Tissue-resident memory features are linked to the magnitude of cytotoxic T cell responses in human lung cancer.

Therapies that boost the anti-tumor responses of cytotoxic T lymphocytes (CTLs) have shown promise; however, clinical responses to the immunotherapeutic agents currently available vary considerably, and the molecular basis of this is unclear. We performed transcriptomic profiling of tumor-infiltrating CTLs from treatment-naive patients with lung cancer to define the molecular features associated with the robustness of anti-tumor immune responses. We observed considerable heterogeneity in the expression of molecules associated with activation of the T cell antigen receptor (TCR) and of immunological-checkpoint molecules such as 4-1BB, PD-1 and TIM-3. Tumors with a high density of CTLs showed enrichment for transcripts linked to tissue-resident memory cells (TRM cells), such as CD103, and CTLs from CD103hi tumors displayed features of enhanced cytotoxicity. A greater density of TRM cells in tumors was predictive of a better survival outcome in lung cancer, and this effect was independent of that conferred by CTL density. Here we define the 'molecular fingerprint' of tumor-infiltrating CTLs and identify potentially new targets for immunotherapy.

A nematode-specific ribonucleoprotein complex mediates interactions between the major nematode spliced leader snRNP and its target pre-mRNAs.

Spliced leader trans-splicing of pre-mRNAs is a critical step in the gene expression of many eukaryotes. How the spliced leader RNA and its target transcripts are brought together to form the trans-spliceosome remains an important unanswered question. Using immunoprecipitation followed by protein analysis via mass spectrometry and RIP-Seq, we show that the nematode-specific proteins, SNA-3 and SUT-1, form a complex with a set of enigmatic non-coding RNAs, the SmY RNAs. Our work redefines the SmY snRNP and shows for the first time that it is essential for nematode viability and is involved in spliced leader trans-splicing. SNA-3 and SUT-1 are associated with the 5' ends of most, if not all, nascent capped RNA polymerase II transcripts, and they also interact with components of the major nematode spliced leader (SL1) snRNP. We show that depletion of SNA-3 impairs the co-immunoprecipitation between one of the SL1 snRNP components, SNA-2, and several core spliceosomal proteins. We thus propose that the SmY snRNP recruits the SL1 snRNP to the 5' ends of nascent pre-mRNAs, an instrumental step in the assembly of the trans-spliceosome.

Disruption of the circadian clock component BMAL1 elicits an endocrine adaption impacting on insulin sensitivity and liver disease.

SignificanceWhile increasing evidence associates the disruption of circadian rhythms with pathologic conditions, including obesity, type 2 diabetes, and nonalcoholic fatty liver diseases (NAFLD), the involved mechanisms are still poorly described. Here, we show that, in both humans and mice, the pathogenesis of NAFLD is associated with the disruption of the circadian clock combined with perturbations of the growth hormone and sex hormone pathways. However, while this condition protects mice from the development of fibrosis and insulin resistance, it correlates with increased fibrosis in humans. This suggests that the perturbation of the circadian clock and its associated disruption of the growth hormone and sex hormone pathways are critical for the pathogenesis of metabolic and liver diseases.

Foot-and-mouth disease virus localisation on follicular dendritic cells and sustained induction of neutralising antibodies is dependent on binding to complement receptors (CR2/CR1).

Previous studies have shown after the resolution of acute infection and viraemia, foot-and-mouth disease virus (FMDV) capsid proteins and/or genome are localised in the light zone of germinal centres of lymphoid tissue in cattle and African buffalo. The pattern of staining for FMDV proteins was consistent with the virus binding to follicular dendritic cells (FDCs). We have now demonstrated a similar pattern of FMDV protein staining in mouse spleens after acute infection and showed FMDV proteins are colocalised with FDCs. Blocking antigen binding to complement receptor type 2 and 1 (CR2/CR1) prior to infection with FMDV significantly reduced the detection of viral proteins on FDCs and FMDV genomic RNA in spleen samples. Blocking the receptors prior to infection also significantly reduced neutralising antibody titres, through significant reduction in their avidity to the FMDV capsid. Therefore, the binding of FMDV to FDCs and sustained induction of neutralising antibody responses are dependent on FMDV binding to CR2/CR1 in mice.

