Resolving the fibrotic niche of human liver cirrhosis at single-cell level.

Liver cirrhosis is a major cause of death worldwide and is characterized by extensive fibrosis. There are currently no effective antifibrotic therapies available. To obtain a better understanding of the cellular and molecular mechanisms involved in disease pathogenesis and enable the discovery of therapeutic targets, here we profile the transcriptomes of more than 100,000 single human cells, yielding molecular definitions for non-parenchymal cell types that are found in healthy and cirrhotic human liver. We identify a scar-associated TREM2+CD9+ subpopulation of macrophages, which expands in liver fibrosis, differentiates from circulating monocytes and is pro-fibrogenic. We also define ACKR1+ and PLVAP+ endothelial cells that expand in cirrhosis, are topographically restricted to the fibrotic niche and enhance the transmigration of leucocytes. Multi-lineage modelling of ligand and receptor interactions between the scar-associated macrophages, endothelial cells and PDGFRα+ collagen-producing mesenchymal cells reveals intra-scar activity of several pro-fibrogenic pathways including TNFRSF12A, PDGFR and NOTCH signalling. Our work dissects unanticipated aspects of the cellular and molecular basis of human organ fibrosis at a single-cell level, and provides a conceptual framework for the discovery of rational therapeutic targets in liver cirrhosis.

Estimating risks for variants of unknown significance according to their predicted pathogenicity classes with application to BRCA1.

Sequence-based testing of disease-susceptibility genes has identified many variants of unknown significance (VUSs) whose pathogenicity is unknown at the time of their measurement. Female breast cancer cases aged 20-49 years at diagnosis and who have VUSs in BRCA1 and no mutations in BRCA2 have previously been identified through the population-based Los Angeles County Cancer Surveillance Program. These nominal BRCA1 VUSs have been classified as "low," "medium," and "high" risk by four classification methods: Align-GVGD, Polyphen, Grantham matrix scores, and sequence conservation in mammalian species. Average hazard ratios (HRs) for classes of variants, i.e., the age-specific incidences of cancer for carriers of such variants divided by the population incidences, were estimated from the cancer family histories of first- and second-degree relatives of the index cases using modified segregation analysis. The study sample comprised 270 index cases and 4,543 of their relatives. There was weak evidence that the risk of breast cancer increases with the degree of sequence conservation (P = 0.03) and that missense variants at highly conserved sites are associated with a 5.6-fold (95 % confidence interval 1.4-22.2; P = 0.05) increased incidence of breast cancer. An upper bound of 2.3 is given for the average breast cancer HRs corresponding to variants classified as "low risk" by any of the four VUS classification methods. In summary, we have given a method to estimate cancer risks for groups of VUSs by combining existing classification methods with traditional penetrance analyses. This analysis suggests that classification methods for BRCA1 variants based on sequence conservation might be useful in a clinical setting. We have shown in principle that our method can be used to classify VUSs into clinically useful risk categories, but our specific findings should not be put into clinical practice unless confirmed by larger studies.

Ethnic differences in serum adipokine and C-reactive protein levels: the multiethnic cohort.

