bluuebunny/crossref_metadata_2025 huggingface dataset:
An integer programming model for the weekly tour scheduling problem
Authors: Çezik Tolga , Günlük Oktay , Luss Hanan
Published: October 2004

We study a workforce planning and scheduling problem in which weekly tours of agents must be designed. Our motivation for this study comes from a call center application where agents serve customers in response to incoming phone calls. Similar to many other applications in the services industry, the demand for service in call centers varies significantly within a day and among days of the week. In our model, a weekly tour of an agent consists of five daily shifts and two days off, where daily shifts within a tour may be different from each other. The starting times of any two consecutive shifts, however, may not differ by more than a specified bound. Furthermore, a tour must also satisfy constraints regarding the days off, for example, it may be required that one of the days off is on a weekend day. The objective is to determine a collection of weekly tours that satisfy the demand for agents' services, while minimizing the total labor cost of the workforce. We describe an integer programming model where a weekly tour is obtained by combining seven daily shift scheduling models and days‐off constraints in a network flow framework. The model is flexible and can accommodate different daily models with varying levels of detail. It readily handles different days‐off rules and constraints regarding start time differentials in consecutive days. Computational results are also presented. © 2001 John Wiley & Sons, Inc. Naval Research Logistics 48: 607–624, 2001.
On‐line algorithms for minimizing makespan on batch processing machines
Authors: Zhang Gouchuan , Cai Xiaoqiang , Wong C.K.
Published: October 2004

We consider problem of scheduling jobs on‐line on batch processing machines with dynamic job arrivals to minimize makespan. A batch machine can handle up to B jobs simultaneously. The jobs that are processed together from a batch, and all jobs in a batch start and complete at the same time. The processing time of a batch is given by the longest processing time of any job in the batch. Each job becomes available at its arrival time, which is unknown in advance, and its processing time becomes known upon its arrival. In the first part of this paper, we address the single batch processing machine scheduling problem. First we deal with two variants: the unbounded model where B is sufficiently large and the bounded model where jobs have two distinct arrival times. For both variants, we provide on‐line algorithms with worst‐case ratio
$(\sqrt{5}+1)/2$
(the inverse of the Golden ratio) and prove that these results are the best possible. Furthermore, we generalize our algorithms to the general case and show a worst‐case ratio of 2. We then consider the unbounded case for parallel batch processing machine scheduling. Lower bound are given, and two on‐line algorithms are presented. © 2001 John Wiley & Sons, Inc. Naval Research Logistics 48: 241–258, 2001
Convergence of the Galerkin approximation of a degenerate evolution problem in electrocardiology
Authors: Sanfelici Simona
Published: October 2004

In this work we consider the reaction‐diffusion system of FitzHugh‐Nagumo type describing the behavior of the electrical conduction in an anisotropic cardiac muscle. The analysis of the Galerkin semidiscrete space approximation to this system is approached by means of a suitable variational formulation in the framework of abstract degenerate evolution equations.

The main results concern convergence analysis and a priori stability estimates for the semidiscrete solution. These abstract results are then applied to the cardiac problem and for the finite element Galerkin approximation we achieve optimal order convergence. © 2002 Wiley Periodicals, Inc. Numer Methods Partial Differential Eq 18: 218–240, 2002; DOI 10.1002/num.1000
Decision Aiding, Not Dispute Resolution: Creating Insights through Structured Environmental Decisions
Authors: Gregory Robin , McDaniels Tim , Fields Daryl
Published: October 2004

Public participation in environmental decisions has become commonplace. A favored model for public input is to use the tools of dispute resolution to seek consensus among members of a multi‐party stakeholder group. The authors believe that a focus on dispute resolution and consensus building can pose impediments to the creation of insights for decisionmakers and lead to the adoption of inferior policy choices. Instead, they advocate an alternative approach to stakeholder participation characterized as “decision aiding” through a structured process based on constructive, multi‐attribute techniques and value‐focused thinking. In this paper some of the major difficulties posed by a dispute‐resolution approach are articulated, the principles of a decision‐aiding process reviewed, and this alternative approach illustrated by describing a stakeholder consultation involving water‐use planning for a hydroelectric facility on the Alouette River in British Columbia, Canada. © 2001 by the Association for Public Policy Analysis and Management.
Testing a Financial Incentive to Promote Re‐employment among Displaced Workers: The Canadian Earnings Supplement Project (ESP)
Authors: Bloom Howard S. , Schwartz Saul , Lui‐Gurr Susanna , Lee Suk‐Won , Peng Jason , Bancroft Wendy
Published: October 2004

This article presents findings from a randomized experiment conducted in four Canadian provinces to measure the effects of a generous financial incentive that was designed to promote rapid re‐employment among workers who were displaced from their jobs by changing economic conditions. The incentive tested was an earnings supplement which, for as long as 2 years and as much as $250 weekly, would replace 75 percent of the earnings loss incurred by displaced workers who took a new lower‐paying full‐time job within six months of receiving a supplement offer. Findings from the experiment indicate that although persons offered the supplement understood its terms and conditions, only 2 out of 10 actually received supplement payments. Furthermore, the supplement offer had little effect on job‐search behavior, employment prospects, or receipt of unemployment insurance. Nevertheless, persons who received supplement payments benefited from them substantially. On average, they received payments for 64 weeks, totaling $8,705. © 2001 by the Association for Public Policy Analysis and Management.
What Research Can Tell Policymakers about School Choice
Authors: Teske Paul , Schneider Mark
Published: October 2004

