bluuebunny/crossref_metadata_2025 huggingface dataset:
Minimal nutrition intervention with high-protein/low-carbohydrate and low-fat, nutrient-dense food supplement improves body composition and exercise benefits in overweight adults: A randomized controlled trial
Authors: Lockwood Christopher M , Moon Jordan R , Tobkin Sarah E , Walter Ashley A , Smith Abbie E , Dalbo Vincent J , Cramer Joel T , Stout Jeffrey R
Published: May 2008

Background

Exercise and high-protein/reduced-carbohydrate and -fat diets have each been shown separately, or in combination with an energy-restricted diet to improve body composition and health in sedentary, overweight (BMI > 25) adults. The current study, instead, examined the physiological response to 10 weeks of combined aerobic and resistance exercise (EX) versus exercise + minimal nutrition intervention designed to alter the macronutrient profile, in the absence of energy restriction, using a commercially available high-protein/low-carbohydrate and low-fat, nutrient-dense food supplement (EXFS); versus control (CON).

Methods

Thirty-eight previously sedentary, overweight subjects (female = 19; male = 19) were randomly assigned to either CON (n = 10), EX (n = 14) or EXFS (n = 14). EX and EXFS participated in supervised resistance and endurance training (2× and 3×/wk, respectively); EXFS consumed 1 shake/d (weeks 1 and 2) and 2 shakes/d (weeks 3–10).

Results

EXFS significantly decreased total energy, carbohydrate and fat intake (-14.4%, -27.2% and -26.7%, respectively; p < 0.017), and increased protein and fiber intake (+52.1% and +21.2%, respectively; p < 0.017). EX and EXFS significantly decreased fat mass (-4.6% and -9.3%, respectively; p < 0.017), with a greater (p < 0.05) decrease in EXFS than EX and CON. Muscle mass increase only reached significance in EXFS (+2.3%; p < 0.017), which was greater (p < 0.05) than CON but not EX (+1.1%). Relative VO2max improved in both exercise groups (EX = +5.0% and EXFS = +7.9%; p < 0.017); however, only EXFS significantly improved absolute VO2max (+6.2%; p = 0.001). Time-to-exhaustion during treadmill testing increased in EX (+9.8%) but was significantly less (p < 0.05) than in EXFS (+21.2%). Total cholesterol and LDL decreased only in the EXFS (-12.0% and -13.3%, respectively; p < 0.017). Total cholesterol-to-HDL ratio, however, decreased significantly (p < 0.017) in both exercise groups.

Conclusion

Absent energy restriction or other dietary controls, provision of a high-protein/low-carbohydrate and -fat, nutrient-dense food supplement significantly, 1) modified ad libitum macronutrient and energy intake (behavior effect), 2) improved physiological adaptations to exercise (metabolic advantage), and 3) reduced the variability of individual responses for fat mass, muscle mass and time-to-exhaustion – all three variables improving in 100% of EXFS subjects.
Serum biomarker profiles and response to neoadjuvant chemotherapy for locally advanced breast cancer
Authors: Nolen Brian M , Marks Jeffrey R , Ta'san Shlomo , Rand Alex , Luong The Minh , Wang Yun , Blackwell Kimberly , Lokshin Anna E
Published: May 2008

Introduction

Neoadjuvant chemotherapy has become the standard of care for the diverse population of women diagnosed with locally advanced breast cancer. Serum biomarker levels are increasingly being investigated for their ability to predict therapy response and aid in the development of individualized treatment regimens. Multianalyte profiles may offer greater predictive power for neoadjuvant treatment response than the individual biomarkers currently in use.

Methods

Serum samples were collected from 44 patients enrolled in a phase I–II, open-label study of liposomal doxorubicin and paclitaxel in combination with whole breast hyperthermia for the neoadjuvant treatment of locally advanced breast cancer (stage IIB or stage III). Samples were collected prior to each of four rounds of treatment and prior to definitive surgery. Samples were assayed by Luminex assay for 55 serum biomarkers, including cancer antigens, growth/angiogenic factors, apoptosis-related molecules, metastasis-related molecules, adhesion molecules, adipokines, cytokines, chemokines, hormones, and other proteins.

Results

Biomarker levels were compared retrospectively with clinical and pathologic treatment responses. Univariate analysis of the data identified several groups of biomarkers that differed significantly among treatment outcome groups early in the course of neoadjuvant chemotherapy. Multivariate statistical analysis revealed multibiomarker panels that could differentiate between treatment response groups with high sensitivity and specificity.

Conclusion

We demonstrate here that serum biomarker profiles may offer predictive power concerning treatment response and outcome in the neoadjuvant setting. The continued development of these findings will be of considerable clinical utility in the design of treatment regimens for individual breast cancer patients.

Trial registration

#NCT00346229.
Chemoselection As a Strategy for Organ Preservation in Advanced Oropharynx Cancer: Response and Survival Positively Associated With HPV16 Copy Number
Authors: Worden Francis P. , Kumar Bhavna , Lee Julia S. , Wolf Gregory T. , Cordell Kitrina G. , Taylor Jeremy M.G. , Urba Susan G. , Eisbruch Avraham , Teknos Theodoros N. , Chepeha Douglas B. , Prince Mark E. , Tsien Christina I. , D’Silva Nisha J. , Yang Kun , Kurnit David M. , Mason Heidi L. , Miller Tamara H. , Wallace Nancy E. , Bradford Carol R. , Carey Thomas E.
Published: May 2008

Purpose

To test induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CRT) or surgery/radiotherapy (RT) for advanced oropharyngeal cancer and to assess the effect of human papilloma virus (HPV) on response and outcome.

