale sequencing efforts. Using genome-scale pooled shRNA screening technology, we mapped negative genetic interactions across a set of isogenic cancer cell lines and confirmed hundreds of these interactions in orthogonal co-culture competition assays to generate a high-confidence genetic interaction network of differentially essential or differential essentiality (DiE) genes. The network uncovered examples of conserved genetic interactions, densely connected functional modules derived from comparative genomics with model systems data, functions for uncharacterized genes in the human genome and targetable vulnerabilities. Finally, we demonstrate a general applicability of DiE gene signatures in determining genetic dependencies of other non-isogenic cancer cell lines. For example, the PTEN−/− DiE genes reveal a signature that can preferentially classify PTEN-dependent genotypes across a series of non-isogenic cell lines derived from the breast, pancreas and ovarian cancers. Our reference network suggests that many cancer vulnerabilities remain to be discovered through systematic derivation of a network of differentially essential genes in an isogenic cancer cell model. PMID:24104479

A comparison of cancer burden and research spending reveals discrepancies in the distribution of research funding

PubMed Central

2012-01-01

Background Ideally, the distribution of research funding for different types of cancer should be equitable with respect to the societal burden each type of cancer imposes. These burdens can be estimated in a variety of ways; “Years of Life Lost” (YLL) measures the severity of death in regard to the age it occurs, "Disability-Adjusted Life-Years" (DALY) estimates the effects of non-lethal disabilities incurred by disease and economic metrics focus on the losses to tax revenue, productivity or direct medical expenses. We compared research funding from the National Cancer Institute (NCI) to a variety of burden metrics for the most common types of cancer to identify mismatches between spending and societal burden. Methods Research funding levels were obtained from the NCI website and information for societal health and economic burdens were collected from government databases and published reports. We calculated the funding levels per unit burden for a wide range of different cancers and burden metrics and compared these values to identify discrepancies. Results Our analysis reveals a considerable mismatch between funding levels and burden. Some cancers are funded at levels far higher than their relative burden suggests (breast cancer, prostate cancer, and leukemia) while other cancers appear underfunded (bladder, esophageal, liver, oral, pancreatic, stomach, and uterine cancers). Conclusions These discrepancies indicate that an improved method of health care research funding allocation should be investigated to better match funding levels to societal burden. PMID:22800364

The cancer anorexia/weight loss syndrome: exploring associations with single nucleotide polymorphisms (SNPs) of inflammatory cytokines in patients with non-small cell lung cancer

PubMed Central

Jatoi, Aminah; Qi, Yingwei; Kendall, Glenda; Jiang, Ruoxiang; McNallan, Sheila; Cunningham, Julie; Mandrekar, Sumithra; Yang, Ping

2010-01-01

Objective The cancer anorexia/weight loss syndrome commonly occurs in patients with non-small cell lung cancer (NSCLC) and is characterized by loss of weight and appetite as well as diminished survival. The current study explored whether any of 22 single nucleotide polymorphisms (SNPs) of certain previously implicated inflammatory cytokines (interleukin-1 beta, interleukin-1RN, interleukin-6, and tumor necrosis factor) are associated with this syndrome. Patients and Methods All NSCLC patients who had been enrolled in the Mayo Clinic Lung Cancer Cohort, had completed a health-related questionnaire approximately 6 months after enrollment, and had blood drawn were included in this study, thus yielding a sample size of 471 patients. Results Sixty-six (14%) patients manifested weight loss shortly after diagnosis, and 152 (32%) reported appetite loss. Only tumor necrosis factor alpha rs800629 was associated with anorexia (odds ratio: 0.46; 95% confidence interval: 0.29, 0.72; p<0.001); patients who were heterozygous and minor homozygous were less likely to suffer anorexia. Otherwise, there were no statistically significant associations between any of the other 21 SNPs and weight loss and/or anorexia. In univariate analyses, weight loss, anorexia, more advanced cancer stage, and interleukin-1 beta rs1143627 were associated with a worse survival, and interleukin-6 rs2069835 was associated with better survival. However, in multivariate analyses, cancer stage and patient age were the only statistically significant predictors of worse survival. Conclusion No specific SNP was associated with all aspects of the cancer anorexia/weight loss syndrome, but rs800629 may merit further study in cancer-associated anorexia. PMID:20012999

Breast Cancer Epidemiology of the Working-Age Female Population Reveals Significant Implications for the South Korean Economy.

PubMed

Park, Jeong Hyun; Lee, Se Kyung; Lee, Jeong Eon; Kim, Seok Won; Nam, Seok Jin; Kim, Ji-Yeon; Ahn, Jin-Seok; Park, Won; Yu, Jonghan; Park, Yeon Hee

2018-03-01

In this study, we aimed to evaluate the economic loss due to the diagnosis of breast cancer within the female South Korean working-age population. A population-based cost analysis was performed for cancer-related diagnoses between 1999 and 2014, using respective public government funded databases. Among the five most common cancers, breast cancer mortality was strongly associated with the growth in gross domestic product between 1999 and 2014 (R=0.98). In the female population, breast cancer represented the greatest productivity loss among all cancers, which was a consequence of the peak in the incidence of breast cancer during mid-working age in the working-age population, in addition to being the most common and fastest growing cancer among South Korean women. Our study shows that breast cancer not only represents a significant disease burden for individual patients, but also contributes a real, nonnegligible loss in productivity in the South Korean economy.

Exome sequencing of a colorectal cancer family reveals shared mutation pattern and predisposition circuitry along tumor pathways.

PubMed

Suleiman, Suleiman H; Koko, Mahmoud E; Nasir, Wafaa H; Elfateh, Ommnyiah; Elgizouli, Ubai K; Abdallah, Mohammed O E; Alfarouk, Khalid O; Hussain, Ayman; Faisal, Shima; Ibrahim, Fathelrahamn M A; Romano, Maurizio; Sultan, Ali; Banks, Lawrence; Newport, Melanie; Baralle, Francesco; Elhassan, Ahmed M; Mohamed, Hiba S; Ibrahim, Muntaser E

2015-01-01

The molecular basis of cancer and cancer multiple phenotypes are not yet fully understood. Next Generation Sequencing promises new insight into the role of genetic interactions in shaping the complexity of cancer. Aiming to outline the differences in mutation patterns between familial colorectal cancer cases and controls we analyzed whole exomes of cancer tissues and control samples from an extended colorectal cancer pedigree, providing one of the first data sets of exome sequencing of cancer in an African population against a background of large effective size typically with excess of variants. Tumors showed hMSH2 loss of function SNV consistent with Lynch syndrome. Sets of genes harboring insertions-deletions in tumor tissues revealed, however, significant GO enrichment, a feature that was not seen in control samples, suggesting that ordered insertions-deletions are central to tumorigenesis in this type of cancer. Network analysis identified multiple hub genes of centrality. ELAVL1/HuR showed remarkable centrality, interacting specially with genes harboring non-synonymous SNVs thus reinforcing the proposition of targeted mutagenesis in cancer pathways. A likely explanation to such mutation pattern is DNA/RNA editing, suggested here by nucleotide transition-to-transversion ratio that significantly departed from expected values (p-value 5e-6). NFKB1 also showed significant centrality along with ELAVL1, raising the suspicion of viral etiology given the known interaction between oncogenic viruses and these proteins.

[Chronic otitis and hearing loss revealing a disseminated tuberculosis in a child].

PubMed

See, H; Aubertin, G; Angoulvant, F; Baculard, F; Soussan, V; Bourrillon, A; Faye, A

2006-09-01

Ear localization is sometimes the first symptom of tuberculosis. We report a case of a teen with a chronic otitis revealing a disseminated tuberculosis. The investigations showed ear, bones and pulmonary localisations. The outcome with treatment showed a persistent hearing loss. Middle ear tuberculosis should be suspected in patients with chronic otitis and risk factors of tuberculosis. A disseminated tuberculosis should be investigated and an early treatment is necessary to prevent hearing loss.

Smad4 loss promotes lung cancer formation but increases sensitivity to DNA topoisomerase inhibitors

PubMed Central

Kalra, Sean; Cleaver, Timothy G.; Merrick, Daniel; Wang, Xiao-Jing; Malkoski, Stephen P.

2015-01-01

Non-small cell lung cancer (NSCLC) is a common malignancy with a poor prognosis. Despite progress targeting oncogenic drivers, there are no therapies targeting tumor suppressor loss. Smad4 is an established tumor suppressor in pancreatic and colon cancer, however, the consequences of Smad4 loss in lung cancer are largely unknown. We evaluated Smad4 expression in human NSCLC samples and examined Smad4 alterations in large NSCLC datasets and found that reduced Smad4 expression is common in human NSCLC and occurs through a variety of mechanisms including mutation, homozygous deletion, and heterozygous loss. We modeled Smad4 loss in lung cancer by deleting Smad4 in airway epithelial cells and found that Smad4 deletion both initiates and promotes lung tumor development. Interestingly, both Smad4−/− mouse tumors and human NSCLC samples with reduced Smad4 expression demonstrated increased DNA damage while Smad4 knockdown in lung cancer cells reduced DNA repair and increased apoptosis after DNA damage. In addition, Smad4 deficient NSCLC cells demonstrated increased sensitivity to both chemotherapeutics that inhibit DNA topoisomerase and drugs that block double strand DNA break repair by non-homologous end joining. In sum, these studies establish Smad4 as a lung tumor suppressor and suggest that the defective DNA repair phenotype of Smad4 deficient tumors can be exploited by specific therapeutic strategies. PMID:25893305

Cancer treatment-induced bone loss in premenopausal women: a need for therapeutic intervention?

PubMed

Hadji, P; Gnant, M; Body, J J; Bundred, N J; Brufsky, A; Coleman, R E; Guise, T A; Lipton, A; Aapro, M S

2012-10-01

Current clinical treatment guidelines recommend cytotoxic chemotherapy, endocrine therapy, or both (with targeted therapy if indicated) for premenopausal women with early-stage breast cancer, depending on the biologic characteristics of the primary tumor. Some of these therapies can induce premature menopause or are specifically designed to suppress ovarian function and reduce circulating estrogen levels. In addition to bone loss associated with low estrogen levels, cytotoxic chemotherapy may have a direct negative effect on bone metabolism. As a result, cancer treatment-induced bone loss poses a significant threat to bone health in premenopausal women with breast cancer. Clinical trials of antiresorptive therapies, such as bisphosphonates, have demonstrated the ability to slow or prevent bone loss in this setting. Current fracture risk assessment tools are based on data from healthy postmenopausal women and do not adequately address the risks associated with breast cancer therapy, especially in younger premenopausal women. We therefore recommend that all premenopausal women with breast cancer be informed about the potential risk of bone loss prior to beginning anticancer therapy. Women who experience amenorrhea should have bone mineral density assessed by dual-energy X-ray absorptiometry and receive regular follow-up to monitor bone health. Regular exercise and daily calcium and vitamin D supplementation are recommended. Women with a Z-score <-2.0 or Z-score ≤-1.0 and/or a 5-10% annual decrease in bone mineral density should be considered for bisphosphonate therapy in addition to calcium and vitamin D supplements. Copyright © 2012 Elsevier Ltd. All rights reserved.

A Review of the Relationship between Tooth Loss, Periodontal Disease, and Cancer

PubMed Central

Meyer, Mara S.; Joshipura, Kaumudi; Giovannucci, Edward; Michaud, Dominique S.

2009-01-01

Recent studies have investigated the association between periodontal disease, tooth loss, and several systemic diseases including cancer, cardiovascular disease, and preterm birth. Periodontal disease, a chronic inflammatory condition, is highly prevalent in adult populations around the world, and may be preventable. Estimates of prevalence vary between races and geographic regions, with a marked increase in the occurrence of periodontal disease with advancing age. Worldwide estimates for the prevalence of severe periodontal disease generally range from 10 to 15 percent. The relationship between oral health and cancer has been examined for a number of specific cancer sites. Several studies have reported associations between periodontal disease or tooth loss and risk of oral, upper gastrointestinal, lung, and pancreatic cancer in different populations. In a number of studies, these associations persisted after adjustment for major risk factors, including cigarette smoking and socioeconomic status. This review provides a summary of these findings, discusses possible biological mechanisms involved, and raises methodological issues related to studying these relationships. PMID:18478344

A review of the relationship between tooth loss, periodontal disease, and cancer.

PubMed

Meyer, Mara S; Joshipura, Kaumudi; Giovannucci, Edward; Michaud, Dominique S

2008-11-01

Recent studies have investigated the association between periodontal disease, tooth loss, and several systemic diseases including cancer, cardiovascular disease, and preterm birth. Periodontal disease, a chronic inflammatory condition, is highly prevalent in adult populations around the world, and may be preventable. Estimates of prevalence vary between races and geographic regions, with a marked increase in the occurrence of periodontal disease with advancing age. Worldwide estimates for the prevalence of severe periodontal disease generally range from 10 to 15%. The relationship between oral health and cancer has been examined for a number of specific cancer sites. Several studies have reported associations between periodontal disease or tooth loss and risk of oral, upper gastrointestinal, lung, and pancreatic cancer in different populations. In a number of studies, these associations persisted after adjustment for major risk factors, including cigarette smoking and socioeconomic status. This review provides a summary of these findings, discusses possible biological mechanisms involved, and raises methodological issues related to studying these relationships.

A cannabinoid 2 receptor agonist attenuates bone cancer-induced pain and bone loss

PubMed Central

Lozano, Alysia; Wright, Courtney; Vardanyan, Anna; King, Tamara; Largent-Milnes, Tally M.; Nelson, Mark; Jimenez-Andrade, Juan Miguel; Mantyh, Patrick W; Vanderah, Todd W.

2010-01-01

Aims Cannabinoid CB2 agonists have been shown to alleviate behavioral signs of inflammatory and neuropathic pain in animal models. AM1241, a CB2 agonist, does not demonstrate central nervous system side-effects seen with CB1 agonists such as hypothermia and catalepsy. Metastatic bone cancer causes severe pain in patients and is treated with analgesics such as opiates. Recent reports suggest that sustained opiates can produce paradoxical hyperalgesic actions and enhance bone destruction in a murine model of bone cancer. In contrast, CB2 selective agonists have been shown to reduce bone loss associated with a model of osteoporosis. Here we tested whether a CB2 agonist administered over a 7 day period inhibits bone cancer-induced pain as well as attenuates cancer-induced bone degradation. Main Methods A murine bone cancer model was used in which osteolytic sarcoma cells were injected into the intramedullary space of the distal end of the femur. Behavioral and radiographic image analysis was performed at days 7, 10 and 14 after injection of tumor cells into the femur. Key Findings Osteolytic sarcoma within the femur produced spontaneous and touch evoked behavioral signs of pain within the tumor-bearing limb. The systemic administration of AM1241 acutely or for 7 days significantly attenuated spontaneous and evoked pain in the inoculated limb. Sustained AM1241 significantly reduced bone loss and decreased the incidence of cancer-induced bone fractures. Significance These findings suggest a novel therapy for cancer-induced bone pain, bone loss and bone fracture while lacking many unwanted side effects seen with current treatments for bone cancer pain. PMID:20176037

Long-term weight loss after colorectal cancer diagnosis is associated with lower survival: The Colon Cancer Family Registry.

PubMed

Kocarnik, Jonathan M; Hua, Xinwei; Hardikar, Sheetal; Robinson, Jamaica; Lindor, Noralane M; Win, Aung Ko; Hopper, John L; Figueiredo, Jane C; Potter, John D; Campbell, Peter T; Gallinger, Steven; Cotterchio, Michelle; Adams, Scott V; Cohen, Stacey A; Phipps, Amanda I; Newcomb, Polly A

2017-12-01

Body weight is associated with colorectal cancer (CRC) risk and survival, but to the authors' knowledge, the impact of long-term postdiagnostic weight change is unclear. Herein, the authors investigated whether weight change over the 5 years after a diagnosis of CRC is associated with survival. CRC cases diagnosed from 1997 to 2008 were identified through 4 population-based cancer registry sites. Participants enrolled within 2 years of diagnosis and reported their height and weight 2 years prior. Follow-up questionnaires were administered approximately 5 years after diagnosis. Associations between change in weight (in kg) or body mass index (BMI) with overall and CRC-specific survival were estimated using Cox regression analysis adjusted for age, sex, American Joint Committee on Cancer stage of disease, baseline BMI, nonsteroidal anti-inflammatory drug use, smoking, time between diagnosis and enrollment, and study site. At the 5-year postdiagnostic survey, 2049 participants reported higher (53%; median plus 5 kg), unchanged (12%), or lower (35%; median -4 kg) weight. Over a median of 5.1 years of subsequent follow-up (range, 0.3-9.9 years), 344 participants died (91 of CRC). Long-term weight loss (per 5 kg) was found to be associated with poorer overall survival (hazard ratio, 1.13; 95% confidence interval, 1.07-1.21) and CRC-specific survival (hazard ratio, 1.25; 95% confidence interval, 1.13-1.39). Significantly lower survival was similarly observed for relative weight loss (>5% vs ≤5% change), BMI reduction (per 1 unit), or BMI category change (overweight to normal vs remaining overweight). Weight loss 5 years after a diagnosis of CRC was found to be significantly associated with decreased long-term survival, suggesting the importance of avoiding weight loss in survivors of CRC. Future research should attempt to further evaluate this association, accounting for whether this weight change was intentional or represents a marker of declining health. Cancer 2017

Prediction model of critical weight loss in cancer patients during particle therapy.

PubMed

Zhang, Zhihong; Zhu, Yu; Zhang, Lijuan; Wang, Ziying; Wan, Hongwei

2018-01-01

The objective of this study is to investigate the predictors of critical weight loss in cancer patients receiving particle therapy, and build a prediction model based on its predictive factors. Patients receiving particle therapy were enroled between June 2015 and June 2016. Body weight was measured at the start and end of particle therapy. Association between critical weight loss (defined as >5%) during particle therapy and patients' demographic, clinical characteristic, pre-therapeutic nutrition risk screening (NRS 2002) and BMI were evaluated by logistic regression and decision tree analysis. Finally, 375 cancer patients receiving particle therapy were included. Mean weight loss was 0.55 kg, and 11.5% of patients experienced critical weight loss during particle therapy. The main predictors of critical weight loss during particle therapy were head and neck tumour location, total radiation dose ≥70 Gy on the primary tumour, and without post-surgery, as indicated by both logistic regression and decision tree analysis. Prediction model that includes tumour locations, total radiation dose and post-surgery had a good predictive ability, with the area under receiver operating characteristic curve 0.79 (95% CI: 0.71-0.88) and 0.78 (95% CI: 0.69-0.86) for decision tree and logistic regression model, respectively. Cancer patients with head and neck tumour location, total radiation dose ≥70 Gy and without post-surgery were at higher risk of critical weight loss during particle therapy, and early intensive nutrition counselling or intervention should be target at this population. © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Weight loss and quality of life in patients surviving 2 years after gastric cancer resection.

PubMed

Climent, M; Munarriz, M; Blazeby, J M; Dorcaratto, D; Ramón, J M; Carrera, M J; Fontane, L; Grande, L; Pera, M

2017-07-01

Malnutrition is common in patients undergoing gastric cancer resection, leading to weight loss, although little is known about how this impacts on health-related quality of life (HRQL). This study aimed to explore the association between HRQL and weight loss in patients 2 years after curative gastric cancer resection. Consecutive patients undergoing curative gastric cancer resection and surviving at least 2 years without disease recurrence were recruited. Patients completed the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and the specific module for gastric cancer (STO22) before and 2 years postoperatively and associations between HRQL scores and patients with and without ≥ 10% body weight loss (BWL) were examined. A total of 76 patients were included, of whom 51 (67%) had BWL ≥10%. At 2 years postoperatively, BWL ≥10% was associated with deterioration of all functional aspects of quality of life, with persistent pain (21.6%), diarrhoea (13.7%) and nausea/vomiting (13.7%). By contrast, none of the patients with BWL <10% experienced severe nausea/vomiting, pain or diarrhoea. Disabling symptoms occurred more frequently in patients with ≥10% BWL than in those with <10% BWL, with a relevant negative impact on HRQL. A cause-effect relationship between weight loss and postoperative outcome remains unsolved. Copyright © 2017 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

Exome sequencing of a colorectal cancer family reveals shared mutation pattern and predisposition circuitry along tumor pathways

PubMed Central

Suleiman, Suleiman H.; Koko, Mahmoud E.; Nasir, Wafaa H.; Elfateh, Ommnyiah; Elgizouli, Ubai K.; Abdallah, Mohammed O. E.; Alfarouk, Khalid O.; Hussain, Ayman; Faisal, Shima; Ibrahim, Fathelrahamn M. A.; Romano, Maurizio; Sultan, Ali; Banks, Lawrence; Newport, Melanie; Baralle, Francesco; Elhassan, Ahmed M.; Mohamed, Hiba S.; Ibrahim, Muntaser E.

2015-01-01

The molecular basis of cancer and cancer multiple phenotypes are not yet fully understood. Next Generation Sequencing promises new insight into the role of genetic interactions in shaping the complexity of cancer. Aiming to outline the differences in mutation patterns between familial colorectal cancer cases and controls we analyzed whole exomes of cancer tissues and control samples from an extended colorectal cancer pedigree, providing one of the first data sets of exome sequencing of cancer in an African population against a background of large effective size typically with excess of variants. Tumors showed hMSH2 loss of function SNV consistent with Lynch syndrome. Sets of genes harboring insertions–deletions in tumor tissues revealed, however, significant GO enrichment, a feature that was not seen in control samples, suggesting that ordered insertions–deletions are central to tumorigenesis in this type of cancer. Network analysis identified multiple hub genes of centrality. ELAVL1/HuR showed remarkable centrality, interacting specially with genes harboring non-synonymous SNVs thus reinforcing the proposition of targeted mutagenesis in cancer pathways. A likely explanation to such mutation pattern is DNA/RNA editing, suggested here by nucleotide transition-to-transversion ratio that significantly departed from expected values (p-value 5e-6). NFKB1 also showed significant centrality along with ELAVL1, raising the suspicion of viral etiology given the known interaction between oncogenic viruses and these proteins. PMID:26442106

The loss of a mother and dealing with genetic cancer risk: women who have undergone prophylactic removal of the ovaries.

PubMed

Mæland, Marie Kvamme; Eriksen, Elin Overaa; Synnes, Oddgeir

2014-10-01

The purpose of this article is to highlight some new findings from a qualitative study that have not been previously considered. The research was based on a qualitative phenomenological method. Data were collected by semi-structured individual interviews. A purposeful sample was recruited from West Norway of 14 women with a possible risk of developing breast and ovarian cancer. Data collection took place at least one year after prophylactic removal of the ovaries. Data from the study was analyzed according to the phenomenological method of Amedeo Giorgi. Two themes were revealed as essential factors of the interviewed women's experiences: "the loss of a mother" and "dealing with genetic cancer risk." For the most part, these two themes also appeared to be interrelated. When a mother died of ovarian cancer while her daughter was a child or a young woman, this often led to her daughter's strong desire to find an explanation for her mother's death, as well as to her efforts to undergo genetic testing and surgery to prevent cancer in her family in the future. The study indicates that women's experiences in families at risk of hereditary cancer are closely related to an understanding of their life stories, particularly their "loss of a mother," and how this influences how they deal with genetic cancer risk. Health care workers can thus help patients identify connections and establish coherence through the act of storytelling, by listening to their illness experiences as part of their life stories. Copyright © 2014 Elsevier Ltd. All rights reserved.

CHARACTERIZATION OF A LOSS OF HETEROZYGOSITY CANCER HAZARD IDENTIFICATION ASSAY.

EPA Science Inventory

Tumor development generally requires the loss of heterozygosity (LOH) at one or more loci. Thus, the ability to determine whether a chemical is capable of causing LOH is an important part of cancer hazard identification. The mouse lymphoma assay detects a broad spectrum of geneti...

Improvement of metabolism among obese breast cancer survivors in differing weight loss regimens.

PubMed

Jen, K-L Catherine; Djuric, Zora; DiLaura, Nora M; Buison, Anne; Redd, Jennifer N; Maranci, Vera; Hryniuk, William M

2004-02-01

To compare the efficacy of different weight loss regimens on body weight loss and metabolic improvement in breast cancer survivors. Forty-eight obese breast cancer survivors were randomly divided into four groups and were followed for 1 year: 1) the Control group (subjects did not receive specific nutrition counseling); 2) the Weight Watchers group (subjects were given free coupons to attend weekly Weight Watchers meetings); 3) the Individualized group (a registered dietitian provided one-on-one nutritional counseling); and 4) the Comprehensive group (subjects received individualized dietary counseling and free coupons for the weekly Weight Watchers meetings). At baseline and 3-, 6-, and 12-month data collection visits, a fasting blood sample was obtained for assays. A three-day dietary record was kept during the week before these visits and dietary intake was analyzed. Subjects in the three intervention groups lost weight (Control: 1.1 +/- 1.7 kg; Weight Watchers: -2.7 +/- 2.1 kg; Individualized: -8.0 +/- 1.9 kg; Comprehensive: -9.5 +/- 2.7 kg) and percentage body fat, but only the Individualized and Comprehensive groups had significant losses. Subjects in the Comprehensive group showed the most improvement in cholesterol levels and had reductions in blood leptin levels. Because insulin resistance and high blood leptin levels are associated with breast cancer, losing weight to improve these parameters may reduce the risk of recurrence. Only subjects in the Comprehensive group showed significant reductions in body weight and fat, energy intake, and leptin levels. For breast cancer survivors, different weight loss strategies should be considered to assist them in losing weight.

Exclusion from spheroid formation identifies loss of essential cell-cell adhesion molecules in colon cancer cells.

PubMed

Stadler, Mira; Scherzer, Martin; Walter, Stefanie; Holzner, Silvio; Pudelko, Karoline; Riedl, Angelika; Unger, Christine; Kramer, Nina; Weil, Beatrix; Neesen, Jürgen; Hengstschläger, Markus; Dolznig, Helmut

2018-01-18

Many cell lines derived from solid cancers can form spheroids, which recapitulate tumor cell clusters and are more representative of the in vivo situation than 2D cultures. During spheroid formation, a small proportion of a variety of different colon cancer cell lines did not integrate into the sphere and lost cell-cell adhesion properties. An enrichment protocol was developed to augment the proportion of these cells to 100% purity. The basis for the separation of spheroids from non-spheroid forming (NSF) cells is simple gravity-sedimentation. This protocol gives rise to sub-populations of colon cancer cells with stable loss of cell-cell adhesion. SW620 cells lacked E-cadherin, DLD-1 cells lost α-catenin and HCT116 cells lacked P-cadherin in the NSF state. Knockdown of these molecules in the corresponding spheroid-forming cells demonstrated that loss of the respective proteins were indeed responsible for the NSF phenotypes. Loss of the spheroid forming phenotype was associated with increased migration and invasion properties in all cell lines tested. Hence, we identified critical molecules involved in spheroid formation in different cancer cell lines. We present here a simple, powerful and broadly applicable method to generate new sublines of tumor cell lines to study loss of cell-cell adhesion in cancer progression.

Contribution of macrophages in the contrast loss in iron oxide-based MRI cancer cell tracking studies

PubMed Central

Danhier, Pierre; Deumer, Gladys; Joudiou, Nicolas; Bouzin, Caroline; Levêque, Philippe; Haufroid, Vincent; Jordan, Bénédicte F.; Feron, Olivier; Sonveaux, Pierre; Gallez, Bernard

2017-01-01

Magnetic resonance imaging (MRI) cell tracking of cancer cells labeled with superparamagnetic iron oxides (SPIO) allows visualizing metastatic cells in preclinical models. However, previous works showed that the signal void induced by SPIO on T2(*)-weighted images decreased over time. Here, we aim at characterizing the fate of iron oxide nanoparticles used in cell tracking studies and the role of macrophages in SPIO metabolism. In vivo MRI cell tracking of SPIO positive 4T1 breast cancer cells revealed a quick loss of T2* contrast after injection. We next took advantage of electron paramagnetic resonance (EPR) spectroscopy and inductively coupled plasma mass spectroscopy (ICP-MS) for characterizing the evolution of superparamagnetic and non-superparamagnetic iron pools in 4T1 breast cancer cells and J774 macrophages after SPIO labeling. These in vitro experiments and histology studies performed on 4T1 tumors highlighted the quick degradation of iron oxides by macrophages in SPIO-based cell tracking experiments. In conclusion, the release of SPIO by dying cancer cells and the subsequent uptake of iron oxides by tumor macrophages are limiting factors in MRI cell tracking experiments that plead for the use of (MR) reporter-gene based imaging methods for the long-term tracking of metastatic cells. PMID:28467814

Loss of imprinting of IGF2 and the epigenetic progenitor model of cancer

PubMed Central

Leick, Mark B; Shoff, Christopher J; Wang, Erwin C; Congress, Jaclyn L; Gallicano, G Ian

2012-01-01

Among the hypotheses discussing cancer formation, the cancer stem cell (CSC) theory is one receiving widespread support. One version of this theory states that changes in otherwise healthy cells can cause formation of tumor- initiating cells (TICs), which have the potential to create precancerous stem cells that can lead to CSC formation. These CSCs can be rare, in contrast to their differentiated progeny, which give rise to the vast majority of the tumor mass in most cancers. Loss of imprinting (LOI) of the insulin-like growth factor-2 (IGF2) gene is one change that can produce these TICs via an epigenetic progenitor model of tumorigenesis. While IGF2 usually supports normal cellular growth, LOI of IGF2 may lead to overexpression of the gene and moreover global chromatin instability. This modification has been observed in many forms of cancer, and given the effect of LOI of IGF2 and its role in cancer, detecting a loss of imprinting in this gene could serve as a valuable diagnostic tool. Preclinical data has shown some progress in identifying therapeutic approaches seeking to exploit this relationship. Thus, further research surrounding LOI of IGF2 could lead to increased understanding of several cancer types and enhance therapies against these diseases. PMID:23671798

Association between raf kinase inhibitor protein loss and prognosis in cancers of the digestive system: a meta-analysis.

PubMed

Yu, Min; Wang, Qian; Ding, Jiang-Wu; Yang, Zhen; Xie, Chuan; Lu, Nong-Hua

2014-01-01

Loss of Raf kinase inhibitor protein (RKIP) may contribute to metastasis in a variety of human cancers. Many studies have evaluated whether loss of RKIP expression is a prognostic factor for survival in cancers of the digestive system, however, its predictive value remains controversial. Thus, we performed a meta-analysis to obtain a more comprehensive estimate of the prognostic value of RKIP expression in digestive system cancers. Studies were identified by searching multiple electronic databases through December 12, 2013, and by reviewing reference lists of obtained articles. Studies reported hazard ratios (HRs) with 95% confidence intervals (CIs) for the association between RKIP and overall survival (OS) and disease-free survival (DFS) in cancers of the digestive system were eligible, including esophageal cancer, gastric cancer, colorectal cancer and pancreatic cancer. Nineteen studies involving approximately 3700 participants were included in the final analysis. The pooled results suggested that loss of RKIP expression was associated with unfavorable OS (HR 0.55, 95% CI 0.46-0.65) and DFS (HR 0.46, 95% CI 0.30-0.62) among patients with digestive system cancers, whereas the difference was not statistically significant in pancreatic cancer specifically (OS, HR 0.76; 95% CI 0.51-1.01; DFS, HR 0.71; 95% CI 0.28-1.13). Loss of RKIP expression might be an independent indicator of poor prognosis in patients with digestive tract cancers, which includes esophageal cancer, gastric cancer and colorectal cancer. More studies are needed to further clarify the prognostic value of RKIP in pancreatic cancer. Future studies, preferably large prospective studies utilizing formal marker assessment processes, are needed to establish the prognostic value of RKIP before these results can be clinically applied.

Loss of function JAK1 mutations occur at high frequency in cancers with microsatellite instability and are suggestive of immune evasion.

PubMed

Albacker, Lee A; Wu, Jeremy; Smith, Peter; Warmuth, Markus; Stephens, Philip J; Zhu, Ping; Yu, Lihua; Chmielecki, Juliann

2017-01-01

Immune evasion is a well-recognized hallmark of cancer and recent studies with immunotherapy agents have suggested that tumors with increased numbers of neoantigens elicit greater immune responses. We hypothesized that the immune system presents a common selective pressure on high mutation burden tumors and therefore immune evasion mutations would be enriched in high mutation burden tumors. The JAK family of kinases is required for the signaling of a host of immune modulators in tumor, stromal, and immune cells. Therefore, we analyzed alterations in this family for the hypothesized signature of an immune evasion mutation. Here, we searched a database of 61,704 unique solid tumors for alterations in the JAK family kinases (JAK1/2/3, TYK2). We used The Cancer Genome Atlas and Cancer Cell Line Encyclopedia data to confirm and extend our findings by analyzing gene expression patterns. Recurrent frameshift mutations in JAK1 were associated with high mutation burden and microsatellite instability. These mutations occurred in multiple tumor types including endometrial, colorectal, stomach, and prostate carcinomas. Analyzing gene expression signatures in endometrial and stomach adenocarcinomas revealed that tumors with a JAK1 frameshift exhibited reduced expression of interferon response signatures and multiple anti-tumor immune signatures. Importantly, endometrial cancer cell lines exhibited similar gene expression changes that were expected to be tumor cell intrinsic (e.g. interferon response) but not those expected to be tumor cell extrinsic (e.g. NK cells). From these data, we derive two primary conclusions: 1) JAK1 frameshifts are loss of function alterations that represent a potential pan-cancer adaptation to immune responses against tumors with microsatellite instability; 2) The mechanism by which JAK1 loss of function contributes to tumor immune evasion is likely associated with loss of the JAK1-mediated interferon response.

Quantitative Proteomic Profiling of Prostate Cancer Reveals a Role for miR-128 in Prostate Cancer*

PubMed Central

Khan, Amjad P.; Poisson, Laila M.; Bhat, Vadiraja B.; Fermin, Damian; Zhao, Rong; Kalyana-Sundaram, Shanker; Michailidis, George; Nesvizhskii, Alexey I.; Omenn, Gilbert S.; Chinnaiyan, Arul M.; Sreekumar, Arun

2010-01-01

Multiple, complex molecular events characterize cancer development and progression. Deciphering the molecular networks that distinguish organ-confined disease from metastatic disease may lead to the identification of biomarkers of cancer invasion and disease aggressiveness. Although alterations in gene expression have been extensively quantified during neoplastic progression, complementary analyses of proteomic changes have been limited. Here we interrogate the proteomic alterations in a cohort of 15 prostate-derived tissues that included five each from adjacent benign prostate, clinically localized prostate cancer, and metastatic disease from distant sites. The experimental strategy couples isobaric tags for relative and absolute quantitation with multidimensional liquid phase peptide fractionation followed by tandem mass spectrometry. Over 1000 proteins were quantified across the specimens and delineated into clinically localized and metastatic prostate cancer-specific signatures. Included in these class-specific profiles were both proteins that were known to be dysregulated during prostate cancer progression and new ones defined by this study. Enrichment analysis of the prostate cancer-specific proteomic signature, to gain insight into the functional consequences of these alterations, revealed involvement of miR-128-a/b regulation during prostate cancer progression. This finding was validated using real time PCR analysis for microRNA transcript levels in an independent set of 15 clinical specimens. miR-128 levels were elevated in benign prostate epithelial cell lines compared with invasive prostate cancer cells. Knockdown of miR-128 induced invasion in benign prostate epithelial cells, whereas its overexpression attenuated invasion in prostate cancer cells. Taken together, our profiles of the proteomic alterations of prostate cancer progression revealed miR-128 as a potentially important negative regulator of prostate cancer cell invasion. PMID:19955085

Diet quality of breast cancer survivors after a six-month weight management intervention: Improvements and association with weight loss

PubMed Central

Christifano, Danielle N.; Fazzino, Tera L.; Sullivan, Debra A.; Befort, Christie A.

2016-01-01

Purpose Obesity and diet quality are two distinct lifestyle factors associated with morbidity and mortality among breast cancer survivors. The purpose of this study was to examine diet quality changes during a weight loss intervention among breast cancer survivors, and whether diet quality change was an important factor related to weight loss. Methods Participants were overweight/obese breast cancer survivors (n=180) participating in a weight loss intervention. Diet quality scores were calculated using the Healthy Eating Index-2010. Paired sample t-tests were run to examine change in diet quality, and a latent difference model was constructed to examine whether change in diet quality was associated with weight change. Results Participants significantly improved diet quality (p=.001) and lost 13.2%± 5.8% (mean± SD) of their weight (p=.001). Six month HEI score was significantly associated with weight loss, controlling for baseline BMI (p=.003). Improvement in diet quality was also significantly associated with weight loss (p=.01). Conclusion Our findings indicate that a weight loss intervention can result in both clinically significant weight loss and improvement in diet quality, and that improved diet quality is predictive of weight loss. Both weight loss and diet quality are implicated in longevity and quality of life for breast cancer survivors. PMID:27635676

Potential Biomarkers of Fat Loss as a Feature of Cancer Cachexia.

PubMed

Ebadi, Maryam; Mazurak, Vera C

2015-01-01

Fat loss is associated with shorter survival and reduced quality of life in cancer patients. Effective intervention for fat loss in cachexia requires identification of the condition using prognostic biomarkers for early detection and prevention of further depletion. No biomarkers of fat mass alterations have been defined for application to the neoplastic state. Several inflammatory cytokines have been implicated in mediating fat loss associated with cachexia; however, plasma levels may not relate to adipose atrophy. Zinc-α2-glycoprotein may be a local catabolic mediator within adipose tissue rather than serving as a plasma biomarker of fat loss. Plasma glycerol and leptin associate with adipose tissue atrophy and mass, respectively; however, no study has evaluated their potential as a prognostic biomarker of cachexia-associated fat loss. This review confirms the need for further studies to identify valid prognostic biomarkers to identify loss of fat based on changes in plasma levels of biomarkers.

Loss of PTEN expression is associated with aggressive behavior and poor prognosis in Middle Eastern triple-negative breast cancer.

PubMed

Beg, Shaham; Siraj, Abdul K; Prabhakaran, Sarita; Jehan, Zeenath; Ajarim, Dahish; Al-Dayel, Fouad; Tulbah, Asma; Al-Kuraya, Khawla S

2015-06-01

PTEN is a tumor suppressor that negatively regulates the PI3 K-AKT signaling pathway which is involved in the pathogenesis of many different tumor types and serves as a prognostic marker in breast cancer. However, the significance of the role of PTEN in Middle Eastern ethnic breast cancer has not been explored especially with the fact that breast cancer originating from this ethnic population tend to behave more aggressively than breast cancer in the west. In this study, we analyzed PTEN alteration in a tissue microarray format containing more than 1000 primary breast cancers with clinical follow-up data. Tissue Microarray sections were analyzed for protein expression and copy number change using immunohistochemistry and fluorescence in situ hybridization. Loss of PTEN immunostaining was observed in 77 % of the cases. PTEN loss was significantly associated with large tumor size (p = 0.0030), high grade (p = 0.0281), tumor recurrence (p = 0.0333), and triple-negative breast cancers (p = 0.0086). PTEN loss in triple-negative breast cancers was significantly associated with rapid tumor cell proliferation (p = 0.0396) and poor prognosis (p = 0.0408). PTEN deletion was found only in 60 cases (6.4 %). Loss of PTEN protein expression occurs at high frequency in Middle Eastern breast cancer. PTEN inactivation may potentially lead to an aggressive behavior of tumor cells through stimulation of tumor cell proliferation. Furthermore, PTEN signaling pathway might be used as potential therapeutic target in triple-negative breast cancers since loss of its expression is shown to be significantly associated with this aggressive subtype of breast cancer.

Presurgical weight loss affects tumour traits and circulating biomarkers in men with prostate cancer

PubMed Central

Demark-Wahnefried, Wendy; Rais-Bahrami, Soroush; Desmond, Renee A; Gordetsky, Jennifer B; Hunter, Gary R; Yang, Eddy S; Azrad, Maria; Frugé, Andrew D; Tsuruta, Yuko; Norian, Lyse A; Segal, Roanne; Grizzle, William E

2017-01-01

Background: Obesity is associated with aggressive prostate cancer. To explore whether weight loss favourably affects tumour biology and other outcomes, we undertook a presurgical trial among overweight and obese men with prostate cancer. Methods: This single-blinded, two-arm randomised controlled trial explored outcomes of a presurgical weight loss intervention (WLI) that promoted ∼1 kg per week loss via caloric restriction and increased physical activity (PA). Forty overweight/obese men with clinically confirmed prostate cancer were randomised to the WLI presurgery or to a control arm; changes in weight, body composition, quality-of-life, circulating biomarkers, gene expression, and immunohistochemical markers in tumour and benign prostatic tissue were evaluated. Results: The study period averaged 50 days. Mean (s.d.) change scores for the WLI vs control arms were as follows: weight: −4.7 (3.1) kg vs −2.2 (4.4) kg (P=0.0508); caloric intake: −500 (636) vs −159 (600) kcal per day (P=0.0034); PA: +0.9 (3.1) vs +1.7 (4.6) MET-hours per day (NS); vitality: +5.3 (7.l4) vs −1.8 (8.1) (P=0.0491); testosterone: +55.1 (86.0) vs −48.3 (203.7) ng dl−1 (P=0.0418); sex hormone-binding globulin: +14.0 (14.6) vs +1.8 (7.6) nmol l−1 (P=0.0023); and leptin: −2.16 (2.6) vs −0.03 (3.75) (P=0.0355). Follow-up Ki67 was significantly higher in WLI vs control arms; median (interquartile range): 5.0 (2.5,10.0) vs 0.0 (0.0,2.5) (P=0.0061) and several genes were upregulated, for example, CTSL, GSK3B, MED12, and LAMC2. Conclusions: Intentional weight loss shows mixed effects on circulating biomarkers, tumour gene expression, and proliferative markers. More study is needed before recommending weight loss, in particular rapid weight loss, among men with prostate cancer. PMID:28881355

Trespassing cancer cells: 'fingerprinting' invasive protrusions reveals metastatic culprits.

PubMed

Klemke, Richard L

2012-10-01

Metastatic cancer cells produce invasive membrane protrusions called invadopodia and pseudopodia, which play a central role in driving cancer cell dissemination in the body. Malignant cells use these structures to attach to and degrade extracellular matrix proteins, generate force for cell locomotion, and to penetrate the vasculature. Recent work using unique subcellular fractionation methodologies combined with spatial genomic, proteomic, and phosphoproteomic profiling has provided insight into the invadopodiome and pseudopodiome signaling networks that control the protrusion of invasive membranes. Here I highlight how these powerful spatial 'omics' approaches reveal important signatures of metastatic cancer cells and possible new therapeutic targets aimed at treating metastatic disease. Copyright © 2012 Elsevier Ltd. All rights reserved.

Loss of DNA Mismatch Repair Protein hMSH6 in Ovarian Cancer is Histotype-Specific

PubMed Central

Zhai, Qihui “Jim”; Rosen, Daniel Gustavo; Lu, Karen; Liu, Jinsong

2008-01-01

Microsatellite instability (MSI) due to defects in DNA mismatch repair genes may be involved in the development of a subset of human ovarian carcinomas. The role of one such gene, hMSH6, in ovarian cancer is not well documented. We investigated the expression of hMSH6 protein in different histotypes of ovarian carcinoma and the associations between loss of hMSH6 protein and tumor grade, disease stage, familial history of cancer and patient survival. We stained an ovarian carcinoma tissue microarray consisting of formalin-fixed, paraffin-embedded tissue samples from 322 patients with an anti-hMSH6 antibody and scored the results semiquantitatively as negative or positive. Twelve cases were excluded owing to loss of cores during staining. Absence of hMSH6 protein was noted in 20 of 230 serous carcinomas (8.7%), in 7 of 16 clear cell carcinomas (43.7%), in 4 of 34 endometrioid carcinomas (11.7%), in 1 of 14 malignant mixed Müllerian tumors, 2 of 6 mucinous carcinomas, 0 of 2 transitional cell carcinomas and in 0 of 8 undifferentiated carcinomas. Loss of hMSH6 protein was not associated with survival, patient age, tumor grade, or disease stage but was associated with clear cell, mucinous and endometrioid carcinoma histology (P<0.007). These findings indicate that loss of hMSH6 expression in ovarian carcinoma is more common in certain histologic subtypes, particularly in clear cell, endometrioid, and mucinous carcinoma, suggesting that loss of hMSH6 function may participate in the pathogenesis of these subtypes of cancer. Loss of hMSH6 expression did not predict survival and was not associated with disease stage, tumor grade, patient age or family history of cancer. PMID:18787632

Return to work in sick-listed cancer survivors with job loss: design of a randomised controlled trial.

PubMed

van Egmond, Martine P; Duijts, Saskia F A; Vermeulen, Sylvia J; van der Beek, Allard J; Anema, Johannes R

2015-02-18

Despite long-term or permanent health problems, cancer survivors are often motivated to return to work. For cancer survivors who have lost their job, return to work can be more challenging compared to employed survivors, as they generally find themselves in a more vulnerable social and financial position. Cancer survivors with job loss may therefore be in need of tailored return to work support. However, there is a lack of return to work intervention programs specifically targeting these cancer survivors. The number of cancer survivors with job loss in developed countries is rising due to, amongst others, increases in the incidence and survivor rate of cancer, the retirement age and the proportion of flexible employment contracts. Hence, we consider it important to develop a tailored return to work intervention program for cancer survivors with job loss, and to evaluate its effectiveness compared to usual care. This study employs a two-armed randomised controlled trial with a follow-up period of 12 months. The study population (n = 164) will be recruited from a national sample of cancer survivors (18-60 years), who have been sick-listed for 12-36 months. Participants will be randomised by using computerized blocked randomisation (blocks of four). All participants will receive usual care as provided by the Dutch Social Security Agency. Additionally, participants in the intervention group will receive a tailored return to work intervention program, which includes vocational rehabilitation and supportive psychosocial components, as well as (therapeutic) placement at work. The primary outcome measure is duration until sustainable return to work; the secondary outcome measure is rate of return to work. Other parameters include, amongst others, fatigue, coping strategy and quality of life. We will perform Cox regression analyses to estimate hazard ratios for time to sustainable return to work. The hypothesis of this study is that a tailored approach for cancer

The applicability of a weight loss grading system in cancer cachexia: a longitudinal analysis.

PubMed

Vagnildhaug, Ola Magne; Blum, David; Wilcock, Andrew; Fayers, Peter; Strasser, Florian; Baracos, Vickie E; Hjermstad, Marianne J; Kaasa, Stein; Laird, Barry; Solheim, Tora S

2017-10-01

A body mass index (BMI) adjusted weight loss grading system (WLGS) is related to survival in patients with cancer. The aim of this study was to examine the applicability of the WLGS by confirming its prognostic validity, evaluating its relationship to cachexia domains, and exploring its ability to predict cachexia progression. An international, prospective observational study of patients with incurable cancer was conducted. For each patient, weight loss grade was scored 0-4. Weight loss grade 0 represents a high BMI with limited weight loss, progressing through to weight loss grade 4 representing low BMI and a high degree of weight loss. Survival analyses were used to confirm prognostic validity. Analyses of variance were used to evaluate the relationship between the WLGS and cachexia domains [anorexia, dietary intake, Karnofsky performance status (KPS), and physical and emotional functioning]. Cox regression was used to evaluate if the addition of cachexia domains to the WLGS improved prognostic accuracy. Predictive ability of cachexia progression was assessed by estimating proportion of patients progressing to a more advanced weight loss grade. One thousand four hundred six patients were analysed (median age 66 years; 50% female, 63% KPS ≤ 70). The overall effect of the WLGS on survival was significant as expressed by change in -2 log likelihood (P < 0.001) and persisted after adjustment for age, sex, and cancer type and stage (P < 0.001). Median survival decreased across the weight loss grades ranging from 407 days (95% CI 312-502)-weight loss grade 0 to 119 days (95% CI 93-145)-weight loss grade 4. All cachexia domains significantly deteriorated with increasing weight loss grade, and deterioration was greatest for dietary intake, with a difference corresponding to 0.87 standard deviations between weight loss grades 0 and 4. The addition of KPS, anorexia, and physical and emotional functioning improved the prognostic accuracy of the WLGS. Likelihood of

Progressive Loss of the Orexin Neurons Reveals Dual Effects on Wakefulness

PubMed Central

Branch, Abigail F.; Navidi, William; Tabuchi, Sawako; Terao, Akira; Yamanaka, Akihiro; Scammell, Thomas E.; Diniz Behn, Cecilia

2016-01-01

Study Objectives: Narcolepsy is caused by loss of the orexin (also known as hypocretin) neurons. In addition to the orexin peptides, these neurons release additional neurotransmitters, which may produce complex effects on sleep/wake behavior. Currently, it remains unknown whether the orexin neurons promote the initiation as well as the maintenance of wakefulness, and whether the orexin neurons influence initiation or maintenance of sleep. To determine the effects of the orexin neurons on the dynamics of sleep/wake behavior, we analyzed sleep/wake architecture in a novel mouse model of acute orexin neuron loss. Methods: We used survival analysis and other statistical methods to analyze sleep/wake architecture in orexin-tTA ; TetO diphtheria toxin A mice at different stages of orexin neuron degeneration. Results: Progressive loss of the orexin neurons dramatically reduced survival of long wake bouts, but it also improved survival of brief wake bouts. In addition, with loss of the orexin neurons, mice were more likely to wake during the first 30 sec of nonrapid eye movement sleep and then less likely to return to sleep during the first 60 sec of wakefulness. Conclusions: These findings help explain the sleepiness and fragmented sleep that are characteristic of narcolepsy. Orexin neuron loss impairs survival of long wake bouts resulting in poor maintenance of wakefulness, but this neuronal loss also fragments sleep by increasing the risk of awakening at the beginning of sleep and then reducing the likelihood of quickly returning to sleep. Citation: Branch AF, Navidi W, Tabuchi S, Terao A, Yamanaka A, Scammell TE, Diniz Behn C. Progressive loss of the orexin neurons reveals dual effects on wakefulness. SLEEP 2016;39(2):369–377. PMID:26446125

LKB1 loss promotes endometrial cancer progression via CCL2-dependent macrophage recruitment.

PubMed

Peña, Christopher G; Nakada, Yuji; Saatcioglu, Hatice D; Aloisio, Gina M; Cuevas, Ileana; Zhang, Song; Miller, David S; Lea, Jayanthi S; Wong, Kwok-Kin; DeBerardinis, Ralph J; Amelio, Antonio L; Brekken, Rolf A; Castrillon, Diego H

2015-11-02

Endometrial cancer is the most common gynecologic malignancy and the fourth most common malignancy in women. For most patients in whom the disease is confined to the uterus, treatment results in successful remission; however, there are no curative treatments for tumors that have progressed beyond the uterus. The serine/threonine kinase LKB1 has been identified as a potent suppressor of uterine cancer, but the biological modes of action of LKB1 in this context remain incompletely understood. Here, we have shown that LKB1 suppresses tumor progression by altering gene expression in the tumor microenvironment. We determined that LKB1 inactivation results in abnormal, cell-autonomous production of the inflammatory cytokine chemokine (C-C motif) ligand 2 (CCL2) within tumors, which leads to increased recruitment of macrophages with prominent tumor-promoting activities. Inactivation of Ccl2 in an Lkb1-driven mouse model of endometrial cancer slowed tumor progression and increased survival. In human primary endometrial cancers, loss of LKB1 protein was strongly associated with increased CCL2 expression by tumor cells as well as increased macrophage density in the tumor microenvironment. These data demonstrate that CCL2 is a potent effector of LKB1 loss in endometrial cancer, creating potential avenues for therapeutic opportunities.

TET2 binds the androgen receptor and loss is associated with prostate cancer

PubMed Central

Nickerson, ML; Das, S; Im, KM; Turan, S; Berndt, SI; Li, H; Lou, H; Brodie, SA; Billaud, JN; Zhang, T; Bouk, AJ; Butcher, D; Wang, Z; Sun, L; Misner, K; Tan, W; Esnakula, A; Esposito, D; Huang, WY; Hoover, RN; Tucker, MA; Keller, JR; Boland, J; Brown, K; Anderson, SK; Moore, LE; Isaacs, WB; Chanock, SJ; Yeager, M; Dean, M; Andresson, T

2016-01-01

Genetic alterations associated with prostate cancer (PCa) may be identified by sequencing metastatic tumor genomes to identify molecular markers at this lethal stage of disease. Previously, we characterized somatic alterations in metastatic tumors in the methylcytosine dioxygenase ten-eleven translocation 2 (TET2), which is altered in 5–15% of myeloid, kidney, colon and prostate cancers. Genome-wide association studies previously identified non-coding risk variants associated with PCa and melanoma. We performed fine-mapping of PCa risk across TET2 using genotypes from the PEGASUS case-control cohort and identified six new risk variants in introns 1 and 2. Oligonucleotides containing two risk variants were bound by the transcription factor octamer-binding protein 1 (Oct1/POU2F1) and TET2 and Oct1 expression were positively correlated in prostate tumors. TET2 is expressed in normal prostate tissue and reduced in a subset of tumors from the Cancer Genome Atlas (TCGA). Small interfering RNA (siRNA)-mediated TET2 knockdown (KD) increases LNCaP cell proliferation, migration, and wound healing, verifying loss drives a cancer phenotype. Endogenous TET2 bound the androgen receptor (AR) and AR-coactivator proteins in LNCaP cell extracts, and TET2 KD increases prostate-specific antigen (KLK3/PSA) expression. Published data reveal TET2 binding sites and hydroxymethylcytosine (hmC) proximal to KLK3. A gene co-expression network identified using TCGA prostate tumor RNA-sequencing identifies co-regulated cancer genes associated with 2-oxoglutarate (2-OG) and succinate metabolism, including TET2, lysine demethylase (KDM) KDM6A, BRCA1-associated BAP1, and citric acid cycle enzymes IDH1/2, SDHA/B, and FH. The co-expression signature is conserved across 31 TCGA cancers suggesting a putative role for TET2 as an energy sensor (of 2-OG) that modifies aspects of androgen-AR signaling. Decreased TET2 mRNA expression in TCGA PCa tumors is strongly associated with reduced patient survival

Beliefs about weight and breast cancer: an interview study with high risk women following a 12 month weight loss intervention.

PubMed

Wright, Claire E; Harvie, Michelle; Howell, Anthony; Evans, D Gareth; Hulbert-Williams, Nick; Donnelly, Louise S

2015-01-01

Breast cancer is the most common cancer in the UK. Lifestyle factors including excess weight contribute to risk of developing the disease. Whilst the exact links between weight and breast cancer are still emerging, it is imperative to explore how women understand these links and if these beliefs impact on successful behaviour change. Overweight/obese premenopausal women (aged 35-45) with a family history of breast cancer (lifetime risk 17-40%) were invited to a semi-structured interview following their participation in a 12 month weight loss intervention aimed at reducing their risk of breast cancer. Interviews were carried out with 9 women who successfully achieved ≥5% weight loss and 11 who were unsuccessful. Data were transcribed verbatim and analysed using thematic analysis. Three themes were developed from the analysis. The first theme how women construct and understand links between weight and breast cancer risk is composed of two subthemes, the construction of weight and breast cancer risk and making sense of weight and breast cancer risk. This theme explores women's understanding of what contributes to breast cancer risk and whether they believe that weight loss could reduce their breast cancer risk. The second theme motivation and adherence to weight loss interventions explains that breast cancer risk can be a motivating factor for adherence to a weight loss intervention. The final theme, acceptance of personal responsibility for health is composed of two subthemes responsibility for one's own health and responsibility for family health through making sensible lifestyle choices. Beliefs about weight and breast cancer risk were informed by social networks, media reports and personal experiences of significant others diagnosed with breast cancer. Our study has highlighted common doubts, anxieties and questions and the importance of providing a credible rationale for weight control and weight loss which addresses individual concerns. Counselling and health

Infrequent Loss of Luminal Differentiation in Ductal Breast Cancer Metastasis

PubMed Central

Calvo, Julia; Sánchez-Cid, Lourdes; Muñoz, Montserrat; Lozano, Juan José; Thomson, Timothy M.; Fernández, Pedro L.

2013-01-01

Lymph node involvement is a major prognostic variable in breast cancer. Whether the molecular mechanisms that drive breast cancer cells to colonize lymph nodes are shared with their capacity to form distant metastases is yet to be established. In a transcriptomic survey aimed at identifying molecular factors associated with lymph node involvement of ductal breast cancer, we found that luminal differentiation, assessed by the expression of estrogen receptor (ER) and/or progesterone receptor (PR) and GATA3, was only infrequently lost in node-positive primary tumors and in matched lymph node metastases. The transcription factor GATA3 critically determines luminal lineage specification of mammary epithelium and is widely considered a tumor and metastasis suppressor in breast cancer. Strong expression of GATA3 and ER in a majority of primary node-positive ductal breast cancer was corroborated by quantitative RT-PCR and immunohistochemistry in the initial sample set, and by immunohistochemistry in an additional set from 167 patients diagnosed of node-negative and –positive primary infiltrating ductal breast cancer, including 102 samples from loco-regional lymph node metastases matched to their primary tumors, as well as 37 distant metastases. These observations suggest that loss of luminal differentiation is not a major factor driving the ability of breast cancer cells to colonize regional lymph nodes. PMID:24205108

Assessing pathophysiology of cancer anorexia.

PubMed

Laviano, Alessandro; Koverech, Angela; Seelaender, Marilia

2017-09-01

Cancer anorexia is a negative prognostic factor and is broadly defined as the loss of the interest in food. However, multiple clinical domains contribute to the phenotype of cancer anorexia. The characterization of the clinical and molecular pathophysiology of cancer anorexia may enhance the efficacy of preventive and therapeutic strategies. Clinical trials showed that cancer anorexia should be considered as an umbrella encompassing different signs and symptoms contributing to appetite disruption in cancer patients. Loss of appetite, early satiety, changes in taste and smell are determinants of cancer anorexia, whose presence should be assessed in cancer patients. Interestingly, neuronal correlates of cancer anorexia-related symptoms have been revealed by brain imaging techniques. The pathophysiology of cancer anorexia is complex and involves different domains influencing eating behavior. Limiting the assessment of cancer anorexia to questions investigating changes in appetite may impede correct identification of the targets to address.

Acute loss of TET function results in aggressive myeloid cancer in mice

PubMed Central

An, Jungeun; González-Avalos, Edahí; Chawla, Ashu; Jeong, Mira; López-Moyado, Isaac F.; Li, Wei; Goodell, Margaret A.; Chavez, Lukas; Ko, Myunggon; Rao, Anjana

2015-01-01

TET-family dioxygenases oxidize 5-methylcytosine (5mC) in DNA, and exert tumour suppressor activity in many types of cancers. Even in the absence of TET coding region mutations, TET loss-of-function is strongly associated with cancer. Here we show that acute elimination of TET function induces the rapid development of an aggressive, fully-penetrant and cell-autonomous myeloid leukaemia in mice, pointing to a causative role for TET loss-of-function in this myeloid malignancy. Phenotypic and transcriptional profiling shows aberrant differentiation of haematopoietic stem/progenitor cells, impaired erythroid and lymphoid differentiation and strong skewing to the myeloid lineage, with only a mild relation to changes in DNA modification. We also observe progressive accumulation of phospho-H2AX and strong impairment of DNA damage repair pathways, suggesting a key role for TET proteins in maintaining genome integrity. PMID:26607761

Cooperativity Between Oncogenic PKC Epsilon and Pten Loss in Prostate Cancer Progression

DTIC Science & Technology

2015-10-01

AWARD NUMBER: W81XWH-14-1-0535 TITLE: “Cooperativity Between Oncogenic PKC Epsilon and Pten Loss in Prostate Cancer Progression” PRINCIPAL...3. DATES COVERED 30 Sep 2014 - 29 Sep 2015 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Cooperativity Between Oncogenic PKC Epsilon and Pten Loss in...the s-econd leadi.ng caus.e of cmcer-related deaths .unong wen in thee United States. Protein kinase C epsilon (PKCs), a me-mber of the PKC £uuily

Clinical outcomes and contributors to weight loss in a cancer cachexia clinic.

PubMed

Del Fabbro, Egidio; Hui, David; Dalal, Shalini; Dev, Rony; Nooruddin, Zohra I; Noorhuddin, Zohra; Bruera, Eduardo

2011-09-01

Cancer cachexia is considered intractable, with few therapeutic options. Secondary nutrition impact symptoms (S-NIS) such as nausea may further contribute to weight loss by decreasing nutrient intake. In addition, treatable metabolic abnormalities such as hypogonadism, vitamin B12 deficiency, hypothyroidism, and hypoadrenalism could exacerbate anorexia and muscle wasting in patients with cancer cachexia. We determined the frequency and type of contributors to appetite and weight loss, and the effect of the cachexia clinic on clinical outcomes. Review of 151 consecutive patients referred to a cachexia clinic. All received dietary counseling and exercise recommendations. Assessments included weight, body mass index (BMI), S-NIS, resting energy expenditure by indirect calorimetry, serum thyroid stimulating hormone (TSH), cortisol, total testosterone, and vitamin B12. Median weight loss in the 100 days before referral was 9% (4%-13%); median BMI at presentation was 20.8. Median number of S-NIS was 3 (2-4), most commonly treated by metoclopramide, laxatives, and antidepressants. Forty-one percent (24/59) of patients were hypermetabolic and 73% (52/71) of males hypogonadic, whereas hypoadrenalism (0/101, 0%), hypothyroidism (4/113, 4%), and low vitamin B12 (3/107, 3%) were uncommon. Poor appetite and weight loss before referral (r = 0.18, p = 0.036) were associated with increased S-NIS (r = 0.22, p = 0.008). Appetite improved (p < 0.001) and 31/92 (34%) of patients returning for a second visit gained weight. Patients had a high frequency of multiple S-NIS, hypogonadism, and hypermetabolism. A combination of simple pharmacological and nonpharmacological interventions improved appetite significantly, and increased weight in one third of patients who were able to return for follow-up. Cachexia clinics are feasible and effective for many patients with advanced cancer.

Site-to-site interdomain communication may mediate different loss-of-function mechanisms in a cancer-associated NQO1 polymorphism

NASA Astrophysics Data System (ADS)

Medina-Carmona, Encarnación; Neira, Jose L.; Salido, Eduardo; Fuchs, Julian E.; Palomino-Morales, Rogelio; Timson, David J.; Pey, Angel L.

2017-03-01

Disease associated genetic variations often cause intracellular enzyme inactivation, dysregulation and instability. However, allosteric communication of mutational effects to distant functional sites leading to loss-of-function remains poorly understood. We characterize here interdomain site-to-site communication by which a common cancer-associated single nucleotide polymorphism (c.C609T/p.P187S) reduces the activity and stability in vivo of NAD(P)H:quinone oxidoreductase 1 (NQO1). NQO1 is a FAD-dependent, two-domain multifunctional stress protein acting as a Phase II enzyme, activating cancer pro-drugs and stabilizing p53 and p73α oncosuppressors. We show that p.P187S causes structural and dynamic changes communicated to functional sites far from the mutated site, affecting the FAD binding site located at the N-terminal domain (NTD) and accelerating proteasomal degradation through dynamic effects on the C-terminal domain (CTD). Structural protein:protein interaction studies reveal that the cancer-associated polymorphism does not abolish the interaction with p73α, indicating that oncosuppressor destabilization largely mirrors the low intracellular stability of p.P187S. In conclusion, we show how a single disease associated amino acid change may allosterically perturb several functional sites in an oligomeric and multidomain protein. These results have important implications for the understanding of loss-of-function genetic diseases and the identification of novel structural hot spots as targets for pharmacological intervention.

[Responsibility for the loss of opportunity in malignant cancer care in the Spanish public healthcare system].

PubMed

Sardinero-García, Carlos; Santiago-Sáez, Andrés; Bravo, M Del Carmen; Perea-Pérez, Bernardo; Albarrán-Juan, M Elena; Labajo-González, Elena; Benito-León, Julián

The loss of chance in healthcare has been forcibly introduced in the adjudications pronounced in recent years. Our objective was to analyse the verdicts of guilt resulting from the loss of chance ordered by the Contentious-Administrative Court (i.e., in the public healthcare system), in which both the origin of the disease to be treated and the sequelae were oncological processes. We analysed 137 cancer-related court judgments from the Contentious-Administrative Court, which referred to the concept of loss of chance, issued in Spain up to May 2014. Of the 137 sentences, 119 (86.9%), were pronounced due to diagnostic error and 14 (10.2%) due to inadequate treatment. Since 2010, 100 sentences have been passed (73.0%), representing an increase of more than 170% with respect to the 37 (27.0%) ordered in the first six years of the study (from 2004 to 2009). Most of the patients (68.6%) died, predominantly from breast cancer and gynaecological cancer (24.1%), and gastrointestinal cancers (21.1%). These malignancies were the ones most often involved in the sentences. The litigant activity due to loss of chance in oncological processes in the public health care has significantly increased in the last years. The judgments were mainly given because of diagnostic error or inadequate treatment. Copyright © 2016 SESPAS. Publicado por Elsevier España, S.L.U. All rights reserved.

