Hope on the horizon: promising novel therapies for necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) remains among the most common and devastating diseases in neonates. Despite advances in neonatal clinical care, specific treatment strategies and diagnostic modalities remain lacking. As a result, morbidity and mortality remain high. Improved understanding of the pathogenesis of NEC has the potential for improved therapeutics. Some of the areas of research leading to promising discoveries include inhibition of Toll-like receptor signaling, modulation of vascular endothelial growth factor signal pathways, defining metabolomic alterations in NEC to discover potential biomarkers, probing for genetic predispositions to NEC susceptibility, determining mechanistic relations between anemia and NEC, and microflora modulation through the use of probiotics. All of these areas may represent novel promising approaches to the prevention and treatment of NEC. This review will focus on these current and possible therapeutic perspectives.

Ticagrelor Inhibits Toll-Like and Protease-Activated Receptor Mediated Platelet Activation in Acute Coronary Syndromes.

PURPOSE: Since ticagrelor inhibits the cellular uptake of adenosine, thereby increasing extracellular adenosine concentration and biological activity, we hypothesized that ticagrelor has adenosine-dependent antiplatelet properties. In the current study, we compared the effects of ticagrelor and prasugrel on platelet activation in acute coronary syndrome (ACS). METHODS: Platelet surface expression of P-selectin and activated glycoprotein (GP) IIb/IIIa in response to adenosine diphosphate (ADP), the toll-like receptor (TLR)-1/2 agonist Pam3CSK4, the TLR-4 agonist lipopolysaccharide (LPS), the protease-activated receptor (PAR)-1 agonist SFLLRN, and the PAR-4 agonist AYPGKF were measured by flow cytometry in blood from 80 ticagrelor- and 80 prasugrel-treated ACS patients on day 3 after percutaneous coronary intervention. Residual platelet aggregation to arachidonic acid (AA) and ADP were assessed by multiple electrode aggregometry and light transmission aggregometry. RESULTS: ADP-induced platelet activation and aggregation, and AA-induced platelet aggregation were similar in patients on ticagrelor and prasugrel, respectively (all p ≥ 0.3). Further, LPS-induced platelet surface expression of P-selectin and activated GPIIb/IIIa did not differ significantly between ticagrelor- and prasugrel-treated patients (both p > 0.4). In contrast, Pam3CSK4-induced platelet surface expression of P-selectin and activated GPIIb/IIIa were significantly lower in ticagrelor-treated patients (both p ≤ 0.005). Moreover, SFLLRN-induced platelet surface expression of P-selectin and activated GPIIb/IIIa were significantly less pronounced in patients on ticagrelor therapy compared to prasugrel-treated patients (both p < 0.03). Finally, PAR-4 mediated platelet activation as assessed by platelet surface expression of activated GPIIb/IIIa following stimulation with AYPGKF was significantly lower in patients receiving ticagrelor (p = 0.02). CONCLUSION: Ticagrelor inhibits TLR-1/2 and PAR mediated platelet activation in ACS patients more strongly than prasugrel.

TLR Agonists as Adjuvants for Cancer Vaccines.

Toll-like receptors (TLRs) are one of the best characterised families of pattern recognition receptors (PRRs) and play a critical role in the host defence to infection. Accumulating evidence indicates that TLRs also participate in maintaining tissue homeostasis by controlling inflammation and tissue repair, as well as promoting antitumour effects via activation and modulation of adaptive immune responses. TLR agonists have successfully been exploited to ameliorate the efficacy of various cancer therapies. In this chapter, we will discuss the rationales of using TLR agonists as adjuvants to cancer treatments and summarise the recent findings of preclinical and clinical studies of TLR agonist-based cancer therapies.

Role of toll-like receptors in liver transplantation.