In silico exploration of anti-prostate cancer compounds from differential expressed genes.

Prostate cancer (PCa) is a complex and biologically diverse disease with no curative treatment options at present. This study aims to utilize computational methods to explore potential anti-PCa compounds based on differentially expressed genes (DEGs), with the goal of identifying novel therapeutic indications or repurposing existing drugs. The methods employed in this study include DEGs-to-drug prediction, pharmacokinetics prediction, target prediction, network analysis, and molecular docking. The findings revealed a total of 79 upregulated DEGs and 110 downregulated DEGs in PCa, which were used to identify drug compounds capable of reversing the dysregulated conditions (dexverapamil, emetine, parthenolide, dobutamine, terfenadine, pimozide, mefloquine, ellipticine, and trifluoperazine) at a threshold probability of 20% on several molecular targets, such as serotonin receptors 2a/2b/2c, HERG protein, adrenergic receptors alpha-1a/2a, dopamine D3 receptor, inducible nitric oxide synthase (iNOS), epidermal growth factor receptor erbB1 (EGFR), tyrosine-protein kinases, and C-C chemokine receptor type 5 (CCR5). Molecular docking analysis revealed that terfenadine binding to inducible nitric oxide synthase (-7.833 kcal.mol-1) and pimozide binding to HERG (-7.636 kcal.mol-1). Overall, binding energy ΔGbind (Total) at 0 ns was lower than that of 100 ns for both the Terfenadine-iNOS complex (-101.707 to -103.302 kcal.mol-1) and Ellipticine-TOPIIα complex (-42.229 to -58.780 kcal.mol-1). In conclusion, this study provides insight on molecular targets that could possibly contribute to the molecular mechanisms underlying PCa. Further preclinical and clinical studies are required to validate the therapeutic effectiveness of these identified drugs in PCa disease.

A novel, essential trans-splicing protein connects the nematode SL1 snRNP to the CBC-ARS2 complex.

Spliced leader trans-splicing is essential for gene expression in many eukaryotes. To elucidate the molecular mechanism of this process, we characterise the molecules associated with the Caenorhabditis elegans major spliced leader snRNP (SL1 snRNP), which donates the spliced leader that replaces the 5' untranslated region of most pre-mRNAs. Using a GFP-tagged version of the SL1 snRNP protein SNA-1 created by CRISPR-mediated genome engineering, we immunoprecipitate and identify RNAs and protein components by RIP-Seq and mass spectrometry. This reveals the composition of the SL1 snRNP and identifies associations with spliceosome components PRP-8 and PRP-19. Significantly, we identify a novel, nematode-specific protein required for SL1 trans-splicing, which we designate SNA-3. SNA-3 is an essential, nuclear protein with three NADAR domains whose function is unknown. Mutation of key residues in NADAR domains inactivates the protein, indicating that domain function is required for activity. SNA-3 interacts with the CBC-ARS2 complex and other factors involved in RNA metabolism, including SUT-1 protein, through RNA or protein-mediated contacts revealed by yeast two-hybrid assays, localisation studies and immunoprecipitations. Our data are compatible with a role for SNA-3 in coordinating trans-splicing with target pre-mRNA transcription or in the processing of the Y-branch product of the trans-splicing reaction.

Systematic analysis of differential rhythmic liver gene expression mediated by the circadian clock and feeding rhythms.

