| 1. |
- Fang, Fang, et al.
(författare)
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Risk of infection-related cancers after the loss of a child : a follow-up study in Sweden
- 2011
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Ingår i: Cancer Research. - Philadelphia, USA : American Association for Cancer Research. - 0008-5472 .- 1538-7445. ; 71:1, s. 116-22
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Tidskriftsartikel (refereegranskat)abstract
- It is unknown whether severe emotional stress due to loss of a child influences the risk of cancers susceptible to immune modulation such as infection-related cancers. We conducted a historic cohort study in 1990 to 2004 on the basis of the Swedish Multi-Generation Register including 4,687,073 parents. Death of a child was identified through the Causes of Death Register. Poisson regression was used to derive the relative risks (RR) and 95% confidence intervals (CI) of infection-related cancers, comparing the incidence rates of parents who lost a child with those who never lost a child. A total of 101,306 parents (2%) had lost a child during follow-up, among whom 1,608 subsequently developed infection-related cancers. After adjustment for age, sex, calendar year, educational level, and civil status, the overall RR of 14 cancers studied was 1.07 (95% CI: 1.02-1.12). Parents who lost a child were particularly at a higher risk for cancers potentially associated with human papilloma virus (HPV) infection such as cervical cancer (RR: 1.46; 95% CI: 1.17-1.80). Higher RRs for most cancers were obtained within 5 years after child loss and excess risk for liver and stomach cancers was confined to that period. No association was observed for lymphoma and nonmelanoma skin cancer at any time point after child loss. Although potential confounding by unmeasured factors cannot be ruled out, our findings lend support to the hypothesis that severe life stressors, such as child loss, may raise the risk for several, chiefly HPV-related, cancers.
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| 2. |
- Fiorentino, Michelangelo, et al.
(författare)
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Immunohistochemical Expression of BRCA1 and Lethal Prostate Cancer
- 2010
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Ingår i: Cancer Research. - Philadelphia, USA : American Association for Cancer Research. - 0008-5472 .- 1538-7445. ; 70:8, s. 3136-3139
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Tidskriftsartikel (refereegranskat)abstract
- BRCA1 functions as a tumor suppressor; recent work suggests that BRCA1 may also induce cell cycle arrest to allow for DNA repair. We hypothesized that BRCA1 expression in prostate tumor tissue may be associated with prostate cancer progression through regulation of the cell cycle. We used immunohistochemistry to evaluate BRCA1 protein expression in archival tumor samples from 393 prostate cancer cases in the Physicians' Health Study. The men were followed prospectively from diagnosis to development of metastases and mortality. Fifteen percent of tumors stained positive for BRCA1. BRCA1-positive tumors had substantially increased tumor proliferation index compared with negative tumors (47.0 Ki67-positive nuclei versus 10.3, P = 0.0016) and were more likely to develop lethal cancer compared with BRCA1-negative tumors (hazard ratio, 4.6; 95% confidence interval, 2.4-8.7). These findings strengthen the hypothesis that BRCA1 plays a role in cell cycle control and show that BRCA1 is a marker of clinical prostate cancer prognosis. Cancer Res; 70(8); 3136-9. (C) 2010 AACR.
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| 3. |
- Hilvo, Mika, et al.