Periodontal disease, tooth loss, and cancer risk in male health professionals: a prospective cohort study.

PubMed

Michaud, Dominique S; Liu, Yan; Meyer, Mara; Giovannucci, Edward; Joshipura, Kaumudi

2008-06-01

Studies suggest that tooth loss and periodontal disease might increase the risk of developing various cancers; however, smoking might have confounded the reported associations. We aimed to assess whether periodontal disease or tooth loss is associated with cancer risk. The analysis was done in a prospective study (the Health Professionals Follow-Up Study [HPFS]), which was initiated in 1986 when US male health professionals aged 40-75 years responded to questionnaires posted by the Department of Nutrition, Harvard University School of Public Health, Boston, MA, USA. In addition to the baseline questionnaires, follow-up questionnaires were posted to all living participants every 2 years and dietary questionnaires every 4 years. At baseline, participants were asked whether they had a history of periodontal disease with bone loss. Participants also reported number of natural teeth at baseline and any tooth loss during the previous 2 years was reported on the follow-up questionnaires. Smoking status and history of smoking were obtained at baseline and in all subsequent questionnaires. Additionally at baseline, participants reported their mean frequency of food intake over the previous year on a 131-item semiquantitative food-frequency questionnaire. Participants reported any new cancer diagnosis on the follow-up questionnaires. Endpoints for this study were risk of total cancer and individual cancers with more than 100 cases. Multivariate hazard ratios (HRs) and 95% CIs were calculated by use of Cox proportional hazard models according to periodontal disease status and number of teeth at baseline. In the main analyses, 48 375 men with median follow-up of 17.7 years (1986 to Jan 31, 2004) were eligible after excluding participants diagnosed with cancer before 1986 (other than non-melanoma skin cancer, n=2076) and those with missing data on periodontal disease (n=1078). 5720 incident cancer cases were documented (excluding non-melanoma skin cancer and non

Trespassing cancer cells: ‘fingerprinting’ invasive protrusions reveals metastatic culprits

PubMed Central

Klemke, Richard L.

2012-01-01

Metastatic cancer cells produce invasive membrane protrusions called invadopodia and pseudopodia, which play a central role in driving cancer cell dissemination in the body. Malignant cells use these structures to attach to and degrade extracellular matrix proteins, generate force for cell locomotion, and to penetrate the vasculature. Recent work using unique subcellular fractionation methodologies combined with spatial genomic, proteomic, and phosphoproteomic profiling has provided insight into the invadopodiome and pseudopodiome signaling networks that control the protrusion of invasive membranes. Here I highlight how these powerful spatial “omics” approaches reveal important signatures of metastatic cancer cells and possible new therapeutic targets aimed at treating metastatic disease. PMID:22980730

Loss of SMAD4 Promotes Lung Metastasis of Colorectal Cancer by Accumulation of CCR1+ Tumor-Associated Neutrophils through CCL15-CCR1 Axis.

PubMed

Yamamoto, Takamasa; Kawada, Kenji; Itatani, Yoshiro; Inamoto, Susumu; Okamura, Ryosuke; Iwamoto, Masayoshi; Miyamoto, Ei; Chen-Yoshikawa, Toyofumi F; Hirai, Hideyo; Hasegawa, Suguru; Date, Hiroshi; Taketo, Makoto M; Sakai, Yoshiharu

2017-02-01

We have reported loss of SMAD4 promotes expression of CCL15 from colorectal cancer to recruit CCR1 + myeloid cells through the CCL15-CCR1 axis, which contributes to invasion and liver metastasis. However, the molecular mechanism of lung metastasis is yet to be elucidated. Our purpose is to determine whether similar mechanism is involved in the lung metastasis of colorectal cancer. In a mouse model, we examined whether SMAD4 could affect the metastatic activity of colorectal cancer cells to the lung through the CCL15-CCR1 axis. We immunohistochemically analyzed expression of SMAD4, CCL15, and CCR1 with 107 clinical specimens of colorectal cancer lung metastases. We also characterized the CCR1 + myeloid cells using several cell-type-specific markers. In a mouse model, CCL15 secreted from SMAD4-deficient colorectal cancer cells recruited CCR1 + cells, promoting their metastatic activities to the lung. Immunohistochemical analysis of lung metastases from colorectal cancer patients revealed that CCL15 expression was significantly correlated with loss of SMAD4, and that CCL15-positive metastases recruited approximately 1.9 times more numbers of CCR1 + cells than CCL15-negative metastases. Importantly, patients with CCL15-positive metastases showed a significantly shorter relapse-free survival (RFS) than those with CCL15-negative metastases, and multivariate analysis indicated that CCL15 expression was an independent predictor of shorter RFS. Immunofluorescent staining showed that most CCR1 + cells around lung metastases were tumor-associated neutrophil, although a minor fraction was granulocytic myeloid-derived suppressor cell. CCL15-CCR1 axis may be a therapeutic target to prevent colorectal cancer lung metastasis. CCL15 can be a biomarker indicating poor prognosis of colorectal cancer patients with lung metastases. Clin Cancer Res; 23(3); 833-44. ©2016 AACR. ©2016 American Association for Cancer Research.

A Pilot Randomized Controlled Trial of a Commercial Diet and Exercise Weight Loss Program in Minority Breast Cancer Survivors

PubMed Central

Greenlee, Heather A.; Crew, Katherine D.; Mata, Jennie M.; McKinley, Paula S.; Rundle, Andrew G.; Zhang, Wenfei; Liao, Yuyan; Tsai, Wei Y.; Hershman, Dawn L.

2015-01-01

Objective Obesity is associated with poorer breast cancer outcomes and losing weight postdiagnosis may improve survival. As Hispanic and black women have poorer breast cancer prognosis than non-Hispanic whites diagnosed at similar age and stage, and have higher rates of obesity, effective weight loss strategies are needed. We piloted a randomized, waitlist-controlled, crossover study to examine the effects and feasibility of the commercial Curves weight loss program among Hispanic, African American and Afro-Caribbean breast cancer survivors. Design and Methods Women with stage 0– IIIa breast cancer ≥6 months posttreatment, sedentary, and BMI ≥25 kg/m2 were randomized to the immediate arm (IA): 6 months of the Curves program followed by 6 months of observation; or the waitlist control arm (WCA): 6 months of observation followed by 6 months of the Curves program. The Curves program uses a 30-min exercise circuit and a high-vegetable/low-fat/calorie-restricted diet. Results A total of 42 women enrolled (79% Hispanic, 21% black), mean age 51 (range 32–69) and mean BMI 33.2(±5.9) kg/m2; 91% were retained at month 12. At month 6, women in the IA lost an average 3.3% (±3.5%) of body weight (range: 1.7% gain to 10.6% loss), as compared with 1.8% (±2.9%) weight loss in the WCA (P = 0.04). At month 12, on average women in the IA regained some but not all of the weight lost during the first 6 months (P = 0.02). Conclusions Minority breast cancer survivors were recruited and retained in a weight loss study. Six months of the Curves program resulted in moderate weight loss, but weight loss was not maintained postintervention. Future interventions should identify methods to increase uptake and maintenance of weight loss behaviors. PMID:23505170

A pilot randomized controlled trial of a commercial diet and exercise weight loss program in minority breast cancer survivors.

PubMed

Greenlee, Heather A; Crew, Katherine D; Mata, Jennie M; McKinley, Paula S; Rundle, Andrew G; Zhang, Wenfei; Liao, Yuyan; Tsai, Wei Y; Hershman, Dawn L

2013-01-01

Obesity is associated with poorer breast cancer outcomes and losing weight postdiagnosis may improve survival. As Hispanic and black women have poorer breast cancer prognosis than non-Hispanic whites diagnosed at similar age and stage, and have higher rates of obesity, effective weight loss strategies are needed. We piloted a randomized, waitlist-controlled, crossover study to examine the effects and feasibility of the commercial Curves weight loss program among Hispanic, African American and Afro-Caribbean breast cancer survivors. Women with stage 0-IIIa breast cancer ≥ 6 months posttreatment, sedentary, and BMI ≥ 25 kg/m(2) were randomized to the immediate arm (IA): 6 months of the Curves program followed by 6 months of observation; or the waitlist control arm (WCA): 6 months of observation followed by 6 months of the Curves program. The Curves program uses a 30-min exercise circuit and a high-vegetable/low-fat/calorie-restricted diet. A total of 42 women enrolled (79% Hispanic, 21% black), mean age 51 (range 32-69) and mean BMI 33.2(± 5.9) kg/m(2); 91% were retained at month 12. At month 6, women in the IA lost an average 3.3% (± 3.5%) of body weight (range: 1.7% gain to 10.6% loss), as compared with 1.8% (± 2.9%) weight loss in the WCA (P = 0.04). At month 12, on average women in the IA regained some but not all of the weight lost during the first 6 months (P = 0.02). Minority breast cancer survivors were recruited and retained in a weight loss study. Six months of the Curves program resulted in moderate weight loss, but weight loss was not maintained postintervention. Future interventions should identify methods to increase uptake and maintenance of weight loss behaviors. Copyright © 2013 The Obesity Society.

[The Evaluation of Medical Demographic and Economic Losses of the Region Conditioned by Mortality of Lung Cancer].

PubMed

Zukov, R A; Modestov, A A; Safontsev, I P; Slepov, E V; Narkevich, A N

2017-11-01

The article presents evaluation of medical demographic and economic losses of population of the Krasnoyarskii kraii conditioned by mortality of lung cancer in 2010-2014 using DALY technology. In the Krasnoyarskii kraii, during 2010-2014 64,712 individuals died because of lung cancer. The mortality of male population surpasses corresponding indices of mortality of females up to 3.9 times. In the region, the standardized indicator mortality of lung cancer among males annually surpasses the same indicator among females at maximum up to 8.1 times. The DALY maximal absolute losses of among males were registered in 2010 and 2013 and fell on age group of 55-59 years and among females on the age group of 60-64 years in 2014. The maximal (up to 5.2 times) difference in values of DALY indicator was established in 2010 between male and female population. the maximal gap in in DALY indices between male and female population was established in the age of 55-59 years. Almost half of DALY losses among males was established in 2013 and among females in 2014. The total losses of gross regional product in the region because of mortality conditioned by lung cancer made up to 29.8 billions of rubles in 2010-2014.

The Effects of Metformin and Weight Loss on Biomarkers Associated With Breast Cancer Outcomes.

PubMed

Patterson, Ruth E; Marinac, Catherine R; Sears, Dorothy D; Kerr, Jacqueline; Hartman, Sheri J; Cadmus-Bertram, Lisa; Villaseñor, Adriana; Flatt, Shirley W; Godbole, Suneeta; Li, Hongying; Laughlin, Gail A; Oratowski-Coleman, Jesica; Parker, Barbara A; Natarajan, Loki

2018-05-18

This study investigated the effects of metformin and weight loss on biomarkers associated with breast cancer prognosis. Overweight/obese postmenopausal breast cancer survivors (n = 333) were randomly assigned to metformin vs placebo and to a weight loss intervention vs control (ie, usual care). The 2 × 2 factorial design allows a single randomized trial to investigate the effect of two factors and interactions between them. Outcomes were changes in fasting insulin, glucose, C-reactive protein (CRP), estradiol, testosterone, and sex-hormone binding globulin (SHBG). The trial was powered for a main effects analysis of metformin vs placebo and weight loss vs control. All tests of statistical significance were two-sided. A total of 313 women (94.0%) completed the six-month trial. High prescription adherence (ie, ≥80% of pills taken) ranged from 65.9% of participants in the metformin group to 81.3% of those in the placebo group (P < .002). Mean percent weight loss was statistically significantly higher in the weight loss group (-5.5%, 95% confidence interval [CI] = -6.3% to -4.8%) compared with the control group (-2.7%, 95% CI = -3.5% to -1.9%). Statistically significant group differences (ie, percent change in metformin group minus placebo group) were -7.9% (95% CI = -15.0% to -0.8%) for insulin, -10.0% (95% CI = -18.5% to -1.5%) for estradiol, -9.5% (95% CI = -15.2% to -3.8%) for testosterone, and 7.5% (95% CI = 2.4% to 12.6%) for SHBG. Statistically significant group differences (ie, percent change in weight loss group minus placebo group) were -12.5% (95% CI = -19.6% to -5.3%) for insulin and 5.3% (95% CI = 0.2% to 10.4%) for SHBG. As adjuvant therapy, weight loss and metformin were found to be a safe combination strategy that modestly lowered estrogen levels and advantageously affected other biomarkers thought to be on the pathway for reducing breast cancer recurrence and mortality.

Erbin loss promotes cancer cell proliferation through feedback activation of Akt-Skp2-p27 signaling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huang, Hao; Laboratory of Cellular and Molecular Immunology, Medical School of Henan University, Kaifeng 475004; Song, Yuhua

2015-07-31

Erbin localizes at the basolateral membrane to regulate cell junctions and polarity in epithelial cells. Dysregulation of Erbin has been implicated in tumorigenesis, and yet it is still unclear if and how disrupted Erbin regulates the biological behavior of cancer cells. We report here that depletion of Erbin leads to cancer cell excessive proliferation in vitro and in vivo. Erbin deficiency accelerates S-phase entry by down-regulating CDK inhibitors p21 and p27 via two independent mechanisms. Mechanistically, Erbin loss promotes p27 degradation by enhancing E3 ligase Skp2 activity though augmenting Akt signaling. Interestingly, we also show that Erbin is an unstable protein whenmore » the Akt-Skp2 signaling is aberrantly activated, which can be specifically destructed by SCF-Skp2 ligase. Erbin loss facilitates cell proliferation and migration in Skp2-dependent manner. Thus, our finding illustrates a novel negative feedback loop between Erbin and Akt-Skp2 signaling. It suggests disrupted Erbin links polarity loss, hyperproliferation and tumorigenesis. - Highlights: • Erbin loss leads to cancer cell excessive proliferation in vitro and in vivo. • Erbin loss accelerates cell cycle though down-regulating p21 and p27 expression. • Erbin is a novel negative modulator of Akt1-Skp2-p27 signaling pathway. • Our study suggests that Erbin loss contributes to Skp2 oncogenic function.« less

Skeletal muscle fiber size and fiber type distribution in human cancer: Effects of weight loss and relationship to physical function.

PubMed

Toth, Michael J; Callahan, Damien M; Miller, Mark S; Tourville, Timothy W; Hackett, Sarah B; Couch, Marion E; Dittus, Kim

2016-12-01

Cancer patients frequently experience weight loss, with negative consequences for functionality and prognosis. The extent to which muscle atrophy contributes to weight loss, however, is not clear, as few studies have directly measured muscle fiber morphology in cancer patients. Whole body and regional tissue composition were measured, along with the cross-sectional area (CSA) and fiber type of mechanically-isolated, single muscle fibers, in 19 cancer patients (8 with a history of weight loss, 11 weight-stable) and 15 non-diseased controls. Whole body fat mass was reduced in cancer patients with a history of weight loss, but no differences in whole body or leg fat-free mass were apparent. In contrast, reductions (∼20%) in single muscle fiber CSA were found in both slow-twitch, myosin heavy chain (MHC) I and fast-twitch, MHC IIA fibers in both weight-stable patients and those with a history of weight loss. Fiber type distribution showed a shift towards a fast-twitch phenotype compared to controls, which may preserve muscle function in cancer patients despite atrophy, as positive relationships were found between the fractions of hybrid MHC IIAX and I/IIA fibers and 6-min walk performance. Our results suggest that, although not apparent from whole body or regional measurements, cancer is associated with reduced skeletal muscle fiber size independent of weight loss history and a shift towards fast-twitch fibers, phenotypes that resemble adaptations to muscle disuse. Copyright © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Living well after breast cancer randomized controlled trial protocol: evaluating a telephone-delivered weight loss intervention versus usual care in women following treatment for breast cancer.

PubMed

Reeves, Marina M; Terranova, Caroline O; Erickson, Jane M; Job, Jennifer R; Brookes, Denise S K; McCarthy, Nicole; Hickman, Ingrid J; Lawler, Sheleigh P; Fjeldsoe, Brianna S; Healy, Genevieve N; Winkler, Elisabeth A H; Janda, Monika; Veerman, J Lennert; Ware, Robert S; Prins, Johannes B; Vos, Theo; Demark-Wahnefried, Wendy; Eakin, Elizabeth G

2016-10-28

Obesity, physical inactivity and poor diet quality have been associated with increased risk of breast cancer-specific and all-cause mortality as well as treatment-related side-effects in breast cancer survivors. Weight loss intervention trials in breast cancer survivors have shown that weight loss is safe and achievable; however, few studies have examined the benefits of such interventions on a broad range of outcomes and few have examined factors important to translation (e.g. feasible delivery method for scaling up, assessment of sustained changes, cost-effectiveness). The Living Well after Breast Cancer randomized controlled trial aims to evaluate a 12-month telephone-delivered weight loss intervention (versus usual care) on weight change and a range of secondary outcomes including cost-effectiveness. Women (18-75 years; body mass index 25-45 kg/m 2 ) diagnosed with stage I-III breast cancer in the previous 2 years are recruited from public and private hospitals and through the state-based cancer registry (target n = 156). Following baseline assessment, participants are randomized 1:1 to either a 12-month telephone-delivered weight loss intervention (targeting diet and physical activity) or usual care. Data are collected at baseline, 6-months (mid-intervention), 12-months (end-of-intervention) and 18-months (maintenance). The primary outcome is change in weight at 12-months. Secondary outcomes are changes in body composition, bone mineral density, cardio-metabolic and cancer-related biomarkers, metabolic health and chronic disease risk, physical function, patient-reported outcomes (quality of life, fatigue, menopausal symptoms, body image, fear of cancer recurrence) and behaviors (dietary intake, physical activity, sitting time). Data collected at 18-months will be used to assess whether outcomes achieved at end-of-intervention are sustained six months after intervention completion. Cost-effectiveness will be assessed, as will mediators and moderators of

Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution.

PubMed

McGranahan, Nicholas; Rosenthal, Rachel; Hiley, Crispin T; Rowan, Andrew J; Watkins, Thomas B K; Wilson, Gareth A; Birkbak, Nicolai J; Veeriah, Selvaraju; Van Loo, Peter; Herrero, Javier; Swanton, Charles

2017-11-30

Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy-number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to determine HLA allele-specific copy number from sequencing data. Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity. The focal nature of HLA LOH alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggests that HLA LOH is an immune escape mechanism that is subject to strong microenvironmental selection pressures later in tumor evolution. Characterizing HLA LOH with LOHHLA refines neoantigen prediction and may have implications for our understanding of resistance mechanisms and immunotherapeutic approaches targeting neoantigens. VIDEO ABSTRACT. Copyright © 2017 The Francis Crick Institute. Published by Elsevier Inc. All rights reserved.

Favorable Changes in Serum Estrogens and Other Biological Factors After Weight Loss in Overweight or Obese Breast Cancer Survivors

PubMed Central

Rock, Cheryl L.; Pande, Chetna; Flatt, Shirley W.; Ying, Carl; Pakiz, Bilge; Parker, Barbara A.; Williams, Kathryn; Bardwell, Wayne A.; Heath, Dennis D.; Nichols, Jeanne F.

2014-01-01

Background Obesity is associated with increased risk for recurrence and all-cause mortality in breast cancer survivors. Excess adiposity is associated with increased estrogen, insulin, and leptin, and decreased sex hormone binding globulin (SHBG) concentrations, which may promote breast cancer progression and recurrence. This study aimed to assess the effects of weight loss on these factors. Patients and Methods Overweight or obese breast cancer survivors (N = 220) who were enrolled in a weight loss intervention study provided baseline and follow-up blood samples and weight data. Serum estrogens, SHBG, insulin, and leptin were measured at baseline, 6 and 18 months. Results Weight loss of ≥5% of initial weight decreased leptin and insulin compared with those who did not achieve that amount of weight loss (P < .0001). Weight loss also increased SHBG at 6 and 18 months (P < .01). Postmenopausal women who lost ≥5% of body weight at 6 months had lower estrone (P = .02), estradiol (P = .002), and bioavailable estradiol (P = .001) concentrations than women who did not lose at least 5% of body weight, and weight loss at 18 months was significantly related to change in serum bioavailable estradiol concentration (P = 0.02). Conclusion Favorable changes in estrogens, SHBG, insulin, and leptin were observed in association with weight loss in these overweight or obese women who had been diagnosed and treated for breast cancer. Weight loss appears to have favorable effects on hormonal and biological factors associated with increased risk for recurrence and poorer prognosis. PMID:23375717

Impact of a Behavioral Weight Loss Intervention on Comorbidities in Overweight and Obese Breast Cancer Survivors

PubMed Central

Sedjo, Rebecca L.; Flatt, Shirley W.; Byers, Tim; Colditz, Graham A.; Demark-Wahnefried, Wendy; Ganz, Patricia A.; Wolin, Kathleen Y.; Elias, Anthony; Krontiras, Helen; Liu, Jingxia; Naughton, Michael; Pakiz, Bilgé; Parker, Barbara A.; Wyatt, Holly; Rock, Cheryl L.

2017-01-01

Purpose Comorbid medical conditions are common among breast cancer survivors, contribute to poorer long-term survival and increased overall mortality, and may be ameliorated by weight loss. This secondary analysis evaluated the impact of a weight loss intervention on comorbid medical conditions immediately following an intervention (12-months) and one-year post-intervention (24-month) using data from the Exercise and Nutrition to Enhance Recovery and Good health for You (ENERGY) trial – a phase III trial which was aimed at and successfully promoted weight loss. Methods ENERGY randomized 692 overweight/obese women who had completed treatment for early stage breast cancer to either a one-year group-based behavioral intervention designed to achieve and maintain weight loss or to a less intensive control intervention. Minimal support was provided post-intervention. New medical conditions, medical conditions in which non-cancer medications were prescribed, hospitalizations, and emergency room visits were compared at baseline, year 1 and 2. Changes over time were analyzed using chi-squared tests, Kaplan-Meier and logistic regression analyses. Results At 12 months, women randomized to the intervention had fewer new medical conditions compared to the control group (19.6% vs. 32.2%, p<0.001); however, by 24 months, there was no longer a significant difference. No difference was observed in each of four conditions for which non-cancer medications were prescribed, hospital visits, or emergency visits at either 12 or 24 months. Conclusions These results support a short-term benefit of modest weight loss on the likelihood of comorbid conditions; however, recidivism and weight regain likely explain no benefit at one-year post-intervention follow-up. PMID:26945570

Cell subpopulation deconvolution reveals breast cancer heterogeneity based on DNA methylation signature.

PubMed

Wen, Yanhua; Wei, Yanjun; Zhang, Shumei; Li, Song; Liu, Hongbo; Wang, Fang; Zhao, Yue; Zhang, Dongwei; Zhang, Yan

2017-05-01

Tumour heterogeneity describes the coexistence of divergent tumour cell clones within tumours, which is often caused by underlying epigenetic changes. DNA methylation is commonly regarded as a significant regulator that differs across cells and tissues. In this study, we comprehensively reviewed research progress on estimating of tumour heterogeneity. Bioinformatics-based analysis of DNA methylation has revealed the evolutionary relationships between breast cancer cell lines and tissues. Further analysis of the DNA methylation profiles in 33 breast cancer-related cell lines identified cell line-specific methylation patterns. Next, we reviewed the computational methods in inferring clonal evolution of tumours from different perspectives and then proposed a deconvolution strategy for modelling cell subclonal populations dynamics in breast cancer tissues based on DNA methylation. Further analysis of simulated cancer tissues and real cell lines revealed that this approach exhibits satisfactory performance and relative stability in estimating the composition and proportions of cellular subpopulations. The application of this strategy to breast cancer individuals of the Cancer Genome Atlas's identified different cellular subpopulations with distinct molecular phenotypes. Moreover, the current and potential future applications of this deconvolution strategy to clinical breast cancer research are discussed, and emphasis was placed on the DNA methylation-based recognition of intra-tumour heterogeneity. The wide use of these methods for estimating heterogeneity to further clinical cohorts will improve our understanding of neoplastic progression and the design of therapeutic interventions for treating breast cancer and other malignancies. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Expression and Functional Significance of HtrA1 Loss in Endometrial Cancer

PubMed Central

Mullany, Sally A.; Moslemi-Kebria, Mehdi; Rattan, Ramandeep; Khurana, Ashwani; Clayton, Amy; Ota, Takayo; Mariani, Andrea; Podratz, Karl C.; Chien, Jeremy; Shridhar, Viji

2010-01-01

Purpose The purpose of this study was to determine if loss of serine protease HtrA1 in endometrial cancer will promote the invasive potential of EC cell lines. Experimental design Western blot analysis and immunohistochemistry methods were used to determine HtrA1 expression in EC cell lines and primary tumors, respectively. Migration, invasion assays and in vivo xenograft experiment were performed to compare the extent of metastasis between HtrA1 expressing and HtrA-1 knocked down clones. Results Western blot analysis of HtrA1 in 13 EC cell lines revealed complete loss of HtrA1 expression in all 7 papillary serous EC cell lines. Downregulation of HtrA1 in Hec1A and Hec1B cell lines resulted in a 3-4 fold increase in the invasive potential. Exogenous expression of HtrA1 in Ark 1 and Ark 2 cells resulted in 3-4 fold decrease in both invasive and migration potential of these cells. There was an increased rate of metastasis to the lungs associated with HtrA1 downregulation in Hec1B cells compared to control cells with endogenous HtrA1 expression. Enhanced expression of HtrA1 in Ark 2 cells resulted in significantly less tumor nodules metastasizing to the lungs compared to parental or protease deficient (SA mutant) Ark 2 cells. Immunohistochemical (IHC) analysis showed 57% (105/184) of primary EC tumors had low HtrA1 expression. The association of low HtrA1 expression with high-grade endometrioid tumors was statistically significant (p=0.016). Conclusions Collectively, these data indicate loss of HtrA1 may contribute to the aggressiveness and metastatic ability of endometrial tumors. PMID:21098697

Impact of Weight Loss on Plasma Leptin and Adiponectin in Overweight-to-Obese Post Menopausal Breast Cancer Survivors

PubMed Central

Thompson, Henry J.; Sedlacek, Scot M.; Wolfe, Pamela; Paul, Devchand; Lakoski, Susan G.; Playdon, Mary C.; McGinley, John N.; Matthews, Shawna B.

2015-01-01

Women who are obese at the time of breast cancer diagnosis have higher overall mortality than normal weight women and some evidence implicates adiponectin and leptin as contributing to prognostic disadvantage. While intentional weight loss is thought to improve prognosis, its impact on these adipokines is unclear. This study compared the pattern of change in plasma leptin and adiponectin in overweight-to-obese post-menopausal breast cancer survivors during weight loss. Given the controversies about what dietary pattern is most appropriate for breast cancer control and regulation of adipokine metabolism, the effect of a low fat versus a low carbohydrate pattern was evaluated using a non-randomized, controlled study design. Anthropometric data and fasted plasma were obtained monthly during the six-month weight loss intervention. While leptin was associated with fat mass, adiponectin was not, and the lack of correlation between leptin and adiponectin concentrations throughout weight loss implies independent mechanisms of regulation. The temporal pattern of change in leptin but not adiponectin was affected by magnitude of weight loss. Dietary pattern was without effect on either adipokine. Mechanisms not directly related to dietary pattern, weight loss, or fat mass appear to play dominant roles in the regulation of circulating levels of these adipokines. PMID:26132992

Impact of Weight Loss on Plasma Leptin and Adiponectin in Overweight-to-Obese Post Menopausal Breast Cancer Survivors.

PubMed

Thompson, Henry J; Sedlacek, Scot M; Wolfe, Pamela; Paul, Devchand; Lakoski, Susan G; Playdon, Mary C; McGinley, John N; Matthews, Shawna B

2015-06-26

Women who are obese at the time of breast cancer diagnosis have higher overall mortality than normal weight women and some evidence implicates adiponectin and leptin as contributing to prognostic disadvantage. While intentional weight loss is thought to improve prognosis, its impact on these adipokines is unclear. This study compared the pattern of change in plasma leptin and adiponectin in overweight-to-obese post-menopausal breast cancer survivors during weight loss. Given the controversies about what dietary pattern is most appropriate for breast cancer control and regulation of adipokine metabolism, the effect of a low fat versus a low carbohydrate pattern was evaluated using a non-randomized, controlled study design. Anthropometric data and fasted plasma were obtained monthly during the six-month weight loss intervention. While leptin was associated with fat mass, adiponectin was not, and the lack of correlation between leptin and adiponectin concentrations throughout weight loss implies independent mechanisms of regulation. The temporal pattern of change in leptin but not adiponectin was affected by magnitude of weight loss. Dietary pattern was without effect on either adipokine. Mechanisms not directly related to dietary pattern, weight loss, or fat mass appear to play dominant roles in the regulation of circulating levels of these adipokines.

Productivity Losses Associated with Head and Neck Cancer Using the Human Capital and Friction Cost Approaches.

PubMed

Pearce, Alison M; Hanly, Paul; Timmons, Aileen; Walsh, Paul M; O'Neill, Ciaran; O'Sullivan, Eleanor; Gooberman-Hill, Rachael; Thomas, Audrey Alforque; Gallagher, Pamela; Sharp, Linda

2015-08-01

Previous studies suggest that productivity losses associated with head and neck cancer (HNC) are higher than in other cancers. These studies have only assessed a single aspect of productivity loss, such as temporary absenteeism or premature mortality, and have only used the Human Capital Approach (HCA). The Friction Cost Approach (FCA) is increasingly recommended, although has not previously been used to assess lost production from HNC. The aim of this study was to estimate the lost productivity associated with HNC due to different types of absenteeism and premature mortality, using both the HCA and FCA. Survey data on employment status were collected from 251 HNC survivors in Ireland and combined with population-level survival estimates and national wage data. The cost of temporary and permanent time off work, reduced working hours and premature mortality using both the HCA and FCA were calculated. Estimated total productivity losses per employed person of working age were EUR253,800 using HCA and EUR6800 using FCA. The main driver of HCA costs was premature mortality (38% of total) while for FCA it was temporary time off (73% of total). The productivity losses associated with head and neck cancer are substantial, and return to work assistance could form an important part of rehabilitation. Use of both the HCA and FCA approaches allowed different drivers of productivity losses to be identified, due to the different assumptions of the two methods. For future estimates of productivity losses, the use of both approaches may be pragmatic.

[FACTORS WHICH INFLUENCE THE LEAN MASS LOSS IN CANCER PATIENTS].

PubMed

Sánchez Sánchez, Eduardo; Muñoz Alferez, Maria José

2015-10-01

cancer is an important illness in the sanitary field due to phisic and functional consequences involved in it. Among these consequences there is the malnutrition which can cause a loss of lean mass and with it a decrease in the Quality of Life, an increase in hospital stays, social and health costs and so on. The aim of this research is to know which factors can influence in the loss of the lean mass. it is a cross-sectional study in a sample of 72 patients who receive a radiotherapy with curative intent during a period from February 07th and May 14th, 2014. from this pattern Of the total 64 patients were studied, of which 43.7% of the patients presented loss of lean mass, with 21.8% the percentage of patients losing < 2%, 4.7% those with a loss between 2-5% and > 5%, 17.2% of patients. Among the factors studied that can influence the loss of lean mass, only the presence of digestive symptoms have statistical significance (OR = 3.3 or 6.6, as we take as a reference the percentage loss). the aim of the health staff who are working with these patients is to avoid the consequences that accompanies the loss of lean mass. For all this, it is very important to act before the digestive symptoms, by anticipating to them, or early implementation of an individualized nutritional intervention. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

Developmentally induced Mll1 loss reveals defects in postnatal haematopoiesis.

PubMed

Gan, T; Jude, C D; Zaffuto, K; Ernst, P

2010-10-01

The mixed lineage leukemia (MLL) gene is disrupted by chromosomal translocations in acute leukemia, producing a fusion oncogene with altered properties relative to the wild-type gene. Murine loss-of-function studies have shown an essential role for Mll in developing the haematopoietic system, yet studies using different conditional knockout models have yielded conflicting results regarding the requirement for Mll during adult steady-state haematopoiesis. In this study, we used a loxP-flanked Mll allele (Mll(F)) and a developmentally regulated, haematopoietic-specific VavCre transgene to reassess the consequences of Mll loss in the haematopoietic lineage, without the need for inducers of Cre recombinase. We show that VavCre;Mll mutants exhibit phenotypically normal fetal haematopoiesis, but rarely survive past 3 weeks of age. Surviving animals are anemic, thrombocytopenic and exhibit a significant reduction in bone marrow haematopoietic stem/progenitor populations, consistent with our previous findings using the inducible Mx1Cre transgene. Furthermore, the analysis of VavCre mutants revealed additional defects in B-lymphopoiesis that could not be assessed using Mx1Cre-mediated Mll deletion. Collectively, these data support the conclusion that Mll has an essential role in sustaining postnatal haematopoiesis.

Calcium and Vitamin D Supplementation and Loss of Bone Mineral Density in Women Undergoing Breast Cancer Therapy

PubMed Central

Datta, Mridul; Schwartz, Gary G.

2013-01-01

An unintended consequence of breast cancer therapies is an increased risk of osteoporosis due to accelerated bone loss. We conducted a systematic review of calcium and/or vitamin D (Ca±D) supplementation trials for maintaining bone mineral density (BMD) in women with breast cancer using the “before-after” data from the Ca±D supplemented comparison group of trials evaluating the effect of drugs such as bisphosphonates on BMD. Whether Ca±D supplements increase BMD in women undergoing breast cancer therapy has never been tested against an unsupplemented control group. However, results from 16 trials indicate that the Ca±D doses tested (500-1500 mg calcium; 200-1000 IU vitamin D) were inadequate to prevent BMD loss in these women. Cardiovascular disease is the main cause of mortality in women with breast cancer. Because calcium supplements may increase cardiovascular disease risk, future trials should evaluate the safety and efficacy of Ca±D supplementation in women undergoing breast cancer therapy. PMID:23932583

Physical Activity and Weight Loss Reduce the Risk of Breast Cancer: A Meta-analysis of 139 Prospective and Retrospective Studies.

PubMed

Hardefeldt, Prue J; Penninkilampi, Ross; Edirimanne, Senarath; Eslick, Guy D

2017-10-17

Physical activity and weight loss have been shown to reduce breast cancer incidence in numerous observational studies. The aim of this meta-analysis was to assess the effect of both physical activity and weight loss on breast cancer incidence. Specifically, we aimed to complete subgroup analyses by the intensity of physical activity and menopausal status at breast cancer diagnosis to further elucidate the relationship between physical activity, weight loss, and breast cancer incidence. Studies were obtained from a database search of MEDLINE, EMBASE, PubMed, Current Contents Connect, and Google Scholar through November 5, 2017. A random-effects model was used for pooled data. There were 139 studies included in the meta-analysis, including 236,955 cases and 3,963,367 controls. Physical activity significantly reduced the risk of breast cancer (odds ratio [OR], 0.78; 95% confidence interval [CI], 0.76-0.81; P < .001), with high-intensity physical activity being slightly more protective (OR, 0.73; 95% CI, 0.65-0.81; P < .001) than low-intensity exercise (OR, 0.79; 95% CI, 0.72-0.86; P < .001). The effect size for general exercise was similar in both premenopausal (OR, 0.79; 95% CI, 0.73-0.87; P < .001) and postmenopausal (OR, 0.82; 95% CI, 0.78-0.86; P < .001) women. Additionally, weight loss reduced the risk of breast cancer incidence (OR, 0.82; 95% CI, 0.67-0.97). Physical activity and weight loss significantly reduce the risk of breast cancer, irrespective of the timing and intensity of the exercise. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

Synchrotron nanoscopy imaging study of scalp hair in breast cancer patients and healthy individuals: Difference in medulla loss and cortical membrane enhancements.

PubMed

Han, Sung-Mi; Chikawa, Jun-Ichi; Jeon, Jae-Kun; Hwang, Min-Young; Lim, Jun; Jeong, Young-Ju; Park, Sung-Hwan; Kim, Hong-Tae; Jheon, Sanghoon; Kim, Jong-Ki

2016-01-01

Nanoscopic synchrotron X-ray imaging was performed on scalp hair samples of patients with breast cancer and healthy individuals to investigate any structural differences as diagnostic tool. Hair strands were divided into 2-3 segments along the strands from root to tip, followed by imaging either in projection or in CT scanning with a monochromatic 6.78-keV X-ray using zone-plate optics with a resolving power of 60 nm. All the examined cancer hairs exhibited medulla loss with cancer stage-dependent pattern; complete loss, discontinuous or trace along the strands. In contrast, medullas were well retained without complete loss in the healthy hair. In the CT-scanned axial images, the cortical spindle compartments had no contrast in the healthy hair, but appeared hypointense in contrast to the surrounding hyperintense cortical membrane complex in the cancer hair. In conclusion, observation of medulla loss and cortical membrane enhancements in the hair strands of breast cancer patients demonstrated structural variations in the cancer hair, providing a new platform for further synchrotron X-ray imaging study of screening breast cancer patients. © 2015 Wiley Periodicals, Inc.

Loss of heterozygosity assay for molecular detection of cancer using energy-transfer primers and capillary array electrophoresis.

PubMed

Medintz, I L; Lee, C C; Wong, W W; Pirkola, K; Sidransky, D; Mathies, R A

2000-08-01

Microsatellite DNA loci are useful markers for the detection of loss of heterozygosity (LOH) and microsatellite instability (MI) associated with primary cancers. To carry out large-scale studies of LOH and MI in cancer progression, high-throughput instrumentation and assays with high accuracy and sensitivity need to be validated. DNA was extracted from 26 renal tumor and paired lymphocyte samples and amplified with two-color energy-transfer (ET) fluorescent primers specific for loci associated with cancer-induced chromosomal changes. PCR amplicons were separated on the MegaBACE-1000 96 capillary array electrophoresis (CAE) instrument and analyzed with MegaBACE Genetic Profiler v.1.0 software. Ninety-six separations were achieved in parallel in 75 minutes. Loss of heterozygosity was easily detected in tumor samples as was the gain/loss of microsatellite core repeats. Allelic ratios were determined with a precision of +/- 10% or better. Prior analysis of these samples with slab gel electrophoresis and radioisotope labeling had not detected these changes with as much sensitivity or precision. This study establishes the validity of this assay and the MegaBACE instrument for large-scale, high-throughput studies of the molecular genetic changes associated with cancer.

Functional photoreceptor loss revealed with adaptive optics: an alternate cause of color blindness.

PubMed

Carroll, Joseph; Neitz, Maureen; Hofer, Heidi; Neitz, Jay; Williams, David R

2004-06-01

There is enormous variation in the X-linked L/M (long/middle wavelength sensitive) gene array underlying "normal" color vision in humans. This variability has been shown to underlie individual variation in color matching behavior. Recently, red-green color blindness has also been shown to be associated with distinctly different genotypes. This has opened the possibility that there may be important phenotypic differences within classically defined groups of color blind individuals. Here, adaptive optics retinal imaging has revealed a mechanism for producing dichromatic color vision in which the expression of a mutant cone photopigment gene leads to the loss of the entire corresponding class of cone photoreceptor cells. Previously, the theory that common forms of inherited color blindness could be caused by the loss of photoreceptor cells had been discounted. We confirm that remarkably, this loss of one-third of the cones does not impair any aspect of vision other than color.

Visual gene-network analysis reveals the cancer gene co-expression in human endometrial cancer

PubMed Central

2014-01-01

Background Endometrial cancers (ECs) are the most common form of gynecologic malignancy. Recent studies have reported that ECs reveal distinct markers for molecular pathogenesis, which in turn is linked to the various histological types of ECs. To understand further the molecular events contributing to ECs and endometrial tumorigenesis in general, a more precise identification of cancer-associated molecules and signaling networks would be useful for the detection and monitoring of malignancy, improving clinical cancer therapy, and personalization of treatments. Results ECs-specific gene co-expression networks were constructed by differential expression analysis and weighted gene co-expression network analysis (WGCNA). Important pathways and putative cancer hub genes contribution to tumorigenesis of ECs were identified. An elastic-net regularized classification model was built using the cancer hub gene signatures to predict the phenotypic characteristics of ECs. The 19 cancer hub gene signatures had high predictive power to distinguish among three key principal features of ECs: grade, type, and stage. Intriguingly, these hub gene networks seem to contribute to ECs progression and malignancy via cell-cycle regulation, antigen processing and the citric acid (TCA) cycle. Conclusions The results of this study provide a powerful biomarker discovery platform to better understand the progression of ECs and to uncover potential therapeutic targets in the treatment of ECs. This information might lead to improved monitoring of ECs and resulting improvement of treatment of ECs, the 4th most common of cancer in women. PMID:24758163

Keap1 loss promotes Kras-driven lung cancer and results in a dependence on glutaminolysis

PubMed Central

Romero, Rodrigo; Sayin, Volkan I.; Davidson, Shawn M.; Bauer, Matthew R.; Singh, Simranjit X.; LeBoeuf, Sarah E.; Karakousi, Triantafyllia R.; Ellis, Donald C.; Bhutkar, Arjun; Sanchez-Rivera, Francisco J.; Subbaraj, Lakshmipriya; Martinez, Britney; Bronson, Roderick T.; Prigge, Justin R.; Schmidt, Edward E.; Thomas, Craig J.; Goparaju, Chandra; Davies, Angela; Dolgalev, Igor; Heguy, Adriana; Allaj, Viola; Poirier, John T.; Moreira, Andre L.; Rudin, Charles M.; Pass, Harvey I.; Vander Heiden, Matthew G.; Jacks, Tyler; Papagiannakopoulos, Thales

2017-01-01

Treating KRAS-mutant lung adenocarcinoma (LUAD) remains a major challenge in cancer treatment given the difficulties associated with directly inhibiting the KRAS oncoprotein1. One approach to addressing this challenge is to define frequently co-occurring mutations with KRAS, which themselves may lead to therapeutic vulnerabilities in tumors. Approximately 20% of KRAS-mutant LUAD tumors carry loss-of-function (LOF) mutations in Kelch-like ECH-associated protein 1 (KEAP1)2-4, a negative regulator of nuclear factor erythroid 2-like 2 (NFE2L2; hereafter NRF2), which is the master transcriptional regulator of the endogenous antioxidant response5-10. The high frequency of mutations in KEAP1 suggests an important role for the oxidative stress response in lung tumorigenesis. Using a CRISPR/Cas9-based approach in a mouse model of Kras-driven LUAD we examined the effects of Keap1 loss in lung cancer progression. We show that loss of Keap1 hyper-activates Nrf2 and promotes Kras-driven LUAD. Combining CRISPR/Cas9-based genetic screening and metabolomic analyses, we show that Keap1/Nrf2-mutant cancers are dependent on increased glutaminolysis, and this property can be therapeutically exploited through the pharmacological inhibition of glutaminase. Finally, we provide a rationale for sub-stratification of human lung cancer patients with KRAS-KEAP1 or -NRF2-mutant tumors as likely to respond to glutaminase inhibition. PMID:28967920

Annual Medical Expenditure and Productivity Loss Among Colorectal, Female Breast, and Prostate Cancer Survivors in the United States

PubMed Central

Yabroff, K. Robin; Guy, Gery P.; Han, Xuesong; Li, Chunyu; Banegas, Matthew P.; Ekwueme, Donatus U.; Jemal, Ahmedin

2016-01-01

Background: There are limited nationally representative estimates of the annual economic burden among survivors of the three most prevalent cancers (colorectal, female breast, and prostate) in both nonelderly and elderly populations in the United States. Methods: The 2008 to 2012 Medical Expenditure Panel Survey data were used to identify colorectal (n = 540), female breast (n = 1568), and prostate (n = 1170) cancer survivors and individuals without a cancer history (n = 109 423). Excess economic burden attributable to cancer included per-person excess annual medical expenditures and productivity losses (employment disability, missed work days, and days stayed in bed). All analyses were stratified by cancer site and age (nonelderly: 18–64 years vs elderly: ≥65 years). Multivariable analyses controlled for age, sex, race/ethnicity, marital status, education, number of comorbidities, and geographic region. All statistical tests were two-sided. Results: Compared with individuals without a cancer history, cancer survivors experienced annual excess medical expenditures (for the nonelderly population, colorectal: $8647, 95% confidence interval [CI] = $4932 to $13 974, P < .001; breast: $5119, 95% CI = $3439 to $7158, P < .001; prostate: $3586, 95% CI = $1792 to $6076, P < .001; for the elderly population, colorectal: $4913, 95% CI = $2768 to $7470, P < .001; breast: $2288, 95% CI = $814 to $3995, P = .002; prostate: $3524, 95% CI = $1539 to $5909, P < .001). Nonelderly colorectal and breast cancer survivors experienced statistically significant annual excess employment disability (13.6%, P < .001, and 4.8%, P = .001) and productivity loss at work (7.2 days, P < .001, and 3.3 days, P = .002) and at home (4.5 days, P < .001, and 3.3 days, P = .003). In contrast, elderly survivors of all three cancer sites had comparable productivity losses as those without a cancer history. Conclusions: Colorectal, breast, and prostate cancer survivors experienced statistically

Integration of Genomic, Biologic, and Chemical Approaches to Target p53 Loss and Gain-of-Function in Triple Negative Breast Cancer

DTIC Science & Technology

2015-09-01

dissertation research is determining the mechanism and “targetability” of a mutant p53-adapted state in triple-negative breast cancer . Tim’s...Negative Breast Cancer PRINCIPAL INVESTIGATOR: Jennifer A. Pietenpol, Ph.D. CONTRACTING ORGANIZATION: The Vanderbilt University Nashville, TN...Loss and Gain-of-Function in Triple Negative Breast Cancer 5a. CONTRACT NUMBER W81XWH-13-1-0287 p53 Loss and Gain-of-Function in Triple Negative

Physical activity levels of overweight or obese breast cancer survivors: Correlates at entry into a weight loss intervention study

PubMed Central

Liu, Fred X.; Flatt, Shirley W.; Pakiz, Bilgé; Sedjo, Rebecca L.; Wolin, Kathleen Y.; Blair, Cindy K.; Demark-Wahnefried, Wendy; Rock, Cheryl L.

2015-01-01

Purpose Physical activity is associated with reduced risk and progression of breast cancer, and exercise can improve physical function, quality of life and fatigue in cancer survivors. Evidence on factors associated with cancer survivors’ adherence to physical activity guidelines from the American Cancer Society and the U.S. Department of Health and Human Services is mixed. This study seeks to help fill this gap in knowledge by examining correlates with physical activity among breast cancer survivors. Methods Overweight or obese breast cancer survivors (N=692) were examined at enrollment into a weight loss intervention study. Questionnaires and medical record review ascertained data on education, race, ethnicity, menopausal status, physical activity, and medical history. Measures of anthropometrics and fitness level were conducted. Regression analysis examined associations between physical activity and demographic, clinical, and lifestyle factors. Results Overall, 23% of women met current guidelines. Multivariate analysis revealed that body mass index (p=0.03), emergency room visits in the past year (p=0.04), and number of co-morbidities (p=0.02) were associated with less physical activity. Geographic region also was associated with level of physical activity (p=0.02), with women in Alabama reporting significantly less activity than those in other participating regions. Conclusions The majority of overweight/obese breast cancer survivors did not meet physical activity recommendations. Physical activity levels were associated with degree of adiposity, geographic location, and number of co-morbidities. The majority of overweight breast cancer survivors should be encouraged to increase their level of physical activity. Individualizing exercise prescriptions according to medical co-morbidities may improve adherence. PMID:25975675

Loss of tight junction barrier function and its role in cancer metastasis.

PubMed

Martin, Tracey A; Jiang, Wen G

2009-04-01

As the most apical structure between epithelial and endothelial cells, tight junctions (TJ) are well known as functioning as a control for the paracellular diffusion of ions and certain molecules. It has however, become increasingly apparent that the TJ has a vital role in maintaining cell to cell integrity and that the loss of cohesion of the structure can lead to invasion and thus metastasis of cancer cells. This article will present data showing how modulation of expression of TJ molecules results in key changes in TJ barrier function leading to the successful metastasis of a number of different cancer types.

PARP inhibition causes premature loss of cohesion in cancer cells

PubMed Central

Kukolj, Eva; Kaufmann, Tanja; Dick, Amalie E.; Zeillinger, Robert; Gerlich, Daniel W.; Slade, Dea

2017-01-01

Poly(ADP-ribose) polymerases (PARPs) regulate various aspects of cellular function including mitotic progression. Although PARP inhibitors have been undergoing various clinical trials and the PARP1/2 inhibitor olaparib was approved as monotherapy for BRCA-mutated ovarian cancer, their mode of action in killing tumour cells is not fully understood. We investigated the effect of PARP inhibition on mitosis in cancerous (cervical, ovary, breast and osteosarcoma) and non-cancerous cells by live-cell imaging. The clinically relevant inhibitor olaparib induced strong perturbations in mitosis, including problems with chromosome alignment at the metaphase plate, anaphase delay, and premature loss of cohesion (cohesion fatigue) after a prolonged metaphase arrest, resulting in sister chromatid scattering. PARP1 and PARP2 depletion suppressed the phenotype while PARP2 overexpression enhanced it, suggesting that olaparib-bound PARP1 and PARP2 rather than the lack of catalytic activity causes this phenotype. Olaparib-induced mitotic chromatid scattering was observed in various cancer cell lines with increased protein levels of PARP1 and PARP2, but not in non-cancer or cancer cell lines that expressed lower levels of PARP1 or PARP2. Interestingly, the sister chromatid scattering phenotype occurred only when olaparib was added during the S-phase preceding mitosis, suggesting that PARP1 and PARP2 entrapment at replication forks impairs sister chromatid cohesion. Clinically relevant DNA-damaging agents that impair replication progression such as topoisomerase inhibitors and cisplatin were also found to induce sister chromatid scattering and metaphase plate alignment problems, suggesting that these mitotic phenotypes are a common outcome of replication perturbation. PMID:29262611

Loss of Nuclear Localized and Tyrosine Phosphorylated Stat5 in Breast Cancer Predicts Poor Clinical Outcome and Increased Risk of Antiestrogen Therapy Failure

PubMed Central

Peck, Amy R.; Witkiewicz, Agnieszka K.; Liu, Chengbao; Stringer, Ginger A.; Klimowicz, Alexander C.; Pequignot, Edward; Freydin, Boris; Tran, Thai H.; Yang, Ning; Rosenberg, Anne L.; Hooke, Jeffrey A.; Kovatich, Albert J.; Nevalainen, Marja T.; Shriver, Craig D.; Hyslop, Terry; Sauter, Guido; Rimm, David L.; Magliocco, Anthony M.; Rui, Hallgeir

2011-01-01

Purpose To investigate nuclear localized and tyrosine phosphorylated Stat5 (Nuc-pYStat5) as a marker of prognosis in node-negative breast cancer and as a predictor of response to antiestrogen therapy. Patients and Methods Levels of Nuc-pYStat5 were analyzed in five archival cohorts of breast cancer by traditional diaminobenzidine-chromogen immunostaining and pathologist scoring of whole tissue sections or by immunofluorescence and automated quantitative analysis (AQUA) of tissue microarrays. Results Nuc-pYStat5 was an independent prognostic marker as measured by cancer-specific survival (CSS) in patients with node-negative breast cancer who did not receive systemic adjuvant therapy, when adjusted for common pathology parameters in multivariate analyses both by standard chromogen detection with pathologist scoring of whole tissue sections (cohort I; n = 233) and quantitative immunofluorescence of a tissue microarray (cohort II; n = 291). Two distinct monoclonal antibodies gave concordant results. A progression array (cohort III; n = 180) revealed frequent loss of Nuc-pYStat5 in invasive carcinoma compared to normal breast epithelia or ductal carcinoma in situ, and general loss of Nuc-pYStat5 in lymph node metastases. In cohort IV (n = 221), loss of Nuc-pYStat5 was associated with increased risk of antiestrogen therapy failure as measured by univariate CSS and time to recurrence (TTR). More sensitive AQUA quantification of Nuc-pYStat5 in antiestrogen-treated patients (cohort V; n = 97) identified by multivariate analysis patients with low Nuc-pYStat5 at elevated risk for therapy failure (CSS hazard ratio [HR], 21.55; 95% CI, 5.61 to 82.77; P < .001; TTR HR, 7.30; 95% CI, 2.34 to 22.78; P = .001). Conclusion Nuc-pYStat5 is an independent prognostic marker in node-negative breast cancer. If confirmed in prospective studies, Nuc-pYStat5 may become a useful predictive marker of response to adjuvant hormone therapy. PMID:21576635

Loss of NR2E3 represses AHR by LSD1 reprogramming, is associated with poor prognosis in liver cancer.

PubMed

Khanal, Tilak; Choi, Kwangmin; Leung, Yuet-Kin; Wang, Jiang; Kim, Dasom; Janakiram, Vinothini; Cho, Sung-Gook; Puga, Alvaro; Ho, Shuk-Mei; Kim, Kyounghyun

2017-09-06

The aryl hydrocarbon receptor (AHR) plays crucial roles in inflammation, metabolic disorder, and cancer. However, the molecular mechanisms regulating AHR expression remain unknown. Here, we found that an orphan nuclear NR2E3 maintains AHR expression, and forms an active transcriptional complex with transcription factor Sp1 and coactivator GRIP1 in MCF-7 human breast and HepG2 liver cancer cell lines. NR2E3 loss promotes the recruitment of LSD1, a histone demethylase of histone 3 lysine 4 di-methylation (H3K4me2), to the AHR gene promoter region, resulting in repression of AHR expression. AHR expression and responsiveness along with H3K4me2 were significantly reduced in the livers of Nr2e3 rd7 (Rd7) mice that express low NR2E3 relative to the livers of wild-type mice. SP2509, an LSD1 inhibitor, fully restored AHR expression and H3K4me2 levels in Rd7 mice. Lastly, we demonstrated that both AHR and NR2E3 are significantly associated with good clinical outcomes in liver cancer. Together, our results reveal a novel link between NR2E3, AHR, and liver cancer via LSD1-mediated H3K4me2 histone modification in liver cancer development.

Pan-cancer analysis reveals technical artifacts in TCGA germline variant calls.

PubMed

Buckley, Alexandra R; Standish, Kristopher A; Bhutani, Kunal; Ideker, Trey; Lasken, Roger S; Carter, Hannah; Harismendy, Olivier; Schork, Nicholas J

2017-06-12

Cancer research to date has largely focused on somatically acquired genetic aberrations. In contrast, the degree to which germline, or inherited, variation contributes to tumorigenesis remains unclear, possibly due to a lack of accessible germline variant data. Here we called germline variants on 9618 cases from The Cancer Genome Atlas (TCGA) database representing 31 cancer types. We identified batch effects affecting loss of function (LOF) variant calls that can be traced back to differences in the way the sequence data were generated both within and across cancer types. Overall, LOF indel calls were more sensitive to technical artifacts than LOF Single Nucleotide Variant (SNV) calls. In particular, whole genome amplification of DNA prior to sequencing led to an artificially increased burden of LOF indel calls, which confounded association analyses relating germline variants to tumor type despite stringent indel filtering strategies. The samples affected by these technical artifacts include all acute myeloid leukemia and practically all ovarian cancer samples. We demonstrate how technical artifacts induced by whole genome amplification of DNA can lead to false positive germline-tumor type associations and suggest TCGA whole genome amplified samples be used with caution. This study draws attention to the need to be sensitive to problems associated with a lack of uniformity in data generation in TCGA data.

HNPCC-like cancer predisposition in mice through simultaneous loss of Msh3 and Msh6 mismatch-repair protein functions.

PubMed

de Wind, N; Dekker, M; Claij, N; Jansen, L; van Klink, Y; Radman, M; Riggins, G; van der Valk, M; van't Wout, K; te Riele, H

1999-11-01

Cancer predisposition in hereditary non-polyposis colon cancer (HNPCC) is caused by defects in DNA mismatch repair (MMR). Mismatch recognition is attributed to two heterodimeric protein complexes: MutSalpha (refs 2, 3, 4, 5), a dimer of MutS homologues MSH2 and MSH6; and MutSbeta (refs 2,7), a dimer of MSH2 and MSH3. These complexes have specific and redundant mismatch recognition capacity. Whereas MSH2 deficiency ablates the activity of both dimers, causing strong cancer predisposition in mice and men, loss of MSH3 or MSH6 (also known as GTBP) function causes a partial MMR defect. This may explain the rarity of MSH6 and absence of MSH3 germline mutations in HNPCC families. To test this, we have inactivated the mouse genes Msh3 (formerly Rep3 ) and Msh6 (formerly Gtmbp). Msh6-deficient mice were prone to cancer; most animals developed lymphomas or epithelial tumours originating from the skin and uterus but only rarely from the intestine. Msh3 deficiency did not cause cancer predisposition, but in an Msh6 -deficient background, loss of Msh3 accelerated intestinal tumorigenesis. Lymphomagenesis was not affected. Furthermore, mismatch-directed anti-recombination and sensitivity to methylating agents required Msh2 and Msh6, but not Msh3. Thus, loss of MMR functions specific to Msh2/Msh6 is sufficient for lymphoma development in mice, whereas predisposition to intestinal cancer requires loss of function of both Msh2/Msh6 and Msh2/Msh3.

SMAD4 Loss Is Associated with Cetuximab Resistance and Induction of MAPK/JNK Activation in Head and Neck Cancer Cells.

PubMed

Ozawa, Hiroyuki; Ranaweera, Ruchira S; Izumchenko, Evgeny; Makarev, Eugene; Zhavoronkov, Alex; Fertig, Elana J; Howard, Jason D; Markovic, Ana; Bedi, Atul; Ravi, Rajani; Perez, Jimena; Le, Quynh-Thu; Kong, Christina S; Jordan, Richard C; Wang, Hao; Kang, Hyunseok; Quon, Harry; Sidransky, David; Chung, Christine H

2017-09-01

Purpose: We previously demonstrated an association between decreased SMAD4 expression and cetuximab resistance in head and neck squamous cell carcinoma (HNSCC). The purpose of this study was to further elucidate the clinical relevance of SMAD4 loss in HNSCC. Experimental Design: SMAD4 expression was assessed by IHC in 130 newly diagnosed and 43 patients with recurrent HNSCC. Correlative statistical analysis with clinicopathologic data was also performed. OncoFinder, a bioinformatics tool, was used to analyze molecular signaling in TCGA tumors with low or high SMAD4 mRNA levels. The role of SMAD4 was investigated by shRNA knockdown and gene reconstitution of HPV-negative HNSCC cell lines in vitro and in vivo Results: Our analysis revealed that SMAD4 loss was associated with an aggressive, HPV-negative, cetuximab-resistant phenotype. We found a signature of prosurvival and antiapoptotic pathways that were commonly dysregulated in SMAD4 -low cases derived from TCGA-HNSCC dataset and an independent oral cavity squamous cell carcinoma (OSCC) cohort obtained from GEO. We show that SMAD4 depletion in an HNSCC cell line induces cetuximab resistance and results in worse survival in an orthotopic mouse model in vivo We implicate JNK and MAPK activation as mediators of cetuximab resistance and provide the foundation for the concomitant EGFR and JNK/MAPK inhibition as a potential strategy for overcoming cetuximab resistance in HNSCCs with SMAD4 loss. Conclusions: Our study demonstrates that loss of SMAD4 expression is a signature characterizing the cetuximab-resistant phenotype and suggests that SMAD4 expression may be a determinant of sensitivity/resistance to EGFR/MAPK or EGFR/JNK inhibition in HPV-negative HNSCC tumors. Clin Cancer Res; 23(17); 5162-75. ©2017 AACR . ©2017 American Association for Cancer Research.

Metabolic abnormalities associated with weight loss during chemoirradiation of head-and-neck cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lin, Alexander; Jabbari, Siavash; Worden, Francis P.

2005-12-01

Purpose: Weight loss caused by acute mucositis and dysphagia is common during concurrent chemoirradiation (chemo-RT) of head-and-neck (HN) cancer. The metabolic consequences of weight loss during chemo-RT were investigated. Patients and Methods: Ninety-six patients with locally advanced HN cancer were treated from 1995 to 2001 on protocols that consisted of 1 to 2 cycles of induction cisplatin/5-fluorouracil followed by irradiation (70 Gy over 7 weeks) concurrent with cisplatin (100 mg/m{sup 2} every 3 weeks). Body weights and metabolic evaluations were obtained before and during induction chemotherapy and chemo-RT. Greatest percent changes in weight and in the laboratory values were calculatedmore » for each phase of therapy. Results: During induction chemotherapy, significant changes were found in BUN, BUN:creatinine ratio, HCO{sub 3}, Mg, and albumin, but not in creatinine, Na, K, or weight. During chemo-RT, significant additional changes were observed in all parameters measured, including increases in BUN, creatinine, BUN: creatinine ratio, and HCO{sub 3} and decreases in Mg, albumin, Na, K, and weight. The magnitude of most of these changes was significantly greater during chemo-RT than during induction chemotherapy. During chemo-RT, 35% of the patients had more than 10% body weight loss and 6 patients had an increase in creatinine of more than 100%, including 5 patients with Grade 2 nephrotoxicity, all of whom had weight loss 10% or more. Significant correlations were found between weight loss and creatinine (p < 0.0001) or BUN (p = 0.0002) rises, but not with BUN:creatinine ratio or other metabolic changes. Age, gender, tobacco history, hypertension, and diabetes mellitus were not significant predictors of nephrotoxicity. Conclusions: Weight loss during cisplatin-containing chemo-RT was found to be associated with reduced kidney function. These findings do not establish cause-effect relationships; however, they highlight the importance of intensive

Productivity losses and public finance burden attributable to breast cancer in Poland, 2010-2014.

PubMed

Łyszczarz, Błażej; Nojszewska, Ewelina

2017-10-10

Apart from the health and social burden of the disease, breast cancer (BC) has important economic implications for the sick, health system and whole economy. There has been a growing interest in the economic aspects of breast cancer and analyses of the disease costs seem to be the most explored topic. However, the results from these studies are hardly comparable. With this study we aim to contribute to the field by providing estimates of productivity losses and public finance burden attributable to BC in Poland. We used retrospective prevalence-based top-down approach to estimate the productivity losses (indirect costs) of BC in Poland in the period 2010-2014. Human capital method (HCM) and societal perspective were used to estimate the costs of: absenteeism of the sick and caregivers, presenteeism of the sick and caregivers, disability, and premature mortality. We also used figures illustrating public finance burden attributable to the disease. Deterministic sensitivity analysis was performed to assess the stability of the estimates. A variety of data sources were used with the social insurance system and Polish National Cancer Registry being the most important ones. Productivity losses associated with BC in Poland were €583.7 million in 2010 and they increased to €699.7 million in 2014. Throughout the period these costs accounted for 0.162-0.171% of GDP, an equivalent of 62,531-65,816 per capita GDP. Losses attributable to disability and premature mortality proved to be the major cost drivers with 27.6%-30.6% and 22.0%-24.6% of the total costs respectively. The costs due to caregivers' presenteeism were negligible (0.1% of total costs). Public finance expenditure for social insurance benefits to BC sufferers ranged from €50.2 million (2010) to €56.6 million (2014), an equivalent of 0.72-0.79% of expenditures for all diseases. Potential losses in public finance revenues accounted for €173.9 million in 2010 and €211.0 million in 2014. Sensitivity

Daughters and Mothers Against Breast Cancer (DAMES): Main outcomes of a randomized controlled trial of weight loss in overweight mothers with breast cancer and their overweight daughters

PubMed Central

Demark-Wahnefried, Wendy; Jones, Lee W; Snyder, Denise C; Sloane, Richard J; Kimmick, Gretchen G; Hughes, Daniel C; Badr, Hoda J; Miller, Paige E; Burke, Lora E; Lipkus, Isaac M

2014-01-01

BACKGROUND Few studies to date have used the cancer diagnosis as a teachable moment to promote healthy behavior changes in survivors of cancer and their family members. Given the role of obesity in the primary and tertiary prevention of breast cancer, the authors explored the feasibility of a mother-daughter weight loss intervention. METHODS A randomized controlled trial of a mailed weight loss intervention was undertaken among 68 mother-daughter dyads (n = 136), each comprised of a survivor of breast cancer (AJCC stage 0-III) and her adult biological daughter. All women had body mass indices ≥ 25 kg/m2 and underwent in-person assessments at baseline, 6 months, and 12 months, with accelerometry and exercise capacity performed on a subset of individuals. All women received a personalized workbook and 6 newsletters over a 1-year period that promoted weight loss; exercise; and a nutrient-rich, low-energy density diet. A total of 25 dyads received individually tailored instruction (INDIVIDUAL), 25 dyads received team-tailored instruction (TEAM), and 18 dyads received standardized brochures (CONTROL). RESULTS The trial met its accrual target, experienced 90% retention, and caused no serious adverse events. Significant differences in baseline to 12-month changes were observed between INDIVIDUAL versus CONTROL mothers for body mass index, weight, and waist circumference (WC); significant differences also were observed in the WC of corresponding daughters (P < .05). Significant differences were found between INDIVIDUAL versus CONTROL and TEAM versus CONTROL dyads for WC (P = .0002 and .018, respectively), minutes per week of physical activity (P = .031 and .036, respectively), and exercise capacity (P = .047 for both). CONCLUSIONS Significant improvements in lifestyle behaviors and health outcomes are possible with tailored print interventions directed toward survivors of cancer and their family members. For greater impact, more research is needed

Annual Medical Expenditure and Productivity Loss Among Colorectal, Female Breast, and Prostate Cancer Survivors in the United States.

