Search

Supplementary Figure from PTEN Loss Contributes to Erlotinib Resistance in EGFR-Mutant Lung Cancer by Activation of Akt and EGFR

Clinical resistance to epidermal growth factor receptor (EGFR) inhibition in lung cancer has been linked to the emergence of the EGFR T790M resistance mutation or amplification of MET. Additional mechanisms contributing to EGFR inhibitor resistance remain elusive. By applying combined analyses of gene expression, copy number, and biochemical analyses of EGFR inhibitor responsiveness, we identified homozygous loss of PTEN to segregate EGFR-dependent and EGFR-independent cells. We show that in EGFR-dependent cells, PTEN loss partially uncouples mutant EGFR from downstream signaling and activates EGFR, thereby contributing to erlotinib resistance. The clinical relevance of our findings is supported by the observation of PTEN loss in 1 out of 24 primary EGFR-mutant non–small cell lung cancer (NSCLC) tumors. These results suggest a novel resistance mechanism in EGFR-mutant NSCLC involving PTEN loss. [Cancer Res 2009;69(8):3256–61]

Supplementary Materials & Methods and Figure Legend from PTEN Loss Contributes to Erlotinib Resistance in EGFR-Mutant Lung Cancer by Activation of Akt and EGFR

Supplementary Table from PTEN Loss Contributes to Erlotinib Resistance in EGFR-Mutant Lung Cancer by Activation of Akt and EGFR

Objective Benzodiazepines have been reported to cause photosensitivity reactions. We characterized the clinical presentation and diagnosis of benzodiazepine-associated photosensitivity and adjudicated these cases for a causal association with benzodiazepines. Methods A literature search on PubMed's "MeSH" search feature and CINAHL (1964 to 2019) was performed using search terms: benzodiazepine, photosensitivity, and photosensitivity disorders/chemically induced. We applied the Naranjo scale, a standardized causality assessment algorithm, to identified cases. Results We identified 8 published cases, with 50% of patients being female with a mean age of 46.3 years. Alprazolam, tetrazepam, clobazam, and clorazepate induced phototoxic reactions. Chlordiazepoxide induced one photoallergic reaction. Photosensitivity occurred between 1-3 days (37.5%), 7-14 days (25%), and >14 days (25%). Photosensitivity resolved after drug discontinuation within 2 weeks (62.5%). Benzodiazepine rechallenge confirmed photosensitivity in 75% of cases. Photopatch testing was negative in two patients; however, these patients had positive oral provocation testing. However, an oral photoprovocation test, an ideal diagnostic test, was not administered to several patients. Despite these challenges, the Naranjo scale identified 5 cases as definite benzodiazepine-induced photosensitivity. Conclusion Five benzodiazepines induced photosensitivity reactions. Five patients showed a definite association with the Naranjo scale. Reporting to pharmacovigilance databases may help identify other benzodiazepines causing photosensitivity reactions.

Mucosal and skin cancers are associated with infections by human papillomaviruses (HPV). The manner how viral oncoproteins hijack the host cell metabolism to meet their own energy demands and how this may contribute to tumorigenesis is poorly understood. We now show that the HPV oncoprotein E7 of HPV8, HPV11 and HPV16 directly interact with the beta subunit of the mitochondrial ATP-synthase (ATP5B), which may therefore represent a conserved feature across different HPV genera. By measuring both glycolytic and mitochondrial activity we observed that the association of E7 with ATP5B was accompanied by reduction of glycolytic activity. Interestingly, there was a drastic increase in spare mitochondrial respiratory capacity in HPV8-E7 and an even more profound increase in HPV16-E7 expressing cells. In addition, we could show that ATP5B levels were unchanged in betaHPV positive skin cancers. However, comparing HPV-positive and HPV-negative oropharyngeal squamous cell carcinomas (OPSCC) we noticed that, while ATP5B expression levels did not correlate with patient overall survival in HPV-negative OPSCC, there was a strong correlation within the HPV16-positive OPSCC patient group. These novel findings provide evidence that HPV targets the host cell energy metabolism important for viral life cycle and HPV-mediated tumorigenesis.

