The ASAS Health Index and Environmental Factors Item Set: validity and reliability of the Swedish translations in Swedish patients with ankylosing spondylitis.

OBJECTIVES: To translate the Assessment of SpondyloArthritis international Society (ASAS) Health Index (HI) Environmental Factors Item Set (EFIS) into Swedish and culturally adapt it for a Swedish context, and to assess the construct validity of the Swedish version of the ASAS HI and test-retest reliability in ASAS HI and EFIS in Swedish patients with ankylosing spondylitis (AS). METHOD: Translation and cross-cultural adaptation of the EFIS were carried out according to a forward-backward procedure consisting of five steps. The construct validity of the ASAS HI was tested using Spearman correlation with standard health outcomes for axial spondyloarthritis (axSpA). Reliability was analysed by internal consistency with the Cronbach's alpha coefficient for ASAS HI, and test-retest reliability with intraclass correlation coefficients (ICCs) for ASAS HI and kappa agreement for the individual items of EFIS. RESULTS: The translation of EFIS showed acceptable face and content validity. ASAS HI showed an acceptable internal consistency (Cronbach's alpha 0.79), and excellent test-retest reliability (ICC 0.87). Test-retest reliability for EFIS showed varied results, with kappa agreement for the individual items ranging from poor (-0.027) to good (0.80). CONCLUSIONS: The Swedish version of ASAS HI proved to be valid and reliable and is recommended for assessing the impact of AS on global functioning and health. A Swedish version of EFIS has been produced and uploaded on the ASAS website. The EFIS proved to have acceptable face and content validity, and may contribute to the contextual interpretation of the ASAS HI.

Synthesis and automated fluorine-18 radiolabeling of new PSMA-617 derivatives with a CuAAC radiosynthetic approach.

In the last decade, the development of new radiopharmaceuticals for the imaging and therapy of prostate cancer has been a highly active and important area of research, especially focusing on the prostate-specific membrane antigen (PSMA), an antigen which is upregulated in prostate, as well as in other tumor cells. A large variety of PSMA ligands have been radiolabeled, to date. Among the various derivatives, PSMA-617 resulted to be one of the most interesting in terms of interaction with the antigen and clinical properties, and its lutetium-177 labeled version has recently been approved by regulatory agencies for therapeutic purposes. For this reasons, the radiolabeling with fluorine-18 of a PSMA-617 derivative might be of interest. Beside other methodologies to radiolabel macromolecules with fluorine-18, the "click-chemistry" approach resulted to be very useful, and the copper-catalyzed azide-alkyne cycloaddition (CuAAC) is considered one of most efficient and reliable. This paper proposes the synthesis of a suitable precursor for the radiolabeling with fluorine-18 of a new PSMA-617 derivative. The whole radiosynthetic procedure has been fully automated, and the final product, which proved to be stable in plasma, has been obtained with radiochemical yield and purity suitable for subsequent preclinical studies.

Adaptation to 5 weeks of intermittent local vascular pressure increments; mechanisms to be considered in the development of primary hypertension?

The aims were to study effects of iterative exposures to moderate elevations of local intravascular pressure on arterial/arteriolar stiffness and plasma levels of vasoactive substances. Pressures in the vasculature of an arm were increased by 150 mmHg in healthy men (n = 11) before and after a 5-wk regimen, during which the vasculature in one arm was exposed to fifteen 40-min sessions of moderately increased transmural pressure (+65 to +105 mmHg). This vascular pressure training and the pressure-distension determinations were conducted by exposing the subjects' arm versus remaining part of the body to differential ambient pressure. During the pressure-distension determinations, venous samples were simultaneously obtained from pressurized and unpressurized vessels. Pressure training reduced arterial pressure distension by 40 ± 23% and pressure-induced flow by 33 ± 30% (P < 0.01), but only in the pressure-trained arm, suggesting local adaptive mechanisms. The distending pressure-diameter and distending pressure-flow curves, with training-induced increments in pressure thresholds and reductions in response gains, suggest that the increased precapillary stiffness was attributable to increased contractility and structural remodeling of the walls. Acute vascular pressure provocation induced local release of angiotensin-II (ANG II) and endothelin-1 (ET-1) (P < 0.05), suggesting that these vasoconstrictors limited the pressure distension. Pressure training increased basal levels of ET-1 and induced local pressure release of matrix metalloproteinase 7 (P < 0.05), suggesting involvement of these substances in vascular remodeling. The findings are compatible with the notion that local intravascular pressure load acts as a prime mover in the development of primary hypertension.NEW & NOTEWORTHY Adaptive responses to arterial/arteriolar pressure elevation have typically been investigated in cross-sectional studies in hypertensive patients or in longitudinal studies in experimental animals. The present investigation shows that in healthy individuals, fifteen 40-min, carefully controlled, moderate transmural pressure elevations markedly increase in vivo stiffness (i.e. reduce pressure distension) in arteries and arterioles. The response is mediated via local mechanisms, and it appears that endothelin-1, angiotensin-II, and matrix metalloproteinase 7 may have key roles.

