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PubMed2004

Pharmacological and genetic modulation of Wnt-targeted Cre-Lox-mediated gene expression in colorectal cancer cells.

Wnt-targeted gene therapy has been proposed as a treatment for human colorectal cancer (CRC). The Cre-Lox system consists of methodology for enhancing targeted expression from tissue-specific or cancer-specific promoters. We analyzed the efficiency of Wnt-specific promoters as drivers of the Cre-mediated activity of a luciferase reporter gene or cell death effector gene in CRC cell lines in the presence and absence of two modulators of Wnt activity, sodium butyrate and lithium chloride. Butyrate is present in the colonic lumen after digestion of fiber-rich foods, whereas the colonic lumen is readily accessible to lithium chloride. In both SW620 and HCT-116 CRC cells, a physiologically relevant concentration of butyrate upregulated reporter and effector activity and altered the Wnt-specific expression pattern. Lithium chloride markedly enhanced Cre-Lox-mediated Wnt-specific reporter expression only in APC wild-type CRC cells. Possibilities for genetic modulation of the proposed CRC therapy included Wnt-specific expression of a floxed Lef1-VP16 fusion that enhanced Wnt-specific cell death and of a floxed dominant-negative Tcf4 that specifically downregulated endogenous Wnt activity. These findings demonstrated that the Cre-Lox system, in combination with pharmacological and genetic modulators, represents effective methodology for enhancing Wnt-targeted gene therapy.

Apoptosis↗
PubMed2006

A UK-wide postal survey to evaluate palliative care education amongst General Practice Registrars.

OBJECTIVES: To evaluate the content of General Practice Registrars' (GPRs) palliative care education in the U.K. METHODS: Postal questionnaires were sent to 492 eligible GPRs across six purposively sampled U.K. postgraduate deaneries. RESULTS: GPRs were satisfied with their course coverage on control of pain, other symptoms and communication skills, and were also moderately confident in applying the knowledge gained in these areas. They showed a high level of knowledge in the management of cancer-related pain. There was less satisfaction with the coverage given to syringe driver use (38%) and bereavement care (36%), with fewer expressing confidence in applying their knowledge to these areas. CONCLUSIONS: GPRs have mixed perceptions about their palliative care education. Future educational packages should ensure that GPRs receive planned systematic training in bereavement care and some practical experience in the use of syringe drivers. Both Postgraduate General Practice Education departments and specialist palliative care providers should explore ways of working more closely together to provide GPRs with more expertize in palliative care.

Adult↗
PubMed2004

Pesticide product use and risk of non-Hodgkin lymphoma in women.

A population-based, incidence case-control study was conducted among women in upstate New York to determine whether pesticide exposure is associated with an increase in risk of non-Hodgkin lymphoma (NHL) among women. The study involved 376 cases of NHL identified through the State Cancer Registry and 463 controls selected from the Medicare beneficiary files and state driver's license records. Information about history of farm work, history of other jobs associated with pesticide exposure, use of common household pesticide products, and potential confounding variables was obtained by telephone interview. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using an unconditional logistic regression model. The risk of NHL was doubled (OR = 2.12; 95% CI, 1.21-3.71) among women who worked for at least 10 years at a farm where pesticides were reportedly used. When both farming and other types of jobs associated with pesticide exposure were combined, there was a progressive increase in risk of NHL with increasing duration of such work (p = 0.005). Overall cumulative frequency of use of household pesticide products was positively associated with risk of NHL (p = 0.004), which was most pronounced when they were applied by subjects themselves. When exposure was analyzed by type of products used, a significant association was observed for mothballs. The associations with both occupational and household pesticides were particularly elevated if exposure started in 1950-1969 and for high-grade NHL. Although the results of this case-control study suggest that exposure to pesticide products may be associated with an increased risk of NHL among women, methodologic limitations related to selection and recall bias suggest caution in inferring causation.

