Quantitative proteomics research has demonstrated to be essential to understand how biological systems work at a molecular level. However, the bioinformatic analysis and processing of this enormous amount of data for meaningful biological and functional interpretation remains to be challenging. Here, we will discuss various current standardized methods and strategies for bioinformatic analysis, and we will highlight some available software programs, computational tools, and meta-analysis resources for proteomic data analysis.

Cancer immunotherapies targeting the PD-L1/PD-1 axis are revolutionizing cancer treatment and transforming the practice of medical oncology. Despite the recent successes, most patients are refractory and present intrinsic or acquired resistance. This is one of the most significant challenges in oncology. However, the mechanisms leading to resistance are still poorly understood. Here, we discuss some of the major molecular mechanisms of resistance to PD-L1/PD-1 blockade. We also argue whether tumor intrinsic or extrinsic factors constitute main determinants of response and resistance. Primary and acquired resistances are important barriers in terms of benefit to the patient. Among others, tumor-intrinsic factors include poor tumor antigenicity, DNA repair mutational load, alterations in the regulation of oncogenic pathways, defects in IFN signal transduction and PD-L1 expression. On the other hand, tumor-extrinsic factors include T cell exhaustion, expression of additional immune checkpoint molecules, differentiation and expansion of immunosuppressive cell populations, and release of immunosuppressive cytokines and metabolites. The relative contribution of tumor cell intrinsic and extrinsic factors to primary, adaptive, and acquired resistance is yet unclear. Our group recently found that NSCLC patients that failed to respond to PD-1/PD-L1 inhibitors had systemic CD4 dysfunctionality, characterized by increased PD-1/LAG-3 co-expression in T cells. These results highlighted dysfunctional CD4 T cells as main contributors to treatment failure. A deeper understanding of the basic mechanisms underlying resistance will provide insight for further development of better therapeutic strategies by overcoming treatment failure. The development of new approaches to improve CD4 responses before immunotherapy could be a solution to overcome resistance (Zuazo et al, EMBO Mol Med 2019; Zuazo et al, EMBO Mol Med 2020; Chocarro de Erauso L et al, Front. Pharmacol. 2020; Zuazo et al, Font Immunol 2020; Bocanegra et al, Int J Mol Sci 2020; Hernández et al, Int J Mol Sci 2020; Arasanz et al, Cancers 2020; Chocarro et al, Int J Mol Sci 2021).

Lymphocyte activation gene 3 (LAG-3) is a cell surface inhibitory receptor with multiple biological activities over T cell activation and effector functions. LAG-3 plays a regulatory role in immunity and emerged some time ago as an inhibitory immune checkpoint molecule comparable to PD-1 and CTLA-4 and a potential target for enhancing anti-cancer immune responses. LAG-3 is the third inhibitory receptor to be exploited in human anti-cancer immunotherapies, and considered a next-generation target in cancer immunotherapy, right next to PD-1 and CTLA-4. Unlike PD-1 and CTLA-4, the exact mechanisms of action of LAG-3 remain poorly understood. Indeed, PD-1/LAG-3 co-expression is a marker for exhausted T lymphocytes infiltrating tumors. This constitutes a high-risk signature, but also a clinical factor associated to overall survival. The lack of understanding of LAG-3 functions is partly caused by the presence of non-conventional signaling motifs in its intracellular domain, different from others present in classical immune checkpoints. Here we summarize the current understanding on LAG-3 and its role in response and resistance to cancer therapy, from its mechanisms of action to clinical applications (Chocarro de Erauso L et al, Front. Pharmacol. 2020; Zuazo et al, Font Immunol 2020; Bocanegra et al, Int J Mol Sci 2020; Hernández et al, Int J Mol Sci 2020; Arasanz et al, Cancers 2020; Chocarro et al, Int J Mol Sci 2021).