The circadian clock and feeding rhythms are both important regulators of rhythmic gene expression in the liver. To further dissect the respective contributions of feeding and the clock, we analyzed differential rhythmicity of liver tissue samples across several conditions. We developed a statistical method tailored to compare rhythmic liver messenger RNA (mRNA) expression in mouse knockout models of multiple clock genes, as well as PARbZip output transcription factors (Hlf/Dbp/Tef). Mice were exposed to ad libitum or night-restricted feeding under regular light-dark cycles. During ad libitum feeding, genetic ablation of the core clock attenuated rhythmic-feeding patterns, which could be restored by the night-restricted feeding regimen. High-amplitude mRNA expression rhythms in wild-type livers were driven by the circadian clock, but rhythmic feeding also contributed to rhythmic gene expression, albeit with significantly lower amplitudes. We observed that Bmal1 and Cry1/2 knockouts differed in their residual rhythmic gene expression. Differences in mean expression levels between wild types and knockouts correlated with rhythmic gene expression in wild type. Surprisingly, in PARbZip knockout mice, the mean expression levels of PARbZip targets were more strongly impacted than their rhythms, potentially due to the rhythmic activity of the D-box-repressor NFIL3. Genes that lost rhythmicity in PARbZip knockouts were identified to be indirect targets. Our findings provide insights into the diurnal transcriptome in mouse liver as we identified the differential contributions of several core clock regulators. In addition, we gained more insights on the specific effects of the feeding-fasting cycle.

Barriers and drivers of public engagement in palliative care, Scoping review.

BACKGROUND: The integral model of Palliative Care recognizes the community as essential element in improving quality of life of patients and families. It is necessary to find a formula that allows the community to have a voice. The aim of this scoping review is to identify barriers and facilitators to engage community in PC. METHODS: Systematic search was conducted in NICE, Cochrane Library, Health Evidence, CINAHL and PubMed database. KEYWORDS: Palliative care, End of life care, community networks, community engagement, public engagement, community participation, social participation, barriers and facilitators. RESULTS: Nine hundred seventy-one results were obtained. Search strategy and inclusion criteria yielded 13 studies that were read in detail to identify factors influencing community engagement in palliative care, categorized into: Public health and public engagement; Community attitudes towards palliative care, death and preferences at the end of life; Importance of volunteers in public engagement programs; Compassionate communities. CONCLUSION: Societal awareness must be a facilitated process to catalyse public engagement efforts. National policy initiatives and regional system support provide legitimacy and focus is essential for funding. The first step is to get a sense of what is important to society, bearing in mind cultural differences and to channel those aspects through health care professionals; connecting the most assistential part with community resources. The process and long-term results need to be systematically evaluated.

Facilitators and barriers of implementing end-of-life care volunteering in a hospital in five European countries: the iLIVE study.

BACKGROUND: End-of-life (EoL) care volunteers in hospitals are a novel approach to support patients and their close ones. The iLIVE Volunteer Study supported hospital volunteer coordinators from five European countries to design and implement an EoL care volunteer service on general wards in their hospitals. This study aimed to identify and explore barriers and facilitators to the implementation of EoL care volunteer services in the five hospitals. METHODS: Volunteer coordinators (VCs) from the Netherlands (NL), Norway (NO), Slovenia (SI), Spain (ES) and United Kingdom (UK) participated in a focus group interview and subsequent in-depth one-to-one interviews. A theory-inspired framework based on the five domains of the Consolidated Framework for Implementation Research (CFIR) was used for data collection and analysis. Results from the focus group were depicted in radar charts per hospital. RESULTS: Barriers across all hospitals were the COVID-19 pandemic delaying the implementation process, and the lack of recognition of the added value of EoL care volunteers by hospital staff. Site-specific barriers were struggles with promoting the service in a highly structured setting with many stakeholders (NL), negative views among nurses on hospital volunteering (NL, NO), a lack of support from healthcare professionals and the management (SI, ES), and uncertainty about their role in implementation among VCs (ES). Site-specific facilitators were training of volunteers (NO, SI, NL), involving volunteers in promoting the service (NO), and education and awareness for healthcare professionals about the role and boundaries of volunteers (UK). CONCLUSION: Establishing a comprehensive EoL care volunteer service for patients in non-specialist palliative care wards involves multiple considerations including training, creating awareness and ensuring management support. Implementation requires involvement of stakeholders in a way that enables medical EoL care and volunteering to co-exist. Further research is needed to explore how trust and equal partnerships between volunteers and professional staff can be built and sustained. TRIAL REGISTRATION: NCT04678310. Registered 21/12/2020.