PubMed

Zheng, Zhiyuan; Yabroff, K Robin; Guy, Gery P; Han, Xuesong; Li, Chunyu; Banegas, Matthew P; Ekwueme, Donatus U; Jemal, Ahmedin

2016-05-01

There are limited nationally representative estimates of the annual economic burden among survivors of the three most prevalent cancers (colorectal, female breast, and prostate) in both nonelderly and elderly populations in the United States. The 2008 to 2012 Medical Expenditure Panel Survey data were used to identify colorectal (n = 540), female breast (n = 1568), and prostate (n = 1170) cancer survivors and individuals without a cancer history (n = 109 423). Excess economic burden attributable to cancer included per-person excess annual medical expenditures and productivity losses (employment disability, missed work days, and days stayed in bed). All analyses were stratified by cancer site and age (nonelderly: 18-64 years vs elderly: ≥ 65 years). Multivariable analyses controlled for age, sex, race/ethnicity, marital status, education, number of comorbidities, and geographic region. All statistical tests were two-sided. Compared with individuals without a cancer history, cancer survivors experienced annual excess medical expenditures (for the nonelderly population, colorectal: $8647, 95% confidence interval [CI] = $4932 to $13 974, P < .001; breast: $5119, 95% CI = $3439 to $7158, P < .001; prostate: $3586, 95% CI = $1792 to $6076, P < .001; for the elderly population, colorectal: $4913, 95% CI = $2768 to $7470, P < .001; breast: $2288, 95% CI = $814 to $3995, P = .002; prostate: $3524, 95% CI = $1539 to $5909, P < .001). Nonelderly colorectal and breast cancer survivors experienced statistically significant annual excess employment disability (13.6%, P < .001, and 4.8%, P = .001) and productivity loss at work (7.2 days, P < .001, and 3.3 days, P = .002) and at home (4.5 days, P < .001, and 3.3 days, P = .003). In contrast, elderly survivors of all three cancer sites had comparable productivity losses as those without a cancer history. Colorectal, breast, and prostate cancer survivors experienced statistically significantly higher economic burden compared with

Cone and Rod Loss in Stargardt Disease Revealed by Adaptive Optics Scanning Light Ophthalmoscopy

PubMed Central

Song, Hongxin; Rossi, Ethan A.; Latchney, Lisa; Bessette, Angela; Stone, Edwin; Hunter, Jennifer J.; Williams, David R.; Chung, Mina

2015-01-01

Importance Stargardt disease (STGD1) is characterized by macular atrophy and flecks in the retinal pigment epithelium. The causative ABCA4 gene encodes a protein localizing to photoreceptor outer segments. The pathologic steps by which ABCA4 mutations lead to clinically detectable retinal pigment epithelium changes remain unclear. We investigated early STGD1 using adaptive optics scanning light ophthalmoscopy. Observations Adaptive optics scanning light ophthalmoscopy imaging of 2 brothers with early STGD1 and their unaffected parents was compared with conventional imaging. Cone and rod spacing were increased in both patients (P <.001) with a dark cone appearance. No foveal cones were detected in the older brother. In the younger brother, foveal cones were enlarged with low density (peak cone density, 48.3 × 103 cones/mm2). The ratio of cone to rod spacing was increased in both patients, with greater divergence from normal approaching the foveal center, indicating that cone loss predominates centrally and rod loss increases peripherally. Both parents had normal photoreceptor mosaics. Genetic testing revealed 3 disease-causing mutations. Conclusions and Relevance This study provides in vivo images of rods and cones in STGD1. Although the primary clinical features of STGD1 are retinal pigment epithelial lesions, adaptive optics scanning light ophthalmoscopy reveals increased cone and rod spacing in areas that appear normal in conventional images, suggesting that photoreceptor loss precedes clinically detectable retinal pigment epithelial disease in STGD1. PMID:26247787

Mechanical phenotype of cancer cells: cell softening and loss of stiffness sensing.

PubMed

Lin, Hsi-Hui; Lin, Hsiu-Kuan; Lin, I-Hsuan; Chiou, Yu-Wei; Chen, Horn-Wei; Liu, Ching-Yi; Harn, Hans I-Chen; Chiu, Wen-Tai; Wang, Yang-Kao; Shen, Meng-Ru; Tang, Ming-Jer

2015-08-28

The stiffness sensing ability is required to respond to the stiffness of the matrix. Here we determined whether normal cells and cancer cells display distinct mechanical phenotypes. Cancer cells were softer than their normal counterparts, regardless of the type of cancer (breast, bladder, cervix, pancreas, or Ha-RasV12-transformed cells). When cultured on matrices of varying stiffness, low stiffness decreased proliferation in normal cells, while cancer cells and transformed cells lost this response. Thus, cancer cells undergo a change in their mechanical phenotype that includes cell softening and loss of stiffness sensing. Caveolin-1, which is suppressed in many tumor cells and in oncogene-transformed cells, regulates the mechanical phenotype. Caveolin-1-upregulated RhoA activity and Y397FAK phosphorylation directed actin cap formation, which was positively correlated with cell elasticity and stiffness sensing in fibroblasts. Ha-RasV12-induced transformation and changes in the mechanical phenotypes were reversed by re-expression of caveolin-1 and mimicked by the suppression of caveolin-1 in normal fibroblasts. This is the first study to describe this novel role for caveolin-1, linking mechanical phenotype to cell transformation. Furthermore, mechanical characteristics may serve as biomarkers for cell transformation.

Productivity loss due to premature mortality caused by blood cancer: a study based on patients undergoing stem cell transplantation.

PubMed

Ortega-Ortega, Marta; Oliva-Moreno, Juan; Jiménez-Aguilera, Juan de Dios; Romero-Aguilar, Antonio; Espigado-Tocino, Ildefonso

2015-01-01

Stem cell transplantation has been used for many years to treat haematological malignancies that could not be cured by other treatments. Despite this medical breakthrough, mortality rates remain high. Our purpose was to evaluate labour productivity losses associated with premature mortality due to blood cancer in recipients of stem cell transplantations. We collected primary data from the clinical histories of blood cancer patients who had undergone stem cell transplantation between 2006 and 2011 in two Spanish hospitals. We carried out a descriptive analysis and calculated the years of potential life lost and years of potential productive life lost. Labour productivity losses due to premature mortality were estimated using the Human Capital method. An alternative approach, the Friction Cost method, was used as part of the sensitivity analysis. Our findings suggest that, in a population of 179 transplanted and deceased patients, males and people who die between the ages of 30 and 49 years generate higher labour productivity losses. The estimated loss amounts to over €31.4 million using the Human Capital method (€480,152 using the Friction Cost method), which means an average of €185,855 per death. The highest labour productivity losses are produced by leukaemia. However, lymphoma generates the highest loss per death. Further efforts are needed to reduce premature mortality in blood cancer patients undergoing transplantations and reduce economic losses. Copyright © 2014 SESPAS. Published by Elsevier Espana. All rights reserved.

Reducing breast cancer recurrence with weight loss, a vanguard trial: the Exercise and Nutrition to Enhance Recovery and Good Health for You (ENERGY) Trial.

PubMed

Rock, Cheryl L; Byers, Tim E; Colditz, Graham A; Demark-Wahnefried, Wendy; Ganz, Patricia A; Wolin, Kathleen Y; Elias, Anthony; Krontiras, Helen; Liu, Jingxia; Naughton, Michael; Pakiz, Bilgé; Parker, Barbara A; Sedjo, Rebecca L; Wyatt, Holly

2013-03-01

Breast cancer is the most common invasive cancer among women in developed countries. Obesity is a major risk factor for breast cancer recurrence and mortality in both pre- and postmenopausal women. Co-morbid medical conditions are common among breast cancer survivors. The Exercise and Nutrition to Enhance Recovery and Good Health for You (ENERGY) study is a 4-year randomized clinical trial of 693 overweight/obese women aged ≥21years diagnosed with any early stage breast cancer (stages I[≥1cm]-III) within the previous five years, designed to demonstrate the feasibility of achieving sustained weight loss and to examine the impact of weight loss on quality of life and co-morbidities, and to enable future exploration of biochemical mechanisms linking obesity to lower likelihood of disease-free survival. This trial is strategically designed as a vanguard for a fully-powered trial of women who will be evaluated for breast cancer recurrence and disease-free survival. Participants were recruited between 2010 and 2012 at four sites, had completed initial therapies, and had a body mass index between 25 and 45kg/m(2). The intervention featured a group-based cognitive-behavioral weight loss program with telephone counseling and tailored newsletters to support initial weight loss and subsequent maintenance, with the goal of 7% weight loss at two years. This study has high potential to have a major impact on clinical management and outcomes after a breast cancer diagnosis. This trial initiates the effort to establish weight loss support for overweight or obese breast cancer survivors as a new standard of clinical care. Copyright © 2012 Elsevier Inc. All rights reserved.

CRISPRi and CRISPRa: New Functional Genomics Tools Provide Complementary Insights into Cancer Biology and Therapeutic Strategies | Office of Cancer Genomics

Cancer.gov

A central goal of research for targeted cancer therapy, or precision oncology, is to reveal the intrinsic vulnerabilities of cancer cells and exploit them as therapeutic targets. Examples of cancer cell vulnerabilities include driver oncogenes that are essential for the initiation and progression of cancer, or non-oncogene addictions resulting from the cancerous state of the cell. To identify vulnerabilities, scientists perform genetic “loss-of-function” and “gain-of-function” studies to better understand the roles of specific genes in cancer cells.

HER2 loss in HER2-positive gastric or gastroesophageal cancer after trastuzumab therapy: Implication for further clinical research.

PubMed

Pietrantonio, F; Caporale, M; Morano, F; Scartozzi, M; Gloghini, A; De Vita, F; Giommoni, E; Fornaro, L; Aprile, G; Melisi, D; Berenato, R; Mennitto, A; Volpi, C C; Laterza, M M; Pusceddu, V; Antonuzzo, L; Vasile, E; Ongaro, E; Simionato, F; de Braud, F; Torri, V; Di Bartolomeo, M

2016-12-15

Mechanisms of acquired resistance to trastuzumab-based treatment in gastric cancer are largely unknown. In this study, we analyzed 22 pairs of tumor samples taken at baseline and post-progression in patients receiving chemotherapy and trastuzumab for advanced HER2-positive [immunohistochemistry (IHC) 3+ or 2+ with in-situ hybridization (ISH) amplification] gastric or gastroesophageal cancers. Strict clinical criteria for defining acquired trastuzumab resistance were adopted. Loss of HER2 positivity and loss of HER2 over-expression were defined as post-trastuzumab IHC score <3+ and absence of ISH amplification, and IHC "downscoring" from 2+/3+ to 0/1+, respectively. HER2 IHC was always performed, while ISH was missing in 3 post-progression samples. Patients with initial HER2 IHC score 3+ and 2+ were 14 (64%) and 8 (36%), respectively. Loss of HER2 positivity and HER2 over-expression was observed in 32 and 32% samples, respectively. The chance of HER2 loss was not associated with any of the baseline clinicopathological variables. The only exception was in patients with initial IHC score 2+ versus 3+, for both endpoints of HER2 positivity (80 vs. 14%; p = 0.008) and HER2 over-expression (63 vs. 14%; p = 0.025). As already shown in breast cancer, loss of HER2 may be observed also in gastric cancers patients treated with trastuzumab-based chemotherapy in the clinical practice. This phenomenon may be one of the biological reasons explaining the failure of anti-HER2 second-line strategies in initially HER2-positive disease. © 2016 UICC.

Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer.

PubMed

Fraga, Mario F; Ballestar, Esteban; Villar-Garea, Ana; Boix-Chornet, Manuel; Espada, Jesus; Schotta, Gunnar; Bonaldi, Tiziana; Haydon, Claire; Ropero, Santiago; Petrie, Kevin; Iyer, N Gopalakrishna; Pérez-Rosado, Alberto; Calvo, Enrique; Lopez, Juan A; Cano, Amparo; Calasanz, Maria J; Colomer, Dolors; Piris, Miguel Angel; Ahn, Natalie; Imhof, Axel; Caldas, Carlos; Jenuwein, Thomas; Esteller, Manel

2005-04-01

CpG island hypermethylation and global genomic hypomethylation are common epigenetic features of cancer cells. Less attention has been focused on histone modifications in cancer cells. We characterized post-translational modifications to histone H4 in a comprehensive panel of normal tissues, cancer cell lines and primary tumors. Using immunodetection, high-performance capillary electrophoresis and mass spectrometry, we found that cancer cells had a loss of monoacetylated and trimethylated forms of histone H4. These changes appeared early and accumulated during the tumorigenic process, as we showed in a mouse model of multistage skin carcinogenesis. The losses occurred predominantly at the acetylated Lys16 and trimethylated Lys20 residues of histone H4 and were associated with the hypomethylation of DNA repetitive sequences, a well-known characteristic of cancer cells. Our data suggest that the global loss of monoacetylation and trimethylation of histone H4 is a common hallmark of human tumor cells.

Identification of eight candidate target genes of the recurrent 3p12-p14 loss in cervical cancer by integrative genomic profiling.

PubMed

Lando, Malin; Wilting, Saskia M; Snipstad, Kristin; Clancy, Trevor; Bierkens, Mariska; Aarnes, Eva-Katrine; Holden, Marit; Stokke, Trond; Sundfør, Kolbein; Holm, Ruth; Kristensen, Gunnar B; Steenbergen, Renske D M; Lyng, Heidi

2013-05-01

The pathogenetic role, including its target genes, of the recurrent 3p12-p14 loss in cervical cancer has remained unclear. To determine the onset of the event during carcinogenesis, we used microarray techniques and found that the loss was the most frequent 3p event, occurring in 61% of 92 invasive carcinomas, in only 2% of 43 high-grade intraepithelial lesions (CIN2/3), and in 33% of 6 CIN3 lesions adjacent to invasive carcinomas, suggesting a role in acquisition of invasiveness or early during the invasive phase. We performed an integrative DNA copy number and expression analysis of 77 invasive carcinomas, where all genes within the recurrent region were included. We selected eight genes, THOC7, PSMD6, SLC25A26, TMF1, RYBP, SHQ1, EBLN2, and GBE1, which were highly down-regulated in cases with loss, as confirmed at the protein level for RYBP and TMF1 by immunohistochemistry. The eight genes were subjected to network analysis based on the expression profiles, revealing interaction partners of proteins encoded by the genes that were coordinately regulated in tumours with loss. Several partners were shared among the eight genes, indicating crosstalk in their signalling. Gene ontology analysis showed enrichment of biological processes such as apoptosis, proliferation, and stress response in the network and suggested a relationship between down-regulation of the eight genes and activation of tumourigenic pathways. Survival analysis showed prognostic impact of the eight-gene signature that was confirmed in a validation cohort of 74 patients and was independent of clinical parameters. These results support the role of the eight candidate genes as targets of the 3p12-p14 loss in cervical cancer and suggest that the strong selection advantage of the loss during carcinogenesis might be caused by a synergetic effect of several tumourigenic processes controlled by these targets. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley

NOTCH pathway inactivation promotes bladder cancer progression

PubMed Central

Maraver, Antonio; Fernandez-Marcos, Pablo J.; Cash, Timothy P.; Mendez-Pertuz, Marinela; Dueñas, Marta; Maietta, Paolo; Martinelli, Paola; Muñoz-Martin, Maribel; Martínez-Fernández, Mónica; Cañamero, Marta; Roncador, Giovanna; Martinez-Torrecuadrada, Jorge L.; Grivas, Dimitrios; de la Pompa, Jose Luis; Valencia, Alfonso; Paramio, Jesús M.; Real, Francisco X.; Serrano, Manuel

2015-01-01

NOTCH signaling suppresses tumor growth and proliferation in several types of stratified epithelia. Here, we show that missense mutations in NOTCH1 and NOTCH2 found in human bladder cancers result in loss of function. In murine models, genetic ablation of the NOTCH pathway accelerated bladder tumorigenesis and promoted the formation of squamous cell carcinomas, with areas of mesenchymal features. Using bladder cancer cells, we determined that the NOTCH pathway stabilizes the epithelial phenotype through its effector HES1 and, consequently, loss of NOTCH activity favors the process of epithelial-mesenchymal transition. Evaluation of human bladder cancer samples revealed that tumors with low levels of HES1 present mesenchymal features and are more aggressive. Together, our results indicate that NOTCH serves as a tumor suppressor in the bladder and that loss of this pathway promotes mesenchymal and invasive features. PMID:25574842

Prognostic significance of the allelic loss of the BRCA1 gene in colorectal cancer

PubMed Central

Garcia, J M; Rodriguez, R; Dominguez, G; Silva, J M; Provencio, M; Silva, J; Colmenarejo, A; Millan, I; Muñoz, C; Salas, C; Coca, S; España, P; Bonilla, F

2003-01-01

Background: Survival at the intermediate stage of colorectal cancer (CRC) is less predictable than in the early and advanced stages. Several genetic markers possibly involved in growth and progression of CRC can be used for prognosis. Aims: This study investigated the proportion of allelic loss (loss of heterozygosity (LOH)) at the BRCA1 locus in sporadic CRC and its value in patient prognosis. Patients and methods: A total of 314 patients were investigated for LOH at the BRCA1 locus using polymerase chain reaction by means of three intragenic polymorphic microsatellite markers. Allelic losses were compared with clinicopathological characteristics of patients, recurrence rate, disease free survival (DFS), and overall survival. Results: Twenty six patients were excluded because of microsatellite instability. Of the remaining 288 cases, 244 (84.7%) were informative, with 97 (39.8%) patients bearing BRCA1 LOH. Recurrence rate was higher in patients with LOH (p = 0.0003), and DFS was 73.3% (SEM 5.7) at five years in patients without LOH, and 49.2% (7.1) in cases with positive allelic loss (p = 0.0004). Retention of alleles at the BRCA1 locus was associated with a favourable DFS in stages I and II (p<0.05). The presence of LOH was also significantly associated with short overall survival (p = 0.02). Multivariate analysis in the complete series showed that stage (p = 0.006) and lymph node metastases (⩾4 nodes, p = 0.0001; 1–3 nodes, p = 0.038) were independent prognostic factors. However, multivariate study by stages revealed that BRCA1 LOH was an independent prognostic factor in stages I and II (p = 0.001). Conclusions: BRCA1 LOH is a molecular alteration present in CRC, with unfavourable repercussions for overall survival, that could be considered as an outstanding independent prognostic factor in stages I and II. PMID:14633957

Combined Secretomics and Transcriptomics Revealed Cancer-Derived GDF15 is Involved in Diffuse-Type Gastric Cancer Progression and Fibroblast Activation.

PubMed

Ishige, Takayuki; Nishimura, Motoi; Satoh, Mamoru; Fujimoto, Mai; Fukuyo, Masaki; Semba, Toshihisa; Kado, Sayaka; Tsuchida, Sachio; Sawai, Setsu; Matsushita, Kazuyuki; Togawa, Akira; Matsubara, Hisahiro; Kaneda, Atsushi; Nomura, Fumio

2016-02-19

Gastric cancer is classified into two subtypes, diffuse and intestinal. The diffuse-type gastric cancer (DGC) has poorer prognosis, and the molecular pathology is not yet fully understood. The purpose of this study was to identify functional secreted molecules involved in DGC progression. We integrated the secretomics of six gastric cancer cell lines and gene expression analysis of gastric cancer tissues with publicly available microarray data. Hierarchical clustering revealed characteristic gene expression differences between diffuse- and intestinal-types. GDF15 was selected as a functional secreted molecule owing to high expression only in fetal tissues. Protein expression of GDF15 was higher in DGC cell lines and tissues. Serum levels of GDF15 were significant higher in DGC patients as compared with healthy individuals and chronic gastritis patients, and positively correlated with wall invasion and lymph node metastasis. In addition, the stimulation of GDF15 on NIH3T3 fibroblast enhanced proliferation and up-regulated expression of extracellular matrix genes, which were similar to TGF-β stimulation. These results indicate that GDF15 contributes to fibroblast activation. In conclusion, this study revealed that GDF15 may be a novel functional secreted molecule for DGC progression, possibly having important roles for cancer progression via the affecting fibroblast function, as well as TGF-β.

Genome sequencing of Ewing sarcoma patients reveals genetic predisposition | Center for Cancer Research

Cancer.gov

The largest and most comprehensive genomic analysis of individuals with Ewing sarcoma performed to date reveals that some patients are genetically predisposed to developing the cancer.  Learn more...

Potential microRNA-mediated oncogenic intercellular communication revealed by pan-cancer analysis

NASA Astrophysics Data System (ADS)

Li, Yue; Zhang, Zhaolei

2014-11-01

Carcinogenesis consists of oncogenesis and metastasis, and intriguingly microRNAs (miRNAs) are involved in both processes. Although aberrant miRNA activities are prevalent in diverse tumor types, the exact mechanisms for how they regulate cancerous processes are not always clear. To this end, we performed a large-scale pan-cancer analysis via a novel probabilistic approach to infer recurrent miRNA-target interactions implicated in 12 cancer types using data from The Cancer Genome Atlas. We discovered ~20,000 recurrent miRNA regulations, which are enriched for cancer-related miRNAs/genes. Notably, miRNA 200 family (miR-200/141/429) is among the most prominent miRNA regulators, which is known to be involved in metastasis. Importantly, the recurrent miRNA regulatory network is not only enriched for cancer pathways but also for extracellular matrix (ECM) organization and ECM-receptor interactions. The results suggest an intriguing cancer mechanism involving miRNA-mediated cell-to-cell communication, which possibly involves delivery of tumorigenic miRNA messengers to adjacent cells via exosomes. Finally, survival analysis revealed 414 recurrent-prognostic associations, where both gene and miRNA involved in each interaction conferred significant prognostic power in one or more cancer types. Together, our comprehensive pan-cancer analysis provided not only biological insights into metastasis but also brought to bear the clinical relevance of the proposed recurrent miRNA-gene associations.

Inhibition of bone loss with surface-modulated, drug-loaded nanoparticles in an intraosseous model of prostate cancer.

PubMed

Adjei, Isaac M; Sharma, Blanka; Peetla, Chiranjeevi; Labhasetwar, Vinod

2016-06-28

Advanced-stage prostate cancer usually metastasizes to bone and is untreatable due to poor biodistribution of intravenously administered anticancer drugs to bone. In this study, we modulated the surface charge/composition of biodegradable nanoparticles (NPs) to sustain their blood circulation time and made them small enough to extravasate through the openings of the bone's sinusoidal capillaries and thus localize into marrow. NPs with a neutral surface charge, achieved by modulating the NP surface-associated emulsifier composition, were more effective at localizing to bone marrow than NPs with a cationic or anionic surface charge. These small neutral NPs (~150nm vs. the more usual ~320nm) were also ~7-fold more effective in localizing in bone marrow than large NPs. We hypothesized that NPs that effectively localize to marrow could improve NP-mediated anticancer drug delivery to sites of bone metastasis, thereby inhibiting cancer progression and preventing bone loss. In a PC-3M-luc cell-induced osteolytic intraosseous model of prostate cancer, these small neutral NPs demonstrated greater accumulation in bone within metastatic sites than in normal contralateral bone as well as co-localization with the tumor mass in marrow. Significantly, a single-dose intravenous administration of these small neutral NPs loaded with paclitaxel (PTX-NPs), but not anionic PTX-NPs, slowed the progression of bone metastasis. In addition, neutral PTX-NPs prevented bone loss, whereas animals treated with the rapid-release drug formulation Cremophor EL (PTX-CrEL) or saline (control) showed >50% bone loss. Neutral PTX-NPs did not cause acute toxicity, whereas animals treated with PTX-CrEL experienced weight loss. These results indicate that NPs with appropriate physical and sustained drug-release characteristics could be explored to treat bone metastasis, a significant clinical issue in prostate and other cancers. Copyright © 2016 Elsevier B.V. All rights reserved.

Genome-wide copy number analysis reveals candidate gene loci that confer susceptibility to high-grade prostate cancer.

PubMed

Poniah, Prevathe; Mohd Zain, Shamsul; Abdul Razack, Azad Hassan; Kuppusamy, Shanggar; Karuppayah, Shankar; Sian Eng, Hooi; Mohamed, Zahurin

2017-09-01

Two key issues in prostate cancer (PCa) that demand attention currently are the need for a more precise and minimally invasive screening test owing to the inaccuracy of prostate-specific antigen and differential diagnosis to distinguish advanced vs. indolent cancers. This continues to pose a tremendous challenge in diagnosis and prognosis of PCa and could potentially lead to overdiagnosis and overtreatment complications. Copy number variations (CNVs) in the human genome have been linked to various carcinomas including PCa. Detection of these variants may improve clinical treatment as well as an understanding of the pathobiology underlying this complex disease. To this end, we undertook a pilot genome-wide CNV analysis approach in 36 subjects (18 patients with high-grade PCa and 18 controls that were matched by age and ethnicity) in search of more accurate biomarkers that could potentially explain susceptibility toward high-grade PCa. We conducted this study using the array comparative genomic hybridization technique. Array results were validated in 92 independent samples (46 high-grade PCa, 23 benign prostatic hyperplasia, and 23 healthy controls) using polymerase chain reaction-based copy number counting method. A total of 314 CNV regions were found to be unique to PCa subjects in this cohort (P<0.05). A log 2 ratio-based copy number analysis revealed 5 putative rare or novel CNV loci or both associated with susceptibility to PCa. The CNV gain regions were 1q21.3, 15q15, 7p12.1, and a novel CNV in PCa 12q23.1, harboring ARNT, THBS1, SLC5A8, and DDC genes that are crucial in the p53 and cancer pathways. A CNV loss and deletion event was observed at 8p11.21, which contains the SFRP1 gene from the Wnt signaling pathway. Cross-comparison analysis with genes associated to PCa revealed significant CNVs involved in biological processes that elicit cancer pathogenesis via cytokine production and endothelial cell proliferation. In conclusion, we postulated that the CNVs

[Malnutrition and weight loss - nurse assessment of nutritional status and counselling: experiences of patients with newly diagnosed or relapsed cancer].

PubMed

Kröner, A; Stoll, H; Spichiger, E

2012-04-01

Due to the anorexia-cachexia syndrome, cancer patients are already suffering from nutritional problems and weight loss by the time they receive their diagnosis and start chemotherapy. In the oncology outpatient clinic of a Swiss university hospital, patients currently undergo a nutritional assessment and receive individual counselling at the beginning of cancer treatment. This qualitative study explored cancer patients' experiences with weight loss and nutritional problems as well as how they experienced the assessment and the consecutive counselling by nurses. Interviews were conducted with 12 patients and qualitative content analysis was used for data analysis. Results showed that patients barely registered the weight loss and did not interpret it as an early warning signal. Nevertheless, they attempted to improve their nutritional habits soon after diagnosis, prior to receiving any counselling. The patients did not experience the assessment as troublesome. They appreciated the nurses' advice and implemented the suggestions they found appropriate. This study highlights the importance of patient education regarding weight loss and nutritional problems early in the course of an illness. Patients may not be aware of nutritional problems at this early stage and may lack the necessary specialised knowledge. Assessment and counselling provided by nurses offer targeted measures for prevention of malnutrition and weight loss.

Periodontal Disease, Tooth Loss and Cancer Risk in a Prospective Study of Male Health Professionals

PubMed Central

Michaud, Dominique S.; Liu, Yan; Meyer, Mara; Giovannucci, Edward; Joshipura, Kaumudi

2008-01-01

SUMMARY Background A number of studies suggest that tooth loss and periodontal disease may increase the risk of various cancers; however, it has been difficult to tease apart the role of oral health from that of smoking. We conducted an analysis to examine whether periodontal disease or tooth loss is associated with cancer risk. Methods The analysis was conducted in a prospective study of U.S. male health professionals aged 40 to 75 years. For this analysis, 48,375 men and 18 years of follow-up were available (1986 to January 31, 2004; median follow-up is 17.7 yrs), during which time 5720 incident cancer cases were documented (excluding nonmelanoma skin cancer and nonaggressive prostate cancer); the five most common cancers were colorectal (n=1043), melanoma of the skin (n=698), lung (n=678), bladder (n=543), and advanced prostate (n=541). Endpoints for this study were total cancer and individual cancers with more than 100 cases. Multivariate hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox proportional hazard models. Findings After adjusting for known risk factors, including detailed smoking history and dietary factors, periodontal disease history was associated with an increased risk of total cancer (HR = 1.14, 95% CI = 1.07–1.22, compared with no history of periodontal disease); by cancer site, statistically significant associations were observed for lung (HR = 1.36, 95% CI = 1.15–1.60), kidney (HR = 1.49, 95% CI = 1.12–1.97), pancreatic (HR = 1.54, 95% CI = 1.16–2.04; results previously published), and hematopoietic cancers (HR = 1.30, 95% CI = 1.11–1.53). Fewer teeth at baseline (0–16) was associated with a non-significant increase in risk of total cancer (HR = 1.09, 95% CI = 0.99–1.20, compared to 25–32 teeth); a statistically significant association was observed for lung cancer (HR = 1.70, 95% CI = 1.37–2.11, for 0–16 vs. 25–32 teeth). Among never smokers, periodontal disease was associated with

Proteomics reveals the effects of sustained weight loss on the human plasma proteome.

PubMed

Geyer, Philipp E; Wewer Albrechtsen, Nicolai J; Tyanova, Stefka; Grassl, Niklas; Iepsen, Eva W; Lundgren, Julie; Madsbad, Sten; Holst, Jens J; Torekov, Signe S; Mann, Matthias

2016-12-22

Sustained weight loss is a preferred intervention in a wide range of metabolic conditions, but the effects on an individual's health state remain ill-defined. Here, we investigate the plasma proteomes of a cohort of 43 obese individuals that had undergone 8 weeks of 12% body weight loss followed by a year of weight maintenance. Using mass spectrometry-based plasma proteome profiling, we measured 1,294 plasma proteomes. Longitudinal monitoring of the cohort revealed individual-specific protein levels with wide-ranging effects of losing weight on the plasma proteome reflected in 93 significantly affected proteins. The adipocyte-secreted SERPINF1 and apolipoprotein APOF1 were most significantly regulated with fold changes of -16% and +37%, respectively (P < 10 -13 ), and the entire apolipoprotein family showed characteristic differential regulation. Clinical laboratory parameters are reflected in the plasma proteome, and eight plasma proteins correlated better with insulin resistance than the known marker adiponectin. Nearly all study participants benefited from weight loss regarding a ten-protein inflammation panel defined from the proteomics data. We conclude that plasma proteome profiling broadly evaluates and monitors intervention in metabolic diseases. © 2016 The Authors. Published under the terms of the CC BY 4.0 license.

Dietary treatment of weight loss in patients with advanced cancer and cachexia: a systematic literature review.

PubMed

Balstad, Trude R; Solheim, Tora S; Strasser, Florian; Kaasa, Stein; Bye, Asta

2014-08-01

A systematical literature review evaluating the effect of dietary counseling in treating weight loss and improving energy intake in patients with advanced cancer with different stages of cachexia. Five publications were retrieved, of which three were randomized. Two out of five studies showed less weight loss with dietary counseling (+1% weight gain vs. -1.5% weight loss, p=0.03, 1.4kg vs. -2kg, p<0.05), two presented positive effect on energy intake (92% of total caloric need vs. 73%, p<0.01, 1865±317kcal vs. 1556±497kcal, ns). Dietary counseling can effect energy intake and body weight, however, apparent heterogeneity between studies is present. Based on these results there is not enough proof of evidence that dietary counseling given to patients with cancer is beneficial for improving weight or energy balance in the different cachexia stages. Nutrition is an essential part of cachexia treatment as it is not considered possible to increase or stabilize weight if nutritional needs are not met. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Loss of insulin-like growth factor II imprinting is a hallmark associated with enhanced chemo/radiotherapy resistance in cancer stem cells.

PubMed

Zhao, Xin; Liu, Xiaoliang; Wang, Guanjun; Wen, Xue; Zhang, Xiaoying; Hoffman, Andrew R; Li, Wei; Hu, Ji-Fan; Cui, Jiuwei

2016-08-09

Insulin-like growth factor II (IGF2) is maternally imprinted in most tissues, but the epigenetic regulation of the gene in cancer stem cells (CSCs) has not been defined. To study the epigenetic mechanisms underlying self-renewal, we isolated CSCs and non-CSCs from colon cancer (HT29, HRT18, HCT116), hepatoma (Hep3B), breast cancer (MCF7) and prostate cancer (ASPC) cell lines. In HT29 and HRT18 cells that show loss of IGF2 imprinting (LOI), IGF2 was biallelically expressed in the isolated CSCs. Surprisingly, we also found loss of IGF2 imprinting in CSCs derived from cell lines HCT116 and ASPC that overall demonstrate maintenance of IGF2 imprinting. Using chromatin conformation capture (3C), we found that intrachromosomal looping between the IGF2 promoters and the imprinting control region (ICR) was abrogated in CSCs, in parallel with loss of IGF2 imprinting in these CSCs. Loss of imprinting led to increased IGF2 expression in CSCs, which have a higher rate of colony formation and greater resistance to chemotherapy and radiotherapy in vitro. These studies demonstrate that IGF2 LOI is a common feature in CSCs, even when the stem cells are derived from a cell line in which the general population of cells maintain IGF2 imprinting. This finding suggests that aberrant IGF2 imprinting may be an intrinsic epigenetic control mechanism that enhances stemness, self-renewal and chemo/radiotherapy resistance in cancer stem cells.

Loss of HSulf-1 expression enhances tumorigenicity by inhibiting Bim expression in ovarian cancer.

PubMed

He, Xiaoping; Khurana, Ashwani; Roy, Debarshi; Kaufmann, Scott; Shridhar, Viji

2014-10-15

The expression of human Sulfatase1 (HSulf-1) is downregulated in the majority of primary ovarian cancer tumors, but the functional consequence of this downregulation remains unclear. Using two different shRNAs (Sh1 and Sh2), HSulf-1 expression was stably downregulated in ovarian cancer OV202 cells. We found that HSulf-1-deficient OV202 Sh1 and Sh2 cells formed colonies in soft agar. In contrast, nontargeting control (NTC) shRNA-transduced OV202 cells did not form any colonies. Moreover, subcutaneous injection of OV202 HSulf-1-deficient cells resulted in tumor formation in nude mice, whereas OV202 NTC cells did not. Also, ectopic expression of HSulf-1 in ovarian cancer SKOV3 cells significantly suppressed tumor growth in nude mice. Here, we show that HSulf-1-deficient OV202 cells have markedly decreased expression of proapoptotic Bim protein, which can be rescued by restoring HSulf-1 expression in OV202 Sh1 cells. Enhanced expression of HSulf-1 in HSulf-1-deficient SKOV3 cells resulted in increased Bim expression. Decreased Bim levels after loss of HSulf-1 were due to increased p-ERK, because inhibition of ERK activity with PD98059 resulted in increased Bim expression. However, treatment with a PI3 kinase/AKT inhibitor, LY294002, failed to show any change in Bim protein level. Importantly, rescuing Bim expression in HSulf-1 knockdown cells significantly retarded tumor growth in nude mice. Collectively, these results suggest that loss of HSulf-1 expression promotes tumorigenicity in ovarian cancer through regulating Bim expression. © 2014 UICC.

Intravital imaging reveals new ancillary mechanisms co-opted by cancer cells to drive tumor progression

PubMed Central

Lucas, Morghan C.; Timpson, Paul

2016-01-01

Intravital imaging is providing new insights into the dynamics of tumor progression in native tissues and has started to reveal the layers of complexity found in cancer. Recent advances in intravital imaging have allowed us to look deeper into cancer behavior and to dissect the interactions between tumor cells and the ancillary host niche that promote cancer development. In this review, we provide an insight into the latest advances in cancer biology achieved by intravital imaging, focusing on recently discovered mechanisms by which tumor cells manipulate normal tissue to facilitate disease progression. PMID:27239290

Met synergizes with p53 loss to induce mammary tumors that possess features of claudin-low breast cancer

PubMed Central

Knight, Jennifer F.; Lesurf, Robert; Zhao, Hong; Pinnaduwage, Dushanthi; Davis, Ryan R.; Saleh, Sadiq M. I.; Zuo, Dongmei; Naujokas, Monica A.; Chughtai, Naila; Herschkowitz, Jason I.; Prat, Aleix; Mulligan, Anna Marie; Muller, William J.; Cardiff, Robert D.; Gregg, Jeff P.; Andrulis, Irene L.; Hallett, Michael T.; Park, Morag

2013-01-01

Triple-negative breast cancer (TNBC) accounts for ∼20% of cases and contributes to basal and claudin-low molecular subclasses of the disease. TNBCs have poor prognosis, display frequent mutations in tumor suppressor gene p53 (TP53), and lack targeted therapies. The MET receptor tyrosine kinase is elevated in TNBC and transgenic Met models (Metmt) develop basal-like tumors. To investigate collaborating events in the genesis of TNBC, we generated Metmt mice with conditional loss of murine p53 (Trp53) in mammary epithelia. Somatic Trp53 loss, in combination with Metmt, significantly increased tumor penetrance over Metmt or Trp53 loss alone. Unlike Metmt tumors, which are histologically diverse and enriched in a basal-like molecular signature, the majority of Metmt tumors with Trp53 loss displayed a spindloid pathology with a distinct molecular signature that resembles the human claudin-low subtype of TNBC, including diminished claudins, an epithelial-to-mesenchymal transition signature, and decreased expression of the microRNA-200 family. Moreover, although mammary specific loss of Trp53 promotes tumors with diverse pathologies, those with spindloid pathology and claudin-low signature display genomic Met amplification. In both models, MET activity is required for maintenance of the claudin-low morphological phenotype, in which MET inhibitors restore cell-cell junctions, rescue claudin 1 expression, and abrogate growth and dissemination of cells in vivo. Among human breast cancers, elevated levels of MET and stabilized TP53, indicative of mutation, correlate with highly proliferative TNBCs of poor outcome. This work shows synergy between MET and TP53 loss for claudin-low breast cancer, identifies a restricted claudin-low gene signature, and provides a rationale for anti-MET therapies in TNBC. PMID:23509284

Loss of intercellular adhesion leads to differential accumulation of hypericin in bladder cancer

NASA Astrophysics Data System (ADS)

Lucky, S. Sasidharan; Bhuvaneswari, Ramaswamy; Chin, William W. L.; Lau, Weber K. O.; Olivo, Malini C. D.

2009-06-01

Photodynamic diagnosis (PDD) exploits the photoactive nature of certain compounds, namely photosensitizers, in order to enhance the visual demarcation between normal and neoplastic tissue. Hypericin is one such potent photosensitizer that preferentially accumulate in neoplastic tissue, and fluoresce in the visible spectrum when illuminated with light of an appropriate wavelength. In our study, we investigated the role of E-cadherin in the selective permeation of hypericin in bladder cancer tissues. Clinical studies were done on a series of 43 histologically graded bladder cancer biopsy specimens, obtained from 28 patients who received intravesical instillations with 8μM hypericin solution for at least 2 hours. Immunohistochemical staining was used to assess the expression of E-cadherin, in the cryosectioned tissues. Hypericin uptake was examined by fluorescence microscopy. Immunohistochemical staining showed a clear expression of E-cadherin along the urothelial lining of the normal and pre-malignant tissues. Partial expression of these cell adhesion molecules were still observed in malignant tissues, however there was a loss of expression to variable extends along the urothelium. Thus, loss of intercellular adhesion can be associated with enhanced hypericin permeation through paracellular diffusion.

Detailed longitudinal sampling of glioma stem cells in situ reveals Chr7 gain and Chr10 loss as repeated events in primary tumor formation and recurrence.

PubMed

Baysan, Mehmet; Woolard, Kevin; Cam, Margaret C; Zhang, Wei; Song, Hua; Kotliarova, Svetlana; Balamatsias, Demosthenes; Linkous, Amanda; Ahn, Susie; Walling, Jennifer; Belova, Galina I; Fine, Howard A

2017-11-15

Intratumoral heterogeneity at the genetic, epigenetic, transcriptomic, and morphologic levels is a commonly observed phenomenon in many aggressive cancer types. Clonal evolution during tumor formation and in response to therapeutic intervention can be predicted utilizing reverse engineering approaches on detailed genomic snapshots of heterogeneous patient tumor samples. In this study, we developed an extensive dataset for a GBM case via the generation of polyclonal and monoclonal glioma stem cell lines from initial diagnosis, and from multiple sections of distant tumor locations of the deceased patient's brain following tumor recurrence. Our analyses revealed the tissue-wide expansion of a new clone in the recurrent tumor and chromosome 7 gain and chromosome 10 loss as repeated genomic events in primary and recurrent disease. Moreover, chromosome 7 gain and chromosome 10 loss produced similar alterations in mRNA expression profiles in primary and recurrent tumors despite possessing other highly heterogeneous and divergent genomic alterations between the tumors. We identified ETV1 and CDK6 as putative candidate genes, and NFKB (complex), IL1B, IL6, Akt and VEGF as potential signaling regulators, as potentially central downstream effectors of chr7 gain and chr10 loss. Finally, the differences caused by the transcriptomic shift following gain of chromosome 7 and loss of chromosome 10 were consistent with those generally seen in GBM samples compared to normal brain in large-scale patient-tumor data sets. © 2017 UICC.

Integrative Analysis of Subcellular Quantitative Proteomics Studies Reveals Functional Cytoskeleton Membrane-Lipid Raft Interactions in Cancer.

PubMed

Shah, Anup D; Inder, Kerry L; Shah, Alok K; Cristino, Alexandre S; McKie, Arthur B; Gabra, Hani; Davis, Melissa J; Hill, Michelle M

2016-10-07

Lipid rafts are dynamic membrane microdomains that orchestrate molecular interactions and are implicated in cancer development. To understand the functions of lipid rafts in cancer, we performed an integrated analysis of quantitative lipid raft proteomics data sets modeling progression in breast cancer, melanoma, and renal cell carcinoma. This analysis revealed that cancer development is associated with increased membrane raft-cytoskeleton interactions, with ∼40% of elevated lipid raft proteins being cytoskeletal components. Previous studies suggest a potential functional role for the raft-cytoskeleton in the action of the putative tumor suppressors PTRF/Cavin-1 and Merlin. To extend the observation, we examined lipid raft proteome modulation by an unrelated tumor suppressor opioid binding protein cell-adhesion molecule (OPCML) in ovarian cancer SKOV3 cells. In agreement with the other model systems, quantitative proteomics revealed that 39% of OPCML-depleted lipid raft proteins are cytoskeletal components, with microfilaments and intermediate filaments specifically down-regulated. Furthermore, protein-protein interaction network and simulation analysis showed significantly higher interactions among cancer raft proteins compared with general human raft proteins. Collectively, these results suggest increased cytoskeleton-mediated stabilization of lipid raft domains with greater molecular interactions as a common, functional, and reversible feature of cancer cells.

Results of the Exercise and Nutrition to Enhance Recovery and Good Health for You (ENERGY) Trial: A Behavioral Weight Loss Intervention in Overweight or Obese Breast Cancer Survivors

PubMed Central

Rock, Cheryl L.; Flatt, Shirley W.; Byers, Tim E.; Colditz, Graham A.; Demark-Wahnefried, Wendy; Ganz, Patricia A.; Wolin, Kathleen Y.; Elias, Anthony; Krontiras, Helen; Liu, Jingxia; Naughton, Michael; Pakiz, Bilgé; Parker, Barbara A.; Sedjo, Rebecca L.; Wyatt, Holly

2015-01-01

Purpose Obesity increases risk for all-cause and breast cancer mortality and comorbidities in women who have been diagnosed and treated for breast cancer. The Exercise and Nutrition to Enhance Recovery and Good Health for You (ENERGY) study is the largest weight loss intervention trial among survivors of breast cancer to date. Methods In this multicenter trial, 692 overweight/obese women who were, on average, 2 years since primary treatment for early-stage breast cancer were randomly assigned to either a group-based behavioral intervention, supplemented with telephone counseling and tailored newsletters, to support weight loss or a less intensive control intervention and observed for 2 years. Weight and blood pressure were measured at 6, 12, 18, and 24 months. Longitudinal mixed models were used to analyze change over time. Results At 12 months, mean weight loss was 6.0% of initial weight in the intervention group and 1.5% in the control group (P < .001). At 24 months, mean weight loss in the intervention and control groups was 3.7% and 1.3%, respectively (P < .001). Favorable effects of the intervention on physical activity and blood pressure were observed. The weight loss intervention was more effective among women older than 55 years than among younger women. Conclusion A behavioral weight loss intervention can lead to clinically meaningful weight loss in overweight/obese survivors of breast cancer. These findings support the need to conduct additional studies to test methods that support sustained weight loss and to examine the potential benefit of intentional weight loss on breast cancer recurrence and survival. PMID:26282657

Loss of PEDF: A Novel Mechanism of Antihormone Resistance in Breast Cancer

DTIC Science & Technology

2013-08-01

phosphorylated ERa, Akt, and RET in these tumors. Discussion Resistance to endocrine therapy presents a major chal- lenge in the management of ERa-positive... Drury S, Dowsett M, Martin LA, Isacke CM: Targeting the receptor tyrosine kinase RET sensitizes breast cancer cells to tamoxifen treatment and reveals

Revealing cancer subtypes with higher-order correlations applied to imaging and omics data.

PubMed

Graim, Kiley; Liu, Tiffany Ting; Achrol, Achal S; Paull, Evan O; Newton, Yulia; Chang, Steven D; Harsh, Griffith R; Cordero, Sergio P; Rubin, Daniel L; Stuart, Joshua M

2017-03-31

Patient stratification to identify subtypes with different disease manifestations, severity, and expected survival time is a critical task in cancer diagnosis and treatment. While stratification approaches using various biomarkers (including high-throughput gene expression measurements) for patient-to-patient comparisons have been successful in elucidating previously unseen subtypes, there remains an untapped potential of incorporating various genotypic and phenotypic data to discover novel or improved groupings. Here, we present HOCUS, a unified analytical framework for patient stratification that uses a community detection technique to extract subtypes out of sparse patient measurements. HOCUS constructs a patient-to-patient network from similarities in the data and iteratively groups and reconstructs the network into higher order clusters. We investigate the merits of using higher-order correlations to cluster samples of cancer patients in terms of their associations with survival outcomes. In an initial test of the method, the approach identifies cancer subtypes in mutation data of glioblastoma, ovarian, breast, prostate, and bladder cancers. In several cases, HOCUS provides an improvement over using the molecular features directly to compare samples. Application of HOCUS to glioblastoma images reveals a size and location classification of tumors that improves over human expert-based stratification. Subtypes based on higher order features can reveal comparable or distinct groupings. The distinct solutions can provide biologically- and treatment-relevant solutions that are just as significant as solutions based on the original data.

Allele Imbalance or Loss of Heterozygosity, in Normal Appearing Breast Epithelium as a Novel Biomarker to Predict Future Breast Cancer

DTIC Science & Technology

2011-07-10

benign biopsy, had no atypia on the benign biopsy, and had no family history of breast cancer. For each breast cancer case, she selected one control...biopsies lacked atypia , and who had no fa mily history of breast cancer. 10-μ sections were cut from paraffin blocks and TDLUs were removed by laser...TITLE: Allele Imbalance or loss of heterozygosity, in normal- appearing breast epithelium as a novel biomarker to predict future breast cancer

Most small bowel cancers are revealed by a complication

PubMed Central

Negoi, Ionut; Paun, Sorin; Hostiuc, Sorin; Stoica, Bodgan; Tanase, Ioan; Negoi, Ruxandra Irina; Beuran, Mircea

2015-01-01

ABSTRACT Objective To characterize the pattern of primary small bowel cancers in a tertiary East-European hospital. Methods A retrospective study of patients with small bowel cancers admitted to a tertiary emergency center, over the past 15 years. Results There were 57 patients with small bowel cancer, representing 0.039% of admissions and 0.059% of laparotomies. There were 37 (64.9%) men, mean age of 58 years; and 72 years for females. Out of 57 patients, 48 (84.2%) were admitted due to an emergency situation: obstruction in 21 (38.9%), perforation in 17 (31.5%), upper gastrointestinal bleeding in 8 (14.8%), and lower gastrointestinal bleeding in 2 (3.7%). There were 10 (17.5%) duodenal tumors, 21 (36.8%) jejunal tumors and 26 (45.6%) ileal tumors. The most frequent neoplasms were gastrointestinal stromal tumor in 24 patients (42.1%), adenocarcinoma in 19 (33.3%), lymphoma in 8 (14%), and carcinoids in 2 (3.5%). The prevalence of duodenal adenocarcinoma was 14.55 times greater than that of the small bowel, and the prevalence of duodenal stromal tumors was 1.818 time greater than that of the small bowel. Obstruction was the complication in adenocarcinoma in 57.9% of cases, and perforation was the major local complication (47.8%) in stromal tumors. Conclusion Primary small bowel cancers are usually diagnosed at advanced stages, and revealed by a local complication of the tumor. Their surgical management in emergency setting is associated to significant morbidity and mortality rates. PMID:26676271

Cervical cancer in Indian women reveals contrasting association among common sub-family of HLA class I alleles.

PubMed

Gokhale, Priyanka; Mania-Pramanik, Jayanti; Sonawani, Archana; Idicula-Thomas, Susan; Kerkar, Shilpa; Tongaonkar, Hemant; Chaudhari, Hemangi; Warke, Himangi; Salvi, Vinita

2014-12-01

We studied the relationship between human leukocyte antigen (HLA) class I alleles and cervical cancer among Indian women. Seventy-five cervical cancer cases were compared with 175 noncancer controls. Cervical biopsy tissue specimen from cancer cases and cervical swab specimen from controls were collected for HPV detection and typing. Blood was taken for HLA typing by PCR-SSOP method. The impact of HLA class I alleles on cervical cancer risk was evaluated using StatCalc program (Epi Info version 6.0.4. CDC Atlanta, GA, USA), and confirmed with Bonferroni correction. Results revealed HLA-B*37, HLA-B*58 were associated significantly with increased risk while HLA-B*40 with decreased risk for cervical cancer. At high-resolution analysis after Bonferroni correction, HLA-B*37:01 allele was associated with increased risk, whereas HLA-B*40:06 was with decreased risk for cervical cancer. HLA-B*37:01 and HLA-B*40:06 belong to the same superfamily of HLA-B44. In silico analysis revealed different binding affinities of HLA-B*37:01 and HLA-B*40:06 for the epitopes predicted for E6 and L1 proteins of HPV16. The higher binding affinity of epitopes to B*40:06, as revealed by docking studies, supports the hypothesis that this allele is able to present the antigenic peptides more efficiently than B*37:01 and thereby can protect the carriers from the risk of cervical cancer. Thus, there is a clear indication that HLA plays an important role in the development of cervical cancer in HPV-infected women. Identification of these factors in high-risk HPV-infected women may help in reducing the cervical cancer burden in India.

Loss of PTEN expression is associated with colorectal cancer liver metastasis and poor patient survival

PubMed Central

Sawai, Hirozumi; Yasuda, Akira; Ochi, Nobuo; Ma, Jiachi; Matsuo, Yoichi; Wakasugi, Takehiro; Takahashi, Hiroki; Funahashi, Hitoshi; Sato, Mikinori; Takeyama, Hiromitsu

2008-01-01

Background The tumour suppressor phosphatase and tensin homolog (PTEN) is an important negative regulator of cell-survival signaling. To evaluate the correlation between PTEN expression and clinicopathological characteristics of colorectal cancer patients with and without liver metastases, we investigated PTEN expression in primary colorectal cancer and colorectal cancer liver metastases. Methods Sixty-nine pairs of primary colorectal cancer and corresponding liver metastasis specimens were analyzed immunohistochemically, and the correlation between immunohistochemical findings and clinicopathological factors was investigated. Seventy primary colorectal cancer specimens from patients without liver metastases were used as controls. Results PTEN was strongly expressed in 44 (62.9%) colorectal cancer specimens from patients without liver metastases. In contrast, PTEN was weakly expressed in 52 (75.4%) primary colorectal cancer specimens from patients with liver metastases, and was absent in liver metastases. Weak PTEN expression in colorectal cancer tissues was significantly associated with advanced TNM stage (p < 0.01) and lymph node metastasis (p < 0.05). PTEN expression was significantly stronger in primary colorectal cancer specimens from patients without liver metastases. Furthermore, among colorectal cancer patients with liver metastases, the 5-year survival rate was significantly higher in patients with positive PTEN expression compared to those with negative PTEN expression (p = 0.012). Conclusion Our results suggest that loss of PTEN expression is involved with colorectal cancer aggressive capacity and that diagnostic evaluation of PTEN expression may provide valuable prognostic information to aid treatment strategies for colorectal cancer patients. PMID:19036165

Suicide Gene-Engineered Stromal Cells Reveal a Dynamic Regulation of Cancer Metastasis

NASA Astrophysics Data System (ADS)

Shen, Keyue; Luk, Samantha; Elman, Jessica; Murray, Ryan; Mukundan, Shilpaa; Parekkadan, Biju

2016-02-01

Cancer-associated fibroblasts (CAFs) are a major cancer-promoting component in the tumor microenvironment (TME). The dynamic role of human CAFs in cancer progression has been ill-defined because human CAFs lack a unique marker needed for a cell-specific, promoter-driven knockout model. Here, we developed an engineered human CAF cell line with an inducible suicide gene to enable selective in vivo elimination of human CAFs at different stages of xenograft tumor development, effectively circumventing the challenge of targeting a cell-specific marker. Suicide-engineered CAFs were highly sensitive to apoptosis induction in vitro and in vivo by the addition of a simple small molecule inducer. Selection of timepoints for targeted CAF apoptosis in vivo during the progression of a human breast cancer xenograft model was guided by a bi-phasic host cytokine response that peaked at early timepoints after tumor implantation. Remarkably, we observed that the selective apoptosis of CAFs at these early timepoints did not affect primary tumor growth, but instead increased the presence of tumor-associated macrophages and the metastatic spread of breast cancer cells to the lung and bone. The study revealed a dynamic relationship between CAFs and cancer metastasis that has counter-intuitive ramifications for CAF-targeted therapy.

Periodontal disease, tooth loss and colorectal cancer risk: Results from the Nurses' Health Study.

PubMed

Momen-Heravi, Fatemeh; Babic, Ana; Tworoger, Shelley S; Zhang, Libin; Wu, Kana; Smith-Warner, Stephanie A; Ogino, Shuji; Chan, Andrew T; Meyerhardt, Jeffrey; Giovannucci, Edward; Fuchs, Charles; Cho, Eunyoung; Michaud, Dominique S; Stampfer, Meir J; Yu, Yau-Hua; Kim, David; Zhang, Xuehong

2017-02-01

Periodontal diseases including tooth loss might increase systemic inflammation, lead to immune dysregulation and alter gut microbiota, thereby possibly influencing colorectal carcinogenesis. Few epidemiological studies have examined the association between periodontal diseases and colorectal cancer (CRC) risk. We collected information on the periodontal disease (defined as history of periodontal bone loss) and number of natural teeth in the Nurses' Health Study. A total of 77,443 women were followed since 1992. We used Cox proportional hazard models to calculate multivariable hazard ratios (HRs) and 95% confidence intervals (95% CIs) after adjustment for smoking and other known risk factors for CRC. We documented 1,165 incident CRC through 2010. Compared to women with 25-32 teeth, the multivariable HR (95% CI) for CRC for women with <17 teeth was 1.20 (1.04-1.39). With regard to tumor site, the HRs (95% CIs) for the same comparison were 1.23 (1.01-1.51) for proximal colon cancer, 1.03 (0.76-1.38) for distal colon cancer and 1.48 (1.07-2.05) for rectal cancer. In addition, compared to those without periodontal disease, HRs for CRC were 0.91 (95% CI 0.74-1.12) for periodontal disease, and 1.22 (95% CI 0.91-1.63) when limited to moderate to severe periodontal disease. The results were not modified by smoking status, body mass index or alcohol consumption. Women with fewer teeth, possibly moderate or severe periodontal disease, might be at a modest increased risk of developing CRC, suggesting a potential role of oral health in colorectal carcinogenesis. © 2016 UICC.

Periodontal disease, tooth loss, and colorectal cancer risk: results from the Nurses’ Health Study

PubMed Central

Momen-Heravi, Fatemeh; Babic, Ana; Tworoger, Shelley S.; Zhang, Libin; Wu, Kana; Smith-Warner, Stephanie A.; Ogino, Shuji; Chan, Andrew T.; Meyerhardt, Jeffrey; Giovannucci, Edward; Fuchs, Charles; Cho, Eunyoung; Michaud, Dominique S.; Stampfer, Meir J.; Yu, Yau-Hua; Kim, David; Zhang, Xuehong

2016-01-01

Periodontal diseases including tooth loss might increase systemic inflammation, lead to immune dysregulation, and alter gut microbiota, thereby possibly influencing colorectal carcinogenesis. Few epidemiological studies have examined the association between periodontal diseases and colorectal cancer (CRC) risk. We collected information on the periodontal disease (defined as history of periodontal bone loss) and number of natural teeth in the Nurses’ Health Study. A total of 77,443 women were followed since 1992. We used Cox proportional hazard models to calculate multivariable hazard ratios (HRs) and 95% confidence intervals (95% CIs) after adjustment for smoking and other known risk factors for CRC. We documented 1,165 incident CRC through 2010. Compared to women with 25–32 teeth, the multivariable HR (95% CI) for CRC for women with < 17 teeth was 1.20 (1.04–1.39). With regard to tumor site, the HRs (95% CIs) for the same comparison were 1.23 (1.01–1.51) for proximal colon cancer, 1.03 (0.76–1.38) for distal colon cancer, and 1.48 (1.07–2.05) for rectal cancer. Additionally, compared to those without periodontal disease, HRs for CRC were 0.91 (95% CI 0.74–1.12) for periodontal disease, and 1.22 (95% CI 0.91–1.63) when limited to moderate to severe periodontal disease. The results were not modified by smoking status, body mass index, or alcohol consumption. Women with fewer teeth, possibly moderate or severe periodontal disease, might be at a modest increased risk of developing CRC, suggesting a potential role of oral health in colorectal carcinogenesis. PMID:27778343

Results of the Exercise and Nutrition to Enhance Recovery and Good Health for You (ENERGY) Trial: A Behavioral Weight Loss Intervention in Overweight or Obese Breast Cancer Survivors.

PubMed

Rock, Cheryl L; Flatt, Shirley W; Byers, Tim E; Colditz, Graham A; Demark-Wahnefried, Wendy; Ganz, Patricia A; Wolin, Kathleen Y; Elias, Anthony; Krontiras, Helen; Liu, Jingxia; Naughton, Michael; Pakiz, Bilgé; Parker, Barbara A; Sedjo, Rebecca L; Wyatt, Holly

2015-10-01

Obesity increases risk for all-cause and breast cancer mortality and comorbidities in women who have been diagnosed and treated for breast cancer. The Exercise and Nutrition to Enhance Recovery and Good Health for You (ENERGY) study is the largest weight loss intervention trial among survivors of breast cancer to date. In this multicenter trial, 692 overweight/obese women who were, on average, 2 years since primary treatment for early-stage breast cancer were randomly assigned to either a group-based behavioral intervention, supplemented with telephone counseling and tailored newsletters, to support weight loss or a less intensive control intervention and observed for 2 years. Weight and blood pressure were measured at 6, 12, 18, and 24 months. Longitudinal mixed models were used to analyze change over time. At 12 months, mean weight loss was 6.0% of initial weight in the intervention group and 1.5% in the control group (P<.001). At 24 months, mean weight loss in the intervention and control groups was 3.7% and 1.3%, respectively (P<.001). Favorable effects of the intervention on physical activity and blood pressure were observed. The weight loss intervention was more effective among women older than 55 years than among younger women. A behavioral weight loss intervention can lead to clinically meaningful weight loss in overweight/obese survivors of breast cancer. These findings support the need to conduct additional studies to test methods that support sustained weight loss and to examine the potential benefit of intentional weight loss on breast cancer recurrence and survival. © 2015 by American Society of Clinical Oncology.

A qualitative evaluation of a group phone-based weight loss intervention for rural breast cancer survivors: Themes and mechanisms of success.

PubMed

Fazzino, Tera L; Sporn, Nora J; Befort, Christie A

2016-07-01

Obesity is prevalent in breast cancer survivors and is a significant risk factor for recurrence and mortality. Weight management interventions for survivors have been diverse in design (in-person vs. phone-based, group vs. individual) and yielded varying weight loss results. Given these issues, participants themselves may provide insight into treatment-based factors that contributed to their weight loss outcomes. Here, we report qualitative results from interviews with survivors in a group phone-based weight loss intervention, with the objective of identifying mechanisms that facilitated or hindered adherence and weight loss. We explored interest in paying for continued treatment as an indicator of dissemination potential. Individual interviews were conducted with 186 rural, obese breast cancer survivors upon completion of a 6-month weight loss intervention that produced clinically meaningful weight loss (>5 %) in 91 % of participants. A thematic analysis of the interview data was performed. Five themes were identified as impacting adherence and success: (1) accountability; (2) importance of the group, with varying levels of connectedness; (3) dietary convenience; (4) difficulty maintaining intervention components that required more effort; and (5) importance of internal motivation to attributions of physical activity success or failure. Most were interested in paying to continue the program if it were extended beyond the study. Key intervention components that participants attributed to their success included supportive group processes and convenience. Results highlight the group phone-based approach as a potential venue for disseminating an effective weight loss program for breast cancer survivors. NCT01441011.

Effectiveness of tranexamic acid in reducing blood loss during cytoreductive surgery for advanced ovarian cancer.

PubMed

Kietpeerakool, Chumnan; Supoken, Amornrat; Laopaiboon, Malinee; Lumbiganon, Pisake

2016-01-23

Ovarian cancer is the third most common gynaecological cancer worldwide, with an age-standardised incidence rate of 6.1 per 10,000 women. Standard therapy for advanced epithelial ovarian cancer (EOC) includes a combination of cytoreductive surgery and platinum-based chemotherapy. Cytoreductive surgery aims to remove as much of the visible tumour as possible. As extensive intraperitoneal metastases are typical of advanced EOC, cytoreductive surgery is usually an extensive procedure with the risk of excessive bleeding. Tranexamic acid given perioperatively is effective in reducing blood loss and allogeneic blood transfusion requirements in a variety of surgical settings. Therefore, tranexamic acid seems to be a promising agent for minimising blood loss and the need for blood transfusion among women with advanced EOC undergoing cytoreductive surgery. To assess the effects of tranexamic acid for reducing blood loss associated with cytoreductive surgery in women with advanced EOC (stage III to IV). We searched the Cochrane Gynaecological, Neuro-oncology and Orphan Cancers Trial Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 5, 2015), MEDLINE, EMBASE and conference proceedings to May 2015. We also checked registers of clinical trials, citation lists of included studies, key textbooks and previous systematic reviews for potentially relevant studies. We included randomised controlled trials (RCTs) comparing tranexamic acid given during surgery versus placebo or no treatment, in adult women diagnosed with advanced EOC. Two review authors (CK, AS) independently selected potentially relevant trials, extracted data, assessed risk of bias, compared results and resolved disagreements by discussion. We found only one study that met our inclusion criteria. This was a randomised double blind, placebo-controlled multicentre study conducted to evaluate the effectiveness of a single dose of intravenous tranexamic acid (15 mg/kg body weight) versus

Behavioral manifestations of audiometrically-defined "slight" or "hidden" hearing loss revealed by measures of binaural detection.

PubMed

Bernstein, Leslie R; Trahiotis, Constantine

2016-11-01

This study assessed whether audiometrically-defined "slight" or "hidden" hearing losses might be associated with degradations in binaural processing as measured in binaural detection experiments employing interaurally delayed signals and maskers. Thirty-one listeners participated, all having no greater than slight hearing losses (i.e., no thresholds greater than 25 dB HL). Across the 31 listeners and consistent with the findings of Bernstein and Trahiotis [(2015). J. Acoust. Soc. Am. 138, EL474-EL479] binaural detection thresholds at 500 Hz and 4 kHz increased with increasing magnitude of interaural delay, suggesting a loss of precision of coding with magnitude of interaural delay. Binaural detection thresholds were consistently found to be elevated for listeners whose absolute thresholds at 4 kHz exceeded 7.5 dB HL. No such elevations were observed in conditions having no binaural cues available to aid detection (i.e., "monaural" conditions). Partitioning and analyses of the data revealed that those elevated thresholds (1) were more attributable to hearing level than to age and (2) result from increased levels of internal noise. The data suggest that listeners whose high-frequency monaural hearing status would be classified audiometrically as being normal or "slight loss" may exhibit substantial and perceptually meaningful losses of binaural processing.

