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Biomedical subjects

C Dong

Publications and source records attributed to C Dong.

At least 37 records · Page 2Linked to original sources
PubMed2001

Multiple primary cancers of the colon, breast and skin (melanoma) as models for polygenic cancers.

To assess the role of family history in the development of multiple primary cancer, the Swedish Family-Cancer Database was used to analyze second primary cancer in patients born in 1935 to 1996 with an initial primary cancer of the colon, breast and skin (melanoma) by familial cancer in first-degree relatives. Standardized incidence ratios (SIRs) were calculated from site-, sex- and age-specific rates for all persons (offspring) born in 1935 to 1996. Familial risk (SIR) was calculated for the first and second primary cancers in offspring. A Poisson regression analysis was also performed to assess the risk factors for occurrence of second primary cancer. The familial proportion of multiple primary cancers was 29.0% (9/31) for colon, 16.3% (122/747) for female breast and 14.5% (17/117) for melanoma. Compared with all offspring, patients with family history were at a much higher and significantly increased risk for subsequent primary cancer at colon (SIR = 59.1), skin (SIR = 48.2) and female breast (SIR = 7.9). The corresponding SIRs in patients without family history were 13.8, 10.5 and 5.2 at the three sites. The ratios for incidence of second primary to first primary were highest when diagnosis age was less than 40 years. A Poisson regression analysis showed that family history was one of the major risk factors for occurrence of multiple primary cancers at colon, breast and skin. The high risk of second cancer, even in the absence of family history, would be consistent with a polygenic model of carcinogenesis.

Age Factors↗
PubMed2001

MKK7 is an essential component of the JNK signal transduction pathway activated by proinflammatory cytokines.

Mitogen-activated protein kinases (MAPK) are activated by phosphorylation on Thr and Tyr by MAPK kinases. Two MAPK kinases (MKK4 and MKK7) can activate the c-Jun NH(2)-terminal kinase (JNK) group of MAPK in vitro. JNK is phosphorylated preferentially on Tyr by MKK4 and on Thr by MKK7. Targeted gene-disruption studies in mice were performed to examine the role of MKK4 and MKK7 in vivo. Simultaneous disruption of the Mkk4 and Mkk7 genes was required to block JNK activation caused by exposure of cells to environmental stress. In contrast, disruption of the Mkk7 gene alone was sufficient to prevent JNK activation caused by proinflammatory cytokines. These data demonstrate that MKK4 and MKK7 serve different functions in the JNK signal transduction pathway.

Animals↗
PubMed2001

Chromosomal sequences flanking an efficiently expressed transgene dramatically enhance its expression.

The expression of transgenes in mice is influenced strongly by their site of integration in the genome. To test whether the chromosomal sequences immediately flanking a site of integration could positively influence expression we isolated the 5' and 3' chromosomal sequences from an efficiently expressed transgenic locus. These chromosomal sequences were incorporated into transgene constructs and these were then introduced into mice. Linking them to the original transgene dramatically enhanced its expression and conferred a degree of position independent expression upon it. However, the results were not as marked when these sequences were linked to other constructs, showing that the effectiveness of such flanking chromosomal sequences is highly dependent on the nature of the transgene used.

Animals↗
PubMed2001

Modification of cancer risks in offspring by sibling and parental cancers from 2,112,616 nuclear families.

Comparisons of cancer risks in persons by sibling cancers and those by parental cancers are informative of elucidating the potential genetic modes in the etiology of the cancers. The Swedish Family-Cancer Database was used to systematically estimate the effects of parental and sibling cancers on the cancer risks in the individuals born after 1934 (offspring). The study population included 5,520,756 offspring and their parents from 2,112,616 nuclear families. Standardized incidence ratios (SIRs) were calculated to analyze the risks for cancers in offspring by parental cancers (offspring risk) and by sibling cancers (sibling risk). For 20 concordant sites, all offspring and sibling risks were significantly increased except for sibling risks for squamous cell carcinoma of the skin and myeloma. Apart from breast cancer, the SIRs were more than 10 when offspring had both an affected parent and an affected sib at the concordant site. The ratio for the sibling to offspring risk was around 2.0 or more for gastric, renal, non-thyroid endocrine, urinary bladder, colon, testicular and prostate cancers and leukemia. For discordant sites, many reported across-site associations were confirmed and several consistent novel associations (rectum-skin, breast-endocrine and lung-endocrine) were found only among sibs. Our findings suggested that low-penetrance polygenic dominant effects or dominant genes of high penetrance but low mutant allele frequency in the population may be involved in the observed familial cancers at many sites. Recessive or X-linked effects may contribute particularly to gastric, renal, non-thyroid endocrine, bladder, colon, testicular and prostate cancers and leukemia. The search for pleiotropic recessive/X-linked susceptibility genes should be well motivated based on our results.

Adolescent↗
PubMed2001

Cutting edge: critical role of inducible costimulator in germinal center reactions.

