Safety, tolerability, and potential clinical activity of a glucocorticoid-induced TNF receptor-related protein agonist alone or in combination with nivolumab for patients with advanced solid tumors: a phase 1/2a dose-escalation and cohort-expansion clinical trial

Importance: Multiple immunostimulatory agonist antibodies have been clinically tested in solid tumors to evaluate the role of targeting glucocorticoid-induced tumor necrosis factor (TNF) receptor-related protein in anticancer treatments. Objective: To evaluate the safety and activity of the fully human glucocorticoid-induced TNF receptor-related protein agonist IgG1 monoclonal antibody BMS-986156 with or without nivolumab in patients with advanced solid tumors. Design, Setting, and Participants: This global, open-label, phase 1/2a study of BMS-986156 with or without nivolumab enrolled 292 patients 18 years or older with advanced solid tumors and an Eastern Cooperative Oncology Group performance status of 1 or less. Prior checkpoint inhibitor therapy was allowed. Monotherapy and combination dose-escalation cohorts ran concurrently to guide expansion doses beginning October 16, 2015; the study is ongoing. Interventions: The protein agonist BMS-986156 was administered intravenously at a dose of 10, 30, 100, 240, or 800 mg every 2 weeks as monotherapy, and in the combination group 30, 100, 240, or 800 mg plus 240 mg of nivolumab every 2 weeks; same-dose cohorts were pooled for analysis. One cohort also received 480 mg of BMS-986156 plus 480 mg of nivolumab every 4 weeks. Main Outcomes and Measures: The primary end points were safety, tolerability, and dose-limiting toxic effects. Additional end points included antitumor activity per Response Evaluation Criteria in Solid Tumors, version 1.1, and exploratory biomarker analyses. Results: With a follow-up range of 1.4 to 101.7 weeks (follow-up ongoing), 34 patients (16 women and 18 men; median age, 56.6 years [range, 28-75 years]) received monotherapy (4 patients completed initial treatment), and 258 patients (140 women and 118 men; median age, 60 years [range, 21-87 years]) received combination therapy (65 patients completed initial treatment). No grade 3 to 5 treatment-related adverse events occurred with BMS-986156 monotherapy; grade 3 to 4 treatment-related adverse events occurred in 24 patients (9.3%) receiving BMS-986156 plus nivolumab, with no grade 5 treatment-related adverse events. One dose-limiting toxic effect (grade 4 elevated creatine phosphokinase levels) occurred in a patient receiving 800 mg of BMS-986156 plus 240 mg of nivolumab every 2 weeks; BMS-986156 with or without nivolumab exhibited linear pharmacokinetics with dose-related increase after a single dose. Peripheral T-cell and natural killer-cell proliferation increased after administration of BMS-986156 with or without nivolumab. No consistent and significant modulation of intratumoral CD8+ T cells and FoxP3+ regulatory T cells was observed. No responses were seen with BMS-986156 alone; objective response rates ranged from 0% to 11.1% (1 of 9) across combination therapy cohorts, with a few responses observed in patients previously treated with anti-programmed death receptor (ligand) 1 therapy. Conclusions and Relevance: Based on this cohort, BMS-986156 appears to have had a manageable safety profile, and BMS-986156 plus nivolumab demonstrated safety and efficacy comparable to historical data reported for nivolumab monotherapy. Trial Registration: ClinicalTrials.gov identifier: NCT02598960

Is Malaysia’s banded langur, Presbytis femoralis femoralis, actually Presbytis neglectus neglectus? Taxonomic revision with new insights on the radiation history of the Presbytis species group in Southeast Asia

