The IRE1α-endonuclease plays a dual role in regulating the XBP1/miRNA-34a axis and PD-1 expression within Natural Killer cells in Hodgkin Lymphoma.

INTRODUCTION: Hodgkin Lymphoma (HL) is deficient in Major Histocompatibility Complex-class I, rendering it susceptible to anti-tumoral immunity by Natural Killer (NK)-cells. Despite the functional impairment of PD-1+ NK-cells in HL, the underlying mechanisms of NK-cell dysfunction remain unclear. METHODS: This study involved 14 HL patients and SNK10/KHYG-1 cell lines to assess NK-cell activation against cancer cells. Activation was measured through transcript (PCR) and protein expression (flow cytometry). Regulatory mechanisms associated with IRE1α activation were validated through knock-down and luciferase reporter assays. RESULTS: Our findings reveal a novel role for IRE1α-endonuclease in fine-tuning NK-cell effector functions by orchestrating the XBP1s/microRNA-34a-5p/PD-1 axis. When NK-cells encounter cancer cells, IRE1α-endonuclease activates the decay of microRNA-34a-5p, resulting in increased expression of XBP1s and PD-1. IRE1α-endonuclease activation enhances NK-cells function while promoting PD-1 expression. In turn, PD-1 is directly regulated by microRNA-34a-5p, which binds to the 3'UTR of PD-1 transcript to repress PD-1 protein on the NK-cell surface. Importantly, IRE1α-pathway activation is impaired in NK-cells from HL patients. CONCLUSION: The IRE1α-endonuclease emerges as a key player, simultaneously regulating the XBP1s/microRNA-34a-5p/PD-1 axis in NK-cells, a process disrupted in HL. Targeting the IRE1α-pathway holds promise as a therapeutic strategy to optimise NK-cell functions in Hodgkin Lymphoma treatments.

Epstein-Barr virus-associated lymphomas decoded.

Epstein-Barr virus (EBV)-associated lymphomas cover a range of histological B- and T-cell non-Hodgkin and Hodgkin lymphoma subtypes. The role of EBV on B-cell malignant pathogenesis and its impact on the tumour microenvironment are intriguing but incompletely understood. Both the International Consensus Classification (ICC) and 5th Edition of the World Health Organization (WHO-HAEM5) proposals give prominence to the distinct clinical, prognostic, genetic and tumour microenvironmental features of EBV in lymphoproliferative disorders. There have been major advances in our biological understanding, in how to harness features of EBV and its host immune response for targeted therapy, and in using EBV as a method to monitor disease response. In this article, we showcase the latest developments and how they may be integrated to stimulate new and innovative approaches for further lines of investigation and therapy.

All-fiber tunable devices based on high-index photonic crystal fibers filled with liquid crystals.

In this paper we present all-in fiber tunable devices based on specially designed and optimized high-index photonic crystal fibers filled with nematic liquid crystals. A special host microstructured optical fibers have been designed and manufactured to ensure low-loss index guiding and mode field diameter matching to SMF-28 fiber, ensuring low losses on interconnections with leading in-out FC/PC connectorized pigtails. We present four types of tunable all-fiber devices: tunable retarders with tuning range as high as 20 λ, tunable polarizers with variable axis of polarization and continuously tunable polarization dependent losses, tunable and fully controllable polarization controller and finally indeterministic depolarizer in which depolarization is caused by random thermodynamic process. We also present a cost-effective method to achieve change in the direction of the steering electric field, which was controlled by custom-made programable controllers. Finally, we present a method for effective packaging for the proposed devices.

Cellular automata approach to modeling self-organized periodic patterns in nanoparticle-doped liquid crystals.

Elementary cellular automata provide one of the simplest ways to generally describe the phenomena of pattern formation. However, they are considered too simple to be able to describe in detail the more complex phenomena occurring in real experimental systems. In this article, we demonstrate the an application of these methods to optical systems, providing an understanding of the mechanisms behind the formation of periodic patterns in nanoparticle-doped liquid crystals. Our extremely simplified model also explains the observed linear relationship between periodicity and system size.

Three-Dimensional-Printed Mechanical Transmission Element with a Fiber Bragg Grating Sensor Embedded in a Replaceable Measuring Head.

Compliant mechanisms have gained an increasing interest in recent years, especially in relation to the possibility of using 3D printers for their production. These mechanisms typically find applications in precise positioning systems of building robotic devices or in sensing where they can be used to characterize displacement. Three-dimensional printing with PLA materials allows fiber optic-based sensors to be incorporated into the structures of properly designed compliant mechanisms. Therefore, in this paper, an innovative technology is described, of a Fiber Bragg Grating (FBG) sensor embedded in a measuring head which was then inserted into a specially designed mechanical transmission element. The shape of this element is based on clippers that allow to freely modify the amplification of displacement amplitude so that the FBG sensor always works in the most optimal regime without any need to modify its external dimensions. Flexural sensitivity of the replaceable measuring head equal to 1.26 (mε/mm) can be adapted to the needs of the flexure design.

