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Diese umfassende Übersichtsarbeit gibt einen Überblick über verschiedene immuntherapeutische Ansätze zur Behandlung von aktinischen Keratosen (AKs), präkanzerösen Hautläsionen, die durch UV-Exposition verursacht werden. Neben Behandlungen, deren Hauptwirkmechanismus die Immunmodulation ist, wie Imiquimod oder Diclofenac, haben auch andere Behandlungen, die hauptsächlich auf dysplastische Zellen abzielen, eine gewisse immunologische Wirkung, die zu ihrer Wirksamkeit beiträgt. Während Behandlungen wie 5-Fluorouracil, Imiquimod, photodynamische Therapie und Nicotinamid bei der Behandlung von AKs vielversprechend sind, vor allem bei immunkompetenten Personen, ist ihre Wirksamkeit bei Empfängern solider Organtransplantate aufgrund der Immunsuppression eingeschränkt. Die Übersicht umfasst die optimale Kombination und fokussiert sich auf die Kryoimmuntherapie als relevanteste. Neue Immuntherapien sind Resimiquimod, Ingenoldisoxat, N-Phosphonacetyl-L-Aspartat (PALA) oder Anti-PD-1, die vielversprechende Ergebnisse erzielt haben, aber weitere Studien erfordern, um ihre Verwendung zu standardisieren.

There is increasing evidence that proactive monitoring is useful in improving the control of inflammatory bowel disease, although it remains controversial. The aim of this study was to evaluate the efficacy of proactive TDM based on the Bayesian approach to optimise the IFX dose compared with the standard of care dosing in patients with IBD.

Inclusion body myositis (IBM) is an inflammatory myopathy clinically characterized by proximal and distal muscle weakness, with inflammatory infiltrates, rimmed vacuoles and mitochondrial changes in muscle histopathology. There is scarce knowledge on IBM aetiology, and non‐established biomarkers or effective treatments are available, partly due to the lack of validated disease models. We have performed transcriptomics and functional validation of IBM muscle pathological hallmarks in fibroblasts from IBM patients (n= 14) and healthy controls (n= 12), paired by age and sex. The results comprise an mRNA‐seq, together with functional inflammatory, autophagy, mitochondrial and metabolic changes between patients and controls. Gene expression profile of IBM vs control fibroblasts revealed 778 differentially expressed genes (P‐value adj < 0.05) related to inflammation, mitochondria, cell cycle regulation and metabolism. Functionally, an increased inflammatory profile was observed in IBM fibroblasts with higher supernatant cytokine secretion (three‐fold increase). Autophagy was reduced considering basal protein mediators (18.4% reduced), time‐course autophagosome formation (LC3BII 39% reduced, P‐value < 0.05), and autophagosome microscopic evaluation. Mitochondria displayed reduced genetic content (by 33.9%, P‐value < 0.05) and function (30.2%‐decrease in respiration, 45.6%‐decline in enzymatic activity (P‐value < 0.001), 14.3%‐higher oxidative stress, 135.2%‐increased antioxidant defence (P‐value < 0.05), 11.6%‐reduced mitochondrial membrane potential (P‐value < 0.05) and 42.8%‐reduced mitochondrial elongation (P‐value < 0.05)). In accordance, at the metabolite level, organic acid showed a 1.8‐fold change increase, with conserved amino acid profile. Correlating to disease evolution, oxidative stress and inflammation emerge as potential markers of prognosis. These findings confirm the presence of molecular disturbances in peripheral tissues from IBM patients and prompt patients' derived fibroblasts as a promising disease model, which may eventually be exported to other neuromuscular disorders. We additionally identify new molecular players in IBM associated with disease progression, setting the path to deepen in disease aetiology, in the identification of novel biomarkers or in the standardization of biomimetic platforms to assay new therapeutic strategies for preclinical studies.

Niemann-Pick type C (NPC) disease is a lysosomal storage disorder characterized by cholesterol accumulation caused by loss-of-function mutations in the Npc1gene. NPC disease primarily affects the brain, causing neuronal damage and affecting motor coordination. In addition, considerable liver malfunction in NPC disease is common. Recently, we found that the depletion of annexin A6 (ANXA6), which is most abundant in the liver and involved in cholesterol transport, ameliorated cholesterol accumulation in Npc1mutant cells. To evaluate the potential contribution of ANXA6 in the progression of NPC disease, double-knockout mice (Npc1−/−/Anxa6−/−) were generated and examined for lifespan, neurologic and hepatic functions, as well as liver histology and ultrastructure. Interestingly, lack of ANXA6 in NPC1-deficient animals did not prevent the cerebellar degeneration phenotype, but further deteriorated their compromised hepatic functions and reduced their lifespan. Moreover, livers of Npc1−/−/Anxa6−/−mice contained a significantly elevated number of foam cells congesting the sinusoidal space, a feature commonly associated with inflammation. We hypothesize that ANXA6 deficiency in Npc1−/−mice not only does not reverse neurologic and motor dysfunction, but further worsens overall liver function, exacerbating hepatic failure in NPC disease.

