Chemical interactions in composites of gellan gum and bioactive glass: self-crosslinking and in vitro dissolution.

We investigated the interactions between the organic-inorganic phases in composites and the impact on in vitro dissolution. The composite consists of a hydrogel-forming polysaccharide gellan gum (GG, organic phase) and a borosilicate bioactive glass (BAG, inorganic phase). The BAG loading in the gellan gum matrix varied from 10 to 50 wt%. While mixing GG and BAG, the ions released from BAG microparticles crosslinked with the carboxylate anions of GG. The nature of the crosslinking was assessed, and its impact on mechanical properties, swelling ratio, and enzymatic degradation profile upon immersion for up to 2 weeks was studied. Loading up to 30 wt% of BAG in GG caused an increase in mechanical properties associated with an increasing crosslinking density. At higher BAG loading, excess divalent ions and percolation of particles led to a decrease in the fracture strength and compressive modulus. Upon immersion, a decrease in the composite mechanical properties was attributed to the dissolution of the BAG and the loosening of the glass/matrix interface. The enzymatic degradation of the composites was inhibited at higher BAG loadings (40 and 50 wt%) even when the specimen was immersed for 48 h in PBS buffer with lysozyme. During in vitro dissolution in both SBF and PBS, the ions released from the glass led to the precipitation of hydroxyapatite already at day 7. In conclusion, we thoroughly discussed the in vitro stability of the GG/BAG composite and established the maximum BAG loading to enhance the GG crosslinking and mechanical properties. Based on this study, 30, 40, and 50 wt% of BAG in GG will be further investigated in an in vitro cell culture study.

Continuation of fluoropyrimidine treatment with S-1 after cardiotoxicity on capecitabine- or 5-fluorouracil-based therapy in patients with solid tumours: a multicentre retrospective observational cohort study.

BACKGROUND: Capecitabine- or 5-fluorouracil (5-FU)-based chemotherapy is widely used in many solid tumours, but is associated with cardiotoxicity. S-1 is a fluoropyrimidine with low rates of cardiotoxicity, but evidence regarding the safety of switching to S-1 after 5-FU- or capecitabine-associated cardiotoxicity is scarce. PATIENTS AND METHODS: This retrospective study (NCT04260269) was conducted at 13 centres in 6 countries. The primary endpoint was recurrence of cardiotoxicity after switch to S-1-based treatment due to 5-FU- or capecitabine-related cardiotoxicity: clinically meaningful if the upper boundary of the 95% confidence interval (CI; by competing risk) is not including 15%. Secondary endpoints included cardiac risk factors, diagnostic work-up, treatments, outcomes, and timelines of cardiotoxicity. RESULTS: Per protocol, 200 patients, treated between 2011 and 2020 [median age 66 years (range 19-86); 118 (59%) males], were included. Treatment intent was curative in 145 (73%). Initial cardiotoxicity was due to capecitabine (n = 170), continuous infusion 5-FU (n = 22), or bolus 5-FU (n = 8), which was administered in combination with other chemotherapy, targeted agents, or radiotherapy in 133 patients. Previous cardiovascular comorbidities were present in 99 (50%) patients. Cardiotoxic events (n = 228/200) included chest pain (n = 125), coronary syndrome/infarction (n = 69), arrhythmia (n = 22), heart failure/cardiomyopathy (n = 7), cardiac arrest (n = 4), and malignant hypertension (n = 1). Cardiotoxicity was severe or life-threatening in 112 (56%) patients and led to permanent capecitabine/5-FU discontinuation in 192 (96%). After switch to S-1, recurrent cardiotoxicity was observed in eight (4%) patients (95% CI 2.02-7.89, primary endpoint met). Events were limited to grade 1-2 and occurred at a median of 16 days (interquartile range 7-67) from therapy switch. Baseline ischemic heart disease was a risk factor for recurrent cardiotoxicity (odds ratio 6.18, 95% CI 1.36-28.11). CONCLUSION: Switching to S-1-based therapy is safe and feasible after development of cardiotoxicity on 5-FU- or capecitabine-based therapy and allows patients to continue their pivotal fluoropyrimidine-based treatment.

