Reprint of: Comparison of the Chemical Properties of Selenocysteine and Selenocystine with Their Sulfur Analogs.

Some chemical properties of cystine and cysteine have been compared with those of their selenium-containing analogs. Major differences were noted between their titration curves, pK values of 2.01, 5.24, and 9.96 were observed for the ionizations of the carboxyl, selenohydryl, and amino groups, respectively, of selenocysteine. These values are compared with a pK of 2.3 for the carboxyl group of cysteine and values in the range of 8-10 for the ionization of the sulfhydryl and amino groups. Selenocysteine is much more reactive with halo acid derivatives than is cysteine, and reacts readily with iodoacetate even at pH values much below the pK of the selenohydryl group. Selenocysteine has an apparent half-wave potential of -0.212 V compared with 0.021 V for cysteine. It is unstable to acid hydrolysis, being completely decomposed by heating at 110° in 6 n HCl. It is also more soluble in water than is cysteine.

Carbon clusters formed from shocked benzene.

Benzene (C6H6), while stable under ambient conditions, can become chemically reactive at high pressures and temperatures, such as under shock loading conditions. Here, we report in situ x-ray diffraction and small angle x-ray scattering measurements of liquid benzene shocked to 55 GPa, capturing the morphology and crystalline structure of the shock-driven reaction products at nanosecond timescales. The shock-driven chemical reactions in benzene observed using coherent XFEL x-rays were a complex mixture of products composed of carbon and hydrocarbon allotropes. In contrast to the conventional description of diamond, methane and hydrogen formation, our present results indicate that benzene's shock-driven reaction products consist of layered sheet-like hydrocarbon structures and nanosized carbon clusters with mixed sp2-sp3 hybridized bonding. Implications of these findings range from guiding shock synthesis of novel compounds to the fundamentals of carbon transport in planetary physics.

Identification of lung adenocarcinoma-specific exosome RNAs in peripheral blood by RNA-Seq analysis.

OBJECTIVE: Several plasma-derived exosome RNAs have been identified as key regulators in cancer development. They have been considered as potential biomarkers for a non-invasive "liquid biopsy" to diagnose and assess the progression of cancer. This study aimed to identify human lung adenocarcinoma-specific exosome RNAs in peripheral blood, while assessing the feasibility and efficiency of this recently developed deep-sequencing technology for transcriptome profiling. PATIENTS AND METHODS: Plasma-derived exosome RNAs were isolated from 13 lung adenocarcinoma patients, 3 patients with benign lung diseases, and 15 healthy volunteers. RNA-seq analysis of ribosomal RNA-depleted total RNA was performed. RNAs differentially expressed between lung adenocarcinoma and benign lung diseases or healthy volunteers were identified, followed by GO and KEGG pathway enrichment analyses for the identification of key exosome RNAs associated with lung adenocarcinomas. RESULTS: Significant differentially expressed RNAs, such as UDP glucuronosyltransferase family 1 member A1 (UGT1A1) and BAI1-associated protein 2 like 1 (BAIAP2L1), were identified as differentially expressed between lung adenocarcinoma patients and patients with benign lung diseases. Eight pseudogenes, including Tropomyosin 1 (Alpha) Pseudogene (LOC100129096), Prothymosin, Alpha Pseudogene 2 (PTMAP2), Cell Division Cycle 14C, Pseudogene (CDC14C), Tropomyosin 1 (Alpha) Pseudogene (LOC643634), Ferritin Heavy Chain 1 Pseudogene 2 (FTH1P2), Actin Related Protein 2/3 Complex Subunit 3 Pseudogene 3 (ARPC3P3), Ferritin Heavy Chain 1 Pseudogene 11 (FTH1P11), and Prothymosin Alpha Pseudogene 5 (PTMAP5) were identified from plasma-derived exosomes in lung adenocarcinoma patients, who were more abundant/detectable than healthy volunteers. CONCLUSIONS: Our data indicate that plasma-derived exosome RNAs, UGT1A1, and BAIAP2L1, as well as the eight isolated pseudogenes could serve as diagnostic and prognostic biomarkers for an effective non-invasive "liquid biopsy" of lung adenocarcinomas.

A multi-centre, parallel-group, randomised controlled trial to assess the efficacy and safety of eurythmy therapy and tai chi in comparison with standard care in chronically ill elderly patients with increased risk of falling (ENTAiER): a trial protocol.

