Quantum Fluctuations in Quasi-One-Dimensional Dipolar Bose-Einstein Condensates.

Recent experiments have revealed that beyond-mean-field corrections are much more relevant in weakly interacting dipolar condensates than in their nondipolar counterparts. We show that in quasi-one-dimensional geometries quantum corrections in dipolar and nondipolar condensates are strikingly different due to the peculiar momentum dependence of the dipolar interactions. The energy correction of the condensate presents not only a modified density dependence, but it may even change from attractive to repulsive at a critical density due to the surprising role played by the transversal directions. The anomalous quantum correction translates into a strongly modified physics for quantum-stabilized droplets and dipolar solitons. Moreover, and for similar reasons, quantum corrections of three-body correlations, and hence of three-body losses, are strongly modified by the dipolar interactions. This intriguing physics can be readily probed in current experiments with magnetic atoms.

HER3 expression in patients with primary colorectal cancer and corresponding lymph node metastases related to clinical outcome.

AIM: To evaluate the expression and prognostic value of the epidermal growth factor receptor HER3 in patients with primary colorectal cancer (CRC) and corresponding lymph node metastases. PATIENT AND METHODS: HER3 expression was analysed immunohistochemically (IHC) in primary tumours and in corresponding lymph node metastases from 236 patients with stage II and III CRC. In 58 primary tumours, fluorescence in situ hybridisation (FISH) detection was performed. RESULTS: HER3 was detected at high frequency in the cell membrane. Seventy percent of the primary tumours had a high HER3 expression compared to 75% in the lymph node metastases. HER3 expression in the primary tumour was an independent prognostic factor for overall survival in the entire group of patients (p=0.026) and in the subgroup of patients with colon cancer stage II (p=0.030). A high HER3 expression in the primary tumour was associated with worse clinical outcome. The expression of HER3 was homogenous within the primary tumour (r=0.9, p<0.0001) and correlated with the HER3 expression in corresponding lymph node metastases (r=0.6, p<0.0001). No gene amplification with respect to HER3 was seen in primary tumours using FISH analysis. CONCLUSION: A high HER3 expression was found in 70% of the primary CRC tumours and in 75% of the corresponding lymph node metastases. HER3 expression in the tumour was an independent prognostic factor, where a high HER3 expression was associated with worse clinical outcome. There was a correlation in HER3 expression between primary tumour and corresponding lymph node metastases.

Association studies on 11 published colorectal cancer risk loci.

BACKGROUND: Recently, several genome-wide association studies (GWAS) have independently found numerous loci at which common single-nucleotide polymorphisms (SNPs) modestly influence the risk of developing colorectal cancer. The aim of this study was to test 11 loci, reported to be associated with an increased or decreased risk of colorectal cancer: 8q23.3 (rs16892766), 8q24.21 (rs6983267), 9p24 (rs719725), 10p14 (rs10795668), 11q23.1 (rs3802842), 14q22.2 (rs4444235), 15q13.3 (rs4779584), 16q22.1 (rs9929218), 18q21.1 (rs4939827), 19q13.1 (rs10411210) and 20p12.3 (rs961253), in a Swedish-based cohort. METHODS: The cohort was composed of 1786 cases and 1749 controls that were genotyped and analysed statistically. Genotype-phenotype analysis, for all 11 SNPs and sex, age of onset, family history of CRC and tumour location, was performed. RESULTS: Of eleven loci, 5 showed statistically significant odds ratios similar to previously published findings: 8q23.3, 8q24.21, 10p14, 15q13.3 and 18q21.1. The remaining loci 11q23.1, 16q22.1, 19q13.1 and 20p12.3 showed weak trends but somehow similar to what was previously published. The loci 9p24 and 14q22.2 could not be confirmed. We show a higher number of risk alleles in affected individuals compared to controls. Four statistically significant genotype-phenotype associations were found; the G allele of rs6983267 was associated to older age, the G allele of rs1075668 was associated with a younger age and sporadic cases, and the T allele of rs10411210 was associated with younger age. CONCLUSIONS: Our study, using a Swedish population, supports most genetic variants published in GWAS. More studies are needed to validate the genotype-phenotype correlations.