(författare)
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Novel theranostic opportunities offered by characterization of altered membrane lipid metabolism in breast cancer progression
- 2011
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Ingår i: Cancer Research. - Philadelphia, PA, USA : American Association for Cancer Research. - 0008-5472 .- 1538-7445. ; 71:9, s. 3236-45
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Tidskriftsartikel (refereegranskat)abstract
- Activation of lipid metabolism is an early event in carcinogenesis and a central hallmark of many cancers. However, the precise molecular composition of lipids in tumors remains generally poorly characterized. The aim of the present study was to analyze the global lipid profiles of breast cancer, integrate the results to protein expression, and validate the findings by functional experiments. Comprehensive lipidomics was conducted in 267 human breast tissues using ultraperformance liquid chromatography/ mass spectrometry. The products of de novo fatty acid synthesis incorporated into membrane phospholipids, such as palmitate-containing phosphatidylcholines, were increased in tumors as compared with normal breast tissues. These lipids were associated with cancer progression and patient survival, as their concentration was highest in estrogen receptor-negative and grade 3 tumors. In silico transcriptomics database was utilized in investigating the expression of lipid metabolism related genes in breast cancer, and on the basis of these results, the expression of specific proteins was studied by immunohistochemistry. Immunohistochemical analyses showed that several genes regulating lipid metabolism were highly expressed in clinical breast cancer samples and supported also the lipidomics results. Gene silencing experiments with seven genes [ACACA (acetyl-CoA carboxylase α), ELOVL1 (elongation of very long chain fatty acid-like 1), FASN (fatty acid synthase), INSIG1 (insulin-induced gene 1), SCAP (sterol regulatory element-binding protein cleavage-activating protein), SCD (stearoyl-CoA desaturase), and THRSP (thyroid hormone-responsive protein)] indicated that silencing of multiple lipid metabolism-regulating genes reduced the lipidomic profiles and viability of the breast cancer cells. Taken together, our results imply that phospholipids may have diagnostic potential as well as that modulation of their metabolism may provide therapeutic opportunities in breast cancer treatment.
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| 4. |
- Jerby, Livnat, et al.
(författare)
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Metabolic associations of reduced proliferation and oxidative stress in advanced breast cancer
- 2012
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Ingår i: Cancer Research. - : American Association for Cancer Research. - 0008-5472 .- 1538-7445. ; 72:22, s. 5712-5720
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Tidskriftsartikel (refereegranskat)abstract
- Aberrant metabolism is a hallmark of cancer, but whole metabolomic flux measurements remain scarce. To bridge this gap, we developed a novel metabolic phenotypic analysis (MPA) method that infers metabolic phenotypes based on the integration of transcriptomics or proteomics data within a human genome-scale metabolic model. MPA was applied to conduct the first genome-scale study of breast cancer metabolism based on the gene expression of a large cohort of clinical samples. The modeling correctly predicted cell lines' growth rates, tumor lipid levels, and amino acid biomarkers, outperforming extant metabolic modeling methods. Experimental validation was obtained in vitro. The analysis revealed a subtype-independent "go or grow" dichotomy in breast cancer, where proliferation rates decrease as tumors evolve metastatic capability. MPA also identified a stoichiometric tradeoff that links the observed reduction in proliferation rates to the growing need to detoxify reactive oxygen species. Finally, a fundamental stoichiometric tradeoff between serine and glutamine metabolism was found, presenting a novel hallmark of estrogen receptor (ER)(+) versus ER(-) tumor metabolism. Together, our findings greatly extend insights into core metabolic aberrations and their impact in breast cancer.
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| 5. |
- Lu, Donghao, et al.
(författare)
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Bereavement is associated with an increased risk of HPV infection and cervical cancer : an epidemiological study in Sweden
- 2016
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Ingår i: Cancer Research. - Philadelphia, United States : American Association for Cancer Research. - 0008-5472 .- 1538-7445. ; 76:3, s. 643-651
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Tidskriftsartikel (refereegranskat)abstract
- Grief over the loss of a family member may cause physical and mental illness, but an association between bereavement and cancer risk has not been established. Based on the Swedish National Cervical Screening Register (1969-2011) including 14,011,269 smears from 2,466,107 women, we conducted two nested case-control studies to examine the associations of bereavement (i.e., loss of a family member due to death) with abnormal cytology (390,310 first abnormal and 1,951,319 normal smears) and in situ/invasive cervical cancer (75,128 case and 375,640 control women), both individually matched on year of birth and screening adherence. Among 1,696 of the control women, we further investigated bereavement in association with HPV infection, both HPV16 and other HPV types. Bereavement was consistently associated with a 4-9% increased risk for first abnormal cytology, in situ and invasive cervical cancer (all P<0.02). The associations became stronger when multiple losses, loss of child, sibling or spouse, and loss due to unnatural cause were analyzed separately (P for trend or difference<0.0001), and for women with high screening adherence (P for difference<0.05). Among 1,696 women who had not developed cervical cancer, we further investigated the link between bereavement and HPV infection. Bereavement was associated with a 62% increased risk of HPV16 infection, high viral load, and recurrent infection, and was also more strongly associated with HPV infections designated as high-risk compared to low-risk determinants of cervical carcinogenesis. Collectively, our findings demonstrate that bereavement is associated with an increased risk of developing cervical cancer. Further, they suggest that this association may be attributed to stress-induced oncogenic HPV infections.
