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BACKGROUND: In the phase II multicohort CheckMate 142 study, nivolumab plus low-dose (1 mg/kg) ipilimumab provided robust and durable clinical benefit with a manageable safety profile in previously treated patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) at 13.4- and 25.4-month median follow-up (Overman MJ, Lonardi S, Wong KYM et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol. 2018;36:773-779. Overman MJ, Lonardi S, Wong KYM, et al. Nivolumab plus low-dose ipilimumab in previously treated patients with microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: long-term follow-up. J Clin Oncol. 2019;37:635). Here, we present results from the 4-year follow-up of these patients. PATIENTS AND METHODS: Patients received nivolumab (3 mg/kg) plus low-dose (1 mg/kg) ipilimumab every 3 weeks (four doses) followed by nivolumab (3 mg/kg) every 2 weeks until disease progression. Primary endpoint was investigator-assessed objective response rate (ORR; as per RECIST version 1.1). RESULTS: A total of 119 patients were treated; 76% had ≥2 prior lines of therapy. Median follow-up was 50.9 months (range 46.9-62.7 months). Median duration of therapy was 24.9 months [95% confidence interval (CI) 15.8-33.2 months]. Investigator-assessed ORR increased from 55% (95% CI 45% to 64%) at 13.4 months to 65% (95% CI 55% to 73%) at 50.9 months with a disease control rate of 81% (95% CI 72% to 87%). The complete response rate increased from 3% at 13.4 months to 13% at 50.9 months. Partial responses were observed in 52% of patients; 21% had stable disease, and 12% had progressive disease. Median time to response was 2.8 months (range 1.1-37.1 months), and median duration of response was not reached (range 1.4+ to 58.0+ months). At data cut-off, 37 (48%) patients had ongoing responses. Median progression-free survival was not reached [95% CI 38.4 months-not estimable (NE)], and median overall survival was not reached (95% CI NE). Grade 3-4 treatment-related adverse events (TRAEs) were observed in 32% of patients; 13% of patients had any-grade TRAEs leading to discontinuation. CONCLUSIONS: The results confirm long-term benefit of nivolumab plus low-dose ipilimumab for previously treated patients with MSI-H/dMMR mCRC. The safety profile was manageable with no new safety signals. ispartof: ANNALS OF ONCOLOGY vol:33 issue:10 pages:1052-1060 ispartof: location:England status: published

BACKGROUND The association, if any, between the effective regurgitant orifice (EROA) to left ventricular end-diastolic volume (LVEDV) ratio and 1-year mortality is controversial in patients undergoing mitral transcatheter edge-to-edge repair (m-TEER) with the MitraClip™ system. The objective is to determine the association between EROA/LVEDV and 1-year mortality among patients undergoing m-TEER with MitraClip™. METHODS In patients with severe secondary (functional) mitral regurgitation (MR), we analyzed registry data from 11 centers using generalized linear models with the generalized estimating equations approach. RESULTS We studied 525 patients with secondary MR who underwent m-TEER in 11 centers. Most patients were male (63%) and were NYHA class III (61%) or IV (21%). MR was caused by ischemic cardiomyopathy in 51% of patients. EROA/LVEDV values varied widely with median=0.19 mm2/mL, interquartile range [0.12,0.28] mm2/mL, and 187 (36%) patients had values

Acral lentiginous melanoma is commonly misdiagnosed, and when detected late it portends a poor prognosis. Acral lentiginous melanoma can be mistaken for verruca, pyogenic granuloma, poroma, an ulcer, or other benign skin conditions. Patients with acral skin growths often present initially to a podiatric physician or their primary care physician. It is at this point when the growth is triaged as benign or potentially malignant. Dermoscopy aids in this decision making. Historically, dermoscopy training has been geared toward dermatologists, but there is increasing recognition of the need for dermoscopy training in primary care and podiatric medicine. Dermoscopy is particularly helpful in pink (amelanotic) growths, which can lack the traditional clinical findings of melanoma. A literature review of acral melanoma and dermoscopy was performed in PubMed. We also describe a case of amelanotic acral melanoma in a 58-year-old with a rapidly enlarging painful mass on her heel. The lesion was initially thought to be a pyogenic granuloma and was treated with debridement (curettage). She was ultimately seen in the dermatology clinic, and the findings under dermoscopy were worrisome for amelanotic melanoma. Biopsy confirmed the diagnosis. The cancer metastasized, and the patient died less than 2 years later.