Patients and Methods

Sixty-six patients (51 male; 15 female) with stage III to IV squamous cell carcinoma of the oropharynx (SCCOP) were treated with one cycle of cisplatin (100 mg/m2) or carboplatin (AUC 6) and with fluorouracil (1,000 mg/m2/d for 5 days) to select candidates for CRT. Those achieving a greater than 50% response at the primary tumor received CRT (70 Gy; 35 fractions with concurrent cisplatin 100 mg/m2 or carboplatin (AUC 6) every 21 days for three cycles). Adjuvant paclitaxel was given to patients who were complete histologic responders. Patients with a response of 50% or less underwent definitive surgery and postoperative radiation. Pretreatment biopsies from 42 patients were tested for high-risk HPV.

Results

Fifty-four of 66 patients (81%) had a greater than 50% response after IC. Of these, 53 (98%) received CRT, and 49 (92%) obtained complete histologic response with a 73.4% (47 of 64) rate of organ preservation. The 4-year overall survival (OS) was 70.4%, and the disease-specific survival (DSS) was 75.8% (median follow-up, 64.1 months). HPV16, found in 27 of 42 (64.3%) biopsies, was associated with younger age (median, 55 v 63 years; P = .016), sex (22 of 30 males [73.3%] and five of 12 females [41.7%]; P = .08), and nonsmoking status (P = .037). HPV titer was significantly associated with IC response (P = .001), CRT response (P = .005), OS (P = .007), and DSS (P = .008).

Conclusion

Although the numbers in this study are small, IC followed by CRT is an effective treatment for SCCOP, especially in patients with HPV-positive tumors; however, for patients who do not respond to treatment, alternative treatments must be developed.
EGFR, p16, HPV Titer, Bcl-xL and p53, Sex, and Smoking As Indicators of Response to Therapy and Survival in Oropharyngeal Cancer
Authors: Kumar Bhavna , Cordell Kitrina G. , Lee Julia S. , Worden Francis P. , Prince Mark E. , Tran Huong H. , Wolf Gregory T. , Urba Susan G. , Chepeha Douglas B. , Teknos Theodoros N. , Eisbruch Avraham , Tsien Christina I. , Taylor Jeremy M.G. , D’Silva Nisha J. , Yang Kun , Kurnit David M. , Bauer Joshua A. , Bradford Carol R. , Carey Thomas E.
Published: May 2008

Purpose

To prospectively identify markers of response to therapy and outcome in an organ-sparing trial for advanced oropharyngeal cancer.

Patients and Methods

Pretreatment biopsies were examined for expression of epidermal growth factor receptor (EGFR), p16, Bcl-xL, and p53 as well as for p53 mutation. These markers were assessed for association with high-risk human papillomavirus (HPV), response to therapy, and survival. Patient variables included smoking history, sex, age, primary site, tumor stage, and nodal status.

Results

EGFR expression was inversely associated with response to induction chemotherapy (IC) (P = .01), chemotherapy/radiotherapy (CRT; P = .055), overall survival (OS; P = .001), and disease-specific survival (DSS; P = .002) and was directly associated with current smoking (P = .04), female sex (P = .053), and lower HPV titer (P = .03). HPV titer was significantly associated with p16 expression (P < .0001); p16 was significantly associated with response to IC (P = .008), CRT (P = .009), OS (P = .001), and DSS (P = .003). As combined markers, lower HPV titer and high EGFR expression were associated with worse OS (ρEGFR = 0.008; ρHPV = 0.03) and DSS (ρEGFR = 0.01; ρHPV = 0.016). In 36 of 42 biopsies, p53 was wild-type, and only one HPV-positive tumor had mutant p53. The combination of low p53 and high Bcl-xL expression was associated with poor OS (P = .005) and DSS (P = .002).

Conclusion

Low EGFR and high p16 (or higher HPV titer) expression are markers of good response to organ-sparing therapy and outcome, whereas high EGFR expression, combined low p53/high Bcl-xL expression, female sex, and smoking are associated with a poor outcome. Smoking cessation and strategies to target EGFR and Bcl-xL are important adjuncts to the treatment of oropharyngeal cancer.
The design of a navigation, guidance, and control system for an unmanned surface vehicle for environmental monitoring
Authors: Naeem W , Xu T , Sutton R , Tiano A
Published: May 2008

Maintaining the ecosystem is one of the main concerns in this modern age. With the fear of ever-increasing global warming, the UK is one of the key players to participate actively in taking measures to slow down at least its phenomenal rate. As an ingredient to this process, the Springer vehicle has been designed and is being developed for environmental monitoring and pollutant tracking. This paper highlights the Springer hardware and software architecture including various navigational sensors, a speed controller, and an environmental monitoring unit. In addition, details regarding the modelling of the vessel are outlined which are based mainly on recent trials data. The formulation of a fault tolerant multi-sensor data fusion technique is also presented. Moreover, control strategy based on a linear quadratic Gaussian controller is developed and simulated on the Springer model.
Autonomous underwater vehicle collision avoidance for under-ice exploration
Authors: Pebody M
Published: May 2008

