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PEGylation is considered a safe mechanism to enhance the pharmacokinetics (PK) and pharmacodynamics (PD) of biotherapeutics. Previous studies using PEGylation as a PK enhancement tool have reported benign PEG-related vacuolation in multiple tissues. This paper establishes a threshold for PEG burden beyond which there are alterations in tissue architecture that could potentially lead to dysfunction. As part of the nonclinical safety assessment of Compound A, a 12 kDa protein conjugated to a 40 kDa branched PEG molecule, monkeys were dosed subcutaneously twice weekly for 3 months at protein doses resulting in weekly PEG doses of 8, 24, 120, or 160 mg/kg. Consistent with previous reports with PEGylated biomolecules, Compound A administration resulted in intracellular vacuoles attributed to the PEG moiety in macrophages in numerous tissues and epithelial cells in the choroid plexus and kidney. Vacuolation occurred at all doses with dose-dependent severity and no evidence of recovery up to 2 months after dosing cessation. The vacuolation was considered nonadverse at PEG doses ≤120 mg/kg/week. However, at 160 mg/kg/week PEG, the vacuolation in choroid plexus, pituitary gland, kidney, and choroid of the eye was considered adverse due to significant alterations of tissue architecture that raised concern for the possibility of compromised tissue function. To our knowledge, this is the first report of potentially adverse cellular consequences of PEG accumulation in tissues other than kidney. Furthermore, the lack of reversibility of vacuolation coupled with the lack of a biomarker for intracellular PEG accumulation highlights a potential risk that should be weighed against the benefits of PK/PD enhancement for long-term administration of PEGylated compounds at high doses.

We estimated the prevalence of oral human papillomavirus (HPV) and assessed risk factors among young heterosexual men participating in the HPV Infection and Transmission among Couples through Heterosexual Activity (HITCH) study. Oral and genital HPV samples were collected from 222 men and their female partners who were participating in the HITCH study, a longitudinal cohort on HPV transmission among heterosexual couples. Demographic and behavioral data were collected through self-administered computer questionnaires and biologic samples were tested with the Linear Array for HPV. Outcome measures were overall and type-specific prevalence of oral HPV. The prevalence of oral HPV among men was 7.2% and was higher among men who were ever smokers (12.2%), in nonmonogamous relationships (17.9%), or had a partner with oral (28.6%) and/or genital (11.5%) HPV infection. Moreover, prevalence increased with frequency of oral sex among men whose partner who had a genital infection with the same HPV type. Our results provide further evidence that oral HPV may be transmitted through either oral–oral or oral–genital routes. Cancer Epidemiol Biomarkers Prev; 23(12); 2959–64. ©2014 AACR.

This article provides observations on the features of sponsor–contract research organization communication that will achieve the best quality pathology report based on our collective experience. Information on the test article and any anticipated findings should be provided, and initial slide examination should be done with knowledge of treatment group (but may be followed by blinded review of target tissues to determine no-effect levels). Only a pathologist should write or revise the pathology report or the pathology section of the overall study report. To address concerns related to undue sponsor influence, comments by sponsors should be presented as suggestions rather than directives. Adversity should be defined for each finding by the study pathologist, but the no-observed adverse effect level should not be discussed in the pathology report. Board-certified pathologists are recommended, but are not essential. Sponsors that have a particular format or report preferences should make them known well in advance. Histologic processing “to glass” of protocol-specified tissues from all dosage groups is recommended for rapid evaluation of target tissues. Telepathology is beneficial in certain situations, but it is usually more efficient for the study pathologist and reviewing pathologist to be in the same physical location to review differences of opinion and reach a consensus.

