Effect of reducing groundwater on the retardation of redox-sensitive radionuclides

Laboratory batch sorption experiments were used to investigate variations in the retardation behavior of redox-sensitive radionuclides. Water-rock compositions were designed to simulate subsurface conditions at the Nevada Test Site (NTS), where a suite of radionuclides were deposited as a result of underground nuclear testing. Experimental redox conditions were controlled by varying the oxygen content inside an enclosed glove box and by adding reductants into the testing solutions

Consumer–brand identification revisited: An integrative framework of brand identification, customer satisfaction, and price image and their role for brand loyalty and word of mouth

Consumer–brand identification has received considerable attraction among scholars and practitioners in recent years. We contribute to previous research by proposing an integrative model that includes consumer–brand identification, customer satisfaction, and price image to investigate the interrelationships among these constructs as well as their effects on brand loyalty and positive word of mouth. To provide general results, we empirically test the model using a sample of 1443 respondents from a representative consumer panel and 10 service/product brands. The results demonstrate that identification, satisfaction, and price image significantly influence both loyalty and word of mouth. Moreover, we find significant interrelationships among the constructs: Identification positively influences both satisfaction and price image, which also increases satisfaction. By disclosing the relative importance of three separate ways of gaining and retaining customers, this study helps managers more appropriately choose the right mix of branding, pricing, and relationship marketing. From an academic point of view, our research is the first to explicitly examine the effects of the concept of identification for price management and to integrate variables from the fields of branding, relationship marketing, and behavioral pricing, which have separately been identified as particularly important determinants of marketing outcomes

Circulating tumour DNA analysis to detect clonal evolution in TP53 mutated CLL treated with sequential precision medicines

Circulating tumour DNA (ctDNA) is increasingly being investigated not only for the early detection of treatment failure but also for the assessment of clonal evolution during treatment, facilitating a more comprehensive assessment of tumour burden compared to existing techniques. Here, we describe the case of a male patient with TP53 mutated CLL, diagnosed in 2000,initially treated with 2 lines of immune-chemotherapy prior to relapse in 2012, when he received sequential treatment with the selective BTKi tiraburitinib followed by the selective BCL2 inhibitor, venetoclax. Using serial ctDNA analysis we studied the dynamics of clonal evolution during treatment with tirabrutinib and venetoclax prior to the development of Richter’s transformation(RT). To elucidate clonal dynamics leading to therapeutic resistance and subsequent RT, we carried out paired whole exome sequencing(WES), deep targeted sequencing using a customised 72 gene panel and digital droplet PCR (ddPCR) on sequential peripheral blood mononuclear cells (PBMCs) and ctDNA. ctDNA was derived from plasma samples obtained pre-, during and post-treatment with tirabrutinib and venetoclax. Tumour tissue was obtained at the point of diagnosis of RT. This patient initially responded for 31 months on a potentially non-saturating dose of 40mg OD of tirabrutinib prior to clinicalrelapse. Analysis of ctDNA did not detect either a BTK or PLCG2 mutation at initial progression and therefore the dose of tirabrutinib was increased to 600mg OD, the maximal dose permitted on study. A further clinical response was seen with a resultant secondary BTKi induced lymphocytosis. The patient remained in partial remission for an additional 12 months. Two months prior to further clinical relapse, the presence of a BTK p.L528W mutation was detected by ctDNA analysis, a mutation disrupts the BTKi binding site which has been previously described in refractory CLL (Sharma et al., 2016). On WES of PBMC, mutations were found in TP53p.V216M at 73% variant allele frequency (VAF) and MSH2 p.E572_Q574del at 29.6% VAF. Analysis of IGHV further demonstrated a single productive IGH clonotype of IGHV2-5*06.Following initiation of venetoclax, ctDNA levels of BTK p.L562W and TP53 p.V216M rapidly became undetectable, correlating with clinical response. The patient remained in remission for 13 months before developing rapidly progressive RT resistant to R-CHOP.WES of the RT tumour showed additional mutations, deletions and chromosomal translocations. However, deep-targeted sequencing uncovered a low level BCL2 p.A113G (1.8% VAF) undetected by WES. This mutation was also detected by ctDNA analysis at this timepoint demonstrating ctDNA offers a non-invasive rout to RT detection. The IGHV clonotype matched the pre-RT PBMC, indicating RT was clonally related to the CLL clone. A striking increase in the frequency of frameshift mutations in post-MSH2 aberration (119%, compared to sequenced samples pre-MSH2 acquisition) was observed, suggestive of chromosomal instability, which likely contributed to treatment resistance. The increase in VAF of MSH2 through sequential relapses in treatment, further suggests an association with RT development (tirabrutinib(16.7%), second relapse (29.6%), and RT (45.3%)).Here we have shown that mutational profiling of ctDNA is an effective tool for detecting clonal resistance to precision medicines prior to the development of clinical or radiological evidence of progression.</p

PD1hi cells associate with clusters of proliferating B-cells in marginal zone lymphoma.

