bluuebunny/crossref_metadata_2025 huggingface dataset:
Rigidity Versus Openness in Late Classical Islamic Law: The Case of the Seventeenth-Century Palestinian Muftī Khayr al-Dīn al-Ramlī
Authors: Gerber Haim
Published: December 2004

In this study I reexamine some well-known generalizations about Islamic law prior to the impact of the West, e.g., the contention that Islamic law became increasingly closed, based more and more on blind imitation. My examination of the fatwā collection of the seventeenth-century Palestinian Muftī Khayr al-Dīn al-Ramlī suggests that increasing closure never took place. On the one hand al-Ramlī faithfully continues the tradition of his classical predecessors, or, in other words, he practices taqlīd by obligating himself to earlier authorities. On the other hand, his fatwās convey a sense of openness, flexibility, and liveliness. These characteristics are concretized in some of the major terms that he uses: ijtihād, or free discretion of the jurist in areas of the law that remained open; iṣtiḥsān, or relaxation of formal rules; and ʿurf, or local customary law, which, by definition, is changeable over time. In my view, the flexibility of Islamic law has been underemphasized in the scholarly literature, and hence it is on this factor in particular that I have chosen to concentrate.
Avoiding Ribā: Credit and Custodianship in Nineteenth- and Early-Twentieth Century ḥaḍramawt
Authors: Boxberger Linda
Published: December 2004

This essay examines a little-known economic institution known as ʿuhda sale which was highly elaborated in the ḥaḍramawt region of southern Arabia, where it was used to facilitate the availability of credit by allowing people to benefit from extending credit without breaking the Qurʾānic prohibition of Ribā. After considering the history of the practice in ḥaḍramawt and controversies associated with it, I analyze how the transactions worked and who participated in them, as reflected in nineteenth- and twentieth-century contracts. In addition, evidence culled from contemporary fatāwā shed light on some of the questions and problems which arose in the course of these transactions. The ʿuhda transaction in ḥaḍramawt illustrates the development of a utilitarian economic institution through the combined influences of local usage based on practical needs and local juristic decisions as to religious legitimacy. The transaction exemplifies the flexibility of the local legal system in response to economic need and social practice. It also illustrates the degree to which people of different genders, ages, and social backgrounds participated in financial transactions in this society.
Forme et Substance en Droit Musulman
Authors: Meron YaʿAkov
Published: December 2004

La distinction aristotélicienne entre forme et substance a laissé son empreinte sur le droit musulman pas moins que sur d'autres systèmes de droit et en fait bien plus que sur ces derniers. L'étude qui suit montre son application dans trois domaines du droit musulman privé.
A Reconsideration of the Development of Basil's Trinitarian Theology: the Dating of Ep. 9 and Contra Eunomium
Authors: Hildebrand Stephen
Published: December 2004

Basil of Caesarea's Trinitarian thought changed in the 360s, and the dates of his Trinitarian works, especially ep. 9 and Contra Eunomium determine the nature of the change. Most have dated these works such that Basil must be judged at least inconsistent if not duplicitous. The evidence recon- sidered, though, yields a date early in the 360s for both ep. 9 and Contra Eunomium. Since it cannot be determined which came first, Basil should be presumed consistent.
Normalizing the Workplace Nap: Blurring the Boundaries between Public and Private Space and Time
Authors: Baxter Vern , Kroll-Smith Steve
Published: December 2004

Napping at work was typically a fugitive behaviour, a small act of resistance against the goals of management and the workplace clock. Increasingly, however, employers are encouraging employees to sleep at the worksite. Indeed, some actively encourage this once deviant behaviour, promoting its restorative features and its relationship to increased productivity. This article examines the emergence of the management organized workplace nap in the US. Attention is paid to how the cultural meaning of sleeping at work is changing to normalize a soporific state that was, at one time, grounds for dismissal. Colonizing the nap at work is part of a larger trend that is reconfiguring the once bounded relationships between home and work and public and private space and time. Importantly, normalizing the workplace nap is not uniform. We identify at least two variants: breaktime napping and worktime napping. Each variant represents a different degree of management oversight and reflects the varying autonomy of the employee. In a final discussion, this initiative to create a more flexible work environment by inviting once private and fugitive acts into the open spaces of the worksite is contrasted with the marked decline of the siesta in China and Spain.
Mass Transfer During Osmotic Dehydration of Pineapple
Authors: Ramallo L. A. , Schvezov C. , Mascheroni R. H.
Published: December 2004

The diffusion coefficients of water and solutes are important parameters in the analysis, design and optimisation of an osmotic dehydration process. This work estimated by Fick’s Law the diffusion coefficients of water and sucrose during the osmotic dehydration of slices of pineapple fruit in sucrose solution at different temperatures. In addition, it analysed the effect of the change in thickness (shrinkage) during the process, and the use of higher order terms in the analytical solution. The model results were in good agreement with experimental data of water loss and solid gain. The best fit was found when the shrinkage was considered in a simple model based on the solution of Fick’s Law. The equilibrium water content ranged between 34 and 36% for a 60% w/w sucrose solution and was practically independent of temperature. Equilibrium sugar content increased from 45 to 54% as the temperature rose from 30 to 50°C. Thickness variation was found to be independent of temperature and was only dependent on water content.
E-Parties: Democratic and Republican State Parties in 2000
Authors: Farmer Rick , Fender Rich
Published: December 2004

