Advances in the Treatment of Monoclonal Gammopaties: The Emerging Role of Targeted Therapy in Plasma Cell Dyscrasias

The paradigm for the treatment of monoclonal gammopaties has dramatically changed: therapeutic options in multiple myeloma (MM) have evolved from the introduction of melphalan and prednisone in the 1960s, high-dose chemotherapy and stem cell transplantation in the late 1980s and 1990s, to the rapid introduction of small novel molecules within the last seven years. Based on the understanding of the complex interaction of the MM cells with the bone marrow microenvironment and the signaling pathways that are dysregulated in this process, a number of novel therapeutic agents are now available. Specifically, three novel agents with a specific-targeted anti-MM activity, have been FDA-approved for the treatment of this disease, namely Bortezomib, thalidomide, and lenalidomide which are now all playing a key role in the treatment of MM. The success of targeted therapy in MM has since led to the development and investigation of more than 30 new compounds in this disease and in other plasma cell dyscrasias such as Waldenström’s macroglobulinemia and primary amyloidosis, both in the preclinical settings and as part of clinical trials

HCK is a survival determinant transactivated by mutated MYD88, and a direct target of ibrutinib

Activating mutations in MYD88 are present in approximately 95% of patients with Waldenstrom Macroglobulinemia (WM), as well as other B-cell malignancies including ABC DLBCL. In WM, mutated MYD88 triggers activation of BTK. Ibrutinib, a pleiotropic kinase inhibitor that targets BTK, is highly active in patients with mutated MYD88. We observed that mutated MYD88 WM and ABC DLBCL cell lines, as well as primary WM cells show enhanced HCK transcription and activation, and that HCK is activated by IL6. Over-expression of mutated MYD88 triggers HCK and IL6 transcription, while knockdown of HCK reduced survival and attenuated BTK, PI3K/AKT, and MAPK/ERK signaling in mutated MYD88 WM and/or ABC DLBCL cells. Ibrutinib and the more potent HCK inhibitor A419259 blocked HCK activation and induced apoptosis in mutated MYD88 WM and ABC DLBCL cells. Docking and pull-down studies confirmed that HCK was a target of ibrutinib. Ibrutinib and A419259 also blocked ATP binding to HCK, while transduction of mutated MYD88 expressing WM cells with a mutated HCK gatekeeper greatly increased the EC50 for ibrutinib and A419259. The findings support that HCK expression and activation is triggered by mutated MYD88, supports the growth and survival of mutated MYD88 WM and ABC DLBCL cells, and is a direct target of ibrutinib. HCK represents a novel target for therapeutic development in MYD88 mutated WM and ABC DLBCL, and possibly other diseases driven by mutated MYD88

The Effects of Imperfect Top-Down Selection on the Accuracy of the Direct Range Restriction Adjustment

Accurate assessment of the effectiveness of personnel psychology functions is vital to the field. Many personnel decisions are made based on correlations between predictor variables and measures of job performance; however, those correlations are often affected by range restriction. As encountered in applied practice, range restriction weakens the strength of the correlation. Equations exist to correct for the effects of range restriction on correlations; these equations are widely accepted and used by Industrial-Organizational psychologists today. This study expands on research by Hall (2016), which examined the accuracy of the direct range restriction correction equation provided by Thorndike (1949) under varying degrees of the violation of the assumption of perfect top-down selection. A Monte Carlo analysis was conducted so that the adjusted sample correlations could be compared to known, unrestricted population correlations. The results of the study indicate that Thorndike’s correction equation provides adjusted sample correlations that were closer to the true population correlation when perfect top-down selection does not occur. Implications and recommendations for future research are discussed

“Home Court Advantage: Comparing International Criminal Tribunals to Domestically-Grown Reconciliation”