BACKGROUND: Ethnic disparities in metabolic disease risk may be the result of differences in circulating adipokines and inflammatory markers related to ethnic variations in obesity and body fat distribution. SUBJECTS/METHODS: In a cross-sectional design, we compared serum levels of leptin, adiponectin, C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in control subjects (321 men and 930 women) from two nested case-control studies conducted within the Multiethnic Cohort Study consisting of whites, Japanese Americans (JA), Latinos, African Americans (AA) and Native Hawaiians (NH). General linear models were applied to evaluate ethnic differences in log-transformed serum biomarker levels before and after adjusting for body mass index (BMI) at cohort entry. RESULTS: In comparison to whites, significant ethnic differences were observed for all biomarkers except TNF-α. JA men and women had significantly lower leptin and CRP levels than whites, and JA women also had lower adiponectin levels. Leptin was significantly higher in AA women (P < 0.01), adiponectin was significantly lower in AA men and women (P = 0.02 and P < 0.001), and CRP and IL-6 were significantly higher in AA men and women. Lower adiponectin (P < 0.0001) and CRP (P = 0.03) levels were the only biomarkers in NH women that differed from whites; no statistically significant differences were seen for NH men and for Latino men and women. When adjusted for BMI at cohort entry, the differences between the lowest and the highest values across ethnic groups decreased for all biomarkers except adiponectin in men indicating that ethnic differences were partially due to weight status. CONCLUSIONS: These findings demonstrate the ethnic variations in circulating adipokine and CRP levels before and after adjustment for BMI. Given the limitation of BMI as a general measure of obesity, further investigation with visceral and subcutaneous adiposity measures are warranted to elucidate ethnicity-related differences in adiposity in relation to disparities in obesity-related disease risk.

A candidate gene approach to searching for low-penetrance breast and prostate cancer genes.

Most cases of breast and prostate cancer are not associated with mutations in known high-penetrance genes, indicating the involvement of multiple low-penetrance risk alleles. Studies that have attempted to identify these genes have met with limited success. The National Cancer Institute Breast and Prostate Cancer Cohort Consortium--a pooled analysis of multiple large cohort studies with a total of more than 5,000 cases of breast cancer and 8,000 cases of prostate cancer--was therefore initiated. The goal of this consortium is to characterize variations in approximately 50 genes that mediate two pathways that are associated with these cancers--the steroid-hormone metabolism pathway and the insulin-like growth factor signalling pathway--and to associate these variations with cancer risk.

Evidence of an X-linked or recessive genetic component to prostate cancer risk.

We used data from a population-based cohort study of blacks, Hispanics, Japanese and whites to examine the frequency of prevalent prostate and breast cancer by family history status of first-degree relatives (parents and siblings). Independent of race, the age-adjusted relative risk for prevalent prostate cancer in subjects with affected brothers was approximately two times that in subjects with affected fathers (P < 0.00005). No such excess risk for breast cancer was observed among subjects with affected sisters compared to those with affected mothers (age- and race-adjusted relative risk = 1.10, P = 0.34). The magnitude of the relative risk for prostate cancer in sibling- versus parent-affected groups was significantly different from that of the comparable relative risk for breast cancer (P < 0.00005). An excess risk of prostate cancer in men with affected brothers compared to those with affected fathers is consistent with the hypothesis of an X-linked, or recessive, model of inheritance.

The association of diabetes with colorectal cancer risk: the Multiethnic Cohort.

BACKGROUND: Diabetics have been found to have a greater risk of colorectal cancer than non-diabetics. METHODS: We examined whether this relationship differed by ethnic group, cancer site or tumour stage in a population-based prospective cohort, including 3549 incident colorectal cancer cases identified over a 13-year period (1993-2006) among 199 143 European American, African American, Native Hawaiian, Japanese American and Latino men and women in the Multiethnic Cohort. RESULTS: Diabetics overall had a significantly greater risk of colorectal cancer than did non-diabetics (relative risk (RR)=1.19, 95% confidence interval (CI)=1.09-1.29, P-value (P)<0.001). Positive associations were observed for colon cancer, cancers of both the right and left colon, and cancers diagnosed at a localised and regional/distant stage. The association with colorectal cancer risk was significantly modified by smoking status (P(Interaction)=0.0044), with the RR being higher in never smokers (RR=1.32, 95% CI=1.15-1.53, P<0.001) than past (RR=1.19, 95% CI=1.05-1.34, P=0.007) and current smokers (RR=0.90, 95% CI=0.70-1.15, P=0.40). CONCLUSION: These findings provide strong support for the hypothesis that diabetes is a risk factor for colorectal cancer.