BACKGROUND: In elderly poeple, multimorbidity and polypharmacy increase while sensory, motor and cognitive functions decrease. Falls occur in 30% of people aged 65 years and older at least once per year, with injuries at 10-20%. Reducing falls and enhancing physical, emotional and cognitive capacities are essential for healthy aging despite chronic disease. Eurythmy therapy (EYT) and Tai Chi train balance, mobility and concentrative and sensory capacities. METHODS: In eight trial sites (academic or community hospitals), 550 outpatients aged 65 years and older with chronic disease and increased risk of falling (history of imbalance, Berg Balance Scale (BBS) score ≤ 49) will be randomly assigned (1:1:1) to receive either EYT or Tai Chi (each provided in one-hour group sessions, twice, later once per week plus practice at home, for over 24 weeks) added to standard care or standard care alone. Standard care includes a detailed written recommendation on fall prevention and the visit of a primary care doctor. Seniors living a reclusive life or economically disadvantaged elderly will be particularly addressed. A motivation and communication concept supports the trial participants' compliance with trial procedures and practicing. Public and patient representatives are involved in the planning and conduction of the trial. Falls will be documented daily in a diary by the participants. These falls as well as injuries and complications will be ascertained during monthly phone visits. The falls efficacy scale, BBS, cognition (MoCA), Mood (GDS-15), quality of life (SF12), instrumental activities of daily living (IADL), use of medical and non-medical services (FIMA) and adherence will be assessed at months 3, 6, and 12 and inner correspondence with practices (ICPH) at month 6. The trial is funded by the Federal Ministry of Education and Research (BMBF 01GL1805). DISCUSSION: This study will determine whether EYT and Tai Chi reduce falls, injurious falls, fear of falling and healthcare utilisation and improve mobility, cognition, mood, quality of life and functional independence. A reduction of fall risk and fear of falling and an improvement of mobility, autonomy, quality of life, mood, and cognition are highly relevant for older people to cope with aging and diseases and to reduce healthcare costs. TRAIL REGISTRATION: www.drks.de. DRKS00016609. Registered 30th July 2019.

Immunotherapeutic maintenance treatment with toll-like receptor 9 agonist lefitolimod in patients with extensive-stage small-cell lung cancer: results from the exploratory, controlled, randomized, international phase II IMPULSE study.

Background: The immune surveillance reactivator lefitolimod (MGN1703), a DNA-based TLR9 agonist, might foster innate and adaptive immune response and thus improve immune-mediated control of residual cancer disease. The IMPULSE phase II study evaluated the efficacy and safety of lefitolimod as maintenance treatment in extensive-stage small-cell lung cancer (ES-SCLC) after objective response to first-line chemotherapy, an indication with a high unmet medical need and stagnant treatment improvement in the last decades. Patients and methods: 103 patients with ES-SCLC and objective tumor response (as per RECIST 1.1) following four cycles of platinum-based first-line induction therapy were randomized to receive either lefitolimod maintenance therapy or local standard of care at a ratio of 3 : 2 until progression or unacceptable toxicity. Results: From 103 patients enrolled, 62 were randomized to lefitolimod, 41 to the control arm. Patient demographics and response patterns to first-line therapy were balanced. Lefitolimod exhibited a favorable safety profile and pharmacodynamic assessment confirmed the mode-of-action showing a clear activation of monocytes and production of interferon-gamma-induced protein 10 (IP-10). While in the intent-to-treat (ITT) population no relevant effect of lefitolimod on progression-free and overall survival (OS) could be observed, two predefined patient subgroups indicated promising results, favoring lefitolimod with respect to OS: in patients with a low frequency of activated CD86+ B cells (hazard ratio, HR 0.53, 95% CI: 0.26-1.08; n = 38 of 88 analyzed) and in patients with reported chronic obstructive pulmonary disease (COPD) (HR 0.48, 95% CI: 0.20-1.17, n = 25 of 103). Conclusions: The IMPULSE study showed no relevant effect of lefitolimod on the main efficacy end point OS in the ITT, but (1) the expected pharmacodynamic response to lefitolimod, (2) positive OS efficacy signals in two predefined subgroups and (3) a favorable safety profile. These data support further exploration of lefitolimod in SCLC.

