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Objectives: Multidrug-resistant organisms (MDRO) are considered an emerging threat worldwide. Data covering the clinical impact of MDRO colonization in patients with solid malignancies, however, is widely missing. We sought to determine the impact of MDRO colonization in patients who have been diagnosed with Non-small cell lung cancer (NSCLC) who are at known high-risk for invasive infections.
Materials and methods: Patients who were screened for MDRO colonization within a 90-day period after NSCLC diagnosis of all stages were included in this single-center retrospective study.
Results: Two hundred and ninety-five patients were included of whom 24 patients (8.1%) were screened positive for MDRO colonization (MDROpos) at first diagnosis. Enterobacterales were by far the most frequent MDRO detected with a proportion of 79.2% (19/24). MDRO colonization was present across all disease stages and more present in patients with concomitant diabetes mellitus. Median overall survival was significantly inferior in the MDROpos study group with a median OS of 7.8 months (95% CI, 0.0–19.9 months) compared to a median OS of 23.9 months (95% CI, 17.6–30.1 months) in the MDROneg group in univariate (p = 0.036) and multivariate analysis (P = 0.02). Exploratory analyses suggest a higher rate of non-cancer-related-mortality in MDROpos patients compared to MDROneg patients (p = 0.002) with an increased rate of fatal infections in MDROpos patients (p = 0.0002).
Conclusions: MDRO colonization is an independent risk factor for inferior OS in patients diagnosed with NSCLC due to a higher rate of fatal infections. Empirical antibiotic treatment approaches should cover formerly detected MDR commensals in cases of (suspected) invasive infections.
Although immune checkpoint inhibitors such as anti-PD-1 antibodies have shown remarkable clinical success in many different tumor types, the proportion of patients benefiting from this treatment option remains low. Therefore, there is a need to sensitize tumors for immune checkpoint blockade. In this study two approaches were tested, a chemoimmunotherapy approach combining PD-1 checkpoint blockade with doxorubicin (DOX) chemotherapy, and ablation of the sphingosine-1-phosphate (S1P) receptor (S1PR4) based on the following rationale. Chemotherapy was shown to induce immune paralysis which contributes to tumor relapse, while PD-1 signaling was shown to facilitate the acquisition of chemoresistance. Thus, combinatorial chemoimmunotherapy is expected to be beneficial by maintaining or even activating anti-tumor immunity during chemotherapy. S1PR4 is an immune cell specific receptor, whose ablation slowed tumor progression by activating anti-tumor immunity in a mouse model that was previously insensitive to anti-PD-1 monotherapy. This suggested that S1PR4 ablation might pre-activate immunity to sensitize for anti-PD-1 therapy.
To test these combinatorial approaches, two tumor mouse models were employed, namely the MC38 murine adenocarcinoma model as well as the transgenic polyoma middle T oncogene (PyMT) breast cancer model. In the MC38 model, a mild synergistic effect of PD-1 immune checkpoint blockade and S1PR4 ablation was observed, indicated by improved tumor progression and survival as compared to the WT control, and an increased number of tumor-free mice compared to anti-PD-1 therapy alone in WT mice. These observations correlated with an enhanced natural killer (NK) cell infiltrate and increased CXCL9 and CXCL10 production in anti-PD-1 treated S1PR4 KO tumors. As noted before, the PyMT model was largely resistant to anti-PD-1 monotherapy in a therapeutic setting. S1PR4 ablation alone showed significant tumor reduction that was not further enhanced by anti-PD-1 treatment. The same was observed when chemotherapy with DOX was added, where WT tumors relapsed, while S1PR4 KO tumor did not. Addition of anti-PD-1 did only mildly increase tumor control in S1PR4 KO mice, indicating that S1PR4 KO per se very efficiently re-activated anti-tumor immunity. Since S1PR4 KO induces type I 12 interferon (IFN-1) over-production in S1PR4 KO PyMT tumors, a link between high IFN-1 levels and tumor immunity was tested by using mice deficient in the IFN-1 receptor (IFNAR1). Unexpectedly, DOX chemotherapy was most efficient in mice with IFNAR ablation only as compared to WT, S1PR4 KO or S1PR4 and IFNAR1 double KO mice, although deficiency in IFNAR signaling is predominantly regarded as tumor promoting. The underlying mechanisms need to be tested in future studies. Interestingly, chemoimmunotherapy in WT mice prevented tumor relapse to a similar extent than S1PR4 KO and was superior to chemotherapy or immune checkpoint blockade alone. To investigate mechanisms of chemoimmunotherapy success compared to monotherapy, whole transcriptome analysis was used, which identified a set of genes that were upregulated specifically upon chemoimmunotherapy. This gene signature and, more specifically, a condensed four-gene signature predicted favorable survival of human mammary carcinoma patients in the METABRIC cohort.
