Neoadjuvant chemotherapy versus neoadjuvant chemoradiotherapy for cancer of the esophagus or gastroesophageal junction: long-term results of a randomized clinical trial.

NeoRes I is a randomized phase II trial comparing neoadjuvant chemoradiotherapy with neoadjuvant chemotherapy in the treatment of resectable cancer of the esophagus or gastroesophageal junction. Patients with biopsy-proven adenocarcinoma or squamous cell carcinoma, T1N1 or T2-3N0-1 and M0-M1a (AJCC 6th ed.), were randomized to receive three 3-weekly cycles of cisplatin 100 mg/m2 day 1 and fluorouracil 750 mg/m2/24 hours, days 1-5 with or without the addition of concurrent radiotherapy 40 Gy, 2 Gy/fraction, 5 days a week, followed by esophageal resection with two-field lymphadenectomy. Primary endpoint was complete histopathological response rate in the primary tumor. Survival and recurrence patterns were evaluated as secondary endpoints. Between 2006 and 2013, 181 patients were enrolled in Sweden and Norway. All three chemotherapy cycles were delivered to 73% of the patients allocated to chemoradiotherapy and to 86% of the patients allocated to chemotherapy. 87% of those allocated to chemoradiotherapy received full dose radiotherapy. 87% in the chemoradiotherapy group and 86% in the chemotherapy group underwent tumor resection. Initial results showed that patients allocated to chemoradiotherapy more often responded with complete histopathological response in the primary tumor (28% vs. 9%). Treatment-related complications were similar between the groups although postoperative complications were more severe in the chemoradiotherapy group. This article reports the long-term results. Five-year progression-free survival was 38.9% (95% CI 28.9%-48.8%) in the chemoradiotherapy group versus 33.0% (95% CI 23.6%-42.7%) in the chemotherapy group, P = 0.82. Five-year overall survival was 42.2% (95% CI 31.9%-52.1%) versus 39.6% (95% CI 29.5%-49.4%), P = 0.60. There were no differences in recurrence patterns between the treatment groups. This is to our knowledge that the largest completed randomized trial comparing neoadjuvant chemotherapy with neoadjuvant chemoradiotherapy followed by esophageal resection in patients with cancer in the esophagus or gastroesophageal junction. Despite a higher tumor tissue response in those who received neoadjuvant chemoradiotherapy, no survival advantages were seen. Consequently, the results do not support unselected addition of radiotherapy to neoadjuvant chemotherapy as a standard of care in patients with resectable esophageal cancer.

Filaggrin loss-of-function mutation R501X and 2282del4 carrier status is associated with fissured skin on the hands: results from a cross-sectional population study.

BACKGROUND: Filaggrin metabolites act as osmolytes and are important for skin hydration. Carriers of filaggrin loss-of-function mutations have a higher prevalence of atopic dermatitis and dry skin. There is also evidence to suggest that filaggrin mutations increase the risk of hand eczema in atopic individuals. In our clinic, we have observed a distinct phenotype of hand eczema in patients with filaggrin mutation carrier status, characterized by fissured dermatitis on the dorsal aspect of the hands and with only sparse involvement of the palms including fine scaling. OBJECTIVES: To investigate whether filaggrin loss-of-function mutations are associated with skin fissures on the hands and/or fingers in the general population. METHODS: Participants in a population-based study were questioned about skin symptoms, genotyped for filaggrin mutation, patch tested for nickel allergy and skin prick tested. RESULTS: In an adjusted logistic regression analysis, filaggrin mutation status was significantly associated with fissured skin on the hands and/or fingers in adults (odds ratio 1·93, 95% confidence interval 1·05-3·55) and showed a nearly significant negative interaction with atopic dermatitis (P=0·055), suggesting that the effect was predominantly in subjects without atopic dermatitis. CONCLUSIONS: Filaggrin loss-of-function mutations seem not only to increase the risk of atopic dermatitis and dry skin but also the risk of fissures on the hands and/or fingers in subjects without atopic dermatitis. Prophylactic emollient therapy should be particularly encouraged in filaggrin loss-of-function mutation carriers.

Association between filaggrin null mutations and concomitant atopic dermatitis and contact allergy.