Antibiotic Coordination Frameworks against Antibiotic Resistance: How to Involve Students through Experimental Practices in the Search for Solutions to Public Health Problems.

For decades, multiple varieties of antibiotics have been successfully used for therapeutic purposes. Nevertheless, antibiotic resistance is currently one of the major threats to global health. This work presents an innovative laboratory practice carried out in an inorganic medicinal chemistry course within the Degrees of Pharmacy and Biochemistry for undergraduate students. This experiment includes three classes of 2 h each. The first class consisted of the mechanochemical synthesis of an antibiotic coordination framework (ACF) using a known antibiotic (nalidixic acid) and zinc as the ligand. The prepared Zn-nalidixic acid ACF (Zn-ACF) was obtained in up to 82% yield with high purity. On the second day, the synthesized Zn-ACF was characterized by Fourier-transform infrared spectroscopy (FTIR) and powder X-ray diffraction (PXRD). Finally, during the last class, the antimicrobial activity was tested against Escherichia coli by the well diffusion method. The students verified the higher antimicrobial activity of Zn-ACF compared to nalidixic acid, proving that small changes in the chemical structure can result in great biological differences. In the end, the students presented their results in a poster format, encouraging the development of their soft skills and scientific results communication and dissemination. In the future, it is expected that such a laboratory experiment at the interface between medicinal chemistry, microbiology, analytical techniques, public health, and pharmacology will lead to the development and implementation of some service-learning practices and will serve as a model to look at for other courses and institutions.

Robust landscapes of ribosome dwell times and aminoacyl-tRNAs in response to nutrient stress in liver.

Translation depends on messenger RNA (mRNA)-specific initiation, elongation, and termination rates. While translation elongation is well studied in bacteria and yeast, less is known in higher eukaryotes. Here we combined ribosome and transfer RNA (tRNA) profiling to investigate the relations between translation elongation rates, (aminoacyl-) tRNA levels, and codon usage in mammals. We modeled codon-specific ribosome dwell times from ribosome profiling, considering codon pair interactions between ribosome sites. In mouse liver, the model revealed site- and codon-specific dwell times that differed from those in yeast, as well as pairs of adjacent codons in the P and A site that markedly slow down or speed up elongation. While translation efficiencies vary across diurnal time and feeding regimen, codon dwell times were highly stable and conserved in human. Measured tRNA levels correlated with codon usage and several tRNAs showed reduced aminoacylation, which was conserved in fasted mice. Finally, we uncovered that the longest codon dwell times could be explained by aminoacylation levels or high codon usage relative to tRNA abundance.

Correction: Pervasive within-host recombination and epistasis as major determinants of the molecular evolution of the foot-and-mouth disease virus capsid.

[This corrects the article DOI: 10.1371/journal.ppat.1008235.].

Pervasive within-host recombination and epistasis as major determinants of the molecular evolution of the foot-and-mouth disease virus capsid.