Moreover, PyMT tumors treated with chemoimmunotherapy contained higher levels of cytotoxic lymphocytes, particularly NK cells. Gene set enrichment analysis and ELISA measurements revealed increased IL-27 production and signaling in PyMT tumors upon chemoimmunotherapy. Moreover, IL-27 improved NK cell cytotoxicity against PyMT cells in vitro. These data supported recent clinical observations indicating a benefit of chemoimmunotherapy compared to monotherapy in breast cancer and suggested potential underlying mechanisms.
Taken together the present work revealed new strategies to reactivate tumor immunity leading to improved chemotherapy response, namely a combination with immune checkpoint blockade and ablation of S1PR4, which activated different lymphocyte compartments within tumors.
The interleukin (IL)-1 family has been described for its numerous involvement in the regulation of inflammatory processes. Certain members are able to induce inflammation, whereas others have the capacity to inhibit inflammation. The newly discovered IL-1 family member IL-38 shows interesting and innovative properties. While most of these cytokines are pro-inflammatory mediators, IL-38 appears to enter the smaller circle of anti-inflammatory mediators. As a pattern, IL-38 appears to suppress IL-17-driven chronic or auto-inflammation by working as receptor antagonist. These properties, as well as its beneficial effects in models of inflammatory and autoimmune diseases suggest the possibility of IL-38-based therapies. Nevertheless, its role in the resolution of acute inflammation, thereby preventing chronic inflammation, remains unclear.
The first part of my thesis elucidated the role of IL-38 in the resolution of inflammation. I found that the complete absence of IL-38 in IL-38 KO mice leads to a delayed resolution of inflammation in the zymosan-induced peritonitis mouse model, compared to WT mice. This was marked by a persistent neutrophilia and a lower production of pro-resolving mediators during the resolution phase, such as TGFβ1 production from macrophages following efferocytosis of apoptotic cells. Reduced TGFβ1 production from macrophages coincided with reduced levels of regulatory T cells (Tregs), which are known to promote the resolution of inflammation. Unexpectedly, the TGFβ1 production capacity of macrophages did not influence the induction of Tregs from naïve T cells. Rather, IL-38 KO mice had an accumulation of Tregs in the thymus compared to WT mice. This was caused by an impairment of CD62L expression at the surface of Tregs, which is required for Tregs migration outside of the thymus. Higher Treg numbers in the thymus correlated with lower level of Tregs in peripheral lymphoid organs. Importantly, CD62L expression at the surface of IL-38 KO Tregs in the thymus was restored by injecting IL-38 i.p. for 24h. These data indicate a potential key function of IL-38 in the regulation of Treg migration, which is triggered in many cases of autoimmunity.
The second part of my thesis was to study the role of IL-38 in experimental autoimmune encephalomyelitis (EAE) development, given that EAE is IL-17-dependent. Unexpectedly, IL-38-deficient mice showed strongly reduced clinical scores and histological markers of EAE. This came with reduced inflammatory cell infiltrates, as well as reduced expression of inflammatory markers in the spinal cord. IL-38 mRNA was detected in the spinal cord, mainly by resident and infiltrated phagocytes, but also by other cells, such as ependymal cells. IL-38 was upregulated upon pro-inflammatory stimulation of bone marrow-derived macrophages, and its presence was necessary for a complete activation of inflammatory macrophages. My data suggest an alternative cell-intrinsic role of IL-38 in macrophages to promote inflammation in the central nervous system.
In the last part of my thesis, I initiated a project on the function of IL-38 in B cell physiology and antibody production, given the fact that IL-38 is expressed by B cells. I generated preliminary data showing that the absence of IL-38 in mice decreased antibody production. Furthermore, I showed that IL-38 is particularly expressed by plasma cells in human tonsils. This project remains open and further studies will be conducted to investigate how IL-38 regulates antibody production, both in physiological and autoimmune settings. Understanding the role of IL-38 in autoantibody production could lead to original and innovative therapy for patients suffering from auto-inflammatory disease.