Toll-like receptors (TLRs) are pathogen recognition receptors that orchestrate the innate immune response and the subsequent adaptive immune response. TLRs can be triggered by exogenous ligands expressed by invading pathogens or by the release of endogenous ligands, such as that occurring through cellular injury during the transplantation process. They are now recognized to play an important role in many facets of transplantation biology, including rejection and tolerance, ischemia/reperfusion injury (IRI), and infections after transplantation. The role of TLRs in liver transplantation is unique with respect to other organ transplants because the portal circulation is a continuous source of TLR2 and TLR4 ligands, and this influences TLR signaling pathways, which have a central role in transplantation immunity. This review provides a critical update on recent data outlining the important role of TLRs in liver transplantation, and there is a particular focus on emerging advances in our understanding of rejection and tolerance, IRI, and infections after transplantation and on the ways in which these events may influence the recurrence of diseases such as hepatitis C infection after liver transplantation.

Plasma-mediated immune suppression: a neonatal perspective.

Plasma is a rich mixture of immune regulatory factors that shape immune cell function. This immunomodulatory role of plasma is especially important in neonates. To maintain in utero feto-maternal tolerance and to allow for microbial colonization after birth, the neonatal immune system is biased against pro-inflammatory responses while favoring immune suppression. Therefore, the neonatal period provides a unique opportunity to study the physiologic mechanisms regulating the immune system. Several recent studies in neonates have identified plasma factors that play a key role in immune regulation. Insight into immune regulation by neonatal and adult plasma may have clinical implications, because plasma is easily accessible, affordable, and widely available. Herein, we review plasma-mediated immune regulation, with specific focus on neonatal plasma. We discuss how immune suppression is a key function of plasma and provide a systematic overview of the published literature regarding plasma-derived immune suppressive proteins, lipids, purines, and sugars. Finally, we outline how immune regulation by these factors, which are particularly abundant in neonatal plasma, may eventually be used to treat immune-mediated diseases, such as autoimmune, allergic, and inflammatory diseases.

Advances in the management of skin cancer.

Skin cancer is one of the most commonly diagnosed cancers in the world today in both humans and our pet population. Advances in molecular techniques are now affording us an opportunity to develop therapeutics targeted at specific cancer-related cellular pathways. However, despite progress in conventional treatments, such as chemotherapy and radiation, and the new targeted therapies, some cancers, such as melanoma and cutaneous lymphoma, continue to cause significant mortality and morbidity. This short synopsis is not complete but is aimed at providing an insight into current advanced treatments and horizon therapies for cutaneous malignancies in dogs and cats with comparative aspects.

[Regulation of Toll-like receptors-dependent inflammatory response]. / Regulacja odpowiedzi zapalnej zaleznej od receptorów Toll-podobnych.

Toll-like receptors (TLRs) are a pivotal part of our innate immune response. They recognize a wide variety of pathogens and instigate an immune response, thus facilitating the removal of the disease-causing agent. Due to the intense nature of this response its strict control is of key importance, as a prolonged inflammatory signal leads to carcinogenesis and autoimmune disorders. The signaling cascade initiated by the activated TLR is complex and consists of multiple stages. It involves a variety of adaptor proteins, protein kinases and effector transcription factors. The number of stages in this process enables many possible checkpoints and ways of regulation. Signal modulation involves differentiated expression of TLRs, splicing variants of their adaptor proteins, enzymes modifying proteins engaged in the cascade and many more. This review focuses on endogenous factors responsible for controlling the TLR-dependent inflammatory response as well as on pharmacological therapies designed for regulating the innate immune response.  

Parasitic worms and inflammatory disease.

PURPOSE OF REVIEW: Parasitic worms have evolved strategies to manipulate the host immune system, some of which may lead to a reduction in inflammation. Characterisation of the ways in which these organisms mediate an anti-inflammatory response and identification of parasite-derived molecules involved in immune modulation paves the way to novel therapeutic approaches for the treatment of inflammatory disease. This review highlights recent findings in this field of research in the context of a broader overview. RECENT FINDINGS: Some parasites and parasite derived products inhibit inflammatory responses through effects on both the innate and adaptive immune response. Considerable progress has been made in identifying parasite derived molecules, the ways in which they interact with the immune system and how they mediate immunomodulation. SUMMARY: There is great interest in the potential usefulness of parasite-mediated immunomodulation for the treatment and prevention of a range of inflammatory disorders. Much remains to be resolved regarding characterisation of potential helminth-derived biomodulators, timing and dose of exposure to the agents as well as characterisation of the modes of action so that synthetic analogues that mimic the effects can be generated.

