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

Avaliação clínica da efetividade do clareamento de consultório sem troca do gel clareador

Esse trabalho teve como objetivo avaliar, clinicamente, a efetividade de dois agentes clareadores aplicados sobre a superfície dentária durante 45 minutos, sem troca do gel. Foram selecionados 10 pacientes de acordo com os critérios de inclusão e exclusão, e a arcada superior dos pacientes foi dividida em duas hemiarcadas (n = 10): na hemiarcada direita (HD), foi aplicado o peróxido de hidrogênio a 35% (PH) Clàriant Office (Angelus); e, na hemiarcada esquerda (HE), o PH 38% Opalescence Boost (Ultradent). Foram realizadas duas sessões clínicas, de 45 minutos cada, com intervalo de uma semana entre as sessões. Inicialmente, ao tratamento clareador, os pacientes receberam profilaxia, moldagem para guia de mensuração de cor com silicone de condensação e avaliação de cor por meio de um aparelho espectrofotômetro Vita Easyshade (Vita Zhanfabrik, Alemanha). Após 14 dias do término do tratamento clareador, foi realizada a mensuração final da cor dos dentes. Os dados foram submetidos ao teste t e de Tukey (p < 0,05). Os resultados demonstraram não haver diferença estatisticamente significativa entre as hemiarcadas quanto à efetividade do clareamento (p = 0,146) e nem quanto à sensibilidade. Pode-se concluir que a aplicação dos materiais avaliados sem troca do gel, por 45 minutos, foi eficaz em promover o clareamento de dentes vitais e com baixa sensibilidade dentária

Avaliação clínica do clareamento no consultório: técnica de aplicação única do agente clareador

This study aimed to evaluate the clinical effectiveness of two bleaching agents without changing the whitening gel during the clinic session 1X45minutos. 10 patients were selected according to the criteria of inclusion and exclusion and upper arch of the patients were divided into two quadrants (n: 10), G1: gel clareador Clàriant Office (hidrogênio35 Angellus) peroxide% (PH) in superior right side (LD) and the gel WhitenessHp Blue (FGM) PH 35% on the superior left side (LE. 2 clinical sessions were accomplished, 45 minutes each, with an interval of one week between sessions. At first the bleaching treatment patients received prophylaxis, molding to guide measurement of color with condensation silicon and the color evaluation through the apparel spectrophotometer VITA Easyshade (Vita Zhanfabrik, Alemanhã). 14 days after the end of the bleaching treatment was performed the measurement final color of the teeth. The patients reported sensitivity in scale 0-4. The result showed that through T Test comparing quadrants presented no statistical differences (p>0,05) in relation to coloration and dental sensibility. It can be concluded that the materials evaluated are effective for bleaching vital teeth with low tooth sensibility.Este trabalho teve como objetivo avaliar clinicamente a efetividade de dois agentes clareadores sem troca do gel clareador durante a sessão clínica 1 x 45 minutos. Foram selecionados 10 pacientes de acordo com os critérios de inclusão e exclusão e arcada superior dos pacientes foram divididas em 2 hemiarcos (n: 10): hemiarco direito (HD) aplicado o peróxido de hidrogênio a 35%(PH) Clàriant Office (Angelus) no hemiarco esquerdo (HE) o PH 35% Whiteness Hp Blue (FGM). Foram realizados 2 sessões clínicas, de 45 minutos cada, com intervalo de 1 semana entre as sessões. Inicialmente ao tratamento clareador os pacientes receberam profilaxia, moldagem para guia de mensuração de cor com silicone de condensação e a avaliação de cor através do aparelho espectrofotômetro VITA Easyshade (Vita Zhanfabrik, Alemanhã). Após 14 dias do término do tratamento clareador foi realizada a mensuração final da cor dos dentes. Os pacientes relataram a sensibilidade em escala 0-4. O resultado demonstrou através do Teste T que, a comparação entre os hemiarcos, não apresenta diferença estatística (p>0,05): o mesmo resultado pode ser em relação à sensibilidade. Pode-se concluir que os materiais avaliados são eficazes para o clareamento de dentes vitais e com baixa sensibilidade dental