Targeted Anticancer Immunotoxins and Cytotoxic Agents with Direct Killing Moieties

Despite the progress of the bioinformatics approach to characterize cell-surface antigens and receptors on tumor cells, it remains difficult to generate novel cancer vaccines or neutralizing monoclonal antibody therapeutics. Among targeted cancer therapeutics, biologicals with targetable antibodies or ligands conjugated or fused to toxins or chemicals for direct cell-killing ability have been developed over the last 2 decades. These conjugated or fused chimeric proteins are termed immunotoxins or cytotoxic agents. Two agents, DAB389IL-2 (ONTAKTM) targeting the interleukin-2 receptor and CD33-calicheamicin (Mylotarg®), have been approved by the FDA for cutaneous T-cell lymphoma (CTCL) and relapsed acute myeloid leukemia (AML), respectively. Such targetable agents, including RFB4(dsFv)-PE38 (BL22), IL13-PE38QQR, and Tf-CRM107, are being tested in clinical trials. Several agents using unique technology such as a cleavable adapter or immunoliposomes with antibodies are also in the preclinical stage. This review summarizes the generation, mechanism, and development of these agents. In addition, possible future directions of this therapeutic approach are discussed

Evaluating Large Language Models with NeuBAROCO: Syllogistic Reasoning Ability and Human-like Biases

This paper investigates whether current large language models exhibit biases in logical reasoning, similar to humans. Specifically, we focus on syllogistic reasoning, a well-studied form of inference in the cognitive science of human deduction. To facilitate our analysis, we introduce a dataset called NeuBAROCO, originally designed for psychological experiments that assess human logical abilities in syllogistic reasoning. The dataset consists of syllogistic inferences in both English and Japanese. We examine three types of biases observed in human syllogistic reasoning: belief biases, conversion errors, and atmosphere effects. Our findings demonstrate that current large language models struggle more with problems involving these three types of biases.Comment: To appear in Proceedings of the 4th Natural Logic Meets Machine Learning Workshop (NALOMA IV

Central administration of dipeptides, beta-alanyl-BCAAs, induces hyperactivity in chicks

<p>Abstract</p> <p>Background</p> <p>Carnosine (β-alanyl-L-histidine) is a putative neurotransmitter and has a possible role in neuron-glia cell interactions. Previously, we reported that carnosine induced hyperactivity in chicks when intracerebroventricularly (i.c.v.) administered. In the present study, we focused on other β-alanyl dipeptides to determine if they have novel functions.</p> <p>Results</p> <p>In Experiment 1, i.c.v. injection of β-alanyl-L-leucine, but not β-alanyl-glycine, induced hyperactivity behavior as observed with carnosine. Both carnosine and β-alanyl-L-leucine stimulated corticosterone release. Thus, dipeptides of β-alanyl-branched chain amino acids were compared in Experiment 2. The i.c.v. injection of β-alanyl-L-isoleucine caused a similar response as β-alanyl-L-leucine, but β-alanyl-L-valine was somewhat less effective than the other two dipeptides. β-Alanyl-L-leucine strongly stimulated, and the other two dipeptides tended to stimulate, corticosterone release.</p> <p>Conclusion</p> <p>These results suggest that central β-alanyl-branched chain amino acid stimulates activity in chicks through the hypothalamus-pituitary-adrenal axis. We named β-alanyl-L-leucine, β-alanyl-L-isoleucine and β-alanyl-L-valine as Excitin-1, Excitin-2 and Excitin-3, respectively.</p

Effect of L-ornithine hydrochloride ingestion on intermittent maximal anaerobic cycle ergometer performance and fatigue recovery after exercise

