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Background: Despite advances in the treatment of chronic urticaria, in a significant percentage of the patients symptoms are not fully controlled with conventional approaches. New strategies under development include blocking intracellular mediators of mast cell and basophil activation. Objective: We aim to investigate the effects of the Bruton's tyrosine kinase (BTK) inhibitor remibrutinib on human blood basophils and CD34+‐derived mast cells activation induced by serum obtained from chronic urticaria patients. Methods: Twenty‐two patients with chronic spontaneous urticaria (mean age 52 years, 27% women) and 22 patients with chronic inducible urticaria (46 years, 27% women) were included in the study together with a sex‐matched control group. Patients were classified as responders or non‐responders to anti‐IgE therapy on the basis of their clinical data, FcεR1a expression on blood basophils and total IgE levels. Changes on CD63 expression—as an activation marker‐, were used to evaluate in vitro the response of basophils and mast cells to serum exposure and the inhibitory effects of remibrutinib. Results: Remibrutinib inhibits degranulation induced by IgE cross‐linking in mast cells and basophils and also the activation triggered by factors present in the sera of spontaneous and inducible chronic urticaria patients. Patient's serum induces a greater degranulation of effector cells than controls. Activation of mast cells and basophils by patient sera and remibrutinib effects were not related to omalizumab responsiveness. Conclusion: Remibrutinib inhibits activation of human basophils and mast cells induced in vitro by exposure to the serum of chronic urticaria patients independently of their response to omalizumab. [ABSTRACT FROM AUTHOR]

Antibodies to SARS-CoV-2 in patients with primary immunodeficiencies treated with nonspecific immunoglobulins N-reactive antibodies are readily increased upon infection [5] and, in convalescent patients, occasionally may even dominate the response [6].We reasoned that if these patients had recently become infected, they should have a prominent cellular response (mediated by T lymphocytes) against different viral antigens. However, when we studied the CD4 SP + sp and CD8 SP + sp T cell-mediated responses against epitopes from SARS-CoV-2 S1 and S2 subunits, we could not detect interferon gamma production in any of the patients ruling out a recent infection as a source of the antibodies. [Extracted from the article]

The massive COVID-19 vaccine purchases made by high-income countries have resulted in important sample losses, mainly due to the complexity of their handling. Here, we evaluated the possibility of preserving the immunogenicity of COVID-19 mRNA vaccines after re-freezing vials, following the extraction of the maximum possible number of samples, as an alternative approach to minimizing their wastage. Thus, we exposed the vaccine vials to different re-freezing conditions and evaluated mRNA integrity and the effects in mice after in vivo administration. We reveal that the mRNA integrity of Comirnaty® and Spikevax® vaccines remained unaffected after re-freezing during 1 month at −20 °C or −80 °C. The immunological responses also remained unchanged in mice after these re-freezing conditions and no apparent side effects were revealed. The preservation of mRNA integrity and immunogenicity under these handling conditions opens the possibility of re-freezing the mRNA COVID-19 vaccine vials to limit their wastage and to facilitate vaccination processes. [ABSTRACT FROM AUTHOR]

Background: IgE and high‐affinity IgE receptor (FcεRI) expression on basophils have been scarcely explored in patients with chronic inducible urticaria (CIndU). Objectives: To investigate baseline serum IgE and FcεRI expression on blood basophils in a large cohort of CIndU patients and its relationship to treatment response. Methods: Baseline total serum IgE and basophil FcεRI expression measured by flow cytometry in 165 patients with CIndU was studied. The relationship of both parameters with the response to antihistamine and anti‐IgE (omalizumab) treatment was considered in a subsample of CIndU patients. FcεRI expression in basophils was assessed by mean fluorescence intensity (MFI) and basophil FcεRI standardized density (receptors/cell). Results: The median FcεRI expression standardized per density in blood basophils was found significantly higher in patients with CIndU compared to HCs. A positive correlation was found between IgE serum levels and basophil FcεRI expression. Basal FcεRI expression was not related to antihistamine treatment response. However, it was related to omalizumab, and patients responding to omalizumab showed higher basal basophil expression of FcεRI levels. Non‐responders to the antihistamine showed significantly higher IgE serum levels. Conclusions: FcεRI receptor overexpression in patients with CIndU shows almost the same pattern than chronic spontaneous urticaria. It seems to be independent of CIndU subtypes. Although additional studies would be welcome, our work highlights the relevance of FcεRI receptor regulation in CIndU supporting autoimmune basophil and mast cell activation and may be a biomarker for response to anti‐IgE therapy. [ABSTRACT FROM AUTHOR]

