Burden of Disease Due to Ambient Particulate Matter in Germany-Explaining the Differences in the Available Estimates.

Ambient particulate matter (PM2.5) pollution is an important threat to human health. The aim of this study is to estimate the environmental burden of disease (EBD) for the German population associated with PM2.5 exposure in Germany for the years 2010 until 2018. The EBD method was used to quantify relevant indicators, e.g., disability-adjusted life years (DALYs), and the life table approach was used to estimate the reduction in life expectancy caused by long-term PM2.5 exposure. The impact of varying assumptions and input data was assessed. From 2010 to 2018 in Germany, the annual population-weighted PM2.5 concentration declined from 13.7 to 10.8 µg/m3. The estimates of annual PM2.5-attributable DALYs for all disease outcomes showed a downward trend. In 2018, the highest EBD was estimated for ischemic heart disease (101.776; 95% uncertainty interval (UI) 62,713-145,644), followed by lung cancer (60,843; 95% UI 43,380-79,379). The estimates for Germany differ from those provided by other institutions. This is mainly related to considerable differences in the input data, the use of a specific German national life expectancy and the selected relative risks. A transparent description of input data, computational steps, and assumptions is essential to explain differing results of EBD studies to improve methodological credibility and trust in the results. Furthermore, the different calculated indicators should be explained and interpreted with caution.

Tannin-Based Hybrid Materials and Their Applications: A Review.

Tannins are eco-friendly, bio-sourced, natural, and highly reactive polyphenols. In the past decades, the understanding of their versatile properties has grown substantially alongside a continuously broadening of the tannins' application scope. In particular, recently, tannins have been increasingly investigated for their interaction with other species in order to obtain tannin-based hybrid systems that feature advanced and/or novel properties. Furthermore, in virtue of the tannins' chemistry and their high reactivity, they either physicochemically or physically interact with a wide variety of different compounds, including metals and ceramics, as well as a number of organic species. Such hybrid or hybrid-like systems allow the preparation of various advanced nanomaterials, featuring improved performances compared to the current ones. Consequently, these diverse-shaped materials have potential use in wastewater treatment or catalysis, as well as in some novel fields such as UV-shielding, functional food packaging, and biomedicine. Since these kinds of tannin-based hybrids represent an emerging field, thus far no comprehensive overview concerning their potential as functional chemical building blocks is available. Hence, this review aims to provide a structured summary of the current state of research regarding tannin-based hybrids, detailed findings on the chemical mechanisms as well as their fields of application.

S1PR4-dependent CCL2 production promotes macrophage recruitment in a murine psoriasis model.

The sphingolipid sphingosine-1-phosphate (S1P) fulfills distinct functions in immune cell biology via binding to five G protein-coupled receptors. The immune cell-specific sphingosine-1-phosphate receptor 4 (S1pr4) was connected to the generation of IL-17-producing T cells through regulation of cytokine production in innate immune cells. Therefore, we explored whether S1pr4 affected imiquimod-induced murine psoriasis via regulation of IL-17 production. We did not observe altered IL-17 production, although psoriasis severity was reduced in S1pr4-deficient mice. Instead, ablation of S1pr4 attenuated the production of CCL2, IL-6, and CXCL1 and subsequently reduced the number of infiltrating monocytes and granulocytes. A connection between S1pr4, CCL2, and Mϕ infiltration was also observed in Zymosan-A induced peritonitis. Boyden chamber migration assays functionally linked reduced CCL2 production in murine skin and attenuated monocyte migration when S1pr4 was lacking. Mechanistically, S1pr4 signaling synergized with TLR signaling in resident Mϕs to produce CCL2, likely via the NF-κB pathway. We propose that S1pr4 activation enhances TLR response of resident Mϕs to increase CCL2 production, which attracts further Mϕs. Thus, S1pr4 may be a target to reduce perpetuating inflammatory responses.

Contact dermatitis: relevant differential diagnoses, simulators, and variants.

Similar to all eczematous disorders, irritant and allergic contact dermatitis are primarily defined by their morphology. In addition, the diagnosis of this specific reaction pattern on the skin (and mucous membranes) also requires prior exposure (direct or indirect) to an allergen or irritant. While it is quite easy to give a textbook description of the typical features of eczema, its clinical manifestations in daily practice are diverse and frequently uncharacteristic. Contact reactions may present as lichenoid, lymphomatoid, granulomatous, pigmented, purpuric, and erythema multiforme-like lesions, thus lacking the typical eczematous appearance and broadening the spectrum of differential diagnoses to be considered. Moreover, a considerable number of agents, acting by mechanisms other than contact, may trigger adverse reactions mimicking the eczematic morphology and distribution pattern of contact dermatitis. Increasingly used in oncology, this is especially true for drugs such as kinase inhibitors. Knowledge of these associations is crucial for the adequate diagnostic and therapeutic care of patients with supposed or actual contact dermatitis.