Although peer crowd affiliations have been studied among emerging adults in college, this work has yet to focus in on LGBT-identifying students. Accordingly, the current study a) surveyed the peer crowd landscape using a sample of 234 LGBT students (

Background:AVID200 is a novel, potent TGF-beta receptor ectodomain-based trap designed to selectively neutralize TGF-beta 1 and 3. These two isoforms have been implicated as central mediators of the pathogenesis of systemic sclerosis (SSc). AVID200 avoids inhibition of TGF-beta 2, the isoform that supports normal cardiac function and hematopoiesis.Objectives:This first-in-human study (AVID200-01;NCT03831438) is a Phase 1, open label, multicenter, cohort dose-escalation trial designed to evaluate safety, tolerability, pharmacokinetic (PK) profile, pharmacodynamic (PD) effects, target engagement, and preliminary efficacy in patients with diffuse cutaneous SSc (dcSSc).Methods:Eligible patients must have dcSSc of Results:The first 2 dose cohorts have completed treatment: male/female 3 each, median age 61y (range 45-70), median MRSS at baseline 31 (range 23-39). Recruitment into cohort 3 is complete. AVID200 was well tolerated with no dose limiting toxicities or serious adverse events (SAEs). AEs, all considered possibly related, included single cases of Grade 1 dizziness and CPK elevation, and Grade 2 anemia. All patients demonstrated a decline in MRSS at 6 weeks by 3, 4, and 9 points in Cohort 1, and 2, 8, and 9 points in Cohort 2. Four of 6 patients demonstrated continued decrease in MRSS 12 weeks after the last dose, with all patients showing a decline in MRSS relative to baseline at this timepoint by 7, 6, and 7 points in Cohort 1 and 4, 8, and 13 points in Cohort 2. AVID200 in plasma engaged endogenous activated TGF-beta and potently neutralized signaling from exogenous TGF-beta 1 and 3, but not TGF-beta 2, across the treatment period. PD effects in skin biopsies, including expression of markers of SSc activity, TGF-beta activity, and myofibroblast-associated genes were assessed. Five of 6 patients showed decreased expression of PD biomarker genes, THBS1 and MS4A4A, comparing end of treatment biopsies to baseline, and all patients showed a decline in SERPINE1 expression, a marker gene for TGF-beta activity. Clustering of RNA-seq expression data showed close coregulation of COMP, THBS1, SERPINE1, LOXL, COL10A1, COL11A1, COL12A1, CTGF, and CDH11, suggesting that blocking TGF-beta inhibits this group of profibrotic genes. Single-cell sequencing data show that expression of these genes is upregulated by subsets of SSc fibroblasts.Conclusion:AVID200 at doses of 1 and 3 mg/kg was well-tolerated in this first study in dcSSc patients. Evidence of anti-fibrotic effects as indicated by rapid, persistent and clinically meaningful declines in MRSS was observed in all patients, as well as AVID200 target engagement and modulation. Recruitment into additional dose and extension cohorts is ongoing. Together, these clinical data support selective TGF-beta 1 and 3 inhibition by AVID200 as a promising therapeutic approach for dcSSc.Disclosure of Interests:Robert Lafyatis Grant/research support from: Forbius, Consultant of: Certa Therapeutics, Forbius, FBM Therapeutics, Robert Spiera Grant/research support from: Roche-Genetech, GSK, Boehringer Ingelheim, Chemocentryx, Corbus, Forbius, Sanofi, Inflarx, Consultant of: Roche-Genetech, GSK, CSL Behring, Sanofi, Janssen, Chemocentryx, Forbius, Mistubishi Tanabe, Robyn Domsic Consultant of: Forbius, Anna Papazoglou: None declared, Colin Ligon Grant/research support from: Forbius, Christina Mae Zinger Morse: None declared, Jean-François Denis Employee of: Forbius, Margaret Davis Employee of: Forbius, Tina Gruosso Employee of: Forbius, Gilles Tremblay Employee of: Forbius, Maureen O’Connor McCourt Employee of: Forbius, Sandra Sinclair Employee of: Forbius, Jonathan Delara Employee of: Forbius, Krista Alvarado Employee of: Forbius, Debra Wood Consultant of: Forbius, Symphogen, Paul Nadler Consultant of: Forbius, Symphogen, Karyopharm, Elizabeth Volkmann Grant/research support from: Forbius, Corbus Pharmaceuticals, Consultant of: Boehringer Ingelheim, Forbius, Speakers bureau: Boehringer Ingelheim

The opisthobranch mollusc Pleurobranchaea californica feeds on whole organisms and the functional morphology of the digestive system reflects this behavior. By a rhythmic behavior involving well-developed extrinsic buccal muscles and hemocoelic fluid, the buccal mass is protracted to the tip of the everted oral tube. Here a series of repeated protractions and retractions of the intrinsic buccal muscles associated with the flat radular ribbon and jaws draws the prey into the buccal cavity and conveys it to the dorsal esophagus, where by peristaltic action it is passed to the expansible crop for storage. Prey entering the buccal cavity is mixed with acid from a large single gland and secretion from the paired salivary glands. Prey is retained in the crop over long periods of time while it is slowly broken down and passed via the stomach into the digestive glands. Special modifications that allow flexibility of the digestive organs include elongated salivary gland ducts with propulsive bulbs, long flexible nerve cords connecting the ganglia, a long, large muscular duct for storage of the acid secretion, large jaws for muscle attachment and grasping the prey, and a broad radular ribbon with many teeth that acts as a conveyor belt to move food. Additional modifications for handling whole prey include a buccal membrane that aids in maintaining hemocoelic fluid pressure, the extensive acid gland for immobilization of prey, and the expansible crop for storage of food.