Adult↗
PubMed1988

A study of the mortality patterns of taxi drivers in Singapore.

The mortality patterns of taxi drivers in Singapore were studied by examining the death certificates of a group of taxi drivers from 1984 to 1986. The drivers were all members of Singapore's largest transport co-operative, with a fleet of 6,377 taxis. This represents over 60% of all taxis in Singapore. One hundred deaths occurred among the taxi drivers during these 3 years. The age and sex standardised mortality ratios (SMRs) were 0.70 in 1984, 0.72 in 1985, and 0.98 in 1986. For the whole period, the age and sex standardised SMR was 0.80 (95% CL 0.65-0.97). Leading causes of death were neoplasms (42%), coronary heart disease (24%), and cerebrovascular disease (15%). Age and sex standardised cause specific SMRs were 1.22 (95% CL 0.88-1.65) for neoplasms, 0.78 (95% CL 0.50-1.16) for coronary heart disease, 1.51 (95% CL 0.84-2.49) for cerebrovascular disease, and 1.03 (95% CL 0.28-2.63) for suicides and homicides. Death from all other causes was significantly lower than the general population (SMR 0.32, 95% CL 0.18-0.53). As compared to the general population, taxi drivers in Singapore do not appear to have an excess mortality risk for cancers, coronary heart disease, cerebrovascular disease or from all other causes of death. Their risk of violent death from homicide or suicide is low when compared to available reports from other countries.

Adult↗
PubMedDate not supplied

Lung cancer and passive smoking at work: the Carroll case.

Passive smoking is now an acknowledged risk to health and this has given rise to a public health liability for employers. More and more workplaces are becoming smoke free, but past practices mean that there is an increasing number of individuals seeking compensation for health damage caused by passive exposure to smoke. The case brought by Sean Carroll, a bus driver, against his employer, the Melbourne Transit Authority, was the first suit in Australia seeking compensation for lung cancer caused by passive smoking. Evidence at the hearing of the case indicated that there was at least a 75% probability that Carroll's cancer was attributable to passive smoking at work. Carroll accepted $65,000 in an out-of-court settlement. The case should prompt other victims of passive smoking to seek compensation and move more employers to ban smoking from the workplace.

Australia↗
PubMed2026

CRISPR screening reveals NPC1L1 as a key driver of glioblastoma progression via cholesterol metabolic regulation.

Glioblastoma (GBM), the most aggressive central nervous system (CNS) malignancy, currently lacks curative therapeutic options. While immunotherapy has revolutionized treatment for many cancers, GBM remains refractory to immune-based interventions due to the absence of effective immunotherapeutic targets. Here, through CRISPR screening, we identify Niemann-Pick C1-like 1 (NPC1L1) as a previously unrecognized key driver of GBM progression. Mechanistically, NPC1L1 modulates cholesterol metabolism to concurrently enhance tumor cell stemness and suppress CD8+ T-cell activation, thus inducing tumor progression. Notably, combined treatment with ezetimibe (NPC1L1 inhibitor) and anti-PD-1 antibody elicited potent antitumor activity in GBM orthotopic mouse models. Collectively, these findings establish NPC1L1 as a critical regulator of GBM pathogenesis, underscoring the translational potential of targeting NPC1L1-mediated cholesterol metabolism for developing novel GBM immunotherapies.

Humans↗
PubMed2025

Advances and challenges in human 3D solid tumor models.

The field of cancer biology and therapeutics has soared in the past several decades with new therapeutic modalities and options for patients, such as chemoradiotherapy, immunotherapy, and combination therapy. This dramatic success in expanding patient options is primarily attributed to the development of various model systems to elucidate drivers of oncogenesis, tumor maturation and evolution, and response to therapeutics. While mouse models have been a workhorse of cancer research, technological progress in ex vivo patient-derived tumor models has afforded more tunable and scrutable systems for patient-predictive platforms and mechanistic study. This review explores the technological innovations in 3D solid tumor models and their applicability to various aspects of cancer biology and identification of therapeutics. Features of the tumor and tumor microenvironment like spatial heterogeneity, multicellular populations and genomic variations are addressed and elaborated through the establishment of new in vitro models. We further address the integration of perfusable vasculature with 3D tumor models and the potentially wide-ranging applications of these more complex platforms in precision medicine and cancer immunotherapy. Finally, we provide an outlook on the future of experimental cancer models for both biological investigation and bench-to-bedside pipeline development.