ALK-Testing in non-small cell lung cancer (NSCLC): Immunohistochemistry (IHC) and/or fluorescence in-situ Hybridisation (FISH)?: Statement of the Germany Society for Pathology (DGP) and the Working Group Thoracic Oncology (AIO) of the German Cancer Society e.V. (Stellungnahme der Deutschen Gesellschaft für Pathologie und der AG Thorakale Onkologie der Arbeitsgemeinschaft Onkologie/Deutsche Krebsgesellschaft e.V.).

The EML4-ALK pathway plays an important role in a significant subset of non-small cell lung cancer patients. Treatment options such as ALK tyrosine kinase inhibitors lead to improved progression free survival and overall survival. These therapeutic options are chosen on the basis of the identification of the underlying genetic signature of the EML-ALK translocation. Efficient and easily accessible testing tools are required to identify eligible patients in a timely fashion. While FISH techniques are commonly used to detect this translocation, the broad implementation of this type of ALK testing into routine diagnostics is not optimal due to technical, structural and financial reasons. Immunohistochemical techniques to screen for EML4-ALK translocations may therefore play an important role in the near future. This consensus paper provides recommendations for the test algorithm and quality of the respective test approaches, which are discussed in the light of the current literature.

Terahertz-Driven Nonlinear Spin Response of Antiferromagnetic Nickel Oxide.

Terahertz magnetic fields with amplitudes of up to 0.4 Tesla drive magnon resonances in nickel oxide while the induced dynamics is recorded by femtosecond magneto-optical probing. We observe distinct spin-mediated optical nonlinearities, including oscillations at the second harmonic of the 1 THz magnon mode. The latter originate from coherent dynamics of the longitudinal component of the antiferromagnetic order parameter, which are probed by magneto-optical effects of second order in the spin deflection. These observations allow us to dynamically disentangle electronic from lattice-related contributions to magnetic linear birefringence and dichroism-information so far only accessible by ultrafast THz spin control. The nonlinearities discussed here foreshadow physics that will become essential in future subcycle spin switching.

Hypocalcaemia of malignancy.

BACKGROUND: Hypercalcaemia of malignancy is well recognised, but hypocalcaemia in cancer patients is not, although it is increasingly encountered. METHODS: Analysis of an exemplary case and a narrative review of the literature based on the search terms cancer and hypocalcaemia. RESULTS: Hypocalcaemia may affect as many as 10% of hospitalised cancer patients. We identified 12 different potential mechanisms of hypocalcaemia of malignancy. Identifying the pathogenesis is essential for the correct treatment and can usually be performed at the bedside, based on serum parathyroid hormone (PTH) levels, creatinine, phosphate, magnesium, creatine kinase, liver enzymes and 25(OH)D. Essentially, decreased or normal PTH hypocalcaemia is seen after removal or destruction of its source, hypomagnesaemia, or cinacalcet treatment. In all other cancer-associated hypocalcaemia, PTH is elevated, including significant renal impairment, critically ill patients, extensive cell destruction (rhabdomyolysis, tumour lysis, haemolysis), acute pancreatitis, adverse drug reactions, cancer or cancer treatment-related malabsorption syndromes, vitamin D deficiency, or osteoblastic metastases. Different mechanisms may often operate in tandem. Pathogenesis determines treatment and affects prognosis. However, hypocalcaemia of malignancy as such did not imply a worse prognosis, in contrast with hypercalcaemia. CONCLUSION: Hypocalcaemia in cancer patients is commonly encountered, particularly in hospitalised patients, may be mediated by diverse mechanisms and should be better recognised.

praja2 regulates KSR1 stability and mitogenic signaling.

The kinase suppressor of Ras 1 (KSR1) has a fundamental role in mitogenic signaling by scaffolding components of the Ras/MAP kinase pathway. In response to Ras activation, KSR1 assembles a tripartite kinase complex that optimally transfers signals generated at the cell membrane to activate ERK. We describe a novel mechanism of ERK attenuation based on ubiquitin-dependent proteolysis of KSR1. Stimulation of membrane receptors by hormones or growth factors induced KSR1 polyubiquitination, which paralleled a decline of ERK1/2 signaling. We identified praja2 as the E3 ligase that ubiquitylates KSR1. We showed that praja2-dependent regulation of KSR1 is involved in the growth of cancer cells and in the maintenance of undifferentiated pluripotent state in mouse embryonic stem cells. The dynamic interplay between the ubiquitin system and the kinase scaffold of the Ras pathway shapes the activation profile of the mitogenic cascade. By controlling KSR1 levels, praja2 directly affects compartmentalized ERK activities, impacting on physiological events required for cell proliferation and maintenance of embryonic stem cell pluripotency.