Objective Caspase-1 is required for nephritis and robust autoantibody development in the pristane model of murine lupus. The objective of this study was to evaluate the immune response and to study the splenic B and T cell populations in wild-type (WT) and caspase-1 -/- mice following pristane injection in order to develop an understanding of why absence of caspase-1 is protective in pristane-induced lupus. Methods Immunization responses to NP-Ficoll and NP-ovalbumin were assessed in WT and caspase-1 -/- mice. In vitro IgM and IgG responses to R848 were measured by ELISA. Serum IgM anti-dsDNA and IL-1β were also measured by ELISA. B and T cell populations 2 weeks and 6 months following pristane injection were measured by flow cytometry in WT and caspase-1 -/- mice. Results Caspase-1 -/- mice generate equivalent IgG responses to NP-Ficoll and NP-ova antigens when compared to wild-type mice. Additionally, they secrete IgM and IgG in response to TLR7 activation. Pristane injected WT and caspase-1 -/- mice generate robust IgM anti-dsDNA responses. Caspase-1 -/- mice have a significant reduction in marginal zone B cell populations compared to WT 6 months after pristane exposure whereas T cell responses are intact in these mice. Conclusions Caspase-1 -/- mice have intact immune responses but do not develop an expanded marginal zone B cell population in response to pristane-induced lupus. This may be one explanation for reduced IgG autoantibody production in these mice.

The hemocyanin-like molecule found in the blood of the most primitive bivalves (protobranchs) reversibly binds O2. Its respiratory properties and its sedimentation behavior are both distinctive. Although its electron-dense image looks like that of the gastropod hemocyanins, its molecular weight differs from those of all other molluscan Hcs and is more consistent with the concept of bivalve hemocyanin as a pair of octopod hemocyanins. Bivalve hemocyanin occurs in the solemyoids as well as the nuculoids, which argues for the integrity of the Protobranchia as a natural taxon. The ancestral bivalve O2 carrier was previously believed to be a simple intracellular hemoglobin, which is found in the less primitive Pteriomorpha. The most obvious interpretation of the present results, however, is that hemocyanin is the primitive bivalve O2 cannier and that it was replaced by the red blood cell, which originated at least twice: once in the pteriomorph bivalves and at least once in other taxa.

Many studies of drug utilization have suffered from the absence of information on the indications for therapy. A few data sets on drug utilization are available which include indication information. In addition, a number of computerized collections of medical billing data now exist in North America which can be used for such studies. These include data from the Kaiser Permanente Medical Plan; the Group Health Cooperative of Puget Sound; the Commission on Professional and Hospital Activities' Professional Activity Study; the U.S. state of Rhode Island; the Saskatchewan Health Plan in Canada; and Medicaid, the state run but federally financed health insurance plan for economically or medically needy individuals in the United States. These databases have a number of general advantages and disadvantages, which are reviewed. In addition, the differences among these databases are also explored. Finally, examples are presented demonstrating how these databases can be used for: 1) descriptive research on drug utilization, 2) evaluating the appropriateness of drug utilization, and 3) interventions designed to improve the appropriateness of prescribing.