Scholars have studied wars and their causes for centuries, but what happens when the tanks roll out and the guns stop firing? The concept of reconciliation is a relatively new field of study in international relations, and the scholarship of specific transitional justice mechanisms remains underdeveloped. I comparatively analyze the differences between external and internal peacebuilding strategies – specifically the effectiveness of international tribunals in establishing long term deep reconciliation. In defining internal and external transitional justice mechanisms, I differentiate between a reconciliation process that prioritizes rebuilding citizens’ lives over one that prioritizes the desires of the international community. It has been almost 30 years since the Bosnian War and the Rwandan Genocide, which marked the first use of international criminal tribunals as a transitional justice mechanism. However, Rwanda prioritized local level, community based trials more than Bosnia did. Scholars are divided on the effectiveness of international tribunals. By analyzing their use in these cases, I demonstrate that internal, domestic level trials are more reconciliatory than internationally conducted criminal tribunals, thus developing more informed guidance for future reconciliation

Effects of dietary supplementation of a blend of Saccharomyces cerevisiae, multiple live probiotic bacteria, and their fermentation products on performance, health, and rumen bacterial community of newly weaned beef steers during a 56-d receiving period

We examined the effects of a blend of Saccharomyces cerevisiae, multiple live probiotic bacteria and their fermentation products on performance, health, and the ruminal bacterial community of newly weaned beef steers during a 56-day receiving period. Forty newly weaned Angus crossbred steers (221 ± 25.6 kg BW; 180 ± 17 d of age) were stratified by body weight into four pens (10 steers per pen) such that each pen had a similar average body weight at the beginning of the experiment. The pens were randomly assigned to receive a corn silage basal diet (CON; n = 20) or the basal diet supplemented with 9 g/steer/d of PRO feed additive (PRO; n = 20). The PRO additive is a blend of Saccharomyces cerevisiae and the fermentation products of Enterococcus faecium, Bacillus licheniformis, Bacillus subtilis, Lactobacillus animalis, Propionibacterium freudenreichii. The DMI and water consumed were monitored using the GrowSafe intake nodes and custom flow meters, respectively. Body weights (BW) were recorded weekly to calculate average daily gain (ADG). Before morning feeding, 10 mL of blood was taken from each steer on days 0-7, and thereafter weekly for analyses of immune cells, plasma glucose and NEFAs. On day 56, rumen fluid samples (200 mL each) were collected from all the steers for microbiome analysis. Over the 56-day receiving period, the supplemental PRO had no effects on DMI, water intake, or ADG. However, compared to CON, beef steers fed supplemental PRO tended to have greater ADG (P = 0.08) and BW (P = 0.07) during the first 14 days of the study. There was a treatment × day interaction (P ≤ 0.05) for WBC, neutrophils and monocytes over the 56 days such that beef steers fed supplemental PRO had lower blood concentrations on certain days during the first 7 days after weaning, indicating reduced inflammation or stress response. The results of the rumen microbiome analysis revealed that the relative abundance of complex fiber degrading or obligate proton-reducing bacterial genera such as Bacteroides, Ruminococcus gauvreauii group, Desulfovibrio, Syntrophococcus, and Acetitomaculum were greater (P ≤ 0.05) in beef steers fed supplemental PRO compared to CON. This study demonstrated that dietary supplementation of PRO improved the growth performance, reduced stress or inflammatory response during the initial days after weaning and altered the ruminal bacterial community towards increased relative abundance of bacterial genera associated with improved rumen function

Familial aggregation of lymphoplasmacytic lymphoma/Waldenström macroglobulinemia with solid tumors and myeloid malignancies.

To access publisher full text version of this article. Please click on the hyperlink in Additional Links field.Lymphoplasmacytic lymphoma (LPL)/Waldenström macroglobulinemia (WM) is a B-cell disorder resulting from the accumulation, predominantly in the bone marrow, of clonally related lymphoplasmacytic cells. LPL/WM is a very rare disease, with an incidence rate of 3-4 cases per million people per year.Currently, the causes of LPL/WM are poorly understood; however, there are emerging data to support a role for immune-related factors in the pathogenesis of LPL/WM. In addition, data show that genetic factors are of importance in the etiology of LPL/WM. In this paper, we will review the current knowledge about familiality of LPL/WM and provide novel data on solid tumors and myeloid malignancies in first-degree relatives of LPL/WM patients.Swedish Cancer Society Stockholm County Council Karolinska Institutet Foundations National Institutes of Health, National Cancer Institute Roch