Journal Article↗
PubMed2025

A pancreatic cancer organoid biobank links multi-omics signatures to therapeutic response and clinical evaluation of statin combination therapy.

Chemotherapy remains the primary treatment for pancreatic ductal adenocarcinoma (PDAC), but most patients ultimately develop resistance. Here, we established 260 pancreatic cancer organoid lines, followed by extensive multi-omics profiling and therapeutic sensitivity assessments. Integrated analyses uncovered 6 novel coding and 35 noncoding driver candidates. We discovered 2,794 multi-omics features associated with drug sensitivity and 322 features linked to radiation sensitivity. Pharmacogenomic analyses revealed that chemoresistant organoids exhibited enrichment in protein glycosylation and cholesterol metabolism pathways. Notably, statins effectively targeted chemoresistant PDAC organoids. Statin treatment attenuated protein glycosylation, cholesterol levels, and the epithelial-to-mesenchymal transition (EMT) signature in PDAC organoids. We conducted a single-center, single-arm, phase 2 clinical trial (NCT06241352) combining atorvastatin with chemotherapy in patients with advanced pancreatic cancer. Among 37 patients, 26 (70.3%) demonstrated a response, with tumor markers decreasing by more than 20%, suggesting durable responses and potential clinical benefits in this challenging patient population.

Humans↗
PubMed2004

Driver's licenses as a source of data on height and weight.

We investigated the feasibility of using driver's license records to obtain height and weight data of individuals. First, we linked Washington State driver's license records (DOL) to the state birth files to assess how well driver's licenses can be linked to a public health database. We were able to match 78.4% of mothers and 71.7% of fathers on birth records to driver's license records. Then we assessed the accuracy of DOL height and weight data by comparing them to heights and weights measured on control women enrolled in a cancer etiology study (CES). There is a close relation between CES and DOL heights, but not a close relation between weights. Our results suggest that driver's license files are a good source of information for women's heights, but are not as good for women's weights.

Automobile Driving↗
PubMed2026

Liquid biopsies reveal dual compartments of cancer risk from tumor and host-derived mutations.

MOTIVATION: Circulating tumor DNA (ctDNA) and clonal hematopoiesis of indeterminate potential (CHIP) are two biologically distinct sources of somatic mutations detectable in blood. While ctDNA captures tumor-intrinsic alterations, CHIP arises from age-related hematopoietic clones and is often considered background noise. Here, we conduct a large-scale, tumor-type-resolved analysis of over 9000 patients with CHIP data and 1500 patients with ctDNA data across solid tumors profiled at Memorial Sloan Kettering Cancer Center. RESULTS: Our results reveal that CHIP and ctDNA mutations exhibit non-overlapping, clinically meaningful signals. CHIP mutations, particularly in DNA damage response and epigenetic regulators (e.g. PPM1D, CHEK2, ATM, TP53, ASXL1), are associated with worse overall survival, increased metastatic potential, and site-specific dissemination. ctDNA mutations in canonical oncogenic drivers (e.g. TP53, EGFR, KRAS, STK11) reflect tumor aggressiveness and correlate with poor prognosis and metastasis across multiple cancer types. Joint modeling in lung adenocarcinoma confirms the independent prognostic contributions of both compartments. Additionally, longitudinal clonal analysis links specific CHIP mutations to the emergence of hematologic malignancies under therapeutic pressure. These findings support a dual-compartment model of liquid biopsy, in which tumor- and host-derived mutations jointly inform on cancer risk, progression, and metastatic behavior. Integrating both compartments may enhance the clinical utility of blood-based biomarkers in oncology. AVAILABILITY: All genomic and clinical data used in this study are available through cBioPortal. Summarized outputs and processed results tables are provided in Supplementary Data.