This research examines the form and content of state party websites in the 2000 US election, and considers whether or not state parties are following the lead of the national parties. Generally, state parties attempted to provide essential party functions online, but lacked technical sophistication in 2000. The range of state party websites was broad - from state parties that lacked simple graphics to those with streaming video. Highly integrated parties (those receiving large soft-money transfers) produced the strongest websites and demonstrated the most expertise in this emerging medium.
Factors Associated with Depression in Pregnant Immigrant Women
Authors: Zelkowitz Phyllis , Schinazi Joy , Katofsky Lilly , Saucier Jean François , Valenzuela Marta , Westreich Ruta , Dayan Joelle
Published: December 2004

This study examined psychosocial risk factors for depressive symptomatology in a community sample of pregnant immigrant women in Montreal, Canada. One hundred and nineteen participants were recruited through hospitals and responded to questionnaires assessing depression, somatic symptoms, functional status, social support, stressful life events and marital adjustment. Forty-two percent of participants scored above the cut-off for depression. Depressive symptoms were associated with poorer functional status and more somatic symptoms. Depressed women reported a lack of social support, more stressful life events and poorer marital adjustment. Transitions associated with migration may place pregnant immigrant women at high risk for depression.
The Crime Reduction Programme in England and Wales
Authors: Maguire Mike
Published: December 2004

The article contrasts the original vision behind the Crime Reduction Programme - an ambitious plan (initially intended to run for 10 years) to accumulate, disseminate and use research-based knowledge about the effectiveness of a wide variety of interventions - with the reality of the multiple problems experienced during its implementation in England and Wales between 1999 and its premature end in 2002. Ultimately, few projects were implemented as planned, with the knock-on effect of a dearth of conclusive research findings. It is argued that the Crime Reduction Programme benefitted initially from an unusual ‘window of opportunity’ when such a programme appeared attractive to politicians, administrators, practitioners and researchers alike, resulting in a level of funding for pilot projects and evaluation which was unprecedented in the UK in the crime reduction field. However, it was undermined significantly by inherent risks and tensions that became increasingly prominent as circumstances (and the political climate) changed. While initially conceived as research-driven, it was ‘sold’ to politicians as contributing to the government’s challenging crime reduction targets, an aim which progressively took priority over research. It was over-ambitious in scale and raised unrealistic expectations of its outcomes. It suffered from major practical problems caused by unfeasible timescales, slow-moving bureaucratic procedures, and shortages of ‘capacity’. Low commitment to project integrity, cultural resistance among practitioners, and insufficient attention to differences between academics’ and policy makers’ understandings of research, also contributed to its problems. While some useful outcomes can be claimed, the results of the Crime Reduction Programme as a whole were unquestionably disappointing. In the light of these experiences, it might be argued that - tempting as it was to seize the rare opportunity of major funding - the ideal of ‘evidence-based policy’ may be more effectively pursued as a quiet iterative process over the longer term, rather than through a risky investment in one high profile and rapidly implemented ‘programme’ which promises more than it can guarantee to deliver.
Domestic Burglary Repeats and Space-Time Clusters
Authors: Bowers Kate J. , Johnson Shane D.
Published: December 2004

Predicting when and where crimes are likely to occur is crucial for prioritizing police resources. In a companion paper (Johnson and Bowers 2004), we showed that burglaries clustered within 1-2 months and up to 300-400 metres of a prior burglary, i.e. a domestic burglary could profitably trigger time- and space-limited resource deployment around the burglary. Research is here presented which refines the priorities that should be given in such deployment. It demonstrates that (a) whereas repeat victimization proper tended to occur in more deprived areas, space-time clustering was more evident in affluent areas, (b) houses next to a burgled home were at a substantially heightened risk relative to those located further away, particularly within one week of an initial burglary, (c) properties located on the same side of the street as a burgled house were at significantly greater risk compared with those opposite, even when corrections are made for differences in linear distances between homes, (d) houses with probably identical layouts (e.g. houses two, four, six, etc., doors away from a burgled property) were slightly more at risk than those with the reverse layout, but these differences are too slight to inform crime reduction practice. Taken together, these patterns may be used to prioritize attention within the two months after, and up to 400 metres from, a prior burglary identified by Johnson and Bowers (2004) as encompassing homes at elevated burglary risk.
Sonographic Assessment of the Epiglottis
Authors: Werner Sandra L. , Jones Robert A. , Emerman Charles L.
Published: December 2004