Peroxisome proliferator-activated receptors (PPAR) are involved in the pathogenesis of insulin resistance, diabetes, and related complications. Consequently, the identification of PPAR subtypes and the potential for their activation provides promising therapeutic targets for the management of type 2 diabetes mellitus. Available data from rodent carcinogenicity studies, however, demonstrate that PPAR agonists can be tumorigenic in one or more species of rodents at multiple sites. In 2005, the Health and Environmental Sciences Institute (HESI) PPAR Agonist Project Committee was established by a group of pharmaceutical companies to advance research on and to understand the modes of action and human relevance of this emerging rodent tumor data for PPAR agonists. Since the most commonly observed tumor types reported in rodents are hemangiosarcomas, fibrosarcomas and liposarcomas, the PPAR Agonist Project Committee approved a Pathology Working Group (PWG) to develop consensus of morphologic criteria for tumor diagnoses and consistency of diagnoses across multiple studies for hemangiosarcomas in mice and hamsters and liposarcomas/fibrosarcomas in rats. Therefore, the focus of the PWG review was to establish consistent tumor diagnostic criteria, to assess evidence of potentially preneoplastic changes and to identify distinguishing morphologic differences which may exist between spontaneous changes present in control animals with similar changes from treated animals. Specific diagnostic criteria and nomenclature are recommended for the classification of proliferative vascular lesions which may be present in mice or hamsters and for proliferative mesenchymal changes in rats in studies that are conducted with PPAR agonists.

Background. We investigated the association between polymorphisms of human papillomavirus (HPV)-33 and squamous intraepithelial lesions (SILs). Methods. Endocervical specimens from 89 women infected with HPV-33, out of a total of 5347 recruited for 2 case-control and 2 cohort studies, were further analyzed by polymerase chain reaction sequencing of the long control region (LCR), E6, and E7. Results. Of the 89 samples, 64 were normal, 7 had low-grade SILs (including 3 determined by histopathologic analysis), 15 had high-grade SILs (HSILs, including 14 determined by histopathologic analysis), and 3 had an unknown diagnosis. Non-prototype-like LCR variants were significantly associated with HSILs (age- and study site-adjusted odds ratio [OR], 9.2 [95% confidence interval {CI}, 1.8-45.9]). The C7732G variation, which results in the loss of a putative binding site for the cellular upstream stimulatory factor, was associated with HSILs (age-and site-adjusted OR, 8.0 [95% CI, 1.5-42.8]). E6 and E7 polymorphisms were not associated with HSILs. Samples collected at 6-month intervals from 14 participants contained the same variant. The HPV-33 MT 1-0-0 variant carrying the G7584A variation was detected more frequently in women from Brazil (7/20 [35%]) than in women from Canada (1/65 [1.5%]; P = .001). Conclusion. Intratypic LCR variants of HPV-33 seem to vary geographically and to differ with respect to their oncogenic potential.

Trastuzumab is indicated for the treatment of patients with breast cancer overexpressing human epidermal growth factor 2 (HER2). Women with HER2-positive tumors have an increased risk of brain metastases. The blood-brain barrier and blood-cerebrospinal fluid (CSF) barrier may prevent trastuzumab from reaching appropriate concentrations in the brain and CSF following standard intravenous administration. To evaluate the potential of effects on the central nervous system, a 4-week toxicology study with weekly intrathecal administration of trastuzumab was performed in cynomolgus monkeys at doses of 0, 3, or 15 mg. No trastuzumab-related effects on body weight, clinical signs, neurological function, clinical pathology, or anatomic pathology were noted. The applied doses and CSF concentrations achieved in the current study exceeded those reported in patients after intrathecal administration. The results support future studies for further evaluation of intrathecal application of trastuzumab in patients with brain metastases in HER2-positive breast cancer.

The INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP) and North America (STP) to develop an internationally-accepted nomenclature for proliferative and non-proliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying microscopic lesions observed in the respiratory tract of laboratory rats and mice, with color photomicrographs illustrating examples of some lesions. The standardized nomenclature presented in this document is also available electronically on the inter-net (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous developmental and aging lesions as well as lesions induced by exposure to test materials. A widely accepted and utilized international harmonization of nomenclature for respiratory tract lesions in laboratory animals will decrease confusion among regulatory and scientific research organizations in different countries and provide a common language to increase and enrich international exchanges of information among toxicologists and pathologists.