To evaluate the analytical performance and clinical utility of the POC-AFIAS assay in comparison with two ELISA established assays for quantifying serum concentrations of ustekinumab.

Bicyclic peptide ligands were found to have good binding affinity and target specificity. However, the method applied to generate bicyclic ligands based on phage-peptide alkylation is technically complex and limits its application to specialized laboratories. Herein, we report a method that involves a simpler and more robust procedure that additionally allows screening of structurally more diverse bicyclic peptide libraries. In brief, phage-encoded combinatorial peptide libraries of the format XmCXnCXoCXpare oxidized to connect two pairs of cysteines (C). This allows the generation of 3 × (m+ n+ o+ p) different peptide topologies because the fourth cysteine can appear in any of the (m+ n+ o+ p) randomized amino acid positions (X). Panning of such libraries enriched strongly peptides with four cysteines and yielded tight binders to protein targets. X-ray structure analysis revealed an important structural role of the disulfide bridges. In summary, the presented approach offers facile access to bicyclic peptide ligands with good binding affinities.

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ABSTRACTAnnexin A6 (AnxA6) belongs to a highly conserved protein family characterized by their calcium (Ca2+)-dependent binding to phospholipids. Over the years, immunohistochemistry, subcellular fractionations, and live cell microscopy established that AnxA6 is predominantly found at the plasma membrane and endosomal compartments. In these locations, AnxA6 acts as a multifunctional scaffold protein, recruiting signaling proteins, modulating cholesterol and membrane transport and influencing actin dynamics. These activities enable AnxA6 to contribute to the formation of multifactorial protein complexes and membrane domains relevant in signal transduction, cholesterol homeostasis and endo-/exocytic membrane transport. Hence, AnxA6 has been implicated in many biological processes, including cell proliferation, survival, differentiation, inflammation, but also membrane repair and viral infection. More recently, we and others identified roles for AnxA6 in cancer cell migration and invasion. This review will discuss how the multiple scaffold functions may enable AnxA6 to modulate migratory cell behavior in health and disease.

Ver la influencia de la interleucina 6 (IL-6) como mediador inflamatorio en pacientes con criterios de systemic inflammatory response syndrome(SIRS, «síndrome de respuesta inflamatoria sistémica») y sepsis valorando si su determinación plasmática durante el ingreso en la unidad de cuidados intensivos (UCI) sirve como marcador precoz de mortalidad.

Presentamos el caso de un adolescente de 12 años de edad derivado a salud mental infanto-juvenil. El paciente presentaba rasgos ansiosos predominando el diagnóstico de fobias específicas que afectaban a su vida diaria.

Background: Studies have investigated the efficacy and safety of switching to the biosimilar infliximab (CT-P13) in patients with inflammatory bowel disease (IBD). However, there is limited research directly comparing the effectiveness, drug survival, and pharmacokinetic profiles of the reference infliximab (IFX) and CT-P13 in real clinical settings.

Cholesterol is considered indispensible for the recruitment and functioning of integrins in focal adhesions for cell migration. However, the physiological cholesterol pools that control integrin trafficking and focal adhesion assembly remain unclear. Using Niemann Pick Type C1 (NPC) mutant cells, which accumulate Low Density lipoprotein (LDL)-derived cholesterol in late endosomes (LE), several recent studies indicate that LDL-cholesterol has multiple roles in regulating focal adhesion dynamics. Firstly, targeting of endocytosed LDL-cholesterol from LE to focal adhesions controls their formation at the leading edge of migrating cells. Other newly emerging literature suggests that this may be coupled to vesicular transport of integrins, Src kinase and metalloproteases from the LE compartment to focal adhesions. Secondly, our recent work identified LDL-cholesterol as a key factor that determines the distribution and ability of several Soluble NSF Attachment Protein (SNAP) Receptor (SNARE) proteins, key players in vesicle transport, to control integrin trafficking to the cell surface and extracellular matrix (ECM) secretion. Collectively, dietary, genetic and pathological changes in cholesterol metabolism may link with efficiency and speed of integrin and ECM cell surface delivery in metastatic cancer cells. This commentary will summarize how direct and indirect pathways enable LDL-cholesterol to modulate cell motility.