A phase 2 study of ibrutinib in combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma

Objective: We evaluated ibrutinib, a once-daily inhibitor of Bruton's tyrosine kinase, combined with bortezomib and dexamethasone in patients with relapsed or relapsed/refractory multiple myeloma who had received 1-3 prior therapies. Methods: This was a phase 2, single-arm, open-label, multicentre study (NCT02902965). The primary endpoint was progression-free survival (PFS). Results: Seventy-six patients were enrolled; 74 received ≥1 dose of study treatment. After median follow-up of 19.6 months, median PFS was 8.5 months (95% CI: 6.2-10.8); median overall survival was not reached. Overall response rate was 57% (95% CI: 45-68), and median duration of response was 9.5 months (95% CI: 6.9-10.6). Grade 3/4 AEs occurred in 73% of patients and fatal AEs occurred in 15% of patients. Incidence of major haemorrhage was 5%; one patient died from cerebral haemorrhage. After an observed increased incidence of serious (42%) and fatal (11%) infections, enrolment was suspended to implement risk-minimisation measures. The safety profile was otherwise consistent with known safety profiles of the individual drugs. Conclusion: Ibrutinib combined with bortezomib and dexamethasone elicited clinical responses. However, efficacy assessments conducted at potential restart of enrolment indicated that the targeted PFS could not be reached with additional patient enrolment, and the study was terminated

Hepatocyte-like cells differentiated from methylmalonic aciduria cblB type induced pluripotent stem cells: A platform for the evaluation of pharmacochaperoning

Methylmalonic aciduria cblB type (MMA cblB type, MMAB OMIM #251110), caused by a deficiency in the enzyme ATP:cob(I)alamin adenosyltransferase (ATR, E.C_2. 5.1.17), is a severe metabolic disorder with a poor prognosis despite treatment. We recently described the potential therapeutic use of pharmacological chaperones (PCs) after increasing the residual activity of ATR in patient-derived fibroblasts. The present work reports the successful generation of hepatocyte-like cells (HLCs) differentiated from two healthy and two MMAB induced pluripotent stem cell (iPSC) lines, and the use of this platform for testing the effects of PCs. The MMAB cells produced little ATR, showed reduced residual ATR activity, and had higher concentrations of methylmalonic acid compared to healthy HLCs. Differential proteome analysis revealed the two MMAB HCLs to show reproducible differentiation, but this was not so for the healthy HLCs. Interestingly, PC treatment in combination with vitamin B12 increased the amount of ATR available, and subsequently ATR activity, in both MMAB HLCs. More importantly, the treatment significantly reduced the methylmalonic acid content of both. In summary, the HLC model would appear to be an excellent candidate for the pharmacological testing of the described PCs, for analyzing the effects of new drugs, and investigating the repurposing of older drugs, before testing in animal modelsThis work was funded by the Fundacion ´ Isabel Gemio-Fundaci´ on La Caixa [LCF/PR/PR16/11110018], the Instituto de Salud Carlos III (ISCIII),-European Regional Development Fund [PI19/01155] and the Consejería de Educaci´ on, Juventud y Deporte, Comunidad de Madrid [B2017/BMD3721

Improving Sales through Inventory Reduction: A Retail Chain Case Study

Today's challenging business environment, with unpredictable demand and volatility, requires a supply chain strategy that handles uncertainty and risks in the right way. Even though inventory models have been previously explored, this paper seeks to apply these concepts on a practical situation. This study involves the inventory replenishment problem, applying techniques that are mainly based on mathematical assumptions and modeling. The primary goal is to improve the retailer’s supply chain processes taking store differences when setting the various target stock levels. Through inventory review policy, picking piece implementation and minimum exposure definition, we were able not only to promote the inventory reduction as well as improve sales results. The inventory management theory from literature review was then tested on a single case study regarding a particular department in one of the largest Latam retail chains

Generation and characterization of two human iPSC lines from patients with methylmalonic acidemia cblB type