Inducible costimulator (ICOS) is a new member of the CD28/CTLA-4 family that is expressed on activated and germinal center (GC) T cells. Recently, we reported that ICOS-deficient mice exhibited profound defects in T cell activation and effector function. Ab responses in a T-dependent primary reaction and in a murine asthma model were also diminished. In the current study, we investigate the mechanism by which ICOS regulates humoral immunity and examine B cell GC reactions in the absence of ICOS. We found that ICOS(-/-) mice, when immunized with SRBC, had smaller GCs. Furthermore, IgG1 class switching in the GCs was impaired. Remarkably, GC formation in response to a secondary recall challenge was completely absent in ICOS knockout mice. These data establish a critical role of ICOS in regulation of humoral immunity.

Animals↗
PubMed2001

Developmental changes of (3)H-labelled mu-opioid receptors in brainstems of intra-uterine growth-restricted rats.

The opioid mu-system is involved in brainstem-mediated respiratory control. Infants with intra-uterine growth restriction (IUGR) have more respiratory disorders in the early postnatal period. Using [(3)H]DAGO, a mu-selective ligand, and a computer-based image analysis of autoradiography, we compared the ontogeny and distribution of mu-opioid binding sites in the brainstem of IUGR and control rats in utero (E21), at birth (P0) and on postnatal days 1 (P1), P7, P10, P14 and P21. The ontogeny pattern was found to be similar in both groups. The density of the binding sites, which was low in E21, increased at P0, slightly declined at P1 and remained relatively constant thereafter. The distribution of DAGO-binding sites, also similar in both groups, was heterogeneous and was much denser in the dorsal areas of medulla and pons. In particular, binding sites were highly concentrated in nuclei involved in the cardio-respiratory function. However, DAGO-binding density was higher at all ages (except for P0 and P1) in IUGR than in control rats. Taken together, these results give at least a partial explanation for the effects of IUGR which lowers the Apgar score at birth and raises the incidence of respiratory disorders in infants.

Aging↗
PubMed2001

Sibling risks in cancer: clues to recessive or X-linked genes?

A systematic analysis of cancer risks to offspring and to siblings of cancer cases was carried out based on the nation-wide Swedish Family-Cancer Database. For all 13 cancer sites examined, risks to both offspring and siblings of cases of cancer at the same site were significantly elevated. The relative risk to siblings was approximately 2 fold more than the offspring risk for cancers of the prostate, testis, kidney and bladder, suggesting that recessive or X-linked susceptibility genes may be important for these cancers. Risks to siblings of cases where a parent was also affected were increased >20 fold over population rates for colorectal, ovarian, prostate and renal cancer, and for leukaemia, consistent with the effects of rare high-risk susceptibility alleles.

Family Health↗
PubMed2001

ICOS co-stimulatory receptor is essential for T-cell activation and function.

T-lymphocyte activation and immune function are regulated by co-stimulatory molecules. CD28, a receptor for B7 gene products, has a chief role in initiating T-cell immune responses. CTLA4, which binds B7 with a higher affinity, is induced after T-cell activation and is involved in downregulating T-cell responses. The inducible co-stimulatory molecule (ICOS), a third member of the CD28/CTLA4 family, is expressed on activated T cells. Its ligand B7H/B7RP-1 is expressed on B cells and in non-immune tissues after injection of lipopolysaccharide into animals. To understand the role of ICOS in T-cell activation and function, we generated and analysed ICOS-deficient mice. Here we show that T-cell activation and proliferation are defective in the absence of ICOS. In addition, ICOS -/- T cells fail to produce interleukin-4 when differentiated in vitro or when primed in vivo. ICOS is required for humoral immune responses after immunization with several antigens. ICOS-/- mice showed greatly enhanced susceptibility to experimental autoimmune encephalomyelitis, indicating that ICOS has a protective role in inflammatory autoimmune diseases.

Amino Acid Sequence↗
PubMed2001

Cancer risks to spouses and offspring in the Family-Cancer Database.

It is generally accepted that cancer is caused by environmental and inherited factors but these are only partially identified. Family studies can be informative but they do not separate shared lifestyles and genes. We estimate familial risks for concordant cancers between spouses in common cancers of both sexes in order to quantify cancer risks from the shared environment. The risks are compared to those seen between parents and offspring in order to estimate the inherited component. The nation-wide Family-Cancer Database was used as the source of family and cancer data. Standardized incidence ratios (SIRs) were calculated for concordant cancer in offspring by parental cancer and in spouses. Among the 23 cancer sites considered, all but two showed an increased SIR for offspring by father or mother. Only two sites, stomach and lung, showed an increase in SIR of concordant cancer among spouses. Additionally, pancreatic cancer and melanoma were increased in couples where at least one spouse was diagnosed before age 50. If both spouses presented melanoma before age 40, SIR was 3.82 for husbands. SIRs of colon, renal, and skin (squamous cell) cancers were unchanged by spouses' concordant cancer. Shared lifestyle among spouses seems to explain only a small proportion of cancer susceptibility. Because lifestyles are likely to differ more between parents and offspring than between spouses, familial cancer risks between parents and offspring are likely to be more due to heritable rather than environmental effects.