American school systems have implemented several different kinds of school choice policies, and most of them
are controversial. The research literature on various forms of school choice reveals some areas of consensus,
but other areas where the results of studies diverge. Consensus results show that parents are more satisfied
with choice, that they report using academic preferences to make choices, and that they tend to be more involved
with their child's education as a consequence of choice. There is some, though mixed, evidence of improved
test scores for children involved with various forms of choice. Actual parental use of choice and gathering of
information, however, show some evidence of stratification, not always by race or income, but often by the level
of parental involvement and motivation. These results provide considerable evidence about the effects on
students whose parents have made an active choice, but more policy research is needed on the effects of
competition on students in schools that have not been chosen. © 2001 by the Association for Public Policy
Analysis and Management.
Poverty across the Life Cycle: Evidence from the PSID
Authors: Rank Mark R. , Hirschl Thomas A.
Published: October 2004

The likelihood of experiencing poverty at some point during the adult life cycle is estimated. These
probabilities are derived through a set of life tables built upon 25 waves of data from the Panel Study of
Income Dynamics, and represent an alternative approach to studying poverty than prior empirical studies. Life
table analyses are divided into early adulthood (ages 20–40), middle adulthood (ages
40–60),and later adulthood (ages 60–80). The findings indicate that individuals
within the sample face a significant risk of poverty at some point during their adult lives, particularly during
the early and later stages of adulthood. Duration tends to be relatively short (1 or 2 years), but
once poverty occurs, it is likely to occur again. Results also reveal the profound life‐course effect
that race, education, and gender have upon the likelihood of encountering poverty during the adult years.
Several policy and research implications are discussed. © 2001 by the Association for Public Policy
Analysis and Management.
Synthesis and characterization of star polymers initiated by hexafunctional discotic initiator through atom transfer radical polymerization
Authors: Feng Xiao‐Shuang , Pan Cai‐Yuan
Published: October 2004

A novel hexafunctional discotic initiator, 2,3,6,7,11,12‐hexakis(2‐bromobutyryloxy)triphenylene (HBTP), was synthesized by the esterification of 2,3,6,7,11,12‐hexahydroxytriphenylene with 2‐bromobutyryl chloride. Atom transfer radical polymerizations of styrene, methyl acrylate, and n‐butyl acrylate were carried out in 50 vol % tetrahydrofuran with HBTP/copper(I) bromide/2,2′‐bipyridyl as an initiation system. The polymers produced had well‐controlled molecular weights and narrow molecular weight distributions (<1.2). On the basis of 1H NMR spectra of the star polymer and its hydrolyzed products, we can conclude that the initiator quantitatively initiated the polymerization of vinyl monomers and that a star polymer with a discotic core was obtained. © 2001 John Wiley & Sons, Inc. J Polym Sci Part A: Polym Chem 39: 2233–2243, 2001
Mechanistic study of trans⇆cis isomerization of the substituted azobenzene moiety bound on a liquid‐crystalline polymer
Authors: Ho Chao‐Hsien , Yang Kai‐Nung , Lee Sung‐Nung
Published: October 2004

A mechanistic study of the trans⇆cis isomerization of the azobenzene moiety in a side‐chain liquid‐crystal polymer system was carried out with six liquid‐crystalline polymethacrylates in which different electron‐withdrawing substituents were attached to the para‐positions of the azobenzene chromophores. Compared to the non‐nitro‐substituted azo polymers, the nitro‐substituted azo polymers exhibited two quite different behaviors: an extraordinarily high reaction rate of the thermal cis–trans isomerization and an unexpected composition of cis–trans isomers obtained from the photochemical trans–cis isomerization process. A potential energy profile for the isomerization process was established on basis of the structures of the proposed transition states and was employed to elucidate the reaction mechanism. The results confirmed that the nitro‐substituted azo polymer system proceeded via a rotation mechanism in either direction of the trans⇆cis isomerization reaction, whereas the non‐nitro‐substituted species were more likely to follow an inversion mechanism. © 2001 John Wiley & Sons, Inc. J Polym Sci Part A: Polym Chem 39: 2296–2307, 2001
Kinetics of the volume phase transition in poly(n‐isopropylacrylamide) gels prepared under high pressure
Authors: Kitada Tadayosi
Published: October 2004

New poly(N‐isopropylacrylamide) gels were prepared under high pressure (ca. 200 MPa) during gelation. The preparation‐pressure dependence of the deswelling speed of the gels was measured with a conventional T‐jump method. The deswelling time of a gel rod 2.2 mm in diameter prepared at 193 MPa was about 200 s, 1000 times faster than that of a homogeneous poly(N‐isopropylacrylamide) gel. Moreover, the collective diffusion coefficient, the thermal fluctuation, and the ensemble‐average intensity of the swollen gel networks were obtained with dynamic light scattering measurements. Both the enthalpy and entropy of the gels were estimated from equilibrium swelling curves with the Flory–Huggins interaction parameter evaluated with mean field theory based on the Flory‐type of the Gibbs free‐energy formula. It was found that the networks of the gels had an inhomogeneous structure newly introduced by the preparation pressure. © 2001 John Wiley & Sons, Inc. J Polym Sci Part A: Polym Chem 39: 2315–2325, 2001
Correlation between local mobility and mechanical properties of high‐speed melt‐spun nylon‐6 fibers
Authors: Kwak Seung‐Yeop , Kim Jun Hyung , Lee Jong‐Chan
Published: October 2004