Dietary ω-3 fatty acids and their influence on inflammation via Toll-like receptor pathways.

Dietary intake of long-chain, highly unsaturated ω-3 fatty acids (FAs) is considered indispensable for humans. The ω-3 FAs have been known to be anti-inflammatory and immunomodulatory dietary factors; however, the modes of action on pathogen recognition receptors (PRRs) and downstream signaling pathways have not been fully elucidated. Dietary sources contain various amounts of ω-3 long-chain fatty acids (LCFAs) of different lengths and the association between intake of these polyunsaturated fatty acids (PUFAs) with underlying mechanisms of various immune-related disorders can be of great interest. The potential anti-inflammatory role for ω-3 LCFAs can be explained by modification of lipid rafts, modulation of inflammatory mediators such as cytokines and PRRs. Toll-like receptors (TLRs) are a group of PRRs that play an important role in the recognition of bacterial infections and ω-3 FAs have been implicated in the modulation of downstream signaling of TLR-4, an important receptor for recognition of gram-negative bacteria. The ω-3 FAs docosahexaenoic acid and eicosapentaenoic acid have been investigated in vivo and in vitro for their effects on the nuclear factor-κB activation pathway. Identification of the effects of ω-3 FAs on other key molecular factors like prostaglandins and leukotrienes and their signals may help the recognition and development of medicines to suppress the main mediators and turn on the expression of anti-inflammatory cytokines and nuclear receptors.

[Role of the infection and inflammation in atherosclerosis development (literature review)].

ecent researches have shown that the atherosclerosis is a chronic inflammatory disease. In particular, chronic inflammation plays a key role in coronary artery plaque instability and subsequent occlusive thrombosis. Inflammatory and immune mechanisms, employing monocytes, innate receptors, cytokines are suggested to be involved in atherogenesis. Among the initiation pathways of atherogenesis are innate mechanisms, such as toll-like-receptors (TLRs). TLRs are expressed in the cardiovascular system and could thus be a key link between cardiovascular diseases and the immune system. Stimulation ofthese receptors results in the activation of a diversity of intracellular signal transduction pathways and the production of pro-inflammatory cytokines, which ultimately can contribute to atherosclerotic lesion development. Thus, bacterial endotoxin is a potential source of vascular inflammation and may be an important risk factor for atherosclerosis. Many prospective studies have shown independent associations between myocardial infarction and C-reactive protein, interleukin-6, fibrinogen, von Willebrandfactor, fibrin D-dimerand tissue plasminogen activator antigen. Numerous researches antiinflammatory therapies at an atherosclerosis, are inconsistent enough, however they allow to hope for success, in preventive maintenance and treatment cardiovascular events.

Recent advances on innate immune pathways related to host-parasite cross-talk in cystic and alveolar echinococcosis.

Cystic echinococcosis (CE) and alveolar echinococcosis (AE) are life-threatening parasitic infections worldwide caused by Echinococcus granulosus (sensu lato) and E. multilocularis, respectively. Very little is known about the factors affecting innate susceptibility and resistance to infection with Echinococcus spp. Although benzimidazolic drugs against CE and AE have definitively improved the treatment of these cestodes; however, the lack of successful control campaigns, including the EG95 vaccine, at a continental level indicates the importance of generating novel therapies. This review represents an update on the latest developments in the regulatory functions of innate immune pathways such as apoptosis, toll-like receptors (TLRs), and inflammasomes against CE and AE. We suggest that apoptosis can reciprocally play a bi-functional role among the host-Echinococcus metabolite relationships in suppressive and survival mechanisms of CE. Based on the available information, further studies are needed to determine whether the orchestrated in silico strategy for designing inhibitors and interfering RNA against anti-apoptotic proteins and TLRs would be effective to improve new treatments as well as therapeutic vaccines against the E. granulosus and E. multilocularis.

