Environmental concerns, among other causes, are leading to meat replacement in the diet by healthy, nutritious and tasty foods. Alternative protein sources of plant origin can be an alternative to meat, but their low biological value proteins can be a problem. Novel foods, such as insect meals, can meet currently consumer demands. Therefore, this research has developed innovative prototypes of analogue burgers with animal and vegetable proteins. Concerned about health and allergies, a prototype incorporating soya to satisfy coeliacs was developed. An iterative and heuristic process was carried out to test the product development feasibility. The main raw materials used were insect flour (Tenebrio molitor), seitan and soya. In addition, oat and sodium alginate were used as binders. Shelf-life of the new product was evaluated by physicochemical (pH, aw, moisture, colour, acidity and peroxide index) and sensory analysis (quantitative analysis -QDA-). The production of the burger analogues was feasible. Product characterisation showed significant differences (p < 0.05) among samples for organoleptic properties, highlighting texture changes. Using a multivariate model, it was established “The best before date” at 7 days for all developed prototypes, conditioned by microbial growth. Finally, the spoilage model indicated an important contribution to bacterial growth with a notable modification in the pastiness and hardness of the burger analogues developed.

Current COVID-19 vaccines can effectively reduce disease severity and hospitalisation; however, they are not considerably effective in preventing infection and transmission. In this context, mucosal vaccines are pertinent to prevent SARS-CoV-2 infection and spread. In this study, we generated a replication-competent recombinant chimeric influenza A virus (IAV) expressing the receptor-binding domain (RBD) of SARS-CoV-2 prototype in the C-terminus of the neuraminidase (NA) of A/Puerto Rico/08/1934 H1N1 (PR8). The remaining seven segments from A/WSN/1933 H1N1 (WSN) were named PR8NARBD/WSN. We observed that the recombinant virus with the WSN backbone demonstrated improved expression of NA and RBD. A single intranasal dose of PR8NARBD/WSN in mice generated robust mucosal immunity, neutralising antibodies, cellular immunity, and tissue-resident memory T cells specific to SARS-CoV-2 and IAV. Importantly, immunisation with PR8NARBD/WSN viruses effectively protected mice against lethal challenges with H1N1, H3N2 IAV, and SARS-CoV-2 Beta variant and significantly reduced lung viral loads. Overall, our research demonstrates the promising potential of PR8NARBD/WSN as an attractive vaccine against emerging SARS-CoV-2 variants and influenza A virus infections.

Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 enters the host by infecting nasal ciliated cells. Then, the virus can spread towards the oropharyngeal cavity and the pulmonary tissues. The antiviral adaptive immunity is promptly induced in response to virus detection, with virus-specific T lymphocytes appearing before antiviral antibodies. Both breadth and potency of the antiviral CD8+ T cell immunity have a key role in containing viral spread and disease severity. Current anti-SARS-CoV-2 vaccines do not impede the virus replication in the upper respiratory tract, and there is consensus on the fact that the best potency of the antiviral immune response in both blood and upper respiratory tract can be reached upon infection in vaccinees (i.e., breakthrough infection). However, whether the antiviral CD8+ T cells developing in response to the breakthrough infection in the upper respiratory tract diffuse to the lungs also is still largely unknown. To fill the gap, we checked the CD8+ T cell immunity elicited after infection of K18-hACE2 transgenic mice both 3 weeks and 3 months after anti-Spike vaccination. The virus-specific CD8+ T cell immunity was monitored in both blood and the lungs before and after infection. By investigating the de novo generation of CD8+ T cells specific for SARS-CoV-2 viral proteins, we found that both membrane (M) and/or nucleocapsid (N)-specific CD8+ T cells were induced at comparable levels in blood of both unvaccinated and vaccinated mice. Conversely, N-specific CD8+ T cells were readily found in the lungs of control mice, but were either rare or absent in those of vaccinated mice. These results support the idea that the hybrid cell immunity developing after asymptomatic/mild breakthrough infection strengthens the antiviral cell immunity at lungs only marginally, implying that the direct exposition of the viral antigens is required for the induction of an efficient antiviral cell immunity in the lungs.

CD4+ T cells orchestrate and regulate immunity within jawed vertebrates, yet our understanding of their evolution, development, and cellular physiology has only begun to be unearthed in the past few decades. Discoveries of genetic diseases that ablate this cellular population have provided insight into their critical functions while transcriptomics, proteomics, and highresolution microscopy have recently revealed new insights into CD4+ T cell anatomy and physiology. This article compiles historical, microscopic, and multi omics data which can be used as a reference atlas to dissect cellular physiology within these influential cells and further understand pathologies like HIV infection that inflict human CD4+ T cells.

ABSTRACT: Recurrent glioblastoma (rGBM) is a highly aggressive form of brain cancer that poses a significant challenge for treatment in neurooncology, and the survival status of patients after relapse usually means rapid deterioration, and also the leading cause of death among patients. In recent years, immunotherapy has emerged as a promising strategy for the treatment of recurrent glioblastoma by stimulate the body's immune system to recognize and attack cancer cells , which could be used as a in combination with other treatments such as surgery, radiation, and chemotherapy to improve outcomes for patients with recurrent glioblastoma, This therapy combines several key methods such as the use of monoclonal antibodies, chimeric antigen receptor T cell (CAR-T) therapy, checkpoint inhibitors, oncolytic viral therapy cancer vaccines, and combination strategies. In this review, we mainly document the latest immunotherapies for the treatment of glioblastoma and focus on the rGBM especially.

Introduction: Obstructive sleep apnea (OSA) is the most common sleep-breathing disorder. OSA is associated with cardiovascular diseases such as coronary artery disease (CAD) and arrhythmias with an increased risk of sudden cardiac death. Some changes in ECG markers are seen as an indicator of arrhythmogenicity, especially ventricular arrhythmias. The goal of this study was to investigate if OSA patients with CAD have QT dispersion and T peak to T end (TpTe) changes as a surrogate of arrhythmogenicity. Methods: We studied 75 patients with CAD who underwent polysomnographic studies. Patients were categorized into mild, moderate, and severe OSA according to the Apnea hypopnea index (AHI). Baseline ECG and echocardiography for assessing LV function and valvular heart disease were done for all of them. Results: Results showed that in patients with moderate and severe sleep apnea QT dispersion was higher in a group with more involvement of coronary artery disease, reduced ejection fraction, and a history of old MI. However, we didn’t find any significant statistical relationship between OSA and TpTe marker. Conclusion: Our results showed a positive relation between ECG arrhythmic indices such as QT dispersion and OSA severity in patients with CAD.

The microenvironment of most tumors is complex, comprising numerous aspects of immunosuppression. Several studies have indicated that the adrenergic system is vital for controlling immunological responses. In the context of tumor microenvironment, Nor-Adrenaline (NA) is poured-in by innervating nerves and tumor tissues itself. The receptors for nor-adrenaline are present on the surface of cancer and immune cells and are often involved in activation of pro-tumoral signaling pathways. β2-adrenergic receptor (β2-AR) is an emerging class of receptors that are capable of modulating the functioning of immune cells. β2-AR is reported to activate the regulatory immune cells and inhibit the effector immune cells. Blocking β2-AR increases activation, proliferation and cytokine release of T lymphocytes. Moreover β2-AR deficiency during metabolic reprograming of T cells increases mitochondrial membrane potential and biogenesis. In the view of available research data, immunosuppressive role of β2-AR in T cells presents it a targetable checkpoint in CAR-T cell therapies. In this review, we have abridged contemporary knowledge about adrenergic stress mediated β2-AR activation on T lymphocytes inside tumor milieu.

miRNAs are major regulators of eukaryotic gene expression, host immunity, and play an important role in the inflammation-mediated pathways in periodontal disease (PD) pathogenesis. Expanding our previous observation with the global miRNA profiling using partial human mouth microbes and lack of in vivo studies involving oral spirochete Treponema denticola induced miRNAs, this study was designed to delineate the global miRNA expression kinetics during progression of periodontitis in mice infected with T. denticola by using NanoString nCounter® miRNA panels. All the T. denticola-infected male and female mice at 8- and 16 weeks demonstrated bacterial colonization (100%) on the gingival surface, and an increase in alveolar bone resorption (p &lt; 0.0001). A total of 70 miRNAs with at least 1.0-fold differential expression/regulation (DE) miRNAs (26 upregulated and 44 downregulated) were identified. nCounter miRNA expression profiling identified 13 upregulated miRNAs (e.g. miR-133a, miR-378) and 25 downregulated miRNAs (e.g. miR-375, miR-34b-5p) in T. denticola-infected mice mandibles during 8-weeks infection whereas 13 upregulated miRNAs (e.g. miR-486, miR-126-5p) and 19 downregulated miRNAs (miR-2135, miR-142-3p) were observed during 16- weeks of infection. One miRNA (miR-126-5p) showed significant difference between 8-and 16-weeks of infection. Interestingly, miR-126-5p has been presented as a potential biomarker in patients with periodontitis and coronary artery disease. Among the 13 upregulated miRNAs, miR-486, miR-126-3p, miR-126-5p were reported in human gingival plaques samples with periodontitis. KEGG analysis revealed various functional pathways of DE miRNAs such as bacterial invasion of epithelial cells, Ras signaling, Fc gamma R- mediated phagocytosis, osteoclast differentiation, adherens signaling and ubiquitin mediated proteolysis. This is the first study of DE miRNAs in mice mandibles at different time-points of T. denticola infection and the combination of three specific miRNAs miR-486, miR-126-3p, miR-126-5p may serve as an invasive biomarker of T. denticola in PD. These miRNAs may have significant role in PD pathogenesis and establishes a link between miRNA, periodontitis, and systemic diseases.

B and T lymphocytes demonstrate important alterations in patients with Systemic Lupus Erythematous (SLE), with significant up-regulation of Double Negative (DN) B cells. Aim of this study was to evaluate correlation of T cell immunity changes with the distinct B cell-pattern SLE. In the present study, Flow cytometry was performed in 30 patients with SLE, on remission, and 31 healthy controls, to detect DN B cells (CD19+IgD-CD27-) and a wide range of T lymphocyte subpopulations, based on the presence of CD45RA, CCR7, CD31, CD28, CD57, defined as naive, memory and advanced differentiated/senescent T cells. Both B and T lymphocytes were significantly reduced in SLE patients. However, the percentage of DN B cells were increased, compared to HC, 12.9(2.3-74.2) vs. 8(1.7-35), p=0.04. Distribution of CD4 and CD8 lymphocytes demonstrated a shift to advanced differentiated subsets. The population of DN B cells had significant positive correlation with most of early differentiated T lymphocytes, CD4CD31+, CD4CD45RA+CD28+, CD4CD45RA+CD57-, CD4CD45RA-CD57-, CD4CD28+CD57-, CD4CD28+CD57+, CD4 CM, CD8 CD31+, CD8 NAÏVE, CD8CD45RA-CD57-, CD8CD28+CD57-, CD8CD28+CD57+. Multiple Regression analysis revealed CD4CD31+, CD8CD45RA-CD57- and CD8CD28+CD57- cells as independent parameters contributing to DN B cells, adjusted R2=0.534, p<0.0001. The predominance of DN B cells in patients with SLE is closely associated with early differentiated T lymphocyte subsets, indicating a potential causality role of DN B cells in T lymphocyte activation.

The intercomparison among different atmospheric monitoring systems is key for instrument calibration and validation. Common cases involve satellites, radiosonde, radio occultation (e.g. GNSS-RO) and atmospheric model outputs (e.g. ERA5 reanalysis). Since instruments and/or measures are not perfectly collocated, the miss-collocation uncertainty must be considered in the related intercomparison uncertainty budgets.

A locally-rotationally-symmetric Bianchi-I model filled with strange quark matter (SQM) is explored in f(R, T) gravity. We take f(R, T) = R + 2 f(T) = R + 2λT, where R is the Ricci scalar, T is the trace of energy-momentum tensor and λ is an arbitrary constant. Exact solutions are obtained by assuming that the expansion scalar is proportional to the shear scalar. This yields a constant value for the deceleration parameter, q = 2, which corresponds to the decelerated phase of the universe. The model is found to be physically viable for λ < −1. SQM during early evolution mimics ultra-relativistic radiation whereas at late times, it behaves as dust, quintessence or even the cosmological constant depending on the value of λ. The effective matter acts as a stiff fluid irrespective of the matter content and of the f(R, T) terms. The model is shear free at late times but remains anisotropic throughout the evolution. In the absence of the f(R, T) terms, SQM accelerates the universe. In the specific case when SQM vanishes at late times, the effect of f(R, T) is to accelerate the universe. The model admits the possibility that SQM could be an alternative to dark energy.

We employ hierarchy of models (HoM) with 2, 3 and 4 parameters to reanalyze the nucleation kinetics in the electrodeposition as quantified by n(t) - “the number of nuclei vs. time” data obtained at different overvoltages from precise experiments on electrodeposition of Hg on two different types of Pt-cathodes by Ivan V. Markov and Evgenia Stoycheva [1]. The obtained two scales, nmax and , are used to rescale the original data mapping it on a master curve in coordinates . Our main result is obtained by studying further the dependence of these two scales on the overvoltage (analogue of supersaturation). Surprisingly, for one of the two cathode types - the “hemispherical single-crystal electrode” (as defined by the authors), there is discontinuity in the “ vs. overvoltage” dependence – an almost horizontal jump from 85 to 86 mV accompanied by a change in the slope of the dependence - it is ~ -1 and ~ -0.5 after. For the other cathode - “plane structureless platinum electrode”,  decreases smoothly. Combined, these two behaviors point at the so called “cusp catastrophe”. We compare our findings with published results on protein nucleation.