Wave propagation and focusing of soft X-rays by spherical bent microchannel plates.

Synchrotron radiation sources have been used to study the focusing properties and angular distribution of X-ray radiation at the exit of spherically bent microchannel plates (MCPs). In this contribution it is shown how soft X-ray radiation at energies up to 1.5 keV can be focused by spherically bent MCPs with curvature radii R of 30 mm and 50 mm. For these devices, a focus spot is detectable at a distance between the detector and the MCP of less than R/2, with a maximum focusing efficiency up to 23% of the flux illuminating the MCP. The soft X-ray radiation collected at the exit of microchannels of spherically bent MCPs are analyzed in the framework of a wave approximation. A theoretical model for the wave propagation of radiation through MCPs has been successfully introduced to explain the experimental results. Experimental data and simulations of propagating radiation represent a clear confirmation of the wave channeling phenomenon for the radiation in spherically bent MCPs.

Coincident angle-resolved state-selective photoelectron spectroscopy of acetylene molecules: a candidate system for time-resolved dynamics.

The acetylene-vinylidene system serves as a benchmark for investigations of ultrafast dynamical processes where the coupling of the electronic and nuclear degrees of freedom provides a fertile playground to explore the femto- and sub-femto-second physics with coherent extreme-ultraviolet (EUV) photon sources both on the table-top as well as free-electron lasers. We focus on detailed investigations of this molecular system in the photon energy range 19-40 eV where EUV pulses can probe the dynamics effectively. We employ photoelectron-photoion coincidence (PEPICO) spectroscopy to uncover hitherto unrevealed aspects of this system. In this work, the role of excited states of the C2H2+ cation, the primary photoion, is specifically addressed. From photoelectron energy spectra and angular distributions, the nature of the dissociation and isomerization channels is discerned. Exploiting the 4π-collection geometry of the velocity map imaging spectrometer, we not only probe pathways where the efficiency of photoionization is inherently high but also perform PEPICO spectroscopy on relatively weak channels.

Disruption of the anaphase-promoting complex confers resistance to TTK inhibitors in triple-negative breast cancer.

TTK protein kinase (TTK), also known as Monopolar spindle 1 (MPS1), is a key regulator of the spindle assembly checkpoint (SAC), which functions to maintain genomic integrity. TTK has emerged as a promising therapeutic target in human cancers, including triple-negative breast cancer (TNBC). Several TTK inhibitors (TTKis) are being evaluated in clinical trials, and an understanding of the mechanisms mediating TTKi sensitivity and resistance could inform the successful development of this class of agents. We evaluated the cellular effects of the potent clinical TTKi CFI-402257 in TNBC models. CFI-402257 induced apoptosis and potentiated aneuploidy in TNBC lines by accelerating progression through mitosis and inducing mitotic segregation errors. We used genome-wide CRISPR/Cas9 screens in multiple TNBC cell lines to identify mechanisms of resistance to CFI-402257. Our functional genomic screens identified members of the anaphase-promoting complex/cyclosome (APC/C) complex, which promotes mitotic progression following inactivation of the SAC. Several screen candidates were validated to confer resistance to CFI-402257 and other TTKis using CRISPR/Cas9 and siRNA methods. These findings extend the observation that impairment of the APC/C enables cells to tolerate genomic instability caused by SAC inactivation, and support the notion that a measure of APC/C function could predict the response to TTK inhibition. Indeed, an APC/C gene expression signature is significantly associated with CFI-402257 response in breast and lung adenocarcinoma cell line panels. This expression signature, along with somatic alterations in genes involved in mitotic progression, represent potential biomarkers that could be evaluated in ongoing clinical trials of CFI-402257 or other TTKis.

