Tildrakizumab in the treatment of psoriasis: latest evidence and place in therapy.

Psoriasis is a chronic inflammatory disorder that is clinically characterized by scaly cutaneous plaques. New evidence suggests that dysregulation of interleukin (IL)-23, a key cytokine in the T-helper-17 pathway, plays a vital role in the development of psoriatic systemic inflammation. The novel biologic medication tildrakizumab is among the first drugs with specific action against IL-23 that has recently been approved by the United States Food and Drug Administration and the European Medicines Agency for moderate-to-severe psoriasis. Tildrakizumab has been shown in large randomized controlled trials to be effective in improving skin manifestations as well as enhancing quality of life outcomes in patients with psoriasis. Its simple dosing, prolonged duration of action, and mild adverse event profile make it a practical option for patients; however, only a small number of trials have investigated the clinical effectiveness of tildrakizumab, and long-term data regarding the drug's efficacy and safety are currently limited. Hence, further research is needed to better understand the risks and benefits of tildrakizumab. This review summarizes and analyzes phase I, phase II, and phase III clinical trials that investigate the mechanism, pharmacokinetics, efficacy, and safety of tildrakizumab. It also identifies areas in which additional studies are warranted to further elucidate the advantages of tildrakizumab over other biologic therapies

Licensed human natural killer cells aid dendritic cell maturation via TNFSF14/LIGHT

Interactions between natural killer (NK) cells and dendritic cells (DC) aid DC maturation and promote T cell responses. Here, we have analysed the response of human NK cells to tumor cells and we identify a pathway by which NK-DC interactions occur. Gene expression profiling of tumor-responsive NK cells identified the very rapid induction of TNFSF14 (also known as LIGHT), a cytokine implicated in the enhancement of anti-tumor responses. TNFSF14 protein expression was induced by three primary mechanisms of NK cell activation, namely via the engagement of CD16, by the synergistic activity of multiple target cell-sensing NK cell activation receptors and by the cytokines IL-2 and IL-15. For anti-tumor responses, TNFSF14 was preferentially produced by the licensed NK cell population, defined by the expression of inhibitory receptors specific for self-MHC class I molecules. In contrast, IL-2 and IL-15 treatment induced TNFSF14 production by both licensed and unlicensed NK cells, reflecting the ability of pro-inflammatory conditions to override the licensing mechanism. Importantly, both tumor and cytokine activated NK cells induced DC maturation in a TNFSF14-dependent manner. The coupling of TNFSF14 production to tumor-sensing NK cell activation receptors links the tumor immune surveillance function of NK cells to DC maturation and adaptive immunity. Furthermore, regulation by NK cell licensing helps to safeguard against TNFSF14 production in response to healthy tissues

Circulating αKlotho influences phosphate handling by controlling FGF23 production

The FGF23 coreceptor αKlotho (αKL) is expressed as a membrane-bound protein (mKL) that forms heteromeric complexes with FGF receptors (FGFRs) to initiate intracellular signaling. It also circulates as an endoproteolytic cleavage product of mKL (cKL). Previously, a patient with increased plasma cKL as the result of a translocation [t(9;13)] in the αKLOTHO (KL) gene presented with rickets and a complex endocrine profile, including paradoxically elevated plasma FGF23, despite hypophosphatemia. The goal of this study was to test whether cKL regulates phosphate handling through control of FGF23 expression. To increase cKL levels, mice were treated with an adeno-associated virus producing cKL. The treated groups exhibited dose-dependent hypophosphatemia and hypocalcemia, with markedly elevated FGF23 (38 to 456 fold). The animals also manifested fractures, reduced bone mineral content, expanded growth plates, and severe osteomalacia, with highly increased bone Fgf23 mRNA (>150 fold). cKL activity in vitro was specific for interactions with FGF23 and was FGFR dependent. These results demonstrate that cKL potently stimulates FGF23 production in vivo, which phenocopies the KL translocation patient and metabolic bone syndromes associated with elevated FGF23. These findings have important implications for the regulation of αKL and FGF23 in disorders of phosphate handling and biomineralization

A high-resolution map of human evolutionary constraint using 29 mammals.