In summary, the different projects of my thesis provide evidence that the pro-resolving function of IL-38 may be indirectly linked to the retention of Tregs in the thymus. Moreover, a possible intracellular role of IL-38 within macrophages was described showing opposite properties in the regulation of inflammation. This function could be causatively involved in EAE development. However, further studies remain to be done to find the mechanism of action by which IL-38 regulates Tregs egression and how it influences the EAE development. Complete understanding of the IL-38 biology and differentiation between its extra- vs potential intracellular functions could make it a promising therapeutic target for chronic inflammatory or autoimmune diseases.
Reliable and efficient recording of the error-related negativity with a speeded Eriksen Flanker task
(2020)
There is accumulating evidence that the error-related negativity (ERN), an event-related potential elicited after erroneous actions, is altered in different psychiatric disorders and may help to guide treatment options. Thus, the ERN is a promising candidate as a psychiatric biomarker. Basic methodological requirements for a biomarker are standardized and reliable measurements. Additional psychiatry specific requirements are time efficiency and patient-friendliness.
The aim of the present study is to establish ERN acquisition in a reliable, time-efficient and patient-friendly way for use in clinical practice.
Healthy subjects (N=27) performed a modified Eriksen Flanker Task with adaptive reaction time window and only incongruent stimuli that maximizes the number of errors. All participants were tested for mental health by the Mini International Neuropsychiatric Interview (M.I.N.I.). The first N=12 subjects were part of a pilot study and further N=14 subjects were included for analysis (one subject was excluded due to technical problems). In a test-retest design with two sessions separated by 28 days the reliability of the ERN has been assessed. To ensure external validity, we aimed to replicate previously reported correlation patterns of ERN amplitude with (1) number of errors and (2) negative affect. State affect of each subject was measured by the Positive and Negative Affect Schedule. In order to optimize the clinical use of the task, we determined to which extent the task can be shortened while keeping reliability >0.80.
We found excellent reliability of the ERN (intraclass correlation coefficient =0.806-0.947) and replicated specific correlation patterns (ERN amplitude with relative number of errors: r=0.394; p=0.082; ERN amplitude with negative affect: r=-0.583, p=0.014). The task can be shortened to a patient-friendly and clinically feasible length of only 8 minutes keeping reliability >0.80.
To conclude, the present modified task provides reliable and efficient recording of the ERN, facilitating its use as a psychiatric biomarker.
Bipolar disorder (BD) and major depressive disorder (MDD) are severe mood disorders that belong to the most debilitating diseases worldwide. Differentiating both mood disorders often poses a major clinical challenge, leading to frequent misdiagnoses. Objective biomarkers able to differentiate individuals with BD and MDD therefore represent a psychiatric research field of utmost importance. Recent studies have applied resting-state fMRI paradigms and found promising results differentiating both disorders based on the acquired data. However, most of these studies have focused their efforts on acutely depressed patients. Thus, it remains unclear whether the aberrations remain in a symptomless disease state.
The here presented study addresses these issues by evaluating the ability to differentiate both disorders from one another by conducting a between-group comparison of functional brain network connectivity (FNC) obtained from resting-state fMRI data. Data were collected from 20 BD, 15 MDD patients and 30 age- and gender-matched healthy controls (HC). Graph theoretical analyses were applied to detect differences in functional network organization between the groups on a global and regional network level.
Network analysis detected frontal, temporal and subcortical nodes in emotion regulation areas such as the limbic system and associated regions exhibiting significant differences in network integration and segregation in BD compared to MDD patients and HC. Participants with MDD and HC only differed in frontal and insular network centrality.
These results indicate that a significantly altered brain network topology in the limbic system might be a trait marker specific to BD. Brain network analysis in these regions may therefore be used to differentiate euthymic BD not only from HC but also from patients with MDD.
