Complex regulation of alarmins S100A8/A9 and secretion via gasdermin D pores exacerbates autoinflammation in familial Mediterranean fever.

Background: Familial Mediterranean fever (FMF), caused by mutations in the pyrin-encoding MEFV gene, is characterized by uncontrolled caspase-1 activation and IL-1β secretion. A similar mechanism drives inflammation in cryopyrin-associated periodic fever syndrome (CAPS) caused by mutations in NLRP3. CAPS and FMF, however, result in largely different clinical manifestations, pointing to additional, autoinflammatory pathways involved in FMF.

Inhibition of cellular RNA methyltransferase abrogates influenza virus capping and replication.

Orthomyxo- and bunyaviruses steal the 5' cap portion of host RNAs to prime their own transcription in a process called "cap snatching." We report that RNA modification of the cap portion by host 2'-O-ribose methyltransferase 1 (MTr1) is essential for the initiation of influenza A and B virus replication, but not for other cap-snatching viruses. We identified with in silico compound screening and functional analysis a derivative of a natural product from , called trifluoromethyl-tubercidin (TFMT), that inhibits MTr1 through interaction at its -adenosyl-l-methionine binding pocket to restrict influenza virus replication.

Potent immunomodulatory and antitumor effect of anti-CD20-IL2no-alpha tri-functional immunocytokine for cancer therapy.

Introduction: The anti-CD20 antibody rituximab (RTX) has substantially improved outcomes of patients with B-cell lymphomas, although more efficient therapies are needed for refractory or relapsing lymphomas. An approach to increase the clinical effectiveness of anti-tumor therapy is the use of antibody-cytokine fusion proteins (immunocytokines (ICKs)) to deliver at the tumor site the antibody effector functions and cytokines that trigger anti-tumor activities. In particular, IL-2-based ICKs have shown significant results in preclinical studies but not in clinical trials due to the toxicity profile associated to high doses IL-2 and the undesired expansion of Tregs.

Inhibition of p38 signaling curtails the SARS-CoV-2 induced inflammatory response but retains the IFN-dependent antiviral defense of the lung epithelial barrier.

SARS-CoV-2 is the causative agent of the immune response-driven disease COVID-19 for which new antiviral and anti-inflammatory treatments are urgently needed to reduce recovery time, risk of death and long COVID development. Here, we demonstrate that the immunoregulatory kinase p38 MAPK is activated during viral entry, mediated by the viral spike protein, and drives the harmful virus-induced inflammatory responses. Using primary human lung explants and lung epithelial organoids, we demonstrate that targeting p38 signal transduction with the selective and clinically pre-evaluated inhibitors PH-797804 and VX-702 markedly reduced the expression of the pro-inflammatory cytokines IL6, CXCL8, CXCL10 and TNF-α during infection, while viral replication and the interferon-mediated antiviral response of the lung epithelial barrier were largely maintained.

Immune, inflammatory and prothrombotic parameters in COVID-19 patients treated with an anti EGFR antibody.

SARS-CoV-2 infection causes a range of clinical presentations and induces changes in both innate and adaptive branches of the immune system. Furthermore, direct viral action to the cells of the lung promotes over-expression of the epidermal growth factor receptor (EGFR) which triggers pro-inflammatory response, contributes to coagulopathy and intravascular thrombi as well as lung fibrosis. Based on the role of this signaling pathway in the pathophysiology of the disease, nimotuzumab, an anti-EGFR monoclonal antibody, was used to treat patients with COVID-19.

Myeloid autophagy genes protect mice against fatal TNF- and LPS-induced cytokine storm syndromes.

ATG5: autophagy related 5; ATG7: autophagy related 7; ATG14: autophagy related 14; ATG16L1: autophagy related 16-like 1 (S. cerevisiae); BECN1: beclin 1, autophagy related; CASP1: caspase 1; CASP4/CASP11: caspase 4, apoptosis-related cysteine peptidase; CIM: conditionally immortalized macrophage; CLP: cecal ligation and puncture; CSS: cytokine storm syndrome; DC: dendritic cell; IFNG/IFNγ: interferon gamma; IFNGR1: interferon gamma receptor 1; ip: intraperitoneal; iv: intravenous; IL12/p70: interleukin 12, p70 heterodimer; IL18: Interleukin 18; ITGAX/CD11c: integrin alpha X; LAP: LC3-associated phagocytosis; LPS: lipopolysaccharide; LYZ2/LYSM: lysozyme 2; MAP1LC3A/LC3: microtubule-associated protein 1 light chain 3 alpha; RB1CC1/FIP200: RB1-inducible coiled-coil 1; S100A8/MRP8: S100 calcium binding protein A8 (calgranulin A); TICAM1/TRIF: TIR domain containing adaptor molecule 1; TLR4: toll-like receptor 4; TNF: tumor necrosis factor.

Domain-level epitope mapping of polyclonal antibodies against HER-1 and HER-2 receptors using phage display technology.