Although recombination is known to occur in foot-and-mouth disease virus (FMDV), it is considered only a minor determinant of virus sequence diversity. Analysis at phylogenetic scales shows inter-serotypic recombination events are rare, whereby recombination occurs almost exclusively in non-structural proteins. In this study we have estimated recombination rates within a natural host in an experimental setting. African buffaloes were inoculated with a SAT-1 FMDV strain containing two major viral sub-populations differing in their capsid sequence. This population structure enabled the detection of extensive within-host recombination in the genomic region coding for structural proteins and allowed recombination rates between the two sub-populations to be estimated. Quite surprisingly, the effective recombination rate in VP1 during the acute infection phase turns out to be about 0.1 per base per year, i.e. comparable to the mutation/substitution rate. Using a high-resolution map of effective within-host recombination in the capsid-coding region, we identified a linkage disequilibrium pattern in VP1 that is consistent with a mosaic structure with two main genetic blocks. Positive epistatic interactions between co-evolved variants appear to be present both within and between blocks. These interactions are due to intra-host selection both at the RNA and protein level. Overall our findings show that during FMDV co-infections by closely related strains, capsid-coding genes recombine within the host at a much higher rate than expected, despite the presence of strong constraints dictated by the capsid structure. Although these intra-host results are not immediately translatable to a phylogenetic setting, recombination and epistasis must play a major and so far underappreciated role in the molecular evolution of the virus at all scales.

Viral dynamics and immune responses to foot-and-mouth disease virus in African buffalo (Syncerus caffer).

Foot-and-mouth disease (FMD) is one of the most important livestock diseases restricting international trade. While African buffalo (Syncerus caffer) act as the main wildlife reservoir, viral and immune response dynamics during FMD virus acute infection have not been described before in this species. We used experimental needle inoculation and contact infections with three Southern African Territories serotypes to assess clinical, virological and immunological dynamics for thirty days post infection. Clinical FMD in the needle inoculated buffalo was mild and characterised by pyrexia. Despite the absence of generalised vesicles, all contact animals were readily infected with their respective serotypes within the first two to nine days after being mixed with needle challenged buffalo. Irrespective of the route of infection or serotype, there were positive associations between the viral loads in blood and the induction of host innate pro-inflammatory cytokines and acute phase proteins. Viral loads in blood and tonsil swabs were tightly correlated during the acute phase of the infection, however, viraemia significantly declined after a peak at four days post-infection (dpi), which correlated with the presence of detectable neutralising antibodies. In contrast, infectious virus was isolated in the tonsil swabs until the last sampling point (30 dpi) in most animals. The pattern of virus detection in serum and tonsil swabs was similar for all three serotypes in the direct challenged and contact challenged animals. We have demonstrated for the first time that African buffalo are indeed systemically affected by FMD virus and clinical FMD in buffalo is characterized by a transient pyrexia. Despite the lack of FMD lesions, infection of African buffalo was characterised by high viral loads in blood and oropharynx, rapid and strong host innate and adaptive immune responses and high transmissibility.

Cognitive and Neuropsychiatric Impairment in Dystonia.

PURPOSE OF REVIEW: To review recent literature evaluating psychiatric and cognitive symptoms in dystonia, the two non-motor symptom groups most frequently evaluated in dystonia research and recognised in clinical practice. RECENT FINDINGS: Recent work has embedded clinical recognition of psychiatric symptoms in dystonia, with depressive and anxiety-related symptoms routinely observed to be the most common. Less explored symptoms, such as self-harm, suicidal ideation, and substance abuse, represent newer areas of investigation, with initial work suggesting higher rates than the background population. Investigation of cognitive function has provided less consistent results, both within individual dystonia subtypes and across the spectrum of dystonias, partly reflecting the heterogeneity in approaches to assessment. However, recent work indicates impairments of higher cognitive function, e.g. social cognition, and disrupted visual and auditory sensory processing. Dystonia demonstrates psychiatric and cognitive symptom heterogeneity, with further work needed to recognise endophenotypes and improve diagnostic accuracy, symptom recognition, and management.

Do we have friendly services to meet the needs of young women exposed to intimate partner violence in the Madrid region?