The vasculature represents a highly plastic compartment, capable of switching from a quiescent to an active proliferative state during angiogenesis. Metabolic reprogramming in endothelial cells (ECs) thereby is crucial to cover the increasing cellular energy demand under growth conditions. Here we assess the impact of mitochondrial bioenergetics on neovascularisation, by deleting cox10 gene encoding an assembly factor of cytochrome c oxidase (COX) specifically in mouse ECs, providing a model for vasculature-restricted respiratory deficiency. We show that EC-specific cox10 ablation results in deficient vascular development causing embryonic lethality. In adult mice induction of EC-specific cox10 gene deletion produces no overt phenotype. However, the angiogenic capacity of COX-deficient ECs is severely compromised under energetically demanding conditions, as revealed by significantly delayed wound-healing and impaired tumour growth. We provide genetic evidence for a requirement of mitochondrial respiration in vascular endothelial cells for neoangiogenesis during development, tissue repair and cancer., During angiogenesis the vasculature switches from a quiescent to a proliferative state. Here the authors show that mitochondrial respiration in endothelial cells controls angiogenesis during development, tumour growth and tissue repair.

The transition between quiescence and activation in neural stem and progenitor cells (NSPCs) is coupled to reversible changes in energy metabolism with key implications for life-long NSPC self-renewal and neurogenesis. How this metabolic plasticity is ensured between NSPC activity states is unclear. We found that a state-dependent rewiring of the mitochondrial proteome by the peptidase YME1L is required to preserve NSPC self-renewal in the adult brain. YME1L-mediated proteome rewiring regulates the rate of fatty acid oxidation (FAO) for replenishing Krebs cycle intermediates and dNTP precursors, which are required to sustain NSPC amplification. Yme1l deletion irreversibly shifts the metabolic profile of NSPCs away from a FAO-dependent state resulting in defective self-renewal, premature differentiation and NSPC pool depletion. Our results disclose an important role for YME1L in coordinating the switch between metabolic states of NSPCs and suggest that NSPC fate is regulated by compartmentalized changes in protein network dynamics.

Maintaining the architecture, size and composition of an intact stem cell (SC) compartment is crucial for tissue homeostasis and regeneration throughout life. In mammalian skin, elevated expression of the anti‐apoptotic Bcl‐2 protein has been reported in hair follicle (HF) bulge SCs (BSCs), but its impact on SC function is unknown. Here, we show that systemic exposure of mice to the Bcl‐2 antagonist ABT‐199/venetoclax leads to the selective loss of suprabasal BSCs (sbBSCs), thereby disrupting cyclic HF regeneration. RNAseq analysis shows that the pro‐apoptotic BH3‐only proteins BIM and Bmf are upregulated in sbBSCs, explaining their addiction to Bcl‐2 and the marked susceptibility to Bcl‐2 antagonism. In line with these observations, conditional knockout of Bcl‐2 in mouse epidermis elevates apoptosis in BSCs. In contrast, ectopic Bcl‐2 expression blocks apoptosis during HF regression, resulting in the accumulation of quiescent SCs and delaying HF growth in mice. Strikingly, Bcl‐2‐induced changes in size and composition of the HF bulge accelerate tumour formation. Our study identifies a niche‐instructive mechanism of Bcl‐2‐regulated apoptosis response that is required for SC homeostasis and tissue regeneration, and may suppress carcinogenesis., Anti‐apoptotic Bcl‐2 protein function is required to maintain a hair follicle subpopulation of stem cells in murine skin. Blocking cell death by Bcl‐2 overexpression affects the hair follicle stem cell niche and hair follicle regeneration.

Children with mitochondrial diseases often present with slow growth and short stature, but the underlying mechanism remains unclear. In this study, Holzer et al. provide in vivo evidence that mitochondrial respiratory chain dysfunction induces cartilage degeneration coincident with altered metabolism, impaired extracellular matrix formation, and cell death at the cartilage–bone junction., In childhood, skeletal growth is driven by transient expansion of cartilage in the growth plate. The common belief is that energy production in this hypoxic tissue mainly relies on anaerobic glycolysis and not on mitochondrial respiratory chain (RC) activity. However, children with mitochondrial diseases causing RC dysfunction often present with short stature, which indicates that RC activity may be essential for cartilage-mediated skeletal growth. To elucidate the role of the mitochondrial RC in cartilage growth and pathology, we generated mice with impaired RC function in cartilage. These mice develop normally until birth, but their later growth is retarded. A detailed molecular analysis revealed that metabolic signaling and extracellular matrix formation is disturbed and induces cell death at the cartilage–bone junction to cause a chondrodysplasia-like phenotype. Hence, the results demonstrate the overall importance of the metabolic switch from fetal glycolysis to postnatal RC activation in growth plate cartilage and explain why RC dysfunction can cause short stature in children with mitochondrial diseases.