The comparison of related genomes has emerged as a powerful lens for genome interpretation. Here we report the sequencing and comparative analysis of 29 eutherian genomes. We confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering ∼4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for ∼60% of constrained bases. These elements reveal a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons. We find 220 candidate RNA structural families, and nearly a million elements overlapping potential promoter, enhancer and insulator regions. We report specific amino acid residues that have undergone positive selection, 280,000 non-coding elements exapted from mobile elements and more than 1,000 primate- and human-accelerated elements. Overlap with disease-associated variants indicates that our findings will be relevant for studies of human biology, health and disease

Mosaic fungal individuals have the potential to evolve within a single generation

Although cells of mushroom-producing fungi typically contain paired haploid nuclei (n + n), most Armillaria gallica vegetative cells are uninucleate. As vegetative nuclei are produced by fusions of paired haploid nuclei, they are thought to be diploid (2n). Here we report finding haploid vegetative nuclei in A. gallica at multiple sites in southeastern Massachusetts, USA. Sequencing multiple clones of a single-copy gene isolated from single hyphal filaments revealed nuclear heterogeneity both among and within hyphae. Cytoplasmic bridges connected hyphae in field-collected and cultured samples, and we propose nuclear migration through bridges maintains this nuclear heterogeneity. Growth studies demonstrate among- and within-hypha phenotypic variation for growth in response to gallic acid, a plant-produced antifungal compound. The existence of both genetic and phenotypic variation within vegetative hyphae suggests that fungal individuals have the potential to evolve within a single generation in response to environmental variation over time and space

Human Tumour Immune Evasion via TGF-β Blocks NK Cell Activation but Not Survival Allowing Therapeutic Restoration of Anti-Tumour Activity

Immune evasion is now recognized as a key feature of cancer progression. In animal models, the activity of cytotoxic lymphocytes is suppressed in the tumour microenvironment by the immunosuppressive cytokine, Transforming Growth Factor (TGF)-β. Release from TGF-β-mediated inhibition restores anti-tumour immunity, suggesting a therapeutic strategy for human cancer. We demonstrate that human natural killer (NK) cells are inhibited in a TGF-β dependent manner following chronic contact-dependent interactions with tumour cells in vitro. In vivo, NK cell inhibition was localised to the human tumour microenvironment and primary ovarian tumours conferred TGF-β dependent inhibition upon autologous NK cells ex vivo. TGF-β antagonized the interleukin (IL)-15 induced proliferation and gene expression associated with NK cell activation, inhibiting the expression of both NK cell activation receptor molecules and components of the cytotoxic apparatus. Interleukin-15 also promotes NK cell survival and IL-15 excluded the pro-apoptotic transcription factor FOXO3 from the nucleus. However, this IL-15 mediated pathway was unaffected by TGF-β treatment, allowing NK cell survival. This suggested that NK cells in the tumour microenvironment might have their activity restored by TGF-β blockade and both anti-TGF-β antibodies and a small molecule inhibitor of TGF-β signalling restored the effector function of NK cells inhibited by autologous tumour cells. Thus, TGF-β blunts NK cell activation within the human tumour microenvironment but this evasion mechanism can be therapeutically targeted, boosting anti-tumour immunity

Lassa Fever in Post-Conflict Sierra Leone

Background: Lassa fever (LF), an often-fatal hemorrhagic disease caused by Lassa virus (LASV), is a major public health threat in West Africa. When the violent civil conflict in Sierra Leone (1991 to 2002) ended, an international consortium assisted in restoration of the LF program at Kenema Government Hospital (KGH) in an area with the world's highest incidence of the disease. Methodology/Principal Findings Clinical and laboratory records of patients presenting to the KGH Lassa Ward in the post-conflict period were organized electronically. Recombinant antigen-based LF immunoassays were used to assess LASV antigenemia and LASV-specific antibodies in patients who met criteria for suspected LF. KGH has been reestablished as a center for LF treatment and research, with over 500 suspected cases now presenting yearly. Higher case fatality rates (CFRs) in LF patients were observed compared to studies conducted prior to the civil conflict. Different criteria for defining LF stages and differences in sensitivity of assays likely account for these differences. The highest incidence of LF in Sierra Leone was observed during the dry season. LF cases were observed in ten of Sierra Leone's thirteen districts, with numerous cases from outside the traditional endemic zone. Deaths in patients presenting with LASV antigenemia were skewed towards individuals less than 29 years of age. Women self-reporting as pregnant were significantly overrepresented among LASV antigenemic patients. The CFR of ribavirin-treated patients presenting early in acute infection was lower than in untreated subjects. Conclusions/Significance: Lassa fever remains a major public health threat in Sierra Leone. Outreach activities should expand because LF may be more widespread in Sierra Leone than previously recognized. Enhanced case finding to ensure rapid diagnosis and treatment is imperative to reduce mortality. Even with ribavirin treatment, there was a high rate of fatalities underscoring the need to develop more effective and/or supplemental treatments for LF