Treatment response of colorectal cancer liver metastases to neoadjuvant or conversion therapy: a prospective multicentre follow-up study using MRI, diffusion-weighted imaging and 1H-MR spectroscopy compared with histology (subgroup in the RAXO trial).

BACKGROUND: Colorectal cancer liver metastases respond to chemotherapy and targeted agents not only by shrinking, but also by morphologic and metabolic changes. The aim of this study was to evaluate the value of advanced magnetic resonance imaging (MRI) methods in predicting treatment response and survival. PATIENTS AND METHODS: We investigated contrast-enhanced MRI, apparent diffusion coefficient (ADC) in diffusion-weighted imaging and 1H-magnetic resonance spectroscopy (1H-MRS) in detecting early morphologic and metabolic changes in borderline or resectable liver metastases, as a response to first-line neoadjuvant or conversion therapy in a prospective substudy of the RAXO trial (NCT01531621, EudraCT2011-003158-24). MRI findings were compared with histology of resected liver metastases and Kaplan-Meier estimates of overall survival (OS). RESULTS: In 2012-2018, 52 patients at four Finnish university hospitals were recruited. Forty-seven patients received neoadjuvant or conversion chemotherapy and 40 liver resections were carried out. Low ADC values (below median) of the representative liver metastases, at baseline and after systemic therapy, were associated with partial response according to RECIST criteria, but not with morphologic MRI changes or histology. Decreasing ADC values following systemic therapy were associated with improved OS compared to unchanged or increasing ADC, both in the liver resected subgroup (5-year OS rate 100% and 34%, respectively, P = 0.022) and systemic therapy subgroup (5-year OS rate 62% and 23%, P = 0.049). 1H-MRS revealed steatohepatosis induced by systemic therapy. CONCLUSIONS: Low ADC values at baseline or during systemic therapy were associated with treatment response by RECIST but not with histology, morphologic or detectable metabolic changes. A decreasing ADC during systemic therapy is associated with improved OS both in all patients receiving systemic therapy and in the resected subgroup.

Centralized repeated resectability assessment of patients with colorectal liver metastases during first-line treatment: prospective study.

BACKGROUND: Metastasectomy is probably underused in metastatic colorectal cancer. The aim of this study was to investigate the effect of centralized repeated assessment on resectability rate of liver metastases. METHODS: The prospective RAXO study was a nationwide study in Finland. Patients with treatable metastatic colorectal cancer at any site were eligible. This planned substudy included patients with baseline liver metastases between 2012 and 2018. Resectability was reassessed by the multidisciplinary team at Helsinki tertiary referral centre upfront and twice during first-line systemic therapy. Outcomes were resectability rates, management changes, and survival. RESULTS: Of 812 patients included, 301 (37.1 per cent) had liver-only metastases. Of these, tumours were categorized as upfront resectable in 161 (53.5 per cent), and became amenable to surgery during systemic treatment in 63 (20.9 per cent). Some 207 patients (68.7 per cent) eventually underwent liver resection or ablation. At baseline, a discrepancy in resectability between central and local judgement was noted for 102 patients (33.9 per cent). Median disease-free survival (DFS) after first resection was 20 months and overall survival (OS) 79 months. Median OS after diagnosis of metastatic colorectal cancer was 80, 32, and 21 months in R0-1 resection, R2/ablation, and non-resected groups, and 5-year OS rates were 68, 37, and 9 per cent, respectively. Liver and extrahepatic metastases were present in 511 patients. Of these, tumours in 72 patients (14.1 per cent) were categorized as upfront resectable, and 53 patients (10.4 per cent) became eligible for surgery. Eventually 110 patients (21.5 per cent) underwent liver resection or ablation. At baseline, a discrepancy between local and central resectability was noted for 116 patients (22.7 per cent). Median DFS from first resection was 7 months and median OS 55 months. Median OS after diagnosis of metastatic colorectal cancer was 79, 42, and 17 months in R0-1 resection, R2/ablation, and non-resected groups, with 5-year OS rates of 65, 39, and 2 per cent, respectively. CONCLUSION: Repeated centralized resectability assessment in patients with colorectal liver metastases improved resection and survival rates.

Quality of life with biweekly docetaxel and capecitabine in advanced gastro-oesophageal cancer.

