Recent studies have suggested that some ovarian and pelvic serous carcinomas could originate from the fimbriated end of the distal fallopian tube. To test this hypothesis, we immortalized a normal human fallopian tube epithelial (FTE) cell line by using retrovirus-mediated overexpression of the early region of the SV40 T/t antigens and the human telomerase reverse transcriptase subunit (hTERT). These immortalized FTEs were then transformed by ectopic expression of oncogenic human HRASV12. Tumorigenicity of the immortalized and/or transformed cells was subsequently tested by anchorage-independence growth assay and inoculation into nude mice via subcutaneous and intraperitoneal injection. As expected, the HRASV12-transformed FTEs produced tumors through both subcutaneous and intraperitoneal injections, whereas no tumor growth was observed in immortalized FTEs. Unexpectedly, histopathological examination of tumors resulting from subcutaneous as well as intraperitoneal injections revealed largely poorly differentiated mucinous adenocarcinoma mixed with undifferentiated carcinoma. The tumor implants invaded extensively to the liver, colon, spleen, omentum, adrenal gland and renal capsule. Immunohistochemical staining of tumor cells showed positive staining for the epithelial cell markers cytokeratin AE1/AE3 and Müllerian lineage marker PAX8. Our study demonstrates that FTEs can generate poorly differentiated mucinous adenocarcinoma mixed with undifferentiated carcinoma through genetic modifications. Thus, we provide the first experimental evidence that fimbrial epithelial cells of the fallopian tube could be a potential source of ovarian mucinous adenocarcinoma.
fallopian tube epithelial cells; mucinous adenocarcinoma; oncogene; retrovirus; transformation
NF-κB is a transcription factor known to promote tumorigenesis. However, NF-κB is also known to be proapoptotic and may potentially function as a tumor suppressor, although such a functional role has not been extensively investigated in human cancer.
A dominant-negative mutant of IκBα with mutations at S32A and S36A was used to inhibit the function of NF-κB in ovarian cancer cell lines. The transcription ability, tumorigenesis, apoptosis, and drug sensitivity were examined in derivative cell lines in comparison with parental cells. We also analyzed the association of nuclear expression of NF-κB p65 with patient survival in an ovarian cancer tissue array.
We show that NF-κB functions as a tumor suppressor in four ovarian cancer cell lines, but it functions as an oncogene in their aggressive chemoresistant isogenic variants. NF-κB can exert its proapoptotic or antiapoptotic effect by activating or repressing mitogen-activated protein kinase (MAPK) phosphorylation in parental or aggressive chemoresistant variant cell lines. We also show that the nuclear accumulation of p65 in epithelial cancer tissue is associated with a good response to chemotherapy and can predict longer overall survival for patients with ovarian cancer.
Our data provide strong evidence that NF-κB can function as a biphasic regulator, either suppressing or enhancing ovarian cancer growth through the regulation of MAPK and cellular apoptosis.
This review reports on the results of a comprehensive literature search of studies examining the physical and mental health characteristics of older adults in the United States who use heroin. Multiple databases were searched for papers meeting the inclusion criteria of heroin users who were age 50 years or older. A total of 14 articles covering 9 different studies met the review inclusion criteria. All of the studies were convenience samples, and seven of the nine studies (77.8%) were entirely drawn from substance abuse treatment programs, primarily methadone maintenance programs. Findings from the qualitative studies suggest that the marginalization of older heroin users was a predominant experience that impacted intent to seek treatment as well as treatment retention. While articles reported high levels of physical and psychological/psychiatric comorbidities with substance misuse, research on heroin use and methadone treatment among older adults is scant and the quantitative findings are inconsistent. The articles reviewed in this study demonstrate that the needs of this population will be significant, yet the development of appropriate interventions and treatment for older adult heroin users will be contingent on empirical research that adequately describes mental and physical health problems.