Colorectal cancer (CRC) is one of the most frequently diagnosed tumor in humans and one of the most common causes of cancer-related death worldwide. The pathogenesis of CRC follows a multistage process which together with somatic gene mutations is mainly attributed to the dysregulation of signaling pathways critically involved in the maintenance of homeostasis of epithelial integrity in the intestine. A growing number of studies has highlighted the critical impact of members of the tripartite motif (TRIM) protein family on most types of human malignancies including CRC. In accordance, abundant expression of many TRIM proteins has been observed in CRC tissues and is frequently correlating with poor survival of patients. Notably, some TRIM members can act as tumor suppressors depending on the context and the type of cancer which has been assessed. Mechanistically, most cancer-related TRIMs have a critical impact on cell cycle control, apoptosis, epithelial–mesenchymal transition (EMT), metastasis, and inflammation mainly through directly interfering with diverse oncogenic signaling pathways. In addition, some recent publications have emphasized the emerging role of some TRIM members to act as transcription factors and RNA-stabilizing factors thus adding a further level of complexity to the pleiotropic biological activities of TRIM proteins. The current review focuses on oncogenic signaling processes targeted by different TRIMs and their particular role in the development of CRC. A better understanding of the crosstalk of TRIMs with these signaling pathways relevant for CRC development is an important prerequisite for the validation of TRIM proteins as novel biomarkers and as potential targets of future therapies for CRC.
Obstructive Sleep Apnea is emerging as a global health epidemic, particularly due to the obesity pandemic. However, comprehensive prevalence data are still lacking and global OSA research has not yet been structurally evaluated. Using the latest comprehensive age/gender-specific BMI and obesity data, a global landscape estimating the risk/burden of OSA was created. Results were presented in relation to an in-depth analysis of OSA research and countries’ socioeconomic/scientific background. While the USA, Canada, and Japan are the highest publishing countries on OSA, Iceland, Greece, and Israel appeared at the forefront when relating the scientific output to socioeconomic parameters. Conversely, China, India, and Russia showed relatively low performances in these relations. Analysis of the estimated population at risk (EPR) of OSA showed the USA, China, India, and Brazil as the leading countries. Although the EPR and OSA research correlated strongly, major regional discrepancies between the estimated demand and actual research performances were identified, mainly in, but not limited to, developing nations. Our study highlights regional challenges/imbalances in the global activity on OSA and allows targeted measures to mitigate the burden of undiagnosed/untreated OSA. Furthermore, the inclusion of disadvantaged countries in international collaborations could stimulate local research efforts and provide valuable insights into the regional epidemiology of OSA.
Reduced external knee adduction moments in the second half of stance after total hip replacement have been reported in hip osteoarthritis patients. This reduction is thought to shift the load from the medial to the lateral knee compartment and as such increase the risk for knee osteoarthritis. The knee adduction moment is a surrogate for the load distribution between the medial and lateral compartments of the knee and not a valid measure for the tibiofemoral contact forces which are the result of externally applied forces and muscle forces. The purpose of this study was to investigate whether the distribution of the tibiofemoral contact forces over the knee compartments in unilateral hip osteoarthritis patients 1 year after receiving a primary total hip replacement differs from healthy controls. Musculoskeletal modeling on gait was performed in OpenSim using the detailed knee model of Lerner et al. (2015) for 19 patients as well as for 15 healthy controls of similar age. Knee adduction moments were calculated by the inverse dynamics analysis, medial and lateral tibiofemoral contact forces with the joint reaction force analysis. Moments and contact forces of patients and controls were compared using Statistical Parametric Mapping two-sample t-tests. Knee adduction moments and medial tibiofemoral contact forces of both the ipsi- and contralateral leg were not significantly different compared to healthy controls. The contralateral leg showed 14% higher medial tibiofemoral contact forces compared to the ipsilateral (operated) leg during the second half of stance. During the first half of stance, the lateral tibiofemoral contact force of the contralateral leg was 39% lower and the ratio 32% lower compared to healthy controls. In contrast, during the second half of stance the forces were significantly higher (39 and 26%, respectively) compared to healthy controls. The higher ratio indicates a changed distribution whereas the increased lateral tibiofemoral contact forces indicate a higher lateral knee joint loading in the contralateral leg in OA patients after total hip replacement (THR). Musculoskeletal modeling using a detailed knee model can be useful to detect differences in the load distribution between the medial and lateral knee compartment which cannot be verified with the knee adduction moment.
Objective: Many patients with localized prostate cancer (PCa) do not immediately undergo radical prostatectomy (RP) after biopsy confirmation. The aim of this study was to investigate the influence of “time-from-biopsy-to- prostatectomy” on adverse pathological outcomes.