Objectives: The ideal diagnostic test for the diagnosis of epiglottitis would be simple, rapid, noninvasive, and highly accurate, performed at the bedside, and would not use ionizing radiation. The purpose of this study was to assess the utility of ultrasound to image the epiglottis and to determine the range of normal epiglottis diameter for men and women. Methods: This was a prospective study of a convenience sample of 100 subjects between the ages of 18 and 50 years who had no known acute or chronic laryngeal diseases or surgeries. The anterior neck of each subject was scanned in both the long and short axis with a 5–10 MHz linear transducer. Sonographically, the epiglottis appeared as a curvilinear, hypoechoic structure with an echogenic pre‐epiglottic space. The sonographic appearance of the epiglottis and the pre‐epiglottic space were recorded and anteroposterior measurements of the epiglottis just distal to the hyoid bone were made. Comparisons between men and women were performed with use of a Student's t‐test. Pearson's correlation analysis was performed to evaluate the relationship between subject height and epiglottic size. Results: The epiglottis was visualized in all 100 subjects including 62 women and 38 men. The average patient age was 35.2 ± 8.1 years. The epiglottic thickness was 2.39 ± 0.15 mm. This was greater in men (2.49 ± 0.13 mm) than in women (2.34 ± 0.13 mm) (p < 0.001). There was moderate correlation between height and epiglottic thickness (R = 0.48). However, when this was analyzed separately for men and women, there was no significant correlation between epiglottic thickness and height. Conclusions: Bedside ultrasonography is easy to perform and can accurately evaluate the epiglottis. Further analysis should include patients with known epiglottic disease to assess the utility of this technique to detect pathologic enlargement.
Impact of a Negative Evaluation for Underlying Coronary Artery Disease on One‐year Resource Utilization for Patients Admitted with Potential Acute Coronary Syndromes
Authors: Shaver Kyle J. , Marsan Robert J. , Sease Keara L. , Shofer Frances S. , Sites Frank D. , Hollander Judd E.
Published: December 2004

Reduction in emergency department (ED) overcrowding is a major Joint Commission on the Accreditation of Healthcare Organizations (JCAHO) initiative. One major source of ED overcrowding is patients waiting for telemetry beds. Objective: To determine whether, in patients admitted with a potential acute coronary syndrome, a negative evaluation for underlying coronary artery disease would reduce ED and hospital revisits over the subsequent year compared with patients who did not receive an evaluation for underlying coronary artery disease. Methods: Nine hundred ninety‐nine consecutive patients admitted for potential acute coronary syndromes through the ED during a one‐year period were screened for inclusion. Patients who had a negative evaluation for underlying coronary disease were compared with patients who were not evaluated for underlying coronary artery disease for subsequent ED visits, hospital admissions, and cardiac resource utilization over the year following the index visit via a health system–wide computerized record review. Patients with positive tests or biomarkers at the index visit were excluded. Each repeat visit was rated as “potentially cardiac” or “noncardiac.” Results of echocardiograms, stress tests, and catheterizations and information about in‐hospital deaths were obtained. Results: Six hundred ninety‐two patients met the inclusion criteria: 556 patients received no evaluation for underlying coronary artery disease, 116 had a negative stress test, and 20 had a negative cardiac catheterization during the index visit. Patients with no evaluation for underlying coronary artery disease and patients with a negative evaluation had similar likelihoods of a repeat ED visit (negative test 39.0% vs. no test 40.3%; p = 0.85) and repeat hospital admission (28.7% vs. 31.5%; p = 0.61). The rates of a potentially cardiac‐related ED visit (21.3 vs. 23.4%; p = 0.65) and hospital admission (17.7% vs. 20.7%; p = 0.48) were not significantly different. The two populations had similar utilization rates of echocardiograms, stress tests, and catheterizations (p > 0.70 for all). Conclusions: For patients admitted to the authors' institution with a potential acute coronary syndrome, there was no association between a negative evaluation for underlying coronary artery disease and overall or potentially cardiac ED visits, admissions, or cardiac resource test utilization over the year following the index visit.
Unanimity Rule and Organizational Decision Making: A Simulation Model
Authors: Romme A. Georges L.
Published: December 2004

Unanimity rule is an important benchmark for evaluating outcomes of decisions in the social sciences. However, organizational researchers tend to ignore unanimous decision making, for example, because unanimity may be difficult to realize in large groups and may suffer from individual participants blocking decisions. This paper reconsiders unanimity rule in view of the development of circular systems for organizing decision making. It focuses on developing a theory of decision making under unanimity rule. The author uses a system dynamics model to explore the conditions under which unanimity rule supports the organization's ability to make decisions. Simulation experiments suggest that the dynamics and outcomes of unanimous decision making under and exceeding a critical threshold level of decision pressure are fundamentally different. Under this critical threshold, the decision-making system is capable of recovering from severe shocks to the system. If decision pressure is close to its threshold, a relatively small change can cause the decision process to collapse. In this respect, large groups operating under unanimity rule are less sustainable because they are more likely to exceed their critical threshold than small groups. Decomposing the decision-making system in small units, embedded in a hierarchical structure, therefore appears to be a necessary condition for sustainable performance in large organizations applying unanimity rule.
Induction of cell death by radiotherapy.
Authors: Ross G M
Published: December 2004