This article concerns the use of an historical event to teach interdisciplinary design and reading strategies to content area preservice teachers at a Connecticut state university. The course, a requirement for state certification, seeks to give secondary content area teachers strategies to help struggling readers. Teachers from all subject areas can build cross-curricular lessons and activities around one historical event. The Hartford circus fire of 1944 was chosen for its local interest. The class was divided into groups of teachers from different content areas and each group produced interdisciplinary units using books, documentaries, news articles, and a song about the fire. لاهتمامها المحلي. وقد انقسم الصف إلى مجموعات معلمين من مجالات المحتوى المختلفة وأنتجت كل مجموعة وحدات متعددة المجالات مستخدمة كتب ووثائقيات ومقالات أخبار وأغنية عن الحريقة.1944تهم هذه المقالة استخدام حدث تاريخي لتعليم تصميم التعلم التكاملي والاستراتيجيات القرائية لمجال المحتوى عند معلمي قبل الخدمة في جامعة من جامعات ولاية كونيتيكت. إذ تمهد الحصة وهي من متطلبات الترخيص في الولاية الطريق لإعطاء معلمي مجال المحتوى الثانوي استراتيجيات لتساعد القراء المواجهين صعوبة في القراءة وبإمكان المعلمين من جميع مجالات المحتوى تصميم دروس وأنشطة متعددتا المناهج حول حدث تاريخي واحد وعلى سبيل المثال قد تم اختيار حريقة سيرك هارتفورد التي اشتعلت عام 本文是有关康涅狄格州大学中的在学科职前教师课程里，利用一项历史事件，教授跨学科课程设计与阅读策略。这课程是州立教师注册必须修读的，其目的是教授中学学科教师教学策略，以此帮助对阅读有困难的学生。围绕着这一项历史事件，不同科目的教师可以建立跨学科的课堂及设计教学活动。1944年哈尔特福德马戏团火灾被选为教材，因为这事件有本地性的兴趣。这班职前教师被分成几个学习小组，每组均由不同科目的教师组成，并利用书本、记录片、新闻报道文章及一首关于这火灾的歌曲等材料，制作出跨学科的教学单元。 Cet article porte sur l'utilisation d'un evenement historique pour faire un enseignement sur un dispositif interdisciplinaire et les strategies de lecture dans les disciplines a l'intention d'enseignants en formation initiale a l'universite d'Etat du Connecticut. Ce cours, qui est obligatoire pour obtenir la certification d'Etat, cherche a donner aux professeurs des disciplines du second degre des strategies pour aider les eleves ayant des difficultes en lecture. Les enseignants de toutes les disciplines peuvent mettre sur pied des lecons et des activites interdisciplinaires se rapportant a un evenement historique particulier. On a choisi l'incendie du cirque Hartford en 1944 du fait de l'interet qu'il presente localement. Les etudiants ont ete divises en groupes d'enseignants venant de differentes disciplines et chaque groupe a produit des unites interdisciplinaires en utilisant des livres, des documentaires, de nouveaux articles, et une chanson se rapportant a l'incendie. В статье описывается, как в Университете штата Коннектикут вокруг исторических событий выстраиваются междисциплинарные проекты и программы по методике преподавания чтения для будущих учителей-предметников. В этом штате курс подготовки к оказанию помощи слабо читающим детям является обязательным для получения диплома учителя. В рамках курса учителям различных предметов предлагается спланировать кросс-культурную учебную деятельность вокруг некоего исторического эпизода. Для примера выбрали пожар в Хартфордском цирке в 1944 году – поскольку для жителей штата это было значимое событие. Студентов разделили на группы так, чтобы в каждой группе оказались представители разных предметных областей. Итог их сотрудничества – междисциплинарные разработки с использованием книг, документальных фильмов, газетных статей и песни о пожаре. Este articulo es sobre el uso de un evento historico para ensenarles estrategias interdisciplinarias de diseno y lectura a maestros de areas de contenido al nivel de preservicio en una universidad estatal de Connecticut. El curso, un requisito para la certificacion estatal, trata de darles, a los maestros de areas de contenido al nivel de secundaria, estrategias para ayudar a estudiantes con dificultades. Maestros de todas las areas pueden crear lecciones y actividades a traves del curriculo basadas en un evento historico. El incendio de un circo en Hartford en 1944 fue escogido debido a su interes local. Se dividio la clase en grupos de maestros de diferentes areas de contenido, y cada grupo creo unidades multidisciplinarias usando libros, documentales, articulos periodisticos, y una cancion sobre el incendio.

We prospectively studied the outcome of a protocol of prophylaxis for deep vein thrombosis (DVT) in 103 consecutive patients undergoing surgical stabilisation of pelvic and acetabular fractures. Low-molecular-weight heparin (LMWH) was administered within 24 hours of injury or on achieving haemodynamic stability. Patients were screened for proximal DVT by duplex ultrasonography performed ten to 14 days after surgery. The incidence of proximal DVT was 10% and of pulmonary embolus 5%. Proximal DVT developed in two of 64 patients (3%) who had received LMWH within 24 hours of injury, but in eight of 36 patients (22%) who received LMWH more than 24 hours after the injury (p < 0.01). We conclude that LMWH, when begun without delay, is a safe and effective method of thromboprophylaxis in high-risk patients with major pelvic or acetabular fractures.

Chiral molecular monolayers deposited on a graphite surface in contact with a bulk liquid crystal (LC) droplet showed unexpected long-range morphological correlations between adjacent crystalline domains. These correlations included tendencies for nearby surface domains to exhibit similar chirality and to possess similar crystallographic orientation. Both correlations were found to decrease with increasing domain separation. Multiple nanocrystalline domains were grown in “molecule corrals”, which are flat-bottomed, nanometer-sized pits produced on the graphite surface by an oxidation reaction. Domain structure was investigated using scanning tunneling microscopy (STM). The observations are explained as arising from anchoring interactions between the adsorbed monolayer and the liquid crystal interfacial fluid. A model based on a modification of the Rapini−Popoular potential for the surface free energy of a nematic LC is developed that quantitatively describes the orientational component of the interaction....

The traditional structure of manufacturing has significantly restricted the effectiveness of integration which can be supported by existing computer systems. An essential requirement for factory-wide integration is reliable communication among various components and programmable devices on the shop floor; this task is far from trivial given the wide variety of incompatible equipment and proprietary networks. Research into networks for manufacturing has resulted in several systems which are compatible with the Open Systems Interconnection reference model. This paper presents a complete review of major industrial networking approaches. A comparative study on industrial communication networks is conducted. The communication requirements of an Automatic Sewing Cell are analyzed and an appropriate protocol is selected. Finally, a set of primitive services that are considered essential for CIM cells in the garment industry is proposed.