Targeted cancer therapy has grown exponentially in the last decade, representing the largest frontier in the modern concept of precision medicine. This renaissance is largely due to our rapidly evolving ability to biochemically harness our immune systems to target cancer-specific antigens. Combined with an increasing armamentarium of surgical and non-invasive techniques for cancer mitigation we have upgraded cancer therapy from a non-specific assault on cell-division to a multi-modal, targeted approach. This renaissance has resulted in an increase in the perioperative footprint of patients with advanced cancer. The scope of the perioperative clinician has evolved from one of passive/reactive management of complications to a proactive approach that starts in the preoperative optimization phase and continues into the postoperative period. The perioperative world should not exist in a silo, and thus involvement of the oncology team is paramount. To provide safe oncologic care, it is essential to be up to date in newer cancer therapies, lest we act on erroneous and/or outdated information. Oncologists should weigh in on immune status, recent chemotherapeutic exposures, and potentially evolving toxicities. These might involve critical changes to perioperative infectious prophylaxis, steroid administration, and coagulopathy management. First, patients living beyond the typical life-expectancy for their cancer will carry a high burden of cancer-related downstream effects. General metabolic issues will include malnutrition, cachexia, and gastric outlet obstruction. Severe protein-calorie malnutrition, as well as hepatic and renal dysfunction can impact the metabolism and clearance of drugs. The cardiovascular, endocrinologic, pulmonary, and central nervous system implications of new cancer therapies will be discussed extensively below. Second, we have to enhance our ability to manage a cancer population who may be experiencing increasing novel chemotherapeutic toxicities. Newer agents differ from historical agents, which were blunt-force tools aimed at nonspecific destruction of cell-division. These drugs are efficacious but physiologically costly. Newer immunogenic therapies have a slightly improved acute safety profile, and a more complex chronic toxicity profile that may be overt or insidious. Chronic toxicities can present overtly or as a smoldering undertone to other active medical conditions such as sepsis, pneumonia, failure to thrive, or renal failure. The new therapies discussed in this review occur in the context of an overall increasingly multi-faceted cancer care machine. An example is screening for esophageal cancer in patients with Barrett's esophagus, or periodic chest CTs for patients with a strong history of tobacco use. These interventions are more likely to detect disease while it is still resectable, and resections will commonly accompany neo-adjuvant therapy. These approaches commonly involve new immunotherapies whose efficacy is higher-yield with a lower disease burden. In a recent example, the immune-checkpoint inhibitors (ICIs) ipilimumab plus nivolumab have significantly increased survival rate for squamous cell esophageal cancer when combined with standard chemotherapy. Surgical resection has evolved to one that often accompanies neoadjuvant chemo and radiation. The increasing efficacy of this approach may de-necessitate many major resections, and increase the number of sub-anatomic resections and minimally invasive procedures. Improved techniques - notably for hepatectomy, whipple procedure, prostatectomy, nephrectomy - have increased the safety profile and decreased the perioperative physiologic burden. This has enabled a broader subset of patients (due to cancer burden or due to medical comorbidities) to qualify for the operation, and increased the involvement of anesthesia and their perioperative services. With an increase in surgical candidacy comes an increase in post-surgical complications, and post-surgical maintenance such as drains, embolizations, imaging studies, etc. In the non-OR anesthesia realm, there have been considerable advancements in cancer “micro-treatments” such as hepatic metastasis embolization, tumor ablation, and peri-tumor vascular embolization. There are an ever-increasing number of IR-guided embolizations for bleeding tumors, aspiration of malignant effusions, and drainage of abscesses. This review serves to provide insight into new categories of chemotherapy and their perioperative implications.

CD8 T cells and Natural Killer (NK) cells are cytotoxic lymphocytes important in the response to intracellular pathogens and cancer. Their activity depends on the integration of a large set of intracellular and environmental cues, including antigenic signal, cytokine stimulation and nutrients availability. This integration is achieved by signaling hubs such as the mechanistic target of Rapamycin (mTOR). mTOR is a conserved protein kinase, controlling cellular growth and metabolism in eukaryotic cells and therefore is essential for lymphocyte development and maturation. However, our current understanding of mTOR signaling comes mostly from studies performed in transformed cell lines, which constitute a poor model to comprehend metabolic pathway regulation. Therefore, it is only quite recently that the regulation of mTOR in primary cells has been assessed. Here we review the signaling pathways leading to mTOR activation in CD8 T and NK cells, focusing on activation by cytokines. We also discussed how this knowledge can contribute to immunotherapy development for intracellular pathogen and cancer treatment.

Background: Cord blood represents a link between intrauterine and early extrauterine development. Cord blood cells map an important time frame in human immune imprinting processes. It is unknown whether sex of the newborn affects the lymphocyte subpopulations in cord blood. Methods: 9 B and 21 T cell subpopulations were characterized by flow cytometry in human cord blood from 16 male and 21 female newborns, respectively. Results: Except for marginal zone B cells and transitional B cells, B cell count in all subsets was higher in cord blood of male newborns than in female newborns. Frequency of naive thymus negative Th cells was significantly higher in male cord blood whereas the remaining T cell subpopulations showed a higher count in cord blood of female newborns. Conclusion: Our study is the first revealing sex differences in B and T cell subpopulations of human cord blood. These results indicate that sex might have a higher impact for the developing immune system urging the need to expand research in this area.

Background: Sulforaphane (SFN) is an isothiocyanate of vegetables origin with potent antioxidant and immunomodulatory properties. The pleiotropic activities characterization in human dendritic cells (DCs) is poorly summarized. The aim of this work was the study of the immunomodulatory power of SFN in response to an inflammatory microenvironment on human monocyte derived DCs (moDCs). Methods: The immunological response induced by SFN was studied, evaluating apoptosis and autophagy assays by flow cytometry in moDCs and cancer cell line (THP-1), including moDCs maturation, lymphocyte proliferation and cytokines production under different experimental conditions associated or not with an inflammatory microenvironment, which was induced by lipopolysaccharide (LPS). Results: Our results demonstrated that SFN can interact with moDCs, significantly reducing autophagy process and enhancing apoptosis, such as THP-1 cells, in chronic inflammatory microenvironment. Under this chronic inflammation, SFN modulated the phenotypical characteristics of moDCs, which reduction the expression of all markers (CD80, CD83, CD86, HLA-DR and PD-L1), and significantly reduced the Th2 proliferative response together with the reduction of the IL-9 and IL-13 levels. Although we did not find changes in the regulatory proliferative response, we observed an increase in IL-10 levels. Conclusion: These findings demonstrate that SFN exerts protective effects against LPS-induced inflammation through moDCs/T-cells modulation towards a regulatory profile. Therefore, SFN may be a potential candidate for use in the treatment of pathologies with an inflammatory profile.

We report the characterization of phenotype, genotype, and functional parameters such as CD4+ T cell, viral load, HIV-1 genotype, class I HLA genotype, CCR5 polymorphism, and IFN-γ producing cells from a cohort of 37 people living with HIV-1 (PLWH) (viremic controllers, were compared those on antiretroviral therapy (ART) from two sites in São Paulo, Brazil. Half the PLWH (51.4%) were classified as viremic controllers (Controller group - CG), compared to 48.6% were on ART. As expected, controllers showed baseline higher levels of CD4+ T cells and nadir compared to those under ART, confirming the ability of HIV-1 controllers to preserve these cells even in the absence of ART. IFN-γ-producing cells showed greater magnitude to the HIV peptides Gag in controllers (p<0.03). Our results demonstrated that HLA protective alleles are associated with strong production of IFN-γ to Gag, Nef and RT epitopes in people living with HIV controllers.

The appearance of brain metastasis is the most serious complication of breast cancer with mostly fatal outcomes. To reach the brain, tumor cells need to pass the blood-brain barrier (BBB). The molecular mechanisms underlying penetration of the BBB are largely unknown. Previously we found that tumor-infiltrating T lymphocytes enhance the development of brain metastasis of estrogen receptor-negative (ER-) breast cancer. In the current study, we investigate the contribution of T lymphocytes and the IFN- pathway in enabling breast cancer cells to pass the in vitro BBB. CD8+ cells display the strongest stimulatory effect on breast cancer cell passage. We show that inhibition of the IFN- receptor in MDA-MB-231 breast cancer cells, or neutralization of soluble IFN-, impairs the in vitro trespassing of breast cancer cells. Importantly, we validated our findings using gene expression data of breast cancer patients. CXCL-9,-10,-11/CXCR3 axis, dependent on IFN- signaling activity, was overexpressed in primary breast cancer samples of patients who developed brain metastasis. The data support a role for T-lymphocytes and the IFN- pathway in the formation of brain metastasis of ER- breast cancer, and offer targets to design future therapies for preventing breast cancer cells to cross the BBB.

Hepatocellular carcinoma (HCC) is one of the most common cancers and the main cause of cancer-related death globally. Immune dysregulation of CD4+ T cells has been identified as a role in the development of HCC. Nevertheless, the underlying molecular pathways of CD4+ T cells in HCC are not completely known. Thus, a better understanding of the dysregulation of lncRNA-miRNA/mRNA network might yield novel insights into the etiology or progression of HCC. In this study, circulating CD4+ T cells were isolated from the whole blood of 10 healthy controls and 10 HCC patients for next-generation sequencing of the expression of lncRNAs, miRNAs, and mRNAs. Our data showed that there was different expression of 34 transcripts (two lncRNAs, XIST and MIR222HG, 29 mRNA, and 3 other types of RNA) and 13 miRNAs in the circulating CD4+ T cells of HCC patients. The expression of the lncRNA XIST-related miRNAs and their target mRNAs was confirmed using real-time quantitative polymerase chain reaction (qPCR) on samples from 100 healthy controls and 60 HCC patients. The lncRNA–miRNA/mRNA regulation network was created using interaction data generated from ENCORI and revealed there are positive correlations in the infiltration of total CD4+ T cells and negative correlations in the infiltration of Th1 CD4+ T cells.

RNA interference is a highly conserved process in which non-coding small RNAs (sRNA) modulate gene expression at the post-transcriptional level influencing plant growth and development. Dicer-like (DCL), Argonaute (AGO) and RNA-dependent RNA polymerase (RDR) are the core elements involved in gene silencing and their gene families have been explored in many plants. However, these genes and their response to abiotic stresses have not yet been well in wheat. In this study, 82 AGO, 31 DCL, and 31 RDR genes were identified and phylogenetic analysis of these proteins showed that clustered into ten, four and four clades respectively. RNA-seq analysis revealed constitutive expression of AGO1, AGO9, and DCL2 family expression analysis in tissues under normal and stress conditions, whereas RDR1 which is known to engage in siRNA biogenesis showed higher expression levels in wheat leaf tissues. Our findings build the foundation for comparative genomics analyses of RNA silencing elements in cereal crops, as well as new insights into the functional complexity of RNA silencing in wheat stress responses, which is critical for understanding the processes underlying wheat stress responses.

CAR-T therapy has achieved considerable treatment success in hematologic tumors by using patient derived autologous αβ T cells. There is an impetus to broaden the applicability of this approach by using a third-party donor derived CAR-T cell product which has a potent anti-tumor function but a constrained GVHD property. In this study, CAR-T cells were prepared from Vγ9Vδ2 T cells expanded by using a novel prodrug PTA and their anti-tumor functions were assessed in conjunction with persistency, localization, and phenotype. γδ T cells were successfully transduced with a CAR specific to CEA with signaling domains of CD3ζ and CD28 (CEA.CAR-γδ T cells), and exhibited potent tumor killing function in vitro. In a xenograft mouse model, CEA.CAR-γδ T cells suppressed CEA+ tumor growth though a limited time window. CEA.CAR-γδ T cells persisted and accumulated in the tumor even after tumor progression, however, ex vivo analysis revealed that those recovered at different time points from PBMC, spleen and tumors gradually lost tumor reactivity as assessed by IFN-γ production. Provision of GITR co-stimulation enhanced anti-tumor function of CEA.CAR-γδ T cells, the result of which imposes additional measurers to be adopted in CAR-γδ T cells for an allogeneic adoptive immunotherapy.

Ultraviolet (UV) radiation is a strong environmental carcinogen responsible for the pathogenesis of most skin cancers, such as malignant melanoma (MM) and non-melanoma (keratinocyte) skin cancers. The carcinogenic role of UV was firmly established based on epidemiological evidence and molecular findings of the characteristic mutation signatures which occur during excision repair of cyclobutane pyrimidine dimers and 6,4-photoproducts. The role of UV in the pathogenesis of mycosis fungoides (MF), the most common primary cutaneous T-cell lymphoma, remains controversial. Here, we performed whole exome sequencing of 61 samples of MF cells microdissected from the cutaneous lesions, and compared their mutational signatures to 340 MM. The vast majority of MM mutations had a typical UV mutational signature (SBS 7, SBS 38, DSB 1) underscoring the key role of ultraviolet as a mutagen. In contrast, the SBS 7 signature in MF comprised &lt;5% of all mutations. SBS 7 was higher in the intraepidermal MF cells (when compared to the dermal cells) and in the cells from tumors as compared to early-stage plaques. In conclusion, our data do not support the pathogenic role of UV in the pathogenesis of MF and suggest that the UV mutations are the result of the cumulative, environmental ultraviolet exposure of cutaneous lesions, rather than an early mutagenic event.