Heroin; methadone maintenance treatment; mental health disorders; physical health problems
Aurora kinase A (AURKA), a serine/threonine kinase, has been shown to regulate the cell cycle checkpoint and maintain genomic integrity. AURKA is overexpressed in various carcinomas. Breast cancer 2, early onset (BRCA2) has an important role in maintaining genomic stability and acts as a tumor suppressor. Our recent study suggested that AURKA regulates genomic instability and tumorigenesis through cell cycle dysregulation and suppression of BRCA2 expression. However, the expression of AURKA, BRCA2 and their clinical significance is unknown in endometrioid ovarian cancer. In this study, we determined AURKA and BRCA2 expression in endometrioid ovarian carcinoma and correlated them with clinicopathologic characteristics and patient survival. Immunohistochemical staining was performed in 51 primary endometrioid ovarian carcinoma tumor samples, using tissue microarray. We then analyzed the associations between AURKA and BRCA2 expression and clinical factors (tumor grade, disease stage, surgical type, clinical response, and relapse) and overall and disease-free survival durations. AURKA and BRCA2 expression were found in 48 and 29% of the samples, respectively. The results of Fisher’s exact test suggested that AURKA expression was significantly associated with no family history of ovarian cancer (P=0.03) and that BRCA2 expression was associated with early-stage disease (P=0.03), low ascites incidence (P=0.03), younger age (<60) at diagnosis (P=0.03), and low-grade tumors (P<0.01). The nuclear BRCA2 score was negatively correlated with AURKA score (P=0.019, two-tailed Pearson correlation). A log-rank test demonstrated that AURKA expression was associated with shorter overall (P=0.001) and disease-free (P=0.009) survival durations, and that BRCA2 expression was associated with longer overall (P=0.000) and disease-free (P=0.002) durations. Patients with BRCA2-positive and AURKA-negative tumors had higher overall (P=0.001) and disease-free (P=0.001) survival rates than did patients with AURKA-positive and BRCA2-negative tumors. Our results demonstrate that a negative regulatory loop exists between AURKA and BRCA2 expression in the ovarian endometrioid carcinoma. AURKA expression is an unfavorable prognostic factor in patients with endometrioid ovarian cancer and BRCA2 is favorable, combination of these two markers may better predict the prognosis of patients with endometrioid ovarian carcinoma than individual marker alone.
AURKA; BRCA2; endometrioid ovarian carcinoma; prognostic factors
Chemokine receptor CXCR2 is associated with malignancy in several cancer models; however, the mechanisms involved in CXCR2-mediated tumor growth remain elusive. Here, we investigated the role of CXCR2 in human ovarian cancer.
CXCR2 expression was silenced by stable small hairpin RNA in ovarian cancer cell lines T29Gro-1, T29H, and SKOV3. Western blotting, immunofluorescence, enzyme-linked immunosorbent assay, flow cytometry, electrophoretic mobility shift assay, and mouse assay were used to detect CXCR2, interleukin-8, Gro-1, cell cycle, apoptosis, DNA binding of NF-κB, and tumor growth. Immunohistochemical staining of CXCR2 was done in 240 high-grade serous ovarian carcinoma samples.
Knockdown of CXCR2 expression by small hairpin RNA reduced tumorigenesis of ovarian cancer cells in nude mice. CXCR2 promoted cell cycle progression by modulating cell cycle regulatory proteins, including p21 (waf1/cip1), cyclin D1, CDK6, CDK4, cyclin A, and cyclin B1. CXCR2 inhibited cellular apoptosis by suppressing phosphorylated p53, Puma, and Bcl-xS; suppressing poly(ADP-ribose) polymerase cleavage; and activating Bcl-xL and Bcl-2. CXCR2 stimulated angiogenesis by increasing levels of vascular endothelial growth factor and decreasing levels of thrombospondin-1, a process likely involving mitogen-activated protein kinase, and NF-κB. Overexpression of CXCR2 in high-grade serous ovarian carcinomas was an independent prognostic factor of poor overall survival (P < 0.001) and of early relapse (P = 0.003) in the univariate analysis.
Our data provide strong evidence that CXCR2 regulates the cell cycle, apoptosis, and angiogenesis through multiple signaling pathways, including mitogen-activated protein kinase and NF-κB, in ovarian cancer. CXCR2 thus has potential as a therapeutic target and for use in ovarian cancer diagnosis and prognosis.