On 22 August 2004 the Autosub-2 autonomous underwater vehicle (AUV) was on its return leg of a 144 km, 24 h under-ice mission in the Arctic sea over the Northwind Shoal off the northeast Greenland coast when it found its path blocked by a deep ice keel that had drifted across its planned mission route. After three attempts, the Autosub found a way around the keel and continued on its way to rendezvous with its mother ship. This paper reports the development, testing, and operation of collision and obstacle avoidance techniques used in the Arctic and Antarctic under-ice expeditions of the Autosub-2 AUV.
Technology development for steering and stabilizers
Authors: Stafford B , Osborne N
Published: May 2008

As part of the All-Electric Ship concept the Ministry of Defence (MoD) Defence Procurement Agency Future Business Group's Marine Engineering Development Programme (MEDP) has been investigating the Electrical Actuation of Hydrodynamic Control Surfaces (ELAHCS) Programme for the Royal Navy. The project is presently examining the replacement of traditional hydraulic actuation systems for fixed-fin ship stabilizers, steering gear, and hydroplane actuation with novel electric actuation methods.

As part of this programme the project has developed a technical demonstrator – a fixed-fin stabilizer actuator – which was fitted to both stabilizers on an operational Type 23 Frigate as part of a System Demonstrator Programme (SDP). This demonstrator is providing system performance and environmental data and contributing to the wider understanding of hydrodynamic control surface requirements. It is also illustrating the potential benefits of this technology which are reduced lifecycle costs, simpler installation and maintenance, improved survivability, cleaner systems, elimination of high-energy fluidic systems, and hence the associated support and training and hazards.

This paper describes the development of the ELAHCS Programme, the progress of the SDP to date, and additional future exploitation of this technology for ship and submarine applications.
Distributed control of underwater vehicles
Authors: Balderud J , Giovanini L , Katebi M R
Published: May 2008

Despite the closed-loop performance of centralized multi-variable controllers, the vast majority of control applications are still based on decentralized controllers. Because of their single-loop structure, decentralized controllers cannot suppress interactions of the system, which are only taken into account in the controller tuning phase. Therefore, it would be useful in many cases to tackle the undesirable effects of the interactions on the closed-loop system. A novel model predictive control scheme based on Nash optimality is presented to achieve this goal. In this algorithm the centralized optimization is decomposed into that of several small coupled optimization problems. The relevant computational convergence, the closed-loop performance, and the effect of communication failures on the closed-loop behaviour are analysed. The control problem is illustrated to verify the effectiveness and practicality of the proposed control algorithm.
Harmonic control of a ‘smart spring’ machinery vibration isolation system
Authors: Daley S , Zazas I , Hatonen J
Published: May 2008

A major problem for isolating vibration from large marine machinery rafts is how best to deal with excited resonances. These generate large forces on the hull that create a significant vibration problem. The passive design of such mounts typically represents a compromise between providing good vibration isolation and good machinery alignment under seaway motion. The ‘Smart Spring’ isolation system, a new hybrid passive—active approach to solving this problem that is being developed by BAE Systems, has been described in a series of earlier papers. The fundamental concept utilizes digitally controlled actuators to apply forces that are independent of local displacement while controlling the response of the structure's rigid body modes. The current paper describes recent work to extend the functionality of the isolation system to deal specifically with discrete-frequency vibration sources. Two novel harmonic control strategies are introduced and evaluated using a six-degrees-of-freedom experimental active mount. It is shown that a strategy that employs recursive least-squares estimation provides both exceptionally high isolation performance and rapid convergence.
Connective Tissue Growth Factor Is Necessary for Retinal Capillary Basal Lamina Thickening in Diabetic Mice
Authors: Kuiper Esther J. , Zijderveld Rogier van , Roestenberg Peggy , Lyons Karen M. , Goldschmeding Roel , Klaassen Ingeborg , Noorden Cornelis J. F. Van , Schlingemann Reinier O.
Published: May 2008

Experimental prevention of basal lamina (BL) thickening of retinal capillaries ameliorates early vascular changes caused by diabetes. Connective tissue growth factor (CTGF) is upregulated early in diabetes in the human retina and is a potent inducer of expression of BL components. We hypothesize that CTGF is causally involved in diabetes-induced BL thickening of retinal capillaries. To test this hypothesis, we compared the effects of streptozotocin (STZ)-induced diabetes on retinal capillary BL thickness between wild-type mice (CTGF+/+) and mice lacking one functional CTGF allele (CTGF+/-). Differences in BL thickness were calculated by quantitative analysis of electron microscopic images of transversally sectioned capillaries in and around the inner nuclear layer of the retina. We show that BL thickening was significant in diabetic CTGF+/+ mice compared with control CTGF+/+ mice, whereas diabetes did not significantly induce BL thickening in CTGF+/- mice. We conclude that CTGF expression is necessary for diabetes-induced BL thickening and suggest that reduction of CTGF levels may be protective against the development of diabetic retinopathy.
Histone Modifications and Nuclear Architecture: A Review
Authors: Bártová Eva , Krejčí Jana , Harničarová Andrea , Galiová Gabriela , Kozubek Stanislav
Published: May 2008

Epigenetic modifications, such as acetylation, phosphorylation, methylation, ubiquitination, and ADP ribosylation, of the highly conserved core histones, H2A, H2B, H3, and H4, influence the genetic potential of DNA. The enormous regulatory potential of histone modification is illustrated in the vast array of epigenetic markers found throughout the genome. More than the other types of histone modification, acetylation and methylation of specific lysine residues on N-terminal histone tails are fundamental for the formation of chromatin domains, such as euchromatin, and facultative and constitutive heterochromatin. In addition, the modification of histones can cause a region of chromatin to undergo nuclear compartmentalization and, as such, specific epigenetic markers are non-randomly distributed within interphase nuclei. In this review, we summarize the principles behind epigenetic compartmentalization and the functional consequences of chromatin arrangement within interphase nuclei.
Cross-Sectional versus Longitudinal Survey Research: Concepts, Findings, and Guidelines
Authors: Rindfleisch Aric , Malter Alan J. , Ganesan Shankar , Moorman Christine
Published: May 2008

