Deep MRD profiling defines outcome and unveils different modes of treatment resistance in standard- and high-risk myeloma.
- 作者列表："Goicoechea I","Puig N","Cedena MT","Burgos L","Cordón L","Vidriales MB","Flores-Montero J","Gutierrez NC","Calasanz MJ","Ramos MM","Lara-Astiaso D","Vilas-Zornoza A","Alignani D","Rodriguez I","Sarvide S","Alameda D","Garcés JJ","Rodriguez S","Fresquet V","Celay J","Garcia-Sanz R","Martinez-Lopez J","Oriol A","Rios R","Martin-Sanchez J","Martinez-Martinez R","Sarra J","Hernandez MT","de la Rubia J","Krsnik I","Moraleda JM","Palomera L","Bargay J","Martinez-Climent JA","Orfao A","Rosiñol L","Mateos MV","Lahuerta JJ","Blade J","San Miguel J","Paiva B
:Patients with multiple myeloma (MM) carrying standard- or high-risk cytogenetic abnormalities (CAs) achieve similar complete response (CR) rates, but the later have inferior progression-free survival (PFS). This questions the legitimacy of CR as a treatment endpoint and represents a biological conundrum regarding the nature of tumor reservoirs that persist after therapy in high-risk MM. We used next-generation flow (NGF) cytometry to evaluate measurable residual disease (MRD) in MM patients with standard- vs high-risk CAs (n = 300 and 90, respectively) enrolled in the PETHEMA/GEM2012MENOS65 trial, and to identify mechanisms that determine MRD resistance in both patient subgroups (n = 40). The 36-month PFS rates were higher than 90% in patients with standard- or high-risk CAs achieving undetectable MRD. Persistent MRD resulted in a median PFS of ∼3 and 2 years in patients with standard- and high-risk CAs, respectively. Further use of NGF to isolate MRD, followed by whole-exome sequencing of paired diagnostic and MRD tumor cells, revealed greater clonal selection in patients with standard-risk CAs, higher genomic instability with acquisition of new mutations in high-risk MM, and no unifying genetic event driving MRD resistance. Conversely, RNA sequencing of diagnostic and MRD tumor cells uncovered the selection of MRD clones with singular transcriptional programs and reactive oxygen species-mediated MRD resistance in high-risk MM. Our study supports undetectable MRD as a treatment endpoint for patients with MM who have high-risk CAs and proposes characterizing MRD clones to understand and overcome MRD resistance. This trial is registered at www.clinicaltrials.gov as #NCT01916252.
: 携带标准或高风险细胞遗传学异常 (CAs) 的多发性骨髓瘤 (MM) 患者获得相似的完全缓解率 (CR)，但后者的无进展生存期 (PFS) 较差。这对CR作为治疗终点的合法性提出了质疑，并代表了一个关于高风险MM治疗后持续存在的肿瘤储库性质的生物学难题。我们使用新一代流式 (NGF) 细胞术评估了参加PETHEMA/GEM2012MENOS65试验的MM患者中标准与高危CAs (分别为n = 300和90) 可测量的残留病 (MRD)，并确定在两个患者亚组 (n = 40) 中确定MRD抗性的机制。在标准或高风险CAs患者中，36个月的PFS率高于90%，达到不可检测的MRD。在标准和高危CAs患者中，持续MRD导致的中位PFS分别为 ∼ 3年和2年.进一步使用NGF分离MRD，然后对配对诊断和MRD肿瘤细胞进行全外显子组测序，发现标准风险CAs患者的克隆选择更大，高风险MM获得新突变的基因组不稳定性更高，并且没有驱动MRD耐药的统一遗传事件.相反，诊断和MRD肿瘤细胞的RNA测序揭示了高风险MM中具有单一转录程序和活性氧介导的MRD抗性的MRD克隆的选择。我们的研究支持不可检测的MRD作为具有高风险CAs的MM患者的治疗终点，并提出表征MRD克隆以理解和克服MRD抗性。该试验在www.clinicaltrials.gov注册为 # nct01916252。
METHODS::The ATP binding-cassette superfamily corresponds the mostly transmembrane transporters family found in humans. These proteins actively transport endogenous and exogenous substrates through biological membranes in body tissues, so they have an important role in the regulation of many physiological functions necessary for human homeostasis, as well as in response regulation to several pharmacological substrates. The development of multidrug resistance has become one of the main troubles in conventional chemotherapy in different illnesses including cancer, being the increased efflux of antineoplastic drugs the main reason for this multidrug resistance, with a key role of the ABC superfamily. Likely, the interindividual variability in the pharmacological response among patients is well known, and may be due to intrinsically