Urinary phytoestrogen excretion and prostate cancer risk: a nested case-control study in the Multiethnic Cohort.

BACKGROUND: Phytoestrogens are of special interest in prostate cancer research because populations in Asia with a high consumption of phytoestrogens have a lower incidence of the disease than comparable populations in Western countries. METHODS: This case-control study is nested within a large multiethnic cohort in Hawaii and California. Urine samples were analysed for daidzein, genistein, equol, and enterolactone among 249 incident prostate cancer cases and 404 controls matched on age, race/ethnicity, date/time of specimen collection, and fasting status. RESULTS: The median excretion of daidzein was 0.173 nmol mg(-1) creatinine in cases and 0.291 in controls (P=0.01), and the median excretion of genistein was 0.048 in cases and 0.078 in controls (P=0.05). An inverse association was seen for daidzein overall (odds ratio for the highest vs lowest quintile=0.55, 95% confidence interval=0.31-0.98, P(trend)=0.03) and seemed to apply to localized (P(trend)=0.08) as well as advanced or high-grade cancer (P(trend)=0.09). This association was consistent across the four ethnic groups examined. Although the relationship was weaker for genistein, the odds ratios and trends were similarly inverse. Urinary excretion of equol and enterolactone was not significantly related to prostate cancer risk. CONCLUSION: Our findings suggest that high intake of isoflavones, as reflected by urinary excretion of daidzein and genistein, may be protective against prostate cancer.

Toward the primary prevention of cancer.

This is the threshold of an era when many of the most prevalent human cancers can, to a significant extent, be prevented through life-style changes or medical interventions. For lung cancer, the leading cause of cancer deaths in the United States, the major cause, cigarette smoking, is known and strategies for reducing smoking are slowly succeeding. Dietary changes can reduce the risk of developing large bowel cancer, the second most common cancer overall. The etiology of the major cancer in women, cancer of the breast, is sufficiently well understood that large-scale medical intervention trials are imminent. Recent changes in the incidence and mortality of these and the other major human cancers are reviewed with a brief explanation as to why these changes have occurred, followed by a summary of the state of knowledge regarding the major causes of cancer.

Hormonal chemoprevention of cancer in women.

The use of oral contraceptives in the United States during the past three decades has led to a dramatic decline in the incidence of cancers of the ovary and endometrium. The magnitude of these declines was predictable both from epidemiologic data and from the biologic effects of oral contraceptives on these tissues. Although the incidence of breast cancer has not been substantially affected by current oral contraceptives, it may be possible to develop alternative forms of contraception that provide protection against all three cancers. The major goal of hormonal chemoprevention of cancer is to reduce cell proliferation in the relevant epithelial tissue. New chemopreventive agents such as tamoxifen exemplify the application of this principle.

Industrial air pollution: possible effect on lung cancer.

Higher lung cancer mortality rates occurred in males living in certain heavily industrialized areas of Los Angeles County, California. These areas were characterized by elevated concentrations of benzo[a]pyrene and other polynuclear aromatic hydrocarbons of primarily industrial origin in the soil and air.

Changing ratio of breast cancer incidence rates with age of black females compared with white females in the United States.

Age-standardized breast cancer rates were approximately 30% lower in U.S. black women compared to white women. This observation concealed the fact that black women under age 40 years had a higher incidence of breast cancer than did white women, whereas white women over 40 years had a higher incidence. The known risk factors for breast cancer development (early age at menarche, late age at first full-term delivery, and a late age of menopause) differed in black and white populations, which might explain this difference in breast cancer incidence between blacks and whites at different ages.

Estrogen exposure during gestation and risk of testicular cancer.