PURPOSE: This study aimed to evaluate the feasibility and tolerability of biweekly docetaxel with capecitabine as first-line treatment in advanced gastro-oesophageal cancer. METHODS: Fifty-three patients at median age of 61 years with advanced gastric cancer were included in this prospective, non-randomized, multicentre phase II trial to receive intravenous docetaxel 50 mg/m2 on days 1 and 15, and oral capecitabine 1250 mg/m2 every 12 h, on days 1-7 and 15-21 of each 28-day cycle. QOL was assessed using EORTC QLQ-C30, together with the gastric module (QLQ-STO 22). RESULTS: Forty-six patients were evaluable for QOL analyses. No deterioration in global health status was found. Social functioning scores improved, and eating difficulties and pain were alleviated during treatment. The most common grade 3 or 4 toxicity was neutropenia (47%), whereas neutropenic fever was uncommon (6%). The clinical benefit rate was 60%, including complete and partial responses as well as stabilized disease. Median overall survival was 8.8 months (95% CI 5.8-11.9 months), and median time to progression was 6.2 months (95% CI 4.9-7.5 months). CONCLUSIONS: Biweekly docetaxel with capecitabine is a feasible treatment in AGC, delivered on an outpatient basis, with no need for central venous access device. No deterioration of global health status was reported. In addition, pain and eating difficulties were alleviated during study treatment. This trial is registered at ClinicalTrials.gov , number NCT00669370.

Photoperiodic regulation of life-history traits before and after eclosion: egg-to-adult development time, juvenile body mass and reproductive diapause in Drosophila montana.

Photoperiod is the main environmental cue used by northern insects to predict the forthcoming seasonal changes and to adjust their life-history traits to fit these changes. We studied the effects of photoperiod on egg-to-adult development time, juvenile body mass and female reproductive diapause in two northern Drosophila montana populations with different patterns of voltinism. The most interesting findings were consistent between the populations: (1) when maintained before eclosion in short day conditions, representing early autumn, the flies developed faster and were lighter than when maintained in long day conditions, representing early summer, (2) photoperiodic time measurement is apparently reset after eclosion, adjusting the flies' development according to post eclosion conditions, (3) the sensitive period for diapause induction took place after eclosion and (4) there was no direct connection between females' egg-to-adult development time and their reproductive state at adulthood, which suggests that these traits can be determined by photoperiodic cues through different time measurement systems. Independence of photoperiodic regulation of life-history traits before and after eclosion enable D. montana flies to respond to changing photoperiods on a short time scale and match their life-history traits according to seasons.

Photoperiodic regulation of cold tolerance and expression levels of regucalcin gene in Drosophila montana.

Temperature-induced plasticity of cold tolerance has been reported in many insect species, but cold tolerance can also be affected by changes in day (or night) length. In the present study we elucidate the direct and indirect effects of photoperiod on the cold tolerance of females of two Drosophila montana strains--one which possesses a robust photoperiodic diapause and another which does not. In the diapause-strain the time needed for recovery from chill coma showed a positive correlation with day length, but diapause itself played only a minor role in photoperiodic acclimation. The strain that was not able to enter to diapause as a response to day length also lacked photoperiodic cold acclimation ability indicating that this strain has deficiencies in its photoperiodic time measurement system. In the diapause-strain, the expression level of regucalcin gene was more than two times higher in diapausing than in non-diapausing females maintained in a single photoperiod, but day length per se did not cause significant changes in expression levels of this gene in either of the strains. In the non-diapausing strain this gene showed no expression changes in any comparison. Overall, the study shows that a decrease in day length can induce cold acclimation in D. montana, while changes in regucalcin expression are linked with photoperiodic diapause.

Cold tolerance and cold-induced modulation of gene expression in two Drosophila virilis group species with different distributions.

The importance of high and low temperature tolerance in adaptation to changing environmental conditions has evoked new interest in modulations in gene expression and metabolism linked with stress tolerance. We investigated the effects of rapid cold hardening and cold acclimatization on the chill coma recovery times of two Drosophila virilis group species, Drosophila montana and D. virilis, with different distributions and utilized a candidate gene approach to trace changes in their gene expression during and after the cold treatments. The study showed that cold acclimatization clearly decreases chill coma recovery times in both species, whereas rapid cold hardening did not have a significant effect. Microarray analysis revealed several genes showing expression changes during different stages of cold response. Amongst the 219 genes studied, two genes showed rather consistent expression changes: hsr-omega, which was up-regulated in both study species during cold acclimatization, and Eip71CD, which was down-regulated in nearly all of the cold treatments. In addition, 29 genes showed expression changes that were more treatment- and/or species specific. Overall, different stages of cold response elicited changes mainly in genes involved in heat shock response, circadian rhythm and metabolism.