Prognostic and predictive value of thymidylate synthase expression in primary colorectal cancer.

AIM: To investigate thymidylate synthase (TS) expression in primary colorectal cancer (CRC) as a prognostic and predictive marker of benefit for adjuvant chemotherapy. PATIENTS AND METHODS: TS expression was immuno0-histochemically (IHC) assessed on tumors from 1,389 patients with stage II and III CRC randomly assigned to either surgery alone or surgery plus 5-fluorouracil (5-FU)-based adjuvant chemotherapy. RESULTS: In the subgroup treated with surgery alone (n=708), TS expression was prognostic using the classification of TS 0-1 versus 2-3 (p=0.045) as well as TS classified as 0-2 versus 3 (p=0.002). A high TS expression was associated with a shorter overall survival. Among patients with TS grade 3 (n=460), the subgroup treated with adjuvant chemotherapy had a significant longer OS (p=0.005). CONCLUSION: In this study TS, immunohistochemically assessed, is a prognostic factor in CRC patients treated with surgery alone. Patients with the highest level of TS expression (grade 3) had an improved clinical outcome following adjuvant 5-FU-based chemotherapy.

Thymidylate synthase expression: an independent prognostic factor for local recurrence, distant metastasis, disease-free and overall survival in rectal cancer.

Several studies have suggested that the intratumoral level of thymidylate synthase (TS) in colorectal tumors correlates with survival. We have studied the correlation between TS expression in primary rectal cancer and locoregional recurrence, distant metastases, and survival. TS enzyme levels were evaluated immunohistochemically using the specific monoclonal antibody TS 106 in paraffin-embedded tumors from 243 patients who had undergone primary surgery for rectal cancer during the years 1980-1993. All patients were included in prospective randomized trials aimed at determining the clinical value of a short preoperative course of local radiation therapy (five doses of 5 Gy each). With a median follow-up of 94 months (range, 43-202 months), it was observed by multivariate analysis that Dukes' stage and TS expression were independent prognostic markers of locoregional recurrence (P < 0.001 and P = 0.038, respectively) distant metastasis (P < 0.001 and P = 0.011, respectively) disease-free survival (P < 0.001 and 0.014, respectively), and overall survival (P < 0.001 and 0.020, respectively). By multivariate analysis, preoperative irradiation therapy showed a borderline improvement in locoregional recurrence (P = 0.051). No other factors, such as age, sex, differentiation of the tumor, or p53 expression, were noted to be independent prognostic factors for clinical outcome in these patients. We concluded that the intratumoral expression of TS in primary rectal cancer is an independent prognostic factor for locoregional recurrence, distant metastases, disease-free survival, and overall survival. Patients with low intratumoral TS expression had a significantly better outcome than those with high TS expression.

Immunohistochemically detected thymidylate synthase in colorectal cancer: an independent prognostic factor of survival.

Intratumoral thymidylate synthase (TS) expression and M(r) 53,000 phosphoprotein (p53) overexpression were studied immunohistochemically in sections from stored paraffin-embedded primary colorectal cancers in 70 patients who had undergone surgery during the years 1987-1990. These cancers were classified according to Dukes' stage A-D, using monoclonal antibodies TS 106 and DO-7. In patients with Dukes' stage A-C tumors, univariate analyses showed that there was a significant correlation (P = 0.048) between disease-free survival and TS expression and between TS expression and time to death with colorectal cancer (P = 0.038). In patients with Dukes' stage A-D tumors, overall survival was correlated to TS expression (P = 0.015), Dukes' stage (P < 0.001), and level of tumor differentiation (P = 0.044) but not to p53 overexpression. Patients with low intratumoral TS expression survived significantly longer than patients with high expression. Cox multivariate analysis showed that Dukes' stage (P < 0.001) and TS expression (P = 0.043) could independently serve as prognostic factors for time to death with colorectal cancer in patients with Dukes' stage A-D tumors.