Penning spectroscopy and structure of acetylene oligomers in He nanodroplets.

Embedded atoms or molecules in a photoexcited He nanodroplet are well-known to be ionized through inter-atomic relaxation in a Penning process. In this work, we investigate the Penning ionization of acetylene oligomers occurring from the photoexcitation bands of He nanodroplets. In close analogy to conventional Penning electron spectroscopy by thermal atomic collisions, the n = 2 photoexcitation band plays the role of the metastable atomic 1s2s 3,1S He*. This facilitates electron spectroscopy of acetylene aggregates in the sub-Kelvin He environment, providing the following insight into their structure: the molecules in the dopant cluster are loosely bound van der Waals complexes rather than forming covalent compounds. In addition, this work reveals a Penning process stemming from the n = 4 band where charge-transfer from autoionized He in the droplets is known to be the dominant relaxation channel. This allows for excited states of the remnant dopant oligomer Penning-ions to be studied. Hence, we demonstrate Penning ionization electron spectroscopy of doped droplets as an effective technique for investigating dopant oligomers which are easily formed by attachment to the host cluster.

Universal Nanocarrier Ink Platform for Biomaterials Additive Manufacturing.

Ink engineering is a fundamental area of research within additive manufacturing (AM) that designs next-generation biomaterials tailored for additive processes. During the design of new inks, specific requirements must be considered, such as flowability, postfabrication stability, biointegration, and controlled release of therapeutic molecules. To date, many (bio)inks have been developed; however, few are sufficiently versatile to address a broad range of applications. In this work, a universal nanocarrier ink platform is presented that provides tailored rheology for extrusion-based AM and facilitates the formulation of biofunctional inks. The universal nanocarrier ink (UNI) leverages reversible polymer-nanoparticle interactions to form a transient physical network with shear-thinning and self-healing properties engineered for direct ink writing (DIW). The unique advantage of the material is that a range of functional secondary polymers can be combined with the UNI to enable stabilization of printed constructs via secondary cross-linking as well as customized biofunctionality for tissue engineering and drug delivery applications. Specific UNI formulations are used for bioprinting of living tissue constructs and DIW of controlled release devices. The robust and versatile nature of the UNI platform enables rapid formulation of a broad range of functional inks for AM of advanced biomaterials.

Concentric-flow electrokinetic injector enables serial crystallography of ribosome and photosystem II.

We describe a concentric-flow electrokinetic injector for efficiently delivering microcrystals for serial femtosecond X-ray crystallography analysis that enables studies of challenging biological systems in their unadulterated mother liquor. We used the injector to analyze microcrystals of Geobacillus stearothermophilus thermolysin (2.2-Å structure), Thermosynechococcus elongatus photosystem II (<3-Å diffraction) and Thermus thermophilus small ribosomal subunit bound to the antibiotic paromomycin at ambient temperature (3.4-Å structure).

Preliminary evidence that vortioxetine may improve sleep quality in depressed patients with insomnia: a retrospective questionnaire analysis.

Insomnia is a frequent symptom in depressed patients. It can present with difficulty in initiating and/or maintaining sleep. We retrospectively evaluated a group of 15 patients affected by major depressive disorder and complaining of insomnia, who started vortioxetine (VOR) treatment for their depressive symptoms. The following questionnaires were captured at baseline and follow-up: Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale and Beck Depression Inventory. Pittsburgh Sleep Quality Index total score significantly decreased between follow-up and baseline (P < 0.01), and in several subitems related to sleep quality and continuity. Moreover, Epworth Sleepiness Scale decreased between follow-up and baseline (P < 0.01). Finally, Beck Depression Inventory reduction was also evident between follow-up and baseline (P < 0.01). This retrospective analysis showing the significant effect of VOR on both depressive symptoms and insomnia in patients showing comorbid major depressive disorder and insomnia invites further research in order to confirm this preliminary evidence. We hypothesize that the VOR mechanism of action may explain the improvement of subjective sleep, other than depressive symptoms.

