An ancestral molecular response to nanomaterial particulates.

The varied transcriptomic response to nanoparticles has hampered the understanding of the mechanism of action. Here, by performing a meta-analysis of a large collection of transcriptomics data from various engineered nanoparticle exposure studies, we identify common patterns of gene regulation that impact the transcriptomic response. Analysis identifies deregulation of immune functions as a prominent response across different exposure studies. Looking at the promoter regions of these genes, a set of binding sites for zinc finger transcription factors C2H2, involved in cell stress responses, protein misfolding and chromatin remodelling and immunomodulation, is identified. The model can be used to explain the outcomes of mechanism of action and is observed across a range of species indicating this is a conserved part of the innate immune system.

Irreversible TrxR1 inhibitors block STAT3 activity and induce cancer cell death.

Because of its key role in cancer development and progression, STAT3 has become an attractive target for developing new cancer therapeutics. While several STAT3 inhibitors have progressed to advanced stages of development, their underlying biology and mechanisms of action are often more complex than would be expected from specific binding to STAT3. Here, we have identified and optimized a series of compounds that block STAT3-dependent luciferase expression with nanomolar potency. Unexpectedly, our lead compounds did not bind to cellular STAT3 but to another prominent anticancer drug target, TrxR1. We further identified that TrxR1 inhibition induced Prx2 and STAT3 oxidation, which subsequently blocked STAT3-dependent transcription. Moreover, previously identified inhibitors of STAT3 were also found to inhibit TrxR1, and likewise, established TrxR1 inhibitors block STAT3-dependent transcriptional activity. These results provide new insights into the complexities of STAT3 redox regulation while highlighting a novel mechanism to block aberrant STAT3 signaling in cancer cells.

Parametrization of nanoparticles: development of full-particle nanodescriptors.

While metal oxide nanoparticles (NPs) are one of the most commonly used nanomaterials, the theoretical models used to analyze and predict their behavior have been mostly based on just the chemical composition or the extrapolation from small metal oxide clusters' calculations. In this study, a set of novel, theoretical full-particle descriptors for modeling, grouping or read-across of metal oxide NP properties and biological activity was developed based on the force-field calculation of the potential energies of whole NPs. The capability of these nanodescriptors to group the nanomaterials acoording to their biological activity was demonstrated by Principal Component Analysis (PCA). The grouping provided by the PCA approach was found to be in good accordance with the algal growth inhibition data of well characterized nanoparticles, synthesized and measured inside the consortia of the EU 7FP framework MODERN project.

IL-6 activated JAK/STAT3 pathway and sensitivity to Hsp90 inhibitors in multiple myeloma.

Modern anti-cancer treatment involves targeted therapy that aims at inactivating particular oncoproteins or signaling pathways in a cancer-type-specific manner. A number of potent targeted therapies affecting oncogenic kinases or receptor tyrosine kinases have revolutionized anti-cancer treatment. These drugs inactivate signaling pathways that cancer cells depend on and therefore inhibit their proliferation and survival. Molecular chaperones of the Hsp90 family (heat shock protein 90) support the integrity, folding and function of many proteins involved in proliferation, survival, DNA damage and repair. Hsp90 proteins are thus required to maintain activity of a large variety of oncogenic proteins, including members of the JAK/STAT and the PI3K pathways. Accordingly cancer cells rely on Hsp90 proteins and their expression is often elevated in malignant cells. In line with this, inhibitors of Hsp90 (Hsp90-Is) have demonstrated potent antitumor activity in preclinical studies. While Hsp90-Is can be considered as targeted therapy, their broad effects on multiple signaling pathways make it difficult to predict the therapeutic outcome. Multiple myeloma (MM) is one of the tumor types with elevated Hsp90 levels. Hsp90-Is demonstrated promising activity in preclinical studies of MM and in several clinical trials. However, large variability in response questioned the use of Hsp90-Is as single drugs in the treatment of myeloma. A critical factor in targeted therapies, including Hsp90-Is, is identification of susceptible subgroups of patients. Predictive biomarkers in each particular tumor type are important in order to use anti-cancer drugs in a rational way. Interestingly, levels of Hsp90 expression has not proven to be decisive for treatment response and hence stratification of myeloma patients. Others and we have recently found that MM cells with an IL-6-activated JAK/STAT3 pathway are particularly sensitive to Hsp90-Is. In this review we will discuss these findings, both in terms of molecular mechanisms and applications for selection of MM patients amenable to Hsp90-I treatment in an individually targeted treatment strategy.