Lymphocyte activation gene 3 (LAG-3) is a cell surface inhibitory receptor with multiple biological activities over T cell activation and effector functions. LAG-3 plays a regulatory role in immunity and emerged some time ago as an inhibitory immune checkpoint molecule. A systematic research was performed using PubMed and ClinicalTrial.gov databases. Up-to-date published articles meeting the inclusion criteria were investigated. LAG-3 expression has been linked to increased pathology in certain inflammatory disorders, such as HDL Hypercholesterolemia and Inflammatory Bowel Disease. LAG-3 protein expression levels have been significantly associated via transcriptomic studies with high HDL cholesterol (HDL-C) and HALP (HDL-C ≥ 60 mg/dL). Indeed, LAG-3 deficiency altered lipid raft formations and cell phosphosignaling, processes leading to an enhanced proinflammatory state, and increased production of inflammatory cytokines such as TNFα (Golden et al, Insight 2016; Rodriguez et al, Curr. Atheroscler. Rep. 2021; Chocarro et al, Int J Mol Sci 2021). LAG-3 has been reported to be a modulator of T cell regulation in inflammatory responses in the intestine (Do et al, Mucosal. Immunol. 2016; Chocarro et al, Int J Mol Sci 2021). In addition, LAG-3+-regulatory T cells are required to suppress the inflammatory activities of CX3CR1+ macrophages to maintain tissue homeostasis during lymphoid cell-driven colitis (Bauché et al, Immunity 2018; Chocarro et al, Int J Mol Sci 2021). Moreover, LAG-3+ cells have been shown to be increased in the inflamed mucosa and correlate with endoscopic severity and disease phenotype in ulcerative colitis. Here, we will discuss the impaired control of cell-mediated immunity associated with high accumulation of LAG-3 in inflammatory disorders (Chocarro et al, Int J Mol Sci 2021). Interestingly, in vitro blockade of PD-1/LAG-3 interactions enhances cytokine production in response to cancer and infections, and it is demonstrating promising results in several clinical trials for the treatment of various cancers, suggesting it could have a similar effect in inflammatory disorders (Chocarro et al, IOTECH 2022). A deeper understanding on the basic mechanisms underlying LAG-3 intracellular signaling will provide insight for further development of novel strategies for autoimmune and inflammatory disorders (Chocarro et al, Int J Mol Sci 2021).

Lymphocyte activation gene 3 (LAG-3) is a cell surface inhibitory receptor with multiple biological activities over T cell activation and effector functions. LAG-3 plays a regulatory role in immunity and emerged some time ago as an inhibitory immune checkpoint molecule. A systematic research was performed using PubMed and ClinicalTrial.gov databases. Up-to-date published articles meeting the inclusion criteria were investigated. LAG-3 expression has been linked to increased pathology in cardiovascular diseases. LAG-3 protein expression has been shown to correlate with increased coronary heart disease and increased myocardial infarction. LAG-3 accumulates in cardiac allografts undergoing rejection episodes to fully vascularized, heterotopic, allogeneic heart transplantation (Haudebourg et al, Transplant 2007; Chocarro et al, Int J Mol Sci 2021). LAG-3 deficiency has also been associated in clinical studies with increased risk of coronary artery disease due to Tr1 dysfunction (Zhu et al, Hum. Immunol. 2018; Chocarro et al, Int J Mol Sci 2021). Here, we will discuss the impaired control of cell-mediated immunity associated with high accumulation of LAG-3 in cardiovascular diseases (Chocarro et al, Int J Mol Sci 2021). Interestingly, in vitro blockade of PD-1/LAG-3 interactions enhances cytokine production in response to cancer and infections, and it is showing promising results in several clinical trials for the treatment of various cancers, suggesting it could have a similar effect in cardiovascular disorders (Chocarro et al, IOTECH 2022). A deeper understanding on the basic mechanisms underlying LAG-3 intracellular signaling will provide insight for further development of novel strategies for cardiovascular disorders (Chocarro et al, Int J Mol Sci 2021).

Lymphocyte activation gene 3 (LAG-3) is a cell surface inhibitory receptor with multiple biological activities over T cell activation and effector functions. LAG-3 plays a regulatory role in immunity and emerged some time ago as an inhibitory immune checkpoint molecule. A systematic research was performed using PubMed and ClinicalTrial.gov databases. Up-to-date published articles meeting the inclusion criteria were investigated. LAG-3 expression has been linked to increased pathology in neurological diseases. Emerging preclinical and clinical evidence suggests that LAG-3 is associated with an increased risk of Parkinson’s disease (PD) (Guo et al, J. Neuroinflammation 2019; Chocarro et al, Int J Mol Sci 2021). A disruption of the immune homeostasis caused by LAG-3 dysfunction in the central nervous system could initiate neuron-to-neuron α-synuclein aggregation and PD progression. Thus, LAG-3 could serve as a possible therapeutic target to slow the progression of α-synucleinopathies. In addition, germline allelic variation of the LAG-3 gene has been described to confer susceptibility to multiple sclerosis (Zhang et al, Genes Immun. 2005; Chocarro et al, Int J Mol Sci 2021.) Here, we will discuss the impaired control of cell-mediated immunity associated with high accumulation of LAG-3 in neurological diseases (Chocarro et al, Int J Mol Sci 2021). Interestingly, in vitro blockade of PD-1/LAG-3 interactions enhances cytokine production in response to cancer and infections, and it is showing promising results in several clinical trials for the treatment of various cancers, suggesting it could have a similar effect in neurological disorders (Chocarro et al, IOTECH 2022). A deeper understanding of the basic mechanisms underlying LAG-3 intracellular signaling will provide insight for further development of novel strategies for autoimmune and neurological disorders (Chocarro et al, Int J Mol Sci 2021).