This article establishes the processing–microstructure–motion–property relationship of high‐speed melt‐spun nylon‐6 fibers. From solid‐state 1H NMR T1ρ (spin–lattice relaxation time in the rotating frame) relaxation studies, all nylon‐6 fibers spun at 4500–6100 m/min showed three‐component exponential decay with the time constants T1ρ,I, T1ρ,II, and T1ρ,III, indicating that there existed three different motional phases. These phases were assigned to immobile crystalline, intermediate rigid amorphous, and mobile amorphous regions. The determination of the correlation time (τc) of the respective phases provided information about the local molecular mobility of each phase with respect to the spinning speed. As the spinning speed increased, τc of the crystalline region increased (4500–5200 m/min) and then reached a plateau. However, τc for the rigid amorphous region increased from 5200 m/min onward, indicating that the rigid amorphous chains were more oriented and constrained in the spinning speed range of 5500–6100 m/min. The drastic increase of the maximum thermal stress for all fibers from 5500 to 6100 m/min was coincident with the τc characteristics of the rigid amorphous region. The significant increase in tenacity and Young's modulus and the large decrease in elongation at break at 5500–6100 m/min were also in good agreement with the local molecular motion of the intermediate rigid amorphous phase in the nylon‐6 fibers. © 2001 John Wiley & Sons, Inc. J Polym Sci B: Polym Phys 39: 993–1000, 2001
Poly(ester amide)s derived from glycine, even‐numbered diols, and dicarboxylic acids: Considerations on the packing
Authors: Paredes N. , Casas M. T. , Puiggalí J.
Published: October 2004

A new sequential poly(ester amide) derived from 1,12‐dodecanediol, sebacic acid, and glycine was synthesized and characterized. Its crystalline structure was studied with transmission electron microscopy and X‐ray diffraction. The results were compared with results for a related polymer, derived from glycine, 1,6‐hexanediol, and succinic acid, that produced a lower methylene/carbonyl ratio. The crystalline structures of both polymers corresponded to a periodic arrangement of two layers of hydrogen‐bonded molecular chains, whose polymethylene sequences mimicked the packing of polyethylene and the majority of polyesters. © 2001 John Wiley & Sons, Inc. J Polym Sci B: Polym Phys 39: 1036–1045, 2001
Effect of aromatic substitution on phase behavior of blends of halogenated polystyrene and conventional polystyrene
Authors: Thaweephan Pawiga , Meng Scott , Sigalov Grigori , Koo Hyun , Sung Kim , Choi Ho , Kyu Thein
Published: October 2004

Miscibility phase behavior in blends of poly(bromostyrene) with polystyrene (PS) has been investigated by means of time‐resolved light scattering, optical microscopy, and DSC. Cloud point phase diagrams of blends of conventional PS with poly‐(2‐bromostyrene) (P2BrS), poly‐(3‐bromostyrene), and poly‐(4‐bromostyrene) of comparable molecular weights were established by light scattering. Of particular interest is the fact that ortho, meta, and para substitutions in the styrenic aromatic rings of poly(bromostyrene) show profound effects on the composition–temperature phase diagrams of their blends with PS, exhibiting a lower critical‐solution temperature (LCST), an upper critical solution temperature (UCST), and combined LCST/UCST diagrams, respectively. Poly‐(2‐chlorostyrene) exhibits an LCST behavior very close to that of the P2BrS blend, suggesting that these types of halogen atoms may be inconsequential to phase behavior. A similar study has been extended to a PS blend containing commercial brominated PS (66 mol % bromine substitution) to determine what location of bromine substitution is crucial for miscibility enhancement in the flame‐retardant brominated PS blends. © 2001 John Wiley & Sons, Inc. J Polym Sci Part B: Polym Phys 39: 1605–1615, 2001
Effects of single‐dose fluticasone on exercise‐induced asthma in asthmatic children: A pilot study*
Authors: Thio B.J. , Slingerland G.L.M. , Nagelkerke A.F. , Roord J.J. , Mulder P.G.H. , Dankert‐Roelse J.E.
Published: October 2004

A single high dose of inhaled corticosteroid (ICS) can increase airway caliber in children with asthma attacks and laryngitis subglottica. Presumably the effect is due to the vasoconstrictive and antiedematous properties of topical steroids. Enlarged vessels have been suggested to play a role in the pathophysiology of exercise‐induced bronchial obstruction (EIB). To investigate this, we evaluated the effect of a single high dose of fluticasone propionate (FP) on EIB in asthmatic children. Nine children aged 8–16 years with mild to moderate asthma were included. All children had a history of EIB, which was confirmed by an exercise test. None was taking ICS maintenance therapy. The children inhaled either a single dose of 1 mg FP or placebo on 2 separate days within 7–14 days. After inhalation, airway caliber (FEV1) was assessed for 4 hr before exercise. Then an exercise challenge was performed on a treadmill to assess EIB (% fall FEV1).

A significant increase in FEV1 was observed 1 hr after inhalation of FP compared to placebo. Response to exercise was expressed as maximal % fall in FEV1 from baseline (% fall) and as area under the curve (AUC) of the 30‐min time/response curve. The % fall FEV1 after exercise and the AUC were significantly reduced when FP was inhaled compared to placebo inhalation (% fall 9.7% vs. 19.2%, respectively, P = 0.038 and AUC 92.0%ċmin vs. 205.7%ċmin, respectively, P = 0.03). There was considerable individual variability in reduction of EIB, with 5 out of 9 children having a clinically significant response.