Recombinant polyamine-binding protein of Synechocystis sp. PCC 6803 specifically binds to and is induced by polyamines.

His-tagged Synechocystis sp. PCC 6803 PotD protein (rPotD) involved in polyamine transport was overexpressed in Escherichia coli. The purified rPotD showed saturable binding kinetics with radioactively labeled polyamines. The rPotD exhibited a similar binding characteristic for three polyamines, with putrescine having less preference. The K(d) values for putrescine, spermine, and spermidine were 13.2, 8.3, and 7.8 µM, respectively. Binding of rPotD with polyamines was maximal at pH 8.0. Docking of these polyamines into the homology model of Synechocystis PotD showed that all three polyamines are able to interact with Synechocystis PotD. The binding modes of the docked putrescine and spermidine in Synechocystis are similar to those of PotF and PotD in E. coli, respectively. Competition experiments showed specific binding of rPotD with polyamines. The presence of putrescine and spermidine in the growth medium could induce an increase in PotD contents, suggesting the role of PotD in mediating the transport of polyamine in Synechocystis sp. PCC 6803.

Exogenous sex hormone use and risk of meningioma: a population-based case-control study in Finland.

BACKGROUND: Previous studies on association of exogenous female sex hormones and risk for meningioma have yielded conflicting results. The aim of this study was to evaluate the potential relation between prior use of menopausal hormone therapy or oral contraception and risk of meningioma. METHODS: This population-based case-control study was conducted during years 2000-2002 in Finland. All women aged 20-69 years with meningioma diagnosis were identified from five university hospitals, and frequency-matched controls were randomly chosen from population register. A total of 264 cases and 505 controls were interviewed on their use of menopausal hormone therapy, oral and other contraception, fertility treatment, treatment for gynecological problems, age at menarche, and number of children. We also analyzed separately tumors expressing progesterone or estrogen receptors. Of the successfully stained tumor specimens, 86.3% were positive for progesterone receptor and 50% for estrogen receptor. RESULTS: Postmenopausal hormonal treatment, use of contraceptives, or fertility treatment did not influence the risk of meningioma. In further analysis by hormone receptor status, there was some indication for an increased risk of progesterone receptor-positive meningiomas associated with oral contraceptive use (OR 1.39, 95% confidence interval 0.92-2.10) and other hormonal contraception (OR 1.50, 95% CI 0.95-2.36). CONCLUSIONS: Overall, we found little indication that reproductive factors or use of exogenous sex hormones affect meningioma risk.

Meningioma and mobile phone use--a collaborative case-control study in five North European countries.

BACKGROUND: Use of mobile telephones has been suggested as a possible risk factor for intracranial tumours. To evaluate the effect of mobile phones on risk of meningioma, we carried out an international, collaborative case-control study of 1209 meningioma cases and 3299 population-based controls. METHODS: Population-based cases were identified, mostly from hospitals, and controls from national population registers and general practitioners' patient lists. Detailed history of mobile phone use was obtained by personal interview. Regular mobile phone use (at least once a week for at least 6 months), duration of use, cumulative number and hours of use, and several other indicators of mobile phone use were assessed in relation to meningioma risk using conditional logistic regression with strata defined by age, sex, country and region. RESULTS: Risk of meningioma among regular users of mobile phones was apparently lower than among never or non-regular users (odds ratio, OR = 0.76, 95% confidence interval, CI 0.65, 0.89). The risk was not increased in relation to years since first use, lifetime years of use, cumulative hours of use or cumulative number of calls. The findings were similar regardless of telephone network type (analogue/digital), age or sex. CONCLUSIONS: Our results do not provide support for an association between mobile phone use and risk of meningioma.

Medical history, cigarette smoking and risk of acoustic neuroma: an international case-control study.