Materials and Methods: Between January 2014 and December 2019, 437 patients with intermediate- and high risk PCa who underwent RP were retrospectively identified within our prospective institutional database. For the aim of our study, we focused on patients with intermediate- (n = 285) and high-risk (n = 151) PCa using D'Amico risk stratification. Endpoints were adverse pathological outcomes and proportion of nerve-sparing procedures after RP stratified by “time-from-biopsy-to-prostatectomy”: ≤3 months vs. >3 and < 6 months. Medians and interquartile ranges (IQR) were reported for continuously coded variables. The chi-square test examined the statistical significance of the differences in proportions while the Kruskal-Wallis test was used to examine differences in medians. Multivariable (ordered) logistic regressions, analyzing the impact of time between diagnosis and prostatectomy, were separately run for all relevant outcome variables (ISUP specimen, margin status, pathological stage, pathological nodal status, LVI, perineural invasion, nerve-sparing).
Results: We observed no difference between patients undergoing RP ≤3 months vs. >3 and <6 months after diagnosis for the following oncological endpoints: pT-stage, ISUP grading, probability of a positive surgical margin, probability of lymph node invasion (LNI), lymphovascular invasion (LVI), and perineural invasion (pn) in patients with intermediate- and high-risk PCa. Likewise, the rates of nerve sparing procedures were 84.3 vs. 87.4% (p = 0.778) and 61.0% vs. 78.8% (p = 0.211), for intermediate- and high-risk PCa patients undergoing surgery after ≤3 months vs. >3 and <6 months, respectively. In multivariable adjusted analyses, a time to surgery >3 months did not significantly worsen any of the outcome variables in patients with intermediate- or high-risk PCa (all p > 0.05).
Conclusion: A “time-from-biopsy-to-prostatectomy” of >3 and <6 months is neither associated with adverse pathological outcomes nor poorer chances of nerve sparing RP in intermediate- and high-risk PCa patients.
MicroRNAs (miRNAs) have emerged as critical posttranscriptional regulators of the immune system, including function and development of regulatory T (Treg) cells. Although this critical role has been firmly demonstrated through genetic models, key mechanisms of miRNA function in vivo remain elusive. Here, we review the role of miRNAs in Treg cell development and function. In particular, we focus on the question what the study of miRNAs in this context reveals about miRNA biology in general, including context-dependent function and the role of individual targets vs. complex co-targeting networks. In addition, we highlight potential technical pitfalls and state-of-the-art approaches to improve the mechanistic understanding of miRNA biology in a physiological context.
Despite the success of immune checkpoint blockade in cancer, the number of patients that benefit from this revolutionary treatment option remains low. Therefore, efforts are being undertaken to sensitize tumors for immune checkpoint blockade, which includes combining immune checkpoint blocking agents such as anti-PD-1 antibodies with standard of care treatments. Here we report that a combination of chemotherapy (doxorubicin) and immune checkpoint blockade (anti-PD-1 antibodies) induces superior tumor control compared to chemotherapy and immune checkpoint blockade alone in the murine autochthonous polyoma middle T oncogene-driven (PyMT) mammary tumor model. Using whole transcriptome analysis, we identified a set of genes that were upregulated specifically upon chemoimmunotherapy. This gene signature and, more specifically, a condensed four-gene signature predicted favorable survival of human mammary carcinoma patients in the METABRIC cohort. Moreover, PyMT tumors treated with chemoimmunotherapy contained higher levels of cytotoxic lymphocytes, particularly natural killer cells (NK cells). Gene set enrichment analysis and bead-based ELISA measurements revealed increased IL-27 production and signaling in PyMT tumors upon chemoimmunotherapy. Moreover, IL-27 signaling improved NK cell cytotoxicity against PyMT cells in vitro. Taken together, our data support recent clinical observations indicating a benefit of chemoimmunotherapy compared to monotherapy in breast cancer and suggest potential underlying mechanisms.
Background: The currently prevailing global threat of COVID-19 caused the publication numbers on coronaviruses to explode. The awareness of the scientific and public community is enormous. But what about the sense of all these undertakings and what can be learned about the future for a better understanding? These questions were answered with established bibliometric analyses of the time until the avalanche of publications unfolded.
Methods: Chronological, geographical aspects of publication output on coronavirus were also evaluated under the influence of epidemiological and socio-economic parameters.
Results: The trend in publication and citation numbers shows the strong influence of the past pandemics SARS and MERS with an untypical decline afterward. Research is becoming increasingly multidisciplinary over time. The USA and China, as the countries with the highest number of publications, are being displaced by other countries in the consideration of socio-economic and epidemiological aspects, which shows the effect of regional interest in corona research. A significant correlation was found between the number of SARS cases per country and related publications, while no correlation was found for MERS cases and articles.