Autoimmune limbic encephalitis (LE) is a rare, but devastating complication of allogeneic hem-atopoietic stem cell transplantation (HSCT). There is currently limited evidence describing the risk factors, laboratory features, and underlying mechanisms of this neurologic adverse event. We retrospectively reviewed available clinical, imaging, and laboratory data from adult patients with hematological malignancies who underwent haploidentical HSCT with cyclophosphamide (PTCy) at Chungnam National University Hospital from June 2016 to May 2020. Patients who developed LE were compared to those who did not based on clinical assessment, serum inflam-matory biomarkers, and reconstitution of various T cell populations. Of 35 patients, four devel-oped LE. There were no differences in patient demographics, donor demographics, or treatment conditions between patients that did and did not develop LE. Overall, patients with LE had worse clinical outcomes and overall survival than those without. In addition, they tended to have higher markers of systemic inflammation in the early post-transplant period, including fever, C-reactive protein (CRP), and cytokines. Remarkably, baseline interleukin-6 levels before HSCT were found to be higher in patients who developed LE than those who did not. In addition, analysis of T cell subsets showed impaired expansion of CD25+FOXP3+ regulatory T (Treg) cells in LE compared to non-LE patients despite appropriate reconstitution of the total CD4+ T cell population. Patients that developed LE within the first 30 days of HSCT were likely to have high serum IL-6 among other inflammatory cytokines coupled with suppression of regulatory T cell differentiation. Further work is needed on the mechanisms underlying impaired Treg expansion following HSCT and potential therapies.

CRCMSS/pMMR contain a significantly increased fraction of TREM2+ macrophages (TAMs) and CD66+ neutrophils (TANs) together with decrease of CD4-CD8-CD3+ double negative T lymphocytes (DNTs); no differences were revealed by the analysis of myeloid and plasmacytoid dendritic cell populations. A fraction of tumor-infiltrating T-cells display an exhausted phenotype, co-expressing PD-1 and TIM-3. Remarkably, expression of PD-L1 on fresh tumor cells and TAMs was undetectable even after in vitro stimulation with interferon-γ. These findings confirm the immune suppressive microenvironment of CRCMSS/pMMR characterized by dense infiltration of TAMs, occurrence of TANs, lack of DNTs, T-cell exhaustion and interferon-γ unresponsiveness by host and tumor cells. Appropriate bypass strategies should consider these combinations of immune escape mechanisms in CRCMSS/pMMR.

Energy is needed by cancer cells to stay alive and communicate with their surroundings. The primary organelles for cellular metabolism and energy synthesis are mitochondria. Researchers recently proved that cancer cells can steal immune cells' mitochondria using nanoscale tubes. This finding demonstrates the dependence of cancer cells on normal cells for their living and function. It also denotes the importance of mitochondria in cancer cells’ biology. Emerging evidence has demonstrated how mitochondria are essential for cancer cells to survive in the harsh tumor microenvironment, evade the immune system, obtain more aggressive features, and resist treatments. For instance, functional mitochondria can improve cancer resistance against radiotherapy by scavenging the released reactive oxygen species. Therefore, targeting mitochondria can potentially enhance oncological outcomes, according to this notion. The patients' reactions to radiation are varied, ranging from a complete response to even cancer progression during treatment. This concept illustrates how different levels of mitochondrial metabolism might contribute to this heterogeneity. Considering this notion can help to improve personalized oncological treatments. This article outlines the importance of mitochondrial metabolism in cancer biology and personalized treatments.

Background: Hepatic interstitial T-lymphocytes (T-Li), Natural Killer (NK) and NK-T cells play an important role in both innate and adaptive immunity and contribute to the regulation of ischemia/reperfusion injury (IRI) after transplantation of abdominal organ. Methods: The cellular concentrations and phenotypes of NK, T-Li, NK-T were analyzed retrospectively in a consecutive series of hepatic perfusates after surgical removal of whole livers on the bench previously collected from adult multi-organ donors after brain death. (DBD), and compared with the demographic and pathological characteristics of the patients transplanted at our Institute with kidneys taken from the same donors. The liver interstitial cells were purified from the perfusate by density gradient centrifugation and the phenotype was determined by flow cytometric investigation using the following immunological markers: CD3, CD4, CD8 and CD56 in order to determine the relative percentage of T-Li, NK-T and NK cells. Results: The perfusates of 42 DBDs, and the related clinical outcome of kidney transplant recipients from 2010 to 2020, were analyzed. T-Li were significantly associated with the time in days of delayed functional recovery of transplanted kidneys (DGF) (p = 0.02), to onset of secondary infection from Cytomegalovirus (p = 0.03). On COX analysis, percent cell concentration of T-Li and time to DGF were significantly associated with an increased relative risk (HR) of organ survival (HR = 1.038, p = 0.04; and HR = 1.029, p = 0.01, respectively). The specificity of the NK and NK-T cell proportions were not associated with any relevant clinical outcomes in kidney transplant patients. Conclusions: The present study points to a new potential role of T-Li cells detected in the context of liver perfusate DBD, and could detect potential impacts in organ allocation, surgical harvesting techniques and in the analysis of IRI pathophysiological events after kidney transplants from multi-organ DBDs.

This paper discusses a passive control issue for Nonlinear Time-Varying (NTV) systems subject to stability and attenuation performance. Based on the modeling approaches of Takagi-Sugeno (T-S) fuzzy model and the Linear Parameter-Varying (LPV) model, a Parameter-Dependent Polynomial Fuzzy (PDPF) model is constructed to represent the NTV systems. According to Parallel Distributed Compensation (PDC) concept, a parameter-dependent polynomial fuzzy controller is built to achieve robust stability and passivity of PDPF model. Furthermore, the passive theory is applied to achieve the performance constraining the disturbance effect on the PDPF systems. To develop the stability criteria, by introducing a parameter-dependent polynomial Lyapunov function, one can derive some stability conditions which belong to the term of Sum-Of-Squares (SOS) form. Based on the Lyapunov function, two stability criteria are proposed to design the corresponding PDPF controller such that the NTV system is robustly stable and passive. Finally, a numerical example is applied to demonstrate the effectiveness of the proposed stability criterion.

To address the problem that it is easy to form coverage blind areas when wireless sensor networks are randomly deployed, an improved coverage optimization algorithm based on improved Salpa swarm Intelligent algorithm (ATSSA) is proposed for wireless sensor networks. Firstly, the pop-ulation is initialized using tent chaotic sequence to enhance the optimization ability of the algo-rithm. Secondly, the T-distribution mutation is added to the update formula of the leaders for improving the ability to jump out of the local optimal value. Finally, an adaptive formula for updating the position of the follower is proposed, which not only guarantees the local searching ability of the algorithm in the late iteration period, but also improves the global searching ability of the algorithm in the early iteration period. The experimental results show that ATSSA algorithm can improve the coverage of the wireless sensor networks and reduce deployment costs com-pared with other algorithms, when it is used in the wireless sensor networks.

Keywords: Hypertensive emergency; diagnosis; lactate dehydrogenase; high sensitivity cardiac troponin T; brain natriuretic peptide; area under the curve.

Incremental stability analysis for time-delay systems has attracted more and more attentions for its contemporary applications in transportation processes, population dynamics, economics, satellite positions, etc. This paper researches criteria on v(t)-incremental stability, which is defined to demonstrate the convergence rate for incremental stability, for time-delay systems. Firstly, the sufficient conditions for v(t)-incremental stability for time-delay systems with continuous right-hands are studied, and several corollaries for specific cases are provided. As for time-delay systems with discontinuous right-hands, after expounding the relevant conditions for the existence and uniqueness of the Filippov solution, by using approximation methods, sufficient conditions for v(t)-incremental stability are obtained. The conclusions are applied to linear switched time-delay systems and Hopfield neural network system with composite right-hand afterwards.

Intestinal commensal microbes, called the gut microbiota, play a critical role in host immune homeostasis through active microbial metabolites and innate and adaptive immune responses. Dysbiosis or imbalance of the gut microbiota composition is associated with inflammatory bowel disease (IBD) which includes Crohn’s disease and ulcerative colitis. The incidence and prevalence rates of IBD have been increasing worldwide. It is well recognized that butyrate, a microbial metabolite of diet fibers, is a major energy source for colonocytes and plays a crucial role in regulating immune function and maintaining epithelial barrier function and intestinal homeostasis. Emerging evidence suggests that butyrate might be a potential therapeutic agent to treat IBD. In this review, we discuss about gut microbial metabolites, particularly butyrate, the synthesis and metabolism of butyrate, mechanisms of butyrate in immune and epithelial barrier function. Furthermore, we review the current research on various therapeutic implications of butyrate in IBD.

Despite exhaustive studies, researchers have made little progress in the field of adoptive cellular therapies for relapsed-refractory acute myeloid leukemia (AML), unlike the notable uptake for B cell malignancies. Various single antigen targeting chimeric antigen receptor (CAR) T cell Phase I trials have been established worldwide and have recruited approximately 100 patients. The high heterogeneity at the genetic and molecular levels within and between AML patients resembles a black hole: a great gravitational field that sucks in everything, considering only around 30% of patients show a response but with consequential off-tumor effects. It is obvious that a new point of view is needed to achieve more promising results. This review first introduces the unique therapeutic challenges of not only CAR T cells but also other adoptive cellular therapies in AML. Next, recent single cell sequencing data for AML to assess somatically acquired alterations at the DNA, epigenetic, RNA and protein levels are discussed to give a perspective on cellular heterogeneity, intercellular hierarchies, and the cellular ecosystem. Finally, promising novel strategies are summarized, including more sophisticated next-generation CAR T, TCR-T and CAR-NK therapies; approaches to tailor the microenvironment and target neoantigens; and allogeneic approaches.

The α(1,2)fucosyltransferase (Se enzyme) encoded by FUT2 is involved in the secretor status of ABH(O) blood group antigens. The sedel2 allele is one of the non-functional FUT2 (se) alleles in which 9.3 kb containing the entire coding region of FUT2 is deleted by Alu-mediated nonhomologous recombination. In addition to this allele, three SNPs of FUT2, c.375A>G, c.385A>T, and c.571C>T, appear to be prevalent in certain Oceanian populations such as Polynesians. Recently, we developed an endpoint genotyping assay to determine the sedel2 zygosity, using a FAM-labeled probe for detection of the sedel2 allele and a VIC-labeled probe for detection of FUT2. In this study, instead of the VIC probe, a HEX-labeled probe covering both c.375A>G and c.385A>T and a Cy5-labeled probe covering c.571C>T were added to the sedel2 allele assay mixture to allow simultaneous detection of these four variations by endpoint genotyping for the sedel2 zygosity and fluorescence melting curve analysis for c.375A>G, c.385A>T, and c.571C>T genotyping. The results obtained from 24 Samoan subjects with this method were identical to those obtained with previous methods. Therefore, it appears that present method can accurately determine these four variations simultaneously.

The term ‘Hallmarks of Cancer’ was coined by Hanahan and Weinberg in their influential reviews and they described genome instability as a property of cells enabling cancer development [1, 2]. Accurate DNA replication of genomes is central to diminish genome instability. Here, the understanding of the initiation of DNA synthesis in origins of DNA replication to start leading strand synthesis and the initiation of Okazaki fragment on the lagging strand are crucial to control genome instability. Recent findings have provided new insights into the mechanism of the remodelling of the prime initiation enzyme, DNA polymerase α-primase, during primer synthesis, how the enzyme complex achieves lagging strand synthesis, and how it is linked to replication forks to achieve optimal initiation of Okazaki fragments. Moreover, the central roles of RNA primer synthesis by Pol-prim in multiple genome stability pathways such as replication fork restart and protection of DNA against degradation by exonucleases during double-strand break repair is discussed.

Abstract: The SARS-CoV-2 pandemic has significantly impacted world health and economic status. In response, much work has been undertaken to provide effective, safe vaccines, antibodies and antiviral drugs with which to address this pandemic. Treatment of a pandemic population presents multiple challenges in addition to the primary issue of drug efficacy and safety, such as large scale drug manufacture and distribution, drug stability, oral dosing and pharmacoeconomic considerations. Ideally, these factors must be addressed if new candidate drugs are to be advanced for treatment of large (pandemic) populations. Subsequently, new antivirals have reached the market but choices are few. According to the NIH Covid Treatment Guidelines, only three small molecule antiviral drugs are available to treat COVID-19 disease. As such, a significant part of the research towards discovery of new antiviral drugs has focused on screening and evaluation of ‘repurposed drugs’ or previously approved or clinical stage drugs. Yet, in spite of this increased research activity, one promising clinical stage candidate drug has received little attention regarding its potential as a monotherapy or component of combination therapy for treatment of COVID-19 disease. Tucaresol, with documented human safety and pharmacokinetic data, is an orally active, stable, small molecule amenable to large scale manufacture by a proprietary two-step synthesis developed by us. Tucaresol functions as a host-targeted antiviral by selective protection/reconstitution of CD4+ T helper cells as demonstrated in HIV patients and SIV macaques. In view of similarities between HIV and SARS-CoV-2, especially with respect to host CD4+ T helper cells, and the suitability of Tucaresol for facile treatment of pandemic populations, Tucaresol is presented herein for treatment of mild-to-moderate COVID-19 patients but may also be useful for treatment of advanced disease accompanied by lymphopenia.