Late life depression is prevalent in older adults who are dependent on opiates. Depressive disorders among opiate abusers have detrimental effects on their well-being and ability to refrain from illegal drugs. There are numerous barriers to the provision of appropriate mental health care to older adults receiving methadone maintenance treatment. This article focuses on problem solving therapy (PST) and presents evidence that PST may be a promising non-pharmacological treatment for older methadone clients with comorbid depressive disorders that can be applied within the staffing and resource limits of methadone maintenance treatment facilities. The advantages of PST relative to other behavioral therapies for this population are based on evidence that PST is less cognitively demanding for an older adult population with mood and substance use disorders. A properly modified PST for an older adult substance dependent population with subsyndromal or diagnosed depression may be a viable option for methadone maintenance programs with limited resources.
Stigma associated with mental illness continues to be a significant barrier to help seeking, leading to negative attitudes about mental health treatment and deterring individuals who need services from seeking care. This study examined the impact of public stigma (negative attitudes held by the public) and internalized stigma (negative attitudes held by stigmatized individuals about themselves) on racial differences in treatment seeking attitudes and behaviors among older adults with depression.
Random digit dialing was utilized to identify a representative sample of 248 African American and White adults older adults (over the age of 60) with depression (symptoms assessed via the Patient Health Questionnaire-9). Telephone based surveys were conducted to assess their treatment seeking attitudes and behaviors, and the factors that impacted these behaviors.
Depressed older adult participants endorsed a high level of public stigma and were not likely to be currently engaged in, nor did they intend to seek mental health treatment. Results also suggested that African American older adults were more likely to internalize stigma and endorsed less positive attitudes toward seeking mental health treatment than their White counterparts. Multiple regression analysis indicated that internalized stigma partially mediated the relationship between race and attitudes toward treatment.
Stigma associated with having a mental illness has a negative influence on attitudes and intentions toward seeking mental health services among older adults with depression, particularly African American elders. Interventions to target internalized stigma are needed to help engage this population in psychosocial mental health treatments.
Stigma; Depression; Treatment; Aging
This study examines how underrepresented older urban and rural-dwelling individuals conceptualize participation in cognitive impairment studies. Nine focus groups were held with urban and rural-dwelling older adults who had participated in a community-based memory screening study. Expected and experienced benefits of research participation were motivators for study participation in all focus groups. Results indicate that participation in memory research was believed to lead to an understanding of memory function. Focus group participants expressed an active interest in research on dementia, and viewed research participation as a way to address memory concerns and provide a benefit to society.
underrepresented older adults; research participation; dementia; mild cognitive impairment; focus groups
F-18-fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) scans are positive in any condition which increases metabolism in a mass or tissue and are therefore not specific for neoplastic conditions. The use of an SUV cutoff value of 2.5 may not always help discriminate between benign and malignant cases. For a practicing cytopathologist doing adequacy checks during an image-guided procedure, it may be of value to be aware that elevated SUV values are not always indicative of a malignant process, and vice versa.
Older adults are particularly vulnerable to the effects of depression, however, they are less likely to seek and engage in mental health treatment. African-American older adults are even less likely than their White counterparts to seek and engage in mental health treatment. This qualitative study examined the experience of being depressed among African-American elders and their perceptions of barriers confronted when contemplating seeking mental health services. In addition, we examined how coping strategies are utilized by African-American elders who choose not to seek professional mental health services.
A total of 37 interviews were conducted with African-American elders endorsing at least mild symptoms of depression. Interviews were audiotaped and subsequently transcribed. Content analysis was utilized to analyze the qualitative data.
Thematic analysis of the interviews with African-American older adults is presented within three areas: (1) Beliefs about Depression Among Older African-Americans: (2) Barriers to Seeking Treatment for Older African-Americans: and (3) Cultural Coping Strategies for Depressed African-American Older Adults.
Older African-Americans in this study identified a number of experiences living in the Black community that impacted their treatment seeking attitudes and behaviors. which led to identification and utilization of more culturally endorsed coping strategies to deal with their depression. Findings from this study provide a greater understanding of the stigma associated with having a mental illness and its influence on attitudes toward mental health services.
depression; beliefs/attitudes; health service use; stigma; aging
The epidemiology of malaria in urban environments is poorly characterized, yet increasingly problematic. We conducted an unmatched case–control study of risk factors for malarial anemia with high parasitemia in urban Kisumu, Kenya, from June 2002 through February 2003. Cases (n = 80) were hospital patients with a hemoglobin level ≤ 8 g/dL and a Plasmodium parasite density ≥ 10,000/μL. Controls (n = 826) were healthy respondents to a concurrent citywide knowledge, attitude, and practice survey. Children who reported spending at least one night per month in a rural area were especially at risk (35% of cases; odds ratio = 9.3, 95% confidence interval [CI] = 4.4–19.7, P < 0.0001), and use of mosquito coils, bed net ownership, and house construction were non-significant, potentially indicating that malaria exposure during rural travel comprises an important element of risk. Control of severe malaria in an urban setting may be complicated by Plasmodium infections acquired elsewhere. Epidemiologic studies of urban malaria in low transmission settings should take travel history into account.