Ionising radiation remains one of the most effective tools in the therapy of cancer. It combines the properties of an extremely efficient DNA-damaging agent with a high degree of spatial specificity. Nonetheless, there remain considerable differences in the outcome for treatment of tumours of differing histological type treated by radiotherapy. Tumours arising from lymphoid or germ cells are significantly more radiocurable than most solid tumours of epithelial origin. The molecular mechanisms underlying such differences in cellular radiosensitivity are the subject of current research. When normal mammalian cells are subjected to stress signals--e.g. radiation, chemotherapeutic drugs, oxygen deficiency--a range of gene products involved in the sensing and signalling of such stresses are activated. The response of eukaryotic cells to ionising radiation includes activation of DNA repair pathways and cell cycle checkpoints, with subsequent full 'biological' recovery or cell death. Radiation induces two different modes of cell death termed mitotic or clonogenic cell death, and apoptosis. Until recent years, there was surprisingly little mechanistic understanding of the events following induction of physical damage by radiation and biological outcome for the cell. There have been recent major advances in our understanding of the signal transduction pathways involved in determining the fate of cells after irradiation.
Activation of p53 by oncogenes.
Authors: Lowe S W
Published: December 2004

p53 is activated by a variety of cellular stresses, including DNA damage, hypoxia, and mitogenic oncogenes, but the extent to which each signal engages p53 as a tumour suppressor remains unknown. In non-immortal cells, the adenovirus E1A oncogene activates p53 to promote apoptosis, whereas oncogenic ras activates p53 to promote cellular senescence. Inactivation of p53 prevents E1A-induced apoptosis or Ras-induced senescence, allowing proliferation to continue unabated. In each instance, the ability of the oncogene to activate p53 involves the same functions as are required for their transforming potential, implying that p53 activation acts as a fail-safe mechanism to counter hyperproliferative signals. Furthermore, p19(ARF) is strictly required for oncogene signalling to p53. The fact that ARF--itself a tumour suppressor--acts as an intermediary in this response argues that the tumour suppressor activity of p53 can arise from its ability to eliminate oncogene-expressing cells.
The role of cytokines in both the normal and malignant ovary.
Authors: Nash M A , Ferrandina G , Gordinier M , Loercher A , Freedman R S
Published: December 2004

Normal ovarian tissue is rich in cytokines. Cytokines and chemokines are important in the physiology of ovarian function and of ovulation. Cytokines and chemokines may recruit cytokine-producing lymphocytes to the site of a developing follicle, and cytokines appear to play an important role in pre and post follicle development. Most of the same cytokines that are found in normal ovarian tissue are also found in association with malignancy in contrast to their functions in normal tissues. It is reasonable to assume that the functions of cytokines associated with malignancy may serve to promote the unregulated growth if tumor cells and metastasis. It is also likely that cytokines produced by tumors will modulate immune responses that favor tumor progression. In the following review, we have highlighted those functions of cytokines that have been identified as having the most significant impact on tumor growth and development. By examining activities of these cytokines in normal and in malignant ovarian tissues, it is hoped that future possible avenues for investigation may be opened up and that the results of these investigations will lead to strategies that can modulate the production or the activity of the cytokines leading to the growth of tumors or their metastases. Such strategies now fall under the general discipline of bioimmunotherapy. This is an expanding discipline as more is learned about growth regulation in cancer, and with the availability and rapid development of new molecules for therapeutic approaches.
Drug and hormone interactions of aromatase inhibitors.
Authors: Dowsett M
Published: December 2004

The clinical development of aromatase inhibitors has been largely confined to postmenopausal breast cancer patients and strongly guided by pharmacological data. Comparative oestrogen suppression has been helpful in circumstances in which at least one of the comparitors has caused substantially non-maximal aromatase inhibition. However, the triazole inhibitors, letrozole and anastrozole, and the steroidal inhibitor, exemestane, all cause >95% inhibition. Comparisons between these drugs therefore require more sensitive approaches such as the direct measurement of enzyme activity by isotopic means. None of these three agents has significant effects on other endocrine pathways at its clinically applied doses. Pharmacokinetic analyses of the combination of tamoxifen and letrozole have revealed that these drugs interact, resulting in letrozole concentrations approximately 35-40% lower than when letrozole is used alone.
Biology of aromatase inhibitors: pharmacology/endocrinology within the breast.
Authors: Miller W R
Published: December 2004

Both mammary adipose tissue and breast cancers have the ability to aromatize androgens into oestrogens. Such potential may maintain the growth of hormone-dependent tumours. It has therefore been important to determine the effects of new aromatase inhibitors such as formestane, exemestane, anastrozole and letrozole on oestrogen biosynthesis and concentrations of endogenous hormones within the breast. Studies based on in vitro incubations of breast cancer and cultures of mammary adipose tissue fibroblasts demonstrate that these drugs are highly effective inhibitors, with IC50 values ranging between 1 and 50 nM (although the relative efficacy varies between tissues and test systems). Despite this potential, in vitro incubations of breast tissues from patients treated with type II inhibitors such as aminoglutethimide and letrozole can display paradoxically high aromatase activity; this appears to be caused by the reversible nature of the inhibition, coupled with induction/stabilization of the aromatase enzyme. To assess in situ effects within the breast, postmenopausal women with large primary breast cancers have been treated neoadjuvantly with aromatase inhibitors using a protocol that included (i) breast biopsy before treatment, (ii) definitive surgery after 3 months of treatment and (iii) infusion of [3H]androstenedione and [14C]oestrone in the 18 h immediately before biopsy and surgery. With this study design, it has been shown that drugs such as letrozole profoundly inhibit in situ aromatase activity and reduce endogenous oestrogens within the breast.
Effects of aromatase inhibitors on the pathobiology of the human breast, endometrial and ovarian carcinoma.
Authors: Sasano H , Sato S , Ito K , Yajima A , Nakamura J , Yoshihama M , Ariga K , Anderson T J , Miller W R
Published: December 2004