PD-1 and LAG-3 Checkpoint Blockade: Potential Avenues for Therapy in B-Cell Lymphoma.

The dependence of cancer on an immunotolerant tumor microenvironment (TME) is well established. Immunotherapies that overcome tumor-induced immune suppression have been central to recent advancements in oncology. This is highlighted by the success of agents that interrupt PD-1 mediated immune suppression in a range of cancers. However, while PD-1 blockade has been paradigm-shifting in many malignancies, the majority of cancers show high rates of primary resistance to this approach. This has led to a rapid expansion in therapeutic targeting of other immune checkpoint molecules to provide combination immune checkpoint blockade (ICB), with one such promising approach is blockade of Lymphocyte Activation Gene 3 (LAG-3). Clinically, lymphoproliferative disorders show a wide spectrum of responses to ICB. Specific subtypes including classical Hodgkin lymphoma have demonstrated striking efficacy with anti-PD-1 therapy. Conversely, early trials of ICB have been relatively disappointing in common subtypes of Non-Hodgkin lymphoma. In this review, we describe the TME of common lymphoma subtypes with an emphasis on the role of prominent immune checkpoint molecules PD-1 and LAG3. We will also discuss current clinical evidence for ICB in lymphoma and highlight key areas for further investigation where synergistic dual checkpoint blockade of LAG-3 and PD-1 could be used to overcome ICB resistance.

Successful treatment of Epstein-Barr virus-associated primary central nervous system lymphoma due to post-transplantation lymphoproliferative disorder, with ibrutinib and third-party Epstein-Barr virus-specific T cells.

Primary central nervous system lymphoma (PCNSL) occurring following organ transplantation (post-transplantation lymphoproliferative disorder [PTLD]) is a highly aggressive non-Hodgkin lymphoma. It is typically treated with high-dose methotrexate-based regimens. Outcomes are dismal and clinical trials are lacking. It is almost always Epstein-Barr virus (EBV) associated. Two patients (CA1-2) presented with EBV-associated PCNSL after renal transplant. CA1 was on hemodialysis and had prior disseminated cryptococcus and pseudomonas bronchiectasis, precluding treatment with methotrexate. CA2 was refractory to methotrexate. Both were treated off-label with the first-generation Bruton's tyrosine kinase inhibitor ibrutinib for 12 months. Cerebrospinal fluid penetration at therapeutic levels was confirmed in CA1 despite hemodialysis. Both patients entered remission by 2 months. Sequencing confirmed absence of genetic aberrations in human leukocyte antigen (HLA) class I/II and antigen-presentation/processing genes, indicating retention of the ability to present EBV-antigens. Between Weeks 10 and 13, they received third-party EBV-specific T cells for consolidation with no adverse effects. They remain in remission ≥34 months since therapy began. The strength of these findings led to an ongoing phase I study (ACTRN12618001541291).

Immunity reloaded: Deconstruction of the PD-1 axis in B cell lymphomas.

Over the past decade therapies targeting the PD-1 axis with monoclonal antibodies to reinstate host immune function have revolutionized the clinical management of some cancers but have had minimal impact on others. This dichotomy is exemplified by B cell lymphomas. Whilst striking results are observed in classical Hodgkin Lymphoma (cHL) and Primary Mediastinal B Cell Lymphoma (PMBL), responses in other B cell lymphomas are infrequent. Even with cHL and PMBL, responses are not always durable and adverse effects can result in treatment discontinuation. A more nuanced approach to manipulate the PD-1 axis is required before the full benefits of PD-1 axis blockade can be realised. In this review, we provide an outline of PD-1 axis biology, including the range of cellular expression, the molecular mechanisms underlying regulation and the impacts of downstream signalling. These may permit the development of alternate strategies to PD-1 axis blockade to enhance the therapeutic efficacy in B cell lymphomas.

UV Sensor Based on Fiber Bragg Grating Covered with Graphene Oxide Embedded in Composite Materials.