Translational Mini-Review Series on Vaccines for HIV: Harnessing innate immunity for HIV vaccine development.

Innate immunity is critical for shaping vaccine-elicited adaptive immune responses. Several classes of immune sensors, including Toll-like receptors, retinoic acid-inducible gene-I-like receptors, nucleotide-binding oligomerization domain-like receptors and cytosolic DNA receptors mediate important innate immune pathways and provide potential targets for novel adjuvant development. Understanding how innate immunity modulates adaptive immune responses will probably be important for optimizing vaccine candidates. Here, we review recent advances in innate immunity, focusing upon their potential applications in developing adjuvants and vectors for HIV vaccines.

Toll-like receptors: novel pharmacological targets for the treatment of neurological diseases.

Toll-like receptors (TLRs) are a family of evolutionarily conserved molecules that directly detect pathogen invasion or tissue damage and initiate a biological response. TLRs can signal through two primary intracellular pathways and as such can induce either immuno-stimulatory or immuno-modulatory molecules. Both sides of this twin-edged sword are being examined for their therapeutic potential in combating neurological disease. The immuno-stimulatory properties of TLRs are being used to generate tumor-specific immune responses to CNS tumors while the immuno-modulatory properties are being used to suppress damaging inflammatory responses to stroke. Recently, a third component of TLR signaling has begun to emerge--that of direct neuroprotection. Hence, the TLRs offer novel targets for the treatment of neurological disease.

The potential use of Toll-like receptor (TLR) agonists and antagonists as prophylactic and/or therapeutic agents.

Toll-like receptors (TLR) and their ligands are one of the main players in the initiation of innate immunity which precedes, and is required, for the establishment of adaptive immunity. Manipulating the immune response by using TLR agonists or antagonists might be of therapeutic and/or prophylactic value. This review covers; 1-TLR. their natural ligands and ligand - TLR signaling events, 2-TLR against and their use in clinical trials as vaccine adjuvants, and to treat allergy, cancer and infectious diseases, 3-TLR antagonists and their use in clinical trials to treat septic shock and autoimmune diseases. Potential drawbacks related to their potential use as prophylactic and/or therapeutic agents are discussed.

The importance of pro-inflammatory signaling in neonatal necrotizing enterocolitis.

Despite modern medical advances, necrotizing enterocolitis (NEC) remains a significant cause of morbidity and mortality in neonatal intensive care units, affecting 10% of premature neonates born weighing less than 1500 g. Although many advances have been made in the understanding of NEC, the etiology and pathophysiology remain incompletely understood, and treatment is limited to supportive care. In recent years, many studies have evaluated the inflammatory cascade that is central to the disease process, and research is ongoing into strategies to prevent and/or ameliorate neonatal NEC. In this review, we examine the key points in the signaling pathways involved in NEC, and potential strategies for prevention and treatment of this dreaded disease.

Toll-like receptor signaling in transplantation.

PURPOSE OF REVIEW: This review summarizes recent advances in the role of endogenous and exogenous Toll-like receptor ligands in the activation and inhibition of immune responses in transplantation. RECENT FINDINGS: During an alloresponse, Toll-like receptors can be engaged by both damage-induced endogenous ligands or microbial-associated molecular patterns. The damage-induced molecule high mobility group box 1 protein and its binding to Toll-like receptor 4 have been identified as major initiators of antitumor and antitransplant immune responses. Type I interferon signaling plays an important role in the pro-rejection effect mediated by Toll-like receptor agonists and some bacteria. Similar pathways, however, in neonates can result in inhibition rather than activation of alloimmune responses. SUMMARY: The consequences of Toll-like receptor engagement by endogenous and exogenous ligands in transplantation may depend on the relative induction of inflammatory and regulatory pathways and the stage of development of the immune system.

[How I treat... some skin disorders from the angle of innate immunity]. / Comment je traite... certaines pathologies cutanées par le biais de l'immunité innée.