[ALK-Diagnostics in NSCLC - Immunohistochemistry (IHC) and/or Fluorescence-in-situ Hybridisation (FISH)]. / ALK-Testung beim nicht-kleinzelligen Lungenkarzinom (NSCLC): Immunhistochemie (IHC) und/oder Fluoreszenz-in-situ-Hybridisierung (FISH)?

The EML4-ALK pathway plays an important role in a significant subset of non-small cell lung cancer patients. Treatment options such as tyrosine kinase inhibitors directed against the EML4-ALK signalling pathway lead to improved progression free and overall survival. These therapeutic options are chosen on the basis of the identification of the underlying genetic signature of the EML-ALK translocation. Efficient and easily accessible testing tools are required to identify the patients in time. While FISH techniques have been implemented to characterize this translocation for some time, the implementation of this testing is hampered by its broad use of resources. Immunohistochemical techniques to identify and screen for EML4-ALK translocations may play an important role in the near future. This consensus paper offers recommendations of the sequence and quality of the respective test approaches which are validated on the basis of the current literature.

Improved diagnostics targeting c-MET in non-small cell lung cancer: expression, amplification and activation?

BACKGROUND: Several c-MET targeting inhibitory molecules have already shown promising results in the treatment of patients with Non-small Cell Lung Cancer (NSCLC). Combination of EGFR- and c-MET-specific molecules may overcome EGFR tyrosine kinase inhibitor (TKI) resistance. The aim of this study was to allow for the identification of patients who might benefit from TKI treatments targeting MET and to narrow in on the diagnostic assessment of MET. METHODS: 222 tumor tissues of patients with NSCLC were analyzed concerning c-MET expression and activation in terms of phosphorylation (Y1234/1235 and Y1349) using a microarray format employing immunohistochemistry (IHC). Furthermore, protein expression and MET activation was correlated with the amplification status by Fluorescence in Situ Hybridization (FISH). RESULTS: Correlation was observed between phosphorylation of c-MET at Y1234/1235 and Y1349 (spearman correlation coefficient rs = 0.41; p < 0.0001). No significant correlation was shown between MET expression and phosphorylation (p > 0.05). c-MET gene amplification was detected in eight of 214 patients (3.7%). No significant association was observed between c-MET amplification, c-MET protein expression and phosphorylation. CONCLUSION: Our data indicate, that neither expression of c-MET nor the gene amplification status might be the best way to select patients for MET targeting therapies, since no correlation with the activation status of MET was observed. We propose to take into account analyzing the phosphorylation status of MET by IHC to select patients for MET targeting therapies. Signaling of the receptor and the activation of downstream molecules might be more crucial for the benefit of therapeutics targeting MET receptor tyrosine kinases than expression levels alone.

Correlation between dihydropyrimidine dehydrogenase and efficacy and toxicity of fluoropyrimidine drugs.

At present, fluoropyrimidine, based on 5-fluorouracil (5-FU), remains one of the most frequently prescribed chemotherapeutics drugs for the treatment of cancer. Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme in the catabolism of 5-FU, and DPD enzymatic activities are usually varied dramatically from individual to individual, including both the intrapatient differences and the interpatient variability. There is a certain correlation between the DPD activity and efficacy and toxicity following the administration of fluoropyrimidine drugs. Partial or complete loss of DPD activity can lead to serious or even lethal toxicity. In this article, we review the relationship between DPD activity and efficacy and toxicity following the administration of fluoropyrimidine drugs, and also the structure, function, and characteristics of DPD. We report here that measurement of DPD activity may become a strategy and be paid much attention to predict the efficacy and toxicity prior to starting a fluoropyrimidine-based therapy.

Structural analysis of the human fibroblast growth factor receptor 4 kinase.