Polymer-matrix composites degrade under the influence of UV radiation in the range of the 290-400 nm band. The degradation of polymer-matrix composites exposed to UV radiation is characterized by extensive aging of the epoxy matrix, resulting in deterioration of their mechanical properties. Glass fibers/epoxy resin composites were made by an out-of-autoclave method whereas a fiber optic sensor was placed between different layers of laminates. In our work, we used a fiber Bragg grating sensor covered with graphene oxide and embedded in a polymer matrix composite to monitor UV radiation intensity. Measurements of UV radiation may allow monitoring the aging process of individual components of the polymer composite. In order to estimate the number of microcracks of epoxy resin, microstructure observations were carried out using a scanning electron microscope.

Increased lipid metabolism impairs NK cell function and mediates adaptation to the lymphoma environment.

Natural killer (NK) cells play critical roles in protection against hematological malignancies but can acquire a dysfunctional state, which limits antitumor immunity. However, the underlying reasons for this impaired NK cell function remain to be uncovered. We found that NK cells in aggressive B-cell lymphoma underwent substantial transcriptional reprogramming associated with increased lipid metabolism, including elevated expression of the transcriptional regulator peroxisome activator receptor-γ (PPAR-γ). Exposure to fatty acids in the lymphoma environment potently suppressed NK cell effector response and cellular metabolism. NK cells from both diffuse large B-cell lymphoma patients and Eµ-myc B-cell lymphoma-bearing mice displayed reduced interferon-γ (IFN-γ) production. Activation of PPAR-γ partially restored mitochondrial membrane potential and IFN-γ production. Overall, our data indicate that increased lipid metabolism, while impairing their function, is a functional adaptation of NK cells to the fatty-acid rich lymphoma environment.

Hybrid Fiber Optic Sensor Systems in Structural Health Monitoring in Aircraft Structures.

'Smart' structural health monitoring of composite materials with optical fiber sensors is becoming more and more important, especially in the aviation industry. This paper presents an overview of hybrid fiber-optic sensing systems based on scattering techniques, fiber Bragg gratings, interferometric techniques, and polarimetric methods in structural health monitoring. The main purpose of this manuscript is to analyze the possibilities of using hybrid sensors based on fiber optics to monitor composite structures, with a particular emphasis on aircraft structures. Since it is difficult to indicate the most comprehensive approach due to different parameters of the described sensors, the review contains a detailed description of available solutions. We hope that this work will allow for a better and faster selection of the right solution for the problem at hand.

Genetic aberrations of NLRC5 are associated with downregulated MHC-I antigen presentation and impaired T-cell immunity in follicular lymphoma.

Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma. Twenty to twenty-five percent of FL patients have progression of disease within 24 months. These patients may benefit from immunotherapy if intact antigen presentation is present. Molecular mechanisms impairing major histocompatibility complex class-I (MHC-I) in FL remain undefined. Here, by sequencing of 172 FL tumours, we found the MHC-I transactivator NLRC5 was the most frequent gene abnormality in the MHC-I pathway. Pyrosequencing showed that epigenetic silencing of the NLRC5 promoter occurred in 30% of cases and was mutually exclusive to copy number loss (CNL) in NLRC5 (∼6% of cases). Hypermethylation and CNLs ("NLRC5 aberrant") had reduced NLRC5 gene expression compared to wild-type (WT) cases. By NanoString, there was reduced gene expression of the MHC-I pathway in aberrant tissues, including immunoproteasome components (PSMB8 and PSMB9), peptide transporters of antigen processing (TAP1), and MHC-I (HLA-A), compared to WT. By immunofluorescent microscopy, fewer NLRC5 protein-expressing malignant B-cells were observed in NLRC5 aberrant tissue sections compared to NLRC5 WT (P < .01). Consistent with a pivotal role in the activation of CD8+ T-cells, both CD8 and CD137 strongly correlated with NLRC5 expression (both r > 0.7; P < .0001). Further studies are required to determine whether patients with aberrant NLRC5 have a diminished response to immunotherapy.

Polymer Fibers Covered by Soft Multilayered Films for Sensing Applications in Composite Materials.

This paper presents the possibility of applying a soft polymer coating by means of a layer-by-layer (LbL) technique to highly birefringent polymer optical fibers designed for laminating in composite materials. In contrast to optical fibers made of pure silica glass, polymer optical fibers are manufactured without a soft polymer coating. In typical sensor applications, the absence of a buffer coating is an advantage. However, highly birefringent polymer optical fibers laminated in a composite material are much more sensitive to temperature changes than polymer optical fibers in a free space as a result of the thermal expansion of the composite material. To prevent this, we have covered highly birefringent polymer optical fibers with a soft polymer coating of different thickness and measured the temperature sensitivity of each solution. The results obtained show that the undesired temperature sensitivity of the laminated optical fiber decreases as the thickness of the coating layer increases.