Marketing academics and practitioners frequently employ cross-sectional surveys. In recent years, editors, reviewers, and authors have expressed increasing concern about the validity of this approach. These validity concerns center on reducing common method variance bias and enhancing causal inferences. Longitudinal data collection is commonly offered as a solution to these problems. In this article, the authors conceptually examine the role of longitudinal surveys in addressing these validity concerns. Then, they provide an illustrative comparison of the validity of cross-sectional versus longitudinal surveys using two data sets and a Monte Carlo simulation. The conceptualization and findings suggest that under certain conditions, the results from cross-sectional data exhibit validity comparable to the results obtained from longitudinal data. This article concludes by offering a set of guidelines to assist researchers in deciding whether to employ a longitudinal survey approach.
As Time Goes By: Do Cold Feet Follow Warm Intentions for Really New versus Incrementally New Products?
Authors: Alexander David L. , Lynch John G. , Wang Qing
Published: May 2008

Combining prior theory about really new products (RNPs) with temporal construal theory, the authors show in four field studies that consumers follow through less often on positive purchase intentions to buy RNPs than on intentions to buy incrementally new products (INPs), and the decrement grows over time. Compared with consumers of INPs, consumers of RNPs are less likely to think concretely about the circumstances of buying and using the products and are more poorly calibrated in their expectations of initial product use. The authors discuss implications for both the marketing of and the market research on RNPs.
Managing Consumer Uncertainty in the Adoption of New Products: Temporal Distance and Mental Simulation
Authors: Castaño Raquel , Sujan Mita , Kacker Manish , Sujan Harish
Published: May 2008

Drawing on theories of new product adoption and intertemporal choice, the authors show in cross-sectional and longitudinal investigations (Study 1) that when adoption is in the distant future, people are more concerned about performance- and symbolic-benefit uncertainties. In contrast, in the near future, the concerns are more about switching- and affective-cost uncertainties. In Studies 2 and 2a, using theories of mental simulation, the authors show that in the distant-future adoption scenario, communication strategies that promote outcome simulations are more effective in reducing performance uncertainty, bolstering positive feelings, and enhancing behavioral intentions. In contrast, in the near-future adoption scenario, communication strategies that promote process simulations are better at reducing switching cost and affective uncertainties, assuaging anxiety, and increasing behavioral intentions. The authors also find positive effects of these communication strategies on actual adoption rates and postconsumption satisfaction (Study 2) and on delayed behavioral intentions (Study 2a). In addition, these communication strategies are more efficacious in increasing behavioral intentions when uncertainty levels are higher (Study 3). The key managerial implications are that communication strategies for new products need to reduce uncertainties about costs and benefits and account for temporal distance to adoption.
Art Infusion: The Influence of Visual Art on the Perception and Evaluation of Consumer Products
Authors: Hagtvedt Henrik , Patrick Vanessa M.
Published: May 2008

In this research, the authors investigate the phenomenon of “art infusion,” in which the presence of visual art has a favorable influence on the evaluation of consumer products through a content-independent spillover of luxury perceptions. In three studies, the authors demonstrate the art infusion phenomenon in both real-world and controlled environments using a variety of stimuli in the contexts of packaging, advertising, and product design.
An Attempt to Characterize the Frequency, Health Impact, and Operational Costs of Oil in the Cabin and Flight Deck Supply Air on U.S. Commercial Aircraft
Authors: Murawski Judith T. L. , Supplee David S.
Published: May 2008

Industry, government, and labor representatives have all acknowledged that air supply systems on commercial aircraft sometimes get contaminated with pyrolyzed engine oil or hydraulic fluid, but efforts to define “sometimes” have been lacking. Despite the lack of attention it has received, the answer to this “how often” question is important because it will influence the willingness of industry, as well as regulators and legislators, to develop and implement control measures to prevent such air supply contamination. To address this data gap, an industrial hygienist collected reports of air supply contamination over an 18-month period (January 2006 through June 2007) from the following sources, all per defined inclusion criteria: (1) Service Difficulty Reports (SDR) and Accident and Incident Data System (AIDS) reports that airlines submitted to the Federal Aviation Administration (FAA); (2) incidents that flight attendants documented with one of 20 airlines and copied to one crewmember labor union; and (3) newspaper clips identified in online searches. A qualified airline mechanic reviewed each SDR and AIDS report with an oil or hydraulic fluid-related mechanical defect that did not explicitly mention oil or hydraulic fluid in combination with a specific word that indicated air supply contamination (i.e., “fume,” “haze,” “mist,” “odor,” “smell,” or “smoke”) to determine its eligibility. The resulting dataset of 470 air supply contamination events reported in the U.S. commercial fleet over an 18-month period translates into an average of 0.86 events per day and includes 350 incidents reported by airlines to the FAA, 115 reported flight attendants to their airline, and 37 incidents reported by at least one newspaper. There was limited overlap between sources. The data are discussed in detail along with commentary on whether and how the data are representative, the health and operational costs associated with air supply contamination, and some preventive measures.
Numerisches Rechnen – wie es ist und wie es sein könnte* (Computer artihmetic – what it is and what it could be)
Authors: Kulisch Ulrich
Published: May 2008