TUSC3 Loss Alters the ER Stress Response and Accelerates Prostate Cancer Growth in vivo

NASA Astrophysics Data System (ADS)

Horak, Peter; Tomasich, Erwin; Vaňhara, Petr; Kratochvílová, Kateřina; Anees, Mariam; Marhold, Maximilian; Lemberger, Christof E.; Gerschpacher, Marion; Horvat, Reinhard; Sibilia, Maria; Pils, Dietmar; Krainer, Michael

2014-01-01

Prostate cancer is the most prevalent cancer in males in developed countries. Tumor suppressor candidate 3 (TUSC3) has been identified as a putative tumor suppressor gene in prostate cancer, though its function has not been characterized. TUSC3 shares homologies with the yeast oligosaccharyltransferase (OST) complex subunit Ost3p, suggesting a role in protein glycosylation. We provide evidence that TUSC3 is part of the OST complex and affects N-linked glycosylation in mammalian cells. Loss of TUSC3 expression in DU145 and PC3 prostate cancer cell lines leads to increased proliferation, migration and invasion as well as accelerated xenograft growth in a PTEN negative background. TUSC3 downregulation also affects endoplasmic reticulum (ER) structure and stress response, which results in increased Akt signaling. Together, our findings provide first mechanistic insight in TUSC3 function in prostate carcinogenesis in general and N-glycosylation in particular.

Loss of estrogen-related receptor α promotes hepatocarcinogenesis development via metabolic and inflammatory disturbances

PubMed Central

Hong, Eui-Ju; Levasseur, Marie-Pier; Dufour, Catherine R.; Perry, Marie-Claude; Giguère, Vincent

2013-01-01

Estrogen-related receptor α (ERRα) is a key regulator of mitochondrial function and metabolism essential for energy-driven cellular processes in both normal and cancer cells. ERRα has also been shown to mediate bone-derived macrophage activation by proinflammatory cytokines. However, the role of ERRα in cancer in which inflammation acts as a tumor promoter has yet to be investigated. Herein we show that global loss of ERRα accelerates the development of diethylnitrosamine (DEN)-induced hepatocellular carcinoma. Biochemical and metabolomics studies revealed that loss of ERRα promotes hepatocyte necrosis over apoptosis in response to DEN due to a deficiency in energy production. We further show that increased hepatocyte death and associated compensatory proliferation observed in DEN-injured ERRα-null livers is concomitant with increased nuclear factor κB (NF-κB)–dependent transcriptional control of cytokine expression in Kupffer cells. In particular, we demonstrate that loss of ERRα-dependent regulation of the NF-κB inhibitor IκBα leads to enhanced NF-κB activity and cytokine gene activation. Our work thus shows that global loss of ERRα activity promotes hepatocellular carcinoma by independent but synergistic mechanisms in hepatocytes and Kupffer cells, implying that pharmacological manipulation of ERRα activity may have a significant clinical impact on carcinogen-induced cancers. PMID:24127579

Optimal management of cancer treatment-induced bone loss: considerations for elderly patients.

PubMed

Tipples, Karen; Robinson, Anne

2011-11-01

Hormone manipulation, commonly used in breast and prostate cancer, can result in significant bone loss. In multiple myeloma (MM), corticosteroids play an important role in therapy but increase the risk of fracture over that expected for any given bone mineral density. These adverse effects on the skeletal system are particularly relevant in the elderly population, in whom osteoporosis can significantly affect not only quality of life but also survival. The associated health and social care costs are becoming increasingly important. Screening with dual energy x-ray absorptiometry (DXA) scans and lifestyle advice on smoking, alcohol and dietary intake are essential parts of the management of patients with cancer treatment-induced bone loss. The value of exercise also cannot be underestimated. A careful drug review should be carried out to eliminate agents that may potentially exacerbate bone toxicity. Therapies to address bone toxicities include bisphosphonates, which have been shown to play an increasingly important role in preventing declines in bone health. The issues of compliance when oral agents are used should not be underestimated. Renal toxicity and osteonecrosis of the jaw are relevant toxicities, especially in the elderly. Cardiac toxicity has not been proven, but there is evidence to suggest that the suppression of bone turnover seen with some, although not all, bisphosphonates is not reversed following cessation of treatment. The implications of this finding need to be borne in mind when treating elderly patients. The possibility of atypical fractures in patients taking bisphosphonates also needs to be given consideration, although this remains a rare complication. Recently, the receptor activator of nuclear factor-κB ligand (RANKL) ligand antibody denosumab has been shown to be of value in fracture prevention, and its subcutaneous route of administration offers a potential advantage. Oncologists should also remember that tamoxifen, which has little

Perceived susceptibility to breast cancer moderates the effect of gain- and loss-framed messages on use of screening mammography.

PubMed

Gallagher, Kristel M; Updegraff, John A; Rothman, Alexander J; Sims, Linda

2011-03-01

This study examined the role of three distinct beliefs about risk (risks associated with screening, construal of the function of screening as health-affirming or illness-detecting, and perceived susceptibility to breast cancer) in moderating women's responses to framed messages that promote mammography. Three hundred fifty-five women recruited from an inner city hospital, nonadherent to guidelines for receiving annual screening mammograms,were randomly assigned to view a gain- or loss-framed video message about the importance of mammography. Mammography screening was self-reported at a 3-month follow-up. Only perceived susceptibility to breast cancer significantly moderated the effect of message framing on screening. Women with average and higher levels of perceived susceptibility for breast cancer were significantly more likely to report screening after viewing a loss-framed message compared to a gain-framed message. No effects of framing on reported screening were observed for women with lower levels of perceived susceptibility. The study identifies a key role for perceived susceptibility in shaping responses to framed messages that promote cancer screenings. (c) 2011 APA, all rights reserved

Loss of Stromal Caveolin-1 Expression: A Novel Tumor Microenvironment Biomarker That Can Predict Poor Clinical Outcomes for Pancreatic Cancer

PubMed Central

Shan, Tao; Lu, Hongwei; Ji, Hong; Li, Yiming; Guo, Jian; Chen, Xi; Wu, Tao

2014-01-01

Aims Cancer development and progression is not only associated with the tumor cell proliferation but also depends on the interaction between tumor cells and the stromal microenvironment. A new understanding of the role of the tumor microenvironment suggests that the loss of stromal caveolin-1 (Cav-1) as a key regulator may become a potential therapy target. This study aims to elucidate whether stromal Cav-1 expression in pancreatic cancer can be a strong prognosis biomarker. Methods Tissue samples from 45 pancreatic cancer patients were studied. Parenchyma and stroma were separated and purified using laser capture microdissection. Stromal Cav-1 expression was measured from pancreatic cancer, paraneoplastic, and normal tissue using immunohistochemistry. We analyzed the correlation of stromal Cav-1 expression with clinicopathologic features and prognostic indicators, such as tumor marker HER-2/neu gene. Results Specimens from six patients (13.3%) showed high levels of stromal Cav-1 staining, those from eight patients (17.8%) showed a lower, intermediate level of staining, whereas those from 31 patients (68.9%) showed an absence of staining. Cav-1 expression in cancer-associated fibroblasts was lower than that in paracancer-associated and in normal fibroblasts. Stromal Cav-1 loss was associated with TNM stage (P = 0.018), lymph node metastasis (P = 0.014), distant metastasis (P = 0.027), and HER-2/neu amplification (P = 0.007). The relationships of age, sex, histological grade, and tumor size with stromal Cav-1 expression were not significant (P>0.05). A negative correlation was found between circulating tumor cells and stromal Cav-1 expression (P<0.05). Conclusion The loss of stromal Cav-1 in pancreatic cancer was an independent prognostic indicator, thus suggesting that stromal Cav-1 may be an effective therapeutic target for patients with pancreatic cancer. PMID:24949874

Breast cancer survivors' experience of making weight, dietary and physical activity changes during participation in a weight loss intervention.

PubMed

Terranova, Caroline O; Lawler, Sheleigh P; Spathonis, Kym; Eakin, Elizabeth G; Reeves, Marina M

2017-05-01

The aim of this study is to explore breast cancer survivors' experience of a weight loss intervention and identify potential facilitators and barriers of initiating and maintaining weight, dietary or physical activity changes. Fourteen women randomised to and completing the 12-month weight loss intervention completed semi-structured interviews 7.5 ± 0.5 months after intervention completion. An inductive thematic analysis was conducted whereby interviews were independently coded and themes identified. Women were (mean ± SD) 55.6 ± 8.5 years, 30.2 ± 4.6 kg/m 2 and 17.1 ± 3.4 months post-diagnosis at study baseline. Four themes emerged: (1) perceived motivation to participate in the intervention, (2) facilitators, (3) challenges and (4) maintenance of weight loss and behaviour changes. All women noted the impact of social/family environments, either to facilitate (e.g., support from family members) or impede (e.g., major family event) changes. The structure and support of the intervention, particularly accountability to their coach, was also seen as facilitating. Formation of habitual physical activity facilitated dietary changes. Dietary change strategies most perceived to facilitate weight loss were reducing energy intake by dietary self-monitoring, increasing vegetable intake and portion control. Challenges included breast cancer-specific issues such as post-diagnosis weight gain, treatment-related side effects and psychological issues around readiness to change and self-regulation. Diminished accountability following intervention completion impacted the maintenance of weight loss and behaviour changes, notably dietary self-monitoring. Results suggest that formal involvement of a support person (e.g. family member/friend) and referring women to ongoing, community-based services to maintain patient-perceived accountability may be particularly useful strategies for future weight loss intervention trials targeting women with breast cancer.

A randomized trial of adjunct testosterone for cancer-related muscle loss in men and women.

PubMed

Wright, Traver J; Dillon, E Lichar; Durham, William J; Chamberlain, Albert; Randolph, Kathleen M; Danesi, Christopher; Horstman, Astrid M; Gilkison, Charles R; Willis, Maurice; Richardson, Gwyn; Hatch, Sandra S; Jupiter, Daniel C; McCammon, Susan; Urban, Randall J; Sheffield-Moore, Melinda

2018-06-01

Cancer cachexia negatively impacts cancer-related treatment options, quality of life, morbidity, and mortality, yet no established therapies exist. We investigated the anabolic properties of testosterone to limit the loss of body mass in late stage cancer patients undergoing standard of care cancer treatment. A randomized, double-blind, placebo-controlled phase II clinical trial was undertaken to assess the potential therapeutic role of adjunct testosterone to limit loss of body mass in patients with squamous cell carcinoma of the cervix or head and neck undergoing standard of care treatment including chemotherapy and chemoradiation. Patients were randomly assigned in blocks to receive weekly injections of either 100 mg testosterone enanthate or placebo for 7 weeks. The primary outcome was per cent change in lean body mass, and secondary outcomes included assessment of quality of life, tests of physical performance, muscle strength, daily activity levels, resting energy expenditure, nutritional intake, and overall survival. A total of 28 patients were enrolled, 22 patients were studied to completion, and 21 patients were included in the final analysis (12 placebo, nine testosterone). Adjunct testosterone increased lean body mass by 3.2% (95% confidence interval [CI], 0-7%) whereas those receiving placebo lost 3.3% (95% CI, -7% to 1%, P = 0.015). Although testosterone patients maintained more favourable body condition, sustained daily activity levels, and showed meaningful improvements in quality of life and physical performance, overall survival was similar in both treatment groups. In patients with advanced cancer undergoing the early phase of standard of care therapy, adjunct testosterone improved lean body mass and was also associated with increased quality of life, and physical activity compared with placebo. © 2018 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia

Side Effects: Hair Loss (Alopecia)

Cancer.gov

Hair loss, also called alopecia, is a side effect of cancer treatments, such as chemotherapy and radiation therapy. Learn how to cope with and manage hair loss. Listen to tips from others who have experienced hair loss.

Proteome-metabolome profiling of ovarian cancer ascites reveals novel components involved in intercellular communication.

PubMed

Shender, Victoria O; Pavlyukov, Marat S; Ziganshin, Rustam H; Arapidi, Georgij P; Kovalchuk, Sergey I; Anikanov, Nikolay A; Altukhov, Ilya A; Alexeev, Dmitry G; Butenko, Ivan O; Shavarda, Alexey L; Khomyakova, Elena B; Evtushenko, Evgeniy; Ashrafyan, Lev A; Antonova, Irina B; Kuznetcov, Igor N; Gorbachev, Alexey Yu; Shakhparonov, Mikhail I; Govorun, Vadim M

2014-12-01

Ovarian cancer ascites is a native medium for cancer cells that allows investigation of their secretome in a natural environment. This medium is of interest as a promising source of potential biomarkers, and also as a medium for cell-cell communication. The aim of this study was to elucidate specific features of the malignant ascites metabolome and proteome. In order to omit components of the systemic response to ascites formation, we compared malignant ascites with cirrhosis ascites. Metabolome analysis revealed 41 components that differed significantly between malignant and cirrhosis ascites. Most of the identified cancer-specific metabolites are known to be important signaling molecules. Proteomic analysis identified 2096 and 1855 proteins in the ovarian cancer and cirrhosis ascites, respectively; 424 proteins were specific for the malignant ascites. Functional analysis of the proteome demonstrated that the major differences between cirrhosis and malignant ascites were observed for the cluster of spliceosomal proteins. Additionally, we demonstrate that several splicing RNAs were exclusively detected in malignant ascites, where they probably existed within protein complexes. This result was confirmed in vitro using an ovarian cancer cell line. Identification of spliceosomal proteins and RNAs in an extracellular medium is of particular interest; the finding suggests that they might play a role in the communication between cancer cells. In addition, malignant ascites contains a high number of exosomes that are known to play an important role in signal transduction. Thus our study reveals the specific features of malignant ascites that are associated with its function as a medium of intercellular communication. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Can loss and grief activate latent neoplasia? A clinical case of possible interaction between genetic risk and stress in breast cancer.

PubMed

Biondi, M; Costantini, A; Parisi, A

1996-01-01

Nineteenth-century physicians working with cancer patients frequently reported that severe emotional losses and grief occurred in some cases before cancer. Research on psychoneuroimmunology seems to reactivate this interest and could give a possible convincing background. We recently observed the case of a 45-year-old woman who developed symptoms of breast cancer (ductal infiltrating carcinoma, T1, N1, M0) 3 years after the loss of her only child. The affection for the child compensated inadequacies of her marriage, which became increasingly unstable. The child died in a dramatic accident at home, while his mother was near him but unable to help. The patient had a moderate genetic-familial risk of mammary cancer. Animal studies strongly suggest that stress, through neuroimmunomodulatory mediatory mechanisms, can significantly affect appearance and progression of mammary cancer. The patient developed long-lasting intense grief, despair and hopelessness. We discuss the case from three main standpoints: genetic and risk factors for breast cancer; findings which demonstrated a relationship between stress, neuroimmunomodulation and cancer in animals; data from autopsy studies which found foci of latent breast cancer in 20% of healthy women in the same age range. Stress does not create cancer. However we hypothesize that in this case it could have contributed by the activation of a latent neoplasia and/or by impairing immunosurveillance during a critical life phase.

Determination of synthetic lethal interactions in KRAS oncogene-dependent cancer cells reveals novel therapeutic targeting strategies

PubMed Central

Steckel, Michael; Molina-Arcas, Miriam; Weigelt, Britta; Marani, Michaela; Warne, Patricia H; Kuznetsov, Hanna; Kelly, Gavin; Saunders, Becky; Howell, Michael; Downward, Julian; Hancock, David C

2012-01-01

Oncogenic mutations in RAS genes are very common in human cancer, resulting in cells with well-characterized selective advantages, but also less well-understood vulnerabilities. We have carried out a large-scale loss-of-function screen to identify genes that are required by KRAS-transformed colon cancer cells, but not by derivatives lacking this oncogene. Top-scoring genes were then tested in a larger panel of KRAS mutant and wild-type cancer cells. Cancer cells expressing oncogenic KRAS were found to be highly dependent on the transcription factor GATA2 and the DNA replication initiation regulator CDC6. Extending this analysis using a collection of drugs with known targets, we found that cancer cells with mutant KRAS showed selective addiction to proteasome function, as well as synthetic lethality with topoisomerase inhibition. Combination targeting of these functions caused improved killing of KRAS mutant cells relative to wild-type cells. These observations suggest novel targets and new ways of combining existing therapies for optimal effect in RAS mutant cancers, which are traditionally seen as being highly refractory to therapy. PMID:22613949

NDH expression marks major transitions in plant evolution and reveals coordinate intracellular gene loss.

PubMed

Ruhlman, Tracey A; Chang, Wan-Jung; Chen, Jeremy J W; Huang, Yao-Ting; Chan, Ming-Tsair; Zhang, Jin; Liao, De-Chih; Blazier, John C; Jin, Xiaohua; Shih, Ming-Che; Jansen, Robert K; Lin, Choun-Sea

2015-04-11

Key innovations have facilitated novel niche utilization, such as the movement of the algal predecessors of land plants into terrestrial habitats where drastic fluctuations in light intensity, ultraviolet radiation and water limitation required a number of adaptations. The NDH (NADH dehydrogenase-like) complex of Viridiplantae plastids participates in adapting the photosynthetic response to environmental stress, suggesting its involvement in the transition to terrestrial habitats. Although relatively rare, the loss or pseudogenization of plastid NDH genes is widely distributed across diverse lineages of photoautotrophic seed plants and mutants/transgenics lacking NDH function demonstrate little difference from wild type under non-stressed conditions. This study analyzes large transcriptomic and genomic datasets to evaluate the persistence and loss of NDH expression across plants. Nuclear expression profiles showed accretion of the NDH gene complement at key transitions in land plant evolution, such as the transition to land and at the base of the angiosperm lineage. While detection of transcripts for a selection of non-NDH, photosynthesis related proteins was independent of the state of NDH, coordinate, lineage-specific loss of plastid NDH genes and expression of nuclear-encoded NDH subunits was documented in Pinaceae, gnetophytes, Orchidaceae and Geraniales confirming the independent and complete loss of NDH in these diverse seed plant taxa. The broad phylogenetic distribution of NDH loss and the subtle phenotypes of mutants suggest that the NDH complex is of limited biological significance in contemporary plants. While NDH activity appears dispensable under favorable conditions, there were likely sufficiently frequent episodes of abiotic stress affecting terrestrial habitats to allow the retention of NDH activity. These findings reveal genetic factors influencing plant/environment interactions in a changing climate through 450 million years of land plant

Productivity losses due to premature mortality from cancer in Brazil, Russia, India, China, and South Africa (BRICS): A population-based comparison.

PubMed

Pearce, Alison; Sharp, Linda; Hanly, Paul; Barchuk, Anton; Bray, Freddie; de Camargo Cancela, Marianna; Gupta, Prakash; Meheus, Filip; Qiao, You-Lin; Sitas, Freddy; Wang, Shao-Ming; Soerjomataram, Isabelle

2018-04-01

Over two-thirds of the world's cancer deaths occur in economically developing countries; however, the societal costs of cancer have rarely been assessed in these settings. Our aim was to estimate the value of productivity lost in 2012 due to cancer-related premature mortality in the major developing economies of Brazil, the Russian Federation, India, China and South Africa (BRICS). We applied an incidence-based method using the human capital approach. We used annual adult cancer deaths from GLOBOCAN2012 to estimate the years of productive life lost between cancer death and pensionable age in each country, valued using national and international data for wages, and workforce statistics. Sensitivity analyses examined various methodological assumptions. The total cost of lost productivity due to premature cancer mortality in the BRICS countries in 2012 was $46·3 billion, representing 0·33% of their combined gross domestic product. The largest total productivity loss was in China ($28 billion), while South Africa had the highest cost per cancer death ($101,000). Total productivity losses were greatest for lung cancer in Brazil, the Russian Federation and South Africa; liver cancer in China; and lip and oral cavity cancers in India. Locally-tailored strategies are required to reduce the economic burden of cancer in developing economies. Focussing on tobacco control, vaccination programs and cancer screening, combined with access to adequate treatment, could yield significant gains for both public health and economic performance of the BRICS countries. Copyright © 2017 Elsevier Ltd. All rights reserved.

Novel role of NOX in supporting aerobic glycolysis in cancer cells with mitochondrial dysfunction and as a potential target for cancer therapy.

PubMed

Lu, Weiqin; Hu, Yumin; Chen, Gang; Chen, Zhao; Zhang, Hui; Wang, Feng; Feng, Li; Pelicano, Helene; Wang, Hua; Keating, Michael J; Liu, Jinsong; McKeehan, Wallace; Wang, Huamin; Luo, Yongde; Huang, Peng

2012-01-01

Elevated aerobic glycolysis in cancer cells (the Warburg effect) may be attributed to respiration injury or mitochondrial dysfunction, but the underlying mechanisms and therapeutic significance remain elusive. Here we report that induction of mitochondrial respiratory defect by tetracycline-controlled expression of a dominant negative form of DNA polymerase γ causes a metabolic shift from oxidative phosphorylation to glycolysis and increases ROS generation. We show that upregulation of NOX is critical to support the elevated glycolysis by providing additional NAD+. The upregulation of NOX is also consistently observed in cancer cells with compromised mitochondria due to the activation of oncogenic Ras or loss of p53, and in primary pancreatic cancer tissues. Suppression of NOX by chemical inhibition or genetic knockdown of gene expression selectively impacts cancer cells with mitochondrial dysfunction, leading to a decrease in cellular glycolysis, a loss of cell viability, and inhibition of cancer growth in vivo. Our study reveals a previously unrecognized function of NOX in cancer metabolism and suggests that NOX is a potential novel target for cancer treatment.

Differences in skeletal muscle loss caused by cytotoxic chemotherapy and molecular targeted therapy in patients with advanced non-small cell lung cancer.

PubMed

Kakinuma, Kazutaka; Tsuruoka, Hazime; Morikawa, Kei; Furuya, Naoki; Inoue, Takeo; Miyazawa, Teruomi; Mineshita, Masamichi

2018-01-01

Recent studies have revealed a reduction in the skeletal muscle area in patients with advanced non-small cell lung cancer (NSCLC) after chemotherapy. EGFR and ALK tyrosine kinase inhibitor (TKI)-based therapies are less cytotoxic than chemotherapy, but differences in skeletal muscle mass between patients receiving EGFR and ALK TKI therapies and patients receiving cytotoxic chemotherapy have not yet been reported. Data of pathologically proven NSCLC patients were reviewed, and chest computed tomography and/or positron emission tomography-computed tomography images obtained from January 2012 to December 2014 were selected. Patients were divided into two groups: cytotoxic chemotherapy (CG) and molecular targeted (MG). Muscle mass was measured with a single cross-sectional area of the muscle at the third lumber vertebra (L3MA). To estimate skeletal muscle changes during chemotherapy, we defined the following L3 skeletal muscle index (L3SMI) ratio: post L3SMI/pre L3SMI. Differences in the SMI ratio between the groups were evaluated using the Wilcoxon signed-rank test. Sixty-five patients were included in this study: 44 patients received cytotoxic chemotherapy and 21 received molecular targeted therapy (EGFR and ALK TKI). The loss of L3MA in the CG was higher than in the MG (P = 0.03). In the CG, the L3SMI ratio defined to evaluate skeletal muscle mass changes was significantly lower than in the MG (P = 0.0188). Our results suggest that skeletal muscle loss during first-line therapy was significantly different between patients receiving cytotoxic chemotherapy and those receiving TKIs. Specifically, skeletal muscle loss was lower in patients receiving TKIs than in patients receiving cytotoxic chemotherapy. © 2017 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

Protocol and recruitment results from a randomized controlled trial comparing group phone-based versus newsletter interventions for weight loss maintenance among rural breast cancer survivors.

PubMed

Befort, Christie A; Klemp, Jennifer R; Fabian, Carol; Perri, Michael G; Sullivan, Debra K; Schmitz, Kathryn H; Diaz, Francisco J; Shireman, Theresa

2014-03-01

Obesity is a risk factor for breast cancer recurrence and death. Women who reside in rural areas have higher obesity prevalence and suffer from breast cancer treatment-related disparities compared to urban women. The objective of this 5-year randomized controlled trial is to compare methods for delivering extended care for weight loss maintenance among rural breast cancer survivors. Group phone-based counseling via conference calls addresses access barriers, is more cost-effective than individual phone counseling, and provides group support which may be ideal for rural breast cancer survivors who are more likely to have unmet support needs. Women (n=210) diagnosed with Stage 0 to III breast cancer in the past 10 years who are ≥ 3 months out from initial cancer treatments, have a BMI 27-45 kg/m(2), and have physician clearance were enrolled from multiple cancer centers. During Phase I (months 0 to 6), all women receive a behavioral weight loss intervention delivered through group phone sessions. Women who successfully lose 5% of weight enter Phase II (months 6 to 18) and are randomized to one of two extended care arms: continued group phone-based treatment or a mail-based newsletter. During Phase III, no contact is made (months 18 to 24). The primary outcome is weight loss maintenance from 6 to 18 months. Secondary outcomes include quality of life, serum biomarkers, and cost-effectiveness. This study will provide essential information on how to reach rural survivors in future efforts to establish weight loss support for breast cancer survivors as a standard of care. Copyright © 2014 Elsevier Inc. All rights reserved.

The Effects of Revealed Information on Catastrophe Loss Projection Models' Characterization of Risk: Damage Vulnerability Evidence from Florida.

PubMed

Karl, J Bradley; Medders, Lorilee A; Maroney, Patrick F

2016-06-01

We examine whether the risk characterization estimated by catastrophic loss projection models is sensitive to the revelation of new information regarding risk type. We use commercial loss projection models from two widely employed modeling firms to estimate the expected hurricane losses of Florida Atlantic University's building stock, both including and excluding secondary information regarding hurricane mitigation features that influence damage vulnerability. We then compare the results of the models without and with this revealed information and find that the revelation of additional, secondary information influences modeled losses for the windstorm-exposed university building stock, primarily evidenced by meaningful percent differences in the loss exceedance output indicated after secondary modifiers are incorporated in the analysis. Secondary risk characteristics for the data set studied appear to have substantially greater impact on probable maximum loss estimates than on average annual loss estimates. While it may be intuitively expected for catastrophe models to indicate that secondary risk characteristics hold value for reducing modeled losses, the finding that the primary value of secondary risk characteristics is in reduction of losses in the "tail" (low probability, high severity) events is less intuitive, and therefore especially interesting. Further, we address the benefit-cost tradeoffs that commercial entities must consider when deciding whether to undergo the data collection necessary to include secondary information in modeling. Although we assert the long-term benefit-cost tradeoff is positive for virtually every entity, we acknowledge short-term disincentives to such an effort. © 2015 Society for Risk Analysis.

Structure-Based Analysis Reveals Cancer Missense Mutations Target Protein Interaction Interfaces.

PubMed

Engin, H Billur; Kreisberg, Jason F; Carter, Hannah

2016-01-01

Recently it has been shown that cancer mutations selectively target protein-protein interactions. We hypothesized that mutations affecting distinct protein interactions involving established cancer genes could contribute to tumor heterogeneity, and that novel mechanistic insights might be gained into tumorigenesis by investigating protein interactions under positive selection in cancer. To identify protein interactions under positive selection in cancer, we mapped over 1.2 million nonsynonymous somatic cancer mutations onto 4,896 experimentally determined protein structures and analyzed their spatial distribution. In total, 20% of mutations on the surface of known cancer genes perturbed protein-protein interactions (PPIs), and this enrichment for PPI interfaces was observed for both tumor suppressors (Odds Ratio 1.28, P-value < 10(-4)) and oncogenes (Odds Ratio 1.17, P-value < 10(-3)). To study this further, we constructed a bipartite network representing structurally resolved PPIs from all available human complexes in the Protein Data Bank (2,864 proteins, 3,072 PPIs). Analysis of frequently mutated cancer genes within this network revealed that tumor-suppressors, but not oncogenes, are significantly enriched with functional mutations in homo-oligomerization regions (Odds Ratio 3.68, P-Value < 10(-8)). We present two important examples, TP53 and beta-2-microglobulin, for which the patterns of somatic mutations at interfaces provide insights into specifically perturbed biological circuits. In patients with TP53 mutations, patient survival correlated with the specific interactions that were perturbed. Moreover, we investigated mutations at the interface of protein-nucleotide interactions and observed an unexpected number of missense mutations but not silent mutations occurring within DNA and RNA binding sites. Finally, we provide a resource of 3,072 PPI interfaces ranked according to their mutation rates. Analysis of this list highlights 282 novel candidate cancer

Sudden loss of vision due to breast cancer metastasis to the eyeball.

PubMed

Antosz, Zbigniew S; Walocha, Jerzy; Poręba, Ryszard; Sioma-Markowska, Urszula

2014-01-01

Intraocular choroidal metastasis is a very rare cause of blindness. Carcinoma of breast is the most common primary malignancy the accounts for choroidal metastasis in females. Other primary neoplasms which can uncommonly metastasize to the choroid are gastrointestinal tract, thyroid, pancreas, prostate and testis. Metastatic neoplasm to the eye outnumbers the primary tumors such as retinoblastoma and malignant melanoma. We present a case of sudden loss of vision due to breast cancer metastasis to the eyeball. The interval between the diagnosis of the primary tumor and the choroidal metastasis was 4 years.

Genome-wide mRNA and miRNA expression profiling reveal multiple regulatory networks in colorectal cancer

PubMed Central

Vishnubalaji, R; Hamam, R; Abdulla, M-H; Mohammed, M A V; Kassem, M; Al-Obeed, O; Aldahmash, A; Alajez, N M

2015-01-01

Despite recent advances in cancer management, colorectal cancer (CRC) remains the third most common cancer and a major health-care problem worldwide. MicroRNAs have recently emerged as key regulators of cancer development and progression by targeting multiple cancer-related genes; however, such regulatory networks are not well characterized in CRC. Thus, the aim of this study was to perform global messenger RNA (mRNA) and microRNA expression profiling in the same CRC samples and adjacent normal tissues and to identify potential miRNA-mRNA regulatory networks. Our data revealed 1273 significantly upregulated and 1902 downregulated genes in CRC. Pathway analysis revealed significant enrichment in cell cycle, integrated cancer, Wnt (wingless-type MMTV integration site family member), matrix metalloproteinase, and TGF-β pathways in CRC. Pharmacological inhibition of Wnt (using XAV939 or IWP-2) or TGF-β (using SB-431542) pathways led to dose- and time-dependent inhibition of CRC cell growth. Similarly, our data revealed up- (42) and downregulated (61) microRNAs in the same matched samples. Using target prediction and bioinformatics, ~77% of the upregulated genes were predicted to be targeted by microRNAs found to be downregulated in CRC. We subsequently focused on EZH2 (enhancer of zeste homolog 2 ), which was found to be regulated by hsa-miR-26a-5p and several members of the let-7 (lethal-7) family in CRC. Significant inverse correlation between EZH2 and hsa-miR-26a-5p (R2=0.56, P=0.0001) and hsa-let-7b-5p (R2=0.19, P=0.02) expression was observed in the same samples, corroborating the belief of EZH2 being a bona fide target for these two miRNAs in CRC. Pharmacological inhibition of EZH2 led to significant reduction in trimethylated histone H3 on lysine 27 (H3K27) methylation, marked reduction in cell proliferation, and migration in vitro. Concordantly, small interfering RNA-mediated knockdown of EZH2 led to similar effects on CRC cell growth in vitro. Therefore, our

Genome-wide mRNA and miRNA expression profiling reveal multiple regulatory networks in colorectal cancer.

PubMed

Vishnubalaji, R; Hamam, R; Abdulla, M-H; Mohammed, M A V; Kassem, M; Al-Obeed, O; Aldahmash, A; Alajez, N M

2015-01-22

Despite recent advances in cancer management, colorectal cancer (CRC) remains the third most common cancer and a major health-care problem worldwide. MicroRNAs have recently emerged as key regulators of cancer development and progression by targeting multiple cancer-related genes; however, such regulatory networks are not well characterized in CRC. Thus, the aim of this study was to perform global messenger RNA (mRNA) and microRNA expression profiling in the same CRC samples and adjacent normal tissues and to identify potential miRNA-mRNA regulatory networks. Our data revealed 1273 significantly upregulated and 1902 downregulated genes in CRC. Pathway analysis revealed significant enrichment in cell cycle, integrated cancer, Wnt (wingless-type MMTV integration site family member), matrix metalloproteinase, and TGF-β pathways in CRC. Pharmacological inhibition of Wnt (using XAV939 or IWP-2) or TGF-β (using SB-431542) pathways led to dose- and time-dependent inhibition of CRC cell growth. Similarly, our data revealed up- (42) and downregulated (61) microRNAs in the same matched samples. Using target prediction and bioinformatics, ~77% of the upregulated genes were predicted to be targeted by microRNAs found to be downregulated in CRC. We subsequently focused on EZH2 (enhancer of zeste homolog 2 ), which was found to be regulated by hsa-miR-26a-5p and several members of the let-7 (lethal-7) family in CRC. Significant inverse correlation between EZH2 and hsa-miR-26a-5p (R(2)=0.56, P=0.0001) and hsa-let-7b-5p (R(2)=0.19, P=0.02) expression was observed in the same samples, corroborating the belief of EZH2 being a bona fide target for these two miRNAs in CRC. Pharmacological inhibition of EZH2 led to significant reduction in trimethylated histone H3 on lysine 27 (H3K27) methylation, marked reduction in cell proliferation, and migration in vitro. Concordantly, small interfering RNA-mediated knockdown of EZH2 led to similar effects on CRC cell growth in vitro. Therefore

Multi-region and single-cell sequencing reveal variable genomic heterogeneity in rectal cancer.

PubMed

Liu, Mingshan; Liu, Yang; Di, Jiabo; Su, Zhe; Yang, Hong; Jiang, Beihai; Wang, Zaozao; Zhuang, Meng; Bai, Fan; Su, Xiangqian

2017-11-23

Colorectal cancer is a heterogeneous group of malignancies with complex molecular subtypes. While colon cancer has been widely investigated, studies on rectal cancer are very limited. Here, we performed multi-region whole-exome sequencing and single-cell whole-genome sequencing to examine the genomic intratumor heterogeneity (ITH) of rectal tumors. We sequenced nine tumor regions and 88 single cells from two rectal cancer patients with tumors of the same molecular classification and characterized their mutation profiles and somatic copy number alterations (SCNAs) at the multi-region and the single-cell levels. A variable extent of genomic heterogeneity was observed between the two patients, and the degree of ITH increased when analyzed on the single-cell level. We found that major SCNAs were early events in cancer development and inherited steadily. Single-cell sequencing revealed mutations and SCNAs which were hidden in bulk sequencing. In summary, we studied the ITH of rectal cancer at regional and single-cell resolution and demonstrated that variable heterogeneity existed in two patients. The mutational scenarios and SCNA profiles of two patients with treatment naïve from the same molecular subtype are quite different. Our results suggest each tumor possesses its own architecture, which may result in different diagnosis, prognosis, and drug responses. Remarkable ITH exists in the two patients we have studied, providing a preliminary impression of ITH in rectal cancer.

Normal Fibroblasts Induce E-Cadherin Loss and Increase Lymph Node Metastasis in Gastric Cancer

PubMed Central

Xu, Wen; Hu, Xinlei; Chen, Zhongting; Zheng, Xiaoping; Zhang, Chenjing; Wang, Gang; Chen, Yu; Zhou, Xinglu; Tang, Xiaoxiao; Luo, Laisheng; Xu, Xiang; Pan, Wensheng

2014-01-01

Background A tumor is considered a heterogeneous complex in a three-dimensional environment that is flush with pathophysiological and biomechanical signals. Cell-stroma interactions guide the development and generation of tumors. Here, we evaluate the contributions of normal fibroblasts to gastric cancer. Methodology/Principal Findings By coculturing normal fibroblasts in monolayers of BGC-823 gastric cancer cells, tumor cells sporadically developed short, spindle-like morphological characteristics and demonstrated enhanced proliferation and invasive potential. Furthermore, the transformed tumor cells demonstrated decreased tumor formation and increased lymphomatic and intestinal metastatic potential. Non-transformed BGC-823 cells, in contrast, demonstrated primary tumor formation and delayed intestinal and lymph node invasion. We also observed E-cadherin loss and the upregulation of vimentin expression in the transformed tumor cells, which suggested that the increase in metastasis was induced by epithelial-to-mesenchymal transition. Conclusion Collectively, our data indicated that normal fibroblasts sufficiently induce epithelial-to-mesenchymal transition in cancer cells, thereby leading to metastasis. PMID:24845259

The rationale for preventing cancer cachexia: targeting excessive fatty acid oxidation.

PubMed

Qian, Chao-Nan

2016-07-21

Cachexia commonly occurs at the terminal stage of cancer and has largely unclear molecular mechanisms. A recent study published in Nature Medicine, entitled "Excessive fatty acid oxidation induces muscle atrophy in cancer cachexia," reveals that cachectic cancer cells can secrete multiple cytokines that induce excessive fatty acid oxidation, which is responsible for muscle loss in cancer cachexia. Inhibition of fatty acid oxidation using etomoxir can increase muscle mass and body weight in cancer cachexia animal models. The usage of stable cachexia animal models is also discussed in this research highlight.

Genome-wide DNA methylation analysis reveals estrogen-mediated epigenetic repression of metallothionein-1 gene cluster in breast cancer.

PubMed

Jadhav, Rohit R; Ye, Zhenqing; Huang, Rui-Lan; Liu, Joseph; Hsu, Pei-Yin; Huang, Yi-Wen; Rangel, Leticia B; Lai, Hung-Cheng; Roa, Juan Carlos; Kirma, Nameer B; Huang, Tim Hui-Ming; Jin, Victor X

2015-01-01

Recent genome-wide analysis has shown that DNA methylation spans long stretches of chromosome regions consisting of clusters of contiguous CpG islands or gene families. Hypermethylation of various gene clusters has been reported in many types of cancer. In this study, we conducted methyl-binding domain capture (MBDCap) sequencing (MBD-seq) analysis on a breast cancer cohort consisting of 77 patients and 10 normal controls, as well as a panel of 38 breast cancer cell lines. Bioinformatics analysis determined seven gene clusters with a significant difference in overall survival (OS) and further revealed a distinct feature that the conservation of a large gene cluster (approximately 70 kb) metallothionein-1 (MT1) among 45 species is much lower than the average of all RefSeq genes. Furthermore, we found that DNA methylation is an important epigenetic regulator contributing to gene repression of MT1 gene cluster in both ERα positive (ERα+) and ERα negative (ERα-) breast tumors. In silico analysis revealed much lower gene expression of this cluster in The Cancer Genome Atlas (TCGA) cohort for ERα + tumors. To further investigate the role of estrogen, we conducted 17β-estradiol (E2) and demethylating agent 5-aza-2'-deoxycytidine (DAC) treatment in various breast cancer cell types. Cell proliferation and invasion assays suggested MT1F and MT1M may play an anti-oncogenic role in breast cancer. Our data suggests that DNA methylation in large contiguous gene clusters can be potential prognostic markers of breast cancer. Further investigation of these clusters revealed that estrogen mediates epigenetic repression of MT1 cluster in ERα + breast cancer cell lines. In all, our studies identify thousands of breast tumor hypermethylated regions for the first time, in particular, discovering seven large contiguous hypermethylated gene clusters.

Appraising the relevance of DNA copy number loss and gain in prostate cancer using whole genome DNA sequence data

PubMed Central

Van Loo, Peter; Kay, Jonathan D.; Matthews, Lucy; Haase, Kerstin; Clark, Jeremy; Thomas, Sarah; Butler, Adam P.; Gundem, Gunes; Merson, Sue; Luxton, Hayley; Hawkins, Steve; Ghori, Mohammed; Marsden, Luke; Lambert, Adam; Pelvender, Gill; Massie, Charlie E.; Hazell, Steven; Livni, Naomi; Fisher, Cyril; Ogden, Christopher; Kumar, Pardeep; Thompson, Alan; Nicol, David; Yu, Yongwei; Zhang, Hongwei; Isaacs, William; Visakorpi, Tapio; Verrill, Clare; Lynch, Andrew G.; Lu, Yong Jie; Whitaker, Hayley C.; Neal, David E.; Cooper, Colin S.

2017-01-01

A variety of models have been proposed to explain regions of recurrent somatic copy number alteration (SCNA) in human cancer. Our study employs Whole Genome DNA Sequence (WGS) data from tumor samples (n = 103) to comprehensively assess the role of the Knudson two hit genetic model in SCNA generation in prostate cancer. 64 recurrent regions of loss and gain were detected, of which 28 were novel, including regions of loss with more than 15% frequency at Chr4p15.2-p15.1 (15.53%), Chr6q27 (16.50%) and Chr18q12.3 (17.48%). Comprehensive mutation screens of genes, lincRNA encoding sequences, control regions and conserved domains within SCNAs demonstrated that a two-hit genetic model was supported in only a minor proportion of recurrent SCNA losses examined (15/40). We found that recurrent breakpoints and regions of inversion often occur within Knudson model SCNAs, leading to the identification of ZNF292 as a target gene for the deletion at 6q14.3-q15 and NKX3.1 as a two-hit target at 8p21.3-p21.2. The importance of alterations of lincRNA sequences was illustrated by the identification of a novel mutational hotspot at the KCCAT42, FENDRR, CAT1886 and STCAT2 loci at the 16q23.1-q24.3 loss. Our data confirm that the burden of SCNAs is predictive of biochemical recurrence, define nine individual regions that are associated with relapse, and highlight the possible importance of ion channel and G-protein coupled-receptor (GPCR) pathways in cancer development. We concluded that a two-hit genetic model accounts for about one third of SCNA indicating that mechanisms, such haploinsufficiency and epigenetic inactivation, account for the remaining SCNA losses. PMID:28945760

Appraising the relevance of DNA copy number loss and gain in prostate cancer using whole genome DNA sequence data.

PubMed

Camacho, Niedzica; Van Loo, Peter; Edwards, Sandra; Kay, Jonathan D; Matthews, Lucy; Haase, Kerstin; Clark, Jeremy; Dennis, Nening; Thomas, Sarah; Kremeyer, Barbara; Zamora, Jorge; Butler, Adam P; Gundem, Gunes; Merson, Sue; Luxton, Hayley; Hawkins, Steve; Ghori, Mohammed; Marsden, Luke; Lambert, Adam; Karaszi, Katalin; Pelvender, Gill; Massie, Charlie E; Kote-Jarai, Zsofia; Raine, Keiran; Jones, David; Howat, William J; Hazell, Steven; Livni, Naomi; Fisher, Cyril; Ogden, Christopher; Kumar, Pardeep; Thompson, Alan; Nicol, David; Mayer, Erik; Dudderidge, Tim; Yu, Yongwei; Zhang, Hongwei; Shah, Nimish C; Gnanapragasam, Vincent J; Isaacs, William; Visakorpi, Tapio; Hamdy, Freddie; Berney, Dan; Verrill, Clare; Warren, Anne Y; Wedge, David C; Lynch, Andrew G; Foster, Christopher S; Lu, Yong Jie; Bova, G Steven; Whitaker, Hayley C; McDermott, Ultan; Neal, David E; Eeles, Rosalind; Cooper, Colin S; Brewer, Daniel S

2017-09-01

A variety of models have been proposed to explain regions of recurrent somatic copy number alteration (SCNA) in human cancer. Our study employs Whole Genome DNA Sequence (WGS) data from tumor samples (n = 103) to comprehensively assess the role of the Knudson two hit genetic model in SCNA generation in prostate cancer. 64 recurrent regions of loss and gain were detected, of which 28 were novel, including regions of loss with more than 15% frequency at Chr4p15.2-p15.1 (15.53%), Chr6q27 (16.50%) and Chr18q12.3 (17.48%). Comprehensive mutation screens of genes, lincRNA encoding sequences, control regions and conserved domains within SCNAs demonstrated that a two-hit genetic model was supported in only a minor proportion of recurrent SCNA losses examined (15/40). We found that recurrent breakpoints and regions of inversion often occur within Knudson model SCNAs, leading to the identification of ZNF292 as a target gene for the deletion at 6q14.3-q15 and NKX3.1 as a two-hit target at 8p21.3-p21.2. The importance of alterations of lincRNA sequences was illustrated by the identification of a novel mutational hotspot at the KCCAT42, FENDRR, CAT1886 and STCAT2 loci at the 16q23.1-q24.3 loss. Our data confirm that the burden of SCNAs is predictive of biochemical recurrence, define nine individual regions that are associated with relapse, and highlight the possible importance of ion channel and G-protein coupled-receptor (GPCR) pathways in cancer development. We concluded that a two-hit genetic model accounts for about one third of SCNA indicating that mechanisms, such haploinsufficiency and epigenetic inactivation, account for the remaining SCNA losses.

Myostatin gene inactivation prevents skeletal muscle wasting in cancer.

PubMed

Gallot, Yann S; Durieux, Anne-Cécile; Castells, Josiane; Desgeorges, Marine M; Vernus, Barbara; Plantureux, Léa; Rémond, Didier; Jahnke, Vanessa E; Lefai, Etienne; Dardevet, Dominique; Nemoz, Georges; Schaeffer, Laurent; Bonnieu, Anne; Freyssenet, Damien G

2014-12-15

Cachexia is a muscle-wasting syndrome that contributes significantly to morbidity and mortality of many patients with advanced cancers. However, little is understood about how the severe loss of skeletal muscle characterizing this condition occurs. In the current study, we tested the hypothesis that the muscle protein myostatin is involved in mediating the pathogenesis of cachexia-induced muscle wasting in tumor-bearing mice. Myostatin gene inactivation prevented the severe loss of skeletal muscle mass induced in mice engrafted with Lewis lung carcinoma (LLC) cells or in Apc(Min) (/+) mice, an established model of colorectal cancer and cachexia. Mechanistically, myostatin loss attenuated the activation of muscle fiber proteolytic pathways by inhibiting the expression of atrophy-related genes, MuRF1 and MAFbx/Atrogin-1, along with autophagy-related genes. Notably, myostatin loss also impeded the growth of LLC tumors, the number and the size of intestinal polyps in Apc(Min) (/+) mice, thus strongly increasing survival in both models. Gene expression analysis in the LLC model showed this phenotype to be associated with reduced expression of genes involved in tumor metabolism, activin signaling, and apoptosis. Taken together, our results reveal an essential role for myostatin in the pathogenesis of cancer cachexia and link this condition to tumor growth, with implications for furthering understanding of cancer as a systemic disease. ©2014 American Association for Cancer Research.

Periodontal Disease and Tooth Loss as Risks for Cancer: A Systematic Review of the Literature

PubMed Central

Sadighi Shamami, M; Sadighi Shamami, M; Amini, S

2011-01-01

Background Periodontal disease is a chronic destructive disease which occurs in adults, young people, and children. Periodontal disease and periodontal pathogens have been associated with several systemic diseases and more recently, several studies have suggested the relationship between periodontal disease and cancer. Studies with adjustment for the effect of smoking exposure, have found significant positive associations with different cancer sites. This review has outlined recent epidemiologic researches pointing to a possible role for tooth loss and periodontal disease in carcinogenesis. Methods In this review, articles were selected from PubMed between1995 and June 2010 including human. Amongst 5,984 articles identified from the electronic search, 17 articles were selected for a full-text reading based on the inclusion and the exclusion criteria. Results Nine out of 10 case-control studies reported a significant increase in the risk of oral cancer in patients with periodontitis and one with no significant association. Among 6 studies examining esophageal cancer and periodontal disease, 5 studies found a significant association between them and one study failed to find a significant increased risk of cancer. Also amongst 5 studies which focused on upper gastrointestinal, gastric cancer, and periodontal disease, 4 studies found an increased risk of cancer while one study did not report any relationship. In lung cancer evaluations, 3 out of 4 studies showed some levels of association between lung cancer and periodontal disease but after adjustment for smoking, no relationship were found. Three cohort studies have evaluated overall cancer rates in periodontal patients; two of them found small but significant association between cancers and periodontal disease. Conclusion The results indicate that there is a possible link between cancer and severe periodontal disease after adjustment for smoking and drinking habits. PMID:26322197

Periodontal Disease and Tooth Loss as Risks for Cancer: A Systematic Review of the Literature.

PubMed

Sadighi Shamami, M; Sadighi Shamami, M; Amini, S

2011-01-01

Periodontal disease is a chronic destructive disease which occurs in adults, young people, and children. Periodontal disease and periodontal pathogens have been associated with several systemic diseases and more recently, several studies have suggested the relationship between periodontal disease and cancer. Studies with adjustment for the effect of smoking exposure, have found significant positive associations with different cancer sites. This review has outlined recent epidemiologic researches pointing to a possible role for tooth loss and periodontal disease in carcinogenesis. In this review, articles were selected from PubMed between1995 and June 2010 including human. Amongst 5,984 articles identified from the electronic search, 17 articles were selected for a full-text reading based on the inclusion and the exclusion criteria. Nine out of 10 case-control studies reported a significant increase in the risk of oral cancer in patients with periodontitis and one with no significant association. Among 6 studies examining esophageal cancer and periodontal disease, 5 studies found a significant association between them and one study failed to find a significant increased risk of cancer. Also amongst 5 studies which focused on upper gastrointestinal, gastric cancer, and periodontal disease, 4 studies found an increased risk of cancer while one study did not report any relationship. In lung cancer evaluations, 3 out of 4 studies showed some levels of association between lung cancer and periodontal disease but after adjustment for smoking, no relationship were found. Three cohort studies have evaluated overall cancer rates in periodontal patients; two of them found small but significant association between cancers and periodontal disease. The results indicate that there is a possible link between cancer and severe periodontal disease after adjustment for smoking and drinking habits.

LOSS OF 5-HYDROXYMETHYLCYTOSINE IS AN EPIGENETIC HALLMARK OF MELANOMA

PubMed Central

Lian, Christine Guo; Xu, Yufei; Ceol, Craig; Wu, Feizhen; Larson, Allison; Dresser, Karen; Xu, Wenji; Tan, Li; Hu, Yeguang; Zhan, Qian; Lee, Chung-wei; Hu, Di; Lian, Bill Q.; Kleffel, Sonja; Yang, Yijun; Neiswender, James; Khorasani, Abraham J.; Fang, Rui; Lezcano, Cecilia; Duncan, Lyn M.; Scolyer, Richard A.; Thompson, John F.; Kakavand, Hojabr; Houvras, Yariv; Zon, Leonard; Mihm, Martin C.; Kaiser, Ursula B.; Schatton, Tobias; Woda, Bruce A.; Murphy, George F.; Shi, Yujiang G.

2013-01-01

SUMMARY DNA methylation at the 5-position of cytosine (5-mC) is a key epigenetic mark critical for various biological and pathological processes. 5-mC can be converted to 5-hydroxymethylcytosine (5-hmC) by the Ten-Eleven Translocation (TET) family of DNA hydroxylases. Here we report that “loss of 5-hmC” is an epigenetic hallmark of melanoma with diagnostic and prognostic implications. Genome-wide mapping of 5-hmC reveals loss of 5-hmC landscape in the melanoma epigenome. We show that down-regulation of Isocitrate Dehydrogenase 2 (IDH2) and TET family enzymes is likely one of the mechanisms underlying 5-hmC loss in melanoma. Rebuilding the 5-hmC landscape in melanoma cells by reintroducing active TET2 or IDH2 suppresses melanoma growth and increases tumor-free survival in animal models. Thus, our study reveals a critical function of 5-hmC in melanoma development and directly links the IDH and TET activity-dependent epigenetic pathway to 5-hmC-mediated suppression of melanoma progression, suggesting a new strategy for epigenetic cancer therapy. PMID:22980977

Identification of a region of frequent loss of heterozygosity at 11q24 in colorectal cancer.

PubMed

Connolly, K C; Gabra, H; Millwater, C J; Taylor, K J; Rabiasz, G J; Watson, J E; Smyth, J F; Wyllie, A H; Jodrell, D I

1999-06-15

Loss of heterozygosity (LOH) at 11q23-qter occurs frequently in ovarian and other cancers, but for colorectal cancer, the evidence is conflicting. Seven polymorphic loci were analyzed between D11S897 and D11S969 in 50 colorectal tumors. Two distinct LOH regions were detected, suggesting possible sites for tumor-suppressor genes involved in colorectal neoplasia: a large centromeric region between D11S897 and D11S925, and a telomeric 4.9-Mb region between D11S912 and D11S969. There was no correlation with clinicopathological features. This analysis describes a region of LOH in the region 11q23.3-24.3 for the first time in colorectal cancer and provides complementary evidence for the ongoing effort to identify the gene(s) involved.

Array painting reveals a high frequency of balanced translocations in breast cancer cell lines that break in cancer-relevant genes

PubMed Central

Howarth, KD; Blood, KA; Ng, BL; Beavis, JC; Chua, Y; Cooke, SL; Raby, S; Ichimura, K; Collins, VP; Carter, NP; Edwards, PAW

2008-01-01

Chromosome translocations in the common epithelial cancers are abundant, yet little is known about them. They have been thought to be almost all unbalanced and therefore dismissed as mostly mediating tumour suppressor loss. We present a comprehensive analysis by array painting of the chromosome translocations of breast cancer cell lines HCC1806, HCC1187 and ZR-75-30. In array painting, chromosomes are isolated by flow cytometry, amplified and hybridized to DNA microarrays. A total of 200 breakpoints were identified and all were mapped to 1Mb resolution on BAC arrays, then 40 selected breakpoints, including all balanced breakpoints, were further mapped on tiling-path BAC arrays or to around 2kb resolution using oligonucleotide arrays. Many more of the translocations were balanced at 1Mb resolution than expected, either reciprocal (eight in total) or balanced for at least one participating chromosome (19 paired breakpoints). Secondly, many of the breakpoints were at genes that are plausible targets of oncogenic translocation, including balanced breaks at CTCF, EP300/p300, and FOXP4. Two gene fusions were demonstrated, TAX1BP1-AHCY and RIF1-PKD1L1. Our results support the idea that chromosome rearrangements may play an important role in common epithelial cancers such as breast cancer. PMID:18084325

A randomized, double-blind, placebo-controlled clinical trial of megestrol acetate as an appetite stimulant in children with weight loss due to cancer and/or cancer therapy.

PubMed

Cuvelier, Geoff D E; Baker, Tina J; Peddie, Elaine F; Casey, Linda M; Lambert, Pascal J; Distefano, Dianne S; Wardle, Marlene G; Mychajlunow, Beth A; Romanick, Marcel A; Dix, David B; Wilson, Beverly A

2014-04-01

Megestrol acetate (MA) is an appetite stimulant with efficacy in promoting weight gain in adults with cancer-associated anorexia-cachexia. Studies documenting MA efficacy in children, however, are limited. We present the first randomized, double-blind, placebo-controlled clinical trial of MA versus placebo in children with cancer and weight loss. Subjects <18 years of age with weight loss (minimum 5% from highest previous weight; or %ideal body weight <90%) due to cancer and/or cancer therapy were randomized to either MA (7.5 mg/kg/day) or placebo for a planned study duration of 90 days. Primary outcome was the difference between groups in mean percent weight change from beginning to end of the study period. Secondary outcomes included effects on anthropometrics, body composition, need for tube feeding or parenteral nutrition, and toxicities. Twenty-six patients were randomly assigned (13 MA, 13 placebo). The MA group experienced a mean weight gain of +19.7% compared to a mean weight loss of -1.2% in the placebo group, for a difference of +20.9% (95%CI: +11.3% to +30.5%, P = 0.003) in favor of MA over placebo. MA subjects experienced significant increases in weight for age z-scores, body mass index z-scores, and mid upper arm circumference compared to placebo. DXA scanning suggested disproportionate increases in fat accrual. Adrenal suppression was the main toxicity of MA. In children with high-risk malignancies, MA resulted in significant increases in mean percent weight change compared to placebo. Further studies of MA should be pursued to better delineate the effect on nutritional status. © 2013 Wiley Periodicals, Inc.

Designing Skin Cancer Prevention Messages: Should We Emphasize Gains or Losses? Message Framing, Risk Type, and Prior Experience.

PubMed

Lee, Moon J; Kang, Hannah

2018-05-01

To test whether message framing (ie, gain vs. loss) and risk type (ie, health vs appearance risk) in skin cancer prevention messages interact with one's prior experience. Two experiments with a 2 (message framing: gain vs loss) × 2 (risk type: health vs appearance risk) factorial design were conducted. The participants were given a URL to the experiment website via e-mail. On the first page of the website, the participants were told that they would be asked to evaluate a skin cancer print public service announcement (PSA): Online experiments. A total of 397 individuals participated (236 for experiment 1 and 161 for experiment 2). Apparatus: Four versions of the skin cancer print PSAs were developed. Four PSAs were identical except for the 2 manipulated components: message framing and risk type. Measures were adopted from Cho and Boster (message framing), Jones and Leary and Kiene et al. (risk type), De Vries, Mesters, van't Riet, Willems, and Reubsaet and Knight, Kirincich, Farmer, and Hood (prior experience), and Hammond, Fong, Zanna, Thrasher, and Borland and Hoffner and Ye (behavioral intent). General linear models were used to test hypotheses. Three-way interactions among message framing, risk type, and prior experience were found: When the intent of the message was to encourage sunscreen use, the effects of message framing and risk type were shown to be the exact opposite directions from when the intent was to discourage indoor/outdoor tanning. To discourage tanning among those with prior experience, messages emphasizing losses in terms of one's health will work better. For those with no prior experience, messages emphasizing potential appearance losses will work better for discouraging tanning while messages emphasizing gains like improving appearance will do a better job in encouraging sunscreen use.

Years of Life and Productivity Loss from Potentially Avoidable Colorectal Cancer Deaths in U.S. Counties with Lower Educational Attainment (2008-2012).

PubMed

Weir, Hannah K; Li, Chunyu; Henley, S Jane; Joseph, Djenaba

2017-05-01

Background: Educational attainment (EA) is inversely associated with colorectal cancer risk. Colorectal cancer screening can save lives if precancerous polyps or early cancers are found and successfully treated. This study aims to estimate the potential productivity loss (PPL) and associated avoidable colorectal cancer-related deaths among screen-eligible adults residing in lower EA counties in the United States. Methods: Mortality and population data were used to examine colorectal cancer deaths (2008-2012) among adults aged 50 to 74 years in lower EA counties, and to estimate the expected number of deaths using the mortality experience from high EA counties. Excess deaths (observed-expected) were used to estimate potential years life lost, and the human capital method was used to estimate PPL in 2012 U.S. dollars. Results: County-level colorectal cancer death rates were inversely associated with county-level EA. Of the 100,857 colorectal cancer deaths in lower EA counties, we estimated that more than 21,000 (1 in 5) was potentially avoidable and resulted in nearly $2 billion annual productivity loss. Conclusions: County-level EA disparities contribute to a large number of potentially avoidable colorectal cancer-related deaths. Increased prevention and improved screening potentially could decrease deaths and help reduce the associated economic burden in lower EA communities. Increased screening could further reduce deaths in all EA groups. Impact: These results estimate the large economic impact of potentially avoidable colorectal cancer-related deaths in economically disadvantaged communities, as measured by lower EA. Cancer Epidemiol Biomarkers Prev; 26(5); 736-42. ©2016 AACR . ©2016 American Association for Cancer Research.

Proteomic Analysis Reveals Aberrant O-GlcNAcylation of Extracellular Proteins from Breast Cancer Cell Secretion.

PubMed

Netsirisawan, Pukkavadee; Chokchaichamnankit, Daranee; Srisomsap, Chantragan; Svasti, Jisnuson; Champattanachai, Voraratt

2015-01-01

O-GlcNAcylation is a unique intracellular protein modification; however, few extracellular O-GlcNAc-modified proteins have been discovered. We have previously demonstrated that many cellular proteins were aberrant in O-GlcNAcylation in breast cancer tissues. In the present study, therefore, we investigated whether O-GlcNAc-modified proteins were abnormally secreted from breast cancer cells. Intracellular and extracellular proteins were prepared from cell lysates of breast cancer cells (MCF-7 and MDA-MB-231) and normal breast cells (HMEC) and from their serum-free media (SFM), respectively. O-GlcNAcylation level was examined by immunoblotting. O-GlcNAc-Modified proteins were identified using two-dimensional gel electrophoresis and Liquid Chromatography-tandem Mass Spectrometry. O-GlcNAcylation level was significantly increased in the extracellular compartment of both types of cancer cells compared to normal cells. Interestingly, O-GlcNAc patterns differed between intracellular and extracellular proteins. Proteomic analysis revealed that many O-GlcNAc spots in MCF-7 secretions were abnormally increased in comparison to those in HMEC secretions. Among these, transitional endoplasmic reticulum ATPase (TER ATPase) and heat-shock 70 kDa (HSP70) were confirmed to be O-GlcNAc-modified. The levels of O-GlcNAc-HSP70 and O-GlcNAc-TER ATPase were higher in SFM from MCF-7 cells than in that from HMEC. O-GlcNAcomic study of the extracellular compartments reveals aberrant O-GlcNAc-secreted proteins, which may be of interest as potential biomarkers in breast cancer. Copyright© 2015, International Institute of Anticancer Research (Dr. John G. Delinasios), All rights reserved.

Feelings of loss and uneasiness or shame after removal of a testicle by orchidectomy: a population-based long-term follow-up of testicular cancer survivors.

PubMed

Skoogh, J; Steineck, G; Cavallin-Ståhl, E; Wilderäng, U; Håkansson, U K; Johansson, B; Stierner, U

2011-04-01

Few data illustrate the man's reaction to orchidectomy. We investigated long-lasting feelings of loss and uneasiness or shame about the body after removal of a testicle by orchidectomy. We identified 1173 eligible men diagnosed with non-seminomatous testicular cancer treated according to the national cancer-care programmes Swedish-Norwegian Testicular Cancer Group I-IV between 1981 and 2004. We asked the survivors about feelings of loss and uneasiness or shame after having had a testicle removed by orchidectomy. We obtained information from 960 (82%) testicular cancer survivors. We found that 32% of these men miss or previously missed their removed testicle(s) and that 26% have or previously had feelings of uneasiness or shame about their body because of the removed testicle(s). Men who had never been offered a prosthesis reported feelings of loss [relative risk (RR): 2.0; 95% confidence interval (CI): 1.3-3.0] and uneasiness or shame (RR: 2.0; 95% CI: 1.3-3.2) to a higher extent than those who had been offered, but rejected a prosthesis. An orchidectomy may result in long-lasting feelings of loss and uneasiness or shame in some men; offering a testicular prosthesis may hinder this experience.

Revealing the Functions of Tenascin-C in 3-D Breast Cancer Models Using Cell Biological and In Silico Approaches

DTIC Science & Technology

2007-03-01

studies of muscular dystrophy show that disappearance of the basement membrane corresponds with the induction of TN-C (71, 72). Since loss of the laminin...Ehrismann R. Tenascin-C induced signaling in cancer. Cancer Lett 2006. 39. Reginato MJ, Mills KR, Becker EB, et al. Bim regulation of lumen formation in...Settles DL, Cihak RA, Erickson HP. Tenascin-C expression in dystrophin-related muscular dystrophy . Muscle Nerve 1996;19(2):147-54. 72. Taverna D

Associations between nutritional status, weight loss, radiotherapy treatment toxicity and treatment outcomes in gastrointestinal cancer patients.

PubMed

Hill, Amanda; Kiss, Nicole; Hodgson, Belinda; Crowe, Timothy C; Walsh, Adam D

2011-02-01

Patients with gastrointestinal cancers are susceptible to nutritional deterioration which may be compounded by radiotherapy treatment toxicities. This study aimed to determine whether nutritional status at radiotherapy commencement or changes in nutritional status throughout radiotherapy were associated with treatment toxicity and outcomes in gastrointestinal cancer patients. Seventy-three gastrointestinal cancer patients receiving curative radiotherapy underwent medical record audits assessing body weight, radiotherapy toxicity, unplanned treatment breaks or hospital admissions and completion of prescribed treatment/s. Nutritional status was assessed in a subset of patients (n = 11) using the Patient-Generated Subjective Global Assessment tool. Seventy-five percent of patients lost weight throughout radiotherapy. Weight loss was significantly greater in patients experiencing unplanned radiotherapy breaks (-3.1% vs -1.6%, p < 0.05) and in patients not completing prescribed chemotherapy (-3.3% vs -1.6%, p < 0.05). Toxicity severity was strongly correlated with Patient-Generated Subjective Global Assessment score (rho = 0.839, p < 0.001) and was increased in patients experiencing unplanned admissions compared to those without admission (42.1% vs 9.3% with grade 3 toxicity respectively, p < 0.001). Deterioration in nutritional status during radiotherapy (as measured by weight loss) may be associated with poorer short-term treatment outcomes in gastrointestinal cancer patients. Patient numbers were too small to definitively determine the effect of nutritional status at radiotherapy commencement or changes in nutritional status throughout radiotherapy (defined by PG-SGA) on treatment outcomes. Further research is required to investigate this in larger, longer-term studies. Copyright © 2010. Published by Elsevier Ltd.