Intra-articular corticoid injection induces circulating glucocorticoid bioactivity and systemic immune activation in juvenile idiopathic arthritis.

OBJECTIVE: To study the systemic effects of intra-articular (IA) glucocorticoid (GC) injections in juvenile idiopathic arthritis (JIA). METHODS: The study group comprised 21 JIA patients being treated with IA methylprednisolone [MP (n = 15) or MP plus triamcinolone hexacetonide (THA) (n = 6)] prescribed on clinical indications. The systemic effect of MP was assessed by measuring circulating glucocorticoid bioactivity (GBA) with a recombinant cell transactivation assay 7 and 24 h after the IA injections, and after 2 months. The systemic immunological responses were studied with a novel assay for testing patient serum-induced changes in the secretion of interferon (IFN)-γ and interleukin (IL)-5 from target cells. RESULTS: Administration of IA GC induced serum GBA (p = 0.001) and suppressed circulating cortisol levels (p = 0.002) 7 h after the injection. Serum withdrawn 24 h after the IA injection induced less IL-5 secretion from mitogen-activated target cells when compared with pre-treatment sera (p = 0.036). This decrease in target cell T helper (Th)2 response (IL-5) was MP dose related (r = -0.550, p = 0.018). High IL-5 secretion from target cells prior to the IA injections was associated with good clinical outcome at 2 months, seen as a low number of active (p = 0.044) and restricted joints (p = 0.049). CONCLUSION: IA GC injections have systemic effects that are reflected in the serum as an immediate elevation of GBA, a decrease of endogenous cortisol as well as a suppressive effect of patient serum on target cell IL-5 secretion. These systemic effects may play a role in the attenuation of disease activity.

Glucocorticoid-induced cell death is mediated through reduced glucose metabolism in lymphoid leukemia cells.

Malignant cells are known to have increased glucose uptake and accelerated glucose metabolism. Using liquid chromatography and mass spectrometry, we found that treatment of acute lymphoblastic leukemia (ALL) cells with the glucocorticoid (GC) dexamethasone (Dex) resulted in profound inhibition of glycolysis. We thus demonstrate that Dex reduced glucose consumption, glucose utilization and glucose uptake by leukemic cells. Furthermore, Dex treatment decreased the levels of the plasma membrane-associated glucose transporter GLUT1, thus revealing the mechanism for the inhibition of glucose uptake. Inhibition of glucose uptake correlated with induction of cell death in ALL cell lines and in leukemic blasts from ALL patients cultured ex vivo. Addition of di-methyl succinate could partially overcome cell death induced by Dex in RS4;11 cells, thereby further supporting the notion that inhibition of glycolysis contributes to the induction of apoptosis. Finally, Dex killed RS4;11 cells significantly more efficiently when cultured in lower glucose concentrations suggesting that modulation of glucose levels might influence the effectiveness of GC treatment in ALL. In summary, our data show that GC treatment blocks glucose uptake by leukemic cells leading to inhibition of glycolysis and that these effects play an important role in the induction of cell death by these drugs.

Cell death induced by dexamethasone in lymphoid leukemia is mediated through initiation of autophagy.

Glucocorticoids are fundamental drugs used in the treatment of lymphoid malignancies with apoptotic cell death as the hitherto proposed mechanism of action. Recent studies, however, showed that an alternative mode of cell death, autophagy, is involved in the response to anticancer drugs. The specific role of autophagy and its relationship to apoptosis remains, nevertheless, controversial: it can either lead to cell survival or can function in cell death. We show that dexamethasone induced autophagy upstream of apoptosis in acute lymphoblastic leukemia cells. Inhibition of autophagy by siRNA-mediated repression of Beclin 1 expression inhibited apoptosis showing an important role of autophagy in dexamethasone-induced cell death. Dexamethasone treatment caused an upregulation of promyelocytic leukemia protein, PML, its complex formation with protein kinase B or Akt and a PML-dependent Akt dephosphorylation. Initiation of autophagy and the onset of apoptosis were both dependent on these events. PML knockout thymocytes were resistant to dexamethasone-induced death and upregulation of PML correlated with the ability of dexamethasone to kill primary leukemic cells. Our data reveal key mechanisms of dexamethasone-induced cell death that may inform the development of improved treatment protocols for lymphoid malignancies.