Die nachfolgende Abhandlung weist anhand einiger Beispiele auf offensichtliche Schwächen der heutigen Rechnerarithmetik und Programmiersprachen hin und zeigt deren Auswirkungen in der Numerik auf. Es wird dann ein Konzept angegeben, welches es erlaubt, diese Schwächen zu vermeiden. Dieses beruht auf einer neuen Definition der Rechnerarithmetik. Die neue Arithmetik wurde systematisch auf einem Kleinrechnersystem implementiert. Der Rechner verfügt über Programmpakete zur Lösung zahlreicher Probleme aus der numerischen Mathematik. Bei 12-stelliger Dezimalrechnung wird dabei die Lösung jeweils auf mindestens 11 Stellen genau in Schranken eingeschlossen. Der Rechner beweist zudem die Existenz und Eindeutigkeit der Lösung innerhalb der berechneten Schranken. Ist diese nicht gegeben, so stellt er dies fest.
Unintended Consequences: Mandatory Tuberculin Skin Testing and Severe Isoniazid Hepatotoxicity
Authors: Lobato Mark N. , Jereb John A. , Starke Jeffrey R.
Published: May 2008

After mandatory school-enrollment tuberculin skin testing, a 4-year-old girl who was at low risk for Mycobacterium tuberculosis infection had severe isoniazid hepatotoxicity that was managed with a liver transplant. Although severe isoniazid hepatotoxicity is very uncommon in children, this case emphasizes the need to limit skin testing to persons who have a risk factor for infection and to educate parents on how to monitor for adverse effects during treatment.
Peptide Phage Display: Opportunities for Development of Personalized Anti-Cancer Strategies
Authors: Samoylova T.I. , Morrison N.E. , Globa L.P. , Cox N.R.
Published: May 2008

Personalized medicine is critical for cancer patients, because (1) cancer is a highly heterogeneous disease with
major molecular differences in the expression and distribution of tumor cell surface markers among patients with the same
type and grade of cancer, (2) cellular mutations tend to accumulate as cancer progresses, further increasing tumor heterogeneity,
and (3) currently used cancer therapies often are toxic to normal cells, causing severe side effects rarely seen in
other diseases. To prevent side effects and to improve effectiveness, cytotoxic therapies should be targeted and each patient
should be profiled for the presence of cancer targets before the therapy is administered. Phage display technology
utilizes combinatorial libraries of proteins expressed on phage particles that can be selected for specific binding to cancer
cells. Such cancer-specific molecules can be used in a variety of applications, including identification of cell-specific targeting
molecules; identification of cell surface biomarkers; profiling of specimens obtained from individual cancer patients,
and the design of peptide-based anti-cancer therapeutics for personalized treatments. This review is focused on
peptide phage display strategies that target cell surfaces because many biomarkers important in cancer are differentially
expressed molecules located on the outside of the cell membranes.
Marine Peptides and Related Compounds in Clinical Trial+
Authors: Rawat Diwan S. , Joshi Mukesh C. , Joshi Penny , Atheaya Himanshu
Published: May 2008

Advances in the sophisticated instruments for the isolation and characterization of marine natural products, and development in the biological assay systems, have resulted in the discovery of various compounds of biomedical application. Marine natural products have been a source of new leads for the treatment of many deadly diseases such as cancer, acquired immuno-deficiency syndrome (AIDS) etc. The compounds of marine origin are diverse in structural class from simple linear peptides to complex macrocyclic polyethers. Number of marine peptides have been isolated in recent years which exhibit potent biological activities, and many of the compounds showed promising anticancer activity. Didemnin was the first marine peptide that entered in human clinical trials in US for the treatment of cancer, and other anticancer peptides such as kahalalide F, hemiasterlin, dolastatins, cemadotin, soblidotin, didemnins and aplidine have entered in the clinical trials. Clinical status of anticancer marine derived pep tides have been discussed and reviewed.
Boron-Containing Chlorins and Tetraazaporphyrins: Synthesis and Cell Uptake of Boronated Pyropheophorbide A Derivatives
Authors: Ratajski Michal , Osterloh Jens , Gabel Detlef
Published: May 2008

The literature on the synthesis and the biological properties of boron-containing chlorins and phthalocyanines is reviewed. A series of homologous derivatives of pyropheophorbide A is described. The compounds contain the B12H11SH2- cluster attached to the single carboxyl group and vary in the length of the alkyl chain (methyl, propyl, pentyl, heptyl and nonyl) attached via an ether linkage to the former vinyl group. Cellular uptake was found for all derivatives except the nonyl sidechain. The compounds were moderately cell-toxic. Localization in lysosomes could be excluded; the compounds localized probably in the mitochondria.
The Synthesis and Use of Boronated Amino Acids for Boron Neutron Capture Therapy
Authors: Kabalka George W. , Yao Min-Liang
Published: May 2008