Chronic hepatitis B infection remains a significant worldwide health burden, placing persons at risk for hepatocellular cancer and hepatic fibrosis. Chronic hepatitis B virus (CHB) infection is characterized by elevated levels of immunosuppressive regulatory T cells (Tregs), which can inhibit the function of effector T cells and lead to an insufficient immune clearance response against HBV in the host. Theoretically, suppression of Treg functionality and percentage could increase anti-HBV reactivity in CHB-infected patients, although this has not yet been explored. We attempted to enhance our previously established anti-CHB protocol utilizing the GM-CSF+IFN-α+rHBVvac regimen (GMI-HBVac) by incorporating Mafosfamide (MAF), which has been utilized in anticancer therapy in the past. Intravenous administration of MAF to rAAV8-1.3HBV-infected mice resulted in a dose-dependent reduction of Tregs in the blood, rebounding to pretreatment levels 10 days later. To determine the efficacy of anti-CHB, 2ug/ml MAF was combined with the GMI-HBVac in an HBV-infected animal model as an anti-Treg treatment. When rAAV8-1.3HBV-infected mice were immunized with MAF+GMI-HBVac, peripheral blood Tregs decreased significantly, leading to dendritic cell activation, HBV-specific T cell proliferation, and upregulation of IFN-gamma producing CD8+T cells. In addition, MAF+GMI-HBVac vaccination stimulates T cell infiltration in HBV-infected liver. These conditions may contribute to an enhanced immune response and the clearance of HBV-associated antigens, including serum HBsAg, serum HBcAg, and HBcAg+ hepatocytes. Overall, this is the first indication that MAF was utilized as an adjuvant to deplete Tregs and paired with GMI-HBVac as a unique therapeutic vaccine regimen against established CHB mice to produce a functional cure, as seen by the remarkable clearance of HBsAg.

Controlling CD4+ immune cells infiltration of the brain is a leading aim in designing therapeutic strategies for a range of neuropathological disorders such as; multiple sclerosis, Alzheimer and depression. CD4+ T cells are a highly heterogeneous and reprogrammable family, that includes various distinctive cell types such as Th17, Th1, and Tregs. Interestingly Th17 and Tregs share a related transcriptomic profile, where the TGFβ-SMADS pathway plays a fundamental role in regulating the differentiation of both of these cell types. However, Th17 could be highly pathogenic and was shown to promote inflammation in various neuropathological disorders. Conversely, Treg is anti-inflammatory and is known to inhibit Th17. It could be noticed that Th17 frequencies of infiltration of the blood-brain barrier (BBB) in various neurological disorders are significantly upregulated. However, Treg infiltration numbers are significantly low. The reasons behind these contradicting observations are still unknown. In this perspective, we propose that the difference in the TCR repertoire diversity, diapedesis pathways, chemokine expression and mechanical properties of these two cell types could be contributing to answering this intriguing question.

We analyze the behavior of relativistic spherical objects within the context of modified $f(R,T)$ gravity considering Tolman VI spacetime, where gravitational lagrangian is a function of Ricci scalar(R) and trace of energy momentum tensor(T) i.e,$ f(R,T)= R+ 2\beta T$, for some arbitrary constant $\beta$. For developing our model, we have chosen $\pounds_{m} = -p$, where $ \pounds_{m}$ represents matter lagrangian. For this investigation, we have chosen three compact stars namely PSR J1614-2230 [Mass=(1.97$\pm$ 0.4)M$_\odot$; Radius= 9.69$_{-0.02} ^{+0.02}$ Km] ,Vela X-1 [Mass=(1.77$\pm$ 0.08)M$_\odot$; Radius= 9.560$_{-0.08} ^{+0.08}$ Km] and 4U 1538-52 [Mass=(9.69)M$_\odot$; Radius= 1.97 Km]. In this theory the equation of pressure isotropy is identical to standard Einstein's theory. So all known metric potential solving Einstein's equations are also valid here. In this paper, we have investigated the effort of coupling parameter ($\beta$) on the local matter distribution. Sound of speed and adiabatic index are higher with grater values of $\beta$ while on contrary mass function and gravitational redshift are lower with higher values of $\beta$ . For supporting the theoretical results, graphical representation are also employed to analyze the physical viability of the compact stars.

The coronavirus 2019 (COVID-19) pandemic was caused by a positive sense single-stranded RNA (ssRNA) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, other human coronaviruses (hCoVs) exist, of which Middle East Respiratory Syndrome (MERS) and SARS-CoV (SARS) showed higher mortality rates without causing a pandemic. As of December 2022, SARS-CoV-2 has resulted in over 6.6 million deaths worldwide through an array of acute to chronic pathologies. Historical pandemics include smallpox and influenza with efficacious therapeutics utilized to reduce overall disease burden. Therefore, immune system process analysis is required to compare innate and adaptive immune system interactions. Lymphatic system organs include bone marrow and thymus using a network of nodes throughout which white blood cells traverse glycolipid membranes utilizing cytokines and chemokine gradients that affect cell development, differentiation, proliferation, and migration processes as well as genetic factors affecting cell receptor expression. Innate processes involve antigen-presenting cells and B lymphocyte cellular responses to pathogens relevant to other viral and bacterial infections but also in oncogenic diseases. Such processes utilize cluster of differentiation (CD) marker expression, major histocompatibility complexes (MHC), pleiotropic interleukins (IL) and chemokines. The adaptive immune system consists of Natural Killer (NK) and T cells. Other viruses are also contributory to cancer including human papillomavirus (cervical carcinoma ), Epstein-Barr virus (EBV) ( lymphoma), hepatitis B and C (hepatocellular carcinoma) and human T cell leukemia virus-1 (adult T-cell leukemia). Bacterial infections also increase the risk of developing cancer( e.g. H. pylori). Therefore, as the above factors can cause both morbidity and mortality along-side being transmitted within clinical and community settings, it is appropriate to now examine advances in single cell sequencing, FACS analysis and many other laboratory techniques that allow insights into discoveries of newer cell types. These developments offer improved clarity and understanding that over-lap with known autoimmune conditions that could be affected by innate B cell or T cell responses to SARS-CoV-2 infection. Thus, this review quantifies and outlines the nature of specific receptors and proteins relevant to clinical laboratories and medical research by documenting both innate and adaptive immune system cells within current coronavirus immunology case study data and other pathologies to date.

The most widely spread and neglected zoonotic disease – Leptospirosis, with an estimated 1.03 million cases and 58,900 deaths occurring annually, is a concern and can be prevented only by effective immunization. Due to the urgent need for a novel vaccine, various research organizations have been evaluating the protective immune response elicited by recombinant vaccines. In this study amino-acid sequences of Outermembrane protein (OMPL) 1, LipL 32, 41 and 46 from ten pathogenic serovars of Leptospira were selected to obtain epitopes that induce CD4+ and CD8+ T cell responses by binding to the MHC molecules. These B cell and T cell epitopes were used to design multi-epitope vaccine to which an adjuvant sequence was added at the N-terminal end and appropriate linkers were used to join the different epitopes to increase the efficiency of the vaccine constructs. Using an immuno-informatics approach, constructs were analyzed for the physiochemical properties, secondary and tertiary structure and its validation, docking with different receptors and prediction of binding affinity for each docked complex, followed by molecular dynamics simulation. Taking in consideration all the results, multi-epitope constructs designed may prove to be promising vaccine candidates against Leptospirosis and warrants experimental validation.

γδT have functions of innate and adaptive immunity, with the potential to induce durable responses while being well-tolerated, with limited adverse effects, making it attractive as a tool for immunotherapy. γδT faces challenges as a frontline tool in clinical oncology, with limited response rates due to difficulties in reaching tumor sites with consistent cytotoxic activity and strength. Modulated Electro-hyperthermia (mEHT) is a loco-regional treatment, whereby energy-transmission from an electromagnetic field selectively targets the plasma membrane of tumor cells, inducing apoptosis and activating immune cells. We hypothesized that mEHT could enhance therapeutic effects by drawing γδT to tumor cells, while also rendering tumor cells to be more susceptible to cytotoxic effects. In this study, NOD/SCID mice harboring subcutaneous human HepG2 tumors were treated with intravenous injections of γδT after mEHT treatment. This method increased infiltration of γδT into the tumor site, significantly inhibiting tumor growth as compared to monotherapy with either modality. These data suggest that γδT could mediate a potent anti-tumor effect when combined with mEHT, and provide a strong rationale for combining these modalities in clinical application for cancer treatment.

Cancer metastasis into the brain constitutes one of the most severe but not uncommon development of cancer growth. Several factors control how cancer types interact with the brain to establish metastasis These factors include system of migration, system of infiltration of the blood-brain barrier and the interaction with host cells (e.g., neurons, astrocytes) and the immune system fight against metastasis in the brain. Although, brain radiotherapy is the main treatment procedure carried out to treat, new therapies are emerging that constitute a glimpse of hope for increasing the diminutive life expectancy currently forecasted to cancer patients who are facing the prospectus of brain metastasis. However applying these therapeutic strategies has been has not been effective. Thus there is a need for better understanding of the metastasis process in order to suggest novel therapeutic targets. In this review, we follow the journey of various cancer cells from their primary location through the various process that they undergo including EMT, penetration of the ECM, intravasation, extravasation and infiltration of the blood brain barrier ending up with colonization and angiogenesis. In each phase, we focus on molecules that could potentially be drug target candidates.

This manuscript provides a new integrated view of the development of allergen-specific TH2 and the lack of their associated Treg cells in a unified model, justifying the need for IL-2 to correct allergy conditions.

Diffuse intrinsic pontine glioma (DIPG) is recognized as a pediatric brainstem cancer with a 0% survival rate. On a molecular basis, DIPG commonly results from mutations in histone H3, specifically a mutation in the H3K27M gene, that promotes tumorigenesis and results in presentation of this fatal brainstem tumor. DIPG is challenging to treat, as surgical intervention is inefficacious due to the location where the glioma resides. To date, traditional treatments such as radiation, chemotherapy, and immunotherapy have not increased survival rates and have only been successful at relieving symptoms. Future therapeutic approaches such as proton beam radiation, Chimeric Antigen Receptor T Cell (CAR-T) immunotherapy, and alternative epigenetic pharmaceuticals are under investigation for potential benefits. Various clinical trials have also explored these treatment procedures to discover potential increases in survival rates in both animal and human studies. In this review, we will evaluate the pathology and molecular characteristics of DIPG, the current and future approaches to DIPG treatment; and, lastly, we will discuss clinical trials that have been completed to develop successful treatment options.

A significant number of persons with coronavirus disease 2019 (COVID-19) experience persistent, recurrent, or new symptoms several months after the acute stage of severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) infection. This phenomenon, termed Post-Acute Sequelae of SARS-CoV-2 (PASC) or Long COVID, is associated with high viral titers during acute infection, a persistently hyperactivated immune system, tissue injury by NETosis-induced micro-thrombofibrosis (NETinjury), microbial translocation, complement deposition, fibrotic macrophages, the presence of auto-antibodies, and lymphopenic immune environments. Here, we review the current literature on the immunological imbalances that occur during PASC. Specifically, we focus on data supporting common immunopathogenesis and tissue injury mechanisms shared across this highly heterogenous disorder including NETosis, coagulopathy, and fibrosis. Mechanisms include changes in leukocyte subsets/functions, fibroblast activation, cytokine imbalances, lower cortisol, autoantibodies, co-pathogen reactivation, and residual immune activation driven by persistent viral antigens and/or microbial translocation. Taken together, we develop the premise that SARS-CoV-2 infection results in PASC as a consequence of acute and/or persistent single or multiple organ injury mediated by PASC determinants to include degree of host response (inflammation, NETinjury), residual viral antigen (persistent antigen) and exogenous factors (microbial translocation). Determinants of PASC may be amplified by co-morbidities, age, and sex. Keywords: long COVID, PASC, long haulers, NETosis, T cell, NK cell, DC, neutrophil,

In recent years, new treatments have been studied for relapsed-refractory multiple myeloma (RRMM), including two CAR-T products and a variety of non CAR-T agents. Since direct comparisons between these innovative treatments are not available, indirect comparisons can be of interest. Reconstruction of individual patient data from Kaplan-Meier graphs (Shiny method) has been employed in numerous reports that have validated its performance. In the present review, we evaluated six treatments proposed for RRMM including two CAR-T products (ciltacabtagene autoleucel and idecabtagene vicleucel) and four treatments not based on a CAR-T (melflufen plus dexamethasone, isatuximab plus dexamethasone, selinexor, and belantamab). The end-point was overall survival (OS); the Shiny method was used to generate reconstructed survival curves. Our results showed statistically significant differences in OS across these treatments. Compared with pharmacological treatments, CAR-T products significantly prolonged OS with an improvement of remarkable clinical relevance. In particular, ciltacabtagene autoleucel showed better OS than idecabtagene vicleucel. As regards non CAR-T treatments, the ranking in OS was headed by isatuximab plus dexamethasone, followed by belantamab, selinexor, and melflufen plus dexamethasone. In conclusion, while the Shiny method has confirmed its validity in reconstructing individual patient data, our indirect comparisons have offered some original clues to better interpret the information on OS published in these studies.

Human oncoviruses are able to subvert telomerase function in cancer cells through multiple strategies. The activity of the catalytic subunit of telomerase (TERT) is commonly enhanced in virus-related cancers. Viral oncoproteins, such as high-risk human papillomavirus (HPV) E6, Epstein-Barr virus (EBV) LMP1, Kaposi sarcoma-associated herpesvirus (HHV-8) LANA, hepatitis B virus (HBV) HBVx, hepatitis C virus (HCV) core protein and human T-cell leukemia virus-1 (HTLV-1) tax protein, interact with regulatory elements in the infected cells and contribute to the transcriptional activation of TERT gene. Specifically, viral oncoproteins have been shown to bind TERT promoter, to induce post-transcriptional alterations of TERT mRNA and to cause epigenetic modifications, which have important effects on the regulation of telomeric and extra-telomeric functions of the telomerase. Other viruses, such as herpesviruses, operate by integrating their genomes within the telomeres or by inducing alternative lengthening of telomeres (ALT) in non-ALT cells. In this review, we recapitulate recent findings on virus-telomerase/telomeres interplay and the importance of TERT-related oncogenic pathways activated by cancer causing viruses.