L-Ornithine plays an important role in ammonia metabolism via the urea cycle. This study aimed to examine the eVect of L-ornithine hydrochloride ingestion on ammonia metabolism and performance after intermittent maximal anaerobic cycle ergometer exercise. Ten healthy young adults (age, 23.8 ± 3.9 year; height, 172.3 ± 5.5 cm; body mass, 67.7 ± 6.1 kg) with regular training experience ingested L-ornithine hydrochloride (0.1 g/kg, body mass) or placebo after 30 s of maximal cycling exercise. Five sets of the same maximal cycling exercise were conducted 60 min after ingestion, and maximal cycling exercise was conducted after a 15 min rest. The intensity of cycling exercise was based on each subject\u27s body mass (0.74 N kg -1). Work volume (watt), peak rpm (rpm) before and after intermittent maximal ergometer exercise and the following serum parameters were measured before ingestion, immediately after exercise and 15 min after exercise: ornithine, ammonia, urea, lactic acid and glutamate. Peak rpm was signiWcantly greater with L-ornithine hydrochloride ingestion than with placebo ingestion. Serum ornithine level was signiWcantly greater with L-ornithine hydrochloride ingestion than with placebo ingestion immediately and 15 min after intermittent maximal cycle ergometer exercise. In conclusion, although maximal anaerobic performance may be improved by L-ornithine hydrochloride ingestion before intermittent maximal anaerobic cycle ergometer exercise, the above may not depend on increase of ammonia metabolism with L-ornithine hydrochloride. © 2011 Springer-Verlag

The effect of L-ornithine hydrochloride ingestion on performance during incremental exhaustive ergometer bicycle exercise and ammonia metabolism during and after exercise

金沢大学人間社会研究域人間科学系Fukui National College of TechnologyObjectives:L-ornithine has an important role in ammonia metabolism via the urea cycle. This study aimed to examine the effect of L-ornithine hydrochloride ingestion on performance during incremental exhaustive ergometer bicycle exercise and ammonia metabolism during and after exercise.Subjects/Methods:In all, 14 healthy young adults (age: 22.2±1.0 years, height: 173.5±4.6 cm, body mass: 72.512.5 kg) who trained regularly conducted incremental exhaustive ergometer bicycle exercises after-ornithine hydrochloride supplementation (0.1 g/kg, body mass) and placebo conditions with a cross-over design. The exercise time (sec) of the incremental ergometer exercise, exercise intensity at exhaustion (watt), maximal oxygen uptake (ml per kg per min), maximal heart rate (beats per min) and the following serum parameters were measured before ingestion, 1 h after ingestion, just after exhaustion and 15 min after exhaustion: ornithine, ammonia, urea, lactic acid and glutamate. All indices on maximal aerobic capacity showed insignificant differences between both the conditions.Results:Plasma ammonia concentrations just after exhaustion and at 15 min after exhaustion were significantly more with ornithine ingestion than with placebo. Plasma glutamate concentrations were significantly higher after exhaustion with ornithine ingestion than with placebo.Conclusions:It was suggested that, although the ingestion of L-ornithine hydrochloride before the exercise cannot be expected to improve performance, it does increase the ability to buffer ammonia, both during and after exercise. © 2010 Macmillan Publishers Limited All rights reserved

Effects of transcutaneous electrical nerve stimulation on physical symptoms in advanced cancer patients receiving palliative care

Transcutaneous electrical nerve stimulation (TENS) is primarily used for pain, butmight be useful for various other physical symptoms, including nausea, fatigue,dyspnea, and constipation. However, few studies have used TENS for treating thephysical symptoms of patients with advanced cancer. In this crossover trial, we assessthe effects of TENS on pain and other physical symptoms in 20 in-patients withadvanced cancer receiving palliative care. For 5-day phases between wash out periodsof 5 days, patients received TENS or non-TENS. TENS was delivered at four points: thecenter of the back for mainly nausea and dyspnea, on the back at the same dermatomallevel as the origin of the pain (100 Hz), and on both ankle joints for constipation (10Hz). The intensity of pain and the total opioid dose used during phases were recorded.Physical symptoms were evaluated using the European Organization for Research andTreatment of Cancer (EORTC) Quality of Life Questionnaire Core 15 Palliative Care(QLQ-C15-PAL). Hematological and biochemical data were recorded before and afterthe TENS phase. The average pain and total number of opioid rescue doses weresignificantly reduced by TENS. TENS tended to improve nausea and appetite loss, butnot constipation. There were no effects on hematological and biochemical parameters.Use of TENS could safely improve pain, nausea, and appetite loss in patients withadvanced cancer. Although it cannot be used as a substitute for opioids and otherpharmaceutical treatment, it may be useful to support palliative care