Describing the gingival involvement in a sample of 182 Italian predominantly oral mucous membrane pemphigoid patients: A retrospective series.

BACKGROUND: The oral cavity has been frequently described as the only site of involvement or as the first manifestation of mucous membrane pemphigoid (MMP), being the gingival tissues often involved, but usually this has been effusively detailed in limited case series. This is a retrospective evaluation of the gingival involvement in 182 Italian patients with oral MMP. MATERIAL AND METHODS: The diagnosis of MMP was established by both clinical morphology and direct immunofluorescence finding. Patient information (age, gender, risk factors and medical status) and parameters of manifestation (lesions' distribution, site and type) were detailed. RESULTS: The mean age was 62 years for women (n=137) and 67 years for men (n=45). Patients had several sites of oral involvement; the gingiva was the most common one, affecting 151 patients (82.96%; 119 f - 32 m). Female subjects had more possibilities to develop gingival lesions than male patients (P = 0.005). Sixty-five patients (35.7%; 58 f - 7 m) had pure gingival involvement. Patients with lower gingival involvement statistically had more complaints (P = 0.006). CONCLUSIONS: This report is one of the largest about predominantly oral MMP cases, detailing the very frequent gingival involvement; this could be crucial not only for oral medicine specialists but also for primary dental healthcare personnel and for periodontists.

Tauroursodeoxycholic acid in the treatment of patients with amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Tauroursodeoxycholic acid (TUDCA) is a hydrophilic bile acid that is produced in the liver and used for treatment of chronic cholestatic liver diseases. Experimental studies suggest that TUDCA may have cytoprotective and anti-apoptotic action, with potential neuroprotective activity. A proof of principle approach was adopted to provide preliminary data regarding the efficacy and tolerability of TUDCA in a series of patients with amyotrophic lateral sclerosis (ALS). METHODS: As a proof of principle, using a double-blind placebo controlled design, 34 ALS patients under treatment with riluzole who were randomized to placebo or TUDCA (1 g twice daily for 54 weeks) were evaluated after a lead-in period of 3 months. The patients were examined every 6 weeks. The primary outcome was the proportion of responders [those subjects with improvement of at least 15% in the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) slope during the treatment period compared to the lead-in phase]. Secondary outcomes included between-treatment comparison of ALSFRS-R at study end, comparison of the linear regression slopes for ALSFFRS-R mean scores and the occurrence of adverse events. RESULTS: Tauroursodeoxycholic acid was well tolerated; there were no between-group differences for adverse events. The proportion of responders was higher under TUDCA (87%) than under placebo (P = 0.021; 43%). At study end baseline-adjusted ALSFRS-R was significantly higher (P = 0.007) in TUDCA than in placebo groups. Comparison of the slopes of regression analysis showed slower progression in the TUDCA than in the placebo group (P < 0.01). CONCLUSIONS: This pilot study provides preliminary clinical data indicating that TUDCA is safe and may be effective in ALS.

The etiology of low-grade gliomas: pathological and clinical considerations about radiation-induced low-grade gliomas.

The only environmental factor undoubtedly linked to an increased risk of brain tumors (including gliomas) is therapeutic X-rays. We aim to conduct a detailed study of radiation-induced low-grade gliomas, in order to better understand the pathogenesis of such gliomas. Furthermore, we want do prove whether or not there are significant differences, according to clinical features and biological behavior, between this type of tumor and general low-grade gliomas. We analyzed the existent literature of low-grade radiation-induced glioma case reports and other epidemiological reports based on the experience of the senior author. We were able to collect 20 cases of such gliomas. Demographic data and previous X-ray details, along with latency intervals of all patients are provided. The amount of radiation able to cause mutations is not necessarily very high, as tumors occur even after low doses of radiation (as 3-5 GY). The incidence of this kind of tumors may be underestimated and may rise in the future. Care must be taken when observing patients who were irradiated more than 10 years before, especially in the recent years in which access to radiosurgical and radiation therapies has increased in the general population for treating many cerebral pathologies. Radiation-induced low-grade gliomas appear to be different from general gliomas only in terms of age in which they occur. In terms of clinical and biological behavior, there seem to be no differences, even though exceptional cases are reported.