The third dimension, elevation, is a vital component of Australiais National Spatial Data Infrastructure. Elevation information in an easily accessible digital form is necessary for efficient and effective management of natural resources and the environment. Elevation is needed for analysis and modelling in areas as diverse as climate, biodiversity, salinisation, the rectification of satellite imagery, hydrology, telecommunications, infrastructure planning, and geology and geophysics. The need for such information on a regional and national basis has been the catalyst for the production of a national gridded digital elevation model using a cell spacing of 9 seconds of latitude and longitude. Production of the recently released GEODATA 9 SECOND DEM was undertaken by the Australian Surveying & Land Information Group, Australian Geological Survey Organisation, Australian Heritage Commission and the Centre for Resource and Environmental Studies at the Australian National University. This paper briefly examine...

Protein and N- acetylamino sugar concentrations are significantly lower in Mercenaria mercenaria pericardial fluid than in blood plasma, although concentrations of Na + , K + , lipid, glucose and carbohydrate are similar in each compartment. Of the > 35 protein subunits identified in plasma by 7.5% SDS-PAGE, up to 24 are found in pericardial fluid, yet only six to 10 are appreciably stained. Three pericardial fluid bands (28, 30 and 53 kDa) are absent from plasma. Densitometric measurements imply that the effective threshold for ultrafiltration is above 51 and below 83 kDa. Comparable qualitative SDS-PAGE results were obtained for Crassedoma giganteum, Patinopecten caurinus , and Mytilus californianus .

This article explores two issues involved in conducting qualitative research: 1) the essentials of data collection and 2) the unique role of the researcher in the data collection process.

Molluscan hemocytes function in the overall defense of the animal by phagocytosing foreign material. When this phagocytic ability is impaired the animal becomes increasingly vulnerable to physiological disruption by foreign agents. As in other bivalves, hemocytes of Mya arenaria have been shown to phagocytose a variety of foreign materials and to possess the hydrolytic enzymes necessary to degrade incorporate substances. However, hemocytes from diseased animals demonstrate almost no phagocytic capabilities. When allowed to settle on glass, diseased (abnormal) hemocytes remain rounded and generally unattached, with only a few short membrane extensions; they do not clump. Whole cell transmission electron microscopy preparations demonstrate an altered cytoskeletal architecture in diseased hemocytes as compared to that found in nondiseased (normal) cells. Hemocyte preparations incubated in rhodamine-conjugated phalloidin and observed with fluorescence microscopy show altered actin filament patterns in diseased hemocytes. The disrupted cytoskeletal structure observed in diseased hemocytes likely accounts for the inability of cells to clump, adhere to glass, and phagocytose foreign materials.

We isolated a flower-specific cDNA, FST (flower-specific thionin), which encodes a novel thionin from tobacco. Thionins are basic and cysteine (Cys)-rich, low molecular weight proteins found in many plants. They are believed to play a role in plant defense against pathogens. The central domain of the FST protein shares homology with three gamma-thionins. Like other thionin precursors, the FST protein has an N-terminal domain characteristic of a signal peptide and an acidic C-terminal domain. FST mRNA accumulates specifically in developing flowers and its level drops as flowers mature. Transcripts are present in petals, stamens and pistil but are not detectable in sepals. In situ hybridization revealed that FST mRNA is most abundant in the epidermal cells along the adaxial surface of petals, and in the surface cell layers of the carpel and anther walls. If the FST protein indeed has a protective role in flowers, this pattern of spatial distribution of FST mRNA would appear to maximize this effect on the two internal reproductive whorls. A possible biological role for FST is discussed.

Large numbers of the soft-shelled clam Mya arenaria from New Bedford Harbor, Massachusetts, exhibit a blood cell disease referred to as hematopoietic neoplasia (HN). Diseased hemocytes differ morphologically from normal hemocytes by their high nucleocytoplasmic ratio. The phagocytic activity, one of the internal defense mechanisms, was compared in the two populations. Surface receptors, essential for recognition during phagocytosis, were demonstrated for both populations using Con A staining. Adherence and uptake were measured after in vitro incubation with yeast. Examination of hemocytes with scanning electron microscopy showed that yeast cells adhered only to the surface of normal hemocytes, and not to diseased hemocytes. Quantitative analysis of adherence and uptake of yeast by hemocytes showed that diseased hemocytes were unable to adhere and ingest yeast. This is thought to be caused by differences in cytoskeletal organization. Finally, the activity of four lysosomal enzymes was used to evaluate intracellular degradation in normal and diseased hemocytes. Histochemical analyses showed diseased hemocytes to have higher than normal acid phosphatase, nonspecific esterases and β-glucuronidase activity. These results indicate that enzyme activity cannot be directly correlated to intracellular degradation. However, it is possible that stress on the lysosomal system may activate certain enzymes.

The expansion of human stem cells and their genetic manipulation represent areas of increasing interest in the field of stem cell transplantation. Previously, stem cell transplantation has been accomplished by using cellular products obtained by large volume bone marrow or peripheral blood harvest. Difficulties with this approach include inadequate cell numbers and tumor cell contamination. Furthermore, for gene transfer modalities requiring proliferating progenitor cells, low gene expression would be expected in these products. To address these difficulties, the AastromReplicell System has been developed as a fully closed and automated system for expanding hematopoietic cells. Investigators at Aastrom have evaluated the conditions needed for optimal growth including the need for unpurified bone marrow or cord blood mononuclear cells, high cell densities, serum-containing medium and certain types of plastic surfaces. Studies have now been initiated to demonstrate the feasibility of generating enough cells to fully reconstitute hematopoiesis from small volumes of cellular progenitors. It has also been demonstrated that tumor cell contamination passively decreases during the culture period. It now remains to be shown in a direct comparison that this approach yields greater efficacy and a lower cost than transplantation with unmanipulated large volume marrow or peripheral blood stem cell products.