BACKGROUND: The phenotypic traits of people with the filaggrin mutation (FLG) genotype and atopic dermatitis (AD) are still under elucidation, and the association with concomitant AD and contact allergy (CA) has not previously been examined. AIM: To assess FLG status in a subset of patients with AD and a minimum of one positive patch-test reaction. METHODS: In total, 430 people from a hospital population and 3335 people from the general population were tested for FLG mutations by DNA hybridization to paramagnetic polystyrene beads and analysis on a multiplex analysis system. All of the individuals in the hospital population had a minimum of one CA. AD was diagnosed according to the UK Working Party Criteria, (questions-only version). Individuals from the hospital population who had both AD and CA were considered as cases, and comparison of mutation carrier frequency was estimated (χ(2) test) against individuals without AD but with CA from the hospital population, individuals from the general population, and individuals with AD from the general population. RESULTS: The mutation frequency in patients with AD and CA in the hospital population was significantly less than that of people with AD from the general population (OR = 0.54; 95% CI 0.30-0.98). No difference in mutation frequency was found between individuals with and without AD in the hospital population (OR = 1.40; 95% CI 0.70-2.79), or between individuals with AD and CA in the hospital population and in the overall general population (OR = 1.29; 95% CI 0.76-2.20). CONCLUSIONS: The spectrum of observable traits characteristic for the FLG mutation genotype in patients with AD is at present not defined. Our results indicate that the subset of patients with both AD and CA represent a phenotype of AD that is not associated with FLG mutations.

Development of a screening method to assess flood risk on danish national roads and highway systems.

A method to assess flood risk on Danish national roads in a large area in the middle and southern part of Jutland, Denmark, was developed for the Danish Road Directorate. Flood risk has gained renewed focus due to the climate changes in recent years and extreme rain events are expected to become more frequent in the future. The assessment was primarily based on a digital terrain model (DTM) covering 7,500 km2 in a 1.6 x 1.6 m grid. The high-resolution terrain model was chosen in order to get an accurate estimation of the potential flooding in the road area and in the immediate vicinity, but also put a high requirement on the methods, hardware and software applied. The outcome of the analysis was detailed maps (as GIS layers) illustrating the location of depressions with depths, surface area and volume data for each depression. Furthermore, preferential flow paths, catchment boundaries and ranking of each depression were calculated. The ranking was based on volume of depressions compared with upstream catchment and a sensitivity analysis of the runoff coefficient. Finally, a method for assessing flood risk at a more advanced level (hydrodynamic simulation of surface and drainage) was developed and used on a specific blue spot as an example. The case study shows that upstream catchment, depressions, drainage system, and use of hydrodynamic calculations have a great influence on the result. Upstream catchments can contribute greatly to the flooding.

The effect of tobacco smoking and alcohol consumption on the prevalence of self-reported hand eczema: a cross-sectional population-based study.

BACKGROUND: Hand eczema is a prevalent disorder that leads to high health care costs as well as a decreased quality of life. Important risk factors include atopic dermatitis, contact allergy and wet work whereas the role of null mutations in the filaggrin gene complex remains to be clarified. It has been debated whether life-style factors such as tobacco smoking and alcohol consumption are associated with hand eczema. OBJECTIVES: The current study aimed to investigate whether self-reported hand eczema was associated with smoking and alcohol consumption in the general population. METHODS: Between June 2006 and May 2008, a cross-sectional study was performed in the general population in Copenhagen, the capital of Denmark. A random sample of 7931 subjects aged 18-69 years old was invited to participate in a general health examination including a questionnaire; 3471 (44%) participated. Data were analysed with logistic regression analyses and associations were expressed as odds ratios (ORs) with 95% confidence intervals (CI). RESULTS: The prevalence of hand eczema was higher among previous smokers (OR = 1.13; CI = 0.90-1.40), current light smokers (OR = 1.51; CI = 1.14-2.02) and current heavy smokers (OR = 1.38; CI = 0.99-1.92) compared with never-smokers. CONCLUSIONS: Tobacco smoking was positively associated with hand eczema among adults from the general population in Denmark. Apparently, current light smokers (< 15 g daily) had a higher prevalence of hand eczema than current heavy smokers (> 15 g daily) but this needs to be reconfirmed. Alcohol consumption was not associated with hand eczema.