Clinical proton MR spectroscopy in central nervous system disorders.

A large body of published work shows that proton (hydrogen 1 [(1)H]) magnetic resonance (MR) spectroscopy has evolved from a research tool into a clinical neuroimaging modality. Herein, the authors present a summary of brain disorders in which MR spectroscopy has an impact on patient management, together with a critical consideration of common data acquisition and processing procedures. The article documents the impact of (1)H MR spectroscopy in the clinical evaluation of disorders of the central nervous system. The clinical usefulness of (1)H MR spectroscopy has been established for brain neoplasms, neonatal and pediatric disorders (hypoxia-ischemia, inherited metabolic diseases, and traumatic brain injury), demyelinating disorders, and infectious brain lesions. The growing list of disorders for which (1)H MR spectroscopy may contribute to patient management extends to neurodegenerative diseases, epilepsy, and stroke. To facilitate expanded clinical acceptance and standardization of MR spectroscopy methodology, guidelines are provided for data acquisition and analysis, quality assessment, and interpretation. Finally, the authors offer recommendations to expedite the use of robust MR spectroscopy methodology in the clinical setting, including incorporation of technical advances on clinical units.

Loss of STAT3 in Lymphoma Relaxes NK Cell-Mediated Tumor Surveillance.

The transcription factors and proto-oncogenes STAT3 and STAT5 are highly activated in hematological malignancies and represent promising therapeutic targets. Whereas the importance of STAT5 as tumor promoter is beyond doubt, the role of STAT3 in hematological cancers is less well understood. Both, enforced as well as attenuated expression of STAT3 were reported in hematopoietic malignancies. Recent evidence implicates STAT3 as key player for tumor immune surveillance as it both mediates the production of and response to inflammatory cytokines. Here we investigated the effects of STAT3 deletion in a BCR/ABL-induced lymphoma model, which is tightly controlled by natural killer (NK) cells in vivo. Upon STAT3 deletion tumor growth is significantly enhanced when compared to STAT3-expressing controls. The increased tumor size upon loss of STAT3 was accompanied by reduced NK cell infiltration and decreased levels of the cytokine IFN-γ and the chemokine RANTES. Upon transplantation into NK cell-deficient mice differences in lymphoma size were abolished indicating that STAT3 expression in the tumor cells controls NK cell-dependent tumor surveillance. Our findings indicate that STAT3 inhibition in lymphoma patients will impair NK cell-mediated tumor surveillance, which needs to be taken into account when testing STAT3 inhibitors in preclinical or clinical trials.

Bcl-2: Live and let die.

Recent findings from our laboratory provide the first indication that overexpression of Bcl-2 in Eµ-myc transgenic cells enhances tumor immunosurveillance by inducing NKG2D ligands. Initial evidence suggests that this model is relevant to human patients. Thus, antitumor therapies that target Bcl-2 harbor the risk of reducing tumor immunogenicity.

Diverging fates of cells of origin in acute and chronic leukaemia.

The large difference in phenotypes among tumour populations may stem from the stochastic origin of tumours from distinct cells - tumour cells are assumed to retain the phenotypes of the cells from which they derive. Yet, functional studies addressing the cellular origin of leukaemia are lacking. Here we show that the cells of origin of both, BCR/ABL-induced chronic myeloid (CML) and B-cell acute lymphoid leukaemia (B-ALL), resemble long-term haematopoietic stem cells (LT-HSCs). During disease-maintenance, CML LT-HSCs persist to function as cancer stem cells (CSCs) that maintain leukaemia and require signalling by the transcription factor STAT5. In contrast, B-ALL LT-HSCs differentiate into CSCs that correspond to pro-B cells. This transition step requires a transient IL-7 signal and is lost in IL-7Rα-deficient cells. Thus, in BCR/ABLp185(+) B-ALL and BCR/ABLp210(+) CML, the final phenotype of the tumour as well as the abundance of CSCs is dictated by diverging differentiation fates of their common cells of origin.

The cooperating mutation or "second hit" determines the immunologic visibility toward MYC-induced murine lymphomas.