Papillary differentiation is one of the most common histological features of ovarian cancer, although the underlying mechanism that leads to such differentiation is not known. We hypothesized that human ovarian surface epithelial cells can be transformed into carcinoma with papillary differentiation by overexpressing HER2/neu in these cells. Mice were injected either subcutaneously or intraperitoneally with two immortalized human ovarian surface epithelial cell lines after enforced expression of HER-2/neu. Mice subcutaneously injected with tumor cells from either the T29Nt or T80Nt developed undifferentiated carcinomas. In contrast, mice injected intraperitoneally with T29Nt cells developed papillary carcinoma, and those injected intraperitoneally with T80Nt cells developed undifferentiated carcinoma. Our results demonstrate that ovarian surface epithelial cells can develop into papillary carcinoma in mice, and that the induction of papillary differentiation depends not only on specific genetic modifications but also on the tumor microenvironment and epithelial cell type from ovary from different patients.
high grade serous carcinoma; HER2/neu; human ovarian surface epithelial cells; transformation
Serous carcinoma is the most common type of epithelial ovarian cancer. In this review, we provide a comprehensive picture of ovarian serous cancers from multiple aspects: the first part of this review summarizes the morphological, histological, and immunological signatures of ovarian serous carcinoma; subsequently, we review the history of the evolvement of different grading systems used in ovarian serous cancer; in the end, we focus on characterizing the genetics that underlie the 2-tiered pathways through which ovarian serous cancers are believed to arise: the low-grade and the high-grade pathways.
ovarian carcinoma; grading; morphology; molecular genetics; tumorigenesis
Cerebral sinus thrombosis has been reported as an uncommon complication of ulcerative colitis (UC), occurring in up to 7.5% of cases. It is suspected to be a consequence of genetic predisposition and the hypercoagulable state occurring during disease relapse. We report a case of a 23-year-old male patient with one-year history of UC. He presented to the Emergency Room with left-sided progressive hemiparesis, numbness, hemiparesthesia, and pain, which followed a recent exacerbation of UC. The patient died 3 days after admission and an autopsy revealed superior and inferior sagittal sinus and cortical vein thrombosis with associated cerebral edema, hemorrhagic infarction, and herniation. The gastrointestinal tract had continuous cobblestone appearance extending from rectum to cecum, with hemorrhage and ulceration, consistent with active UC. Awareness of this rare complication of UC can contribute to early recognition and attempts at treatment of this serious and often fatal condition.
Epithelial ovarian cancer, which comprises several histologic types and grades, is the most lethal cancer among women in the United States. In this review, we summarize recent progress in understanding the pathology and biology of this disease and in development of models for preclinical research. Our new understanding of this disease suggests new targets for therapeutic intervention and novel markers for early detection of disease.
Ovarian cancer; Pathology; Senescence; Disease Models; Review
Aldehyde dehydrogenase 1 (ALDH1), a detoxifying enzyme responsible for the oxidation of intracellular aldehydes, was shown to play a role in the early differentiation of stem cells, through its role in oxidizing retinol to retinoic acid. It has been shown that ALDH1 is a predictor of poor clinical outcome in breast cancer. The authors hypothesized that the level of ALDH1 expression may be correlated with the clinical outcome of patients with ovarian cancer. Immunohistochemical staining of ALDH1 expression was analyzed in 442 primary ovarian carcinomas using tissue microarray. The associations between the expression of the ALDH1 and clinical factors (diagnosis, tumor grade, stage, and clinical response to chemotherapy), as well overall and disease-free survival were analyzed. Expression of ALDH1 was found in 48.9% of the samples. Fisher's exact test suggested that high expression of ALDH1 was significantly associated with endometrioid adenocarcinoma (P < 0.0001), early-stage disease (P = 0.006), complete response to chemotherapy (P <0.05) and a low serum level of CA125 (P = 0.02). High percentage of cells expressing ALDH1 was associated with a longer overall survival time (P =0.01) and disease free survival time (P = 0.006) by Log rank test. In contrast to its role in breast cancer, ALDH1 was a favorable prognostic factor in ovarian carcinoma. ALDH1 therefore may play a different role in ovarian cancer than it does in breast cancer.