Pimecrolimus vs. tacrolimus for the topical treatment of unresponsive oral erosive lichen planus: a 8 week randomized double-blind controlled study.

BACKGROUND: Oral lichen planus (OLP) is a chronic inflammatory disease, affecting nearly 1-2% of the population; Proposed therapies are usually symptomatic and numerous drugs have been used, but recently, it has been published that there is insufficient evidence to support the effectiveness of any specific treatment as being superior. To the best of our knowledge, direct evaluation of the efficacy of topically applied pimecrolimus and tacrolimus in the treatment of atrophic-erosive OLP, refractory to topical steroids, is still lacking. OBJECTIVES: To assess the efficacy and safety of topical calcineurin inhibitors for unresponsive OLP. An 8 week randomized, double-blind controlled trial, followed by a 6 month follow-up period. Patients were treated with either pimecrolimus 1% cream or tacrolimus 0.1% ointment, both mixed with an equivalent amount of 4% hydroxyethyl cellulose gel. The medications were to be applied twice daily for 2 months. Each patient was examined at the beginning of therapy, and then every 2 weeks during the treatment and every 3 months of follow-up. Main outcome measures were: (i) to compare the effectiveness of topically applied pimecrolimus and tacrolimus; (ii) to evaluate which is more cost-effective; (iii) to determine which drug is faster in reducing signs and symptoms and (iv) which gives the longest remission. RESULTS: Thirty patients were involved in the study. Both drugs were effective at inducing clinical improvement, with no statistical difference. Pimecrolimus creams revealed a significantly better stability of the therapeutic effectiveness (P = 0.031). CONCLUSION: Both medications would currently appear to be a treatment of choice for patients with unresponsive atrophic-erosive OLP. Pimecrolimus seemed to be more effective in providing long-term resolution of signs and symptoms. Future efforts are however needed to obtain more objective evidence of the benefit of these medications in the treatment of immunologically mediated oral mucosal lesion.

Molecular changes underlying pulmonary emphysema and chronic bronchitis in Chronic Obstructive Pulmonary Disease: An updated review.

The aim of this review is to update and synthesize the molecular mechanisms that lead to the heterogeneous effect on tissue remodeling observed in the two most important clinical phenotypes of chronic obstructive pulmonary disease (COPD), pulmonary emphysema (PE) and chronic bronchitis (CB). Clinical and experimental evidence suggests that this heterogeneous response to promote PE, CB, or both, is related to differentiated genetic, epigenetic, and molecular conditions. Specifically, a tendency toward PE could be related to a variant in the DSP gene, SIRT1 downregulation, macrophage polarization to M1, as well as the involvement of the noncanonical Wnt5A signaling pathway, among other alterations. Additionally, in advanced stages of COPD, PE development is potentiated by dysregulations in autophagy, which promotes senescence and subsequently cell apoptosis, through exacerbated inflammasome activation and release of caspases. On the other hand, CB or the pro-fibrotic phenotype could be potentiated by the downregulated activity of HDAC2, the activation of the TGF-ß/Smad or Wnt/ß-catenin signaling pathways, macrophage polarization to M2, upregulation of TIMP-1, and/or the presence of the epithelial-mesenchymal transition (EMT) mechanism. Interestingly, the upregulated activity of MMPs, especially MMP-9, is widely involved in the development of both phenotypes. Furthermore, MMP-9 and MMP-12 enhance the severity, perpetuation, and exacerbation of COPD, as well as the development of autoimmunity in this disease.

Designed modular protein hydrogels for biofabrication.

