Speech Communication

Contains reports on five research projects.U. S. Air Force (Electronic Systems Division) under Contract AF 19(628)-3325National Science Foundation (Grant GP-Z495)National Institutes of Health (Grant MH-04737-04)National Institutes of Health (Grant NB-0433Z-02)National Aeronautics and Space Administration (Grant NsG-496

Anti-tubulin drugs conjugated to anti-ErbB antibodies selectively radiosensitize.

Tumour resistance to radiotherapy remains a barrier to improving cancer patient outcomes. To overcome radioresistance, certain drugs have been found to sensitize cells to ionizing radiation (IR). In theory, more potent radiosensitizing drugs should increase tumour kill and improve patient outcomes. In practice, clinical utility of potent radiosensitizing drugs is curtailed by off-target side effects. Here we report potent anti-tubulin drugs conjugated to anti-ErbB antibodies selectively radiosensitize to tumours based on surface receptor expression. While two classes of potent anti-tubulins, auristatins and maytansinoids, indiscriminately radiosensitize tumour cells, conjugating these potent anti-tubulins to anti-ErbB antibodies restrict their radiosensitizing capacity. Of translational significance, we report that a clinically used maytansinoid ADC, ado-trastuzumab emtansine (T-DM1), with IR prolongs tumour control in target expressing HER2+ tumours but not target negative tumours. In contrast to ErbB signal inhibition, our findings establish an alternative therapeutic paradigm for ErbB-based radiosensitization using antibodies to restrict radiosensitizer delivery

A questionnaire based study on the knowledge, attitude, and the practice of ecopharmacology among the healthcare professionals in a teaching hospital in India

Background: Ecopharmacology which deals with the health hazards posed by discarded or used medicinal products in the environment, is a globally emerging issue. There are guidelines for pharmaceutical waste management (Like GMP and FDA guidelines) for the manufacturing units, pharmacists and consumers. However, it is uncertain whether consumers are aware of it. Before beginning the process of creating awareness, it is first necessary to assess the existing knowledge of the issue in the community. This study was planned to assess the knowledge, attitude and practice (KAP) of ecopharmacology in the medical personnel and students in our institute.Methods: It was a questionnaire based cross-sectional observational study. Study population included MBBS students, nursing students and resident doctors. Total 500 consenting participants were enrolled and subjected to a structured KAP questionnaire and data was expressed in percentage. Questionnaire consisted of 20 questions out of which 3 were open ended and remaining closed ended.Results: Present study result showed that 73% respondents had heard of term ecopharmacology and majority (98%) felt that it was their responsibility to protect environment from pharmaceutical waste. Responses from 83% of participants indicated that they were worried about the excess medicines at their homes. 87% of participants threw it in garbage bin, but (58%) were unsure whether their drug disposing method was safe and 25 % knew it was unsafe. Most respondents (94%) felt that there should be guidelines for safe disposal of expired/unused drug and were enthusiastic about participating in campaign for this issue. Medical personnel also suggested some solutions to deal with this problem.Conclusions: Awareness and concern regarding the problem is high however in absence of knowledge of methods of safe disposal of unused drug, it is not transforming into safe disposal practices

A phase II study of dacetuzumab (SGN-40) in patients with relapsed diffuse large B-cell lymphoma (DLBCL) and correlative analyses of patient-specific factors

BACKGROUND: Patients with DLBCL who are ineligible for or have relapsed after aggressive salvage chemotherapy have a poor prognosis. CD40 is expressed on multiple B-cell neoplasms including DLBCL and is a potential target for immunotherapy. Dacetuzumab (SGN-40), a non-blocking, partial agonist, humanized IgG1, anti-CD40 monoclonal antibody, has previously demonstrated anti-lymphoma activity in a phase I study. METHODS: A phase II study was undertaken to evaluate the rate and duration of objective responses and safety of single-agent dacetuzumab in relapsed DLBCL. Forty-six adult patients with relapsed/refractory DLBCL received up to 12 cycles of intravenous dacetuzumab using intrapatient dose-escalation to a target dose of 8 mg/kg/week in an initial 5-week cycle, followed by 4-week cycles of 8 mg/kg/week. Study endpoints included rate and duration of objective responses, safety, survival, pharmacokinetics, immunogenicity, and exploratory correlative studies. RESULTS: Overall response rate was 9% and disease control rate (complete remission + partial remission + stable disease) was 37%. Common non-hematologic adverse events (AEs) included fatigue, headache, chills, fever, and nausea. The most frequent Grade 3–4 non-hematologic AE was deep venous thrombosis (3 patients). Grade 3–4 lymphopenia (41%), neutropenia (13%), or thrombocytopenia (19%) occurred without associated infection or bleeding. Reversible ocular events, including conjunctivitis and ocular hyperemia, occurred in 8 patients (17%). Patient-specific factors, including Fc-gamma-RIIIa polymorphism, did not appear to correlate with antitumor activity. CONCLUSIONS: Single-agent dacetuzumab has modest activity and manageable toxicity in unselected patients with relapsed DLBCL. Combination regimens and robust methods of patient selection may be necessary for further development. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00435916