We conclude that a single high dose of inhaled FP has an acute protective effect on the bronchial response to exercise in a substantial proportion of asthmatic children. Pediatr Pulmonol. 2001; 32:115–121. © 2001 Wiley‐Liss, Inc.
Intratracheal administration of perfluorochemical‐gentamicin suspension: A comparison to intravenous administration in normal and injured lungs*
Authors: Cox Cynthia A. , Cullen Aaron B. , Wolfson Marla R. , Shaffer Thomas H.
Published: October 2004

Respiratory infections can lead to acute lung injury and perfusion abnormalities. We hypothesized that intratracheal (IT) administration of a perfluorochemical (PFC) gentamicin (G) suspension as compared to intravenous (IV) administration of gentamicin will result in higher lung tissue levels of gentamicin, while maintaining safe serum levels. To test this hypothesis, 21 lambs with normal and acid injured lungs were studied for 4 hr, using 2 different drug delivery methods, IT and IV. Lungs were injured with warm HCl acid in saline lavage, followed by partial liquid ventilation with perflubron (bolus FRC = 20 mL/kg). G at a dose of 5 mg/kg was delivered either IT (G‐PFC; 20 mL/kg) or IV (aqueous injection with IT 20 mL/kg PFC alone). Throughout the study, serum G levels, arterial blood gases, respiratory system compliance, and mean arterial blood pressure were measured. Lung tissue G levels were measured at 4 hr and averaged across lobes. Physiologic gas exchange and pulmonary function were maintained throughout the protocol for both the normal and injured lungs.

Intravenously administered G resulted in an initial 5‐min serum concentration of 43 ± 2.5 mcg/mL, followed by an exponential decline over the 4‐hr protocol to a level of 2.1 ± 0.23 mcg/mL at hr 4. The intratracheally administered G suspension resulted in a 5‐min serum concentration of 1.8 ± 0.98 mcg/mL and remained relatively constant throughout the protocol, with a 4‐hr level of 1.6 ± 0.29 mcg/mL. With respect to lung tissue G levels, IT administration was significantly more effective in delivering the drug to the normal lungs than IV (31.4 ± 3.3 mcg/g vs. 4.0 ± 0.7 mcg/g) 4 hr after administration. In the lung injury group, there was a small but significant difference in lung tissue G levels, with the IT‐administered perfluorochemical‐G suspension achieving greater levels than the IV‐administered G (11.9 ± 0.52 mcg/g vs. 10.1 ± 0.8 mcg/g). Additionally, the drug delivered IV and IT in both the normal and injured lung models was homogeneously distributed throughout the lung.

These data show that G lung tissue levels in both normal and injured lungs were higher in the IT group when compared to IV administration. The results of this study demonstrate that in normal and injured lungs, homogeneous G lung tissue levels can be more effectively achieved at lower serum levels when delivered IT in a G‐PFC suspension as compared to IV administration. Pediatr Pulmonol. 2001; 32:142–151. © 2001 Wiley‐Liss, Inc.
Pulmonary involvement in a child with ligneous conjunctivitis and homozygous type I plasminogen deficiency
Authors: Özçelik Uǧur , Akçören Zuhal , Anadol Deniz , Kiper Nural , Orhon Mehmet , Göçmen Ayhan , Irkeç Murat , Schuster Volker
Published: October 2004

Ligneous conjunctivitis (LC) is a rare disorder characterized by a chronic course of recurrent membranous lesions at conjunctivae. Pseudomembranes of other mucous membranes have been reported in patients with LC, but to the best of our knowledge, no case with alveolar involvement has been described. Here, we report a 2.5‐year‐old girl with LC who had tracheoaveolar involvement and homozygous type I plasminogen deficiency. Tracheal involvement was diagnosed by bronchoscopic biopsy and alveolar involvement with postmortem biopsy. She was shown to be homozygous for frameshift mutation in plasminogen exon 14 (Gly565ins‐G) with molecular genetic examination of DNA which was obtained from parafin embedded postmortem lung tissue. Ligneous inflammation of the upper and lower respiratory tract must be considered in children with LC and recurrent respiratory tract problems. Pediatr Pulmonol. 2001; 32:179–183. © 2001 Wiley‐Liss, Inc.
Androgen regulation of spermidine synthase expression in the rat prostate*
Authors: Cyriac Jomol , Haleem Riffat , Cai Xiaoyan , Wang Zhou
Published: October 2004

BACKGROUND

Spermidine synthase, an essential enzyme in the polyamine synthesis pathway, was identified as one of the androgen‐response genes in the rat ventral prostate. Characterization of androgen regulation of spermidine synthase is important to the understanding of androgenic regulation of polyamine synthesis.

METHODS

Full‐length cDNA encoding rat spermidine synthase was isolated from a λZAP cDNA phage library. Young male adult Sprague‐Dawley rats were used for castration and androgen replacement. Northern blot and in situ hybridization were used to characterize gene expression.

RESULTS

The amino acid sequence of rat spermidine synthase shares 99% and 94% identity with that of mouse and human spermidine synthase, respectively. Spermidine synthase gene is abundantly expressed and regulated by androgens in the ventral, dorsal, and lateral lobes of the rat prostate, and its expression is localized to the epithelial cells. Spermidine synthase also is regulated by androgens in the seminal vesicles but not in the muscle, brain, kidney, thymus, heart, or liver, suggesting that this enzyme is responsive to androgen in the male sex accessory organs only. The expression of spermidine synthase and two other enzymes involved in polyamine synthesis, S‐adenosylmethionine decarboxylase and ornithine decarboxylase, are regulated by androgens coordinately.

CONCLUSIONS

Spermidine synthase is most abundantly expressed and regulated by androgens in the prostatic epithelial cells, suggesting that regulation of spermidine synthase is likely a key step in coordinated androgen regulation of polyamine synthesis in the prostate. Prostate 50: 252–261, 2002. © Wiley‐Liss, Inc.
Effectiveness of mass screening for the prognosis of prostate cancer patients in Japanese communities
Authors: Kubota Yutaka , Ito Kazuto , Imai Kyoichi , Yamanaka Hidetoshi
Published: October 2004

BACKGROUND

A study was conducted to investigate the effectiveness of mass screening (MS) for prostate cancer in Japanese communities using the long‐term follow‐up results.