Filaggrin null mutations increase the risk and persistence of hand eczema in subjects with atopic dermatitis: results from a general population study.

BACKGROUND: Hand eczema is prevalent in the general population. It remains unclear whether or not filaggrin gene (FLG) null mutations increase the overall risk of hand eczema or only increase the risk of hand eczema in subjects with atopic dermatitis. OBJECTIVES: To investigate the association between FLG null mutations and hand eczema. METHODS: A random sample of 3335 adults from the general population in Denmark was patch tested, FLG genotyped for R501X and 2282del4 null mutations and questioned about hand eczema. RESULTS: Participants with combined presence of atopic dermatitis and FLG null mutation status had a significantly higher prevalence of hand eczema, an earlier onset of hand eczema and a higher persistence of hand eczema compared with subjects with normal FLG status and absence of atopic dermatitis. Logistic regression analyses revealed positive associations between hand eczema within the past 12 months and FLG null mutation status in participants with a history of atopic dermatitis [odds ratio (OR) 2.98; 95% confidence interval (CI) 1.27-7.01], but not in subjects without atopic dermatitis (OR 0.82; 95% CI 0.41-1.67). CONCLUSIONS: FLG null mutations were significantly associated with hand eczema (< 12 months) in subjects with atopic dermatitis. Combined atopic dermatitis and filaggrin null mutation status was strongly associated with early onset of hand eczema and hand eczema persistence.

The association between null mutations in the filaggrin gene and contact sensitization to nickel and other chemicals in the general population.

BACKGROUND: It was recently shown that filaggrin gene (FLG) null mutations are positively associated with nickel sensitization. We have hypothesized that histidine-rich filaggrin proteins in the epidermis chelate nickel ions and prevent their skin penetration and exposure to Langerhans cells. Furthermore, we have proposed that the low degree of genetic predisposition to nickel sensitization found by a Danish twin study was explained by a high prevalence of ear piercing among participants resulting in 'bypassing' of the filaggrin proteins. OBJECTIVES: To investigate the association between FLG null mutations and (nickel) contact sensitization. METHODS: A random sample of 3335 adults from the general population in Denmark was patch tested and genotyped for R501X and 2282del4 in the FLG gene. RESULTS: The combined carrier frequency of FLG null mutations was 8·1%. Nickel, fragrance and contact sensitization to at least one allergen were not associated with FLG null mutations. A crude analysis on women who did not have ear piercings revealed a positive association between FLG null mutations and nickel sensitization [8·3% vs. 2·4%; odds ratio (OR) 3·71, 95% confidence interval (CI) 0·73-18·96] as well as between FLG null mutations and allergic nickel dermatitis (8·3% vs. 1·3%; OR 6·75, 95% CI 1·17-38·91). FLG mutation status and atopic dermatitis were positively associated with neomycin or ethylenediamine sensitization. CONCLUSIONS: This study suggests that FLG null mutations may be a risk factor for the development of nickel sensitization. However, ear piercing was a much stronger risk factor in our general population and we could therefore identify a positive association only in women without ear piercings. Contact sensitization to specific chemicals is related to treatment exposure.

No association between nickel allergy and reporting cosmetic dermatitis from mascara or eye shadow: a cross-sectional general population study.

BACKGROUND: In theory, all pigmented make-up products may contain metal allergens including nickel. Eyelid dermatitis has previously been observed among nickel allergic dermatitis patients following exposure to nickel containing mascara and eye shadow. However, an association between nickel eyelid dermatitis and nickel in make-up products remains controversial. OBJECTIVE: This cross-sectional patch test study investigated whether the frequency of self-reported cosmetic dermatitis from mascara or eye shadow use was higher among nickel allergic Danish women than women without nickel allergy. METHODS: In 2006, a total of 1843 18-69 year old women completed a postal questionnaire including questions on cosmetic dermatitis and were patch tested with nickel sulphate. Data were analysed by logistic regression analyses and associations were expressed as odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: The prevalence of nickel allergy was similar among women who reported cosmetic dermatitis from eye shadow or mascara and among women who did not report such symptoms. Cosmetic dermatitis was positively associated with self-reported atopic dermatitis and age. CONCLUSION: Overall, no association between having nickel allergy and reporting cosmetic dermatitis from mascara or eye shadow use was found in the general population. This does not exclude a causal relationship in selected cases.