Detailed knowledge of tumor biology is necessary for tumor reprogramming. Tumor associated macrophages (TAMs) and monocytic myeloid suppressor cells (m-MDSCs) are major tumor-promoting cells within the tumor microenvironment (TME). Differentiation of m-MDSC and TAMs is shaped by tumor microenvironment. Several factors have been shown to drive m-MDSC differentiation into TAMs, indicating that they are two different populations. However, TAMs and m-MDSC closely related functions, phenotypic similarities and differentiation plasticity contributes to the confusion over their ontogeny and differential characteristics. Here, we revealed the key differences between m-MDSC and TAMs, focused on differential pathways by high-throughput proteomics.

With the development of the chemical industry, phytoconstituents have become bioactive targets with numerous functionalities, highlighting the pharmacological, herbicide and aromatherapy use. In this spectrum, alpha-pinene stands out, an organic compound of the terpenoid class and subclass of monoterpenes. In fact, the presence of this phytoconstituent is of a wide spectrum in world soil, highlighting the Brazilian northeast, especially in plants such as rosemary (Rosmarinus officinalis). This, in turn, due to its bioactive properties, already has reports of antibacterial, anti-inflammatory and immunomodulatory effects. In this perspective, due to this approach to human beings, attention is gained in terms of its possible toxicity in its use. In this bias, it is necessary to expand the discussion on this possible toxicity of this phytoconstituent, since reports of acute and chronic toxicity involving monoterpenes are already corroborated. In this sense, this study aims to consolidate the main correlations of toxicity existing with the use of alpha-pinene already provided in the literature. For this, a narrative-type bibliographic review was carried out in December 2021 using the descriptors available in the Health Sciences Descriptors (DeCS): “alpha-pinene”, “anti-inflammatory”, “immunomodulator” and “ toxicity”, in Portuguese, English and Spanish. The inclusion criteria were: studies that promote the understanding of alpha-pinene functionalities. It is noteworthy that studies referring to possible toxic effects were also included. On the other hand, the exclusion criteria were: articles that addressed other effects of alpha-pinene and that considered alpha-pinene only with a minority composition of the essential oil used in the study. In view of this method, it is mentioned that alpha-pinene is already a compound with affinity for some specific systems and organs, highlighting the affinity for the nervous system, urinary system, liver and mammary glands, causing a possibility of overloading these systems. and organs. Therefore, the study showed the possibility of toxicity, especially considering the neurotoxic effects associated with nephropathies, evidencing that alpha-pinene becomes a possibility in its use but it must be considered by the toxicological possibility.

This overview concerns the International Patent Classification of hydrogels. More specifically, this study presents the state of the art by introducing what has been innovated and patented in relation to hydrogels through the PCT global system. A detailed analysis is then given regarding to publication years, patent classifications, and jurisdictions.

The aim of this study was to characterize the general characteristics of the completed interventions by the Voivodeship Rescue Service in Katowice in the period between 1st January 2018 to 31st December 2018. Particular attention was paid to the type of intervention taken by the EMT as well as the reasons for the calling it based on the international qualification of ICD-10 illnesses. Analysis of the characteristics of the trips was done based on the information contained in the dispatch order cards and medical emergency services. cards. In the statistical analysis the Chi-Square (p<0.05) test was utilized. The total number of interventions was 211,548 cases. It is also worth observing, that the general number of interventions out of town amounted to 20,344 interventions, whereas, in town, there were 191,204 interventions. It can be observed that the most common decision made by the Emergency Medical Team was the decision to directly transported and received by the emergency department (126,553 cases; p<0.05). The definite most common reason for symptoms, signs and abnormal clinical and laboratory findings, not elsewhere classified (ICD-10 code : R; p<0.05). The largest number of interventions completed by the Voivodeship Rescue Service in Katowice in 2018 was due to injuries and poisonings, symptoms, diseases features and incorrect results of diagnostic tests, and in third place were cardiovascular diseases.