The family of fibroblast growth factor receptors (FGFRs) plays an important and well-characterized role in a variety of pathological disorders. FGFR4 is involved in myogenesis and muscle regeneration. Mutations affecting the kinase domain of FGFR4 may cause cancer, for example, breast cancer or rhabdomyosarcoma. Whereas FGFR1-FGFR3 have been structurally characterized, the structure of the FGFR4 kinase domain has not yet been reported. In this study, we present four structures of the kinase domain of FGFR4, in its apo-form and in complex with different types of small-molecule inhibitors. The two apo-FGFR4 kinase domain structures show an activation segment similar in conformation to an autoinhibitory segment observed in the hepatocyte growth factor receptor kinase but different from the known structures of other FGFR kinases. The structures of FGFR4 in complex with the type I inhibitor Dovitinib and the type II inhibitor Ponatinib reveal the molecular interactions with different types of kinase inhibitors and may assist in the design and development of FGFR4 inhibitors.

Mode of action of cupping--local metabolism and pain thresholds in neck pain patients and healthy subjects.

OBJECTIVES: Cupping worldwide has been part of traditional medicine systems and is in the western world used as CAM therapy mainly for treating pain syndromes. The mode of action is up to now unclear. In order to investigate its mechanism we measured in parallel metabolic changes in the tissue under the cupping glass and pressure pain thresholds. DESIGN AND INTERVENTIONS: In 12 volunteers (6 healthy subjects and 6 patients with chronic neck pain) a microdialysis system was implanted subcutaneously on both sides (left and right) above the trapezius muscle. After baseline measures cupping was performed at one randomly selected side (left or right), the other side served as control. Every 20 min during baseline measures and for 280 min after cupping, microdialysis probes for detection of lactate, pyruvate, glucose and glycerin were taken. In addition, pain thresholds were measured before and after cupping with algometry. RESULTS: Cupping resulted in a strong increase of lactate (beginning 160 min after cupping until the end of the measurements) and the lactate/pyruvate ratio, indicating an anaerobe metabolism in the surrounding tissue. Baseline pain thresholds were non-significantly lower in neck pain patients compared to healthy controls and slightly increased immediately after cupping (p<0.05 compared to baseline close to the area of cupping in healthy subjects and on the foot in neck pain patients). After 280 min no more significant changes of pain thresholds were detected. CONCLUSIONS: Cupping induces >280 min lasting anaerobe metabolism in the subcutaneous tissue and increases immediate pressure pain thresholds in some areas.

Cystic fibrosis in adults: short-term and long-term reproducibility of the Brody score for lung morphology in low-dose MDCT scans.

PURPOSE: The semi-quantitative Brody score measures the severity of cystic fibrosis (CF)-related lung disease. We investigated the short-term (28 - 60 days) and long-term (2 - 7 years) intra- and inter-observer reproducibility of the Brody score in low-dose multidetector row computed tomography examinations performed in inspiration (LDCTs) of adult CF patients. MATERIALS AND METHODS: Composite Brody scores and respective underlying bronchiectasis, mucus plugging, peribronchial thickening, parenchymal opacity, and hyperinflation subscores were evaluated twice (time interval, 1 - 84 months) by each of 3 independent radiologists (1 - 20 years of professional diagnostic radiology experience) in LDCTs (4 - 64 rows, 120 KVp, 10 - 15  mAs/slice, CTDIw approx. 1.0  mGy, effective dose approx. 0.5  mSv) of 15 adult patients with CF-related lung disease (8 female, 7 male, age, 18 - 50 years, mean, 33 years). RESULTS: The average reproducibility of the Brody score was within +/-7 % (range, 2 - 30 %) between radiologists, and +/-6 % (3 - 12 %) within radiologists (short-term, 28 - 60 days, 4 %, 0 - 12 %, long-term, 2 - 7 years, 12 %, 1 - 36 %). For the different subscores, the reproducibility was within +/-25 % (15 - 41 %) between radiologists and +/-23 % (12 - 46 %) within radiologists. CONCLUSION: The Brody score shows high average inter-observer reproducibility in LDCTs of adult CF patients. The Brody score also demonstrates high average intra-observer reproducibility if subsequent assessments are made within 28 - 61 days. With time intervals of 2 - 7 years between subsequent evaluations, however, intra-observer reproducibility decreases. Respective subscores each demonstrate lower intra- and inter-observer reproducibility than does the composite Brody score.