Qualitative Simulation for Early-Stage Service Design

Currently, the importance of services is widely accepted in various industries. Given this background, fundamental research on service engineering is carried out quite actively. Service engineering seeks to provide design methodology for services from an engineering perspective. In product and service design, designers are generally forced to spend a lot of redesign works if design changes occur at a late stage of the design process. Thus, it is important for designers to validate design solutions in the early stage(s) of the design process by using simulation methods. However, simulation models in the existing methods are built with quantitative information. In the early stages of the service design process, most of the information about a design solution is still not defined; therefore, it is difficult to obtain sufficient quantitative information. For obtaining such quantitative information, service providers need to offer a designed service to their customers as a trial, which impose much effort for building quantitative simulation models. In order to reduce such risks, this research applies a qualitative simulation method, which can be used to analyze the behavior of systems with fuzzy qualitative information. In this paper, we propose a method to build a qualitative simulation model with the design information available at the early stage(s) of the service design process. This method would enable designers to evaluate a design solution in the early stage of a service design process and would increases quality of the service design.サービス学会主催 The 3rd International Conference on Serviceology (ICServ 2015) July 7-9, 2015 in San Jose, CA, USA

Influence of Diabetes Mellitus on Surgical Outcomes in Patients with Cervical Myelopathy: A Prospective, Multicenter Study

[Study Design] Multicenter, prospective study. [Purpose] To investigate the effects of diabetes mellitus (DM) on surgical outcomes in patients with cervical myelopathy. [Overview of Literature] To date, few studies have investigated the influence of postoperative blood glucose or glycated hemoglobin (HbA1c) levels on surgical outcomes. [Methods] The participants were patients who underwent surgery for the treatment of cervical spondylotic myelopathy and ossification of the posterior longitudinal ligament. The 61 cases were evaluated preoperatively and 1 year postoperatively using the Japanese Orthopaedic Association (JOA) scores and the JOA Cervical Myelopathy Evaluation Questionnaire (JOACMEQ). The study variables included fasting blood glucose and HbA1c levels measured preoperatively and at 1 week, 4 weeks, and 1 year postoperatively; the F-wave conduction velocity, latency, rate of occurrence, and M-wave latency in the ulnar and tibial nerves were measured preoperatively and at 1 year postoperatively. The patients were divided into a group without diabetes (N group, 42 patients) and a group with diabetes (DM group, 19 patients). We then assessed the associations between the surgical outcomes and each of the study variables. [Results] JOA scores significantly improved in both groups; however, no significant between-group differences were found. There was no significant improvement in the JOACMEQ scores, which assessed cervical function, upper and lower limb function, and bladder function in both groups. We then subdivided the DM group into those with a good control of HbA1c after 1 year (DMG group, 12 patients) and those with HbA1c deterioration after 1 year (DMB group, seven patients), prior to comparing the surgical outcomes. The JOACMEQ scores for upper and lower limb function significantly improved in the DMG group (p<0.01). Compared with the DMB group, there were no significant increases in upper or lower limb function scores in the DMG group. [Conclusions] Poor glycemic control might prevent postoperative functional recovery of the spinal cord

Possible chiral phase transition in two-dimensional solid 3^3He

We study a spin system with two- and four-spin exchange interactions on the triangular lattice, which is a possible model for the nuclear magnetism of solid $^3$He layers. It is found that a novel spin structure with scalar chiral order appears if the four-spin interaction is dominant. Ground-state properties are studied using the spin-wave approximation. A phase transition concerning the scalar chirality occurs at a finite temperature, even though the dimensionality of the system is two and the interaction has isotropic spin symmetry. Critical properties of this transition are studied with Monte Carlo simulations in the classical limit.Comment: 4 pages, Revtex, 4 figures, to appear in Phys.Rev.Let

Development of UV-responsive catch-and-release system of a cysteine protease model peptide

Cysteine proteases are attractive drug targets due to their involvement in a wide variety of diseases. To evaluate the potential of a particular protease as a drug target, use of a reagent that controls activity of the protease is indispensable. In this context, we have developed a catch-and-release reagent that first forms a covalent bond with the active center thiol of a cysteine protease to suppress its activity and then is removed by UV-irradiation to release the parent active protease. In this paper, the design and synthesis of a catch-and-release reagent of thiols are described. Its application to caging (catch) and UV-induced uncaging (release) of a model peptide derived from an active site of caspase-9 and introduction of a recognition moiety on the reagent are also reported