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Background Use of neoadjuvant therapy for elderly patients with pancreatic cancer has been debatable. With FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan, oxaliplatin) or gemcitabine plus nab-paclitaxel (GnP) showing tremendous effects in improving the overall survival of patients with borderline resectable and locally advanced pancreatic cancer, there is no definitive consensus regarding the use of this regimen in the elderly. Methods This study evaluated the eligibility of elderly patients with borderline resectable or locally advanced pancreatic cancer for neoadjuvant therapy. Patients registered in the database of pancreatic cancer at the University of Colorado Cancer Center, who underwent neoadjuvant treatment between January 2011 and March 2019, were separated into three age groups (less than 70, 70–74, 75 or more years) and respective treatment outcomes were compared. Results The study included 246 patients with pancreatic cancer who underwent neoadjuvant treatment, of whom 154 and 71 received chemotherapy with FOLFIRINOX and GnP respectively. Among these 225 patients, 155 were younger than 70 years, 36 were aged 70–74 years, and 34 were aged 75 years or older. Patients under 70 years old received FOLFIRINOX most frequently (124 of 155 versus 18 of 36 aged 70–74 years, and 12 of 34 aged 75 years or more; P Conclusion The safety and efficacy of multiagent chemotherapy in patients aged 75 years or over were similar to those in younger patients. Modern multiagent regimens could be a safe and viable treatment option for clinically fit patients aged at least 75 years.

An optimised water-in-oil-in-water double emulsion process for the microencapsulation of plasmid DNA in poly(D,L-lactic-co-glycolic acid) (PLGA) was used to prepare microparticles from a range of different PLGA formulations. This process has been developed using pharmaceutically accepted solvents and is potentially scaleable. Incorporation of plasmid DNA in the microparticles of up to 11 microg/mg was obtained and the retention of plasmid DNA integrity was considerably greater than previously reported. Microparticle structure was determined, by scanning electron microscopy, to be hollow and size distribution characteristics were found to be independent of polymer formulation. The ability to vary the plasmid DNA release profile by changing the PLGA formulation and polymer concentration used in the encapsulation process was also demonstrated. This ability to control the release profile of the microparticles was shown to be especially important as the physical integrity of the encapsulated plasmid DNA was found to deteriorate with extended release times in vitro.

Fresh pork Canadian backs, cut into boneless pork chops, were cooked to 71C internal temperature by grilling at 93, 121, 148, 176, or 204C. Cooking times were significantly longer for chops grilled at 93C than for those grilled at the higher temperatures. Yield, moisture, and crude fat values of the chops in the different treatments were similar. Chops grilled at 204C had significantly lower retention values for thiamin and vitamin E and had lower mean retention values for vitamin B-6. Retention values for selenium were similar for all treatment groups. Shorter cooking times along with higher vitamin retentions were obtained in boneless pork chops grilled at 121, 148, and 176C.

Many soaring bird species migrate southwards in autumn from their breeding grounds in Europe and Central Asia towards their wintering grounds. Our knowledge about interactions between migrating birds, thermal selection during migration and mechanisms that lead to flocking or convergent travel networks is still very limited. To start investigating these aspects we developed an individual-based simulation model that describes the local interactions between birds and their environment during their migratory flight, leading to emergent patterns at larger scales. The aim of our model is to identify likely decision rules with respect to thermal selection and navigation. After explaining the model, it is applied to analyse the migration of white storks (Ciconia ciconia) over part of its migration domain. A model base-run is accompanied by a sensitivity analysis. It appears that social interactions lead to the use of fewer thermals and slight increases in distance travelled. Possibilities for different model extensions and further model application are discussed.

The recent change in the Tokamak Fusion Test Reactor (TFTR) program schedule has introduced a postponement of tritium operation for at least three years (currently scheduled for 1993). In the interim, TFTR research will place greater emphasis on understanding the physics of transport in tokamaks. This increased emphasis will result in the addition of more diagnostics and upgrades to existing diagnostics, significantly increasing the amount of data acquired for each TFTR experimental pulse. As the total data per shot increases, providing adequate facilities for acquiring, storing, analyzing, and archiving data will be a continual challenge. An overview of the functions of the TFTR central computing system is presented, and the areas which will need to be addressed to provide support for the larger data loads are identified. >