ALDH1; Ovarian Cancer; Immunohistochemistry; Prognosis
Phospho-enriched protein in astrocytes (PEA-15) is a 15-kDa phosphoprotein that slows cell proliferation by binding to and sequestering extracellular signal-regulated kinase (ERK) in the cytoplasm, thereby inhibiting ERK-dependent transcription and proliferation. In previous studies of E1A human gene therapy for ovarian cancer, we discovered that PEA-15 induced the antitumor effect of E1A by sequestering activated ERK in the cytoplasm of cancer cells. Here, we investigated the role of PEA-15 in ovarian cancer tumorigenesis, the expression levels of PEA-15 in human ovarian cancer, and whether PEA-15 expression correlated with overall survival in women with ovarian cancer. We overexpressed PEA-15 in low-PEA-15-expressing cells and knocked down PEA-15 in high-PEA-15-expressing cells and analyzed the effect on proliferation, anchorage-independent growth, and cell cycle progression. We then assessed PEA-15 expression in an annotated tissue microarray of tumor samples from 395 women with primary epithelial ovarian cancer and tested whether PEA-15 expression was linked with overall survival. PEA-15 expression inhibited proliferation, and cell cycle analysis did not reveal apoptosis but did reveal autophagy, which was confirmed by an increase in LC3 cleavage. Inhibition of the ERK1/2 pathway decreased PEA-15-induced autophagy. These findings suggested that the antitumor activity of PEA-15 is mediated in part by the induction of autophagy involving activation of the ERK1/2 pathway. Multivariable analyses indicated that the women with high-PEA-15-expressing tumors survived longer than those with low-PEA-15-expressing tumors (hazard ratio = 1.973, P = 0.0167). Our findings indicate that PEA-15 expression is an important prognostic marker in ovarian cancer.
survival; autophagy; ovarian neoplasms; PEA-15; ERK
Research into the biological role of the Ca2+-releasing second messenger NAADP (nicotinic acid adenine dinucleotide phosphate) has been hampered by a lack of chemical probes. To find new chemical probes for exploring NAADP signaling, we turned to virtual screening, which can evaluate millions of molecules rapidly and inexpensively. We used NAADP as the query ligand to screen the chemical library ZINC for compounds with 3D-shape and electrostatic similarity. We tested the top-ranking hits in a sea urchin egg bioassay and found that one hit, Ned-19, blocks NAADP signaling at nanomolar concentrations. In intact cells, Ned-19 blocked NAADP signaling and fluorescently labeled NAADP receptors. Moreover, we show the utility of Ned-19 as a chemical probe by using it to demonstrate that NAADP is a key causal link between glucose sensing and Ca2+ increases in mouse pancreatic beta cells.
Geohelminth infections are common in rural western Kenya, but risk factors and effects among pregnant women are not clear.
During a community-based cross-sectional survey, pregnant women were interviewed and asked to provide a blood sample and a single fecal sample. Hemoglobin was measured and a blood slide examined for malaria. Geohelminth infections were identified using the concentration and Kato-Katz method.
Among 390 participants who provided a stool sample, 76.2% were infected with at least one geohelminth: 52.3% with Ascaris lumbricoides, 39.5% with hookworm, and 29.0% with Trichuris trichiura. Infection with at least one geohelminth species was associated with the use of an unprotected water source (adjusted odds ratio [AOR] 1.8, 95% confidence interval [CI] 1.1–3.0) and the lack of treatment of drinking water (AOR 1.8, 95% CI 1.1–3.1). Geohelminth infections were not associated with clinical symptoms, or low body mass index. A hookworm infection was associated with a lower mid upper arm circumference (adjusted mean decrease 0.7 cm, 95% CI 0.3–1.2 cm). Hookworm infections with an egg count ≥1000/gram feces (11 women) were associated with lower hemoglobin (adjusted mean decrease 1.5 g/dl, 95% CI 0.3–2.7). Among gravidae 2 and 3, women with A. lumbricoides were less likely to have malaria parasitemia (OR 0.4, 95% CI 0.2–0.8) compared to women without A. lumbricoides, unlike other gravidity groups.