METHODS

Subjects were 279 patients with prostate cancer detected by MS in Gunma prefecture (MS group) and 624 patients with prostate cancer who did not undergo screening (non‐MS group). From the follow‐up data, the prognoses were compared between the groups.

RESULTS

The ratio of patients with Stage II cancer was higher for the MS group (59.1%) when compared to non‐MS group (25.3%). As a whole, the prognosis of the MS group was more favorable than that of the non‐MS group for relative survival rate. Prognosis was especially favorable for patients with Stage III prostate cancer in mass screening group considering the effect of lead‐time bias.

CONCLUSIONS

Early detection and longer survival of the patients with prostate cancer detected by mass screening suggested the effectiveness of prostate cancer screening. Prostate 50: 262–269, 2002. © Wiley‐Liss, Inc.
Antitumor effect of an HER2‐specific antibody–toxin fusion protein on human prostate cancer cells
Authors: Wang Ling , Liu Bolin , Schmidt Mathias , Lu Yang , Wels Winfried , Fan Zhen
Published: October 2004

BACKGROUND

HER2/neu has been implicated in the oncogenesis of human prostate cancer. Clinical studies have suggested that overexpression of HER2 may be one of the indicators of poor prognosis in prostate cancer patients.

METHODS

We used Western blot analysis to examine the expression of HER2 in a panel of established human prostate cancer cell lines and used an MTT assay to evaluate the cytotoxicity on these cells of a recombinant fusion protein consisting of an HER2‐specific single‐chain antibody and the Pseudomonas exotoxin A, scFv(FRP5)‐ETA.

RESULTS

LNCaP cells express high levels of HER2 protein. Exposure of LNCaP cells to scFv(FRP5)‐ETA caused remarkable cell death. In contrast, PC3M cells, which express an undetectable level of HER2 protein, were resistant to scFv(FRP5)‐ETA‐induced cytotoxicity. MDA PCa 2a, MDA PCa 2b, and DU145 cells express low‐to‐medium levels of HER2 protein and showed an HER2 level‐dependent response to scFv(FRP5)‐ETA‐induced cytotoxicity. The scFv(FRP5)‐ETA‐induced cytotoxicity of LNCaP cells could be inhibited by an anti‐HER2 monoclonal antibody (mAb), which downregulated the levels of HER2 protein, indicating the specificity of scFv(FRP5)‐ETA in inducing cytotoxicity in LNCaP cells. Using an apoptosis ELISA, we demonstrated that scFv(FRP5)‐ETA induced apoptosis in LNCaP cells. The apoptosis was inhibited by the presence of dihydrotestosterone (DHT) in culture medium. Exposure of LNCaP cells to scFv(FRP5)‐ETA caused reduction in the level of the prostate‐specific antigen (PSA).

CONCLUSIONS

Our data suggest that scFv(FRP5)‐ETA might be a useful agent for the treatment of human prostate cancer cells with high levels of HER2 expression. Prostate 47:21–28, 2001. © 2001 Wiley‐Liss, Inc.
Pathological features of prostate cancer detected on initial and repeat prostate biopsy: Results of the prospective European prostate cancer detection study
Authors: Djavan Bob , Mazal Peter , Zlotta Alex , Wammack Robert , Ravery Vincent , Remzi Mesut , Susani Martin , Borkowski Andrzej , Hruby Stefan , Boccon‐Gibod Laurent , Schulman Claude C. , Marberger Michael
Published: October 2004

BACKGROUND

We evaluated pathological features of prostate cancer detected on repeat prostate biopsy in men with a serum total prostate‐specific antigen (PSA) level between 4 and 10 ng/ml who were diagnosed with benign prostatic tissue after an initial biopsy and compared them to those cancers detected on initial prostate biopsy.

METHODS

In this prospective European prostate cancer detection study, 1,051 men with a total PSA level between 4 and 10 ng/ml underwent transrectal ultrasound (TRUS)–guided sextant biopsy and two additional transition zone biopsies. All subjects whose biopsy samples were negative for prostate cancer (CaP) underwent a repeat biopsy after 6 weeks. Those with clinically localized cancers underwent radical prostatectomy. Pathological and clinical features of patients diagnosed with cancer on either initial or repeat biopsy and clinically organ confined disease who agreed to undergo radical prostatectomy were compared.

RESULTS

Initial biopsy was positive (CaP) in 231 of 1,051 enrolled subjects and negative (benign histology) in 820 subjects. Of these 820 subjects, CaP was detected in 10% (83/820) upon repeat biopsy. Of cancers detected on initial and repeat biopsy, 148/231 (64%) and 56/83 (67.5%) had clinically localized disease, respectively, and were offered radical prostatectomy. 10/148 (6.7%) and 3/56 (5.3%), respectively, opted for radiation therapy and thus, 138/148 (93.3%) and 53/56 (94.7%), respectively, underwent radical retropubic prostatectomy. There were statistically significant differences with respect to multifocality (P = 0.009) and cancer location (P < 0.001) with cancers on repeat biopsy showing a lower rate of multifocality and a more apico‐dorsal location. In contrast, there were no differences with respect to stage (P = 0.2), Gleason score (P = 0.36), percentage Gleason grade 4/5 (P = 0.1), serum PSA (P = 0.62), and patient age (P = 0.517).

