Cyclophosphamide resets dendritic cell homeostasis and enhances antitumor immunity through effects that extend beyond regulatory T cell elimination

Using a model of established malignancy, we found that cyclophosphamide (Cy), administered at a dose not requiring hematopoietic stem cell support, is superior to low-dose total body irradiation in augmenting antitumor immunity. We observed that Cy administration resulted in expansion of tumor antigen-specific T cells and transient depletion of CD4⁺Foxp3⁺ regulatory T cells (Tregs). The antitumor efficacy of Cy was not improved by administration of anti-CD25 monoclonal antibody given to induce more profound Treg depletion. We found that Cy, through its myelosuppressive action, induced rebound myelopoiesis and perturbed dendritic cell (DC) homeostasis. The resulting DC turnover led to the emergence of tumor-infiltrating DCs that secreted more IL-12 and less IL-10 compared to those from untreated tumor-bearing animals. These newly recruited DCs, originating from proliferating early DC progenitors, were fully capable of priming T cell responses and ineffective in inducing expansion of Tregs. Together, our results show that Cy-mediated antitumor effects extend beyond the well-documented cytotoxicity and lymphodepletion and include resetting the DC homeostasis, thus providing an excellent platform for integration with other immunotherapeutic strategies.     

Predictive impact of coronary risk factors in southern Croatia: a case control study

The aim of study was to compare the impact of coronary risk factors on the incidence of acute myocardial infarction (MI) between Croatia, Central and Eastern Europe, and the rest of the world. As a part of the large international INTERHEART case-control study of acute MI in 52 countries (15,152 cases and 14,820 controls) we have investigated the relationship between several known risk factors (smoking, history of hypertension or diabetes, waist/hip ratio, dietary patterns, physical activity, consumption of alcohol, blood apolipoproteins, and psychosocial factors) and MI among patients without previously known coronary heart disease in Southern Croatia. The main identified MI risk factors in Southern Croatia were heavy smoking (>20 cig/day; OR 3.86; 95% CI 2.31-6.46), diabetes mellitus (OR 2.83; 95% CI 1.58-5.23), abnormal ratio of B-100 and A-1 apolipoproteins (OR 2.23; 95% CI 1.28-3.89), elevated waist to hip ratio (OR 1.96; 95% CI 1.21-3.18), and arterial hypertension (OR 1.68; 95% CI 1.15-2.45). Protective was moderate alcohol consumption (OR 0.63; 95% CI 0.40-0.99). The prevalence of major MI risk factors in Croatia is similar to that in the surrounding countries and in the world, accounting for over 90% of the population attributable risk. However, physical activity, dietary and psychosocial factors are seemingly less important in this country, while moderate alcohol consumption is more protective than regionally or globally.     

Plant resistome profiling in evolutionary old bog vegetation provides new clues to understand emergence of multi-resistance

The expanding antibiotic resistance crisis calls for a more in depth understanding of the importance of antimicrobial resistance genes (ARGs) in pristine environments. We, therefore, studied the microbiome associated with Sphagnum moss forming the main vegetation in undomesticated, evolutionary old bog ecosystems. In our complementary analysis of culture collections, metagenomic data and a fosmid library from different geographic sites in Europe, we identified a low abundant but highly diverse pool of resistance determinants, which targets an unexpectedly broad range of 29 antibiotics including natural and synthetic compounds. This derives both, from the extraordinarily high abundance of efflux pumps (up to 96%), and the unexpectedly versatile set of ARGs underlying all major resistance mechanisms. Multi-resistance was frequently observed among bacterial isolates, e.g. in Serratia, Rouxiella, Pandoraea, Paraburkholderia and Pseudomonas. In a search for novel ARGs, we identified the new class A β-lactamase Mm3. The native Sphagnum resistome comprising a highly diversified and partially novel set of ARGs contributes to the bog ecosystem´s plasticity. Our results reinforce the ecological link between natural and clinically relevant resistomes and thereby shed light onto this link from the aspect of pristine plants. Moreover, they underline that diverse resistomes are an intrinsic characteristic of plant-associated microbial communities, they naturally harbour many resistances including genes with potential clinical relevance.Subject terms: Environmental microbiology, Metagenomics, Microbial ecology     

Motifs and Images in a Balinese Ritual Drama: Their Mythic References and ‘Metaphorical Truth’

For insofar as dialectical thinking is thought about thought,… such self-consciousness must be inscribed in the sentence itself. And insofar as dialectical thinking characteristically involves a conjunction of opposites or at least conceptually disparate phenomena, it may be truly said of the dialectical sentence what Surrealists said about the image, namely that its strength increases proportionately as the realities linked are distant and distinct from each other (Jameson 1971: 53–4).     

Cystopteris dickieana R.Sim (Cystopteridaceae), a new fern in the continental Balkans flora

Abstract

Cystopteris dickieana, a rare circum-Holarctic species, is recorded for the first time for the NW part of the Balkan area. Mature spores rugose characterize this fern within the C. fragilis species complex.     

Treatment of osteoporosis with a modified zeolite shows beneficial effects in an osteoporotic rat model and a human clinical trial

The severity of osteoporosis in humans manifests in its high incidence and by its complications that diminish quality of life. A societal consequence of osteoporosis is the substantial burden that it inflicts upon patients and their families. Several bone-modifying drugs have been prescribed to patients with osteoporosis. However, evidence for their anti-fracture efficacy remains inconclusive. To the contrary, long-term use of anti-osteoporotic drugs such as bisphosphonates and Denosumab, an RANKL inhibitor, have resulted in adverse events. We now present an alternative and adjuvant approach for treatment of osteoporosis. The data derive from in vivo studies in an ovariectomized rat model and from a randomized double blind, placebo-controlled human clinical study. Both studies involved treatment with Panaceo Micro Activation (PMA)-zeolite-clinoptilolite, a defined cation exchange clinoptilolite, which clearly improved all bone histomorphometric parameters examined from ovariectomized animals, indicative for increased bone formation. Moreover, intervention with PMA-zeolite-clinoptilolite for one year proved safe in humans. Furthermore, patients treated with PMA-zeolite-clinoptilolite showed an increase in bone mineral density, an elevated level of markers indicative of bone formation, a significant reduction in pain, and significantly improved quality of life compared with patients in the control (placebo) group. These encouraging positive effects of PMA-zeolite-clinoptilolite on bone integrity and on osteoporosis warrant further evaluation of treatment with PMA-zeolite-clinoptilolite as a new alternative adjuvant therapy for osteoporosis.