HER-1 and HER-2 are tumor-associated antigens overexpressed in several epithelial tumors, and successfully targeted by therapeutic approaches against cancer. Vaccination with their recombinant extracellular domains has had encouraging results in the pre-clinical setting. As complex humoral responses targeting multiple epitopes within each antigen are the ultimate goal of such active immunotherapy strategies, molecular dissection of the mixture of antibody specificities is required.

Murine Mammary Carcinoma Induces Chronic Systemic Inflammation and Immunosuppression in BALB/c Mice.

Purpose: The F3II cell line is a highly invasive variant of mammary carcinoma. Although it is frequently used as a model to evaluate the efficacy of immunotherapy, its impact on the immune system remains poorly understood. The main objectives of this study were to evaluate the effects of F3II tumors on the development of chronic inflammation and to characterize tumor-associated immunosuppression.

Erythropoietin in Spinocerebellar Ataxia Type 2: Feasibility and Proof-of-Principle Issues from a Randomized Controlled Study.

Background: Several pieces of evidence have shown the neurotrophic effect of erythropoietin (EPO) and its introduction in the therapeutic practice of neurological diseases. However, its usefulness in the treatment of spinocerebellar ataxia type 2 (SCA2) has not been proven despite the fact that it is endogenously reduced in these patients.

Objective: The study aims to investigate the safety, tolerability, and clinical effects of a nasally administered recombinant EPO in SCA2 patients.

Multicentre oncology clinical trials in primary health care in Cuba: evaluation of programme implementation in Villa Clara Province, 2010-2020.

Background: The Center of Molecular Immunology of Cuba has developed a programme for the conducting of multicentre oncology clinical trials in primary healthcare centres since 2009.

Aim: To evaluate the ability to conduct oncology clinical trials in primary health care.

Design & Setting: A longitudinal, prospective, analytical study was developed between July 2010 and August 2020 in the Villa Clara province.

Repeat-dose and local tolerance toxicity of SARS-CoV-2 FINLAY-FR-02 vaccine candidate in Sprague Dawley rats.

This study evaluates safety of FINLAY-FR-02, a vaccine candidate against SARS-CoV-2 based on the recombinant receptor binding domain conjugated to tetanus toxoid, in a preclinical, repeat-dose toxicity and local tolerance study. Sprague Dawley rats were randomly allocated to three experimental groups: control (receiving physiological saline solution); placebo (receiving all vaccine components except antigens) and vaccine group (receiving three doses of the vaccine candidate, 37.5 µg of RBD) administered intramuscularly in hind limbs at 24 h intervals during three days.

Development and Validation of a Novel Anaerobic Carbapenem Inactivation Method (Ana-CIM) for the Detection of Carbapenemase Production in Bacteroides fragilis.

Antibiotic resistance, particularly to carbapenems, is of increasing concern in Bacteroides fragilis. Carbapenem resistance in B. fragilis is most often mediated by the activation of chromosomally encoded metallo-β-lactamase by the presence of an upstream insertion sequence (IS).

Blocking EGFR with nimotuzumab: a novel strategy for COVID-19 treatment.

Lung injury and STAT1 deficit induce EGFR overexpression in SARS-CoV-2 infection. A phase I/II trial was done to evaluate the safety and preliminary effect of nimotuzumab, an anti-EGFR antibody, in COVID-19 patients. Patients received from one to three infusions together with other drugs included in the national guideline.

A cell-based ELISA as surrogate of virus neutralization assay for RBD SARS-CoV-2 specific antibodies.

SARS-CoV-2, the cause of the COVID-19 pandemic, has provoked a global crisis and death of millions of people. Several serological assays to determine the quality of the immune response against SARS-CoV-2 and the efficacy of vaccines have been developed, among them the gold standard conventional virus neutralization assays. However, these tests are time consuming, require biosafety level 3 (BSL3), and are low throughput and expensive.

The MEK1/2-inhibitor ATR-002 efficiently blocks SARS-CoV-2 propagation and alleviates pro-inflammatory cytokine/chemokine responses.

Coronavirus disease 2019 (COVID-19), the illness caused by a novel coronavirus now called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to more than 260 million confirmed infections and 5 million deaths to date. While vaccination is a powerful tool to control pandemic spread, medication to relieve COVID-19-associated symptoms and alleviate disease progression especially in high-risk patients is still lacking. In this study, we explore the suitability of the rapid accelerated fibrosarcoma/mitogen-activated protein kinase/extracellular signal-regulated kinase (Raf/MEK/ERK) pathway as a druggable target in the treatment of SARS-CoV-2 infections.

Anthrax toxins regulate pain signaling and can deliver molecular cargoes into ANTXR2 DRG sensory neurons.

Bacterial products can act on neurons to alter signaling and function. In the present study, we found that dorsal root ganglion (DRG) sensory neurons are enriched for ANTXR2, the high-affinity receptor for anthrax toxins. Anthrax toxins are composed of protective antigen (PA), which binds to ANTXR2, and the protein cargoes edema factor (EF) and lethal factor (LF).

The Effects of Human Milk Oligosaccharides on Gut Microbiota, Metabolite Profiles and Host Mucosal Response in Patients with Irritable Bowel Syndrome.