The treatment of cancer remains one of the most challenging problems for humanity. Boron neutron capture therapy (BNCT) is a binary approach for cancer treatment that is particularly attractive in treating high-grade gliomas and metastatic brain tumors. Among types of boron-containing molecules used as BNCT agents, boronated amino acids have received significant attention for their preferentially uptake by growing tumor cells. This review emphasizes the synthesis of boronated amino acids.
3-Carboranyl Thymidine Analogues (3CTAs) and Other Boronated Nucleosides for Boron Neutron Capture Therapy
Authors: Byun Youngjoo , Narayanasamy Sureshbabu , Johnsamuel Jayaseharan , Bandyopadhyaya Achintya K. , Tiwari Rohit , Al-Madhoun Ashraf S. , Barth Rolf F. , Eriksson Staffan , Tjarks Werner
Published: May 2008

One category of boron neutron capture therapy (BNCT) agents that has received extensive attention during recent years is 3-carboranyl thymidine analogues (3CTAs). These molecules are phosphorylated to the corresponding 5´- monophosphates by human thymidine kinase 1 (TK1), an enzyme that is up-regulated in dividing malignant cells. Thus, these phosphorylated molecules are selectively entrapped in tumor cells due to the acquired negative charge. This review will analyze design strategies applied for the synthesis of boron-containing nucleosides in general and in particular reference to 3CTAs. Results of biological studies with these molecules will be discussed.
Betulinic Acid Derivatives as Anticancer Agents: Structure Activity Relationship
Authors: Mukherjee Rama , Kumar Vivek , Srivastava Sanjay K. , Agarwal Shiv K. , Burman Anand C.
Published: May 2008

Betulinic acid, a pentacyclic triterpene, is widely distributed throughout the tropics. It possesses several biological properties such as anticancer, anti-inflammatory, antiviral, antiseptic, antimalarial, spermicidal, antimicrobial, antileshmanial, antihelmentic and antifeedent activities. However, betulinic acid was highly regarded for its anticancer and anti-HIV activities. Anticancer role of betulinic acid appeared by inducing apoptosis in cells irrespective of their p53 status. Due to high order safety in betulinic acid, a number of structural modifications carried out to improve its potency and efficacy. The C-1, C-2, C-3, C-4, C-20 and C-28 positions are the diversity centers in betulinic acid, and the derivatives resulted on various structural modifications at these positions screened for their anticancer activity. This review presents the structure activity relationship carried out on C-1, C-2, C-3, C-4, C-20, C-28, A-ring, D-ring and E-ring modified betulinic acid derivatives. We have compiled the most active betulinic acid derivatives along with their activity profile in each series. Structure activity relationship studies revealed that C-28 carboxylic acid was essential for the cytotoxicity. The halo substituent at C-2 position in betulinic acid enhanced the cytotoxicity. Though the relation of the cytotoxicity with the nature of substituents at C-3 position could not be generalized but the ester functionality appeared to be a better substituent for enhancing the cytotoxicity. An interesting observation is that the three rings skeleton (A, B and C rings) had played an important role in eliciting anticancer activity, which could be a new molecular skeleton to design new anticancer drugs.
The Use of Nimesulide and Its Analogues in Cancer Chemoprevention
Authors: Renard Jean-Francois , Julemont Fabien , Leval Xavier d. , Pirotte Bernard
Published: May 2008

Non-steroidal anti-inflammatory drugs (NSAIDs), which are known to be cyclooxygenase (COX) inhibitors, have been reported to exert anti-proliferative and pro-apoptotic effects on a variety of cancer cells. Since the COX-2 isoform was found to be overexpressed in a many human cancers, a particular attention was paid on the possible use of selective COX-2 inhibitors in cancer chemoprevention. The present review focuses on the state of the art in cancer research developed with COX-2 preferential/selective inhibitors belonging to the family of N-arylmethanesulfonamides, in particular nimesulide and NS-398.
Mechanisms Leading to COX-2 Expression and COX-2 Induced Tumorigenesis: Topical Therapeutic Strategies Targeting COX-2 Expression and Activity
Authors: Telliez Aurelie , Furman Christophe , Pommery Nicole , Henichart Jean-Pierre
Published: May 2008

The biological role of COX-2, the inducible form of cyclooxygenase, is to convert arachidonic acid into prostaglandins (PGs) and thromboxanes (TXs). Overexpressed in many tumors, COX-2 plays a crucial role in cancer through synthesis of PGs which stimulate PGs receptors with subsequent enhancement of cellular proliferation, promotion of angiogenesis, inhibition of apoptosis, stimulation of invasion/motility, and suppression of immune responses. Depending on the tissue specificity and the cell type, several signaling pathways (Kinases, Rho, cGMP and Wnt), and transcription factors such as AP1, NFAT or NF-kB, are involved in COX-2 expression. In this review, we will describe mechanisms required by COX-2 metabolites to promote cancer development, and also the signaling pathways leading to COX-2 expression. In order to counteract the negative effects of COX-2 in cancerogenesis, chemicals interfering with COX-2 activity and expression were designed. We will give in the last part of this article, an overview of these potent chemicals interfering with the COX-2 signaling pathways involved in its expression or with its activity.
A Computational View of COX-2 Inhibition
Authors: Chavatte Philippe , Farce Amaury
Published: May 2008

Selective inhibition of COX-2 provided a new class of anti-inflammatory, analgesic and antipyretic drugs with significantly reduced side effects and could also be an important strategy for preventing or treating a number of cancers. This review illustrates the molecular modeling methods used for the knowledge of the molecular mechanism of inhibition as well as for the design of selective compounds.
Synthetic Src-Kinase Domain Inhibitors and Their Structural Requirements
Authors: Schenone Silvia , Manetti Fabrizio , Botta Maurizio
Published: May 2008