The impact of rising sea temperatures on an Arctic top predator, the narwhal.

Arctic top predators are expected to be impacted by increasing temperatures associated with climate change, but the relationship between increasing sea temperatures and population dynamics of Arctic cetaceans remains largely unexplored. Narwhals (Monodon monoceros) are considered to be among the most sensitive of Arctic endemic marine mammals to climate change due to their limited prey selection, strict migratory patterns and high site fidelity. In the context of climate change, we assume that the population dynamics of narwhals are partly influenced by changes in environmental conditions, with warm areas of increasing sea temperatures having lower abundance of narwhals. Using a unique large dataset of 144 satellite tracked narwhals, sea surface temperature (SST) data spanning 25 years (1993-2018) and narwhal abundance estimates from 17 localities, we (1) assessed the thermal exposure of this species, (2) investigated the SST trends at the summer foraging grounds, and (3) assessed the relationship between SST and abundance of narwhals. We showed a sharp SST increase in Northwest, Mideast and Southeast Greenland, whereas no change could be detected in the Canadian Arctic Archipelago (CAA) and in the Greenland Sea. The rising sea temperatures were correlated with the smallest narwhal abundance observed in the Mideast and Southeast Greenland (< 2000 individuals), where the mean summer sea temperatures were the highest (6.3 °C) compared to the cold waters of the CAA (0.7 °C) that were associated with the largest narwhal populations (> 40,000 individuals). These results support the hypothesis that warming ocean waters will restrict the habitat range of the narwhal, further suggesting that narwhals from Mideast and Southeast Greenland may be under pressure to abandon their traditional habitats due to ocean warming, and consequently either migrate further North or locally go extinct.

The prevalence and morbidity of sensitization to fragrance mix I in the general population.

BACKGROUND: The prevalence of sensitization to fragrance mix (FM) I and Myroxylon pereirae (MP, balsam of Peru) has decreased in recent years among Danish women with dermatitis. OBJECTIVES: This study investigated whether the decrease could be confirmed among women in the general population. Furthermore, it addressed the morbidity of FM I sensitization. METHODS: In 1990, 1998 and 2006, 4299 individuals aged 18-69 years (18-41 years only in 1998) completed a premailed questionnaire and were patch tested to FM I and MP. Data were analysed by logistic regression analyses and associations were expressed as odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: The prevalence of FM I and MP sensitization followed an inverted V-pattern among women aged 18-41 years (i.e. an increase from 1990 to 1998, followed by a decrease from 1998 to 2006). Logistic regression analyses showed that 'medical consultation due to cosmetic dermatitis' (OR 3.37, 95% CI 1.83-6.20) and 'cosmetic dermatitis within the past 12 months' (OR 3.53, CI 2.02-6.17) were significantly associated with sensitization to FM I. CONCLUSIONS: In line with trends observed in Danish patients with dermatitis, our results supported a recent decrease in the prevalence of FM I and MP sensitization in Denmark. The study also showed that fragrance sensitization was associated with self-reported cosmetic dermatitis and use of health care related to cosmetic dermatitis.

Contact allergy to allergens of the TRUE-test (panels 1 and 2) has decreased modestly in the general population.

BACKGROUND: The prevalence of contact allergy in the general population is nearly 20%. OBJECTIVES: This study aimed to monitor the development of contact allergy to allergens from the TRUE-test (panels 1 and 2) between 1990 and 2006. METHODS: Two random samples of adults from the general population in Copenhagen, Denmark, were invited to participate in a general health examination including patch testing. In 1990 and 2006, we patch tested and questioned 543 and 3460 adult Danes. Patch test readings were performed on day 2 only. RESULTS: The overall prevalence decreased significantly from 15.5% in 1990 to 10.0% in 2006, mainly as a result of a decrease in thimerosal allergy from 3.4% to 0.8%. Furthermore, the prevalence of cobalt allergy and rubber-related allergens decreased from 1.1% to 0.2% and from 1.5% to 0.2%, respectively. Stratification by sex and age group revealed decreasing prevalences of contact allergy in all male age groups and in young and middle-aged female age groups (18-55 years) whereas increasing prevalences were observed among older women (56-69 years). The diverging trend observed in women was probably explained by a cohort effect due to a change in the prevalence of nickel allergy following the Danish regulation on nickel exposure. CONCLUSIONS: Although the overall prevalence of contact allergy decreased in the general population, frequent contact allergens such as fragrance mix II and methyldibromo glutaronitrile were not tested. Thus, contact allergy remains prevalent in the general population.