Evolution of a light-harvesting protein by addition of new subunits and rearrangement of conserved elements: crystal structure of a cryptophyte phycoerythrin at 1.63-A resolution.

Cryptophytes are unicellular photosynthetic algae that use a lumenally located light-harvesting system, which is distinct from the phycobilisome structure found in cyanobacteria and red algae. One of the key components of this system is water-soluble phycoerythrin (PE) 545 whose expression is enhanced by low light levels. The crystal structure of the heterodimeric alpha(1)alpha(2)betabeta PE 545 from the marine cryptophyte Rhodomonas CS24 has been determined at 1.63-A resolution. Although the beta-chain structure is similar to the alpha and beta chains of other known phycobiliproteins, the overall structure of PE 545 is novel with the alpha chains forming a simple extended fold with an antiparallel beta-ribbon followed by an alpha-helix. The two doubly linked beta50/beta61 chromophores (one on each beta subunit) are in van der Waals contact, suggesting that exciton-coupling mechanisms may alter their spectral properties. Each alpha subunit carries a covalently linked 15,16-dihydrobiliverdin chromophore that is likely to be the final energy acceptor. The architecture of the heterodimer suggests that PE 545 may dock to an acceptor protein via a deep cleft and that energy may be transferred via this intermediary protein to the reaction center.

Immunohistochemical determination of thymidylate synthase in colorectal cancer--methodological studies.

With the aid of specific monoclonal antibodies, an immunohistochemical technique has recently been developed for the detection of intratumoral thymidylate synthase (TS). This technique can be applied to paraffin-embedded material suitable for retrospective studies. In order to examine this technique further, the TS enzyme activity of lysates from frozen-stored colorectal cancer (CRC) specimens were compared with their immunohistochemical TS staining intensity (arbitrarily graded from 0 to 3). A statistically significant correlation between these two methods on a total of 25 tumour specimens (P < 0.001) was observed. The staining intensity in different areas of 48 paraffin-embedded CRCs was examined. Sixty-seven per cent of the tumours were homogeneously stained (either grades 0-1 or 2-3), 33% showed a heterogeneity in TS staining. Increased TS expression correlated with more advanced Dukes' stage (P < 0.001). It is concluded that TS immunostaining intensity reflects TS enzyme activity in colorectal tumours and is well suited for paraffin-embedded material. The TS immunostaining pattern is heterogeneous in up to one-third of the tumours.

Dual effects of folinic acid in 5-fluorouracil induced killing of human tumor cell lines in vitro.

Folinic acid (leucovorin) is frequently used to augment and modulate the clinical activity of 5-fluorouracil (5-FU) in patients with advanced gastrointestinal (Gl) cancer. However, there are conflicting opinions concerning the optimal doses for these patients, and whether folinic acid modulates the clinical activity of 5-FU in patients with non-Gl cancer. To elucidate these questions, model experiments have been performed on human tumor cell lines in vitro to determine the modulatory activity of various concentrations of folinic acid on 5-FU mediated cytotoxicity using a clonogenic assay. Three cell lines of colon cancer and 3 of glioblastoma origin were exposed to 5-FU alone or with folinic acid for 24 hours. It was observed that relatively low concentrations of folinic acid enhanced the cytotoxicity of 5-FU against the colon cancer lines whereas higher concentrations were less effective. Folinic acid did not enhance the 5-FU mediated killing of the glioma cell lines at any concentration (0.01-100 micrograms/ml). On the contrary, folinic acid seemed to counteract the cytotoxic effect of 5-FU in a reasonably dose-dependent fashion. These results may suggest that the value of folinic acid in the treatment of non-Gl cancer with 5-FU should be evaluated within the framework of controlled clinical trials, and that high doses of folinic acid may not necessarily be more effective than low.

Different dose regimens of 5-fluorouracil and interferon-alpha in patients with metastatic colorectal carcinoma.