In Eµ-myc transgenic animals lymphoma formation requires additional genetic alterations, which frequently comprise loss of p53 or overexpression of BCL-2. We describe that the nature of the "second hit" affects the ability of the immune system to contain lymphoma development. Tumors with disrupted p53 signaling killed the host more rapidly than BCL-2 overexpressing ones. Relaxing immunologic control, using Tyk2(-/-) mice or by Ab-mediated depletion of CD8(+) T or natural killer (NK) cells accelerated formation of BCL-2-overexpressing lymphomas but not of those lacking p53. Most strikingly, enforced expression of BCL-2 prolonged disease latency in the absence of p53, whereas blocking p53 function in BCL-2-overexpressing tumors failed to accelerate disease. This shows that blocking apoptosis in p53-deficient cells by enforcing BCL-2 expression can mitigate disease progression increasing the "immunologic visibility." In vitro cytotoxicity assays confirmed that high expression of BCL-2 protein facilitates NK and T cell-mediated killing. Moreover, we found that high BCL-2 expression is accompanied by significantly increased levels of the NKG2D ligand MULT1, which may account for the enhanced killing. Our findings provide first evidence that the nature of the second hit affects tumor immunosurveillance in c-MYC-driven lymphomas and define a potential shortcoming of antitumor therapies targeting BCL-2.

Stat5 is indispensable for the maintenance of bcr/abl-positive leukaemia.

Tumourigenesis caused by the Bcr/Abl oncoprotein is a multi-step process proceeding from initial to tumour-maintaining events and finally results in a complex tumour-supporting network. A key to successful cancer therapy is the identification of critical functional nodes in an oncogenic network required for disease maintenance. So far, the transcription factors Stat3 and Stat5a/b have been implicated in bcr/abl-induced initial transformation. However, to qualify as a potential drug target, a signalling pathway must be required for the maintenance of the leukaemic state. Data on the roles of Stat3 or Stat5a/b in leukaemia maintenance are elusive. Here, we show that both, Stat3 and Stat5 are necessary for initial transformation. However, Stat5- but not Stat3-deletion induces G(0)/G(1) cell cycle arrest and apoptosis of imatinib-sensitive and imatinib-resistant stable leukaemic cells in vitro. Accordingly, Stat5-abrogation led to effective elimination of myeloid and lymphoid leukaemia maintenance in vivo. Hence, we identified Stat5 as a vulnerable point in the oncogenic network downstream of Bcr/Abl representing a case of non-oncogene addiction (NOA).

Signal transducer and activator of transcription 3 protects from liver injury and fibrosis in a mouse model of sclerosing cholangitis.

BACKGROUND & AIMS: Signal transducer and activator of transcription 3 (Stat3) is the main mediator of interleukin-6-type cytokine signaling required for hepatocyte proliferation and hepatoprotection, but its role in sclerosing cholangitis and other cholestatic liver diseases remains unresolved. METHODS: We investigated the role of Stat3 in inflammation-induced cholestatic liver injury and used mice lacking the multidrug resistance gene 2 (mdr2(-/-)) as a model for SC. RESULTS: We show that conditional inactivation of Stat3 in hepatocytes and cholangiocytes (stat3(Deltahc)) of mdr2(-/-) mice strongly aggravated bile acid-induced liver injury and fibrosis. A similar phenotype was observed in mdr2(-/-) mice lacking interleukin-6 production. Biochemical and molecular characterization suggested that Stat3 exerts hepatoprotective functions in both hepatocytes and cholangiocytes. Loss of Stat3 led to increased expression of tumor necrosis factor alpha, which might reduce the barrier function of bile ducts. Moreover, Stat3-deficient hepatocytes displayed up-regulation of bile acid biosynthesis genes and down-regulation of hepatoprotective epidermal growth factor receptor and insulin-like growth factor 1 signaling pathways. Consistently, stat3(Deltahc) mice were more sensitive to cholic acid-induced liver damage than control mice. CONCLUSIONS: Our data suggest that Stat3 prevents cholestasis and liver damage in sclerosing cholangitis via regulation of pivotal functions in hepatocytes and cholangiocytes.

Leukemic challenge unmasks a requirement for PI3Kdelta in NK cell-mediated tumor surveillance.