Chimeric Antigen Receptor (CAR)-T cell immunotherapy revolutionized cancer treatment and consists of the genetic modification of T lymphocytes with a CAR gene, aiming to increase their ability to recognize and kill antigen-specific tumor cells. The dynamics of CAR-T cell responses in patients presents a multiphasic kinetics with distribution, expansion, contraction, and persistence phases. The characteristics and duration of each phase depend on the tumor type, the infused product, and on patient-specific characteristics. We present a mathematical model which describes the multiphasic CAR-T cell dynamics resulting from the interplay between CAR-T and tumor cells, considering patient and product heterogeneities. The CAR-T cell population is divided into functional (distributed and effector), memory, and exhausted CAR-T cell phenotypes. The model is able to describe the diversity of CAR-T cell dynamic behaviors in different patients and hematological cancers as well as their therapy outcomes. Our results indicate that the joint assessment of the area under the concentration-time curve in the first 28 days and the corresponding fraction of non-exhausted CAR-T cells may be considered as potential markers to classify therapy responses. Overall, the analysis of different CAR-T cell phenotypes can be a key aspect for a better understanding of the whole CAR-T cell dynamics.

COVID-19, the infectious disease caused by SARS-CoV-2, has spread on a pandemic scale. The virus infection can evolve asymptomatically or generate severe symptoms, influenced by the presence of comorbidities. Lymphopenia in patients affected with COVID-19 according to the severity of symptoms is frequent. However, the profile of CD4+ and CD8+ T-cells regarding cytotoxicity and antiviral factor expression has not yet been completely elucidated in acute SARS-CoV-2 infections. The purpose of this study is to evaluate the phenotypic and functional profile of T-lymphocytes in patients with moderate and severe/critical COVID-19. During this pandemic period, we analyzed a cohort of 62 confirmed patients with SARS-CoV-2 (22 moderate cases and 40 severe/critical cases). Albeit lymphopenia, we observed an increase in the expression of CD28, co-stimulator molecule, and activation markers (CD38 and HLA-DR) in T-lymphocytes as well as an increase in the frequency of CD4+ T-cells, CD8+ T-cells, and NK cells that express the immunological checkpoint protein, PD-1, in patients with severe/critical condition compared to healthy controls. Regarding the cytotoxic profile of peripheral blood mononuclear cells, an increase in the response of CD4+ T-cells already at baseline level was observed, scarcely changed upon PMA and Ionomycin stimulation. Meanwhile, CD8+ T-lymphocytes decreased cytotoxic response, evidencing a profile of exhaustion in patients with severe COVID-19. As observed in the t-SNE technique CD4+ T-cytotoxic and CD8+ T with low granzyme production evidencing their dysfunctionality in severe/critical conditions. In addition, purified CD8+ T-lymphocytes from patients with severe COVID-19 showed an increased constitutive expression of differentially expressed genes associated with the caspase pathway, inflammasome, and antiviral factors, and curiously, reduced expression of TNF-α. The cytotoxic profile, by CD4+ T-cells, may compensate for the dysfunction/exhaustion of TCD8+ in acute SARS-CoV-2 infection. These findings may provide an understanding of the interplay of cytotoxicity between CD4+ T-cells and CD8+ T-cells in the severity of acute COVID-19 infection.

In this paper we prove that if the product $X^{n}$ of a space $X$ has some tightness-type properties, then the space of permutation degree ${\sf SP^{n}}X$ also has these properties. It is proved that the set tightness (resp. $T$-tightness) of the space of permutation degree ${\sf SP^{n}}X$ is equal to the set tightness (resp. $T$-tightness) of the product $X^{n}$.

Background and Aim. Since virus-related hepatocellular carcinoma (HCC) pathogenesis involves liver inflammation, therefore, post-hepatitis C virus (HCV) infection would be a cause for liver cirrhosis that would progress to HCC. Cytotoxic T cells (Tc) are known to be involved in post-HCV complications and HCC pathogenesis. The inhibitory checkpoint Leukocyte-Associated Immunoglobulin-like Receptor-1 (LAIR-1) is expressed on Tc. Therefore, we aimed to determine whether the Tc expression level of LAIR-1 is associated with HCC progression post-HCV and moreover, to evaluate LAIR-1 expression as a non-invasive biomarker for HCC progression in the context of liver cirrhosis post-HCV genotype 4 (G4) in Egyptian patients’ peripheral venous blood liquid biopsy. We studied LAIR-1 expression on Tc related to the progression of liver cirrhosis in a case-controlled study enrolled 64 patients with post-HCV G4-HCC and 37 patients with post-HCV G4-liver cirrhosis. Methods: LAIR-1 expression was analyzed by flow cytometry. Results: LAIR-1 expression on Tc and the percentage of Tc positive for LAIR-1 (LAIR-1+Tc %) were significantly higher in the post-HCV G4-HCC group compared to the post-HCV G4-liver cirrhosis

We obtain exact solutions to the field equations for 5 dimensional LRS Bianchi type-I spacetime in $f(R,T)$ theory of gravity where specifically the following three cases are considered: (i) $f(R,T)=\mu(R+T)$, (ii) $f(R,T)=R \mu + R T \mu^2$ and (iii) $f(R,T)=R+\mu R^2+\mu T$ where $R$ and $T$ respectively the Ricci scalar and trace of the energy-momentum tensor. It is found that the equation of state (EOS) parameter $w$ is governed by the parameter $\mu$ involved in the $f(R,T)$ expressions. We fine-tune the parameter $\mu$ to obtain effect of phantom energy in the model, however we also restrict this parameter to obtain a stable model of the universe. It is noted that the model isotropizes at finite cosmic time.

Six-Transmembrane Epithelial Antigen of the Prostate 1-4 (STEAP1-4) compose a family of metalloproteinases involved in iron and copper homeostasis and other cellular processes. Thus far, five homologs are known: STEAP1, STEAP1B, STEAP2, STEAP3, and STEAP4. In prostate cancer, STEAP1, STEAP2, and STEAP4 are overexpressed while STEAP3 expression is downregulated. Although the metalloreductase activities of STEAP1-4 are well-documented, their other biological functions are not. Furthermore, the properties and expression levels of STEAP heterotrimers, homotrimers, heterodimers, and homodimers are not well-understood. Nevertheless, studies over the last few decades have provided sufficient impetus to investigate STEAP1-4 as potential biomarkers and therapeutic targets for prostate cancer. In particular, STEAP1 is the target of many emerging immunotherapies. Herein, we give an overview of the structure, physiology, and pathophysiology of STEAP1-4 to provide context for past and current efforts to translate STEAP1-4 into the clinic.

Malaria comprises a spectrum of disease syndromes and the immune system is a major participant in malarial disease. This is particularly true in relation to the immune responses elicited against blood stages of Plasmodium-parasites that are responsible for the pathogenesis of infection. Mouse models of malaria are commonly used to dissect the immune mechanisms underlying disease. While no one mouse model of Plasmodium infection completely recapitulates all the features of malaria in humans, collectively the existing models are invaluable for defining the events that lead to the immunopathogenesis of malaria. Here we review the different mouse models of Plasmodium infection that are available, and highlight some of the main contributions these models have made with regards to identifying immune mechanisms of parasite control and the immunopathogenesis of malaria.

Therapeutic vaccine studies should be designed to elicit durable, high magnitude, and efficacious T cell responses, all of which can be impacted by the choice of vaccination schedule. Here, we compare different prime-boost intervals (PBI) in a human papillomavirus (HPV) model using HPV16E6E7 Venezuelan equine encephalitis virus replicon particle (VRP) vaccination to address the optimal boosting schedule, quality of immune response, and overall in vivo efficacy. Six different vaccine regimens were tested with each group receiving booster vaccinations at different time intervals. Analysis of T-cell responses demonstrated a significant HPV16 E7 specific CD8+T cell response with minimally a one-week PBI between antigen re-exposure. Significant E7-specific in vivo cytotoxicity was also observed with longer PBIs. Additionally, longer PBIs led to an enhanced memory recall response to tumor challenge, which correlated with differential expansion of T cell memory subsets. Our findings imply that when using alphavirus vector platforms as a vaccination strategy, a one-week PBI is sufficient to induce high magnitude effector T cells with potent anti-tumor activity. However, longer PBIs lead to enhanced long-term protective anti-tumor immunity. These findings have implications for therapeutic vaccine clinical trials in which shorter intervals of prime-boost regimens may lead to suboptimal durable immune responses.

The importance of a properly regulated immune response has been explored through various research-oriented methods. It has proved that having an effective and well-regulated immune response helps prevent many minors and serious diseases. Any kind of dysregulation in the working of the immune system may lead to severe consequences. An autoimmune disorder is one such consequence in which the component of the immune system starts targeting self-cells of the body, treating them as self-antigen producing autoantibodies and immune complexes resulting from the failure of immune responses both at a central and peripheral level. Currently, many autoimmune disorders are prevailing across the world, and new diseases need attention.In this review, we have written about the functions of T cell, LncRNAs and also some interactions between the LncRNAs and miRNAs in the pathogenesis of Multiple sclerosis (MS), Systemic lupus erythematosus (SLE), Type 1 diabetes (T1D), Rheumatoid arthritis (RA). To find the functions of these autoimmune disorders we have done intensive literature search during this we also found that GAS5 and MALAT are common in MS, SLE, T1D, RA. And finally, we have also mentioned the therapeutic drugs which neutralizes the different cluster of differentiation (CDs) and also suppresses the T cell differentiation in MS, SLE and RA. For T1D therapeutic strategies and various types of insulin are mentioned.

Like living organisms, cancer cells require energy to survive and interact with their environment. Mitochondria are the main organelles for energy production and cellular metabolism. Recently, investigators demonstrated that cancer cells can hijack mitochondria from immune cells. This behavior sheds light on a pivotal piece in the cancer puzzle, the ‘dependence’ on the normal cells. This article illustrates the benefits of new, functional mitochondria for cancer cells that urge them to hijack mitochondria. It describes how functional mitochondria help cancer cells’ survival in the harsh tumor microenvironment, immune evasion, progression, and treatment resistance. Recent evidence has put forward the pivotal role of mitochondria in cancer stem cells’ metabolism. This theory highlights the mitochondria in cancer biology and explains how targeted anti-mitochondrial treatments can improve oncological outcomes.

In this paper, the concept of fuzzy locally convex spaces generated by a family of fuzzy seminorms is introduced. We prove that a Minkowski functional of zero neighborhoods generates a seminorm and finally deduce that the topology generated by the family of seminorms coincides with that of the Minkowski functional.

The complete regression of clear cell renal cell carcinoma (ccRCC) obtained pre-clinically with anti-carbonic anhydrase IX (CAIX) G36 chimeric antigen receptor (CAR) T cells in doses equivalent to 10e8 CAR T cells/ Kg renewed the potential of this target to treat ccRCC and other tumors in hypoxia. The immune checkpoint blockade (ICB) brought durable clinical responses in advanced ccRCC and other tumors. Here we tested CD8/4-1BB compared to CD28-based anti-CAIX CAR PBMCs cells-releasing anti-programmed cell death ligand-1 (PD-L1) IgG4 for human ccRCC treatment in vitro and in an orthotopic NSG mice model in vivo. Using a 10e7 CAR PBMCs cells/ Kg dose, anti-CAIX CD28 CAR T cells releasing anti-PD-L1 IgG highly decrease both tumor volume and weight in vivo, avoiding the occurrence of metastasis. This antitumoral superiority of CD28-based CAR PBMCs cells compared to 4-1BB occurred under ICB via PD-L1. Furthermore, T cell exhaustion status in peripheral CD4 T cells, additionally to CD8 was critical for CAR T cells efficiency. The lack of hepatotoxicity and nephrotoxicity upon administration of 10e7 CAR PMBCs cells/Kg dose is the basis for carrying out clinical trials using anti-CAIX CD28 CAR PBMCs cells releasing anti-PD-L1 antibodies or anti-CAIX 4-1BB CAR T cells, offering exciting new prospects for the treatment of refractory ccRCC and hypoxic tumors.

Inactivated SARS-CoV-2 vaccine (CoronaVac) is commonly used in national immunization programs. However, the immune response significantly declined within a few months. Our study assessed the immune response against SARS-CoV-2 after receiving booster shots of BNT162b2 or ChAdOx1 among health care workers who previously received CoronaVac as their primary immunization. Fifty-six participants received ChAdOx1 and forty-two participants received BNT162b2 were enrolled into this study which evaluated the immune responses including anti-SARS-CoV-2 spike total antibodies (Elecsys®), surrogated viral neutralization test (sVNT) to ancestral strain (cPass™; GenScript) and five variants of concern (Alpha, Beta, Gamma, Delta, and Omicron) (Luminex; multiplex sVNT) and the ELISpot with spike (S1 and S2) peptide pool against the ancestral SARS-CoV-2 strain. The samples were analyzed at baseline, 4, and 12 weeks after primary immunization as well as 4 and 12 weeks after receiving the booster. This study showed a significantly higher B-cell response among the BNT162b2 than the ChAdOx1 booster group, particularly against the Omicron variant, as well as a trend of good T-cell immune response in the BNT162b2 group. Moreover, the immune response rapidly declined at 12 weeks after the booster. A fourth dose or a second booster should be recommended, especially for reducing Omicron severity.