In this case--control study of 108 cases of testicular cancer in men under 30 years of age, cryptorchidism was a major risk factor [relative risk (RR) = 9.0]. Low birth weight was also associated with increased risk (RR = 3.2). Having severe acne at puberty was protective (RR = 0.37). Interviews with mothers of cases revealed that exposure of the mother to exogenous estrogen during pregnancy created a significant risk in the son (RR = 8.0). In first pregnancies, excessive nausea indicated an increased risk of testicular cancer (RR = 4.2). Increased body weight in the mother also increased the risk. The relation between these factors and testicular hypoplasia is discussed. Severe perimenopausal menorrhagia was a factor in the mother associated with reduced risk of testicular cancer in the son (RR = 0.10). A modified hormonal milieu in the mother appears to be important in the later development of testicular cancer in her sons.

Secular trends in histologic types of lung cancer.

The histology pattern of lung cancer in Los Angeles County was reviewed for a 10-year period, 1972-81. In men, the total lung cancer incidence has been fairly constant, but there has been a shift in the histology pattern with an increase in adenocarcinoma and a decrease in "other" cell type (i.e., carcinoma not otherwise specified, large-cell and undifferentiated tumors). This changing histology pattern may be partly due to changes in diagnostic standards and practices. With the assumption that these changes are comparable in men and women, the "true" annual rate of change was estimated for each lung cancer cell type in women. All lung cancer types have increased in women; of the cell types squamous cell carcinoma, small-cell carcinoma, and adenocarcinoma, small-cell carcinoma showed the largest rate of annual increase and adenocarcinoma, the smallest.

Cancer of the gastrointestinal tract among Japanese and white immigrants in Los Angeles County.

With the use of age-adjusted incidence rates and proportional incidence ratios, investigators studied the risk of cancer of the stomach and 3 subdivisions of the large bowel in three race-ethnic groups--Spanish surnamed whites, other whites, and Japanese--and compared Los Angeles County native residents, immigrants, and representative "homeland" populations. The risk pattern for each of the four anatomic sites was quite distinctive, suggesting at least four different etiologic complexes. For each site the observed gradients of risk are nearly identical for each sex, usually with risk for immigrants intermediary between that for homeland residents and that for local natives; the differences between race-ethnic groups are consistent with known international patterns. Particularly notable is the contrast between the low risks of cancer of both the sigmoid and the rectum in Japan and the high risks for Japanese immigrants to Los Angeles, which are nearly double those of their U.S. white neighbors. In all instances, and especially for both the upper and lower colon, the influence of the adult environment predominates over that of the early environment. The environmental determinants of stomach cancer do not always appear in inverse correlation with those of colon cancer, since Japanese immigrants to Los Angeles and their descendants are at high absolute and relative risk of both neoplasms. Our findings suggest that patterns of risk in relation to migration are complex and defy simple dietary or other interpretation. Without more information about the impact of migration to the United States on qualitative and quantitative aspects of lifestyle, it is not possible to put forward simple hypotheses that explain all available facts.

Vitamin A, beta-carotene, and the risk of cancer: a prospective study.

A cohort of 10,473 residents of Leisure World, Laguna Hills, CA, who were initially free of cancer were followed from 1981 to 1986. A health survey questionnaire completed by all cohort members included usual frequencies of consumption of certain food items, including vegetables, fruits, dairy products, liver, and cereal, as well as specific information on brand and formulation of vitamin supplements containing vitamins A, C, or E. Pathologic diagnosis of incident cancer was confirmed in 643 persons (56 lung, 110 colon, 59 bladder, 93 prostate, 123 female breast, and 202 cancers of other sites). Our study found little indication that increased intake of vitamin A or beta-carotene from the diet or supplements protects against the development of cancer overall. Dietary vitamin A intake was highly associated with smoking status; 25% of current smokers were in the highest third of dietary vitamin A consumption versus 32% of past smokers and 36% of never-smokers. In males who never smoked there was some indication that cancer rates decreased with increasing vitamin A intake, but the results were not statistically significant.

Risk factors for meningiomas in men in Los Angeles County.