The authors estimated plausible ranges of the probability of human papillomavirus (HPV) transmission per coital act among newly forming couples by using stochastic computer simulation. Comparative empirical data were obtained in 1996-2001 from a cohort study of female university students in Montreal, Canada. Female prevalence and frequency of sexual intercourse and condom use were set equal to those in the cohort. Simulations included 240 combinations of male prevalence, the relative risk for protected versus unprotected sex, and per-act transmission probabilities. Those that produced expected HPV incidence within the 95% confidence interval observed in the cohort were selected. The observed 6-month cumulative incidence following acquisition of a new partner was 17.0% (95% confidence interval: 11.4, 23.0). Expected incidences consistent with those from cohort findings occurred in 54/240 simulations. The range of per-act transmission probabilities was 5-100% (median, 40%). Male HPV prevalence was the same as or greater than that for women in all consistent simulations. Varying condom effectiveness did not produce better-fitting data. This simulation suggests that HPV transmissibility is several-fold higher than that for other viral sexually transmitted infections such as human immunodeficiency virus or herpes simplex virus 2. With high transmissibility, any potential protective effect of condoms would disappear over multiple intercourse acts, underlining the need for an effective HPV vaccine.

Little is known about the average duration of type-specific human papillomavirus (HPV) infections and their patterns of persistence. The objectives of this study were to evaluate the rate of acquisition and clearance of specific HPV types in young women. Female university students (n = 621) in Montreal were followed for 24 months at 6-month intervals. At each visit, a cervical specimen was collected. HPV DNA was detected using the MY09/MY11 PCR protocol followed by typing for 27 HPV genotypes by a line blot assay. The Kaplan-Meier technique was used to estimate the cumulative probability of acquiring or clearing a HPV infection considering types individually or in high-risk (HR) or low-risk (LR) groups defined by oncogenic potential. Incidence rates were 14.0 cases/1000 women-months (95% confidence interval, 11.4-16.3) and 12.4 cases/1000 women-months (95% confidence interval, 10.4-14.8) for acquiring HR and LR HPV infections, respectively. The 24-month cumulative rates of acquisition were highest for HPV-16 (12%), HPV-51, and HPV-84 (8%). Of the incident infections, HPV-16 was the most persistent (mean duration, 18.3 months), followed by HPV-31 and HPV-53 (14.6 and 14.8 months, respectively). HPV-6 and HPV-84 had the shortest mean duration time (10 months) The mean durations of incident, same-type LR or HR HPV infections were 13.4 months and 16.3 months, respectively. Whereas the majority of episodes with a type-specific HPV infection cleared within 2 years, there were many women who were either reinfected with a new HPV genotype or presumably experienced reactivation of their initial infection.

Background Previous studies have been inconsistent about the degree of sexual transmissibility of cervical human papillomavirus (HPV) infection. The authors hypothesize that risk factors for HPV infection vary according to HPV type. Goal To estimate the prevalence of HPV infection in asymptomatic women and to identify risk factors for overall HPV infection and HPV infection by oncogenic and nononcogenic type. Study design A cross-sectional survey was conducted at the McGill University clinic in Montreal. Cervical specimens were collected from 489 female students presenting at the clinic for a routine Papanicolaou test. Data on potential risk factors was obtained by questionnaire. Human papillomavirus DNA was detected by the polymerase chain reaction using consensus primers (MY09/11) followed by hybridization with generic and type-specific probes using Southern blot and dot blot techniques. Results The overall HPV prevalence was 21.8%. A low-risk HPV infection was found in 6.2% of the women, 11.8% had a high-risk HPV infection (types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58), 7.1% had an unknown HPV type, and 2.7% had a multiple type infection. Two profiles emerged for sexual activity and risk of HPV infection according to oncogenic risk after multivariate analysis. Lifetime frequency of sexual intercourse and lifetime number of oral sex partners was associated with high-oncogenic-risk HPV infections; however, HPV infection with low-oncogenic-risk types was invariant with respect to markers of sexual activity. Conclusion These results suggest that there are differences in epidemiologic correlates of transmission between low-risk and high-oncogenic-risk HPV types based on oncogenicity. This finding has important implications for primary prevention of HPV infection and cervical cancer precursors.