The disjunct distribution of Presbytis femoralis subspecies across Sumatra (P. f. percura), southern (P. f. femoralis) and northern (P. f. robinsoni) Peninsular Malaysia marks the unique vicariance events in the Sunda Shelf. However, the taxonomic positions and evolutionary history of P. f. femoralis are unresolved after decades of research. To elucidate this evolutionary history, we analyzed 501 base pairs of the mitochondrial HVSI gene from 25 individuals representing Malaysia’s banded langur, with the addition of 29 sequences of Asian Presbytis from Genbank. Our results revealed closer affinity of P. f. femoralis to P. m. mitrata and P. m. sumatrana while maintaining the monophyletic state of P. f. femoralis as compared to P. f. robinsoni. Two central theses were inferred from the results; (1) P. f. femoralis does not belong in the same species classification as P. f. robinsoni, and (2) P. f. femoralis is the basal lineage of the Presbytis in Peninsular Malaysia. Proving the first hypothesis through genetic analysis, we reassigned P. f. femoralis of Malaysia to Presbytis neglectus (Schlegel’s banded langur) (Schlegel in Revue Methodique, Museum d’Histoire Naturelle des Pays-Bas 7:1, 1876) following the International Code of Zoological Nomenclature (article 23.3). The ancestors of P. neglectus are hypothesized to have reached southern Peninsular Malaysia during the Pleistocene and survived in refugium along the western coast. Consequently, they radiated upward, forming P. f. robinsoni and P. siamensis resulting in the highly allopatric distribution in Peninsular Malaysia. This study has successfully resolved the taxonomic position of P. neglectus in Peninsular Malaysia while providing an alternative biogeographic theory for the Asian Presbytis

Dominant culture and bullying : personal accounts of workers in Malaysia

Workplace bullying has been termed the cancer of the workplace; it is a widespread and often intractable problem. Internationally, a wealth of research has examined the prevalence of workplace bullying and its negative effects. This research base and the scientific definition of workplace bullying are, however, based on Western perspectives and supported by theories, models, and research studies conducted in Western cultures. The differences in cultural perspectives of Western and Eastern countries mean that workplace bullying may not be understood in the same way across different cultural groups, particularly when cultures differ along the Individualism-Collectivism dimension. Given that Malaysia is an Eastern country with a number of ethnic groups, a more comprehensive understanding of workplace bullying in the Malaysian context is important. Through a case study comprising in-depth qualitative interviews with 20 employees from different organisations in Malaysia, this chapter reveals six lay beliefs of workplace bullying and 19 lay beliefs about bullying behaviors. The study also found that the 12 bullying behaviors are work related while the other seven are personal-nature bullying behaviors. These results emphasize the influence of culture on how bullying is perceived within the Malaysian context, and the importance of understanding lay representations of workplace bullying from the Eastern context that apparent across nation. Based on the interviews, a general definition of workplace bullying from Malaysian employees' perspectives is presented and developed. The chapter concludes with implications for understanding bullying as an important psychosocial hazard at work and recommendations for future research and practice across the Asia Pacific region

Influence of Room-Temperature Ionic Liquids on the Electrosynthesis of CuBDC Type Metal-Organic Frameworks: Crystallite Size and Productivity

The influence of imidazolium- and ammonium-based room-temperature ionic liquids (RTILs) i.e., [bmim][BF₄], [bmim][DCA], and MTBS, respectively, as electrolytes on the crystallite size and productivity of CuBDC (BDC=1,4-benzenedicarboxylate) type metal-organic frameworks (MOFs) by electrosynthesis method via anodic dissolution was investigated. CuBDC was characterized by Fourier transform infrared spectroscopy (FTIR), powder X-ray diffraction (PXRD), scanning electron microscopy (SEM), thermogravimetric analysis (TGA), and nitrogen physisorption. The crystallite size and productivity of CuBDC using [bmim][BF₄], [bmim][DCA], MTBS as electrolytes were 24.7 nm, 22.1 nm, 20.5 nm, and 236 mg/h, 69 mg/h, 291 mg/h, respectively. Bulkier structure of ammonium-based RTILs resulted CuBDC with a smaller crystallite size and higher productivity compared to imidazolium-based RTILs

Alinhamento entre estrutura organizacional de projetos e estratégia de manufatura: uma análise comparativa de múltiplos casos Alignment between project management organizational structure and manufacture strategy: a comparative analysis of multiple cases

O principal objetivo deste trabalho é estabelecer uma relação entre a estrutura de gerenciamento de projetos de uma organização e sua estratégia de manufatura. Pretende-se verificar também se existe um alinhamento entre a configuração da estrutura organizacional e o tipo de estratégia de manufatura de uma organização. A abordagem metodológica utilizada foi o estudo de múltiplos casos, realizado em três empresas dos setores de cosméticos, eletro-eletrônico e aeroespacial. Os principais resultados apontam para estruturas mais complexas de gerenciamento de projetos à medida que se caminha no continuum entre volume e variedade.<br>The main goal of this paper is to establish a relation between the project management organization for a company and its manufacture strategy. Another objective is also to verify whether there is an alignment between the configuration of the organizational structure and the model of the manufacture strategy for a company. The methodological approach used was the multiple cases analysis conducted in three companies of the cosmetics, electronic, and airspace sectors. The main results point to more complex project management structures in the process along the continuum between volume and variety