Conclusions: The results underline the need for sustainable and forward-looking approaches that should not end with the containment of COVID-19.
Spinocerebellar ataxia type 2 (SCA2) is caused by polyglutamine expansion in Ataxin-2 (ATXN2). This factor binds RNA/proteins to modify metabolism after stress, and to control calcium (Ca2+) homeostasis after stimuli. Cerebellar ataxias and corticospinal motor neuron degeneration are determined by gain/loss in ATXN2 function, so we aimed to identify key molecules in this atrophic process, as potential disease progression markers. Our Atxn2-CAG100-Knock-In mouse faithfully models features observed in patients at pre-onset, early and terminal stages. Here, its cerebellar global RNA profiling revealed downregulation of signaling cascades to precede motor deficits. Validation work at mRNA/protein level defined alterations that were independent of constant physiological ATXN2 functions, but specific for RNA/aggregation toxicity, and progressive across the short lifespan. The earliest changes were detected at three months among Ca2+ channels/transporters (Itpr1, Ryr3, Atp2a2, Atp2a3, Trpc3), IP3 metabolism (Plcg1, Inpp5a, Itpka), and Ca2+-Calmodulin dependent kinases (Camk2a, Camk4). CaMKIV–Sam68 control over alternative splicing of Nrxn1, an adhesion component of glutamatergic synapses between granule and Purkinje neurons, was found to be affected. Systematic screening of pre/post-synapse components, with dendrite morphology assessment, suggested early impairment of CamKIIα abundance together with the weakening of parallel fiber connectivity. These data reveal molecular changes due to ATXN2 pathology, primarily impacting excitability and communication.
Lichen-forming fungi are symbiotic organisms that synthesize unique natural products with potential for new drug leads. Here, we explored the pharmacological activity of six lichen extracts (Evernia prunastri, Pseudevernia furfuracea, Umbilicaria pustulata, Umbilicaria crustulosa, Flavoparmelia caperata, Platismatia glauca) in the context of cancer and inflammation using a comprehensive set of 11 functional and biochemical in vitro screening assays. We assayed intracellular Ca2+ levels and cell migration. For cancer, we measured tumor cell proliferation, cell cycle distribution and apoptosis, as well as the angiogenesis-associated proliferation of endothelial cells (ECs). Targeting inflammation, we assayed leukocyte adhesion onto ECs, EC adhesion molecule expression, as well as nitric oxide production and prostaglandin (PG)E2 synthesis in leukocytes. Remarkably, none of the lichen extracts showed any detrimental influence on the viability of ECs. We showed for the first time that extracts of F. caperata induce Ca2+ signaling. Furthermore, extracts from E. prunastri, P. furfuracea, F. caperata, and P. glauca reduced cell migration. Interestingly, F. caperata extracts strongly decreased tumor cell survival. The proliferation of ECs was significantly reduced by E. prunastri, P. furfuracea, and F. caperata extracts. The extracts did not inhibit the activity of inflammatory processes in ECs. However, the pro-inflammatory activation of leukocytes was inhibited by extracts from E. prunastri, P. furfuracea, F. caperata, and P. glauca. After revealing the potential biological activities of lichen extracts by an array of screening tests, a correlation analysis was performed to evaluate particular roles of abundant lichen secondary metabolites, such as atranorin, physodic acid, and protocetraric acid as well as usnic acid in various combinations. Overall, some of the lichen extracts tested in this study exhibit significant pharmacological activity in the context of inflammation and/or cancer, indicating that the group lichen-forming fungi includes promising members for further testing.