CONCLUSIONS

At least 10% of patients with negative prostatic biopsy results will be diagnosed with CaP on repeat biopsy. Despite differences in location and multifocality, pathological and biochemical features of cancers detected on initial and repeat biopsy are similar, suggesting similar biological behavior and thus advocating for a repeat prostate biopsy in case of a negative finding on initial biopsy. Cancers missed on initial biopsy and subsequently detected on repeat biopsy are located in a more apico‐dorsal location. Repeat biopsies should thus be directed to this rather spared area in order to improve cancer detection rates. Prostate 47:111–117, 2001. © 2001 Wiley‐Liss, Inc.
Comparison of prazosin, terazosin and tamsulosin: Functional and binding studies in isolated prostatic and vascular human tissues
Authors: Amadesi Silvia , Varani Katia , Spisani Lorella , Daniele Carlo , Turini Alessandro , Agnello Giovanni , Zamboni Paolo , Borea Pier Andrea , Geppetti Pierangelo
Published: October 2004

BACKGROUND

Terazosin and tamsulosin are drugs currently used in the treatment of benign prostatic hypertrophy (BPH). The potency of these two α1 receptor antagonists and that of prazosin to inhibit contractions induced by noradrenaline and the binding of [3H]‐prazosin in human prostate and four different human arterial and venous vessels (saphenous and umbilical veins, renal and mesenteric arteries) was studied.

METHODS

By bioassay and binding studies, we examined the receptor affinities of different α1 receptor antagonists in different human tissues.

RESULTS

pKb of terazosin, tamsulosin, and prazosin obtained in the prostatic tissues (8.15, 9.64, and 8.59, respectively) were not different from those obtained in the umbilical veins (8.07, 9.56, and 8.30, respectively), in the mesenteric artery (8.27, 10.29, and 9.01, respectively), renal artery (8.35, 10.13, and 8.76, respectively) and saphenous vein (7.8, 10.3, and 9.32, respectively). IC50 (nM) of prazosin, terazosin, and tamsulosin obtained from binding studies in membrane preparations from prostate tissue were similar to those from umbilical veins, saphenous vein, and renal artery.

CONCLUSIONS

All of the evaluated drugs showed similar selectivity for prostatic vs. vascular tissues. Thus, different clinical profiles of the present drugs should not result from their differential affinity for prostatic versus vascular α1‐adrenoceptors. Prostate 47:231–238, 2001. © 2001 Wiley‐Liss, Inc.
Phage display selection of peptides that affect prostate carcinoma cells attachment and invasion
Authors: Romanov Victor I. , Durand David B. , Petrenko Valery A.
Published: October 2004

BACKGROUND

Prostate cancer‐specific proteins must be identified to serve as diagnostic and prognostic markers. Cell surface proteins are especially important, because they have potential utility as diagnostic markers and therapeutic targets. Identification of ligands for these proteins will allow use of these ligands as diagnostic and therapeutic tools and permit the investigation of receptor function. We performed a search for peptide ligands to prostate cancer cell‐specific receptors.

METHODS

Peptide phage display library was used to isolate specific ligands to LNCaP prostate carcinoma cells receptors. Selected phage and cognate peptides were investigated for their cancer‐related functions, such as the ability to interfere with cell adhesion, spreading, motility, and invasion.

RESULTS

Phage designated pg35, blocked spreading of LNCaP cells and their derivatives C4–2 and C4–2b. Cognate peptide did not inhibit spreading, but incubation of C4–2 and C4–2b cells with cognate peptide increased their affinity for endothelial cells and invasiveness. In addition, the peptide activates matrix metalloproteinase (MMP)‐2 and 9 in C4–2 and C4–2b cells.

CONCLUSIONS

These results indicate that identified ligands may play a role in tumorigenicity and metastatic transformation of prostate cancer. To our knowledge, this is the first identification of a functional cancer‐specific peptide ligand using the phage display approach. Prostate 47:239–251, 2001. © 2001 Wiley‐Liss, Inc.
Tumor characteristics in screening for prostate cancer with and without rectal examination as an initial screening test at low PSA (0.0–3.9 ng/ml)
Authors: Vis André N. , Hoedemaeker Robert F. , Roobol Monique , van der Kwast Theo H. , Schröder Fritz H.
Published: October 2004

BACKGROUND

The value of rectal examination as initial screening test for prostate cancer at low PSA values (0.0–3.9 ng/ml) was determined by evaluating the number and tumor characteristics of the cancers detected.

METHODS

Two study populations were subjected to screening with (n = 10,226) and without (n = 10,753) rectal examination as initial screening test. The number of cancers detected at low PSA values for both screening regimens, the corresponding biopsy and radical prostatectomy tumor characteristics were assessed. Possibly harmless cancers were defined as small (< 0.5 ml) organ‐confined tumors without Gleason growth‐patterns 4/5.

RESULTS

At low PSA, 26.6% (117/440) of screen‐detected cancers were detected after the evaluation of a suspicious rectal examination. The number of cancers and tumor aggressiveness features were highly associated with serum‐PSA level. The proportion of possibly harmless disease steadily declined from 100% (PSA 0.0–0.9 ng/ml) to 15.4% (PSA 3.0–3.9 ng/ml). Rectal examinations were performed unnecessarily in 94.7–100% of cases, when detection of clinically significant disease was aimed at. Using PSA (and a cut‐off of 3.0 ng/ml) as the only screening tool, 24.3% (121/498) of screen‐detected cancers were in the PSA range 3.0–3.9 ng/ml, and 60.0% were assessed as clinically significant.