Triple-negative breast cancer (TNBC) is characterized by an active immune response. We evalu-ated intratumoral interrelation between FOXP3+ tumor-infiltrating lymphocytes and other cy-tokines in TNBC. Network analysis refined cytokines significantly correlate with FOPX3 in TNBC. Treatment response and prognosis imformation of patients and survival data from the TGCA and METABRIC databases were analyzed according to refined cytokines. Interleukin (IL)-33 was sig-nificantly expressed by TNBC cell lines than luminal cell lines (log2 fold change: 5.31, p <0.001) and IL-33 and TGFB2 showed a strong correlation with FOXP3 in the TNBC cell line. Immunohisto-chemistry demonstrated IL-33 high group was a significant predictor of complete response of neoadjuvant chemotherapy (odds ratio (OR) 4.12, p<0.05) and a favorable survival compared to IL-33 low group (OR 6.48, p<0.05) in TNBC. Survival data from TGCA and METABRIC revealed that FOXP3 was a significantly favorable marker in IL-33 high group com-pared to the low IL-33 low group (hazard ratio (HR) 2.1, p=0.02), and IL-33 high/TGFB2 high subgroup showed significant favorable prognosis in the FOXP3 high group compared to the FOPX3 low group in TNBC (HR 3.5, p=0.01). IL-33 and TGFB2 were key cytokines of intratumoral interrelation among FOXP3 in TNBC.

New setting is introduced to study co-neighborhood, neutrosophic t-neighborhood, neutrosophic quasi-vertex set, neutrosophic quasi-order, neutrosophic neighborhood, neutrosophic co-t-neighborhood, neutrosophic quasi-edge set, neutrosophic quasi-size, Neutrosophic number, neutrosophic co-neighborhood, co-neutrosophic number, quasi-number and quasi-co-number. Some classes of neutrosophic graphs are investigated.

To detect aberrant human behaviors from large volume of passive data collected by smartphones in real time, we propose an online anomaly detection method using Hotelling’s T-squared test. The test statistic is a weighted average, with more weight on the between-individual component when there are little data available for the individual and more weight on the within-individual component when the data are adequate. The algorithm takes only O(1) run time in each update and the required memory usage is fixed after a pre-specified number of updates. The performance of the proposed method, in terms of accuracy, sensitivity and specificity, is consistently better than or equal to the offline method that it builds upon depending on the sample size of the individual data.

Extracellular vesicles (EV) are a very heterogeneous group of cell-derived vesicles released by almost all kind of living cells. EV are involved in intercellular communication, both locally and systemically, since they induce signals and transfer their contents (proteins, lipids, RNAs) to other cells, which subsequently trigger a wide variety of biological responses in the target cells. How-ever, cell surface receptor-induced EV release is limited to cells from the immune system, includ-ing T lymphocytes. T cell receptor activation of T lymphocytes induces secretion of EV containing T cell receptor for antigen and several bioactive molecules, including proapoptotic proteins. These EV are thus specific for antigen-bearing cells, which make them ideal candidates for a cell-free, EV-dependent cancer therapy. In this review we discuss the generation of EV by T lymphocytes and some potential therapeutic approaches of these EV.

Our bodies produce a host of electrophilic species that can label specific endogenous proteins in cells. The signaling roles of these molecules are underactive debate. However, in our opinion it is becoming increasingly likely that electrophiles can rewire cellular signaling processes at endogenous levels. Attention is turning more to understanding how nuanced electrophile signaling in cells is. In this perspective, we describe recent work from our laboratory that has started to inform on different levels of context-specific regulation of proteins by electrophiles. We discuss the relevance of these data to the field, and to the broader application of electrophile signaling to precision medicine development, beyond the traditional views of their pleiotropic cytotoxic roles.

The aim of the studies was to test the hydraulic pressure losses along the length, local pressure losses, absolute and relative roughness values of the pipeline walls made of modern polymer material. The article presents the results of the experimental studies of hydraulic resistance of pipelines from modern polymer materials, the method of theoretical determination of resistance coefficients in the VALTEC ISO 21003 metal polymer pipeline, the classification and method of determining the values of local hydraulic resistance coefficients of T-Junctions are given, the dependence for determining the Darcy λ hydraulic friction coefficient associated with the value of the equivalent hydraulic roughness coefficient of the inner surface of pipes and the Reynolds number. The experimental data of the hydraulic coefficient of friction Darcy λ was compared with the known theoretical relationships of A.D. Altschul, Colbrooke for smooth pipes, Colbrooke and White, an alternative to the Colbrooke-White, Offengenden equation for low-shear pipes and pipes from polymer materials with Reynolds numbers Re>10^4. Dependence of hydraulic coefficient of friction on relative equivalent roughness of pipeline walls and Reynolds number, specific energy loss per one linear meter on total flow rate in system of hydraulically short pipeline is obtained. The empirical dependence of values of coefficients of local resistance ζ=f(Q2/Q3) from a ratio of the divided expenses of Q2/Q3 of the equal-pass T-Junction α=90 the pipeline to a branch up, on pass in the direct T-Junction and division of streams at various internal pipeline diameters of VALTEC.

An overview of the chemical compounds forming the rare smectic T phases is cited with references to the historical context. Thermodynamics (transition temperatures, enthalpies) along with the factors (stereochemical constraints, electrostatic interactions, aliphatic chain stacking, intermolecular forces) contributing to the adoption of tetragonal scaffolds are also discussed. Characteristic optical microscopy textures and x-rays diffraction patterns are presented. In parallel, a comparison of the geometrical parameters such as distances between atoms, molecular areas, volumes, and lattice parameters with the closest two-dimensional and three-dimensional organizations, is performed.

Adaptive T cell immunotherapy holds great promise for the successful treatment of leukemia as well as other types of cancers. More recently, it was also shown to be an effective treatment option for chronic virus infections in immunosuppressed patients. Autologous or allogeneic T cells used for immunotherapy are usually genetically modified to express novel T cell or chimeric antigen receptors. The production of such cells was significantly simplified with the CRISPR/Cas system allowing deletion or insertion of novel genes at specific locations within the genome. In this review, we describe recent methodological breakthroughs important for the conduction of these genetic modifications, summarize crucial points to be considered when conducting such experiments, and highlight the potential pitfalls of these approaches.

Hospital-based programs democratize mRNA therapeutics by facilitating the processes to translate a novel RNA idea from the bench to the clinic. Because mRNA is essentially biological software, therapeutic RNA constructs can be rapidly developed. The generation of small batches of clinical grade mRNA to support IND applications and first-in-man clinical trials, as well as personalized mRNA therapeutics delivered at the point-of-care, is feasible at a modest scale of cGMP manufacturing. Advances in mRNA manufacturing science and innovations in mRNA biology, are increasing the scope of mRNA clinical applications.

Though early-stage colorectal cancer has a high 5-year survival rate of 65-92% depending on the specific stage, this probability drops to 13% after the cancer metastasizes. Frontline treatments for colorectal cancer such as chemotherapy and radiation often produce dose-limiting toxicities in patients and acquired resistance in cancer cells. Additional targeted treatments are needed to improve patient outcomes and quality of life. Immunotherapy involves treatment with peptides, cells, antibodies, viruses, or small molecules to engage or train the immune system to kill cancer cells. Preclinical and clinical investigations of immunotherapy for treatment of colorectal cancer including immune checkpoint blockade, adoptive cell therapy, monoclonal antibodies, oncolytic viruses, anti-cancer vaccines, and immune system modulators have been promising, but demonstrate limitations for patients with proficient mismatch repair enzymes. In this review, we discuss preclinical and clinical studies investigating immunotherapy for treatment of colorectal cancer and predictive biomarkers for response to these treatments. We also consider open questions including optimal combination treatments to maximize efficacy, minimize toxicity, and prevent acquired resistance and approaches to sensitize mismatch repair proficient patients to immunotherapy.

The domestic pig (Sus scrofa) is a species representative of the Suina, one of the four suborders within Cetartiodactyla. In this paper, we reported our analysis of the pig TRG locus in comparison with the loci of species representative of the Ruminantia, Tylopoda and Cetacea suborders. The pig TRG genomic structure reiterates the peculiarity of the organization of Cetartiodactyla loci in TRGC “cassettes”, each containing the basic V-J-J-C unit. Eighteen genes arranged in four TRGC cassettes, form the pig TRG locus. All the functional TRG genes were expressed, and the TRGV genes preferentially rearrange with the TRGJ genes within their own cassette, which correlates the diversity of the gamma-chain repertoire with the number of cassettes. Among them, the TRGC5, located at the 5’ end of the locus, is the only cassette that retains a marked homology with the corresponding TRGC cassettes of all the analyzed species. The preservation of the TRGC5 cassette for such a long evolutionary time presumes a highly specialized function of its genes, which could be essential for the survival of species. Therefore, the maintenance of this cassette in pigs confirms that it is the most evolutionarily ancient within Cetartiodactyla, and it has undergone a process of duplication to give rise to the other TRGC cassettes in the different artiodactyl species in a lineage-specific manner.

Hepatitis B virus (HBV) is known to cause severe liver diseases such as acute or chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Chronic hepatitis B (CHB) infection is a major health problem with nearly 300 million individuals infected worldwide. Currently, nucleos(t)ide analogs (NAs) and interferon alpha are clinically approved treatments for HBV infection. NAs are potent antiviral agents that bind to HBV polymerase and block viral reverse transcription and replication. Besifovir dipivoxil maleate (BSV) is a newly developed NA against HBV in the form of acyclic nucleotide phosphonate that is available for oral administration similar to adefovir and tenofovir. Until now, resistance to BSV treatment has not been reported. In this study, we found a CHB patient who showed viral breakthrough after long-term treatment with BSV. The isolated HBV DNA from patient’s serum were cloned into the replication-competent HBV 1.2mer and the sequence of reverse transcriptase (RT) domain of HBV polymerase were analyzed. We also examined the drug susceptibility of generated clones in vitro. Several mutations were identified in HBV RT domain. A particular mutant harboring ten RT mutations showed resistance to BSV treatment in vitro. The ten mutations include rtV23I (I), rtH55R (R), rtY124H (H), rtD134E (E), rtN139K (K), rtL180M (M), rtM204V (V), rtQ267L (L), rtL269I (I) and rtL336M (M). To further identify the responsible mutations for BSV resistance, we performed in vitro drug susceptibility assay on several artificial clones. As a result, our study revealed that rtL180M (M) and rtM204V (V) mutations, already known as lamivudine-resistant mutations, confer resistance to BSV in the CHB patient.

Background: Takayasu Arteritis (TAK) increases vascular stiffness and arterial resistance. Hypertension and atherosclerosis lead to similar changes. We investigated possible differences in cardiovascular remodeling between these diseases and whether the differences are correlated with immune cell expression. Methods: Patients with active TAK arteritis were compared with age- and sex-matched hypertensive and atherosclerotic patients. In a subpopulation of TAK patients, Treg/Th17 cells were measured before (T0) and after 18 months (T18) of infliximab treatment. Echocardiogram, supraaortic Doppler ultrasound, and lymphocytogram were performed in all patients. Histological and immunohistochemical evaluation of the vessel wall was performed to compare the in vivo results. Results: TAK patients have increased aortic valve dysfunction and diastolic dysfunction. These data have been associated with uric acid levels. A significant increase in aortic stiffness was also noted and associated with peripheral T lymphocyte levels. CD3+CD4+ cell infiltrates were detected in the vessel wall samples of these patients. They had a lower mean percentage of Tregs at T0 than controls, but levels increased significantly at T18. Opposite results were found in Th17 cells. Finally, TAK patients were found to have an increased risk of atherosclerotic cardiovascular disease (ASCVD). Conclusion: Our data suggest that different pathogenic mechanisms of vessel damage, including atherosclerosis, underlie TAK patients compared with control subjects. The increased risk of ASCVD in TAK patients correlates directly with the degree of inflammatory cell infiltration in the vessel wall. Infliximab restores the normal frequency of Tregs/Th17 in TAK patients and allows a possible reduction of steroids and immunosuppressants.

Findings of new targeted treatments with adequate safety evaluations is essential for better cancer cures and mortality rates. Immunotherapy holds promise for patients with relapsed disease, with the ability to elicit long-term remissions. Emerging promising clinical results in B-cell malignancy using gene-altered T-lymphocytes uttering chimeric antigen receptors have sparked a lot of interest. This treatment could open the path for a major difference in the way we treat tumors that are resistant or recurring. Genetically altered T cells used to produce tumor-specific chimeric antigen receptors are resurrected field of adoptive cell therapy by demonstrating remarkable success in the treatment of malignant tumors. Because of the molecular complexity of chimeric antigen receptors -T cells, a variety of engineering approaches to improve safety and effectiveness are necessary to realize larger therapeutic uses. In this study, we investigate at new strategies for enhancing chimeric antigen receptors-T cell therapy by altering chimeric antigen receptors proteins, T lymphocytes, and their relations with other solid tumor microenvironment (TME) aspects.

Carboxypeptidase A4 (CPA4) has shown the potential possibility as a biomarker in the early diagnosis for certain cancers. However, no previous research has linked CPA4 to therapeutic or prognostic significance in bladder cancer. Using data from The Cancer Genome Atlas (TCGA) database, we set out to determine the full extent of the link between CPA4 and BLCA. We further analyzed the interacting proteins of CPA4 and infiltrated immune cells via TIMER2，STRING and GEPIA2 databases. The expression of CPA4 in tumor and normal tissues was compared using the TCGA+GETx database. The connection between CPA44 expression and clinicopathologic characteristics and overall survival (OS) was investigated using multivariate methods and Kaplan-Meier survival curves. The potential functions and pathways were investigated via gene set enrichment analysis. Furthermore, we analyze the associations between CPA4 expression and infiltrated immune cells with their respective gene marker sets using the ssGSEA, TIMER2, and GEPIA2 databases. Compared to matching normal tissues, human CPA4 was found to be substantially expressed. We confirmed that overexpression of CPA4 is linked with shorter OS, DSF, PFI, and increased diagnostic potential using Kaplan-Meier and ROC analysis. The expression of CPA4 is related to T-bet, IL12RB2, CTLA4, and LAG3, among which T-bet and IL12RB2 are Th1 marker genes, while CTLA4 and LAG3 are related to T cell exhaustion, which may be used to guide the application of checkpoint blockade and the adoption of T cell transfer therapy.