It is very important to examine the influence of inhibition of in situ estrogen production on the pathobiology of human sex steroid-dependent tumors in order to understand the clinical effects of aromatase inhibitors. We have examined the biological changes before and after aromatase inhibitor treatment in vitro (endometrial and ovarian cancer) and in vivo (breast cancer). First, we analyzed these changes using histoculture of 15 human endometrial cancers and 9 ovarian cancers. Five of the fifteen endometrial cancers and four of the nine ovarian cancers demonstrated decreased [3H]thymidine uptake or Ki67 labeling index after 14alpha-hydroxy-4-androstene-3,6,17-trione (NKS01) treatment. In ovarian cancer cases, the responsive cases tended to be associated with higher aromatase and estrogen receptor alpha (ER) expression compared with the other cases but this was not seen in the endometrial cancer cases. There were no changes in ER and aromatase expression before and after NKS01 treatment in either ovarian or endometrial cancer cases. We then studied the same primary human breast tumors before and after aminoglutethimide (AMG, n=3) and 4-hydroxyandrostenedione (4-OHA, n=3) treatment. Tumor aromatase activity increased in 3 cases and decreased or was unchanged in 3 cases but aromatase immunoreactivity in stroma and adipocytes was unaltered in 5 cases. There were no changes in the ER labeling index before or after treatment. Five of the six cases including the responsive cases tended to be associated with decreased cell proliferation or Ki67 expression and increased apoptosis when examined by the TUNEL method. These results indicate that aromatase inhibitors may exert their effects on human breast and other cancers through decreasing proliferation and increasing apoptosis, possibly without altering ER status.
Aromatase inhibitors and their antitumor effects in model systems.
Authors: Brodie A , Lu Q , Liu Y , Long B
Published: December 2004

The potential of aromatase (estrogen synthetase) within the breast to provide a significant source of estrogen mediating tumor proliferation is suggested by studies reporting 4- to 6-fold higher estrogen levels in tumors than in plasma of postmenopausal patients with breast cancer. Recent studies in our laboratory have identified aromatase and its mRNA in tumor epithelial cells using immunocytochemistry and in situ hybridization. In addition, significant aromatase activity, which was stimulated 7-fold by dexamethasone, was measured in metastatic cells isolated from a breast cancer patient. Increase in proliferation, as measured by proliferating cell nuclear antigen immunostaining in tumor sections and by thymidine incorporation into DNA in response to testosterone, was observed in histocultures of breast cancer samples. This latter effect could be inhibited by 4-hydroxyandrostenedione. These results imply that intratumoral aromatase has functional significance and may be an important target for successful inhibitor treatment of breast cancer patients. To investigate treatment strategies with aromatase inhibitors and antiestrogens, we developed an intratumoral aromatase model to simulate the hormone responsive postmenopausal breast cancer patient. Tumors of estrogen receptor positive human breast carcinoma cells (MCF-7) transfected with the human aromatase gene are grown in ovariectomized nude mice. These cells synthesize sufficient estrogen to stimulate tumor formation. We have utilized this model to investigate the effects on tumor growth of the antiestrogens, tamoxifen and ICI 182780, and the aromatase inhibitors, letrozole and anastrozole (arimidex), alone and in combination. Both the aromatase inhibitors and the antiestrogens were effective in suppressing tumor growth. However, letrozole was significantly more effective than the antiestrogens. When the aromatase inhibitors were combined with the antiestrogen, tamoxifen, tumor growth was suppressed to about the same extent as with the aromatase inhibitors alone. Furthermore, the results do not suggest any benefit from combining tamoxifen with the pure antiestrogen, ICI 182780. Thus sequential use of these agents is likely to be more advantageous to the patient in terms of longer duration of effective treatment.
Role of aromatase inhibitors in advanced breast cancer.
Authors: Buzdar A U
Published: December 2004

A number of potent and selective non-steroidal aromatase inhibitors are now available for treatment of advanced breast cancer in postmenopausal women, of which anastrozole and letrozole, in particular, represent a significant advantage over the earlier agents in terms of both efficacy and tolerability. These agents are rapidly becoming established as the second-line therapy of choice in postmenopausal women with advanced disease, progressing on tamoxifen, and data on their efficacy as first-line treatment compared with tamoxifen will be available in the near future. Exemestane, a new, steroidal aromatase inhibitor which potentially lacks cross-resistance with non-steroidal agents is still in clinical development. The full potential of the new-generation aromatase inhibitors in the treatment of breast cancer is currently being investigated in a large program of clinical trials evaluating their use as adjuvant treatment following surgery in postmenopausal patients with early disease.
Use of aromatase inhibitors in the adjuvant treatment of breast cancer.
Authors: Baum M
Published: December 2004