The use of complementary and alternative medicine (CAM) therapies continues to rise worldwide. The cultural importance of various CAM techniques and systems cannot be overlooked. As data become available on the use and adverse events, misuse, adulterations, toxicities and interactions of various dietary supplements (DS) and other CAM therapies, the clinician can piece together appropriate patient care approaches. Reporting mechanisms in many countries continue to be sporadic and inconsistent. Information may be biased or inaccurate in the public domain, causing consumer distrust of healthcare provider guidance. As with any therapeutic decision-making, the patient/consumer should be included in the process and given evidence-based information to weigh the risks and benefits for the individual's needs. Healthcare providers should familiarize themselves with CAM practices and the benefits and associated risks to best care for their patient populations. In this review of the current literature from January through December 2019, the adverse effects of herbal dietary supplements (HDS) are organized as affecting different physiological systems. Systematic reporting and monitoring of AEs from mind/body therapies are extremely limited though reported as found. The full impact caused by side effects (SE) of various CAM therapies may be underappreciated due to this lack of complete data.

Objective Zolpidem is associated with sleep-related eating disorder (SRED). We compiled case reports and performed a descriptive study to identify etiology and aggravating factors. Methods A literature search on PubMed's MeSH search feature, CINAHL, and SciFinder was performed using search terms “Zolpidem,” “Feeding and Eating Disorders/chemically induced,” “Dyssomnias,” “sleep eating disorder,” and “sleep-related eating disorder.” Three reviewers examined all English and Spanish citations and extracted pertinent information. A narrative synthesis of the evidence was prepared. Results We identified 40 case reports of which 65% were female, and the mean age was 53 years. SRED onset was most commonly seen with daily zolpidem doses of 10 mg or higher (95% of patients). Prior medical history included obstructive sleep apnea (OSA) (35%), depression (32.5%), and restless leg syndrome (RLS) (25%). Even with controlled RLS and OSA, SRED developed in some patients. All patients had either partial or full amnesia with compulsive eating. Onset of SRED occurred as early as the first dose to after 9 years of use. SRED symptoms occurred nightly in 57.5% of patients. Discontinuation of zolpidem resolved SRED in all patients (n = 36). Conclusion SRED associated with zolpidem can occur with any dose, but was most common with higher doses of zolpidem. Therefore, prescribers should initiate lower doses of zolpidem. Interestingly, many patients had underlying disorders known to affect sleep (RLS, OSA, depression). Although it is recommended to control these underlying disorders prior to initiating zolpidem, SRED may still occur. Zolpidem discontinuation resolved all cases of SRED., Graphical abstract Image 1, Highlights • Sleep-Related Eating Disorder (SRED) can occur with any dose of zolpidem. • Patients most vulnerable include females receiving higher doses of zolpidem. • SRED is more common with underlying disorders known to affect sleep. • Discontinuation of zolpidem resolves SRED.

The 2014–2015 H5N2/H5N8 highly pathogenic avian influenza (HPAI) epidemic required $879 million dollars in public expenditures to eradicate the disease from poultry production, making it the most costly animal health incident in US history. Cost and resource availability are important considerations when determining optimal response plans. However, limited information was available, historically, on which to base the evaluation of response plans for large-scale HPAI events on farms in the US and across the world. Response cost data collected during the 2014–2015 HPAI outbreak by the United States Department of Agriculture – Animal and Plant Health Inspection Service and associated response information such as responder type and activity were examined as a preliminary effort to enhance understanding of the cost associated with alternative response plans under real resource and labor constraints. Results indicated that differences did exist by state and poultry facility type that affected both total and incremental cost, indicating the importance of local and state policies and resources on farm level eradication cost. On-farm response activities associated with depopulation and disposal resulted in costs that were most sensitive to bird inventory size. Exploring the responder characteristics revealed that contractors hired directly by the federal government or sub-contractors that are hired by a producer, while most expensive in absolute terms, contributed the lowest incremental increase in cost for each additional bird housed on a farm when depopulating. Identifying and quantifying response activity costs for poultry assists planning efforts for local, state and federal response agencies and private firms that are faced with high consequence avian health threats. The data, while still limited in certain facets, facilitate impact assessments and cost-benefit analyses in future planning. This study illustrates the importance of collecting livestock disease outbreak cost data ex post for observing cost relationships during large-scale animal disease events in countries with commercial poultry production.