Targeted radionuclide therapy (TRT) has recently seen a surge in popularity, with the use of radionuclides conjugated to small molecules and antibodies. Similarly, immunotherapy also has shown promising results – an example being chimeric antigen receptor (CAR) T-cells therapy in hematologic malignancies. Moreover, TRT and CAR T therapies possess unique features that require special consideration when determining how to dose, time, and sequence combination treatments, including the distribution of TRT dose in the body, the decay rate of the radionuclide, and the proliferation and persistence of the CAR-T cells. These characteristics complicate additive or synergistic effects of combination therapies and warrant a mathematical treatment which includes these dynamics in relation to the proliferation and clearance rates of the target tumor cells. Here we combine two previously published mathematical models in a multiple myeloma setting to explore the effects of dose, timing, and sequencing of TRT and CAR-T cell based therapies. We find that for a fixed TRT and CAR-T cell dose, the tumor proliferation rate is the most important parameter in determining the best timing of TRT and CAR T therapies.

Multiple Myeloma (MM) is one of the incurable types of cancer in plasma cells. While immense progress has been made in the treatment of this malignancy, a large percentage of patients were unable to adapt to such therapy. Additionally, these therapies might be associated with significant diseases and are not always tolerated well in all patients. Since cancer in plasma cells has no cure, patients develop resistance to treatments, resulting in R/R MM. BCMA is primarily produced on mature B cells. Its up-regulation and activation are associated with multiple myeloma in both murine and human models, indicating that this might be an effective therapeutic target for this type of malignancy. Additionally, BCMA's predictive value, association with effective clinical trials, and capacity to be utilized in previously difficult to observe patient populations, imply that it might be used as a biomarker for multiple myeloma. Numerous kinds of BCMA-targeting medicines have demonstrated antimyeloma efficacy in individuals with refractory/relapsed MM, including CAR T-cell treatments, ADCs, bispecific antibody constructs. Among these medications, CART cell-mediated BCMA therapy has shown significant outcomes in multiple myeloma clinical trials. This review article outlines CAR T cell mediated BCMA medicines have the efficiency to change the therapeutic pattern for multiple myeloma significantly.

Visceral Leishmaniasis is a neglected tropical disease affecting 12 million people annually. Even in the second decade of the 21st century, it has remained without an effective vaccine for human use. In the current study, we have designed three multiepitope vaccine candidates by the selection of multiple IFN-γ inducing MHC-I and MHC-II binder T-cell specific epitopes from 3 previously identified antigen genes of Leishmania donovani from our lab, by immune-informatic approach using IFNepiotpe, NET-MHC-1 and NET MHC-2 webservers. We have tested the protective potential of these three multiepitope proteins as vaccine in a hamster model of visceral leishmaniasis. The immunization data revealed that the vaccine candidates induced a very high level of Th-1 biased protective immune response in-vivo in a hamster model of experimental visceral Leishmaniasis, with one of the candidates inducing a sterile immunity. The vaccinated animals displayed highly activated monocyte macrophages with the capability of clearing intracellular parasites due to increased respiratory burst. Additionally, these proteins induced activation of polyfunctional T cells secreting INF-γ, TNF-α, and IL-2 in ex-vivo stimulation of human peripheral blood mononuclear cells, further supporting the protective nature of designed candidates.

Superantigens are unconventional antigens which recognise immune receptors outside the usual binding sites e.g. complementary determining regions (CDRs), to elicit a response within the target cell. T-cell superantigens crosslink T-cell receptors and MHC Class II molecules on antigen-presenting cells, leading to lymphocyte recruitment, induction of cytokine storms and T-cell anergy or apoptosis among many other effects. B-cell superantigens, on the other hand, bind immunoglobulin receptors on B-cells affecting opsonisation, IgG-mediated phagocytosis, and drive B-cells into apoptosis. Here, through a review of the structural basis for recognition of immune receptors by superantigens, we show that their binding interfaces share specific physicochemical characteristics when compared with other protein-protein interaction complexes. Given that antibody-binding superantigens have been exploited extensively in industrial antibody purification, these observations could facilitate further protein engineering to optimize the use of superantigens in this and other areas of biotechnology.

Novel Cellular Immunotherapy with engineered T cells has improved cancer treatment and established therapeutic promises to prevent tumor formation in clinical studies. Due to certain restrictions and difficulties, CAR and TCR T cells therapies were inadequate at points. CRISPR Cas9 genome-editing tool has a significant potential for these two cell-based therapies. As a specialized gene-editing technique, CRISPR Cas9 is used to repair genetic alternation with minimum damage. It is used as an adjunct to Immunotherapy to stimulate a more robust immune response. CRISPR has long outpaced other target-specific genome editing methods such as ZFNs and TALEN due to its high efficiency, competence in targeting, and stable operating condition. CRISPR can overcome the two major drawbacks of universal CAR T cells: allorejection and graft-vs-host disease. TCR-based T cell treatment can reduce inappropriate binding between endogenous and transgenic TCR, resulting in a reduction of severe toxicity. The CAR and TCR T based cell therapies uphold an excellent future for tumor malignancies This article has elucidated the administration of CRISPR Cas9 in Novel Cellular Immunotherapy, CAR, and TCR T cell therapy. However, this article did not fail to observe this technology's ethical concerns, limitations, and challenges. Furthermore, the article compares CRISPR-mediated allogeneic CAR T cell to TCR-T cell therapy.

Naive CD4+ T cells engage cognate peptide MHC-II complexes (pMHC-IIs) to differentiate and acquire one of several T helper (Th) fates whose specific trajectories are guided by a dynamic cytokine milieu that develops in response to antigenic entity. This physiological process is often erroneously conflated with a pathological one termed Th polarization. Using the SPIRAL model, we argue here that unlike Th fate choice, innate signaling alone is insufficient to initiate Th polarization in naive CD4+ T cells, that it instead develops from pre-existing memory CD4+ T cells that express cross-reactive TCRs, and that it inevitably leads to immunopathology.

The analytical method for the calculation of the properties of a bolted connection established by the structural Eurocodes proposes the T-stub as a component for the characterization of the tension and compression zones in moment joints. In this article, a review of the state of the art on the T-stub component is developed, where the works developed since it was initially defined, and from the perspectives of formulation, experimentation and numerical simulation are summarized and discussed. Additionally, possible future lines of work are proposed.

Human Rhinovirus (HRV) is the most common cause of upper respiratory infections and exacerbations of asthma. In this work, we selected 14 peptides (6 from HRV A and 8 from HRV C) encompassing potential CD4 T cell epitopes. Peptides were selected for being highly conserved in HRV A and C serotypes and predicted to bind to multiple HLA II molecules. We found positive T cell recall responses by IFNγ-ELISPOT assays to 8 peptides, validating 7 of them (3 from HRV A and 4 from HRV C) as CD4 T cell epitopes through intracellular cytokine staining assays. Additionally, we verified their promiscuous binding to multiple HLA II molecules by quantitative binding assays. According to their experimental HLA II binding profile, the combination of all these 7 epitopes could be presented and recognized by > 95 % of the world population. We actually determined IFNγ responses to a pool encompassing these CD4 T cell epitopes by intracellular cytokine staining, finding positive responses in 29 out of 30 donors. The CD4 T cell epitopes identified in this study could be key to monitor HRV infections and to develop peptide-based vaccines against most HRV A and C serotypes.

Solid tumor cells have an altered metabolism that can protect them from cytotoxic lymphocytes. The antidiabetic drug metformin modifies tumor cell metabolism and several clinical trials are testing its effectiveness for the treatment of solid cancers. The use of metformin in hematologic cancers has received much less attention, although allogeneic cytotoxic lymphocytes are very effective against these tumors. We show here that metformin induces expression of Natural Killer G2-D (NKG2D) ligands (NKG2DL) and intercellular adhesion molecule-1 (ICAM-1), a ligand of the lymphocyte function-associated antigen 1 (LFA-1). This leads to enhance sensitivity to cytotoxic lymphocytes. Overexpression of antiapoptotic Bcl-2 family members decrease both metformin effects. The sensitization to activated cytotoxic lymphocytes is mainly mediated by the increase on ICAM-1 levels, which favors cytotoxic lymphocytes binding to tumor cells. Finally, metformin decreases the growth of human hematological tumor cells in xenograft models, mainly in presence of monoclonal antibodies that recognize tumor antigens. Our results suggest that metformin could improve cytotoxic lymphocyte-mediated therapy.

Chimeric antigen receptor and T-cell receptor (CAR-T/TCR) cellular immunotherapies have shown remarkable success in the treatment of some refractory B-cell malignancies, with potential to provide durable clinical response for other types of cancer. In this paper, we look at all available FDA CAR-T/TCR clinical trials for the treatment of cancer, and analyze them with respect to different disease tissues, targeted antigens, products, and originator locations. We found that 627 of 1,007 registered are currently active and of those 273 (44%) originated in China and 280 (45%) in the US. Our analysis suggests that the rapid increase in the number of clinical trials is driven by the development of different CAR-T products that use a similar therapeutic approach. We coin the term bioparallels to describe such products. Our results suggest that one feature of the CAR-T/TCR industry may be a robust response to success and failure of competitor products.

Staphylococcus aureus mastitis remains a major challenge for dairy farming. Here, 24 mice were immunized and divided into four groups: G1: control; G2: Granulocyte Macrophage Colony-Stimulating Factor (GM-CSF) DNA vaccine; G3: F0F1 ATP synthase subunit α (SAS), succinyl-diaminopimelate (SDD), and cysteinyl-tRNA synthetase (CTS) recombinant proteins; and G4: SAS+SDD+CTS plus GM-CSF DNA vaccine. The lymphocyte subpopulations and the intracellular interleukin-17A (IL-17A) and interferon-γ production in the draining lymph node cells were immunophenotyped by flow cytometry. The immunophenotyping and lymphocyte proliferation was determined in spleen cells cultured with and without S. aureus stimulus. Immunization with S. aureus recombinant proteins generated memory cells in draining lymph nodes. Immunization with the three recombinant proteins plus GM-CSF DNA led to an increase in the percentage of IL-17A+ cells among overall CD44+ (memory), T CD4+, CD4+ T CD44+ CD27-, γδ TCR, γδ TCR+ CD44+ CD27+ and TCRVγ4+ cells. Vaccination with S. aureus recombinant proteins associated with GM-CSF DNA vaccine downregulates TH2 immunity. Immunization with the three recombinant proteins plus the GM-CSF DNA led to a proliferation of overall memory T, CD4+ and CD4+ TEM cells upon S. aureus stimulus. This approach fostered type 3 immunity, suggesting the development of a protective immune response against S. aureus.

Prostaglandin E2 (PGE2) is an important biological mediator involved in the defense against Mycobacterium tuberculosis (Mtb) infection. Currently, there are no reports on the mycobacterial components that regulate PGE2 production. Previously, we have reported that RpfE-treated dendritic cells (DCs) effectively expanded the Th1 and Th17 cell responses simultaneously; however, the mechanism underlying Th1 and Th17 cell differentiation is unclear. Here, we show that PGE2 produced by RpfE-activated DCs via the MAPK and cyclooxygenase 2 signaling pathways induces Th1 and Th17 cell responses mainly via the EP4 receptor. Furthermore, mice administered intranasally with PGE2 displayed RpfE-induced antigen-specific Th1 and Th17 responses with a significant reduction in bacterial load in the lungs. Furthermore, the addition of optimal PGE2 amount to IL-2-IL-6-IL-23p19-IL-1β was essential for promoting differentiation into Th1/Th17 cells with strong bactericidal activity. These results suggest that RpfE-matured DCs produce PGE2 that induces Th1 and Th17 cell differentiation with potent anti-mycobacterial activity.

Background: CD169 has been found overexpressed in the blood of COVID-19 patients and identified as a biomarker in the early disease. We have analysed CD169 in blood cells of COVID-19 patients to assess its role as predictive marker of the disease. Methods : The ratio of the CD169 Median median Fluorescence fluorescence Intensity intensity of CD169 between monocytes and lymphocytes (CD169 RMFI ) was analysed by flow cytometry in blood samples of COVID-19 patients (COV) and healthy donors (HD ) and correlated with immunophenotyping, inflammatory markers, cytokines mRNA expression, pulmonary involvement and disease progression. Results: CD169 RMFI increased in COV but not in HD. CD169 RMFI correlated with T-cell differentiation and exhaustion markers as well as with B cells maturation and differentiation. In vitro stimulation of PBMCs of HD with SARS-CoV-2 Spike spike protein induced CD169 RMFI together with IL-6 and IL-10 gene expression. Likewise, CD169 RMFI correlated with blood cytokine mRNA levels, inflammatory markers, and pneumonia severity in patients which that had not received any treatment at sampling. Notably, in untreated patients, CD169 RMFI reflected the respiratory outcome during hospitalization. Conclusion : Considering the immunological role of CD169 and its involvement during the infection and the progression of COVID-19, it could be considered as an early biomarker to evaluate disease progression and clinical outcome.

In this tutorial review, we compare and contrast the chemical mechanisms of electrophile/oxidant sensing, and the molecular mechanisms of signal propagation. We critically analyze biological systems in which these different pathways are believed to be manifest and what the data really mean. Finally, we discuss applications of this knowledge to disease treatment and drug development.