Designing proteins that fold and assemble over different length scales provides a way to tailor the mechanical properties and biological performance of hydrogels. In this study, we designed modular proteins that self-assemble into fibrillar networks and, as a result, form hydrogel materials with novel properties. We incorporated distinct functionalities by connecting separate self-assembling (A block) and cell-binding (B block) domains into single macromolecules. The number of self-assembling domains affects the rigidity of the fibers and the final storage modulus G' of the materials. The mechanical properties of the hydrogels could be tuned over a broad range (G' = 0.1 - 10 kPa), making them suitable for the cultivation and differentiation of multiple cell types, including cortical neurons and human mesenchymal stem cells. Moreover, we confirmed the bioavailability of cell attachment domains in the hydrogels that can be further tailored for specific cell types or other biological applications. Finally, we demonstrate the versatility of the designed proteins for application in biofabrication as 3D scaffolds that support cell growth and guide their function. STATEMENT OF SIGNIFICANCE: Designed proteins that enable the decoupling of biophysical and biochemical properties within the final material could enable modular biomaterial engineering. In this context, we present a designed modular protein platform that integrates self-assembling domains (A blocks) and cell-binding domains (B blocks) within a single biopolymer. The linking of assembly domains and cell-binding domains this way provided independent tuning of mechanical properties and inclusion of biofunctional domains. We demonstrate the use of this platform for biofabrication, including neural cell culture and 3D printing of scaffolds for mesenchymal stem cell culture and differentiation. Overall, this work highlights how informed design of biopolymer sequences can enable the modular design of protein-based hydrogels with independently tunable biophysical and biochemical properties.

Partial rescue of Brca1 (5-6) early embryonic lethality by p53 or p21 null mutation.

Mutations in the mouse Brca1 gene cause lethality at different embryonic stages. We have shown that Brca1 mutant embryos, in which the fifth and sixth exons of Brca1 are deleted die before E7.5 and show decreased cellular proliferation. Brca1 mutants also show decreased expression of mdm2, a gene encoding an inhibitor of p53 activity. Thus, we have proposed that the reduction in mdm2 expression in Brca1 (5-6) mutants might lead to increased p53 activity. Consistent with this finding, the expression of p21, which encodes a G1 cell cycle inhibitor and is a target for p53 transcriptional activation was dramatically increased in the Brca1 (5-6) mutants, suggesting that impaired cellular proliferation could be due to a G1 cell-cycle arrest, caused by increased p21 levels. To test this hypothesis, we generated mice double mutant for Brca1 (5-6) and p53, or Brca1 (5-6) and p21. Mutation in either p53 or p21 prolonged the survival of Brca1 (5-6) mutant embryos from E7.5 to E9.5. The development of most Brca1 (5-6): p21 double-mutant embryos was comparable to that of their wild-type littermates, although no mutant survived past E10.5. The fact that mutation of neither p53 nor p21 completely rescued Brca1 (5-6) embryos suggests that their lethality is likely due to a multi-factorial process.

Extension of Drosophila lifespan by overexpression of human SOD1 in motorneurons.

Reactive oxygen (RO) has been identified as an important effector in ageing and lifespan determination. The specific cell types, however, in which oxidative damage acts to limit lifespan of the whole organism have not been explicitly identified. The association between mutations in the gene encoding the oxygen radical metabolizing enzyme CuZn superoxide dismutase (SOD1) and loss of motorneurons in the brain and spinal cord that occurs in the life-shortening paralytic disease, Familial Amyotrophic Lateral Sclerosis (FALS; ref. 4), suggests that chronic and unrepaired oxidative damage occurring specifically in motor neurons could be a critical causative factor in ageing. To test this hypothesis, we generated transgenic Drosophila which express human SOD1 specifically in adult motorneurons. We show that overexpression of a single gene, SOD1, in a single cell type, the motorneuron, extends normal lifespan by up to 40% and rescues the lifespan of a short-lived Sod null mutant. Elevated resistance to oxidative stress suggests that the lifespan extension observed in these flies is due to enhanced RO metabolism. These results show that SOD activity in motorneurons is an important factor in ageing and lifespan determination in Drosophila.