Innate immunity represents a complex biological organization exhibiting some implications in diverse disorders, in particular at the level of the skin. Its functioning relies on two main groups of components encompassing the PRRs (Protein Recognition Receptors) and the antimicrobial peptides. In humans, particularly in the skin, the major PRRs are represented by the Toll-like receptors (TLRs). The main antimicrobial peptides encompass the alpha- and beta-defensins, and cathelicidins. The expression of the innate immunity compounds is modulated by some drugs. This feature represents a mode of action that remained ignored in the past.

Toll-like Receptors 2, 3, and 4 in Childhood Acute Lymphocytic Leukemia / Receptores do Tipo Toll 2, 3 e 4 em Leucemia Linfocítica Aguda Infanti / Receptores Tipo Toll 2, 3 y 4 en la Leucemia Linfocítica Aguda Infantil

Introduction: Acute lymphocytic leukemia (ALL) is the most common cancer type in children and accounts for 80% of pediatric leukemias. Novel targets are necessary to improve survival rates for refractory and relapsed disease. There is accumulating evidence that Toll-like Receptor (TLR) signaling may be associated with outcomes in cancer however little has been described in leukemias. Objective: Analyze the expression and contribution of TLRs to the development of childhood ALL. Method: To evaluate the effect of specific TLR2, TLR3, and TLR4 agonists on the viability and proliferation of childhood ALL cell lines and to analyzed the mRNA expression of these types of TLR in bone marrow blast cells at diagnosis (D0) and induction (D35) in pediatric ALL patients. Results: Treatment with TLR agonists reduced the cell viability of Jurkat and Sup-B15 cell lines. Cell cycle distribution in Jurkat was altered, reducing polyploid cells and increasing sub-G1 phase. Conclusion: It was observed that the cell viability of the cell lines responded with different sensitivities to the agonists. The polyploidy associated with tumor malignancy was reduced, in addition to the increase in the sub-G1 phase indicating an increase in apoptosis. There were differences in TLR expression at D35 between groups at risk of the disease. Patients with high expression of TLR2 and low expression of TLR4 on D35 demonstrated a worse prognosis

Introdução: A leucemia linfoblástica aguda (LLA) é o tipo de câncer mais comum em crianças e representa 80% das leucemias pediátricas. Novos alvos são necessários para melhorar as taxas de sobrevivência para doença refratária e recidivante. Há evidências acumuladas de que a sinalização de receptores Toll-Like (TLR) pode estar associada a resultados em câncer, embora pouco tenha sido descrito em leucemias. Objetivo: Analisar a expressão e a contribuição dos TLR para o desenvolvimento da LLA infantil. Método: Avaliar o efeito de agonistas específicos de TLR2, TLR3 e TLR4 na viabilidade e proliferação de linhagens celulares de LLA infantil e analisar a expressão do RNAm desses tipos de TLR em células blásticas da medula óssea no diagnóstico (D0) e na indução (D35) em pacientes LLA pediátricos. Resultados: O tratamento com agonistas de TLR reduziu a viabilidade celular das linhagens celulares Jurkat e Sup-B15. A distribuição do ciclo celular em Jurkat foi alterada, reduzindo as células poliploides e aumentando a fase sub-G1. Houve aumento na expressão dos receptores entre D0 e D35 em amostras de pacientes. Conclusão: Observou-se que a viabilidade celular das linhagens celulares respondeu com diferentes sensibilidades aos agonistas. A poliploidia associada à malignidade tumoral foi reduzida, além de o aumento da fase sub-G1 indicar aumento da apoptose. Houve diferenças na expressão de TLR em D35 entre os grupos de risco da doença. Pacientes com alta expressão de TLR2 e baixa expressão de TLR4 no D35 demonstraram pior prognóstico.