Physical activity assessments in obese and non-obese adolescents using the Bouchard diary

Background Obesity is now a global epidemic problem. Increased prevalence of obesity is associated with increased sedentary behavior and low physical activity.\ud \ud Objective To assess the physical activity patterns of adolescents aged 10-15 years and to compare mean energy output, intensity of physical activity, duration of moderate-vigorously intensity of physical activity, and length of screen time in obese and non-obese adolescents.\ud \ud Methods This cross-sectional study was conducted on 7th and 8th grade students aged 12-15 years at 216 junior high schools in West Jakarta. Physical activity was assessed using the Bouchard diary for 2 school days and 1 holiday.\ud \ud Results There was no significant difference in mean energy output between the obese and non-obese adolescents. The median intensity of physical activity of obese adolescents was lower than that of non-obese adolescents [1.5 (range 0.8 to 1.8) vs. 2 (range 1.6 to 2.8) METs, respectively; P <0.001]. The mean duration of moderate-vigorous intensity of physical activity in obese adolescents was shorter than that of non-obese adolescents [19.3 (SD 6.9) vs. 26.4 (SD 3.4) minutes, respectively; P=0.000]. Median length of screen time was longer for obese adolescents than for non-obese adolescents [2.8 (range 1 to 6.6) vs. 1.8 (range 0.3 to 6.1) hours, respectively; P <0.001]. There was no adolescent who met the recommended physical activity intensity and duration criteria.\ud \ud Conclusion Physical activity varies among adolescents aged 10-15 years. Obese adolescents have significantly less physical activity duration and intensity than non-obese adolescents, but significantly longer screen time. All adolescents’ physical activity is less than the recommended intensity and duration

Peningkatan Prestasi Belajar CAD Mahasiswa Teknik Otomotif Non-Reguler FT UNY melalui Pembuatan “Pohon Kata” Perintah dalam Program AutoCAD

Penelitian ini bertujuan meningkatkan prestasi belajar mata kuliah Computer Aided Design (CAD) mahasiswa prodi Teknik Otomotif Non-Reguler yang dinyatakan dalam bentuk rerata nilai akhir semester yang berasal dari komponen nilai tugas harian, nilai ujian tengah semester dan nilai ujian akhir semester. Penelitian quasi-eksperimen ini terdiri dari tahapan penelitian diawali dengan penyusunan materi pembelajaran sejumlah pokok bahasan tertentu dalam satu job sheet (lembar kerja), dilanjutkan dengan pembuatan bantuan “Pohon Kata” perintah dalam Auto CAD kepada kelas eksperimen yang ditentukan secara random dari dua kelas peserta kuliah Auto CAD pada Semester Genap 2008/2009. Kedua kelas diamati prestasinya, baik kecepatan penyelesaiannya maupun kualitas kebenaran gambarnya. Prestasi belajar kedua kelas juga diukur melalui pemberian ujian tengah semester dan ujian akhir semester. Setelah data prestasi kedua kelas terkumpul dilanjutkan dengan analisis statistik melalui uji beda (t-test) setelah sebelumnya dilakukan uji persyaratan analisis yang ternyata dapat dipenuhi. Hasil penelitian ini disimpulkan bahwa: prestasi belajar CAD mahasiswa pada kelas yang diberi perlakuan strategi pembelajaran menggunakan “Pohon Kata” perintah dalam Program Auto CAD lebih baik dibanding prestasi belajar CAD mahasiswa pada kelas yang tidak diberi perlakuan (75,41>70,89), dengan demikian pembelajaran CAD menggunakan media “Pohon Kata” perintah dalam Program Auto CAD dapat meningkatkan prestasi belajar mahasiswa Teknik Otomotif Program Non-Reguler

A Real-Coded Hybrid Genetic Algorithm to Determine Optimal Resin Injection Locations in the Resin Transfer Molding Process