Specific inhibitors of PI3K isoforms are currently evaluated for their therapeutic potential in leukemia. We found that BCR/ABL(+) human leukemic cells express PI3Kdelta and therefore explored its impact on leukemia development. Using PI3Kdelta-deficient mice, we define a dual role of PI3Kdelta in leukemia. We observed a growth-promoting effect in tumor cells and an essential function in natural killer (NK) cell-mediated tumor surveillance: Abelson-transformed PI3Kdelta-deficient cells induced leukemia in RAG2-deficient mice with an increased latency, indicating that PI3Kdelta accelerated leukemia progression in vivo. However, the absence of PI3Kdelta also affected NK cell-mediated tumor surveillance. PI3Kdelta-deficient NK cells failed to lyse a large variety of target cells because of defective degranulation, as also documented by capacitance recordings. Accordingly, transplanted leukemic cells killed PI3Kdelta-deficient animals more rapidly. As a net effect, no difference in disease latency in vivo was detected if both leukemic cells and NK cells lack PI3Kdelta. Other tumor models confirmed that PI3Kdelta-deficient mice succumbed more rapidly when challenged with T- or B-lymphoid leukemic or B16 melanoma cells. Thus, the action of PI3Kdelta in the NK compartment is as relevant to survival of the mice as the delayed tumor progression. This dual function must be taken into account when using PI3Kdelta inhibitors as antileukemic agents in clinical trials.

Selective serotonin reuptake inhibitors--a new modality for the treatment of lymphoma/leukaemia?

Selective serotonin reuptake inhibitors (SSRIs) have recently been reported to specifically kill malignant cells of B-lymphoid origin, i.e., cells derived from Burkitt lymphoma. Accordingly, SSRIs have been proposed as lead compounds in the development of new approaches to the treatment of lymphoma/leukaemia. Here we attempted to dissect the underlying signaling pathways by comparing susceptible and resistant cell lines. However, we found that all cell lines investigated underwent apoptotic cell death when exposed to SSRI concentrations exceeding 10 microM regardless of whether the cell lines were derived from B- (e.g., Namalwa, Ramos, Daudi, RL7), T-lymphoid tumors (e.g., Molt-4, Jurkat, CCRF-CEM) or other sources. The structure-activity relationship readily distinguished the pro-apoptotic and growth inhibitory effect of SSRIs from their eponymous action (blockage of the serotonin transporter): acetylation of the SSRIs fluvoxamine and paroxetine abrogated the ability of these compounds to inhibit 5HT-uptake, but did not impair their cytotoxic action. Based on these data we conclude that (i) SSRIs inhibit growth of transformed cells, but that (ii) this effect is neither specific for malignant cells nor specific for any particular cellular subset. (iii) The pro-apoptotic effect of SSRIs (at microM concentrations) is unrelated to their principal pharmacological action, i.e., inhibition of serotonin uptake (at nM concentrations). SSRIs or improved versions thereof are therefore unlikely to represent useful lead compounds for inducing apoptosis in B-cell derived tumors: the underlying mechanism is not confined to any specific cell lineage.

Inhibition of xenograft tumor growth and down-regulation of ErbB receptors by an antibody directed against Lewis Y antigen.

The blood group-related Lewis Y antigen is expressed on the majority of human cancers of epithelial origin with only limited expression on normal tissue. Therefore, the Lewis Y antigen represents an interesting candidate for antibody-based treatment strategies. Previous experiments showed that the humanized Lewis Y-specific monoclonal antibody, IGN311, reduced ErbB-receptor-mediated stimulation of mitogen-activated protein kinase by altering receptor recycling. Here, we tested whether binding of IGN311 to growth factor receptors is relevant also to inhibition of tumor growth in vivo. Prolonged incubation with IGN311 of human tumor cell lines, which express high levels of ErbB1 (A431) or ErbB2 (SK-BR-3), resulted in down-regulation of the receptors and inhibition of cell proliferation. IGN311 inhibited the growth of tumors derived from A431 cells xenografted in nude mice. Treatment with IGN311 was associated with a down-regulation of ErbB1 in the excised tumor tissue. Importantly, these effects of IGN311 were also mimicked by the Fab fragment of IGN311. These data indicate that tumor cell growth inhibition by IGN311 cannot solely be accounted for by invoking cellular and humoral immunological mechanisms. A direct effect on signaling via binding to Lewis Y glycosylated growth factor receptors on tumor cells is also likely to contribute to the therapeutic effect of IGN311 in vivo.

Simultaneous sustained release of fludarabine monophosphate and Gd-DTPA from an interstitial liposome depot in rats: potential for indirect monitoring of drug release by magnetic resonance imaging.