Geohelminth infections are common in this pregnant population; however, there were few observed detrimental effects. Routine provision of antihelminth treatment during an antenatal clinic visit is recommended, but in this area an evaluation of the impact on pregnancy, malaria, and birth outcome is useful.
In rural western Kenya, both malaria and intestinal infections with worms are common. Pregnant women are particularly vulnerable to infection with malaria, but the effect on pregnancy of intestinal infections with worms is not clear and may depend both on how heavy the worm infection is and on the type of worm. Additionally, it is not clear whether infections with worms may affect malaria infections. In this article, we begin to disentangle some of these issues. Intestinal infections with worms were diagnosed in three-quarters of 390 pregnant women in western Kenya who provided a stool sample. In these women, intestinal worm infections caused a modest decrease both in haemoglobin levels and indicators of nutritional status. Women in their second and third pregnancies who were diagnosed with one particular type of worm infection (Ascaris lumbricoides) were less likely to have malaria than other women in their second or third pregnancies who did not have this type of worm infection. Although our results suggest that it would be good advice to treat women with drugs for intestinal worm infections during their pregnancy in this area, the effect on maternal and infant health and malaria infection needs further study.
We describe reproductive health issues among pregnant women in a rural area of Kenya with a high coverage of insecticide treated nets (ITNs) and high prevalence of HIV (15%).
We conducted a community-based cross-sectional survey among rural pregnant women in western Kenya. A medical, obstetric and reproductive history was obtained. Blood was obtained for a malaria smear and haemoglobin level, and stool was examined for geohelminths. Height and weight were measured.
Of 673 participants, 87% were multigravidae and 50% were in their third trimester; 41% had started antenatal clinic visits at the time of interview and 69% reported ITN-use. Malaria parasitemia and anaemia (haemoglobin < 11 g/dl) were detected among 36% and 53% of the women, respectively. Geohelminth infections were detected among 76% of the 390 women who gave a stool sample. Twenty percent of women were underweight, and sixteen percent reported symptoms of herpes zoster or oral thrush in the last two months. Nineteen percent of all women reported using a contraceptive method to delay or prevent pregnancy before the current pregnancy (injection 10%, pill 8%, condom 0.4%). Twenty-three percent of multigravidae conceived their current pregnancy within a year of the previous pregnancy. More than half of the multigravidae (55%) had ever lost a live born child and 21% had lost their last singleton live born child at the time of interview.
In this rural area with a high HIV prevalence, the reported use of condoms before pregnancy was extremely low. Pregnancy health was not optimal with a high prevalence of malaria, geohelminth infections, anaemia and underweight. Chances of losing a child after birth were high. Multiple interventions are needed to improve reproductive health in this area.
Urban malaria is likely to become increasingly important as a consequence of the growing proportion of Africans living in cities. A novel sampling strategy was developed for urban areas to generate a sample simultaneously representative of population and inhabited environments. Such a strategy should facilitate analysis of important epidemiological relationships in this ecological context.
Census maps and summary data for Kisumu, Kenya, were used to create a pseudo-sampling frame using the geographic coordinates of census-sampled structures. For every enumeration area (EA) designated as urban by the census (n = 535), a sample of structures equal to one-tenth the number of households was selected. In EAs designated as rural (n = 32), a geographically random sample totalling one-tenth the number of households was selected from a grid of points at 100 m intervals. The selected samples were cross-referenced to a geographic information system, and coordinates transferred to handheld global positioning units. Interviewers found the closest eligible household to the sampling point and interviewed the caregiver of a child aged < 10 years. The demographics of the selected sample were compared with results from the Kenya Demographic and Health Survey to assess sample validity. Results were also compared among urban and rural EAs.