The Tokamak Physics Experiment (TPX) is the next major device planned by the US fusion program. The device will be located at the Princeton Plasma Physics Laboratory and is currently scheduled to begin operation in the Spring of the year 2000. TPX will be a steady state device which is designed, constructed, and operated as a national experiment in collaboration with a number of major institutions. Most current fusion experiments operate in a pulsed mode and rely on data capture during the pulse with later data retrieval, analysis, and display. TPX, however, will require a real time data handling and analysis capability. This paper discusses the conceptual design for the TPX Central Instrumentation and Control (I&C) System. The design supports both the collaborative and steady state nature of the experiment. The design incorporates full integration of audio and video systems at the desktop and the use of standardized commercially available hardware and software systems. Key components of the Central I&C systems include guidance for subsystem design and prototype development and standardized operating stations for engineering and physics subsystems. It includes synchronization, safety, interlock, and controlled access systems and the control room facility with networks and data handling systems. The conceptual design include's a description of implementation philosophy as well as cost and schedules.

The Tokamak Physics Experiment (TPX) and the International Thermonuclear Engineering Reactor (ITER) are the major national design efforts currently underway by the US fusion program. These design efforts are being performed at many different sites consisting of national laboratories, universities, and industrial partners. This paper presents the current status of work in support of expediting communication and enhancing the collaborative process by providing a framework of common tools and resources for all collaborators. The key components of this framework are common applications which support desktop mail, directory services, and convenient desktop access to project design documents. A discussion of the issues associated with the deployment, support, and future evolution of this framework will be presented.

Collaboration is increasing in importance as physics research continues to become concentrated on a few large and expensive facilities. This is particularly true in magnetic fusion energy research, where the next generation experiments will be operated as facilities with national and international participation. In addition, these facilities are designed for steady state operation, for which interactive, real-time experimentation becomes an important issue. We are developing tools to provide for the establishment of geographically distant centers for interactive operations; such centers would allow scientists to participate in experiments from their home institutions. We are developing a testbed for a Remote Experimental Environment (REE), a "Collaboratory" The testbed will be used to evaluate the ability of a remotely located group of scientists to conduct research on the DIII-D Tokamak at General Atomics (GA). The REE will serve as a testing environment for advanced control and collaboration concepts applicable to future experiments. Process-to-process communications over high speed wide area networks provide real-time synchronization and exchange of data among multiple computer networks, while the ability to conduct research is enhanced by adding audio/video communication capabilities. The Open Software Foundation's (OSF) Distributed Computing Environment (DCE) is being used to test concepts in distributed control, security, naming, remote procedure calls and distributed file access using the Distributed File Services (DFS). We are exploring the technology and sociology of remotely participating in the operation of a large scale experimental facility.

Numerous studies have demonstrated that a variety of hormones have receptors and exert biologic actions on tissues of the immune system. Conversely, cytokines exert biologic actions on the endocrine system. This bidirectional interaction is likely involved in maintenance of physiological and immunologic homeostasis. This paper summarizes a variety of actions of growth hormone (GH), prolactin (PRL), insulin-like growth factor-I (IGF-I), glucocorticoids and thyroid hormones (TH) on the immune system. It then proceeds to put these actions into a hypothetical context whereby these hormones may mediate some changes in immune system function in response to environmental stimuli such as physical and emotional stress, nutritional deprivation and environmental temperature. In the first example, it is proposed that PRL secretion in response to stress may serve an immunomodulatory role in two ways. The first is by stimulating the immune system directly and the second is by dampening or reducing the degree to which glucocorticoids are secreted in response to stress. The second example suggests that the increase in GH secretion and reduced IGF-I secretion in response to protein/energy restriction may have two potential immunomodulatory actions. One action is a direct effect of GH on several components of the immune system. The other is the partitioning of nutrient use away from skeletal muscle growth and toward tissues of higher priority such as the immune system. The third example proposes that the increased secretion of TH during cold environmental temperatures not only increases basic metabolic rate, but also directly stimulates both primary and secondary lymphoid tissues. It is suggested, therefore, that these three hormones are involved in maintaining immune system homeostasis in response to environmental change.