Inverse relationship between contact allergy and psoriasis: results from a patient- and a population-based study.

BACKGROUND: An inverse association between contact allergy and autoimmune diseases has been suggested. Psoriasis is an autoimmune disease and it has been debated whether contact allergy is less prevalent among patients with psoriasis. Previous studies have shown conflicting results. OBJECTIVES: To examine a possible association between contact allergy and psoriasis in two conceptually different epidemiological studies. PATIENTS AND METHODS: Two study populations were included: (i) a clinic-based register linkage study population, achieved by record linking information from the Danish National Hospital Registry identifying patients with psoriasis with information on contact allergy from a comprehensive patch test database of 15,641 patients; and (ii) a population-based cross-sectional study population organized in 1990, 1998 and 2006 and obtained by random samples from the Danish Central Personal Register. Information was obtained by questionnaire and patch testing of 4989 subjects. RESULTS: An inverse association was found between a psoriasis diagnosis and a positive patch test in both studies. The odds ratio for a person with a psoriasis diagnosis of having a positive patch test was, adjusted for sex and age, 0.58 [95% confidence interval (CI) 0.49-0.68] and 0.64 (95% CI 0.42-0.98), respectively, in the two studies. CONCLUSIONS: The finding of an inverse association between psoriasis and contact allergy may express opposite immunological mechanisms and calls for additional research in this field.

Clinical severity and prognosis of hand eczema.

BACKGROUND: Hand eczema (HE) is a frequent, long-lasting disease with both personal and societal repercussions. Consequently, more information is needed on factors that maintain symptoms. OBJECTIVES: In this study, patients with HE were followed for 6 months from the first visit to a dermatologist to identify factors associated with severe disease and a poor prognosis. METHODS: Study participants were 799 patients with HE from nine dermatological clinics in Denmark. Severity assessment of the HE was done at baseline and at the 6-month follow-up using the Hand Eczema Severity Index (HECSI) and by patients using a self-administered photographic guide. Additional information was obtained from a baseline questionnaire. RESULTS: At baseline, 60.3% assessed their HE as moderate to very severe using the self-administered photographic guide compared with 36.1% at follow-up. The mean HECSI value decreased from 19.9 points at baseline to 11.2 points at follow-up (P < 0.001). In a multivariable logistic regression analysis, statistically significant associations with severe HE at baseline were older age (P < 0.001), atopic dermatitis (P = 0.01) and > or = 1 positive patch test (P < 0.001). Being an unskilled worker was a predictor for a poor prognosis at follow-up (P = 0.04), and the presence of frequent symptoms during the previous 12 months was associated with severe initial disease (P = 0.02) and a poor prognosis (P = 0.04). CONCLUSIONS: Overall, the disease had improved 6 months after the dermatological examination: nevertheless, many patients continued to have significant symptoms. Dermatologists should pay special attention to patients with frequent eruptions and to unskilled workers.

Monitoring the startup of a wet detention pond equipped with sand filters and sorption filters.

The startup of a wet retention pond designed for extended stormwater treatment was monitored by more than one year of continual measurement of hydraulic parameters, nutrients and quality parameters in the pond itself (pH, temperature, dissolved oxygen, turbidity). The data revealed that photosynthesis played an important role for dissolved oxygen and pH for most of the year. Another important observation was that the pond behaved more like a completely mixed reactor than like a plug flow reactor--even though the length to width ratio was as high as 4.5:1. The pond was equipped with sand filters and sorption filters whereby very good nutrient removal efficiencies were achieved.

Virus-associated cancers in Greenland: frequent hepatitis B virus infection but low primary hepatocellular carcinoma incidence.