Humans↗
PubMed2000

Left-handedness in relation to breast cancer risk in postmenopausal women.

Breast cancer risk may be influenced by intrauterine exposure to steroid hormones. We evaluated left-handedness, a marker of intrauterine hormone exposure, in relation to breast cancer risk in our population-based, case-control study. Case women 50-79 years of age with a first diagnosis of invasive breast cancer were ascertained through statewide cancer registries in Wisconsin, Massachusetts, and New Hampshire. Control women were identified in each state through lists of licensed drivers (for ages 50-64) and Medicare beneficiaries (for ages 65-79), and selected at random to correspond with the age distribution of case women. Exposure information, including handedness, was obtained through a telephone interview. Our results indicated a modest association between left-handedness and breast cancer risk (OR = 1.42; 95% CI = 1.10-1.83). The effect of left-handedness was modified by age; we observed the greatest risk ratio in the oldest age group. Left-handedness was not associated with breast tumor laterality. Our results are consistent with the hypothesis that intrauterine hormone exposures play a role in the development of breast cancer.

Aged↗
PubMed2001

[Suppression subtractive hybridization in the cloning of gene fragments in relation to lung cancer metastasis].

OBJECTIVE: In order to provide important information about early diagnosis and treatment of tumor metastasis, a study on the biological regulation of metastasis at the molecular level was carried out by isolating and identifying human metastatic suppressor gene or related DNA sequences from a pair of cell clones with different metastatic phenotypes. METHODS: Suppression subtractive hybridization technique (SSH), gene cloning and analysis by bioinformatics were applied to this study. Two cell clones of pulmonary giant cell carcinoma originating from the same patient were used. The PLA-801C cell clone which shows lower metastatic potentiality was used as tester and the PLA-801D as a driver. RESULTS: Five cDNA clones so obtained were expressed on much higher levels in the poorly metastatic cancer cell clone than the highly metastatic one. Homology analysis of all five cDNA fragments by BLASTN through GenBank showed high homology with the known human genes. CONCLUSION: Through using SSH, we have identified five cDNA fragments which are expressed at much higher levels in the poorly metastatic cancer cell clone than the highly metastatic variety. Therefore, it is supposed that they might play an important role in the suppression of metastatic tumor cells and may very well have potential application in the diagnosis and treatment of metastasis.

Base Sequence↗
PubMed2006

Decreased internalisation of erbB1 mutants in lung cancer is linked with a mechanism conferring sensitivity to gefitinib.

A majority of gefitinib (IRESSA)-responsive tumours in non-small cell lung cancer have been found to carry mutations in ErbB1. Previously, it has been observed that internalisation-deficient ErbB1 receptors are strong drivers of oncogenesis. Using a computational model of ErbB1 trafficking and signalling, it is found that a deficiency in ErbB1 internalisation is sufficient to explain the observed signalling phenotype of these gefitinib-responsive ErbB1 mutants in lung cancer cell lines. Experimental tests confirm that gefitinib-sensitive cell lines with and without ErbB1 mutations exhibit markedly slower internalisation rates than gefitinib-insensitive cell lines. Moreover, the computational model demonstrates that reduced ErbB1 internalisation rates are mechanistically linked to upregulated AKT signalling. Experimentally it is confirmed that impaired internalisation of ErbB1 is associated with increased AKT activity, which can be blocked by gefitinib. On the basis of these experimental and computational results, it is surmised that gefitinib sensitivity is a marker of a reliance on AKT signalling for cell survival that may be brought about by impaired ErbB1 internalisation.