Adhesion Awareness: A National Survey of Surgeons

Contains fulltext : 87943.pdf (publisher's version ) (Closed access)BACKGROUND: Postoperative adhesions are the most frequent complication of abdominal surgery, leading to high morbidity, mortality, and costs. However, the problem seems to be neglected by surgeons for largely unknown reasons. METHODS: A survey assessing knowledge and personal opinion about the extent and impact of adhesions was sent to all Dutch surgeons and surgical trainees. The informed-consent process and application of antiadhesive agents were questioned in addition. RESULTS: The response rate was 34.4%. Two thirds of all respondents (67.7%) agreed that adhesions exert a clinically relevant, negative effect. A negative perception of adhesions correlated with a positive attitude regarding adhesion prevention (rho = 0.182, p < 0.001). However, underestimation of the extent and impact of adhesions resulted in low knowledge scores (mean test score 37.6%). Lower scores correlated with more uncertainty about indications for antiadhesive agents which, in turn, correlated with never having used any of these agents (rho = 0.140, p = 0.002; rho = 0.095, p = 0.035; respectively). Four in 10 respondents (40.9%) indicated that they never inform patients on adhesions and only 9.8% informed patients routinely. A majority of surgeons (55.9%) used antiadhesive agents in the past, but only a minority (13.4%) did in the previous year. Of trainees, 82.1% foresaw an increase in the use of antiadhesive agents compared to 64.5% of surgeons (p < 0.001). CONCLUSIONS: The magnitude of the problem of postoperative adhesions is underestimated and informed consent is provided inadequately by Dutch surgeons. Exerting adhesion prevention is related to the perception of and knowledge about adhesions.1 december 201

HST/WFC3 grism observations of z∼1z\sim1 clusters: evidence for evolution in the mass-size relation of quiescent galaxies from poststarburst galaxies

Minor mergers have been proposed as the driving mechanism for the size growth of quiescent galaxies with decreasing redshift. The process whereby large star-forming galaxies quench and join the quiescent population at the large size end has also been suggested as an explanation for this size growth. Given the clear association of quenching with clusters, we explore this mechanism by studying the structural properties of 23 spectroscopically identified recently quenched (or "poststarburst" (PSB)) cluster galaxies at $z\sim1$. Despite clear PSB spectral signatures implying rapid and violent quenching, 87\% of these galaxies have symmetric, undisturbed morphologies in the stellar continuum. Remarkably, they follow a mass-size relation lying midway between the star-forming and quiescent field relations, with sizes $0.1$ dex smaller than $z\sim1$ star-forming galaxies at log$(M_{*}/M_{\odot})=10.5$. This implies a rapid change in the light profile without directly effecting the stellar distribution, suggesting changes in the mass-to-light ratio gradients across the galaxy are responsible. We develop fading toy models to explore how star-forming galaxies move across the mass-size plane as their stellar populations fade to match those of the PSBs. "Outside-in" fading has the potential to reproduce the contraction in size and increase in bulge-dominance observed between star-forming and PSB cluster galaxies. Since cluster PSBs lie on the large size end of the quiescent mass-size relation, and our previous work shows cluster galaxies are smaller than field galaxies, the sizes of quiescent galaxies must grow both from the quenching of star-forming galaxies and dry minor mergers.Comment: 25 pages, 10 figures, accepted for publication in MNRA