Clinical Utilization of Chimeric Antigen Receptor T Cells in B Cell Acute Lymphoblastic Leukemia: An Expert Opinion from the European Society for Blood and Marrow Transplantation and the American Society for Blood and Marrow Transplantation

On August 30, 2017 the US Food and Drug Administration approved tisagenlecleucel (Kymriah; Novartis, Basel, Switzerland), a synthetic bioimmune product of anti-CD19 chimeric antigen receptor T cells (CAR-T), for the treatment of children and young adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL). With this new era of personalized cancer immunotherapy, multiple challenges are present, ranging from implementation of a CAR-T program to safe delivery of the drug, long-term toxicity monitoring, and disease assessments. To address these issues experts representing the American Society for Blood and Marrow Transplant, the European Society for Blood and Marrow Transplantation, the International Society of Cell and Gene Therapy, and the Foundation for the Accreditation of Cellular Therapy formed a global CAR-T task force to identify and address key questions pertinent for hematologists and transplant physicians regarding the clinical use of anti CD19 CAR-T therapy in patients with B-ALL. This article presents an initial roadmap for navigating common clinical practice scenarios that will become more prevalent now that the first commercially available CAR-T product for B-ALL has been approved.     

Consequences of dosing and timing on the antibacterial effects of ADEP antibiotics

Antibiotic acyldepsipeptides (ADEPs) exert potent antibacterial activity in rodent models of bacterial infection and exceptional efficacy against persister cells of methicillin-resistant Staphylococcus aureus (MRSA). The mechanism of ADEP action is unusual in that the antibiotic releases the destructive capacity of over-activated ClpP, the proteolytic core of the bacterial Clp protease. The essential bacterial cell division protein FtsZ had emerged in a previous study as a preferred protein substrate of ADEP-activated ClpP but it is definitely not the only cellular substrate.In the current study, we set out to follow the morphological changes that lead to ADEP-mediated bacterial death in S. aureus and Bacillus subtilis, differentiating between antibacterial effects at low and high ADEP concentrations. Here, fluorescence and time-lapse microscopy data show that cells adopt a characteristic phenotype of cell division inhibition at ADEP levels close to the MIC, but retain the capacity to form viable daughter cells for a substantial period of time when transferred to ADEP-free growth medium. After extended exposure to low ADEP concentrations, nucleoids of B. subtilis started to disorganize and upon compound removal many cells failed to re-organize nucleoids, re-initiate cytokinesis and consequently died. Survival versus cell death of filamentous cells attempting recovery depended on the timing of completion of new septa in relation to the loss of cell envelope integrity. We show that the potential to recover after ADEP removal depends on the antibiotic concentration as well as the treatment duration. When exposed to ADEP at concentrations well above the MIC, biomass production ceased rapidly as did the potential to recover. In time-kill studies both long-time exposure to low ADEP levels as well as short-time exposure to high concentrations proved highly effective, while intermittent concentrations and time frames were not. We here provide new insights into the antimicrobial activity of ADEP antibiotics and the consequences of dosing and timing for bacterial physiology which should be considered in view of a potential therapeutic application of ADEPs.     

Flexibility in joint coordination remains unaffected by force and balance demands in young and old adults during simple sit-to-stand tasks

European Journal of Applied Physiology - We examined the possibility that old adults use flexibility in joint coordination as a compensatory mechanism for the age-related decline in muscle strength...     

The impact of descriptive norms on motivation to participate in cancer screening – Evidence from online experiments

ObjectiveThe current study tested in two online experiments whether manipulating normative beliefs about cancer screening uptake increases intention to attend colorectal screening among previously disinclined individuals.Methods2461 men and women from an Internet panel (Experiment 1 N = 1032; Experiment 2, N = 1423) who initially stated that they did not intend to take up screening were asked to guess how many men and women they believe to get screened for colorectal cancer. Across participants, we varied the presence/absence of feedback on the participant’s estimate, as well as the stated proportion of men and women doing the screening test.ResultsAcross the two experiments, we found that receiving one of the experimental messages stating that uptake is higher than estimated significantly increased the proportion of disinclined men and women becoming intenders. While, we found a positive relationship between the communicated uptake and screening intentions, we did not find evidence that providing feedback on the estimate has an added benefit.ConclusionScreening intention can be effectively manipulated through a high uptake message.Practice implicationsCommunication of high screening uptake is an easy and effective way to motivate disinclined individuals to engage in colorectal cancer screening.     