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| 6. |
- Lu, Donghao, et al.
(författare)
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Psychologic Distress Is Associated with Cancer-Specific Mortality among Patients with Cervical Cancer
- 2019
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Ingår i: Cancer Research. - : American Association for Cancer Research Inc.. - 0008-5472 .- 1538-7445. ; 79:15, s. 3965-3972
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Tidskriftsartikel (refereegranskat)abstract
- Emerging evidence suggests a role of psychologic factors in the progression of different cancer types. However, it is unclear whether psychologic distress around the time of diagnosis of invasive cervical cancer places patients at a higher risk of cancer-specific mortality, independently of tumor characteristics and treatment modalities. We conducted a nationwide cohort study, including 4,245 patients with newly diagnosed cervical cancer during 2002-2011 in Sweden. Psychologic distress was indicated by a clinical diagnosis of depression, anxiety, or stress reaction and adjustment disorders, or the experience of a stressful life event, including death or severe illness of a family member, divorce, or between jobs, from one year before cancer diagnosis and onwards. We calculated the HRs of cancer-specific mortality among the patients exposed to psychologic distress, compared with unexposed patients, controlling for socioeconomic characteristics and other known prognostic indicators such as tumor and treatment characteristics. We found that patients exposed to psychologic distress had an increased risk of cancer-specific mortality (HR 1.33; 95% CI, 1.14-1.54). The association was primarily driven by distress experienced within one year before or after diagnosis (HR 1.30; 95% CI, 1.11-1.52), but not thereafter (HR 1.12; 95% CI, 0.84-1.49). In summary, our study shows that psychiatric disorders and stressful life events around cancer diagnosis are associated with increased cancer-specific mortality among patients with cervical cancer, independent of tumor characteristics and treatment modality.Significance: These findings support the integration of psychologic screening and intervention in the clinical management of patients with cervical cancer, particularly around the time of cancer diagnosis.
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| 7. |
- Stopsack, Konrad H., et al.
(författare)
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Cholesterol Metabolism and Prostate Cancer Lethality
- 2016
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Ingår i: Cancer Research. - : American Association for Cancer Research Inc.. - 0008-5472 .- 1538-7445. ; 76:16, s. 4785-4790
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Tidskriftsartikel (refereegranskat)abstract
- Cholesterol metabolism has been implicated in prostate cancer pathogenesis. Here, we assessed the association of intratumoral mRNA expression of cholesterol synthesis enzymes, transporters, and regulators in tumor specimen at diagnosis and lethal prostate cancer, defined as mortality or metastases from prostate cancer in contrast to nonlethal disease without evidence of metastases after at least 8 years of follow-up. We analyzed the prospective prostate cancer cohorts within the Health Professionals Follow-up Study (n = 249) and the Physicians' Health Study (n = 153) as well as expectantly managed patients in the Swedish Watchful Waiting Study (n = 338). The expression of squalene monooxygenase (SQLE) was associated with lethal cancer in all three cohorts. Men with high SQLE expression (>1 standard deviation above the mean) were 8.3 times (95% confidence interval, 3.5 to 19.7) more likely to have lethal cancer despite therapy compared with men with the mean level of SQLE expression. Absolute SQLE expression was associated with lethal cancer independently from Gleason grade and stage, as was a SQLE expression ratio in tumor versus surrounding benign prostate tissue. Higher SQLE expression was tightly associated with increased histologic markers of angiogenesis. Collectively, this study establishes the prognostic value of intratumoral cholesterol synthesis as measured via SQLE, its second rate-limiting enzyme. SQLE expression at cancer diagnosis is prognostic for lethal prostate cancer both after curative-intent prostatectomy and in a watchful waiting setting, possibly by facilitating micrometastatic disease.