The value of endocrine treatment of early breast cancer has been illustrated by the antioestrogen, tamoxifen, which has now been available for nearly 30 years. However, if the recognised side effects and pharmacological properties of tamoxifen are taken into consideration, it is possible that other endocrine treatments that are now available can provide equal or superior efficacy, along with improved tolerability. One such group of agents is the aromatase inhibitors specifically the new-generation triazole aromatase inhibitors, such as anastrozole and letrozole, which have both shown tolerability and efficacy advantages over standard treatments in postmenopausal women with advanced breast cancer. There are convincing reasons why the new generation of aromatase inhibitors have advantages over tamoxifen. For instance, from their agonist properties, the effects on the endometrium and tumour stimulation seen with tamoxifen would not be expected, nor would the visual disturbances that have been associated with the triphenylethylene compounds, including tamoxifen. A number of aromatase inhibitors, for instance, anastrozole, letrozole and exemestane, are currently being investigated for treatment of early breast cancer. The results of the trials of aromatase inhibitors and tamoxifen will, in the next few years, define whether or not the new-generation aromatase inhibitors have a role to play in the treatment of postmenopausal women with early breast cancer.
Combination hormonal therapy involving aromatase inhibitors in the management of women with breast cancer.
Authors: Ingle J N , Suman V J , Jordan V C , Dowsett M
Published: December 2004

Numerous comparative clinical trials have been conducted evaluating combination hormonal therapy involving the aromatase inhibitor aminoglutethimide, but there is no evidence for any superiority of this approach over single-agent therapy alone. The advent of new aromatase inhibitors with greater potency, selectivity, and better tolerability has prompted a reconsideration of the combined therapy approach, with attention being focused on pharmacologic and endocrinologic clinical research. The value of combining newer aromatase inhibitors with other hormonal agents remains to be established.
Changes in neoplastic cell features and sensitivity to mitotane during mitotane-induced remission in a patient with recurrent, metastatic adrenocortical carcinoma.
Authors: Seki M , Nomura K , Hirohara D , Kanazawa M , Sawada T , Takasaki K , Demura H
Published: December 2004

A 58-year-old man had adrenocortical carcinoma in the right adrenal gland. The tumour secreted excessive cortisol and dehydroepiandrosterone-sulphate (DHEA-S), and had invaded the right hepatic lobe and vena cava. Eleven months after surgical tumour resection, the serum DHEA-S levels again increased. Local tumour recurrence and a metastasis was found in the lung. Eleven months after surgery chemotherapy with mitotane (o,p'-DDD) was initiated. Twelve weeks of mitotane reduced serum DHEA-S levels and caused these tumours to disappear. The patient was then treated with low-dose mitotane (1.5-2.0 g/day) for 2 years. Serum levels of mitotane remained at less than 10 microg/ml. Although such low serum levels of mitotane and delayed initiation of mitotane after surgery have been proposed to weaken the antineoplastic effect of mitotane, the patient had a remission for 2 years. However, there was then local re-recurrence with an increase in serum DHEA-S and death 4 months later. The histological features of neoplastic cells were quite different comparing tumour resected at surgery and tumour at autopsy. The latter had more frequent mitotic nuclei. This tumour was initially sensitive to mitotane, but later became insensitive.
Hormonal contraception and chemoprevention of female cancers.
Authors: Pike M C , Spicer D V
Published: December 2004

Oral contraceptive (OC) use significantly reduces the risk of endometrial and ovarian cancer, has only a minimal effect on breast cancer, but may increase the risk of cervical cancer. These effects can be readily explained in terms of the effects of OCs on cell proliferation in these tissues. This analysis suggests how a hormonal contraceptive based on a GnRH agonist plus low-dose add-back sex steroids could be made that would greatly reduce lifetime risk of breast and ovarian cancer. Such a hormonal contraceptive is also likely to significantly reduce the lifetime risk of cervical cancer. It is also likely to reduce the risk of endometrial cancer, although not to the same extent as OCs.
Tissue architecture and breast cancer: the role of extracellular matrix and steroid hormones.
Authors: Hansen R K , Bissell M J
Published: December 2004

The changes in tissue architecture that accompany the development of breast cancer have been the focus of investigations aimed at developing new cancer therapeutics. As we learn more about the normal mammary gland, we have begun to understand the complex signaling pathways underlying the dramatic shifts in the structure and function of breast tissue. Integrin-, growth factor-, and steroid hormone-signaling pathways all play an important part in maintaining tissue architecture; disruption of the delicate balance of signaling results in dramatic changes in the way cells interact with each other and with the extracellular matrix, leading to breast cancer. The extracellular matrix itself plays a central role in coordinating these signaling processes. In this review, we consider the interrelationships between the extracellular matrix, integrins, growth factors, and steroid hormones in mammary gland development and function.
The EGF-CFC family: novel epidermal growth factor-related proteins in development and cancer.
Authors: Saloman D S , Bianco C , Ebert A D , Khan N I , De Santis M , Normanno N , Wechselberger C , Seno M , Williams K , Sanicola M , Foley S , Gullick W J , Persico G
Published: December 2004