The 1980's introduced an era of intense interest and activIty in the area of post-marketing drug surveillance (PMS). Under the leadership of the World Health Organization, this period also saw a reaffirmation of the commitment of the major national health systems of the world to monitoring medication prescribing and use: drug utilization review (DUR). Although these two concepts emerged separately with different sponsors and justifications, they are inextricably linked by the need for a common methodologic framework. This methodologic framework - record linkage - provides the key ingredient for successful PMS and DUR: longitudinal drug/ diagnosis data on a patient specific basis.

Five hundred consecutive attempted lower limb angioplasties for ischaemic disease (370 patients, mean age 65.6 years, range 33–91 years) were reviewed. Significant complications occurred in 44 cases (8.8%). Nine patients (1.8%) underwent emergency surgery related to a complication. A further 12 patients (2.4%) underwent elective surgery related to a complication. In addition, four patients died within 30 days of the procedure; one following surgery performed because of a complication of angioplasty, one following a myocardial infarction, one following severe bleeding associated with subsequent thrombolytic therapy and one during emergency surgery related to a complication of angioplasty. A correlation was found between complication rate and age. This relationship was independent of the approach to, the position of, and the severity of the treated lesion. Elderly patients are at increased risk of complication in lower limb angioplasty.

Standard radioactive sources of known element abundances are essential for the calibration of airborne gamma-ray spectrometers. The conventional approach to calibration has been the determination of 3-channel stripping ratios and sensitivity constants from large airport calibration pads, and a well calibrated test strip, respectively. However, calibration pads are expensive to build and suitable test strips are difficult to find and expensive to calibrate. Also, both pads and test strips are subject to variations in radiation output due to variable moisture content and radon loss, and this can lead to considerable calibration errors. This paper describes an alternative approach to the calibration of airborne gamma-ray spectrometers. We have built a set of portable calibration sources, and have used these to simulate the response of an airborne spectrometer to infinite sources over a range of altitudes. The calibration has produced conventional 3-channel stripping ratios and sensitivity constants as a function of altitude, as well as good quality, pure multichannel spectra which are fundamental to any research into improved processing techniques. The sources are inexpensive, and since they are completely sealed, they do not suffer from variations in radiation output.

The expansion of human stem cells and their genetic manipulation represent areas of increasing interest in the field of stem cell transplantation. Previously, stem cell transplantation has been accomplished by using cellular products obtained by large volume bone marrow or peripheral blood harvest. Difficulties with this approach include inadequate cell numbers and tumor cell contamination. Furthermore, for gene transfer modalities requiring proliferating progenitor cells, low gene expression would be expected in these products. To address these difficulties, the AastromReplicell System has been developed as a fully closed and automated system for expanding hematopoietic cells. Investigators at Aastrom have evaluated the conditions needed for optimal growth including the need for unpurified bone marrow or cord blood mononuclear cells, high cell densities, serum-containing medium and certain types of plastic surfaces. Studies have now been initiated to demonstrate the feasibility of generating enough cells to fully reconstitute hematopoiesis from small volumes of cellular progenitors. It has also been demonstrated that tumor cell contamination passively decreases during the culture period. It now remains to be shown in a direct comparison that this approach yields greater efficacy and a lower cost than transplantation with unmanipulated large volume marrow or peripheral blood stem cell products.

The American Society of Clinical Oncology (ASCO) 36th Annual Meeting, which took place from 20-23 May 2000 in New Orleans, was, as usual, a large, well-attended, internationally-represented meeting of cancer specialists. Both clinical trials of well established drugs for the treatment of cancer, as well as novel agents under development were presented in poster sessions, poster discussion sessions and large oral sessions. The prominent areas of new drug development presented were anti-angiogenic agents, tyrosine kinase inhibitors, immunotherapeutics and agents that modify the pharmacology or pharmacodynamics of chemotherapeutic agents. Sessions highlighting the translational development of several compounds with other mechanisms of action were also well attended. While there were no agents with unexpectedly dramatic clinical benefit, there were a number of promising developments.

It has been suggested that preoperative biliary drainage increases the risk of infectious complications of pancreaticoduodenectomy.The aim of this study was to assess complications related to biliary stents/drains and postoperative morbidity in patients undergoing neoadjuvant chemoradiotherapy for periampullary cancer.One hundred and eighty-four patients with periampullary neoplasms were prospectively selected for neoadjuvant external beam radiation therapy and 5-fluorouracil-based chemotherapy between 1995 and 2002.The data were retrospectively completed and analysed with respect to biliary drainage, efficacy and complications of endoscopic biliary stents and postoperative morbidity. Patients who had undergone a surgical biliary bypass were excluded.Data were completed in 168 patients. One hundred and nineteen patients were treated with endoscopic biliary stents, 18 patients had a percutaneous biliary drain and 31 patients did not require biliary drainage. Hospitalisation for stent-related complications was necessary in 15% of the patients with endoscopic biliary stents. Seventy-two patients underwent pancreaticoduodenectomy. There was no significant difference in the rate of wound infections, intra-abdominal abscesses and overall complications between the groups with and without preoperative biliary drainage.Postoperative infectious complications are common in patients both with and without preoperative biliary drainage. A statistically significant difference in complication rates was not observed between these groups.