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| 8. |
- Udumyan, Ruzan, 1971-, et al.
(författare)
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Beta-Blocker Drug Use and Survival among Patients with Pancreatic Adenocarcinoma
- 2017
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Ingår i: Cancer Research. - : American Association for Cancer Research Inc.. - 0008-5472 .- 1538-7445. ; 77:13, s. 3700-3707
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Tidskriftsartikel (refereegranskat)abstract
- Preclinical studies have suggested that beta-adrenergic signaling is involved in pancreatic cancer progression. Prompted by such studies, we investigated an association between beta-blocker drug use with improved cancer-specific survival in a large, general population-based cohort of patients with pancreatic ductal adenocarcinoma (PDAC). All patients diagnosed with a first primary PDAC in Sweden between 2006 and 2009 were identified through the Swedish Cancer Register (n = 2,394). We obtained information about use of beta-blockers and other medications through linkage with the national Prescribed Drug Register. Cancer-specific mortality was assessed using the Swedish Cause of Death Register. We used multivariable Cox regression adjusted for sociodemographic factors, tumor characteristics, comorbidity score, and other medications to estimate HRs and 95% confidence intervals (CI) for cancer-specific mortality associated with beta-blocker use during the 90-day period before cancer diagnosis. A total of 2,054 (86%) died, with pancreatic cancer recorded as the underlying cause of death during a maximum of 5-year follow-up (median 5 months). Patients who used beta-blockers (n = 522) had a lower cancer-specific mortality rate than nonusers (adjusted HR, 0.79; 95% CI, 0.70-0.90; P < 0.001). This observed rate reduction was more pronounced among patients with localized disease at diagnosis (n = 517; adjusted HR, 0.60; 95% CI, 0.43-0.83; P = 0.002), especially for users with higher daily doses (HR, 0.54; 95% CI, 0.35-0.83; P = 0.005). No clear rate differences were observed by beta-blocker receptor selectivity. Our results support the concept that beta-blocker drugs may improve the survival of PDAC patients, particularly among those with localized disease.
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| 9. |
- Akre [Fall], Katja, 1971-, et al.
(författare)
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Risk for gastric cancer after antibiotic prophylaxis in patients undergoing hip replacement
- 2000
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Ingår i: Cancer Research. - Birmingham, USA : American Asoociation for Cancer Research. - 0008-5472 .- 1538-7445. ; 60, s. 6376-
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Tidskriftsartikel (refereegranskat)abstract
- Despite strong evidence of an association between Helicobacter pylori and gastric cancer, the benefit of eradicating H. pylori infection is unknown. Our aim was to test the hypothesis that exposure to high doses of antibiotics reduces risk for gastric cancer via possible eradication of H. pylori We conducted a nationwide case-control study nested in a cohort of 39,154 patients who underwent hip replacement surgery between 1965 and 1983. Such patients frequently receive prophylactic antibiotic treatment. During follow-up through 1989, we identified 189 incident cases of gastric cancer. For each case, three controls were selected from the cohort. Exposure data were abstracted from hospital records. Blood samples from a separate cohort undergoing hip replacement surgery were analyzed for anti-H. pylori IgG before and after surgery. Both long-term antibiotic treatment before surgery [odds ratio (OR), 0.3; 95% confidence interval (CI), 0.1-0.7] and prophylactic antibiotic treatment (OR, 0.7; 95% CI, 0.5-1.1) conferred a reduction in gastric cancer risk. The reduction appeared stronger after 5 years (OR, 0.6; 95% CI, 0.3-1.2) than during shorter follow-up after hip replacement (OR, 0.8; 95% CI, 0.4-1.7). There was an apparent decrease in risk with increasing body weight-adjusted doses of antibiotics (P = 0.13). However, the rate of H. pylori antibody disappearance was not strikingly higher in the cohort of patients undergoing hip replacement than in a control cohort. Our findings provide indirect support for the hypothesis that treatment with antibiotics at a relatively advanced age reduces the risk of gastric cancer.