Acoustic neuroma (vestibular schwannoma) is a benign tumor of the vestibulocochlear nerve. Its recorded incidence is increasing but risk factors for this tumor have scarcely been investigated. We conducted a population-based case-control study of risk factors for acoustic neuroma in the UK and Nordic countries, including 563 cases and 2,703 controls. Tumor risk was analyzed in relation to medical history and cigarette smoking. Risk of acoustic neuroma was significantly raised in parous compared with nulliparous women (OR = 1.7, 95% CI: 1.1-2.6), but was not related to age at first birth or number of children. Risk was not associated with a history of allergic disease, past head injury, past diagnosis of a neoplasm or birth characteristics, but was significantly raised for past diagnosis of epilepsy (OR = 2.5, 95% CI: 1.3-4.9). Tumor risk was significantly reduced in subjects who had ever regularly smoked cigarettes (OR = 0.7, 95% CI: 0.6-0.9), but the reduction applied only to current smokers (OR = 0.5, 95% CI: 0.4-0.6), not ex-smokers (OR = 1.0, 95% CI: 0.8-1.3). The reduced risk of acoustic neuroma in smokers and raised risk in parous women might relate to sex hormone levels, or smoking might suppress tumor growth, but effects of parity and smoking on timing of diagnosis of the tumor are also a potential explanation. The raised risk in relation to past diagnosis of epilepsy might be a surveillance artefact or imply that epilepsy and/or antiepileptic medication use predispose to acoustic neuroma. These findings need replication by other studies and possible mechanisms need to be clarified.

Validation of short term recall of mobile phone use for the Interphone study.

AIM: To validate short term recall of mobile phone use within Interphone, an international collaborative case control study of tumours of the brain, acoustic nerve, and salivary glands related to mobile telephone use. METHODS: Mobile phone use of 672 volunteers in 11 countries was recorded by operators or through the use of software modified phones, and compared to use recalled six months later using the Interphone study questionnaire. Agreement between recalled and actual phone use was analysed using both categorical and continuous measures of number and duration of phone calls. RESULTS: Correlations between recalled and actual phone use were moderate to high (ranging from 0.5 to 0.8 across countries) and of the same order for number and duration of calls. The kappa statistic demonstrated fair to moderate agreement for both number and duration of calls (weighted kappa ranging from 0.20 to 0.60 across countries). On average, subjects underestimated the number of calls per month (geometric mean ratio of recalled to actual = 0.92, 95% CI 0.85 to 0.99), whereas duration of calls was overestimated (geometric mean ratio = 1.42, 95% CI 1.29 to 1.56). The ratio of recalled to actual use increased with level of use, showing underestimation in light users and overestimation in heavy users. There was substantial heterogeneity in this ratio between countries. Inter-individual variation was also large, and increased with level of use. CONCLUSIONS: Volunteer subjects recalled their recent phone use with moderate systematic error and substantial random error. This large random error can be expected to reduce the power of the Interphone study to detect an increase in risk of brain, acoustic nerve, and parotid gland tumours with increasing mobile phone use, if one exists.

Mobile phone use and risk of acoustic neuroma: results of the Interphone case-control study in five North European countries.

There is public concern that use of mobile phones could increase the risk of brain tumours. If such an effect exists, acoustic neuroma would be of particular concern because of the proximity of the acoustic nerve to the handset. We conducted, to a shared protocol, six population-based case-control studies in four Nordic countries and the UK to assess the risk of acoustic neuroma in relation to mobile phone use. Data were collected by personal interview from 678 cases of acoustic neuroma and 3553 controls. The risk of acoustic neuroma in relation to regular mobile phone use in the pooled data set was not raised (odds ratio (OR) = 0.9, 95% confidence interval (CI): 0.7-1.1). There was no association of risk with duration of use, lifetime cumulative hours of use or number of calls, for phone use overall or for analogue or digital phones separately. Risk of a tumour on the same side of the head as reported phone use was raised for use for 10 years or longer (OR = 1.8, 95% CI: 1.1-3.1). The study suggests that there is no substantial risk of acoustic neuroma in the first decade after starting mobile phone use. However, an increase in risk after longer term use or after a longer lag period could not be ruled out.

Survival of multiple sclerosis in Finland between 1964 and 1993.

