Rare Presentation of Rosai-Dorfman Disease in Soft Tissue: Diagnostic Findings and Surgical Treatment.

Introduction and Importance. Rosai-Dorfman disease (RDD) is a rare, benign type II histiocytosis characterized by the infiltration of S100+ histiocytes and emperipolesis. The disease may present in the lymph nodes (nodal RDD), in extranodal sites, or in both nodal and extranodal sites. Among those patients who present exclusively in extranodal sites, only a minority of cases present in the soft tissue. Case Presentation. An 18-year-old female presented to orthopedic oncology clinic with a chief complaint of a mass located in her lower back. The patient underwent excision of the lumbosacral mass. Pathologic review demonstrated emperipolesis of lymphocytes and plasma cells within enlarged, eosinophilic histiocytes in a background of lymphoplasmacytic infiltration and collagenous stroma. Immunohistochemical staining demonstrated S100+ and CD163+ histiocytes, consistent with diagnosis of soft tissue RDD. Clinical Discussion. Histologically, RDD is generally characterized by emperipolesis-the presence of intact lymphocytes within the histiocyte cytoplasm-and a mixed infiltrate of S100+ histiocytes, mononuclear cells, plasma cells, and lymphocytes. Although soft tissue RDD may histologically resemble nodal RDD, soft tissue RDD also demonstrates some notable histologic differences including the lack of nodal architecture, the presence of increased fibrosis and collagen deposition, and generally fewer RDD cells. Conclusion. This case presentation demonstrates one few reports of isolated soft tissue RDD within the lumbosacral region without associated lymphadenopathy or skin changes and highlights the heterogeneity that still exists in the treatment paradigm of extranodal RDD

Cardiovascular co morbidity in cancer patients:The role of psychological distress

Due to aging of the population and cardiotoxic cancer treatment, there is an increasing group of patients with cancer and co-morbid cardiovascular disease (CVD). In order to find a balance between the risk of undertreating the malignancy on the one hand and inducing CVD on the other hand, CVD risk stratification at the time of cancer diagnosis and knowledge on the pathway for developing incident CVD in cancer patients is vital. In this paper, we propose an adapted multiple-hit hypothesis for developing CVD in cancer patients describing that patients with cancer are exposed to a series of sequential or concurrent events that together make them more vulnerable to reduced cardiovascular reserves, development of incident CVD and ultimately death. We highlight the possible impact of psychological distress secondary to a cancer diagnosis and/or treatment, which in turn may increase the risk of incident CVD in patients diagnosed with cancer. Furthermore, we discuss potential behavioral and pathophysiological mechanisms underlying the link between psychological distress and the pathophysiology of incident CVD. In addition, key unanswered questions for future research are posed. In the future, researching the adapted multiple-hit hypothesis for developing CVD among cancer patients will hopefully advance the care of cancer patients by finding some of the missing pieces of the puzzle. To do so, we need to focus on minimizing cardiovascular risk and promoting cardiovascular health in cancer patients by addressing the knowledge gaps formulated in this paper

New in vitro interaction-parasite reduction ratio assay for early derisk in clinical development of antimalarial combinations

The development and spread of drug-resistant phenotypes substantially threaten malaria control efforts. Combination therapies have the potential to minimize the risk of resistance development but require intensive preclinical studies to determine optimal combination and dosing regimens. To support the selection of new combinations, we developed a novel in vitro-in silico combination approach to help identify the pharmacodynamic interactions of the two antimalarial drugs in a combination which can be plugged into a pharmacokinetic/pharmacodynamic model built with human monotherapy parasitological data to predict the parasitological endpoints of the combination. This makes it possible to optimally select drug combinations and doses for the clinical development of antimalarials. With this assay, we successfully predicted the endpoints of two phase 2 clinical trials in patients with the artefenomel-piperaquine and artefenomel-ferroquine drug combinations. In addition, the predictive performance of our novel in vitro model was equivalent to that of the humanized mouse model outcome. Last, our more informative in vitro combination assay provided additional insights into the pharmacodynamic drug interactions compared to the in vivo systems, e.g., a concentration-dependent change in the maximum killing effect (Emax) and the concentration producing 50% of the killing maximum effect (EC50) of piperaquine or artefenomel or a directional reduction of the EC50 of ferroquine by artefenomel and a directional reduction of Emax of ferroquine by artefenomel. Overall, this novel in vitro-in silico-based technology will significantly improve and streamline the economic development of new drug combinations for malaria and potentially also in other therapeutic areas

Renormalized spin coefficients in the accumulated orbital phase for unequal mass black hole binaries

We analyze galactic black hole mergers and their emitted gravitational waves. Such mergers have typically unequal masses with mass ratio of the order 1/10. The emitted gravitational waves carry the inprint of spins and mass quadrupoles of the binary components. Among these contributions, we consider here the quasi-precessional evolution of the spins. A method of taking into account these third post-Newtonian (3PN) effects by renormalizing (redefining) the 1.5 PN and 2PN accurate spin contributions to the accumulated orbital phase is developed.Comment: 10 pages, to appear in Class. Quantum Grav. GWDAW13 Proceedings Special Issue, v2: no typos conjectur