Application of the Finite Element Method to Reveal the Causes of Loss of Planeness of Hot-Rolled Steel Sheets during Laser Cutting

NASA Astrophysics Data System (ADS)

Garber, E. A.; Bolobanova, N. L.; Trusov, K. A.

2018-01-01

A finite element technique is developed to simulate the stresses and the strains during strip flattening to reveal the causes of the cutting-assisted loss of planeness of hot-rolled steel sheets processed in roller levelers. The loss of planeness is found to be caused by a nonuniform distribution of the flattening-induced longitudinal tensile stresses over the strip thickness and width. The application of tensile forces to a strip in a roller leveler decreases this nonuniformity and prevents loss of planeness in cutting.

HLA class I loss and PD-L1 expression in lung cancer: impact on T-cell infiltration and immune escape

PubMed Central

Perea, Francisco; Sánchez-Palencia, Abel; Gómez-Morales, Mercedes; Bernal, Mónica; Concha, Ángel; García, Míguela Méndez; González-Ramírez, Amanda Rocío; Kerick, Martin; Martin, Javier; Garrido, Federico; Ruiz-Cabello, Francisco; Aptsiauri, Natalia

2018-01-01

Immune-checkpoint inhibitors show encouraging results in cancer treatment, but the clinical benefit is limited exclusively to a subset of patients. We analyzed the density and composition of tumor T-cell infiltration in non-small-cell lung carcinoma (NSCLC) in relation to PD-L1 and HLA class I (HLA-I) expression. We found that positive HLA-I expression, independently on PD-L1 status, is the key factor determining the increased density of the immune infiltrate. When both markers were analyzed simultaneously, we identified four phenotypes of HLA-I and PD-L1 co-expression. They demonstrated different patterns of tumor infiltration and clinicopathologic characteristics, including the tumor size and lymphatic spread. All HLA-I+/PD-L1+ tumors had a high degree of intratumoral infiltration with CD8+T-lymphocytes, whereas HLA-I loss was associated with a significantly reduced number of tumor infiltrating T-lymphocytes mostly restrained in the stroma surrounding the tumor nest. HLA-I-negative/PD-L1-positive tumors had bigger size (T) and lower grade of infiltration with CD8+T-cells. It represents a cancer immune escape phenotype that combines two independent mechanisms of immune evasion: loss of HLA-I and upregulation of PD-L1. Using GCH-array analysis of human lung cancer cell lines we found that the loss of heterozygosity (LOH) with complete or partial deletion of HLA-I genes is the principal mechanism of HLA-I alterations. This irreversible defect, which could potentially decrease the clinical efficacy of lung cancer immunotherapy, appears to be underestimated. In conclusion, our results suggest that the analysis of HLA-I is very important for the selection of potential responders to cancer immunotherapy. PMID:29423109

Randomized trial of a telephone-based weight loss intervention in postmenopausal women with breast cancer receiving letrozole: the LISA trial.

PubMed

Goodwin, Pamela J; Segal, Roanne J; Vallis, Michael; Ligibel, Jennifer A; Pond, Gregory R; Robidoux, André; Blackburn, George L; Findlay, Brian; Gralow, Julie R; Mukherjee, Som; Levine, Mark; Pritchard, Kathleen I

2014-07-20

Obesity is associated with poor outcomes in women with operable breast cancer. Lifestyle interventions (LIs) that help women reduce their weight may improve outcomes. We conducted a multicenter randomized trial comparing mail-based delivery of general health information alone or combined with a 24-month standardized, telephone-based LI that included diet (500 to 1,000 kcal per day deficit) and physical activity (150 to 200 minutes of moderate-intensity physical activity per week) goals to achieve weight loss (up to 10%). Women receiving adjuvant letrozole for T1-3N0-3M0 breast cancer with a body mass index (BMI) ≥ 24 kg/m(2) were eligible. Weight was measured in the clinic, and self-report physical activity, quality-of-life (QOL), and diet questionnaires were completed. The primary outcome was disease-free survival. Accrual was terminated at 338 of 2,150 planned patients because of loss of funding. Mean weight loss was significantly (P < .001) greater in the LI arm versus the comparison arm (4.3 v 0.6 kg or 5.3% v 0.7% at 6 months and 3.1 v 0.3 kg or 3.6% v 0.4% at 24 months) and occurred consistently across strata (BMI 24 to < 30 v ≥ 30 kg/m(2); prior v no prior adjuvant chemotherapy). Weight loss was greatest in those with higher baseline levels of moderate-intensity physical activity or improvement in QOL. Hospitalization rates and medical events were similar. A telephone-based LI led to significant weight loss that was still evident at 24 months, without adverse effects on QOL, hospitalizations, or medical events. Adequately powered randomized trials with cancer end points are needed. © 2014 by American Society of Clinical Oncology.

A murine model of autosomal dominant neurohypophyseal diabetes insipidus reveals progressive loss of vasopressin-producing neurons

PubMed Central

Russell, Theron A.; Ito, Masafumi; Ito, Mika; Yu, Richard N.; Martinson, Fred A.; Weiss, Jeffrey; Jameson, J. Larry

2003-01-01

Familial neurohypophyseal diabetes insipidus (FNDI) is an autosomal dominant disorder caused by mutations in the arginine vasopressin (AVP) precursor. The pathogenesis of FNDI is proposed to involve mutant protein–induced loss of AVP-producing neurons. We established murine knock-in models of two different naturally occurring human mutations that cause FNDI. A mutation in the AVP signal sequence [A(–1)T] is associated with a relatively mild phenotype or delayed presentation in humans. This mutation caused no apparent phenotype in mice. In contrast, heterozygous mice expressing a mutation that truncates the AVP precursor (C67X) exhibited polyuria and polydipsia by 2 months of age and these features of DI progressively worsened with age. Studies of the paraventricular and supraoptic nuclei revealed induction of the chaperone protein BiP and progressive loss of AVP-producing neurons relative to oxytocin-producing neurons. In addition, Avp gene products were not detected in the neuronal projections, suggesting retention of WT and mutant AVP precursors within the cell bodies. In summary, this murine model of FNDI recapitulates many features of the human disorder and demonstrates that expression of the mutant AVP precursor leads to progressive neuronal cell loss. PMID:14660745

Loss of nuclear p27 (CDKN1B/KIP1) in colorectal cancer is correlated with microsatellite instability and CIMP.

PubMed

Ogino, Shuji; Kawasaki, Takako; Kirkner, Gregory J; Yamaji, Taiki; Loda, Massimo; Fuchs, Charles S

2007-01-01

Downregulation of p27 (cyclin-dependent kinase inhibitor-1B, CDKN1B or KIP1) is caused by increased ubiquitin-mediated proteasomal degradation in colorectal cancer, and has been associated with poor prognosis. CpG island methylator phenotype (CIMP) is a phenotype of colorectal cancer with extensive promoter methylation, and associated with high degree of microsatellite instability (MSI-H) and BRAF mutations. We have recently shown that both CIMP and MSI-H are inversely associated with downregulation of p21 (CDKN1A or CIP1), another cyclin-dependent kinase inhibitor. However, no study to date has examined relationship between p27 and CIMP status in colorectal cancer. Using MethyLight assays, we measured DNA methylation in five CIMP-specific gene promoters {CACNA1G, CDKN2A (p16), CRABP1, MLH1 and NEUROG1} in 706 colorectal cancer samples obtained from two large prospective cohorts. Among the 706 tumors, 112 (16%) were CIMP-high tumors with >or=4/5 methylated promoters. We assessed p27 and p53 expressions by immunohistochemistry. Loss of nuclear p27 expression {observed in 231 tumors (33%)} was significantly associated with CIMP-high, MSI-H and BRAF mutations, and these associations were much more pronounced among p53-negative tumors than p53-positive tumors. When CIMP-high and non-CIMP-high tumors were stratified by MSI status (or KRAS and BRAF status), CIMP-high and MSI-H (but not BRAF mutations) were still significantly associated with nuclear p27 loss. Nuclear p27 loss did not appear to be directly related to CDKN2A (p16) methylation. We conclude that downregulation of nuclear p27 is associated with CIMP-high and MSI-H in colorectal cancer. These associations are stronger among p53 wild-type tumors, implying important interplay of p27 and p53 functions (or dysfunctions) in the development of various molecular subtypes of colorectal cancer.

Excitatory Hindbrain–Forebrain Communication Is Required for Cisplatin-Induced Anorexia and Weight Loss

PubMed Central

Alhadeff, Amber L.; Holland, Ruby A.; Zheng, Huiyuan; Rinaman, Linda; Grill, Harvey J.

2017-01-01

loss. The current data characterize the excitatory nature of neural projections activated by cisplatin in rats and reveal the necessity of specific hindbrain–forebrain projections for cisplatin-induced anorexia and weight loss. Together, these findings help to characterize the neural mechanisms mediating cisplatin-induced anorexia, advancing opportunities to develop better-tolerated chemotherapies and adjuvant therapies to prevent anorexia and concurrent nutritional deficiencies during cancer treatment. PMID:28077715

Endogenous molecular network reveals two mechanisms of heterogeneity within gastric cancer.

PubMed

Li, Site; Zhu, Xiaomei; Liu, Bingya; Wang, Gaowei; Ao, Ping

2015-05-30

Intratumor heterogeneity is a common phenomenon and impedes cancer therapy and research. Gastric cancer (GC) cells have generally been classified into two heterogeneous cellular phenotypes, the gastric and intestinal types, yet the mechanisms of maintaining two phenotypes and controlling phenotypic transition are largely unknown. A qualitative systematic framework, the endogenous molecular network hypothesis, has recently been proposed to understand cancer genesis and progression. Here, a minimal network corresponding to such framework was found for GC and was quantified via a stochastic nonlinear dynamical system. We then further extended the framework to address the important question of intratumor heterogeneity quantitatively. The working network characterized main known features of normal gastric epithelial and GC cell phenotypes. Our results demonstrated that four positive feedback loops in the network are critical for GC cell phenotypes. Moreover, two mechanisms that contribute to GC cell heterogeneity were identified: particular positive feedback loops are responsible for the maintenance of intestinal and gastric phenotypes; GC cell progression routes that were revealed by the dynamical behaviors of individual key components are heterogeneous. In this work, we constructed an endogenous molecular network of GC that can be expanded in the future and would broaden the known mechanisms of intratumor heterogeneity.

Endogenous molecular network reveals two mechanisms of heterogeneity within gastric cancer

PubMed Central

Li, Site; Zhu, Xiaomei; Liu, Bingya; Wang, Gaowei; Ao, Ping

2015-01-01

Intratumor heterogeneity is a common phenomenon and impedes cancer therapy and research. Gastric cancer (GC) cells have generally been classified into two heterogeneous cellular phenotypes, the gastric and intestinal types, yet the mechanisms of maintaining two phenotypes and controlling phenotypic transition are largely unknown. A qualitative systematic framework, the endogenous molecular network hypothesis, has recently been proposed to understand cancer genesis and progression. Here, a minimal network corresponding to such framework was found for GC and was quantified via a stochastic nonlinear dynamical system. We then further extended the framework to address the important question of intratumor heterogeneity quantitatively. The working network characterized main known features of normal gastric epithelial and GC cell phenotypes. Our results demonstrated that four positive feedback loops in the network are critical for GC cell phenotypes. Moreover, two mechanisms that contribute to GC cell heterogeneity were identified: particular positive feedback loops are responsible for the maintenance of intestinal and gastric phenotypes; GC cell progression routes that were revealed by the dynamical behaviors of individual key components are heterogeneous. In this work, we constructed an endogenous molecular network of GC that can be expanded in the future and would broaden the known mechanisms of intratumor heterogeneity. PMID:25962957

Loss of LRIG1 locus increases risk of early and late relapse of stage I/II breast cancer.

PubMed

Thompson, Patricia A; Ljuslinder, Ingrid; Tsavachidis, Spyros; Brewster, Abenaa; Sahin, Aysegul; Hedman, Håkan; Henriksson, Roger; Bondy, Melissa L; Melin, Beatrice S

2014-06-01

Gains and losses at chromosome 3p12-21 are common in breast tumors and associated with patient outcomes. We hypothesized that the LRIG1 gene at 3p14.1, whose product functions in ErbB-family member degradation, is a critical tumor modifier at this locus. We analyzed 971 stage I/II breast tumors using Affymetrix Oncoscan molecular inversion probe arrays that include 12 probes located within LRIG1. Copy number results were validated against gene expression data available in the public database. By partitioning the LRIG1 probes nearest exon 12/13, we confirm a breakpoint in the gene and show that gains and losses in the subregions differ by tumor and patient characteristics including race/ethnicity. In analyses adjusted for known prognostic factors, loss of LRIG1 was independently associated with risk of any relapse (HR, 1.90; 95% CI, 1.32-2.73), relapse≥5 years (HR, 2.39; 95% CI, 1.31-4.36), and death (HR, 1.55; 95% CI, 1.11-2.16). Analyses of copy number across chromosome 3, as well as expression data from pooled, publicly available datasets, corroborated the hypothesis of an elevated and persistent risk among cases with loss of or low LRIG1. We concluded that loss/low expression of LRIG1 is an independent risk factor for breast cancer metastasis and death in stage I/II patients. Increased hazard in patients with loss/low LRIG1 persists years after diagnosis, suggesting that LRIG1 is acting as a critical suppressor of tumor metastasis and is an early clinical indicator of risk for late recurrences in otherwise low-risk patients. ©2014 American Association for Cancer Research.

Molecular profiles of pre- and postoperative breast cancer tumours reveal differentially expressed genes.

PubMed

Riis, Margit L H; Lüders, Torben; Markert, Elke K; Haakensen, Vilde D; Nesbakken, Anne-Jorun; Kristensen, Vessela N; Bukholm, Ida R K

2012-01-01

Gene expression studies on breast cancer have generally been performed on tissue obtained at the time of surgery. In this study, we have compared the gene expression profiles in preoperative tissue (core needle biopsies) while tumor is still in its normal milieu to postoperative tissue from the same tumor obtained during surgery. Thirteen patients were included of which eleven had undergone sentinel node diagnosis procedure before operation. Microarray gene expression analysis was performed using total RNA from all the samples. Paired significance analysis of microarrays revealed 228 differently expressed genes, including several early response stress-related genes such as members of the fos and jun families as well as genes of which the expression has previously been associated with cancer. The expression profiles found in the analyses of breast cancer tissue must be evaluated with caution. Different profiles may simply be the result of differences in the surgical trauma and timing of when samples are taken and not necessarily associated with tumor biology.

Molecular Profiles of Pre- and Postoperative Breast Cancer Tumours Reveal Differentially Expressed Genes

PubMed Central

Riis, Margit L. H.; Lüders, Torben; Markert, Elke K.; Haakensen, Vilde D.; Nesbakken, Anne-Jorun; Kristensen, Vessela N.; Bukholm, Ida R. K.

2012-01-01

Gene expression studies on breast cancer have generally been performed on tissue obtained at the time of surgery. In this study, we have compared the gene expression profiles in preoperative tissue (core needle biopsies) while tumor is still in its normal milieu to postoperative tissue from the same tumor obtained during surgery. Thirteen patients were included of which eleven had undergone sentinel node diagnosis procedure before operation. Microarray gene expression analysis was performed using total RNA from all the samples. Paired significance analysis of microarrays revealed 228 differently expressed genes, including several early response stress-related genes such as members of the fos and jun families as well as genes of which the expression has previously been associated with cancer. The expression profiles found in the analyses of breast cancer tissue must be evaluated with caution. Different profiles may simply be the result of differences in the surgical trauma and timing of when samples are taken and not necessarily associated with tumor biology. PMID:23227362

A gene expression signature of retinoblastoma loss-of-function is a predictive biomarker of resistance to palbociclib in breast cancer cell lines and is prognostic in patients with ER positive early breast cancer.

PubMed

Malorni, Luca; Piazza, Silvano; Ciani, Yari; Guarducci, Cristina; Bonechi, Martina; Biagioni, Chiara; Hart, Christopher D; Verardo, Roberto; Di Leo, Angelo; Migliaccio, Ilenia

2016-09-13

Palbociclib is a CDK4/6 inhibitor that received FDA approval for treatment of hormone receptor positive (HR+) HER2 negative (HER2neg) advanced breast cancer. To better personalize patients treatment it is critical to identify subgroups that would mostly benefit from it. We hypothesize that complex alterations of the Retinoblastoma (Rb) pathway might be implicated in resistance to CDK4/6 inhibitors and aim to investigate whether signatures of Rb loss-of-function would identify breast cancer cell lines resistant to palbociclib. We established a gene expression signature of Rb loss-of-function (RBsig) by identifying genes correlated with E2F1 and E2F2 expression in breast cancers within The Cancer Genome Atlas. We assessed the RBsig prognostic role in the METABRIC and in a comprehensive breast cancer meta-dataset. Finally, we analyzed whether RBsig would discriminate palbociclib-sensitive and -resistant breast cancer cells in a large RNA sequencing-based dataset. The RBsig was associated with RB1 genetic status in all tumors (p <7e-32) and in luminal or basal subtypes (p < 7e-11 and p < 0.002, respectively). The RBsig was prognostic in the METABRIC dataset (discovery: HR = 1.93 [1.5-2.4] p = 1.4e-08; validation: HR = 2.01 [1.6-2.5] p = 1.3e-09). Untreated and endocrine treated patients with estrogen receptor positive breast cancer expressing high RBsig had significantly worse recurrence free survival compared to those with low RBsig (HR = 2.37 [1.8 - 3.2] p = 1.87e-08 and HR = 2.62 [1.9- 3.5] p = 8.6e-11, respectively). The RBsig was able to identify palbociclib resistant and sensitive breast cancer cells (ROC AUC = 0,7778). Signatures of RB loss might be helpful in personalizing treatment of patients with HR+/HER2neg breast cancer. Further validation in patients receiving palbociclib is warranted.

Chromosome 3p loss of heterozygosity is associated with a unique metabolic network in clear cell renal carcinoma

PubMed Central

Gatto, Francesco; Nookaew, Intawat; Nielsen, Jens

2014-01-01

Several common oncogenic pathways have been implicated in the emergence of renowned metabolic features in cancer, which in turn are deemed essential for cancer proliferation and survival. However, the extent to which different cancers coordinate their metabolism to meet these requirements is largely unexplored. Here we show that even in the heterogeneity of metabolic regulation a distinct signature encompassed most cancers. On the other hand, clear cell renal cell carcinoma (ccRCC) strongly deviated in terms of metabolic gene expression changes, showing widespread down-regulation. We observed a metabolic shift that associates differential regulation of enzymes in one-carbon metabolism with high tumor stage and poor clinical outcome. A significant yet limited set of metabolic genes that explained the partial divergence of ccRCC metabolism correlated with loss of von Hippel-Lindau tumor suppressor (VHL) and a potential activation of signal transducer and activator of transcription 1. Further network-dependent analyses revealed unique defects in nucleotide, one-carbon, and glycerophospholipid metabolism at the transcript and protein level, which contrasts findings in other tumors. Notably, this behavior is recapitulated by recurrent loss of heterozygosity in multiple metabolic genes adjacent to VHL. This study therefore shows how loss of heterozygosity, hallmarked by VHL deletion in ccRCC, may uniquely shape tumor metabolism. PMID:24550497

Effects of a parallel arm randomized controlled weight loss pilot study on biological and psychosocial parameters of overweight and obese breast cancer survivors

USDA-ARS?s Scientific Manuscript database

Background: Weight gain often occurs after breast cancer (BC) diagnosis, and obesity along with sedentary behavior, are associated with increased risk of BC recurrence and mortality. The purpose of this study was to examine effects of weight loss and exercise on body composition, fitness, cancer-rel...

Prognostic significance of CDKN2A (p16) promoter methylation and loss of expression in 902 colorectal cancers: Cohort study and literature review.

PubMed

Shima, Kaori; Nosho, Katsuhiko; Baba, Yoshifumi; Cantor, Mami; Meyerhardt, Jeffrey A; Giovannucci, Edward L; Fuchs, Charles S; Ogino, Shuji

2011-03-01

A cyclin-dependent kinase inhibitor CDKN2A (p16/Ink4a) is a tumor suppressor and upregulated in cellular senescence. CDKN2A promoter methylation and gene silencing are associated with the CpG island methylator phenotype (CIMP) in colon cancer. However, prognostic significance of CDKN2A methylation or loss of CDKN2A (p16) expression independent of CIMP status remains uncertain. Using a database of 902 colorectal cancers in 2 independent cohort studies (the Nurses' Health Study and the Health Professionals Follow-up Study), we quantified CDKN2A promoter methylation and detected hypermethylation in 269 tumors (30%). By immunohistochemistry, we detected loss of CDKN2A (p16) expression in 25% (200/804) of tumors. We analyzed for LINE-1 hypomethylation and hypermethylation at 7 CIMP-specific CpG islands (CACNA1G, CRABP1, IGF2, MLH1, NEUROG1, RUNX3 and SOCS1); microsatellite instability (MSI); KRAS, BRAF and PIK3CA mutations; and expression of TP53 (p53), CTNNB1 (β-catenin), CDKN1A (p21), CDKN1B (p27), CCND1 (cyclin D1), FASN (fatty acid synthase) and PTGS2 (cyclooxygenase-2). CDKN2A promoter methylation and loss of CDKN2A (p16) were associated with shorter overall survival in univariate Cox regression analysis [hazard ratio (HR): 1.36, 95% CI: 1.10-1.66, p = 0.0036 for CDKN2A methylation; HR: 1.30, 95% CI: 1.03-1.63, p = 0.026 for CDKN2A (p16) loss] but not in multivariate analysis that adjusted for clinical and tumor variables, including CIMP, MSI and LINE-1 methylation. Neither CDKN2A promoter methylation nor loss of CDKN2A (p16) was associated with colorectal cancer-specific mortality in uni- or multivariate analysis. Despite its well-established role in carcinogenesis, CDKN2A (p16) promoter methylation or loss of expression in colorectal cancer is not independently associated with patient prognosis. Copyright © 2010 UICC.

A novel analysis strategy for integrating methylation and expression data reveals core pathways for thyroid cancer aetiology

PubMed Central

2015-01-01

Background Recently, a wide range of diseases have been associated with changes in DNA methylation levels, which play a vital role in gene expression regulation. With ongoing developments in technology, attempts to understand disease mechanism have benefited greatly from epigenetics and transcriptomics studies. In this work, we have used expression and methylation data of thyroid carcinoma as a case study and explored how to optimally incorporate expression and methylation information into the disease study when both data are available. Moreover, we have also investigated whether there are important post-translational modifiers which could drive critical insights on thyroid cancer genetics. Results In this study, we have conducted a threshold analysis for varying methylation levels to identify whether setting a methylation level threshold increases the performance of functional enrichment. Moreover, in order to decide on best-performing analysis strategy, we have performed data integration analysis including comparison of 10 different analysis strategies. As a result, combining methylation with expression and using genes with more than 15% methylation change led to optimal detection rate of thyroid-cancer associated pathways in top 20 functional enrichment results. Furthermore, pooling the data from different experiments increased analysis confidence by improving the data range. Consequently, we have identified 207 transcription factors and 245 post-translational modifiers with more than 15% methylation change which may be important in understanding underlying mechanisms of thyroid cancer. Conclusion While only expression or only methylation information would not reveal both primary and secondary mechanisms involved in disease state, combining expression and methylation led to a better detection of thyroid cancer-related genes and pathways that are found in the recent literature. Moreover, focusing on genes that have certain level of methylation change improved the

Multi-omics analysis reveals that ornithine decarboxylase contributes to erlotinib resistance in pancreatic cancer cells

PubMed Central

Song, Sang-Hoon; Lee, Naeun; Kim, Dong-Joon; Lee, Sooyeun; Jeong, Chul-Ho

2017-01-01

Molecular and metabolic alterations in cancer cells are one of the leading causes of acquired resistance to chemotherapeutics. In this study, we explored an experimental strategy to identify which of these alterations can induce erlotinib resistance in human pancreatic cancer. Using genetically matched erlotinib-sensitive (BxPC-3) and erlotinib-resistant (BxPC-3ER) pancreatic cancer cells, we conducted a multi-omics analysis of metabolomes and transcriptomes in these cells. Untargeted and targeted metabolomic analyses revealed significant changes in metabolic pathways involved in the regulation of polyamines, amino acids, and fatty acids. Further transcriptomic analysis identified that ornithine decarboxylase (ODC) and its major metabolite, putrescine, contribute to the acquisition of erlotinib resistance in BxPC-3ER cells. Notably, either pharmacological or genetic blockage of ODC was able to restore erlotinib sensitivity, and this could be rescued by treatment with exogenous putrescine in erlotinib-resistant BxPC-3ER cells. Moreover, using a panel of cancer cells we demonstrated that ODC expression levels in cancer cells are inversely correlated with sensitivity to chemotherapeutics. Taken together, our findings will begin to uncover mechanisms of acquired drug resistance and ultimately help to identify potential therapeutic markers in cancer. PMID:29190951

Profiling and bioinformatics analyses reveal differential circular RNA expression in radioresistant esophageal cancer cells.

PubMed

Su, Huafang; Lin, Fuqiang; Deng, Xia; Shen, Lanxiao; Fang, Ya; Fei, Zhenghua; Zhao, Lihao; Zhang, Xuebang; Pan, Huanle; Xie, Deyao; Jin, Xiance; Xie, Congying

2016-07-28

Acquired radioresistance during radiotherapy is considered as the most important reason for local tumor recurrence or treatment failure. Circular RNAs (circRNAs) have recently been identified as microRNA sponges and involve in various biological processes. The purpose of this study is to investigate the role of circRNAs in the radioresistance of esophageal cancer. Total RNA was isolated from human parental cell line KYSE-150 and self-established radioresistant esophageal cancer cell line KYSE-150R, and hybridized to Arraystar Human circRNA Array. Quantitative real-time PCR was used to confirm the circRNA expression profiles obtained from the microarray data. Bioinformatic tools including gene ontology (GO) analysis, KEGG pathway analysis and network analysis were done for further assessment. Among the detected candidate 3752 circRNA genes, significant upregulation of 57 circRNAs and downregulation of 17 circRNAs in human radioresistant esophageal cancer cell line KYSE-150R were observed compared with the parental cell line KYSE-150 (fold change ≥2.0 and P < 0.05). There were 9 out of these candidate circRNAs were validated by real-time PCR. GO analysis revealed that numerous target genes, including most microRNAs were involved in the biological processes. There were more than 400 target genes enrichment on Wnt signaling pathway. CircRNA_001059 and circRNA_000167 were the two largest nodes in circRNA/microRNA co-expression network. Our study revealed a comprehensive expression and functional profile of differentially expressed circRNAs in radioresistant esophageal cancer cells, indicating possible involvement of these dysregulated circRNAs in the development of radiation resistance.

Diagnostic criteria for the classification of cancer-associated weight loss.

PubMed

Martin, Lisa; Senesse, Pierre; Gioulbasanis, Ioannis; Antoun, Sami; Bozzetti, Federico; Deans, Chris; Strasser, Florian; Thoresen, Lene; Jagoe, R Thomas; Chasen, Martin; Lundholm, Kent; Bosaeus, Ingvar; Fearon, Kenneth H; Baracos, Vickie E

2015-01-01

Existing definitions of clinically important weight loss (WL) in patients with cancer are unclear and heterogeneous and do not consider current trends toward obesity. Canadian and European patients with cancer (n = 8,160) formed a population-based data set. Body mass index (BMI) and percent WL (%WL) were recorded, and patients were observed prospectively until death. Data were entered into a multivariable analysis controlling for age, sex, cancer site, stage, and performance status. Relationships for BMI and %WL to overall survival were examined to develop a grading system. Mean overall %WL was -9.7% ± 8.4% and BMI was 24.4 ± 5.1 kg/m(2), and both %WL and BMI independently predicted survival (P < .01). Differences in survival were observed across five categories of BMI (< 20.0, 20.0 to 21.9, 22.0 to 24.9, 25.0 to 27.9, and ≥ 28.0 kg/m(2); P < .001) and five categories of %WL (-2.5% to -5.9%, -6.0% to -10.9%, -11.0% to -14.9%, ≥ -15.0%, and weight stable (± 2.4%); P < .001). A 5 × 5 matrix representing the five %WL categories within each of the five BMI categories was graded based on median survival and prognostic significance. Weight-stable patients with BMI ≥ 25.0 kg/m(2) (grade 0) had the longest survival (20.9 months; 95% CI, 17.9 to 23.9 months), and %WL values associated with lowered categories of BMI were related to shorter survival (P < .001), as follows: grade 1, 14.6 months (95% CI, 12.9 to 16.2 months); grade 2, 10.8 months (95% CI, 9.7 to 11.9 months); grade 3, 7.6 months (95% CI, 7.0 to 8.2 months); and grade 4, 4.3 months (95% CI, 4.1 to 4.6 months). Survival discrimination by grade was observed within specific cancers, stages, ages, and performance status and in an independent validation sample (n = 2,963). A robust grading system incorporating the independent prognostic significance of both BMI and %WL was developed. © 2014 by American Society of Clinical Oncology.

Systems Perturbation Analysis of a Large-Scale Signal Transduction Model Reveals Potentially Influential Candidates for Cancer Therapeutics

PubMed Central

Puniya, Bhanwar Lal; Allen, Laura; Hochfelder, Colleen; Majumder, Mahbubul; Helikar, Tomáš

2016-01-01

Dysregulation in signal transduction pathways can lead to a variety of complex disorders, including cancer. Computational approaches such as network analysis are important tools to understand system dynamics as well as to identify critical components that could be further explored as therapeutic targets. Here, we performed perturbation analysis of a large-scale signal transduction model in extracellular environments that stimulate cell death, growth, motility, and quiescence. Each of the model’s components was perturbed under both loss-of-function and gain-of-function mutations. Using 1,300 simulations under both types of perturbations across various extracellular conditions, we identified the most and least influential components based on the magnitude of their influence on the rest of the system. Based on the premise that the most influential components might serve as better drug targets, we characterized them for biological functions, housekeeping genes, essential genes, and druggable proteins. The most influential components under all environmental conditions were enriched with several biological processes. The inositol pathway was found as most influential under inactivating perturbations, whereas the kinase and small lung cancer pathways were identified as the most influential under activating perturbations. The most influential components were enriched with essential genes and druggable proteins. Moreover, known cancer drug targets were also classified in influential components based on the affected components in the network. Additionally, the systemic perturbation analysis of the model revealed a network motif of most influential components which affect each other. Furthermore, our analysis predicted novel combinations of cancer drug targets with various effects on other most influential components. We found that the combinatorial perturbation consisting of PI3K inactivation and overactivation of IP3R1 can lead to increased activity levels of apoptosis

Hair Loss (Alopecia)

MedlinePlus

... Pediatrician Health Issues Conditions Abdominal ADHD Allergies & Asthma Autism Cancer Chest & Lungs Chronic Conditions Cleft & Craniofacial Developmental ... with certain abnormalities of the nails and the teeth. Later in childhood, hair loss may be due ...

Unresolved grief and its consequences. A nationwide follow-up of teenage loss of a parent to cancer 6-9 years earlier.

PubMed

Bylund-Grenklo, T; Fürst, C J; Nyberg, T; Steineck, G; Kreicbergs, U

2016-07-01

The early loss of a parent is a tragedy and a serious life event. This study investigated grief resolution and morbidity in cancer-bereaved teenagers 6 to 9 years after the loss of a parent to cancer. In a nationwide population-based study of 622 of 851 (73 %) youths who as teenagers 6 to 9 years earlier had lost a parent to cancer, we explored the magnitude of unresolved grief and its association with psychological and physiological morbidity. Participants answered a study-specific anonymous questionnaire including questions about if they had worked through their grief and about their current health. Six to nine years post-loss 49 % reported unresolved grief (8 % no and 41 % a little grief resolution). They had, in comparison with youths reporting resolved grief, statistically significantly elevated risks, e.g. for insomnia (sons' relative risk (RR) 2.3, 95 % CI 1.3-4.0; daughters' RR 1.7, 95 % CI 1.1-2.7), fatigue (sons' RR 1.8, 95 % CI 1.3-2.5; daughters' RR 1.4, 95 % CI 1.1-1.7) and moderate to severe depression, i.e. score >9, PHQ-9 (sons' RR 3.6, 95 % CI 1.4-8.8; daughters' RR 1.8, 95 % CI 1.1-3.1). Associations remained for insomnia in sons, exhaustion in daughters and fatigue in both sons and daughters when depression, negative intrusive thoughts and avoiding reminders of the parents' disease or death were included in a model. Approximately half of cancer-bereaved youth report no or little grief resolution 6 to 9 years post-loss, which is associated with fatigue, sleeping problems and depressive symptoms.

Raman spectroscopy reveals biophysical markers in skin cancer surgical margins

NASA Astrophysics Data System (ADS)

Feng, Xu; Moy, Austin J.; Nguyen, Hieu T. M.; Zhang, Yao; Fox, Matthew C.; Sebastian, Katherine R.; Reichenberg, Jason S.; Markey, Mia K.; Tunnell, James W.

2018-02-01

The recurrence rate of nonmelanoma skin cancer is highly related to the residual tumor after surgery. Although tissueconserving surgery, such as Mohs surgery, is a standard method for the treatment of nonmelanoma skin cancer, they are limited by lengthy and costly frozen-section histopathology. Raman spectroscopy (RS) is proving to be an objective, sensitive, and non-destructive tool for detecting skin cancer. Previous studies demonstrated the high sensitivity of RS in detecting tumor margins of basal cell carcinoma (BCC). However, those studies rely on statistical classification models and do not elucidate the skin biophysical composition. As a result, we aim to discover the biophysical differences between BCC and primary normal skin structures (including epidermis, dermis, hair follicle, sebaceous gland and fat). We obtained freshly resected ex vivo skin samples from fresh resection specimens from 14 patients undergoing Mohs surgery. Raman images were acquired from regions containing one or more structures using a custom built 830nm confocal Raman microscope. The spectra were grouped using K-means clustering analysis and annotated as either BCC or each of the five normal structures by comparing with the histopathology image of the serial section. The spectral data were then fit by a previously established biophysical model with eight primary skin constituents. Our results show that BCC has significant differences in the fit coefficients of nucleus, collagen, triolein, keratin and elastin compared with normal structures. Our study reveals RS has the potential to detect biophysical changes in resection margins, and supports the development of diagnostic algorithms for future intraoperative implementation of RS during Mohs surgery.

Periodontal Disease, Tooth Loss, and Cancer Risk

PubMed Central

Michaud, Dominique S.; Fu, Zhuxuan; Shi, Jian; Chung, Mei

2017-01-01

Abstract Periodontal disease, which includes gingivitis and periodontitis, is highly prevalent in adults and disease severity increases with age. The relationship between periodontal disease and oral cancer has been examined for several decades, but there is increasing interest in the link between periodontal disease and overall cancer risk, with systemic inflammation serving as the main focus for biological plausibility. Numerous case-control studies have addressed the role of oral health in head and neck cancer, and several cohort studies have examined associations with other types of cancers over the past decade. For this review, we included studies that were identified from either 11 published reviews on this topic or an updated literature search on PubMed (between 2011 and July 2016). A total of 50 studies from 46 publications were included in this review. Meta-analyses were conducted on cohort and case-control studies separately when at least 4 studies could be included to determine summary estimates of the risk of cancer in relation to 1) periodontal disease or 2) tooth number (a surrogate marker of periodontal disease) with adjustment for smoking. Existing data provide support for a positive association between periodontal disease and risk of oral, lung, and pancreatic cancers; however, additional prospective studies are needed to better inform on the strength of these associations and to determine whether other cancers are associated with periodontal disease. Future studies should include sufficiently large sample sizes, improved measurements for periodontal disease, and thorough adjustment for smoking and other risk factors. PMID:28449041

Relationship between weight loss and parameters of skeletal muscle function in patients with advanced cancer and fatigue.

PubMed

Morgado, P Cresta; Giorlando, A; Castro, M; Navigante, A

2016-09-01

This study aims to determine the influence of significant weight loss on parameters of skeletal muscle function in a population of advanced cancer patients with fatigue. A cross-sectional and comparative study was designed between two arms of advanced cancer patients with fatigue (fatigue numeral scale (FNS) ≥4). A arm (n = 27) with ≥5 % weight loss in the last 6 months, and B arm (n = 22) without weight loss. Muscle strength was examined by hand grip technique and measurements of body composition by bioimpedance analysis (BIA), values of hemoglobin, albumin, lactic dehydrogenase (LDH), c-reactive protein (CRP), urine creatinine, and FNS. These variables were compared between both groups and correlated within each group. here were no differences concerning parameters of muscle strength between both arms. A arm had values of CRP ≥10 ug/dl in 77 % compared with 38.5 % of B arm (p = 0.004). A arm showed a higher percentage of body cell mass (%BCM) than B arm (p = 0.005). The A arm also showed a lower percentage of fat mass (%FM) (p = 0.014) when compared to the B arm. FNS was higher in A arm (median 7 vs 5; p = 0.047). All the variables of muscle strength had a significant positive correlation. In A arm, BCM had a negative significant correlation with CRP (p = 0.021). In this study, significant weight loss and high CRP did not have influence on parameters of skeletal muscular function. We consider that further studies should be necessary, preferably with longitudinal designs to evaluate these findings.

The role of TGF-β/SMAD4 signaling in cancer.

PubMed

Zhao, Ming; Mishra, Lopa; Deng, Chu-Xia

2018-01-01

Transforming growth factor β (TGF-β) signaling pathway plays important roles in many biological processes, including cell growth, differentiation, apoptosis, migration, as well as cancer initiation and progression. SMAD4, which serves as the central mediator of TGF-β signaling, is specifically inactivated in over half of pancreatic duct adenocarcinoma, and varying degrees in many other types of cancers. In the past two decades, multiple studies have revealed that SMAD4 loss on its own does not initiate tumor formation, but can promote tumor progression initiated by other genes, such as KRAS activation in pancreatic duct adenocarcinoma and APC inactivation in colorectal cancer. In other cases, such as skin cancer, loss of SMAD4 plays an important initiating role by disrupting DNA damage response and repair mechanisms and enhance genomic instability, suggesting its distinct roles in different types of tumors. This review lists SMAD4 mutations in various types of cancer and summarizes recent advances on SMAD4 with focuses on the function, signaling pathway, and the possibility of SMAD4 as a prognostic indicator.

The role of TGF-β/SMAD4 signaling in cancer

PubMed Central

Zhao, Ming; Mishra, Lopa; Deng, Chu-Xia

2018-01-01

Transforming growth factor β (TGF-β) signaling pathway plays important roles in many biological processes, including cell growth, differentiation, apoptosis, migration, as well as cancer initiation and progression. SMAD4, which serves as the central mediator of TGF-β signaling, is specifically inactivated in over half of pancreatic duct adenocarcinoma, and varying degrees in many other types of cancers. In the past two decades, multiple studies have revealed that SMAD4 loss on its own does not initiate tumor formation, but can promote tumor progression initiated by other genes, such as KRAS activation in pancreatic duct adenocarcinoma and APC inactivation in colorectal cancer. In other cases, such as skin cancer, loss of SMAD4 plays an important initiating role by disrupting DNA damage response and repair mechanisms and enhance genomic instability, suggesting its distinct roles in different types of tumors. This review lists SMAD4 mutations in various types of cancer and summarizes recent advances on SMAD4 with focuses on the function, signaling pathway, and the possibility of SMAD4 as a prognostic indicator. PMID:29483830

Solutions to Peto's paradox revealed by mathematical modelling and cross-species cancer gene analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Caulin, Aleah F.; Graham, Trevor A.; Wang, Li-San

Whales have 1000-fold more cells than humans and mice have 1000-fold fewer; however, cancer risk across species does not increase with the number of somatic cells and the lifespan of the organism. This observation is known as Peto's paradox. How much would evolution have to change the parameters of somatic evolution in order to equalize the cancer risk between species that differ by orders of magnitude in size? Analysis of previously published models of colorectal cancer suggests that a two- to three-fold decrease in the mutation rate or stem cell division rate is enough to reduce a whale's cancer riskmore » to that of a human. Similarly, the addition of one to two required tumour-suppressor gene mutations would also be sufficient. Also, we surveyed mammalian genomes and did not find a positive correlation of tumour-suppressor genes with increasing body mass and longevity. However, we found evidence of the amplification of TP53 in elephants, MAL in horses and FBXO31 in microbats, which might explain Peto's paradox in those species. Lastly, exploring parameters that evolution may have fine-tuned in large, long-lived organisms will help guide future experiments to reveal the underlying biology responsible for Peto's paradox and guide cancer prevention in humans.« less

Solutions to Peto's paradox revealed by mathematical modelling and cross-species cancer gene analysis

DOE PAGES

Caulin, Aleah F.; Graham, Trevor A.; Wang, Li-San; ...

2015-06-08

Whales have 1000-fold more cells than humans and mice have 1000-fold fewer; however, cancer risk across species does not increase with the number of somatic cells and the lifespan of the organism. This observation is known as Peto's paradox. How much would evolution have to change the parameters of somatic evolution in order to equalize the cancer risk between species that differ by orders of magnitude in size? Analysis of previously published models of colorectal cancer suggests that a two- to three-fold decrease in the mutation rate or stem cell division rate is enough to reduce a whale's cancer riskmore » to that of a human. Similarly, the addition of one to two required tumour-suppressor gene mutations would also be sufficient. Also, we surveyed mammalian genomes and did not find a positive correlation of tumour-suppressor genes with increasing body mass and longevity. However, we found evidence of the amplification of TP53 in elephants, MAL in horses and FBXO31 in microbats, which might explain Peto's paradox in those species. Lastly, exploring parameters that evolution may have fine-tuned in large, long-lived organisms will help guide future experiments to reveal the underlying biology responsible for Peto's paradox and guide cancer prevention in humans.« less

Mutational profiles of breast cancer metastases from a rapid autopsy series reveal multiple evolutionary trajectories.

PubMed

Avigdor, Bracha Erlanger; Cimino-Mathews, Ashley; DeMarzo, Angelo M; Hicks, Jessica L; Shin, James; Sukumar, Saraswati; Fetting, John; Argani, Pedram; Park, Ben H; Wheelan, Sarah J

2017-12-21

Heterogeneity within and among tumors in a metastatic cancer patient is a well-established phenomenon that may confound treatment and accurate prognosis. Here, we used whole-exome sequencing to survey metastatic breast cancer tumors from 5 patients in a rapid autopsy program to construct the origin and genetic development of metastases. Metastases were obtained from 5 breast cancer patients using a rapid autopsy protocol and subjected to whole-exome sequencing. Metastases were evaluated for sharing of somatic mutations, correlation of copy number variation and loss of heterozygosity, and genetic similarity scores. Pathological features of the patients' disease were assessed by immunohistochemical analyses. Our data support a monoclonal origin of metastasis in 3 cases, but in 2 cases, metastases arose from at least 2 distinct subclones in the primary tumor. In the latter 2 cases, the primary tumor presented with mixed histologic and pathologic features, suggesting early divergent evolution within the primary tumor with maintenance of metastatic capability in multiple lineages. We used genetic and histopathological evidence to demonstrate that metastases can be derived from a single or multiple independent clones within a primary tumor. This underscores the complexity of breast cancer clonal evolution and has implications for how best to determine and implement therapies for early- and late-stage disease.

Mutational profiles of breast cancer metastases from a rapid autopsy series reveal multiple evolutionary trajectories

PubMed Central

Avigdor, Bracha Erlanger; Cimino-Mathews, Ashley; DeMarzo, Angelo M.; Hicks, Jessica L.; Shin, James; Sukumar, Saraswati; Fetting, John; Argani, Pedram; Park, Ben H.; Wheelan, Sarah J.

2017-01-01

Heterogeneity within and among tumors in a metastatic cancer patient is a well-established phenomenon that may confound treatment and accurate prognosis. Here, we used whole-exome sequencing to survey metastatic breast cancer tumors from 5 patients in a rapid autopsy program to construct the origin and genetic development of metastases. Metastases were obtained from 5 breast cancer patients using a rapid autopsy protocol and subjected to whole-exome sequencing. Metastases were evaluated for sharing of somatic mutations, correlation of copy number variation and loss of heterozygosity, and genetic similarity scores. Pathological features of the patients’ disease were assessed by immunohistochemical analyses. Our data support a monoclonal origin of metastasis in 3 cases, but in 2 cases, metastases arose from at least 2 distinct subclones in the primary tumor. In the latter 2 cases, the primary tumor presented with mixed histologic and pathologic features, suggesting early divergent evolution within the primary tumor with maintenance of metastatic capability in multiple lineages. We used genetic and histopathological evidence to demonstrate that metastases can be derived from a single or multiple independent clones within a primary tumor. This underscores the complexity of breast cancer clonal evolution and has implications for how best to determine and implement therapies for early- and late-stage disease. PMID:29263308

Phase III Randomized, Placebo-Controlled, Double-Blind Trial of Risedronate for the Prevention of Bone Loss in Premenopausal Women Undergoing Chemotherapy for Primary Breast Cancer

PubMed Central

Hines, Stephanie L.; Mincey, Betty Anne; Sloan, Jeff A.; Thomas, Sachdev P.; Chottiner, Elaine; Loprinzi, Charles L.; Carlson, Mark D.; Atherton, Pamela J.; Salim, Muhammad; Perez, Edith A.

2009-01-01

Purpose Risedronate prevents bone loss in postmenopausal women. The purpose of this study was to determine whether risedronate prevents bone loss in premenopausal women undergoing chemotherapy for breast cancer. Patients and Methods Premenopausal women undergoing chemotherapy for breast cancer were treated with oral calcium 600 mg and vitamin D 400 U daily and randomly assigned to receive oral risedronate 35 mg weekly or placebo, with all these therapies beginning within a month of the start of chemotherapy. Most chemotherapy regimens included anthracyclines, taxanes, or cyclophosphamide. Bone mineral density (BMD) was measured at baseline and 1 year. The primary end point was the change in lumbar spine (LS) BMD from baseline to 1 year. Results A total of 216 women enrolled; 170 women provided BMD data at 1 year. There was no difference in the mean change or percent change in LS BMD between groups, with a loss of 4.3% in the risedronate arm and 5.4% for placebo at 1 year (P = .18). Loss of BMD at the femoral neck and total hip were also similar between treatment groups. Risedronate was well tolerated, with no significant differences in adverse events compared with placebo, except that arthralgias and chest pain were worse in those receiving the placebos. Conclusion Risedronate did not prevent bone loss in premenopausal women undergoing adjuvant chemotherapy for breast cancer. PMID:19075260

Cancer-induced anorexia and malaise are mediated by CGRP neurons in the parabrachial nucleus.

PubMed

Campos, Carlos A; Bowen, Anna J; Han, Sung; Wisse, Brent E; Palmiter, Richard D; Schwartz, Michael W

2017-07-01

Anorexia is a common manifestation of chronic diseases, including cancer. Here we investigate the contribution to cancer anorexia made by calcitonin gene-related peptide (CGRP) neurons in the parabrachial nucleus (PBN) that transmit anorexic signals. We show that CGRP PBN neurons are activated in mice implanted with Lewis lung carcinoma cells. Inactivation of CGRP PBN neurons before tumor implantation prevents anorexia and loss of lean mass, and their inhibition after symptom onset reverses anorexia. CGRP PBN neurons are also activated in Apc min/+ mice, which develop intestinal cancer and lose weight despite the absence of reduced food intake. Inactivation of CGRP PBN neurons in Apc min/+ mice permits hyperphagia that counteracts weight loss, revealing a role for these neurons in a 'nonanorexic' cancer model. We also demonstrate that inactivation of CGRP PBN neurons prevents lethargy, anxiety and malaise associated with cancer. These findings establish CGRP PBN neurons as key mediators of cancer-induced appetite suppression and associated behavioral changes.

Cancer-induced anorexia and malaise are mediated by CGRP neurons in the parabrachial nucleus

PubMed Central

Campos, Carlos A.; Bowen, Anna J.; Han, Sung; Wisse, Brent E.; Palmiter, Richard D.; Schwartz, Michael W.

2017-01-01

Anorexia is a common manifestation of chronic diseases, including cancer. Here we investigate the contribution to cancer anorexia made by calcitonin gene-related peptide (CGRP) neurons in the parabrachial nucleus (PBN) that transmit anorexic signals. We show that CGRPPBN neurons are activated in mice implanted with Lewis lung carcinoma (LLC) cells. Inactivation of CGRPPBN neurons before tumor implantation prevents anorexia and loss of lean mass, and their inhibition after symptom onset reverses anorexia. CGRPPBN neurons are also activated in Apcmin/+ mice that develop intestinal cancer and lose weight despite the absence of reduced food intake. Inactivation of CGRPPBN neurons in Apcmin/+ mice permits hyperphagia that counteracts weight loss, revealing a role for these neurons in a “non-anorexic” cancer model. We also demonstrate that inactivation of CGRPPBN neurons prevents lethargy, anxiety and malaise associated with cancer. These findings establish CGRPPBN neurons as key mediators of cancer-induced appetite suppression and associated behavioral changes. PMID:28581479

Loss of FBXW7 and accumulation of MCL1 and PLK1 promote paclitaxel resistance in breast cancer.

PubMed

Gasca, Jessica; Flores, Maria Luz; Giráldez, Servando; Ruiz-Borrego, Manuel; Tortolero, María; Romero, Francisco; Japón, Miguel A; Sáez, Carmen

2016-08-16

FBXW7 is a component of SCF (complex of SKP1, CUL1 and F-box-protein)-type ubiquitin ligases that targets several oncoproteins for ubiquitination and degradation by the proteasome. FBXW7 regulates cellular apoptosis by targeting MCL1 for ubiquitination. Recently, we identified PLK1 as a new substrate of FBXW7 modulating the intra-S-phase DNA-damage checkpoint. Taxanes are frequently used in breast cancer treatments, but the acquisition of resistance makes these treatments ineffective. We investigated the role of FBXW7 and their substrates MCL1 and PLK1 in regulating the apoptotic response to paclitaxel treatment in breast cancer cells and their expression in breast cancer tissues. Paclitaxel-sensitive MDA-MB-468 and a paclitaxel-resistant MDA-MB-468R subclone were used to study the role of FBXW7 and substrates in paclitaxel-induced apoptosis. Forced expression of FBXW7 or downregulation of MCL1 or PLK1 restored sensitivity to paclitaxel in MDA-MB-468R cells. By contrary, FBXW7-silenced MDA-MB-468 cells became resistant to paclitaxel. The expression of FBXW7 and substrates were studied in 296 invasive carcinomas by immunohistochemistry and disease-free survival was analyzed in a subset of patients treated with paclitaxel. In breast cancer tissues, loss of FBXW7 correlated with adverse prognosis markers and loss of FBXW7 and MCL1 or PLK1 accumulation were associated with diminished disease-free survival in paclitaxel-treated patients. We conclude that FBXW7 regulates the response to paclitaxel by targeting MCL1 and PLK1 in breast cancer cells and thus targeting these substrates may be a valuable adjunct for paclitaxel treatment. Also, FBXW7, MCL1 and PLK1 may be relevant predictive markers of tumor progression and response to paclitaxel treatment.

Loss of FBXW7 and accumulation of MCL1 and PLK1 promote paclitaxel resistance in breast cancer

PubMed Central

Gasca, Jessica; Flores, Maria Luz; Giráldez, Servando; Ruiz-Borrego, Manuel; Tortolero, María; Romero, Francisco; Japón, Miguel A.; Sáez, Carmen

2016-01-01

FBXW7 is a component of SCF (complex of SKP1, CUL1 and F-box-protein)-type ubiquitin ligases that targets several oncoproteins for ubiquitination and degradation by the proteasome. FBXW7 regulates cellular apoptosis by targeting MCL1 for ubiquitination. Recently, we identified PLK1 as a new substrate of FBXW7 modulating the intra-S-phase DNA-damage checkpoint. Taxanes are frequently used in breast cancer treatments, but the acquisition of resistance makes these treatments ineffective. We investigated the role of FBXW7 and their substrates MCL1 and PLK1 in regulating the apoptotic response to paclitaxel treatment in breast cancer cells and their expression in breast cancer tissues. Paclitaxel-sensitive MDA-MB-468 and a paclitaxel-resistant MDA-MB-468R subclone were used to study the role of FBXW7 and substrates in paclitaxel-induced apoptosis. Forced expression of FBXW7 or downregulation of MCL1 or PLK1 restored sensitivity to paclitaxel in MDA-MB-468R cells. By contrary, FBXW7-silenced MDA-MB-468 cells became resistant to paclitaxel. The expression of FBXW7 and substrates were studied in 296 invasive carcinomas by immunohistochemistry and disease-free survival was analyzed in a subset of patients treated with paclitaxel. In breast cancer tissues, loss of FBXW7 correlated with adverse prognosis markers and loss of FBXW7 and MCL1 or PLK1 accumulation were associated with diminished disease-free survival in paclitaxel-treated patients. We conclude that FBXW7 regulates the response to paclitaxel by targeting MCL1 and PLK1 in breast cancer cells and thus targeting these substrates may be a valuable adjunct for paclitaxel treatment. Also, FBXW7, MCL1 and PLK1 may be relevant predictive markers of tumor progression and response to paclitaxel treatment. PMID:27409838

Suicide ideation in stomach cancer survivors and possible risk factors.

PubMed

Choi, Ye-Ni; Kim, Young-Ae; Yun, Young Ho; Kim, Sung; Bae, Jae-Moon; Kim, Young-Woo; Ryu, Keun Won; Lee, Jun Ho; Noh, Jae-Hyung; Sohn, Tae-Sung

2014-02-01

Although the suicide rate of cancer survivors is higher than that of the general population, few studies have examined the potential risk factors. We assessed suicide ideation (SI) and investigated its correlates among survivors of stomach cancer, which is one of the most prevalent cancers in Korea. We surveyed 378 stage I-III stomach cancer survivors who had been disease free for at least 1 year. The survey contained demographic questions and quality of life assessments from the European Organization for Research and Treatment of Cancer QLQ-C30 and its stomach cancer-specific module, the McGill Quality of Life Questionnaire, the Brief Fatigue Inventory, and one question from the Beck Depression Inventory. We found that 131/378 stomach cancer survivors (34.7 %) experienced SI. Univariate analyses showed that SI was significantly associated with income, comorbidity, smoking, and the following quality of life factors: general health status, emotional functioning, fatigue, nausea/vomiting, dyspnea, appetite loss, constipation, diarrhea, financial problems, eating restriction, anxiety, dry mouth, trouble belching, hair loss, body image, existential well-being, and social support. Multivariate logistic regression confirmed that SI was independently associated with diarrhea (adjusted odds ratio (aOR) 2.84; 95 % confidence interval (CI) 1.44-5.62), hair loss (aOR 2.77; 95 % CI 1.04-7.36), existential well-being (aOR 6.18; 95 % CI 2.91-13.1), and usual fatigue (aOR 2.29; 95 % CI 1.30-4.06). Our findings reveal a high prevalence of SI among stomach cancer survivors and identify health-related quality of life issues such as diarrhea, hair loss, existential well-being, and fatigue as important risk factors of SI.

PTEN Loss as Determined by Clinical-grade Immunohistochemistry Assay Is Associated with Worse Recurrence-free Survival in Prostate Cancer.

PubMed

Lotan, Tamara L; Wei, Wei; Morais, Carlos L; Hawley, Sarah T; Fazli, Ladan; Hurtado-Coll, Antonio; Troyer, Dean; McKenney, Jesse K; Simko, Jeffrey; Carroll, Peter R; Gleave, Martin; Lance, Raymond; Lin, Daniel W; Nelson, Peter S; Thompson, Ian M; True, Lawrence D; Feng, Ziding; Brooks, James D

2016-06-01

PTEN is the most commonly deleted tumor suppressor gene in primary prostate cancer (PCa) and its loss is associated with poor clinical outcomes and ERG gene rearrangement. We tested whether PTEN loss is associated with shorter recurrence-free survival (RFS) in surgically treated PCa patients with known ERG status. A genetically validated, automated PTEN immunohistochemistry (IHC) protocol was used for 1275 primary prostate tumors from the Canary Foundation retrospective PCa tissue microarray cohort to assess homogeneous (in all tumor tissue sampled) or heterogeneous (in a subset of tumor tissue sampled) PTEN loss. ERG status as determined by a genetically validated IHC assay was available for a subset of 938 tumors. Associations between PTEN and ERG status were assessed using Fisher's exact test. Kaplan-Meier and multivariate weighted Cox proportional models for RFS were constructed. When compared to intact PTEN, homogeneous (hazard ratio [HR] 1.66, p = 0.001) but not heterogeneous (HR 1.24, p = 0.14) PTEN loss was significantly associated with shorter RFS in multivariate models. Among ERG-positive tumors, homogeneous (HR 3.07, p < 0.0001) but not heterogeneous (HR 1.46, p = 0.10) PTEN loss was significantly associated with shorter RFS. Among ERG-negative tumors, PTEN did not reach significance for inclusion in the final multivariate models. The interaction term for PTEN and ERG status with respect to RFS did not reach statistical significance ( p = 0.11) for the current sample size. These data suggest that PTEN is a useful prognostic biomarker and that there is no statistically significant interaction between PTEN and ERG status for RFS. We found that loss of the PTEN tumor suppressor gene in prostate tumors as assessed by tissue staining is correlated with shorter time to prostate cancer recurrence after radical prostatectomy.

Comparative sequencing analysis reveals high genomic concordance between matched primary and metastatic colorectal cancer lesions.

PubMed

Brannon, A Rose; Vakiani, Efsevia; Sylvester, Brooke E; Scott, Sasinya N; McDermott, Gregory; Shah, Ronak H; Kania, Krishan; Viale, Agnes; Oschwald, Dayna M; Vacic, Vladimir; Emde, Anne-Katrin; Cercek, Andrea; Yaeger, Rona; Kemeny, Nancy E; Saltz, Leonard B; Shia, Jinru; D'Angelica, Michael I; Weiser, Martin R; Solit, David B; Berger, Michael F

2014-08-28

Colorectal cancer is the second leading cause of cancer death in the United States, with over 50,000 deaths estimated in 2014. Molecular profiling for somatic mutations that predict absence of response to anti-EGFR therapy has become standard practice in the treatment of metastatic colorectal cancer; however, the quantity and type of tissue available for testing is frequently limited. Further, the degree to which the primary tumor is a faithful representation of metastatic disease has been questioned. As next-generation sequencing technology becomes more widely available for clinical use and additional molecularly targeted agents are considered as treatment options in colorectal cancer, it is important to characterize the extent of tumor heterogeneity between primary and metastatic tumors. We performed deep coverage, targeted next-generation sequencing of 230 key cancer-associated genes for 69 matched primary and metastatic tumors and normal tissue. Mutation profiles were 100% concordant for KRAS, NRAS, and BRAF, and were highly concordant for recurrent alterations in colorectal cancer. Additionally, whole genome sequencing of four patient trios did not reveal any additional site-specific targetable alterations. Colorectal cancer primary tumors and metastases exhibit high genomic concordance. As current clinical practices in colorectal cancer revolve around KRAS, NRAS, and BRAF mutation status, diagnostic sequencing of either primary or metastatic tissue as available is acceptable for most patients. Additionally, consistency between targeted sequencing and whole genome sequencing results suggests that targeted sequencing may be a suitable strategy for clinical diagnostic applications.

Loss of Cytoplasmic CDK1 Predicts Poor Survival in Human Lung Cancer and Confers Chemotherapeutic Resistance

PubMed Central

Zhang, Chunyu; Elkahloun, Abdel G.; Robertson, Matthew; Gills, Joell J.; Tsurutani, Junji; Shih, Joanna H.; Fukuoka, Junya; Hollander, M. Christine; Harris, Curtis C.; Travis, William D.; Jen, Jin; Dennis, Phillip A.

2011-01-01

The dismal lethality of lung cancer is due to late stage at diagnosis and inherent therapeutic resistance. The incorporation of targeted therapies has modestly improved clinical outcomes, but the identification of new targets could further improve clinical outcomes by guiding stratification of poor-risk early stage patients and individualizing therapeutic choices. We hypothesized that a sequential, combined microarray approach would be valuable to identify and validate new targets in lung cancer. We profiled gene expression signatures during lung epithelial cell immortalization and transformation, and showed that genes involved in mitosis were progressively enhanced in carcinogenesis. 28 genes were validated by immunoblotting and 4 genes were further evaluated in non-small cell lung cancer tissue microarrays. Although CDK1 was highly expressed in tumor tissues, its loss from the cytoplasm unexpectedly predicted poor survival and conferred resistance to chemotherapy in multiple cell lines, especially microtubule-directed agents. An analysis of expression of CDK1 and CDK1-associated genes in the NCI60 cell line database confirmed the broad association of these genes with chemotherapeutic responsiveness. These results have implications for personalizing lung cancer therapy and highlight the potential of combined approaches for biomarker discovery. PMID:21887332

The Cables Gene on Chromosome 18q Is Silenced by Promoter Hypermethylation and Allelic Loss in Human Colorectal Cancer

PubMed Central

Park, Do Youn; Sakamoto, Hideo; Kirley, Sandra D.; Ogino, Shuji; Kawasaki, Takako; Kwon, Eunjeong; Mino-Kenudson, Mari; Lauwers, Gregory Y.; Chung, Daniel C.; Rueda, Bo R.; Zukerberg, Lawrence R.

2007-01-01

Cables is a cyclin-dependent kinase-binding nuclear protein that maps to chromosome 18q11-12. Here, we assessed Cables expression in 160 colorectal cancers (CRCs), its role in colon cancer cell growth, and the potential mechanisms of Cables inactivation. Expression levels, promoter methylation, and mutational status of Cables were investigated in colon cancer cell lines and primary colon tumors. Chromosome 18q loss of heterozygosity (LOH) was evaluated with multiple polymorphic markers. Cables inhibited cellular proliferation and colony formation in colon cancer cell lines. Cables expression was reduced in 65% of primary CRCs. No mutations were detected in 10 exons of Cables in 20 primary colon tumors. Cables promoter was methylated in cell lines with decreased Cables expression and vice versa. 5-Aza-2′-deoxycytidine resulted in increased Cables expression in methylated cell lines. There was a significant correlation between promoter methylation and Cables gene expression in primary colon tumors. Sixty-five percent of primary colon tumors demonstrated chromosome 18q LOH. LOH involving the Cables region was observed in 35% of cases, including those in which more distal portions of chromosome 18q were retained, and Cables expression was decreased in all such cases. Loss of Cables expression in 65% of CRCs suggests that it is a common event in colonic carcinogenesis, with promoter methylation and LOH appearing to be important mechanisms of Cables gene inactivation. PMID:17982127

Identification of differentially expressed proteins during human urinary bladder cancer progression.

PubMed

Memon, Ashfaque A; Chang, Jong W; Oh, Bong R; Yoo, Yung J

2005-01-01

Comparative proteome analysis was performed between RT4 (grade-1) and T24 (grade-3) bladder cancer cell lines, in an attempt to identify differentially expressed proteins during bladder cancer progression. Among those relatively abundant proteins, seven spots changed more than two-fold reproducibly and identified by peptide mass fingerprinting using mass spectrometry and database search. We found most extensive and reproducible down-regulation of NADP dependent isocitrate dehydrogenase cytoplasmic (IDPc) and peroxiredoxin-II (Prx-II), in poorly differentiated T24 compared to well-differentiated RT4 bladder cancer cell line. Subsequent Western blotting analysis of human biopsy samples from bladder cancer patient revealed significant loss of IDPc and Prx-II in more advance tumor samples, in agreement with data on cell lines. These results suggest that loss of IDPc and Prx-II during tumor development may involve in tumor progression and metastasis. However, additional investigations are needed on large number of human samples to further verify these findings.

Effect of dietary patterns differing in carbohydrate and fat content on blood lipid and glucose profiles based on weight-loss success of breast-cancer survivors.

PubMed

Thompson, Henry J; Sedlacek, Scot M; Paul, Devchand; Wolfe, Pamela; McGinley, John N; Playdon, Mary C; Daeninck, Elizabeth A; Bartels, Sara N; Wisthoff, Mark R

2012-01-06

Healthy body weight is an important factor for prevention of breast cancer recurrence. Yet, weight loss and weight gain are not currently included in clinical-practice guidelines for posttreatment of breast cancer. The work reported addresses one of the questions that must be considered in recommending weight loss to patients: does it matter what diet plan is used, a question of particular importance because breast cancer treatment can increase risk for cardiovascular disease. Women who completed treatment for breast cancer were enrolled in a nonrandomized, controlled study investigating effects of weight loss achieved by using two dietary patterns at the extremes of macronutrient composition, although both diet arms were equivalent in protein: high fat, low carbohydrate versus low fat, high carbohydrate. A nonintervention group served as the control arm; women were assigned to intervention arms based on dietary preferences. During the 6-month weight-loss program, which was menu and recipe defined, participants had monthly clinical visits at which anthropometric data were collected and fasting blood was obtained for safety monitoring for plasma lipid profiles and fasting glucose. Results from 142 participants are reported. Adverse effects on fasting blood lipids or glucose were not observed in either dietary arm. A decrease in fasting glucose was observed with progressive weight loss and was greater in participants who lost more weight, but the effect was not statistically significant, even though it was observed across both diet groups (P = 0.21). Beneficial effects of weight loss on cholesterol (4.7%; P = 0.001), triglycerides (21.8%; P = 0.01), and low-density lipoprotein (LDL) cholesterol (5.8%; P = 0.06) were observed in both groups. For cholesterol (P = 0.07) and LDL cholesterol (P = 0.13), greater reduction trends were seen on the low-fat diet pattern; whereas, for triglycerides (P = 0.01) and high-density lipoprotein (HDL) cholesterol (P = 0.08), a decrease

Periodontal Disease, Tooth Loss, and Cancer Risk.