The EGF-CFC gene family encodes a group of structurally related proteins that serve as important competence factors during early embryogenesis in Xenopus, zebrafish, mice and humans. This multigene family consists of Xenopus FRL-1, zebrafish one-eyed-pinhead (oep), mouse cripto (Cr-1) and cryptic, and human cripto (CR-1) and criptin. FRL-1, oep and mouse cripto are essential for the formation of mesoderm and endoderm and for correct establishment of the anterior/posterior axis. In addition, oep and cryptic are important for the establishment of left-right (L/R) asymmetry. In zebrafish, there is strong genetic evidence that oep functions as an obligatory co-factor for the correct signaling of a transforming growth factor-beta (TGFbeta)-related gene, nodal, during gastrulation and during L/R asymmetry development. Expression of Cr-1 and cryptic is extinguished in the embryo after day 8 of gestation except for the developing heart where Cr-1 expression is necessary for myocardial development. In the mouse, cryptic is not expressed in adult tissues whereas Cr-1 is expressed at a low level in several different tissues including the mammary gland. In the mammary gland, expression of Cr-1 in the ductal epithelial cells increases during pregnancy and lactation and immunoreactive and biologically active Cr-1 protein can be detected in human milk. Overexpression of Cr-1 in mouse mammary epithelial cells can facilitate their in vitro transformation and in vivo these Cr-1-transduced cells produce ductal hyperplasias in the mammary gland. Recombinant mouse or human cripto can enhance cell motility and branching morphogenesis in mammary epithelial cells and in some human tumor cells. These effects are accompanied by an epithelial-mesenchymal transition which is associated with a decrease in beta-catenin function and an increase in vimentin expression. Expression of cripto is increased several-fold in human colon, gastric, pancreatic and lung carcinomas and in a variety of different types of mouse and human breast carcinomas. More importantly, this increase can first be detected in premalignant lesions in some of these tissues. Although a specific receptor for the EGF-CFC proteins has not yet been identified, oep depends upon an activin-type RIIB and RIB receptor system that functions through Smad-2. Mouse and human cripto have been shown to activate a ras/raf/MAP kinase signaling pathway in mammary epithelial cells. Activation of phosphatidylinositol 3-kinase and Akt are also important for the ability of CR-1 to stimulate cell migration and to block lactogenic hormone-induced expression of beta-casein and whey acidic protein. In mammary epithelial cells, part of these responses may depend on the ability of CR-1 to transactivate erb B-4 and/or fibroblast growth factor receptor 1 through an src-like tyrosine kinase.
The role of inhibins and activins in prostate cancer pathogenesis.
Authors: Dowling C R , Risbridger G P
Published: December 2004

Successful prostate cancer diagnosis and management continue to provide challenges for the clinician. While interventions aimed at the containment of both early and late disease continue to fail in a significant number of patients, the search for answers must incorporate an analysis of the processes of normal and aberrant growth and development within the gland itself. Inhibin and its structurally related protein, activin, are members of the transforming-growth-factor beta (TGFbeta) superfamily. Originally identified as regulators of FSH, these proteins are now recognised to have widespread biological functions. This might be expected of proteins that are structurally homologous to TGFbeta itself, which is recognised to have regulatory roles in both normal and malignant prostate tissue. The aim of this review is to examine the relationship between inhibins, activins and their related proteins and the development of prostate cancer. The homology with TGF, the pluripotent effects of activin on various tissues and the roles for inhibins in ovarian cancer make activins and inhibins candidate growth factors for involvement at multiple sites in the progression from benign disease to cancer. In compiling this review, we aim to delineate the changes in inhibins and activins in this pathway and in doing so implicate their potential roles in the progression of carcinogenesis. We will compare the changes in inhibin and its related proteins in prostate cancer to those that are known in ovarian cancer. We will discuss the similarities and differences between the putative role of activins and TGFbeta in prostate carcinogenesis. The importance of this review lies in demonstrating that inhibin, an endocrine hormone, and its related proteins may contribute to endocrine-related cancers, such as that of the prostate gland.
The Type 1 growth factor receptors and their ligands considered as a complex system.
Authors: Gullick W J
Published: December 2004

The Type 1 family of growth factors and their receptors play an important role in normal development, wound healing and in diseases such as cancer. The products of the four receptor genes and the ten genes specifying ligands interact in a complex pattern. Such systems may develop emergent properties which cannot be predicted from a reductionist analysis of the interactions of individual components. New methods of determining these higher level properties are, however, being developed. These include microscopic analysis of live cells expressing fluorescently tagged ligands, receptors and second messengers which can provide positional information on components of the system. Computational simulations of the complex interactions are being developed which can help to predict the properties of the system.
Oncogenic co-operation in beta-cell tumorigenesis.
Authors: Pelengaris S , Khan M
Published: December 2004