Traditional models describing microorganisms growth assume that changes in the environmental conditions generate immediate responses in microbial population. However, reports are available indicating that in some cases this may not be the case. The existence of a delayed inhibition response (DIR) was studied, exposing a microalgae culture to inhibitory ammonia concentrations. Results revealed the existence of considerable delays in the microalgae response, even when imposing conditions promoting null microalgal activity. Even an extremely unfavourable condition such as 1500 mg L −1 of total ammonia nitrogen and pH 9 takes about 24 h to induce complete inhibition. The existence of DIR may cause serious deviations between predictions given by traditional models and real behaviour of a culture. Inclusion of DIR in traditional models may be accomplished by assuming model parameters as variables depending on time. In other words, assuming that inhibition “constant” is no longer constant, but a function of exposure time.

Complementary and alternative (CAM) treatment systems are being studied more intensely in recent years. Adverse events (AEs), errors, toxicities and interactions have reporting mechanisms in many countries but continue to be inconsistent in aggregation and causality assessment. The information available regarding dietary supplements (DS) and other CAM modalities with a prejudice toward “safe and natural” can deceive the consumer. DS are pharmacologically active moieties that act differently depending on the individual's state of being. Contamination of DS with heavy metals, unlabeled medications or other plant or animal products continues to plague the industry but newer methods of detection are being developed and used to assure quality of manufacturing. Manipulative and mind–body therapies are also undergoing scrutiny for appropriateness and efficacy without harm. Healthcare providers should familiarize themselves with CAM practices and their benefits and the associated risks to best care for their patient populations. In this review of the current literature from January through December 2018, the adverse effects of herbal dietary supplements (HDS) are organized as affecting different physiological systems. Many examples of unintentional and intentional contamination of HDS and methods of detection were recorded. The AEs reported for mind–body therapies were fewer in number and severity as compared to HDS, but without systematic reporting and monitoring it can be difficult to grasp the full extent of the impact side effects (SE) of various CAM therapies can have.

The spliceosomal B complex-specific protein Prp38 forms a complex with the intrinsically unstructured proteins MFAP1 and Snu23. Our binding and crystal structure analyses show that MFAP1 and Snu23 contact Prp38 via ER/K motif-stabilized single α helices, which have previously been recognized only as rigid connectors or force springs between protein domains. A variant of the Prp38-binding single α helix of MFAP1, in which ER/K motifs not involved in Prp38 binding were mutated, was less α-helical in isolation and showed a reduced Prp38 affinity, with opposing tendencies in interaction enthalpy and entropy. Our results indicate that the strengths of single α helix-based interactions can be tuned by the degree of helix stabilization in the unbound state. MFAP1, Snu23, and several other spliceosomal proteins contain multiple regions that likely form single α helices via which they might tether several binding partners and act as intermittent scaffolds that facilitate remodeling steps during assembly of an active spliceosome.