Protein tyrosine kinases catalyze the transfer of phosphoryl groups from ATP to amino acids on proteins and play a fundamental role in signal transduction pathways in mammalian cells. In particular, Src and Src-family are non-receptor tyrosine kinases that regulate cell growth, differentiation, migration, adhesion and apoptosis. Src-family members share common features, with well defined domains. The activation of these enzymes in response to a variety of stimuli leads from a close and inactive conformation to an open and active one, through a balance of phosphorylation and dephosphorylation of the enzyme structure, characterized in different cases by Xray crystallography. Overexpression, deregulation or mutations of these enzymes have been observed and studied in many diseases, first of all in many human malignancies, such as colon, breast, pancreatic and other cancers. Src-family is also involved in other pathologic situations, such as osteoporosis, cardiovascular diseases, immune system disorders, and, recently, it has been also demonstrated the involvement of Src in prion diseases.Therefore, Src-family is an attractive and fundamental target for the design of new therapeutic agents against different pathologies, in particular cancer and bone diseases. Currently, there is no approved drug acting as Src kinase inhibitor, but new molecules, very potent and selective toward this family of kinases and also in vivo, are continuously synthesized, as demonstrated by the high number of publications and patents in this field. Here, we report several examples of Src kinase domain inhibitors, focusing our attention on chemical structures, structure-activity relationships and mechanism of action.
Role of Focal Adhesion Kinase in Human Cancer: A Potential Target for Drug Discovery
Authors: Han Edward Kyu-Ho , McGonigal Thomas
Published: May 2008

The focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that localizes to the points of cell contact with the extracellular matrix, called focal adhesions. FAK is involved in several cellular processes including invasion, motility, proliferation and apoptosis. In in vivo animal studies, FAK has been shown to contribute to tumor development and malignancy. Furthermore, FAK expression was shown to be elevated in a number of human cancers. Increased FAK expression and activity are correlated with malignant phenotype and poor prognosis in patients. Taken together, these studies suggest that FAK is a potentially good target for drug discovery. In this review, FAK and its relationship to cancer, as well as approaches to therapeutic intervention of FAK will be discussed.
Targeting JAK3 Tyrosine Kinase-Linked Signal Transduction Pathways with Rationally-Designed Inhibitors
Authors: Uckun Fatih M. , Vassilev Alexei , Dibirdik Ilker , Tibbles Heather
Published: May 2008

Inhibitors of Janus Kinase 3 (JAK3) show potential as a new class of apoptosis-inducing anti-cancer drugs. In addition, JAK3 inhibitors may also be useful as immunosuppressive agents. Rationally designed selective inhibitors of JAK3 such as JANEX-1, that do not inhibit other Janus kinases have recently undergone extensive preclinical testing that revealed a favorable pharmacodynamic profile. Here we discuss the clinical potential of targeting JAK3-linked signal transduction pathways with small molecule inhibitors such as JANEX-1.
Brutons Tyrosine Kinase as a New Therapeutic Target
Authors: Uckun Fatih M. , Tibbles Heather E. , Vassilev Alexei O.
Published: May 2008

Targeting Brutons tyrosine kinase (BTK) with a small molecule inhibitor may be useful in treatment of BTK-expressing malignancies because of the anti-apoptotic function of BTK in cancer cells. Furthermore, BTK inhibitors also exhibit anti-thrombotic properties that may be desirable in the context of the increased risk of thromboembolic complications in cancer patients. This review will focus on the role of BTK in drug resistance in cancer, thromboembolism, and various pathologic immune responses, such as graft versus host disease. The therapeutic potential of targeting BTK is illustrated by discussion of the biologic activity profile of the rationally designed BTK inhibitor LFM-A13.
Oncogenic Fusion Tyrosine Kinases as Molecular Targets for Anti-Cancer Therapy
Authors: Gunby Rosalind H. , Sala Elisa , Tartari Carmen J. , Puttini Miriam , Gambacorti-Passerini Carlo , Mologni Luca
Published: May 2008

Deregulated activation of protein tyrosine kinases (PTKs) is a frequent event underlying malignant transformation in many types of cancer. The formation of oncogenic fusion tyrosine kinases (FTKs) resulting from genomic rearrangements, represents a common mechanism by which kinases escape the strict controls that normally regulate their expression and activation. FTKs are typically composed of an N-terminal dimerisation domain, provided by the fusion partner protein, fused to the kinase domain of receptor or nonreceptor tyrosine kinases (non-RTKs). Since FTKs do not contain extracellular domains, they share many characteristics with non-RTKs in terms of their properties and approaches for therapeutic targeting. FTKs are cytoplasmic or sometimes nuclear proteins, depending on the normal distribution of their fusion partner. FTKs no longer respond to ligand and are instead constitutively activated by dimerisation induced by the fusion partner. Unlike RTKs, FTKs cannot be targeted by therapeutic antibodies, instead they require agents that can cross the cell membrane as with non-RTKs. Here we review the PTKs known to be expressed as FTKs in cancer and the strategies for molecularly targeting these FTKs in anti-cancer therapy.
Thalidomide and Analogs as Anti-Inflammatory and Immunomodulator Drug Candidates
Authors: Lima Lidia M. , Manssour Fraga Carlos A. , Goncalves Koatz Vera L. , Barreiro Eliezer J.
Published: May 2008