Empirical classification of children with JIA: a multidimensional approach to pain and well-being.

OBJECTIVE: To investigate the relationship between children's arthritis self-efficacy, trait-anxiety, depression, clinical state of the disease (pain, disability, number of somatic complaints and active joints) and age of the child. METHODS: Trait anxiety and depression of JIA patients were measured by standardized scales (STAIC and CDI). For assessing self-efficacy CASE-scale was used. Pain, CHAQ and active joint count were used as indicators of the disease severity. The K-means cluster procedure was used to classify 145 consecutively recruited patients aged 8 to 15, regarding age, trait-anxiety and depression. One-way multivariate analysis of variance (MANOVA) followed by separate ANOVA's was used for comparisons between the cluster groups. Associations between the cluster groups and the children's self-efficacy were then evaluated using multivariate analysis of variance (MANOVA). RESULTS: Four cluster groups were identified based on the degree of depression and trait-anxiety. Clinical disease-related parameters differed significantly in the cluster groups. Pain was not necessarily related to the severity of the disease or to the diagnosis (oligoarthritis, oligoextended and polyarthritis). A higher level of self-efficacy was related to lower levels of depression, trait anxiety and pain. CONCLUSION: In JIA, the clinical classification of disease activity and severity did not directly correspond with depression and trait-anxiety in children with JIA. Instead, these were regulated by a self-efficacy, which was associated with less pain and somatic complaints.

Autoantibodies to the extracellular and intracellular domain of bullous pemphigoid 180, the putative key autoantigen in bullous pemphigoid, belong predominantly to the IgG1 and IgG4 subclasses.

BACKGROUND: Autoantibodies to the extracellular domain (ECD) of bullous pemphigoid (BP) antigen 180 (BP180) are thought to play a crucial part in the pathophysiology of BP. OBJECTIVES: As the various IgG subclasses have different biological properties, we have sought to assess the relative isotype distribution of IgG to BP180 and their reactivity against the ECD and intracellular domain (ICD) of BP180. METHODS: The reactivity of 27 sera from patients with BP was assayed by immunoblotting against recombinant proteins covering the ECD and ICD of BP180. RESULTS: Twenty-seven (100%) and 21 (77%) of 27 BP sera, respectively, contained IgG1 and IgG4 autoantibodies binding to the ECD of BP180. Fourteen (82%) and six (35%) of the 17 BP sera that were reactive with the ICD of BP180 had autoantibodies of the IgG1 and IgG4 subclass, respectively. The profile of the isotype restriction appeared to be similar when the response to the ECD vs. that to the ICD was compared. IgG2 and IgG3 reactivity with BP180 was found less frequently. Patients with BP of longer duration showed a tendency to have, in addition to IgG1, an IgG4 response. CONCLUSIONS: Consistent with prior evidence indicating that subepidermal blister formation in BP is dependent upon complement activation, the frequent finding of complement-fixing IgG1 autoantibodies to both the ECD and ICD of BP180 might have pathogenic relevance in BP. These findings provide new insights relevant for our understanding of the immune response to BP180, the putative key autoantigen in BP.

Plectin, an unusual target antigen in bullous pemphigoid.

BACKGROUND: Bullous pemphigoid (BP) is a blistering disease associated with autoantibodies directed against two components of hemidesmosomes, BP180 and BP230. OBJECTIVES: To assess whether BP patients have autoantibodies targeting plectin, another hemidesmosomal component showing extensive homology to BP230. METHODS: Examination of sera from 16 patients with BP, using immunoprecipitation studies followed by immunoblotting. RESULTS: Serum of one of the 16 (6%) patients with BP contain autoantibodies binding to plectin, while no reactivity was found with sera from three control subjects. Sera from all 16 BP patients immunoprecipitated BP230 from extracts of biosynthetically radiolabelled human keratinocytes. CONCLUSIONS: Our results indicate that sera from BP patients might contain autoantibodies binding to plectin. Although this protein and BP230 are closely sequence-related, the occurrence of autoantibodies binding to plectin is a rare phenomenon in BP.