Engineered Polysaccharides: α‐1,3‐Glucan Acetates Showing Upper Critical Solution Temperature in Organic Solvents

Acetates of α‐1,3‐glucan dissolved in N,N‐dimethyl acetamide/LiCl are prepared by converting the polysaccharide with acetyl chloride, acetic acid anhydride/pyridine, or with acetic acid/N,N′‐carbonyl diimidazole. Values of the degree of substitution for the acetyl groups (DS_Ac) of up to 2.6 are realized. NMR spectroscopic measurements reveal a preferred conversion of the primary hydroxyl group at position 6 followed by positions 2 and 4. Depending on the DS_Ac, the samples may be soluble in solvents of different polarity at room temperature or at elevated temperatures showing upper critical solution temperature at DS of about 2.5. This process is found to be reversible.     

Advanced Electrocardiogram Analysis in the Amitriptyline‐poisoned Pig Treated with Activated Charcoal Haemoperfusion

Coated activated charcoal haemoperfusion (CAC‐HP) does not reduce the plasma concentration in amitriptyline (AT)‐poisoned pigs. The aim of this non‐blinded, randomized, controlled animal trial was to determine if CAC‐HP reduces the pathological ECG changes caused by AT poisoning. Fourteen female Danish Landrace pigs (mean weight 27.7 kg, range 20–35 kg (CAC‐HP) and 24.4 kg, range 18–30 kg (control group, CG), n = 7 in each group) were included. After randomization, the pigs were anaesthetized and intravenously poisoned with AT. The intervention group underwent 4 hr of CAC‐HP plus standard care (oral activated charcoal). Intervention was compared to standard care alone. From each pig, a 12‐lead ECG and haemodynamic variables were obtained at baseline, at full AT loading dose, before and during CAC‐HP. Baseline ECG variables (RR, PR, QRS, QTc, QTp, QTe, TpTe and TpTe/QT) for lead II, v2 and v5 were not significantly different (F = 0.035–0.297, p‐values 0.421–0.919). Differences within groups over time and between groups were tested by anova repeated measures. For all variables, the time‐plus‐group level of significance revealed a p‐value > 0.05. Severe cardiovascular arrhythmias occurred in both groups with 3 in the CAC‐HP group versus 1 incident with premature death in the CG. The attenuating effect of CAC‐HP to orally instilled activated charcoal alone on AT‐induced ECG alterations did not differ significantly. We conclude that the use of modern CAC‐HP as an adjunctive treatment modality in AT‐poisoned pigs is inadequate.     

Use of a case-mix approach to study the trends in the incidence of second primary cancers

Purpose

To analyze trends in second primary cancer (SPC) incidence by using a case-mix approach to standardize on first cancer site distribution.

Introducing Motivational Interviewing in a Sickness Insurance Context: Translation and Implementation Challenges

Purpose Motivational interviewing (MI) is a conversational method to support clients in need of behavioral change. In an organizational reform, most Swedish sickness insurance officials were trained in MI to promote clients’ return to work (RTW) after sick leave. The aim of this article is to investigate experiences of introducing MI as a tool to promote clients’ RTW within a sickness insurance context, with special focus on the translation and implementation of the method. Methods A qualitative approach, comprising 69 interviews with officials, managers, and regional coordinators on two occasions. The material was analyzed through qualitative content analysis. Results Officials were positive about MI, but the application was limited to using certain tools with extensive individual variation. Officials struggled with translating MI into a sickness insurance context, where the implementation strategy largely failed to offer adequate support, due to low managerial priority, competing initiatives, and a high workload. Results of the educational intervention could therefore be seen on an individual but not an organizational level. Conclusions In order to translate MI into a sickness insurance context, training needs to be supported by organizational approaches that promote collective learning and sharing of experiences among officials. The results also illustrate how a method cannot be assumed to be implemented simply because training has been provided. Consequently, the application of the method needs to be carefully monitored in studies of interventions where MI is claimed to be used, in order to measure its effectiveness.