Background: Real‐world data are essential to accurately assessing efficacy and toxicity of approved agents in everyday practice. PRINCIPAL, a prospective, observational study, was designed to confirm the real‐world safety and efficacy of pazopanib in patients with advanced renal cell carcinoma (RCC). Subjects, Materials, and Methods: Patients with clear cell advanced/metastatic RCC and a clinical decision to initiate pazopanib treatment within 30 days of enrollment were eligible. Primary objectives included progression‐free survival (PFS), overall survival (OS), objective response rate (ORR), relative dose intensity (RDI) and its effect on treatment outcomes, change in health‐related quality of life (HRQoL), and safety. We also compared characteristics and outcomes of clinical‐trial‐eligible (CTE) patients, defined using COMPARZ trial eligibility criteria, with those of non‐clinical‐trial‐eligible (NCTE) patients. Secondary study objectives were to evaluate clinical efficacy, safety, and RDI in patient subgroups. Results: Six hundred fifty‐seven patients were enrolled and received ≥1 dose of pazopanib. Median PFS and OS were 10.3 months (95% confidence interval [CI], 9.2–12.0) and 29.9 months (95% CI, 24.7 to not reached), respectively, and the ORR was 30.3%. HRQoL showed no or little deterioration over time. Treatment‐related serious adverse events (AEs) and AEs of special interest occurred in 64 (9.7%), and 399 (60.7%) patients, respectively. More patients were classified NCTE than CTE (85.2% vs. 14.8%). Efficacy of pazopanib was similar between the two groups. Conclusion: PRINCIPAL confirms the efficacy and safety of pazopanib in patients with advanced/metastatic RCC in a real‐world clinical setting. Implications for Practice: PRINCIPAL is the largest (n = 657) prospective, observational study of pazopanib in patients with advanced/metastatic renal cell carcinoma, to the authors' knowledge. Consistent with clinical trial results that often contain specific patient types, the PRINCIPAL study demonstrated that the effectiveness and safety of pazopanib is similarly safe and effective in patients with advanced kidney cancer in a real‐world clinical setting. The PRINCIPAL study showed that patients with advanced kidney cancer who are treated with first‐line pazopanib generally do not show disease progression for approximately 10 months and generally survive for nearly 30 months. The PRINCIPAL study evaluated the efficacy and safety of pazopanib in patients with advanced/metastatic renal cell carcinoma in a multinational, real‐world clinical setting. Results are reported here. [ABSTRACT FROM AUTHOR]

Cytomegalovirus encephalitis is a challenging life‐threatening complication following hematopoietic stem cell transplantation for which medical treatment is usually ineffective or toxic. However, in recent years, adoptive T‐cell therapy has been reported to provide a significant chance of cure for patients with viral infections. Herein, two cases of pediatric patients successfully treated with third‐party donor‐derived virus‐specific T cells for CMV meningoencephalitis are reported. [ABSTRACT FROM AUTHOR]

In order to achieve the objectives of Smart Cities, public administrations need to take measures to regulate mobility, which undoubtedly requires a high level of information and sensorization. Until the implementation of the connected vehicle takes place, it is still necessary to install sensors to obtain information about mobility. Bluetooth sensors are becoming a useful tool due to the low cost of equipment and installation. The use of Bluetooth sensors in cities, with short distances between sensors, makes it necessary to propose new classification algorithms that allow the trips of pedestrians and vehicles to be differentiated. This article presents the study carried out in the city of Valencia to determine the use of motor vehicles in the historic center and propose a new classification algorithm to distinguish between an onboard Bluetooth device and the same device carried by a pedestrian when it is not possible to use the travel time for the classification due to the short distance between sensors. This causes very similar or even indistinguishable travel times for vehicles and for pedestrians. We also propose an algorithm that allows vehicles to be classified according to what type of trip is made always through the historical center of Valencia, whether it is to make a shorter itinerary through the city or to access the center for any type of business. This algorithm would enable the Origin-Destination matrix of an urban network with short distances between sensors if they are available in all entries and exits. Likewise, the results obtained have allowed to positively evaluate the algorithm defined to distinguish between trips made by a pedestrian or a vehicle in a city, using the MAC address of their mobile devices with very short distances among sensors. The results of this study show that it is possible to use Bluetooth technology, with low cost installations, to evaluate the use of the city by motor vehicles. [ABSTRACT FROM AUTHOR]

Experimental autoimmune encephalomyelitis (EAE) constitutes a paradigm of antigen (Ag)-specific T cell driven autoimmune diseases. In this study, we transferred bone marrow cells (BMCs) expressing an autoantigen (autoAg), the peptide 40–55 of the myelin oligodendrocytic glycoprotein (MOG40–55), to induce preventive and therapeutic immune tolerance in a murine EAE model. Transfer of BMC expressing MOG40–55 (IiMOG-BMC) into partially myeloablated mice resulted in molecular chimerism and in robust protection from the experimental disease. In addition, in mice with established EAE, transfer of transduced BMC with or without partial myeloablation reduced the clinical and histopathological severity of the disease. In these experiments, improvement was observed even in the absence of engraftment of the transduced hematopoietic cells, probably rejected due to the previous immunization with the autoAg. Splenocytes from mice transplanted with IiMOG-BMC produced significantly higher amounts of interleukin (IL)-5 and IL-10 upon autoAg challenge than those of control animals, suggesting the participation of regulatory cells. Altogether, these results suggest that different tolerogenic mechanisms may be mediating the preventive and the therapeutic effects. In conclusion, this study demonstrates that a cell therapy using BMC expressing an autoAg can induce Ag-specific tolerance and ameliorate established EAE even in a nonmyeloablative setting.Molecular Therapy (2009) 17 5, 897–905 doi:10.1038/mt.2009.42 [ABSTRACT FROM AUTHOR]

In early stages of metastasis malignant cells must acquire phenotypic changes to enhance their migratory behavior and their ability to breach the matrix surrounding tumors and blood vessel walls. Epigenetic regulation of gene expression allows the acquisition of these features that, once tumoral cells have escape from the primary tumor, can be reverted. Here we report that the expression of the Polycomb epigenetic repressor Ring1B is enhanced in tumoral cells that invade the stroma in human ductal breast carcinoma and its expression is coincident with that of Fak in these tumors. Ring1B knockdown in breast cancer cell lines revealed that Ring1B is required to sustain Fak expression in basal conditions as well as in Tgfβ-treated cells. Functionally, endogenous Ring1B is required for cell migration and invasion in vitro and for in vivo invasion of the mammary fat pad by tumoral cells. Finally we identify p63 as a target of Ring1B to regulate Fak expression: Ring1B depletion results in enhanced p63 expression, which in turns represses Fak expression. Importantly, Fak downregulation upon Ring1B depletion is dependent on p63 expression. Our findings provide new insights in the biology of the breast carcinoma and open new avenues for breast cancer prognosis and therapy.