In many arid regions, the reuse of wastewater is an economic option for crop irrigation. To avoid health risks for consumers, pathogens must be eliminated prior to application. Slow sand filtration (SSF) represents an effective low-tech treatment technology for pathogen removal from water. To further improve the time-space yield of SSF, innovative filter configurations were investigated regarding the removal of the pathogen indicators Escherichia coli , enterococci, Clostridium perfringens spores, somatic and F-specific RNA coliphages as well as heterotrophic bacteria. A standard filter ( N ), a recirculating filter ( R ), a static cascade ( N + N ) and a rotating cascade ( C ) were tested at high and low hydraulic loading rates, two recirculation rates and two rotation frequencies. Results showed that only C and N + N concurrently complied with European standards for E. coli and enterococci, achieving mean log removal of 2.7-4.7 and 2.1-2.4, respectively. The best performance was reached by C with weekly rotation; N + N may be a promising, technically simpler alternative. The crucial role of biological removal mechanisms for E. coli and enterococci elimination was indicated by (i) the increased efficiency of the standard SSF N after 1½ years of operation and (ii) the positive impact of several Schmutzdecke layers. C. perfringens spore removal performance was good for all SSFs. Considerable sorption of spores was indicated by decreased efficiency in N and C at long operation times. Somatic coliphages were reduced to concentrations close to the detection limit, while F-specific RNA coliphage removal was ∼1.1 log. Removal of heterotrophic bacteria was generally limited.

Background:IgG4-related disease (IgG4-RD) is a polymorphic autoimmune disease leading to tumourous swelling and/or fibrosis of affected organs. Riedel’s thyroiditis is – besides chronic periaortitis, Mikulicz Syndrome and many others – an organ manifestation of IgG4-RD that has been thought to be an independent disease for a long time. About 40% of patients have single organ IgG4-RD while the others suffer from multisystemic disease [1].Objectives:Glucocorticoids, sometimes combined with other immunosuppressives are the standard treatment of IgG4-RD, in some situations (e.g. mechanical complications or suspected malignancy) surgery may be necessary but little is known about the management of fully resected single-organ IgG4-RD [1].Methods:We report a case of single-organ IgG4-RD (Riedel’s thyroiditis) after complete resection and perform a brief review of the literature to guide clinical management in this situation.Results:A woman (51 y) with pre-existing Hashimoto’s thyroiditis (thyroid peroxidase antibody positive) developed a rapidly growing struma with very firm consistency (not allowing fine needle biopsy). Besides slightly increased C-reactive protein (5,3 mg/l) there was no laboratory sign suggestive for IgG4-RD (normal serum IgG4, complement, eosinophils and IgE). Within 4 months the patient suffered from hoarseness and progredient dyspnea. Surgical thyroidectomy was performed and histopathology revealed IgG4-related Riedel’s thyroiditis with extensive (storiform) fibrosis, a dense lymphoplasmacytic infiltrate, obliterative phlebitis, eosinophilia and 13 IgG4-positive plasma cells per high power field.After referral to our department a comprehensive work-up showed no signs of other manifestations of IgG4-RD. Treatment with glucocorticoids is clearly recommended for patients with symptomatic IgG4-RD in an international consensus statement, whereas “watchful waiting” may be appropriate in some cases of asymptomatic or mild disease. While some highly fibrotic lesions may not respond well to glucocorticoids and may require surgical intervention, no clear guidance is available for the management of fully resected single organ IgG4-RD [2].A brief review of the literature revealed that few cases of single-organ IgG4-RD remaining in remission after resection without medical treatment have been reported e.g. IgG4-related cholecystitis, autoimmune-pancreatitis, tumours of the intestinal tract, lung, thymus, meninges, paravertebral space and others [3–9].After discussion of the options with the patient no systemic immunosuppression was given under close follow up without signs of relapse in clinical examinations, laboratory or imaging during the first 6 months.Conclusion:Limited evidence from case reports suggests that a “watchful waiting” strategy without systemic immunosuppressive treatment may be reasonable in some cases of single-organ IgG4-RD after the affected organ was completely resected (e.g. due to mechanical complications or suspected malignoma). However, close follow-up monitoring should be applied due to the risk of relapse or development of new organ manifestations.References:[1]Brito-Zerón et al.Best Pract. Res. Clin. Rheumatol.2016[2]Khosroshahi et al.Arthritis Rheumatol.2015[3]Takahashi et al.Surg. Case Rep.2015[4]Akbari et al.ACG Case Rep. J.2018[5]Oda et al.Thorac. Cancer2019[6]Nambirajan et al.Childs Nerv. Syst. ChNS Off. J. Int. Soc. Pediatr. Neurosurg.2019[7]Uchida et al.Asian J. Endosc. Surg.2018[8]Hart et al.Mod. Pathol. Off. J. U. S. Can. Acad. Pathol. Inc2015[9]Kim et al.Tuberc. Respir. Dis.2014Disclosure of Interests:Jan Schirmer: None declared, Marcus Seeger: None declared, Dominik Schulte Paid instructor for: Ferring, Speakers bureau: Amgen, Astra Zeneca, Braun, Fresenius, Ipsen, Johnson & Johnson, Lilly, MSD, Novartis, Novo Nordisk, Sanofi, Matthias Laudes Speakers bureau: Roche, Sanofi, Chugai, Stefan Schreiber Consultant of: AbbVie, Arena, BMS, Biogen, Celltrion, Celgene, IMAB, Gilead, MSD, Mylan, Pfizer, Fresenius, Janssen, Takeda, Theravance, provention Bio, Protagonist and Falk, Bimba F. Hoyer: None declared