INTRODUCTION: Cytostatic depot preparations are interstitially administered for local chemotherapy and prevention of tumor recurrence. It would be of interest to monitor in patients as to when, to what extent, and exactly where, the drug is actually released. Liposomes containing a hydrophilic cytostatic and a hydrophilic contrast agent might be expected to release both agents simultaneously. If so, then drug release could be indirectly followed by monitoring contrast enhancement at the injection site. METHODS: Multivesicular liposomes containing the antimetabolite fludarabine monophosphate and the magnetic resonance imaging (MRI) contrast agent Gd-DTPA were subcutaneously injected in rats and both agents were monitored at the injection site for 6 weeks by 19F nuclear magnetic resonance spectroscopy (MRS) in vivo and contrast-enhanced 1H MRI (T1w 3D FLASH), respectively, in a 1.5-T whole-body tomograph. The MRS and MRI data were analyzed simultaneously by pharmacokinetic modeling using NONMEM. RESULTS: During an initial lag time, the amount of drug at the injection site stayed constant while the contrast-enhanced depot volume expanded beyond the volume injected. Drug amount and depot volume then decreased in parallel. Lag time and elimination half-life were 9 and 6 days, respectively, in three animals, and were about 50% shorter in another animal where the depot split into sub-depots. CONCLUSION: The preliminary data in rats suggest that simultaneous release of a hydrophilic cytostatic and a hydrophilic contrast agent from an interstitial depot can be achieved by encapsulation in liposomes. Thus, there seems to be a potential for indirect drug monitoring through imaging.

TYK2 is a key regulator of the surveillance of B lymphoid tumors.

Aberrant activation of the JAK-STAT pathway has been implicated in tumor formation; for example, constitutive activation of JAK2 kinase or the enforced expression of STAT5 induces leukemia in mice. We show here that the Janus kinase TYK2 serves an opposite function. Mice deficient in TYK2 developed Abelson-induced B lymphoid leukemia/lymphoma as well as TEL-JAK2-induced T lymphoid leukemia with a higher incidence and shortened latency compared with WT controls. The cell-autonomous properties of Abelson murine leukemia virus-transformed (A-MuLV-transformed) TYK2(-/-) cells were unaltered, but the high susceptibility of TYK2(-/-) mice resulted from an impaired tumor surveillance, and accordingly, TYK2(-/-) A-MuLV-induced lymphomas were easily rejected after transplantation into WT hosts. The increased rate of leukemia/lymphoma formation was linked to a decreased in vitro cytotoxic capacity of TYK2(-/-) NK and NKT cells toward tumor-derived cells. RAG2/TYK2 double-knockout mice succumbed to A-MuLV-induced leukemia/lymphoma faster than RAG2(-/-)TYK2(+/-) mice. This defines NK cells as key players in tumor surveillance in Abelson-induced malignancies. Our observations provide compelling evidence that TYK2 is an important regulator of lymphoid tumor surveillance.

Successful treatment of recalcitrant chronic actinic dermatitis with tacrolimus.

Therapeutically, chronic actinic dermatitis is a problematic condition. Frequently applied sunscreen usually fails to mitigate the clinical symptoms, and steroids--while efficient--exert many undesired side-effects with prolonged usage. We present a case of chronic actinic dermatitis responding well to topically applied tacrolimus (Protopic) in combination with chemical and physical UV protection.

Epidemiology of skin cancer.

The skin is the most common site of malignancy. Due to several mostly unknown factors, the frequency of skin tumors is increasing. Except for malignant melanoma, reliable statistical data on the frequency of skin tumors are scarce. Discussion on the epidemiology of skin tumors may take different aspects and factors into consideration: (1) histogenetic type; (2) race, (3) sex; (4) age, (5) localization; (6) environment. Moreover, precancerous conditions also may play an important role in this context. Epithelial tumors, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the most frequent tumors of the skin. Figures show a wide range between 40 and over 700 or 5 and 250 respectively per 100 000 inhabitants per year depending on the country or area of report. Malignant melanoma is more frequently seen in Caucasians living in sunny regions (40) than in northern countries or in dark skinned races (4-12 per 100 000 per year), representing 4% of all skin tumors, but being responsible for 79% of skin cancer deaths. Other types of skin tumors like cutaneous lymphoma, Kaposi sarcoma, lipomas, adnexal tumors etc. are either not reported regularly and reliable epidemiologic data is not available, or are rare cutaneous tumors (taken all together < 1%).