INTRODUCTION: Women experiencing intimate partner violence (IPV) do not tend to go very frequently to formal support services. The objective of this study is to identify barriers related to the accessibility, acceptability, equity, appropriateness and effectiveness of IPV services from the perspective of the professionals working in the IPV public services. METHODS: A qualitative study was carried out in the Madrid region based on 13 semi-structured interviews of young women who had survived IPV as well as 17 interviews with professionals. A thematic content analysis was performed, guided by the dimensions proposed by the World Health Organization (WHO) for friendly services for young people. RESULTS: From the perspective of the young women and professionals, barriers were identified for all the dimensions of the WHO's friendly services for young people: accessibility: lack of information and support from the social setting, scarce dissemination of the services, economic cost, non-adapted schedules, inadequate locations or lack of services in settings close to young people; acceptability: lack of protocols to guarantee confidentiality, lack of speed in the provision of services or their referral, unwelcoming environments or unsympathetic professional malpractice; equity: discriminatory professional attitudes towards groups with different social status and lack of protocols to ensure the care of these groups; appropriateness: unmet needs and lack of multidisciplinary teams; and effectiveness: shortage of time, resources, competent professionals, protocols and coordination. CONCLUSIONS: Strategies are needed to make the necessary changes to promote friendly services for the care of young people exposed to IPV. Additionally, it must be emphasized that resources are needed to raise awareness and disseminate IPV services, as well as to train professionals in this area. PATIENT OR PUBLIC CONTRIBUTION: This paper is based on professionals' perspectives of public IPV-related services of different areas such as Psychology, Social Work, Nursing, Psychiatry, Social Education and young women exposed to IPV. They either work in the public administration at the local, regional or state level or in NGOs in Spain.

Phytochemical Study and Antiglioblastoma Activity Assessment of Plectranthus hadiensis (Forssk.) Schweinf. ex Sprenger var. hadiensis Stems.

Glioblastoma (GB) is the most malignant form of primary astrocytoma, accounting for more than 60% of all brain tumors in adults. Nowadays, due to the development of multidrug resistance causing relapses to the current treatments and the development of severe side effects resulting in reduced survival rates, new therapeutic approaches are needed. The genus Plectranthus belongs to the Lamiaceae family and is known to be rich in abietane-type diterpenes, which possess antitumor activity. Specifically, P. hadiensis (Forssk.) Schweinf. ex Sprenger has been documented for the use against brain tumors. Therefore, the aim of this work was to perform the bioguided isolation of compounds from the acetonic extract of P. hadiensis stems and to investigate the in vitro antiglioblastoma activity of the extract and its isolated constituents. After extraction, six fractions were obtained from the acetonic extract of P. hadiensis stems. In a preliminary biological screening, the fractions V and III showed the highest antioxidant and antimicrobial activities. None of the fractions were toxic in the Artemia salina assay. We obtained different abietane-type diterpenes such as 7α-acetoxy-6ß-hydroxyroyleanone (Roy) and 6ß,7ß-dihydroxyroyleanone (DiRoy), which was also in agreement with the HPLC-DAD profile of the extract. Furthermore, the antiproliferative activity was assessed in a glioma tumor cell line panel by the Alamar blue assay. After 48 h treatment, Roy exerted strong antiproliferative/cytotoxic effects against tumor cells with low IC50 values among the different cell lines. Finally, we synthesized a new fluorescence derivative in this study to evaluate the biodistribution of Roy. The uptake of BODIPY-7α-acetoxy-6ß-hydroxyroyleanone by GB cells was associated with increased intracellular fluorescence, supporting the antiproliferative effects of Roy. In conclusion, Roy is a promising natural compound that may serve as a lead compound for further derivatization to develop future therapeutic strategies against GB.

Comorbid diseases among bullous pemphigoid patients in Germany: new insights from a case-control study.