CONCLUSIONS

Rectal examination as initial screening test for prostate cancer at low PSA values may be replaced by screening using serum‐PSA only. At PSA levels below 3.0 ng/ml, 289 rectal examinations are required to find one case of clinically significant disease, and 96 rectal examinations are needed to diagnose prostate cancer of any size, grade, or stage. Prostate 47:252–261, 2001. © 2001 Wiley‐Liss, Inc.
The association of fatty acids with prostate cancer risk
Authors: Newcomer Laura M. , King Irena B. , Wicklund Kristine G. , Stanford Janet L.
Published: October 2004

BACKGROUND

Animal studies indicate that omega‐6 fatty acids promote and omega‐3 fatty acids inhibit tumor development. This pilot study was designed to evaluate whether these fatty acids are associated with human prostate cancer.

METHODS

Levels of erythrocyte membrane omega‐3 and omega‐6 fatty acids were determined for 67 incident prostate cancer cases and 156 population‐based controls.

RESULTS

Prostate cancer risk was increased in the highest compared to the lowest quartile of α‐linolenic acid (OR = 2.6, 95% CI = 1.1–5.8, trend P = 0.01). Positive associations were also observed with higher levels of linoleic acid (OR = 2.1, 95% CI = 0.9–4.8) and total omega‐6 fatty acids (OR = 2.3, 95% CI = 1.0–5.4).

CONCLUSIONS

Results are consistent with other studies showing that linoleic and total omega‐6 fatty acids increase risk of prostate cancer. Contrary to animal studies, α‐linolenic acid was also positively associated with risk. Further research will be required to clarify the role of these fatty acids in human prostate cancer. Prostate 47:262–268, 2001. © 2001 Wiley‐Liss, Inc.
Reduced expression of hMSH2 and hMLH1 and risk of prostate cancer: A case‐control study
Authors: Strom Sara S. , Spitz Margaret R. , Yamamura Yuko , Babaian Richard J. , Scardino Peter T. , Wei Qingyi
Published: October 2004

BACKGROUND

Although prostate cancer is the most common incident cancer in men, not much is known about its etiology. We tested the hypothesis that expression levels of hMSH2 and hMLH1 in unaffected (normal) tissue play a role in the etiology of prostate cancer.

METHODS

Total RNA was extracted from peripheral blood lymphocytes of subjects ascertained by a case‐control study (70 patients and 97 age‐ and ethnicity‐matched controls). A multiplex reverse transcription‐polymerase chain reaction assay was used to simultaneously evaluate the relative expression of hMSH2 and hMLH1, using β‐actin as the internal control.

RESULTS

The relative gene expression levels of hMSH2 and hMLH1 were significantly lower in cases than in controls (P < 0.05 for both genes). When compared with the highest tertile of the controls, low expression levels (the middle and lowest tertiles) of hMLH1 were associated with significantly increased risk of prostate cancer in a dose–response relationship (ORs = 2.68, and 4.31; 95% confidence interval = 1.00–7.23 and 1.64–11.30, respectively) after adjustment for age, ethnicity, smoking status, and family history of prostate cancer.

CONCLUSIONS

These results suggest that reduced expression of hMLH1 in peripheral lymphocytes may be a risk factor for prostate cancer. However, it cannot be ruled out that the reduced expression we observed may be caused by the disease status. Our findings and the factors that may affect the expression of hMLH1 need further confirmation in larger prospective studies. Prostate 47:269–275, 2001. © 2001 Wiley‐Liss, Inc.
Gonadotropin‐releasing hormone receptor expression in the human prostate
Authors: Tieva Åse , Stattin Pär , Wikström Pernilla , Bergh Anders , Damber Jan‐Erik
Published: October 2004

BACKGROUND

Inhibitory effects of gonadotropin‐releasing hormone (GnRH) analogs on prostate cancer cell proliferation, both in vivo and in vitro, indicate the presence of specific binding sites for GnRH on prostate cancer cells. To investigate this issue further, we examined the expression of GnRH receptor (GnRH‐R) mRNA and protein in human prostate biopsies as well as in other extrapituitary tissues.

METHODS

The relative quantity of GnRH‐R mRNA was determined by reverse transcriptase–polymerase chain reaction (RT‐PCR) and immunohistochemistry (IHC) in human prostate biopsies. Extrapituitary GnRH‐R levels were determined by a semiquantitative PCR reaction.

RESULTS

Using PCR, a relatively high expression level of GnRH‐R mRNA was found in prostate tumor tissue followed by normal prostate, thymus, and kidney expression levels. The levels showed by heart, brain, placenta, lung, liver, skeletal muscle, pancreas, colon, ovary, small intestine, spleen, and testis were low but detectable, whereas peripheral blood leukocyte showed no demonstrable product. GnRH‐R immunoreactivity was localized in both luminal and basal epithelial cells in benign and malignant prostate tissue, and GnRH‐R were also observed in intraprostatic lymphocytes. The relative GnRH‐R mRNA levels in prostate biopsies from 16 patients showed a wide range of individual differences, but these differences were not related to histological grade. Castration therapy did not significantly influence GnRH‐R mRNA expression in normal and malignant prostate tissue.

CONCLUSIONS

These results suggest that epithelial cells and infiltrating lymphocytes are targets for GnRH action in the human prostate. Comparative data show relatively high GnRH‐R expression in human prostate tissue compared to other human tissues. Prostate 47:276–284, 2001. © 2001 Wiley‐Liss, Inc.
Therapeutic potential of curcumin in human prostate cancer. III. Curcumin inhibits proliferation, induces apoptosis, and inhibits angiogenesis of LNCaP prostate cancer cells in vivo
Authors: Dorai Thambi , Cao Yi‐Chen , Dorai Bhuvaneswari , Buttyan Ralph , Katz Aaron E.
Published: October 2004

BACKGROUND

Earlier work from our laboratory highlighted the therapeutic potential of curcumin (turmeric), used as a dietary ingredient and as a natural anti‐inflammatory agent in India and other Southeast Asian countries. This agent was shown to decrease the proliferative potential and induce the apoptosis potential of both androgen‐dependent and androgen‐independent prostate cancer cells in vitro, largely by modulating the apoptosis suppressor proteins and by interfering with the growth factor receptor signaling pathways as exemplified by the EGF‐receptor. To extend these observations made in vitro and to study the efficacy of this potential anti‐cancer agent in vivo, the growth of LNCaP cells as heterotopically implanted tumors in nude mice was followed.