Two human induced pluripotent stem cell (iPSC) lines were generated from fibroblasts of two siblings with methylmalonic acidemia cblB type carrying mutations in the MMAB gene: c.287T➔C (p.Ile96Thr) and a splicing loss-of-function variant c.584G➔A affecting the last nucleotide of exon 7 in MMAB (p.Ser174Cysfs*23). Reprogramming factors OCT3/4, SOX2, KLF4 and c-MYC were delivered using a non-integrative method based on the Sendai virus. Once established, iPSCs have shown full pluripotency, differentiation capacity and genetic stability

Influence of light curing source on microhardness of composite resins of different shades Influência da fonte de luz polimerizadora na microdureza da resina composta de diferentes cores

INTRODUCTION: The evolution of light curing units can be noticed by the different systems recently introduced. The technology of LED units promises longer lifetime, without heating and with production of specific light for activation of camphorquinone. However, further studies are still required to check the real curing effectiveness of these units. PURPOSE: This study evaluated the microhardness of 4 shades (B-0.5, B-1, B-2 and B-3) of composite resin Filtek Z-250 (3M ESPE) after light curing with 4 light sources, being one halogen (Ultralux - Dabi Atlante) and three LED (Ultraled - Dabi Atlante, Ultrablue - DMC and Elipar Freelight - 3M ESPE). METHODS: 192 specimens were distributed into 16 groups, and materials were inserted in a single increment in cylindrical templates measuring 4mm x 4mm and light cured as recommended by the manufacturer. Then, they were submitted to microhardness test on the top and bottom aspects of the cylinders. RESULTS: The hardness values achieved were submitted to analysis of variance and to Tukey test at 5% confidence level. It was observed that microhardness of specimens varied according to the shade of the material and light sources employed. The LED appliance emitting greater light intensity provided the highest hardness values with shade B-0.5, allowing the best curing. On the other hand, appliances with low light intensity were the least effective. It was also observed that the bottom of specimens was more sensitive to changes in shade. CONCLUSION: Light intensity of LED light curing units is fundamental for their good functioning, especially when applied in resins with darker shades.<br>INTRODUCTION: A evolução dos aparelhos fotopolimerizadores pode ser notada nos diferentes sistemas introduzidos recentemente no mercado. A tecnologia apresentada pelos aparelhos LED promete maior tempo de vida útil, não gerar aquecimento e produzir luz específica para a ativação da canforoquinona. No entanto, ainda são necessários estudos complementares para se conhecer a real efetividade destes aparelhos na polimerização dos materiais. PROPOSTA: Neste trabalho foi verificada a microdureza de 4 cores (B-0,5, B-1, B-2 e B-3) da resina composta Filtek Z-250 (3M ESPE) quando polimerizadas com 4 fontes de luz, sendo uma halógena (Ultralux - Dabi Atlante) e três LED (Ultraled - Dabi Atlante, Ultrablue - DMC e Elipar Freelight - 3M ESPE). MÉTODOS: Os 192 corpos-de-prova foram distribuídos em 16 grupos e os materiais foram inseridos em único incremento em matrizes cilíndricas de 4mm X 4mm, sendo polimerizados pelo tempo preconizado pelo fabricante. Em seguida, foram submetidos ao teste de microdureza na superfície superior e inferior dos cilindros. RESULTADOS: Os valores de dureza obtidos foram submetidos à análise de variância e ao teste de Tukey ao nível de 5%. Foi observado que a dureza dos corpos-de-prova variou conforme a cor do material e aparelhos utilizados. O aparelho LED que emite maior intensidade luminosa proporcionou a obtenção dos maiores valores de dureza, com o croma B-0,5 possibilitando a melhor polimerização. Por outro lado aparelhos com baixa intensidade luminosa foram os menos efetivos. Também foi observado que a região do fundo dos corpos-de-prova foi mais sensível à mudança das cores. CONCLUSÕES: A intensidade de luz dos fotopolimerizadores LED é fundamental para seu bom funcionamento, principalmente quando empregadas resinas com croma mais acentuado