Parasite viability as a measure of in vivo drug activity in preclinical and early clinical antimalarial drug assessment

The rate at which parasitemia declines in a host after treatment with an antimalarial drug is a major metric for assessment of antimalarial drug activity in preclinical models and in early clinical trials. However, this metric does not distinguish between viable and nonviable parasites. Thus, enumeration of parasites may result in underestimation of drug activity for some compounds, potentially confounding its use as a metric for assessing antimalarial activity in vivo. Here, we report a study of the effect of artesunate on Plasmodium falciparum viability in humans and in mice. We first measured the drug effect in mice by estimating the decrease in parasite viability after treatment using two independent approaches to estimate viability. We demonstrate that, as previously reported in humans, parasite viability declines much faster after artesunate treatment than does the decline in parasitemia (termed parasite clearance). We also observed that artesunate kills parasites faster at higher concentrations, which is not discernible from the traditional parasite clearance curve and that each subsequent dose of artesunate maintains its killing effect. Furthermore, based on measures of parasite viability, we could accurately predict the in vivo recrudescence of infection. Finally, using pharmacometrics modeling, we show that the apparent differences in the antimalarial activity of artesunate in mice and humans are partly explained by differences in host removal of dead parasites in the two hosts. However, these differences, along with different pharmacokinetic profiles, do not fully account for the differences in activity. (This study has been registered with the Australian New Zealand Clinical Trials Registry under identifier ACTRN12617001394336.)

Cloning of the Repertoire of Individual Plasmodium falciparum var Genes Using Transformation Associated Recombination (TAR)

One of the major virulence factors of the malaria causing parasite is the Plasmodium falciparum encoded erythrocyte membrane protein 1 (PfEMP1). It is translocated to It the membrane of infected erythrocytes and expressed from approximately 60 var genes in a mutually exclusive manner. Switching of var genes allows the parasite to alter functional and antigenic properties of infected erythrocytes, to escape the immune defense and to establish chronic infections. We have developed an efficient method for isolating VAR genes from telomeric and other genome locations by adapting transformation-associated recombination (TAR) cloning, which can then be analyzed and sequenced. For this purpose, three plasmids each containing a homologous sequence representing the upstream regions of the group A, B, and C var genes and a sequence homologous to the conserved acidic terminal segment (ATS) of var genes were generated. Co-transfection with P. falciparum strain ITG2F6 genomic DNA in yeast cells yielded 200 TAR clones. The relative frequencies of clones from each group were not biased. Clones were screened by PCR, as well as Southern blotting, which revealed clones missed by PCR due to sequence mismatches with the primers. Selected clones were transformed into E. coli and further analyzed by RFLP and end sequencing. Physical analysis of 36 clones revealed 27 distinct types potentially representing 50% of the var gene repertoire. Three clones were selected for sequencing and assembled into single var gene containing contigs. This study demonstrates that it is possible to rapidly obtain the repertoire of var genes from P. falciparum within a single set of cloning experiments. This technique can be applied to individual isolates which will provide a detailed picture of the diversity of var genes in the field. This is a powerful tool to overcome the obstacles with cloning and assembly of multi-gene families by simultaneously cloning each member

A whole cell pathway screen reveals seven novel chemosensitizers to combat chloroquine resistant malaria

Due to the widespread prevalence of resistant parasites, chloroquine (CQ) was removed from front-line antimalarial chemotherapy in the 1990s despite its initial promise of disease eradication. Since then, resistance-conferring mutations have been identified in transporters such as the PfCRT, that allow for the efflux of CQ from its primary site of action, the parasite digestive vacuole. Chemosensitizing/ chemoreversing compounds interfere with the function of these transporters thereby sensitizing parasites to CQ once again. However, compounds identified thus far have disappointing in vivo efficacy and screening for alternative candidates is required to revive this strategy. In this study, we propose a simple and direct means to rapidly screen for such compounds using a fluorescent-tagged CQ molecule. When this screen was applied to a small library, seven novel chemosensitizers (octoclothepin, methiothepin, metergoline, loperamide, chlorprothixene, L-703,606 and mibefradil) were quickly elucidated, including two which showed greater potency than the classical chemosensitizers verapamil and desipramine

Potent dual inhibitors of Plasmodium falciparum M1 and M17 aminopeptidases through optimization of S1 pocket interactions

Malaria remains a global health problem, and though international efforts for treatment and eradication have made some headway, the emergence of drug-resistant parasites threatens this progress. Antimalarial therapeutics acting via novel mechanisms are urgently required. P. falciparum M1 and M17 are neutral aminopeptidases which are essential for parasite growth and development. Previous work in our group has identified inhibitors capable of dual inhibition of PfA-M1 and PfA-M17, and revealed further regions within the protease S1 pockets that could be exploited in the development of ligands with improved inhibitory activity. Herein, we report the structure-based design and synthesis of novel hydroxamic acid analogues that are capable of potent inhibition of both PfA-M1 and PfA-M17. Furthermore, the developed compounds potently inhibit Pf growth in culture, including the multi-drug resistant strain Dd2. The ongoing development of dual PfA-M1/PfA-M17 inhibitors continues to be an attractive strategy for the design of novel antimalarial therapeutics