Ecthyma gangrenosum-like lesions: a sign of disseminated Fusarium infection in the neutropenic patient.

Fusarium is a saprophytic fungus of soil causing disease in plants and animals. In the immunocompetent patient, Fusarium is non-invasive, colonizing wounds, ulcers or nails. In the immunocompromised host, however, especially in those whose neutrophil and macrophage function is deficient, it can cause devastating systemic infections. Skin lesions are an early feature of the disseminated disease. Rapid diagnosis and treatment are mandatory in order to give the patient a better chance of survival, reported mortality rates being as high as 90%.

IgM autoantibodies to 180- and 230- to 240-kd human epidermal proteins in pregnancy.

BACKGROUND AND DESIGN: A previous study has suggested that there is a novel entity among the polymorphous eruptions of pregnancy (PEP) associated with circulating anti-basement membrane zone IgM autoantibodies. To determine if the presence of anti-basement membrane zone IgM autoantibodies is a feature of PEP, serum samples from 52 patients with a PEP, 69 healthy pregnant women, and 42 nonpregnant women were prospectively evaluated by indirect immunofluorescence using salt-split human skin as substrate. Serum samples were also tested by immunoblotting using keratinocyte extracts and anti-human IgM antibodies. The reactivity of some serum samples was examined using two recombinant bullous pemphigoid antigen proteins. RESULTS: The percentage of women with a PEP, healthy pregnant women, and nonpregnant women who had anti-basement membrane zone IgM antibodies by indirect immunofluorescence was similar: 12%, 10%, and 14% of cases, respectively. By immunoblotting, 14% of the serum samples from the patients with a PEP, 12% of the serum samples from the healthy pregnant women, but only 2% of the serum samples from the nonpregnant women contained IgM antibodies that reacted with epidermal proteins of 180 and/or 230 to 240 kd. The recombinant bullous pemphigoid antigen proteins were not recognized by any of the serum samples that showed a reactivity by immunoblotting using keratinocyte extracts. CONCLUSION: There is no evidence for the existence of a novel entity of pregnancy defined by circulating anti-basement membrane zone IgM autoantibodies. Immunoblotting detects IgM autoantibodies that react with epidermal proteins of 180 and/or 230 to 240 kd. These autoantibodies appear to be more frequent in pregnant than in nonpregnant women. Although the nature of the target antigen(s) remains to be established, pregnancy may be associated with low levels of IgM autoreactivity against epidermal proteins.

[Indications for surgical treatment in ischemic heart disease and its results]. / Pokazaniia k khirurgicheskomu lecheniiu ishemicheskoi bolezni serdtsa i ego rezul'taty.

Of the 210 patients who underwent direct coronary surgery for stable and unstable angina pectoris and acute myocardial ischemia, 187 were followed up after the operation for 11 months on the average. Operative mortality was 11%. Among the 187 patients, 46.5% were completely relieved of angina, 36.4% showed moderate improvement, and 16.9% had no improvement in their condition. Patients with prior myocardial infarction had a substantially diminished success rate for relief of angina. Postoperative angiography in 125 patients demonstrated high correlation between clinical response and graft patency. It is concluded that direct coronary surgery provides partial or complete relief of angina pectoris in 82.9% of patients, and this response to operative treatment may be directly related to the success of the surgery ensuring patency of the graft, evidence of which is demonstrated by angiography.

[Congenital partial defect of the pericardium with herniation of the left atrial appendage (author's transl)]. / Angeborener und unvollständiger Verschluss des Perikards mit Prolaps des linken Herzohres.

Congenital partial pericardial defect with herniation of the left atrial appendage presents a rare anomaly. Clinical appearance of a 25-year-old man with this anomaly combined with adherance to the left lung hilus and the pericardial sac is described. He suffered from cardiac arrhythmias and dyspnea during exertion. The chest X-ray film at unremarkable physical examination and routine laboratory data within normal limits showed a prominent shadow of the left cardiac border, the cineangiocardiographic findings revealed that the prominence was due to a large left atrial appendage. Since strangulation of the left atrial appendage is a well-known and described potential hazard, thoracic surgery was performed without any complication.