Antineoplastic Agents↗
PubMed2006

Determinants of resource utilization in four palliative care units.

OBJECTIVE: To assess resources mobilized per day and per patient receiving palliative care (PC) and to explain the observed cost variability. STUDY SETTING: We conducted a prospective study in four French PC units. STUDY DESIGN/DATA COLLECTION: For each patient, socio-demographic and medical data were collected (using a case-report form developed specifically for this purpose) and a daily cost for the provision of care was estimated. Three methods were used to analyse causal relationships. The first method was to ask the PC staff, individually and in group meetings, their own perception of the relationship between daily costs and the other variables; the remaining two methods used the data collected in the prospective study: correlational analysis and segmentation. The database contained 140 hospitalization sequences. PRINCIPAL FINDINGS: The daily cost per patient was, on average, Euro 434 (standard deviation: Euro 73) and ranged from Euro 301 to Euro 667. Beyond differences in resources between PC units in this study, six variables were predictive of higher costs: degree of anxiety of patients and/or their families; proximity of death; extreme dependence; ENT cancer; relatively young age of the patient; and provision of certain procedures (drip, syringe driver, aspiration, oxygen therapy). CONCLUSIONS: These elements suggest using, not a single rate to finance this type of care, but modifying this tariff according to the characteristics of the patients. They raise the question about the criteria to be used if such a step were to be taken.

Aged↗
PubMed1981

Alcohol-related deaths in Wisconsin: the impact of alcohol on mortality.

Analysis of the impact of alcohol as an underlying and non-underlying cause of death in Wisconsin showed a marked increase between 1963 and 1977 in the frequency of deaths reported with mention of alcohol. The rate of deaths for which alcohol was a non-underlying cause rose more sharply during this period (2.4 per 100,000 to 9.3) than that of alcohol-related causes (4.6/100,000 to 9.0). Nearly 90 per cent of alcohol-related deaths at ages 15-24 reported alcohol as a non-underlying cause, compared to 40.7 per cent at ages 45-54 and 57 per cent at ages 75+. This proportion was higher (50.8 per cent) among males than among females (32.8 per cent). Deaths related to alcohol are attributed to a number of underlying causes in addition to alcohol. In 1975-77, nearly half of the reported alcohol-related deaths were attributed to other causes, including accidents (14.8 per cent), heart disease (14.3 per cent), respiratory diseases (4.9 per cent), suicide (3.7 per cent), and cancer (31 per cent). These percentages may reflect substantial underreporting. Comparison of motor vehicle driver death certificates with blood alcohol test reports for these drivers shows 90 per cent underreporting of alcohol on death certificates. This fact, along with other information on underreporting, shows that the approximately 650 deaths now being reported with mention of alcohol annually in Wisconsin, represent only a portion of such deaths.

Adolescent↗
PubMed2025

CINner: Modeling and simulation of chromosomal instability in cancer at single-cell resolution.

Cancer development is characterized by chromosomal instability, manifesting in frequent occurrences of different genomic alteration mechanisms ranging in extent and impact. Mathematical modeling can help evaluate the role of each mutational process during tumor progression, however existing frameworks can only capture certain aspects of chromosomal instability (CIN). We present CINner, a mathematical framework for modeling genomic diversity and selection during tumor evolution. The main advantage of CINner is its flexibility to incorporate many genomic events that directly impact cellular fitness, from driver gene mutations to copy number alterations (CNAs), including focal amplifications and deletions, missegregations and whole-genome duplication (WGD). We apply CINner to find chromosome-arm selection parameters that drive tumorigenesis in the absence of WGD in chromosomally stable cancer types from the Pan-Cancer Analysis of Whole Genomes (PCAWG, [Formula: see text]). We found that the selection parameters predict WGD prevalence among different chromosomally unstable tumors, hinting that the selective advantage of WGD cells hinges on their tolerance for aneuploidy and escape from nullisomy. Analysis of inference results using CINner across cancer types in The Cancer Genome Atlas ([Formula: see text]) further reveals that the inferred selection parameters reflect the bias between tumor suppressor genes and oncogenes on specific genomic regions. Direct application of CINner to model the WGD proportion and fraction of genome altered (FGA) in PCAWG uncovers the increase in CNA probabilities associated with WGD in each cancer type. CINner can also be utilized to study chromosomally stable cancer types, by applying a selection model based on driver gene mutations and focal amplifications or deletions (chronic lymphocytic leukemia in PCAWG, [Formula: see text]). Finally, we used CINner to analyze the impact of CNA probabilities, chromosome selection parameters, tumor growth dynamics and population size on cancer fitness and heterogeneity. We expect that CINner will provide a powerful modeling tool for the oncology community to quantify the impact of newly uncovered genomic alteration mechanisms on shaping tumor progression and adaptation.