The incidence of primary hepatocellular carcinoma (PHC) in Greenland between 1960 and 1981 was determined and compared with the rate of this disease in Denmark. The annual age and sex rate (per 100,000) was not significantly different (overall, 1.9 vs. 2.2) despite a large difference in the prevalence of hepatitis B surface antigen (HBsAg) and anti-HBs markers of hepatitis. On the basis of a recent report of a very strong risk of PHC among male HBsAg carriers, 4.0 cases of PHC per year were expected in male Eskimos, but only 0.2 cases per year were observed. The incidence rates of other cancers suggested to be virally associated, including nasopharyngeal carcinoma, salivary gland cancer, and carcinoma of the cervix, were all high in Greenland compared to rates for the Danish population, and these high incidence rates are in accord with the markedly higher prevalences in Greenland Eskimos of viruses with which these other cancers have been associated. Thus Greenland Eskimos do not have a high incidence of PHC despite a high prevalence of HBsAg carriers, which suggests that other carcinogenic factors in this environment may be absent or that protective factors are present.

Telomerase activity is associated with cell cycle deregulation in human breast cancer.

Deregulation of the cell cycle by abnormal expression of one or several cell cycle regulatory proteins is a common finding in malignant tumors and might be a prerequisite for cancer development. Telomerase activity is an immortalization marker that is found in most cancers and for which an association with an active cell cycle has been implicated. In the tissue of 106 human breast carcinomas, we analyzed the relationship between telomerase activity levels and defects in the cell cycle machinery with a focus on the retinoblastoma protein (pRB) pathway(s). The fraction of telomerase-positive tumors was 85%, and large differences in telomerase activity were found. Overexpression of cyclin D1 and/or cyclin E, in combination with a normal pRB, was a typical feature of tumors with high telomerase activity levels. Down-regulation of p16INK4 was not related per se to telomerase activity, but tumors with low p16INK4 in combination with cyclin D1 or E overexpression demonstrated high activity. Tumor cell proliferation, determined by Ki-67 expression, correlated significantly to telomerase activity levels. There was, however, not a strict association between proliferation rate and telomerase activity, because tumors with inactivated pRB had the highest Ki-67 fractions but intermediate telomerase activity. Also, cyclin D1 overexpression was associated with high telomerase levels without an increase in tumor cell proliferation. The present study indicates that telomerase activation occurs preferentially in breast cancers with certain cell cycle regulatory defects and that telomerase activity levels may depend on the specific defect(s).

Deregulation of cyclin E and D1 in breast cancer is associated with inactivation of the retinoblastoma protein.

Inactivation of the retinoblastoma protein (pRB) by mutations or abnormal phosphorylation is a mechanism by which tumour cells can subdue normal growth control. Among molecules involved in control of pRB phosphorylation, cyclin D1 and E have been found to be deregulated and overexpressed in various types of cancers. In order to study the cell cycle regulatory mechanisms in breast cancer, we have analysed the protein expression of cyclin D1 and E in 114 tumour specimens from patients with primary breast cancer using Western blotting. Twenty-five out of 34 tumours with overexpression of cyclin E showed uniform low cyclin D1 expression, and by immunohistochemical analysis of pRB we present evidence for the existence of pRB defects in approximately 40% of these tumours in contrast to no pRB defects in the other group of tumours. This result was supported by a high protein expression of the cyclin-dependent kinase inhibitor p16 in 44% of the tumours with high cyclin E and low D1 expression, and all immunohistochemical pRB defect tumours showed a high p16 protein level. Additionally, an abnormal low pRB phosphorylation in relation to a high proliferative activity and loss of heterozygosity of the retinoblastoma susceptibility gene locus were found in all but one tumour with immunohistochemical defect pRB. Interestingly, tumours with high cyclin E and low D1 expression were generally oestrogen receptor negative suggesting a role for cell cycle regulators in the mechanisms leading to oestrogen independent tumour growth. Furthermore, the prognosis differed markedly for the patients in the various groups of tumours, indicating that the heterogeneous nature of breast cancer pathogenesis and the clinical course in part could be explained by different and distinctive sets of cell cycle defects.

Cyclin E dependent kinase activity in human breast cancer in relation to cyclin E, p27 and p21 expression and retinoblastoma protein phosphorylation.