Thalidomide ([2-(2,6-dioxo-hexahydro-3-(R,S)-pyridinyl)-1,3-isoindolinedione]), well known by its teratogenic effect, caused birth defects in up to 12,000 children in the 1960s. More recently, this drug was approved by the US Food and Drug Administration for the treatment of erythema nodosum leprosum, under restricted-use program, and a variety of new possible therapeutic applications have been described. This article will accomplish a review of medicinal chemistry aspects of thalidomide and state of the art in the development of new anti-inflammatory and immunomodulator drug candidates designed using thalidomide as lead-compound.
Inflammatory and Vascular Alterations in Sepsis: The Role of Nitric Oxide- Dependent Mechanisms
Authors: Assreuy Jamil , Cunha Fernando d. Q. , Barja-Fidalgo Christina , Tavares-Murta Beatriz M.
Published: May 2008

Sepsis and septic shock continue to be a major cause of morbidity and mortality in critically ill patients. During the onset of sepsis, a massive inflammatory reaction is mediated via cell-derived cytokines and chemokines that target end-organ receptors in response to injury or infection. Polymorphonuclear leucocytes are critical effector cells during the inflammatory process and their migration to the infectious focus is extremely important for the local control of bacterial growth and consequently for the prevention of bacterial dissemination. In addition to the inflammatory process, sepsis and septic shock cause a profound loss in the peripheral vasomotor tone resulting in a huge decrease in the peripheral resistance, a central event in the derangement of hemodynamic and perfusional parameters. Nitric oxide (NO) is a simple molecule produced by numerous cell types that has been implicated in a wide range of physiological and pathological processes, exerting both detrimental and beneficial effects. It is an important modulator of neutrophil adherence and activation, of cardiovascular homeostasis and end organ perfusion. The induction of the inducible isoform of NO synthase leads to an increased NO production which is involved both in the impairment of neutrophil migration and in the cardiovascular disfunction present in sepsis and septic shock. Thus, a better knowledge of the role of NO in the inflammatory, cardiovascular and immune aspects of sepsis may provide us with more efficient therapeutic alternatives to treat sepsis and septic shock.
Immediate and Late Adverse Reactions to Iodinated Contrast Media: A Pharmacological Point of View
Authors: Dewachter Pascale , Laroche Dominique , Mouton-Faivre Claudie , Clement Olivier
Published: May 2008

Iodinated contrast media (CM) are widely used in radiological procedures, and carry a risk of adverse reactions with possible sequelae or death. Various and numerous reactions have been reported, most of which are transient ones and do not threaten the patients life. Immediate adverse reactions include adverse effects directly related to the osmotic load or to the CM chemotoxicity, and immediate hypersensitivity reactions. The exact incidence of the different types of reactions is difficult to establish because not all cases are reported and because a unique severity scale is lacking. All the underlying mechanisms have not been evidenced yet, as patients are rarely properly investigated. Allergic immediate hypersensitivity probably provokes the most severe reactions, whereas non-allergic hypersensitivity determines moderate reactions. Diagnostic tools are available and consist in tryptase and histamine measurements and in skin testing. Late reactions include skin or systemic reactions due to T-lymphocytes-mediated delayed hypersensitivity, nephropathy and dysthyroidism. Delayed allergic hypersentivity can be diagnosed by skin testing with delayed reading. Allergic hypersensitivity, immediate or delayed, means immune mechanisms and is a contraindication of further administration of the culprit CM.
Group II Secretory PLA2: A New Cardiovascular Risk Factor
Authors: Krijnen Paul A.J. , Nijmeijer Remco , Hack C. E. , Niessen Hans W.M.
Published: May 2008

Inflammatory mediators contribute significantly to the induction and progression of cardiovascular diseases such as atherosclerosis and acute myocardial infarction (AMI). A mediator that has been shown to play a crucial role in both cardiovascular events is group-II secretory phospholipase A2 (sPLA2-II), as this mediator has been suggested to modulate atherosclerotic plaque formation, for example by increasing the accumulation of intracellular lipids in macrophages and stimulating the formation of foam cells. Furthermore, increased levels of sPLA2-II in the blood form a risk marker for the development of complications of coronary artery disease. In line with this, we recently found that extracellular sPLA 2-II is more abundantly present in the extracellular matrix of atherosclerotic culprit lesions of coronary arteries in patients who developed AMI than in those of patients with stable or unstable angina pectoris. Another important feature of sPLA2-II is its ability to bind to and hydrolyze membrane phospholipids. Notably, sPLA2-II cannot bind to the tightly packed hydrophobic phospholipids in the outer leaflet of a normal membrane, but only to the disarranged or flip-flopped membranes of damaged cells, as is the case in ischemic jeopardized cardiomyocytes. Interestingly, we recently have observed that sPLA2-II cannot only bind to reversible damaged cardiomyocytes but also induces these cells to die, partly by potentiating binding of C-reactive protein and thus inducing an inflammatory response in the ischemically challenged heart. This review will discuss the pros and cons of therapy with inhibitors of sPLA2-II to prevent complications of the process of atherosclerosis, and/or to limit the amount of cell death of cardiomyocytes subsequent to AMI.
Synthetic Inhibitors of Group IVA and Group VIA Phospholipase A2
Authors: Magrioti Victoria , Kokotos George
Published: May 2008

PLA2 is an important signaling enzyme that generates multiple downstream effectors, such as arachidonic acid and PAF, which are key mediators of inflammation as well as other pathophysiological conditions. Inhibition of PLA2 is potentially an effective therapy for several inflammatory diseases. In this review, we discuss the various classes of synthetic inhibitors of Group IVA and Group VIA phospholipase A2.