Pancreatic islet neoplasms are rare endocrine tumours. The most common type is of beta-cell origin and is known as insulinoma, which can be either benign or malignant. The majority of insulinomas arise sporadically, but a small proportion develop as part of the hereditary multiple endocrine neoplasia type 1 (MEN1) syndrome. As for many human tumours, the genetic events that occur during the initiation and progression of insulinoma are poorly known. The men1 gene product, menin, is deficient in most hereditary cases, but is not obviously affected in the majority of sporadic tumours. Activation of the proto-oncogenes c-myc and ras has been observed during malignant progression, but their role in tumour initiation remains unproven. To address these questions, transgenic mouse models have been increasingly used to explore molecular and genetic events that might also precipitate human neoplasia. Transgenic mice expressing SV40 large T-antigen (Tag) oncogene in beta-cells develop tumours in a multi-stage progression from hyperplasia, angiogenesis, to solid encapsulated tumours. However, Tag, which inactivates the key tumour suppressors p53 and Rb, is not known to be involved in the pathogenesis of human insulinoma. The proto-oncogene, c-myc is implicated in beta-cell growth in both diabetes and tumorigenesis. Activation of Myc appears to be an early event in progression of human insulinoma. The effect of deregulated Myc expression on adult beta-cells in vivo has recently been investigated by developing transgenic mouse models in which the activity of Myc can be regulated ectopically. Although Myc activation initially promotes both proliferation and apoptosis in pancreatic beta-cells, apoptosis is the predominant outcome, giving rise to islet involution and diabetes. Importantly, inhibiting Myc-induced apoptosis (by co-expression of Bcl-x(L)) leads to significantly enlarged islets, many becoming highly vascularized, hyperplastic and invasive. These results suggest that, in the pancreatic beta-cells, early suppression of apoptosis is essential for the survival of Myc-activated beta-cells and islet neoplasia.
Vaccination against the HER-2/neu oncogenic protein.
Authors: Bernhard H , Salazar L , Schiffman K , Smorlesi A , Schmidt B , Knutson K L , Disis M L
Published: December 2004

The HER-2/neu oncogenic protein is a well-defined tumor antigen. HER-2/neu is a shared antigen among multiple tumor types. Patients with HER-2/neu protein-overexpressing breast, ovarian, non-small cell lung, colon, and prostate cancers have been shown to have a pre-existent immune response to HER-2/neu. No matter what the tumor type, endogenous immunity to HER-2/neu detected in cancer patients demonstrates two predominant characteristics. First, HER-2/neu-specific immune responses are found in only a minority of patients whose tumors overexpress HER-2/neu. Secondly, immunity, if detectable, is of low magnitude. These observations have led to the development of vaccine strategies designed to boost HER-2/neu immunity in a majority of patients. HER-2/neu is a non-mutated self-protein, therefore vaccines must be developed based on immunologic principles focused on circumventing tolerance, a primary mechanism of tumor immune escape. HER-2/neu-specific vaccines have been tested in human clinical trials. Early results demonstrate that significant levels of HER-2/neu immunity can be generated with active immunization. The T-cell immunity elicited is durable after vaccinations have ended. Furthermore, despite the generation of CD8(+) and CD4(+) T-cells responsive to HER-2/neu in a majority of patients, there is no evidence of autoimmunity directed against tissues that express basal levels of the protein. Cancer vaccines targeting the HER-2/neu oncogenic protein may be useful adjuvants to standard therapy and aid in the prevention of relapse in patients whose tumors overexpress the protein. Furthermore, boosting HER-2/neu-specific T-cell frequencies via active immunization may allow the ex vivo expansion of HER-2/neu-specific T-cells for use in adoptive immunotherapy, a therapeutic strategy directed against the treatment of established disease.
Inhibitory activity of luteinizing hormone-releasing hormone on tumor growth and progression.
Authors: Moretti R M , Monagnani Marelli M , van Groeninghen J C , Motta M , Limonta P
Published: December 2004

Luteinizing hormone-releasing hormone (LHRH) is the key hormone in the control of reproductive functions. In recent years, it has become evident that LHRH might act as a growth modulatory factor in tumors of the reproductive system. We have shown that in prostate cancer cells LHRH is expressed, together with its receptors, to negatively regulate cell proliferation. In these cells, LHRH acts as an antimitogenic factor through the activation of the Gi-cAMP intracellular signaling pathway. More recently, we investigated whether an LHRH-based autocrine system might also be expressed in tumors that are not classically related to the reproductive tract, such as melanoma. Malignant melanoma is known to be characterized not only by a high proliferation rate, but also by an aggressive metastatic behavior. We have demonstrated that both LHRH and LHRH receptors are expressed in human melanoma cells (BLM and Me15392). Activation of LHRH receptors by means of a potent LHRH agonist (Zoladex) significantly inhibited cell proliferation. The LHRH agonist also reduced the ability of melanoma cells to invade a reconstituted basement membrane (Matrigel) and to migrate in response to a chemotactic stimulus. These data indicate that: (a) in prostate cancer cells the LHRH receptor is coupled to a Gi-cAMP signal transduction pathway; (b) LHRH and LHRH receptors are also expressed in tumors that are not classically related to the reproductive system, such as melanoma; in melanoma cells, LHRH might act as an inhibitory factor on both cell proliferation and metastatic behavior. It is suggested that, in melanoma, LHRH receptors might represent a diagnostic marker and a possible molecular target for new therapeutic approaches for this pathology.