PubMed

Michaud, Dominique S; Fu, Zhuxuan; Shi, Jian; Chung, Mei

2017-01-01

Periodontal disease, which includes gingivitis and periodontitis, is highly prevalent in adults and disease severity increases with age. The relationship between periodontal disease and oral cancer has been examined for several decades, but there is increasing interest in the link between periodontal disease and overall cancer risk, with systemic inflammation serving as the main focus for biological plausibility. Numerous case-control studies have addressed the role of oral health in head and neck cancer, and several cohort studies have examined associations with other types of cancers over the past decade. For this review, we included studies that were identified from either 11 published reviews on this topic or an updated literature search on PubMed (between 2011 and July 2016). A total of 50 studies from 46 publications were included in this review. Meta-analyses were conducted on cohort and case-control studies separately when at least 4 studies could be included to determine summary estimates of the risk of cancer in relation to 1) periodontal disease or 2) tooth number (a surrogate marker of periodontal disease) with adjustment for smoking. Existing data provide support for a positive association between periodontal disease and risk of oral, lung, and pancreatic cancers; however, additional prospective studies are needed to better inform on the strength of these associations and to determine whether other cancers are associated with periodontal disease. Future studies should include sufficiently large sample sizes, improved measurements for periodontal disease, and thorough adjustment for smoking and other risk factors. © The Author 2017. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Functional proteomic analysis reveals the involvement of KIAA1199 in breast cancer growth, motility and invasiveness

PubMed Central

2014-01-01

Background KIAA1199 is a recently identified novel gene that is up-regulated in human cancer with poor survival. Our proteomic study on signaling polarity in chemotactic cells revealed KIAA1199 as a novel protein target that may be involved in cellular chemotaxis and motility. In the present study, we examined the functional significance of KIAA1199 expression in breast cancer growth, motility and invasiveness. Methods We validated the previous microarray observation by tissue microarray immunohistochemistry using a TMA slide containing 12 breast tumor tissue cores and 12 corresponding normal tissues. We performed the shRNA-mediated knockdown of KIAA1199 in MDA-MB-231 and HS578T cells to study the role of this protein in cell proliferation, migration and apoptosis in vitro. We studied the effects of KIAA1199 knockdown in vivo in two groups of mice (n = 5). We carried out the SILAC LC-MS/MS based proteomic studies on the involvement of KIAA1199 in breast cancer. Results KIAA1199 mRNA and protein was significantly overexpressed in breast tumor specimens and cell lines as compared with non-neoplastic breast tissues from large-scale microarray and studies of breast cancer cell lines and tumors. To gain deeper insights into the novel role of KIAA1199 in breast cancer, we modulated KIAA1199 expression using shRNA-mediated knockdown in two breast cancer cell lines (MDA-MB-231 and HS578T), expressing higher levels of KIAA1199. The KIAA1199 knockdown cells showed reduced motility and cell proliferation in vitro. Moreover, when the knockdown cells were injected into the mammary fat pads of female athymic nude mice, there was a significant decrease in tumor incidence and growth. In addition, quantitative proteomic analysis revealed that knockdown of KIAA1199 in breast cancer (MDA-MB-231) cells affected a broad range of cellular functions including apoptosis, metabolism and cell motility. Conclusions Our findings indicate that KIAA1199 may play an important role in breast

Smad4 loss in mice causes spontaneous head and neck cancer with increased genomic instability and inflammation.

PubMed

Bornstein, Sophia; White, Ruth; Malkoski, Stephen; Oka, Masako; Han, Gangwen; Cleaver, Timothy; Reh, Douglas; Andersen, Peter; Gross, Neil; Olson, Susan; Deng, Chuxia; Lu, Shi-Long; Wang, Xiao-Jing

2009-11-01

Smad4 is a central mediator of TGF-beta signaling, and its expression is downregulated or lost at the malignant stage in several cancer types. In this study, we found that Smad4 was frequently downregulated not only in human head and neck squamous cell carcinoma (HNSCC) malignant lesions, but also in grossly normal adjacent buccal mucosa. To gain insight into the importance of this observation, we generated mice in which Smad4 was deleted in head and neck epithelia (referred to herein as HN-Smad4-/- mice) and found that they developed spontaneous HNSCC. Interestingly, both normal head and neck tissue and HNSCC from HN-Smad4-/- mice exhibited increased genomic instability, which correlated with downregulated expression and function of genes encoding proteins in the Fanconi anemia/Brca (Fanc/Brca) DNA repair pathway linked to HNSCC susceptibility in humans. Consistent with this, further analysis revealed a correlation between downregulation of Smad4 protein and downregulation of the Brca1 and Rad51 proteins in human HNSCC. In addition to the above changes in tumor epithelia, both normal head and neck tissue and HNSCC from HN-Smad4-/- mice exhibited severe inflammation, which was associated with increased expression of TGF-beta1 and activated Smad3. We present what we believe to be the first single gene-knockout model for HNSCC, in which both HNSCC formation and invasion occurred as a result of Smad4 deletion. Our results reveal an intriguing connection between Smad4 and the Fanc/Brca pathway and highlight the impact of epithelial Smad4 loss on inflammation.

Loss of Chromosome 18 in Neuroendocrine Tumors of the Small Intestine: The Enigma Remains.

PubMed

Nieser, Maike; Henopp, Tobias; Brix, Joachim; Stoß, Laura; Sitek, Barbara; Naboulsi, Wael; Anlauf, Martin; Schlitter, Anna M; Klöppel, Günter; Gress, Thomas; Moll, Roland; Bartsch, Detlef K; Heverhagen, Anna E; Knoefel, Wolfram T; Kaemmerer, Daniel; Haybaeck, Johannes; Fend, Falko; Sperveslage, Jan; Sipos, Bence

2017-01-01

Neuroendocrine tumors of the small intestine (SI-NETs) exhibit an increasing incidence and high mortality rate. Until now, no fundamental molecular event has been linked to the tumorigenesis and progression of these tumors. Only the loss of chromosome 18 (Chr18) has been shown in up to two thirds of SI-NETs, whereby the significance of this alteration is still not understood. We therefore performed the first comprehensive study to identify Chr18-related events at the genetic, epigenetic and gene/protein expression levels. We did expression analysis of all seven putative Chr18-related tumor suppressors by quantitative real-time PCR (qRT-PCR), Western blot and immunohistochemistry. Next-generation exome sequencing and SNP array analysis were performed with five SI-NETs with (partial) loss of Chr18. Finally, we analyzed all microRNAs (miRNAs) located on Chr18 by qRT-PCR, comparing Chr18+/- and Chr18+/+ SI-NETs. Only DCC (deleted in colorectal cancer) revealed loss of/greatly reduced expression in 6/21 cases (29%). No relevant loss of SMAD2, SMAD4, elongin A3 and CABLES was detected. PMAIP1 and maspin were absent at the protein level. Next-generation sequencing did not reveal relevant recurrent somatic mutations on Chr18 either in an exploratory cohort of five SI-NETs, or in a validation cohort (n = 30). SNP array analysis showed no additional losses. The quantitative analysis of all 27 Chr18-related miRNAs revealed no difference in expression between Chr18+/- and Chr18+/+ SI-NETs. DCC seems to be the only Chr18-related tumor suppressor affected by the monoallelic loss of Chr18 resulting in a loss of DCC protein expression in one third of SI-NETs. No additional genetic or epigenetic alterations were present on Chr18. © 2016 S. Karger AG, Basel.

Loss of skeletal muscle mass during neoadjuvant treatments correlates with worse prognosis in esophageal cancer: a retrospective cohort study.

PubMed

Järvinen, Tommi; Ilonen, Ilkka; Kauppi, Juha; Salo, Jarmo; Räsänen, Jari

2018-02-12

Nutritional deficits, cachexia, and sarcopenia are extremely common in esophageal cancer. The aim of this article was to assess the effect of loss of skeletal muscle mass during neoadjuvant treatment on the prognosis of esophageal cancer patients. Esophageal cancer patients (N = 115) undergoing neoadjuvant therapy and surgery between 2010 and 2014 were identified from our surgery database and retrospectively analyzed. Computed tomography imaging of the total cross-sectional muscle tissue measured at the third lumbar level defined the skeletal muscle index, which defined sarcopenia (SMI < 52.4 cm2/m2 for men and < 38.5 cm2/m2 for women). Images were collected before and after neoadjuvant treatments. Sarcopenia in preoperative imaging was prevalent in 92 patients (80%). Median overall survival was 900 days (interquartile range 334-1447) with no difference between sarcopenic (median = 900) and non-sarcopenic (median = 914) groups (p = 0.872). Complication rates did not differ (26.1% vs 32.6%, p = 0.725). A 2.98% decrease in skeletal muscle index during neoadjuvant treatment correlated with poor 2-year survival (log-rank p = 0.04). Loss of skeletal muscle tissue during neoadjuvant treatment correlates with worse overall survival.

Expression analysis of cancer-testis genes in prostate cancer reveals candidates for immunotherapy.

PubMed

Faramarzi, Sepideh; Ghafouri-Fard, Soudeh

2017-09-01

Prostate cancer is a prevalent disorder among men with a heterogeneous etiological background. Several molecular events and signaling perturbations have been found in this disorder. Among genes whose expressions have been altered during the prostate cancer development are cancer-testis antigens (CTAs). This group of antigens has limited expression in the normal adult tissues but aberrant expression in cancers. This property provides them the possibility to be used as cancer biomarkers and immunotherapeutic targets. Several CTAs have been shown to be immunogenic in prostate cancer patients and some of the have entered clinical trials. Based on the preliminary data obtained from these trials, it is expected that CTA-based therapeutic options are beneficial for at least a subset of prostate cancer patients.

Loss of heterozygosity patterns provide fingerprints for genetic heterogeneity in multistep cancer progression of tobacco smoke-induced non-small cell lung cancer.

PubMed

Pan, Hongjie; Califano, Joseph; Ponte, Jose F; Russo, Andrea L; Cheng, Kuang-hung; Thiagalingam, Arunthathi; Nemani, Pratima; Sidransky, David; Thiagalingam, Sam

2005-03-01

Dilution end point loss of heterozygosity (LOH) analysis, a novel approach for the analysis of LOH, was used to evaluate allelic losses with the use of 21 highly polymorphic microsatellite markers at nine chromosomal sites most frequently affected in smoking-related non-small cell lung cancers. Allelotyping was done for bronchial epithelial cells and matching blood samples from 23 former and current smokers and six nonsmokers as well as in 33 adenocarcinomas and 25 squamous cell carcinomas (SCC) and corresponding matching blood from smokers. Major conclusions from these studies are as follows: (a) LOH at chromosomal sites 8p, 9p, 11q, and 13q (P >0.05, Fisher's exact test) are targeted at the early stages, whereas LOH at 1p, 5q, 17p, and 18q (P <0.05, Fisher's exact test) occur at the later stages of non-small cell lung cancer progression; (b) LOH at 1p, 3p, 5q, 8p, 9p, 11q, 13q, 17p, and 18q occurs in over 45% of the tobacco smokers with SCC and adenocarcinoma; (c) compared with bronchial epithelial cells from smokers, there is a significantly higher degree of LOH at 1p, 5q, and 18q in adenocarcinoma and at 1p, 3p, and 17p in SCC (P <0.05, Fisher's exact test). We propose that lung cancer progression induced by tobacco smoke occurs in a series of target gene inactivations/activations in defined modules of a global network. The gatekeeper module consists of multiple alternate target genes, which is inclusive of but not limited to genes localized to chromosomal loci 8p, 9p, 11q, and 13q.

Excitatory Hindbrain-Forebrain Communication Is Required for Cisplatin-Induced Anorexia and Weight Loss.

PubMed

Alhadeff, Amber L; Holland, Ruby A; Zheng, Huiyuan; Rinaman, Linda; Grill, Harvey J; De Jonghe, Bart C

2017-01-11

characterize the excitatory nature of neural projections activated by cisplatin in rats and reveal the necessity of specific hindbrain-forebrain projections for cisplatin-induced anorexia and weight loss. Together, these findings help to characterize the neural mechanisms mediating cisplatin-induced anorexia, advancing opportunities to develop better-tolerated chemotherapies and adjuvant therapies to prevent anorexia and concurrent nutritional deficiencies during cancer treatment. Copyright © 2017 the authors 0270-6474/17/370362-09$15.00/0.

Deconstruction of a Metastatic Tumor Microenvironment Reveals a Common Matrix Response in Human Cancers.

PubMed

Pearce, Oliver M T; Delaine-Smith, Robin M; Maniati, Eleni; Nichols, Sam; Wang, Jun; Böhm, Steffen; Rajeeve, Vinothini; Ullah, Dayem; Chakravarty, Probir; Jones, Roanne R; Montfort, Anne; Dowe, Tom; Gribben, John; Jones, J Louise; Kocher, Hemant M; Serody, Jonathan S; Vincent, Benjamin G; Connelly, John; Brenton, James D; Chelala, Claude; Cutillas, Pedro R; Lockley, Michelle; Bessant, Conrad; Knight, Martin M; Balkwill, Frances R

2018-03-01

We have profiled, for the first time, an evolving human metastatic microenvironment by measuring gene expression, matrisome proteomics, cytokine and chemokine levels, cellularity, extracellular matrix organization, and biomechanical properties, all on the same sample. Using biopsies of high-grade serous ovarian cancer metastases that ranged from minimal to extensive disease, we show how nonmalignant cell densities and cytokine networks evolve with disease progression. Multivariate integration of the different components allowed us to define, for the first time, gene and protein profiles that predict extent of disease and tissue stiffness, while also revealing the complexity and dynamic nature of matrisome remodeling during development of metastases. Although we studied a single metastatic site from one human malignancy, a pattern of expression of 22 matrisome genes distinguished patients with a shorter overall survival in ovarian and 12 other primary solid cancers, suggesting that there may be a common matrix response to human cancer. Significance: Conducting multilevel analysis with data integration on biopsies with a range of disease involvement identifies important features of the evolving tumor microenvironment. The data suggest that despite the large spectrum of genomic alterations, some human malignancies may have a common and potentially targetable matrix response that influences the course of disease. Cancer Discov; 8(3); 304-19. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 253 . ©2017 American Association for Cancer Research.

Genetic Mechanisms of Immune Evasion in Colorectal Cancer.

PubMed

Grasso, Catherine S; Giannakis, Marios; Wells, Daniel K; Hamada, Tsuyoshi; Mu, Xinmeng Jasmine; Quist, Michael; Nowak, Jonathan A; Nishihara, Reiko; Qian, Zhi Rong; Inamura, Kentaro; Morikawa, Teppei; Nosho, Katsuhiko; Abril-Rodriguez, Gabriel; Connolly, Charles; Escuin-Ordinas, Helena; Geybels, Milan S; Grady, William M; Hsu, Li; Hu-Lieskovan, Siwen; Huyghe, Jeroen R; Kim, Yeon Joo; Krystofinski, Paige; Leiserson, Mark D M; Montoya, Dennis J; Nadel, Brian B; Pellegrini, Matteo; Pritchard, Colin C; Puig-Saus, Cristina; Quist, Elleanor H; Raphael, Ben J; Salipante, Stephen J; Shin, Daniel Sanghoon; Shinbrot, Eve; Shirts, Brian; Shukla, Sachet; Stanford, Janet L; Sun, Wei; Tsoi, Jennifer; Upfill-Brown, Alexander; Wheeler, David A; Wu, Catherine J; Yu, Ming; Zaidi, Syed H; Zaretsky, Jesse M; Gabriel, Stacey B; Lander, Eric S; Garraway, Levi A; Hudson, Thomas J; Fuchs, Charles S; Ribas, Antoni; Ogino, Shuji; Peters, Ulrike

2018-06-01

To understand the genetic drivers of immune recognition and evasion in colorectal cancer, we analyzed 1,211 colorectal cancer primary tumor samples, including 179 classified as microsatellite instability-high (MSI-high). This set includes The Cancer Genome Atlas colorectal cancer cohort of 592 samples, completed and analyzed here. MSI-high, a hypermutated, immunogenic subtype of colorectal cancer, had a high rate of significantly mutated genes in important immune-modulating pathways and in the antigen presentation machinery, including biallelic losses of B2M and HLA genes due to copy-number alterations and copy-neutral loss of heterozygosity. WNT/β-catenin signaling genes were significantly mutated in all colorectal cancer subtypes, and activated WNT/β-catenin signaling was correlated with the absence of T-cell infiltration. This large-scale genomic analysis of colorectal cancer demonstrates that MSI-high cases frequently undergo an immunoediting process that provides them with genetic events allowing immune escape despite high mutational load and frequent lymphocytic infiltration and, furthermore, that colorectal cancer tumors have genetic and methylation events associated with activated WNT signaling and T-cell exclusion. Significance: This multi-omic analysis of 1,211 colorectal cancer primary tumors reveals that it should be possible to better monitor resistance in the 15% of cases that respond to immune blockade therapy and also to use WNT signaling inhibitors to reverse immune exclusion in the 85% of cases that currently do not. Cancer Discov; 8(6); 730-49. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 663 . ©2018 American Association for Cancer Research.

Robust gene network analysis reveals alteration of the STAT5a network as a hallmark of prostate cancer.

PubMed

Reddy, Anupama; Huang, C Chris; Liu, Huiqing; Delisi, Charles; Nevalainen, Marja T; Szalma, Sandor; Bhanot, Gyan

2010-01-01

We develop a general method to identify gene networks from pair-wise correlations between genes in a microarray data set and apply it to a public prostate cancer gene expression data from 69 primary prostate tumors. We define the degree of a node as the number of genes significantly associated with the node and identify hub genes as those with the highest degree. The correlation network was pruned using transcription factor binding information in VisANT (http://visant.bu.edu/) as a biological filter. The reliability of hub genes was determined using a strict permutation test. Separate networks for normal prostate samples, and prostate cancer samples from African Americans (AA) and European Americans (EA) were generated and compared. We found that the same hubs control disease progression in AA and EA networks. Combining AA and EA samples, we generated networks for low low (<7) and high (≥7) Gleason grade tumors. A comparison of their major hubs with those of the network for normal samples identified two types of changes associated with disease: (i) Some hub genes increased their degree in the tumor network compared to their degree in the normal network, suggesting that these genes are associated with gain of regulatory control in cancer (e.g. possible turning on of oncogenes). (ii) Some hubs reduced their degree in the tumor network compared to their degree in the normal network, suggesting that these genes are associated with loss of regulatory control in cancer (e.g. possible loss of tumor suppressor genes). A striking result was that for both AA and EA tumor samples, STAT5a, CEBPB and EGR1 are major hubs that gain neighbors compared to the normal prostate network. Conversely, HIF-lα is a major hub that loses connections in the prostate cancer network compared to the normal prostate network. We also find that the degree of these hubs changes progressively from normal to low grade to high grade disease, suggesting that these hubs are master regulators of

The costs of reducing loss to follow-up in South African cervical cancer screening

PubMed Central

Goldhaber-Fiebert, Jeremy D; Denny, Lynette E; De Souza, Michelle; Wright, Thomas C; Kuhn, Louise; Goldie, Sue J

2005-01-01

Background This study was designed to quantify the resources used in reestablishing contact with women who missed their scheduled cervical cancer screening visits and to assess the success of this effort in reducing loss to follow-up in a developing country setting. Methods Women were enrolled in this Cape Town, South Africa-based screening study between 2000 and 2003, and all had scheduled follow-up visits in 2003. Community health worker (CHW) time, vehicle use, maintenance, and depreciation were estimated from weekly logs and cost accounting systems. The percentage of women who attended their scheduled visit, those who attended after CHW contact(s), and those who never returned despite attempted contact(s) were determined. The number of CHW visits per woman was also estimated. Results 3,711 visits were scheduled in 2003. Of these, 2,321 (62.5%) occurred without CHW contact, 918 (24.8%) occurred after contact(s), and 472 (12.7%) did not occur despite contact(s). Loss to follow-up was reduced from 21% to 6%, 39% to 10%, and 50% to 24% for 6, 12, and 24-month visits. CHWs attempted 3,200 contacts in 530 trips. On average, 3 CHWs attempted to contact 6 participants over each 111 minute trip. The per-person cost (2003 Rand) for these activities was 12.75, 24.92, and 40.50 for 6, 12, and 24-month visits. Conclusion CHW contact with women who missed scheduled visits increased their return rate. Cost-effectiveness analyses aimed at policy decisions about cervical cancer screening in developing countries should incorporate these findings. PMID:16288646

Seed-effect modeling improves the consistency of genome-wide loss-of-function screens and identifies synthetic lethal vulnerabilities in cancer cells.

PubMed

Jaiswal, Alok; Peddinti, Gopal; Akimov, Yevhen; Wennerberg, Krister; Kuznetsov, Sergey; Tang, Jing; Aittokallio, Tero

2017-06-01

Genome-wide loss-of-function profiling is widely used for systematic identification of genetic dependencies in cancer cells; however, the poor reproducibility of RNA interference (RNAi) screens has been a major concern due to frequent off-target effects. Currently, a detailed understanding of the key factors contributing to the sub-optimal consistency is still a lacking, especially on how to improve the reliability of future RNAi screens by controlling for factors that determine their off-target propensity. We performed a systematic, quantitative analysis of the consistency between two genome-wide shRNA screens conducted on a compendium of cancer cell lines, and also compared several gene summarization methods for inferring gene essentiality from shRNA level data. We then devised novel concepts of seed essentiality and shRNA family, based on seed region sequences of shRNAs, to study in-depth the contribution of seed-mediated off-target effects to the consistency of the two screens. We further investigated two seed-sequence properties, seed pairing stability, and target abundance in terms of their capability to minimize the off-target effects in post-screening data analysis. Finally, we applied this novel methodology to identify genetic interactions and synthetic lethal partners of cancer drivers, and confirmed differential essentiality phenotypes by detailed CRISPR/Cas9 experiments. Using the novel concepts of seed essentiality and shRNA family, we demonstrate how genome-wide loss-of-function profiling of a common set of cancer cell lines can be actually made fairly reproducible when considering seed-mediated off-target effects. Importantly, by excluding shRNAs having higher propensity for off-target effects, based on their seed-sequence properties, one can remove noise from the genome-wide shRNA datasets. As a translational application case, we demonstrate enhanced reproducibility of genetic interaction partners of common cancer drivers, as well as identify novel

Patient-Reported Measures of Hearing Loss and Tinnitus in Pediatric Cancer and Hematopoietic Stem Cell Transplantation: A Systematic Review

ERIC Educational Resources Information Center

Stark, Daniel; Rosenberg, Abby R.; Johnston, Donna; Knight, Kristin; Caperon, Lizzie; Uleryk, Elizabeth; Frazier, A. Lindsay; Sung, Lillian

2016-01-01

Purpose: We identified studies that described use of any patient-reported outcome scale for hearing loss or tinnitus among children and adolescents and young adults (AYAs) with cancer or hematopoietic stem cell transplantation (HSCT) recipients. Method: In this systematic review, we performed electronic searches of OvidSP MEDLINE, EMBASE, and…

Tumor invasion unit in gastric cancer revealed by QDs-based in situ molecular imaging and multispectral analysis.

PubMed

Hu, Wen-Qing; Fang, Min; Zhao, Hao-Liang; Yan, Shu-Guang; Yuan, Jing-Ping; Peng, Chun-Wei; Yang, Gui-Fang; Li, Yan; Li, Jian-Ding

2014-04-01

In tumor tissues, cancer cells, tumor infiltrating macrophages and tumor neo-vessels in close spatial vicinity with one another form tumor invasion unit, which is a biologically important tumor microenvironment of metastasis to facilitate cancer invasion and metastasis. Establishing an in situ molecular imaging technology to simultaneously reveal these three components is essential for the in-depth investigation of tumor invasion unit. In this report, we have developed a computer-aided algorithm by quantum dots (QDs)-based multiplexed molecular imaging technique for such purpose. A series of studies on gastric cancer tumor tissues demonstrated that the tumor invasion unit was correlated with major unfavorable pathological features and worse clinical outcomes, which illustrated the significantly negative impacts and predictive power of tumor invasion unit on patient overall survival. This study confirmed the technical advantages of QDs-based in situ and simultaneous molecular imaging of key cancer molecules to gain deeper insights into the biology of cancer invasion. Copyright © 2014 Elsevier Ltd. All rights reserved.

Mammary tumorigenesis causes bone loss and dietary selenium supplementation does not affect such bone loss in male MMTV-PyMT mice

USDA-ARS?s Scientific Manuscript database

Cancer progression is accompanied by wasting that eventually results in cachexia characterized by significant weight loss and multi-organ functional failures. Limited clinical trials indicate that bone is adversely affected by cancer-associated wasting. To determine the effects of breast cancer on...

Using artificial microRNA sponges to achieve microRNA loss-of-function in cancer cells.

PubMed

Tay, Felix Chang; Lim, Jia Kai; Zhu, Haibao; Hin, Lau Cia; Wang, Shu

2015-01-01

Widely observed dysregulation of microRNAs (miRNAs) in human cancer has led to substantial speculation regarding possible functions of these short, non-coding RNAs in cancer development and manipulation of miRNA expression to treat cancer. To achieve miRNA loss-of-function, miRNA sponge technology has been developed to use plasmid or viral vectors for intracellular expression of tandemly arrayed, bulged miRNA binding sites complementary to a miRNA target to saturate its ability to regulate natural mRNAs. A strong viral promoter can be used in miRNA sponge vectors to generate high-level expression of the competitive inhibitor transcripts for either transient or long-term inhibition of miRNA function. Taking the advantage of sharing a common seed sequence by members of a miRNA family, this technology is especially useful in knocking down the expression of a family of miRNAs, providing a powerful means for simultaneous inhibition of multiple miRNAs of interest with a single inhibitor. Knockdown of overexpressed oncogenic miRNAs with the technology can be a rational therapeutic strategy for cancer, whereas inhibition of tumor-suppressive miRNAs by the sponges will be useful in deciphering functions of miRNAs in oncogenesis. Herein, we discuss the design of miRNA sponge expression vectors and the use of the vectors to gain better understanding of miRNA's roles in cancer biology and as an alternative tool for anticancer gene therapy. Copyright © 2014 Elsevier B.V. All rights reserved.

Gain-framed messages do not motivate sun protection: a meta-analytic review of randomized trials comparing gain-framed and loss-framed appeals for promoting skin cancer prevention.

PubMed

O'Keefe, Daniel J; Wu, Daisy

2012-06-01

Persuading people to undertake actions to prevent skin cancer is an important public health challenge. A number of studies have compared the effectiveness of gain-framed and loss-framed appeals in this domain, often expecting gain-framed appeals to be more persuasive. A meta-analytic review (k = 33, N = 4,168), however, finds no significant difference in the persuasiveness of gain- and loss-framed appeals for encouraging skin cancer prevention. This conclusion is unaffected by differences in the specific protective action advocated or by differences in the kind of outcomes invoked. But the results offer an intimation that men might be more susceptible to framing variations in this domain--with loss-framed appeals potentially having a persuasive advantage.

Brain abscess mimicking lung cancer metastases; a case report.

PubMed

Asano, Michiko; Fujimoto, Nobukazu; Fuchimoto, Yasuko; Ono, Katsuichiro; Ozaki, Shinji; Kimura, Fumiaki; Kishimoto, Takumi

2013-01-01

A 76-year-old woman came to us because of staggering, fever, dysarthria, and appetite loss. Magnetic resonance imaging (MRI) of the brain revealed multiple masses with surrounding edema. Chest X-ray and computed tomography demonstrated a mass-like lesion in the left lung and left pleural effusion. Lung cancer and multiple brain metastases were suspected. However, the brain lesions demonstrated a high intensity through diffusion-weighted MRI. The finding was an important key to differentiate brain abscesses from lung cancer metastases. Copyright © 2013 Elsevier Inc. All rights reserved.

Changes in diet quality in a randomized weight loss trial in breast cancer survivors: the lifestyle, exercise, and nutrition (LEAN) study.

PubMed

Anderson, Chelsea; Harrigan, Maura; George, Stephanie M; Ferrucci, Leah M; Sanft, Tara; Irwin, Melinda L; Cartmel, Brenda

2016-01-01

Obesity is associated with increased breast cancer recurrence and mortality. Though some post-diagnosis weight loss interventions have achieved weight loss outcomes, it is unclear whether they also improve diet quality. In the Lifestyle, Exercise, and Nutrition (LEAN) study, overweight or obese breast cancer survivors were randomized to either usual care group ( n =33) or the 6-month lifestyle intervention ( n =67). Dietary intake was assessed at baseline and 6 months using a validated food frequency questionnaire, and overall diet quality was calculated using the Healthy Eating Index (HEI)-2010 (range 0-100). Intervention effects on diet were evaluated with generalized linear models. Among the 81 participants (51 intervention, 30 usual care) with dietary data, the mean baseline HEI score was 70.5 (s.d.=8.8) and was improved at 6 months (intervention group=6.8 point increase vs usual care=3.1, P =0.09). Intervention group participants achieved greater reductions in percent of energy from total fat (-4.2% vs -1.2%; P =0.013) and saturated fat (-2.2% vs -1.1%; P =0.003), and greater increases in fiber (4.8 g per 1000 kcal vs 1.3 g per 1000 kcal; P =0.007) and fruit (0.5 servings vs 0.0 servings; P =0.006) intake. Intervention group participants who lost ⩾5% body weight ( n =27) demonstrated significantly greater improvements in HEI score (10.4 vs 2.8) than those who lost <5% ( n =23). The intervention increased fruit and fiber intake and decreased percent energy from fat, and those with greater weight loss achieved greater increases in overall diet quality. These findings support the ability of a weight loss intervention to improve diet among breast cancer survivors.

In-depth investigation of archival and prospectively collected samples reveals no evidence for XMRV infection in prostate cancer.

PubMed

Lee, Deanna; Das Gupta, Jaydip; Gaughan, Christina; Steffen, Imke; Tang, Ning; Luk, Ka-Cheung; Qiu, Xiaoxing; Urisman, Anatoly; Fischer, Nicole; Molinaro, Ross; Broz, Miranda; Schochetman, Gerald; Klein, Eric A; Ganem, Don; Derisi, Joseph L; Simmons, Graham; Hackett, John; Silverman, Robert H; Chiu, Charles Y

2012-01-01

XMRV, or xenotropic murine leukemia virus (MLV)-related virus, is a novel gammaretrovirus originally identified in studies that analyzed tissue from prostate cancer patients in 2006 and blood from patients with chronic fatigue syndrome (CFS) in 2009. However, a large number of subsequent studies failed to confirm a link between XMRV infection and CFS or prostate cancer. On the contrary, recent evidence indicates that XMRV is a contaminant originating from the recombination of two mouse endogenous retroviruses during passaging of a prostate tumor xenograft (CWR22) in mice, generating laboratory-derived cell lines that are XMRV-infected. To confirm or refute an association between XMRV and prostate cancer, we analyzed prostate cancer tissues and plasma from a prospectively collected cohort of 39 patients as well as archival RNA and prostate tissue from the original 2006 study. Despite comprehensive microarray, PCR, FISH, and serological testing, XMRV was not detected in any of the newly collected samples or in archival tissue, although archival RNA remained XMRV-positive. Notably, archival VP62 prostate tissue, from which the prototype XMRV strain was derived, tested negative for XMRV on re-analysis. Analysis of viral genomic and human mitochondrial sequences revealed that all previously characterized XMRV strains are identical and that the archival RNA had been contaminated by an XMRV-infected laboratory cell line. These findings reveal no association between XMRV and prostate cancer, and underscore the conclusion that XMRV is not a naturally acquired human infection.

Dietary counselling and nutritional support in oropharyngeal cancer patients treated with radiotherapy: persistent weight loss during 1-year follow-ups.

PubMed

Vlooswijk, C P; van Rooij, P H E; Kruize, J C; Schuring, H A; Al-Mamgani, A; de Roos, N M

2016-01-01

The need for dietary counselling and nutritional support in oropharyngeal cancer patients is generally accepted. However, evidence for the effectiveness is sparse. The aim of this study was to describe dietary counselling, nutritional support, body weight and toxicity during and after treatment, and investigate the effect of pre-treatment body mass index (BMI) on survival in oropharyngeal cancer patients. A retrospective chart review was made in 276 oropharyngeal cancer patients treated with radiotherapy (RT). End points were dietary consultations, weight loss, toxicity, overall survival and disease-free survival. Almost all oropharyngeal cancer patients received dietary counselling (94%) and nutritional support (99%). Dietary counselling decreased sharply shortly after treatment to 38% at 1 year after treatment. Overall weight loss increased during the first year of follow-up and ranged from 3% at start of RT, until 11% at 1 year after RT. Overall survival was significantly longer for patients with a BMI above average (P=0.01). Acute dysphagia (P=0.001), mucositis (P=0.000) and toxicity grade 3 (P=0.002) were significantly more prevalent in patients who had lost 10% or more of their body weight. This study showed that patients continue to lose body weight during and until 1 year after treatment, despite nutrition support and frequent dietetic consultation. A BMI above average appears to increase survival time. Future studies, preferably randomized trials, are needed to compare standard dietary counselling with more intensive dietary counselling that consists of earlier and/or prolonged treatment.

Data-Independent Acquisition-Based Quantitative Proteomic Analysis Reveals Potential Biomarkers of Kidney Cancer.

PubMed

Song, Yimeng; Zhong, Lijun; Zhou, Juntuo; Lu, Min; Xing, Tianying; Ma, Lulin; Shen, Jing

2017-12-01

Renal cell carcinoma (RCC) is a malignant and metastatic cancer with 95% mortality, and clear cell RCC (ccRCC) is the most observed among the five major subtypes of RCC. Specific biomarkers that can distinguish cancer tissues from adjacent normal tissues should be developed to diagnose this disease in early stages and conduct a reliable prognostic evaluation. Data-independent acquisition (DIA) strategy has been widely employed in proteomic analysis because of various advantages, including enhanced protein coverage and reliable data acquisition. In this study, a DIA workflow is constructed on a quadrupole-Orbitrap LC-MS platform to reveal dysregulated proteins between ccRCC and adjacent normal tissues. More than 4000 proteins are identified, 436 of these proteins are dysregulated in ccRCC tissues. Bioinformatic analysis reveals that multiple pathways and Gene Ontology items are strongly associated with ccRCC. The expression levels of L-lactate dehydrogenase A chain, annexin A4, nicotinamide N-methyltransferase, and perilipin-2 examined through RT-qPCR, Western blot, and immunohistochemistry confirm the validity of the proteomic analysis results. The proposed DIA workflow yields optimum time efficiency and data reliability and provides a good choice for proteomic analysis in biological and clinical studies, and these dysregulated proteins might be potential biomarkers for ccRCC diagnosis. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Rosiglitazone delayed weight loss and anorexia while attenuating adipose depletion in mice with cancer cachexia.

PubMed

Asp, Michelle L; Tian, Min; Kliewer, Kara L; Belury, Martha A

2011-12-01

Cachexia is characterized by severe weight loss, including adipose and muscle wasting, and occurs in a large percentage of cancer patients. Insulin resistance contributes to dysregulated metabolism in cachexia and occurs prior to weight loss in mice with colon-26 tumor-induced cachexia. Therefore, we hypothesized that the insulin sensitizer, rosiglitazone, would attenuate the loss of adipose and muscle to result in improved outcomes for mice with late-stage cachexia. Male CD2F1 mice were inoculated with colon-26 adenocarcinoma cells or vehicle. Treatments included vehicle, rosiglitazone (10 mg/kg body weight/day) or rosiglitazone plus pair-feeding to food intake of vehicle-treated mice with tumors. Rosiglitazone delayed weight loss onset by 2 d over the 16 d duration of this aggressive tumor model. This finding was associated, in part, with increased food intake. In addition, adipose mass, adipocyte cross-sectional area and inflammation were improved with rosiglitazone. However, at the time of necropsy 16 d after tumor inoculation rosiglitazone had no effect on retention of muscle mass, strength or proteolysis in late-stage cachexia. We did not measure stamina or endurance in this study. In early-stage cachexia, rosiglitazone normalized PDK4 and PPAR-delta mRNA in quadriceps muscle and rescued the decrease in insulin-stimulated glucose disappearance in mice with tumors. Rosiglitazone may delay weight loss onset by decreasing tumor-induced markers of metabolic change in early-stage cachexia. These changes predict for modest improvement in adipose, but no improvement in muscle strength in late-stage cachexia.

Rosiglitazone delayed weight loss and anorexia while attenuating adipose depletion in mice with cancer cachexia

PubMed Central

Asp, Michelle L.; Tian, Min; Kliewer, Kara L.

2011-01-01

Cachexia is characterized by severe weight loss, including adipose and muscle wasting, and occurs in a large percentage of cancer patients. Insulin resistance contributes to dysregulated metabolism in cachexia and occurs prior to weight loss in mice with colon-26 tumor-induced cachexia. Therefore, we hypothesized that the insulin sensitizer, rosiglitazone, would attenuate the loss of adipose and muscle to result in improved outcomes for mice with late-stage cachexia. Male CD2F1 mice were inoculated with colon-26 adenocarcinoma cells or vehicle. Treatments included vehicle, rosiglitazone (10 mg/kg body weight/day) or rosiglitazone plus pair-feeding to food intake of vehicle-treated mice with tumors. Rosiglitazone delayed weight loss onset by 2 d over the 16 d duration of this aggressive tumor model. This finding was associated, in part, with increased food intake. In addition, adipose mass, adipocyte cross-sectional area and inflammation were improved with rosiglitazone. However, at the time of necropsy 16 d after tumor inoculation rosiglitazone had no effect on retention of muscle mass, strength or proteolysis in late-stage cachexia. We did not measure stamina or endurance in this study. In early-stage cachexia, rosiglitazone normalized PDK4 and PPAR-delta mRNA in quadriceps muscle and rescued the decrease in insulin-stimulated glucose disappearance in mice with tumors. Rosiglitazone may delay weight loss onset by decreasing tumor-induced markers of metabolic change in early-stage cachexia. These changes predict for modest improvement in adipose, but no improvement in muscle strength in late-stage cachexia. PMID:22104958

Ethnocultural women's experiences of breast cancer: a qualitative meta-study.

PubMed

Howard, A Fuchsia; Balneaves, Lynda G; Bottorff, Joan L

2007-01-01

A growing number of studies have been conducted that explore the breast cancer experiences of women from diverse ethnocultural groups. To advance knowledge and provide a foundation for future research, a synthesis was conducted of 15 qualitative research studies focusing on women from ethnocultural groups diagnosed with breast cancer. A qualitative meta-study approach was used that included analysis of the theoretical orientations and methodological approaches underlying the research, and an interpretive synthesis of research findings. Ethnocultural groups represented in the studies included Asian American, Aboriginal, Hispanic, and African American women. The synthesis revealed diverse experiences within and among these ethnocultural groups represented in 5 major themes: (a) the "othered" experience of a breast cancer diagnosis, (b) the treatment experience as "other," (c) losses associated with breast cancer, (d) the family context of breast cancer experiences, and (e) coping with cancer through spirituality and community involvement. The integration of findings from the 15 studies also revealed how methodological and theoretical approaches to conducting this research influenced understandings of the experiences of breast cancer. Further experiential breast cancer research with ethnocultural groups is needed, as well as the use of research methods that illuminate the ways that ethnicity, class, age, and gender relations are played out in healthcare settings.

Years of Life and Productivity Loss from Potentially Avoidable Colorectal Cancer Deaths in U.S. Counties with Lower Educational Attainment (2008–2012)

PubMed Central

Weir, Hannah K.; Li, Chunyu; Henley, S. Jane; Joseph, Djenaba

2018-01-01

Background Educational attainment (EA) is inversely associated with colorectal cancer risk. Colorectal cancer screening can save lives if precancerous polyps or early cancers are found and successfully treated. This study aims to estimate the potential productivity loss (PPL) and associated avoidable colorectal cancer–related deaths among screen-eligible adults residing in lower EA counties in the United States. Methods Mortality and population data were used to examine colorectal cancer deaths (2008–2012) among adults aged 50 to 74 years in lower EA counties, and to estimate the expected number of deaths using the mortality experience from high EA counties. Excess deaths (observed–expected) were used to estimate potential years life lost, and the human capital method was used to estimate PPL in 2012 U.S. dollars. Results County-level colorectal cancer death rates were inversely associated with county-level EA. Of the 100,857 colorectal cancer deaths in lower EA counties, we estimated that more than 21,000 (1 in 5) was potentially avoidable and resulted in nearly $2 billion annual productivity loss. Conclusions County-level EA disparities contribute to a large number of potentially avoidable colorectal cancer–related deaths. Increased prevention and improved screening potentially could decrease deaths and help reduce the associated economic burden in lower EA communities. Increased screening could further reduce deaths in all EA groups. Impact These results estimate the large economic impact of potentially avoidable colorectal cancer–related deaths in economically disadvantaged communities, as measured by lower EA. PMID:28003180

Quantitative measures to reveal coordinated cytoskeleton-nucleus reorganization during in vitro invasion of cancer cells

NASA Astrophysics Data System (ADS)

Dvir, Liron; Nissim, Ronen; Alvarez-Elizondo, Martha B.; Weihs, Daphne

2015-04-01

Metastasis formation is a major cause of mortality in cancer patients and includes tumor cell relocation to distant organs. A metastatic cell invades through other cells and extracellular matrix by biochemical attachment and mechanical force application. Force is used to move on or through a 2- or 3-dimensional (3D) environment, respectively, or to penetrate a 2D substrate. We have previously shown that even when a gel substrate is impenetrable, metastatic breast cancer cells can still indent it by applying force. Cells typically apply force through the acto-myosin network, which is mechanically connected to the nucleus. We develop a 3D image-analysis to reveal relative locations of the cell elements, and show that as cells apply force to the gel, a coordinated process occurs that involves cytoskeletal remodeling and repositioning of the nucleus. Our approach shows that the actin and microtubules reorganize in the cell, bringing the actin to the leading edge of the cell. In parallel, the nucleus is transported behind the actin, likely by the cytoskeleton, into the indentation dimple formed in the gel. The nucleus volume below the gel surface correlates with indentation depth, when metastatic breast cancer cells indent gels deeply. However, the nucleus always remains above the gel in benign cells, even when small indentations are observed. Determining mechanical processes during metastatic cell invasion can reveal how cells disseminate in the body and can uncover targets for diagnosis and treatment.

PTEN Loss as Determined by Clinical-grade Immunohistochemistry Assay Is Associated with Worse Recurrence-free Survival in Prostate Cancer

PubMed Central

Lotan, Tamara L.; Wei, Wei; Morais, Carlos L.; Hawley, Sarah T.; Fazli, Ladan; Hurtado-Coll, Antonio; Troyer, Dean; McKenney, Jesse K.; Simko, Jeffrey; Carroll, Peter R.; Gleave, Martin; Lance, Raymond; Lin, Daniel W.; Nelson, Peter S.; Thompson, Ian M.; True, Lawrence D.; Feng, Ziding; Brooks, James D.

2015-01-01

Background PTEN is the most commonly deleted tumor suppressor gene in primary prostate cancer (PCa) and its loss is associated with poor clinical outcomes and ERG gene rearrangement. Objective We tested whether PTEN loss is associated with shorter recurrence-free survival (RFS) in surgically treated PCa patients with known ERG status. Design, setting, and participants A genetically validated, automated PTEN immunohistochemistry (IHC) protocol was used for 1275 primary prostate tumors from the Canary Foundation retrospective PCa tissue microarray cohort to assess homogeneous (in all tumor tissue sampled) or heterogeneous (in a subset of tumor tissue sampled) PTEN loss. ERG status as determined by a genetically validated IHC assay was available for a subset of 938 tumors. Outcome measurements and statistical analysis Associations between PTEN and ERG status were assessed using Fisher’s exact test. Kaplan-Meier and multivariate weighted Cox proportional models for RFS were constructed. Results and limitations When compared to intact PTEN, homogeneous (hazard ratio [HR] 1.66, p = 0.001) but not heterogeneous (HR 1.24, p = 0.14) PTEN loss was significantly associated with shorter RFS in multivariate models. Among ERG-positive tumors, homogeneous (HR 3.07, p < 0.0001) but not heterogeneous (HR 1.46, p = 0.10) PTEN loss was significantly associated with shorter RFS. Among ERG-negative tumors, PTEN did not reach significance for inclusion in the final multivariate models. The interaction term for PTEN and ERG status with respect to RFS did not reach statistical significance (p = 0.11) for the current sample size. Conclusions These data suggest that PTEN is a useful prognostic biomarker and that there is no statistically significant interaction between PTEN and ERG status for RFS. Patient summary We found that loss of the PTEN tumor suppressor gene in prostate tumors as assessed by tissue staining is correlated with shorter time to prostate cancer recurrence after radical

Primary peritoneal serous carcinoma presenting as inflammatory breast cancer.

PubMed

Khalifeh, Ibrahim; Deavers, Michael T; Cristofanilli, Massimo; Coleman, Robert L; Malpica, Anais; Gilcrease, Michael Z

2009-01-01

Metastasis to the breast from extramammary malignancies is rare. Nevertheless, its recognition is important because the prognosis and treatment differ from that of primary breast cancer. We report a unique case of primary peritoneal serous carcinoma that initially presented as inflammatory breast cancer. The patient received neoadjuvant chemotherapy for breast cancer and subsequently underwent bilateral total mastectomy and bilateral sentinel lymph node biopsy. She was found to have extensive intralymphatic carcinoma in both breasts, with only focal minimal breast parenchymal involvement, and residual metastatic carcinoma in bilateral sentinel lymph nodes. Further work-up revealed pelvic ascites and omental nodularities. The patient underwent laparoscopic bilateral salpingo-oophorectomy, which revealed high-grade serous carcinoma involving both ovaries and fallopian tubes. Molecular testing of tumor from the ovary and axillary lymph node showed an identical pattern of allelic loss, confirming a common origin for both tumors. To our knowledge, this is the first reported case of an extramammary primary malignancy that not only presented as inflammatory breast cancer but also was diagnosed and initially treated as such.

ARID1B is a specific vulnerability in ARID1A-mutant cancers

PubMed Central

Helming, Katherine C.; Wang, Xiaofeng; Wilson, Boris G.; Vazquez, Francisca; Haswell, Jeffrey R.; Manchester, Haley E.; Kim, Youngha; Kryukov, Gregory V.; Ghandi, Mahmoud; Aguirre, Andrew J.; Jagani, Zainab; Wang, Zhong; Garraway, Levi A.; Hahn, William C.; Roberts, Charles W. M.

2014-01-01

Summary Recent studies have revealed that ARID1A is frequently mutated across a wide variety of human cancers and also has bona fide tumor suppressor properties. Consequently, identification of vulnerabilities conferred by ARID1A mutation would have major relevance for human cancer. Here, using a broad screening approach, we identify ARID1B, a related but mutually exclusive homolog of ARID1A in the SWI/SNF chromatin remodeling complex, as the number one gene preferentially required for the survival of ARID1A-mutant cancer cell lines. We show that loss of ARID1B in ARID1A-deficient backgrounds destabilizes SWI/SNF and impairs proliferation. Intriguingly, we also find that ARID1A and ARID1B are frequently co-mutated in cancer, but that ARID1A-deficient cancers retain at least one ARID1B allele. These results suggest that loss of ARID1A and ARID1B alleles cooperatively promotes cancer formation but also results in a unique functional dependence. The results further identify ARID1B as a potential therapeutic target for ARID1A-mutant cancers. PMID:24562383

Aromatase Inhibitors and Bone Loss

PubMed Central

PEREZ, EDITH A.; M., Serene; Durling, Frances C.; WEILBAECHER, KATHERINE

2009-01-01

The aromatase inhibitors (AIs) anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin) are significantly more effective than the selective estrogen-receptor modulator (SERM) tamoxifen in preventing recurrence in estrogen receptor–positive early breast cancer. Aromatase inhibitors are likely to replace SERMs as first-line adjuvant therapy for many patients. However, AIs are associated with significantly more osteoporotic fractures and greater bone mineral loss. As antiresorptive agents, oral and intravenous bisphosphonates such as alendronate (Fosamax), risedronate (Actonel), ibandronate (Boniva), pamidronate (Aredia), and zoledronic acid (Zometa) have efficacy in preventing postmenopausal osteoporosis, cancer treatment–related bone loss, or skeletal complications of metastatic disease. Clinical practice guidelines recommend baseline and annual follow-up bone density monitoring for all patients initiating AI therapy. Bisphosphonate therapy should be prescribed for patients with osteoporosis (T score < −2.5) and considered on an individual basis for those with osteopenia (T score < −1). Modifiable lifestyle behaviors including adequate calcium and vitamin D intake, weight-bearing exercise, and smoking cessation should be addressed. Adverse events associated with bisphosphonates include gastrointestinal toxicity, renal toxicity, and osteonecrosis of the jaw. These safety concerns should be balanced with the potential of bisphosphonates to minimize or prevent the debilitating effects of AI-associated bone loss in patients with early, hormone receptor–positive breast cancer. PMID:16986348

Rationale and design of REWARD (revving-up exercise for sustained weight loss by altering neurological reward and drive): a randomized trial in obese endometrial cancer survivors.

PubMed

Nock, Nora L; Dimitropoulos, Anastasia; Rao, Stephen M; Flask, Chris A; Schluchter, Mark; Zanotti, Kristine M; Rose, Peter G; Kirwan, John P; Alberts, Jay

2014-11-01

Obesity is a leading risk factor for endometrial cancer (EC), particularly Type I forms, which are increasing in the U.S. Although death rates from most cancers have been decreasing, overall mortality in EC is increasing in the U.S. EC survivors' poor fitness combined with their surgical treatments may make weight loss particularly challenging. High intensity exercise increases neurotrophins and neurological reward via altered striatal dopamine in animals, and, in humans, chronic high intensity exercise enhances meal-induced satiety and may reduce hedonic eating. "Assisted" exercise, a mode of exercise whereby a patient's voluntary exercise rate is augmented mechanically, may modulate brain dopamine levels in Parkinson's Disease patients but has not been previously evaluated as a treatment for obesity. We describe the rationale and design of the REWARD trial, which has the overarching goal of randomizing 120 obese EC survivors to "assisted" or voluntary rate cycling to evaluate the efficacy of "assisted" exercise in enhancing and sustaining weight loss. Patients in both arms will receive 3 days/week of supervised exercise and 1 day/week of a group dietary behavioral intervention for 16 weeks and, then, will be followed for 6 months. The primary outcome is weight loss. Secondary outcomes include measures for body composition, fitness, eating behavior, exercise motivation and, quality of life as well as cognition and food reward and motivation as assessed by functional magnetic resonance imaging (fMRI) tasks. If successful, the REWARD program could be extended to help sustain weight loss in obese cancer and non-cancer patients. Copyright © 2014 Elsevier Inc. All rights reserved.

Genomic profiling of ER+ breast cancers after short-term estrogen suppression reveals alterations associated with endocrine resistance.

PubMed

Giltnane, Jennifer M; Hutchinson, Katherine E; Stricker, Thomas P; Formisano, Luigi; Young, Christian D; Estrada, Monica V; Nixon, Mellissa J; Du, Liping; Sanchez, Violeta; Ericsson, Paula Gonzalez; Kuba, Maria G; Sanders, Melinda E; Mu, Xinmeng J; Van Allen, Eliezer M; Wagle, Nikhil; Mayer, Ingrid A; Abramson, Vandana; Gόmez, Henry; Rizzo, Monica; Toy, Weiyi; Chandarlapaty, Sarat; Mayer, Erica L; Christiansen, Jason; Murphy, Danielle; Fitzgerald, Kerry; Wang, Kai; Ross, Jeffrey S; Miller, Vincent A; Stephens, Phillip J; Yelensky, Roman; Garraway, Levi; Shyr, Yu; Meszoely, Ingrid; Balko, Justin M; Arteaga, Carlos L

2017-08-09

Inhibition of proliferation in estrogen receptor-positive (ER + ) breast cancers after short-term antiestrogen therapy correlates with long-term patient outcome. We profiled 155 ER + /human epidermal growth factor receptor 2-negative (HER2 - ) early breast cancers from 143 patients treated with the aromatase inhibitor letrozole for 10 to 21 days before surgery. Twenty-one percent of tumors remained highly proliferative, suggesting that these tumors harbor alterations associated with intrinsic endocrine therapy resistance. Whole-exome sequencing revealed a correlation between 8p11-12 and 11q13 gene amplifications, including FGFR1 and CCND1 , respectively, and high Ki67. We corroborated these findings in a separate cohort of serial pretreatment, postneoadjuvant chemotherapy, and recurrent ER + tumors. Combined inhibition of FGFR1 and CDK4/6 reversed antiestrogen resistance in ER + FGFR1 / CCND1 coamplified CAMA1 breast cancer cells. RNA sequencing of letrozole-treated tumors revealed the existence of intrachromosomal ESR1 fusion transcripts and increased expression of gene signatures indicative of enhanced E2F-mediated transcription and cell cycle processes in cancers with high Ki67. These data suggest that short-term preoperative estrogen deprivation followed by genomic profiling can be used to identify druggable alterations that may cause intrinsic endocrine therapy resistance. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Smad4 loss in mice causes spontaneous head and neck cancer with increased genomic instability and inflammation

PubMed Central

Bornstein, Sophia; White, Ruth; Malkoski, Stephen; Oka, Masako; Han, Gangwen; Cleaver, Timothy; Reh, Douglas; Andersen, Peter; Gross, Neil; Olson, Susan; Deng, Chuxia; Lu, Shi-Long; Wang, Xiao-Jing

2009-01-01

Smad4 is a central mediator of TGF-β signaling, and its expression is downregulated or lost at the malignant stage in several cancer types. In this study, we found that Smad4 was frequently downregulated not only in human head and neck squamous cell carcinoma (HNSCC) malignant lesions, but also in grossly normal adjacent buccal mucosa. To gain insight into the importance of this observation, we generated mice in which Smad4 was deleted in head and neck epithelia (referred to herein as HN-Smad4–/– mice) and found that they developed spontaneous HNSCC. Interestingly, both normal head and neck tissue and HNSCC from HN-Smad4–/– mice exhibited increased genomic instability, which correlated with downregulated expression and function of genes encoding proteins in the Fanconi anemia/Brca (Fanc/Brca) DNA repair pathway linked to HNSCC susceptibility in humans. Consistent with this, further analysis revealed a correlation between downregulation of Smad4 protein and downregulation of the Brca1 and Rad51 proteins in human HNSCC. In addition to the above changes in tumor epithelia, both normal head and neck tissue and HNSCC from HN-Smad4–/– mice exhibited severe inflammation, which was associated with increased expression of TGF-β1 and activated Smad3. We present what we believe to be the first single gene–knockout model for HNSCC, in which both HNSCC formation and invasion occurred as a result of Smad4 deletion. Our results reveal an intriguing connection between Smad4 and the Fanc/Brca pathway and highlight the impact of epithelial Smad4 loss on inflammation. PMID:19841536

Loss of Smad4 in colorectal cancer induces resistance to 5-fluorouracil through activating Akt pathway.

PubMed

Zhang, B; Zhang, B; Chen, X; Bae, S; Singh, K; Washington, M K; Datta, P K

2014-02-18

Higher frequency of Smad4 inactivation or loss of expression is observed in metastasis of colorectal cancer (CRC) leading to unfavourable survival and contributes to chemoresistance. However, the molecular mechanism of how Smad4 regulates chemosensitivity of CRC is unknown. We evaluated how the loss of Smad4 in CRC enhanced chemoresistance to 5-fluorouracil (5-FU) using two CRC cell lines in vitro and in vivo. Immunoblotting with cell and tumour lysates and immunohistochemical analyses with tissue microarray were performed. Knockdown or loss of Smad4 induced tumorigenicity, migration, invasion, angiogenesis, metastasis, and 5-FU resistance. Smad4 expression in mouse tumours regulated cell-cycle regulatory proteins leading to Rb phosphorylation. Loss of Smad4 activated Akt pathway that resulted in upregulation of anti-apoptotic proteins, Bcl-2 and Bcl-w, and Survivin. Suppression of phosphatidylinositol-3-kinase (PI3K)/Akt pathway by LY294002 restored chemosensitivity of Smad4-deficient cells to 5-FU. Vascular endothelial growth factor-induced angiogenesis in Smad4-deficient cells might also lead to chemoresistance. Low levels of Smad4 expression in CRC tissues correlated with higher levels of Bcl-2 and Bcl-w and with poor overall survival as observed in immunohistochemical staining of tissue microarrays. Loss of Smad4 in CRC patients induces resistance to 5-FU-based therapy through activation of Akt pathway and inhibitors of this pathway may sensitise these patients to 5-FU.

Loss of Smad4 in colorectal cancer induces resistance to 5-fluorouracil through activating Akt pathway

PubMed Central

Zhang, B; Zhang, B; Chen, X; Bae, S; Singh, K; Washington, M K; Datta, P K

2014-01-01

Background: Higher frequency of Smad4 inactivation or loss of expression is observed in metastasis of colorectal cancer (CRC) leading to unfavourable survival and contributes to chemoresistance. However, the molecular mechanism of how Smad4 regulates chemosensitivity of CRC is unknown. Methods: We evaluated how the loss of Smad4 in CRC enhanced chemoresistance to 5-fluorouracil (5-FU) using two CRC cell lines in vitro and in vivo. Immunoblotting with cell and tumour lysates and immunohistochemical analyses with tissue microarray were performed. Results: Knockdown or loss of Smad4 induced tumorigenicity, migration, invasion, angiogenesis, metastasis, and 5-FU resistance. Smad4 expression in mouse tumours regulated cell-cycle regulatory proteins leading to Rb phosphorylation. Loss of Smad4 activated Akt pathway that resulted in upregulation of anti-apoptotic proteins, Bcl-2 and Bcl-w, and Survivin. Suppression of phosphatidylinositol-3-kinase (PI3K)/Akt pathway by LY294002 restored chemosensitivity of Smad4-deficient cells to 5-FU. Vascular endothelial growth factor-induced angiogenesis in Smad4-deficient cells might also lead to chemoresistance. Low levels of Smad4 expression in CRC tissues correlated with higher levels of Bcl-2 and Bcl-w and with poor overall survival as observed in immunohistochemical staining of tissue microarrays. Conclusion: Loss of Smad4 in CRC patients induces resistance to 5-FU-based therapy through activation of Akt pathway and inhibitors of this pathway may sensitise these patients to 5-FU. PMID:24384683

A Systems-Level Analysis Reveals Circadian Regulation of Splicing in Colorectal Cancer.

PubMed

El-Athman, Rukeia; Fuhr, Luise; Relógio, Angela

2018-06-20

Accumulating evidence points to a significant role of the circadian clock in the regulation of splicing in various organisms, including mammals. Both dysregulated circadian rhythms and aberrant pre-mRNA splicing are frequently implicated in human disease, in particular in cancer. To investigate the role of the circadian clock in the regulation of splicing in a cancer progression context at the systems-level, we conducted a genome-wide analysis and compared the rhythmic transcriptional profiles of colon carcinoma cell lines SW480 and SW620, derived from primary and metastatic sites of the same patient, respectively. We identified spliceosome components and splicing factors with cell-specific circadian expression patterns including SRSF1, HNRNPLL, ESRP1, and RBM 8A, as well as altered alternative splicing events and circadian alternative splicing patterns of output genes (e.g., VEGFA, NCAM1, FGFR2, CD44) in our cellular model. Our data reveals a remarkable interplay between the circadian clock and pre-mRNA splicing with putative consequences in tumor progression and metastasis. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Remnant living cells that escape cell loss in late-stage tumors exhibit cancer stem cell-like characteristics

PubMed Central

Chen, Y-L; Wang, S-Y; Liu, R-S; Wang, H-E; Chen, J-C; Chiou, S-H; Chang, C A; Lin, L-T; Tan, D T W; Lee, Y-J

2012-01-01

A balance between cell proliferation and cell loss is essential for tumor progression. Although up to 90% of cells are lost in late-stage carcinomas, the progression and characteristics of remnant living cells in tumor mass are unclear. Here we used molecular imaging to track the progression of living cells in a syngeneic tumor model, and ex vivo investigated the properties of this population at late-stage tumor. The piggyBac transposon system was used to stably introduce the dual reporter genes, including monomeric red fluorescent protein (mRFP) and herpes simplex virus type-1 thymidine kinase (HSV1-tk) genes for fluorescence-based and radionuclide-based imaging of tumor growth in small animals, respectively. Iodine-123-labeled 5-iodo-2′-fluoro-1-beta-𝒟-arabinofuranosyluracil was used as a radiotracer for HSV1-tk gene expression in tumors. The fluorescence- and radionuclide-based imaging using the single-photon emission computed tomography/computed tomography revealed that the number of living cells reached the maximum at 1 week after implantation of 4T1 tumors, and gradually decreased and clustered near the side of the body until 4 weeks accompanied by enlargement of tumor mass. The remnant living cells at late-stage tumor were isolated and investigated ex vivo. The results showed that these living cells could form mammospheres and express cancer stem cell (CSC)-related biomarkers, including octamer-binding transcription factor 4, SRY (sex-determining region Y)-box 2, and CD133 genes compared with those cultured in vitro. Furthermore, this HSV1-tk-expressing CSC-like population was sensitive to ganciclovir applied for the suicide therapy. Taken together, the current data suggested that cells escaping from cell loss in late-stage tumors exhibit CSC-like characteristics, and HSV1-tk may be considered a theranostic agent for targeting this population in vivo. PMID:23034334

Gain-Framed Messages Do Not Motivate Sun Protection: A Meta-Analytic Review of Randomized Trials Comparing Gain-Framed and Loss-Framed Appeals for Promoting Skin Cancer Prevention

PubMed Central

O’Keefe, Daniel J.; Wu, Daisy

2012-01-01

Persuading people to undertake actions to prevent skin cancer is an important public health challenge. A number of studies have compared the effectiveness of gain-framed and loss-framed appeals in this domain, often expecting gain-framed appeals to be more persuasive. A meta-analytic review (k = 33, N = 4,168), however, finds no significant difference in the persuasiveness of gain- and loss-framed appeals for encouraging skin cancer prevention. This conclusion is unaffected by differences in the specific protective action advocated or by differences in the kind of outcomes invoked. But the results offer an intimation that men might be more susceptible to framing variations in this domain—with loss-framed appeals potentially having a persuasive advantage. PMID:22829794

Lipolytic and thermogenic depletion of adipose tissue in cancer cachexia.

PubMed

Tsoli, Maria; Swarbrick, Michael M; Robertson, Graham R

2016-06-01

Although muscle wasting is the obvious manifestation of cancer cachexia that impacts on patient quality of life, the loss of lipid reserves and metabolic imbalance in adipose tissue also contribute to the devastating impact of cachexia. Depletion of fat depots in cancer patients is more pronounced than loss of muscle and often precedes, or even occurs in the absence of, reduced lean body mass. Rapid mobilisation of triglycerides stored within adipocytes to supply the body with fatty acids in periods of high-energy demand is normally mediated through a well-defined process of lipolysis involving the lipases ATGL, HSL and MGL. Studies into how these lipases contribute to fat loss in cancer cachexia have revealed the prominent role for ATGL in initiating lipolysis during adipose tissue atrophy, together with links between tumour-derived factors and the signalling pathways that control lipid flux within fat cells. The recent findings of increased thermogenesis in brown fat during cancer cachexia indicate that metabolically active adipose tissue contributes to the imbalance in energy homeostasis involved in catabolic wasting. Such energetically futile use of fatty acids liberated from adipose tissue to generate heat represents a maladaptive response in conjunction with anorexia experienced by cancer patients. As IL-6 release by tumours provokes lipolysis and activates the thermogenic programme in brown fat, this review explores the overlap in dysregulated metabolic processes due to inflammatory mediators in cancer cachexia and other disease states characterised by elevated cytokines such as obesity and diabetes. Crown Copyright © 2015. Published by Elsevier Ltd. All rights reserved.