ISIS-2503, a 20-mer antisense oligonucleotide that inhibits Ha-Ras expression, is being developed by Isis Pharmaceuticals Inc as a potential treatmentfor cancer, particularly tumors that commonly have abnormalities of Ras function. It is in phase II trials. According to an April 2001 report by Bear StearnsCo, Elan Corp plc had an unspecified collaboration with Isis for the development of ISIS-2503 [419357], but Isis later clarified that there was no agreement between the two companies and that ISIS-2503 had merely been used for the 'OraSense' joint venture that explores the use of antisense oligonucleotidesfor oral administration [419673].

For elderly women, insufficient data exist to assess the accuracy of the assumed mean protein requirement of 0.6 g of protein x kg(-1) x day(-1), and the adequacy of the current Recommended Dietary Allowance (RDA) of 0.8 g of protein x kg(-1) x day(-1). The aims of this study were to assess the mean protein requirement and suggested safe and adequate protein intake (protein allowance) of elderly women using a shorter-term nitrogen balance protocol.During three separate 18-day trials, 11 elderly women (age range, 70-81 years) were randomly fed eucaloric diets designed to provide either 0.50, 0.75, or 1.00 g of protein x kg(-1) x day(-1). Nitrogen balance was determined at Weeks 2 and 3 (Days 7-10 and 14-17, respectively) of each trial using data from total nitrogen analyses of duplicate food composites, 24-hour urine collections, and stool collections. The mean protein requirement was calculated using linear regression of individual women's data from all three trials and inverse prediction.At protein intakes of 0.53 +/- 0.02, 0.76 +/- 0.02, or 1.06 +/- 0.05 g of protein x kg(-1) x day(-1), net nitrogen balances during Week 2 were -14.5 +/- 3.1, 3.8 +/- 2.5 and 23.4 +/- 3.3 mg of nitrogen x kg(-1) x day(-1), respectively, for these body weight- and body composition-stable women. At Week 3, the net nitrogen balances were -0.1 +/- 2.7, 8.5 +/- 3.6 and 42.0 +/- 3.0 mg of nitrogen x kg(-1) x day(-1). From Week 2 to Week 3, shifts to more positive nitrogen balances occurred due to decreases in urinary nitrogen excretion. The mean protein requirement at Week 2 was calculated to be 0.70 +/- 0.09 g of protein. kg(-1) x day(-1) (coefficient of variation [CV] = 13%) and at Week 3 was calculated to be 0.56 +/- 0.09 g of protein x kg(-1) x day(-1) (CV = 17%). From these data, an adequate protein allowance was estimated to be greater than the RDA at Week 2 (0.90 g of protein x kg(-1) x day [d](-1)), and not different than the RDA at Week 3 (0.76 g of protein x kg(-1) x d(-1)).The decrease over time in urinary nitrogen excretion from Week 2 to Week 3 suggests that these elderly women did not achieve a metabolic steady state during this shorter-term nitrogen balance study. Collectively, these data suggest that the total protein needs of elderly women are at or above the current RDA for protein. However, the results of this study indicate that shorter-term nitrogen balance protocols are insufficient to firmly establish the RDA for protein of elderly women, and further research is required using alternative criteria measures.

Therion Biologics, the NCI and Aventis Pasteur are investigating CEA-TRICOM, a recombinant, pox virus-based vaccine that incorporates a triple dose of costimulatory molecules as well as the carcinoembryonic antigen (CEA) tumor antigen, for the potential treatment of colorectal cancer. CEA-TRICOM is designed to stimulate and strengthen the body's immune system to kill colorectal cancer cells. CEA-TRICOM is administered in a priming and boosting protocol using two unique pox virus vectors, rV-CEA-TRICOM (recombinant vaccinia vector) and rF-CEA-TRICOM (recombinant fowlpox vector). The TRICOM component of both rV-CEA-TRICOM and rF-CEA-TRICOM comprises three costimulatory molecule transgenes (B7-1, ICAM-1 and LFA-3) [414643], [414645], known to elicit strong cellular immune responses necessary for complete tumor destruction. In preclinical studies conducted by the NCI and Therion, researchers have demonstrated that this combination of three costimulatory molecules dramatically boosts the immune response to eradicate cancer in murine models [399610], [414631]. In February 2001, Therion Biologics and the NCI initiated a phase I trial of CEA-TRICOM [399610]. The phase I trial of CEA-TRICOM is designed to demonstrate proof-of-principle for using multiple costimulatory molecules in conjunction with a tumor antigen to improve the strength of cellular immune responses. It is a multistage, dose-escalation study that will assess the safety and immunologic effects of CEA-TRICOM in up to 42 patients who have advanced metastatic colorectal cancer. Subjects will receive rF-CEA-TRICOM alone, rV-CEA-TRICOM followed by booster vaccinations with rF-CEA-TRICOM or rV-CEA-TRICOM followed by rF-CEA-TRICOM and GM-CSF adjuvant. The primary measure of immune response will be the level of CEA-specific T-cells stimulated by vaccination, with levels of CEA-expressing tumor cells in the blood used as a potential secondary measure of treatment effect [399610].