The long-term survival of multiple sclerosis (MS) was studied during 1964-1993 in a cohort of 1614 patents in Finland. Survival to death from the initial MS symptoms was analysed by the life-table method, separately for MS related and all causes of deaths. Survival at 40 years was 64% for MS deaths and 53% for all deaths. Higher proportions of violent deaths and neoplasms were observed among MS patients as compared to the general population, whereas the proportion of cardiovascular causes of death was low. MS-related causes accounted for 70% of the recorded 219 deaths. Favourable survival in MS was associated with relapsing-remitting disease course, age at onset below 30 years and optic neuritis or other sensory symptoms at presentation. We were unable to show any significant effect due to calendar time of diagnosis or gender, as the risk of men was similar (risk ratio [RR] = 1.1, confidence interval [CI] 0.8-1.6) as compared to women.

Amplification of c-myc oncogene by chromogenic and fluorescence in situ hybridization in archival breast cancer tissue array samples.

Fluorescence in situ hybridization (FISH) is currently considered to be the most specific and sensitive method for detection of oncogene amplifications in human tumor samples. However, FISH requires fluorescence microscopy, which is tedious and does not allow histopathologic evaluation of the cells and tissues examined. Here we compared FISH with the newly developed chromogenic in situ hybridization (CISH), which uses peroxidase enzyme for probe detection instead of fluorescent dyes. CISH was found to be highly concordant with FISH in a tissue array series of 177 archival breast cancer samples. This was true both when comparing CISH with single-color and two-color FISH, the latter including the chromosome 8 centromere probe as reference (the kappa coefficients were 0.67 and 0.76, respectively). Clinicopathologic correlations of c-myc amplification as detected by FISH and CISH were generally the same. By both methods, c-myc amplification was significantly associated with high histologic grade, negative progesterone receptor status, DNA aneuploidy, and high S-phase fraction. c-myc amplification was strongly associated with poor distant metastasis-free survival when amplification was detected by CISH (p = 0.0013), but this association was weaker when FISH was used (p = 0.16 for two-color FISH and p = 0.065 for single-color FISH). These data suggest that CISH is at least as sensitive and specific as FISH in the detection of oncogene amplification in human tumor samples. The possibility for concomitant tissue architecture evaluation using an ordinary transmitted light microscope may favor the use of CISH over FISH in oncogene amplification detection in large tumor series, and tissue arrays and, ultimately, in routine clinical diagnostics.

Amplification of c-myc by fluorescence in situ hybridization in a population-based breast cancer tissue array.

A total of 261 primary breast carcinomas were analyzed for amplification of the c-myc oncogene by fluorescence in situ hybridization performed on tumor tissue array samples. Results were compared with individual clinicopathologic and follow-up data. Thirty-eight (14.6%) of the tumors showed c-myc gene amplification (defined as two or more additional copies of c-myc gene in relation to the number of chromosome 8 centromere). The reproducibility of fluorescence in situ hybridization assay (defined by hybridization with two different myc probes) was good (kappa coefficient 0.402). Statistically significant associations were found between c-myc amplification and DNA aneuploidy (P =.0011), and progesterone receptor negativity (P =.0071), and c-myc amplification also tended to be associated with high histologic grade (P =.064), positive axillary nodal status (P =.080), and a high S-phase fraction (P =.052). c-myc amplification was not significantly associated with overall survival of patients with invasive cancer (P =.32). These data from a population-based tumor material suggest that c-myc amplification is a feature of aggressive breast cancers, but that it is unlikely to be a clinically useful prognostic factor.

N-in-one determination of retention factors for drugs by immobilized artificial membrane chromatography coupled to atmospheric pressure chemical ionization mass spectrometry.

Immobilized artificial membrane (IAM) chromatography is widely used in drug discovery for ranking the absorption properties of drug candidates. In this work an IAM chromatography method using atmospheric pressure chemical ionization mass spectrometric detection (IAM/APCI-MS) was developed for the determination of log k(IAM) values for a mixture of compounds (9-in-one). Values were calculated from isocratic runs (0, 10, 20, 30, 35% acetonitrile) in both positive and negative modes. Good correlation (r(2) = 0.97) was achieved for n-in-one results obtained with ammonium acetate buffer and mass spectrometry, compared with the traditional method involving single compound analysis with phosphate buffered saline and an ultraviolet detector. A gradient elution method providing fast determination of relative log k(IAM) values in a single IAM/APCI-MS run was demonstrated for the same compounds.