BACKGROUND: Abnormally sustained immune reactions drive B-cell proliferation in some cases of marginal zone lymphoma but the CD4+ T-cell subsets, which are likely to contribute to the B-cell responses in the tumour microenvironment, are not well characterised and neither has the spatial distribution of the different subsets in involved lymph nodes been investigated. METHODS: Employing a workflow of multiplex semi-automated immunohistochemistry combined with image processing we investigated association between infiltrating T-cells and proliferating lymphoma B-cells. RESULTS: Both total numbers of activating follicular helper (Tfh) cells (defined by high expression of PD1) and suppressive regulatory (Treg) T-cells (defined by FOXP3+ expression) and the Tfh:Treg ratio, assessed over relatively large areas of tissue, varied among cases of marginal zone lymphoma. We determined spatial distribution and demonstrated that PD1hi cells showed significantly more clustering than did FOXP3+. To investigate the association of infiltrating T-cells with lymphoma B-cells we employed Pearson correlation and Morisita-Horn index, statistical measures of interaction. We demonstrated that PD1hi cells were associated with proliferating B-cells and confirmed this by nearest neighbour analysis. CONCLUSIONS: The unexpected architectural complexity of T-cell infiltration in marginal zone lymphoma, revealed in this study, further supports a key role for Tfh cells in driving proliferation of lymphoma B-cells. We demonstrate the feasibility of digital analysis of spatial architecture of T-cells within marginal zone lymphoma and future studies will be needed to determine the clinical importance of these observations

Structural and diffusion weighted MRI demonstrates responses to ibrutinib in a mouse model of follicular helper (Tfh) T-cell lymphoma.

Recent analyses of the genetics of peripheral T-cell lymphoma (PTCL) have shown that a large proportion of cases are derived from normal follicular helper (Tfh) T-cells. The sanroque mouse strain bears a mutation that increases Tfh cell number and heterozygous animals (Roquinsan/+) develop lymphomas similar to human Tfh lymphoma. Here we demonstrate the usefulness of Roquinsan/+ animals as a pre-clinical model of Tfh lymphoma. Long latency of development and incomplete penetrance in this strain suggests the lymphomas are genetically diverse. We carried out preliminary genetic characterisation by whole exome sequencing and detected tumor specific mutations in Hsp90ab1, Ccnb3 and RhoA. Interleukin-2-inducible kinase (ITK) is expressed in Tfh lymphoma and is a potential therapeutic agent. A preclinical study of ibrutinib, a small molecule inhibitor of mouse and human ITK, in established lymphoma was carried out and showed lymphoma regression in 8/12 (67%) mice. Using T2-weighted MRI to assess lymph node volume and diffusion weighted MRI scanning as a measure of function, we showed that treatment increased mean apparent diffusion coefficient (ADC) suggesting cell death, and that change in ADC following treatment correlated with change in lymphoma volume. We suggest that heterozygous sanroque mice are a useful model of Tfh cell derived lymphomas in an immunocompetent animal

Successful treatment of primary cutaneous diffuse large B cell lymphoma leg type with single agent venetoclax

Successful treatment of primary cutaneous diffuse large B cell lymphoma leg type with single agent venetocla

Limitations of Monitoring Disease Progression Using Circulating Tumor DNA in Lymphoma: An Example from Primary Cutaneous DLBCL Leg-type

Chemotherapy-refractory diffuse large B-cell lymphoma (DLBCL) remains a significant clinical problem. The ability to predict patients likely to have poor outcomes with conventional therapies may facilitate rational use of alternative, targeted treatment approaches before fulminant relapse. The utility of circulating tumor DNA (ctDNA) in DLBCL is currently being investigated. Initial studies have reported high levels of sensitivity for detection of residual disease, outperforming imaging techniques such as 18FDG-PET/CT scans.1 For example, Alizadeh et al recently demonstrated the feasibility of CAncer Personalized Profiling by deep Sequencing (CAPP-Seq) approach in DLBCL; the mean elapsed time between the first ctDNA-positive time point and radiological relapse was 188 days.2 Kurtz et al detected pretreatment ctDNA in 98% of patients with DLBCL receiving treatment with frontline or salvage immunochemotherapy.3 Early and major molecular responses after 1 and 2 cycles of treatment, resulted in superior outcome at 24 months. However, only 9% and 23% of patients within these validation sets had stage I and II disease, respectively. Limitations to the use of ctDNA to detect early stage malignancy have been identified; for example, in lung, where low-volume disease cannot be reliably detected using mutation profiles in ctDNA.4 Furthermore, some specific subtypes of disease (lung adenocarcinoma) do not shed detectable ctDNA into the peripheral blood.5</p