Chromosomal Instability↗
PubMed2001

A meta-analysis of bladder cancer and diesel exhaust exposure.

The aim of this study is to review and summarize the available epidemiologic studies of bladder cancer and occupational exposure to diesel exhaust. We retrieved relevant studies and abstracted their characteristics and results. We assessed the heterogeneity of the results to decide whether to perform a fixed-effects model meta-analysis. We identified 35 relevant studies. No overall meta-analysis was performed because of heterogeneity in results. Results of railroad workers (N = 14) suggested an increased occurrence of bladder cancer, but we did not conduct a meta-analysis. The summary relative risk (RR) among truck drivers was 1.17 (95% confidence interval [CI] = 1.06-1.29, 15 studies) and that among bus drivers was 1.33 (95% CI = 1.22-1.45, 10 studies). Ten studies considered diesel exhaust exposure based on a job exposure matrix or a similar approach; the summary RR for these studies was 1.13 (95% CI = 1.00-1.27). A positive dose-response relation was suggested by 10 of the 12 studies that provided relevant information. The summary RR for high diesel exposure was 1.44 (95% CI = 1.18-1.76). There was some evidence of publication bias, however, with a lack of small studies with null or negative results. Our review suggests that exposure to diesel exhaust may increase the occurrence of bladder cancer, but the effects of misclassification, publication bias, and confounding cannot be fully taken into account.

Europe↗
PubMed1998

Menstrual factors in relation to breast cancer risk.

We evaluated menstrual factors in relation to breast cancer risk in a large, population-based, case-control study. Case women were ascertained through state-wide registries covering Wisconsin, Western Massachusetts, Maine, and New Hampshire; control women were randomly selected from driver's license and Medicare lists in each state. Information regarding menstrual characteristics was obtained through a telephone interview. The study population comprised 6888 breast cancer cases and 9529 control women. Because exogenous hormones influence menstrual cycle patterns, we repeated our analyses in a subgroup of women who had never used oral contraceptives or hormone replacement therapy. Our results indicate decreased breast cancer risk with menarcheal age of 15 years or more, relative to menarche at age 13; the relation was stronger among premenopausal [odds ratio (OR), 0.72; 95% confidence interval (CI), 0.57-0.91] as opposed to postmenopausal women (OR, 0.90; 95% CI, 0.80-1.03). Risk was slightly reduced among premenopausal women whose menstrual cycles did not become regular until at least 5 years after onset of menses, relative to those whose cycles became regular within 1 year (OR, 0.80; 95% CI, 0.63-1.02). There was no clear relation between breast cancer risk and irregular menstrual cycles, episodes of amenorrhea, or menstrual cycle length. Early menopause, whether natural or surgical, was associated with decreased breast cancer risk; surgical menopause before age 40 conferred the strongest protective effect (OR, 0.57; 95% CI, 0.47-0.71). We found no evidence of increased risk with late natural menopause (OR, 0.92; 95% CI, 0.80-1.06). Results in the subgroup of women who never used exogenous hormones were similar to those for the entire group.

Adult↗