Regorafenib is a novel multikinase inhibitor that has demonstrated broad antitumor activity across various solid tumor types, in preclinical and clinical studies. Preclinical data show inhibitory activity of angiogenic, stromal and oncogenic tyrosine kinases through the targeting of vascular endothelial growth factor receptors 1, 2 and 3, tyrosine-protein kinase receptor TIE-2, platelet-derived growth factor receptor β, fibroblast growth factor receptor 1, proto-oncogene tyrosine-protein kinase receptor Ret, mast/stem cell growth factor receptor Kit, RAF proto-oncogene serine/threonine-protein kinase and wild-type and V600E mutant serine/threonine-protein kinase B-raf. Phase I trials have shown that the drug is relatively well tolerated at doses of 160 mg daily on a 3-weeks-on/1-week-off schedule, or 100 mg daily on a continuous schedule, with adverse effects typical of other multikinase inhibitors. Phase II studies demonstrated clinical benefit in a variety of tumor types, mostly associated with prolonged stable disease. Phase III studies include the CORRECT trial, which ultimately led to FDA approval of the drug in the setting of metastatic colorectal cancer previously treated with standard therapies. There is still much work to be done to determine the role of regorafenib in the future of cancer therapy. This review will focus on the development of regorafenib, from early preclinical work through phase I, II and III trials, as well as highlighting the current role and potential future directions of this novel agent.

The presence of growth hormone receptors (GHR) on sheep peripheral blood mononuclear (PBMN) cells was studied in two ways. The first was to directly measure specific GH-binding sites on PBMN cells drawn from lambs from birth to 5 months of age. The second was to measure the effect of GH on resting and interleukin-2 (IL-2)-activated PBMN cells in vitro and also the effect of other hormones such as prolactin (PRL), insulin-like growth factor-1 (IGF-1), and glucocorticoid. The specific binding of [125I]human GH (hGH) was low on PBMN cells but increased (P < 0.05) with age up to 5 months. Interestingly, serum concentrations of GH-binding protein also increased (P < 0.01) with age and were highly correlated (r = 0.89; P < 0.05) with the specific binding of GH to PBMN cells. The addition of ovine GH (oGH) to PBMN cells in vitro resulted in increased (P < 0.01) proliferation (at a dose of 100 ng/ml). Higher doses of oGH (2 μg/ml) also increased PBMN cell proliferation. When PBMN cells were previously stimulated with IL-2, the dose of 100 ng/ml oGH was no longer able to stimulate proliferation. IGF-1 inhibited (P < 0.04) resting PBMN cell proliferation at 100 ng/ml but had no effect on IL-2-activated PBMN cells. Other hormones such as PRL caused a stimulation of PBMN cell proliferation (P < 0.01) at 100 ng/ml, whereas dexamethasone (dex) inhibited PBMN cell proliferation at doses as low as 63 ng/ml. These studies show that GH, PRL, IGF-1, and glucocorticoids are effective in modulating the proliferation of PBMN cells from sheep and therefore suggest that a modulation of immune system function in vitro by these hormones is consistent with a purpose in vivo.

LEARNING OUTCOME: To understand the relationships between grill temperature and grilled boneless pork chop quality. Foodservice units play major roles in maintaining the quality of meat served to consumers. A randomized complete block experimental design with five replications (blocks) was used to evaluate the effects of equipment temperature (ET) {93, 121, 148, 176, 204°C} on grilled boneless pork chop quality. Regression analysis using stepwise selection was used to determine significant (P

Thirteen Targhee rams selected for rate and efficiency of gain for 4 yr (1.5 generations) were compared with 10 rams from a Targhee line with no selection for over 20 yr to determine if selection for these traits would be associated with changes in the secretion of growth hormone (GH), thyrotropin (TSH) and(or) prolactin (PRL). Selected rams exhibited greater birth weight, average daily gain (ADG) and feed consumed/day during a 6-wk individual feeding regimen, and exhibited greater overall ADG during a 16-wk feeding trial as compared with the unselected rams. Temporal blood plasma samples were collected at 15-min intervals for 8 h from each of the 23 rams for hormone analysis. Selected rams exhibited greater overall mean GH (6.1 +/- .4 vs 4.6 +/- .5 ng/ml), overall mean TSH (8.6 +/- 1.2 vs 6.2 +/- .7 ng/ml) and baseline mean TSH (8.0 +/- 1.1 vs 5.6 +/- .5 ng/ml) than the unselected rams. Although the adjusted GH spike amplitude value was higher in the selected line (12.1 +/- 3.0 vs 7.4 +/- .8 ng/ml), this difference was not significant. No differences were observed with any of the variables of PRL secretion. In addition, there were no significant correlations between any of the hormone variables and any of the feed or gain data. These data support the hypothesis that Targhee rams selected for rate and efficiency of gain exhibit higher plasma levels of GH and TSH than unselected rams of the same breed.