Self-Organized, One-Dimensional Periodic Structures in a Gold Nanoparticle-Doped Nematic Liquid Crystal Composite.

Composite structures exhibiting a periodic arrangement of building blocks can be found in natural systems at different length scales. Recreating such systems in artificial composites using the principles of self-assembly has been a great challenge, especially for 1D microscale systems. Here, we present a purposely designed composite material consisting of gold nanoparticles and a nematic liquid crystal matrix that has the ability to self-create a periodic structure in the form of a one-dimensional photonic lattice through a phase separation process occurring in a confined space. Our strategy is based on the use of a thermoswitchable medium that reversibly and quickly responds to both heating and cooling. We find that the period of the structure is strongly related to the size of the confining space. We believe that our findings will allow us to not only better understand the phase separation process in multicomponent soft/colloid mixtures with useful optical properties but also improve our understanding of the precise assembly of advanced materials into one-dimensional periodic systems, with prospective applications in future photonic technologies.

Influenza in Poland in 2013 and 2013/2014 epidemic season

OBJECTIVE: Analysis of epidemiological situation of influenza in Poland in 2013 and 2013/14 epidemic season in reference to previous years and seasons. MATERIAL AND METHODS: Analysis was based on: 1) data collected within influenza routine surveillance system in Poland, including data published in annual bulletins "Infectious diseases and poisonings in Poland" as well as unpublished data gathered in the Department of Epidemiology of the NIPH-NIH; 2) data collected within influenza system - Sentinel, and beyond this system, concerning results of virological tests carried out in 2013/14 epidemic season in the Department of Influenza Research, National Influenza Center in the NIPHNIH and/or laboratories of provincial sanitary and epidemiological stations which are gathered in the National Influenza Center. RESULTS: Compared to 2012, the number of influenza and influenza-like cases increased more than twofold in 2013 in Poland. A total of 3 164 405 cases were reported. Incidence was 8 218.7 per 100,000 population (33 733.2 in 0-4 age group). As many as 0.45% of patients were referred to hospitals. According to the data of the Central Statistical Office, 115 deaths due to influenza were notified. Based on the data of the sanitary inspection (incomplete data), the percentage of population vaccinated against influenza was 2.4% (7.7% of persons aged more than 64 years). A total of 2 780 945 cases were registered in 2013/14 epidemic season. Its peak was reported in March 2014. Incidence was 7 224.0 per 100,000 population (35 172.8 in 0-4 age group). Compared to 2012/13 epidemic season, it was lower by 8.0%. Incidence rates ranged from 29 339.6 in pomorskie voivodeship to 1 306.5 in lubuskie voivodeship. Nearly a half of all cases (48.7%) were registered in children and adolescents up to 15 years. As many as 0.34% of patients were referred to hospitals (0.87% of persons aged more than 64 years). From the data of the Central Statistical Office transpires that 8 deaths due to influenza were reported in epidemic season. Type A influenza subtype H3N2 predominated in all influenza cases. Human respiratory syncytial virus (RSV) was the dominant agent in other viral infections of respiratory tract. Antigenic analysis of influenza strains showed their affinity with vaccine strains of the vaccine recommended for this epidemic season. CONCLUSIONS: In spite of slow improvements, influenza and influenza-like surveillance system in Poland is still not homogeneous and stable enough. It hinders the assessment of current epidemiological situation. For instance, there are difficulties in determining what is the effect of modifications in the surveillance on the increase in the number of influenza and influenza-like cases observed in Poland in recent years. A low percentage of population vaccinated against influenza (with a decreasing trend beginning from 2005) suggests a necessity of revising the methods of promotion and organization of these vaccines used so far. One of the public health priorities should be to increase the percentage of vaccinated population up to the average level in EU countries.

[Influenza surveillance]. / Nadzór nad grypa.

Influenza surveillance was established in 1947. From this moment WHO (World Health Organization) has been coordinating international cooperation, with a goal of monitoring influenza virus activity, effective diagnostic of the circulating viruses and informing society about epidemics or pandemics, as well as about emergence of new subtypes of influenza virus type A. Influenza surveillance is an important task, because it enables people to prepare themselves for battle with the virus that is constantly mutating, what leads to circulation of new and often more virulent strains of influenza in human population. As vaccination is the most effective method of fighting the virus, one of the major tasks of GISRS is developing an optimal antigenic composition of the vaccine for the current epidemic season. European Influenza Surveillance Network (EISN) has also developed over the years. EISN is running integrated epidemiological and virological influenza surveillance, to provide appropriate data to public health experts in member countries, to enable them undertaking relevant activities based on the current information about influenza activity. In close cooperation with GISRS and EISN are National Influenza Centres--national institutions designated by the Ministry of Health in each country.