The effect of age and density of the breast on the sensitivity of breast cancer diagnostic by mammography and ultasonography.

PURPOSE: We studied which, age of the patient or density of the breast accounts for the sensitivity of mammography and ultrasonography (US). Furthermore we studied whether the overall impression on the density of the breast or the density in tumour area accounts for the sensitivity of mammography and ultrasonography. MATERIALS AND METHODS: The material consisted of 572 consecutive histologically and 5 cytologically verified breast cancer cases. Mammography and US examinations were performed immediately before breast cancer operations and information on the findings were received from the original patient files and classified as malignant or benign. The density of breast parenchyma to fatty, mixed or dense in total breast and separately in tumour area was defined by a radiologist group from the original mammograms by comparing to model mammograms. The sensitivity (Se) of mammography and US was compared in 3 age groups (26-49, 50-59 and 60-92) and in the different density classes. RESULTS: Sensitivity of mammography increased by age (density-adjusted OR = 0.2, 95%, CI 0.1-0.5) in age group 26-49 compared to age group 60-92) and with fattiness of the breast (age-adjusted OR= 0.4, 95%, CI 0.1-1.0 for dense breast parenchyma in tumour area compared to fatty breast). Sensitivity of US was inversely related to age (density-adjusted OR = 2.3, 95%, CI 1.0-5.2 in age group 26-49 compared to age group 60-92) and directly related with fattiness of breast (age-adjusted OR = 0.5, 95%, CI 0.2-0.9 by dense breast parenchyma in tumour area compared to fatty breast). Density in the tumour area compared to total breast density was related only mariginally better sensitivity both of mammography (0.4 vs. 0.6) and of US (0.5 vs. 0.6). CONCLUSION: Sensitivity of both mammography and sensitivity of US are independently related both to the age of the patient and to the density of the breast. The effect of age is inverse and that of density parallel between mammography and US on sensitivity. The effect of overall breast density was close to the effect of density at the site of the tumour on the sensitivity of both mammography and US.

Molecular mechanism for agonist-promoted alpha(2A)-adrenoceptor activation by norepinephrine and epinephrine.

We present a mechanism for agonist-promoted alpha(2A)-adrenergic receptor (alpha(2A)-AR) activation based on structural, pharmacological, and theoretical evidence of the interactions between phenethylamine ligands and alpha(2A)-AR. In this study, we have: 1) isolated enantiomerically pure phenethylamines that differ both in their chirality about the beta-carbon, and in the presence/absence of one or more hydroxyl groups: the beta-OH and the catecholic meta- and para-OH groups; 2) used [(3)H]UK-14,304 [5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine; agonist] and [(3)H]RX821002 [2-(2-methoxy-1,4-benzodioxan-2-yl)-2-imidazoline; antagonist] competition binding assays to determine binding affinities of these ligands to the high- and low-affinity forms of alpha(2A)-AR; 3) tested the ability of the ligands to promote receptor activation by measuring agonist-induced stimulation of [(35)S]GTPgammaS binding in isolated cell membranes; and 4) used automated docking methods and our alpha(2A)-AR model to predict the binding modes of the ligands inside the alpha(2A)-AR binding site. The ligand molecules are sequentially missing different functional groups, and we have correlated the structural features of the ligands and ligand-receptor interactions with experimental ligand binding and receptor activation data. Based on the analysis, we show that structural rearrangements in transmembrane helix (TM) 5 could take place upon binding and subsequent activation of alpha(2A)-AR by phenethylamine agonists. We suggest that the following residues are important in phenethylamine interactions with alpha(2A)-AR: Asp113 (D(3.32)), Val114 (V(3.33)), and Thr118 (T(3.37)) in TM3; Ser200 (S(5.42)), Cys201 (C(5.43)), and Ser204 (S(5.46)) in TM5; Phe391 (F(6.52)) and Tyr394 (Y(6.55)) in TM6; and Phe411 (F(7.38)) and Phe412 (F(7.39)) in TM7.