Concentrations of luteinizing hormone (LH) and prolactin (Prl) in the serum of anestrous and cycling ewes were compared. The concentration of LH in serum and the frequency of episodic releases of LH were lower in anestrous than in cycling ewes. Concentrations of LH in serum rose as rapidly after ovariectomy of anestrous ewes as after ovariectomy of cycling ewes. Prl levels were higher during anestrus than at any stage of the estrous cycle; however, high Prl levels were not necessarily associated either with low LH levels or the absence of episodic release of LH. These data suggest: (1) that anestrus is not due to a reduction in the intrinsic ability of the hypothalamo-hypophyseal system to secrete LH, and (2) that high Prl levels may be a symptom rather than a cause of seasonal anestrus.

A series of experiments were conducted in ewes and whether (castrate male) lambs to evaluate the influence of prostaglandins on secretion of anabolic hormones and to determine if repeated injections of prostaglandin (PG) F2alpha would chronically influence the secretion of these hormones and perhaps growth rate as well. A single intravenous injection of PGA1 and PGB1 (100 microgram/kg) exerted no significant (P greater than .10) influence on plasma concentrations of prolactin (PRL), growth hormone (GH) or thyrotropin (TSH) in ewes. PGA1, but not PGB1, stimulated an increase in the plasma concentration of insulin. Infusion of PGF2alpha for 5.5 hr into ewes resulted in increased (P less than .05) plasma concentrations of both GH and ARL while TSH and insulin were not significantly influenced. Prostaglandin F2alpha, when injected subcutaneously into wether lambs (10 mg twice weekly) stimulated (P less than .05) plasma GH concentrations after the first injection, but not after 3 weeks of treatment. Changes in plasma PRL or TSH were not observed consistently in the lambs treated chronically with PGF2alpha or TRH. Prostaglandin F2alpha, in the present studies, and PGE1 in previously reported studies (1-3), has been demonstrated to be stimulatory to the secretion of PRL and GH. In contrast, PGA1 and PGB1, which lack an 11-hydroxyl group, failed to influence the secretion of either PRL or GH. It would, therefore, appear that the 11-hydroxyl group is a structural requirement for prostaglandins to influence the secretion of these two hormones in sheep. Treatment with thyrotropin releasing hormone (TRH), alone or in combination with PGF 2alpha, significantly (P less than .05) increased growth rate (average daily gains) while PGF2alpha did not, despite the fact that both compounds exerted similar effects on plasma GH.

Plasma levels of thyrotropin (TSH), prolactin (Prl), growth hormone (GH), thyroxine (T4), and triiodothyronine (T3) were measured in response to continuous 24-h infusion of synthetic thyrotropin-releasing hormone (TRH) in normal and surgically thyroidectomized (THYX) calves in a series of 2 experiments. In the 1st experiment, the low dose of TRH (0.077 microgram/min) had no effect on any hormone levels measured. Plasma TSH concentration increased significantly (p less than 0.05) in response to TRH infusion (0.77 microgram/min) in both experiments, but plasma TSH levels plateaued and then declined in both cases despite continued TRH infusion and irrespective of the presence or absence of a thyroid gland. A similar pattern of secretion, though less markedly decreased over time, was observed for plasma Prl in both experiments. The higher dose (0.77 microgram/min) of TRH had no effect on plasma GH concentration in the 1st infusion, but did result in a significant (p less than 0.05) increase in overall mean concentration of GH in both normal and THYX calves in the 2nd experiment. Removal of the thyroid gland, thus removing the source of increasing T4 and T3 levels seen in normal calves infused with TRH, failed to alter the secretory patterns of TSH and Prl. These data suggest that feedback inhibition by increasing plasma thyroid hormone concentrations was not responsible for the failure of TSH and, to a lesser extent, Prl to maintain chronically elevated plasma levels in response to continuous 24-h TRH infusion. It is suggested that a depletion of pituitary TSH and Prl stores readily secretable in response to a constant dosage level of TRH may be responsible for the secretory patterns observed.