Background: Human milk oligosaccharide supplementation safely modulates fecal bifidobacteria abundance and holds the potential to manage symptoms in irritable bowel syndrome (IBS). Here, we aimed to determine the role of a 4:1 mix of 2'-O-fucosyllactose and lacto-N-neotetraose (2'FL/LNnT) on the modulation of the gut microbiota composition and host mucosal response, as well as the link between the bifidobacteria abundance and metabolite modulation, in IBS patients.

Methods: Biological samples were collected from IBS patients ( = 58) at baseline and week 4 post-supplementation with placebo, 5 g or 10 g doses of 2'FL/LNnT.

Nimotuzumab for COVID-19: case series.

In COVID-19, EGFR production is upregulated in the alveolar epithelial cells. EGFR overexpression further activates STAT-3 and increases lung pathology. The EGFR pathway is also one of the major nodes in pulmonary fibrosis.

Purification and Conformational Characterization of a Novel Interleukin-2 Mutein.

Toxicity of high-dose IL-2-based therapies have motivated the development of the IL-2 mutein, which has low expansion properties for regulatory T lymphocytes. The development of two variants (A and B) for the IL-2 mutein purification as well as a conformational comparative study by Circular dichroism (CD) and fluorescence spectroscopy of these products were evaluated. For the first time, in our center, were used of DTT and 2% SDS in the solubilization step to decrease the aggregates on intermediate product, which favors that disulfide bridges are correctly formed during re-folding.

The microglial NLRP3 inflammasome is involved in human SARS-CoV-2 cerebral pathogenicity: A report of three post-mortem cases.

We herein report, by using confocal immunofluorescence, the colocalization of the SARS-CoV-2 nucleocapsid within neurons, astrocytes, oligodendrocytes and microglia in three deceased COVID-19 cases, of between 78 and 85 years of age at death. The viral nucleocapsid was detected together with its ACE2 cell entry receptor, as well as the NLRP3 inflammasome in cerebral cortical tissues. It is noteworthy that NLRP3 was colocalized with CD68 + macrophages in the brain and lung of the deceased, suggesting the critical role of this type of inflammasome in SARS-CoV-2 lesions of the nervous system/lungs and supporting its potential role as a therapeutic target.

Panorama of the Intracellular Molecular Concert Orchestrated by Actinoporins, Pore-Forming Toxins from Sea Anemones.

Actinoporins (APs) are soluble pore-forming proteins secreted by sea anemones that experience conformational changes originating in pores in the membranes that can lead to cell death. The processes involved in the binding and pore-formation of members of this protein family have been deeply examined in recent years; however, the intracellular responses to APs are only beginning to be understood. Unlike pore formers of bacterial origin, whose intracellular impact has been studied in more detail, currently, we only have knowledge of a few poorly integrated elements of the APs' intracellular action.

Sticholysin II shows similar immunostimulatory properties to LLO stimulating dendritic cells and MHC-I restricted T cell responses of heterologous antigen.

Induction of CD8 T cell responses against tumor cells and intracellular pathogens is an important goal of modern vaccinology. One approach of translational interest is the use of liposomes encapsulating pore-forming proteins (PFPs), such as Listeriolysin O (LLO), which has shown efficacy at priming strong and sustained CD8 T cell responses. Recently, we have demonstrated that Sticholysin II (StII), a PFP from the sea anemone Stichodactyla helianthus, co-encapsulated into liposomes with ovalbumin (OVA) was able to stimulate, antigen presenting cells, antigen-specific CD8 T cells and anti-tumor activity in mice.

A Distinct Faecal Microbiota and Metabolite Profile Linked to Bowel Habits in Patients with Irritable Bowel Syndrome.

Patients with irritable bowel syndrome (IBS) are suggested to have an altered intestinal microenvironment. We therefore aimed to determine the intestinal microenvironment profile, based on faecal microbiota and metabolites, and the potential link to symptoms in IBS patients. The faecal microbiota was evaluated by the GA-map dysbiosis test, and tandem mass spectrometry (GC-MS/MS) was used for faecal metabolomic profiling in patients with IBS and healthy subjects.

Molecular determinants of response to PD-L1 blockade across tumor types.

Immune checkpoint inhibitors targeting the PD-1/PD-L1 axis lead to durable clinical responses in subsets of cancer patients across multiple indications, including non-small cell lung cancer (NSCLC), urothelial carcinoma (UC) and renal cell carcinoma (RCC). Herein, we complement PD-L1 immunohistochemistry (IHC) and tumor mutation burden (TMB) with RNA-seq in 366 patients to identify unifying and indication-specific molecular profiles that can predict response to checkpoint blockade across these tumor types. Multiple machine learning approaches failed to identify a baseline transcriptional signature highly predictive of response across these indications.

Systematic Comparison of Three Commercially Available Combination Disc Tests and the Zinc-Supplemented Carbapenem Inactivation Method (zCIM) for Carbapenemase Detection in Isolates.

Detection of carbapenemases in is crucial for patient treatment and infection control. Among others, combination disc tests (CDTs) with different inhibitors (e.g.