Adolescent↗
PubMed2001

Abnormal DNA-binding of transcription factors in minimal change nephrotic syndrome.

The activation of transcription factors such as nuclear factor kappaB (NF-kappaB) and activator protein 1 (AP-1) plays an important role in regulating the expression of target genes, including those for cytokines involved in pathogenesis of minimal change nephrotic syndrome (MCNS). The therapeutic effects of glucocorticoids depend on the glucocorticoid receptor (GR) acting on gene transcription and interacting with certain transcription factors. To explore the role of transcription factors in the pathogenesis of MCNS and the therapeutic effects of glucocorticoids, we examined the DNA-binding abilities of NF-kappaB, AP-1, and GR in peripheral blood mononuclear cells (PBMC) from 6 children with MCNS and 6 healthy controls by electrophoretic mobility shift assay (EMSA). NF-kappaB and AP-1 DNA-binding abilities were significantly increased both at baseline and after stimulation by phorbol 12-myristate 13-acetate (TPA) in PBMC from MCNS patients compared with controls, but declined to normal levels after treatment with dexamethasone (DEX). GR DNA-binding abilities were significantly reduced at baseline and after treatment with TPA, but were enhanced markedly by DEX. There were strong correlations between urinary protein and the baseline DNA binding ability of NF-kappaB or AP-1, or GR. These results suggested that the abnormal activation of NF-kappaB and AP-1 and the reduction of GR DNA-binding abilities may be involved in the pathogenesis of MCNS. Inhibition of NF-kappaB and AP-1 and enhancement of GR DNA-binding abilities by DEX may form the molecular basis of the effects of glucocorticoids in MCNS.

Child↗
PubMed2001

Familial testicular cancer and second primary cancers in testicular cancer patients by histological type.

The Swedish Family-Cancer Database was used to assess familial cancer risks in first-degree relatives and the risks of second primary cancers in testicular cancer patients by the histological type of their testicular cancers. Standardised incidence ratios (SIRs) were employed to estimate cancer risks. Among 4650 patients, 1.3% were familial testicular cancer. Seminomas showed a 10 years later median age of onset than teratomas (30 versus 40 years). The familial risks of testicular cancer were 3.8 for fathers, 8.3 for brothers and 3.9 for sons; they were similar for the two histologies. The fraternal risks were elevated 2- to 2.8-fold for pure histologies compared with the mixed histologies. Significantly increased risks for subsequent cancers were observed in the stomach, pancreas, testis, kidney, bladder, thyroid and connective and lymphatic tissues in the patients. Our data support the contention that genetic predisposition is one of the major contributors to familial and multiple testicular cancers.

Adult↗
PubMed2001

Signaling by the JNK group of MAP kinases. c-jun N-terminal Kinase.

c-Jun N-terminal kinase (JNK) is one of the several main MAP kinase groups identified in mammals. Original studies by use of Jurkat T cells implicated JNK in T cell activation and interleukin (IL-2) expression. Recent advances using mouse genetic approaches have revealed novel functions of this pathway in primary mouse T cells. JNK is not essential for T-cell activation; instead, it is required for helper T differentiation into effector cells and their cytokine production. In this review, we summarize these advances in understanding the expression, function, and regulation of the JNK pathway in T-lymphocyte activation and differentiation.

Animals↗
PubMed2001

Population-based study of familial medullary thyroid cancer.

BACKGROUND: We wanted to carry out a population-based study on medullary thyroid cancer (MTC) in order to quantify familial risks. METHODS: MTC was studied in the Swedish Family-Cancer Database, updated in 1999 to cover individuals and offspring, born after 1934 with their biological parents, totaling 9.6 million persons. Cancer data were obtained from the Swedish Cancer Registry from year 1958 to 1996 and included 2,435 thyroid cancers among offspring. RESULTS: 65 offspring were identified with MTC, which was coded as a separate entity since 1985. 62% had neither affected parent nor sib. Most familial cases were diagnosed at ages 15 to 24 and sporadic cases 25 years later. The familial SIRs of MTC were 3,080 and 3,650 when either a parent or a sib had MTC; when both had MTC the SIR was 35,800. All the familial risks were highest in young age groups, 0-9 years. MEN 2 or MEN 2-like families were considered when one family member had a TC and an adrenal pheochromocytoma. SIR of MTC in offspring was 61,000 when a parent had a MEN 2-like cancer and a sib had MTC. CONCLUSIONS: We described familial and sporadic MTC in a population-based database. The familial risks of MTC may be the highest ever reported in population based studies.

Adolescent↗