4,336 interviews were completed in 473 of the 567 study area EAs from June 2002 through February 2003. EAs without completed interviews were randomly distributed, and non-response was approximately 2%. Mean distance from the assigned sampling point to the completed interview was 74.6 m, and was significantly less in urban than rural EAs, even when controlling for number of households. The selected sample had significantly more children and females of childbearing age than the general population, and fewer older individuals.
This method selected a sample that was simultaneously population-representative and inclusive of important environmental variation. The use of a pseudo-sampling frame and pre-programmed handheld GPS units is more efficient and may yield a more complete sample than traditional methods, and is less expensive than complete population enumeration.
Although sub-Saharan Africa (SSA) is rapidly urbanizing, the terms used to classify urban ecotypes are poorly defined in the context of malaria epidemiology. Lack of clear definitions may cause misclassification error, which likely decreases the accuracy of continent-wide estimates of malaria burden, limits the generalizability of urban malaria studies, and makes identification of high-risk areas for targeted interventions within cities more difficult. Accordingly, clustering techniques were applied to a set of urbanization- and malaria-related variables in Kisumu, Kenya, to produce a quantitative classification of the urban environment for malaria research.
Seven variables with a known or expected relationship with malaria in the context of urbanization were identified and measured at the census enumeration area (EA) level, using three sources: a) the results of a citywide knowledge, attitudes and practices (KAP) survey; b) a high-resolution multispectral satellite image; and c) national census data. Principal components analysis (PCA) was used to identify three factors explaining higher proportions of the combined variance than the original variables. A k-means clustering algorithm was applied to the EA-level factor scores to assign EAs to one of three categories: "urban," "peri-urban," or "semi-rural." The results were compared with classifications derived from two other approaches: a) administrative designation of urban/rural by the census or b) population density thresholds.
Urban zones resulting from the clustering algorithm were more geographically coherent than those delineated by population density. Clustering distributed population more evenly among zones than either of the other methods and more accurately predicted variation in other variables related to urbanization, but not used for classification.
Effective urban malaria epidemiology and control would benefit from quantitative methods to identify and characterize urban areas. Cluster analysis techniques were used to classify Kisumu, Kenya, into levels of urbanization in a repeatable and unbiased manner, an approach that should permit more relevant comparisons among and within urban areas. To the extent that these divisions predict meaningful intra-urban differences in malaria epidemiology, they should inform targeted urban malaria interventions in cities across SSA.
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.
hMSH6; microsatellite instability; ovarian carcinoma; tissue microarrays
Aberrant DNA methylation has been found frequently in human breast cancers, associated with the loss of expression of a number of regulatory genes for growth and correlated to clinical outcomes. The present study was undertaken to determine whether methylation of a set of growth-suppressor genes would correlate to the expression of estrogen receptors (ERs) and progesterone receptors (PRs).
We used a pyrosequencing methylation analysis to study the methylation of 12 known growth-suppressor genes in 90 pairs of malignant/normal breast tissues. We also examined the expression of ERs and PRs in those specimens by immunohistochemistry. Mutations of p53 in tumor cells were detected by direct sequencing.
Twelve tumor-suppressor genes: ARHI, RASSF1A, HIN-1, RARβ2, hMLH1, 14-3-3 σ, RIZ1, p16, E-cadherin, RIL, CDH13, and NKD2 were selected for this methylation study. Five of them (RIL, HIN-1, RASSF1A, CDH13, and RARβ2) were frequently methylated in breast cancers (57%, 49%, 58%, 44%, and 17%, respectively) but not the normal breast (0–4%). Two panels of methylation profiles were defined. The methylation of the HIN-1/RASSFIA panel strongly correlated to the expression of ERs, PRs, and hormone receptors (HRs; which were defined as 'positive' if ERs and/or PRs were positive; p < 0.001). Conversely, the methylation of the RIL/CDH13 panel strongly correlated to negative ER, PR, and HR expression (p = 0.001, 0.025, and 0.001, respectively). The subset of triple-negative breast cancers (in other words, those with negative ER, PR, and HER-2/neu status) was positively associated with the methylation of the RIL/CDH13 panel and negatively associated with the HIN-1/RASSF1A panel. Mutations of p53 were found in nine breast tumors (11%), seven of which lacked methylation in both panels.
We have defined two panels (HIN-1/RASSFIA, and RIL/CDH13) of methylation profiles, which correlated, either positively or negatively, to HR status.