Three different 5-fluorouracil (5-FU)-interferon-alpha-2b (IFN)-containing regimens were designed for treatment of patients with advanced colorectal cancer. 87 patients with a Karnofsky index > or = 70 were included in three sequential non-randomised phase II trials. Regimen A consisted of 5-FU (750 mg/m2/day) given as a continuous infusion on days 1-5 followed by weekly 1-h intravenous infusions until week 8. IFN (5 MU) was given subcutaneously on days 1, 3 and 5 followed by injections (9 MU) every second day until week 8. The cycle was then repeated. Regimen B consisted of 5-FU (750 mg/m2/day) given as a continuous infusion on days 1-5 followed by 5-min intravenous injections on days 12 and 19. IFN (3 MU) was given subcutaneously on days 1-5 followed by injections (5 MU) on days 11-13 and 18-20. The cycle was repeated every fourth week. Regimen C consisted of 5-FU (750 mg/m2/day) given as a continuous infusion on days 1-5. IFN (3 MU) was given subcutaneously on days 1-5. The cycle was repeated every third week. The objective response rates (complete response (CR) and partial response (PR)) after approximately 4 months of therapy or longer were as follows: regimen A (n = 27) 22% (2 CR, 4 PR), regimen B (n = 33) 42% (4 CR, 10 PR) and regimen C (n = 27) 22% (1 CR, 5 PR). The corresponding response figures for previously untreated patients were regimen A 50%, regimen B 64% and regimen C 38%. Response durations varied from a few weeks up to 142 + weeks. Toxicities were generally mild and reversible, and the treatments were convenient for the patients and cost effective since the 5-day infusions could be given by a portable pump without hospitalisation. Our results are in agreement with those of others showing that 5-FU/IFN combinations can be highly effective in advanced colorectal cancer, and that a number of factors such as doses, dose intensities, infusion rates and timing of the two drugs may be crucial for the anti-tumour activity of this drug combination.

Injury surveillance at emergency departments in an urban area. Methodology and quality control.

An injury surveillance system has been developed and tested in a pilot study at two emergency departments in the Stockholm area. The object was to develop an all-age, all-injury registration at all hospital emergency departments and primary care units treating injured patients. The information will be used at the local level for preventive measures, and on a national level for comparison with other areas. All injured patients were given a record-sheet that served both as a registration form and a medical record. The NOMESKO-code was used as a basis for classifying intent, activity, type of location, and injury mechanism. Altogether, 11,327 injured patients were registered. One day each month was randomly selected from the registration for control of registry completeness. The drop-out rate was on average 13%. The reasons were that patients had not been provided with the injury form, or that the copy of the form had not been sent to, or had not reached the Epidemiological Unit where data entry was performed. 6% of the injuries occurred in patients living outside the Stockholm area. The average shortfall-rate in filling in the NOMESKO-code on the registration form was 10%. The rate of registry drop-outs and incomplete forms should decrease when registration has become a routine procedure, provided that the staff can be engaged in the preventive work and the registration procedure can be adjusted to the routines of trauma management in each emergency department.

Combination ELISAs for antiviral antibodies in CSF and serum in patients with neurological symptoms and in healthy controls.

A combination enzyme-linked immunosorbent assay (ELISA) was designed to improve the estimation of serum: cerebrospinal fluid (CSF) antiviral IgG ratios. Microplate wells were coated with five different virus antigens. Serum and CSF from 66 patients referred for CSF serology and from 21 healthy controls were studied. In a comparison with serum: CSF IgG titre ratios, absorbance ratios were found to be suitable for the evaluation of intrathecal antiviral IgG synthesis. A slight blood-brain barrier (BBB) disturbance affected only the passage of albumin over the BBB, whereas a more pronounced BBB defect resulted in increased IgG levels in the CSF. Intrathecal antiviral IgG synthesis was demonstrated in 15 patients with viral CNS infections or inflammatory diseases. Very high serum: CSF antiviral IgG titre ratios and absorbance ratios, found in six patients, were interpreted as signs of diminished IgG passage over the BBB due to impaired CSF circulation.