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| 10. |
- Bekele, Maheteme, et al.
(författare)
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Tumor and immune cell profiling in breast cancer using highly multiplexed imaging mass cytometry single-cell technology demonstrates tumor heterogeneity and immune phenotypic abnormality in Ethiopian women
- 2020
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Ingår i: Cancer Research. - : American Association for Cancer Research. - 0008-5472 .- 1538-7445. ; 80:21 Suppl.
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Tumor heterogeneity represents a complex challenge to cancer treatment, disease recurrence, and patient survival. Imaging mass cytometry (IMC) is an emerging proteomic tool for cancer profiling in tumor tissue samples. IMC enables digital image analysis by multiplexed immunostaining of cells and proteins within tissue and preserves spatial relations within tumor environment. We have applied IMC based approach to study the heterogeneity of invasive breast carcinoma protein expression pattern in formalin fixed paraffin embedded tissues.Methods: A total of 10 region of interest (ROI) derived from 5 patients with primary invasive breast carcinoma representing three molecular subclasses (HR+/HER2-,HER2+/HR- and TNBC) were stained with a 30-marker IMC metal labeled antibody panel (α-SMA, EGFR, p53, CD33, CD16, CD163, CD11b, PDL1, CD31, CD45, D44,Vimentin, FoxP3, CD4, ECadherin, CD68, CD20, CD8a, Cytokeratin7, PD1, GranzymeB, Ki67, ColTypeI, CD3, CD45RO, HLADR, DARC & CD11c). Tissue imaging was done by quantifying the abundance of bound antibody with a Hyperion IMC. MCD Viewer was used for visualization purpose and to export raw 16-bit tiff images for segmentation on CellProfiler. Segmentation masks were combined with the individual tiff files to extract single-cell information from each individual image. HistoCAT was applied to perform unbiased clustering of cell populations using the PhenoGraph algorithm and clustered cell populations was overlaid on t-SNE plot. The relative marker expression was used to generate heat-maps and each cluster was manually assigned a phenotype based on its expression profile.Results: The t-SNE generated from each ROI revealed different distinct cell populations and we report the presence of diverse tumor and immune cell populations in our samples. The (min, max) number of PhenoGraph clustered tumor cell populations in HR+/HER2-, HER2+ and TNBC Cases were (5,8) (7,9) and (5,7) respectively. Similarly, the (min, max) number of PhenoGraph clustered immune cell populations in HR+/HER2-, HER2+ and TNBC Cases were (5,8) (7,9) and (5,7) respectively. We also document the presence of inter and intra-tumor heterogeniety in expression of PD1 and PDL1 in all the tumor subtypes studied. Additionally, we report a phenotypic abnormality in the immune cell populations identified with dual or triple markers expression of the canonical CD antigens of T-Cells, B-Cells and macrophages.Conclusion: The current study demonstrates high-dimensional visualization with the simultaneous analysis of epithelial, immune, and stromal components using IMC can be used to explore cell populations in tumor tissue to quantify tumor heterogeneity or identification of novel clustering patterns that has potential for translational research and clinical practice. Significance: This study presents the potential of Imaging Mass Cytometry and single cell analysis algorithms in multiplex high throughput tumor tissue studies.
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