BACKGROUND AND OBJECTIVES: Bullous pemphigoid (BP) is associated with neuropsychiatric disorders. Other comorbid diseases are discussed controversially. We evaluated the prevalence of comorbidity in BP patients in a representative area of Germany. PATIENTS AND METHODS: Medical files of all BP patients treated at the Department of Dermatology, University Hospital Würzburg, Germany, between June 2002 and May 2013 were retrospectively reviewed. Bullous pemphigoid was diagnosed based on established criteria. For each patient, two controls were individually matched. Records were evaluated for age, sex, laboratory values, concomitant medication and comorbidity. Conditional logistic regression, multivariable regression analysis and complex regression models were performed to compare results. RESULTS: 300 BP patients were identified and compared to 583 controls. Bullous pemphigoid was associated with neuropsychiatric disorders as well as laboratory abnormalities including leukocytosis and eosinophilia. Importantly, a highly significant association of BP with anemia (OR 2.127; 95 % CI 1.532-2.953) and renal impairment (OR 2.218; 95 % CI 1.643-2.993) was identified. No association was found with malignancy and arterial hypertension. CONCLUSIONS: Our data revealed an increased frequency of anemia and renal impairment in BP patients. In accordance with previous studies the strong association for neuropsychiatric disorders was confirmed (p < 0.0005).

Siglec-15 recognition of sialoglycans on tumor cell lines can occur independently of sialyl Tn antigen expression.

Siglec-15 is a conserved sialic acid-binding Ig-like lectin expressed on osteoclast progenitors, which plays an important role in osteoclast development and function. It is also expressed by tumor-associated macrophages and by some tumors, where it is thought to contribute to the immunosuppressive microenvironment. It was shown previously that engagement of macrophage-expressed Siglec-15 with tumor cells expressing its ligand, sialyl Tn (sTn), triggered production of TGF-ß. In the present study, we have further investigated the interaction between Siglec-15 and sTn on tumor cells and its functional consequences. Based on binding assays with lung and breast cancer cell lines and glycan-modified cells, we failed to see evidence for recognition of sTn by Siglec-15. However, using a microarray of diverse, structurally defined glycans, we show that Siglec-15 binds with higher avidity to sialylated glycans other than sTn or related antigen sequences. In addition, we were unable to demonstrate enhanced TGF-ß secretion following co-culture of Siglec-15-expressing monocytic cell lines with tumor cells expressing sTn or following Siglec-15 cross-linking with monoclonal antibodies. However, we did observe activation of the SYK/MAPK signaling pathway following antibody cross-linking of Siglec-15 that may modulate the functional activity of macrophages.

Oral immunotherapy in severe cow's milk allergic patients treated with omalizumab: Real life survey from a Spanish registry.

BACKGROUND: Oral immunotherapy is a frequent treatment for the management of food allergies, but adverse events (AE) are common. This study assessed the outcome of cow's milk oral immunotherapy (MOIT) in severe cow`s milk-allergic patients treated with omalizumab in a real-life setting. METHODS: OmaBASE was a national, multicenter, open, and observational registry that collected clinical, immunologic, and treatment from patients with food allergy receiving omalizumab. RESULTS: Data derived from 58 patients aged 10.3 years (IQR 6.3-13.2) and median milk-specific IgE 100 kUA /L at the start of omalizumab treatment. Most had experienced anaphylaxis by accidental exposures (70.7%) and had asthma (81.0%). Omalizumab in monotherapy induced tolerance to ≥6000 mg of cow's milk protein (CMP) to 34.8% of patients tested by oral food challenge. Omalizumab combined with MOIT conferred desensitization to ≥6000 mg of CMP to 83.0% of patients. Omalizumab withdrawal triggered more AE (P = .013) and anaphylaxis (P = .001) than no discontinuation. Anaphylaxis was observed in 36.4% of patients who discontinued omalizumab, and more in those with sudden (50.0%) rather than progressive (12.5%) discontinuation. At database closure, 40.5% of patients who had completed follow-up tolerated CMP without omalizumab (7.2% 1500-4500 mg; 33.3% ≥6000 mg). CONCLUSION: Milk oral immunotherapy initiated under omalizumab allows the desensitization of subjects with severe cow's milk allergy even after omalizumab discontinuation. However, discontinuation of omalizumab can lead to severe AE and should be carefully monitored.