IL-1β is a cytokine of pivotal importance to the orchestration of inflammatory responses. Synthesized as an inactive pro-cytokine, IL-1β requires proteolytic maturation to gain biological activity. Here, we identify intrinsic apoptosis as a non-canonical trigger of IL-1β maturation. Guided by the discovery of the immunomodulatory activity of vioprolides, cyclic peptides isolated from myxobacteria, we observe IL-1β maturation independent of canonical inflammasome pathways, yet dependent on intrinsic apoptosis. Mechanistically, vioprolides inhibit MCL-1 and BCL2, which in turn triggers BAX/BAK-dependent mitochondrial outer membrane permeabilization (MOMP). Induction of MOMP results in the release of pro-apoptotic factors initiating intrinsic apoptosis, as well as the depletion of IAPs (inhibitors of apoptosis proteins). IAP depletion, in turn, operates upstream of ripoptosome complex formation, subsequently resulting in caspase-8-dependent IL-1β maturation. These results establish the ripoptosome/caspase-8 complex as a pro-inflammatory checkpoint that senses the perturbation of mitochondrial integrity.

The cytosolic appearance and propagation of bacteria cause overwhelming cellular stress responses that induce apoptosis under normal conditions. Therefore, successful bacterial colonization depends on the ability of intracellular pathogens to block apoptosis and to safeguard bacterial replicative niches. Here, we show that the cytosolic Gram-negative bacterium Shigella flexneri stalls apoptosis by inhibiting effector caspase activity. Our data identified lipopolysaccharide (LPS) as a bona fide effector caspase inhibitor that directly binds caspases by involving its O-antigen (O Ag) moiety. Bacterial strains that lacked the O Ag or failed to replicate within the cytosol were incapable of blocking apoptosis and exhibited reduced virulence in a murine model of bacterial infection. Our findings demonstrate how Shigella inhibits pro-apoptotic caspase activity, effectively delays coordinated host-cell demise and supports its intracellular propagation. Next to the recently discovered pro-inflammatory role of cytosolic LPS, our data reveal a distinct mode of LPS action that, through the disruption of the early coordinated non-lytic cell death response, ultimately supports the inflammatory breakdown of infected cells at later time points. The lipopolysaccharide of the intracellular pathogen Shigella, in particular its O antigen, interacts with caspases and blocks their activation to prevent apoptosis.

Background Immune infiltration is implicated in the development of acquired resistance to anti-angiogenic cancer therapy. We therefore investigated the correlation between neutrophil infiltration in metastasis of colorectal cancer (CRC) patients and survival after treatment with bevacizumab. Our study identifies CD177+ tumour neutrophil infiltration as an adverse prognostic factor for bevacizumab treatment. We further demonstrate that a novel anti-VEGF/anti-Ang2 compound (BI-880) can overcome resistance to VEGF inhibition in experimental tumour models. Methods A total of 85 metastatic CRC patients were stratified into cohorts that had either received chemotherapy alone (n = 39) or combined with bevacizumab (n = 46). Tumour CD177+ neutrophil infiltration was correlated to clinical outcome. The impact of neutrophil infiltration on anti-VEGF or anti-VEGF/anti-Ang2 therapy was studied in both xenograft and syngeneic tumour models by immunohistochemistry. Results The survival of bevacizumab-treated CRC patients in the presence of CD177+ infiltrates was significantly reduced compared to patients harbouring CD177− metastases. BI-880 treatment reduced the development of hypoxia associated with bevacizumab treatment and improved vascular normalisation in xenografts. Furthermore, neutrophil depletion or BI-880 treatment restored treatment sensitivity in a syngeneic tumour model of anti-VEGF resistance. Conclusions Our findings implicate CD177 as a biomarker for bevacizumab and suggest VEGF/Ang2 inhibition as a strategy to overcome neutrophil associated resistance to anti-angiogenic treatment.