The cell cycle machinery is regulated by cyclin dependent kinases and sets of activating and inhibitory proteins. The G1-S control mechanism is often deregulated in tumours supposedly leading to increased kinase activity, phosphorylation of substrates and subsequent S phase entrance. Increased kinase activity has been proposed to be essential in cell cycle aberrations, but few studies have actually shown enhanced kinase activity related to specific cell cycle defects in primary tumours. In the present study we have determined the cyclin E dependent kinase activity (cyclin E(kinase)) in 59 primary breast cancers, using an H1-kinase assay, and related the activity to the expression of cyclin E, p27 and p21. In a subgroup of 48 tumours, we further characterized the association between cyclin E(kinase), in vivo phosphorylation of the retinoblastoma protein (pRb) and proliferation. The cyclin E(kinase) correlated significantly with cyclin E content and inversely with p27 and p21 expression. P27, but not p21, was associated with low cyclin E(kinase) in specimens with normal/low levels of cyclin E. At elevated cyclin E levels, suppression of cyclin E(kinase) seemed to require high levels of both p21 and p27. The cyclin E(kinase) correlated with the phosphorylation status of pRb as well as with proliferation. Surprisingly, pRb phosphorylation did not correlate with proliferation. Our results support that pRb is a substrate for cyclin E(kinase) in primary breast cancer and that deregulation of cyclin E and p27 act through increased CDK-kinase activity, but cyclin E associated events beside pRb phosphorylation might be rate-limiting for entrance into S phase.

Downregulation of the potential suppressor gene IGFBP-rP1 in human breast cancer is associated with inactivation of the retinoblastoma protein, cyclin E overexpression and increased proliferation in estrogen receptor negative tumors.

The complex insulin-like growth factor network of ligands, receptors and binding proteins has been shown to be disturbed in breast cancer. In addition to defects in proteins controlling cell cycle checkpoints, this type of aberrations could affect tumor growth and survival thereby influencing both tumor aggressiveness and potential response to treatments. We have previously identified the T1A12/mac25 protein, which is identical to the IGFBP-rP1, as a differentially expressed gene product in breast cancer cells compared with normal cells. Here we compare the expression of IGFBP-rP1 in 106 tumor samples with known status of cell cycle aberrations and other clinicopathological data. This was done using a tumor tissue section array system that allows for simultaneous immunohistochemical staining of all samples in parallel. Cytoplasmic staining of variable intensity was observed in most tumors, 15% lacked IGFBP-rP1 staining completely, 20% had weak staining, 32% intermediate and 33% showed strong staining. Low IGFBP-rP1 was associated with high cyclin E protein content, retinoblastoma protein (pRb) inactivation, low bcl-2 protein, poorly differentiated tumors and higher stage. There was a significantly impaired prognosis for patients with low IGFBP-rP1 protein tumors. Interestingly, IGFBP-rP1 showed an inverse association with proliferation (Ki-67%) in estrogen receptor negative tumors as well as in cyclin E high tumors suggesting a separate cell cycle regulatory function for IGFBP-rP1 independent of interaction with the estrogen receptor or the pRb pathway.

Screening nonimmigrant visitors to the United States for tuberculosis: report of the Council on Scientific Affairs.

OBJECTIVE: To assess the desirability of requiring proof of tuberculosis (TB) screening for nonimmigrant visitors to the United States. DATA SOURCES: Literature review using the MEDLINE database for 1966 to 1999 and the Lexis-Nexis database for 1998 to 1999 on the terms tuberculosis and transmission, combined with the qualifiers foreign visitors, foreign students, foreign born, and policy. Experts in TB control from the Centers for Disease Control and Prevention, Atlanta, Ga, and the Canadian government were consulted. The World Wide Web was searched using the terms tuberculosis and transmission. DATA EXTRACTION: English-language articles with information directly related to control of TB transmission among foreign-born persons were selected. RESULTS AND CONCLUSIONS: Eliminating TB in the United States will depend significantly on the ability to control it within the foreign-born population; however, strict border screening guidelines used as exclusionary measures can actually worsen the epidemic. Overseas TB screening of nonimmigrant visitors, who are unlikely to have active TB and even less likely to transmit it, will be of extremely low yield, would significantly deviate from the US "open-door" policy for nonimmigrants, and would have great logistical and political implications. Foreign-born persons 15 years and older who intend to stay in the United States are the high-risk population most likely to affect public health and thus will provide the best yield for TB control resources. Screening and monitoring the nonimmigrant foreign-born population would divert valuable resources from now established, successful TB control programs for foreign-born immigrants.