Fruit and vegetable consumption has consistently been associated with decreased risk of a number of aerodigestive tract cancers, including esophageal cancer. We have taken a "food-based" chemopreventive approach to evaluate the inhibitory potential of lyophilized black raspberries (LBRs) against N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumorigenesis in the F344 rat, during initiation and postinitiation phases of carcinogenesis. Anti-initiation studies included a 30-week tumorigenicity bioassay, quantification of DNA adducts, and NMBA metabolism study. Feeding 5 and 10% LBRs, for 2 weeks prior to NMBA treatment (0.25 mg/kg, weekly for 15 weeks) and throughout a 30-week bioassay, significantly reduced tumor multiplicity (39 and 49%, respectively). In a short-term bioassay, 5 and 10% LBRs inhibited formation of the promutagenic adduct O(6)-methylguanine (O(6)-meGua) by 73 and 80%, respectively, after a single dose of NMBA at 0.25 mg/kg. Feeding 5% LBRs also significantly inhibited adduct formation (64%) after NMBA administration at 0.50 mg/kg. The postinitiation inhibitory potential of berries was evaluated in a second bioassay with sacrifices at 15, 25, and 35 weeks. Administration of LBRs began after NMBA treatment (0.25 mg/kg, three times per week for 5 weeks). LBRs inhibited tumor progression as evidenced by significant reductions in the formation of preneoplastic esophageal lesions, decreased tumor incidence and multiplicity, and reduced cellular proliferation. At 25 weeks, both 5 and 10% LBRs significantly reduced tumor incidence (54 and 46%, respectively), tumor multiplicity (62 and 43%, respectively), proliferation rates, and preneoplastic lesion development. Yet, at 35 weeks, only 5% LBRs significantly reduced tumor incidence and multiplicity, proliferation indices and preneoplastic lesion formation. In conclusion, dietary administration of LBRs inhibited events associated with both the initiation and promotion/progression stages of carcinogenesis, which is promising considering the limited number of chemopreventives with this potential.

This study investigated whether local delivery of 10-hydroxycamptothecin provides effective inductive chemotherapy as assessed by significant tumor reduction. Established tumorigenic human oral squamous cell carcinoma cells were used for these experiments. The experimental groups were comprised of: control (blank (no drug) poly(lactide-co-glycolide) (PLGA) microspheres), intraperitoneal 10-hydroxycamptothecin delivery + blank microspheres, local bolus 10-hydroxycamptothecin + blank microspheres, and PLGA controlled-release microspheres. The 10-hydroxycamptothecin dose administered was 12 mg/kg (bolus-intraperitoneal, local) or controlled-release over 10 days. Regardless of delivery route, 10-hydroxycamptothecin significantly reduces tumor volume. However, PLGA microspheres provide significantly higher intratumor-drug concentrations (approximately 10 and 100 fold higher) relative to local bolus and intraperitoneal routes, respectively. Also, only the PLGA microspheres significantly reduced tumor weights. Camptothecin clinical applications are limited by drug inactivation at physiological pH and the need for sustained infusions. However, due to their acidic, camptothecin-stabilizing microclimate, PLGA microspheres could provide a novel delivery system for camptothecin-based induction chemotherapy.

Physiological angiogenesis in skeletal muscle is an adaptive response to physical training and electrical stimulation. This study investigated the role of angiotensin II (Ang II) in regulating both angiogenesis and vascular endothelial growth factor (VEGF) protein expression induced by electrical stimulation.The right tibialis anterior (TA) and extensor digitorum longus (EDL) muscles of Sprague-Dawley rats were stimulated for 8 hours per day for 7 days. The contralateral muscles served as controls. Two days before the surgery and throughout the stimulation protocol, the rats received either lisinopril or losartan in their drinking water. Rats without any drug treatment were used as control. Immunohistochemistry and Western blot analysis were performed to identify the source and quantify the VEGF protein expression in these muscles. The relationship between angiogenesis and VEGF expression was explored using a VEGF-neutralizing antibody.Chronic electrical stimulation of the skeletal muscles led to significant increases in vessel density (14% and 30% for EDL and TA, respectively) within 7 days. In addition, stimulation increased VEGF protein levels in the stimulated muscles. Both lisinopril and losartan blocked elevation in VEGF expression and inhibited the angiogenesis induced by stimulation. VEGF neutralization also inhibited angiogenesis, confirming the relationship between Ang II, VEGF, and vessel growth.The current study suggests a pathway involving angiotensin II receptors (AT1) and VEGF in electrically stimulated angiogenesis.