Use of complementary and alternative medicine (CAM) practices and treatments is increasing around the world due to perceived health benefits, low cost and relatively low risk. The current literature on the safety and reported adverse, and especially toxic, effects of CAM treatments and practices was reviewed. A literature search of PubMed, Google Scholar, NIH, CINAHL, Science Direct and WHO databases for meta-analyses, case studies, and case reports published in English in the year 2016 was conducted to obtain data on the safety of CAM therapies and any reported adverse effects or contaminants. In this review, adverse effects of herbal dietary supplements (HDS) are organized by the different physiological systems affected. As expected, hepatotoxicity was the most frequently associated adverse effect with the HDS since the vast majority are consumed orally. Many examples of unintentional and intentional contamination of HDS, the latter most prevalent with sexual and performance enhancing HDS, were recorded. The adverse effects reported for mind–body therapies were fewer in number and severity as compared to HDS. The increasing use of CAM therapies and instances of toxicity and other adverse effects underscore the need for a better reporting and monitoring system for CAM. Safety of CAM practices and treatments is not prospectively regulated. In many cases, there is a lack of information until complaints against a particular product or practice are brought to governmental authorities. Healthcare providers should familiarize themselves with CAM practices and their benefits and risks to best care for their patient population.

We developed a high repetition rate optical parametric chirped-pulse amplification (OPCPA) laser system based on fiber-laser-seeded Innoslab to generate few-cycle pulses around 2 µm with passively stable carrier-envelope phase (CEP) by difference frequency generation (DFG). Incorporating a piezo mirror before the DFG stage permits rapid CEP control. The OPCPA system is seeded by a stable supercontinuum generated in bulk material with the picosecond Innoslab pulses. Few-cycle pulses with durations of 17 fs and energies of over 100 μJ were produced in a single OPCPA stage. Three different nonlinear crystals: BBO, BiBO, and LNB were tested in the final parametric amplifier, and their average power related limitations are addressed.

Background Mastocytosis is characterized by the accumulation of mast cells (MCs) associated with activating mutations of KIT. Tumor necrosis factor-related apoptosis-inducing ligand receptors (TRAIL-Rs) are preferentially expressed on neoplastic cells and induce the extrinsic apoptotic pathway. Recent studies reported on the expression of TRAIL-Rs and TRAIL-induced apoptosis in cultured human MCs, which depend on stem cell factor (SCF)-induced or constitutive KIT activation. Material and methods We sought to further define the impact of TRAIL-Rs on MCs in vivo and in vitro. Using Cre/loxP recombination, we generated mice with MC-specific and ubiquitous knockout of TRAIL-R. In these mice, anaphylaxis and numbers of MCs were investigated. We also explored the expression and function of TRAIL-Rs in cultured murine and human MCs upon activation of KIT. By conducting immunofluorescence staining, we analyzed the expression of TRAIL-Rs in MCs infiltrating the bone marrow of patients with mastocytosis. Results MC-specific deletion of TRAIL-R was associated with a slight, but significant increase in anaphylaxis. Numbers of MCs in MC-specific knockouts of TRAIL-R were comparable to controls. Whereas cultured IL-3-dependent murine MCs from wild-type mice were resistant to TRAIL-induced apoptosis, SCF-stimulated MCs underwent apoptosis in response to TRAIL. Interestingly, activating KIT mutations also promoted sensitivity to TRAIL-mediated apoptosis in human MCs. In line with these findings, MCs infiltrating the bone marrow of patients with mastocytosis expressed TRAIL-R1. Conclusions Activation of KIT regulates the function of TRAIL-Rs in MCs. TRAIL-R1 may represent an attractive diagnostic and therapeutic target in diseases associated with KIT mutations, such as mastocytosis.