A case-control study among men in Los Angeles County was conducted to investigate further the causes of intracranial meningiomas. Meningioma patients and a neighbor of each one were interviewed about past experiences that might be associated with tumor development. Analysis of information from the 105 matched pairs showed an association with meningioma occurrence for various factors relating to head trauma and head X-rays: 1) ever boxed as a sport [odds ratio (OR) = 2.0, P = 0.03], 2) had a serious head injury (OR = 1.9, P = 0.01), and 3) had X-ray treatment to the head before 20 years of age and/or had five or more full mouth dental X-ray series before 1945 (OR = 3.5, P = 0.02). Of the 105 subjects, 72 (69%) had a history of exposure to at least one of these factors.

Lung cancer risk among beauticians and other female workers: brief communication.

Lung cancer risk among occupational groups of women was reviewed. A previous suggestion of a sixfold risk of developing lung cancer among beauticians was not confirmed; however, an approximately twofold risk was found.

Lung cancer risk among beauticians and other female workers: brief communication.

Lung cancer risk among occupational groups of women was reviewed. A previous suggestion of a sixfold risk of developing lung cancer among beauticians was not confirmed; however, an approximately twofold risk was found.

Nonviral risk factors for hepatocellular carcinoma in a low-risk population, the non-Asians of Los Angeles County, California.

We conducted interviews on 74 patients with histologically confirmed hepatocellular carcinoma. These patients, aged 18-74 years, were black or white residents of Los Angeles County. We also interviewed 162 population control subjects who were comparable to the case patients by age, sex, and race. Cigarette smoking was a significant risk factor for hepatocellular carcinoma [relative risk (RR) = 2.1; 95% confidence limits (CL) = 1.1, 4.0]; the effects were similar in men and in women. Heavy alcohol consumption was another risk factor for hepatocellular carcinoma in men; men who consumed 80 g or more of ethanol per day had an RR of 4.7 (95% CL = 1.4, 15.4) relative to those who had never drunk alcohol on a weekly basis. The level of alcohol intake was relatively low in women, and no significant effect on risk of hepatocellular carcinoma was observed. Use of oral contraceptives was significantly related to risk of hepatocellular carcinoma in women (RR = 3.0; 95% CL = 1.0, 8.8); those who were exposed for more than 5 years exhibited a 5.5-fold increased risk (95% CL = 1.2, 24.8). The effects of these three risk factors on hepatocellular carcinoma development were independent of each other and independent of serologically determined viral hepatitis. Our data suggest that cigarette smoking, alcohol consumption, and use of oral contraceptives are major risk factors for hepatocellular carcinoma among non-Asian residents of Los Angeles County. We also observed a significant association between a history of diabetes and hepatocellular carcinoma (RR = 3.3; 95% CL = 1.5, 7.2), especially among those who had received insulin treatment (RR = 18.5; 95% CL = 2.2, 156.0). This association may have etiological significance.

Consumption of salted fish and other risk factors for nasopharyngeal carcinoma (NPC) in Tianjin, a low-risk region for NPC in the People's Republic of China.

The dietary habits, occupational exposures, use of tobacco and alcohol, and medical history were compared among 100 patients with histologically confirmed nasopharyngeal carcinoma (NPC) in Tianjin City, People's Republic of China, and 300 neighborhood controls who were individually matched to the patients with regard to age (within 5 yr), sex, and race (Han). Exposure to salted fish was significantly associated with an increased risk of NPC. Four characteristics of exposure to salted fish independently contributed to the increased risk: (a) earlier age at first exposure, (b) increasing duration of consumption, (c) increasing frequency of consumption, and (d) cooking the fish by steaming it rather than frying, grilling, or boiling it. In addition, significant associations were observed for consumption in childhood of salted shrimp paste (increased risk) and carrots (reduced risk), and the three dietary effects (i.e., those from consumption of salted fish, salted shrimp paste, and carrots) were independent of each other. None of the non-dietary factors studied were significantly associated with NPC risk.