MEL-18 loss mediates estrogen receptor–α downregulation and hormone independence

PubMed Central

Lee, Jeong-Yeon; Won, Hee-Young; Park, Ji-Hye; Kim, Hye-Yeon; Choi, Hee-Joo; Shin, Dong-Hui; Kang, Ju-Hee; Woo, Jong-Kyu; Oh, Seung-Hyun; Son, Taekwon; Choi, Jin-Woo; Kim, Sehwan; Kim, Hyung-Yong; Yi, Kijong; Jang, Ki-Seok; Oh, Young-Ha; Kong, Gu

2015-01-01

The polycomb protein MEL-18 has been proposed as a tumor suppressor in breast cancer; however, its functional relevance to the hormonal regulation of breast cancer remains unknown. Here, we demonstrated that MEL-18 loss contributes to the hormone-independent phenotype of breast cancer by modulating hormone receptor expression. In multiple breast cancer cohorts, MEL-18 was markedly downregulated in triple-negative breast cancer (TNBC). MEL-18 expression positively correlated with the expression of luminal markers, including estrogen receptor–α (ER-α, encoded by ESR1). MEL-18 loss was also associated with poor response to antihormonal therapy in ER-α–positive breast cancer. Furthermore, whereas MEL-18 loss in luminal breast cancer cells resulted in the downregulation of expression and activity of ER-α and the progesterone receptor (PR), MEL-18 overexpression restored ER-α expression in TNBC. Consistently, in vivo xenograft experiments demonstrated that MEL-18 loss induces estrogen-independent growth and tamoxifen resistance in luminal breast cancer, and that MEL-18 overexpression confers tamoxifen sensitivity in TNBC. MEL-18 suppressed SUMOylation of the ESR1 transactivators p53 and SP1, thereby driving ESR1 transcription. MEL-18 facilitated the deSUMOylation process by inhibiting BMI-1/RING1B-mediated ubiquitin-proteasomal degradation of SUMO1/sentrin-specific protease 1 (SENP1). These findings demonstrate that MEL-18 is a SUMO-dependent regulator of hormone receptors and suggest MEL-18 expression as a marker for determining the antihormonal therapy response in patients with breast cancer. PMID:25822021

Medicines and Bone Loss

MedlinePlus

... The doses of thyroid hormone used to treat hypothyroidism (underactive thyroid) don’t harm bone and shouldn’t be cause for concern. Only high doses, used for thyroid cancer treatment, can cause bone loss. High doses or long- ...

Clozapine-associated weight loss.

PubMed

Hanwella, R; de Silva, V; Wijeratne, C; Ketharanathan, T; de Silva, J

2010-07-01

Clozapine is associated with weight gain. We report three patients with substantial weight loss following treatment with clozapine. The weight loss observed in the three patients was 33, 18 and 14.4 kg with percentage loss of body weight of 49, 18 and 21 respectively. Two patients had diabetes mellitus. History, physical examination and extensive investigations in the three patients did not reveal any cause that could account for the weight loss.

Antigen Loss Variants: Catching Hold of Escaping Foes.

PubMed

Vyas, Maulik; Müller, Rolf; Pogge von Strandmann, Elke

2017-01-01

Since mid-1990s, the field of cancer immunotherapy has seen steady growth and selected immunotherapies are now a routine and preferred therapeutic option of certain malignancies. Both active and passive cancer immunotherapies exploit the fact that tumor cells express specific antigens on the cell surface, thereby mounting an immune response specifically against malignant cells. It is well established that cancer cells typically lose surface antigens following natural or therapy-induced selective pressure and these antigen-loss variants are often the population that causes therapy-resistant relapse. CD19 and CD20 antigen loss in acute lymphocytic leukemia and chronic lymphocytic leukemia, respectively, and lineage switching in leukemia associated with mixed lineage leukemia (MLL) gene rearrangements are well-documented evidences in this regard. Although increasing number of novel immunotherapies are being developed, majority of these do not address the control of antigen loss variants. Here, we review the occurrence of antigen loss variants in leukemia and discuss the therapeutic strategies to tackle the same. We also present an approach of dual-targeting immunoligand effectively retargeting NK cells against antigen loss variants in MLL-associated leukemia. Novel immunotherapies simultaneously targeting more than one tumor antigen certainly hold promise to completely eradicate tumor and prevent therapy-resistant relapses.

An Initial Investigation into Naturally Occurring Loss- and Gain-Framed Memorable Breast Cancer Messages

PubMed Central

LaPlante, Carolyn; Smith, Sandi; Kotowski, Michael; Nazione, Samantha; Stohl, Cynthia; Prestin, Abby; So, Jiyeon; Nabi, Robin

2012-01-01

Memorable message research examines interpersonal messages “…remembered for extremely long periods of time and which people perceive as a major influence on the course of their lives” (Knapp, Stohl, & Reardon, 1981, p. 27). They can also guide actions, such as health behaviors. This exploratory research examined self-reported memorable messages about breast cancer to determine if they were framed, emphasizing either the benefits (gain-framed) or the costs (loss-framed) of a behavior. About one-fourth of the messages were framed, with most being gain-framed. The messages tended to emphasize early detection actions. Study limitations and implications for future research are discussed. PMID:22539867

HPV DNA testing with cytology triage in cervical cancer screening: Influence of revealing HPV infection status.

PubMed

Richardson, Lyndsay Ann; El-Zein, Mariam; Ramanakumar, Agnihotram V; Ratnam, Samuel; Sangwa-Lugoma, Ghislain; Longatto-Filho, Adhemar; Cardoso, Marly Augusto; Coutlée, Francois; Franco, Eduardo L

2015-12-01

Knowledge of cervical human papillomavirus (HPV) status might influence a cytotechnician's assessment of cellular abnormalities. The authors compared original cytotechnicians' Papanicolaou (Pap) readings for which HPV status was concealed with Pap rereads for which HPV status was revealed separately for 3 screening populations. Previously collected cervical Pap smears and clinical data were obtained from the Canadian Cervical Cancer Screening Trial (study A), the Democratic Republic of Congo Community-Based Screening Study (study B), and the Brazilian Investigation into Nutrition and Cervical Cancer Prevention (study C). Smears were reread with knowledge of HPV status for all HPV-positive women as well as a sample of HPV-negative women. Diagnostic performance of Pap cytology was compared between original readings and rereads. A total of 1767 Pap tests were reread. Among 915 rereads for HPV-positive women, the contrast between "revealed" and "concealed" Pap readings demonstrated revisions from negative to positive results for 109 women (cutoff was atypical squamous cells of undetermined significance or worse) and 124 women (cutoff was low-grade squamous intraepithelial lesions [LSIL] or worse). For a disease threshold of cervical intraepithelial neoplasia of grade 2 or worse, specificity significantly declined at the atypical squamous cells of undetermined significance cutoff for studies A (86.6% to 75.3%) and C (42.5% to 15.5%), and at the LSIL cutoff for study C (61.9% to 37.6%). Sensitivity remained nearly unchanged between readings, except in study C, in which reread performance was superior (91.3% vs 71.9% for the LSIL cutoff). A reduction in the diagnostic accuracy of Pap cytology was observed when revealing patients' cervical HPV status, possibly due to a heightened awareness of potential abnormalities, which led to more false-positive results. © 2015 American Cancer Society.

Loss of miR-1258 contributes to carcinogenesis and progression of liver cancer through targeting CDC28 protein kinase regulatory subunit 1B.

PubMed

Hu, Minghua; Wang, Mingwei; Lu, Huihong; Wang, Xiaoming; Fang, Xiaoshan; Wang, Jinguo; Ma, Chenyang; Chen, Xiaobing; Xia, Hongping

2016-07-12

Hepatocellular carcinoma (HCC) is the leading cause of cancer related death worldwide. The number of deaths is proportional to the global incidence, which highlights the aggressive tumor biology and lack of effective therapies. Dysregulation of microRNAs has been implicated in carcinogenesis and progression of liver cancer. Here, we identified that miR-1258 was significantly downregulated in HCC and associated with poor patients' survival. Overexpression of miR-1258 significantly inhibits liver cancer cell growth, proliferation and tumorigenicity through increasing cell cycle arrest in G0/G1 phase and promotes cell apoptosis. Interestingly, stable overexpression of miR-1258 suppresses cell migration, stemness and increases sensitivity of HCC cells to chemotherapy drug like doxorubicin. The CDC28 protein kinase regulatory subunit 1B (CKS1B) was identified as a functional downstream target of miR-1258. Re-expression of CKS1B overcomes miR-1258 induced apoptosis and increases stemness of HCC cells, suggesting that loss of miR-1258 contributes to carcinogenesis and progression of liver cancer through targeting CKS1B . Therefore, loss of miR-1258 may be a potential diagnostic and prognostic biomarker and blocking miR-1258-CKS1B axis is a potential therapeutic strategy in HCC.

Mapping the HLA ligandome of Colorectal Cancer Reveals an Imprint of Malignant Cell Transformation.

PubMed

Löffler, Markus W; Kowalewski, Daniel J; Backert, Linus; Bernhardt, Jörg; Adam, Patrick; Schuster, Heiko; Dengler, Florian; Backes, Daniel; Kopp, Hans-Georg; Beckert, Stefan; Wagner, Silvia; Königsrainer, Ingmar; Kohlbacher, Oliver; Kanz, Lothar; Königsrainer, Alfred; Rammensee, Hans-Georg; Stevanovic, Stefan; Haen, Sebastian P

2018-05-22

Immune cell infiltrates have proven highly relevant for colorectal carcinoma (CRC) prognosis, making CRC a promising candidate for immunotherapy. Since tumors interact with the immune system via HLA-presented peptide ligands, exact knowledge of the peptidome constitution is fundamental for understanding this relationship. Here we comprehensively describe the naturally presented HLA-ligandome of CRC and corresponding non-malignant colon (NMC) tissue. Mass spectrometry identified 35,367 and 28,132 HLA-class I ligands on CRC and NMC, attributable to 7,684 and 6,312 distinct source proteins, respectively. Cancer-exclusive peptides were assessed on source protein level using Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein analysis through evolutionary relationships (PANTHER), revealing pathognomonic CRC-associated pathways including Wnt, TGF-β, PI3K, p53, and RTK-RAS. Relative quantitation of peptide presentation on paired CRC and NMC tissue further identified source proteins from cancer- and infection-associated pathways to be over-represented merely within the CRC ligandome. From the pool of tumor-exclusive peptides, a selected HLA-ligand subset was assessed for immunogenicity, with the majority exhibiting an existing T cell repertoire. Overall, these data show that the HLA-ligandome reflects cancer-associated pathways implicated in CRC oncogenesis, suggesting that alterations in tumor cell metabolism could result in cancer-specific, albeit not mutation-derived tumor-antigens. Hence, a defined pool of unique tumor peptides, attributable to complex cellular alterations that are exclusive to malignant cells might comprise promising candidates for immunotherapeutic applications. Copyright ©2018, American Association for Cancer Research.

Clinicopathological characteristics of patients with upper urinary tract urothelial cancer with loss of immunohistochemical expression of the DNA mismatch repair proteins in universal screening.

PubMed

Urakami, Shinji; Inoshita, Naoko; Oka, Suguru; Miyama, Yu; Nomura, Sachio; Arai, Masami; Sakaguchi, Kazushige; Kurosawa, Kazuhiro; Okaneya, Toshikazu

2018-02-01

To assess the detection rate of putative Lynch syndrome-associated upper urinary tract urothelial cancer among all upper urinary tract urothelial cancers and to examine its clinicopathological characteristics. A total of 143 patients with upper urinary tract urothelial cancer who had received total nephroureterectomy were immunohistochemically stained for the expression of mismatch repair proteins MLH1, PMS2, MSH2 and MSH6. For all suspected mismatch repair-deficient cases, MMR genetic testing was recommended and clinicopathological features were examined. Loss of mismatch repair proteins was found in seven patients (5%) who were thus categorized as putative Lynch syndrome-associated upper urinary tract urothelial cancer. Five of these patients showed dual loss of MSH2/MSH6. Two patients were confirmed to be MSH2 germline mutation carriers. Histologically, all seven tumors were low-grade atypical urothelial carcinoma and showed its unique histological features, such as an inverted papilloma-like growth pattern and a villous to papillary structure with mild stratification of tumor cells. Six tumors had no invasion of the muscularis propria. No recurrence or cancer-related deaths were reported in these seven patients. Just three patients met the revised Amsterdam criteria. This is the first report that universally examined mismatch repair immunohistochemical screening for upper urinary tract urothelial cancers. The prevalence (5%) of putative Lynch syndrome-associated upper urinary tract urothelial cancers is much higher than we had expected. We ascertained that putative Lynch syndrome-associated upper urinary tract urothelial cancers were clinically in the early stage and histologically classified into low-grade malignancy with its characteristic pathological features. The clinicopathological characteristics that we found in the present study could become additional possible markers in the diagnosis of Lynch syndrome-associated upper urinary tract urothelial cancers

Differential network entropy reveals cancer system hallmarks

PubMed Central

West, James; Bianconi, Ginestra; Severini, Simone; Teschendorff, Andrew E.

2012-01-01

The cellular phenotype is described by a complex network of molecular interactions. Elucidating network properties that distinguish disease from the healthy cellular state is therefore of critical importance for gaining systems-level insights into disease mechanisms and ultimately for developing improved therapies. By integrating gene expression data with a protein interaction network we here demonstrate that cancer cells are characterised by an increase in network entropy. In addition, we formally demonstrate that gene expression differences between normal and cancer tissue are anticorrelated with local network entropy changes, thus providing a systemic link between gene expression changes at the nodes and their local correlation patterns. In particular, we find that genes which drive cell-proliferation in cancer cells and which often encode oncogenes are associated with reductions in network entropy. These findings may have potential implications for identifying novel drug targets. PMID:23150773

Molecular pathways leading to loss of skeletal muscle mass in cancer cachexia--can findings from animal models be translated to humans?

PubMed

Mueller, Tara C; Bachmann, Jeannine; Prokopchuk, Olga; Friess, Helmut; Martignoni, Marc E

2016-02-08

Cachexia is a multi-factorial, systemic syndrome that especially affects patients with cancer of the gastrointestinal tract, and leads to reduced treatment response, survival and quality of life. The most important clinical feature of cachexia is the excessive wasting of skeletal muscle mass. Currently, an effective treatment is still lacking and the search for therapeutic targets continues. Even though a substantial number of animal studies have contributed to a better understanding of the underlying mechanisms of the loss of skeletal muscle mass, subsequent clinical trials of potential new drugs have not yet yielded any effective treatment for cancer cachexia. Therefore, we questioned to which degree findings from animal studies can be translated to humans in clinical practice and research. A substantial amount of animal studies on the molecular mechanisms of muscle wasting in cancer cachexia has been conducted in recent years. This extensive review of the literature showed that most of their observations could not be consistently reproduced in studies on human skeletal muscle samples. However, studies on human material are scarce and limited in patient numbers and homogeneity. Therefore, their results have to be interpreted critically. More research is needed on human tissue samples to clarify the signaling pathways that lead to skeletal muscle loss, and to confirm pre-selected drug targets from animal models in clinical trials. In addition, improved diagnostic tools and standardized clinical criteria for cancer cachexia are needed to conduct standardized, randomized controlled trials of potential drug candidates in the future.

Copy number of the Adenomatous Polyposis Coli gene is not always neutral in sporadic colorectal cancers with loss of heterozygosity for the gene.

PubMed

Zauber, Peter; Marotta, Stephen; Sabbath-Solitare, Marlene

2016-03-12

Changes in the number of alleles of a chromosome may have an impact upon gene expression. Loss of heterozygosity (LOH) indicates that one allele of a gene has been lost, and knowing the exact copy number of the gene would indicate whether duplication of the remaining allele has occurred. We were interested to determine the copy number of the Adenomatous Polyposis Coli (APC) gene in sporadic colorectal cancers with LOH. We selected 38 carcinomas with LOH for the APC gene region of chromosome 5, as determined by amplification of the CA repeat region within the D5S346 loci. The copy number status of APC was ascertained using the SALSA® MLPA® P043-B1 APC Kit. LOH for the DCC gene, KRAS gene mutation, and microsatellite instability were also evaluated for each tumor, utilizing standard polymerase chain reaction methods. No tumor demonstrated microsatellite instability. LOH of the DCC gene was also present in 33 of 36 (91.7%) informative tumors. A KRAS gene mutation was present in 16 of the 38 (42.1%) tumors. Twenty-four (63.2%) of the tumors were copy number neutral, 10 (26.3%) tumors demonstrated major loss, while two (5.3%) showed partial loss. Two tumors (5.3%) had copy number gain. Results of APC and DCC LOH, KRAS and microsatellite instability indicate our colorectal cancer cases were typical of sporadic cancers following the 'chromosomal instability' pathway. The majority of our colorectal carcinomas with LOH for APC gene are copy number neutral. However, one-third of our cases showed copy number loss, suggesting that duplication of the remaining allele is not required for the development of a colorectal carcinoma.

ARID1B is a specific vulnerability in ARID1A-mutant cancers.

PubMed

Helming, Katherine C; Wang, Xiaofeng; Wilson, Boris G; Vazquez, Francisca; Haswell, Jeffrey R; Manchester, Haley E; Kim, Youngha; Kryukov, Gregory V; Ghandi, Mahmoud; Aguirre, Andrew J; Jagani, Zainab; Wang, Zhong; Garraway, Levi A; Hahn, William C; Roberts, Charles W M

2014-03-01

Recent studies have revealed that ARID1A, encoding AT-rich interactive domain 1A (SWI-like), is frequently mutated across a variety of human cancers and also has bona fide tumor suppressor properties. Consequently, identification of vulnerabilities conferred by ARID1A mutation would have major relevance for human cancer. Here, using a broad screening approach, we identify ARID1B, an ARID1A homolog whose gene product is mutually exclusive with ARID1A in SWI/SNF complexes, as the number 1 gene preferentially required for the survival of ARID1A-mutant cancer cell lines. We show that loss of ARID1B in ARID1A-deficient backgrounds destabilizes SWI/SNF and impairs proliferation in both cancer cells and primary cells. We also find that ARID1A and ARID1B are frequently co-mutated in cancer but that ARID1A-deficient cancers retain at least one functional ARID1B allele. These results suggest that loss of ARID1A and ARID1B alleles cooperatively promotes cancer formation but also results in a unique functional dependence. The results further identify ARID1B as a potential therapeutic target for ARID1A-mutant cancers.

Impact of loss-of-function mutations at the RNF43 locus on colorectal cancer development and progression.

PubMed

Eto, Tsugio; Miyake, Keisuke; Nosho, Katsuhiko; Ohmuraya, Masaki; Imamura, Yu; Arima, Kota; Kanno, Shinichi; Fu, Lingfeng; Kiyozumi, Yuki; Izumi, Daisuke; Sugihara, Hidetaka; Hiyoshi, Yukiharu; Miyamoto, Yuji; Sawayama, Hiroshi; Iwatsuki, Masaaki; Baba, Yoshifumi; Yoshida, Naoya; Furukawa, Toru; Araki, Kimi; Baba, Hideo; Ishimoto, Takatsugu

2018-05-13

RNF43 mutations are frequently detected in colorectal cancer cells and lead to a loss of function of the ubiquitin E3 ligase. Here, we investigated the clinical significance of RNF43 mutations in a large Japanese cohort and the role of RNF43 at various stages of colorectal cancer development and progression. Mutation analysis of the RNF43 gene locus using pyrosequencing technology detected RNF43 hotspot mutations in 1 (0.88%) of 113 colorectal polyp cases and 30 (6.45%) of 465 colorectal cancer cases. Moreover, patients with colorectal cancer harboring mutated RNF43 experienced a higher recurrence rate than those harboring non-mutated RNF43. In addition, the growth of RNF43 wild-type colorectal cancer cell lines was significantly increased by RNF43 silencing. We generated Rnf43 knock-out mice in a C57BL/6N background using the CRISPR-Cas9 system. Although intestinal organoids from the Rnf43 knock-out mice did not show continuous growth compared with those from the wild-type mice in the absence of R-spondin, an azoxymethane (AOM)/dextran sodium sulfate (DSS) mouse model demonstrated that the tumors were markedly larger in the Rnf43 knock-out mice than in the wild-type mice. These findings provide evidence that Wnt signaling activation by RNF43 mutations during the tumorigenic stage enhances tumor growth and promotes a high recurrence rate in colorectal cancer patients. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Randomized Trial Comparing Telephone Versus In-Person Weight Loss Counseling on Body Composition and Circulating Biomarkers in Women Treated for Breast Cancer: The Lifestyle, Exercise, and Nutrition (LEAN) Study.

PubMed

Harrigan, Maura; Cartmel, Brenda; Loftfield, Erikka; Sanft, Tara; Chagpar, Anees B; Zhou, Yang; Playdon, Mary; Li, Fangyong; Irwin, Melinda L

2016-03-01

Obesity is associated with a higher risk of breast cancer mortality. The gold standard approach to weight loss is in-person counseling, but telephone counseling may be more feasible. We examined the effect of in-person versus telephone weight loss counseling versus usual care on 6-month changes in body composition, physical activity, diet, and serum biomarkers. One hundred breast cancer survivors with a body mass index ≥ 25 kg/m(2) were randomly assigned to in-person counseling (n = 33), telephone counseling (n = 34), or usual care (UC) (n = 33). In-person and telephone counseling included 11 30-minute counseling sessions over 6 months. These focused on reducing caloric intake, increasing physical activity, and behavioral therapy. Body composition, physical activity, diet, and serum biomarkers were measured at baseline and 6 months. The mean age of participants was 59 ± 7.5 years old, with a mean BMI of 33.1 ± 6.6 kg/m(2), and the mean time from diagnosis was 2.9 ± 2.1 years. Fifty-one percent of the participants had stage I breast cancer. Average 6-month weight loss was 6.4%, 5.4%, and 2.0% for in-person, telephone, and UC groups, respectively (P = .004, P = .009, and P = .46 comparing in-person with UC, telephone with UC, and in-person with telephone, respectively). A significant 30% decrease in C-reactive protein levels was observed among women randomly assigned to the combined weight loss intervention groups compared with a 1% decrease among women randomly assigned to UC (P = .05). Both in-person and telephone counseling were effective weight loss strategies, with favorable effects on C-reactive protein levels. Our findings may help guide the incorporation of weight loss counseling into breast cancer treatment and care. © 2015 by American Society of Clinical Oncology.

Effects of Serum Albumin, Calcium Levels, Cancer Stage and Performance Status on Weight Loss in Parathyroid Hormone-Related Peptide Positive or Negative Patients with Cancer.

PubMed

Lee, Ji Yeon; Hong, Namki; Kim, Hye Ryun; Lee, Byung Wan; Kang, Eun Seok; Cha, Bong Soo; Lee, Yong Ho

2018-03-01

A recent animal study showed that parathyroid hormone-related peptide (PTHrP) is associated with cancer cachexia by promoting adipose tissue browning, and we previously demonstrated that PTHrP predicts weight loss (WL) in patients with cancer. In this study, we investigated whether prediction of WL by PTHrP is influenced by clinical factors such as serum albumin, corrected calcium levels, cancer stage, and performance status (PS). A cohort of 219 patients with cancer whose PTHrP level was measured was enrolled and followed for body weight (BW) changes. Subjects were divided into two groups by serum albumin (cutoff value, 3.7 g/dL), corrected calcium (cutoff value, 10.5 mg/dL), cancer stage (stage 1 to 3 or 4), or PS (Eastern Cooperative Oncology Group 0 to 1 or 2 to 4), respectively. Clinically significant WL was defined as either percent of BW change (% BW) <-5% or % BW <-2% plus body mass index (BMI) <20 kg/m². After a median follow-up of 327 days, 74 patients (33.8%) experienced clinically significant WL. A positive PTHrP level was associated with a 2-fold increased risk of WL after adjusting for age, baseline BMI, serum albumin, corrected calcium level, cancer stage, and PS. The effect of PTHrP on WL remained significant in patients with low serum albumin, stage 4 cancer, and good PS. Regardless of calcium level, the effect of PTHrP on WL was maintained, although there was an additive effect of higher calcium and PTHrP levels. Early recognition of patients with advanced cancer who are PTHrP positive with hypercalcemia or hypoalbuminemia is needed for their clinical management. Copyright © 2018 Korean Endocrine Society.

Progressive polarity loss and luminal collapse disrupt tissue organization in carcinoma

PubMed Central

Halaoui, Ruba; Rejon, Carlis; Chatterjee, Sudipa June; Szymborski, Joseph; Meterissian, Sarkis; Muller, William J.; Omeroglu, Atilla; McCaffrey, Luke

2017-01-01

Epithelial cancers (carcinoma) account for 80%–90% of all cancers. The development of carcinoma is associated with disrupted epithelial organization and solid ductal structures. The mechanisms underlying the morphological development of carcinoma are poorly understood, but it is thought that loss of cell polarity is an early event. Here we report the characterization of the development of human breast lesions leading to carcinoma. We identified a unique mechanism that generates solid ducts in carcinoma through progressive loss of polarity and collapse of the luminal architecture. This program initiates with asymmetric divisions of polarized cells that generate a stratified epithelium containing both polarized and depolarized cells. Stratified regions form cords that penetrate into the lumen, subdividing it into polarized secondary lumina. The secondary lumina then collapse with a concomitant decrease in RhoA and myosin II activity at the apical membrane and ultimately lose apical–basal polarity. By restoring RhoA activity in mice, ducts maintained lumen and cell polarity. Notably, disrupted tissue architecture through luminal collapse was reversible, and ducts with a lumen were re-established after oncogene suppression in vivo. This reveals a novel and common mechanism that contributes to carcinoma development by progressively disrupting cell and tissue organization. PMID:28887414

Pre-clinical study of drug combinations that reduce breast cancer burden due to aberrant mTOR and metabolism promoted by LKB1 loss

PubMed Central

Andrade-Vieira, Rafaela; Goguen, Donna; Bentley, Heidi A.; Bowen, Chris V.; Marignani, Paola A.

2014-01-01

Cancer therapies that simultaneously target activated mammalian target of rapamycin (mTOR) and cell metabolism are urgently needed. The goal of our study was to identify therapies that effectively inhibited both mTOR activity and cancer cell metabolism in primary tumors in vivo. Using our mouse model of spontaneous breast cancer promoted by loss of LKB1 expression in an ErbB2 activated model; referred to as LKB1−/−NIC mice, we evaluated the effect of novel therapies in vivo on primary tumors. Treatment of LKB1−/−NIC mice with AZD8055 and 2-DG mono-therapies significantly reduced mammary gland tumorigenesis by inhibiting mTOR pathways and glycolytic metabolism; however simultaneous inhibition of these pathways with AZD8055/2-DG combination was significantly more effective at reducing tumor volume and burden. At the molecular level, combination treatment inhibited mTORC1/mTORC2 activity, selectively inhibited mitochondria function and blocked MAPK pro-survival signaling responsible for the ERK-p90RSK feedback loop. Our findings suggest that loss of LKB1 expression be considered a marker for metabolic dysfunction given its role in regulating AMPK and mTOR function. Finally, the outcome of our pre-clinical study confirms therapies that simultaneously target mTORC1/mTORC2 and glycolytic metabolism in cancer produce the best therapeutic outcome for the treatment of patients harboring metabolically active HER2 positive breast cancers. PMID:25436981

Comparative and evolutionary analysis of the HES/HEY gene family reveal exon/intron loss and teleost specific duplication events.

PubMed

Zhou, Mi; Yan, Jun; Ma, Zhaowu; Zhou, Yang; Abbood, Nibras Najm; Liu, Jianfeng; Su, Li; Jia, Haibo; Guo, An-Yuan

2012-01-01

HES/HEY genes encode a family of basic helix-loop-helix (bHLH) transcription factors with both bHLH and Orange domain. HES/HEY proteins are direct targets of the Notch signaling pathway and play an essential role in developmental decisions, such as the developments of nervous system, somitogenesis, blood vessel and heart. Despite their important functions, the origin and evolution of this HES/HEY gene family has yet to be elucidated. In this study, we identified genes of the HES/HEY family in representative species and performed evolutionary analysis to elucidate their origin and evolutionary process. Our results showed that the HES/HEY genes only existed in metazoans and may originate from the common ancestor of metazoans. We identified HES/HEY genes in more than 10 species representing the main lineages. Combining the bHLH and Orange domain sequences, we constructed the phylogenetic trees by different methods (Bayesian, ML, NJ and ME) and classified the HES/HEY gene family into four groups. Our results indicated that this gene family had undergone three expansions, which were along with the origins of Eumetazoa, vertebrate, and teleost. Gene structure analysis revealed that the HES/HEY genes were involved in exon and/or intron loss in different species lineages. Genes of this family were duplicated in bony fishes and doubled than other vertebrates. Furthermore, we studied the teleost-specific duplications in zebrafish and investigated the expression pattern of duplicated genes in different tissues by RT-PCR. Finally, we proposed a model to show the evolution of this gene family with processes of expansion, exon/intron loss, and motif loss. Our study revealed the evolution of HES/HEY gene family, the expression and function divergence of duplicated genes, which also provide clues for the research of Notch function in development. This study shows a model of gene family analysis with gene structure evolution and duplication.

SASH1: a candidate tumor suppressor gene on chromosome 6q24.3 is downregulated in breast cancer.

PubMed

Zeller, Constanze; Hinzmann, Bernd; Seitz, Susanne; Prokoph, Helmuth; Burkhard-Goettges, Elke; Fischer, Jörg; Jandrig, Burkhard; Schwarz, Lope-Estevez; Rosenthal, André; Scherneck, Siegfried

2003-05-15

Loss of heterozygosity (LOH) and in silico expression analysis were applied to identify genes significantly downregulated in breast cancer within the genomic interval 6q23-25. Systematic comparison of candidate EST sequences with genomic sequences from this interval revealed the genomic structure of a potential target gene on 6q24.3, which we called SAM and SH3 domain containing 1 (SASH1). Loss of the gene-internal marker D6S311, found in 30% of primary breast cancer, was significantly correlated with poor survival and increase in tumor size. Two SASH1 transcripts of approximately 4.4 and 7.5 kb exist and are predominantly transcribed in the human breast, lung, thyroid, spleen, placenta and thymus. In breast cancer cell lines, SASH1 is only expressed at low levels. SASH1 is downregulated in the majority (74%) of breast tumors in comparison with corresponding normal breast epithelial tissues. In addition, SASH1 is also downregulated in tumors of the lung and thyroid. Analysis of the protein domain structure revealed that SASH1 is a member of a recently described family of SH3/SAM adapter molecules and thus suggests a role in signaling pathways. We assume that SASH1 is a new tumor suppressor gene possibly involved in tumorigenesis of breast and other solid cancers. We were unable to find mutations in the coding region of the gene in primary breast cancers showing LOH within the critical region. We therefore hypothesize that other mechanisms as for instance methylation of the promoter region of SASH1 are responsible for the loss of expression of SASH1 in primary and metastatic breast cancer.

Activation of PTHrP-cAMP-CREB1 signaling following p53 loss is essential for osteosarcoma initiation and maintenance.

PubMed

Walia, Mannu K; Ho, Patricia Mw; Taylor, Scott; Ng, Alvin Jm; Gupte, Ankita; Chalk, Alistair M; Zannettino, Andrew Cw; Martin, T John; Walkley, Carl R

2016-04-12

Mutations in the P53 pathway are a hallmark of human cancer. The identification of pathways upon which p53-deficient cells depend could reveal therapeutic targets that may spare normal cells with intact p53. In contrast to P53 point mutations in other cancer, complete loss of P53 is a frequent event in osteosarcoma (OS), the most common cancer of bone. The consequences of p53 loss for osteoblastic cells and OS development are poorly understood. Here we use murine OS models to demonstrate that elevated Pthlh (Pthrp), cAMP levels and signalling via CREB1 are characteristic of both p53-deficient osteoblasts and OS. Normal osteoblasts survive depletion of both PTHrP and CREB1. In contrast, p53-deficient osteoblasts and OS depend upon continuous activation of this pathway and undergo proliferation arrest and apoptosis in the absence of PTHrP or CREB1. Our results identify the PTHrP-cAMP-CREB1 axis as an attractive pathway for therapeutic inhibition in OS.

Activation of PTHrP-cAMP-CREB1 signaling following p53 loss is essential for osteosarcoma initiation and maintenance

PubMed Central

Walia, Mannu K; Ho, Patricia MW; Taylor, Scott; Ng, Alvin JM; Gupte, Ankita; Chalk, Alistair M; Zannettino, Andrew CW; Martin, T John; Walkley, Carl R

2016-01-01

Mutations in the P53 pathway are a hallmark of human cancer. The identification of pathways upon which p53-deficient cells depend could reveal therapeutic targets that may spare normal cells with intact p53. In contrast to P53 point mutations in other cancer, complete loss of P53 is a frequent event in osteosarcoma (OS), the most common cancer of bone. The consequences of p53 loss for osteoblastic cells and OS development are poorly understood. Here we use murine OS models to demonstrate that elevated Pthlh (Pthrp), cAMP levels and signalling via CREB1 are characteristic of both p53-deficient osteoblasts and OS. Normal osteoblasts survive depletion of both PTHrP and CREB1. In contrast, p53-deficient osteoblasts and OS depend upon continuous activation of this pathway and undergo proliferation arrest and apoptosis in the absence of PTHrP or CREB1. Our results identify the PTHrP-cAMP-CREB1 axis as an attractive pathway for therapeutic inhibition in OS. DOI: http://dx.doi.org/10.7554/eLife.13446.001 PMID:27070462

Base changes in tumour DNA have the power to reveal the causes and evolution of cancer

DOE PAGES

Hollstein, M.; Alexandrov, L. B.; Wild, C. P.; ...

2016-06-06

Next-generation sequencing (NGS) technology has demonstrated that the cancer genomes are peppered with mutations. Although most somatic tumour mutations are unlikely to have any role in the cancer process per se, the spectra of DNA sequence changes in tumour mutation catalogues have the potential to identify the mutagens, and to reveal the mutagenic processes responsible for human cancer. Very recently, a novel approach for data mining of the vast compilations of tumour NGS data succeeded in separating and precisely defining at least 30 distinct patterns of sequence change hidden in mutation databases. At least half of these mutational signatures canmore » be readily assigned to known human carcinogenic exposures or endogenous mechanisms of mutagenesis. A quantum leap in our knowledge of mutagenesis in human cancers has resulted, stimulating a flurry of research activity. We trace here the major findings leading first to the hypothesis that carcinogenic insults leave characteristic imprints on the DNA sequence of tumours, and culminating in empirical evidence from NGS data that well-defined carcinogen mutational signatures are indeed present in tumour genomic DNA from a variety of cancer types. The notion that tumour DNAs can divulge environmental sources of mutation is now a well-accepted fact. This approach to cancer aetiology has also incriminated various endogenous, enzyme-driven processes that increase the somatic mutation load in sporadic cancers. The tasks now confronting the field of molecular epidemiology are to assign mutagenic processes to orphan and newly discovered tumour mutation patterns, and to determine whether avoidable cancer risk factors influence signatures produced by endogenous enzymatic mechanisms. As a result, innovative research with experimental models and exploitation of the geographical heterogeneity in cancer incidence can address these challenges.« less

Base changes in tumour DNA have the power to reveal the causes and evolution of cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hollstein, M.; Alexandrov, L. B.; Wild, C. P.

Next-generation sequencing (NGS) technology has demonstrated that the cancer genomes are peppered with mutations. Although most somatic tumour mutations are unlikely to have any role in the cancer process per se, the spectra of DNA sequence changes in tumour mutation catalogues have the potential to identify the mutagens, and to reveal the mutagenic processes responsible for human cancer. Very recently, a novel approach for data mining of the vast compilations of tumour NGS data succeeded in separating and precisely defining at least 30 distinct patterns of sequence change hidden in mutation databases. At least half of these mutational signatures canmore » be readily assigned to known human carcinogenic exposures or endogenous mechanisms of mutagenesis. A quantum leap in our knowledge of mutagenesis in human cancers has resulted, stimulating a flurry of research activity. We trace here the major findings leading first to the hypothesis that carcinogenic insults leave characteristic imprints on the DNA sequence of tumours, and culminating in empirical evidence from NGS data that well-defined carcinogen mutational signatures are indeed present in tumour genomic DNA from a variety of cancer types. The notion that tumour DNAs can divulge environmental sources of mutation is now a well-accepted fact. This approach to cancer aetiology has also incriminated various endogenous, enzyme-driven processes that increase the somatic mutation load in sporadic cancers. The tasks now confronting the field of molecular epidemiology are to assign mutagenic processes to orphan and newly discovered tumour mutation patterns, and to determine whether avoidable cancer risk factors influence signatures produced by endogenous enzymatic mechanisms. As a result, innovative research with experimental models and exploitation of the geographical heterogeneity in cancer incidence can address these challenges.« less

Genomic landscape of gastric cancer: molecular classification and potential targets.

PubMed

Guo, Jiawei; Yu, Weiwei; Su, Hui; Pang, Xiufeng

2017-02-01

Gastric cancer imposes a considerable health burden worldwide, and its mortality ranks as the second highest for all types of cancers. The limited knowledge of the molecular mechanisms underlying gastric cancer tumorigenesis hinders the development of therapeutic strategies. However, ongoing collaborative sequencing efforts facilitate molecular classification and unveil the genomic landscape of gastric cancer. Several new drivers and tumorigenic pathways in gastric cancer, including chromatin remodeling genes, RhoA-related pathways, TP53 dysregulation, activation of receptor tyrosine kinases, stem cell pathways and abnormal DNA methylation, have been revealed. These newly identified genomic alterations await translation into clinical diagnosis and targeted therapies. Considering that loss-of-function mutations are intractable, synthetic lethality could be employed when discussing feasible therapeutic strategies. Although many challenges remain to be tackled, we are optimistic regarding improvements in the prognosis and treatment of gastric cancer in the near future.

Breast cancer diagnosis: biographical disruption, emotional experiences and strategic management in Thai women with breast cancer.

PubMed

Liamputtong, Pranee; Suwankhong, Dusanee

2015-09-01

In this article we draw on Bury's theory of biographical disruption to discuss the meanings of, and emotional experiences related to, being diagnosed with breast cancer among southern Thai women. Qualitative methods, including in-depth interviewing and drawing methods, were used to collect data from 20 women with breast cancer. The women perceived breast cancer to be a rhok raai; an evil or dread disease. They believed that breast cancer would lead to death. The disruption in their biography occurred when they detected abnormalities indicating breast cancer. The women's narratives revealed their chaotic lives upon this diagnosis and the news precipitated in them shock, fear, anxiety and loss of hope. Although they experienced chaos and disruption, the women cultivated strategies that helped them cope with their experiences by accepting their fate and adhering to Buddhist beliefs and practices. Through their narratives of biographical disruption, the women in our study offer healthcare providers knowledge that could lead to an appreciation of their needs and concerns. This knowledge is crucial for health professionals who wish to provide emotional support to women who have been diagnosed with breast cancer in Thailand and elsewhere. © 2015 Foundation for the Sociology of Health & Illness.

Loss of MLH1 sensitizes colon cancer cells to DNA-PKcs inhibitor KU60648.

PubMed

Hinrichsen, Inga; Ackermann, Anne; Düding, Tonja; Graband, Annika; Filmann, Natalie; Plotz, Guido; Zeuzem, Stefan; Brieger, Angela

2017-07-01

Germline mutations of MLH1 are responsible for tumor generation in nearly 50% of patients with Lynch Syndrome, and around 15% of sporadic colorectal cancers show MLH1-deficiency due to promotor hypermethylation. Although these tumors are of lower aggressiveness the benefit for these patients from standard chemotherapy is still under discussion. Recently, it was shown that the sensitivity to the DNA-PKcs inhibitor KU60648 is linked to loss of the MMR protein MSH3. However, loss of MSH3 is rather secondary, as a consequence of MMR-deficiency, and frequently detectable in MLH1-deficient tumors. Therefore, we examined the expression of MLH1, MSH2, MSH6, and MSH3 in different MMR-deficient and proficient cell lines and determined their sensitivity to KU60648 by analyzing cell viability and survival. MLH1-dependent ability of double strand break (DSB) repair was monitored after irradiation via γH2AX detection. A panel of 12 colon cancer cell lines, two pairs of cells, where MLH1 knock down was compared to controls with the same genetic background, and one MLH1-deficient cell line where MLH1 was overexpressed, were included. In summary, we found that MLH1 and/or MSH3-deficient cells exhibited a significantly higher sensitivity to KU60648 than MMR-proficient cells and that overexpression of MLH1 in MLH1-deficient cells resulted in a decrease of cell sensitivity. KU60648 efficiency seems to be associated with reduced DSB repair capacity. Since the molecular testing of colon tumors for MLH1 expression is a clinical standard we believe that MLH1 is a much better marker and a greater number of patients would benefit from KU60648 treatment. © 2017 Wiley Periodicals, Inc.

Study reveals potentially prognostic gene, metabolism changes in kidney cancers | Center for Cancer Research

Cancer.gov

The Cancer Genome Atlas Research Network investigators, including CCR scientists, identified genetic and metabolic pathway changes linked to reduced survival of patients within and across subtypes of renal cell carcinoma (RCC), a type of kidney cancer. The study, published April 5, 2018, in Cell Reports, is part of The Cancer Genome Atlas (TCGA) Program, a joint effort of the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI).

RNA Expression Profiling Reveals Differentially Regulated Growth Factor and Receptor Expression in Redirected Cancer Cells.

PubMed

Schmucker, Hannah S; Park, Jang Pyo; Coissieux, Marie-May; Bentires-Alj, Mohamed; Feltus, F Alex; Booth, Brian W

2017-05-01

Tumorigenic cells can be redirected to adopt a normal phenotype when transplanted into cleared mammary fat pads of juvenile female mice in specific ratios with normal epithelial cells. The redirected tumorigenic cells enter stem cell niches and provide progeny that differentiate into all mammary epithelial subtypes. We have developed an in vitro model that mimics the in vivo phenomenon. The shift in phenotype to redirection should be accomplished through a return to a normal gene expression state. To measure this shift, we interrogated the transcriptome of various in vitro model states in search for casual genes. For this study, expression of growth factors, cytokines, and their associated receptors was examined. In all, we queried 251 growth factor and cytokine-related genes. We found numerous growth factor and cytokine genes whose expression levels switched from expression levels seen in cancer cells to expression levels observed in normal cells. The comparisons of gene expression between normal mammary epithelial cells, tumor-derived cells, and redirected cancer cells have revealed insight into active and inactive growth factors and cytokines in cancer cell redirection.

Effect of a low fat versus a low carbohydrate weight loss dietary intervention on biomarkers of long term survival in breast cancer patients ('CHOICE'): study protocol.

PubMed

Sedlacek, Scot M; Playdon, Mary C; Wolfe, Pamela; McGinley, John N; Wisthoff, Mark R; Daeninck, Elizabeth A; Jiang, Weiqin; Zhu, Zongjian; Thompson, Henry J

2011-07-06

Weight loss in overweight or obese breast cancer patients is associated with an improved prognosis for long term survival. However, it is not clear whether the macronutrient composition of the chosen weight loss dietary plan imparts further prognostic benefit. A study protocol is presented for a dietary intervention to investigate the effects of weight loss dietary patterns that vary markedly in fat and carbohydrate contents on biomarkers of exposure to metabolic processes that may promote tumorigenesis and that are predictive of long term survival. The study will also determine how much weight must be lost for biomarkers to change in a favorable direction. Approximately 370 overweight or obese postmenopausal breast cancer survivors (body mass index: 25.0 to 34.9 kg/m²) will be accrued and assigned to one of two weight loss intervention programs or a non-intervention control group. The dietary intervention is implemented in a free living population to test the two extremes of popular weight loss dietary patterns: a high carbohydrate, low fat diet versus a low carbohydrate, high fat diet. The effects of these dietary patterns on biomarkers for glucose homeostasis, chronic inflammation, cellular oxidation, and steroid sex hormone metabolism will be measured. Participants will attend 3 screening and dietary education visits, and 7 monthly one-on-one dietary counseling and clinical data measurement visits in addition to 5 group visits in the intervention arms. Participants in the control arm will attend two clinical data measurement visits at baseline and 6 months. The primary outcome is high sensitivity C-reactive protein. Secondary outcomes include interleukin-6, tumor necrosis factor-α, insulin-like growth factor-1 (IGF), IGF binding protein-3, 8-isoprostane-F2-alpha, estrone, estradiol, progesterone, sex hormone binding globulin, adiponectin, and leptin. While clinical data indicate that excess weight for height is associated with poor prognosis for long term

Epigenetic Reprogramming Strategies to Reverse Global Loss of 5-Hydroxymethylcytosine, a Prognostic Factor for Poor Survival in High-grade Serous Ovarian Cancer

PubMed Central

Tucker, Douglass W.; Getchell, Christopher R.; McCarthy, Eric T.; Ohman, Anders W.; Sasamoto, Naoko; Xu, Shuyun; Ko, Joo Yeon; Gupta, Mamta; Shafrir, Amy; Medina, Jamie E.; Lee, Jonathan J.; MacDonald, Lauren A.; Malik, Ammara; Hasselblatt, Kathleen T; Li, Wenjing; Zhang, Hong; Kaplan, Samuel J.; Murphy, George F.; Hirsch, Michelle S.; Liu, Joyce F.; Matulonis, Ursula A.; Terry, Kathryn L.; Lian, Christine G.; Dinulescu, Daniela M.

2018-01-01

Purpose A major challenge in platinum-based cancer therapy is the clinical management of chemoresistant tumors, which have a largely unknown pathogenesis at the level of epigenetic regulation. Experimental Design We evaluated the potential of using global loss of 5-hydroxymethylcytosine (5-hmC) levels as a novel diagnostic and prognostic epigenetic marker to better assess platinum-based chemotherapy response and clinical outcome in high-grade serous tumors (HGSOC), the most common and deadliest subtype of ovarian cancer. Furthermore, we identified a targetable pathway to reverse these epigenetic changes, both genetically and pharmacologically. Results This study shows that decreased 5-hmC levels are an epigenetic hallmark for malignancy and tumor progression in HGSOC. In addition, global 5-hmC loss is associated with a decreased response to platinum-based chemotherapy, shorter time to relapse, and poor overall survival in patients newly diagnosed with HGSOC. Interestingly, the rescue of 5-hmC loss restores sensitivity to platinum chemotherapy in vitro and in vivo, decreases the percentage of tumor cells with cancer stem cell markers, and increases overall survival in an aggressive animal model of platinum-resistant disease. Conclusions Consequently, a global analysis of patient 5-hmC levels should be included in future clinical trials, which use pretreatment with epigenetic adjuvants to elevate 5-hmC levels and improve the efficacy of current chemotherapies. Identifying prognostic epigenetic markers and altering chemotherapeutic regimens to incorporate DNMTi pretreatment in tumors with low 5-hmC levels could have important clinical implications for newly diagnosed HGSOC disease. PMID:29263182

Loss of Bad expression confers poor prognosis in non-small cell lung cancer.

PubMed

Huang, Yi; Liu, Dan; Chen, Bojiang; Zeng, Jing; Wang, Lei; Zhang, Shangfu; Mo, Xianming; Li, Weimin

2012-09-01

Proapoptotic BH-3-only protein Bad (Bcl-Xl/Bcl-2-associated death promoter homolog, Bad) initiates apoptosis in human cells, and contributes to tumorigenesis and chemotherapy resistant in malignancies. This study explored association between the Bad expression level and prognosis in patients with non-small cell lung cancer (NSCLC). In our study, a cohort of 88 resected primary NSCLC cases were collected and analyzed. Bad expression level was determined via immunohistochemical staining assay. The prognostic significances of Bad expression were evaluated with univariate and multivariate survival analysis. The results showed that compared with normal lung tissues, Bad expression level significantly decreased in NSCLC (P < 0.05). Bad expression was associated with adjuvant therapy status. Loss of Bad independently predicted poor prognosis in whole NSCLC cohort and early stage subjects (T1 + T2 and N0 + N1) (all P < 0.05). Overall survival time was also drastically shortened for Bad negative phenotype in NSCLC patients with smoking history, especially lung squamous cell carcinoma (all P < 0.05). In conclusion, this study provided clinical evidence that loss of Bad is an independent and powerful predictor of adverse prognosis in NSCLC. Bad protein could be a new biomarker for selecting individual therapy strategies and predicting therapeutic response in subjects with NSCLC.

Evaluation of a "loss-framed" minimal intervention to increase mammography utilization among medically un- and under-insured women.

PubMed

Abood, Doris A; Coster, Daniel C; Mullis, Ann K; Black, David R

2002-01-01

This study was conducted because mammography is under-utilized, even though it is the most effective early detection screening device for breast cancer. A loss-framed telephonic message based on prospect theory was evaluated for the effects on mammography utilization among medically un- and under-insured women living in demographically similar rural counties in Florida. The sample consisted mostly of White women (approximately 89%) 50-64 years old. Experimental group participants received the loss-framed message telephonically and those in the comparison group received the "usual telephone procedure." Logistic regression analyses revealed that women who received the loss-framed message were six times more likely to obtain a mammogram (OR = 6.6, P < 0.0001). The impact of the loss-framed message persisted even after adjustment for initial versus re-screen mammogram effects. This in-reach, loss-framed, minimal intervention seems to have viability and may serve as an alternative or adjunct program for encouraging women to receive mammograms.

Loss of Activating EGFR Mutant Gene Contributes to Acquired Resistance to EGFR Tyrosine Kinase Inhibitors in Lung Cancer Cells

PubMed Central

Kubo, Takuya; Murakami, Yuichi; Kawahara, Akihiko; Azuma, Koichi; Abe, Hideyuki; Kage, Masayoshi; Yoshinaga, Aki; Tahira, Tomoko; Hayashi, Kenshi; Arao, Tokuzo; Nishio, Kazuto; Rosell, Rafael; Kuwano, Michihiko; Ono, Mayumi

2012-01-01

Non-small-cell lung cancer harboring epidermal growth factor receptor (EGFR) mutations attains a meaningful response to EGFR-tyrosine kinase inhibitors (TKIs). However, acquired resistance to EGFR-TKIs could affect long-term outcome in almost all patients. To identify the potential mechanisms of resistance, we established cell lines resistant to EGFR-TKIs from the human lung cancer cell lines PC9 and11–18, which harbored activating EGFR mutations. One erlotinib-resistant cell line from PC9 and two erlotinib-resistant cell lines and two gefitinib-resistant cell lines from 11–18 were independently established. Almost complete loss of mutant delE746-A750 EGFR gene was observed in the erlotinib-resistant cells isolated from PC9, and partial loss of the mutant L858R EGFR gene copy was specifically observed in the erlotinib- and gefitinib-resistant cells from 11–18. However, constitutive activation of EGFR downstream signaling, PI3K/Akt, was observed even after loss of the mutated EGFR gene in all resistant cell lines even in the presence of the drug. In the erlotinib-resistant cells from PC9, constitutive PI3K/Akt activation was effectively inhibited by lapatinib (a dual TKI of EGFR and HER2) or BIBW2992 (pan-TKI of EGFR family proteins). Furthermore, erlotinib with either HER2 or HER3 knockdown by their cognate siRNAs also inhibited PI3K/Akt activation. Transfection of activating mutant EGFR complementary DNA restored drug sensitivity in the erlotinib-resistant cell line. Our study indicates that loss of addiction to mutant EGFR resulted in gain of addiction to both HER2/HER3 and PI3K/Akt signaling to acquire EGFR-TKI resistance. PMID:22815900

Bone loss from Wnt inhibition mitigated by concurrent alendronate therapy.

PubMed

Madan, Babita; McDonald, Mitchell J; Foxa, Gabrielle E; Diegel, Cassandra R; Williams, Bart O; Virshup, David M

2018-01-01

Dysregulated Wnt signaling is associated with the pathogenesis of cancers, fibrosis, and vascular diseases. Inhibition of Wnt signaling has shown efficacy in various pre-clinical models of these disorders. One of the key challenges in developing targeted anti-cancer drugs is to balance efficacy with on-target toxicity. Given the crucial role Wnts play in the differentiation of osteoblasts and osteoclasts, acute inhibition of Wnt signaling is likely to affect bone homeostasis. In this study, we evaluated the skeletal effect of small molecule inhibitor of an o-acyl transferase porcupine (PORCN) that prevents Wnt signaling by blocking the secretion of all Wnts. Micro-computed tomography and histomorphometric evaluation revealed that the bones of mice treated with two structurally distinct PORCN inhibitors LGK974 and ETC-1922159 (ETC-159) had loss-of-bone volume and density within 4 weeks of exposure. This decreased bone mass was associated with a significant increase in adipocytes within the bone marrow. Notably, simultaneous administration of a clinically approved anti-resorptive, alendronate, a member of the bisphosphonate family, mitigated loss-of-bone mass seen upon ETC-159 treatment by regulating activity of osteoclasts and blocking accumulation of bone marrow adipocytes. Our results support the addition of bone protective agents when treating patients with PORCN inhibitors. Mitigation of bone toxicity can extend the therapeutic utility of Wnt pathway inhibitors.

High-Resolution Chromosome 3p Allelotyping of Breast Carcinomas and Precursor Lesions Demonstrates Frequent Loss of Heterozygosity and a Discontinuous Pattern of Allele Loss

PubMed Central

Maitra, Anirban; Wistuba, Ignacio I.; Washington, Constance; Virmani, Arvind K.; Ashfaq, Raheela; Milchgrub, Sara; Gazdar, Adi F.; Minna, John D.

2001-01-01

We performed high-resolution allelotyping for loss of heterozygosity (LOH) analysis on microdissected samples from 45 primary breast cancers, 47 mammary preneoplastic epithelial foci, and 18 breast cancer cell lines, using a panel of 27 polymorphic chromosome 3p markers. Allele loss in some regions of chromosome 3p was detected in 39 of 45 (87%) primary breast tumors. The 3p21.3 region had the highest frequency of LOH (69%), followed by 3p22-24 (61%), 3p21.2-21.3 (58%), 3p25 (48%), 3p14.2 (45%), 3p14.3 (41%), and 3p12 (35%). Analysis of all of the data revealed at least nine discrete intervals showing frequent allele loss: D3S1511-D3S1284 (U2020/DUTT1 region centered on D3S1274 with a homozygous deletion), D3S1300-D3S1234 [fragile histidine triad (FHIT)/FRA3B region centered on D3S1300 with a homozygous deletion], D3S1076-D3S1573, D3S4624/Luca2.1-D3S4597/P1.5, D3S1478-D3S1029, D3S1029 (with a homozygous deletion), D3S1612-D3S1537, D3S1293-D3S1597, and D3S1597-telomere; it is more than likely that additional localized regions of LOH not examined in this study also exist on chromosome 3p. In multiple cases, there was discontinuous allele loss at several 3p sites in the same tumor. Twenty-one of 47 (45%) preneoplastic lesions demonstrated 3p LOH, including 12 of 13 (92%) ductal carcinoma in situ, 2 of 7 (29%) apocrine metaplasia, and 7 of 25 (28%) usual epithelial hyperplasia. The 3p21.3 region had the highest frequency of LOH in preneoplastic breast epithelium (36%), followed by 3p21.2-21.3 (20%), 3p14.2/FHIT region (11%), 3p25 (10%), and 3p22-24 (5%). In 39 3p loci showing LOH in both the tumor and accompanying preneoplasia, 34 (87%) showed loss of the same parental allele (P = 1.2 × 10−6, cumulative binomial test). In addition, when 21 preneoplastic samples showing LOH were compared to their accompanying cancers, 67% were clonally related, 20% were potentially clonally related but were divergent, and 13% were clonally unrelated. Overall this demonstrated the

The Central Role of Meaning in Adjustment to the Loss of a Child to Cancer: Implications for the Development of Meaning-Centered Grief Therapy

PubMed Central

Lichtenthal, Wendy G.; Breitbart, William

2015-01-01

Purpose of review This review describes research on meaning and meaning-making in parents who lost a child to cancer, suggesting the need for a meaning-centered therapeutic approach to improve their sense of meaning, purpose, and identity and to help with management of prolonged grief symptoms. Recent findings Several studies have demonstrated that parents bereaved by cancer experience unique meaning related challenges associated with the caregiving and illness experience, including struggles with making sense of their loss, benefit-finding, their sense of identity and purpose, disconnection from sources of meaning, and sustaining a sense of meaning in their child’s life. Meaning-Centered Grief Therapy, adapted from Meaning-Centered Psychotherapy, directly addresses these issues, highlighting the choices parents have in how they face their pain, how they honor their child and his/her living legacy, the story they create, and how they live their lives. Summary Given the important role that meaning plays in adjustment to the loss of a child to cancer, a meaning-focused approach such as Meaning-Centered Grief Therapy, may help improve parents’ sense of meaning and grief symptoms. It seems particularly appropriate for parents who lost a child to cancer because it does not pathologize their struggles and directly targets issues they frequently face. PMID:25588204

Mobilizing Transit-Amplifying Cell-Derived Ectopic Progenitors Prevents Hair Loss from Chemotherapy or Radiation Therapy.

PubMed

Huang, Wen-Yen; Lai, Shih-Fan; Chiu, Hsien-Yi; Chang, Michael; Plikus, Maksim V; Chan, Chih-Chieh; Chen, You-Tzung; Tsao, Po-Nien; Yang, Tsung-Lin; Lee, Hsuan-Shu; Chi, Peter; Lin, Sung-Jan

2017-11-15

Genotoxicity-induced hair loss from chemotherapy and radiotherapy is often encountered in cancer treatment, and there is a lack of effective treatment. In growing hair follicles (HF), quiescent stem cells (SC) are maintained in the bulge region, and hair bulbs at the base contain rapidly dividing, yet genotoxicity-sensitive transit-amplifying cells (TAC) that maintain hair growth. How genotoxicity-induced HF injury is repaired remains unclear. We report here that HFs mobilize ectopic progenitors from distinct TAC compartments for regeneration in adaptation to the severity of dystrophy induced by ionizing radiation (IR). Specifically, after low-dose IR, keratin 5 + basal hair bulb progenitors, rather than bulge SCs, were quickly activated to replenish matrix cells and regenerated all concentric layers of HFs, demonstrating their plasticity. After high-dose IR, when both matrix and hair bulb cells were depleted, the surviving outer root sheath cells rapidly acquired an SC-like state and fueled HF regeneration. Their progeny then homed back to SC niche and supported new cycles of HF growth. We also revealed that IR induced HF dystrophy and hair loss and suppressed WNT signaling in a p53- and dose-dependent manner. Augmenting WNT signaling attenuated the suppressive effect of p53 and enhanced ectopic progenitor proliferation after genotoxic injury, thereby preventing both IR- and cyclophosphamide-induced alopecia. Hence, targeted activation of TAC-derived progenitor cells, rather than quiescent bulge SCs, for anagen HF repair can be a potential approach to prevent hair loss from chemotherapy and radiotherapy. Cancer Res; 77(22); 6083-96. ©2017 AACR . ©2017 American Association for Cancer Research.

Novel cancer gene variants and gene fusions of triple-negative breast cancers (TNBCs) reveal their molecular diversity conserved in the patient-derived xenograft (PDX) model.

PubMed

Jung, Jaeyun; Jang, Kiwon; Ju, Jung Min; Lee, Eunji; Lee, Jong Won; Kim, Hee Jung; Kim, Jisun; Lee, Sae Byul; Ko, Beom Seok; Son, Byung Ho; Lee, Hee Jin; Gong, Gyungyup; Ahn, Sei Yeon; Choi, Jung Kyoon; Singh, Shree Ram; Chang, Suhwan

2018-08-01

Despite the improved 5-year survival rate of breast cancer, triple-negative breast cancer (TNBC) remains a challenge due to lack of effective targeted therapy and higher recurrence and metastasis than other subtypes. To identify novel druggable targets and to understand its unique biology, we tried to implement 24 patient-derived xenografts (PDXs) of TNBC. The overall success rate of PDX implantation was 45%, much higher than estrogen receptor (ER)-positive cases. Immunohistochemical analysis revealed conserved ER/PR/Her2 negativity (with two exceptions) between the original and PDX tumors. Genomic analysis of 10 primary tumor-PDX pairs with Ion AmpliSeq CCP revealed high degree of variant conservation (85.0%-96.9%) between primary and PDXs. Further analysis showed 44 rare variants with a predicted high impact in 36 genes including Trp53, Pten, Notch1, and Col1a1. Among them, we confirmed frequent Notch1 variant. Furthermore, RNA-seq analysis of 24 PDXs revealed 594 gene fusions, of which 163 were in-frame, including AZGP1-GJC3 and NF1-AARSD1. Finally, western blot analysis of oncogenic signaling proteins supporting molecular diversity of TNBC PDXs. Overall, our report provides a molecular basis for the usefulness of the TNBC PDX model in preclinical study. Published by Elsevier B.V.

Molecular profiling of ALDH1+ colorectal cancer stem cells reveals preferential activation of MAPK, FAK, and oxidative stress pro-survival signalling pathways.

PubMed

Vishnubalaji, Radhakrishnan; Manikandan, Muthurangan; Fahad, Mohamed; Hamam, Rimi; Alfayez, Musaad; Kassem, Moustapha; Aldahmash, Abdullah; Alajez, Nehad M

2018-03-02

Tumour heterogeneity leads to variable clinical response and inaccurate diagnostic and prognostic assessment. Cancer stem cells (CSCs) represent a subpopulation responsible for invasion, metastasis, therapeutic resistance, and recurrence in many human cancer types. However, the true identity of colorectal cancer (CRC) SCs remains elusive. Here, we aimed to characterize and define the gene expression portrait of CSCs in CRC-model SW403 cells. We found that ALDH + positive cells are clonogenic and highly proliferative; their global gene expression profiling-based molecular signature revealed gene enrichment related to DNA damage, MAPK, FAK, oxidative stress response, and Wnt signalling. ALDH + cells showed enhanced ROS stress resistance, whereas MAPK/FAK pathway pharmacologic inhibition limited their survival. Conversely, 5-fluorouracil increased the ALDH + cell fraction among the SW403, HCT116 and SW620 CRC models. Notably, analysis of ALDH1A1 and POU5F1 expression levels in cohorts of 462 or 420 patients for overall (OS) or disease-free (DFS) survival, respectively, obtained from the Cancer Genome Atlas CRC dataset, revealed strong association between elevated expression and poor OS ( p = 0.006) and poor DFS ( p = 0.05), thus implicating ALDH1A1 and POU5F1 in CRC prognosis. Our data reveal distinct molecular signature of ALDH + CSCs in CRC and suggest pathways relevant for successful targeted therapies and management of CRC.

Molecular profiling of ALDH1+ colorectal cancer stem cells reveals preferential activation of MAPK, FAK, and oxidative stress pro-survival signalling pathways

PubMed Central

Vishnubalaji, Radhakrishnan; Manikandan, Muthurangan; Fahad, Mohamed; Hamam, Rimi; Alfayez, Musaad; Kassem, Moustapha; Aldahmash, Abdullah; Alajez, Nehad M.

2018-01-01

Tumour heterogeneity leads to variable clinical response and inaccurate diagnostic and prognostic assessment. Cancer stem cells (CSCs) represent a subpopulation responsible for invasion, metastasis, therapeutic resistance, and recurrence in many human cancer types. However, the true identity of colorectal cancer (CRC) SCs remains elusive. Here, we aimed to characterize and define the gene expression portrait of CSCs in CRC-model SW403 cells. We found that ALDH+ positive cells are clonogenic and highly proliferative; their global gene expression profiling-based molecular signature revealed gene enrichment related to DNA damage, MAPK, FAK, oxidative stress response, and Wnt signalling. ALDH+ cells showed enhanced ROS stress resistance, whereas MAPK/FAK pathway pharmacologic inhibition limited their survival. Conversely, 5-fluorouracil increased the ALDH+ cell fraction among the SW403, HCT116 and SW620 CRC models. Notably, analysis of ALDH1A1 and POU5F1 expression levels in cohorts of 462 or 420 patients for overall (OS) or disease-free (DFS) survival, respectively, obtained from the Cancer Genome Atlas CRC dataset, revealed strong association between elevated expression and poor OS (p = 0.006) and poor DFS (p = 0.05), thus implicating ALDH1A1 and POU5F1 in CRC prognosis. Our data reveal distinct molecular signature of ALDH+ CSCs in CRC and suggest pathways relevant for successful targeted therapies and management of CRC. PMID:29568377

Formoterol attenuates increased oxidative stress and myosin protein loss in respiratory and limb muscles of cancer cachectic rats

PubMed Central

Salazar-Degracia, Anna; Busquets, Sílvia; Argilés, Josep M.; López-Soriano, Francisco J.