Randomized Study of Double Cord Blood Transplantation (CBT) with Versus without Ex-Vivo Expansion (EXP)

Abstract The use of CB for stem cell transplantation is increasing. A major disadvantage of CB is delayed and failed engraftment when compared to marrow or blood transplantation. Double CBT and ex-vivo expansion are both strategies being investigated in order to improve hematopoietic reconstitution. We compared these approaches with the aim of improving the clinical outcomes of CBT patients. 48 patients were randomized to receive either two unmanipulated (UNM) CB units (N=24) or one UNM unit and one unit from which all the cells were EXP ex-vivo (N=24). Most CB units were HLA 4/6 matches. Diagnoses were AML (N=16), ALL(N=13), NHL(N= 5), HD(N=7), CML (N=5), and CLL(N=2). Patients (Table 1) were heavily pre-treated, with a median of 3 (1–8) prior regimens including autotransplants in 18%. Preparative regimens included ATG and either fludara plus dose-adjusted busulfan(N=13; myeloid diseases), or melphalan and thiotepa (N=21; lymphoid malignancies/HD); patients not eligible for high-dose therapy received non-myeloablative fludara plus cyclophosphamide and 200 GyTBI (=11) or melphalan(n=3). GVHD prophylaxis was tacrolimus plus either 3 doses of 5 mg/m2 methotrexate or MMF (table 1). Ex-vivo expansion: the smallest unit was CD133-selected using the CliniMACS device (day -14). The T cell-containing CD133-negative fraction was frozen. The CD133+ fraction was cultured for 14 days in media containing SCF, G-CSF and TPO. On day 0, the 2nd UNM unit was infused, followed by the CD133-negative and the EXP fractions. Results. Infused median total nucleated cells (TNC)×108/Kg was 0.36 and 0.36, and median CD34×106/Kg was 0.16 and 0.13, respectively for EXP and UNM pts. Median TNC fold-expansion was 26 (0.44–275) and for CD34+ cells, 2.2 (0–18). There was a nonsignificant trend to more rapid engraftment in patients receiving EXP cells. Patients with >50-fold versus 20K/ul at a median of 29 days(17–44) versus 42(29–56). 25 patients are alive [median follow up is 11.1 mo (2–33.6)]. 100-day and 1-year non-relapse mortality rates are 10% and 22%, respectively (table 2). Chimerism showed that 1 CB unit dominated in all patients. Among 19 evaluable EXP patients, in 63% the UNM unit provided 100% of the hematopoiesis from day +30; the EXP unit was predominant in 3 cases (for 12, 2 and 2 mo.) and present but not predominant in 4 (5–25%, for 12, 7, 3 and 3 mo). Conclusion: EXP CBT was safe. The range of fold-expansion was highly variable. Accrual continues focusing on strategies which improve CB expansion. Outcomes Expanded Unmanipulated P C.Incid.: cumulative incidence Time to ANC500 (median/95%CI) 20 days (15, 31) 23.5 (21, 34) 0.4 Proportion engrafting ANC500 82% (n=19) 79% (n=19) 1 Time to PLT20K (median/95%CI) 41 (32, NA) 54 (40, NA) 0.4 Proportion engrafting PLT 67% (n=16) 58% (n=14) 0.38 1-year survival 60% 40% 0.45 aGVHD gd II–IV/ III–IV 32% / 5% 41% / 9% NS C.Incid. cGVHD 47% (28–78) 31% (15–65) NS Expanded Unmanipulated P Complete remission at UCBT 42% 67% 0.15 Median weight 82 (20-113) 76 (51-144) 0.6 Median age 40.4 (4-66) 38.1 (9-65) 0.8 Ablative preparative regimen 67% 75% 0.8 GVHD prophylaxis with methotrexate 48% 48% N