factors of the disease, genetic and environmental ones. Thus, the understanding of this variability, especially the genetic variability associated with the efficacy and toxicity of drugs, can provide a safer and more effective pharmacological treatment, so ABC genes are considered as important regulators due to their relationship with the reduction in pharmacological response. In this review, updated information about transporters belonging to this superfamily was collected, the possible role of these transporters in cancer, the role of genetic variability in their genes, as well as some therapeutic tools that have been tried to raise against main transporters associated with chemoresistance in cancer.
METHODS:BACKGROUND:Cholinergic neurotransmission regulates neuroinflammation in Parkinson disease (PD). RESEARCH DESIGN AND METHODS:The authors conducted a delayed-start study of donepezil for cognitive decline in non-demented PD patients. The study consisted of a 96-week randomized placebo-controlled double-blind phase 1, followed by a 24-week donepezil extension phase 2. The primary outcome measure was a change in the Mini-Mental State Examination (MMSE) at week 120. RESULTS:A total of 98 patients were randomly allocated to the early-start (donepezil-to-donepezil) and delayed-start (placebo-to-donepezil) groups. Mean (SD) of the baseline MMSE was 27.6 (2.0) and 28.0 (2.1), respectively. MMSE change at week 120 was better in the early-start group than in the delayed-start group, but the difference was not significant. The MMSE declined in apolipoprotein ε4 carriers, but not in non-carriers, and the factor interaction (intervention × ε4 genotype) was highly significant (P < 0.001). Analyzed with the interaction, the difference was significant (group difference 1.95 [0.33 to 3.57], P = 0.018). The MMSE decline slope in phase 1 was significantly better in the early-start group than in the delayed-start group (P = 0.048). CONCLUSIONS:Cognitive function deteriorated in ε4 carriers, but not in non-carriers, and early-start donepezil may postpone cognitive decline in the former.
METHODS::Since the discovery of dental pulp stem cells, a lot of teams have expressed an interest in dental pulp regeneration. Many approaches, experimental models and biological explorations have been developed, each including the use of stem cells and scaffolds with the final goal being clinical application in humans. In this review, the authors' objective was to compare the experimental models and strategies used for the development of biomaterials for tissue engineering of dental pulp with stem cells. Electronic queries were conducted on PubMed using the following terms: pulp regeneration, scaffold, stem cells, tissue engineering and biomaterial. The extracted data included the following information: the strategy envisaged, the type of stem cells, the experimental models, the exploration or analysis methods, the cytotoxicity or viability or proliferation cellular tests, the tests of scaffold antibacterial properties and take into account the vascularization of the regenerated dental pulp. From the 71 selected articles, 59% focused on the "cell-transplantation" strategy, 82% used in vitro experimentation, 58% in vivo animal models and only one described an in vivo in situ human clinical study. 87% used dental pulp stem cells. A majority of the studies reported histology (75%) and immunohistochemistry explorations (66%). 73% mentioned the use of cytotoxicity, proliferation or viability tests. 48% took vascularization into account but only 6% studied the antibacterial properties of the scaffolds. This article gives an overview of the methods used to regenerate dental pulp from stem cells and should help researchers create the best development strategies for research in this field.