As purchasers of health care increasingly rely on hospital resource use and outcomes profiles to guide quality improvement efforts and contract decisions, a better understanding of the contribution of the most severely ill patients to aggregate resource use and outcomes is needed to develop measures that make fair comparisons between hospitals. In this article, the authors examine the distribution, resource utilization, and outcomes of transferred patients ("transfers"), a group known to be highly complex. The study examines the contributions to resource use and outcomes of these patients at academic medical centers (AMCs) and non-teaching hospitals. The authors go beyond previous work by comparing AMCs with non-teaching hospitals, and by using a nationally representative sample for the year 1992. The detailed findings demonstrated that AMCs provided a disproportionate share of care to transfers in 1992, and that transfers to AMCs are more complex and require more specialized care than do transfers to non-teaching hospitals. The study also determined that, during the time studied, AMCs received a disproportionate share of Medicaid and indigentcare transfers. Finally, the findings demonstrated that transfers increased in absolute numbers and as a percentage of total patient volumes for all hospitals from 1988 to 1994. The rate of increase was greatest for AMCs. The authors explain why they believe that their findings are applicable today, although they caution that study of more recent data should be made. The authors comment that purchasers of health care may find the study useful in better understanding benchmarking tools used to evaluate hospitals. This study may also help those involved in health policy to more fully understand the magnitude of the contribution to transfer patient care provided by AMCs. Finally, health policymakers and planners may find this work useful as they prepare for increasing numbers of transfers in the future, particularly at AMCs.

This paper put an emphasis on the importance of two points which are crucial when the aim is physically based lighting simulation. The first one is the spectral approach which considers emitted, reflected, diffused and transmitted light as wavelength dependent. The second corresponds to the different steps aiming at converting into RGB components the radiance arriving at the viewpoint through the pixels of a screen.© (1996) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

This paper provides tools to implement a physics-based lighting model. This latter uses a physics-based reflection model, spectral distribution of light powers and does not make any assumption on the specular behaviour of materials. The scenes are discretized into points instead of patches. A data structure named visibility graph is built to efficiently evaluate the visibility between two sample points. This global model is implemented according to a two-pass method.

Background HPV burden is a predictor for high-grade cervical intraepithelial neoplasia and cancer. The natural history of HPV load in young women being recently exposed to HPV is described in this paper. Methods A total of 636 female university students were followed for 2 years. Cervical specimens with HPV-16, -18, -31, or -45 DNA by consensus PCR were further evaluated with type-specific and β-globin real-time PCR assays. Proportional hazards regression was used to estimate hazard ratios (HR) of infection clearance. Generalized estimating equations assessed whether HPV loads was predictive of HPV infection at the subsequent visit. Results HPV loads were consistently higher among women Conclusions The association between HPV load and persistence is not uniform across high-risk genital genotypes. HPV-16 integration was only rarely demonstrated in young women.

This paper provides a general theoretical framework in which any previous global illumination model can be described. It gives a theoretical background which is based on radiometric quantities and on a physical approach to insure generality and consistency. A system of energy balance equations is obtained. Two approaches are possible depending on the way the radiometric properties of surfaces are characterized. Furthermore, the problem of solving this system of equations with the two-component method is addressed, and we show how we can take advantage of the characteristics of each component to select an appropriate method.