Evaluation of the Activity of Influenza and Influenza-Like Viruses in the Epidemic Season 2013/2014.

Infections caused by respiratory viruses can have different clinical symptoms, while specific set of symptoms can be induced by different viruses. Despite usually mild course of disease, some viruses causing certain disease entity can result in serious complications. Therefore, quick and appropriate diagnostic is crucial for administering proper treatment. In the epidemic season 2013/2014, 2,497 specimens were tested. Infections caused by influenza viruses were confirmed in 9.8%, while infections caused by influenza-like viruses (ILI) in 13.2%. The co-domination of A/H1N1/pdm09 (29.4%) with A/H3N2/ (30.6%) was observed among circulating subtypes of influenza virus type A. Analysis of positive specimens categorized into 7 age groups indicated that most of morbidity to influenza was noted in the age intervals: 26-44 (22.9%) and 45-64 years old (21.6%). Considering infections caused by influenza-like viruses, the highest amount of positive cases was registered in the age group 0-4 years old (92.7%) with the highest ratio of RSV (87.9%) and PIV-3 (10.5%). Judging by the epidemiological and virological indicators, the 2013/14 influenza season was mild and only low virus activity was reported in Poland as well as in most European countries. Still, 9,000 hospitalizations and 17 deaths were registered in Poland during this epidemic season.

Influenza in Poland in 2011-2012 and in 2011/2012 and 2012/2013 epidemic seasons.

UNLABELLED: This paper aimed at evaluating the epidemiological situation of influenza in Poland in 2011-2012 and in 2011/2012 and 2012/2013 epidemic seasons and comparing it with the situation observed in the previous years. MATERIAL AND METHODS: An analysis was mainly based on three sources of data: (1) bulletins "Infectious diseases and poisonings in Poland in 2012" and "Vaccinations in Poland in 2012" (NIPH-NIH, CSI. Warsaw 2013) and analogically former bulletins, (2) "Reports on influenza cases and persons suspected of influenza", sent in 2013 and previous years to the Department of Epidemiology, NIPH-NIH by the Voivodeship Sanitary- Epidemiological Stations, (3) data of the Department of Influenza Research, National Influenza Centre, NIPH- NIH - results of virological testing performed in 2011/2012 and 2012/2013 epidemic seasons in the National Influenza Centre and/or laboratories of the Voivodeship Sanitary-Epidemiological Stations (VSES) within influenza surveillance - Sentinel as well as beyond this system. Data on influenza cases come from aggregated notifications which are sent obligatorily to the VSES by all health care units and physician practices. Influenza, influenza-like illness and acute respiratory infections, i.e. cases meeting the criteria recommended in influenza surveillance in the European Union are subject to mandatory notification. RESULTS: In 2011-2012, there was an increase in the number of influenza and influenza-like illness cases in Poland compared to 2010, i.e. 2- and 2,5-fold, respectively. In 2011, a total of 1 156 357 cases were reported and incidence amounted to 3 001.5 per 100,000 population (11 014.5 in age group 0-4 years). As many as 0.51% of infected persons were referred to hospital. According to the CSO data, 95 fatal cases of influenza were notified. Influenza vaccination coverage was 2.8%. In 2012, 1 460 037 cases were registered and incidence was 3 789.0 (17 807,1 in age group 0-4 years). A total of 0.33% of influenza cases were referred to hospital. As many as 4 deaths due to influenza were reported. Percentage of population vaccinated against influenza amounted to 2.3%. In 2011/12 epidemic season, 1 085 471 cases were noted and incidence was 2 816.6 per 100,000 population (12 792.3 in age group 0-4 years) while in 2012/13 epidemic season its number was nearly 3-fold higher, i.e. 3 025 258 cases and incidence - 7 851.0 (30 591.7 in age group 0-4 years). In both epidemic seasons, type A influenza subtype H1N1 and human respiratory syncytial virus (RSV) predominated in infections with influenza virus and other viral respiratory infections, respectively. Antigenic analysis of influenza strains showed their affinity with vaccine strains of the vaccines recommended for these epidemic seasons. SUMMARY: An increase in the number of notified cases of influenza and influenza-like illness, which is recently observed in Poland, is significantly affected by the improving quality (especially sensitivity) of surveillance system, commenced in the 2009 influenza pandemic. This surveillance system, however, is still not sufficiently uniform and stable. Low percentage of population vaccinated against influenza suggests the ineffectiveness of influenza vaccine promotion campaigns conducted so far. An increase in the influenza vaccination coverage to the average observed in the EU countries should be one of the priorities for the sanitary-epidemiological stations.