2017-01-01

Muscle mass loss and wasting are characteristic features of patients with chronic conditions including cancer. Therapeutic options are still scarce. We hypothesized that cachexia-induced muscle oxidative stress may be attenuated in response to treatment with beta2-adrenoceptor-selective agonist formoterol in rats. In diaphragm and gastrocnemius of tumor-bearing rats (108 AH-130 Yoshida ascites hepatoma cells inoculated intraperitoneally) with and without treatment with formoterol (0.3 mg/kg body weight/day for seven days, daily subcutaneous injection), redox balance (protein oxidation and nitration and antioxidants) and muscle proteins (1-dimensional immunoblots), carbonylated proteins (2-dimensional immunoblots), inflammatory cells (immunohistochemistry), and mitochondrial respiratory chain (MRC) complex activities were explored. In the gastrocnemius, but not the diaphragm, of cancer cachectic rats compared to the controls, protein oxidation and nitration levels were increased, several functional and structural proteins were carbonylated, and in both study muscles, myosin content was reduced, inflammatory cell counts were greater, while no significant differences were seen in MRC complex activities (I, II, and IV). Treatment of cachectic rats with formoterol attenuated all the events in both respiratory and limb muscles. In this in vivo model of cancer-cachectic rats, the diaphragm is more resistant to oxidative stress. Formoterol treatment attenuated the rise in oxidative stress in the limb muscles, inflammatory cell infiltration, and the loss of myosin content seen in both study muscles, whereas no effects were observed in the MRC complex activities. These findings have therapeutic implications as they demonstrate beneficial effects of the beta2 agonist through decreased protein oxidation and inflammation in cachectic muscles, especially the gastrocnemius. PMID:29255650

Identification of constitutional MLH1 epimutations and promoter variants in colorectal cancer patients from the Colon Cancer Family Registry

PubMed Central

Ward, Robyn L.; Dobbins, Timothy; Lindor, Noralane M.; Rapkins, Robert W.; Hitchins, Megan P.

2013-01-01

Purpose: Constitutional MLH1 epimutations manifest as promoter methylation and silencing of the affected allele in normal tissues, predisposing to Lynch syndrome–associated cancers. This study investigated their frequency and inheritance. Methods: A total of 416 individuals with a colorectal cancer showing loss of MLH1 expression and without deleterious germline mutations in MLH1 were ascertained from the Colon Cancer Family Registry (C-CFR). Constitutive DNA samples were screened for MLH1 methylation in all 416 subjects and for promoter sequence changes in 357 individuals. Results: Constitutional MLH1 epimutations were identified in 16 subjects. Of these, seven (1.7%) had mono- or hemi-allelic methylation and eight had low-level methylation (2%). In one subject the epimutation was linked to the c.-27C>A promoter variant. Testing of 37 relatives from nine probands revealed paternal transmission of low-level methylation segregating with a c.+27G>A variant in one case. Five additional probands had a promoter variant without an MLH1 epimutation, with three showing diminished promoter activity in functional assays. Conclusion: Although rare, sequence changes in the regulatory region of MLH1 and aberrant methylation may alone or together predispose to the development of cancer. Screening for these changes is warranted in individuals who have a negative germline sequence screen of MLH1 and loss of MLH1 expression in their tumor. PMID:22878509

The Impact of SMAD4 Loss on Outcome in Patients with Advanced Pancreatic Cancer Treated with Systemic Chemotherapy.

PubMed

Ormanns, Steffen; Haas, Michael; Remold, Anna; Kruger, Stephan; Holdenrieder, Stefan; Kirchner, Thomas; Heinemann, Volker; Boeck, Stefan

2017-05-19

The role of the tumor suppressor mothers against decapentaplegic homolog 4 (SMAD4) has not yet been defined in patients (pts) with advanced pancreatic cancer (aPC). This translational research study was designed to evaluate the impact of tumoral SMAD4 loss on clinicopathological parameters and outcome in PC patients receiving palliative chemotherapy. Using immunohistochemistry, we examined SMAD4 expression in tumor tissue of 143 aPC pts treated within completed prospective clinical and biomarker trials. In uni- and multivariate analyses, SMAD4 expression status was correlated to clinicopathological patient characteristics and outcome. At chemotherapy initiation, 128 pts had metastatic PC; most pts ( n = 99) received a gemcitabine-based regimen. SMAD4 loss was detected in 92 pts (64%); patient characteristics such as gender, age, tumor grading, disease stage or number of metastatic sites had no significant impact on tumoral SMAD4 status. In univariate analyses, SMAD4 loss had no impact on overall survival (hazard ratio (HR) 1.008, p = 0.656); however, we observed a prolonged progression-free survival (HR 1.565, p = 0.038) in pts with tumoral SMAD4 loss. This finding was confirmed in multivariate analyses (HR 1.790, p = 0.040), but only for gemcitabine-treated pts. In contrast to previous studies in resectable PC, loss of SMAD4 expression was not associated with a negative outcome in patients with advanced PC receiving systemic chemotherapy.

Gain versus loss-framed messaging and colorectal cancer screening among African Americans: A preliminary examination of perceived racism and culturally targeted dual messaging.

PubMed

Lucas, Todd; Hayman, Lenwood W; Blessman, James E; Asabigi, Kanzoni; Novak, Julie M

2016-05-01

This preliminary study examined the effect of gain versus loss-framed messaging as well as culturally targeted personal prevention messaging on African Americans' receptivity to colorectal cancer (CRC) screening. This research also examined mechanistic functions of perceived racism in response to message framing. Community samples of African Americans (N = 132) and White Americans (N = 50) who were non-compliant with recommended CRC screening completed an online education module about CRC, and were either exposed to a gain-framed or loss-framed message about CRC screening. Half of African Americans were exposed to an additional and culturally targeted self-control message about personal prevention of CRC. Theory of planned behavior measures of attitudes, normative beliefs, perceived behavioural control, and intentions to obtain a CRC screen served as primary outcomes. The effect of messaging on perceived racism was also measured as an outcome. Consistent with prior research, White Americans were more receptive to CRC screening when exposed to a loss-framed message. However, African Americans were more receptive when exposed to a gain-framed message. The contrary effect of loss-framed messaging on receptivity to screening among African Americans was mediated by an increase in perceived racism. However, including an additional and culturally targeted prevention message mitigated the adverse effect of a loss-framed message. This study identifies an important potential cultural difference in the effect of message framing on illness screening among African Americans, while also suggesting a culturally relevant linking mechanism. This study also suggests the potential for simultaneously presented and culturally targeted messaging to alter the effects of gain and loss-framed messaging on African Americans. What is already known on this subject? African Americans are at an increased risk of both developing and dying from colorectal cancer (CRC). These disparities can be

Loss of the integral nuclear envelope protein SUN1 induces alteration of nucleoli

PubMed Central

Matsumoto, Ayaka; Sakamoto, Chiyomi; Matsumori, Haruka; Katahira, Jun; Yasuda, Yoko; Yoshidome, Katsuhide; Tsujimoto, Masahiko; Goldberg, Ilya G; Matsuura, Nariaki; Nakao, Mitsuyoshi; Saitoh, Noriko; Hieda, Miki

2016-01-01

ABSTRACT A supervised machine learning algorithm, which is qualified for image classification and analyzing similarities, is based on multiple discriminative morphological features that are automatically assembled during the learning processes. The algorithm is suitable for population-based analysis of images of biological materials that are generally complex and heterogeneous. Here we used the algorithm wndchrm to quantify the effects on nucleolar morphology of the loss of the components of nuclear envelope in a human mammary epithelial cell line. The linker of nucleoskeleton and cytoskeleton (LINC) complex, an assembly of nuclear envelope proteins comprising mainly members of the SUN and nesprin families, connects the nuclear lamina and cytoskeletal filaments. The components of the LINC complex are markedly deficient in breast cancer tissues. We found that a reduction in the levels of SUN1, SUN2, and lamin A/C led to significant changes in morphologies that were computationally classified using wndchrm with approximately 100% accuracy. In particular, depletion of SUN1 caused nucleolar hypertrophy and reduced rRNA synthesis. Further, wndchrm revealed a consistent negative correlation between SUN1 expression and the size of nucleoli in human breast cancer tissues. Our unbiased morphological quantitation strategies using wndchrm revealed an unexpected link between the components of the LINC complex and the morphologies of nucleoli that serves as an indicator of the malignant phenotype of breast cancer cells. PMID:26962703

Loss of the integral nuclear envelope protein SUN1 induces alteration of nucleoli.

PubMed

Matsumoto, Ayaka; Sakamoto, Chiyomi; Matsumori, Haruka; Katahira, Jun; Yasuda, Yoko; Yoshidome, Katsuhide; Tsujimoto, Masahiko; Goldberg, Ilya G; Matsuura, Nariaki; Nakao, Mitsuyoshi; Saitoh, Noriko; Hieda, Miki

2016-01-01

A supervised machine learning algorithm, which is qualified for image classification and analyzing similarities, is based on multiple discriminative morphological features that are automatically assembled during the learning processes. The algorithm is suitable for population-based analysis of images of biological materials that are generally complex and heterogeneous. Here we used the algorithm wndchrm to quantify the effects on nucleolar morphology of the loss of the components of nuclear envelope in a human mammary epithelial cell line. The linker of nucleoskeleton and cytoskeleton (LINC) complex, an assembly of nuclear envelope proteins comprising mainly members of the SUN and nesprin families, connects the nuclear lamina and cytoskeletal filaments. The components of the LINC complex are markedly deficient in breast cancer tissues. We found that a reduction in the levels of SUN1, SUN2, and lamin A/C led to significant changes in morphologies that were computationally classified using wndchrm with approximately 100% accuracy. In particular, depletion of SUN1 caused nucleolar hypertrophy and reduced rRNA synthesis. Further, wndchrm revealed a consistent negative correlation between SUN1 expression and the size of nucleoli in human breast cancer tissues. Our unbiased morphological quantitation strategies using wndchrm revealed an unexpected link between the components of the LINC complex and the morphologies of nucleoli that serves as an indicator of the malignant phenotype of breast cancer cells.

Magnitude of Myocutaneous Flaps and Factors Associated With Loss of Volume in Oral Cancer Reconstructive Surgery.

PubMed

Sakamoto, Yuki; Yanamoto, Souichi; Ota, Yoshihide; Furudoi, Shungo; Komori, Takahide; Umeda, Masahiro

2016-03-01

Myocutaneous flaps are often used to repair oral and maxillofacial defects after surgery for oral cancer; however, their volume decreases during the postoperative period. To facilitate treatment planning, the authors measured the extent of such postoperative flap volume loss and identified associated factors in patients who underwent oral reconstruction with myocutaneous flaps. The authors designed and performed a retrospective observational study of patients who underwent reconstructive procedures involving rectus abdominal myocutaneous (RAM) or pectoralis major myocutaneous (PMMC) flaps at Tokai University Hospital, Kobe University Hospital, or Nagasaki University Hospital from April 2009 through March 2013. Flap type and other clinical variables were examined as potential predictors of flap loss. The primary outcome was flap loss at 6 months postoperatively. Correlations between each potential predictor and the primary outcome were examined using multiple regression analysis. The subjects were 75 patients whose oral defects were reconstructed with RAM flaps (n = 57) or PMMC flaps (n = 18). RAM flaps exhibited a mean volume shrinkage of 22% at 6 months postoperatively, which was less than the 27.5% displayed by the PMMC flaps, but the difference was not important. Renal failure, previous surgery of the oral region, postoperative radiotherapy, and postoperative serum albumin level were found to be meaningful risk factors for postoperative flap volume loss. The results of this study suggest that larger flaps should be used in patients who possess these risk factors or are scheduled to undergo postoperative radiotherapy. Future studies should examine the utility of postoperative nutritional management for preventing flap volume loss. Copyright © 2016 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

Differences in skeletal muscle loss caused by cytotoxic chemotherapy and molecular targeted therapy in patients with advanced non‐small cell lung cancer

PubMed Central

Tsuruoka, Hazime; Morikawa, Kei; Furuya, Naoki; Inoue, Takeo; Miyazawa, Teruomi; Mineshita, Masamichi

2017-01-01

Background Recent studies have revealed a reduction in the skeletal muscle area in patients with advanced non‐small cell lung cancer (NSCLC) after chemotherapy. EGFR and ALK tyrosine kinase inhibitor (TKI)‐based therapies are less cytotoxic than chemotherapy, but differences in skeletal muscle mass between patients receiving EGFR and ALK TKI therapies and patients receiving cytotoxic chemotherapy have not yet been reported. Methods Data of pathologically proven NSCLC patients were reviewed, and chest computed tomography and/or positron emission tomography‐computed tomography images obtained from January 2012 to December 2014 were selected. Patients were divided into two groups: cytotoxic chemotherapy (CG) and molecular targeted (MG). Muscle mass was measured with a single cross‐sectional area of the muscle at the third lumber vertebra (L3MA). To estimate skeletal muscle changes during chemotherapy, we defined the following L3 skeletal muscle index (L3SMI) ratio: post L3SMI/pre L3SMI. Differences in the SMI ratio between the groups were evaluated using the Wilcoxon signed‐rank test. Results Sixty‐five patients were included in this study: 44 patients received cytotoxic chemotherapy and 21 received molecular targeted therapy (EGFR and ALK TKI). The loss of L3MA in the CG was higher than in the MG (P = 0.03). In the CG, the L3SMI ratio defined to evaluate skeletal muscle mass changes was significantly lower than in the MG (P = 0.0188). Conclusion Our results suggest that skeletal muscle loss during first‐line therapy was significantly different between patients receiving cytotoxic chemotherapy and those receiving TKIs. Specifically, skeletal muscle loss was lower in patients receiving TKIs than in patients receiving cytotoxic chemotherapy. PMID:29067769

Randomized trial of a phone- and web-based weight loss program for women at elevated breast cancer risk: the HELP study.

PubMed

Cadmus-Bertram, Lisa; Nelson, Sandahl H; Hartman, Sheri; Patterson, Ruth E; Parker, Barbara A; Pierce, John P

2016-08-01

Excess weight and physical inactivity are modifiable risk factors for breast cancer. Behavioral intervention is particularly important among women with an elevated risk profile. This trial tested an intervention that trained women to use a self-monitoring website to increase activity and lose weight. Women with BMI ≥27.5 kg/m(2) at elevated breast cancer risk were randomized to the intervention (N = 71) or usual care (N = 34). The intervention group received telephone-based coaching and used web-based self-monitoring tools. At 6 months, significant weight loss was observed in the intervention group (4.7 % loss from starting weight; SD = 4.7 %) relative to usual care (0.4 % gain; SD = 3.0 %) (p < 0.0001). By 12 months, the intervention group had lost 3.7 % of weight (SD = 5.4 %), compared to 1.3 % (SD = 4.2) for usual care (p = 0.003). At 12 months, accelerometer-measured moderate-to-vigorous physical activity increased by 12 min/day (SD = 24) compared to no change in usual care (p = 0.04. In summary, this web- and phone-based approach produced modest but significant improvements in weight and physical activity for women at elevated breast cancer risk.

Conformational dynamics is key to understanding loss-of-function of NQO1 cancer-associated polymorphisms and its correction by pharmacological ligands

NASA Astrophysics Data System (ADS)

Encarnación, Medina-Carmona; Palomino-Morales, Rogelio J.; Fuchs, Julian E.; Esperanza, Padín-Gonzalez; Noel, Mesa-Torres; Salido, Eduardo; Timson, David J.; Pey, Angel L.

2016-02-01

Protein dynamics is essential to understand protein function and stability, even though is rarely investigated as the origin of loss-of-function due to genetic variations. Here, we use biochemical, biophysical, cell and computational biology tools to study two loss-of-function and cancer-associated polymorphisms (p.R139W and p.P187S) in human NAD(P)H quinone oxidoreductase 1 (NQO1), a FAD-dependent enzyme which activates cancer pro-drugs and stabilizes several oncosuppressors. We show that p.P187S strongly destabilizes the NQO1 dimer in vitro and increases the flexibility of the C-terminal domain, while a combination of FAD and the inhibitor dicoumarol overcome these alterations. Additionally, changes in global stability due to polymorphisms and ligand binding are linked to the dynamics of the dimer interface, whereas the low activity and affinity for FAD in p.P187S is caused by increased fluctuations at the FAD binding site. Importantly, NQO1 steady-state protein levels in cell cultures correlate primarily with the dynamics of the C-terminal domain, supporting a directional preference in NQO1 proteasomal degradation and the use of ligands binding to this domain to stabilize p.P187S in vivo. In conclusion, protein dynamics are fundamental to understanding loss-of-function in p.P187S, and to develop new pharmacological therapies to rescue this function.

Expression between African American and Caucasian Prostate Cancer Tissue Reveals that Stroma is the Site of Aggressive Changes

PubMed Central

Kinseth, Matthew A.; Jia, Zhenyu; Rahmatpanah, Farahnaz; Sawyers, Anne; Sutton, Manuel; Wang-Rodriguez, Jessica; Mercola, Dan; McGuire, Kathleen L.

2013-01-01

In prostate cancer, race/ethnicity is the highest risk factor after adjusting for age. African Americans have more aggressive tumors at every clinical stage of the disease, resulting in poorer prognosis and increased mortality. A major barrier to identifying crucial gene activity differences is heterogeneity, including tissue composition variation intrinsic to the histology of prostate cancer. We hypothesized differences in gene expression in specific tissue types would reveal mechanisms involved in the racial disparities of prostate cancer. We examined seventeen pairs of arrays for African Americans and Caucasians that were formed by closely matching the samples based on the known tissue type composition of the tumors. Using pair wise T-test we found significantly altered gene expression between African Americans and Caucasians. Independently, we performed multiple linear regression analyses to associate gene expression with race considering variation in percent tumor and stroma tissue. The majority of differentially expressed genes were associated with tumor-adjacent stroma rather than tumor tissue. Extracellular matrix, Integrin family and signaling mediators of the epithelial-to-mesenchymal transition pathways were all down regulated in stroma of African Americans. Using MetaCore (GeneGo Inc.) analysis, we observed that 35% of significant (p < 10-3) pathways identified EMT and 25% identified immune response pathways especially for Interleukins -2, -4, -5, -6, -7, -10, -13, -15 and -22 as the major changes. Our studies reveal that altered immune and EMT processes in tumor-adjacent stroma may be responsible for the aggressive nature of prostate cancer in African Americans. PMID:23754304

Loss of tumor suppressor KDM6A amplifies PRC2-regulated transcriptional repression in bladder cancer and can be targeted through inhibition of EZH2.

PubMed

Ler, Lian Dee; Ghosh, Sujoy; Chai, Xiaoran; Thike, Aye Aye; Heng, Hong Lee; Siew, Ee Yan; Dey, Sucharita; Koh, Liang Kai; Lim, Jing Quan; Lim, Weng Khong; Myint, Swe Swe; Loh, Jia Liang; Ong, Pauline; Sam, Xin Xiu; Huang, Dachuan; Lim, Tony; Tan, Puay Hoon; Nagarajan, Sanjanaa; Cheng, Christopher Wai Sam; Ho, Henry; Ng, Lay Guat; Yuen, John; Lin, Po-Hung; Chuang, Cheng-Keng; Chang, Ying-Hsu; Weng, Wen-Hui; Rozen, Steven G; Tan, Patrick; Creasy, Caretha L; Pang, See-Tong; McCabe, Michael T; Poon, Song Ling; Teh, Bin Tean

2017-02-22

Trithorax-like group complex containing KDM6A acts antagonistically to Polycomb-repressive complex 2 (PRC2) containing EZH2 in maintaining the dynamics of the repression and activation of gene expression through H3K27 methylation. In urothelial bladder carcinoma, KDM6A (a H3K27 demethylase) is frequently mutated, but its functional consequences and therapeutic targetability remain unknown. About 70% of KDM6A mutations resulted in a total loss of expression and a consequent loss of demethylase function in this cancer type. Further transcriptome analysis found multiple deregulated pathways, especially PRC2/EZH2, in KDM6A -mutated urothelial bladder carcinoma. Chromatin immunoprecipitation sequencing analysis revealed enrichment of H3K27me3 at specific loci in KDM6A -null cells, including PRC2/EZH2 and their downstream targets. Consequently, we targeted EZH2 (an H3K27 methylase) and demonstrated that KDM6A -null urothelial bladder carcinoma cell lines were sensitive to EZH2 inhibition. Loss- and gain-of-function assays confirmed that cells with loss of KDM6A are vulnerable to EZH2. IGFBP3, a direct KDM6A/EZH2/H3K27me3 target, was up-regulated by EZH2 inhibition and contributed to the observed EZH2-dependent growth suppression in KDM6A -null cell lines. EZH2 inhibition delayed tumor onset in KDM6A -null cells and caused regression of KDM6A -null bladder tumors in both patient-derived and cell line xenograft models. In summary, our study demonstrates that inactivating mutations of KDM6A , which are common in urothelial bladder carcinoma, are potentially targetable by inhibiting EZH2. Copyright © 2017, American Association for the Advancement of Science.

Study reveals potentially prognostic gene, metabolism changes in kidney cancers | Center for Cancer Research

Cancer.gov

The Cancer Genome Atlas Research Network investigators, including CCR scientists, identified genetic and metabolic pathway changes linked to reduced survival of patients within and across subtypes of renal cell carcinoma (RCC), a type of kidney cancer. The study, published April 5, 2018, in Cell Reports, is part of The Cancer Genome Atlas (TCGA) Program, a joint effort of the

Pan-cancer stratification of solid human epithelial tumors and cancer cell lines reveals commonalities and tissue-specific features of the CpG island methylator phenotype.

PubMed

Sánchez-Vega, Francisco; Gotea, Valer; Margolin, Gennady; Elnitski, Laura

2015-01-01

The term CpG island methylator phenotype (CIMP) has been used to describe widespread DNA hypermethylation at CpG-rich genomic regions affecting clinically distinct subsets of cancer patients. Even though there have been numerous studies of CIMP in individual cancer types, a uniform analysis across tissues is still lacking. We analyze genome-wide patterns of CpG island hypermethylation in 5,253 solid epithelial tumors from 15 cancer types from TCGA and 23 cancer cell lines from ENCODE. We identify differentially methylated loci that define CIMP+ and CIMP- samples, and we use unsupervised clustering to provide a robust molecular stratification of tumor methylomes for 12 cancer types and all cancer cell lines. With a minimal set of 89 discriminative loci, we demonstrate accurate pan-cancer separation of the 12 CIMP+/- subpopulations, based on their average levels of methylation. Tumor samples in different CIMP subclasses show distinctive correlations with gene expression profiles and recurrence of somatic mutations, copy number variations, and epigenetic silencing. Enrichment analyses indicate shared canonical pathways and upstream regulators for CIMP-targeted regions across cancer types. Furthermore, genomic alterations showing consistent associations with CIMP+/- status include genes involved in DNA repair, chromatin remodeling genes, and several histone methyltransferases. Associations of CIMP status with specific clinical features, including overall survival in several cancer types, highlight the importance of the CIMP+/- designation for individual tumor evaluation and personalized medicine. We present a comprehensive computational study of CIMP that reveals pan-cancer commonalities and tissue-specific differences underlying concurrent hypermethylation of CpG islands across tumors. Our stratification of solid tumors and cancer cell lines based on CIMP status is data-driven and agnostic to tumor type by design, which protects against known biases that have hindered

From elasticity to inelasticity in cancer cell mechanics: A loss of scale-invariance

NASA Astrophysics Data System (ADS)

Laperrousaz, B.; Drillon, G.; Berguiga, L.; Nicolini, F.; Audit, B.; Satta, V. Maguer; Arneodo, A.; Argoul, F.

2016-08-01

Soft materials such as polymer gels, synthetic biomaterials and living biological tissues are generally classified as viscoelastic or viscoplastic materials, because they behave neither as pure elastic solids, nor as pure viscous fluids. When stressed beyond their linear viscoelastic regime, cross-linked biopolymer gels can behave nonlinearly (inelastically) up to failure. In living cells, this type of behavior is more frequent because their cytoskeleton is basically made of cross-linked biopolymer chains with very different structural and flexibility properties. These networks have high sensitivity to stress and great propensity to local failure. But in contrast to synthetic passive gels, they can "afford" these failures because they have ATP driven reparation mechanisms which often allow the recovery of the original texture. A cell pressed in between two plates for a long period of time may recover its original shape if the culture medium brings all the nutrients for keeping it alive. When the failure events are too frequent or too strong, the reparation mechanisms may abort, leading to an irreversible loss of mechanical homeostasis and paving the way for chronic diseases such as cancer. To illustrate this discussion, we consider a model of immature cell transformation during cancer progression, the chronic myelogenous leukemia (CML), where the formation of the BCR-ABL oncogene results from a single chromosomal translocation t(9; 22). Within the assumption that the cell response to stress is scale invariant, we show that the power-law exponent that characterizes their mechanosensitivity can be retrieved from AFM force indentation curves. Comparing control and BCR-ABL transduced cells, we observe that in the later case, one month after transduction, a small percentage the cancer cells no longer follows the control cell power law, as an indication of disruption of the initial cytoskeleton network structure.

Energy metabolism analysis reveals the mechanism of inhibition of breast cancer cell metastasis by PEG-modified graphene oxide nanosheets.

PubMed

Zhou, Teng; Zhang, Bo; Wei, Peng; Du, Yipeng; Zhou, Hejiang; Yu, Meifang; Yan, Liang; Zhang, Wendi; Nie, Guangjun; Chen, Chunying; Tu, Yaping; Wei, Taotao

2014-12-01

Recent advances in nanomedicine provide promising alternatives for cancer treatment that may improve the survival of patients with metastatic disease. The goal of the present study was to evaluate graphene oxide (GO) as a potential anti-metastatic agent. For this purpose, GO was modified with polyethylene glycol (PEG) to form PEG-modified GO (PEG-GO), which improves its aqueous stability and biocompatibility. We show here that PEG-GO exhibited no apparent effects on the viability of breast cancer cells (MDA-MB-231, MDA-MB-436, and SK-BR-3) or non-cancerous cells (MCF-10A), but inhibited cancer cell migration in vitro and in vivo. Analysis of cellular energy metabolism revealed that PEG-GO significantly impaired mitochondrial oxidative phosphorylation (OXPHOS) in breast cancer cells; however, PEG-GO showed no effect on OXPHOS in non-cancerous cells. To explore the underlying mechanisms, a SILAC (Stable Isotope Labeling by Amino acids in Cell culture) labeling strategy was used to quantify protein expression in PEG-GO-exposed breast cancer versus non-cancerous cells. The results indicated that PEG-GO selectively down-regulated PGC-1α in breast cancer cells and thus modified the expression of diverse energy generation-related proteins, which accounts for the inhibition of OXPHOS. The inhibition of OXPHOS by PEG-GO significantly reduced ATP production and impaired assembly of the F-actin cytoskeleton in breast cancer cells, which is required for the migratory and invasive phenotype of cancer cells. Taken together, these effects of PEG-GO on cancer cell metastasis may allow the development of a new approach to treat metastatic breast cancer. Copyright © 2014 Elsevier Ltd. All rights reserved.

Competing endogenous RNA network crosstalk reveals novel molecular markers in colorectal cancer.

PubMed

Samir, Nehal; Matboli, Marwa; El-Tayeb, Hanaa; El-Tawdi, Ahmed; Hassan, Mohmed K; Waly, Amr; El-Akkad, Hesham A E; Ramadan, Mohamed G; Al-Belkini, Tarek N; El-Khamisy, Sherif; El-Asmar, Farid

2018-05-08

The competing endogenous RNA networks play a pivotal role in cancer diagnosis and progression. Novel properstrategies for early detection of colorectal cancer (CRC) are strongly needed. We investigated a novel CRC-specific RNA-based integrated competing endogenous network composed of lethal3 malignant brain tumor like1 (L3MBTL1) gene, long non-coding intergenic RNA- (lncRNA RP11-909B2.1) and homo sapiens microRNA-595 (hsa-miRNA-595) using in silico data analysis. RT-qPCR-based validation of the network was achieved in serum of 70 patients with CRC, 40 patients with benign colorectal neoplasm, and 20 healthy controls. Moreover, in cancer tissues of 20 of the 70 CRC cases were involved in the study. The expression of RNA-based biomarker network in both CRC and adjacent non-tumor tissues and their correlation with the serum levels of this network members was investigated. Lastly, the expression levels of the chosen ceRNA was verified in CRC cell line. Our results revealed that the three RNAs-based biomarker network (long non-coding intergenic RNA-[lncRNA RP11-909B2.1], Homo sapiens microRNA-595 [hsa-miRNA-595], and L3MBTL1 mRNA), had high sensitivity and specificity for discriminating CRC from healthy controls and also from benign colorectal neoplasm. The data suggest that among these three RNAs, serum lncRNA RP11-909B2.1 could be a promising independent prognostic factors in CRC. The circulatory RNA based biomarker panel can act as potential biomarker for CRC diagnosis and prognosis. © 2018 Wiley Periodicals, Inc.

Technology- and Phone-Based Weight Loss Intervention

PubMed Central

Hartman, Sheri J.; Nelson, Sandahl H.; Cadmus-Bertram, Lisa A.; Patterson, Ruth E.; Parker, Barbara A.; Pierce, John P.

2017-01-01

Introduction For women with an increased breast cancer risk, reducing excess weight and increasing physical activity are believed to be important approaches for reducing their risk. This study tested a weight loss intervention that combined commercially available technology-based self-monitoring tools with individualized phone calls. Design Women were randomized to a weight loss intervention arm (n=36) or a usual care arm (n=18). Setting/Participants Participants were women with a BMI ≥ 27.5 kg/m2 and elevated breast cancer risk recruited from the mammography clinic at the Moores Cancer Center at the University of California San Diego. Intervention Intervention participants used the MyFitnessPal website and phone app to monitor diet and a Fitbit to monitor physical activity. Participants received 12 standardized coaching calls with trained counselors over 6 months. Usual care participants received the U.S. Dietary Guidelines for Americans at baseline and two brief calls over the 6 months. Main outcome measures Weight and accelerometer-measured physical activity were assessed at baseline and 6 months. Data were collected in San Diego, CA, from 2012 to 2014 and analyzed in 2015. Results Participants (n=54) had a mean age of 59.5 (SD=5.6) years, BMI of 31.9 (SD=3.5), and a mean Gail Model score of 2.5 (SD=1.4). At 6 months, intervention participants had lost significantly more weight (4.4 kg vs 0.8 kg, p=0.004) and a greater percentage of starting weight (5.3% vs 1.0%, p=0.005) than usual care participants. Across arms, greater increases in moderate-to-vigorous physical activity resulted in greater weight loss (p=0.01). Conclusions Combining technology-based self-monitoring tools with phone counseling supported weight loss over 6 months in women at increased risk for breast cancer. PMID:27593420

Differential Effects of IL6 and Activin A in the Development of Cancer-Associated Cachexia.

PubMed

Chen, Justin L; Walton, Kelly L; Qian, Hongwei; Colgan, Timothy D; Hagg, Adam; Watt, Matthew J; Harrison, Craig A; Gregorevic, Paul

2016-09-15

Cachexia is a life-threatening wasting syndrome lacking effective treatment, which arises in many cancer patients. Although ostensibly induced by multiple tumor-produced cytokines (tumorkines), their functional contribution to initiation and progression of this syndrome has proven difficult to determine. In this study, we used adeno-associated viral vectors to elevate circulating levels of the tumorkines IL6 and/or activin A in animals in the absence of tumors as a tactic to evaluate hypothesized roles in cachexia development. Mice with elevated levels of IL6 exhibited 8.1% weight loss after 9 weeks, whereas mice with elevated levels of activin A lost 11% of their body weight. Co-elevation of both tumorkines to levels approximating those observed in cancer cachexia models induced a more rapid and profound body weight loss of 15.4%. Analysis of body composition revealed that activin A primarily triggered loss of lean mass, whereas IL6 was a major mediator of fat loss. Histologic and transcriptional analysis of affected organs/tissues (skeletal muscle, fat, and liver) identified interactions between the activin A and IL6 signaling pathways. For example, IL6 exacerbated the detrimental effects of activin A in skeletal muscle, whereas activin A curbed the IL6-induced acute-phase response in liver. This study presents a useful model to deconstruct cachexia, opening a pathway to determining which tumorkines are best targeted to slow/reverse this devastating condition in cancer patients. Cancer Res; 76(18); 5372-82. ©2016 AACR. ©2016 American Association for Cancer Research.

Association of gain and loss of weight before and after menopause with risk of postmenopausal breast cancer in the Iowa women's health study.

PubMed

Harvie, Michelle; Howell, Anthony; Vierkant, Robert A; Kumar, Nagi; Cerhan, James R; Kelemen, Linda E; Folsom, Aaron R; Sellers, Thomas A

2005-03-01

Obesity and adult weight gain are well-established risk factors for postmenopausal breast cancer. Although there are a few studies demonstrating the contribution of adult weight gain to breast cancer risk, whether weight gain during a critical time period is specifically associated with risk, or whether subsequent weight loss among women who have gained weight will reduce the excess risk, is not firmly established. We investigated the association of changes in weight (loss or gain in excess of 5% of body weight) using two risk factor models: (a) age 18 to 30 years and age 30 years to menopause and (b) age 30 years to menopause and after the menopause to the baseline study in 1986 on risk of postmenopausal breast cancer in a prospective cohort of 33,660 postmenopausal women in Iowa. Over 15 years of follow-up, 1,987 cases of breast cancer occurred. Data were analyzed using proportional hazards regression models adjusted for established breast cancer risk factors. The most frequently observed pattern of body weight over time was a consistent increase; these women were observed to have the highest rates of breast cancer and served as the reference category for all comparisons. The lowest-risk groups were (a) women who maintained or lost weight from age 18 to 30 years and then lost weight from age 30 years to menopause [risk ratio (RR), 0.36; 95% confidence interval (95% CI), 0.22-0.60] and (b) women who maintained or lost weight from age 30 years to menopause and then lost weight after the menopause (RR, 0.48; 95% CI, 0.22-0.65). Women who gained weight from age 30 years to menopause but then lost weight after the menopause experienced risk reductions (RR, 0.77; 95% CI, 0.64-0.92) although perhaps slightly smaller in magnitude than women who maintained their weight in both time intervals (RR, 0.63; 95% CI, 0.55-0.73). Women who gained weight from age 18 to 30 years and then lost weight from age 30 years to menopause had comparable risk reductions (RR, 0.61; 95% CI, 0

Comparative and Evolutionary Analysis of the HES/HEY Gene Family Reveal Exon/Intron Loss and Teleost Specific Duplication Events

PubMed Central

Ma, Zhaowu; Zhou, Yang; Abbood, Nibras Najm; Liu, Jianfeng; Su, Li; Jia, Haibo; Guo, An-Yuan

2012-01-01

Background HES/HEY genes encode a family of basic helix-loop-helix (bHLH) transcription factors with both bHLH and Orange domain. HES/HEY proteins are direct targets of the Notch signaling pathway and play an essential role in developmental decisions, such as the developments of nervous system, somitogenesis, blood vessel and heart. Despite their important functions, the origin and evolution of this HES/HEY gene family has yet to be elucidated. Methods and Findings In this study, we identified genes of the HES/HEY family in representative species and performed evolutionary analysis to elucidate their origin and evolutionary process. Our results showed that the HES/HEY genes only existed in metazoans and may originate from the common ancestor of metazoans. We identified HES/HEY genes in more than 10 species representing the main lineages. Combining the bHLH and Orange domain sequences, we constructed the phylogenetic trees by different methods (Bayesian, ML, NJ and ME) and classified the HES/HEY gene family into four groups. Our results indicated that this gene family had undergone three expansions, which were along with the origins of Eumetazoa, vertebrate, and teleost. Gene structure analysis revealed that the HES/HEY genes were involved in exon and/or intron loss in different species lineages. Genes of this family were duplicated in bony fishes and doubled than other vertebrates. Furthermore, we studied the teleost-specific duplications in zebrafish and investigated the expression pattern of duplicated genes in different tissues by RT-PCR. Finally, we proposed a model to show the evolution of this gene family with processes of expansion, exon/intron loss, and motif loss. Conclusions Our study revealed the evolution of HES/HEY gene family, the expression and function divergence of duplicated genes, which also provide clues for the research of Notch function in development. This study shows a model of gene family analysis with gene structure evolution and

Effects of weight loss interventions for adults who are obese on mortality, cardiovascular disease, and cancer: systematic review and meta-analysis.

PubMed

Ma, Chenhan; Avenell, Alison; Bolland, Mark; Hudson, Jemma; Stewart, Fiona; Robertson, Clare; Sharma, Pawana; Fraser, Cynthia; MacLennan, Graeme

2017-11-14

Objective  To assess whether weight loss interventions for adults with obesity affect all cause, cardiovascular, and cancer mortality, cardiovascular disease, cancer, and body weight. Design  Systematic review and meta-analysis of randomised controlled trials (RCTs) using random effects, estimating risk ratios, and mean differences. Heterogeneity investigated using Cochran's Q and I 2 statistics. Quality of evidence assessed by GRADE criteria. Data sources  Medline, Embase, the Cochrane Central Register of Controlled Trials, and full texts in our trials' registry for data not evident in databases. Authors were contacted for unpublished data. Eligibility criteria for selecting studies  RCTs of dietary interventions targeting weight loss, with or without exercise advice or programmes, for adults with obesity and follow-up ≥1 year. Results  54 RCTs with 30 206 participants were identified. All but one trial evaluated low fat, weight reducing diets. For the primary outcome, high quality evidence showed that weight loss interventions decrease all cause mortality (34 trials, 685 events; risk ratio 0.82, 95% confidence interval 0.71 to 0.95), with six fewer deaths per 1000 participants (95% confidence interval two to 10). For other primary outcomes moderate quality evidence showed an effect on cardiovascular mortality (eight trials, 134 events; risk ratio 0.93, 95% confidence interval 0.67 to 1.31), and very low quality evidence showed an effect on cancer mortality (eight trials, 34 events; risk ratio 0.58, 95% confidence interval 0.30 to 1.11). Twenty four trials (15 176 participants) reported high quality evidence on participants developing new cardiovascular events (1043 events; risk ratio 0.93, 95% confidence interval 0.83 to 1.04). Nineteen trials (6330 participants) provided very low quality evidence on participants developing new cancers (103 events; risk ratio 0.92, 95% confidence interval 0.63 to 1.36). Conclusions  Weight reducing diets, usually low

The Impact of SMAD4 Loss on Outcome in Patients with Advanced Pancreatic Cancer Treated with Systemic Chemotherapy

PubMed Central

Ormanns, Steffen; Haas, Michael; Remold, Anna; Kruger, Stephan; Holdenrieder, Stefan; Kirchner, Thomas; Heinemann, Volker; Boeck, Stefan

2017-01-01

The role of the tumor suppressor mothers against decapentaplegic homolog 4 (SMAD4) has not yet been defined in patients (pts) with advanced pancreatic cancer (aPC). This translational research study was designed to evaluate the impact of tumoral SMAD4 loss on clinicopathological parameters and outcome in PC patients receiving palliative chemotherapy. Using immunohistochemistry, we examined SMAD4 expression in tumor tissue of 143 aPC pts treated within completed prospective clinical and biomarker trials. In uni- and multivariate analyses, SMAD4 expression status was correlated to clinicopathological patient characteristics and outcome. At chemotherapy initiation, 128 pts had metastatic PC; most pts (n = 99) received a gemcitabine-based regimen. SMAD4 loss was detected in 92 pts (64%); patient characteristics such as gender, age, tumor grading, disease stage or number of metastatic sites had no significant impact on tumoral SMAD4 status. In univariate analyses, SMAD4 loss had no impact on overall survival (hazard ratio (HR) 1.008, p = 0.656); however, we observed a prolonged progression-free survival (HR 1.565, p = 0.038) in pts with tumoral SMAD4 loss. This finding was confirmed in multivariate analyses (HR 1.790, p = 0.040), but only for gemcitabine-treated pts. In contrast to previous studies in resectable PC, loss of SMAD4 expression was not associated with a negative outcome in patients with advanced PC receiving systemic chemotherapy. PMID:28534865

Preoperative weight loss program involving a 20-day very low-calorie diet for obesity before laparoscopic gastrectomy for gastric cancer.

PubMed

Inoue, Kentaro; Yoshiuchi, Sawako; Yoshida, Mika; Nakamura, Natsuko; Nakajima, Sachiko; Kitamura, Akiko; Mouri, Keiko; Michiura, Taku; Mukaide, Hiromi; Ozaki, Takashi; Miki, Hirokazu; Yanagimoto, Hiroaki; Satoi, Sohei; Kaibori, Masaki; Hamada, Madoka; Kimura, Yutaka; Kon, Masanori

2018-03-25

The increased visceral fat in patients with obesity can increase the technical difficulty of surgery. This study was performed to evaluate a preoperative 20-day very low-calorie diet for obesity before laparoscopic gastrectomy for gastric cancer. This prospective single-center study involved patients with obesity who were planning to undergo laparoscopic gastrectomy for gastric cancer. Obesity was defined according to the Japanese criteria: BMI ≥25 kg/m 2 or waist circumference ≥85 cm in men and ≥90 cm in women. The patients underwent a preoperative 20-day very low-calorie diet and received nutritional counseling. Weight loss, body composition, visceral fat mass, and operative outcomes were evaluated. Thirty-three patients were enrolled from September 2013 to August 2015. Their median age was 71 years, and 78.8% were men. Their median bodyweight and BMI were 72.3 kg (range, 53.8-82.5 kg) and 26.0 kg/m 2 (range, 23.5-31.0 kg/m 2 ), respectively. The patients achieved a mean weight loss of 4.5% (95% confidence interval [CI]: 3.8-5.1), corresponding to 3.2 kg (95%CI: 2.7-3.7 kg). Body fat mass was significantly decreased by a mean of 2.5 kg (95%CI: 1.9-3.1), whereas skeletal muscle mass was unaffected (mean: -0.20 kg [95%CI: -0.55-0.15]). The visceral fat mass reduction rate was high as 16.8% (range, 11.6%-22.0%). All patients underwent laparoscopic gastrectomy as planned. Severe postoperative morbidity (Clavien-Dindo grade ≥III) was seen in only one patient (3.0%). The preoperative 20-day very low-calorie diet weight loss program is promising for the treatment of obesity before laparoscopic gastrectomy for gastric cancer. © 2018 The Authors. Asian Journal of Endoscopic Surgery published by John Wiley & Sons Ltd on behalf of Japan Society for Endoscopic Surgery, Asia Endosurgery Task Force.

Genomic pathway analysis reveals that EZH2 and HDAC4 represent mutually exclusive epigenetic pathways across human cancers

PubMed Central

2013-01-01

aberrations in genes from the TGF and phosphatidylinositol pathways and HDAC4 activation with aberrations in inflammatory and chemokine related genes. Conclusion Gene expression patterns can reveal the activation level of epigenetic pathways. Epigenetic pathways define biologically relevant subsets of human cancers. EZH2 activation and HDAC4 activation correlate with growth factor signaling and inflammation, respectively, and represent two distinct states for cancer cells. This understanding may allow us to identify targetable drivers in these cancer subsets. PMID:24079712

Intestinal Cancer

MedlinePlus

... connects your stomach to your large intestine. Intestinal cancer is rare, but eating a high-fat diet ... increase your risk. Possible signs of small intestine cancer include Abdominal pain Weight loss for no reason ...

Loss of GPER identifies new targets for therapy among a subgroup of ERα-positive endometrial cancer patients with poor outcome

PubMed Central

Krakstad, C; Trovik, J; Wik, E; Engelsen, I B; Werner, H M J; Birkeland, E; Raeder, M B; Øyan, A M; Stefansson, I M; Kalland, K H; Akslen, L A; Salvesen, H B

2012-01-01

Background: The G protein-coupled oestrogen receptor, GPER, has been suggested as an alternative oestrogen receptor. Our purpose was to investigate the potential of GPER as a prognostic and predictive marker in endometrial carcinoma and to search for new drug candidates to improve treatment of aggressive disease. Materials and method: A total of 767 primary endometrial carcinomas derived from three patient series, including an external dataset, were studied for protein and mRNA expression levels to investigate and validate if GPER loss identifies poor prognosis and new targets for therapy in endometrial carcinoma. Gene expression levels, according to ERα/GPER status, were used to search the connectivity map database for small molecular inhibitors with potential for treatment of metastatic disease for receptor status subgroups. Results: Loss of GPER protein is significantly correlated with low GPER mRNA, high FIGO stage, non-endometrioid histology, high grade, aneuploidy and ERα loss (all P-values ⩽0.05). Loss of GPER among ERα-positive patients identifies a subgroup with poor prognosis that until now has been unrecognised, with reduced 5-year survival from 93% to 76% (P=0.003). Additional loss of GPER from primary to metastatic lesion counterparts further supports that loss of GPER is associated with disease progression. Conclusion: These results support that GPER status adds clinically relevant information to ERα status in endometrial carcinoma and suggest a potential for new inhibitors in the treatment of metastatic endometrial cancers with ERα expression and GPER loss. PMID:22415229

Emma: Art Therapy Illustrating Personal and Universal Images of Loss.

ERIC Educational Resources Information Center

Mango, Christina

1992-01-01

Art work produced by geriatric patient on psychiatric ward illustrated metaphors of loss. After three months, patient was diagnosed with liver cancer; she died three weeks later. All work was produced before cancer diagnosis, yet it showed similarities to work by cancer patients, suggesting that client unconsciously knew she was dying and worked…

Loss of Nrf2 promotes alveolar type 2 cell loss in irradiated, fibrotic lung.

PubMed

Traver, Geri; Mont, Stacey; Gius, David; Lawson, William E; Ding, George X; Sekhar, Konjeti R; Freeman, Michael L

2017-11-01

The development of radiation-induced pulmonary fibrosis represents a critical clinical issue limiting delivery of therapeutic doses of radiation to non-small cell lung cancer. Identification of the cell types whose injury initiates a fibrotic response and the underlying biological factors that govern that response are needed for developing strategies that prevent or mitigate fibrosis. C57BL/6 mice (wild type, Nrf2 null, Nrf2 flox/flox , and Nrf2 Δ/Δ ; SPC-Cre) were administered a thoracic dose of 12Gy and allowed to recover for 250 days. Whole slide digital and confocal microscopy imaging of H&E, Masson's trichrome and immunostaining were used to assess tissue remodeling, collagen deposition and cell renewal/mobilization during the regenerative process. Histological assessment of irradiated, fibrotic wild type lung revealed significant loss of alveolar type 2 cells 250 days after irradiation. Type 2 cell loss and the corresponding development of fibrosis were enhanced in the Nrf2 null mouse. Yet, conditional deletion of Nrf2 in alveolar type 2 cells in irradiated lung did not impair type 2 cell survival nor yield an increased fibrotic phenotype. Instead, radiation-induced ΔNp63 stem/progenitor cell mobilization was inhibited in the Nrf2 null mouse while the propensity for radiation-induced myofibroblasts derived from alveolar type 2 cells was magnified. In summary, these results indicate that Nrf2 is an important regulator of irradiated lung's capacity to maintain alveolar type 2 cells, whose injury can initiate a fibrotic phenotype. Loss of Nrf2 inhibits ΔNp63 stem/progenitor mobilization, a key event for reconstitution of injured lung, while promoting a myofibroblast phenotype that is central for fibrosis. Copyright © 2017 Elsevier Inc. All rights reserved.

ATM-Deficient Colorectal Cancer Cells Are Sensitive to the PARP Inhibitor Olaparib.

PubMed

Wang, Chen; Jette, Nicholas; Moussienko, Daniel; Bebb, D Gwyn; Lees-Miller, Susan P

2017-04-01

The ataxia telangiectasia mutated (ATM) protein kinase plays a central role in the cellular response to DNA damage. Loss or inactivation of both copies of the ATM gene (ATM) leads to ataxia telangiectasia, a devastating childhood condition characterized by neurodegeneration, immune deficiencies, and cancer predisposition. ATM is also absent in approximately 40% of mantle cell lymphomas (MCLs), and we previously showed that MCL cell lines with loss of ATM are sensitive to poly-ADP ribose polymerase (PARP) inhibitors. Next-generation sequencing of patient tumors has revealed that ATM is altered in many human cancers including colorectal, lung, prostate, and breast. Here, we show that the colorectal cancer cell line SK-CO-1 lacks detectable ATM protein expression and is sensitive to the PARP inhibitor olaparib. Similarly, HCT116 colorectal cancer cells with shRNA depletion of ATM are sensitive to olaparib, and depletion of p53 enhances this sensitivity. Moreover, HCT116 cells are sensitive to olaparib in combination with the ATM inhibitor KU55933, and sensitivity is enhanced by deletion of p53. Together our studies suggest that PARP inhibitors may have potential for treating colorectal cancer with ATM dysfunction and/or colorectal cancer with mutation of p53 when combined with an ATM kinase inhibitor. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Single cell sequencing reveals heterogeneity within ovarian cancer epithelium and cancer associated stromal cells.

PubMed

Winterhoff, Boris J; Maile, Makayla; Mitra, Amit Kumar; Sebe, Attila; Bazzaro, Martina; Geller, Melissa A; Abrahante, Juan E; Klein, Molly; Hellweg, Raffaele; Mullany, Sally A; Beckman, Kenneth; Daniel, Jerry; Starr, Timothy K

2017-03-01

The purpose of this study was to determine the level of heterogeneity in high grade serous ovarian cancer (HGSOC) by analyzing RNA expression in single epithelial and cancer associated stromal cells. In addition, we explored the possibility of identifying subgroups based on pathway activation and pre-defined signatures from cancer stem cells and chemo-resistant cells. A fresh, HGSOC tumor specimen derived from ovary was enzymatically digested and depleted of immune infiltrating cells. RNA sequencing was performed on 92 single cells and 66 of these single cell datasets passed quality control checks. Sequences were analyzed using multiple bioinformatics tools, including clustering, principle components analysis, and geneset enrichment analysis to identify subgroups and activated pathways. Immunohistochemistry for ovarian cancer, stem cell and stromal markers was performed on adjacent tumor sections. Analysis of the gene expression patterns identified two major subsets of cells characterized by epithelial and stromal gene expression patterns. The epithelial group was characterized by proliferative genes including genes associated with oxidative phosphorylation and MYC activity, while the stromal group was characterized by increased expression of extracellular matrix (ECM) genes and genes associated with epithelial-to-mesenchymal transition (EMT). Neither group expressed a signature correlating with published chemo-resistant gene signatures, but many cells, predominantly in the stromal subgroup, expressed markers associated with cancer stem cells. Single cell sequencing provides a means of identifying subpopulations of cancer cells within a single patient. Single cell sequence analysis may prove to be critical for understanding the etiology, progression and drug resistance in ovarian cancer. Copyright © 2017 Elsevier Inc. All rights reserved.

A comprehensive custom panel design for routine hereditary cancer testing: preserving control, improving diagnostics and revealing a complex variation landscape.

PubMed

Castellanos, Elisabeth; Gel, Bernat; Rosas, Inma; Tornero, Eva; Santín, Sheila; Pluvinet, Raquel; Velasco, Juan; Sumoy, Lauro; Del Valle, Jesús; Perucho, Manuel; Blanco, Ignacio; Navarro, Matilde; Brunet, Joan; Pineda, Marta; Feliubadaló, Lidia; Capellá, Gabi; Lázaro, Conxi; Serra, Eduard

2017-01-04

We wanted to implement an NGS strategy to globally analyze hereditary cancer with diagnostic quality while retaining the same degree of understanding and control we had in pre-NGS strategies. To do this, we developed the I2HCP panel, a custom bait library covering 122 hereditary cancer genes. We improved bait design, tested different NGS platforms and created a clinically driven custom data analysis pipeline. The I2HCP panel was developed using a training set of hereditary colorectal cancer, hereditary breast and ovarian cancer and neurofibromatosis patients and reached an accuracy, analytical sensitivity and specificity greater than 99%, which was maintained in a validation set. I2HCP changed our diagnostic approach, involving clinicians and a genetic diagnostics team from panel design to reporting. The new strategy improved diagnostic sensitivity, solved uncertain clinical diagnoses and identified mutations in new genes. We assessed the genetic variation in the complete set of hereditary cancer genes, revealing a complex variation landscape that coexists with the disease-causing mutation. We developed, validated and implemented a custom NGS-based strategy for hereditary cancer diagnostics that improved our previous workflows. Additionally, the existence of a rich genetic variation in hereditary cancer genes favors the use of this panel to investigate their role in cancer risk.

Grief, Bereavement, and Coping With Loss (PDQ®)—Patient Version

Cancer.gov

Grief, bereavement (mourning), and coping with loss are common challenges following the loss of a loved one from cancer. Learn about coping and the grief process in adults and children in this expert-reviewed information summary.

Comprehensive analysis of miRNAs expression profiles revealed potential key miRNA/mRNAs regulating colorectal cancer stem cell self-renewal.

PubMed

Xu, Peng; Wang, Junhua; Sun, Bo; Xiao, Zhongdang

2018-05-20

Self-renewal is essential for the malignant biological behaviors of colorectal cancer stem cells. While the self-renewal molecular mechanisms of colorectal cancer stem cells are not yet fully understood. Recently, miRNAs are reported to be relevant to the self-renewal ability of cancer stem cells. In this study, we first isolated colorectal cancer stem cell from colorectal cancer cell line HCT-116 by 1% low serum culture. Then we conducted a comprehensive analysis based on the miRNAs profiles data of both colorectal cancer stem cells and normal cultured colorectal cancer cells. Pathway analysis revealed multiple pathways including Jak-STAT, TGF-beta, PI3K-Akt and MAPK signaling pathway that are correlated to colorectal cancer. Further, we constructed a miRNA-mRNA network, based on which, several miRNA/mRNA pairs were ranked according to their impact index to the self-renewal of colorectal cancer stem cells. Further biological experiment showed that up-regulation of miR-92a-3p led to cell cycle arrest and reduced colony formation. This work provides clues to find the new potential biomarkers for colorectal cancer stem cell diagnosis and select effective miRNAs for targeted therapy. Copyright © 2018 Elsevier B.V. All rights reserved.

Oestrogen receptor negativity in breast cancer: a cause or consequence?

PubMed Central

Gajulapalli, Vijaya Narasihma Reddy; Malisetty, Vijaya Lakshmi; Chitta, Suresh Kumar; Manavathi, Bramanandam

2016-01-01

Endocrine resistance, which occurs either by de novo or acquired route, is posing a major challenge in treating hormone-dependent breast cancers by endocrine therapies. The loss of oestrogen receptor α (ERα) expression is the vital cause of establishing endocrine resistance in this subtype. Understanding the mechanisms that determine the causes of this phenomenon are therefore essential to reduce the disease efficacy. But how we negate oestrogen receptor (ER) negativity and endocrine resistance in breast cancer is questionable. To answer that, two important approaches are considered: (1) understanding the cellular origin of heterogeneity and ER negativity in breast cancers and (2) characterization of molecular regulators of endocrine resistance. Breast tumours are heterogeneous in nature, having distinct molecular, cellular, histological and clinical behaviour. Recent advancements in perception of the heterogeneity of breast cancer revealed that the origin of a particular mammary tumour phenotype depends on the interactions between the cell of origin and driver genetic hits. On the other hand, histone deacetylases (HDACs), DNA methyltransferases (DNMTs), miRNAs and ubiquitin ligases emerged as vital molecular regulators of ER negativity in breast cancers. Restoring response to endocrine therapy through re-expression of ERα by modulating the expression of these molecular regulators is therefore considered as a relevant concept that can be implemented in treating ER-negative breast cancers. In this review, we will thoroughly discuss the underlying mechanisms for the loss of ERα expression and provide the future prospects for implementing the strategies to negate ER negativity in breast cancers. PMID:27884978

PRMT1-Mediated Translation Regulation Is a Crucial Vulnerability of Cancer.

PubMed

Hsu, Jessie Hao-Ru; Hubbell-Engler, Benjamin; Adelmant, Guillaume; Huang, Jialiang; Joyce, Cailin E; Vazquez, Francisca; Weir, Barbara A; Montgomery, Philip; Tsherniak, Aviad; Giacomelli, Andrew O; Perry, Jennifer A; Trowbridge, Jennifer; Fujiwara, Yuko; Cowley, Glenn S; Xie, Huafeng; Kim, Woojin; Novina, Carl D; Hahn, William C; Marto, Jarrod A; Orkin, Stuart H

2017-09-01

Through an shRNA screen, we identified the protein arginine methyltransferase Prmt1 as a vulnerable intervention point in murine p53/Rb-null osteosarcomas, the human counterpart of which lacks effective therapeutic options. Depletion of Prmt1 in p53-deficient cells impaired tumor initiation and maintenance in vitro and in vivo Mechanistic studies reveal that translation-associated pathways were enriched for Prmt1 downstream targets, implicating Prmt1 in translation control. In particular, loss of Prmt1 led to a decrease in arginine methylation of the translation initiation complex, thereby disrupting its assembly and inhibiting translation. p53/Rb-null cells were sensitive to p53-induced translation stress, and analysis of human cancer cell line data from Project Achilles further revealed that Prmt1 and translation-associated pathways converged on the same functional networks. We propose that targeted therapy against Prmt1 and its associated translation-related pathways offer a mechanistic rationale for treatment of osteosarcomas and other cancers that exhibit dependencies on translation stress response. Cancer Res; 77(17); 4613-25. ©2017 AACR . ©2017 American Association for Cancer Research.

ActRII blockade protects mice from cancer cachexia and prolongs survival in the presence of anti-cancer treatments.

PubMed

Hatakeyama, Shinji; Summermatter, Serge; Jourdain, Marie; Melly, Stefan; Minetti, Giulia C; Lach-Trifilieff, Estelle

2016-01-01

Cachexia affects the majority of patients with advanced cancer and is associated with reduced treatment tolerance, response to therapy, quality of life, and life expectancy. Cachectic patients with advanced cancer often receive anti-cancer therapies against their specific cancer type as a standard of care, and whether specific ActRII inhibition is efficacious when combined with anti-cancer agents has not been elucidated yet. In this study, we evaluated interactions between ActRII blockade and anti-cancer agents in CT-26 mouse colon cancer-induced cachexia model. CDD866 (murinized version of bimagrumab) is a neutralizing antibody against the activin receptor type II (ActRII) preventing binding of ligands such as myostatin and activin A, which are involved in cancer cachexia. CDD866 was evaluated in association with cisplatin as a standard cytotoxic agent or with everolimus, a molecular-targeted agent against mammalian target of rapamycin (mTOR). In the early studies, the treatment effect on cachexia was investigated, and in the additional studies, the treatment effect on progression of cancer and the associated cachexia was evaluated using body weight loss or tumor volume as interruption criteria. Cisplatin accelerated body weight loss and tended to exacerbate skeletal muscle loss in cachectic animals, likely due to some toxicity of this anti-cancer agent. Administration of CDD866 alone or in combination with cisplatin protected from skeletal muscle weight loss compared to animals receiving only cisplatin, corroborating that ActRII inhibition remains fully efficacious under cisplatin treatment. In contrast, everolimus treatment alone significantly protected the tumor-bearing mice against skeletal muscle weight loss caused by CT-26 tumor. CDD866 not only remains efficacious in the presence of everolimus but also showed a non-significant trend for an additive effect on reversing skeletal muscle weight loss. Importantly, both combination therapies slowed down time

Selective reversible inhibition of autophagy in hypoxic breast cancer cells promotes pulmonary metastasis

PubMed Central

Dower, Christopher M.; Bhat, Neema; Wang, Edward W.; Wang, Hong-Gang

2016-01-01

Autophagy influences how cancer cells respond to nutrient deprivation and hypoxic stress, two hallmarks of the tumor microenvironment (TME). In this study, we explored the impact of autophagy on the pathophysiology of breast cancer cells, using a novel hypoxia-dependent, reversible dominant negative strategy to regulate autophagy at the cellular level within the TME. Suppression of autophagy via hypoxia-induced expression of the kinase-dead unc-51 like autophagy activating kinase (ULK1) mutant K46N increased lung metastases in MDA-MB-231 xenograft mouse models. Consistent with this effect, expressing a dominant-negative mutant of ULK1 or ATG4b or a ULK1-targeting shRNA facilitated cell migration in vitro. Functional proteomic and transcriptome analysis revealed that loss of hypoxia-regulated autophagy promotes metastasis via induction of the fibronectin integrin signaling axis. Indeed, loss of ULK1 function increased fibronectin deposition in the hypoxic TME. Together, our results indicated that hypoxia-regulated autophagy suppresses metastasis in breast cancer by preventing tumor fibrosis. These results also suggest cautions in the development of autophagy-based strategies for cancer treatment. PMID:28115361

Integrative Genomics Reveals Mechanisms of Copy Number Alterations Responsible for Transcriptional Deregulation in Colorectal Cancer

PubMed Central

Camps, Jordi; Nguyen, Quang Tri; Padilla-Nash, Hesed M.; Knutsen, Turid; McNeil, Nicole E.; Wangsa, Danny; Hummon, Amanda B.; Grade, Marian; Ried, Thomas; Difilippantonio, Michael J.

2016-01-01

To evaluate the mechanisms and consequences of chromosomal aberrations in colorectal cancer (CRC), we used a combination of spectral karyotyping, array comparative genomic hybridization (aCGH), and array-based global gene expression profiling on 31 primary carcinomas and 15 established cell lines. Importantly, aCGH showed that the genomic profiles of primary tumors are recapitulated in the cell lines. We revealed a preponderance of chromosome breakpoints at sites of copy number variants (CNVs) in the CRC cell lines, a novel mechanism of DNA breakage in cancer. The integration of gene expression and aCGH led to the identification of 157 genes localized within high-level copy number changes whose transcriptional deregulation was significantly affected across all of the samples, thereby suggesting that these genes play a functional role in CRC. Genomic amplification at 8q24 was the most recurrent event and led to the overexpression of MYC and FAM84B. Copy number dependent gene expression resulted in deregulation of known cancer genes such as APC, FGFR2, and ERBB2. The identification of only 36 genes whose localization near a breakpoint could account for their observed deregulated expression demonstrates that the major mechanism for transcriptional deregulation in CRC is genomic copy number changes resulting from chromosomal aberrations. PMID:19691111

Cytoplasmic Drosha Is Aberrant in Precancerous Lesions of Gastric Carcinoma and Its Loss Predicts Worse Outcome for Gastric Cancer Patients.

PubMed

Zhang, Hailong; Hou, Yixuan; Xu, Liyun; Zeng, Zongyue; Wen, Siyang; Du, Yan-E; Sun, Kexin; Yin, Jiali; Lang, Lei; Tang, Xiaoli; Liu, Manran

2016-04-01

The nuclear localization of Drosha is critical for its function as a microRNA maturation regulator. Dephosphorylation of Drosha at serine 300 and serine 302 disrupts its nuclear localization, and aberrant distribution of Drosha has been detected in some tumors. The purpose of the present study was to assess cytoplasmic/nuclear Drosha expression in gastric cancer carcinogenesis and progression. Drosha expression and its subcellular location was investigated by immunohistochemical staining of a set of tissue microarrays composed of normal adjacent tissues (374), chronic gastritis (137), precancerous lesions (94), and gastric adenocarcinoma (829) samples, and in gastric cancer cell lines with varying differentiation by immunofluorescence and western blot assay. Gradual loss of cytoplasmic Drosha was accompanied by tumor progression in both gastric cancer tissues and cell lines, and was inversely associated with tumor volume (P = 0.002), tumor grade (P < 0.001), tumor stage (P = 0.018), and distant metastasis (P = 0.026). Aberrant high levels of cytoplasmic Drosha were apparent in intestinal metaplasia and dysplasia tissues. The levels of nuclear Drosha were sharply decreased in chronic gastritis and maintained through precancerous lesions to gastric cancer. High levels of cytoplasmic Drosha predicted longer survival (LR = 7.088, P = 0.008) in gastric cancer patients. Our data provide novel insights into gastric cancer that cytoplasmic Drosha potentially plays a role in preventing carcinogenesis and tumor progression, and may be an independent predictor of patient outcome.

Endogenous Voltage Potentials and the Microenvironment: Bioelectric Signals that Reveal, Induce and Normalize Cancer

PubMed Central

Chernet, Brook; Levin, Michael

2014-01-01

Cancer may be a disease of geometry: a misregulation of the field of information that orchestrates individual cells’ activities towards normal anatomy. Recent work identified molecular mechanisms underlying a novel system of developmental control: bioelectric gradients. Endogenous spatio-temporal differences in resting potential of non-neural cells provide instructive cues for cell regulation and complex patterning during embryogenesis and regeneration. It is now appreciated that these cues are an important layer of the dysregulation of cell: cell interactions that leads to cancer. Abnormal depolarization of resting potential (Vmem) is a convenient marker for neoplasia and activates a metastatic phenotype in genetically-normal cells in vivo. Moreover, oncogene expression depolarizes cells that form tumor-like structures, but is unable to form tumors if this depolarization is artificially prevented by misexpression of hyperpolarizing ion channels. Vmem triggers metastatic behaviors at considerable distance, mediated by transcriptional and epigenetic effects of electrically-modulated flows of serotonin and butyrate. While in vivo data on voltages in carcinogenesis comes mainly from the amphibian model, unbiased genetic screens and network profiling in rodents and human tissues reveal several ion channel proteins as bona fide oncogene and promising targets for cancer drug development. However, we propose that a focus on specific channel genes is just the tip of the iceberg. Bioelectric state is determined by post-translational gating of ion channels, not only from genetically-specified complements of ion translocators. A better model is a statistical dynamics view of spatial Vmem gradients. Cancer may not originate at the single cell level, since gap junctional coupling results in multi-cellular physiological networks with multiple stable attractors in bioelectrical state space. New medical applications await a detailed understanding of the mechanisms by which organ

Epsin is required for Dishevelled stability and Wnt signaling activation in colon cancer development