Introduction: Trastuzumab is indicated for the treatment of patients with breast cancer whose tumors overexpress the HER2 protein. Brain metastases have been observed in breast cancer patients, being the highest in women with HER2-overexpressing tumors. The blood-brain barrier, however, may prevent trastuzumab from reaching appropriate concentrations in the cerebrospinal fluid (CSF). Case studies have been reported in which trastuzumab was intrathecally administered for the treatment of metastatic brain cancer in humans. However, no extensive preclinical safety evaluation has been performed for intrathecal application after repeat-dosing in a trastuzumab cross-reactive species using doses equivalent to or higher than those used in patients. To evaluate the potential of local effects, a 28-day toxicology study with weekly intrathecal administration of trastuzumab was performed in cynomolgus monkeys, a trastuzumab cross-reactive species. Preservative-free trastuzumab was used in this preclinical safety study, as caution has been raised for the intrathecal use of benzyl alcohol-containing solutions. Methods: Five male and five female monkeys were evaluated per dose group, of which two monkeys/sex/group were evaluated after a 4-week recovery period. Animals were assigned to 3 groups which received 4 weekly 30-minute intrathecal infusions at 0, 3, or 15 mg per dose at an infusion rate of 1.5 mL/hour. Endpoints evaluated included clinical signs, body weight, appetite, neurological examinations, clinical pathology, gross pathology, and histopathology of the brain (with inclusion of meninges), spinal cord, and infusion site. In addition, CSF and serum samples were collected for toxicokinetic evaluations. Results and Discussion: No test article-related effects on clinical signs, body weight, appetite, neurological examinations, clinical pathology, gross pathology or histopathology were noted. Of note is the absence of demyelination as was discussed as an uncertainty of intrathecally administered proteins. The doses used of 3 and 15 mg per dose resulted in 0.051 and 0.24 mg/g brain doses, respectively. Doses administered in clinical case reports ranged from 5 to 100 mg per dose. For a 1500 g human brain weight, these intrathecal doses would be equivalent to 0.0033 and 0.067 mg/g brain weight. At the high dose of 15 mg, maximum CSF concentrations (Cmax) were as high as 403 µg/mL. The applied doses and CSF concentrations achieved in the current study greatly exceeded those reported in patients (6.4 µg/mL at an intrathecal dose of 20 mg). Conclusion: The results of this 4-week toxicology study in monkeys with the results of the clinical case studies support future studies to evaluate intrathecal application of trastuzumab in patients with brain metastasis in HER2-positive breast cancer. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5101.

From the study of complex impedance diagrams applied to a symmetric cell Pt-Yb 2 O 3 -Pt, the authors have shown the mixed character of electrical conduction within the ytterbium sesquioxide. The measurements were performed at thermodynamic equilibrium in the temperature range from 1423 to 1623 K and the partial pressure of oxygen range from 10 −12 to 1 atm. The variations of ionic and electronic conductivity as a function of P O 2 , were interpreted in terms of point defects e′, ḣ, V‴ Yb and Yb I , in the general case of a Frenkel disorder. The relative contributions and the activation energies of conduction of these different defects were determined.

Tilings of the discrete plane Z2 generated by quasi-linear transformations (QLT) have been introduced by Nehlig [P. Nehlig, Applications quasi-affines: Pavages par images réciproques, Theoretical Computer Science 156 (1995) 1–38]. We studied these tilings and gave some results, such as periodicity and the number of neighbours of each of them [M.-A. Jacob-Da Col, Applications quasi-affines et pavages du plan discret, Theoretical Computer Science 259 (2001) 245–269. Also available in English: http://dpt-info.u-strasbg.fr/~jacob/articles/paving.pdf].The aim of this paper is to go on with this study in the discrete n-dimensional space Z2; we give a lower and an upper bound to the number of distinct tiles. We also give an algorithm to determine the points of a given tile, this algorithm will induce another algorithm to determine the number of distinct tiles associated to a QLT.