Nitro fatty acids (NFAs) are endogenously generated lipid mediators deriving from reactions of unsaturated electrophilic fatty acids with reactive nitrogen species. Furthermore, Mediterranean diets can be a source of NFA. These highly electrophilic fatty acids can undergo Michael addition reaction with cysteine residues, leading to post-translational modifications (PTM) of selected regulatory proteins. Such modifications are capable of changing target protein function during cell signaling or in biosynthetic pathways. NFA target proteins include the peroxisome proliferator-activated receptor γ (PPAR-γ), the pro-inflammatory and tumorigenic nuclear factor-κB (NF-κB) signaling pathway, the pro-inflammatory 5-lipoxygenases (5-LO) biosynthesis pathway as well as soluble epoxide hydrolase (sEH), which is essentially involved in the regulation of vascular tone. In several animal models of inflammation and cancer, the therapeutic efficacy of well-tolerated NFA has been demonstrated. This has already led to clinical phase II studies investigating possible therapeutic effects of NFA in subjects with pulmonary arterial hypertension. Albeit Michael acceptors feature a broad spectrum of bioactivity, they have for a rather long time been avoided as drug candidates owing to their presumed unselective reactivity and toxicity. However, targeted covalent modification of regulatory proteins by Michael acceptors became recognized as a promising approach to drug discovery with the recent FDA approvals of the cancer therapeutics, afatanib (2013), ibrutinib (2013), and osimertinib (2015). Furthermore, the Michael acceptor, neratinib, a dual inhibitor of the human epidermal growth factor receptor 2 and epidermal growth factor receptor, was recently approved by the FDA (2017) and by the EMA (2018) for the treatment of breast cancer. Finally, a number of further Michael acceptor drug candidates are currently under clinical investigation for pharmacotherapy of inflammation and cancer. In this review, we focus on the pharmacology of NFA and other Michael acceptor drugs, summarizing their potential as an emerging class of future antiphlogistics and adjuvant in tumor therapeutics.
Post-exercise hypotension (PEH) is the phenomenon of lowered blood pressure after a single bout of exercise. Only a fraction of people develops PEH but its occurrence correlates well with long-term effects of sports on blood pressure. Therefore, PEH has been suggested as a suitable predictor for the effectivity of exercise as therapy in hypertension. Local vascular bioactive lipids might play a potential role in this context. We performed a cross-over clinical pilot study with 18 healthy volunteers to investigate the occurrence of PEH after a single short-term endurance exercise. Furthermore, we investigated the plasma lipid profile with focus on arachidonic acid (AA)-derived metabolites as potential biomarkers of PEH. A single bout of ergometer cycling induced a significant PEH in healthy volunteers with the expected high inter-individual variability. Targeted lipid spectrum analysis revealed significant upregulation of several lipids in the direct post-exercise phase. Among these changes, only 15- hydroxyeicosatetranoic acid (HETE) correlated significantly with the extent of PEH but in an AA-independent manner, suggesting that 15-HETE might act as specific PEH-marker. Our data indicate that specific lipid modulation might facilitate the identification of patients who will benefit from exercise activity in hypertension therapy. However, larger trials including hypertonic patients are necessary to verify the clinical value of this hypothesis.
The risk of increasing dengue (DEN) and chikungunya (CHIK) epidemics impacts 240 million people, health systems, and the economy in the Hindu Kush Himalayan (HKH) region. The aim of this systematic review is to monitor trends in the distribution and spread of DEN/CHIK over time and geographically for future reliable vector and disease control in the HKH region. We conducted a systematic review of the literature on the spatiotemporal distribution of DEN/CHIK in HKH published up to 23 January 2020, following Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. In total, we found 61 articles that focused on the spatial and temporal distribution of 72,715 DEN and 2334 CHIK cases in the HKH region from 1951 to 2020. DEN incidence occurs in seven HKH countries, i.e., India, Nepal, Bhutan, Pakistan, Bangladesh, Afghanistan, and Myanmar, and CHIK occurs in four HKH countries, i.e., India, Nepal, Bhutan, and Myanmar, out of eight HKH countries. DEN is highly seasonal and starts with the onset of the monsoon (July in India and June in Nepal) and with the onset of spring (May in Bhutan) and peaks in the postmonsoon season (September to November). This current trend of increasing numbers of both diseases in many countries of the HKH region requires coordination of response efforts to prevent and control the future expansion of those vector-borne diseases to nonendemic areas, across national borders.
Background: While swallowing disorders are frequent sequela following posterior fossa tumor (PFT) surgery in children, data on dysphagia frequency, severity, and outcome in adults are lacking. The aim of this study was to investigate dysphagia before and after surgical removal of PFT. Additionally, we tried to identify clinical predictors for postsurgical swallowing disorders. Furthermore, this study explored the three-month outcome of dysphagic patients.
Methods: In a cohort of patients undergoing PFT surgery, dysphagia was prospectively assessed pre- and postoperatively using fiberoptic endoscopic evaluation of swallowing. Patients with severe dysphagia at discharge were re-evaluated after three months. Additionally, clinical and imaging data were collected to identify predictors for post-surgical dysphagia. Results: We included 26 patients of whom 15 had pre-operative swallowing disorders. After surgery, worsening of pre-existing dysphagia could be noticed in 7 patients whereas improvement was observed in 2 and full recovery in 3 subjects. New-onset dysphagia after surgery occurred in a minority of 3 cases. Postoperatively, 47% of dysphagic patients required nasogastric tube feeding. Re-evaluation after three months of follow-up revealed that all dysphagic patients had returned to full oral intake.