Significant heating with the fast magnetosonic wave near the ion cyclotron frequency has been demonstrated in the present generation of tokamaks. Effective wave absorption and heating can be achieved either by using the second harmonic or by heating at the fundamental of a minority ion component. Recent experiments in PLT have facilitated the refinement of a heating model which both shows good agreement with experiment and predicts favorable scaling to hotter, denser plasmas. Details of the model, including full wave theory, power deposition, Fokker-Planck theory, and scaling are discussed.

We examined constancy of release of purified ovine growth hormone from an implant containing soybean oil and bees-wax. Implants contained an amount of growth hormone that was sufficient to increase concentrations in blood plasma by 20 and 40ng/ml and to maintain those concentrations over 1 wk. Growth hormone in plasma increased to approximately 65ng/ml in lambs receiving low dose implants the 1st day after implantation, returned to 31ng/ml on day 2, and remained near this concentration for the remainder of the week. Pulse release of growth hormone was not similar in the high dose lambs where growth hormone concentration in plasma averaged 45ng/ml 1 day after implantation, then gradually increased to 60ng/ml on day 6. Unimplanted control lambs had mean growth hormone concentrations of 2.9 to 3.9ng/ml throughout the 6-day observation. This approach should interest investigators studying the chronic influence of purified or synthetic growth hormone on dairy cows, beef steers, or lambs.

Plasma heating experiments at frequencies near the lower hybrid frequency have been carried out at modest powers (.05 to 4kW). The antenna structure operating at 68 MHz was comprised of two plates driven out of phase on the exterior of the plasma. High electron heating efficiency (greater than 40 percent) in both helium and argon plasmas was observed with only a weak density dependence. At low densities (n/sub e/ less than or equal to 1 x 10$sup 11$ cm$sup -3$), the heating was uniform across the plasma while at higher densities the heating was preferentially on the exterior portion of the plasma. The heating of the exterior of the plasma was found not to correspond to absorption at the lower hybrid resonance layer. The electron heating efficiency was found to be a weak function of rf power when the incident rf power was varied from 1 to 15 times the experimentally observed threshold power for parametric instabilities. Ion temperatures were determined by measuring the Doppler broadening of an Argon ion line using a Fabry-Perot interferometer. Low efficiency main body ion heating (1 to 3 percent) was observed. (auth)

A compilation and analysis of charge exchange ion temperature measurements obtained duriang recent high power neutral beam heating experiments on PLT is presented. For titanium gettered discharges using water-cooled carbon limiters (a = 40 cm), PLT produced ion temperatures up to 6.6 keV (T/sub e/ = 3.5 - 4.0 keV) with 2.4 MW-level neutral deuterium injection into low density hydrogen and deuterium plasmas. Over the beam power (P/sub B/ approx. 0.7 - 2.4 MW) and line average electron density (anti n/sub e/ approx. 1.6 - 3.6 x 10/sup 13/ cm/sup -3/) parameter space thus far explored, the ion temperature increase, ..delta..T/sub i/, is observed to scale according to the empirical relation: ..delta..T/sub i/ (keV) = 4.5 +- 0.5 P/sub B/ (MW)/anti n/sub e/(x 10/sup 13/ cm/sup -3/), where anti n/sub e/ is the line average electron density at peak ion temperature.

The influence of anabolic steroids on growth hormone (GH) secretion in ruminants remains unclear, perhaps because of the dynamic nature of GH secretion. In the present study, blood samples were obtained at 15-min intervals for 12 h from intact ram lambs, ram lambs castrated postpubertally, and castrated ram lambs treated with either testosterone propionate (TP) or diethylstilbestrol (DES). Intact rams exhibited GH secretory episodes of greater (P less than 0.01) amplitude than did castrated lambs. Similarly, mean base-line and mean overall GH concentrations were higher (P less than 0.01) in rams than in castrates. Treatment of castrates with either TP or DES resulted in increased base-line (P less than 0.05) and overall (P less than 0.05) GH concentrations compared to untreated castrates. Although amplitude of GH spikes was larger in TP and DES groups, this difference was not statistically significant (P greater than 0.05). Because numerous studies have demonstrated that intact rams and castrates treated with TP or DES grow faster than untreated castrates, the data in the present study support the hypothesis that the anabolic action of androgens and estrogens is due, at least in part, to their influence on GH secretion.