Introducción: La leucemia linfocítica aguda (LLA) es el tipo de cáncer más común en los niños y representa el 80 % de las leucemias pediátricas. Se necesitan nuevos objetivos para mejorar las tasas de supervivencia de la enfermedad refractaria y recidivante. Cada vez hay más pruebas de que la señalización del receptor Toll-Like (TLR) puede estar asociada con resultados en el cáncer, aunque se ha descrito poco en las leucemias. Objetivo: Analizar la expresión y la contribución de los TLR al desarrollo de la LLA infantil. Método: Evaluar el efecto de agonistas específicos de TLR2, TLR3 y TLR4 en la viabilidad y proliferación de líneas celulares de LLA infantil y analizar la expresión de ARNm de estos tipos de TLR en células blásticas de médula ósea en el momento del diagnóstico (D0) y la inducción (D35) en pacientes pediátricos con LLA. Resultados: El tratamiento con agonistas de TLR redujo la viabilidad celular de las líneas celulares Jurkat y sup-B15. Se alteró la distribución del ciclo celular en Jurkat, reduciendo las células poliploides y aumentando la fase sub-G1. Hubo un aumento en la expresión de los receptores entre D0 y D35 en muestras de pacientes. Conclusión: Se observó que la viabilidad celular de las líneas celulares respondía con distintas sensibilidades a los agonistas. Se redujo la poliploidía asociada con la malignidad del tumor, además de un aumento de la fase sub-G1 que indica un aumento de la apoptosis. Hubo diferencias en la expresión de TLR en D35 entre los grupos de riesgo de enfermedad. Los pacientes con alta expresión de TLR2 y baja expresión de TLR4 en D35 mostraron peor pronóstico

Safety and efficacy of Y-90 microsphere treatment in patients with primary and metastatic liver cancer: the tumor selectivity of the treatment as a function of tumor to liver flow ratio.

BACKGROUND: Treatment records and follow-up data on 40 patients with primary and metastatic liver malignancies who underwent a single whole-liver treatment with Y-90 resin microspheres (SIR-Spheres Sirtex Medical, Lake Forest, IL) were retrospectively reviewed. The objective of the study was to evaluate the anatomic and physiologic determinants of radiation dose distribution, and the dose response of tumor and liver toxicity in patients with liver malignancies who underwent hepatic arterial Y-90 resin microsphere treatment. METHODS: Liver and tumor volume calculations were performed on pre-treatment CT scans. Fractional tumor and liver flow characteristics and lung shunt fractions were determined using hepatic arterial Tc-99m MAA imaging. Absorbed dose calculations were performed using the MIRD equations. Liver toxicity was assessed clinically and by liver function tests. Tumor response to therapy was assessed by CT and/or tumor markers. RESULTS: Of the 40 patients, 5 had hepatocellular cancer (HCC), and 35 had metastatic liver tumors (15 colorectal cancer, 10 neuroendocrine tumors, 4 breast cancer, 2 lung cancer, 1 ovarian cancer, 1 endometrial cancer, and 2 unknown primary adenocarcinoma). All patients were treated in a salvage setting with a 3 to 80 week follow-up (mean: 19 weeks). Tumor volumes ranged from 15.0 to 984.2 cc (mean: 294.9 cc) and tumor to normal liver uptake ratios ranged from 2.8 to 15.4 (mean: 5.4). Average administered activity was 1.2 GBq (0.4 to 2.4 GBq). Liver absorbed doses ranged from 0.7 to 99.5 Gy (mean: 17.2 Gy). Tumor absorbed doses ranged from 40.1 to 494.8 Gy (mean: 121.5 Gy). None of the patients had clinical venoocclusive disease or therapy-induced liver failure. Seven patients (17.5 %) had transient and 7 patients (17.5 %) had persistent LFT abnormalities. There were 27 (67.5%) responders (complete response, partial response, and stable disease). Tumor response correlated with higher tumor flow ratio as measured by Tc-99m MAA imaging. CONCLUSION: Doses up to 99.5 Gy to uninvolved liver are tolerated with no clinical venoocclusive disease or liver failure. The lowest tumor dose producing a detectable response is 40.1 Gy. The utilization of MAA-based imaging techniques to determine tumor and liver blood flow for clinical treatment planning and the calculation of administered activity may improve clinical outcomes.