Conclusion: Dysphagia is a frequent finding in patients with PFT already before surgery. Surgical intervention can infer a deterioration of impaired swallowing function placing affected patients at temporary risk for aspiration. In contrast, surgery can also accomplish beneficial results resulting in both improvement and full recovery. Overall, our findings show the need of early dysphagia assessment to define the safest feeding route for the patient.
Background:Aedes aegypti is a potential vector for several arboviruses including dengue and Zika viruses. The species seems to be restricted to subtropical/tropical habitats and has difficulties in establishing permanent populations in southern Europe, probably due to constraints during the winter season. The aim of this study was to systematically analyze the cold tolerance (CT) of Ae. aegypti in its most cold-resistant life stage, the eggs.
Methods: The CT of Ae. aegypti eggs was compared with that of Ae. albopictus which is well established in large parts of Europe. By systematically studying the literature (meta-analysis), we recognized that CT has been rarely tested in Ae. aegypti eggs, but eggs can survive at zero and sub-zero temperatures for certain exposure periods. To overcome potential bias from experimental differences between studies, we then conducted species comparisons using a harmonized high-resolution CT measuring method. From subtropical populations of the same origin, the survival (hatching in %) and emergence of adults of both species were measured after zero and sub-zero temperature exposures for up to 9 days (3 °C, 0 °C and − 2 °C: ≤ 9 days; − 6 °C: ≤ 2 days).
Results: Our data show that Ae. aegypti eggs can survive low and sub-zero temperatures for a short time period similar to or even better than those of Ae. albopictus. Moreover, after short sub-zero exposures of eggs of both species, individuals still developed into viable adults (Ae. aegypti: 3 adults emerged after 6 days at − 2 °C, Ae. albopictus: 1 adult emerged after 1 day at − 6 °C).
Conclusions: Thus, both the literature and the present experimental data indicate that a cold winter may not be the preventing factor for the re-establishment of the dengue vector Ae. aegypti in southern Europe.
Psoriasis (PsO) is one of the common chronic inflammatory skin diseases. Approximately 3% of the European Caucasian population is affected. Psoriatic arthritis (PsA) is a chronic immune-mediated disease associated with PsO characterized by distinct musculoskeletal inflammation. Due to its heterogeneous clinical manifestations (e.g., oligo- or polyarthritis, enthesitis, dactylitis, and axial inflammation), early diagnosis of PsA is often difficult and delayed. Approximately 30% of PsO patients will develop PsA. The responsible triggers for the transition from PsO only to PsA are currently unclear, and the impacts of different factors (e.g., genetic, environmental) on disease development are currently discussed. There is a high medical need, recently unmet, to specifically detect those patients with an increased risk for the development of clinically evident PsA early to initiate sufficient treatment to inhibit disease progression and avoid structural damage and loss of function or even intercept disease development. Increased neoangiogenesis and enthesial inflammation are hypothesized to be early pathological findings in PsO patients with PsA development. Different disease states describe the transition from PsO to PsA. Two of those phases are of value for early detection of PsA at-risk patients to prevent later development of PsA as changes in biomarker profiles are detectable: the subclinical phase (soluble and imaging biomarkers detectable, no clinical symptoms) and the prodromal phase (imaging biomarkers detectable, unspecific musculoskeletal symptoms such as arthralgia and fatigue). To target the unmet need for early detection of this at-risk population and to identify the subgroup of patients who will transition from PsO to PsA, imaging plays an important role in characterizing patients precisely. Imaging techniques such as ultrasound (US), magnetic resonance imaging (MRI), and computerized tomography (CT) are advanced techniques to detect sensitively inflammatory changes or changes in bone structure. With the use of these techniques, anatomic structures involved in inflammatory processes can be identified. These techniques are complemented by fluorescence optical imaging as a sensitive method for detection of changes in vascularization, especially in longitudinal measures. Moreover, high-resolution peripheral quantitative CT (HR-pQCT) and dynamic contrast-enhanced MRI (DCE-MRI) may give the advantage to identify PsA-related early characteristics in PsO patients reflecting transition phases of the disease.