METHODS

The androgen‐dependent LNCaP prostate cancer cells were grown, mixed with Matrigel and injected subcutaneously into nude mice. Experimental group received a synthetic diet containing 2% curcumin for up to 6 weeks. At the end point, sections taken from the excised tumors were evaluated for pathology, cell proliferation, apoptosis, and vascularity.

RESULTS

Curcumin causes a marked decrease in the extent of cell proliferation as measured by the BrdU incorporation assay and a significant increase in the extent of apoptosis as measured by an in situ cell death assay. Moreover, a significant decrease in the microvessel density as measured by the CD31 antigen staining was also seen.

CONCLUSIONS

Curcumin could be a potentially therapeutic anti‐cancer agent, as it significantly inhibits prostate cancer growth, as exemplified by LNCaP in vivo, and has the potential to prevent the progression of this cancer to its hormone refractory state. Prostate 47:293–303, 2001. © 2001 Wiley‐Liss, Inc.
Concentration of enzymatically active prostate‐specific antigen (PSA) in the extracellular fluid of primary human prostate cancers and human prostate cancer xenograft models
Authors: Denmeade Samuel R. , Sokoll Lori J. , Chan Daniel W. , Khan Saeed R. , Isaacs John T.
Published: October 2004

BACKGROUND

Prostate‐specific antigen (PSA) targeted prodrugs are under development in our laboratory. Concentrations of total PSA and enzymatically active PSA produced by various human prostate cancer xenograft models have not been well characterized.

METHODS

The concentration of PSA secreted into the extracellular fluid (ECF) in normal human prostate tissue, primary prostate cancers obtained directly from patients, and serially passageable human prostate cancer xenografts (PC‐82, LNCaP, LAPC‐4) were determined using Tandem assays. Percent enzymatically active PSA in the ECF and in conditioned media was also determined using a previously validated assay employing a monoclonal antibody to the PSA catalytic site. In addition, the concentration and activity of PSA within sera from men with and without prostate cancer, as well as from tumor‐bearing animals, was likewise assayed.

RESULTS

Normal human prostate tissue and primary human prostate cancers have high concentrations of PSA in the ECF (i.e., 1600–2100 nM). The majority of this PSA is enzymatically active (i.e., 80–90%). Human PC‐82 prostate cancer xenografts also have high concentrations of PSA in the ECF (624 ± 360 nM), and the majority of this PSA is also enzymatically active (i.e., 66 ± 4%). In contrast, much lower concentrations of PSA are found in the ECF from LNCaP (45 ± 9 nM) and LAPC‐4 (7.3 ± 0.6 nM). Only a small portion of the total PSA isolated from DHT‐containing, serum‐free, conditioned media from these cell lines is enzymatically active (i.e., ∼18%). While PSA was detected in all serum samples regardless of the type of host, no enzymatically active PSA was detected in any of these serum samples.

CONCLUSIONS

Prostate cancers obtained directly from patients produce and secrete large amounts of PSA, the majority of which is highly enzymatically active. In contrast, while PSA was detected in the sera, none of this PSA was enzymatically active. This is also the case for the human PC‐82 prostate cancer xenografts. In contrast, LNCaP and LAPC‐4 human prostate cancer xenograft models secrete ∼70–300‐fold less PSA in the ECF than prostate cancers from patients and the majority of this PSA is enzymatically inactive. Also, the serum from these animals had detectable PSA, but none of this PSA was enzymatically active. Thus, these latter two prostate cancer models define the least and the PC‐82, the most, optimized xenograft model for screening PSA targeted prodrugs. Prostate 48:1–6, 2001. © 2001 Wiley‐Liss, Inc.
Charge centers and formation of the protein folding core
Authors: Torshin Ivan Y. , Harrison Robert W.
Published: October 2004

Electrostatic interactions are important for protein folding. At low resolution, the electrostatic field of the whole molecule can be described in terms of charge center(s). To study electrostatic effects, the centers of positive and negative charge were calculated for 20 small proteins of known structure, for which hydrogen exchange cores had been determined experimentally. Two observations seem to be important. First, in all 20 proteins studied 30–100% of the residues forming hydrogen exchange core(s) were clustered around the charge centers. Moreover, in each protein more than half of the core sequences are located near the centers of charge. Second, the general architecture of all‐α proteins from the set seems to be stabilized by interactions of residues surrounding the charge centers. In most of the α‐β proteins, either or both of the centers are located near a pair of consecutive strands, and this is even more characteristic for α/B and all‐β structures. Consecutive strands are very probable sites of early folding events. These two points lead to the conclusion that charge centers, defined solely from the structure of the folded protein may indicate the location of a protein's hydrogen exchange/folding core. In addition, almost all the proteins contain well‐conserved continuous hydrophobic sequences of three or more residues located in the vicinity of the charge centers. These hydrophobic sequences may be primary nucleation sites for protein folding. The results suggest the following scheme for the order of events in folding: local hydrophobic nucleation, electrostatic collapse of the core, global hydrophobic collapse, and slow annealing to the native state. This analysis emphasizes the importance of treating electrostatics during protein‐folding simulations. Proteins 2001;43:353–364. © 2001 Wiley‐Liss, Inc.