Real number-coded hybrid genetic algorithms for optimal design of resin injection locations for the resin transfer molding process are evaluated in this paper. Resin transfer molding (RTM) is widely used to manufacture composite parts with material and geometric complexities, especially in automotive and aerospace sectors. The sub-optimal location of the resin injection locations (gates) can leads to the formation of resin starved regions and require long mold fill times, thus affecting the part quality and increasing manufacturing costs. There is a need for automated design algorithms and software that can determine the best gate and vent locations for a composite part by using the current simulation capabilities. In the work presented here, the gates are encoded into real number strings for the GA. A sensitivity gradient-based fill time optimization algorithm was developed using the process physics, which can be used as a local optimization algorithm. The global search capabilities of the GA and the local search capabilities of the sensitivity gradient-based fill time optimization algorithm were combined in two separate hybrid optimization algorithms: a serial hybrid optimization algorithm and an interactive optimization algorithm. In addition, the sensitivity gradient-based algorithm involves the computation of the gradient of the fill time with respect to the gate location coordinates. This gradient information was included in the criteria for optimization to increase the capabilities of the hybrid GA. Several RTM molds with geometric and material complexities were selected and discretized. A number of studies were performed using the pure genetic algorithm, the gradient-based optimization algorithm and the two hybrid optimization algorithms using the mold fill time and it's gradient with respect to gate location coordinates as the cost criteria. These studies were performed for the cases of a single gate and two gates. The results were benchmarked against known best solutions in terms of quality of final solutions and the computational effort required

Assessment of ibrutinib plus rituximab in front-line CLL (FLAIR trial): study protocol for a phase III randomised controlled trial

Background Treatment of chronic lymphocytic leukaemia (CLL) has seen a substantial improvement over the last few years. Combination immunochemotherapy, such as fludarabine, cyclophosphamide and rituximab (FCR), is now standard first-line therapy. However, the majority of patients relapse and require further therapy, and so new, effective, targeted therapies that improve remission rates, reduce relapses, and have fewer side effects, are required. The FLAIR trial will assess whether ibrutinib plus rituximab (IR) is superior to FCR in terms of progression-free survival (PFS). Methods/design FLAIR is a phase III, multicentre, randomised, controlled, open, parallel-group trial in patients with previously untreated CLL. A total of 754 participants will be randomised on a 1:1 basis to receive standard therapy with FCR or IR. Participants randomised to FCR will receive a maximum of six 28-day treatment cycles. Participants randomised to IR will receive six 28-day cycles of rituximab, and ibrutinib taken daily for 6 years until minimal residual disease (MRD) negativity has been recorded for the same amount of time as it took to become MRD negative, or until disease progression. The primary endpoint is PFS according to the International Workshop on CLL (IWCLL) criteria. Secondary endpoints include: overall survival; proportion of participants with undetectable MRD; response to therapy by IWCLL criteria; safety and toxicity; health-related quality of life (QoL); and cost-effectiveness. Discussion The trial aims to provide evidence for the future first-line treatment of CLL patients by assessing whether IR is superior to FCR in terms of PFS, and whether toxicity rates are favourable. Trial registration ISRCTN01844152. Registered on 8 August 2014, EudraCT number 2013-001944-76. Registered on 26 April 2013

Altered Ca(2+ )homeostasis in polymorphonuclear leukocytes from chronic myeloid leukaemia patients

BACKGROUND: In polymorphonuclear leukocytes (PMNL), mobilization of calcium ions is one of the early events triggered by binding of chemoattractant to its receptors. Besides chemotaxis, a variety of other functional responses are dependent on calcium ion mobilization. PMNL from chronic myeloid leukaemia (CML) patients that were morphologically indistinguishable from normal PMNL were found to be defective in various functions stimulated by a chemoattractant – fMLP. To study the mechanism underlying defective functions in CML PMNL, we studied calcium mobilization in CML PMNL in response to two different classical chemoattractants, fMLP and C5a. RESULTS: Release of calcium estimated by flow cytometry and spectrofluorimetry using fluo-3 as an indicator showed that the [Ca(2+)](i )levels were lower in CML PMNL as compared to those in normal PMNL. But, both normal and CML PMNL showed maximum [Ca(2+)](i )in response to fMLP and C5a at 10 sec and 30 sec, respectively. Spectrofluorimetric analysis of the total calcium release in chemoattractant treated PMNL indicated more and faster efflux of [Ca(2+)](i )in CML PMNL as compared to normal PMNL. CONCLUSION: Fine-tuning of Ca(2+ )homeostasis was altered in CML PMNL. The altered Ca(2+ )homeostasis may contribute to the defective functions of CML PMNL