Chimeric Antigen Receptor (CAR) T-cell therapy has demonstrated high rates of response in recurrent B-cell Acute Lymphoblastic Leukemia in children and young adults. Despite this success, a fraction of patients experience relapse after treatment. Relapse is often preceded by recovery of healthy B cells, which suggests loss or dysfunction of CAR T cells in bone marrow. This site is harder to access, and thus is not monitored as frequently as peripheral blood. Understanding the interplay between B cells, leukemic cells and CAR T cells in bone marrow is paramount in ascertaining the causes of lack of response. In this paper, we put forward a mathematical model representing the interaction between constantly renewing B cells, CAR T cells and leukemic cells in the bone marrow. Our model accounts for the maturation dynamics of B cells and incorporates effector and memory CAR T cells. The model provides a plausible description of the dynamics of the various cellular compartments in bone marrow after CAR T infusion. After exploration of the parameter space, we found that the dynamics of CAR T product and disease were independent of the dose injected, initial B-cell load and tumor burden. We also show theoretically the importance of CAR T product attributes in determining therapy outcome, and have studied a variety of possible response scenarios, including second dosage schemes. We conclude by setting out ideas for the refinement of the model.

Abstract:Shown is the derivation of Lorentz-Einstein k-factor in SRT as an amplitude-term of oscillation-differential equations of second order.This case is shown for classical Lorentz-factor as solution of an equation for undamped oscillation as well as the developed theorem as a second solution for advanced SRT of fourth order with an equation for damped oscillation-states.This advanced term allows a calculation for any velocities by real rest mass

HLA class-I (HLA-I) polyreactive monoclonal antibodies (mAbs) reacting to all HLA-I alleles were developed by immunizing HLA-E monomeric heavy chain (HC) (Open Conformers, OCs). Two of the mAbs (TFL-006 and TFL-007) bound to the HC’s coated on a solid matrix. The binding was inhibited by a peptide 117AYDGKDY123, present in all alleles of the six HLA-I isoforms but masked by 2-microglobulin -m) in intact HLA-I trimers (Closed Conformers, CCs). Identical HLA-I polyreactivity is observed in IVIg administered to lower anti-HLA antibodies (Abs) in HLA-sensitized patients, but the mechanism is unknown. We hypothesized that the mAbs that mimic IVIg HLA-I polyreactivity might mimic the immunomodulatory functions of IVIg. We tested the relative binding affinity of the mAbs and IVIg for both OCs- and CCs and compared their effects on (a) the phytohemagglutinin (PHA)-activation T-cells, (b) the production of anti-HLA-II antibody (Ab) by B-memory cells, and anti-HLA-I Ab by immortalized B-cells, and (c) the upregulation of CD4+, CD25+, and Fox P3+ T-regs. The mAbs bound only to OCs, whereas IVIg is bound to both CCs and OCs. The mAbs suppressed blastogenesis and proliferation of PHA-activated T-cells, anti-HLA Ab production by B-cells and expanded the T-regs, better than IVIg. We conclude that a humanized version of the TFL-mAbs could be an ideal therapeutic IVIg-mimetic.

The mechanisms involved in immune responses to cancer have been extensively studied for several decades and, considerable attention has been paid to harnessing the immune system's therapeutic potential. Cancer immunotherapy has established itself as a promising new treatment option for a variety of cancer types. Various strategies including cancer vaccines, monoclonal antibodies (mAbs), adoptive T-cell-cancer therapy and immune test therapy have gained prominence through immunotherapy. However, it remains to be accomplished the full potential of cancer immunotherapy. In spite of having startling aspects, the cancer immunotherapies have some difficulties including the inability to effectively targeting the cancer antigens and the abnormalities in patient response. With the advancement of technology, this system has changed the genome-based immunotherapy process in the human body including generation of engineered T cells. Due to its high specificity, CRISPR-Cas9 has become a simple and flexible genome-editing tool to target nearly any genomic locus. Recently, the CD19-mediated CAR-T cell (chimeric antigen receptor T cell) therapy has opened a new avenue for the treatment of human cancer, though low efficiency is a major drawback of this process. Thus, increasing the efficiency of the CAR-T cell (engineered T cells that induce the chimeric antigen receptor) by using CRISPR-Cas9 technology could be a better weapon to fight against the cancer. In this review, we have broadly focused on the use of CRISPR-Cas9 technology for the modification of the T-cell, which can specifically recognize cancer cells and be used as immune therapeutics against cancer. We have also demonstrated the other potential strategies for the treatment of cancer.

Recent evidence has highlighted the critical role of memory cells in maintaining lifelong food allergies, thereby identifying these cells as therapeutic targets. IgG⁺ memory B cells replenish pools of IgE-secreting cells upon allergen exposure, which contract thereafter due to the short lifespan of tightly regulated IgE-expressing cells. Advances in the detection and highly dimensional analysis of allergen-specific B and T cells from allergic patients have provided insight on their phenotype and function. The newly identified Th2A and Tfh13 populations represent a leap in our understanding of allergen-specific T cell phenotypes, though how these populations contribute to IgE memory responses remains poorly understood. Within, we discuss the mechanisms by which memory B and T cells are activated, integrating knowledge from human systems and fundamental research. We then focus on memory reactivation; specifically, on the pathways of secondary IgE responses. Throughout, we identify areas of future research which will help identify immunotargets for a transformative therapy for food allergy.

During their complex life cycles, the Apicomplexan parasites, Plasmodium falciparum and Toxoplasma gondii employ several genetic switches to regulate their gene expression. One such switch is mediated at the level of translation through upstream Open Reading Frames (uORFs). As uORFs are found in the upstream regions of a majority of genes in both the parasites, it is essential that their roles in translational regulation be appreciated to a greater extent. This review provides a comprehensive summary of studies that show uORF-mediated gene regulation in these parasites and highlights examples of clinically and physiologically relevant proteins that exhibit uORF-mediated regulation. In addition to these examples, several studies that use bioinformatics, transcriptomics, proteomics, and ribosome profiling also indicate the possibility of widespread translational regulation by uORFs. Further analysis of genome-wide datasets will reveal novel genes involved in key biological pathways such as cell-cycle progression, stress-response, and pathogenicity. The cumulative evidence from studies presented in this review suggests that uORFs will play crucial roles in regulating gene expression during clinical disease caused by these important human pathogens.

Anti-CD19 chimeric antigen receptor (CAR) T-cells represent a novel immunotherapy that has shown remarkable success in the treatment of adult relapsed or refractory (R/R) B-cell non-Hodgkin's lymphoma, adult R/R mantle cell lymphoma, and R/R acute paediatric lymphoblastic leukaemia. One barrier to the widespread use of CAR T-cell therapy is toxicity, primarily cytokine release syndrome (CRS) with a variable grade of severity. The main manifestations of CRS are fever, hypotension, cytopenia, organ dysfunction among others. Neurological toxicities vary widely and range from headaches to encephalopathy. In addition, anti-CD19 CAR T-cell therapy provokes an array of less frequent events, such as coagulopathies, delayed cytopenia, and cardiovascular toxicities. In general, toxicities are usually reversible and resolve on their own in most cases, though severe cases may require intensive care and immunosuppressive therapy. Deaths due to CRS, neurologic toxicity and infectious complications have been reported, which highlights the gravity of these syndromes and the critical nature of appropriate intervention. In this paper, we look at all available FDA- and EMA-approved information about the pathophysiology, clinical manifestations, risk factor reviews of existing toxicity grading systems, current management strategies, and guidelines for anti-CD19 CAR T-cell toxicities. We also present new approaches, which are under investigation, to mitigate these adverse events.

Inhibition of amyloid fibril formation could benefit patients with systemic amyloidosis. In this group of diseases, deposition of amyloid fibrils derived from normally soluble proteins leads to progressive tissue damage and organ failure. Although many small molecules have been proposed as inhibitors of amyloid formation, few have been successful in clinical trials. Amyloid formation is complex and several individual steps could be targeted by small molecules. However, the exact mechanism of action for a molecule is often not known, which impedes medicinal chemistry efforts to develop more potent molecules. Furthermore, commonly used assays are prone to artifacts that must be controlled for. Here, potential mechanisms by which small molecules could inhibit aggregation of immunoglobulin light chain dimers, the precursor proteins for AL amyloidosis are studied in assays that recapitulate different aspects of amyloidogenesis in vitro. One molecule reduced unfolding-coupled proteolysis of light chains, but no molecules inhibited aggregation of light chains or disrupted pre-formed amyloid fibrils. This work demonstrates the challenges associated with drug development for amyloidosis, but also highlights the potential to combine therapies that target different aspects of amyloidogenesis.

The role of T cell immunity has been acknowledged in recent vaccine development and evaluation. We tested the humoral and cellular immune responses to Flucelvax®, a quadrivalent inactivated seasonal influenza vaccine containing two influenza A (H1N1 Singapore/GP1908/2015 IVR-180 and H3N2 North Carolina/04/2016) and two influenza B (Iowa/06/2017 and Singapore/INFTT-16-0610/2016) virus strains, using peripheral blood mononuclear cells stimulated by pools of peptides overlapping all the individual influenza viral protein components. Baseline reactivity was detected against all four strains both at the level of CD4 and CD8 responses and targeting different proteins. CD4 T cell reactivity was mostly directed to HA/NA proteins in influenza B strains, and NP/M1/M2/NS1/NEP proteins in the case of the Influenza A strains. CD8 responses to both influenza A and B viruses preferentially targeted the more conserved core viral proteins. Following vaccination, both CD4 and CD8 responses against the various influenza antigens were increased in day 15 to day 91 post vaccination period and maintained a Th1 polarized profile. Importantly, no vaccine interference was detected, with the increased responses balanced across all 4 included viral strains for both CD4 and CD8 T cells, and targeting HA and multiple additional viral antigens.

Chronic HCV infection and associated liver cancer impose a heavy burden on the healthcare system. Direct acting antivirals eliminate HCV, unless it is drug resistant, and partially reverse liver disease, but they cannot cure HCV-related cancer. Possible remedy could be a multi-component immunotherapeutic vaccine targeting both HCV-infected and malignant cells, also those not infected with HCV. To meet this need we developed a two-component DNA vaccine based on the highly conserved core protein of HCV to target HCV-infected cells, and a renowned tumor associated antigen telomerase reverse transcriptase (TERT) based on the rat TERT, to target malignant cells. Their synthetic genes were expression-optimized, and HCV core was truncated after aa 152 (Core152opt) to delete the domain interfering with immunogenicity. Core152opt and TERT DNA were highly immunogenic in BALB/c mice, inducing IFN-γ/IL-2/TNF-α response of CD4+ and CD8+ T cells. Also, DNA-immunization with TERT enhanced cellular immune response against luciferase encoded by a co-delivered plasmid (Luc DNA). However, DNA-immunization with Core152opt and TERT mix resulted in abrogation of immune response against both components. A loss of bioluminescent signal after co-delivery of TERT and Luc DNA into mice indicated that TERT affects the in vivo expression of luciferase directed by the immediate early cytomegalovirus and interferon-β promoters. Panel of mutant TERT variants was created and tested for their expression effects. TERT with deleted N-terminal nucleoli localization signal and mutations abrogating telomerase activity still suppressed the IFN-β driven Luc expression, while the inactivated reverse transcriptase domain of TERT and its analogue, enzymatically active HIV-1 reverse transcriptase, exerted only weak suppressive effects, implying that suppression relied on the presence of the full-length/nearly full-length TERT, but not its enzymatic activity. The effect(s) could be due to interference of the ectopically expressed xenogeneic rat TERT with biogenesis of mRNA, ribosomes and protein translation in murine cells, affecting the expression of immunogens. HCV core can aggravate this effect, leading to early apoptosis of co-expressing cells, preventing the induction of immune response.

Immunotherapy has gained great momentum with chimeric antigen receptor T cell (CAR-T) therapy, in which patient’s T lymphocytes are genetically manipulated to recognize tumor-specific antigens increasing tumor elimination efficiency. In the last years, CAR-T cell immunotherapy for hematological malignancies achieved a great response rate on patients and is a very promising therapy for several other malignancies. Each new CAR design requires a preclinical proof-of-concept experiment using immunodeficient mouse models. The absence of a functional immune system in these mice makes them simple and suitable to be mathematically modeled. In this work, we developed a three population mathematical model to describe tumor response to CAR-T cell immunotherapy in immunodeficient mouse models, encompassing interactions between a non-solid tumor and CAR-T cells (effector and long-term memory). We account for several phenomena, such as tumor-induced immunosuppression, memory pool formation, and conversion of memory into effector CAR-T cells in the presence of new tumor cells. Individual donor and tumor specificities were considered as uncertainties in the model parameters. Our model is able to reproduce several CAR-T cell immunotherapy scenarios, with different CAR receptors and tumor targets reported in the literature. We found that therapy effectiveness mostly depends on some specific parameters such as the differentiation of effector to memory CAR-T cells, CAR-T cytotoxic capacity, tumor growth rate, and tumor-induced immunosuppression. In summary, our model can contribute to reduce and optimize the number of in vivo experiments with in silico tests to select specific scenarios that could be tested in experimental research. Such in silico laboratory was made available in a Shiny R-based platform called CARTmath. It is an open-source, easy to run simulator, available at github.com/tmglncc/CARTmath or directly on the webpage cartmath.lncc.br, containing this manuscript results as examples and documentation. The developed model, together with the CARTmath platform, provides potential use for assessing different CAR-T cell immunotherapy protocols and associated efficacy, becoming an accessory towards in silico trials.